reumatologia / rheumatology 4/2026

issn 0034 - 6233

bimonthly journal

2026

vol. 64, 4

Advancing clinical trial designing, reporting, and publishing Inclusivity in clinical trials Fracture risk prediction in Polish women aged ≥ 50 Methotrexate-related beliefs and fears in rheumatoid arthritis Central nervous system autoimmunity: advances in therapy Thrombosis in Sjögren’s disease Treatment of idiopathic retroperitoneal fibrosis CD19-targeted chimeric antigen receptor T-cell therapy in systemic sclerosis Clinical trials in rheumatology MicroRNAs in osteoporosis: current evidence and clinical perspectives Tjalma syndrome in late-onset systemic lupus erythematosus

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

4/2026 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)

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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

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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

Publication funded by the state budget under the program of the Minister of Science and Higher Education named „ Wektory Nauki”, project no. WNK/SN/0130/2025/01, project funding amount: PLN 117,570.00, total project value: PLN 147,070.00.

Publikacja finansowana ze środków budżetu państwa w ramach programu Ministra Nauki i Szkolnictwa Wyższego pod nazwą „Wektory Nauki” nr projektu WNK/SN/0130/2025/01, kwota finansowania projektu 117 570,00 zł, całko­ wita wartość projektu 147 070,00 zł.

Contents

Reumatologia 2026; 64, 4: 263–352

Editorial papers 263

Advancing clinical trial designing, reporting, and publishing Burhan Fatih Kocyigit, Olena Zimba

266

Inclusivity in clinical trials Maria Maślińska

Original papers 270

Fracture risk prediction based on multivariable diagnostic models incorporating dual-energy X-ray absorptiometry‑based bone mineral density, trabecular bone score, and clinical risk factors in women aged ≥ 50 years: a prospective study Maja Warzecha, Edward Czerwiński, Jarosław Amarowicz

280 Methotrexate-related beliefs, fears, and use among patients with rheumatoid arthritis: a cross-sectional survey L’heri Hind, Rkain Hanan, Farih Sara, Tahiri Latifa, Kronbi Fatine, Abouqal Redouane, Hajjaj-Hassouni Najia, Allali Fadoua

Review papers 287

Autoimmune inflammatory diseases of the central nervous system: advances in clinical trials and immunotherapeutic strategies Mateusz Gumienny

296

Risk of venous, arterial, and rare thrombotic events in adults with Sjögren’s disease: a systematic review and meta-analysis Anamitra Hait, Arbind Kumar Choudhary, Panneerselvam Periasamy, Kothai Ramalingam, Balasubramanian Arul

313 322

Pharmacological treatment of idiopathic retroperitoneal fibrosis Adrianna Niksińska, Robert Kruszewski, