Issuu

issn 0034 - 6233

bimonthly journal

2026

vol. 64, 3

Metastatic Crohn’s disease: bridge between gastroenterology, rheumatology and dermatology Machine learning-based analysis of rheumatoid arthritis treatment and complications Changes in hematological indices during adalimumab therapy in ankylosing spondylitis Hyperbaric oxygen therapy for women with fibromyalgia ANO6 in ankylosing spondylitis Magnesium and juvenile idiopathic arthritis Pulmonary challenges in systemic sclerosis: Iraqi insight Ambiguities in the effect of physical activity on bone remodelling in spondyloarthritis Ocular complications in psoriasis and psoriatic arthritis Granulomatosis with polyangiitis and cranial nerves Pleuropericardial effusion in early systemic lupus erythematosus

Official journal of the National Institute of Geriatrics, Rheumatology and Rehabilitation and Polish Society for Rheumatology

3/2026 h t t p s : // r e u . t e r m e d i a . p l

r h e u m a t o l o g y

Termedia Wydawnictwo Termedia Publishing House

r h e u m a t o l o g y Editor-in-Chief Maria Maślińska

Social media Editors Olga Brzezińska

Department of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation (Warsaw, Poland) ORCID 0000-0002-2211-0302 e-mail: maria.maslinska@spartanska.pl; maslinskam@gmail.com

Department of Rheumatology, Medical University of Lodz (Lodz, Poland) ORCID 0000-0002-3885-8497

Deputy Editor-in-Chief Anna Masiak

Department of Rheumatology, Colentina Clinical Hospital (Bucharest, Romania) ORCID 0000-0001-8743-3236

Department of Internal Diseases, Connective Tissue Disorders and Geriatrics, Medical University of Gdansk and University Clinical Centre (Gdansk, Poland) ORCID 0000-0001-6687-2408

Feature Editors – basic science Katarzyna Fischer Independent Laboratory for Rheumatologic Diagnostics, Pomeranian Medical University (Szczecin, Poland) ORCID 0000-0003-4792-2099

Barbara Stypińska Molecular Biology Department, Clinical Trials Support Centre, National Institute of Geriatrics, Rheumatology and Rehabilitation (Warsaw, Poland) ORCID 0000-0002-0230-4927

Associated Editors Kinga Kostyra-Grabczak Early Arthritis Clinic, National Institute of Geriatrics, Rheumatology and Rehabilitation (Warsaw, Poland) ORCID 0000-0003-1146-2975

Katarzyna Romanowska-Próchnicka Department of General and Experimental Pathology with Centre for Preclinical Research and Technology (CEPT), Medical University of Warsaw (Warsaw, Poland) ORCID 0000-0003-1326-2600

Consulting Editors Joanna Makowska Department of Rheumatology, Medical University of Lodz (Lodz, Poland) ORCID 0000-0003-2036-375X

Ciro Manzo Rheumatologic Outpatient Clinic, Health District no. 59, Azienda Sanitaria Locale Napoli 3 (Sant’Agnello, Italy) ORCID 0000-0002-4800-1817

Agnieszka Skoczylas Department of Geriatric and Internal Medicine, Wolski Hospital named Dr. Anna Gostynska (Warsaw, Poland) ORCID 0000-0001-6311-4820

Katarzyna Wieczorowska-Tobis Department of Palliative Medicine, Poznan University of Medical Sciences (Poznan, Poland) 0000-0003-4017-3013

Editorial Coordinator for social media Olena Zimba University Hospital in Krakow (Krakow, Poland) National Institute of Geriatrics, Rheumatology and Rehabilitation (Warsaw, Poland) ORCID 0000-0002-4188-8486

Alina Dima

Tsvetoslav Georgiev Medical University (Varna, Bulgaria) University Hospital “St. Marina” (Varna, Bulgaria) ORCID 0000-0002-1652-4648

Neslihan Gokcen Department of Internal Medicine, Kocaeli, University (İzmit, Kocaeli, Turkey) ORCID 0000-0003-3022-493X

Durga Prasanna Misra Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS) (Lucknow, India) ORCID 0000-0002-5035-7396

Editor/Secretary of the Editorial Office Monika Ślusarska National Institute of Geriatrics, Rheumatology and Rehabilitation (Warsaw, Poland)

Editor/Operations and Project Manager Agnieszka Urban-Tychmanowicz National Institute of Geriatrics, Rheumatology and Rehabilitation (Warsaw, Poland)

Publishing Editor Marzena Demska Language Editors Richard Ashcroft Krzysztof Maśliński Statistical Editors Małgorzata Mańczak National Institute of Geriatrics, Rheumatology and Rehabilitation (Warsaw, Poland) ORCID 0000-0002-0736-0389

Paweł Żuchowski Jan Biziel University Hospital No 2, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University (Torun, Poland) ORCID 0000-0002-5605-7554

Distribution and Subscription & Marketing and Adverising redakcja@spartanska.pl Journal’s bank account number PL 19 2490 0005 0000 4600 0026 0626 (EUR) PL 76 2490 0005 0000 4600 7468 6439 (PLN)

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IF 2025: 2.5 MNiSW: 70 Reumatologia is indexed in: Academic Journals Database, BIOSIS Previews, Chemical Abstracts CAS, DOAJ, EBSCO, Electronic Journals Library (EZB), EMBASE, Emerging Sources Citation Index, Free Medical Journals, Genamics/JournalSeek, Geneva Foundation Free Medical Journals, Google Scholar, Harvard Libraries – University of California Libraries, HINARI Access to Research, International Committee of Medical Journal Editors (ICMJE), Index Copernicus, J-Gate, NewJour, Polish Minsitry of Science and Higher Education (PMSHE), Polish Medical Library (GBL), ProQuest, PubMed Central, RedLink, SCIRUS, SCOPUS, Swiss University Library Network (RERO), Web of Science Core Collection, WorldCat, ZETOC.

Internet: https://reu.termedia.pl Index: 37425 Published since 1963. The journal is originally published in the print version.

Honorary Reviewers Anna Filipowicz-Sosnowska (Warsaw, Poland) Sławomir Maśliński (Warsaw, Poland) Włodzimierz Maśliński (Warsaw, Poland) Mariusz Puszczewicz (Poznan, Poland) Stanisław Sierakowski (Bialystok, Poland) Tadeusz Styczyński (Warsaw, Poland) Jacek Szechiński (Wroclaw, Poland) Irena Zimmermann-Górska (Poznan, Poland)

The advertisers shall be liable for the contents of advertisements placed in Reumatologia. Advertisements of prescription drugs are intended only for physicians licensed to prescribe them. Copyright: © 2026 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie. This is an Open Access journal, all articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license. Copyright: The rights to the article are usually transferred by the authors to the owner of the journal, who makes it available under the Creative Commons license. However, if the author does not want to transfer the copyright to the publisher, he/she may contact the editorial office and set separate rules – under which the editorial office may publish an article in the journal. On the detailed information, please contact with editorial office.

International Editorial Board Sakir Ahmed Department of Clinical Immunology and Rheumatology, Kalinga Institute of Medical Sciences (KIMS), KIIT University (Bhubaneswar, India) ORCID 0000-0003-4631-311X

Maria Majdan Department of Rheumatology and Systemic Connective Tissue Disorders, Medical University of Lublin (Lublin, Poland) ORCID 0000-0002-4345-1675

Howard Amital Department of Medicine “B” and Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center (Tel-Hashomer, Israel) ORCID 0000-0002-5406-7716

Paweł Małdyk Clinic of Orthopedics and Traumatology, The Infant Jesus Clinical Hospital (Warsaw, Poland) ORCID 0000-0002-9856-6998

Andra Balanescu University of Medicine and Pharmacy “Carol Davila” Research Center on Rheumatic Diseases Internal Medicine and Rheumatology Department “Sf. Maria” Clinical Hospital (Bucharest, Romania) ORCID 0000-0003-0688-9173

György Nagy Department of Rheumatology and Immunology, Semmelweis University (Budapest, Hungary) ORCID 0000-0003-1198-3228

Peter V. Balint National Institute Of Rheumatology And Physiotherapy (Budapest, Hungary) ORCID 0000-0002-1183-8437

Violetta Opoka-Winiarska Department of Pediatric Pulmonology and Rheumatology, Medical University of Lublin (Lublin, Poland) ORCID 0000-0003-1644-5568

Marek Brzosko Department of Rheumatology, Internal Medicine, and Geriatrics, Pomeranian Medical University (Szczecin, Poland) ORCID 0000-0001-7681-4367

Carlo Perricone Department of Internal Medicine and Medical Specialties, Rheumatology, Sapienza University of Rome (Rome, Italy) ORCID 0000-0003-4771-6981

Caterina de Carolis Past Head Gynecology and Obstetrics, San Giovanni and San Giacomo Hospital (Rome, Italy) ORCID 0000-0002-6597-6253

Lidia Rutkowska-Sak National Institute of Geriatrics, Rheumatology and Rehabilitation (Warsaw, Poland) ORCID 0000-0002-9738-8923

Ricard Cervera Department of Autoimmune Diseases Hospital Clinic (Barcelona, Spain) ORCID 0000-0001-6085-492X

Włodzimierz Samborski Department of Rheumatology and Rehabilitation, Poznan University of Medical Sciences (Poznan, Poland) ORCID 0000-0002-0338-894X

Hector Chinoy University of Manchester (Manchester, United Kingdom) ORCID 0000-0001-6492-1288 Maurizio Cutolo Research Laboratory and Academic Unit of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Ospedale Policlinico San Martino (Genova, Italy) ORCID 0000-0002-4548-5334 László Czirják Department of Rheumatology and Immunology Medical School University of Pécs (Pécs, Hungary) ORCID 0000-0002-6775-067X Nemanja Damjanov Internal Medicine and Rheumatology Belgrade University School of Medicine (Belgrade, Serbia) ORCID 0000-0001-6249-7428

Oliver Distler

Division of Rheumatology, University Hospital (Zurich, Switzerland) ORCID: 0000-0002-0546-8310 Frauke Förger Department of Rheumatology, Immunology and Allergology Inselspital, University Hospital (Bern, Switzerland) ORCID 0000-0003-1134-993X Armen Yuri Gasparyan Departments of Rheumatology and Research and Development, Dudley Group NHS Foundation Trust (Teaching Trust of the University of Birmingham) Russells Hall Hospital, Dudley, West Midlands (Birmingham, United Kingdom) ORCID 0000-0001-8749-6018

Yehuda Shoenfeld Department of Medicine B and Center for Autoimmune Diseases Chaim Sheba Medical Center (Tel-Hashomer, Israel) ORCID 0000-0003-2802-4090 Josef Smolen Clinic for Internal Medicine III, Institute of Rheumatology (Vienna, Austria) ORCID 0000-0002-4302-8877 Elżbieta Smolewska Department of Pediatric Cardiology and Rheumatology, Medical University of Lodz (Lodz, Poland) ORCID 0000-0002-8421-0448 Zoltán Szekanecz Division of Rheumatology, Third Department of Medicine, University of Debrecen Medical and Health Sciences Center (Debrecen, Hungary) ORCID 0000-0002-7794-6844 Gabriella Szűcs Department of Rheumatology, University of Debrecen (Debrecen, Hungary) ORCID: 0000-0002-0958-9531 Bożena Targońska-Stępniak Department of Rheumatology and Connective Tissue Disorders, Medical University of Lublin (Lublin, Poland) ORCID 0000-0003-3916-4291 Angela Tincani Department of Clinical and Experimental Science, Rheumatology and Immunology Clinic (Brescia, Italy) ORCID 0000-0003-4355-9333

Piotr Głuszko Clinic of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation (Warsaw, Poland) ORCID 0000-0001-5717-4472

Witold Tłustochowicz Department of Internal Medicine and Rheumatology, Military Institute of Medicine in Warsaw (Warsaw, Poland) ORCID 0000-0001-7868-9272

José Hernández-Rodríguez

Piotr Wiland Department of Rheumatology and Internal Medicine, Wroclaw Medical University (Wroclaw, Poland) ORCID 0000-0001-9999-0267

Clinical Unit of Autoinflammatory Diseases and Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (Barcelona, Spain) ORCID: 0000-0002-2357-2015 Eugeniusz J. Kucharz Department of Internal Medicine and Rheumatology, Upper Silesian Medical Center in Katowice, Medical Uniwersity of Silesia (Katowice, Poland) ORCID 0000-0001-5571-8114 Brygida Kwiatkowska Early Arthritis Clinic, National Institute of Geriatrics, Rheumatology and Rehabilitation (Warsaw, Poland) ORCID 0000-0002-9622-1830 Piotr Leszczyński Department of Rheumatology and Rehabilitation, Poznan University of Medical Sciences (Poznan, Poland) ORCID 0000-0003-2174-8811

Roman Yatsyshyn Ivano-Frankivsk National Medical University (Ivano-Frankivsk, Ukraine) ORCID 0000-0003-1262-5609 Zbigniew Żuber Department of Pediatrics, Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Cracow University; Ward for Older Children with Neurology and Rheumatology Subdivision, St. Louis Regional Specialised Children’s Hospital (Krakow, Poland) ORCID 0000-0001-9581-0601

Contents

Reumatologia 2026; 64, 3: 163–262

Editorial paper 163 Metastatic Crohn’s disease as a granulomatous bridge between gastroenterology, rheumatology and dermatology Raman Nitskovich, Konrad Lewandowski, Irena Walecka

Original papers 166

Machine learning analysis of treatment and complication patterns in rheumatoid arthritis case reports (1995–2025) Naruaki Ogasawara

174

Changes in hematological indices during adalimumab therapy in ankylosing spondylitis: a one-year retrospective study Dominika Szlichta, Magdalena Dryglewska, Ewa Łyś-Toporowska, Maria Majdan

181

Efficacy and safety of hyperbaric oxygen therapy for women with fibromyalgia: a systematic review and meta-analysis of randomized controlled trials Maggie Liberty, Andi Raga Ginting, Dewi Masyithah Darlan, Peggy Liberty, Satria Gohtama

192

Association of ANO6 gene polymorphism and expression with ankylosing spondylitis in a Chinese Han population Mingcan Yang, Xianghui Wen, Xinyu Wu, Yanli Zhang, Jieruo Gu

200 209

Dietary and serum magnesium in children with juvenile idiopathic arthritis: a case-control study Oksana Boyarchuk, Nataliia Kovalchuk, Vira Synytska Screening and management of systemic sclerosis-associated pulmonary complications in Iraq: insights from a national survey of rheumatologists and pulmonologists Asal Adnan Ridha, Nabaa Ihsan Awadh, Faiq Isho Gorial, Nizar Jassim

Review papers 218

Ambiguities in the effect of physical activity on bone remodelling in spondyloarthritis Agnieszka Alicja Kowalczyk, Mateusz Wilk, Mariusz Korkosz

230

Ocular complications in psoriasis and psoriatic arthritis Raman Nitskovich, Anna Suchecka, Maria Maślińska, Dorota Kopacz, Weronika Herniczek, Irena Walecka

Case-based reviews 242 Orbital pseudotumor and skull base infiltration as the sole manifestation of granulomatosis with polyangiitis Nicole Kivelä, William Karlsen, Karolina Markiet, Anna Masiak 252

Pleuropericardial effusion as a first presentation of systemic lupus erythematosus Raja Bakhsh, Khaled Saleh Dairi, Zaher Althaqafi, Shifaa Sharaf Aljefri, Ward Hisham Skaik, Sheren Ismail Saleh, Enas Ali AlRubayyi

EULAR – European Congress of Rheumatology London, June 3–6, 2026 The largest European congress of rheumatologists has come to a close. This time, London hosted over 14,000 participants, representing countries not only from the old continent. There were also many Polish accents, as Polish rheumatologists participated in the General Assembly. The scientific sessions were chaired by Prof. Marzena Olesińska, MD, PhD, for the session called “The Enigma of Mixed Connective Tissue Disease in Challenging the Rheumatologist Clinical Care,” and by Maria Maślińska, MD, PhD, Professor at the National Institute of Geriatrics, Rheumatology, and Rehabilitation in Warsaw, for the session: “New Perspectives in IgG4-Associated Diseases.” Prof. Otylia Kowal-Bielecka from the Clinic of Rheumatology and Internal Medicine of the Medical University of Bialystok was a speaker, presenting the problem of gastro intestinal involvement in systemic sclerosis. Among the poster presentations, Anna Gwoźdź-Broczkowska, MD (National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw) deliver ed an abstract entitled „Calcinosis in Juvenile Auto immune Rheumatic Diseases – Observations from One Pediatric Rheumatology Clinic” (DOI: 10.1136/annrheumdis-2026-eular.B.4031) during the poster tour. Fig. Polish rheumatologists after the Gene Ewa Więsik-Szewczyk, MD, PhD and Prof. Karina ral Assembly. From the right: Bogdan Batko, Jahnz-Rozyk (Military Institute of Medicine, National ReMarcin Stajszczyk, Magdalena Krajewskasearch Institute, Warsaw) presented, among others, the -Włodarczyk, Brygida Kwiatkowska, Zbigniew subject of “Missed Red Flags of Monogenic Immune Żuber, Piotr Krawiec.

Fig. Prof. Marzena Olesińska, MD, PhD – chair of one of the scientific session “The Enigma of Mixed Connective Tissue Disease in Chal lenging the Rheumatologist Clinical Care”.

Fig. First author: Anna Gwoźdź-Broczkowska, MD, and her abstract presentation “Calci nosis in Juvenile Autoimmune Rheumatic Diseases – Observations from One Pediatric Rheumatology Clinic”.

Fig. Prof. Otylia Kowal-Bielecka presented the problem of gastro in systemic sclerosis. Fig. Audience Award during a session dedi cated to compelling clinical cases. From the right: Prof. Agata Sebastian, Piotr Waw ryka, MD, Jakub Rogalewicz, MD.

Fig. Maria Maślińska (Poland) and Tobias Aleksander (Berlin), Chairpersons of the ses sion “New Perspectives in IgG4-Associated Diseases”.

Fig. Aleksandra Opinc-Rosiak, MD, PhD.

Reumatologia 2026; 64/3

Fig. Maria Maślińska and Tobias Aleksander during the session “New Perspectives in IgG4-Associated Diseases”. Dysregulation: A Case Report of Late-Onset STAT3 Gain-of-Function–Related Disease” (DOI: 10.1136/ annrheumdis-2026-eular.E.877). Katarzyna Wawrzycka-Adamczyk, MD, PhD (University Hospital in Krakow, POLVAS – Polish Vasculitis Registry) discussed “Time to Renal Replacement Therapy Determinants in ANCAAssociated Vasculitis – Data from Polish Vasculitis Registry (POLVAS)” (DOI: 10.1136/annrheumdis2026-eular.B.2965), while Kinga Tyczyńska, MD (University Clinical Hospital, Wroclaw) showcased “Renal Outcomes in Ankylosing Spondylitis: A Retrospective, Population-Based Cohort Study” (DOI: 10.1136/ annrheumdis-2026-eular.A.1736). Moreover, Krzysztof Wójcik, MD, PhD (Jagiellonian University, Krakow) presented “Stimulated Emission Depletion (STED) Microscopy for ANA Pattern Identification: First Dataset and Machine Learning Comparison with Fluorescence Microscopy” (DOI: 10.1136/annrheumdis-2026eular.B.1480). Other poster presentations were deli

vered by Joanna Sarnik, PhD in Biology (Medical University of Lodz), who submitted „Nasal Epithelial PADI Expression Driven by Airborne Pollutants: Implications for Local Citrullination in Rheumatoid Arthritis” (DOI: 10.1136/annrheumdis-2026-eular.A.602), and Olga Brzezińska, MD, PhD (Medical University of Lodz) demonstrating „Pain Beyond Inflammation: Underdiagnosed Neuropathic and Neuroplastic Pain in Systemic Connective Tissue Diseases” (DOI: 10.1136/annrheumdis-2026-eular.B.3958). Additionally, Anna Nowakowska-Płaza, MD, PhD with her colleagues (K. Jahnz-Rozyk, E. Więsik-Szewczyk), along with other center representative, i.e., Jakub Wronski from the National Institute of Geriatrics, Rheumatology, and Rehabilitation in Warsaw, delivered an abstract titled “Immune-Mediated Bone Loss in Adults with Primary Immunodeficiencies: Secondary Osteoporosis, Sarcopenia, and Lymphocyte Correlates – are NK Cells Protective?” (DOI: 10.1136/ annrheumdis-2026-eular.B.620). A Polish team from Wroclaw, comprising Piotr Wawryka, Agata Sebastian, Jakub Rogalewicz, and Krzysztof Proc, was recognized for an outstanding presentation “Eosinophilic Granulomatosis With Polyangiitis And Eosinophilic Fasciitis – Two Diseases Treated with One Targeted Drug – Benralizumab” (DOI: 10.1136/ annrheumdis-2026-eular.E.284), and honored with the Audience Award during a session dedicated to compelling clinical cases. The EULAR Congress also provided an opportunity for active involvement of Polish rheumatologists in EULAR activities. Prof. Maria Maślińska participated in the EULAR Education Committee meeting, and Prof. Przemysław Kotyla in the Quality of Care Committee meeting. The activities of young rheumatologists in EMEUNET (EMerging EULAR NETwork) are significant. Agata Schramm-Luc represented EMEUNET during the EULAR–ACR–PANLAR Research Exchange Programme, organized by King’s College London during the EULAR 2026 Congress. Aleksandra Opinc-Rosiak, MD, PhD placed third, and received the EMEUNET Country Liaison Award for her work on behalf of young rheumatologists and for her commitment to developing international collaboration. Being actively involved in such a great, global rheumatology community is a tremendous privilege and strong motivation to continue working on advancing rheumatology in Poland. Permission was obtained for the publication of photos.

A step further for the Reumatologia journal In June every year, the ranking of scientific journals is announced, and new impact factors for the previous year are published – this time for 2025. For the editorial teams of many journals, it is a time of celebration and to plan further intensive work. The journal of Reumatologia was rated 2.5 IF, indicating an increase of over 50%. This demonstrates the interest in publications, their citation rates, and hence, the hard work of the edi torial team, reviewers, authors, and readers. As the Editor-in-Chief, I would like to express my gratitude, particularly to the Editor Monika Ślusarska, Olena Zimba, and Anna Masiak. Export 100%

2.250

75%

1.500

JIF: 2.5

1 0.750 0

2021

2022

2023

2024

2025

50% 35 25% 0%

JIF percentile in category

Journal Impact Factor

Journal Impact Factor Trend 2025 3.000

JCR years Journal Impact Factor Rheumatology

Fig. Evolution of the Reumatologia journal’s Journal Impact Factor (JIF), highlighting the JIF value of 2.5 achieved in 2025.

Reumatologia 2026; 64/3

Also, I would like to thank the Editorial Team of Termedia Publishing House for their contribution and collaborative work with the Reumatologia. The new indicators are both rewarding and demanding. As the Editor-in-Chief, I thank each and every one of you involved in thriving of the Reumatologia journal. I hope that another year of work will confirm the value of the journal, and continue to serve as a platform for the international exchange of scientific ideas for authors, researchers, and readers. Maria Maślińska Editor-in-Chief

Editorial paper

Reumatologia 2026; 64, 3: 163–165 DOI: https://doi.org/10.5114/reum/225373

Metastatic Crohn’s disease as a granulomatous bridge between gastroenterology, rheumatology and dermatology Raman Nitskovich1 ID , Konrad Lewandowski2 ID , Irena Walecka1 ID 1

Department of Dermatology, National Medical Institute of the Ministry of the Interior and Administration, Warsaw, Poland Department of Gastroenterology and Internal Medicine, National Medical Institute of the Ministry of the Interior and Administration, Warsaw, Poland

Introduction Among the cutaneous extraintestinal manifestations of inflammatory bowel disease (IBD), metastatic Crohn’s disease (MCD) occupies a unique position, being both the rarest and one of the most disfiguring of these entities. It is defined as non-caseating granulomatous inflammation arising in the skin or mucous membranes at sites unconnected with the gastrointestinal tract. Histologically, MCD thus represents the cutaneous counterpart of the lesions seen in Crohn’s disease [1, 2]. Although until recently regarded as a rarity, patients with MCD now require collaboration between gastroenterology, dermatology and, frequently, rheumatology.

A granulomatous disease that crosses specialty boundaries Metastatic Crohn’s disease was first described in 1965 by Parks [1]. Over the subsequent 6 decades, only about 500 cases have been reported worldwide, most of them solely as single case reports and small case series [2, 3]. It is generally accepted that, owing to low disease awareness among clinicians, the true incidence is markedly underestimated, with many cases remaining unrecognised or misclassified. A source of diagnostic difficulty is the fact that MCD shares a diagnostic challenge similar to that of other granulomatous dermatoses. Clinically, the lesions are polymorphic: isolated, chronic swelling of the labia, scrotum or perineum, erythematous-infiltrative changes, and nodules, often with characteristic linear “knife-cut” fissures

that are particularly pronounced in the genital and intertriginous skin (Fig. 1). The lesions frequently leave scars or permanent deformity in the anogenital region. Because there is no pathognomonic feature, MCD may be confused with infections, hidradenitis suppurativa, pyoderma gangrenosum, erythema nodosum and – most closely on histology – sarcoidosis and Behçet’s disease [2, 4]. The diagnosis is further complicated by the temporal course. Cutaneous lesions most often appear after the diagnosis of intestinal Crohn’s disease, concurrently with it, or precede it; moreover, the skin lesions follow a course entirely distinct from intestinal activity, flaring during remission of bowel disease and persisting despite endoscopic remission [2, 5]. This discordance between cutaneous and intestinal activity is more than a clinical inconvenience

Fig. 1. Heterogeneity of the clinical presentation of metastatic Crohn’s disease across anatomical sites.

Address for correspondence Raman Nitskovich, Department of Dermatology, National Medical Institute of the Ministry of the Interior and Administration, 137 Wołoska St., 02-507 Warsaw, Poland, e-mail: nitskovich@gmail.com Submitted: 23.06.2026; Accepted: 23.06.2026; Published online: 30.06.2026

Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)

164

– it indicates that the immune response in the skin behaves autonomously, independently of the process in the gut. It is explained by the contemporary model of MCD pathogenesis. Its central effector axis is well recognised in rheumatology: dysregulation of Th17/ interleukin-23 (IL-23) signalling acting in concert with tumor necrosis factor (TNF), with recruitment of neutrophils and macrophages, drives granuloma formation in both the gut and the skin [6, 7]. Metastatic Crohn’s disease is therefore a condition in which cytokinesmediated mechanisms trigger granulomatous inflammation at extraintestinal sites, with therapeutic agents overlapping those used in dermatology, gastroenterology and rheumatology.

The particular relevance of childhood Subclinical intestinal inflammation is found in a substantial proportion of patients with spondyloarthropathies, and this association may be particularly strong in children: juvenile spondyloarthropathy, arthritis accompanied by enthesitis, and IBD frequently coexist or occur sequentially, sharing a common genetic and immunological background [8, 15]. Moreover, the occurrence of a single extraintestinal manifestation of IBD significantly increases the risk of developing further manifestations later in the disease course [8]. In this context, MCD and other granulomatous or inflammatory skin lesions take on additional significance as potentially the earliest detectable signal of an ongoing systemic inflammatory process. This applies not only to granulomatous lesions, other dermatoses that co-occur with arthritis, such as bowel-associated dermatosis–arthritis syndrome (BADAS), are also reco gnised concurrently with IBD, further indicating that the co-occurrence of skin lesions, arthritis and systemic symptoms should prompt gastroenterological evaluation [10]. Cutaneous manifestations – misinterpreted as eczema, urticaria or other conditions of allergic origin – may precede by years both the diagnosis of bowel disease and the emergence of a coexisting rheumatic disease, frequently delaying the correct diagnosis by many years [9, 11]. Awareness of this sequence has direct practical implications: a chronic, treatment-resistant dermatosis in a child or young adult – particularly in an anogenital or oro-facial location, and especially in the presence of joint or gastrointestinal symptoms – should raise suspicion of MCD and prompt interdisciplinary assessment extending beyond an allergological work-up.

The therapeutic ladder Because no randomised trial data exist, management remains empirical and relies on agents used in

Reumatologia 2026; 64/3

Raman Nitskovich, Konrad Lewandowski, Irena Walecka

inflammatory diseases. The 2014 American scheme begins with topical glucocorticosteroids (GCs), followed by metronidazole; for both its immunomodulatory and antimicrobial properties, in the absence of improvement, systemic GCs are introduced, followed by conventional immunosuppressive agents: azathioprine, methotrexate and mercaptopurine [2, 12]. In treatment-resistant disease, the next step is TNF inhibitors, which carry the strongest evidence of clinical efficacy in MCD, with reported response rates of around 64–71% [2, 12]. Beyond TNF, IL-23 inhibitors are increasingly used, a choice supported by the demonstrated expression of IL-23 by dendritic cells and macrophages within the skin lesions [6, 7]. The most recent reports also describe the efficacy of Janus kinase (JAK) inhibitors (upadacitinib) in cases resistant to anti-TNF agents and IL-23 blockers [13].

Improving care in rare diseases Despite advances in diagnosis and treatment, MCD remains a disease in which therapeutic decisions are often made on the basis of clinical intuition. A breakthrough was the publication in 2025, by an international interdisciplinary team, of the first diagnostic criteria based on the Delphi method and the existing literature and expert experience [3]. Criteria developed in this way nonetheless require validation in larger cohorts, which can be achieved only through systematic and international case collection. In response to this need, a project has been undertaken within the European Crohn’s and Colitis Organisation (ECCO CONFER, Round 12), entitled “Metastatic Crohn’s disease – a rare extraintestinal manifestation challenging diagnosis and management,” continuing earlier initiatives to collect cases of cutaneous IBD manifestations within the ECCO CONFER network [14]. The project is led by the Department of Dermatology of the National Medi cal Institute of the Ministry of the Interior and Admini stration (PIM MSWiA) in Warsaw, under the direction of Prof. Irena Walecka, MD, PhD, which in itself underscores its interdisciplinary character; the research group comprises dermatologists and gastroenterologists (who are the authors of this work) representing ECCO and PIM MSWiA. The aim of the project is to assemble the largest series of MCD cases to date through the ECCO collaborative network, linking gastroenterological and dermatological centres across almost all continents. The designated tasks include: validation of the 2025 Delphi criteria, refinement of the diagnostic framework, identification of predictors of treatment response, and assessment of the role and safety of newer advanced the rapies.

Metastatic Crohn’s disease: bridge between gastroenterology, rheumatology and dermatology

Conclusions Metastatic Crohn’s disease is rare, yet it constitutes a disproportionately rich model of immune-mediated, granulomatous and systemic inflammation. It shares the IL-23/Th17/TNF axis with spondyloarthropathies and psoriasis [8, 15], granulomatous histology with sarcoidosis and Behçet’s disease [4], and a therapeutic armamentarium – methotrexate, anti-TNF agents, IL-23 inhibitors and JAK inhibitors – with dermatological and rheumatological tools [12, 13]. Its tendency to dissociate from intestinal activity and to precede the underlying disease, and at times a coexisting rheumatic disease, should prompt the inclusion of MCD in the differential diagnosis of any chronic, treatment-resistant dermatosis, particularly in children and young adults [9, 11]. The approach to patients with rare diseases requires interdisciplinary and, at times, international collaboration. *** We invite clinicians who have encountered comparable presentations or who suspect metastatic Crohn’s disease in their patients to contact us. Contributions from centres across all specialities are essential to building a robust, international case series. Please contact the principal investigator of the project, Raman Nitsko vich, at roman.nitskovich@pimmswia.gov.pl or nitskovich@gmail.com.

Disclosures Conflict of interest: The authors declare no conflict of interest. Funding: No external funding. Ethics approval: Not applicable. Data availability: Not applicable. References 1. Parks AG, Morson BC, Pegum JS. Crohn’s disease with cuta neous involvement. Proc R Soc Med 1965; 58: 241–242, DOI: 10.1177/003591576505800419 2. Palamaras I, El-Jabbour J, Pietropaolo N, et al. Metastatic Crohn’s disease: a review. J Eur Acad Dermatol Venereol 2008; 22: 1033–1043, DOI: 10.1111/j.1468-3083.2008.02741.x. 3. Ebriani J, Santiago-Soltero K, Anshelevich EE, et al. Delphi Pa nel for the Development of Diagnostic Criteria for Metasta tic Cutaneous Crohn Disease: A Consensus Statement. JAMA Dermatol 2025; 161: 642–647, DOI: 10.1001/jamadermatol. 2025.1115.

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4. Sève P, Pacheco Y, Durupt F, et al. Sarcoidosis: A Clinical Over view from Symptoms to Diagnosis. Cells 2021; 10: 766, DOI: 10.3390/cells10040766. 5. Beysens S, Wellens J, De Hertogh G, et al. Managing metastatic Crohn’s disease: a single center experience, review of the cur rent evidence, and treatment algorithm. Scand J Gastroenterol 2023; 58: 1122–1130, DOI: 10.1080/00365521.2023.2209689. 6. Verstockt B, Van Assche G, Vermeire S, et al. Biological the rapy targeting the IL-23/IL-17 axis in inflammatory bowel disease. Expert Opin Biol Ther 2017; 17: 31–47, DOI: 10.1080/ 14712598.2017.1258399. 7. Chen L, Ruan G, Cheng Y, et al. The role of Th17 cells in inflam matory bowel disease and the research progress. Front Im munol 2023; 13: 1055914, DOI: 10.3389/fimmu.2022.1055914. 8. Gordon H, Burisch J, Ellul P, et al. ECCO Guidelines on Extra intestinal Manifestations in Inflammatory Bowel Disease. J Crohns Colitis 2024; 18: 1–37, DOI: 10.1093/ecco-jcc/jjad108. 9. Kyriakou G, Gkermpesi M, Thomopoulos K, et al. Metastatic vulvar Crohn’s disease preceding intestinal manifestations: a case report and short review. Acta Dermatovenerol Alp Pannonica Adriat 2019; 28: 131–133, DOI: 10.15570/actaapa. 2019.32. 10. Nitskovich R, Jóźwik A, Sobolewski P, et al. Bowel-Associated Dermatosis and Arthritis Syndrome (BADAS) – A Literature Re view With Diagnostic and Therapeutic Implications and a Re port of Two Cases of BADAS Associated With Inflammatory Bowel Disease. Arch Immunol Ther Exp (Warsz) 2026; 74: 10, DOI: 10.2478/aite-2026-0010. 11. Schneider SL, Foster K, Patel D, Shwayder T. Cutaneous mani festations of metastatic Crohn’s disease. Pediatr Dermatol 2018; 35: 566–574, DOI: 10.1111/pde.13565. 12. Kurtzman DJ, Jones T, Lian F, et al. Metastatic Crohn’s disease: a review and approach to therapy. J Am Acad Dermatol 2014; 71: 804–813, DOI: 10.1016/j.jaad.2014.04.002. 13. Burningham KM, Verma KK, Patel AB, et al. Resolution of metastatic cutaneous Crohn’s disease with upadacitinib monotherapy. JAAD Case Rep 2024; 46: 81–84, DOI: 10.1016/ j.jdcr.2024.02.017 14. Phillips FM, Verstockt B, Sebastian S, et al. Inflammatory Cutaneous Lesions in Inflammatory Bowel Disease Treated With Vedolizumab or Ustekinumab: An ECCO CONFER Multi centre Case Series. J Crohns Colitis 2020; 14: 1488–1493, DOI: 10.1093/ecco-jcc/jjaa078. 15. Fragoulis GE, Liava C, Daoussis D, et al. Inflammatory bowel diseases and spondyloarthropathies: From pathogenesis to treatment. World J Gastroenterol 2019; 25: 2162–2176, DOI: 10.3748/wjg.v25.i18.2162.

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Original paper

Reumatologia 2026; 64, 3: 166–173 DOI: https://doi.org/10.5114/reum/220541

Machine learning analysis of treatment and complication patterns in rheumatoid arthritis case reports (1995–2025) Naruaki Ogasawara ID  The Japanese Society of Internal Medicine, Bunkyo-Ward, Tokyo, Japan

Abstract Introduction: This study aimed to identify research trends and thematic structures in case reports related to rheumatoid arthritis (RA) and complications published between 1995 and September 2025. By applying unsupervised machine learning (ML), the study sought to uncover longitudinal patterns and cross-domain relationships that may not be fully captured in traditional reviews or large-scale epidemiological studies. Material and methods: Bibliographic data were collected from the Web of Science Core Collection using the search term “rheumatoid arthritis and complications,” limited to case reports published between 1995 and 2025. Titles, key words, and abstracts were combined into unified text documents and processed with natural language processing (NLP) techniques. Term Frequency–Inverse Document Frequency was applied for text vectorization. Topic extraction employed non-negative matrix factorization, and clustering was performed using K-means. The optimal number of clusters was determined based on the highest Silhouette Score (0.636). Analyses were conducted in Python (Version 3.10.5) within the PyCharm environment (Version 2022.1.3). Results: The unsupervised ML framework identified two major and stable clusters among 1,200 case reports: a pharmacological and immunological management cluster and a surgical and postoperative complications cluster. Cluster 1 included 890 reports characterized by pharmacological and immunological terms such as “TNF,” “therapy,” and “anti,” while cluster 2 contained 310 reports dominated by orthopedic terms such as “arthroplasty,” “knee,” and “revision.” Reproducibility tests across five runs demonstrated consistent clustering patterns, supporting methodological reliability. Conclusions: This NLP and ML-based analysis revealed a dual structure in RA complication literature, reflecting immunological treatment-related complications and surgical outcomes. Beyond confirming known domains, the study provides a data-driven characterization of their evolution and overlap, offering insights into the evolution of research themes in RA management. This approach demonstrates the potential of unsupervised ML for longitudinal mapping of clinical research domains. Key words: rheumatoid arthritis, complications, case reports, natural language processing, machine learning, topic modeling, pharmacovigilance.

Introduction Rheumatoid arthritis (RA) is a typical autoimmune disease characterized by chronic inflammation of the synovial membrane of joints. Delayed early diagnosis and treatment can lead to joint destruction and functional impairment, significantly impairing patients’ quality of life [1, 2]. In recent years, significant progress has been

made in controlling RA with the introduction of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate (MTX), biologic disease-modifying antirheumatic drugs (bDMARDs) including tumor necrosis factor (TNF) inhibitors, and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) such as Janus kinase (JAK) inhibitors and other agents with specific molecular targets [3, 4].

Address for correspondence Naruaki Ogasawara, The Japanese Society of Internal Medicine, 3-28-8 Hongo Bunkyo-Ward, Tokyo 113-8433, Japan, e-mail: n-ogasawara@naika.or.jp Submitted: 16.12.2025; Accepted: 10.04.2026; Published online: 30.06.2026

Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)

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However, approximately 30–50% of patients do not respond adequately to csDMARDs such as MTX [5, 6]. Furthermore, up to 40% of patients may develop difficultto-treat RA, defined by the European Alliance of Associations for Rheumatology (EULAR) as failure of ≥ 2 bDMARDs or tsDMARDs with different mechanisms of action, persistent disease activity, and problematic disease management as perceived by the clinician or patient. These patients experience intolerable adverse events or require complex treatment strategies [7, 8]. In drug-resistant or advanced cases, surgical interventions, including synovectomy, joint-preserving surgery, and total joint arthroplasty, have become an important treatment option [9, 10]. One Japanese study recorded 1,569 cases between 2004 and 2019 [11]. Treatment strategies for RA are broadly divided into medical management (pharmacological treatment with disease-modifying antirheumatic drugs [DMARDs] and adjunctive therapies) and surgical management (including synovectomy, joint-preserving surgery, and total joint replacement). Case reports provide detailed descriptions of the treatment course and decision-making for individual cases, providing a wealth of clinical information. Additio nally, case reports capture rare complications, unexpected treatment responses, and nuanced clinical decisionmaking processes that are often absent in large-scale cohort studies or randomized controlled trials. These reports serve as valuable resources for hypothesis generation, personalized medicine, and clinical education [12–15]. This study used natural language processing (NLP) and unsupervised machine learning (ML) to analyze bibliographic data on case reports related to “rheumatoid arthritis and complications” listed in the Web of Science (WoS) from 1995 to September 2025. Unlike traditional reviews or meta-analyses that rely on manual selection and thematic coding, NLP/ML methods enable scalable, reproducible, and data-driven identification of hidden patterns across thousands of reports. This approach can capture both prevailing pharmacological and surgical management trends and emerging clinical challenges, providing a more nuanced picture of RA management. However, to date, few studies have specifically applied NLP or ML techniques to RA case reports. By using NLP and ML, this study aims not only to confirm known complication domains but also to quantify their relative prominence, temporal evolution, and inter-cluster relationships, providing a more data-driven and longitudinal understanding of RA management.

Study purpose and scope The purpose of this study is to systematically analyze case reports listed in the WoS database regarding RA treatment and complications, aiming to extract clinical

characteristics and challenges that are not fully captured by existing large-scale epidemiological studies. It is expected that this study will provide new insights into treatment selection and complication management for RA patients.

Significance and contribution This study represents a large-scale analysis of RA and its complications using case report data from WoS, applying NLP and ML techniques. By systematically extracting and categorizing clinical topics, this research identifies prevailing trends in RA-related complications and treatment strategies while highlighting previously underexplored areas such as the distinct role of arthroplasty in surgical management. The findings may support clinicians, researchers, and policymakers in understanding evolving research priorities, identifying safety-related concerns, and guiding future investigations.

Material and methods Data collection and preprocessing This study collected case reports related to “rheumatoid arthritis and complications” from the WoS database in September 2025. Each case report contained an article title, key words, and abstract. The study selection procedure consisted of the following steps: 1. Initial search: A total of 8,435 records were retrieved using the topic search query “rheumatoid arthritis and complications”. 2. Document type filtering: The dataset was further restricted to include case reports, by adding the filter “case reports,” yielding a dataset of 1,283 records. 3. Year filtering: The records were refined to include only those published between 1995 and 2025, resulting in 1,200 records. These three fields were concatenated into a single text string per case report. The preprocessing pipeline handled missing values by replacing them with empty strings. All text data underwent conversion to lowercase and tokenization for subsequent analysis.

Text vectorization using Term Frequency– Inverse Document Frequency The study applied Term Frequency–Inverse Document Frequency (TF-IDF) vectorization to transform textual data into numerical representations using the TfidfVectorizer from the scikit-learn Python library [16], a widely used open-source ML tool in Python. The vectorization process removed common English stop words and excluded terms appearing in more than 95% of documents or fewer than 2 documents (Max_df = 0.95,

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Min_df = 2). This approach generated a sparse matrix that captured the relative importance of each term across the corpus [17] and has been effectively applied in emotional text classification tasks [18].

Topic modeling with non-negative matrix factorization The analysis implemented topic modeling employing non-negative matrix factorization (NMF) [19] with an optimal number of components (topics) determined by silhouette score evaluation ranging from 2 to 15. The optimal number of components (topics) was selected based on the average silhouette score across 10 independent runs for each topic count ranging from 2 to 15.

Clustering with K-means The study applied K-means clustering [20], a widely used unsupervised learning algorithm based on iterative centroid optimization, to the NMF feature matrix to categorize case reports based on their topic distributions. The number of clusters was set equal to the optimal number of topics identified through NMF. The clustering was performed multiple times with random initialization to assess stability. Each report received cluster label assignment, and visualization displayed the distribution of reports across clusters. The clustering algorithm used random initialization (i.e., the random state was not fixed); therefore, the results may vary across runs.

Statistical characterization of clusters The analysis calculated the number of reports, mean, and standard deviation of the NMF feature values for each cluster. These metrics provided insights into the internal consistency and density of individual clusters. The study compiled all results into summary tables and exported them as Excel files for further examination.

Validation of clustering quality Clustering quality was evaluated using three established metrics: the Silhouette Score [21], the CalinskiHarabasz Index [22], and the Davies-Bouldin Index [23].

Reproducibility assessment of topic modeling The analysis conducted five independent runs of the NMF topic modeling process using different random seeds

to evaluate model stability. For each topic, the study compared the top 10 key words across all runs and calculated their overlap with the original key word set. The average key word overlap across runs served as a reproducibility score, indicating the consistency of topic identification. Note that this study used the simple number of key word matches (overlap count) to evaluate NMF reproducibility and did not use ratio-based metrics such as the Jaccard Index or percentage overlap.

Bioethical standards Due to the nature of the study, the consent of the bioethics committee was not required.

Results Overview of clustering outcomes Using TF-IDF vectorization, NMF, and K-means clustering, two major thematic clusters were identified among the case reports related to “rheumatoid arthritis and complications” published between 1995 and September 2025. This study used a method to quantify the importance of words in a text (TF-IDF), a method to identify hidden features and trends within the text (NMF), and a method to group papers with similar content (K-means clustering). As a result, the optimal number of clusters was determined as 2, based on the Silhouette Score (0.636), along with the Calinski-Harabasz Index (2733.643) and the Davies-Bouldin Index (0.531), indicating that the clusters are well separated and internally cohesive, as reflected by the high Silhouette Score and Calinski-Harabasz Index and the low Davies-Bouldin Index (Table I). Cluster 1 contained 890 case reports (n = 890), while cluster 2 contained 310 case reports (n = 310). The rela tively low standard deviations of the average TF-IDF scores across both clusters (cluster 1 = 0.0364, cluster 2 = 0.0645) indicate consistent internal text similarity and term importance (Table II). The temporal evolution over the 30-year literature is characterized by the rapid growth of cluster 1 after 2000, with an explosive increase especially after 2020, while cluster 2 has only shown a gradual increase (Fig. 1).

Topic-specific key words and weight distribution The top-ranked key words and their corresponding TF-IDF scores within each cluster are presented in Table III.

Table I. Clustering validity Optimal topic count

Silhouette Score

Calinski-Harabasz Index

Davies-Bouldin Index

0.63638533

2,733.643464

0.531957014

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Table II. Cluster statistics Cluster

Topic label

Number of reports

Mean TF-IDF score

TF-IDF standard deviation

RA, arthritis, rheumatoid

890

0.043621009

0.03643496

Patients, arthroplasty, total

310

0.067337745

0.06456454

RA – rheumatoid arthritis, TF-IDF – Term Frequency–Inverse Document Frequency.

Number of case reports

Cluster 1 Cluster 2

60 50 40 30 20 10 0 1995

2000

2005

2010

2015

2020

2025

Publication year

Fig. 1. Temporal evolution of two clusters (1995–2025).

and “anti”, suggesting a focus on disease pathogenesis and biologic treatment (Fig. 2, Table III). By contrast, cluster 2 centered around “arthroplasty,” “knee,” “elbow,” and “revision,” indicating a distinct focus on surgical complications and orthopedic outcomes (Fig. 3, Table III). These findings indicate an initial clear separation between medical-therapeutic and surgical-mechanical domains of RA complications, particularly in earlier publication periods. Within each cluster, the words used were internally consistent, supporting stable cluster assignment despite increasing inter-cluster overlap over time (Figure 4).

Clustering validity and reproducibility To evaluate the quality of the clustering results, this study employed three metrics: the Silhouette Score, the Calinski-Harabasz Index, and the Davies-Bouldin In-

Topic 1: RA, arthritis, rheumatoid Case Anti

Table III. Topic key word scores

Alpha

Topic

Key word

TF-IDF score

Therapy

0.491735426

Disease

Arthritis

0.468112257

TNF

Rheumatoid

0.468084563

Rheumatoid

TNF

0.460721937

Arthritis

Disease

0.447705025

Therapy

0.422323735

Patients

0.397992105

Alpha

0.382348399

Anti

0.37630643

Case

0.37118593

Patients

0.47450481

Arthroplasty

0.432641023

Total

0.363353083

Knee

0.351021459

Elbow

0.318907035

Surgery

0.266615052

Revision

0.263702504

Years

0.249892609

0.236676265

Fusion

0.232738428

Key word

Patients

RA 0

0.1

0.2

0.3

0.4

0.5

TF-IDF score

Fig. 2. Analysis of rheumatoid arthritis treat ment and complications using Term Frequency– Inverse Document Frequency scores cluster 1. RA – rheumatoid arthritis, TF-IDF – Term Frequency–Inverse Document Frequency, TNF – tumor necrosis factor.

The analysis of case reports related to “rheumatoid arthritis and complications” published between 1995 and September 2025 revealed the following clusters: the first cluster (cluster 1) consisted of case reports related to “rheumatoid arthritis disease and treatment” (890 cases), and the second cluster (cluster 2) consisted of case reports related to “rheumatoid arthritis surgery and follow-up” (310 cases). Cluster 1 was characterized by immunological and pharmacological terms such as “TNF,” “therapy,” “alpha,”

RA – rheumatoid arthritis, TF-IDF – Term Frequency–Inverse Document Frequency, TNF – tumor necrosis factor.

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Table IV. Reproducibility summary

Topic 2: Patients, arthroplasty, total Fusion

Topic

Average overlap count

Years

Key word

Revision Surgery Elbow Knee Total Arthroplasty Patients 0

0.1

0.2

0.3

0.4

TF-IDF score

Fig. 3. Analysis of rheumatoid arthritis treat ment and complications using Term Frequency– Inverse Document Frequency scores, cluster 2.

Key word overlap score

RA – rheumatoid arthritis, TF-IDF – Term Frequency–Inverse Document Frequency.

80 60 40 20 0

1995

2000

2005

2010

2015

2020

2025

Publication year

Fig. 4. Interrelationship between two clusters over time. dex. The optimal topic number of two clusters achieved the best clustering validity with the indicators (Table I). Validation metrics indicated that the model produced well-separated and compact clusters, supporting the robustness of topic differentiation. Reproducibility tests were conducted across 5 independent runs, each yielding highly consistent topic assignments with full overlap (average overlap count = 10 for both clusters). These results suggest high stability and reproducibility of the clustering model (Table IV).

Interpretation of topic structures Cluster 1 (“RA, arthritis, rheumatoid”) primarily included reports describing systemic inflammatory mecha nisms, immunotherapy responses, and biologic drugrelated complications such as TNF inhibitor-induced

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infections or autoimmune exacerbations. The presence of high-weight key words such as “TNF,” “therapy,” and “anti” further suggests a dominant focus on pharmacological management and immunological outcomes. Cluster 2 (“patients, arthroplasty, total”) represented literature dealing with orthopedic complications following joint replacement procedures in RA patients, particularly knee and elbow arthroplasties. Terms such as “revision,” “fusion,” and “follow” reflected the clinical and surgical follow-up nature of these case reports. This cluster therefore captures the mechanical and postoperative dimension of RA-related complications.

Summary The unsupervised ML framework successfully revealed two distinct and stable thematic structures within 30 years of RA complication literature: – pharmacological/medical management cluster: focusing on pathophysiology, TNF-related therapy, and biologic drug–induced complications; – surgical and postoperative complication cluster: concentrating on postoperative complications, prosthesis outcomes, and joint revision surgery. These findings highlight the dual landscape of RA complications research, encompassing both conservative treatment and surgical treatment, and suggest that future interdisciplinary approaches should integrate both aspects to achieve comprehensive patient mana gement. The strong reproducibility of the clustering results further supports the robustness of this ML-based framework for long-term bibliometric trend analysis.

Discussion This ML-based analysis of case reports on “rheumatoid arthritis and complications” from 1995 to September 2025 revealed two major thematic clusters that correspond to distinct clinical domains: pharmacological/ medical complications and surgical and postoperative complications. The former was characterized by pharmacological and immunological terms such as “TNF,” “therapy,” “alpha,” and “anti,” highlighting the domi nance of biologic treatments and their associated adverse effects, such as infection and secondary autoimmune responses. The latter cluster was centered around surgical and orthopedic terminology such as “arthro-

Machine learning-based analysis of rheumatoid arthritis treatment and complications

plasty,” “knee,” “elbow,” and “revision,” indicating the ongoing challenges of joint replacement, prosthesis management, and surgical complications in patients with advanced RA. These findings indicate that research on RA complications has evolved into two parallel streams over the past three decades: one driven by advances in pharmacological and immunological management, and another by surgical and postoperative interventions. While these domains are clinically recognized, this study provides a novel contribution by systematically quantifying their representation, temporal evolution, and intercluster relationships across 30 years of literature. This longitudinal mapping offers a data-driven perspective that complements traditional expert reviews. The increasing co-occurrence of terms related to immunosuppressive therapy and surgical revision suggests a growing intersection between pharmacological failure and orthopedic intervention – an emerging clinical pattern not systematically captured in prior reviews. This insight may inform future research on treatment sequencing and risk stratification in difficult-to-treat RA.

Clinical and research implications The results of this study revealed that research and treatment trends related to RA complications can be broadly divided into two clusters. Each cluster has important implications for medical practice and research. The first cluster is related to drug therapy. Since the 2000s, new drugs such as TNF inhibitors and JAK inhibitors have emerged, bringing significant advances in RA treatment [24, 25]. However, these drugs are associated with safety concerns, such as the risk of infection (particularly herpes zoster reactivation) and thrombosis [26, 27]. This study applied unsupervised ML techniques to quantitatively identify how these side effect risks are manifested in the literature. The second cluster is related to surgical procedures. Although the introduction of new drugs such as TNF and JAK inhibitors has led to significant advances in the treatment of RA, patients with severe RA may deve lop joint damage that requires orthopedic intervention (joint replacement) [28, 29]. In this second cluster, terms such as “revision,” “fusion,” and “prosthesis” frequen tly appear, revealing that issues include post-operative complications, the lifespan of artificial joints, infection, and mechanical problems.

Significance as a research method In this study, unsupervised ML was used to identify meaningful groups (clusters) from a large amount of WoS research data without human intervention.

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The clusters were also highly reproducible (Silhouette Score = 0.636, number of overlaps in repeated runs = 10), confirming the reliability of this method. This type of ML-based analysis can help discover new trends and rare complications that would be difficult to find using traditional human reviews alone and is expected to serve as a starting point for precision medicine and new research [30]. While the complication categories identified in this study are clinically established, the reproducible application of data-driven temporal quantification and automated clustering is a novel contribution that may be useful for future longitudinal and pharmacovigilance analyses. Moreover, the reproducibility test across five independent runs confirmed the model’s stability, which is important for ensuring the reliability and validity of unsupervised ML applications in medical literature analysis.

Study limitations Despite its contributions, several limitations should be acknowledged. First, the study relies exclusively on the WoS database, which, while comprehensive, may introduce selection bias. Certain journals, case series, or non-English publications not indexed in WoS could have been excluded, potentially leading to incomplete representation of the global literature. Second, case reports inherently reflect publication bias, favoring unusual, severe, or novel complications rather than typical or negative outcomes. This may overemphasize rare phenomena at the expense of everyday clinical expe rience. Third, the study’s text-based modeling approach does not incorporate full-text content or structured clinical data such as patient demographics, laboratory results, or treatment duration. Consequently, the extracted topics reflect textual emphasis rather than detailed clinical causality. Lastly, as unsupervised ML involves algorithmic abstraction without expert supervision, topic labeling was inferred from high-frequency terms rather than domain-curated validation, which may limit semantic precision. Future research should aim to integrate data from multiple bibliographic sources (e.g., PubMed, Scopus), incorporate multilingual text mining, and apply hybrid supervised–unsupervised approaches to enhance both the accuracy and interpretability of topic identification. The inclusion of full-text and metadata analysis would further deepen understanding of complication mechanisms and risk stratification in RA.

Conclusions This study used NLP and unsupervised ML to identify two distinct and stable thematic structures (pharmaco-

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therapy cluster and surgical cluster) in case reports on “rheumatoid arthritis and its complications” published between 1995 and September 2025. The former focuses on complications related to drug therapy, driven by advances in biological and molecular-targeted drug therapies such as TNF and JAK inhibitors. The latter focuses on postoperative complications following arthroplasty and arthrodesis, reflecting the ongoing challenges of surgical management in patients with advanced RA. This study applies ML-based analytic methods, reflecting the recent expansion of ML-related research in the medical field [30]. Methodologically, this study demonstrates the potential of unsupervised ML for extracting clinically meaningful insights from large-scale literature data. The high reproducibility of the clustering results supports the robustness of this analytical method. By uncovering longitudinal trends, cross-domain overlaps, and emerging intersections between pharmacological and surgical complications, this study demonstrates how ML-based text analysis can complement expert-driven reviews and support future applications in precision medicine, pharmacovigilance, and automated literature surveillance. This framework provides a scalable and reproducible approach that may be extended to track evolving treatment paradigms and safety-related trends in rheumatology.

Disclosures Conflicts of interest: The author declares no conflicts of interest. Funding: No external funding. Ethics approval: Due to the nature of the study, consent is not required. Availability of data and material: The data that support the findings of this study are available on request from the author (N.O.). References 1. Zhu M, Ding Q, Lin Z, et al. New targets and strategies for rheumatoid arthritis: from signal transduction to epige netic aspect. Biomolecules 2023; 13: 766, DOI: 10.3390/ biom13050766. 2. Athanasiou A, Papazachou O, Rovina N, et al. The effects of exercise training on functional capacity and quality of life in patients with rheumatoid arthritis: a systematic review. J Cardiovasc Dev Dis 2024; 11: 161, DOI: 10.3390/jcdd11060161. 3. Alivernini S, Firestein GS, McInnes IB. The pathogenesis of rheumatoid arthritis. Immunity 2022; 55: 2255–2270, DOI: 10.1016/j.immuni.2022.11.009. 4. Jain A, Bishnoi M, Prajapati SK, et al. Targeting rheumatoid arthritis: a molecular perspective on biologic therapies and clinical progress. J Biol Eng 2025; 19: 67, DOI: 10.1186/s13036025-00534-8.

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5. Gupta V, Katiyar S, Singh A, et al. CD39 positive regulatory T cell frequency as a biomarker of treatment response to metho trexate in rheumatoid arthritis. Int J Rheum Dis 2018; 21: 1548– 1556, DOI: 10.1111/1756-185X.13333. 6. Yu J, Zhou P. The advances of methotrexate resistance in rheu matoid arthritis. Inflammopharmacology 2020; 28: 1183–1193, DOI: 10.1007/s10787-020-00741-3. 7. Qiao Y, Li F, Zhang L, et al. A systematic review and meta-anal ysis comparing outcomes following total knee arthroplasty for rheumatoid arthritis versus for osteoarthritis. BMC Musculo skelet Disord 2023; 24: 484, DOI: 10.1186/s12891-023-06601-9. 8. Hawker G, Ravi B, Goodman S. Outcomes in rheumatoid ar thritis patients undergoing total joint arthroplasty. Int J Clin Rheumatol 2014; 9: 585–593, DOI: 10.2217/ijr.14.47. 9. Sigmund A, Russell LA. Optimizing rheumatoid arthritis patients for surgery. Curr Rheumatol Rep 2018; 20: 48, DOI: 10.1007/ s11926-018-0757-x. 10. Taylor-Williams O, Nossent J, Inderjeeth CA. Incidence and complication rates for total hip arthroplasty in rheumatoid arthritis: a systematic review and meta-analysis across four decades. Rheumatol Ther 2020; 7: 685–702, DOI: 10.1007/ s40744-020-00238-z. 11. Hotta Y, Nasu Y, Nishida K, et al. FRI0523. The recent trend of orthopaedic surgeries for rheumatoid arthritis: an analysis of 1569 cases from 2004 to 2019. Ann Rheum Dis 2020; 79 (Suppl 1): 860–861, DOI: 10.1136/annrheumdis-2020eular.1974. 12. Jackson D, Daly J, Saltman DC. Aggregating case reports: a way for the future of evidence-based health care? Clin Case Rep 2014; 2: 23–24, DOI: 10.1002/ccr3.58. 13. Cheung A, O’Sullivan F, Walker S, et al. MSR77. Making a case for case reports: a scoping review of the use of and challenges with case report data in quantitative synthesis. Value Health 2023; 26 (Suppl): S291. 14. Lowenfels AB, Mamtani R, Solomon LW, et al. The value of case reports for graduate medical education. J Grad Med Educ 2022; 14: 529–532, DOI: 10.4300/JGME-D-21-01115.1. 15. Ogasawara N, Matsunaga K, Isomoto H, Shimizu W. Internal medicine year in review 2022. Intern Med 2023; 62: 3431–3435, DOI: 10.2169/internalmedicine.2266-23. 16. Pedregosa F, Varoquaux G, Gramfort A, et al. Scikit-learn: machine learning in Python. J Mach Learn Res 2011; 12: 2825–2830. 17. Manning CD, Raghavan P, Schütze H. Introduction to informa tion retrieval. Cambridge University Press, Cambridge 2008. 18. Alfarizi MI, Syafaah L, Lestandy M. Emotional text classifica tion using TF-IDF (Term Frequency–Inverse Document Fre quency) and LSTM (Long Short-Term Memory). JUITA J Inform 2022; 10: 225–234, DOI: 10.30595/juita.v10i2.13262. 19. Lee DD, Seung HS. Learning the parts of objects by non-negative matrix factorization. Nature 1999; 401: 788–791, DOI: 10.1038/ 44565. 20. Lloyd S. Least squares quantization in PCM. IEEE Trans Inf Theory 1982; 28: 129–137, DOI: 10.1109/TIT.1982.1056489. 21. Rousseeuw PJ. Silhouettes: a graphical aid to the interpreta tion and validation of cluster analysis. J Comput Appl Math 1987; 20: 53–65, DOI: 10.1016/0377-0427(87)90125-7. 22. Caliński T, Harabasz J. A dendrite method for cluster analysis. Commun Stat 1974; 3: 1–27, DOI: 10.1080/03610927408827109.

Machine learning-based analysis of rheumatoid arthritis treatment and complications

23. Davies DL, Bouldin DW. A cluster separation measure. IEEE Trans Pattern Anal Mach Intell 1979; PAMI-1: 224–227, DOI: 10.1109/TPAMI.1979.4766909. 24. Angelini J, Talotta R, Roncato R, et al. JAK-Inhibitors for the treatment of rheumatoid arthritis: a focus on the present and an outlook on the future. Biomolecules 2020; 10: 1002, DOI: 10.3390/biom10071002. 25. Domańska-Poboża J, Wisłowska M. Evolving strategies in the treatment of rheumatoid arthritis: a historical perspective. Reumatologia 2025; 63: 116–130, DOI: 10.5114/reum/195012. 26. Riley TR, George MD. Risk for infections with glucocorticoids and DMARDs in patients with rheumatoid arthritis. RMD Open 2021; 7: e001235, DOI: 10.1136/rmdopen-2020-001235. 27. Venetsanopoulou AI, Voulgari PV, Drosos AA. Janus kinase versus TNF inhibitors: where we stand today in rheumatoid

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arthritis. Expert Rev Clin Immunol 2022; 18: 485–493, DOI: 10.1080/1744666X.2022.2064275. 28. Goodman SM, George MD. Should we stop or continue con ventional synthetic (including glucocorticoids) and targeted DMARDs before surgery in patients with inflammatory rheu matic diseases? RMD Open 2020; 6: e001214, DOI: 10.1136/ rmdopen-2020-001214. 29. Girdler SJ, Ye I, Tang R, Kirschner N. Altering the natural history of rheumatoid arthritis: the role of immunotherapy and biolo gics in orthopaedic care. J Orthop 2019; 17: 17–21, DOI: 10.1016/ j.jor.2019.06.030. 30. Ogasawara N, Matsunaga K, Isomoto H, Shimizu W. Internal medicine year in review 2023. Intern Med 2024; 63: 3137–3140, DOI: 10.2169/internalmedicine.4396-24.

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Original paper

Reumatologia 2026; 64, 3: 174–180 DOI: https://doi.org/10.5114/reum/214444

Changes in hematological indices during adalimumab therapy in ankylosing spondylitis: a one-year retrospective study Dominika Szlichta ID , Magdalena Dryglewska ID , Ewa Łyś-Toporowska ID , Maria Majdan ID Department of Rheumatology and Systemic Connective Tissue Diseases, Medical University of Lublin, Poland

Abstract Introduction: Ankylosing spondylitis (AS) is a chronic inflammatory disease that can be managed with tumor necrosis factor (TNF) inhibitors. This study evaluated the effects of adalimumab, a TNF inhibitor, on inflammatory markers, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Monitoring disease activity during therapy is important for assessing treatment response. Material and methods: We analyzed the medical history of 28 patients with confirmed AS, treated with adalimumab. The inflammatory markers neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), monocyte–lymphocyte ratio (MLR), CRP, ESR, and the Bath Ankylosing Spondylitis Disease Activity Index were assessed at the beginning of the observation (month 0) and after 3, 6, and 12 months of therapy. Results: The mean NLR value after 3 months of treatment was 1.48 (95% confidence interval, CI: 0.92–2.03, p < 0.001), after 6 months was 1.48 (95% CI: 0.92–2.12, p < 0.001), and after 12 months was 1.67 (95% CI: 1.08–2.30, p < 0.001). Mean MLR value after 3 months of treatment was 0.07 (95% CI: 0.03–0.13, p = 0.005), after 6 months was 0.05 (95% CI: 0.00–0.11, p = 0.101), and after 12 months was 0.06 (95% CI: 0.01–0.11, p = 0.047), showing statistical significance only after 3 and 12 months. The mean PLR value after 3 months of treatment was 52.8 (95% CI: 30.1–79.60, p < 0.001), after 6 months was 65.50 (95% CI: 31.60–83.90, p < 0.001), and after 12 months was 68.80 (95% CI: 42.70–93.70, p < 0.001). Conclusions: Neutrophil–lymphocyte ratio may be a useful marker of inflammation in patients with AS. Monocyte–lymphocyte ratio and PLR require further investigation. Peripheral blood tests are simple and inexpensive to perform, making hematological markers promising tools for monitoring inflammatory diseases. Key words: ankylosing spondylitis, adalimumab, blood platelets, neutrophils.

Introduction Ankylosing spondylitis (AS) is an inflammatory auto immune disease mainly affecting the sacroiliac joints and spine, which leads to a decrease in the quality of life, chronic pain, and consequently disability [1]. Ankylosing spondylitis is the most common disease among seronegative spondyloarthropathies and is associated with human leukocyte antigen B27 positivity in most cases. Men are more prone to this disease than women. Ankylosing spondylitis typically starts in the second decade of life and rarely occurs after the age of 45. The first symptoms are pain in the lower back and morning stiffness of the spine.

The pathogenesis of the disease is not fully known, but the triggers of inflammation are recognized. It is hypo thesized that in genetically predisposed individuals, exposure to bacterial or environmental antigens may trigger an immune response. This can lead to increased production of pro-inflammatory cytokines, including interleukin-12, interleukin-17 (IL-17), and tumor necrosis factor (TNF) [2]. Following the diagnosis of AS, patient education and multidisciplinary care are essential. The cornerstone of treatment is physiotherapy and exercisebased rehabilitation. The first line of pharmacotherapy

Address for correspondence Dominika Szlichta, Department of Rheumatology and Systemic Connective Tissue Diseases, Medical University of Lublin, 8 Jaczewskiego St., 20-090 Lublin, Poland, e-mail: dominika.janeczko@gmail.com Submitted: 19.10.2025; Accepted: 19.11.2025; Published online: 29.06.2026

Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)

Changes in hematological indices during adalimumab therapy in ankylosing spondylitis

in AS is nonsteroidal anti-inflammatory drugs, which can be used at the maximum tolerated dose, taking both benefits and risks into consideration. The second line of treatment is TNF inhibitors (anti-TNFs), IL-17 inhibitors (IL-17i), or Janus kinase inhibitors [3]. They are shown to be effective in reducing inflammation and disease acti vity in AS [4, 5]. In this study, we investigated the TNF inhibitor adalimumab (ADA), which is the first fully human monoclonal antibody directed against TNF. Adalimumab is well known for reducing the inflammatory markers C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) [6, 7]. To initiate, continue, or discontinue therapy, disease activity should be monitored regularly. It can be assessed with CRP, ESR, and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scale. The neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), and monocyte–lymphocyte ratio (MLR) are hematological markers, which correlate with CRP and ESR values, currently being investigated by researchers to determine the severity of inflammation [8]. Data show NLR, MLR, and PLR are higher in patients with AS than in healthy controls [1, 9, 10]. The NLR, PLR, and MLR indexes are well-known predictive indicators in infectious and inflammatory diseases; however, optimal cut-off values have not yet been established [11–13]. There are no universally accepted thresholds for these hematological markers, as they are likely influenced by disease type and individual patient-related factors [14–16]. The aim of this study was to investigate the response to treatment with ADA in patients with AS using hematological markers such as NLR, PLR, and MLR during oneyear treatment and assess the correlation with other inflammatory markers.

Material and methods A retrospective analysis of the medical history of 28 patients (4 women and 24 men) with confirmed AS who were under constant, long-term care of a clinical rheumatology department was conducted. The study included patients treated between January 2018 and March 2023. Diagnosis of AS was based on Assessment of SpondyloArthritis International Society 2010 criteria. All of the patients were newly initiated on ADA therapy, and it was their first biological treatment. Patients who had received prior biologic therapy other than ADA or who discontinued ADA within 12 months were excluded. In addition, patients older than 70 years were not included in the study. We assessed full blood count for each patient. Neutrophil–lymphocyte ratio was calculated by dividing the neutrophil count by the lymphocyte count, PLR was calculated by dividing the platelet count by the lymphocyte count, and MLR was calculated by dividing the monocyte count by the lymphocyte count. The in-

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flammatory markers (NLR, PLR, MLR, CRP, ESR) and BASDAI scale were assessed at the beginning of the observation (month 0) and after 3, 6, and 12 months of ADA therapy for every patient. The results were analyzed using the Wilcoxon signed-rank test and Spearman’s rank correlation coefficient.

Bioethical standards The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Medical University of Lublin, Poland (number: KE-0254/123/04/2023 on 27th April 2023). Due to the retrospective and anonymized nature of the study, the requirement for written informed consent from individual patients was waived by the Ethics Committee. All patient data were handled confidentially and anonymized prior to analysis.

Results A total of 28 patients (median age was 37 years; range: 26–56) were included. The majority of patients were male (85.71%). Median disease duration at the moment of starting ADA treatment was 7 years (range: 2–28). The median NLR value after 3 months of treatment was 1.48 (95% confidence interval, CI: 0.92–2.03; p < 0.001), after 6 months 1.48 (95% CI: 0.92–2.12; p < 0.001), and after 12 months 1.67 (95% CI: 1.08–2.30; p < 0.001). All differences compared to baseline were statistically significant. Differences between months 3 and 6 (median difference 0.07; 95% CI: from –0.33 to 0.44; p = 1.000), between months 3 and 12 (0.17; 95% CI: from –0.16 to 0.57; p = 0.774), and between months 6 and 12 (0.08; 95% CI: from –0.21 to 0.40; p = 1.000) were not statistically significant (Tables I and II). The median MLR value after 3 months of treatment was 0.07 (95% CI: 0.03–0.13; p = 0.005), after 6 months 0.05 (95% CI: 0.00–0.11; p = 0.101), and after 12 months 0.06 (95% CI: 0.01–0.11; p = 0.047). Statistically significant differences were observed after 3 and 12 months, but not after 6 months (Tables I and II). The median PLR value after 3 months of treatment was 52.8 (95% CI: 30.1–79.6; p < 0.001), after 6 months 65.5 (95% CI: 31.6–83.9; p < 0.001), and after 12 months 68.8 (95% CI: 42.7–93.7; p < 0.001). All changes compared to baseline were statistically significant (Table I). At baseline, PLR showed a strong negative correlation with lymphocyte count (ρ = –0.83; 95% CI: from –0.92 to –0.65; p < 0.001), and a strong positive correlation was observed between CRP and ESR (ρ = 0.77; 95% CI: 0.56–0.89; p < 0.001; Table III).

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Table I. Summary statistics of key biomarkers and disease activity scores at baseline and during therapy follow-up Characteristic

Baseline (n = 28)

3 months (n = 26)

6 months (n = 26)

12 months (n = 24)

CRP [mg/l]

17.78 (6.6, 35.66) 95% CI: 13.00–27.00 [0.50, 69.62]

0.50 (0.45, 3.90) 95% CI: 0.48–4.00 [0.05, 51.65]

0.70 (0.45, 1.95) 95% CI: 0.56–2.20 [0.09, 8.93]

0.84 (0.45, 3.09) 95% CI: 0.66–4.10 [0.10, 11.42]

ESR [mm/h]

22.00 (13.50, 37.50) 95% CI: 19.00–33.00 [7.00, 56.00]

2.00 (2.00, 7.00) 95% CI: 2.00–5.00 [2.00, 25.00]

3.00 (2.00, 6.00) 95% CI: 2.50–5.50 [2.00, 18.00]

4.00 (2.00, 6.50) 95% CI: 3.50–6.00 [2.00, 17.00]

Neutrophils [×109/l]

5.44 (3.81, 6.78) 95% CI: 4.60–6.00 [1.88, 9.01]

3.25 (2.05, 4.55) 95% CI: 2.80–3.90 [1.51, 7.31]

2.98 (2.21, 4.08) 95% CI: 2.70–3.80 [1.65, 6.58]

2.90 (2.23, 3.76) 95% CI: 2.50–3.70 [1.63, 10.79]

Monocytes [×109/l]

0.47 (0.36, 0.61) 95% CI: 0.42–0.61 [0.20, 1.07]

0.42 (0.32, 0.48) 95% CI: 0.36–0.48 [0.16, 0.84]

0.45 (0.31, 0.59) 95% CI: 0.39–0.57 [0.22, 1.07]

0.43 (0.40, 0.54) 95% CI: 0.41–0.52 [0.21, 0.79]

Platelets [×109/l]

294.0 (262.0, 333.0) 95% CI: 279.0–319.0 [211.0, 404.0]

246.5 (219.0, 262.0) 95% CI: 231.0–258.0 [182.0, 306.0]

230.0 (212.0, 256.00) 95% CI: 222.0–251.0 [161.0, 294.0]

222.5 (206.0, 249.0) 95% CI: 213.0–241.0 [170.0, 293.0]

Lymphocytes [×109/l]

1.85 (1.41, 2.01) 95% CI: 1.50–1.90 [0.90, 2.67]

2.03 (1.64, 2.39) 95% CI: 1.80–2.30 [1.09, 3.21]

1.95 (1.72, 2.46) 95% CI: 1.80–2.30 [0.34, 3.17]

2.02 (1.70, 2.66) 95% CI: 1.90–2.40 [1.22, 3.30]

NLR

3.11 (2.41, 4.13) 95% CI: 2.70–3.70 [1.60, 6.75]

1.61 (1.02, 2.15) 95% CI: 1.40–2.00 [0.72, 3.04]

1.48 (1.15, 1.80) 95% CI: 1.30–2.00 [0.76, 17.32]

1.52 (1.13, 1.67) 95% CI: 1.20–1.60 [0.59, 8.84]

MLR

0.25 (0.23, 0.43) 95% CI: 0.24–0.37 [0.17, 0.61]

0.20 (0.17, 0.24) 95% CI: 0.18–0.24 [0.10, 0.38]

0.20 (0.17, 0.30) 95% CI: 0.19–0.30 [0.09, 2.09]

0.22 (0.17, 0.26) 95% CI: 0.20–0.25 [0.14, 0.35]

PLR

173.6 (134.0, 210.1) 95% CI: 162.0–206.0 [119.4, 377.6]

124.7 (97.1, 150.3) 95% CI: 111.0–139.0 [73.6, 211.0]

113.9 (95.3, 150.4) 95% CI: 105.0–138.0 [59.3, 638.2]

107.2 (85.4, 130.8) 95% CI: 97.0–124.0 [55.15, 209.84]

BASDAI

6.60 (5.60, 7.40) 95% CI: 6.10–7.10 [4.80, 8.80]

2.25 (1.60, 3.00) 95% CI: 2.00–2.70 [0.00, 3.60]

1.80 (1.00, 2.20) 95% CI: 1.40–2.00 [0.20, 2.80]

1.45 (1.20, 1.90) 95% CI: 1.20–1.80 [0.20, 5.70]

All values are reported as median (first quartile, third quartile), followed by 95% confidence interval (CI) (lower limit, upper limit) for the median, and range [minimum, maximum]. Time points refer to baseline (prior to therapy initiation) and follow-up assessments at 3, 6, and 12 months of therapy. Sample sizes (n) reflect available data at each time point; the total cohort size is 28. Confidence intervals for medians were derived using the Wilcoxon method. BASDAI – Bath Ankylosing Spondylitis Disease Activity Index, CRP – C-reactive protein, ESR – erythrocyte sedimentation rate, MLR – monocyte– lymphocyte ratio, NLR – neutrophil–lymphocyte ratio, PLR – platelet–lymphocyte ratio.

After 3 months of ADA therapy, PLR remained strongly and inversely correlated with lymphocytes (ρ = –0.92; 95% CI: from –0.96 to –0.82; p < 0.001). In addition, significant positive correlations were found between CRP and neutrophil count (ρ = 0.63; 95% CI: 0.31–0.82; p = 0.014) and between neutrophils and monocytes (ρ = 0.63; 95% CI: 0.32–0.82; p = 0.014; Table III). At 6 and 12 months, the inverse relationship between PLR and lymphocyte count persisted (ρ = –0.88 and –0.87, respectively; both p < 0.001), indicating a stable negative association throughout the treatment period. No other statistically significant correlations were observed (Table III). There was no correlation between NLR, PLR, and MLR and BASDAI score.

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Discussion The search for more reliable inflammatory markers in rheumatic diseases is ongoing. Although CRP and ESR are traditionally used, hematological markers may also be useful, particularly due to their lower cost and in patients with persistently low CRP or ESR levels despite ongoing inflammation [17, 18]. Hematological marker values decrease over the course of ADA treatment in patients with AS [8]. This suggests an association with disease activity, which also decreases during therapy. In our calculations NLR value is correlating with CRP and ESR values, as other studies are indicating [8, 19–22]. And it probably makes it alternative biomarker, when

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Changes in hematological indices during adalimumab therapy in ankylosing spondylitis

Table II. Pairwise comparisons of median differences in key biomarkers and disease activity scores between time points Characteristic Baseline vs. 3 months

Baseline vs. 6 months

Baseline vs. 12 months

3 vs. 6 months

3 vs. 12 months

6 vs. 12 months

CRP [mg/l]

14.20 95% CI: 6.76–21.60 padj < 0.001

15.60 95% CI: 7.40–21.90 padj < 0.001

14.30 95% CI: 6.89–21.80 padj < 0.001

0.01 95% CI: from –0.40 to 0.68 padj = 1.000

–0.06 95% CI: from –0.54 to 0.40 padj = 1.000

–0.10 95% CI: from –0.61 to 0.28 padj = 1.000

ESR [mm/h]

16.00 16.30 17.00 95% CI: 12.00–30.00 95% CI: 11.00–30.00 95% CI: 11.0–29.00 padj < 0.001 padj < 0.001 padj < 0.001

0.00 95% CI: from –1.00 to 0.00 padj = 0.862

0.00 95% CI: from –2.00 to 0.00 padj = 0.621

0.00 95% CI: from –2.00 to 1.00 padj = 0.862

Neutrophils [×109/l]

2.01 95% CI: 1.00–2.94 padj < 0.001

2.06 95% CI: 1.15–3.01 padj < 0.001

2.25 95% CI: 1.24–3.13 padj < 0.001

0.06 95% CI: from –0.67 to 0.83 padj = 1.000

0.18 95% CI: from –0.51 to 1.01 padj = 1.000

0.10 95% CI: from 0.45 to 0.75 padj = 1.000

Monocytes [×109/l]

0.07 95% CI: –0.02–0.16 padj = 0.726

0.02 95% CI: –0.09–0.13 padj = 1.000

0.02 95% CI: –0.07–0.12 padj = 1.000

–0.04 95% CI: from –0.15 to 0.05 padj = 1.000

–0.05 95% CI: from –0.12 to 0.03 padj = 1.000

0.00 95% CI: from –0.10 to 0.09 padj = 1.000

Platelets [×109/l]

51.00 61.00 95% CI: 30.00–76.00 95% CI: 37.00–86.00 padj < 0.001 padj < 0.001

Lymphocytes [×109/l]

–0.33 95% CI: from –0.62 to –0.05 padj =0.076

–0.33 95% CI: –0.65–0.01 padj = 0.223

–0.50 95% CI: from –0.74 to –0.12 padj = 0.032

0.03 95% CI: from –0.31 to 0.32 padj = 1.000

–0.08 95% CI: from –0.43 to 0.22 padj = 1.000

–0.13 95% CI: from –0.47 to 0.23 padj = 1.000

NLR

1.48 95% CI: 0.92–2.03 padj < 0.001

1.48 95% CI: 0.92–2.12 padj < 0.001

1.67 95% CI: 1.08–2.30 padj < 0.001

0.07 95% CI: from –0.33 to 0.44 padj = 1.000

0.17 95% CI: from –0.16 to 0.57 padj = 0.774

0.08 95% CI: from –0.21 to 0.40 padj = 1.000

MLR

0.07 95% CI: 0.03–0.13 padj = 0.005

0.05 95% CI: 0.00–0.11 padj = 0.101

0.06 95% CI: 0.01–0.11 padj = 0.047

–0.02 95% CI: from –0.07 to 0.03 padj =1.000

–0.01 95% CI: from –0.05 to 0.02 padj = 1.000

0.00 95% CI: from –0.04 to 0.05 padj = 1.000

PLR

52.8 95% CI: 30.1–79.60 padj < 0.001

65.50 68.80 4.37 95% CI: 31.60–83.90 95% CI: 42.70–93.70 95% CI: from 15.70 padj < 0.001 padj < 0.001 to 25.30 padj = 0.792

14.00 95% CI: from –3.84 to 35.60 padj = 0.399

10.20 95% CI: from –7.96 to 29.30 padj = 0.484

68.00 8.70 95% CI: 45.00–94.00 95% CI: from –9.00 padj < 0.001 to 27.00 padj =0.754

17.00 8.02 95% CI: 0.00–37.00 95% CI: from –10.00 padj = 0.167 to 26.00 padj = 0.754

Time points refer to baseline (prior to therapy initiation) and follow-up assessments at 3, 6, and 12 months of therapy. Sample sizes (n) reflect available data at each time point; the total cohort size is 28. Confidence intervals for medians were derived using the Wilcoxon method. BASDAI – Bath Ankylosing Spondylitis Disease Activity Index, CRP – C-reactive protein, ESR – erythrocyte sedimentation rate, MLR – monocyte/lymphocyte ratio, NLR – neutrophil/lymphocyte ratio, PLR – platelet/lymphocyte ratio.

it is impossible to use CRP or ESR for AS. We need further studies to confirm this hypothesis. In our study MLR and PLR were not correlating with CRP and ESR values, which suggests they might be not good indicators of inflammation, but research show divergencies [17, 19, 20, 23], we probably need larger group of patients to observe more correlations and comparison with other anti-TNFs. In our study, hematological markers did not correlate with the BASDAI score, which is a fully subjective patient-reported measure. A limitation of this score is its susceptibility to inter-individual variability in perceived

well-being. In contrast to our findings, some studies have reported that NLR correlated with the BASDAI score [8, 17, 24, 25]. According to current recommendations, the ASDAS score is considered more reliable for assessing AS disease activity and may correlate with hematological markers, which warrants further investigation [3, 26, 27]. Neutrophil–lymphocyte ratio value is easy to calculate and inexpensive test, which makes it useful marker to assess disease activity. Peripheral blood testing is a widely used diagnostic approach worldwide and may be a useful tool for assessing inflammation. Neutrophil–lymphocyte ratio is a rapidly responsive biomarker characterized by

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Table III. Significant Spearman correlations between biomarkers at baseline and follow-up time points Time point

Pairs

Rho

95% CI

padj

Baseline

PLR vs. lymphocytes

–0.83

From –0.92 to –0.65

< 0.001

CRP vs. ESR

0.77

0.56–0.89

< 0.001

Three months after treatment

PLR vs. lymphocytes

–0.92

From –0.96 to –0.82

< 0.001

CRP vs. neutrophils

0.63

0.31–0.82

0.014

Neutrophils vs. monocytes

0.63

0.32–0.82

0.014

Six months after treatment

PLR vs. lymphocytes

–0.88

From –0.94 to –0.73

< 0.001

Twelve months after treatment

PLR vs. lymphocytes

–0.87

From –0.94 to –0.70

< 0.001

Correlations are reported as Spearman’s rank correlation coefficient (Rho) with 95% confidence intervals (CI) and adjusted p-values (padj) using the Holm-Bonferroni method for multiple comparisons. Only significant correlations (padj < 0.05) are included. Units for biomarkers are as defined in previous tables (e.g., CRP in mg/l, cell counts in ×109/l). Confidence intervals for Spearman’s correlations are computed using the Fieller et al. (1957) correction (see Bishara and Hittner, 2017). CRP – C-reactive protein, ESR – erythrocyte sedimentation rate, PLR – platelet-to-lymphocyte ratio.

high sensitivity and low specificity, which may complicate interpretation in the presence of other inflammatory conditions such as infectious diseases or malignancy [28]. In our study, these conditions were more easily excluded, as all patients underwent a full diagnostic evaluation for comorbid diseases associated with elevated inflammatory markers prior to initiation of biological therapy. The PLR value has several limitations in research. In patients with rheumatic diseases, the PLR may be inaccurately estimated due to the use of glucocorticosteroids, analgesics, and antirheumatic drugs, which can affect blood cell counts – a factor that was not consi dered in our study. Moreover, studies lasting longer than 6 months should consider potential seasonal variability of hematologic indices [29]. A recent study by Sadioglu et al. [30] analyzed hema tologic inflammatory markers in 54 biologic-naive AS patients treated with biologic agents and observed a significant decrease in NLR, PLR, and MLR after 12 months of therapy, compared with baseline values, with no significant differences between the 3-, 6-, and 12-month follow-ups. Importantly, the authors did not find correlations between these indices and BASDAI, although they observed associations with traditional inflammatory markers such as CRP and ESR. Our results are largely consistent with these findings, confirming that NLR, PLR, and MLR significantly decreased during 12 months of ADA treatment. However, our study adds a new aspect to the existing evidence. It focuses exclusively on patients who initiated ADA as their first biologic therapy, which allows clearer attribution of hematologic changes to the effect of this specific TNF inhibitor [30]. In our study, a strong negative correlation between PLR and lymphocyte count was observed at baseline and persisted throughout all follow-up points. This means that higher PLR values were consistently associated with lower lymphocyte counts, reflecting ongoing systemic

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inflammation despite clinical improvement. The stability of this correlation over 12 months suggests that PLR may serve as a reliable indicator of immune response during therapy with ADA. Similar findings showed that PLR was inversely related to lymphocyte count and disease activity in AS [12, 20]. In contrast, the temporary correlations between neutrophils, monocytes, and CRP observed after 3 months probably reflected an early inflammatory response that normalized with treatment. An important advantage of hematological markers is that they are fast-responding markers. According to many research papers [15, 29], they change faster than other inflammatory markers such as CRP and ESR. This may allow them to better reflect real-time disease activity. According to the latest scientific reports, hematological markers are promising indicators of inflammation and correlate with the activity of many other rheumatic diseases [31–34].

Conclusions In our study, the most prominent hematological marker was NLR, which may be a useful indicator of inflammation in patients with AS and could serve as an adjunct to ESR and CRP. Other biomarkers, such as MLR and PLR, require further investigation in relation to AS disease activity, in view of the inconsistent research results. Our data show BASDAI did not correlate with disease activity markers, including the most commonly used markers, ESR and CRP. This may limit its usefulness in research and in assessing response to ADA therapy. Peripheral blood testing is easy and inexpensive to perform worldwide, making hematological markers worthy of further investigation in inflammatory diseases. However, further research on a large cohort of patients

Changes in hematological indices during adalimumab therapy in ankylosing spondylitis

is required to determine their utility as inflammatory markers in AS.

Disclosures Conflicts of interest: The authors declare no conflicts of interest. Funding: No external funding. Ethics approval: The study was approved by the Ethics Committee of Medical University of Lublin, Poland (number: KE-0254/123/04/2023 on 27th April 2023). Availability of data and material: The data that support the findings of this study are available on request from the author (D.Sz.). Presentation: Related congress abstract: Reumatologia 2024; 62 (Suppl 1): 123, DOI: https://doi.org/10.5114/ reum/193309. References 1. Moon DH, Kim A, Song BW, et al. High baseline neutrophilto-lymphocyte ratio could serve as a biomarker for tumor necrosis factor-alpha blockers and their discontinuation in patients with ankylosing spondylitis. Pharmaceuticals (Basel) 2023; 16: 379, DOI: 10.3390/ph16030379. 2. Ebrahimiadib N, Berijani S, Ghahari M, Pahlaviani FG. Ankylos ing spondylitis. J Ophthalmic Vis Res 2021; 16: 462–469, DOI: 10.18502/jovr.v16i3.9440. 3. Ortolan A, Webers C, Sepriano A, et al. Efficacy and safety of non-pharmacological and non-biological interventions: a systematic literature review informing the 2022 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis. Ann Rheum Dis 2023; 82: 142–152, DOI: 10.1136/ard-2022-223297. 4. Wroński J, Fiedor P. The safety profile of tumor necrosis factor inhibitors in ankylosing spondylitis: are TNF inhibitors safer than we thought? J Clin Pharmacol 2019; 59: 445–462, DOI: 10.1002/jcph.1348. 5. Hou LQ, Jiang GX, Chen YF, et al. The comparative safety of TNF inhibitors in ankylosing spondylitis: a meta-analysis update of 14 randomized controlled trials. Clin Rev Allergy Immunol 2018; 54: 234–243, DOI: 10.1007/s12016-017-8623-6. 6. Lapadula G, Marchesoni A, Armuzzi A, et al. Adalimumab in the treatment of immune-mediated diseases. Int J Immunopathol Pharmacol 2014; 27(1 Suppl): 33–48, DOI: 10.1177/ 03946320140270S103. 7. Sukhanova AM, Gilavian MA, Melnik EV, et al. An overview of adalimumab therapy for ankylosing spondylitis. Curr Rheu matol Rev 2024; 20: 501–513, DOI: 10.2174/0115733971289295240223095751. 8. Coşkun BN, Öksüz MF, Ermurat S, et al. Neutrophil-to-lympho cyte ratio can be a valuable marker in defining disease activity in patients who have started anti-tumor necrosis factor drugs for ankylosing spondylitis. Eur J Rheumatol 2014; 1: 101–105, DOI: 10.5152/eurjrheumatol.2014.034. 9. Xu S, Ma Y, Wu M, et al. Neutrophil-to-lymphocyte ratio in patients with ankylosing spondylitis: a systematic review and meta-

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Dominika Szlichta, Magdalena Dryglewska, Ewa Łyś-Toporowska, Maria Majdan

dict clinical response to bDMARD in naïve spondyloarthritis pa tients. ARP Rheumatol 2024; 3: 18–28, DOI: 10.63032/utgy3244. 24. Kucuk A, Uslu AU, Ugan Y, et al. Neutrophil-to-lymphocyte ra tio is involved in the severity of ankylosing spondylitis. Bratisl Lek Listy 2015; 116: 722–725, DOI: 10.4149/bll_2015_142. 25. Ratios of neutrophils to lymphocytes and platelets to lympho cytes in ankylosing spondylitis with disease activity relation ship. Adv Med J 2024; 9: 15–22, DOI: 10.56056/amj.2024.293. 26. Siddique S, Zahoor S, Mahboob HM, et al. Correlation of neu trophil-to-lymphocyte ratio and disease activity in patients with ankylosing spondylitis on etanercept therapy. Pak J Med Res 2020; 59: 157–160. 27. Kim SK, Choe JY. Clinical significance of hematological indices as disease activity markers in patients with ankylosing spondylitis following treatment with tumor necrosis factor inhibitors. Int J Rheum Dis 2025; 28: e70166, DOI: 10.1111/1756-185X.70166. 28. Zahorec R. Neutrophil-to-lymphocyte ratio: past, present and future perspectives. Bratisl Lek Listy 2021; 122: 474–488, DOI: 10.4149/BLL_2021_078. 29. Gasparyan AY, Ayvazyan L, Mukanova U, et al. The plateletto-lymphocyte ratio as an inflammatory marker in rheumatic diseases. Ann Lab Med 2019; 39: 345–357, DOI: 10.3343/alm. 2019.39.4.345.

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30. Sadioglu CO, Gokcen N, Yazici A, Cefle A. Monitoring disease activity and treatment response in ankylosing spondylitis: a retrospective study of hematologic inflammatory markers. Rheumatol Int 2024; 45: 10, DOI: 10.1007/s00296-024-05763-6. 31. Wu Y, Huang Y, Wu Y, et al. Systemic immune-inflammation index as a versatile biomarker in autoimmune disorders: in sights from rheumatoid arthritis, lupus, and spondyloarthri tis. Front Immunol 2025; 16: 1621209, DOI: 10.3389/fimmu. 2025.1621209. 32. Liu S, Liu J, Cheng X, et al. Application value of platelet-tolymphocyte ratio as a novel indicator in rheumatoid arthritis: a review based on clinical evidence. J Inflamm Res 2024; 17: 7607–7617, DOI: 10.2147/JIR.S477262. 33. Rostamian A, Aghayani S, Najafizadeh SR, et al. Exploring the association between blood indices and skin and joint activity of psoriatic arthritis. Iran J Allergy Asthma Immunol 2024; 23: 651–661, DOI: 10.18502/ijaai.v23i6.17375. 34. Meena VP, Meena PD, Chejara RS, et al. Analysis of hematolo gical indices in patients of systemic lupus erythematosus and its correlation with SLEDAI-2K. J Assoc Physicians India 2023; 71: 40–42, DOI: 10.59556/japi.71.0375.

Original paper

Reumatologia 2026; 64, 3: 181–191 DOI: https://doi.org/10.5114/reum/217148

Efficacy and safety of hyperbaric oxygen therapy for women with fibromyalgia: a systematic review and meta-analysis of randomized controlled trials Maggie Liberty1 ID , Andi Raga Ginting2 ID , Dewi Masyithah Darlan3,4 ID , Peggy Liberty1 ID , Satria Gohtama1 ID 1

Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia 3 Department of Doctoral Program in Medical Sciences, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia 4 Department of Parasitology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia 2

Abstract Introduction: The use of currently recommended treatments for fibromyalgia (FM), combining pharmacological and exercise-based therapies, is often challenging in clinical practice. Poor efficacy and adverse effects of the available drugs and low adherence to exercise-based therapies resulting from physical fatigue have often led to inadequate FM-related chronic pain relief. Hyperbaric oxygen the rapy (HBOT) has been reported to be a potential emerging therapy for FM, offering pain relief with minimal physical burden and adverse effects. This review aims to evaluate the efficacy and safety of HBOT in managing FM, explicitly in female populations. Material and methods: A systematic review and meta-analysis was performed in accordance with the PRISMA flowchart in three databases, PubMed/MEDLINE, Cochrane Library, and ScienceDirect, to identify studies published up to the year 2025. The Cochrane risk of bias 2.0 tool was used to assess the quality of the included studies. Statistical analyses were conducted using RevMan 5.4.1 software on studies that reported the required numerical outcomes. Results: This review included 5 eligible studies with a total of 227 female participants with FM. The results indicated that HBOT was associated with a significantly greater reduction in pain compared to the control (mean difference [MD] = –3.41, 95% CI: from –6.24 to –0.59). Patients treated with HBOT showed reduced symptom severity compared to the control (MD = 5.27, 95% CI: 2.11–8.44). Quality of life was enhanced in HBOT, though it was not statistically significant. Furthermore, HBOT was well tolerated, with no serious adverse events reported. Conclusions: HBOT appears to be a promising adjunctive treatment for FM, demonstrating signi ficant pain reduction, with no serious adverse events reported. However, the current evidence is limited, and further high-quality studies are needed to confirm its effects on quality of life and longterm outcomes. Key words: hyperbaric oxygen therapy, fibromyalgia, pain.

Introduction Fibromyalgia (FM) is a central pain regulation disorder, characterized by chronic generalized musculoskeletal pain, stiffness, and tenderness [1]. Fibromyalgia is often accompanied by somatic and psychological

symptoms such as chronic fatigue, sleep disturbances, anxiety, and depression [2]. The etiology of FM is unknown, with no evidence of musculoskeletal inflammation. Patients with FM experience central sensitization in the brain, resulting in lower nociceptive tolerances that induce hyperalgesia and increase pain catastro-

Address for correspondence Andi Raga Ginting, Jalan Dr. T. Mansur No. 9, Kampus USU Padang Bulan, Faculty of Medicine, Universitas Sumatera Utara, Medan 20155, Indonesia, e-mail: andi.raga@usu.ac.id Submitted: 08.10.2025; Accepted: 06.11.2025; Published online: 29.06.2026

Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)

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phizing [3]. Fibromyalgia impacts approximately 5% of the population worldwide. It predominantly affects women, who represent up to 90% of the cases [4]. Moreover, FM symptoms, particularly generalized pain, often present more severely in women than in men [5]. Fibromyalgia imposes not only physical but also economic burdens due to its debilitating pain, which hinders the ability to engage in daily activities and significantly diminishes both the quality of life (QoL) and work productivity [6]. Furthermore, managing the chronic widespread pain associated with FM may be challenging in clinical practice [7]. Currently, the treatment for FM is a multidisciplinary approach, combining pharmacological the rapies with physical exercise and behavioral therapy [8]. Recent guidelines have recommended limited medications. The Food and Drug Administration has only approved three drugs for FM treatment: pregabalin, duloxetine, and milnacipran. However, pharmacological intervention alone provides limited benefit, with long-term side effects such as dizziness, somnolence, headache, weight gain, and edema [9, 10]. Research has demonstrated that exercise is an essential complementary component in the management of functional impairment and pain associated with FM. Nevertheless, it is challenging to provide specific exercise interventions for FM due to the lack of a definitive mechanism and specific pain patterns [11]. Furthermore, the high levels of fatigue that individuals with FM experience may limit adherence to exercise-based interventions [12]. Consequently, there is a need for novel and efficient chronic pain interventions that impose minimal physical burden and are associated with few adverse effects. Hyperbaric oxygen therapy (HBOT) has benefited several chronic pain conditions, reportedly including complex regional pain syndrome, trigeminal neuralgia, chronic headaches, and other pain conditions. Hyperbaric oxygen therapy is a non-invasive treatment modality that involves the intermittent inhalation of 100% oxygen (O2) within a chamber pressurized to greater than one atmosphere absolute (ATA) [13]. Hyperbaric oxygen therapy may alter the central pain regulation, which has been reported to positively improve FM symptoms. However, the recent update of European Alliance of Associations for Rheumatology (EULAR) recommendations do not recommend HBOT as a complementary treatment for FM due to insufficient evidence regarding its efficacy and safety [8]. Given its proposed analgesic effects and favorable tole rability profile, further investigation of its potential role in the management of FM is warranted. This review aims to evaluate the efficacy and safety of HBOT as complementary care in managing FM syndrome, particularly in predominant female populations.

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Our goal is to determine whether HBOT can serve as a viable alternative by potentially offering a better safety profile without compromising on pain and symptom relief.

Material and methods Search strategy A comprehensive literature search was performed in three databases – PubMed/MEDLINE, Cochrane Library, and ScienceDirect – to identify studies published up to the year 2025. The literature search was conducted using the key words “hyperbaric oxygen therapy,” “fibromyalgia,” and “pain.” The key words were inputted into the advanced search function of the databases using the Boolean operator “AND” to identify records containing all concepts of interest. Synonyms and related terms were combined using the Boolean operator “OR” and adapted according to Medical Subject Headings (MeSH) where applicable. The final search strategy was: (“hyperbaric oxygenation” OR “hyperbaric oxygen therapy” OR “HBOT”) AND (“fibromyalgia” OR “FMS” OR “chronic pain”) AND (“pain” OR “visual analogue scale”). The protocol for this review was registered on 24th January 2025 with the International Prospective Register of Systematic Reviews (PROSPERO) with identification number CRD42025642759.

Eligibility criteria The inclusion criteria for this systematic review were: 1) female patients diagnosed with FM; 2) treatment with HBOT administered in 90-minute sessions, in five sessions per week; 3) a control group receiving standard care (pharmacological therapy, physical exercise, or behavioral therapy) or no treatment as a comparison; and 4) reported outcomes including pain intensity and FM symptoms. Eligible studies were randomized controlled trials (RCTs), published in English, with full-text availability. Exclusion criteria were: patients younger than 18 years, pregnant women, a history of brain injury or neuro logical complications, or a history of pre-existing conditions that may alter the results, such as chest pathology incompatible with HBOT and claustrophobia. Additio nally, studies with inadequate data, such as a lack of baseline or follow-up numerical data (mean and standard deviation), reviews, case reports, editorials, and duplicates were excluded.

Study selection This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)

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Hyperbaric oxygen therapy for women with fibromyalgia

guidelines [14]. Following completed searches, duplicates were removed using the Rayyan AI tool. Three authors working independently (ML, PL, and SG) screen ed the identified studies manually based on the title and abstract. An article was retrieved for full-text review if at least one reviewer considered it to fulfill the criteria and be within the scope of this systematic review. The reviewers then assessed the full-text articles for eligibility. Any disagreements were resolved by discussion with the fourth and fifth authors (AG and DM).

Quality assessment The Cochrane risk of bias 2.0 tool (RoB-2) was used to evaluate all included RCTs. The tool is structured into five domains through which bias might be categorized as having a “low” or “high” risk of bias, or “some concerns” [15]. Each successfully retrieved full-text article was rated independently by three authors. Any disagreements were resolved by discussion with the fourth and fifth authors.

Data collection process and outcome measures The studies that fulfilled the inclusion criteria were analyzed, and data were synthesized narratively. Data extracted from the studies were the following: the name of the main author, the year of publication, sample sizes, characteristics of the sample, inclusion and exclusion criteria, types of treatment given to control group, number of patients treated as control group, number of patients treated with HBOT, outcomes of the patients treated with control treatment, and outcomes of the patients treated with HBOT. The primary outcomes for this study were the effect of HBOT on pain relief measured with Visual Analogue Scale (VAS) and Widespread Pain Index (WPI)/ tender point counts. The secondary outcomes anti cipated were evaluation of FM symptom severity measured using the Fibromyalgia Impact Questionnaire (FIQ) and Symptom Severity Scale (SSS); QoL measured using the RAND 36-Item Short Form Health Survey (SF-36); and adverse events. The statistical analyses were conducted using RevMan 5.4.1 software. Outcomes of the study were analyzed using mean difference (MD) as the measure of effect and 95% confidence intervals (CIs). A p-value of < 0.05 was considered statistically significant.

Bioethical standards As this study was based exclusively on previously published data and did not involve human participants directly, ethics committee approval and informed consent were not required.

Results Study selection After conducting searches, a total of 497 studies were obtained from the 3 scientific databases: 417 studies from ScienceDirect, 57 studies from PubMed, and 23 studies from Cochrane Library. Sixty-two duplicate studies were detected using automation tools and were excluded, leaving 435 studies for screening. After screening the remaining studies, 411 studies were excluded for various reasons, such as not meeting the inclusion criteria, having irrelevant titles, having inappropriate abstracts that did not meet our criteria, and being in a language other than English. The final 24 studies were assessed for eligibility, and an attempt at full-text retrieval was successful for 18 studies. Of these 18 studies, 2 studies were excluded because they were review papers, 4 were excluded because they were commentaries, 2 were excluded because they were meeting abstracts, and 5 were excluded due to having different study models. Therefore, only 5 studies ultimately satisfied the inclusion criteria and were included in the systematic review. The study selection process of this review is shown in the PRISMA flowchart in Figure 1A.

Risk of bias assessment The Cochrane RoB-2 instrument for RCTs was used to evaluate the quality of the studies in this review. A total of 5 randomized controlled studies were included in this meta-analysis and systematic review. The quality assessment results indicate that 2 studies were consi dered to have some concerns, while the other 3 studies have a low risk of bias. The risk of bias assessments conducted in this review are summarized in Figure 1B [12, 16–19].

Study characteristics The study characteristics from the 5 studies included in this review are summarized in Table I [12, 16–19]. The total sample size for the 5 studies was 227 participants. All participants were female, which is consistent with the higher prevalence of FM in women. The mean follow-up duration was 2.4 months, ranging from 2 to 3 months. The mean age of participants was 50 years, with a range from 30 and 60 years. The participants were diagnosed with FM by a certified rheumatologist and/or according to the American College of Rheumatology (ACR) diagnosis criteria. In all the included studies, participants were required to meet the diagnostic criteria of WPI ≥ 7 and SSS ≥ 5 or WPI ≥ 4–6 and SSS ≥ 9. Exclusion criteria applied across the studies were con-

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Identification of studies via databases and registers

Screening

Identification

Records identified from: Databases (n = 3, total = 497) ScienceDirect (n = 417) PubMed (n = 57) Cochrane (n = 23)

Records screened (n = 435)

Records excluded (n = 411)

Reports sought for retrieval (n = 24)

Reports not retrieved (n = 6)

Reports assessed for eligibility (n = 18) Included

Records removed before screening: – Duplicate records removed (n = 62)

Studies included in review (n = 5)

Reports excluded: – Review articles (n = 2) – Meeting abstracts (n = 2) – Editorial comments (n = 4) – Different study models (n = 5)

Risk of bias domains D3 D4

Overall

Boussi-Gross et al. 2024 [16]

Study

Izquierdo-Alventosa et al. 2024 [12, 17] Hadanny et al. 2018 [18] Efrati et al. 2015 [19] Izquierdo-Alventosa et al. 2020 [17] Domains: D1: Bias arising from the randomization process D2: Bias due to deviations from intended intervention D3: Bias due to missing outcome data D4: Bias in measurement of the outcome D5: Bias in selection of the reported result

Judgement Some concerns Low

Fig. 1. A) Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart. B) Risk of bias of studies. traindications to HBOT, thoracic disorder, ear conditions, claustrophobia, pre-existing neurovascular diseases, and pregnancy. The inclusion and exclusion criteria were consistent across studies, focusing on female patients without significant comorbidities that could influence pain perception or treatment response. Each study provided detailed information on the interventions and comparisons. In the HBOT groups, participants received low-pressure HBOT by the inhalation of 100% O2 by mask for 90 min, with a variety of exposure times (40 to 60 sessions). In the control groups, participants were assigned to either standard care, including

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pharmacological therapy and/or complementary therapy such as physical exercise or behavioral therapy, or no treatment as the comparison in this review. The outcome data extracted from the studies were pain relief, impact of FM on physical function, evaluation of FM symptoms severity, QoL, and adverse events.

Pain relief Figure 2 presents the results of the meta-analysis of pain outcomes after treatment with HBOT compared with the control [12, 16–19]. Two of the 5 RCTs used

Sample size

Total: 52 HBOT group: 27 Control group: 25

Total: 33 HBOT group: 17 Control group: 16

Total: 49 HBOT group: 17 Physical exercise group: 16 Control group: 16

Authors of the study, country

Boussi‑Gross et al. [16], 2024, Israel

Izquierdo-Alventosa et al. [12], 2024, Spain

Izquierdo-Alventosa et al. [17], 2020, Spain

Table I. Study characteristics

Women aged 30–70 years; diagnosed with FM by rheumatologist following the criteria: generalized pain for at least 3 months, WPI ≥ 7 and SSS ≥ 5 or WPI ≥ 4–6 and SSS ≥ 9; no improvement following 3 months of pharmacological treatment; never received hyperbaric treatment and physical exercise 2 months prior

Female aged 30-70; diagnosed with FM according to the 2016 diagnostic criteria; showed no recovery after treatment for more than three months

Female participants aged 18–45; diagnosed with FM by certified rheumatologist based on the updated 2016 diagnostic criteria; had a history of childhood sexual abuse and engaged in psychotherapy

Inclusion criteria

Low-intensity physical exercise or No treatment

Pain intensity assessed with 100-mm VAS prepost intervention; follow-up 2 months

Pain intensity measured using a 10-cm VAS prepost intervention; follow-up 2 months

No treatment

HBOT protocol of inhalation 100% oxygen at 1.45 ATA, 40 daily sessions, 5 days/week, 90 minutes each

Participants taking epilepsy or convulsion medications, pregnant or breastfeeding, had a history of intense headaches, and/or contraindicated to HBOT HBOT protocol of inhalation 100% oxygen at 1.45 ATA, 40 daily sessions, 5 days/week, 90 minutes each

FM functional impairment measured using FIQ, FM symptoms severity measured using tender point counts and SSS; quality of life measured using SF-36 questionnaire pre-post intervention; follow-up 3 months

Pregabalin 75 mg or duloxetine 30 mg a day

HBOT protocol of inhalation 100% oxygen at 2.0 ATA, 60 daily sessions, 5 days/week, 90 minutes each

Participants with a history of TBI, received pregabalin or duloxetine in the past year, had a history of major psychiatric disorder, and/or contraindicated to HBOT

Participants taking epilepsy or convulsion medications, pregnant or breastfeeding, had a history of intense headaches, had a history of joints inflammation and/or contraindicated to HBOT

Outcomes measured

Control

Intervention

Exclusion criteria

Female participants with mean age of 53.30 ±7.86 years • Pain intensity before intervention: – HBOT group: VAS 7.35 ±1.66 – Control group: VAS 5.63 ±1.75 • Physical exercise group: – VAS 6.13 ±2.22

Female participants with a mean age of 52.76 ±8.18 years • Pain intensity before intervention: – HBOT group: VAS 7.35 ±1.66 – Control group: VAS 5.63 ±1.75

Female participants with mean age of: – HBOT group: 32.8 ±6.3 years – Control group: 34.0 ±5.6 years FM measures: • FIQ score: – HBOT group: 67.5 ±13.4 – Control group: 69.2 ±13.6 • Tender point counts: – HBOT group: 13.9 ±4.1 – Control group: 13.1 ±3.9 • SSS: – HBOT group: 10.3 ±1.6 – Control group: 10.5 ±1.1

Baseline demographics

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Total: 43 HBOT group: 28 Control group: 15

Total: 50 HBOT group: 24 Control group: 26

Hadanny et al. [18], 2018, Israel

Efrati et al. [19], 2015; Israel

Patients aged between 21–67, diagnosed with FM at least 2 years prior based on two criteria: 1) pain affecting bilateral, and vertical sides of the body; 2) widespread pain with at least 11 of 18 tender points

Women over 18 years old; diagnosed with FM according to the ACR 2010 diagnostic criteria for at least 5 years; had a history of undergoing psychotherapy for childhood sexual abuse for at least 1 year

Inclusion criteria

No treatment

HBOT protocol of inhalation 100% oxygen at 2.0 ATA, 40 daily sessions, 5 days/week, 90 minutes each

Patients with chest pathology, ear conditions, claustrophobia, and other neurological conditions incompatible with HBOT

No treatment

HBOT protocol of inhalation 100% oxygen at 2.0 ATA, 60 daily sessions, 5 days/week, 90 minutes each

Participants in pregnancy, had chest pathology, ear conditions, claustrophobia, and other neurological conditions incompatible with HBOT

Outcomes measured

Control

Intervention

Exclusion criteria

• Female participants with mean age of: – HBOT group: 50.4 ±10.9 years – Control group: 48.1 ±11.1 years FM measures: • FIQ score: – HBOT group: 3.76 ±0.73 – Control group: 3.76 ±1.06 • Tender point counts: – HBOT group: 17.33 ±1.4 – Control group: 17.71 ±0.69

• Female participants with mean age of: – HBOT group: 48.3 ±10.6 years – Control group: 43.1 ±10.6 years FM measures: • FIQ score: – HBOT group: 64.2 ±32.9 – Control group: 76.3 ±10.9 • Tender point counts: – HBOT group: 11.6 ±4.8 – Control group: 11.6 ±3.8 • SSS: – HBOT group: 8.93 ±2.1 – Control group: 9.6 ±1.9

Baseline demographics

ACR – American College of Rheumatology, ATA – atmosphere absolute, FIQ – Fibromyalgia Impact Questionnaire, FM – fibromyalgia, HBOT – hyperbaric oxygen therapy, SF-36 – 36-Item Short Form Health Survey, SSS – Symptom Severity Scale, TBI – traumatic brain injury, VAS – Visual Analogue Scale; WPI – Widespread Pain Index.

Sample size

Authors of the study, country

Table I. Cont.

186 Maggie Liberty, Andi Raga Ginting, Dewi Masyithah Darlan, et al.

187

Hyperbaric oxygen therapy for women with fibromyalgia

Study or subgroup Mean

HBOT Control Mean difference SD Total Mean SD Total Weight IV, Random, 95% CI Year

1.1.1. Visual Analogue Scale (VAS) lzguierdo-Alventosa et al. 2020 [17] 4.88 2.32 17 5.38 2.16 16 lzguierdo-Alventosa et al. 2024 [12] 4.88 2.32 17 5.5 2.25 16 Subtotal (95% CI) 34 32 Heterogeneity. t2 0.00; c2 0.01, df = 1 (p = 0.91); I2 = 0% Test for overall effect: Z = 1.00 (p = 0.32) 1.1.2. Tender point counts Efrati et al. 2015 [19] 8.87 6.03 24 17.24 1.15 26 Hadanny et al. 2018 [18] 7.9 5.4 28 12.1 4.2 15 Boussi-Gross et al. 2024 [16] 9.4 6 24 13.4 2.9 24 Subtotal (95% CI) 76 65 Heterogeneity: t2 4.76; c2 7.12, df = 2 (p = 0.03); I2 = 72% Test for overall effect: Z = 3.76 (p = 0.0002) Total (95% CI) 110 97 Heterogeneity: t2 9.04; c2 36.50, df = 4 (p < 0.00001); I2 = 89% Test for overall effect: Z. 2.37 (p = 0.02) Test for subgroup differences: c2 10.04, df = 1 (p = 0.002), I2 = 90.0%

21.5% 21.5% 43.0%

–0.50 [2.03, 1.03] –0.62 [2.18, 0.94] –0.56 [–1.65, 0.53]

19.6% 18.4% 19.1%

–8.37 [–10.82, –5.92] 2015 –4.20 [7.12, –1.28] 2018 –4.00 [–6.67, –1.33] 2024

100%

–3.419 [–6.24, –0.59]

Mean difference IV, Random, 95% CI

2020 2024

–10

–5 0 5 Control HBPT

Fig. 2. Analysis of pain assessment. Study or subgroup

HBOT Control Mean difference Mean SD Total Mean SD Total Weight IV, Random, 95% CI 1.2.1. Fibromalgia Impact Questionnaire (FIQ) Efrati et al. 2015 [19] 1.31 0.99 24 1.02 1.15 26 29.4% 0.29 [–0.30, 0.88] Hadanny et al. 2018 [18] 29.9 27.3 28 3.2 8.4 15 6.5% 26.70 [15.73, 37.67] Boussi-Gross et al. 2024 [16] 24.3 20.9 24 2.9 11.1 24 8.1% 21.40 [11.93, 30.87] Subtotal (95% CI) 76 65 44.0% 15.58 [–3.37, 34.52] Heterogeneity. t2 262.70; c2 41.09, df = 2 (p = 0.000091); I2 = 0% Test for overall effect: Z = 1.61 (p = 0.11)

1.1.2. Symptoms Severity Score (SSS) Hadanny et al. 2018 [18] 4 3.1 28 0.07 Boussi-Gross et al. 2024 [16] 2.3 2.8 24 0.1 Subtotal (95% CI) 52 Heterogeneity: t2 = 0.97; c2 = 2.86, df = 1 (p = 0.09); I2 = 65% Test for overall effect: Z = 3.48 (p = 0.0005)

2.1 1.4

15 24 39

27.7% 3.93 [2.37, 5.49] 28.3% 2.20 [0.95, 3.45] 56.0% 3.00 [1.31, 4.69]

Total (95% C) 128 Heterogeneity: t2 = 8.80; c2 = 61.27, df = 4 (p < 0.00001); I2 = 93% Test for overall effect: Z = 3.26 (p = 0.001) Test for subgroup differences: c2 = 1.68. df = 1 (p = 0.19) I2 = 40.5%

104

100% 5.27 [2.11, 8.44]

Mean difference IV, Random, 95% CI

Year 2015 2018 2024

2018 2024

–20

–10 0 10 Control HBPT

Fig. 3. Analysis of symptom severity. FIQ – Fibromyalgia Impact Questionnaire, HBOT – hyperbaric oxygen therapy, SD – standard deviation, SSS – Symptom Severity Scale.

the VAS as outcome measure at the end of HBOT sessions, while 3 studies used tender point counts. Hyperbaric oxygen therapy was associated with a significant reduction in pain compared with the control (MD –3.41, 95% CI: from –6.24 to –0.59, p = 0.02). These findings suggest that HBOT may be effective in alleviating pain in patients with FM. However, substantial heterogeneity (I² = 89%) was observed across studies, indicating consi derable variability in the effect estimates, which warrants further research to identify sources of heterogeneity.

Fibromyalgia symptoms severity The results of the meta-analysis of FM symptom severity are presented in Figure 3 [16, 18, 19]. The FM symptom severity was described in 3 studies, assessed using

the FIQ in all 3 studies and the SSS in 2 studies. Symptom severity was lower in patients treated with HBOT compared to those treated with control interventions (MD = 5.27, 95% CI: 2.11–8.44, p = 0.001). A random-effect model was adopted because of the substantial heterogeneity observed across the included studies (I² = 93%). Consequently, the findings should be interpreted with caution, and further research is needed to explore potential sources of heterogeneity.

Quality of life The meta-analysis of QoL is shown in Fig ure 4 [16, 18, 19]. Three of the 5 RCTs assessed the QoL using SF-36. Although the pooled estimate favored HBOT over control interventions, it was not statistically significant

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Maggie Liberty, Andi Raga Ginting, Dewi Masyithah Darlan, et al.

Study or subgroup Mean Efrati et al. 2015 [19] 0.34 Hadanny et al. 2018 [18] 33.3 Boussi-Gross et al. 2024 [16] 24.1

HBOT SD 0.33 34.9 17.9

Total 24 15 24

Control Mean SD Total 0.23 0.39 26 3.3 24.1 15 0.9 36.5 24

Total (95% C) 63 65 Heterogeneity: t2 = 267.72; c2 = 30.57, df = 2 (p < 0.00001); I2 = 93% Test for overall effect: Z = 1.53 (p = 0.13)

Mean difference Weight IV, Random, 95% CI Year 39.4% 0.11 [–0.09, 0.31] 2015 24.1% 30.00 [4.48, 55.52] 2018 36.5% 21.40 [14.21, 32.19] 2024 100%

Mean difference IV, Random, 95% CI

15.75 [–4.38, 35.87] –100

–50

0 Control HBPT

Fig. 4. Analysis of quality of life.

100

HBOT – hyperbaric oxygen therapy, SD – standard deviation.

Study or Subgroup Efrati et al. 2015 [19] Hadanny et al. 2018 [18]

HBOT Evens Total 32 48 13 28

Control Evens Total 0 26 0 15

Total (95% C) 76 41 Total events 45 0 Heterogeneity: t2 = 0.00; c2 = 0.43, df = 1 (p < 0.51); I2 = 0% Test for overall effect: Z = 3.83 (p = 0.0001)

Mean difference Weight IV, Random, 95% CI Year 50.9% 104.39 [5.98, 1822.65] 2015 49.1% 27.00 [1.47, 495.21] 2018 100%

Mean difference IV, Random, 95% CI

53.71 [6.99,412.81]

0.001

0.1

1000

Control HBPT

Fig. 5. Adverse events. HBOT – hyperbaric oxygen therapy.

(MD 15.75, 95% CI: from –4.38 to 35.87, p = 0.13). Considerable heterogeneity was identified among these studies (I2 = 93%).

Adverse events The meta-analysis data presented in Figure 5 show the occurrence of adverse events following HBOT and control interventions [18, 19]. Two studies reported adverse events; the pooled analysis showed a significantly higher incidence of adverse events in the HBOT group compared with the control group [odds ratio (OR) = 53.71, 95% CI: 6.99–412.81, p = 0.0001]. Reported adverse events included dizziness, headache, claustrophobia, increased pain sensation, and mild barotrauma. However, these adverse events were mild and self-limiting, with no serious adverse events reported. Overall, HBOT in patients with FM appeared to be well tolerated despite the higher frequency of adverse events.

Discussion Fibromyalgia has been associated with disrupted muscle O2 saturation, which may contribute to the fatigue experienced by patients suffering from the condition [20]. The pathophysiology of FM has been linked to autonomic nervous system dysregulation, which may contribute to abnormal vascular constriction and consequently poor O2 delivery. It was also proposed as a potential mechanism underlying microcirculatory dysfunction, thereby limiting the flow of O2-rich blood to muscles [7]. Moreover, mitochondrial dysfunction may

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increase the production of reactive O2 species, provoking oxidative stress and thus promoting cellular damage and inflammation, which may eventually increase the O2 consumption in the muscle [21]. Hyperbaric oxygen therapy is a non-invasive treatment modality that involves intermittent inhalation of 100% O2 inside an increased ATA chamber [22]. During HBOT, inhalation of 100% O2 produces a positive gradient, thus enhancing O2 diffusion from the hyperoxy genated lung to the circulation. This mechanism increases O2 availability and hemoglobin saturation, which modulate the transport of O2 to hypoxic tissues [23]. Oxygen therapy may have therapeutic potential in FM, as increased O2 delivery to hypoxic musculoskeletal tissues may modulate peripheral and central pain-processing mechanisms, resulting in reduced hyperalgesia and improved pain symptoms [24]. Hyperbaric oxygen therapy was initially used to treat decompression sickness, which occurs when a diver surfaces before the dissolved gases have had time to equi librate, resulting in space-occupying embolic nitrogen bubbles in the tissues and vasculature. Hyperbaric oxy gen therapy elevates the partial pressure of gases and causes a reduction in the volume of the gas-filled spaces, allowing them to dissolve into solution [25]. Over the past few years, HBOT has been increasingly explored for its potential therapeutic benefits. Hyperbaric oxygen therapy has been shown to facilitate myocardial repair and improve left ventricular ejection fraction in acute myocardial infarction and heart failure. HBOT enhances O2 delivery to ischemic tissues, pro-

Hyperbaric oxygen therapy for women with fibromyalgia

motes angiogenesis, and significantly suppresses oxidative stress, as well as inflammatory cascades that induce cardiomyocyte apoptosis [26]. Furthermore, HBOT has been observed to improve myelination processes, enhance angiogenesis, and decrease neuroinflammation in the central nervous system of subjects with neurological disorders [27]. Neuroinflammation is a common feature of many neurodegenerative disorders and has been associated with hypoxia-related cellular and molecular changes. Hyperbaric oxygen therapy attenuates neuroinflammation by increasing O2 delivery and enhancing anti-inflammatory cytokine production, resulting in tissue repair and secondary cell death prevention by hindering the apoptotic pathway [28]. In patients with traumatic brain injury, cerebral blood vessels are damaged, causing hypoxia. Hyperbaric oxygen therapy may increase cerebral blood flow through the induction of angiogenesis. Hyperbaric oxygen therapy has been reported to upregulate vascular endothelial growth factor expression, which plays a key role in angiogenesis and vascular repair [29]. Additionally, HBOT has been shown to improve tissue hypoxia, neovascularization, and reperfusion in burns and chronic wounds [30]. In this study, we comprehensively evaluated the efficacy and safety of HBOT for managing FM in female populations. Male and female patients may have different pain thresholds; therefore, this study focused on female patients for more consistent results [31]. After analyzing 5 studies with a total of 227 female participants, our findings suggest that HBOT offers comparable efficacy in pain relief (MD = –3.41, 95% CI: from –6.24 to –0.59, p = 0.02, I² = 89%) compared to the control. Studies by Izquierdo-Alventosa et al. [12, 17] demonstrated that HBOT was associated with a significant reduction of pain intensity, with VAS scores decreasing by 2.47 points (p < 0.001). Moreover, HBOT was associated with a significant reduction in widespread pain in FM, as reflected by lower tender point counts. Boussi-Gross et al. [16] reported a reduction in tender point counts by 4.5 points following HBOT (p = 0.001), while the control group receiving pharmacological therapy showed no change. Hadanny et al. [18] observed a significant reduction of tender point counts by 3.7 points (p < 0.001) in the HBOT group compared to no change in the control group. A study by Efrati et al. [19] revealed an 8.46-point (p < 0.001) reduction in the HBOT group, with no change in the control group. The analgesic effects of HBOT may be ascribed to several potential mechanisms. Evidence suggests that HBOT lowers the activation of glial cells and inflammatory mediators, exerting an anti-inflammatory effect that may contribute to the alleviation of chronic pain [32].

189

Hyperbaric oxygen therapy may potentially repair persistent brain function damage via promoting neuro plasticity, altering the abnormal pain-related area acti vity in the brain [33]. Increased O2 in circulation after HBOT also stimulates the synthesis of nitric oxide, which is involved in the pain signaling pathway that activates nitric oxide-dependent opioid anti-analgesic effects [34]. This review indicated that HBOT was associated with alleviation of FM symptoms (MD = 5.27, 95% CI: 2.11–8.44, p = 0.001, I² = 93%). Boussi-Gross et al. [16] and Hadanny et al. [18] reported that HBOT was associated with alleviation of FM symptoms, with a significant reduction (both p < 0.001) in SSS score compared to no change in the control group [16]. Studies by Efrati et al. [19], Hadanny et al. [18], and Boussi-Gross et al. [16] found a significant (all p < 0.001) reduction in the impact of FM symptoms measured with the FIQ, while the control group showed no effect. Although the pooled analysis favored HBOT for QoL outcomes, the difference did not reach statistical significance (MD = 15.75, 95% CI: –4.38 to 35.87; p = 0.13), and substantial heterogeneity was observed among studies (I² = 93%). Nevertheless, the 3 studies that assessed QoL reported significant improvements following HBOT (all p < 0.05) compared to the control [16, 18, 19]. These benefits may be attributable to promotion of blood perfusion to fatigued muscles, hence reducing pain and fatigue [35]. Pain intensity is a significant predictor of QoL in FM patients [36]. Hyperbaric oxygen therapy may also improve QoL by alleviating widespread pain, which has a major negative impact on QoL, since it affects daily activities and work productivity [37]. With respect to safety, adverse events were significantly more frequent among patients receiving HBOT than among controls (OR = 63.30, 95% CI: 8.01–500.05, p < 0.0001, I2 = 0.0%). However, the reported events were predominantly mild and self-limiting. In a study by Hadanny et al. [18], the reported adverse effects following HBOT were headaches and mild spontaneously resolved barotrauma. Efrati et al. [19] reported mild barotrauma following HBOT, and a few patients discontinued HBOT intervention due to ear pain, claustrophobia, and dizziness. Consistent with the findings of this review, another study reported that adverse events in HBOT with a low chamber pressure below 2.0 ATA were ear discomfort, ocular problems and self-limiting barotrauma, which may be mitigated by compression adjustment and ear-clearing techniques [37]. Although HBOT has demonstrated strong efficacy with minimal safety concerns, its availability remains restricted, and its high cost poses challenges in clinical application [13]. In this context, a more accessible and

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affordable alternative, such as normobaric oxygen therapy (NBOT), could serve as another practical alternative. Normobaric oxygen therapy involves breathing 100% O2, as in HBOT, but in normal atmospheric pressure. It is widely used to treat chronic pain, such as severe cluster headache [38]. Nonetheless, a trial evaluating the efficacy of HBOT and NBOT in cluster headache pain management indicated a marked reduction in pain intensity within the HBOT group, whereas the NBOT group exhibited no such reduction. However, direct comparisons between HBOT and NBOT did not yield statistically significant differences in pain intensity reduction. Furthermore, evidence regarding the efficacy and safety of NBOT, particularly in FM, remains scarce [39]. Therefore, further comparative studies are needed to clarify the relative benefits of HBOT and NBOT in this population.

Study limitations Despite the encouraging findings, the study has several limitations. First, only 5 studies with a total of 227 participants were included, which may restrict the generalizability of the results. Second, the small sample sizes of the included studies may account for the wide CI and reduce the precision of the pooled estimates. Third, the substantial heterogeneity (I² = 91.4%) among the included studies raises concerns about the consistency of the results. The variability observed may result from the differences in intervention protocols, notably the varied pressures and exposure times of HBOT, which are closely related to the effectiveness of HBOT. Future largescale, multicenter RCTs are warranted to further validate these findings. Additionally, future research should aim to establish standardized HBOT protocols, including optimal pressure and the number of HBOT sessions. Addressing these limitations will help strengthen the evidence base and clarify the role of HBOT in the management of FM female patients.

Conclusions Hyperbaric oxygen therapy appears to be a promising adjunctive treatment for FM, particularly in female patients. The available evidence suggests that HBOT is associated with significant improvements in pain and symptom severity. Although adverse events were more frequent among patients receiving HBOT, they were generally mild and self-limiting, with no serious adverse events reported. However, the current evidence remains limited by the small number of studies, modest sample sizes, and substantial heterogeneity. Further highquality, multicenter RCTs are needed to confirm the efficacy, safety, and long-term effects of HBOT in FM patients.

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Maggie Liberty, Andi Raga Ginting, Dewi Masyithah Darlan, et al.

Disclosures Conflict of interest: The authors declare no conflict of interest. Funding: No external funding. Ethical approval: Due to the nature of the article, the consent of the bioethics committee was not required. Data availability: The data that support the findings of this study are available on request from the corresponding author (A.R.G.). References 1. Dizner-Golab A, Lisowska B, Kosson D. Fibromyalgia – etiology, diagnosis and treatment including perioperative manage ment in patients with fibromyalgia. Reumatologia 2023; 61: 137–148, DOI: 10.5114/reum/163094. 2. Bhargava J, Hurley JA. Fibromyalgia. In: StatPearls. StatPearls Publishing, Treasure Island (FL) 2025. Available at: https:// www.ncbi.nlm.nih.gov/books/NBK540974/. 3. Brown CE, Nelson AR. Symptom management and lifestyle in terventions for people with fibromyalgia. Adv Exerc Health Sci 2024; 1: 231–240, DOI: 10.1016/j.aehs.2024.09.004. 4. Ruschak I, Montesó-Curto P, Rosselló L, et al. Fibromyalgia syn drome pain in men and women: a scoping review. Healthcare (Basel) 2023; 11: 223, DOI: 10.3390/healthcare11020223. 5. Jiang L, D’Souza RS, Oh T, et al. Sex-related differences in symp toms and psychosocial outcomes in patients with fibromyal gia: a prospective questionnaire study. Mayo Clin Proc Innov Qual Outcomes 2020; 4: 767–774. DOI: 10.1016/j.mayocpiqo. 2020.06.009. 6. D’Onghia M, Ciaffi J, Ruscitti P, et al. The economic burden of fibromyalgia: a systematic literature review. Semin Arthritis Rheum 2022; 56: 152060, DOI: 10.1016/j.semarthrit.2022. 152060. 7. Qureshi AG, Jha SK, Iskander J, et al. Diagnostic challenges and management of fibromyalgia. Cureus 2021; 13: e18692, DOI: 10.7759/cureus.18692. 8. Macfarlane GJ, Kronisch C, Dean LE, et al. EULAR revised re commendations for the management of fibromyalgia. Ann Rheum Dis 2017; 76: 318–328, DOI: 10.1136/annrheumdis2016-209724. 9. Tzadok R, Ablin JN. Current and emerging pharmacotherapy for fibromyalgia. Pain Res Manag 2020; 2020: 6541798, DOI: 10.1155/2020/6541798. 10. Perrot S. Fibromyalgia: do I tackle you with pharmacolog ical treatments? Pain Rep 2025; 10: e1222, DOI: 10.1097/ PR9.0000000000001222. 11. Neelapala YVR, Mercuri D, Macedo L, et al. Mechanisms hypo thesized for pain-relieving effects of exercise in fibromyal gia: a scoping review. Ther Adv Musculoskelet Dis 2023; 15: 1759720X231182894, DOI: 10.1177/1759720x231182894. 12. Izquierdo-Alventosa R, Inglés M, Cortés-Amador S, et al. Effects of a low-pressure hyperbaric oxygen therapy on psychological constructs related to pain and quality of life in women with fibromyalgia: a randomized clinical trial. Med Clin (Barc) 2024; 162: 516–522, DOI: 10.1016/j.medcli.2023.12.016.

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Reumatologia 2026; 64/3

Original paper

Reumatologia 2026; 64, 3: 192–199 DOI: https://doi.org/10.5114/reum/213485

Association of ANO6 gene polymorphism and expression with ankylosing spondylitis in a Chinese Han population Mingcan Yang1* ID , Xianghui Wen2* ID , Xinyu Wu1 ID , Yanli Zhang1 ID , Jieruo Gu1 ID 1

Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China Shenzhen Longhua District Central Hospital, Shenzhen, China

*These authors had equal contribution to this work.

Abstract Introduction: This study investigated genetic polymorphisms and aberrant expression of anoctamin-6 (ANO6) in ankylosing spondylitis (AS) patients to clarify the role of ANO6 in AS pathogenesis. Material and methods: Genetic sequencing was performed to identify disease-associated single nucleotide polymorphisms (SNPs) within the exonic and transcriptional regulatory regions of ANO6 in 417 AS patients and 541 healthy controls (HCs). Linkage disequilibrium (LD) and haplotype analy ses were conducted to assess the association of the candidate SNPs with disease susceptibility. A cohort of 2,144 AS patients was stratified based on the presence or absence of risk-associated haplotypes, and clinical phenotypes were compared between the 2 groups. Reverse transcriptionpolymerase chain reaction was employed to quantify messenger RNA (mRNA) expression levels in peripheral blood mononuclear cells (PBMCs) from 40 AS patients and 32 HCs. Immunohistoche mistry was used to evaluate ANO6 protein expression in tendon tissues from 9 AS patients and 5 control subjects. Results: Five SNP loci (rs79662606, rs76186361, rs17095830, rs80224086, and rs75712006) exhi bited significant associations with AS susceptibility, with strong LD observed between pairwise loci. Haplotype analysis revealed a higher prevalence of GTGCG, ATGTA, and ACGTA haplotypes in AS patients (p < 0.001). No significant differences in clinical phenotypes were observed between AS patients with or without risk-associated haplotypes. The mRNA expression in PBMCs was significantly lower in AS patients (0.49 ±0.21) compared to HCs (0.86 ±0.38, p < 0.001). Conversely, ANO6 protein expression was significantly elevated in tendon tissues of AS patients, with an average histoscore of 182.22 ±30.732 compared to 62.00 ±35.637 in controls (p = 0.001). Conclusions: ANO6 may represent a novel AS susceptibility gene, with GTGCG, ATGTA, and ACGTA as risk-associated haplotypes. Dysregulated ANO6 expression in PBMCs and tendon tissues suggests its potential role in AS pathogenesis. Key words: gene expression, gene polymorphism, ankylosing spondylitis, ANO6.

Introduction Ankylosing spondylitis (AS) is a chronic, progressive inflammatory disorder primarily characterized by inflammatory low back pain, often accompanied by periphe ral arthritis, enthesitis, uveitis, spinal deformity, and ankylosis. The prevalence of AS varies geographically, ranging from 0.1% to 1.8% in Europe and approximately 0.24% in China [1, 2]. While genetic factors are widely

recognized as significant contributors to AS pathoge nesis [3], the specific molecular mechanisms and gene tic determinants underlying the disease remain incompletely understood. Notably, human leukocyte antigen B27 (HLA-B27) and other genetic loci have been implicated in disease susceptibility, with HLA-B27 accounting for familial aggregation of AS [4]. However, HLA-B27 is estimated to contribute to no more than 50% of the overall genetic risk for AS [5, 6].

Address for correspondence Yanli Zhang, Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Tianhe St. 510630, Guangzhou, China, e-mail: zhangyanli04386@163.com Submitted: 07.04.2025; Accepted: 22.10.2025; Published online: 29.06.2026

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Recent genome-wide association studies (GWAS) in Chinese populations have identified additional susceptibility loci, including 2p15, 5q14.3, and 12q12 [7]. The single nucleotide polymorphism (SNP) rs4552569 at 5q14.3 is located between the hyaluronan and proteoglycan link protein 1 and epidermal growth factor-like repeats and discoidin I-like domains 3 (EDIL3) genes. The hyaluronan and proteoglycan link protein 1 has been associated with spinal osteophyte formation and disc degeneration in Japanese women [8], while EDIL3 modulates bone formation through inhibition of the Wnt signaling pathway [9]. Another SNP, rs17095830 at 12q12, resides within an intron of anoctamin-6 (ANO6), which encodes a multipass transmembrane protein with Ca²+-dependent phospholi pid scramblase activity. The ANO6 has been implicated in osteoclast formation and bone remodeling [10, 11]. Recent studies have reported associations between ANO6 SNPs (rs4768085 and rs17095830) and both AS susceptibility and disease severity [12], although no such association was observed in a Taiwanese population [13]. To further elucidate the role of ANO6 in AS pathogenesis within the Chinese Han population, we conducted a large-scale case-control association study and investigated potential aberrations in ANO6 expression among AS patients.

Material and methods Subjects All participants provided written informed consent for the collection and utilization of their blood and tissue samples, and the study protocol was approved by the Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University (No. [2022]02-007-02). For preliminary screening of informative SNPs in the exon and transcription regulatory region of ANO6, 29 patients homozygous for the rs17095830G/G mutation and 30 healthy controls (HCs) were recruited. The validation cohort included 388 patients with AS who were heterozygous for the rs17095830A/G mutation and 511 ethnically matched controls. Additionally, 40 patients and 32 ethnically matched HCs were enrolled for reverse transcription-polymerase chain reaction (RT-PCR) analysis of messenger RNA (mRNA) in peripheral blood mononuclear cells (PBMCs). Immunohistochemical analysis of tendon tissue was conducted on samples obtained from 9 AS patients and 5 HCs during hip replacement or spinal orthopedic surgery. All AS patients met the 1984 revised New York criteria for AS and were diagnosed by at least 2 qualified rheumatologists [14]. Demographic data, including age and sex, as well as clinical manifestations such as family history of AS, age at disease onset, symptoms (e.g. dactylitis, peripheral

arthritis), hip joint involvement, uveitis, enthesitis, and laboratory markers (e.g. erythrocyte sedimentation rate and C-reactive protein), were systematically collected.

Genotyping Genomic DNA was extracted from peripheral blood samples using the standard salting-out method [14]. To identify candidate SNPs in the exonic and transcription regulatory regions of the ANO6 gene, PCR was performed with specific primers (Suppl. Tables I, II). The purified PCR products were subsequently sequenced using an ABI 3,700 automated sequencer. Single nucleotide polymorphisms were selected based on a minor allele frequency > 5% and a Hardy-Weinberg equilibrium (HWE) p-value > 0.01 in controls.

Ribonucleic acid preparation and reverse transcription-polymerase chain reaction Total RNA was isolated from PBMCs using Trizol reagent (Invitrogen, 15596-026, Germany) following the manufacturer’s protocol. After DNase digestion, reverse transcription of total RNA was carried out using the PrimeScript RT Reagent Kit with gDNA Eraser (Takara, DRR047A, Japan). The polymerase chain reaction amplification was performed in a 20 µl reaction volume containing 40 ng of complementary DNA, 800 nM forward and reverse primers, and SYBR Premix Ex Taq II (Takara, DRR820A, Japan), in accordance with the manufacturer’s instructions. The PCR cycling conditions were optimized as follows: initial denaturation at 95°C for 30 seconds, followed by 40 cycles of denaturation at 95°C for 5 seconds, annealing at 60°C for 34 seconds, and extension at 72°C for 1 minute, with a final denaturation step at 95°C for 15 seconds. The following primers were used for amplification: ANO6 (F: 5´-CCTCAGTGTGATAGGCTTTGTCCA-3´, R: 5´-ACTGCAAAGACCAGGGTTCCA-3´) and b-actin (F: 5´-TGGCACCCAGCACAATGAA-3´, R: 5´-CTAAGTCATAGTCCGCCTAGAAGCA-3´). The specificity of PCR products was validated through melting curve analysis. Real-time PCR amplifications were conducted using a PRISM 7500 Real Time System (ABI), with all experiments performed in duplicate. The housekeeping gene β-actin was amplified to normalize the quantity of sample RNA. Relative gene expression quantification was determined using the ΔΔCt method (where Ct represents the threshold cycle), as previously described [14]. Additionally, PCR products were subjected to agarose gel electrophoresis for further analysis.

Immunohistochemistry For immunohistochemistry, tendon tissues were fixed in 10% neutral buffered formalin for 12 hours at

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room temperature, subsequently embedded in paraffin, and sectioned following standard protocols. Tissue sections were deparaffinized and rehydrated using established procedures. To enhance immunostaining intensity, sections were heated at 95°C for 10 minutes in citrate buffer (0.01 M, pH 6.0). Sections were then incubated with the primary antibody overnight at 4°C. Following incubation, sections were washed 3 times for 3 minutes each in phosphate-buffered saline and processed with the ChemMate EnVision HRP (DAKO, China) according to the manufacturer’s instructions. Immunoreactive signals were visualized using the 3,3´-diaminobenzidine substrate, which imparts a brown color to the target protein. Tissue architecture was delineated by counterstaining with hematoxylin. Immunostaining scoring was performed by 2 experienced pathologists blinded to the subject group, with the final score calculated using the histoscore method [15]. Histoscore was calculated as the product of staining intensity (0–3: negative, weak, moderate, strong) and the percentage of positive cells (0–100%).

Statistical analysis The genotyping accuracy of each SNP was assessed through HWE analysis. Genotype and allele frequencies in both AS patients and control groups were evaluated using the χ2 test to verify HWE. Allelic associations and haplotype analyses between cases and controls were performed using PLINK, with adjustments for sex, age, and geographic origin. The strength of associations was quantified as odds ratios (OR) per additional minor allele, accompanied by 95% confidence intervals. Linkage disequilibrium (LD) coefficients (D´ and r²) were calculated using Haploview 4.1 [18]. Relative gene expression quantification and histoscore data were presented as mean ± standard error, where n denotes the number of independent experiments. Statistical significance was determined using Student’s unpaired two-tailed t-test or analysis of variance (ANOVA), with p < 0.05 considered statistically significant, as analyzed using SPSS 17.0.

Bioethical standards This study was approved by the Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University (No. [2022]02-007-02).

Results Demographic data In the initial screening cohort, which included 29 AS patients and 30 HCs, the mean age of AS patients was 28.0 ±7.4 years, with a male-to-female ratio of 4.8 : 1,

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while the control group had a mean age of 27.3 ±7.1 years and a male-to-female ratio of 6.5 : 1. In the validation cohort, the mean age of AS patients was 28.1 ±8.7 years, with a male-to-female ratio of 5.7 : 1, and the control group had a mean age of 28.4 ±5.5 years, with a maleto-female ratio of 4.2 : 1. No significant differences in age or sex distribution were observed between AS patients and controls in either cohort (p > 0.05). In the RT-PCR analysis cohort, the mean age of AS patients was 27.00 ±5.57 years, with a male-to-female ratio of 15 : 1, while the control group had a mean age of 27.53 ±5.46 years, and a male-to-female ratio of 12.3 : 1. Again, no significant differences in age or sex distribution were detected between the groups (p > 0.05).

Identification of candidate single nucleotide polymorphisms Sequencing analysis identified 9 SNPs within the transcription regulatory region of the ANO6 gene. Following stringent quality control measures, including exclusion of SNPs with HWE p-values > 0.01, minor allele frequencies < 5%, and missing data, 5 SNPs (rs79662606, rs75712006, rs76186361, rs17095830, rs80224086) were retained for further validation and analysis. A statistically significant difference (p < 0.05) in genotype frequencies was observed for these SNPs between the AS and control groups (Suppl. Table III).

Validation of single nucleotide polymorphisms in a larger population The 5 SNPs were validated through PCR-based direct sequencing in a cohort comprising 388 AS cases and 511 HCs. Samples from 2 distinct stages were pooled to faci litate comprehensive analysis. All 5 SNPs were found to be in HWE. Genotype frequency analysis demonstrated statistically significant differences (p < 0.05) between AS cases and controls across the entire sample set. Notably, the frequency of all risk-associated loci was significantly elevated in AS patients compared to HCs (Table I).

Identification of 5 haplotypes associated with ankylosing spondylitis in a Chinese Han population Linkage disequilibrium analysis demonstrated strong pairwise associations among the 5 SNPs (Suppl. Fig. 1), prompting subsequent haplotype analysis. The analysis revealed significant associations between specific haplotypes and AS susceptibility. Nota bly, the haplotypes GTGCG (OR = 65.76, p = 2.684 × 1059), ATGTA (OR = 14.76, p = 1.168 × 1016), and ACGTA (OR = 5.02, p = 5.937 × 1026) exhibited higher frequencies in AS cases, suggesting their role as risk factors.

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Table I. Risk allele association analysis of the 5 single-nucleotide polymorphisms in anoctamin 6 in 417 ankylosing spondylitis cases and 541 controls SNP

Risk allele

Case %

Control %

MAF

95% CI

rs79662606

24.22

4.436

0.1305

6.88

4.95–9.576

3.24 × 10–37

rs76186361

32.85

4.529

0.1686

10.31

7.483–14.22

1.39 × 10–60

rs17095830

53.48

9.797

0.2881

10.58

8.307–13.49

2.75 × 10–97

rs80224086

25.66

1.201

0.1185

28.38

16.07–50.12

1.28 × 10–60

rs75712006

25.18

0.7394

0.1138

45.18

22.15–92.16

1.24 × 10–62

CI – confidence interval, MAF – minor allele frequency, OR – odds ratio, SNPs – single-nucleotide polymorphisms.

Table II. Significantly associated haplotypes for the 5 single-nucleotide polymorphisms. All haplotypes with a frequency < 0.03 were ignored in analysis. Loci analyzed: rs79662606, rs75712006, rs76186361, rs17095830, rs80224086 Haplotype

Case %

Control %

GTGCG

23.68

0.4696

65.761392

2.684 × 10–59

GTGTA

0.01792

2.615

0.006674769

4.625 × 10–6

ATGTA

7.924

0.5797

14.759437

1.168 × 10–16

ACGTA

20.88

4.99

5.024732985

5.937 × 10–26

ACATA

47.5

91.35

0.085672583

4.081 × 10–98

OR – odds ratio.

Expression of ANO6 messenger RNA in peripheral blood mononuclear cells of ankylosing spondylitis patients and healthy controls The expression levels of ANO6 mRNA were norma lized to β-actin mRNA as an internal control. The mean relative expression of ANO6 in patients with AS (0.49 ±0.21) was significantly lower compared to HCs (0.86 ±0.38, p < 0.001; Fig. 1, Suppl. Table IV).

lymphocytes (brown staining), whereas control tissues showed minimal or no staining (Fig. 2). In tendon tissue, the average histoscore of ANO6 protein expression, as determined by IHC, was significantly higher in 9 AS patients (182.22 ±30.732) than in 5 controls (62.00 ±35.637, p = 0.001; Suppl. Table V). The ANO6 protein was positively expressed in myofibroblasts, lymphocytes, and endothelial cells. 2.000000

1.500000 Relative expression

Conversely, the haplotypes GTGTA (OR = 0.007, p = 4.625 × 106) and ACATA (OR = 0.09, p = 4.081 × 1098) were more prevalent in controls, indicating potential protective effects (Table II). To further investigate the clinical implications, 2,144 AS patients with comprehensive clinical data were selected from our previous GWAS dataset [7]. These patients were stratified based on the presence or absence of the identified risk haplotypes. However, no significant association was observed between the risk haplotypes and AS phenotypic manifestation (Table III).

1.000000

0.500000

Expression of ANO6 protein in tendon tissue of ankylosing spondylitis patients and controls In ankylosing spondylitis patients, ANO6 protein was predominantly localized in myofibroblasts and

AS patients

Healthy controls Group

Fig. 1. Relative expression of ANO6 in ankylos ing spondylitis patients and controls. AS – ankylosing spondylitis.

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Table III. Analysis of the clinical manifestations and anoctamin 6 risk haplotypes in ankylosing spondylitis patients Variable

With risk haplotypes (n = 228)

Without risk haplotypes (n = 1.916)

Male (%)

82.5

78.1

0.073

HLA-B27(+) (%)

77.6

78.5

0.798

Family history (%)

24.1

23.5

0.88

Axial

32.9

32.5

0.97

Axial + peripheral

67.1

67.5

Lumbar spine

53.1

54.4

0.707

Thoracic vertebrae

27.2

25.3

0.521

Cervical spine

23.2

20.3

0.299

Hip involvement (%)

33.8

35.9

0.535

Arthritis (%)

38.5

42.35

0.07

Enthesitis (%)

37.3

35.6

0.616

Uveitis (%)

10.1

8.8

0.509

Dactylitis (%)

5.7

0.981

Age [years], mean ±SD

27.5 ±8.5

27.0 ±8.9

0.452

Age onset [years], mean ±SD

20.3 ±7.5

20.98 ±7.4

0.199

Morning stiffness (VAS) [cm]

2.94 ±2.91

3.12 ±2.87

0.620

Total back pain (VAS)

3.21 ±2.97

2.78 ±2.95

0.269

Pain at night (VAS)

3.18 ±3.12

2.71 ±2.96

0.225

BASDAI

3.21 ±2.02

3.35 ±2.03

0.584

BASFI

1.68 ±1.93

1.45 ±1.94

0.365

ESR [mm/h]

22.41 ±23.50

20.35 ±21.50

0.465

CRP [mg/dl]

21.27 ±28.36

17.50 ±25.62

0.263

Clinical subtypes (%)

Spine involvement (%)

BASDAI – Bath Ankylosing Spondylitis Disease Activity Index, BASFI – Bath Ankylosing Spondylitis Functional Index, CRP – C-reactive protein, ESR – erythrocyte sedimentation rate, HLA-B27(+) – human leukocyte antigen B27 positive, SD – standard deviation, VAS – Visual Analogue Scale.

Discussion Ankylosing spondylitis is widely recognized as a here ditary disease with polygenic involvement [19]. However, the mechanisms underlying aberrant bone formation and structural damage remain poorly understood, though they are likely influenced by multiple factors, including the localization of inflammatory lesions, entheseal stress, and the nature of the inflammatory response [20]. Following our initial GWAS identifying ANO6 as a susceptibility gene for AS [7], subsequent research reported that SNPs rs4768085 and rs17095830 in ANO6 were associated with AS susceptibility and disease seve rity [12]. However, no such association was observed for rs17095830 in a Taiwanese population [13]. To further investigate the genetic polymorphisms of ANO6 in relation to AS risk, we performed direct sequencing of exons and transcription regulatory regions in a Han

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Chinese cohort, followed by haplotype association ana lysis. Five SNPs with suggestive significance were validated in a larger Han Chinese population. All 5 SNPs within the transcription regulatory regions of ANO6 (rs79662606, rs75712006, rs76186361, rs17095830, rs80224086) demonstrated significant associations with AS, indicating a potential role of ANO6 in AS susceptibility in this population. Additionally, strong LD was observed among the SNP loci, and haplotype analysis revealed a higher prevalence of GTGCG (OR = 65.76, p = 2.684e-059), ATGTA (OR = 14.76, p = 1.168e-016), and ACGTA (OR = 5.02, p = 5.937e-026) in AS cases. Single nucleotide polymorphisms in ANO6 may have direct functional implications in the molecular pathogenesis of AS. We hypothesize that the SNP located within the transcription control region could serve as a binding site for transcription factors, and that a spe-

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HE × 200 (Control)

HE × 200 (AS)

× 200 (AS)

× 200 (Control)

× 400 (Control)

× 400 (AS)

Fig. 2. Immunohistochemical staining of ANO6 in tendon tissue in ankylosing spondylitis (AS) patients and controls. A and B) Magnification of hematoxylin and eosin staining (HE): × 200. C and D) Magnification of immunohistochemical staining: × 200. E and F) Magnification of immunohistochemical staining × 400.

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cific combination of these factors may influence mRNA splicing modifications, ultimately affecting gene expression. Functional studies on ANO6 have demonstrated that interleukin-4 upregulates calcium-activated chloride channels during inflammation, which are regulated by ANO6 [21, 22]. In a murine model, ANO6 expression was observed in dendritic cells (DCs), and chemokine-induced migration of both immature and lipopolysaccharide (LPS)-matured DCs was attenuated following ANO6 knockdown [23]. Additionally, ANO6 activation is crucial for macrophage function [24]. Stu dies using knockout mouse models have revealed that ANO6 deletion results in a phenotype characterized by reduced skeletal size and deformities, evidenced by increased regions of non-mineralized, Ibsp-expressing osteoblasts in the periosteum during embryonic deve lopment and larger areas of uncalcified osteoid postnatally. Furthermore, primary ANO6(–/–) osteoblasts exhibit delayed mineralization, indicating a cell-autonomous role of ANO6 [25]. Notably, ANO6 expression is significantly elevated in mesenchymal stem cells compared to induced pluripotent stem cells or peripheral blood cells derived from axial spondylitis patients [26]. Ankylosing spondylitis is an inflammatory disorder associated with bone metabolism dysregulation. Emerging evidence suggests that ANO6, a protein implicated in phospholipid scrambling, may contribute to the pathogenesis of immunological processes and bone metabolism in AS, as supported by its association with disease susceptibility and severity in the Chinese Han population [12]. However, research on the functional role of ANO6 in AS and other autoimmune diseases remains limited. To address this gap, we conducted a preliminary study to compare ANO6 expression levels between AS patients and HCs at both mRNA and protein levels. Reverse transcription-polymerase chain reaction analysis revealed a significantly lower relative mRNA expression level of ANO6 in PBMCs of AS patients compared to HCs. A hallmark pathological feature of AS is tendon inflammation. In 1972, John Ball first described the pathological characteristics of AS, noting that structural damage initiates at the tendon insertion sites, including ligaments, tendons, and joint capsules attached to bone, with particular emphasis on the significant involvement of the outer fibers of the intervertebral disc. Subsequent observations indicated bone loss followed by new bone formation, leading to osteophyte and syndesmophyte development [27]. Further studies identified infiltrations of T cells, B cells, bone marrowderived macrophages, osteoclasts, and angiogenic cells within the tendon tissue insertion site, alongside the observation of inflammatory processes, bone destruction, bone formation, and other related phenomena

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[28, 29]. Semi-quantitative immunohistochemical ana lyses of tendon tissue revealed significantly elevated expression of ANO6, a gene encoding a calcium-activated phospholipid scramblase implicated in osteoclast diffe rentiation and bone remodeling. Our findings suggest that risk haplotypes may disrupt ANO6-mediated phosphatidylserine exposure, potentially exacerbating inflammation-driven ectopic ossification in AS entheses [25, 26]. Given the multifactorial nature of AS and its impact on diverse physiological processes, it is plausible that ANO6 may contribute to AS pathogenesis through its involvement in tissue-specific mechanisms.

Study limitations Among the study limitations, the limited sample size for tendon tissue analysis (9 AS vs. 5 controls) may have reduced the statistical power of the protein expression analysis. Larger cohorts are needed to confirm and extend these findings, including assessment of their gene ralizability to non-Chinese populations.

Conclusions We identified disease-associated LD loci and haplo types of ANO6 in AS and conducted a preliminary investigation into its expression. Our findings corroborate GWAS results, indicating that ANO6 gene polymorphisms are significantly associated with AS susceptibility in the Chinese population. These results provide novel insights into the complex interplay of genetic, immunological, and infectious factors in the etiology and pathogenesis of AS.

Disclosures Conflict of interest: The authors declare no conflict of interest. Funding: This work was supported by grants from Guangdong Clinical Research Center of Immune disease (2020B1111170008); Key-Area Research and Development Program of Guangdong Province (2023B1111030002). Ethical approval: This study was approved by the Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University (approval number: [2022]02-007-02). Data availability: The data that support the findings of this study are available on request from the corresponding author (Y.Z.). References 1. Ng SC, Liao Z, Yu DT, et al. Epidemiology of spondyloarthritis in the People’s Republic of China: review of the literature and commentary. Semin Arthritis Rheum 2007; 37: 39–47, DOI: 10.1016/j.semarthrit.2007.01.003.

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Reumatologia 2026; 64/3

Original paper

Reumatologia 2026; 64, 3: 200–208 DOI: https://doi.org/10.5114/reum/214398

Dietary and serum magnesium in children with juvenile idiopathic arthritis: a case-control study Oksana Boyarchuk ID , Nataliia Kovalchuk ID , Vira Synytska ID Department of Children’s Diseases and Pediatric Surgery, I. Horbachevsky Ternopil National Medical University, Ukraine

Abstract Introduction: Magnesium is essential in numerous physiological processes, including the inflammatory response. However, its role in the pathogenesis and progression of juvenile idiopathic arthritis (JIA) remains underexplored. This study aimed to assess dietary magnesium intake and serum magnesium levels in children with JIA and to evaluate their potential impact on the clinical course of the disease. Material and methods: This case-control study included 42 children with JIA and 67 healthy controls aged 2 to 18 years. Juvenile idiopathic arthritis was diagnosed according to International League of Associations for Rheumatology criteria. Dietary magnesium intake was assessed in 26 JIA patients using a food frequency questionnaire, which collected information on the weekly consumption of foods rich in magnesium. The average weekly and daily magnesium intake was calculated and compared with national and international dietary recommendations. Serum magnesium levels were measured using the colorimetric method. Results: Children with JIA had significantly lower dietary magnesium intake (median: 227.71 mg/day vs. 261.18 mg/day, p = 0.040) and serum magnesium concentrations (mean: 0.79 mmol/l vs. 0.94 mmol/l, p = 0.009) than healthy controls. Insufficient dietary intake was more prevalent in the JIA group (50.0%) compared to controls (26.9%) (p < 0.034). Juvenile idiopathic arthritis patients with insufficient dietary magnesium intake were more likely to be male (p = 0.006), older than 12 years (p = 0.049), and residing in urban areas (p = 0.002). Hypomagnesemia was more common in boys (p = 0.030). However, neither low magnesium intake nor hypomagnesemia significantly influenced JIA disease activity. Conclusions: Children with JIA demonstrate significantly lower dietary and serum magnesium levels than their healthy peers. Larger pediatric studies are needed to clarify the potential contribution of magnesium to the development and clinical course of JIA. Key words: magnesium, dietary intake, hypomagnesemia, juvenile idiopathic arthritis.

Introduction Magnesium is an essential mineral involved in numerous physiological processes, playing a key role in maintaining the function of different systems in the human body [1, 2]. It participates in numerous enzymatic reactions, influencing energy metabolism, protein synthesis, and neurotransmission [1]. About 60% of magnesium is primarily stored in bones and 40% in soft tissues, with only a small fraction (approximately 1%) circulating in the blood [3, 4].

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children, characterized by persistent joint inflammation and immune dysregulation [5, 6]. Emerging evidence suggests that micronutrient imbalances may contribute to disease activity and symptom severity in JIA patients [7, 8]. Magnesium is known to modulate inflammatory pathways by regulating cytokine production, oxidative stress, and immune cell function [9, 10]. Deficiency of this essential mineral may exacerbate inflammatory responses, potentially worsening joint damage and systemic manifestations in JIA [11].

Address for correspondence Oksana Boyarchuk, Department of Children’s Diseases and Pediatric Surgery, I. Horbachevsky Ternopil National Medical University, Maidan Voli 1, 46001 Ternopil, Ukraine, e-mail: boyarchuk@tdmu.edu.ua Submitted: 09.04.2025; Accepted: 18.11.2025; Published online: 28.04.2026

Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)

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Several factors can contribute to inadequate magnesium levels in children with JIA, including insufficient dietary intake, chronic inflammation, malabsorption, and renal losses [12]. Studies have indicated that dietary magnesium intake is often below recommended levels in pediatric populations, particularly among adolescents [13–16]. Given the potential implications of magnesium deficiency on immune function and inflammation, understanding its role in JIA is essential for optimizing disease management and improving patient outcomes. The aim of this study was to assess dietary magnesium intake and serum magnesium levels in children with JIA and to evaluate their potential impact on the clinical course of the disease.

Material and methods Study design and methodology This case-control study included 42 children with JIA aged 2 to 18 years and 67 healthy children aged 6 to 18 years. The examination of children with JIA was conducted both during hospitalization and at outpatient visits during routine check-ups. Children in the control group were assessed during scheduled preventive medical examinations. Patients were included in the JIA group if they met the International League of Associations for Rheumatology (ILAR) criteria for JIA [17] and provided informed consent from the child and/or their parents. Exclusion criteria included the presence of acute or other chronic diseases and renal dysfunction, and intake of magnesium supplements in the last 6 months. The control group consisted of children without acute or chronic diseases, with no intake of magnesium supplements in the last 6 months, and with informed consent from the child and/or their parents.

Data collection and assessment Data collection was conducted through interviews, where basic characteristics such as age, sex, place of residence, and parental education were recorded. Medical records were reviewed to determine JIA subtypes, disease duration, and treatment regimens. Physical examinations included anthropometric measurements and disease activity assessment. The classification of inactive disease followed the Wallace criteria [18]. Dietary magnesium intake was assessed using a food frequency questionnaire, which collected information on the weekly consumption of specific foods rich in magnesium. Data on dietary magnesium intake were available for 26 out of 42 JIA patients because only these participants (and their caregivers) completed the validated

food frequency questionnaire in full. For the remaining 16 subjects, incomplete or unreliable dietary data were excluded from the analysis to ensure accuracy. The food list included key dietary items commonly consumed by children of various ages, considering their magnesium content. Each child, with parental assistance, reconstructed their weekly diet, specifying portion sizes for each food item. For younger children (aged 2 to 9 years), parental guidance was essential in recalling dietary intake. Using a database of magnesium content in foods [15, 19], the average weekly and daily magnesium intake was calculated. The total dietary magnesium intake was compared with national and international dietary recommendations for vitamins and minerals in children [19]. Nutrient intakes below 67% of the recommended daily allowance were considered deficient, as this level indicates a risk of inadequate intake [14, 15]. Additionally, serum magnesium levels were measured using an ELISA assay kit (Elabscience, USA) via a colorimetric method. In children older than 5 months, normal serum magnesium levels range from 0.70 to 0.95 mmol/l, with hypomagnesemia defined as levels below 0.7 mmol/l [1, 2].

Statistical analysis Statistical analysis was performed using STATISTICA 10.0 and Microsoft Excel 2003. For normally distributed data, the mean (m) and standard deviation (SD) were calculated. Data were processed using variation statistics, and Student’s t-test was applied to compare mean values. For non-normally distributed data, values are presented as the median and interquartile range (IQR) [25%; 75%]. Comparisons between two independent groups were conducted using nonparametric statistics, specifically the Mann-Whitney U test. Frequency distributions between groups were compared using the chisquare (χ²) test. Differences were considered statistically significant at p < 0.05. To assess the impact of potential risk factors, odds ratios (OR) and 95% confidence intervals (CI) were calculated based on variables that demonstrated statistical significance.

Bioethical standards The study protocol adhered to the principles outlined in the Declaration of Helsinki (1975, revised in 2000) and was approved by the Ethics Committee of I. Horbachevsky Ternopil National Medical University (Minutes No. 60, September 1, 2020).

Results Among 42 patients with JIA, there was an equal distribution of boys and girls (Table I). No significant differ-

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Table I. Baseline characteristics of patients with JIA and healthy children Characteristic

JIA patients (n = 42)

Healthy children (n = 67)

Male

21 (50.0)

35 (52.2)

Female

21 (50.0)

32 (47.8)

Rural

22 (52.4)

17 (25.4)*^

Urban

20 (47.8)

50 (74.6)

Higher

15/42 (35.7)*

35/67 (52.2)

Sex [n (%)]

Place of residence [n (%)]

Parents’ education [n (%)] Secondary

27/42 (64.3)

32/67 (47.8)

Age at visit [years], mean ±SD

10.98 ±4.61

11.69 ±3.67

BMI, mean ±SD (min–max)

18.89 ±3.66 (14.35–27.45)

19.65 ±4.09 (13.17–28.26)

JIA duration [years], mean ±SD (min–max)

3.52 ±2.17 (6 months–8 years)

JIA [n (%)] Active disease

16 (38.1)*

Inactive disease

26 (61.9)

*The difference is significant (p < 0.05) between categories within the group of patients with JIA or in healthy children. ^The difference is significant (p < 0.05) between the groups of patients with JIA and healthy children. BMI – body mass index, JIA – juvenile idiopathic arthritis, SD – standard deviation.

ences were observed regarding urban or rural residence within this cohort. A smaller proportion of parents had higher education (p = 0.09). The mean disease duration was 3.52 ±2.17 years, ranging from 6 months to 8 years. Among the JIA types, oligoarthritis was the most prevalent (19/45.2%), followed by systemic arthritis (9/21.4%). Other JIA types were less common (Fig. 1A). The majority of children (26/61.9%) were in an inactive disease stage at the time of evaluation (p = 0.029). Methotrexate was the most frequently used medication

(32/76.2%), while 15/35.7% received biologic therapy, most commonly adalimumab (9/21.4%) (Fig. 1B). Among healthy children, no differences were found in sex distribution or parental education; however, urban residents predominated (p < 0.001). A comparison of patients with JIA and healthy controls based on baseline characteristics (Table I) revealed a significant difference only in place of residence: children with JIA were more likely to live in rural areas (p = 0.004). No significant differences were observed be-

2.4 2.4

Tocilizumab 14.3

14.3

21.4 Adalimumab

21.4

Intraarticular GCs

14.3

33.2

Systemic GCs

38.1

Methotrexate

76.2

45.2 0 (%) Systemic Polyarthritis Psoriatic

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Oligoarthritis Enthesitis related Undifferentiated

50 (%)

100

Fig. 1. Clinical characteristics of patients with JIA: A) types of JIA, B) JIA treatment. GCs – glucocorticosteroids, JIA – juvenile idiopathic arthritis.

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Magnesium and juvenile idiopathic arthritis

Table II. Daily dietary magnesium intake and serum magnesium concentration in JIA and healthy patients Patient group

Daily dietary intake, mg/day, median (IQR)

Insufficient dietary intake [n (%)]

Serum magnesium, [mmol/l], mean ±SD

Hypomagnesemia [n (%)]

JIA patients

227.71 (166.58; 258.55)

13/26 (50.0)

0.79 ±0.16

10/42 (23.8)

Healthy children

261.18 (189.89; 328.90)

18/67 (26.9)

0.94 ±0.24

8/67 (11.9)

0.040

0.034

0.009

0.104

Statistically significant values are highlighted in bold. JIA – juvenile idiopathic arthritis, SD – standard deviation.

Table III. Insufficient dietary magnesium intake in patients with JIA and healthy children according to age Group

Insufficient dietary magnesium intake Before 12 years

After 12 years

JIA patients [n (%)]

4/13 (30.8)

9/13 (69.2)

Healthy children [n (%)]

2/37 (5.4)

16/30 (53.3)

0.016

0.332

Statistically significant values are highlighted in bold. IQR – interquartile range, JIA – juvenile idiopathic arthritis.

tween the 2 groups in terms of sex, parental education, age, or body mass index (BMI). Daily dietary magnesium intake and serum magnesium levels in children with JIA and healthy controls are presented in Table II. Daily magnesium intake was assessed in 26 of the 42 JIA patients, whereas serum magnesium levels were available for all participants. The median daily magnesium intake was significantly lower in children with JIA compared to healthy children (p = 0.040). Additionally, a greater proportion of children in the JIA cohort had inadequate dietary magnesium intake (p = 0.034). The risk of JIA was 2.72 times higher in children with insufficient magnesium intake (OR = 2.722; 95% CI: 1.064–6.966; p = 0.037). When stratified by age, it was found that among children under 12 years old, the proportion of those with inadequate magnesium intake was significantly higher in the JIA group than in healthy controls (p = 0.016). However, this difference was not observed in children over 12 years of age (Table III), as the percentage of healthy adolescents with low dietary magnesium intake was also high. The mean serum magnesium concentration was lower in children with JIA compared to healthy controls (p = 0.009) (Fig. 2), although the proportion of children with hypomagnesemia did not differ significantly between the groups. When comparing the baseline and clinical characteristics of JIA patients based on dietary magnesium intake, it was found that children with insufficient dietary magnesium intake were more likely to be male (p = 0.006), over 12 years of age (p = 0.049), and residing in urban areas (p = 0.002) (Table IV). No significant dif-

Box and Whisker Plot 1.05

1.00

0.95

0.90

0.85

0.80

0.75

0.70

JIA patients Mean

Mean ±SE

Healthy children Mean ±1.96 x SE

Fig. 2. Mean serum magnesium (mmol/l) in JIA patients and healthy controls (p = 0.009). JIA – juvenile idiopathic arthritis.

ferences were observed concerning parents’ education level, BMI, disease duration, or disease activity. Serum magnesium concentration was also not associated with dietary magnesium intake. Hypomagnesemia was more common in boys (p = 0.030). Comparing the other baseline and clinical characteristics of JIA patients based on the presence or absence of hypomagnesemia showed no statistically significant differences in terms of age, place of residence, parents’

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Table IV. Basic and clinical characteristics of patients with JIA according to magnesium dietary intake Characteristic

JIA patients

Normal magnesium dietary intake (n = 13)

Insufficient dietary magnesium intake (n = 13)

Male

4 (30.8)

11 (84.6)

Female

9 (69.2)

2 (15.4)

Under 12 years

9 (69.2)

4 (30.8)

After 12 years

4 (30.8)

9 (69.2)

Rural

13 (100.0)

4 (30.8)

Urban

0 (0.0)

9 (69.2)

0.006

Sex [n (%)]

0.049

Age [n (%)]

0.0002

Place of residence [n (%)]

0.107

Parents’ education level [n (%)] Higher

3 (31.3)

7 (50.0)

Secondary

10 (68.7)

6 (50.0)

Age at visit [years], mean ±SD

9.85 ±3.69

14.31 ±2.98

0.002

BMI, mean ±SD

17.40 ±3.13

20.21 ±3.42

0.072

JIA duration [years], mean ±SD

3.31 ±2.10

4.54 ±2.93

0.230

JIA, active disease

5 (38.5)

7 (53.8)

0.431

Magnesium [mmol/l], mean ±SD

0.80 ±0.21

0.77 ±0.09

0.687

Daily dietary intake, Me [IQR]

236.01 [226.42; 284.49]

174.86 [146.58; 236.45]

0.024

Statistically significant values are highlighted in bold. Daily magnesium intake was available for 26 JIA patients (13 with normal and 13 with insufficient intake). BMI – body mass index, IQR – interquartile range, JIA – juvenile idiopathic arthritis, Me – median, SD – standard deviation.

education level, age at visit, BMI, disease duration, or disease activity (Table V). Although daily dietary magnesium intake was lower among children with hypomagnesemia, the difference was not statistically significant.

Discussion The main clinical characteristics of patients with JIA, such as age, disease subtype, and duration, are consistent with findings from previous studies [20, 21], although a predominance of females has been reported in other JIA cohorts [21]. Our study demonstrated that children with JIA had significantly lower median dietary magnesium intake than healthy controls (p = 0.040), and the proportion of children with insufficient dietary magnesium intake was significantly higher in the JIA group (p = 0.034). Most previous studies examining the role of magnesium in arthritis focused on adult populations, particularly in the context of rheumatoid arthritis (RA) and osteoarthritis, and findings remain conflicting. A U.S. study indicated that adults with RA consumed suboptimal levels of magnesium along with other nutrients [22]. Another large cross-sectional study from the United States,

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including 13,324 women aged 18–80 years (12,306 with RA and 1,018 controls), found an inverse association between dietary magnesium intake and RA (OR = 0.84, 95% CI: 0.75–0.95; p = 0.006) [23]. Interestingly, RA prevalence decreased with magnesium intake below 181 mg/day and increased above 446 mg/day, reaching its lowest point between 181 and 446 mg/day. The authors proposed a U-shaped relationship between magnesium intake and RA risk, suggesting a potential protective role for moderate magnesium consumption. None of the children in our JIA cohort reported magnesium intake exceeding 446 mg/day. In contrast, Cheng et al. [24] observed that higher serum magnesium levels correlated with increased RA risk but reduced the risk of osteoporosis. Our analysis of magnesium intake and serum magnesium levels within the JIA cohort did not reveal significant associations with disease activity. However, the relatively small number of patients in some subgroups limits the statistical power and the generalizability of these findings. Some studies suggest that a low-magnesium diet may decrease RA activity [25]. Conversely, other reports showed that greater magnesium intake was inversely associated with RA risk among U.S. adults [26].

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Magnesium and juvenile idiopathic arthritis

Table V. Basic and clinical characteristics of patients with JIA according to magnesium status Characteristic

JIA patients

Normal magnesium (n = 32)

Hypomagnesemia (n = 10) 0.030

Sex [n (%)] Male

13 (40.6)

8 (80.0)

Female

19 (59.4)

2 (20.0)

Age

0.210

Under 12 years

20 (62.5)

4 (40.0)

After 12 years

12 (37.5)

6 (60.0)

Rural

16 (50.0)

6 (60.0)

Urban

16 (50.0)

4 (40.0)

0.581

Place of residence [n (%)]

0.280

Parents’ education level [n (%)] Higher

10 (31.3)

5 (50.0)

Secondary

22 (68.7)

5 (50.0)

Age at visit [years], mean ±SD

10.76 ±4.60

12.10 ±4.93

0.431

BMI, mean ±SD

18.81 ±3.50

19.29 ±5.34

0.808

JIA duration [years], mean ±SD

4.18 ±2.38

2.00 ±1.22

0.060

JIA, active disease

12 (37.5)

4 (40.0)

0.887

Magnesium [mmol/l], mean ±SD

0.84 ±0.14

0.62 ±0.06

0.004

Daily dietary intake, Me [IQR]

226.42 [156.07; 243.75]

176.69 [174.86; 229.00]

0.485

Statistically significant values are highlighted in bold. BMI – body mass index, IQR – interquartile range, JIA – juvenile idiopathic arthritis, Me – median, SD – standard deviation.

Liu et al. [27] demonstrated that adequate magnesium intake, either through diet or supplementation, reduced all-cause mortality in RA patients – especially among women and those under 65 years of age. However, another study found no association between low magnesium intake and inflammatory markers [28]. Several findings support the anti-inflammatory potential of magnesium in RA. Higher dietary magnesium has been negatively associated with prostaglandin E2 (PGE2) levels [29]. Magnesium deficiency can enhance NMDA receptor stimulation, leading to the release of substance P and pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor (TNF) [30]. In murine models, magnesium supplementation reduced arthritis severity, joint damage, and expression of IL-1β, IL-6, and TNF [31], possibly by promoting the expansion of IL-10-producing T cells and Foxp3+ Tregs, mediated via the gut microbiome. Other murine studies suggested that short-term magnesium restriction reduced synovial IL-6 expression, opening new avenues for managing autoimmune diseases such as RA and psoriatic arthritis [32]. More recent experiments also supported magnesium supplementation as protective in RA, highlighting

transcriptomic changes in oxidative stress and aging pathways [33]. Negative correlations have been observed between magnesium intake and inflammatory cytokines (PGE2, IL-1β, IL-2) in RA patients [34]. However, Hejazi et al. [35] found no impact of magnesium intake on disease activity, despite identifying insufficient intake among women with RA – findings consistent with our results, where neither magnesium intake nor serum levels influenced JIA activity. We also observed lower serum magnesium levels in the JIA group than in healthy children (p = 0.009). However, the prevalence of hypomagnesemia did not differ significantly between groups. Studies assessing serum magnesium levels have largely focused on RA, revealing decreased magnesium and calcium levels compared to healthy controls (p < 0.001). Serum magnesium levels were negatively correlated with total and low-density lipoprotein cholesterol, and positively correlated with high-density lipoprotein cholesterol, suggesting a potential cardiovascular risk in RA patients [36]. Other studies confirmed significantly lower magnesium concentrations in blood, serum, and hair samples of RA patients compared to controls [37]. Earlier research indicated that although more than 50%

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of RA patients consumed insufficient magnesium, mean serum levels remained within the normal range [38], reflecting the weak correlation between intake and serum magnesium levels – a finding consistent with our results and other studies [16]. In our study, boys with JIA were more likely to have insufficient dietary magnesium intake and hypomagnesemia. This observation may reflect differences in dietary habits, nutrient requirements, or disease-related factors between sexes. Similar patterns have been noted in other pediatric populations, suggesting the need for targeted nutritional counseling for male patients [16]. Older children (> 12 years) showed a higher prevalence of inadequate magnesium intake compared to younger children. This may be related to increased nutrient requirements during adolescence, independent dietary habits, or lower adherence to dietary recommendations. These findings highlight the importance of monitoring dietary magnesium, especially in adolescent JIA patients. Children living in urban areas were more likely to have insufficient dietary magnesium intake. Possible explanations include differences in diet composition, access to magnesium-rich foods, and lifestyle factors. This suggests that environmental and socioeconomic factors may contribute to nutrient deficiencies in children with JIA. Monitoring magnesium intake remains important for overall health and growth. Overall, our findings provide insight into the demographic and lifestyle factors associated with low magnesium intake in children with JIA, emphasizing the need for individualized dietary assessment and intervention. Future studies with larger cohorts are needed to clarify potential clinical implications.

Study strengths and limitations A major strength of our study is its comprehensive approach: we assessed both dietary magnesium intake and serum magnesium concentration, as well as their relationship with JIA disease activity. This dual analysis provides a more complete picture of magnesium status in children with JIA. Additionally, our study is among the few to investigate this relationship in pediatric po pulations, as most prior research has focused on adults with RA. However, the study has limitations. The sample size of children with JIA was relatively small, which may limit the generalizability of our findings. The relatively small sample size limited the possibility of performing multivariate analyses to identify independent factors asso ciated with low magnesium intake or low serum magnesium levels. Therefore, the results should be interpreted with caution and confirmed in larger cohorts. Further-

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more, magnesium intake was assessed through dietary recall, which is subject to reporting bias and does not account for magnesium bioavailability or losses through excretion. Dietary magnesium intake data were available for only 26 out of 42 JIA patients, as some participants did not fully complete the dietary questionnaire, which may represent a potential source of selection bias.

Conclusions Insufficient dietary magnesium intake was identified in 50% of children with JIA. Median magnesium intake was significantly lower in the JIA group compared to healthy children. Among children with JIA and low magnesium intake, boys, adolescents older than 12 years, and urban residents were more prevalent. Serum magnesium levels were also lower in children with JIA, and hypomagnesemia was more common in boys. However, neither low magnesium intake nor hypomagnesemia significantly influenced JIA disease activity. Given the conflicting data on magnesium’s role in arthritis pathogenesis and progression, larger pediatric studies are needed to clarify its potential contribution to the development and clinical course of JIA.

Disclosures Conflict of interest: The authors declare no conflict of interest. Funding: This study was funded by the Ministry of Health of Ukraine as part of the project titled “Features of Vitamin and Mineral Status in Healthy Children and in Children with Socially Significant Diseases” (State Registration No. 0121U100069). Ethics approval: The study protocol was approved by the Ethics Committee of I. Horbachevsky Ternopil National Medical University (Minutes No. 60, September 1, 2020). Data availability: The data that support the findings of this study are available on request from the corresponding author (O.B.). References 1. Pham PC, Pham PA, Pham SV, et al. Hypomagnesemia: a clin ical perspective. Int J Nephrol Renovasc Dis 2014; 7: 219–230, DOI: 10.2147/IJNRD.S42054. 2. de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: im plications for health and disease. Physiol Rev 2015; 95: 1–46, DOI: 10.1152/physrev.00012.2014. 3. Piuri G, Zocchi M, Della Porta M, et al. Magnesium in Obesity, Metabolic Syndrome, and Type 2 Diabetes. Nutrients 2021; 13: 320, DOI: 10.3390/nu13020320. 4. Jahnen-Dechent W, Ketteler M. Magnesium basics. Clin Kid ney J 2012; 5: 3–14, DOI: 10.1093/ndtplus/sfr163.

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cal parameters as risk factors of cardiovascular diseases in patients with rheumatoid arthritis. J Clin Diagn Res 2015; 9: BC01–5, DOI: 10.7860/JCDR/2015/12206.5740. 37. Afridi HI, Kazi TG, Kazi N, et al. Evaluation of calcium, magne sium, potassium, and sodium in biological samples (scalp hair, serum, blood, and urine) of Pakistani referents and arthritis patients of different age groups. Clin Lab 2012; 58: 7–18. 38. Morgan SL, Hine RJ, Vaughn WH, Brown A. Dietary intake and circulating vitamin levels of rheumatoid arthritis patients treated with methotrexate. Arthritis Care Res 1993; 6: 4–10, DOI: 10.1002/art.1790060103.

Original paper

Reumatologia 2026; 64, 3: 209–217 DOI: https://doi.org/10.5114/reum/215233

Screening and management of systemic sclerosis-associated pulmonary complications in Iraq: insights from a national survey of rheumatologists and pulmonologists Asal Adnan Ridha* ID , Nabaa Ihsan Awadh* ID , Faiq Isho Gorial ID , Nizar Jassim ID Rheumatology Unit, Department of Internal Medicine, College of Medicine, University of Baghdad, Iraq *These authors had equal contribution to this work.

Abstract Introduction: This study evaluated the screening and management approaches of Iraqi rheumatologists and pulmonologists regarding systemic sclerosis interstitial lung disease (SSc-ILD) and pulmonary hypertension (PHT), identifying key gaps and areas for improvement. Material and methods: An internet-based survey was distributed to Iraqi rheumatologists and pulmonologists from August to October 2024. The survey collected demographic data, screening methods, treatment initiation criteria, and therapeutic preferences. Descriptive statistics were used to analyse the responses, and trends were identified on the basis of physician speciality and experience level. Results: A total of 116 participants responded (75.9% rheumatologists, 24.1% pulmonologists). Routine screening for ILD was reported by 88.8% of respondents, with 62.1% screening at diagnosis. High-resolution computed tomography (HRCT) was the preferred screening tool (61.7%), followed by pulmonary function tests (52.2%). However, only 31% of patients are routinely screened for PHT, with most relying on unexplained dyspnoea or annual assessments. Mycophenolate mofetil was the preferred first-line treatment for SSc-ILD (87.5%), whereas rituximab and azathioprine were less commonly used. Treatment decisions were guided primarily by HRCT findings and pulmonary function trends. Despite 89.3% reporting multidisciplinary collaboration, variability in screening and treatment approaches suggests inconsistencies in guideline adherence. Conclusions: This study revealed inconsistencies in the screening and management of SSc-ILD and PHT among Iraqi specialists. While ILD screening is commonly performed via HRCT, PHT screening remains suboptimal. Mycophenolate mofetil is the preferred treatment, but adherence to international guidelines varies. Strengthening standardised protocols and multidisciplinary collaboration is essential to improve patient care. Future research should prioritise the identification of barriers to the effective implementation of clinical guidelines and the evaluation of the effects of standardised care practices on patient outcomes. Key words: interstitial lung disease, pulmonary hypertension, multidisciplinary approach, systemic sclerosis.

Introduction Systemic sclerosis (SSc) is a complex autoimmune disease characterised by widespread fibrosis, vascular dysfunction, and immune dysregulation. Pulmonary complications, notably interstitial lung disease (ILD) and pulmonary hypertension (PHT), are leading causes

of morbidity and mortality in SSc patients. Early identification and treatment of these complications are critical for improving patient outcomes [1]. Despite significant advances in diagnostic tools and treatment strategies, variations in screening practices persist, particularly in resource-limited settings such as Iraq.

Address for correspondence Nabaa Ihsan Awadh, Rheumatology Unit, Department of Internal Medicine, College of Medicine, University of Baghdad, Bab Al-Muadham, Baghdad, 00964, Iraq, e-mail: dr.nabaaihsan@yahoo.com Submitted: 16.05.2025; Accepted: 05.12.2025; Published online: 29.06.2026

Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)

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High-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) are the primary modali ties for ILD detection, whereas echocardiography and right heart catheterisation are recommended for PHT screening. International guidelines emphasise the importance of early and systematic screening to detect lung involvement before irreversible fibrosis develops [2]. Studies have shown that ILD affects up to 50% of SSc patients, with progression rates varying on the basis of disease subtype and risk factors such as the presence of anti-topoisomerase I antibodies [3]. However, global disparities exist in screening and treatment approaches, which are influenced by factors such as physician experience, resource availability, and adherence to guidelines [4]. Multidisciplinary collaboration between rheumato logists and pulmonologists has been shown to improve SSc-ILD and PHT management by integrating imaging findings, functional assessments, and therapeutic interventions [5]. However, there is a lack of documented data on how Iraqi rheumatologists and pulmonologists approach screening and treatment for these pulmonary complications. Understanding current practices in Iraq is essential for identifying gaps in care, improving adhe rence to evidence-based guidelines, and ensuring early intervention for SSc patients at risk of lung involvement. This study aimed to assess the attitudes and practices of Iraqi rheumatologists and pulmonologists regarding the screening and management of SSc-ILD and PHT. Iraq represents a middle-income country where access to advanced diagnostic tools and structured multidisciplinary care may be variable. Evaluating local clinical practice patterns may help identify barriers to guideline implementation and inform future efforts to standardise care for patients with SSc-associated pulmonary complications. The findings may also provide insights relevant to other healthcare systems facing similar resource constraints.

Material and methods Study design Between August and October 2024, an internetbased survey was administered to Iraqi rheumatologists, pulmonologists, and fellows to survey their attitudes and practices with respect to screening for SSc-related lung disease. The survey consisted of 23 items used to collect data about the participants’ attitudes and practices for the screening and treatment of patients with SSc.

Survey structure The questionnaire consisted of both checkbox answers and questions that asked about the respondent’s demographic and screening data. The demographic data

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included age, sex, highest medical qualifications, years of speciality practice, and the average number of SSc patients seen in practice per year. The parameters for screening assessment included questions about whether patients are routinely screened for ILD, the timing for screening patients for ILD, the preferred methods of screening (such as PFTs, HRCT, or serological markers), and the timing for PHT screening. A list of parameters was used to comprehensively evaluate decision-making processes, treatment initiation, monitoring, and criteria for treatment success.

Distribution and participation The survey was disseminated via social media platforms, specifically through WhatsApp groups for the Iraqi League for Bone and Joint Health and for pulmo nologists, with a link to a Google Form. To enhance participation, we sent a reminder in mid-September to stimulate further responses. The majority of participants were from Baghdad Teaching Hospital, Medical City, and other reference centres in Baghdad, Mosul, Basra, and Najaf, representing the main tertiary rheumatology and pulmonology units in Iraq.

Questionnaire design The questionnaire was developed by the research team based on a comprehensive review of current lite rature, international practice guidelines (e.g., ACR and EUSTAR), and previously published surveys on SScassociated ILD and PHT, including those by Hoa et al. [4] and Nicolas et al. [6]. Key domains included clinician demographics, screening practices, diagnostic preferences, treatment decision-making criteria, and interdiscipli nary collaboration. The initial draft was reviewed by 2 senior rheumatologists for relevance and clarity. Based on their feedback, minor modifications were made to improve item phrasing and ensure clinical appropriateness. The final version was piloted among 3 rheumato logists to assess comprehensibility and time required to complete the survey. Their feedback supported the clarity and acceptability of the questionnaire.

Data analysis Responses were analysed by the authors and categorised into themes to summarise the findings effectively.

Bioethical standards The study was reviewed by the Institutional Review Board of the College of Medicine, University of Baghdad, and received a waiver of formal ethical approval as it involved a voluntary, anonymous survey of healthcare

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professionals with no patient data collection. Healthcare professionals viewed the invitation to participate in social media. Clicking on the button to “fill out the form” is considered the equivalent of consenting to participate in the survey.

Results Survey response and participant characteristics A total of 116 participants completed the survey. The participant characteristics and features of patient recruitment are summarised in Table I. Among the responders, 88 (75.9%) were rheumatologists, and 28 (24.1%) were pulmonologists who were ILD experts. Fifty-nine (51.8%) had a diploma degree, 33 (29.8%) had a board-certified degree, and 24 (18.4%) had a fellowship in rheumatology and pulmonology as their highest medical qualifications. Six (5.1%) had more than 30 years of practice in the speciality, 46 (38.8%) had 10–20 years of practice, 30 (25.9%) had 5–10 years, and 34 (30.2%) had 0–5 years. The estimated proportions of SSc patients per participant were as follows: < 5 (47%), 6–9 (10%), 10–30 (33%), 31–50 (5%), 51–99 (3%), > 100 (4%).

Interstitial lung disease screening in newly diagnosed systemic sclerosis patients Out of 116 participants, 103 (88.8%) reported routinely screening newly diagnosed patients for ILD; 10 screened only occasionally, while 3 did not screen for ILD. Table I indicates that 72 participants (62.1%) conducted screenings at the time of diagnosis, whereas 39 participants (33.6%) performed screenings only when patients exhibited symptoms. Additionally, 2 participants screened based on serological findings, and 3 participants indicated that their screenings are related to other findings. Seventy-one individuals, representing 61.7%, depended on HRCT scans. Sixty individuals, representing 52.2%, systematically prescribe PFTs. Thirty participants, representing 26.1%, reported using spirometry with diffusing capacity of the lungs for carbon monoxide (DLCO). Thirty-nine participants (33.9%) conducted autoantibody screening for ILD, 59 (51.3%) assessed chest auscultation, and 63 (54.8%) performed all the aforementioned measures during the screening process (Fig. 1).

Screening for pulmonary hypertension in systemic sclerosis patients with interstitial lung disease Routine screening for PHT was reported by 36 (31%) participants; 48 (41.4%) screened for PHT only when shortness of breath (SOB) was not explained by ILD pro-

Table I. Demographic and clinical practice characteristics of surveyed specialists Characteristics of participants

n (%)

Specialty Rheumatologists

88 (75.9)

Pulmonologists

28 (24.1)

Highest medical qualifications Diploma degree

59 (51.8)

Board-certified degree

33 (29.8)

Fellowship

24 (18.4)

Experience in specialty Experience of < 5 years

34 (30.2)

Experience of 5–10 years

30 (25.9)

Experience of 10–20 years

46 (38.8)

Experience of > 30 years

6 (5.1)

Estimated proportion of SSc patients per year < 5 patients

6–9 patients

10–30 patients

31–50 patients

51–99 patients

> 100 patients

Timing for ILD screening Screen at time of diagnosis

72 (62.1)

Screen at time of symptoms development

39 (33.6)

Screening based on serological findings

2 (1.7)

Screen based on other findings

3 (2.5)

Timing for PHT screening Routinely

36 (31)

When SOB is present but not due to ILD progression

48 (41.4)

Once per year

25 (21.6)

No screening

7 (6)

ILD – interstitial lung disease, PHT – pulmonary hypertension, SOB – shortness of breath, SSc – systemic sclerosis.

gression; 25 (21.6%) screened once per year; and 7 (6%) did not screen for PHT (Table I). Table II shows the descriptive differences in answers between rheumatologists and pulmonologists.

Treatment decision-making criteria The treatment decision survey was completed by 56 out of the 116 participants. The key features for initiating treatment for SSc-ILD, listed in descending order of frequency, include the extent of ILD or fibrosis on HRCT (94.6%), clinically meaningful changes with

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Chest auscultation

59 (51.3%)

PFTs

60 (52.2%)

Spirometry with DLCO

30 (26.1%) 71 (61.7%)

HRCT 39 (33.9%)

Autoantibody testing

63 (54.8%)

All of the above 0

Fig. 1. Percentages for screening tools. DLCO – diffusing capacity of the lungs for carbon monoxide, HRCT – high-resolution computed tomography, PFTs – pulmonary function tests.

Table II. Comparison of interstitial lung disease and pulmonary hypertension screening practices between rheuma tologists and pulmonologists Screening criteria

Rheumatologists n = 88

Pulmonologists n = 28

Routinely

Occasionally or not

At time of diagnosis

At time of symptoms development

According to serology or others

HRCT

PFTs

DLCO

Autoantibodies

Chest auscultation

HRCT only

Routine screen

Screen when SOB is not explained by ILD progression

Screen once per year

Do not screen

Screen for ILD

Timing of screen

Screening tools

Screen for PHT

DLCO – diffusing capacity of the lungs for carbon monoxide, HRCT – high-resolution computed tomography, ILD – interstitial lung disease, PFTs – pulmonary function tests, SOB – shortness of breath.

a decline in PFT values (64.3%), the presence of PHT (51.8%), the duration and degree of dyspnoea (48.2%), and the baseline PFT value (44.6%). Among HRCT findings, the most commonly used parameter for initiating treatment is the worsening of HRCT in conjunction with symptoms or declining PFTs (80.4%). This is followed by > 20% total lung involvement on HRCT with abnormal

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PFTs (69.6%), high-risk patients (early diffuse disease) exhibiting mild ILD (< 10%) and abnormal PFTs (60.7%), > 20% total lung involvement on HRCT with normal PFTs (55.4%), and > 10% total lung involvement on HRCT with abnormal PFTs (35.7%) (Fig. 2). Among PFT parameters, assuming the presence of ILD on HRCT, a decline in forced vital capacity (FVC) by > 10% in 1 year was considered

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Worsening HRCT with symptoms or declining PFTs

45 (80.4%)

> 20% total lung involvement on HRCT with normal PFTs

31 (55.4%)

> 20% total lung involvement on HRCT with abnormal PFTs

39 (69.6%)

> 10% total lung involvement on HRCT with abnormal PFTs

20 (35.7%)

High-risk patients (early diffuse disease) with evidence of mild ILD

34 (60.7%) 0

Fig. 2. Considerations for starting treatments based on high-resolution computed tomography findings. HRCT – high-resolution computed tomography, ILD – interstitial lung disease, PFTs – pulmonary function tests.

FVC > 80% with ILD on HRCT in a high-risk patient

22 (39.3%)

FVC < 80% with any degree of ILD on HRCT

25 (44.6%) 20 (35.7%)

FVC < 80% and dyspnoea FVC < 70% and dyspnoea

28 (50%)

Decline in FVC by greater than measurement error

11 (19.6%) 30 (53.6%)

Decline in FVC by > 10% in 1 year 5 (8.9%)

Not used for follow-up 0

Fig. 3. Considerations for starting treatments based on pulmonary function tests and symptom status. FVC – forced vital capacity, HRCT – high-resolution computed tomography, ILD – interstitial lung disease.

to be the most frequently used parameter for initiating treatment (53.6%). This was followed by FVC < 70% and dyspnoea (50%), FVC < 80% with any degree of ILD on HRCT (44.6%), FVC > 80% with ILD on HRCT in a highrisk patient (early diffuse disease, positive anti-topoisomerase antibody) in 39.3%, FVC < 80% and dyspnoea in 35.7%, and a decline in FVC by greater than measurement error in 19.6%, whereas 8.9% did not use PFTs for follow-up (Fig. 3). In response to the question regarding which patients should not receive treatment, 69.6% indicated no progression of ILD over recent years; 25% cited stable PFTs, whereas 5.4% referred to patients with longstanding disease nearing 10 years. The most commonly reported triggers for immediate treatment at initial presentation were moderate-to-severe ILD on HRCT (80.4%), hypoxia at rest (69.6%), and HRCT showing ILD > 20% lung involvement (66.1%). Other triggers included moderate-to-severe symptoms (60.7%), an early, rapidly progressive diffuse subset even with mild abnormalities on HRCT chest scan and mild abnormalities on PFT

(53.6%), an early, rapidly progressive diffuse subset even with mild abnormalities on HRCT chest scan (51.8%), desaturation on exercise (42.9%), an early, rapidly progressive diffuse subset even with mild abnormalities on PFT (37.5%), and FVC and/or DLCO below the lower limit of normal (35.7%). The criteria for identifying treatment responders were findings or changes on HRCT (80.4%), findings or changes on PFTs (50%), and duration of symptoms (48.2%).

Therapeutic approaches Mycophenolate mofetil (MMF) is the first-choice treatment for SSc-ILD in 87.5% of cases. Rituximab was chosen by 7.2% of respondents, azathioprine by 1.8%, and nintedanib by 1.8%. Their most likely course of action was determined on the basis of the response to treatment regarding the progression or worsening of ILD. Although MMF was the most frequently prescribed therapy, some respondents also reported using

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cyclophosphamide, particularly in cases of severe or rapidly progressive ILD, consistent with historical evidence supporting its role in SSc-ILD management. Specifically, 83.9% would add another agent for progression or worsening, 76.8% would continue the current treatment for stability, 3.6% would add another agent despite stability, and 1.8% would switch to another agent for stability. The primary circumstances prompting weaning from therapy included drug toxicity (including side effects and adverse events) in 55.4%, the patient’s strong desire to discontinue treatment in 46.4%, a lack of efficacy in 46.4%, stability for 2 or more years in both lung and skin conditions in 39.3%, and all of the above factors in 55.4%.

Tapering approach Participants undertake tapering or weaning over 1–2 years with monitored PFTs every 6 months, with or without a low maintenance dose of MMF in 75% and 21.4% would taper to a lower maintenance dose within months to a year, and 3.6% would stop therapy quickly (over weeks). Parameters considered for disease progression were highest for changes in PFT over time, 82.1%. Their response to the defined criteria for treatment success was highest for symptom stabilisation/improvement (76.8%), followed by FVC improvement (64.3%), FVC stabilisation (58.9%), HRCT improvement (58.9%), HRCT stabilisation (58.9%), DLCO improvement (50%), DLCO stabilisation (46.4%), O2 saturation with exercise (44.6%), 6-minute walk distance stabilisation/improvement (41.1%), and functional status (New York Heart Association functional class or cardiopulmonary exercise testing) (28.6%). When managing patients, 89.3% of participants collaborate frequently with other specialists in clinical practice, while 10.7% collaborate occasionally.

Discussion This study offers valuable insights into the screening attitudes and practices of Iraqi rheumatologists and pulmonologists regarding ILD and PHT in SSc patients. The findings reveal notable variability in screening practices, decision-making, treatment approaches, and outcome assessment, which are influenced by clinical experience, resource availability, and individual attitudes toward early detection and treatment.

Participant characteristics and expertise The participant cohort primarily consisted of rheumatologists (75.9%) and ILD pulmonologists (24.1%), with a smaller proportion of postgraduate trainees. The diversity in medical qualifications and years of prac-

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tice, particularly with 46.6% having less than 10 years of experience, may have contributed to the observed heterogeneity in the responses. This suggests a tendency among less experienced clinicians to adhere more strictly to guideline-based approaches. The study highlights the need for standardised, evidence-based protocols for SSc screening to address this variability.

Interstitial lung disease screening practices A significant proportion of clinicians (88.8%) routi nely screen for ILD in patients with SSc, yet notable variability exists in the timing and methods employed. While 62.1% of practitioners initiate screening at diagnosis, 33.6% defer until symptom onset. This delay may be influenced by resource limitations or differing interpretations of guidelines, despite the critical importance of early ILD detection for optimal management and prevention of irreversible damage [7]. The observed variability in screening practices may be attributed to several factors, including differences in clinical experience, resource availability, and personal attitudes towards guideline recommendations. Compared with the findings reported by Nicolas et al. [6] in France, the use of chest computed tomography (CT) scans for our study (61.7%) is in line with the track record sensitivity of CT for the detection of ILD at initial stages. However, the limited use of PFTs and DLCO assessments in our cohort is a significant contrast. Nicolas et al. [6] also highlighted the common use of PFTs and DLCO in practice worldwide, notably as adjunctive diagnostic support to CT scans in the detection of ILD. Furthermore, the study by Rahaghi et al. [8] reinforced the recommendation for a multidisciplinary approach to ILD screening in SSc patients by emphasising the combined application of clinical reasoning, imaging, and functional capacity (i.e., PFTs, DLCO). However, in this study, only 52.2% of respondents reported that they actually used PFTs, and only 26.1% reported performing DLCO tests, which suggests incomplete adherence to evidence-based screening recommendations. This underutilisation can also be explained by access problems or limited access to equipment in specific areas and has therefore created the need for better resource management and clinician training to better comply with the guidelines. Our findings also align with the expert consensus of Rahaghi et al. [8], which emphasises the need for systematic and multidisciplinary approaches combining HRCT, PFTs, and DLCO. The underutilisation of DLCO in our Iraqi cohort contrasts with the consensus recommendation, highlighting the gap between evidence-based recommendations and real-world practice in resource-limited settings.

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Pulmonary challenges in systemic sclerosis: Iraqi insight

Similarly, the study by Hoa et al. [4] revealed significant international variability in ILD screening approaches, with differing reliance on HRCT, PFTs, and DLCO testing. While our findings align with their observation that HRCT remains the preferred screening tool globally, our cohort demonstrated a lower frequency of DLCO use than international data did. This discrepancy highlights regional disparities in screening accessibility and practice, reinforcing the need for localised adaptations of international guidelines.

Pulmonary hypertension screening practices Our survey highlighted considerable variability in PHT screening practices among SSc patients with ILD. While 31% of the respondents reported routine screening for PHT, a significant proportion (41.4%) restricted screening to cases of unexplained SOB, and 21.6% conducted annual screenings. This discrepancy suggests suboptimal adherence to guidelines and thus highlights the need for routine PHT screening to identify and treat PHT early. Given the significant mortality of PHT in SSc patients, these data highlight an important area for improvement and underscore the need to strengthen adherence to guideline-recommended screening practices. The reluctance to perform routine PHT screening, even among symptomatic patients, may be attributed to resource constraints, particularly limited access to echocardiography and right heart catheterisation, both of which are resource-intensive diagnostic modalities. This finding is supported by Johnson et al. [7], who suggested the use of echocardiography as a fundamental part of PHT screening by SSc-related clinical screening centres but noted that the practice of using echocardio graphy is heterogeneous due to discrepancies in resource usage. Similarly, Nicolas et al. [6] noted an increase in echocardiography and invasive diagnostic workups in “resource-rich” countries that have direct consequences for economics and infrastructure for screening activity. According to current recommendations, the DETECT algorithm is endorsed for pulmonary arterial hypertension screening in SSc [9]. Our survey did not specifically include DETECT in the questionnaire; thus, it remains unclear to what extent this algorithm is applied in Iraqi practice. Our findings align with broader literature, which identifies resource limitations and varying clinical practices as significant barriers to implementing guidelinebased screening protocols. The variation observed in this study can be explained by global patterns, especially in low- and middle-income countries where the application of complete screening algorithm recommendations is still a challenge. Addressing these disparities through targeted resource allocation and clinician education

may help bridge the gap and improve outcomes for SSc patients at risk of PHT. Hoa et al. [4] also reported global disparities in PHT screening, with some centres adhering strictly to guidelinebased echocardiographic evaluations and others relying on clinical suspicion. Our findings reflect a similar pattern, with a reliance on symptom-based screening rather than proactive assessment. This further underscores the necessity of strengthening systematic screening approaches to enhance early detection and management.

Treatment decision practices Our survey revealed that only 50% of the respondents completed the predefined treatment decision survey for SSc-ILD. In addition, 94.6% of the respondents rated the extent of ILD or fibrosis on HRCT as the most important factor for starting the treatment. This practice is in accordance with recent recommendations that favour HRCT as the reference standard for the detection and quantification of ILD [10]. Furthermore, 80.4% of participants rated symptoms or deterioration in PFTs as being the most important factor in making treatment decisions, while 69.6% considered more than 20% lung involvement on HRCT in conjunction with abnormal PFTs as a criterion. Together, these findings emphasise the importance of integrating structural imaging with functional assessment in the management of SSc-ILD. However, there was notable variability in PFT thresholds for initiating therapy: 50% of respondents used a FVC of less than 70% as a criterion, whereas 44.6% employed a threshold of less than 80%. This disparity highlights the absence of a universal consensus and underscores the need for standardised protocols to guide treatment initiation. Regarding therapeutic approaches, our finding is that 87.5% of respondents prefer MMF as first-line the rapy. This preference reflects evidence supporting the efficacy of MMF in stabilizing or improving lung function in SSc-ILD patients [11, 12]. This finding is also consistent with the preferences reported by Nicolas et al. [6], who noted the prominence of MMF in clinical practice because of its ability to stabilise or improve lung function. These findings are also consistent with the latest European Alliance of Associations for Rheumatology 2023 recommendations, which emphasise MMF as first-line therapy, while recognising cyclophosphamide, nintedanib, and biologics in specific scenarios [13]. Additionally, we report that changes in therapy in stable patients were managed cautiously, which mirrors the findings of a French study that reflects concerns about toxicities and a lack of data for combination therapies. In contrast, rituximab (7.2%) and azathioprine (1.8%) were less

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Asal Adnan Ridha, Nabaa Ihsan Awadh, Faiq Isho Gorial, Nizar Jassim

commonly selected, possibly owing to limited supporting evidence in this context [13, 14]. In cases of disease progression, 83.9% of participants indicated that they would escalate therapy by adding another agent, whereas 76.8% would continue MMF in patients exhibiting disease stability. Notably, only 3.6% would consider adding another agent despite stability, and a mere 1.8% would opt to switch therapy in stable patients. This cautious approach to modifying treatment in stable cases likely reflects concerns over potential toxicity and the limited data on combination therapies for SSc-ILD. When considering tapering strategies, 75% of respondents favoured a gradual reduction in therapy over 1–2 years, with PFT monitoring every 6 months. This approach aligns with clinical practices aimed at minimising drug-related toxicity while maintaining disease stability [15]. However, 21.4% preferred a more rapid tapering regimen, and 3.6% discontinued therapy abruptly, potentially increasing the risk of disease progression. This variation underscores the need for robust evidence to guide tapering strategies, particularly in long-term responders. Our findings parallel those of Hoa et al. [4], who noted that treatment initiation criteria varied widely among international centres. While HRCT remains the cornerstone for decision-making, there is no universal agreement on PFT thresholds, reflecting the ongoing debate regarding the optimal timing for intervention. This suggests that international guideline harmonisation remains a key priority for improving patient outcomes.

Criteria for treatment success Symptom stabilisation or improvement (76.8%) and FVC improvement (64.3%) were the most frequently mentioned indicators of treatment success, followed by HRCT stabilisation (58.9%). These parameters are in line with existing recommendations for monitoring SSc-ILD progression with prioritisation of functional and structural stability over significant improvement owing to this condition’s chronic, fibrotic nature. Multidisciplinary cooperation forms the bulwark of SSc-ILD management, where 89.3% of respondents would often collaborate with other specialists, such as pulmonologists and radiologists. This finding indicates that complex SSc-ILD usually involves experts who assess pulmonary and systemic involvement and tailor individualised treatment plans accordingly [15].

Study limitations This study has several limitations. The reliance on self-reported data may introduce response bias, and the survey’s cross-sectional design limits the ability to establish causality. Additionally, although participants

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represented a range of specialties, experience levels, and clinical practice settings, the sample may not fully capture the diversity of practices across different healthcare settings in Iraq. Similar studies in other regions have reported similar challenges, indicating that methodological limitations are a common issue in this field [16]. While the findings provide valuable insights into screening practices within the Iraqi context, their gene ralisability to other regions may be limited by differences in healthcare infrastructure and resource availability. Nonetheless, the results highlight common challenges that may be applicable in similar resource-constrained settings. This is consistent with global studies emphasising the need for adaptable guidelines tailored to varying resource environments [17]. As emphasised by Hoa et al. [4], variability in ILD and PHT management is not unique to Iraq but rather a global issue, reinforcing the need for more adaptable and region-specific guideline implementation. Furthermore, while studies from high-income countries have documented adherence trends and outcomes related to SSc-ILD management, data from the Middle East – and Iraq in particular – remain scarce. This study fills a critical gap by providing the first national-level insight into SSc pulmonary screening practices in Iraq, highlighting both areas of strength (e.g., widespread HRCT use) and key gaps (e.g., underuse of DLCO and inconsistent PHT screening). These findings contribute to the global understanding of barriers to optimal care and may support the development of scalable, regionally adapted protocols for SSc-ILD management.

Conclusions This study underscores the need for standardised, evidence-based screening protocols for ILD and PHT in SSc patients in Iraq. Addressing the identified gaps requires improving access to diagnostic tools, enhancing clinician education, and fostering multidisciplinary collaboration. The comparison with international practices highlights areas for improvement and adaptation of global guidelines to local contexts. Future research should focus on identifying barriers to guideline implementation and evaluating the impact of standardised practices on patient outcomes.

Disclosures Conflict of interest: The authors declare no conflict of interest. Funding: No external funding. Ethics approval: Not applicable. Data availability: Not applicable.

Pulmonary challenges in systemic sclerosis: Iraqi insight

References 1. Elhai M, Meune C, Avouac J, et al. Trends in mortality in pa tients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies. Rheumatology 2012; 51: 1017–1026, DOI: 10.1093/rheumatology/ker269. 2. Khanna D, Distler O, Cottin V, et al. Diagnosis and monitoring of systemic sclerosis-associated interstitial lung disease using high-resolution computed tomography. J Scleroderma Relat Disord 2022; 7: 168–178, DOI: 10.1177/23971983211064463. 3. Perelas A, Silver RM, Arrossi AV, Highland KB. Systemic scle rosis-associated interstitial lung disease. Lancet Respir Med 2020; 8: 304–320, DOI: 10.1016/S2213-2600(19)30480-1. 4. Hoa S, Baron M, Hudson M. Screening and management of subclinical interstitial lung disease in systemic sclerosis: an international survey. Rheumatology (Oxford, England) 2022; 61: 3401–3407, DOI: 10.1093/rheumatology/keab929. 5. Chatterjee S, Perelas A, Yadav R, et al. A multidisciplinary ap proach to the assessment of patients with systemic sclerosisassociated interstitial lung disease. Clin Rheumatol 2023; 42: 653–661, DOI: 10.1007/s10067-022-06408-4. 6. Nicolas A, Leroy S, Mouthon L, et al. Systemic sclerosis-associated interstitial lung disease: a survey of current practices in France. Ther Adv Musculoskelet Dis 2023; 15: 1759720X 231159712, DOI: 10.1177/1759720X231159712. 7. Johnson S, Bernstein E, Bolster M, et al. American College of Rheumatology (ACR) guideline for the treatment of intersti tial lung disease in people with systemic autoimmune rheu matic disease. Arthritis Rheumatol 2023; 76: 1201–1213, DOI: 10.1002/art.42860. 8. Rahaghi FF, Hsu VM, Kaner RJ, et al. Expert consensus on the management of systemic sclerosis-associated interstitial lung disease. Respir Res 2023; 24: 6, DOI: 10.1186/s12931-022-02292-3. 9. Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary

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hypertension. Eur Heart J 2022; 43: 3618–3731, DOI: 10.1093/ eurheartj/ehac237. 10. Rea G, Bocchino M. The challenge of diagnosing interstitial lung disease by HRCT: state of the art and future perspectives. J Bras Pneumol 2021; 47: e20210199, DOI: 10.36416/18063756/e20210199. 11. Owen C, Ngian GS, Elford K, et al. Mycophenolate mofetil is an effective and safe option for the management of systemic sclerosis-associated interstitial lung disease: results from the Australian Scleroderma Cohort Study. Clin Exp Rheumatol 2016; 34 (Suppl 100): 170–176. 12. Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med 2016; 4: 708–719, DOI: 10.1016/S2213-2600(16)30152-7. 13. Del Galdo F, Lescoat A, Conaghan PG, et al. EULAR recommenda tions for the treatment of systemic sclerosis: 2023 update. Ann Rheum Dis 2025; 84: 29–40, DOI: 10.1136/ard-2024-226430. 14. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006; 354: 2655–2666, DOI: 10.1056/NEJMoa055120. 15. Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med 2019; 380: 2518–2528, DOI: 10.1056/NEJMoa1903076. 16. Setia MS. Methodology series module 3: cross-sectional studies. Indian J Dermatol 2016; 61: 261–264, DOI: 10.4103/0019-5154. 182410. 17. Dizon JM, Machingaidze S, Grimmer K. To adopt, to adapt, or to contextualise? The big question in clinical practice guide line development. BMC Res Notes 2016; 9: 442, DOI: 10.1186/ s13104-016-2244-7.

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Review paper

Reumatologia 2026; 64, 3: 218–229 DOI: https://doi.org/10.5114/reum/213511

Ambiguities in the effect of physical activity on bone remodelling in spondyloarthritis Agnieszka Alicja Kowalczyk1 ID , Mateusz Wilk1 ID , Mariusz Korkosz2 ID 1

Department of Rheumatology, Immunology and Internal Medicine, University Hospital, Krakow, Poland Department of Rheumatology and Immunology, Jagiellonian University Medical College, Krakow, Poland

Abstract Spondyloarthritis (SpA) is characterized by inflammation of joints and entheses, leading to structural damage and loss of bone mineral density. The goal of this narrative review was to analyse the impact of physical activity on bone remodelling in patients with SpA. Two investigators searched the PubMed, Scopus, Directory of Open Access Journals, and Web of Science bibliographic databases (May 20, 2024; October 4, 2024; and May 19, 2025), then screened the articles for compliance with the inclusion criteria. Six related articles were included. No studies directly assessed the impact of physical activity on bone density in SpA. Prior research showed that short-term exercise does not affect ultrasound or magnetic resonance imaging findings, while repeated activities, such as certain job types, may worsen structural damage. Data regarding the effect of physical activity on bone remodelling are scarce, and results are divergent. More research regarding biomechanical stress and bone remodelling is needed. Key words: osteogenesis, exercise, bone density, axial spondyloarthritis.

Introduction Spondyloarthritis (SpA) describes a group of rheumatic disorders that share a set of symptoms, including inflammatory back pain, asymmetric peripheral arthritis and enthesitis. The most frequent forms of SpA are axial SpA (axSpA) and psoriatic arthritis (PsA). Axial spondyloarthritis is characterised by progressive inflammation of the sacroiliac joints and joints of the spine, leading to bone formation and ankylosis. Its estimated prevalence is between 0.5% and 2% of the population [1, 2]. Psoriatic arthritis affects 6–41% of people with skin psoriasis [3], leading to various clinical phenotypes, including polyarthritis, oligoarthritis, dactylitis and the axial predominant type. Both axSpA and PsA are pathophysiologically associated with structural damage leading to significant disability [4]. Moreover, biomechanics might play a substantial role in the above processes, especially related to entheses [5]. Another pathology related to the skeletal system in axSpA is the loss of bone mineral density (BMD) and the deterioration of bone quality, leading to

osteopenia, osteoporosis [6, 7] and vertebral fractures [8]. Although the association between SpA and osteoporosis is well established, the relationship in PsA remains insufficiently defined [9]. Current treatment guidelines in SpA focus on pharmacological and non-pharmacological approaches [10]. Pharmacotherapy aims to reduce pain and signs of inflammation by prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) and immunosuppressive drugs. The latter modulate the background dysregulation of the immunological system, leading to clinical improvement. The use of various conventional synthetic, biological (bDMARDs) and targeted synthetic disease-modifying anti-rheumatic drugs is emphasized due to their high efficiency and reducing costs as so-called biosimilar medications are becoming increasingly affordable [11–13]. Additionally, the importance of exercise and appropriate physical therapy is highlighted as a complementary form of treatment [14]. Tailored exercise programmes were proven to alleviate symptoms, enhance global functioning and improve the disease course in previous studies [15–18].

Address for correspondence Agnieszka Alicja Kowalczyk, Department of Rheumatology, Immunology and Internal Medicine, University Hospital, 2 Macieja Jakubowskiego St., 30-688 Krakow, Poland, e-mail: kasjana.lis@gmail.com Received: 10.04.2025; Accepted: 22.10.2025; Published online: 10.06.2026

Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)

Ambiguities in the effect of physical activity on bone remodelling in spondyloarthritis

Despite the suspected involvement of biomechani cal stress in the pathophysiology of SpA, the underlying mechanisms and clinical implications of physical exercise on bone remodelling remain largely unidentified. Therefore, investigating and consolidating existing knowledge on the relationship between physical activity and bone remodelling in patients with SpA is of considerable clinical significance. Furthermore, given that SpA, particularly axSpA, predominantly affects younger individuals, the potential impact of mechanical stress, particularly from manual labour, may exacerbate the course of the disease [19–21]. To our knowledge, no comprehensive review addressing these factors has been published. This makes such an endeavour particularly relevant, espe cially in light of management approaches recommended in current clinical guidelines. Thus, the aim of this narrative review was to determine the impact of physical activity on bone remodelling and bone density in patients with SpA.

Lessons learnt from basic sciences It is hypothesized that cascades of maladaptive bonerelated processes, most prominent in entheses, are triggered by biomechanical factors. McGonagle et al. [22] proposed a model of enthesitis-based pathogenesis for SpA over 20 years ago. It underlined a possible association of repetitive compressive and shear forces occurring in entheses, in close relationship to bone and tendon, with microtrauma and activation of proinflammatory genes and healing responses. The authors emphasized that the sites of internal organ involvement in ankylosing spondylitis (AS), the radiographic subtype of axSpA (r-axSpA), e.g. the aortic root, the lung apex, the ciliary body in the eye and skin extensor surfaces are places of repetitive biomechanical forces [22]. Since that discovery, researchers have been examin ing the correlation between mechanical stress and SpA with regard to its potential role in the pathogenesis of the disease and its impact on disease-associated factors, including disease activity, physical functionality, pain and radiographic damage [15–17, 23]. The outcomes so far are diverse, and the impact of mechanical stress on immune system interactions and bone remodelling seems to have both positive and negative effects simultaneously [24]. Jacques et al. [5] performed an important basic science study concerning whether mechanical stress triggers inflammation and new bone formation in SpA. By molecular modification of tumour necrosis factor (TNF) production, mouse models of SpA-like arthritis were obtained. Histopathological examination of tissue speci mens resulted in a conclusion that early signs of inflammation were present at entheses, eventually spreading

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out into the synovium. Moreover, it was found that a lack of mechanical stress prevented the development of signs of inflammation, measured both clinically and histopathologically. In 2008, McGonagle et al. [25] confirmed a physio logical reaction to repetitive biomechanical stress by discovering the formation of small spurs in healthy individuals in microanatomic studies of cadaveric entheses. In this study of SpA patients with enthesitis using ultrasound (US), McGonagle et al. [25] proved that bone erosions and osteoproliferation are distinct anatomically and temporally. He noted that erosions and new bone formation are linked to biomechanics since erosions occurred in areas of compression, while spur formation took place in regions where tensile forces are likely to be greater. In a 2014 animal study, Jacques et al. [5] proved that mechanical load is necessary for disease onset and correlates with arthritis and new bone progression. In tail-suspended TNF delta AU-rich element (TNFΔARE) mice (with chronic and deregulated TNF production), clinical signs of arthritis in the hind paws were not observed on clinical examination, and inflammatory changes on histological examination were minor. In collagen antibody-induced arthritis tail-suspended mice, osteophytes were markedly smaller on radiological and histopathological evaluation. The author corroborated the role of stromal cells in the initiation of enthesitis. In mature T-cell-deficient mouse models [recombination activating gene 1 (RAG-1) deficient TNFΔARE], the incidence of enthesitis was similar to that in the control group, which indicates that both T-cell-dependant and -independent mechanisms lead to enthesitis [5].

Conclusions drawn from clinical research The evaluation of SpA imaging measures supports the hypothesis of biomechanics-related osteoprolife ration in SpA. Tan et al. [19] analysed the spatial distribution of spine syndesmophytes in r-axSpA. He found that syndesmophytes occur and first develop along the vertebral rim, a place exposed to mechanical forces. Therefore, this particular occurrence suggests a possible role of biomechanics in the development of syndesmophytes in axSpA. Moreover, Tan et al. [26] observed syndesmophytes, which were less common and smaller and were located at the thoracolumbar vertebral rim near the aorta. This observation added further evidence that not only inflammation but also biomechanical forces extrinsic to the spine play a role in new bone formation in axSpA. A key topic in many studies is the presence of bone marrow oedema (BME) in sacroiliac joints (SIJ) on magnetic resonance imaging (MRI). The bone marrow

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oedema is hallmark of axSpA, but it may also be pre sent in healthy individuals such as postpartum women, athletes and others [27, 28]. The bone marrow oedema is often present in SIJ exposed to high biomechanical forces found in postpartum women, patients with disc herniation, athletes (runners, hockey players), military recruits and professionals, which suggests an impact of mechanical stress [27, 28]. Although in the study by Varkas et al. [29], no differences were observed in SIJ MRI findings in military recruits after 6 weeks of intense physical training, it is noteworthy that a high prevalence of MRI lesions (40.9%) was already present in this population before the training began. In studies investigating the correlation between the presence of syndesmophytes in patients with r-axSpA, associations were found with disease duration, patient age, and elevated levels of osteocalcin (a marker of osteoproliferation), whereas no association was observed with disease activity or low BMD [30, 31]. Obesity has been associated with higher disease activity and with axial and peripheral osteoproliferation and entheseal inflammation, as reported by Maas et al. [32] and Bakirci et al. [33]. Although involved in immunological reactions [34], obesity increases biomechanical forces in axial and peripheral joints.

Bone density in spondyloarthropathies Low BMD is already present in 47% of patients with early SpA (with a median disease duration of 6 years), including osteoporosis in 9–18% [7, 9]. It is associated with male sex, in contrast to the healthy population, as well as with high disease activity and decreased functional performance [7, 31]. However, in PsA, osteopenia and osteoporosis appear to occur with a prevalence similar to that of the general population [9]. Current studies underline the role of proinflammatory cytokines in bone resorption and the pathogenesis of low bone mass in SpA [35]. Studies on bone turnover markers indicate that the level of N-terminal telopeptide – a marker of bone resorption – in patients with r-axSpA is associated with disease activity, C-reactive protein levels, low BMD, and the occurrence of fractures, while it is not associated with the presence of syndesmophytes [30]. Inflammatory cytokines elevated in SpA, such as TNF and interleukin-17, impact bone remodelling. Under physiological conditions, inflammation, bone resorption, and formation are essential for tissue healing. In pathological conditions, however, these processes contribute to low BMD, osteoporosis, syndesmophyte formation, and ankylosis. Several osteoimmunological pathways play a role in r-axSpA, including bone morphogenetic proteins (BMPs), the Wnt signalling pathway, and Hedgehog signalling (Hh) [36]. A fundamental pathway in bone

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metabolism is Wnt. In the presence of inflammation, TNF promotes the expression of Dickkopf-1 (DKK1) and sclerostin (Wnt inhibitors), inhibits osteoblast differentiation, and enhances bone resorption by increasing the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio [36]. Physical activity acts in the opposite manner: it reduces the expression of DKK1, sclerostin, and RANKL; increases the expression of OPG; and overall promotes osteoblast proliferation and activity while inhibiting osteoclast differentiation and activation [37, 38]. Molecular mechanisms of the effect of physical activity on bone metabolism are shown in Figure 1. Tumour necrosis factor blockers in r-axSpA lower DKK1 and BMP 7 levels [39], decrease expression of Indian Hh [40], and increase the OPG/sRANKL ratio [41]. Several meta-analyses have demonstrated that anti-TNF agents improve BMD [42, 43]. The effect of antiresorptive drugs on bone metabo lism in r-axSpA remains insufficiently explored. To date, no double-blind randomized clinical trial evaluating the impact of bisphosphonates or RANKL inhibitors on BMD in SpA patients has been conducted. In a meta-analysis comparing outcomes of r-axSpA patients treated with and without bisphosphonates, published between January 2000 and March 2020, only 6 comparative studies were identified [44]. According to this meta-analysis, bisphosphonates do not improve lumbar or femoral BMD or disease activity in r-axSpA; however, limitations such as small sample sizes and short follow-up durations should be taken into consideration [44]. In spondyloarthritis, bone loss is driven by inflammation, which promotes increased osteoclastogenesis through both RANKL-dependent and -independent pathways, while simultaneously limiting osteoblast formation [45]. Thus, antiresorptive therapies, such as bis phosphonates and RANKL inhibitors, may be expected to improve bone mass in patients with low BMD and active inflammation. Studies investigating the effects of denosumab in SpA are scarce. A South Korean pilot study demonstrated the efficacy of denosumab in improving lumbar and total hip BMD, without affecting disease activity or spinal new bone formation [46]. One case series reported an increase in BMD, measured by quantitative computed tomography, after 1 and 2 years of denosumab treatment [47]. Large, long-term randomised clinical trials evaluating the effect of denosumab in SpA are required. Consi derably more data are available regarding the efficacy of denosumab in rheumatoid arthritis: a meta-analysis of 6 randomised controlled trials showed that denosu mab improves BMD and prevents joint erosions in patients with osteoporosis and rheumatoid arthritis [48].

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Ambiguities in the effect of physical activity on bone remodelling in spondyloarthritis

DKK1

SCLEROSTIN

LRP5/6/Wnt/β-catenin Stimulation Inhibition Total impact of physical activity

Physical activity OPG

RANKL

Osteoblast

Osteoclast

Fig. 1. Molecular mechanisms underlying the effects of physical activity on bone metabolism [37, 38]. DKK1 – Dickkopf-1, LRP5/6 – low-density lipoprotein receptor-related protein 5 and 6, OPG – osteoprotegerin, RANKL – receptor activator of nuclear factor k-B ligand, Wnt/β-catenin – Wnt/β-catenin signalling pathway.

Numerous clinical studies have shown that physical activity increases peak bone mass and reduces the risk of osteoporosis; therefore, it is recommended for both its treatment and prevention in the general population [49]. Given the inflammatory nature of osteoporosis in SpA, it is important to further explore the effects of physical activity on both disease activity and bone density in this population.

Methods This narrative review article was conducted in accordance with methodology provided by expert guideline articles, including a manuscript by Gasparyan et al. [50]. Also, to improve the quality of the obtained results, the validity of the methodology and possible reproducibility of this study, the article selection process followed the PRISMA 2020 statement. The PubMed, Scopus, Directory of Open Access Journals, and Web of Science bibliographic databases were searched. Search terms included Medical Subject Headings terminology and additional concepts to obtain the maximum number of results. Specific search queries used in the process are provided in the appendix. The initial data extraction, including article titles and authors’ names, was performed on 20 May 2024. The initial search was repeated in October 2024 and shortly before submission of this arti cle (May 2025), to provide the most up-to-date information regarding the examined phenomena. The articles were then screened by 2 authors (AK, MW), according to

the provided literature selection flowchart. The search strategy is presented in Figure 2. The following inclusion criteria were applied: • studies conducted on adult patients (over 18 years of age); • participants meeting the appropriate classification criteria, relevant to the aim of the study (the 1984 New York criteria for the r-axSpA (AS), the 2010 ASAS criteria for the non-radiographic form of SpA and the 2006 CASPAR criteria for PsA) [51–53]; • studies comparing the assessed indicators (imaging studies or bone density assessment) in populations with high or low physical activity (recreational or occu pational); • randomized controlled trials (RCTs), non-RCTs, rando mized uncontrolled trials, or uncontrolled studies (e.g. before vs. after trials), cross-sectional studies, observational studies, including prospective and retrospective studies; • studies in the English language; • full-text manuscript available. Studies were excluded if: • the study scope was outside the aim of the current analysis (e.g. physical activity was not assessed, or the study focused on the impact of physical activity solely on indicators other than imaging or bone density, such as range of motion, functionality, disease activity, qua lity of life, etc.); • the diagnostic criteria and selection of patients were inadequate;

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Query for advanced search in PubMed (“Axial Spondyloarthritis” [MeSH Terms] OR spondyl* [tw]) AND (“Exercise” [MeSH Terms] OR lifestyle [tw] OR job [tw] OR “employment” [MeSH Terms]) AND (“Osteogenesis” [MeSH Terms] OR “Diagnostic Imaging” [MeSH Terms] OR radio* [tw] AND English [la]) Query for advanced search in SCOPUS TITLE-ABS-KEY (“spondylarthritis” or “spondyloarthritis” or “ankylosing”) AND TITLE-ABS-KEY (“exercise” OR “lifestyle” OR “employment” OR “job”) AND TITLE-ABSKEY (“osteogenesis” OR radio*) AND (LIMIT-TO (LANGUAGE, “English”)) Query for advanced search in DOAJ and Web of Science (spondylarthritis OR spondyloarthritis OR ankylosing OR spondyl*) AND (exercise OR lifestyle OR job OR employment) AND (osteogenesis OR “diagnostic imaging” OR radio*)

Fig. 2. Search strategy. DOAJ – Directory of Open Access Journals, MeSH – Medical Subject Headings.

• the risk of biased results, due to methodological issues, was considerable, as assessed by 2 authors (AK, MW); • the full-text manuscript was unavailable or was in a language other than English. Also, other review articles (systematic analyses, meta-analyses), case studies, study protocols, congress abstracts, editorials and letters to the editor were not included in the current analysis. No restrictions were applied regarding the date of publication. If uncertainty arose considering the inclusion of a specific article, it was further discussed among all authors, leading to a mutual decision. After completing the search on the impact of physical activity on radiological progression in patients with SpA, 2 researchers selected articles in the following stages: removal of duplicates, review of titles and abstracts, review of full texts and review of the references and citations of selected articles. We also included additional papers recommended by all co‑authors, deemed significant for the context of this review. The final reference list was compiled based on their relevance to the key concepts the authors intended to emphasize in the manuscript. The article selection process is presented in Figure 3. From the included articles, the following data were systematically extracted: study population (type of SpA, disease duration, use of biologic treatment), study type, type of physical activity (physical work, exercises) and results of radiological studies.

Results The initial and additional database searches found 869 articles: 179 articles in PubMed, 287 in Scopus, 403 articles in Web of Science, and no article was identified in Directory of Open Access Journals. After remov-

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ing duplicates, 778 articles remained. Title and abstract screening left 34 articles that qualified for full-text ana lysis. After full text analysis, 6 eligible articles remained. The search was further expanded by citation screening and reference screening, and no more articles were included in the final analysis. Despite searching 4 major bibliographic databases, using liberal search criteria, and having the searches conducted by 2 team members, to the authors’ best knowledge, at the time of the additional search (May 2025), no studies assessing the impact of physical activity on bone density in patients with SpA were conducted. The following research concerned the impact of physical activity on bone remodelling in axSpA patients: after searching 4 databases, using liberal search criteria, and searches being conducted by 2 team members, only 6 articles met the inclusion criteria and were analysed.

Characteristics of included studies The analysed populations varied significantly. Three studies included patients with PsA, including one with axial PsA, while the remaining three involved patients with r-axSpA. The characteristics of the patients also differed significantly. Three studies focused on early SpA (2 on PsA and 1 on r-axSpA), with a median disease duration of 3–6 years [54–56], whereas three other studies examined longstanding SpA (2 on r-axSpA and 1 on PsA), with a mean disease duration ranging from 11 to 32 years [19–21]. Notably, the proportion of patients treated with bDMARDs differed across studies. In 1 study, none of the patients received bDMARD treatment at baseline, whereas in the others, this percentage ranged from 27% to 48%. Among the analysed studies, only 1 provided information about steroid therapy; moreover,

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Included

Screening

Identification

Identification of studies via databases

Identification of studies via other methods

Records identified from PubMed database (n = 179) Scopus database (n = 287) DOAJ database (n = 0) Web of Science database (n = 403)

Records removed before screening: Duplicate records removed (n = 91)

Records screened (n = 778)

Records excluded (n = 744)

Reports sought for retrieval (n = 34)

Reports not retrieved (n = 3)

Reports sought for retrieval (n = 11)

Reports not retrieved (n = 0)

Reports assessed for eligibility (n = 31)

Reports excluded: did not concern spondyloarthritis (n = 2) did not concern physical activity (n = 11) did not investigate the correlation between physical activity and bone remodelling (n = 12)

Reports assessed for eligibility (n = 11)

Reports excluded: animal study (n = 1) review (n = 1) not concerning physical activity (n = 5) not concerning bone remodelling (n = 3) consensus statement (n = 1)

Records identified from citation searching (n = 11)

Studies included in the review (n = 6)

Fig. 3. Article selection process according to the PRISMA 2020 flow diagram. DOAJ – Directory of Open Access Journals.

not all of them reported on the use of NSAIDs or synthetic DMARDs. In the study by Ward [19], glucocorticosteroids were used in only 7% of patients [57–59]. Two of the included studies were randomized controlled trials exploring the impact of high-intensity interval training (HIIT) on numerous outcomes, including radiographic structural damage, among PsA patients. Thomsen et al. [56] assessed the impact of 11 weeks of HIIT on imaging of the spine, peripheral joints and entheses in MRI (axial) and US (peripheral) compared to the control group. The analysed cohort comprised early PsA patients, and 31% of them were treated with bDMARDs. Similarly, Chronaiou et al. [55] analysed the impact of 11 weeks of HIIT on MRI of the spine in early axial PsA patients compared to the control group. In both studies, early inflammatory changes of the spine were scored using the Spondylarthritis Research Consortium of Canada (SPARCC) BME score, and inflammation of peripheral joints and entheses was assessed using semiquantitative gradation of brightness mode and Power Doppler images from 0 to 3. In the study by Chronaiou et al. [55], the images were scored by 1 reader in radiological evaluation for BME using the Assessment in SpondyloArthritis International Society criteria, by another reader in SPARCC score and by extraction of textural features. Slouma et al. [54] investigated a correlation between levels of physical activity measured by 2 scales, the Uni-

versity of California and Los Angeles activity scale and the Tegner activity scale, supplemented with information regarding the weekly duration of exercise and phy sical activity, and disease progression as assessed by US imaging of 14 predefined entheses in patients with early r-axSpA. Ultrasound imaging was scored using the Spanish Enthesitis Index, Glasgow Ultrasound Enthesitis Scoring System and Madrid Sonographic Enthesitis Index. The remaining 3 studies analysed the association between professional work and radiographic structural damage. Participants were categorized by their occupational activity into 2 groups: blue-collar workers with physically demanding jobs and white-collar workers with physically undemanding jobs. The rationale for this approach is that physically demanding jobs are presumably associated with more mechanical stress to the spine than sedentary ones. In a study by Ramiro et al. [21], the job type was determined by consensus, and Zhou et al. [20] and Ward et al. [19] used the Occupatio nal Information Network (job classification database) to determine specific attributes of jobs (such as workers’ abilities, measures of work context, etc.) and found associations between particular activities and radiographic progression. The included studies involved participants with longstanding r-axSpA [19, 21] and PsA [20]. Radiograms were taken every 2 years in the Ramiro et al. [21]

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Table I. Characteristics of included studies Author, year, country, reference

Disorder

Study design

Study population

Disease duration (years)

bDMARDs

csDMARDs

GCs

NSAIDs

Thomsen et al. 2023, Norway [56]*

PsA

RCT

3–5.5 (median)

31%

85%

No data

Chronaiou et al. 2022, Norway [55, 57]*

axPsA

RCT

4–6 (median)

33%

87%

No data

Ramiro et al. 2015, Netherlands/Belgium/ France [21, 58]

r-axSpA

Crosssectional

184

11 (mean)

0% at year 0, 29% at year 12

No data

68%

Zhou et al. 2019, Canada [20]

PsA

Crosssectional

307

21 (mean)

48% (ever)

76% (ever)

No data

92% (ever)

Ward et al. 2008, USA [19, 59]

r-axSpA

Crosssectional

397

31.9 (mean)

27%

24%

83%

Slouma et al. 2024, Tunisia [54]

r-axSpA

Crosssectional

5.3 (median)

27%

No data

92% (32% continuous)

*Thomsen’s and Chronaiou’s studies are based on a common cohort of patients recruited from St. Olavs Hospital and Norwegian University of Science and Technology, Trondheim, Norway, between 2013 and 2015. axPsA – axial psoriatic arthritis, bDMARDs – biological disease-modifying anti-rheumatic drugs, csDMARDs – conventional synthetic diseasemodifying anti-rheumatic drugs, GCs – glucocorticosteroids, NSAIDs – nonsteroidal anti-inflammatory drugs, PsA – psoriatic arthritis, r-axSpA – radiographic axial spondyloarthritis, RCT – randomized controlled trial.

and Zhou et al. [20] studies and once in the study by Ward et al. [19] Cervical and lumbar spine X-rays were scored using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) [21, 20] or the Bath Ankylosing Spondylitis Radiology Index for the spine (BASRI-s) [19]. Peripheral joint radiograms were scored using the modi fied Steinbrocker score [20]. Of concern, in the study by Ward et al. [19], the images were scored by only 1 reader. Both scoring systems, mSASSS and BASRI-s, rate the degree of structural damage (including erosions, sclerosis or fusion) in the cervical and lumbar spine. The Bath Ankylosing Spondylitis Radiology Index for the spine additionally rates damage to SIJ. Detailed characteristics of the included studies are presented in Table I.

Outcomes of the analysed studies Detailed information about the results of the ana lysed studies is presented in Table II. Briefly, in a study by Thomsen et al. [56], the authors concluded that there is no significant influence of HIIT on the severity of inflammation in the peripheral joints, entheses, SIJ and spine assessed by US and MRI. In an analysis by Chronaiou et al. [55], the number of participants with BME changes on radiological evaluation, in SPARCC scores or in textural features did not differ significantly between the 11-week HIIT group and the control group. Slouma et al. [54] found no significant differences in US image of entheses in patients with r-axSpA between individuals practising and not practising exercise. More-

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over, in the multivariate analysis, they found a lower occurrence of 3 or more enthesophytes in patients who exercised. Ramiro et al. [21] concluded that patients with high mSASSS are mainly men, blue-collar workers and smokers. They suggested that blue-collar jobs amplified the effect of disease activity on radiographic damage in comparison with white-collar jobs. Zhou et al. [20], analysing 307 patients with longstanding PsA, found a direct association between damage to the peripheral joints and prolonged repetitive hand movements and a high level of finger dexterity. No correlation was found between mSASSS and occupation-related mechanical factors. Ward et al. [19] found that occupational activities, such as bending, twisting, reaching and stretching, and exposure to whole-body vibration are associated with greater radiographic damage in axial joints.

Discussion The authors of the analysed studies reached different conclusions concerning the impact of physical activity on the clinical progression of SpA. Researchers assessing the role of HIIT found no significant changes in inflammation of the spine, peripheral joints and enthesis on MRI and US [54–56]. However, concerning these results, a few methodological issues appear. The relatively short follow-up period of 11 weeks might not be sufficient to reveal an impact on bone, joint and entheses structures. The remodelling processes are time consuming; thus,

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Ambiguities in the effect of physical activity on bone remodelling in spondyloarthritis

Table II. Results of analysed studies Author, year, country, reference

Physical activity type

Intervals of measurements

Instruments used

Scales

Thomsen et al. 2023, Norway [56]

Intervention group: HIIT for 11 weeks; control group: not to change their physical exercise habits

At baseline and at 3-month follow-up

MRI of the SIJ and the spine (C, Th, L), US of the peripheral joints and entheses (mandatory: 34 joints, 10 entheses and additional swollen or tender)

SPARCC-BME score of the SIJ and spine; B-mode and PD signals in joints and entheses were semi-quantitatively graded 0–3

Conclusions No evidence of an increased risk of inflammation. Chronaiou et al. 2022, Norway [55]

Intervention group: HIIT for 11 weeks; control group: not to change their physical exercise habits

At baseline and at 3-month follow-up

MRI of the spine (C, Th, L)

SPARCC

2-year intervals

X-rays of the spine (C, L)

mSASSS

Conclusions No significant changes Ramiro et al. 2015, Netherlands/Belgium/ France [21]

Job type

Zhou et al. 2019, Canada [20]

Job type

Conclusions Physically demanding jobs may amplify the potentiating effects of inflammation on bone formation in AS 2-year intervals

X-rays of the spine (C, L) and peripheral joints (hands and feet)

mSS and mSASSS

Conclusions Repetitive hand movements and finger dexterity were independently associated with peripheral radiographic damage. None of the occupational exposures were significantly associated with axial damage Ward et al. 2008, USA [19]

Job type

One time

X-rays of the spine and the pelvic

BASRI-s

Conclusions Those whose past jobs required more dynamic flexibility (the ability to repeatedly bend, stretch, twist, or reach), extensive flexibility and exposure to whole body vibration had significantly higher BASRI-s scores Slouma et al. 2024, Tunisia [54]

UCLA activity scale, Tegner activity scale, patient’s estimated duration of exercise and of physical activity weekly

One time

Ultrasound of 14 entheses in each patient

SEI, GUESS, MASEI, presence of enthesophyte, hypoechogenicity, calcification, or bony erosion

Conclusions Lack of a significant difference in enthesis ultrasound characteristics between patients practising or not practising exercise. Patients performing exercise had a lower risk of having ≥ 3 ultrasonographic enthesophytes. BASRI-s – Bath AS Radiology Index for the spine, BME – bone marrow oedema, GUESS – Glasgow Ultrasound Enthesitis Scoring System, HIIT – high-intensity interval training, MASEI – Madrid Sonographic Enthesitis Index, MRI – magnetic resonance imaging, mSASSS – modified Stokes Ankylosing Spondylitis Spine Score, mSS – modified Steinbrocker score, SIJ – sacroiliac joints, SPARCC – Spondyloarthritis Research Consortium of Canada, SEI – Spanish Enthesitis Index, UCLA – University of California and Los Angeles.

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a longer follow-up study could improve the validity of the obtained results. On the other hand, the authors of studies exploring the influence of occupational activity type demonstrated an association between job type and radiographic structural damage. However, these cross-sectional studies can only draw conclusions about possible correlations, not potential causality. Many questions remain unanswered, and thus highquality, prospective interventional studies are necessary. However, developing such studies poses several challenges. Spondyloarthritis is a heterogeneous condition, and different stages of the disease may impact bone remodelling in various ways, making it difficult to standardize the study population. Moreover, the various forms of spondyloarthropathies differ from one another in their bone metabolism. Despite some common pathophysiological mechanisms, in contrast to r-axSpA, in PsA osteoporosis does not seem to be a significant comorbidity [9]. Bone remodelling in SpA involves both new bone formation (e.g. syndesmophyte growth, juxtaarticular bone formation, ankylosis) and bone loss (e.g. osteoporosis, erosions), and physical activity may affect these processes differently, complicating the measurement of clear outcomes related to bone tissue [6, 7, 36]. The type, intensity and duration of physical activity can vary significantly between individuals, making it challenging to design a regimen that is both feasible for enrolled participants and possible to capture in imaging measurements. Furthermore, factors such as medication use (e.g. DMARDs, NSAIDs, glucocorticosteroids, antiresorptive drugs), diet and vitamin D levels also affect bone health in SpA, making it difficult to isolate the impact of phy sical activity alone. Furthermore, some studies suggest that vitamin D supplementation may improve disease activity and, in doing so, influence bone metabolism by reducing inflammation [60, 61]. It may take months or even years to capture a least significant change in bone remodelling, especially in axSpA, necessitating longterm follow-up, which increases study cost, complexity and the risk of participant dropout [62]. Measuring bone remodelling accurately is another challenge. Imaging methods such as MRI or dual-energy X-ray absorptiometry (DXA) may not detect early or subtle changes in bone tissue, and biomarkers of bone turnover can be variable and influenced by several irrelevant factors [63]. Although DXA is the gold-standard method for fracture risk assessment, the presence of syndesmophytes may lead to false-negative results, making it unsuitable for axSpA patients. Nevertheless, there is currently no other widely available and recommended alternative [64]. Additionally, ethical considerations may arise in designing studies that prescribe or limit physical activity,

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particularly for patients with more severe forms of SpA. Recruiting participants who are willing and able to adhere to a specific physical activity protocol can also be challenging [65]. Moreover, the assessment of physical activity may be imprecise, particularly as patients tend to overestimate the duration of their physical activity [66]. The current narrative review article has several strengths. It addresses a clinically relevant topic with potential implications for clinical practice. Currently, clinicians managing patients with axSpA complicated by osteoporosis adhere to osteoporosis treatment guidelines developed for the general population. In the context of increasing availability and more widespread use of biologic therapy – known to have a positive effect on bone mass – there is a clear need for studies evaluating the effectiveness of antiresorptive agents, DMARDs, and combined therapeutic approaches. In our research an extensive search process, including citation and reference screening of 4 major bibliographic databases, covered relevant studies. A rigorous metho dological approach also enhanced the validity of the findings. However, the study also has a few limitations. Despite the thorough search process, only a few articles were ultimately included. There is also a risk of subjective author bias. Furthermore, due to the nature of the studies and the limited number of suitable articles, it was not possible to perform a quantitative synthesis. In conclusion, the impact of physical activity on bone remodelling in SpA warrants greater attention due to its important clinical implications, which could contribute to overall patient health. However, it is important to re cognize that significant knowledge gaps remain, and further high-quality, prospective research is crucial to address these gaps and deepen our understanding of this complex relationship.

Acknowledgment The article has been proofread by Proof Reading Service.

Ambiguities in the effect of physical activity on bone remodelling in spondyloarthritis

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Reumatologia 2026; 64/3

Review paper

Reumatologia 2026; 64, 3: 230–241 DOI: https://doi.org/10.5114/reum/217810

Ocular complications in psoriasis and psoriatic arthritis Raman Nitskovich1,* ID , Anna Suchecka1,* ID , Maria Maślińska2 ID , Dorota Kopacz3 ID , Weronika Herniczek4 ID , Irena Walecka1 ID 1

Clinical Department of Dermatology, National Medical Institute of the Ministry of the Interior and Administration, Warsaw, Poland Early Arthritis Clinic, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland 3 Department of Ophthalmology, Warsaw Medical University, Poland 4 Department of Psychiatry, Combat Stress and Psychotraumatology, Military Institute of Medicine, Warsaw, Poland 2

*These authors had equal contribution to this work.

Abstract Ophthalmologic symptoms are reported in 10–67% of psoriasis (Ps) cases and affect up to 31% of patients with psoriatic arthritis (PsA). The most common include blepharitis, eyelid involvement, uveitis, dry eye syndrome, conjunctivitis, corneal changes, and cataract. Despite the relatively common eye involvement, these symptoms are often overlooked or inadequately managed. Therefore, dermatologists and rheumatologists should interview patients for eye-related complaints to effectively identify and treat patients with ocular manifestations. In some cases, direct collaboration with ophthalmologists is also necessary for comprehensive patient management. The purpose of this intradisciplinary review is to discuss the most common eye symptoms among Ps and PsA patients, which should be considered as a basis for formulating guidelines for Ps treatment by dermatologists, ophthalmologists, rheumatologists, general practitioners and other specialists. In addition, we propose a simple diagnostic and therapeutic algorithm to facilitate the management of patients with Ps and accompanying symptoms of uveitis. Key words: psoriasis, psoriatic arthritis, dry eye syndrome, uveitis, conjunctivitis.

Introduction Psoriasis (Ps) is a chronic, systemic inflammatory disease affecting 0.09–11.4% of the population according to the “Global report on psoriasis” presented in 2016 by the World Health Organization (WHO). The most common type (up to 80% of all cases) of this disease is plaque Ps; erythrodermic, pustular, flexural, guttate, and follicular types occur much less frequently [1, 2]. The etiology of the disease is not fully understood. Genetic, environmental, and immunological factors play a substantial role in its pathogenesis. Hypotheses suggest that the disease is triggered in genetically predisposed patients by environmental factors, such as bacterial, viral, and fungal infections, as well as alcohol, tobacco, stress, certain medications, and injuries [1, 3–9]. Genetic factors make the disease occur in a hereditary manner in about 30% of the cases. The mode of inheritance seems to be multifactorial and polygenic [10–13]. The genetic studies

identified fifteen Ps-susceptibility regions, known as PSORS1–15 [6, 13]. Psoriasis has been found to be associated with human leukocyte antigen class I (HLA), including HLA-B13, HLA-B17, HLA-B57, and HLA-Cw6. Interestingly, HLA-Cw6 is associated with more severe skin changes, but less with psoriatic arthritis (PsA) development [6, 13–15]. Genetic studies have shown that the HLA-Cw2 and HLACw6 alleles appear to increase PsA susceptibility, while HLA-Cw4 may have a protective effect [16]. The association of HLA-B27 antigen and uveitis is well documented, and its presence may predict development of arthritis, sacroiliitis, and uveitis in Ps patients [1, 13, 17].

Outline of immunological system dysfunctions in psoriasis The basic pathological mechanism responsible for the development of Ps is a dysfunction in the Th lymphocyte system, which leads to uncontrolled secretion

Address for correspondence Anna Suchecka, Clinical Department of Dermatology, National Medical Institute of the Ministry of the Interior and Administration, 137 Wołoska St., 02-507 Warsaw, Poland, e-mail: suchecka.anna@icloud.com Submitted: 14.07.2025; Accepted: 05.02.2026; Published online: 23.04.2026

Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)

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of inflammatory cytokines, including tumor necrosis factor (TNF) and interleukins (IL) – IL-17 and IL-22 [1, 3, 14, 15, 17–20]. However, dendritic cells also play a major role in the initial stages of the disease as antigen-presenting cells. Their activation and production of interferons (IFN) α and β, as well as the activation of type I IFN signaling, promote Th1 and Th17 differentiation and activity including IFN-γ and IL-17 production. Th17 cells produce IL-17, IL-21, and IL-22, which activate keratinocyte proliferation [15, 21–23]. The proliferation of keratinocytes is stimulated by the inflammatory environment, in particular the activity of TNF, IL-17, and IFN-γ. Keratinocytes themselves are involved in the inflammatory process through the secretion of pro-inflammatory cytokines (IL-1, IL-6, and TNF), chemokines, and antimicrobial peptides (AMPs), such as LL37, β-defensins, and S100 proteins [18]. The TNF–IL-23– Th17 pathway is particularly important in the etiopathogenesis of plaque Ps. In view of the above, currently available biological therapies are directed primarily at inhibiting described pathways (anti-TNF, IL-12/IL-23, IL-17). They also target the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, which are pleiotropic cascades interacting with other signaling pathways as a regulatory mechanism [19, 20, 24, 25].

Clinical picture of psoriasis Psoriasis is a chronic, immune-mediated inflammatory disease that manifests itself in a variable manner, in various morphologies (hyperkeratotic, pustular, or mixed) and in various body localizations [7]. Skin Ps is generally divided into plaque Ps (the most common), guttate Ps (second most common), pustular, erythrodermic (severe form, unstable plaque Ps), and inverse Ps. Depending on the age of onset and clinical features, we also divide Ps into two basic types. Type I develops before age 40 and type II after age 40 [7]. The differences between the two main subtypes of Ps are presented in Table I [1, 17]. Psoriasis is often associated with several diseases such as PsA, obesity (abdominal or central), diabetes

mellitus type 2, and cardiovascular disease. Quite often, symptoms of depression may occur [21, 26]. The prevalence of PsA in the psoriatic group is estimated at up to 30%. Psoriatic arthritis is a heterogeneous disease that may affect either the axial (spine and sacroiliac joints) or peripheral skeleton, and patients often show overlapping domains. Because of this variability, clinical presentation can range from isolated enthesitis or dactylitis to widespread peripheral arthritis or predominant axial involvement, making diagnosis and management challenging. Notably, skin changes usually precede joint involvement, but there is no strict association between the skin disease activity and arthritis [10, 11, 27, 28]. The GRAPPA group (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis) recognizes five key clinical subtypes (domains) of PsA, reflecting the heterogeneous nature of the disease: 1) peripheral arthritis (both asymmetric oligoarthritis and symmetric polyarthritis); 2) axial disease (sacroiliitis and spondylitis); 3) enthesitis; 4) dactylitis; and 5) skin and nail involvement [27]. The GRAPPA domain-based classification directly guides treatment: therapy is chosen according to the dominant clinical domain. Thus, treatment in PsA is personalized and domain-specific rather than uniform across all patients. In the GRAPPA framework, uveitis is considered an important extra-articular domain that significantly influences treatment selection in PsA; the presence of uveitis shifts biologic preference toward monoclonal TNF inhibitors (TNFi), which have the strongest and most consistent evidence for controlling ocular inflammation. This recommendation is consistent with European Alliance of Associations for Rheumatology (EULAR) recommendations for the management of PsA with pharmacological therapies (2023) [27, 28]. In patients with Ps and/or PsA, ophthalmological symptoms may be a symptom of the underlying disease or a coincidence; therefore, an ophthalmological consultation should always be considered to deepen the diagnosis and exclude potential causes (including infectious ones).

Table I. Differences between two psoriasis subtypes distinguished on the basis of disease onset [1, 17] Variable

Type I

Type II

Age of onset

< 40 years old

> 40 years old

Prevalence

75%

25%

Family history

Positive family history

Usually no family history of Ps

Genes presence

HLA-Cw6

HLA-Cw2 and HLA-B27

Weight

Normal weight

Obesity, metabolic disorders

Clinical presentation

More severe skin disease

Plaque Ps and PsA common

Ps – psoriasis, PsA – psoriatic arthritis.

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Table II. Risk factors for eye involvement in psoriasis [17, 32–34, 37]

Risk factors for eye involvement Age > 40 years PASI moderate/severe for keratitis PASI mild for blepharitis HLA-B27 for uveitis Eye dryness for DED Metabolic diseases (especially diabetes mellitus) PsA Treatment with acitretin or possibly MTX DED – dry eye disease, MTX – methotrexate, PASI – Psoriasis Area Severity Index, PsA – psoriatic arthritis.

Eye involvement in psoriasis Eye involvement in Ps is usually discussed in the context of PsA or wider spondyloarthropathies (SpA) and co-occurring uveitis. However, more attention should also be paid to other ocular symptoms emerging in the course of Ps. According to various authors, ocular symptoms occur in 10–67% of patients with PS and in 31% of patients with PsA. More than one eye complication is present in 20% of cases of Ps, with both eyes being affected in 48% of such cases [29–31]. All parts of the eye may become affected in the course of Ps [32, 33]. The most frequently detected ocular pathologies include eyelid involvement, blepharitis, keratoconjunctivitis sicca (dry eye disease [DED]), conjunctivitis, corneal lesions, uveitis, episcleritis, and cataract [3, 14, 17–19, 34–39]. Table II presents the risk factors of eye involvement in Ps. Ocular symptoms appear most often during the disease exacerbation; for this reason, they can be observed first by a rheumatologist or dermatologist rather than an ophthalmologist [17, 23, 40]. There is a statistically significant correlation bet ween the occurrence of ocular symptoms and the seve rity of the disease assessed by the Psoriasis Area Severity Index (PASI) score. Significantly more often these symptoms are observed among patients with PASI > 5, with an average PASI of 17 at the time of diagnosis [33, 34, 37]. Studies have also shown that ocular symptoms are more common among patients with nail involvement, pustular Ps, PsA (particularly polyarticular type), as well as among patients treated with methotrexate (MTX) or acitretin [3, 14, 19, 41, 42]. However, in most studies no correlation between the occurrence of ocular complications and duration of the disease, age, or sex was found. However, it should be emphasized that recurrent inflammation of eye structures causes gradual tissue

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Fig. 1. Eye and facial manifestation of Ps: A) psoriatic changes in the angle of the eye; B) seborrheic form of facial psoriasis with changes on the eyelids and with blepharitis. damage, which leads to scars, visual disturbances, and even loss of vision. It should also be noted that one of the most recent studies has documented the protective effects of biological treatment against corneal changes and Meibomian gland dysfunction in Ps [33]. All patients with Ps and PsA should undergo ophthalmologic consultation annually. Patients with active PsA and active skin Ps with PASI of 10 or above should undergo ophthalmologic consultation biannually.

Eyelid involvement The face and particularly the eyelids are a rare localization of Ps. Facial manifestations of Ps with involvement of the eyelids, nasolabial folds, and perioral area are relatively rare; in these seborrheic areas, sebo-Ps can be expected to emerge more often than Ps vulgaris (Fig. 1) [43]. Such a manifestation is more common among patients with severe disease, protracted disease,

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and those with a family history of Ps. Topical vitamin D analogs and calcineurin inhibitors (tacrolimus, pimecrolimus) can be used in the treatment [12, 44, 45]. Recently, there has been growing evidence that these medications are also effective and safe for the treatment of eyelid inflammation and even result in improvement among patients with corneal changes in the course of Ps [12, 44, 46].

with paraffin before sleep in order to relieve nocturnal symptoms [1, 34]. Immunosuppressive therapy (cyclosporine drops) or eye drops containing the patient’s serum are used in severe cases of eye dryness. Lacrimal punctum occlusion is used in those cases with low lacrimal secretion (Schirmer test less than 5 mm/5 minutes). Relatively new methods of treatment include meibomian gland stimulation and electrostimulation of tear secretion [35].

Blepharitis

Conjunctivitis

Blepharitis is the most common ocular complication of Ps (Fig. 1). It is caused by hyperkeratosis, Meibomian gland dysfunction, and mechanical obstruction of the Meibomian glands or lacrimal duct [3, 32, 34, 37]. Overgrowth of Staphylococcus aureus is also involved in the pathogenesis of blepharitis. The patient may report symptoms of red eye, the sensation of having a foreign body in the ophthalmic region, severe eye burning, or intolerance of contact lenses [23, 37]. During physical examination it is worth paying attention to dandruff occurring mainly at the base of the eyelashes and red, swollen eyelids [1, 34]. The eyelid margins may also be affected by ulceration and crust formation. The most important aspect in the treatment of blepharitis is proper hygiene, which consists of using warm compresses, as well as mechanical washing of the eyelids using specially designed cleaners or baby shampoo [1, 34, 37, 44]. In addition, a weak topical glucocorticosteroid (GC) may be used for a short period. Topical antibiotics are particularly useful for treatment of acute inflammation [37, 38]. Untreated eyelid inflammation may lead to contact lens intolerance, trichiasis, madarosis, cicatricial ectropion, and even visual impairment [1, 37, 39].

The incidence of conjunctivitis among patients with Ps is 10–13%, which is well above corresponding figures for the general population [3, 17, 19, 23]. A large percentage of patients with Ps presents in a conjunctival cytology examination a squamous metaplasia at mild or moderate stage [33]. Conjunctivitis can coexist with or can be caused by DED and eyelid inflammation [36, 47]. It manifests with pain, foreign body sensation under the eyelids, tearing, burning, and conjunctival injection [29–31, 37]. Mucopurulent discharge occurs in a bacterial infection, whereas bilateral watery discharge together with swollen preauricular lymph nodes indicates viral etiology. For a presumed bacterial etiology, artificial tears and antibiotics are recommended.

Dry eye disease According to the latest research, DED affects 20 to 37% of patients with Ps and is significantly more common in Ps than among the healthy population [14, 17, 19, 39]. This syndrome is most likely the result of a disorder in the production of the tear aqueous component and tear film instability, as confirmed in studies using Schirmer’s test (without anesthesia and with anesthesia) and the tear break-up time (TBUT) test. Symptoms of DED include dryness, foreign body sensation, burning increasing during daytime, red eyes, and flakes on eyelids [29, 31, 34]. Artificial tears (drops or gel) are commonly used for the treatment (preferably medications without preservatives). It is also necessary to use ophthalmic ointments

Corneal involvement Corneal problems are found in 4–16% of cases, more often among patients with PsA and are usually secondary to DED, conjunctivitis, or blepharitis. This indicates the importance of treatment of these symptoms for the prevention of corneal involvement [29, 41]. Histological changes such as parakeratosis, inflammatory cell infiltrates, and angiogenesis are similar to psoriatic lesions on the skin or in joints, which suggests the involvement of common primary mechanisms [1, 44]. The most common corneal pathologies include punctuate epithelial keratitis, opacities, erosions, neovascularization, and scarring. Significant pain, photophobia, and blurred vision indicate corneal pathology, which requires urgent ophthalmologic consultation. In the Lee et al. [41] study, there was an increased risk of keratopathy in Ps patients even without preexisting prominent corneal disease. The authors concluded that this risk increases with exposure to Ps [41].

Uveitis Uveitis is a serious complication occurring among 0.7–2.6% of patients with Ps and 7–9% of patients with PsA [43, 44, 48]. Studies have confirmed elevated levels of TNF, IL-2, IL-6, and IL-17 not only in patients with Ps but also in the aqueous humor of patients with uveitis,

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suggesting common pathogenetic pathways for these diseases [49]. In patients with Ps, uveitis most often affects the anterior part of the eye (anterior uveitis) and is characterized by a more chronic course, recurrence, tendency to occur bilaterally, and a more frequent need for non-steroidal anti-inflammatory drugs. A correlation has been identified between the severity of Ps and prevalence of uveitis. Moreover, positive HLA-B27 in patients with Ps predisposes to uveitis and its more severe course [42, 50, 51]. Uveitis is one of the most common extra-articular manifestations of the disease in PsA patients [46]. Recent studies report a bidirectional relationship between PsA and uveitis. This means that patients with coexisting Ps and PsA develop uveitis more often, whereas patients with Ps and uveitis have a higher risk of developing PsA. These three diseases usually appear in the following order: Ps, uveitis, and PsA, which makes uveitis a possible harbinger of PsA [12, 46, 52]. This is most likely due to a common genetic basis, as HLA-B27 is present in 50% of uveitis cases. The presence of uveitis and HLA-B27 is also commonly observed among patients with PsA, where it is related to the axial form of the disease and worse prognosis. In addition, in PsA, uveitis may be more insidious in the early stages [1, 46, 53–55]. The occurrence of HLA-B27 was included in the new Dublin Uveitis Evaluation Tool (DUET) algorithm as one of the features determining the referral of the patient with uveitis to a rheumatologist [46, 53]. The DUET algorithm is a novel evidence-based detection tool with high sensitivity and specificity. It facilitates cooperation between ophthalmologists and rheumatologists [53]. The course of uveitis associated with PsA is related to the PsA type. Uveitis associated with axial PsA is characterized by early onset and unilateral occurrence, and usually involves the anterior part of the uvea. Uveitis associated with the peripheral form of PsA occurs with equal frequency as unilateral or bilateral disease [12, 44, 46, 53]. Uveitis manifests with dryness and redness of the eyes, sudden acute pain, photophobia, and impaired visual acuity. In the case of posterior uveal involvement, perception of floaters within the visual field may additionally be present [23, 37, 42, 44, 56]. Clinical examination shows ciliary injection, keratic precipitates, the Tyndall effect, aqueous cells, hypopyon, small or irregular pupil, and cells in the anterior part of the vitreous [56]. Patients with such symptoms require urgent ophthalmological consultation, as untreated, recurrent, or chronic uveitis can lead to serious complications including posterior synechiae, secondary glaucoma, cataract, pupillary block, macular edema, retinal vasculitis, and loss of vision [56, 57].

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Treatment of uveitis The first-line treatment for uveitis is topical GCs. Mydriatics are used for pain relief and to prevent iris adhesions. For more severe uveitis, intraocular, oral, or intravenous GCs or immunosuppressive drugs (MTX, cyclosporine, azathioprine, mycophenolate mofetil) should be implemented. Methotrexate offers several practical benefits in patients who have uveitis, Ps, and PsA simultaneously. As a conventional synthetic disease-modifying antirheumatic drug (csDMARD) with both immunomodulatory and antiproliferative effects, it can reduce peripheral joint inflammation and slow structural damage in PsA, while also improving cutaneous Ps and serving as a systemic, GC-sparing agent for non-infectious uveitis. Using a single, well-known drug to target all three manifestations simplifies treatment regimens, may reduce cumulative GC exposure (topical, periocular, and systemic), and is less expensive and more widely available than biologics. In addition, MTX can be combined later with biologic agents when disease activity remains high, providing a flexible backbone therapy across skin, joint, and ocular domains. Biologic therapies have become important options for non-infectious uveitis in general, especially when GCs or conventional immunosuppressants are insufficient or cause side-effects. Major biologic therapies for non-infectious uveitis include TNFi (adalimumab, infliximab), IL-6 inhibitors (tocilizumab, sarilumab), IL-1 inhibitors (anakinra, canakinumab), anti-CD20 therapy (rituximab), JAK-inhibitors, anti-IL-17 agents (secukinumab), and antiIL-12/23-agents (ustekinumab). The choice of biologic depends on the type of uveitis, underlying systemic condition, severity, and previous treatment response. Anti-TNF agents are the most commonly used biologics for uveitis. Adalimumab is the first FDA-approved biologic for non-infectious uveitis, which is effective for anterior, intermediate, posterior uveitis, and panuveitis [58–61]. It is often used for Behçet’s disease-related uveitis. Infliximab is frequently used off-label, especially for severe or refractory cases such as Behçet’s uveitis [59–61]. Interleukin-6 inhibitors are used when TNFi fail or are not tolerated. This group includes tocilizumab, which is useful for refractory uveitis’ macular edema (including in juvenile idiopathic arthritis-associated uveitis), and sarilumab [62, 63]. Especially relevant for Beh çet’s disease or autoinflammatory syndromes are IL-1 inhibitors including anakinra (IL-1 receptor antagonist) and canakinumab (monoclonal antibody against IL-1β), which is used for resistant cases [64]. Anti-CD20 therapy (rituximab) is considered in severe refractory uveitis, especially related to systemic autoimmune disease [65].

Ocular complications in psoriasis and psoriatic arthritis

Among the JAK-inhibitors, tofacitinib, upadacitinib, and baricitinib are used off-label in uveitis [66]. Both in the pathogenesis of Ps and uveitis, overactivity of T cells and overproduction of pro-inflammatory cytokines (e.g., TNF and IL-17) is observed, which allows for appropriate selection of biological treatment for patients in the case of co-occurrence of these diseases including TNFi, IL-17 and IL-23 inhibitors, and JAK inhibitors. Biological treatment has an immunomodulatory effect, which limits active inflammation of the eye and reduces the risk of relapses and complications of chronically used GC therapy [42, 57]. Tumor necrosis factor inhibitors are considered the main biologics when uveitis coexists with Ps or PsA. Adalimumab is an FDA-approved first-line treatment for uveitis. It reduces uveitis flares in psoriatic disease [27, 58–61, 68]. Infliximab is often used in severe or recurrent uveitis, including cases associated with spondyloarthropathies such as PsA, and has demonstrated efficacy in control of ocular inflammation [27, 58–61, 68]. Both the GRAPPA guidelines and the 2023 EULAR recommendations for the pharmacological management of PsA state that, in patients with PsA who present with concomitant uveitis, monoclonal TNFi should be considered the preferred therapeutic option. [27]. There are data on the efficacy of golimumab and certolizumab pegol in uveitis in patients with Ps/PsA, but they are limited [68–70]. On the other hand, etanercept (another TNFi) is not effective for uveitis and may even increase flare risk, so it is not preferred when uveitis is present [27, 51, 58–60, 68]. Interleukin-17 inhibitors (secukinumab, ixekizumab, bimekizumab), IL-12/23 inhibitors (ustekinumab) and IL-23 inhibitors (guselkumab, risankizumab, tildrakizumab) are commonly used in the treatment of Ps/PsA, but their effect on uveitis is variable, and therefore they are not first-line drugs for uveitis [27, 50, 51, 58, 68, 71]. Interleukin-6 inhibitors are not effective in treating Ps, but are sometimes used to treat resistant uveitis, especially when TNFi are ineffective [62, 63]. The GRAPPA recommends monoclonal TNFi as the preferred first-line therapy for patients with PsA and concomitant uveitis, with conventional synthetic DMARDs such as MTX or cyclosporine considered as alternative options when biologic treatment is not feasible. Second-line considerations may include other csDMARDs or IL-17 and IL-12/23 inhibitors, although the evidence supporting their use in uveitis is more limited [27].

Genetic phenotypes in patients with psoriasis Due to the complex pathogenesis of Ps and PsA, determined by multiple genetic factors with widely docu-

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mented disease conditioning, some patients may benefit from genetic testing, especially patients with uveitis, as it is often genetically determined. In particular, in differential diagnosis, it is worth considering testing for the presence of the HLA-Cw6 and HLA-B27 antigens, due to the fact that carriers of these antigens are characterized by a specific genetic phenotype that determines the clinical manifestation and course of the disease, as well as the response to the implemented treatment. Human leukocyte antigen Cw6 is a genetic biomarker that predisposes to the development of skin manifestation of Ps (20× higher risk) and determines the course of the disease. Patients with HLA-Cw6 have a greater predisposition to type I Ps (the gene is present in 80% of patients with type I and about 15% with type II), which is characterized by: 1) early onset of disease (usually begins before 40 years of age, often in childhood or adolescence); 2) positive family history; 3) large extent of psoriatic lesions; 4) more severe, recurrent course; 5) worse response to treatment than type II. In these patients, plaques on arms, legs, and trunk and Koebner’s phenomenon occur more often, whereas nail and scalp involvement is observed less frequently. In addition, guttate Ps and photosensitive Ps are more common. It has been shown that in this group of patients, common triggers for Ps include streptococcal pharyngitis/tonsillitis, stress (20× increased risk), obesity (35× increased risk), and smoking. The risk of developing PsA is slightly increased in Ps patients with HLA-Cw6, but its occurrence is usually preceded by skin lesions long before joint symptoms appear (late-onset PsA). In addition, PsA in these patients correlates with a positive family history, and early and severe Ps. Moreover, HLA-Cw6 is a marker of a stronger response to MTX and biological treatment with and IL-12/23 or IL-23 inhibitor (but with no clear association with TNF and IL-17 inhibitors). Studies have also shown that HLA-Cw2 significantly increases the risk of developing PsA. In contrast, HLA-Cw4 does not appear to confer increased risk; in fact, some studies have even suggested a possible protective effect [16, 42, 72–75]. Human leukocyte antigen B27 is a strong genetic marker that predisposes to joint involvement in patients with Ps and correlates with the severity of joint manifestations in PsA. Greater predisposition to PsA is characterized by: 1) early onset of joint involvement; 2) increased risk of severe joint involvement; 3) aggressive course of the disease; 4) most often the axial form of PsA (while HLA-B38 and HLA-B39 predispose to peripheral polyarthritis); and 5) is a marker of disease poor prognosis. Patients with HLA-B27 have a greater risk of enthesitis, dactylitis, and uveitis. The HLA-B27 positive patients with a first episode of acute anterior uveitis have a higher risk of developing PsA in the future.

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Moreover, HLA-B27(+) Ps patients have an increased risk of early-onset PsA. The presence of the HLA-B27 antigen predisposes to higher incidence of pustular and peripheral Ps. In addition, patients with positive HLA-B27 have increased risk of other SpA (such as ankylosing spondylitis, reactive arthritis) and inflammatory bowel disease, which may coexist with Ps. Studies have shown that HLA-B27(+) patients with uveitis respond better to TNFi (especially adalimumab, infliximab), IL-17, and IL-12/23 inhibitors [72–75]. In summary, genetic tests allow us to predict the clinical manifestation of the disease, which can help in selecting the appropriate treatment for the patient. Nevertheless, it should be noted that some patients with Ps and PsA do not have any of these genes, and this does not exclude the disease [51]. Based on the above genetic and clinical data, we propose an original diagnostic-therapeutic scheme – the DROP (Dermatologist-Rheumatologist-Ophthalmologist Pathway) – designed to facilitate the management of patients with Ps and uveitis symptoms in multidisciplinary clinical practice (Fig. 2).

Cataract The latest studies have not revealed a statistically significant difference between the occurrence of cataract among patients with Ps and control groups [33, 36]. However, long-term use of topical or systemic GCs, anterior uveitis, increased age and metabolic diseases (e.g. diabetes) may promote cataract [29, 36–38]. Therefore, regular screening of cataract is recommended for patients, especially those undergoing long-term GC therapy. Some studies have suggested that PUVA therapy may be associated with an increased risk of ocular lens abnormalities, but other observations did not confirm these reports [76, 77]. In the case of symptoms and signs of dry eye, conjunctivitis, or blepharitis, the first therapeutic decision can be undertaken by the leading dermatologist or rheumatologist. However, in each case of ocular changes, the patient should be referred to an ophthalmologist for a full examination, final diagnosis, and initiation of targeted therapy. Table III presents the main symptoms, basic symptoms, and advanced treatment of the ophthalmic symptoms in

A Ps patient with symptoms of uveitis

Suspected infectious etiology of ocular symptoms

Treatment of infection

–

HLA-Cw6 positive and/or – early onset of disease (< 40 year) – positive family history – large extensiveness of psoriatic lesions – more severe, recurrent course

HLA-B27 positive and/or – diagnosed with PsA – onset of disease after the age of 40 – peripheral or nail Ps – pustular Ps

–

OPHTHALMOLOGIST DERMATOLOGIST

RHEUMATOLOGIST

In the first line: – MTX or – IL-23 or IL-12/23 inhibitor

In the first line: – MTX or – TNF (adalimumab/infliximab) or – IL-17 inhibitors or – IL-12/23 inhibitors

Continued persistence of ocular symptoms with improvement in skin lesions

TREATMENT (depending on the severity of the disease): – GC (local, intralesional, general) – NSAIDs (local, general) – mydriatics – immunosuppressive treatment – biological treatment (TNF inhibitors, IL-17 and IL-23 inhibitors) – treatment of complications

Continued persistence of ocular symptoms with improvement in joint lesions

Fig. 2. DROP scheme: diagnostic-therapeutic approach in a patient with psoriasis and uveitis symptoms. GC – glucocorticosteroid, IL – interleukin, MTX – methotrexate, NSAIDs – non-steroidal anti-inflammatory drugs, Ps – psoriasis, PsA – psoriatic arthritis, TNF – tumor necrosis factor.

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Antiviral therapy may be considered

––Artificial tears ––Topical antibiotics (if evidence of bacterial etiology) ––Topical GCs and/or antiallergics ––Contact lenses avoidance ––Cold compress

––Red eye ––Foreign body sensation ––Swollen eyelids ––Burning ––Itchiness ––Soreness ––Discharge

––Significant pain ––Photophobia ––Burning ––Blurred vision ––Tearing

––Pain of the eye ––Photophobia ––Increased visual acuity ––Small/irregula, minimally reactive pupil

––Increased visual acuity ––One eye diplopia

Conjunctivitis

Corneal involvement

Uveitis (most common anterior uveitis)

Cataract

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DED – dry eye disease, GC – glucocorticosteroid, Ps – psoriasis, TBUT – tear break-up time.

––Lens opacities up to the stage of the mature cataract ––Subcapsular posterior opacities (secondary to GC therapy)

Cataract surgery

––Ciliary injection ––Topical GCs, non-steroid ––Keratic precipitates anti-inflammatory drops, ––Tyndall effect immunosuppressants ––Aqueous inflammatory cells, hypopyon ––Mydriatics, cycloplegics ––Posterior synechiae (irregular pupil) ––Inflammatory cells in the anterior part of the vitreous

––Punctuate epitheliopathy ––Epithelial keratitis ––Superficial or deep opacities ––Stromal infiltrates ––Neovascularization ––Erosions ––Scarring ––Stromal melting

If necessary: drops reducing intraocular pressure or anti-inflammatory ones

––General GCs ––General immunosuppressants and biological therapy ––If necessary: drops reducing intraocular pressure ––Therapy of complications (e.g. cataract, glaucoma, macular edema)

––Oral antiviral, anti-inflammatory, immunosuppressive treatment ––Surgical procedures to treat corneal complications

––Cyclosporine A ophthalmic solutions ––Autologous serum application ––Lacrimal point occlusion ––Modern techniques to treat Meibomian gland dysfunction and tear production stimulation ––Surgical procedures to reduce evaporation or to treat complications

––Artificial tears (drops or gel) ––Paraffin/vitamin A ointment before sleep

––Flakes on eyelids ––Problems increase during daytime ––Decreased Schirmer’s test and TBUT results ––Epitheliopathy ––Conjunctival injection

––Dryness ––Foreign body sensation ––Burning ––Eye redness ––Blurred vision

DED

––Artificial tears (without preservatives) ––Topical GCs, immunosuppressants, antibiotics ––Corneal regenerative therapy

––Short-term therapy with topical GCs ––General and/or topical antibiotics ––Diet including omega-3 and omega-6 acids ––Modern techniques to treat Meibomian gland dysfunction (e.g., LipiFlow)

––Warm compresses ––Eyelid hygiene using special cleansers or baby shampoo

––Red swollen eyelids ––Dandruff at the base of eyelashes ––Meibomian gland dysfunction ––Tylosis ––Trichiasis ––Poliosis

––Red eye – eyelid hyperemia ––Foreign body sensation ––Burning ––Moderate photophobia ––Problems with the eyelashes ––Intolerance of contact lenses

Blepharitis

––Conjunctival injection and edema ––Mucopurulent (bacterial) or watery discharge (viral, allergic) ––Swollen preauricular lymph nodes (viral infection)

––Topical vitamin D analogs ––Topical calcineurin inhibitors

Comprehensive Ps treatment

––Typical psoriatic erythematosquamous plaques or sebopsoriatic lesions ––Eyebrow loss and/or greying

––Red eye – eyelid changes ––Eyebrow problems

Additional/advanced procedures

Eyelid and eyebrow involvement

Basic management

Signs

Ocular problem Symptoms

Table III. Ocular problems in Ps and PsA: signs and symptoms, basic and advanced treatment [12, 46, 53, 67, 76–78] Ocular complications in psoriasis and psoriatic arthritis

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Fig. 3. Photographs of discussed ocular changes in Ps: A) blepharitis; B) conjunctivitis; C) dry eye syndrome; D) corneal epitheliopathy; E) anterior uveitis; F) cataract. Ps and PsA. Figure 3 presents pictures of the discussed ocular changes. To sum up: ocular complications affect a significant percentage of patients with Ps and PsA. Their occurrence correlates with Ps activity, PASI score, and nail involvement, but is not significantly associated with disease duration. It means that they may be present even among newly diagnosed patients [33, 34, 36]. Ocular problems can affect every part of the eye and the most common manifestations include blepharitis, DED and conjunctivitis. A separate and widely described topic is uveitis in the course of PsA and, more broadly, SpA as an indicator of active disease, often associated

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with HLA-B27 and the need for biological treatment [24, 25, 29, 46, 53, 78]. These conditions can significantly worsen patient quality of life and lead to serious complications that may endanger eyesight. It is worth mentioning that many patients do not complain of ocular discomfort [29, 34]. This may be a consequence of focus on skin conditions or joint symptom reduction, causing symptoms concerning other organs to be underestimated or assumed not to be associated with Ps. In patients with Ps and PsA, periodic ophthalmological check-ups should be considered, even in asym ptomatic patients, due to the often insidious onset

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of the disease, as well as the chronic and recurrent nature of the lesions, which may lead to irreversible complications that can be prevented with early diagnosis and selection of appropriate treatment tailored to the source of the problem. As a practical guideline, dermatologists and rheumatologists should therefore ask patients about ocular symptoms at every visit, including pain, foreign body sensation, periodic or persistent eye redness, light sensitivity, blurred vision, and visual field disorders. In physical examination, attention should be paid to the presence of eye discharge, flakes on eyelashes, conjunctival injection, and size and symmetry of the pupils. In the event of a sudden acute pain, photophobia, decreased visual acuity, eye redness or a small/irregular, minimally reactive pupil, the patient should immediately be referred to an ophthalmologist, as these conditions can seriously endanger eyesight.

Conclusions The systemic nature of the Ps requires close cooperation of different specialists: dermatologists, rheumatologists, and ophthalmologists. The role of the dermatologist and rheumatologist in the early diagnosis of the most common ocular complications of Ps and switching from Ps to PsA is very important. Another task of these specialists should be the patient’s education regarding the possibility of eye complications in Ps and PsA. If ocular symptoms occur, an ophthalmologic consultation should be arranged as soon as possible. Every patient with Ps and PsA without a large area of skin involvement (PASI < 10) and without active skin involvement should undergo ophthalmologic examination annually. Patients with PASI > 10 or those who receive systemic GCs, MTX, acitretin, phototherapy, or photochemotherapy (indicating a more active disease) should undergo ophthalmologic examination every 6 months. Those patients should be particularly closely monitored by rheumatologists and dermatologists for the occurrence of ophthalmologic symptoms.

Disclosures Conflict of interest: The authors declare no conflict of interest. Funding: No external funding. Ethics approval: Not applicable. Data availability: The data that support the findings of this study are available on request from the corresponding author (A.S.).

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Case-based review

Reumatologia 2026; 64, 3: 242–251 DOI: https://doi.org/10.5114/reum/219888

Orbital pseudotumor and skull base infiltration as the sole manifestation of granulomatosis with polyangiitis Nicole Kivelä1,2 ID , William Karlsen1,3 ID , Karolina Markiet4 ID , Anna Masiak5 ID  1

Student Clinical Rheumatology Circle, Medical University of Gdansk, Poland Central Hospital of Vaasa, Finland 3 Visby Lasarett, Visby, Sweden 4 Second Department of Radiology, Medical University of Gdansk, Poland 5 Department of Rheumatology, Clinical Immunology, Geriatrics and Internal Medicine, Medical University of Gdansk, Poland 2

Abstract Granulomatosis with polyangiitis (GPA) is a vasculitis affecting small and medium-sized blood vessels. It typically presents with upper respiratory tract, lung, and kidney involvement. However, the disease may involve multiple other organs, and not all cases present with these classic mani festations. Periocular lesions are described in the GPA and, especially in the case of isolated, single-site disease, require extensive differentiation from other diseases, such as IgG4-related disease or myofibroblastic tumor. However, periocular lesions and coexisting symptoms suggesting changes in the central nervous system without other organ changes are undoubtedly a diagnostic challenge. Such situations are described in the literature mainly as case reports, not as a rule in connection with GPA. The impetus for writing this article and analyzing the literature was a case of GPA manifesting as infiltration of the skull base presenting as multiple cranial nerve palsies. A review of atypical cases of GPA in the literature suggests that skull-based involvement is an important yet easily overlooked presentation. Through this case-based review, we aim to raise awareness that GPA may present with isolated cranial nerve palsies. Key words: granulomatosis with polyangiitis, isolated, cranial nerve involvement, initial presentation.

Introduction Granulomatosis with polyangiitis (GPA) is an autoim mune small- and medium-sized vessel vasculitis. According to classification criteria, it belongs to the group of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) [1]. It is characterized by necrotizing granulomatous inflammation and pauci-immune glome rulonephritis. The classical presentation typically involves a triad of organ systems: the upper respiratory tract (including the paranasal sinuses, nose, ears, and larynx), the lungs (pulmonary nodules, infiltrates, cavitary lesions, diffuse alveolar hemorrhage, bronchial stenosis) and the kidneys (rapidly progressive glomerulonephritis). However, GPA may impact nearly any organ system, complicating both diagnosis and management. Manifestations of central nervous system (CNS) involvement

may include generalized symptoms such as headaches, meningitis, and seizures, as well as localized focal lesions such as stroke, cranial nerve paralysis, sensorineural hearing loss, and intracranial mass lesions [2]. Ocular and orbi tal manifestations are common in almost half of patients with either the limited or the systemic form of GPA [3]. Granulomatosis with polyangiitis can have a variable clinical course. It may have a localized form (often ANCAnegative) over extended periods of time, making reco gnition of the condition challenging for physicians lacking expertise in vasculitis. This type of AAV may remain loca lized or progress to a generalized form, causing damage to other organs. Infiltrative lesions may also spread locally, requiring extensive differential diagnosis. The diagnosis of GPA is based on clinical manifestations and complementary tests, including laboratory (detection of ANCA

Address for correspondence Anna Masiak, Department of Rheumatology, Clinical Immunology, Geriatrics and Internal Medicine, Medical University of Gdańsk, 7 Dębinki St., 80-211 Gdańsk, Poland, e-mail: anna.masiak@gumed.edu.pl Submitted: 23.07.2025; Accepted: 25.01.2026; Published online: 29.06.2026

Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)

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Identification

Identification of studies via databases and registers Articles identified: PubMed (n = 23) ScienceDirect (n = 428)

Screening

Abstracts and case presentations screened: PubMed (n = 23) ScienceDirect (n = 428)

Included

Identification of studies via other methods

Articles excluded: PubMed (n = 15) ScienceDirect (n = 408)

Articles sought for retrieval: PubMed (n = 8) ScienceDirect (n = 20)

Articles assessed for eligibility: PubMed (n = 8) ScienceDirect (n = 20)

Articles excluded: PubMed (n = 5) ScienceDirect (n = 16)

Articles identified as eligible from outside the search code (n = 6)

Articles from search code (n = 7) Articles from other sources (n = 15)

Fig. 1. PRISMA flow diagram of the search procedure for the narrative review. antibody), histopathology, and imaging studies. Histopathological confirmation is frequently unfeasible due to the complexity of acquiring tissue for microscopic examination and the presence of non-specific findings [4]. Although most patients with a clinical diagnosis of GPA are proteinase-3 ANCA positive, cases of myeloperoxidase (MPO) ANCA positivity and ANCA negativity have also been described. Although ANCA antibodies are involved in the pathogenesis of GPA [5], they may also be present in other conditions, e.g. connective tissue diseases, infectious diseases and drug-induced symptoms. Atypical perinuclear ANCA (pANCA) may be present in patients with inflammatory bowel disease and autoimmune liver diseases, including autoimmune hepatitis (AIH) [6]. They react primarily with MPO, less frequently with elastase, lysozyme, lactoferrin, cathepsin G, and catalase [7]. Here we describe the case of a female patient with AIH who developed a pseudotumor of the orbit followed by isolated cranial nerve palsies as a primary presentation of GPA. In addition, positivity for pANCA directed against elastase made it difficult to establish the correct diagnosis. The aim of this study is to raise awareness of this rare but significant clinical manifestation of GPA.

Material and methods A literature search for patients with GPA manifesting as infiltration of the skull base presenting as multiple cranial nerves palsies was carried out using PubMed and ScienceDirect without date restriction. The search was conducted using the following key words in PubMed: (“Granulomatosis with Polyangiitis” [MeSH] OR “Granu lomatosis with Polyangiitis”) AND (“Cranial Nerve Diseases” [MeSH] OR “Cranial Nerves” OR “Cranial Nerve

Involvement”) AND (“Onset” OR “Initial Presentation” OR “Early Symptoms” OR “Isolated”). The following key words were used in ScienceDirect: (“Granulomatosis with polyangiitis”) AND (“Cranial nerve involvement” OR “Cranial nerve” OR “Cranial nerve disease”) AND (“Onset” OR “Initial presentation” OR “Early symptoms” OR “Isolated”). Using a combination of these search terms, we undertook a systematic review of the literature published in English, limited to full-text publications of original articles, letters to the editor, and case reports in peer-reviewed journals (the search strategy is presented in Figure 1). This study was conducted in accordance with the principles of the Declaration of Helsinki from 1975 (revised in 2000), and written informed consent was obtained from the patient.

Search results A review of the literature revealed only single reports of cranial nerve palsy as an initial symptom of GPA. Table I summarizes 4 case reports (aged 36–74 years; 3 men and 1 woman) with CNS involvement in the form of cranial nerve palsies. Otological and facial-orbital symptoms predominate: ear pain, hearing loss, VII nerve palsy, diplopia/limited eye movement, facial sensory disturbances, and taste and smell disorders. Most patients had multiple nerve involvement (including cranial nerves II, V, VI, VII, VIII, IX), and in 1 case the authors did not specify which nerves were affected. Imaging shows recurrent inflammatory/infiltrative changes in the sinuses and temporal bone (mastoid, tympanic cavity, thickening of the bone walls, lysis of the ossicles), sometimes with thickening of the dura mater or infiltration spread-

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Table I. Review of cases with cranial nerve palsy as the initial manifestation of GPA Age, sex

Cranial nerve involvement

Initial symptom

Additional complaints

Findings on radiological imaging

74, female

Left-sided cranial nerve V3, VII, VIII, and IX palsies

Glossopharyngeal neuralgia

Left ear pain Bilateral hearing impairment Cloudy tympanic membranes Bilateral hypoesthesia of the skin below the mouth

Pseudotumoral Marini nasopharyngeal lesion et al. [25] infiltrating cranial nerve V3 and intracranial invasion through foramen ovale Bilateral pulmonary infiltrates

73, male

Cranial nerves not specified by the authors

Bilateral ptosis Redness of eyes Right facial weakness Right-sided hearing loss

Bilateral hyposmia Diminished right pupillary light reflex Limited right eye abduction Reduced sensation of the upper right facial region Dysgeusia Facial and bilateral orbital pain

Bilateral temporal Horiuchi thickening of dura et al. [26] Mucosal thickening of maxillary sinuses and bone wall thickening

63, male

Right-sided cranial nerve II, V, VI, VII, and VIII palsies

Right-sided facial weakness Diplopia Inability to close right eye Right-sided tongue ageusia

Right-sided hearing loss Right-sided blindness Paralysis of right abductor muscle Right maxillary sinusitis

Soft tissue densities in right mastoid area Osteoblastic activity in right mastoid bone and sphenoid bone Densities in lower lung fields

Daderian et al. [27]

36, male

Left-sided cranial nerve VII palsy

Left-sided cranial nerve VII palsy Left-sided otalgia and hearing loss

Left-sided perforated eardrum with purulent effusion

Opacification of mastoid air cells and tympanic cavity with ossicular lysis

Batinović et al. [28]

ing to the cranial cavity; in 2 cases, changes in the lungs were also noted.

Case description A 39-year-old female patient with cirrhosis of the liver due to AIH and autoimmune hypothyroidism was admitted to the rheumatology department for the presence of a pseudotumor of the left orbit with suspicion of an immunoglobulin G4-related disease (IgG4RD) for further diagnosis and management. Patient reported a 2-year history of ptosis of the left eye with left-sided numbness and flushing of the entire face. Magnetic resonance imaging (MRI) revealed a pathological mass in the upper part of the left orbit infiltrating the lacrimal gland, levator palpebrae superioris, superior rectus muscle and upper part of the lateral muscle. This mass extended deep into the orbit and was adjacent to the optic nerve just posterior to its exit from the globe (Fig. 2 A–D). Systemic glucocorticosteroid (GC) therapy was initiated with prednisone 60 mg daily, which resulted in resolution of the symptoms. However, the symptoms returned when the steroid dose was tapered. A biopsy of the orbital mass revealed only non-specific collagenous fibrous tissue. The patient experienced gradually

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Article

increasing weakness, decline in physical performance, significant weight loss, dysphagia and hoarseness. The patient denied hypersensitivity to ultraviolet radia tion, diarrhea, constipation, dysuria, cough, shortness of breath, chest/abdominal pain, swelling, and runny nose. On physical examination, the patient had left eyelid ptosis with associated swelling of the periorbital tissues. The neurological examination revealed discrete symptoms of damage to the ophthalmic branch of the trigeminal nerve (V1) and cranial nerves IX–XII on the left side. The consulting laryngologist diagnosed inflammatory changes in the larynx, paralysis of the left vocal fold, paresis of the right vocal fold, absence of reflexes from the posterior pharyngeal wall, and large retention of secretions in the lower pharynx. Laboratory tests revealed microcytic anemia (hemoglobin 10.7 g/dl; mean corpuscular volume [MCV] 78 fl), slightly elevated inflammatory parameters (C-reactive protein [CRP] 16 mg/l, normal < 5 mg/l), and presence of antinuclear antibodies (antinuclear antibodies human epithelial type 2 > 1 : 2,560, homogeneous + fine-grained type). The immunoblot profile showed positive p/SSA Ro-52 antibodies. The presence of pANCA 1 : 2,560 pANCA was also found, corresponding to anti-elastase antibodies in the ANCA profile. The liver immunoblot profile was posi

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Fig. 2. Initial magnetic resonance imaging (MRI) showed a pseudotumorous, infiltrative lesion in the left orbit. The lesion enhanced after contrast administration (arrows in A, B) with infiltration of the lacrimal gland (asterisk in C), lateral rectus muscle, and superior rectus/levator palpebrae muscle complex, along with the supraorbital nerve. The lesion was in close proximity to the globe and the retrobulbar segment of the optic nerve (arrow in D), although these structures were not infiltrated. The supraorbital nerve is marked (circle in C) for reference. A brain MRI revealed a left-sided skull base infiltration at the level of the internal jugular vein foramen (asterisks in E, F) extending into the hypoglossal nerve canal. tive for Gp210 (anti-glycoprotein-210 antibodies), antibodies to soluble liver antigen/liver pancreas, anti-SSA Ro-52 antibodies, and anti-smooth muscle antibodies 1 : 320 (normal < 1 : 20). Despite the absence of pulmonary symptoms, chest computed tomography revealed, in the upper lobes of both lungs and in segments VI

and X of the left lung, ground-glass opacities and a few areas of consolidation that could correspond to changes in the course of vasculitis (Fig. 3). Magnetic resonance imaging of the brain showed a left-sided skull base infiltration located between the bulb of the internal jugular vein extending into the hypoglossal nerve canal

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Fig. 3. High-resolution computed tomography of the thorax (lung window) in coronal (A) and axial (B) planes showed bilateral ground-glass opacities and a few areas of consolidation, which may correspond to chang es in the course of vasculitis. (Figs. 2 E, F). Due to the initial suspicion of IgG4RD, serum immunoglobulin G and immunoglobulin G4 (IgG4) levels were tested, but both were within the normal range. Additionally, IgG4 staining was performed on a liver biopsy obtained during the diagnosis of AIH showing staining in isolated plasmacytes, while a lacrimal gland biopsy exhibited negative staining. The neurosurgeon decid-

ed against diagnostic sampling of the posterior cranial fossa due to high procedural risk. Based on the comprehensive clinical evaluation along with immunological, radiological, and histopathological findings (negative IgG4 staining), a diagnosis of pANCA-positive vasculitis was established. Immunosuppressive treatment with methylprednisolone was administered (methylprednis-

Fig. 4. Follow-up magnetic resonance imaging performed 6 months after introduction of treatment showed remission of the orbital (A, B) and skull base lesions (C, D).

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olone 3 g i.v. in total), followed by prednisone therapy (1 mg/kg/day, 50 mg/day with a gradually reduced dose). Therapy with cyclophosphamide (CYC) at a dose of 15 mg/kg according to the European Vasculitis Study Group regimen was initiated. The patient’s clinical condition quickly improved after intense immunosuppressive therapy. She received 9 infusions of CYC with a cumulative dose of 8.42 g. Six months after initiating treatment, the patient showed remission of orbital and skull changes on MRI (Fig. 4), with a Birmingham Vasculitis Activity Score of 0. Cyclophosphamide was discontinued, and azathioprine (AZA) was initiated as maintenance therapy. Currently, 5 years after the start of treatment, the patient is in remission. Treatment continues with AZA 100 mg and low-dose prednisone (5 mg/day).

Discussion Granulomatosis with polyangiitis is a multi-organ systemic autoimmune disease that manifests with a variety of symptoms. Clinical features may result from both inflammatory granuloma formation and small vessel inflammation. In addition to the classic presentation of upper respiratory, pulmonary, and renal symptoms, eye and nervous system involvement are among the symptoms associated with GPA. Ocular and orbital manifestations are present in almost half of patients with either the limited or the systemic form of GPA. Frequently, they may be present as the initial features of the disease [1]. The clinical spectrum of ophthalmic symptoms is highly variable, since almost every part of the eye and orbital structures may be affected. Inflammation of the conjunctiva, cornea, episclera, sclera, retina, lacrimal gland, and orbital blood vessels leads to a diverse range of symptoms, including ocular pain, erythema and edema of the eyelids, conjunctival injection, nasolacrimal duct obstruction, limited extraocular muscle movements, proptosis, diplopia, and vision loss [8]. The occurrence of an orbital mass is less frequent in patients with GPA. In most patients, such a mass manifests with reduced vision, diplopia, and proptosis. In a study that included 1,142 patients with GPA, only 5% developed orbital masses during a 5-year follow-up. An orbital tumor may be the sole location of the disease (limited form of GPA) or may coexist with involvement of other organs [9]. The differential diagnosis of orbital infiltration must consider a wide spectrum of diseases, including infections, neoplasms, and other inflammatory orbital diseases such as idiopathic sclerosing orbital inflammation, thyroid or Graves orbitopathy, sarcoidosis, as well as IgG4RD (Table II) [10–17]. The non-specific fibrous tissue found on histopathology of the orbital infiltrate biopsy in our patient initially suggested IgG4RD. However, the lack of elevated serum IgG4 levels and negative IgG4 staining

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on biopsy, as well as positive ANCA and lung and skull involvement, favored the diagnosis of GPA. Central nervous system involvement in GPA has been reported in 7–11% of cases [18]. Cranial nerve palsy occurs in 2–10% of cases. Wójcik et al. [19], based on the Polish vasculitis registry, stated that CNS involvement affects approximately 10% of patients with GPA. Similarly, Bonek et al. [20] estimated the frequency of cranial base involvement to be 3–10% of GPA, with a potentially severe disease course and resistance to treatment. Symptoms of CNS involvement may result from a variety of lesions: a granulomatous disease spreading from the ear, nose, and throat to neighboring structures, direct meningeal involvement due to adjacent granulomatous disease in the skull base, paranasal or orbital region, or the formation of a granuloma primarily in the nervous system [21]. In the present case, the disease began with an orbital pseudotumor, but it was not until the onset of cranial nerve palsy that the diagnosis was made and appro priate treatment initiated. Interestingly, the patient had no symptoms of lung involvement, and the lesions were visualized only by computed tomography. This indicates the need for a multi-organ assessment of every patient with GPA regardless of reported symptoms. Skull base infiltration refers to the spread or invasion of a tumor, infection, or inflammatory condition into the skull base, the bony structure at the base of the skull. This can lead to various symptoms and complications depending on the underlying cause and the extent of the infiltration. Causes of this clinical state include neoplastic processes such as lymphoma, primary bone tumors, and metastatic lesions. However, these would not normally present with raised inflammatory parameters. Other causes include inflammatory pseudotumor, osteomyelitis, tuberculosis, sarcoidosis, as well as fibrous dysplasia and Paget disease. Table I provides detailed information on differential diagnosis of skull base and orbital infiltration. Kiessling et al. [2] conducted a retrospective analysis of 29 patients with skull base GPA. Out of the patients 72% presented skull base symptoms as the initial manifestation of the disease. They also concluded that 83% of the studied patients at some point experienced cranial neuropathies. De Groot et al. [22] analyzed the neurological manifestations of GPA and concluded that in most cases, the cranial nerve involvement is a result of infiltration of gra nuloma from the paranasal sinuses. In their study, 6 out of 128 patients had cranial nerve involvement. A cohort study conducted by Wojciechowska et al. [23] compared clinical signs of GPA and microscopic polyangiitis (MPA). Out of 41 patients with GPA, 8 presented with nervous system involvement, 3 of which had cranial nerve palsies. Interestingly, all cases with nervous system invol

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Orbital pain

Exophthalmos

Orbital infiltration Uni-/bilateral

Skull base infiltration

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Yes

Fungal orbital inflammation

Yes

Graves’ disease

Sarcoidosis

GPA

Behçet’s disease

IgG4-related disease (IgG4RD)

Yes

Occasionally

Yes

Often

Usually bilateral

Usually unilateral, rare

Usually unilateral

Usually bilateral

Usually unilateral

Yes

Rare

Yes

Rare

Yes

Orbital lymphoma

Langerhans cell histiocytosis

Cancer metastases

Cavernous sinus thrombosis

Yes

Usually bilateral

Unilateral

Usually unilateral

Yes

Rare

Yes

Neoplasms and non-neoplastic lesions with an inflammatory pattern

Yes

Idiopathic orbital pseudotumor

Autoimmune and inflammatory diseases

Yes

Purulent (bacterial) orbital inflammation

Infectious orbital inflammation (most common cause of acute orbital infiltration)

Disease

Table II. Differential diagnosis of orbital and skull base infiltration

May cause symptoms of bilateral orbital infiltration; severe general condition; cranial nerve palsy (III, IV, VI, V1/V2), eyelid swelling

Primary tumor dependent (e.g. breast, prostate, lung); often pain and rapidly increasing exophthalmos

Painful infiltration accompanied by exophthalmos; occasionally bone lesions; mainly children

Painless, slow-growing tumor; more common in older adults; MALT lymphoma; may resemble inflammatory pseudotumor

Slow, painless, bilateral enlargement of the lacrimal glands or other orbital structures; IgG4+

Recurrent oral aphthae, genital ulcers, ocular disease (uveitis/retinal vasculitis), skin lesions; thrombosis

Painful infiltration, may mimic infection; nose, lungs, kidneys; often nonspecific general symptoms

Chronic painless infiltration; pulmonary lesions, lymphadenopathy

The most common chronic cause of bilateral orbital infiltration; thyroid disease; painless, slowly progressing

No general symptoms; may involve muscles, lacrimal gland, sclera, optic nerve

Fever, especially in immunosuppressed patients, e.g. diabetes, neutropenia

Fever, pain, redness, swelling, restriction of eye movement, exophthalmos; related to the paranasal sinuses (most commonly the ethmoid sinus)

Systemic symptoms

Angio-CT/MRI (cavernous sinus thrombosis), neurological symptoms

CT/MRI, histopathology

X-ray, CT, MRI (lytic bone lesion)/histopathology

Histopathology

High serum IgG4; IgG4+ plasma cell infiltration on histopathology

Ophthalmic assessment/imaging for ocular involvement; MRI/CT if neuro-/orbital apex/ cavernous sinus involvement suspected

ANCA/PR3, CT, histopathology

ACE, CT lungs

TSH, TRAb, thyroid ultrasound

CT/MRI, CRP/ESR; rapid response to GCs

CT/MRI, pathogens: Aspergillus, Mucor (mucormycosis – highly aggressive form)

CT, CRP; positive cultures, main pathogens: Staphylococcus aureus, Streptococcus pyogenes, Haemophilus influenzae

Additional studies

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ACE – angiotensin-converting enzyme, CRP – C-reactive protein, CT – computed tomography, GCs – glucocorticosteroids, GPA – granulomatosis with polyangiitis, IgG4 - immunoglobulin G4, IGRA – interferon-γ release assay, MALT – mucosa-associated lymphoid tissue, MRI – magnetic resonance imaging, TB – tuberculosis, TSH – thyroid-stimulating hormone, TRAb – thyroid-stimulating hormone receptor antibodies.

CT (typical for craniofacial assessment); MRI as needed; ophthalmologic monitoring Asymptomatic or pain, craniofacial deformities, vision/hearing impairment Rare No Fibrous dysplasia

Usually unilateral

Yes (craniofacial bones including skull base may be involved)

CT, X-ray Bone pain, deformities, neurological symptoms with skull base involvement Rare No Paget disease (osteitis deformans)

Usually unilateral

Mechanical deformity of the orbit and skull base bones without inflammatory infiltration

MRI of cavernous sinus (inflammatory infiltrate in cavernous sinus, no thrombus) Cranial nerve palsy III, IV, VI; painful ophthalmoplegia Yes Absent or mild Yes, severe Tolosa-Hunt syndrome

Usually unilateral

CT/MRI, histopathology, positive TB tests (IGRA) Cough, pulmonary lesions Yes Usually unilateral Occasionally Yes Orbital tuberculosis

Usually unilateral Yes No Orbital amyloidosis

Exophthalmos Orbital pain Rare causes

Disease

Table II. Cont.

Orbital infiltration

Uni-/bilateral

Rare

Skull base infiltration

Systemic symptoms

Systemic diseases with amyloidosis

Additional studies

Histopathology, Congo red staining

Granulomatosis with polyangiitis and cranial nerves

vement were in the course of GPA. Tsuzuki et al. [24] analyzed the clinical profiles of GPA in 16 patients; 1 patient presented with hearing loss, tinnitus and paralysis of cranial nerves VII, IX, and XII, and another patient presented with otalgia and paralysis of nerve VII. The following studies report cases in which cranial nerve dysfunction was the initial symptom and further investigation resulted in the diagnosis of GPA. Detailed information on each case is provided in Table II. Marini et al. [25], Horiuchi et al. [26], and Daderian et al. [27] all described patients who had a history of several cranial nerve palsies for a few weeks. The patients were ultimately diagnosed with GPA after radiological imaging, laboratory tests, and biopsy. Batinović et al. [28] described a patient who experienced acute otitis media complicated with facial nerve palsy. The diagnosis of GPA was confirmed after finding elevated cytoplasmic ANCA (cANCA) and histological findings of transbronchial biopsy. Clinical and experimental data demonstrate that ANCAs play a crucial role in the pathogenesis of AAV [29]. Depending on their immunofluorescence pattern on ethanol-fixed neutrophils, ANCAs were termed cANCA, pANCA, and atypical ANCA [5]. Perinuclear ANCA predominantly targets MPO. However, in non-vasculitic autoimmune diseases, pANCAs are often directed against other antigens such as elastase, lactoferrin, and cathepsin G [30]. In a study by Roosendaal et al. [6], ANCAs were found in 74% of patients with AIH. Due to the well-documented occurrence of pANCA in association with autoimmune liver diseases, our patients’ autoimmune profile, characterized by AIH and pANCA targeting elastase, was initially consistent with the underlying AIH. However, the development of skull base infiltration, cranial nerve palsies, and pulmonary infiltration indicated progression to a systemic vasculitic process, ultimately leading to the diagnosis of GPA. Skull base infiltration with neurological symptoms is a potentially organ/life-threatening manifestation of GPA requiring rapid and intensive immunosuppression. According to the European Alliance of Associations for Rheumatology guidelines, treatment with a combination of GCs and either rituximab or CYC is recommended for patients with new-onset or relapsing GPA with organ-threatening or life-threatening disease, in order to induce remission. Avacopan in combination with rituximab or CYC previously recommended for induction of remission in GPA, as part of a strategy to substantially reduce exposure to GCs was withdrawn by the FDA and EMA based on an analysis of the registration clinical trial data and reported adverse events, and the article from the clinical trial published in NEJM was retracted [31].

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Conclusions Cranial nerve palsy as an initial manifestation of GPA is most likely caused by cranial nerve compression by an inflammatory tumor of the skull base. Considering our case alongside the existing literature, we note that cranial nerve impairment is not a common manifestation of GPA. Given the small number of cases, a typical clinical presentation cannot be defined. However, this manifestation is important to recognize, since it may lead to delayed diagnosis and disease progression if overlooked. Our findings highlight that all patients with suspected GPA, regardless of the presented symptoms, require a comprehensive multi-organ assessment. Larger patient cohorts are needed to better characterize this rare presentation and facilitate earlier diagnosis in such cases.

Disclosures Conflicts of interest: The authors declare no conflicts of interest. Funding: No external funding. Ethics approval: Due to the nature of the study, consent is not required. Availability of data and material: The data that support the findings of this study are available on request from the author (A.M.). References 1. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculiti des. Arthritis Rheum 2013; 65: 1–11, DOI: 10.1002/art.37715. 2. Kiessling PT, Marinelli JP, Peters PA, et al. Cranial base manifes tations of granulomatosis with polyangiitis. Otolaryngol Head Neck Surg 2020; 162: 666–673, DOI: 10.1177/0194599820912025. 3. Tarabishy AB, Schulte M, Papaliodis GN, Hoffman GS. Wegener’s granulomatosis: clinical manifestations, differential diagnosis, and management of ocular and systemic disease. Surv Ophthal mol 2010; 55: 429–444, DOI: 10.1016/j.survophthal.2009.12.003. 4. Masiak A, Zdrojewski Z, Pęksa R, et al. The usefulness of histo pathological examinations of non-renal biopsies in the diag nosis of granulomatosis with polyangiitis. Reumatologia 2017; 55: 230–236, DOI: 10.5114/reum.2017.71638. 5. Kronbichler A, Lee KH, Denicolo S, et al. Immunopathogenesis of ANCA‑Associated Vasculitis. Int J Mol Sci 2020; 21: 7319, DOI: 10.3390/ijms21197319. 6. Roozendaal C, de Jong MA, van den Berg AP, et al. Clinical sig nificance of anti‑neutrophil cytoplasmic antibodies (ANCA) in autoimmune liver diseases. J Hepatol 2000; 32: 734–741. DOI: 10.1016/S0168-8278(00)00060-5. 7. Terjung B, Spengler U, Sauerbruch T, Worman HJ. Atypical p‑ANCA in inflammatory bowel and hepatobiliary diseases: reactivity with a 50‑kDa nuclear envelope protein of neutro

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phils. Gastroenterology 2000; 119: 310–322, DOI: 10.1053/gast. 2000.9366. 8. Muller K, Lin JH. Orbital granulomatosis with polyangiitis (Wegener granulomatosis): clinical and pathologic findings. Arch Pathol Lab Med 2014; 138: 1110–1114, DOI: 10.5858/ arpa.2013‑0006‑RS. 9. Holle JU, Voigt C, Both M, et al. Orbital masses in granuloma tosis with polyangiitis are associated with a refractory course and a high burden of local damage. Rheumatology (Oxford) 2013; 52: 875–882, DOI: 10.1093/rheumatology/kes382. 10. Sakai M, Hiyama T, Kuno H, et al. Imaging of the skull base and orbital tumors. Jpn J Radiol 2025; 43: 152–163, DOI: 10.1007/ s11604-024-01662-9. 11. Aygün D, Doğan C, Hepokur M, et al. Evaluation of patients with orbital infections. Turk Pediatri Ars 2017; 52: 221–225, DOI: 10.5152/TurkPediatriArs.2017.5511. 12. Zayet S, Zaghdoudi A, Ammari L, et al. Cerebro-rhino-orbital mucormycosis and aspergillosis coinfection in a patient with diabetes mellitus: A case report. IDCases 2021; 23: e01022, DOI: 10.1016/j.idcr.2020.e01022. 13. Bartalena L, Kahaly GJ, Baldeschi L, et al. The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guide lines for the medical management of Graves’ orbitopathy. Eur J Endocrinol 2021; 185: G43–G67, DOI: 10.1530/EJE-21-0479. 14. Manish MG, Goswamy J, Solanki K, Bhalla R. Infiltrative mass of the skull base and nasopharynx: a diagnostic conundrum. Ann Med Surg (Lond) 2015; 4: 103–106, DOI: 10.1016/j.amsu. 2015.03.005. 15. Abdullaeva U, Pape B, Hirvonen J. Diagnostic accuracy of MRI for orbital and intracranial invasion of sinonasal malignan cies: a systematic review and meta-analysis. J Clin Med 2024; 13: 7556, DOI: 10.3390/jcm13247556. 16. Chapman PR, Choudhary G, Singhal A. Skull base osteomyeli tis: a comprehensive imaging review. AJNR Am J Neuroradiol 2021, DOI: 10.3174/ajnr.A7015. 17. Salfrant M, Garcia GCTE, Guichard JP, et al. Imaging of skull base and orbital invasion in sinonasal cancer: correlation with histopathology. Cancers (Basel) 2021; 13: 4963, DOI: 10.3390/ cancers13194963. 18. Nishino H, Rubino FA, DeRemee RA, et al. Neurological involve ment in Wegener’s granulomatosis: an analysis of 324 conse cutive patients at the Mayo Clinic. Ann Neurol 1993; 33: 4–9, DOI: 10.1002/ana.410330103. 19. Wójcik K, Wawrzycka‑Adamczyk K, Włudarczyk A, et al. Clinical characteristics of Polish patients with ANCA‑asso ciated vasculitides – retrospective analysis of POLVAS regi stry. Clin Rheumatol 2019; 38: 2553–2563, DOI: 10.1007/ s10067‑019‑04538‑w. 20. Bonek K, Brożek-Mądry E, Wroński J, et al. Combination treat ment of locoregionally aggressive granulomatosis with poly angiitis and cranial base infiltration. Brain Sci 2023; 13: 1140, DOI: 10.3390/brainsci13081140. 21. De Luna G, Terrier B, Kaminsky P, et al. Central nervous sys tem involvement of granulomatosis with polyangiitis: clinical‑ radiological presentation distinguishes different outcomes. Rheumatology (Oxford) 2015; 54: 424–432. DOI: 10.1093/ rheumatology/keu336.

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22. De Groot K, Schmidt DK, Arlt AC, et al. Standardized neuro logic evaluations of 128 patients with Wegener granuloma tosis. Arch Neurol 2001; 58: 1215–1221, DOI: 10.1001/archneur. 58.8.1215. 23. Wojciechowska J, Kręcicki T. Clinical characteristics of patients with granulomatosis with polyangiitis and microscopic poly angiitis in ENT practice: a comparative analysis. Acta Otorhino laryngol Ital 2018; 38: 517–527, DOI: 10.14639/0392-100X-1776. 24. Tsuzuki K, Fukazawa K, Takebayashi H, et al. Difficulty of dia gnosing Wegener’s granulomatosis in the head and neck region. Auris Nasus Larynx 2009; 36: 64–70. DOI: 10.1016/ j.anl.2008.02.003. 25. Marini K, Garefis K, Skliris JP, et al. Granulomatosis with poly angiitis: multiple cranial nerve manifestations and nasopha ryngeal pseudotumor. Ear Nose Throat J 2024; 103: 470–472, DOI: 10.1177/01455613211069925. 26. Horiuchi K, Oshima Y, Kudo A. Successful treatment with ritux imab for granulomatosis with polyangiitis and multiple cranial neuropathies. Intern Med 2021; 60: 1095–1099, DOI: 10.2169/ internalmedicine.4881-20.

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27. Daderian AD, Chayasirisobhon S. An unusual case of multi ple cranial nerve palsies in Wegener’s granulomatosis. J Natl Med Assoc 2000; 92: 455–457, DOI: 10.1016/S0027-9684(15)31484-3. 28. Batinović F, Krnić Martinić M, Glavina Durdov M, Sunara D. A case of unilateral otologic symptoms as initial manifesta tions of granulomatosis with polyangiitis. J Audiol Otol 2023; 27: 161–167, DOI: 10.7874/jao.2022.00311. 29. Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomeru lonephritis and vasculitis in mice. J Clin Invest 2002; 110: 955–963, DOI: 10.1172/JCI15918. 30. Argyropoulou OD, Goules AV, Boutzios G, et al. Occurrence and antigenic specificity of perinuclear anti-neutrophil cytoplas mic antibodies (P-ANCA) in systemic autoimmune diseases. Cells 2021; 10: 2128, DOI: 10.3390/cells10082128. 31. Hellmich B, Sanchez-Alamo B, Schirmer JH, et al. EULAR re commendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis 2024; 83: 30–47, DOI: 10.1136/ard-2022-223764.

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Case-based review

Reumatologia 2026; 64, 3: 252–261 DOI: https://doi.org/10.5114/reum/209914

Pleuropericardial effusion as a first presentation of systemic lupus erythematosus Raja Bakhsh ID , Khaled Saleh Dairi ID , Zaher Althaqafi ID , Shifaa Sharaf Aljefri ID , Ward Hisham Skaik ID , Sheren Ismail Saleh ID , Enas Ali AlRubayyi ID King Faisal Hospital, Makkah, Kingdom of Saudi Arabia

Abstract Systemic lupus erythematosus is a multisystem autoimmune disease with varied manifestations involving pulmonary features of pleuritis and pericarditis. These complications may be difficult to diagnose in early stages, as they mimic infectious symptoms. The paper sheds light on diagnostic and treatment challenges associated with lupus pleuropericardial effusions. Glucocorticosteroids (GCs) are usually the first-line treatment, but some patients do not respond to this therapy and require escalation to immunosuppressants or biologics. This is review based on studies published in peerreviewed journals within past 20 years. The case of a patient with pleural effusion included in the article, in whom the diagnosis of SLE was made through the diagnosis of infection, as well as the cases from the available literature presented in the discussion, well illustrate the problem of symptoms that are part of the picture of SLE, but are non-specific and require differential diagnosis. Early diagnosis and treatment with immunosuppressive, immunemodulating drugs and biologics may lead to better outcomes; further research is needed to explore therapeutic options in difficult cases. Key words: lupus erythematosus, pleuropericardial effusion, immunosuppressive therapies.

Introduction Systemic lupus erythematosus (SLE) is a chronic auto immune inflammatory condition displaying variability in its clinical manifestations, histological features, and disease course. This disease arises from a complex interplay between genetic, hormonal, environmental, and immunological factors that results in the loss of immunologic tolerance and the production of autoantibodies, which invade various tissues and organs [1]. Epidemio logical studies reveal a higher prevalence in women, particularly of reproductive age, with a striking femaleto-male ratio of 9 : 1. Sex, ethnic as well as racial diffe rences exist, with Africans, Asians, and Hispanics being more prone to suffer from moderate to severe forms [2]. Systemic lupus erythematosus is an autoimmune disease that impacts the skin, joints, kidneys, the central nervous system, and other organs of the body. It may present as mild, such as skin rash and arthritis, but may result in severe complications such as glomerulonephritis or neuropsychiatric lupus. The heterogeneous nature

of the disease entails significant diagnostic and therapeutic difficulties, necessitating the use of many serological markers and the application of American College of Rheumatology and European Alliance of Associations for Rheumatology (formerly European League Against Rheumatism) classification criteria [3]. Pleuropulmonary involvement, as one of the forms of SLE manifestation, is both common and severe, ranging from 20% to 90% depending on the diagnostic techniques and population. These manifestations are suggestive of SLE severity and more often reflective of systemic disease activities [4]. Pleuropulmonary complications encompass a wide spectrum, including pleuritis, pleural effusions, interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and less commonly, acute lupus pneumonitis, diffuse alveolar hemorrhage (DAH), and shrinking lung syndrome. Of these, pleuritis and pleural effusions are the most frequent manifestations, with a prevalence rate of 24–61% [4, 5]. Pulmonary arterial hypertension and ILD, while less common, are known to play a major role in morbidity and mortality.

Address for correspondence Raja Bakhsh, King Faisal Hospital, Ibn Khairon Al Mugri St., Al Qashashia Al Jad, 24577 Makkah, Kingdom of Saudi Arabia, e-mail: rajaabakhsh@gmail.com Received: 29.06.2025; Accepted: 26.08.2025; Published online: 26.06.2026

Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)

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The pathogenesis of the pleuropulmonary system in SLE is due to the deposition of immune complexes, systemic inflammation, and vascular injury. Autoantibo dies such as Sjögren’s-syndrome-related antigen A and antigen B are considered to be related to pleuropulmonary disorders and are immunopathogenic. High-resolution computed tomography (CT), chest X-ray, pulmonary function tests, and bronchoalveolar lavage reveal complications such as DAH or infection-induced changes. Most importantly, DAH is a fatal complication that is characterized by high mortality rates, varying from 68 to 75%, and demands intervention [4]. Immunosuppressive therapy remains the cornerstone of modulating the pleuropulmonary manifestations and includes glucocorticosteroids (GCs), cyclophosphamide (CYC), and mycophenolate mofetil (MMF). Rituximab (RTX) and belimumab have been reported in refractory forms [4]. Other supportive treatments include oxygen therapy and anticoagulation therapy for PAH or a thromboembolic process [4]. This case presentation and systematic literature review aimed to examine pleuropericardial effusion in SLE as a diagnostic challenge and a marker of disease, focusing on clinical, immunological, and pathological perspectives. The rationale for this approach is to improve the understanding of the pleuropulmonary involvement of SLE, which affects 90% of patients and has a direct correlation with morbidity and mortality. The main aim is to report a rare case of a 19-year-old female patient with pleuropericardial effusion as the initial manifestation of SLE, evaluate the immunopathological processes and clinical course, and review previous literature for diagnostic, therapeutic, and management approaches. Presentation of this rare case aims to advance recognition, facilitate treatment, and enhance understanding of SLE’s diverse clinical spectrum. The clinical importance of pleuropericardial effusion as one of the manifestations of SLE, as well as the diagnostic and therapeutic difficulties, is discussed in this case report. The report also presents a case of recurrent pleuropericardial effusion in a 19-year-old female patient, underlining the problem of differentiation between lupus activity and infection.

This case is further explored by integrating with prior literature demonstrating the benefits of imaging, serological markers, and targeted treatments in patients with SLE-associated serositis. Thus, documenting this rare manifestation of the disease, the report adds to the identification of the SLE clinical spectrum, and helps raise awareness of atypical symptoms, as well as the necessity for an individualized immunosuppression approach to enhance the results of treatment in such cases.

Material and methods Search strategy This review is based on studies published in peerreviewed journals from the past 20 years. Literature was retrieved from widely used databases such as Google Scholar, Springer, Web of Science and PubMed. A time frame filter was applied to include studies published between 2005 and 2024. As indicated in Table I, specific search strategies were applied to identify relevant data.

Selection criteria Regarding data extraction, the inclusion criteria were papers that appeared in peer-reviewed journals with clearly defined policies on review and that contained the phrases “pleuropericardial effusion” and “systemic lupus erythematosus” either in the title, abstract, or key words. Subsequently, articles published between 2005 and 2024 were included in the search. Only papers that were full text and open access or available through authorized databases were considered. Papers were excluded if they had not undergone peer review, did not include the chosen key words, were published before 2005, or were under some form of restricted access.

Data analysis Thirty studies were selected based on their titles, publishers, and main objective of the review aligned with the current study’s rationale. The analysis of the data obtained from the 30 articles was conducted using

Table I. Search strategies No.

Search strategy

(“Systemic lupus erythematosus (SLE)”) AND (“pleuropericardial effusion”) OR (“recurrent pleuropericardial effusion”) AND (“pleuropulmonary involvement”) OR (“pleuropulmonary complications”) OR (“pleural effusion”)

(“Pericardial effusion”) AND (“pleuritis”) AND (“pleural fluid analysis”) AND (“pleural effusion treatment”) AND (“pleuropulmonary disease”) AND (“serositis”) AND (“autoantibodies”)

(“Anti-dsDNA”) AND (“inflammatory markers”) AND (“corticosteroids”) AND (“immunosuppressive therapy”) AND (“lupus”) AND (“hydroxychloroquine”) AND (“cytokine inhibitors”) AND (“rituximab”)

(“Mycophenolate mofetil”) AND (“immunopathology”) AND (“SLE diagnostic challenges”) AND (“autoimmune markers”)

Anti-dsDNA – anti-double-stranded DNA.

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Identification

Records excluded (n = 935)

Eligibility

Records screened (title and abstract) (n = 978)

Full-text articles assessed for eligibility (n = 43) Full-text articles excluded (n = 13) (Reasons: insufficient clinical data, unrelated outcomes)

Included

Duplicates removed (n = 672)

Screening

Case presentation

Records identified through database searching (Google Scholar, Springer, Web of Science, PubMed) (n = 1,650)

Studies included in qualitative synthesis (n = 30)

Fig. 1. PRISMA flow diagram. thematic analysis as presented in the discussion. The data were obtained by using recurrent key words in the paper such as “pleuropericardial effusion” and “systemic lupus erythematosus.”

Quality assessment The review addresses the study quality based on pleuropericardial effusion as a first presentation of SLE. It includes the criteria based on which the chosen publications were most relevant to the aim of the review and were published between 2005 and 2024. Availability of full-text studies was another important requirement that was given priority. These criteria contribute to the quality and reliability of the synthesized data by developing discussions and conclusions on the efficacy of the studies included in this review. The review’s main objective is to provide a thorough understanding of pleuropericardial effusion as a first presentation of SLE, while incorporating the most recent data.

Bioethical standards This study was conducted in accordance with the principles of the Declaration of Helsinki from 1975 (revised in 2000) and a written informed consent was obtained from the patient.

Results Search results One thousand six hundred and fifty articles were identified in Google Scholar, Springer, Web of Science and PubMed. Only 30 research studies (one of them reported 8 cases) were included for review, as shown in Figure 1.

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The case concerns a 19-year-old Saudi female patient with a known history of SLE, diagnosed 3 weeks prior at a private hospital based on inflammatory arthritis and pleural effusion (serositis), with positive anti-nuclear anti body (ANA) and anti-double-stranded DNA (anti-dsDNA) antibodies. Three days after the diagnosis, she had been admitted to another hospital for 5 days due to pleuritic chest pain and joint pain, receiving antibiotic coverage with GCs before being discharged. The patient was stable and had no further complaints. One day after discharge, patient experienced recurrent symptoms of chest pain and shortness of breath, prompting her visit to our emergency department. The patient was admitted under internal medicine as a case of pneumonia and started on intravenous (i.v.) antibiotics with rheumatology consultation to investigate the underlying cause of her symptoms, whether related to infection or disease activity.

Patient history Upon reviewing the patient’s history, patient reported having pleuritic chest pain associated with shortness of breath upon exertion and hair loss for the last 3 days. The patient denied any history of headache, seizures, depression, blurred vision, double vision, malar rash, photosensitivity, Raynaud’s phenomenon, dry eyes, dry mouth, abdominal pain, or bleeding from other sites, and other systemic reviews were unremarkable. There was no family history of underlying connective tissue disease.

Physical examination Upon examination, the patient was conscious, alert, and oriented. Vital signs were stable (blood pressure: 120/68, heart rate: 82, oxygen saturation: 96% on room air, temperature: 36.9°C). Chest examination revealed decreased air entry on the left side with crackles. Cardiovascular examination showed normal heart sounds (S1, S2 + 0). The abdomen was soft and lax, and there was no edema in the lower limbs. Systemic examination was otherwise unremarkable.

Clinical examination The laboratory findings revealed several significant abnormalities suggestive of an underlying autoimmune and inflammatory disorder. The patient presented with marked anemia, evidenced by low hemoglobin (Hb; 8.1 g/dl), reduced serum iron (9.22 µg/dl), low total iron-binding capacity (62.15 µg/dl), and decreased transferrin saturation (15%), consistent with anemia of chronic disease or autoimmune hemolytic anemia.

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This was further supported by a positive Coombs test. Inflammatory markers were elevated, with an erythrocyte sedimentation rate (ESR) of 120 mm/h and a mildly elevated rheumatoid factor of 30 IU/ml, indicating an active systemic inflammatory process. The immunological evaluation revealed hypergammaglobulinemia (immunoglobulin G: 3,010 mg/dl) with low complement C4 levels and normal C3, and a normal thyroid profile, also favoring autoimmune etiology. There was an additional notable observation of severe vitamin D deficiency at 11 ng/ml, which is commonly found in chronic inflammatory conditions. Renal parameters were relatively preserved, with a mild reduction in creatinine (39 µmol/l), still within the normal reference range. Hence, overall findings indicate systematic active autoimmunity. Imaging studies revealed bilateral pleural effusion, more pronounced on the left side, moderate pericardial effusion (PCE), and evidence of compression atelectasis on CT chest. A transthoracic echocardiogram confirmed normal left ventricular systolic function (ejection fraction > 65%) with no tamponade. These findings pointed to SLE activity with possible concurrent infection.

Chest X-ray findings and contrast-enhanced computed tomography of the chest A chest X-ray was performed to assess the extent of pulmonary and pericardial involvement. As illustrated in Figure 2, the chest X-ray showed bilateral pleural effusion, with more fluid present in the left lung. Also, the patient underwent contrast-enhanced CT of the chest, which showed that the main pulmonary trunk and bilateral main branches appeared patent with no clear filling defect. The trachea and bilateral main airways were patent. No pneumothorax could be noted, with mild to moderate bilateral pleural effusion, more marked on the left side. To sum up, the CT chest and X-ray findings were consistent with SLE-related serositis, presenting as moderate PCE and bilateral pleural effusions, more marked on the left. The associated basal lung atelectasis was likely secondary to compressive effects of the effusion. No evidence of pulmonary embolism, airway obstruction, or parenchymal consolidation was noted. These findings support a diagnosis of active SLE with pleuropericardial involvement and no current radiological evidence of infection or other complications.

Final diagnosis and impression The rheumatology team’s impression pointed towards SLE activity, specifically serositis, possibly triggered by an underlying infection. Antibiotic coverage was initiated. Another differential diagnosis to consider

Fig. 2. Chest X-ray showing bilateral pleural effu sion, with more fluid present in the left lung. is lupus pneumonitis, potentially secondary to infection or SLE activity. To determine the cause, the patient will be observed on antibiotics for 72 hours. If there is no response or deterioration, SLE activity is considered the more likely cause. Additionally, infection from Pneumocystis jirovecii pneumonia should be considered, particularly if the patient has been on high doses of GCs, although this information is not currently confirmed.

Treatment plan Figure 3 outlines a comprehensive treatment plan involving various investigations and procedures aimed at assessing organ function, detecting infections, monitoring disease activity, and evaluating immune and renal functions.

Pharmacological management Patient was treated with methylprednisolone (500 mg i.v. for 3 days), hydroxychloroquine (HCQ; 200 mg p.o. twice daily), and supportive measures including calcium supplementation and intravenous immunoglobulins (IVIG; 1 mg/kg for 2 days), as shown in Figure 4. After starting the previously mentioned management, her condition improved significantly during the hospital stay, and she was discharged on a high-dose GC taper. One month later, the patient presented with recurrent symptoms despite treatment adherence. In the rheumatology outpatient clinic, patient was started on MMF 2 g daily, with RTX considered as a potential escalation in therapy for refractory disease.

Discussion This case illustrates a rare presentation of pleuropericardial effusion as the initial sign of SLE and highlights the difficulty in managing SLE-related serositis in a young patient. A 19-year-old female patient came to the hospital with bilateral pleural effusion, moderate

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CBCD, LFFT, KFT, bone profile

SLE-related pleuropericardial effusion

To assess baseline organ function and electrolytes

Cardiac panel

AND

Full septic screen

ESR, CRP To monitor inflammatory markers and assess disease activity

To evaluate heart function and detect any abnormality

AND

Infection suspected/confirmed

Yes

Continue antibiotics Start methylprednisolone 500 mg i.v. for 3 days

HIV, HCV, HBV Screening for viral infections

To rule out underlying infections

Add hydroxychloroquine 200 mg p.o. twice daily VDRL, vitamin D, vitamin B12

AND

To evaluate immune response and detect infections

To screen for syphilis

C3, C4, RF

AND

To assess for proteinuria indicating kidney involvement

Repeat CXR To monitor pleural effusion and lung condition

Lupus anticoagulant Add calcium 600 mg p.o. once daily for bone health

Urine protein-creatinine ratio

Intravenous immunoglobulin 1 mg/kg i.v. for 2 days

To evaluate renal function and proteinuria levels

AND

Follow the results of COVID-19 To assess for any COVID-19 related complications

Fig. 3. Investigative algorithm for systemic lupus erythematosus-related pleuropericardial effusion. C3 – complement component 3, C4 – complement component 4, CBCD – complete blood count with differential, COVID-19 – coronavirus disease 2019, CRP – C-reactive protein, CXR – chest X-ray, ESR – erythrocyte sedimentation rate, HBV – hepatitis B virus, HCV – hepatitis C virus, HIV – human immunodeficiency virus, IgA – immunoglobulin A, IgG – immunoglobulin G, IgM – immunoglobulin M, KFT – kidney function tests, LFFT – liver function tests, RF – rheumatoid factor, VDRL – Venereal Disease Research Laboratory test.

PCE, and moderate activity of SLE according to laboratory markers including ESR, positive ANA, and anti-dsDNA antibodies. Even after treatment with GCs and antibiotics for presumed infection, her recurrence of symptoms highlighted the importance of differentiating between the infection and SLE activity in the patient. Immunosuppressive therapy is also highlighted in the management of the disease in ensuring disease control when she improved clinically following a high dose of GCs, HCQ, and IVIG, with the addition of MMF for refractory symptoms.

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Add omeprazole 40 mg i.v. once daily for gastrointestinal protection

To evaluate for anticoagulant presence related to SLE

To assess for autoimmune activity, specifically SLE

24-hour urine protein

IgM, IgG, IgA

Refractory/recurrent? Yes

Start mycophenolate mofetil 2 g daily + rituximab

Continue maintenance + taper GCs

Fig. 4. Therapeutic algorithm for pharmacologi cal management of systemic lupus erythemato sus (SLE)-related pleuropericardial effusion. GCs – glucocorticosteroids.

A study carried out in 2024 revealed an uncommon manifestation of SLE with cardiac tamponade and pleural effusion as apparent signs at the initial assessment. Their patient presented with severe dyspnea and systemic inflammation with both ESR levels and anti-dsDNA antibodies upregulated. Hence, GCs were used. This correlates with the pleuropericardial involvement in our case, but in terms of severity, our patient had no tamponade but had only moderate pleural effusion. However, both cases underscore the diagnostic challenge of distinguishing between SLE serositis and infection, a recurring theme in SLE management. The researcher focus on echocardiography for monitoring tamponade is reflected in our case, emphasizing its utility in evaluating effusion dynamics [6, 7].

Pleuropericardial effusion in early systemic lupus erythematosus

In 2015, a group of scientists investigated pleural effusions associated with SLE and distinguished lupus pleuritis from non-lupus causes. They observed increased pleural fluid ANA titers (≥ 1 : 160) and strikingly low pleural fluid-to-serum complement ratios in lupus pleuritis, consistent with inflammatory activity. The unexplained pleural fluid ANA and complement tests were instrumental in ruling out non-lupus effusions and created a diagnostic path for the patient. While this case turned out positive for the Coombs test and low C4, the pleural fluid analysis that was performed in the study could have provided the much-needed diagnostic clarity. Glucocorticosteroids were effective, the scientists reported, with remission on these drugs mirroring that of our patient after GC treatment [8]. A study investigated the management of systemic inflammatory conditions such as adult-onset Still’s disease, emphasizing the role of interleukin (IL)-1 and IL-6 inhibitors alongside GCs. While the focus was not directly on SLE, the principles of managing systemic inflammation overlap with our case. The study advocated minimizing GC dependence to reduce adverse effects, an approach echoed in our patient’s transition to MMF for long-term management. The recurrent pleuropericardial effusion in our patient reflects the persistent inflammatory mechanisms reported by Cheo and Low [9], reinforcing the importance of targeted immunosuppressive therapy in chronic autoinflammatory conditions. A group of scientists analyzed 5,679 pediatric SLE admissions, identifying 705 cases with PCE and noting higher mortality (2.4%) and readmission risks. This aligns with our case, where PCE marked severe SLE activity, but our 19-year-old patient responded well to GCs and HCQ without complications. This is in concordance with our case wherein PCE indicated severe SLE activity although the 19-year-old patient had a favorable response to GC and HCQ with no complications. Also, our patient had systemic inflammation with anemia (Hb 8.1 g/dl) and low C4, but she had a less severe disease duration with moderate pleuropericardial effusion and stabilization after early treatment. The pediatric population researcher had higher severity and the recurrence of symptoms. In contrast, our patient remained stable without requiring intensive intervention [10]. A 40-year-old female patient was diagnosed with SLE after having moderate PCE and exertional dyspnea. Diagnostic strategies include echocardiography, ANA, and positive anti-dsDNA as well as ruling out other causes including viral infections and malignancies. Methylpredni solone in high dose brought about complete improvement in symptomatology and disappearance of effusion. This case is in concordance with our case, primarily associated with pleuropericardial involvement and GC treatment

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which improved acute manifestations. However, due to the presence of effusion and disease activity in our patient, the clinical course was more severe and refractory, requiring treatment with MMF. In both cases, imaging and serological markers are discussed as tools for differentiating SLE activity from other causes of serositis [11]. Tocilizumab (TOCI), an IL-6 receptor antagonist, was used for managing recurrent, nonresponsive effusions involving the pleura and pericardium of a 22-year-old patient with SLE. The patient, whose condition did not improve with GCs and immunosuppressants, had no effusion after receiving TOCI, exhibiting the effectiveness of cytokine-targeted therapy in SLE-associated serositis. In contrast, our patient initially responded positively to GCs and HCQ, but recurrent symptoms required the introduction of MMF. The potential future treatment approach is biologic therapies in cases of refractory or recurrent serositis, providing a future pathway. Both cases highlight inflammation of serositis in SLE and the role of new immunosuppressive approaches [12]. In one report, a 47-year-old Iranian woman with massive PCE as the initial manifestation of SLE was dia gnosed through ANA positivity, elevated anti-dsDNA, and Systemic Lupus International Collaborating Clinics (SLICC) criteria, and successfully treated with prednisolone, HCQ, and MMF over 6 months. While our patient presented with moderate pericardial and pleural effusion without tamponade, this case aligns with our case in highlighting the importance of immunosuppressive therapy in managing SLE-associated serositis. Our patient’s earlier need for MMF suggests a more refractory disease course. These cases underscore the role of echocardiography in monitoring effusion resolution and disease activity, despite differences in severity. Both cases emphasize the challenge of distinguishing lupus activity from infection [13]. In another case, an 11-year-old girl with pediatric lupus, who developed myocarditis, pulmonary hypertension, and a huge PCE, was treated successfully with methylprednisolone, IVIG, and CYC, entering long-term remission. Although our case was not complicated by myocarditis or pulmonary hypertension, it shares the inflammatory nature of SLE-associated serositis and the requirement for immunosuppressive therapies. Unlike the pediatric case that needed more advanced therapies, our patient did respond to GCs and HCQ, but with the recurrence of pleuropericardial effusion, advanced treatment options may need to be explored. Both cases highlight the difficulty of discriminating the activity of lupus from infection, which was addressed in our case by close monitoring and coverage with antibiotics [14]. In another report, a 35-year-old Sudanese woman, afflicted by a massive unilateral pleural effusion caused

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by SLE, as confirmed by systemic markers of inflammation and serological tests, required RTX after conventional treatment failed. Compared to this, our case showed bilateral pleural and moderate PCE with a good initial response to GCs and HCQ, implying a mild course. However, the recurrence of pleuropericardial effusion may be an indication for more aggressive biologics such as RTX, as used in the other case. Both cases highlight pleural effusion as a serious lupus manifestation with indications for aggressive immunosuppression and thorough diagnostic workup. The report stresses that in refractory or recurrent SLE-associated serositis, treatment escalation is crucial [15]. A pediatric case of pericarditis and PCE as the initial manifestation of SLE was described in a 7-year-old girl diagnosed through serological markers and echocardio graphy. Likewise, in our case, a 19-year-old patient with recurrent pleuropericardial effusion and SLE markers presented in a milder clinical state without severe systemic manifestations. Both cases were treated with GCs and appropriately tailored immunosuppressive therapy, using azathioprine in the pediatric case and MMF for our patient in view of the recurrence. The studies stress timely intervention, clinical imaging, and serological investigation, lessening age-related distinctions in the severity of the illness. Pediatric cases tend to need aggressive early immunosuppression due to the more severe initial presentation [16]. A 63-year-old woman with SLE was diagnosed via cytology of pleural effusion, experiencing chest pain, dyspnea, and recurrent effusions which resolved with GCs and HCQ. In our case, however, pleuropericardial effusion was ANA and anti-dsDNA positive, and SLE was confirmed on serological markers and imaging. Both cases highlight the inflammatory basis of SLE-associated serositis and the effectiveness of GCs, though our patient’s chronic symptoms necessitated MMF. These findings emphasize detailed diagnostics for atypical SLE and underscore the need for vigilant follow-up and advanced treatments for recurrent disease [17]. Another rare initial manifestation of SLE could be fibrinous constrictive pericarditis with large PCE, as has been recorded in a 36-year-old man who was found to have raised ANA and anti-dsDNA levels, confirming the diagnosis. The patient received treatment with non-steroidal anti-inflammatory drugs, GCs, and HCQ, and was free of symptoms in 6 weeks. Our patient had pleuropericardial involvement just as in that case; however, the effusion was of moderate quantity, without any fibrinous constrictive feature, and it proceeded to have a relapsing course after a brief remission with immunosuppressive therapy, thus requiring MMF therapy. These cases illustrate the importance of imaging, such

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as Doppler echocardiography, in diagnosing SLE-related pericarditis and effusion but also highlight the need to carefully rule out infection. The patient previously discussed improved rapidly; however, our case serves as a reminder that these patients may develop a recurrence requiring longer-term immunosuppressive treatment [18]. Severe cardiac compromise in new-onset SLE, including tamponade and antiphospholipid syndrome (APS), represents a grave autoimmune serositis mani festation. An 18-year-old girl with such a presentation needed emergency pericardiocentesis, GCs, and plasmapheresis in view of complications of respiratory failure. Both cases highlight the autoimmune nature of serositis and the importance of early diagnosis to avert severe outcomes, unlike our patient, who never experienced tamponade. Though our patient stabilized initially with GC therapy and HCQ, the later exacerbation of symptoms reflects the difficulties in treating refractory SLE. Complement monitoring (low C3 and C4) proved instrumental in evaluating disease activity in both instances. This emphasizes SLE’s aggregate systemic inflammatory burden, its overlap with APS, and the need for indivi dualized multimodal therapy [19]. A patient with juvenile-onset SLE and treatmentresistant pleural effusion was, after only a modest response to GCs and MMF, successfully treated with TOCI, illustrating the importance of IL-6 in lupus pleuritis. Our patient, having bilateral pleural and PCE, responded first to GCs and HCQ and then later to MMF, showing that the illness course was less refractory. These 2 cases emphasize the inflammatory nature of SLE-associated serositis and support effective immunosuppression. In contrast to our case, managed according to standard protocols, the second report suggests IL-6 blockade as a potential option for persistent effusions. These cases, therefore, highlight the need for early intervention and later escalation to target therapy in refractory scenarios [20]. A 20-year-old woman with lupus myocarditis and PCE initially presented with left ventricular failure and was diagnosed with SLE upon ANA and anti-dsDNA anti bodies. Since myocardial involvement is rare in lupus patients compared with pericarditis, early diagnosis and treatment with high-dose GCs significantly improved the situation. Our patient, on the other hand, developed moderate PCE with no myocarditis and cardiac failure but shared the diagnostic challenge of deciding between lupus activity and infection. The diagnosis in both cases was aided by echocardiography and biomarkers, with low complement levels indicating active lupus. The above-mentioned patient then responded well to GCs, whereas ours required MMF for recurring symptoms. This clearly delineates the distinct type of respons-

47 F

35 F

11 F

8 cases

24 F

22 F

Adult F

24 F

37 F

Kavandi et al. [13]

Khatieb et al. [15]

Chen et al. [14]

Weich et al. [24]

Alghamdi et al. [25]

Ocampo et al. [12]

Shalomi and Ramesh [26]

Amro et al. [6]

Barradas et al. [27]

–

Saudi Arabia

–

Canada

–

South Africa

Taiwan

Sudan

Iran

Saudi Arabia

Country

Pericardial effusion; initial manifestation

Large pericardial effusion with early tamponade

Pericardial; tamponade

Pleural + pericardial; moderate

Pleural + pericardial; tamponade

Large pericardial effusion (some with tamponade)

Pericardial; severe

Pleural; massive, refractory

Pericardial; massive

Bilateral pleural + moderate pericardial; no tamponade

Effusion type and severity

Empyematous pleural Sterile empyematous effusion pleural effusion (associated with SLE)

Chest pain, SOB

Severe pulmonary hypertension + chest pain

Cardiac tamponade

Recurrent effusions

Dyspnea, chest pain

Myocarditis, PAH, massive PE

Unilateral effusion

Dyspnea

Chest pain, SOB

Initial presentation

ANA+, anti-dsDNA+

ANA+, anti-dsDNA+, low complements

ANA+, anti-dsDNA+

CXR: pleural effusion

Echo: moderate effusion

Echo: large pericardial effusion

Echo: tamponade

Echo and CXR: recurrent effusions

Echo: tamponade

↑ ESR, ANA+, ↑ anti-dsDNA ANA+, ↑ anti-dsDNA

Echo: large effusion; some tamponade

Echo: massive pericardial effusion

CXR: unilateral PE

ANA+, anti-dsDNA+, low C3/C4

ANA+, ↑ anti-dsDNA, low C3/C4

ANA+, ↑ anti-dsDNA

Echo: large effusion

CXR and CT: bilateral pleural effusion; echo: moderate pericardial effusion

↑ ESR, ANA+, ↑ anti-dsDNA, low C4 ANA+, ↑ anti-dsDNA

Imaging findings

Key labs

GCs; management of infection suspicion

GCs

GCs, diuretics, immunosuppressives

GCs + pericardiocentesis

TOCI

GCs

GCs + drainage

GCs, IVIG, CYC

RTX

GCs, MMF, HCQ

GCs, HCQ, IVIG, MMF

Treatment

Resolved

No recurrence

Remission

Resolved

Improved; stable

Outcome

ANA – anti-nuclear antibody, anti-dsDNA – anti-double-stranded DNA, C3 – complement component 3, C4 – complement component 4, CT – computed tomography, CYC – cyclophosphamide, CXR – chest X-ray, ESR – erythrocyte sedimentation rate, F – female, GCs – glucocorticosteroids, HCQ – hydroxychloroquine, IVIG – intravenous immunoglobulins, MMF – mycophenolate mofetil, PAH – pulmonary arterial hypertension, PE – pulmonary embolism, RTX – rituximab, SLE – systemic lupus erythematosus, SOB – shortness of breath, TOCI – tocilizumab, ↑ – increased.

Adult F

19 F

Bakhsh – current case (2024)

Kriegel et al. [28]

Age, sex

Author

Table II. Clinical characteristics, differences, and treatment outcomes of SLE-associated pleuropericardial effusion cases (including the present case)

Pleuropericardial effusion in early systemic lupus erythematosus

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es to treatment, which means that long-term monitoring and physician-guided treatment are warranted [21]. The initial SLE manifestation was myopericarditis and PCE in a 35-year-old female patient with complaints of chest pain, dyspnea, and systemic inflammation confirmed by elevated cardiac biomarkers, low complement levels, and positive ANA. High-dose intravenous methylprednisolone treatment led to symptom resolution, with no recurrence being reported following therapy. In contrast, our patient had SLE-associated serositis without myocardial involvement or elevated cardiac enzymes, subsequently being diagnosed with transthoracic echocardiography and laboratory markers for SLE-associated serositis and requiring further immunosuppressive the rapy. Glucocorticosteroids as treatment and imaging for cardiac involvement were significant therapeutic considerations in both cases, suggesting that more advanced imaging methods such as cardiac magnetic resonance imaging may be useful for investigating future suspected myocardial involvement. Differences in clinical evolution and treatment outcomes were also observed in these cases [22]. The upcoming therapies are biologics, and they serve well in refractory SLE-associated serositis. A 51-yearold woman with SLE-associated pleuropericarditis not responding to standard treatment was able to achieve an extended remission period on belimumab, a B-celltargeted biologic. This case highlights the role of biolo gics in managing refractory SLE-associated serositis, contrasting with our patient, who responded initially to GCs and HCQ but required MMF for symptom recurrence. Both cases emphasize early intervention and treatment escalation in refractory disease, with belimumab as a potential option if conventional therapies fail. The study underscores the evolving role of biologics in reducing disease activity and GC dependency, stressing personalized strategies for managing SLE-associated serositis [23]. Table II summarizes the characteristics of the presented cases (including the current case) and additional reported cases of SLE-associated pleuropericardial effusion, including clinical differences and treatment approaches.

Study limitations and future implications The patient’s treatment response varies, which is a limitation of this study. It suggests that the differing effects of GC regimens require individualized therapeutic approaches. On the other hand, duality in diagnosis – abnormal echocardiography and increased biomarkers – may fail to convey the very essence of lupus cardiac angina, thus requiring further diagnostic criteria. The future management of SLE-associated serositis is likely to emphasize early diagnosis and specific individualized

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treatment plans. A biologic agent such as belimumab may become an appropriate alternative for treating refractory cases and thus reducing GC use. Cardiac MRI may further refine diagnosis, and targeted therapies along with immunosuppressive agents will be refined through ongoing research to provide better treatment outcomes that offer better solutions to face the challenges of SLE, and to prevent recurrence of pleuropericardial effusions.

Conclusions Pulmonary manifestations, especially pleuritis with pleural effusion, raise significant diagnostic challenges in SLE. Early recognition and differentiation from infectious to autoimmune causes are crucial for treatment. Treatment mainly consists of GCs in an autoimmune scenario. If the symptoms persist or recur, immunosuppressants should be considered. Such differences in therapeutic responses suggest an individualized approach. Early aggressive treatment to reduce disease activity and prevent recurrence is paramount.

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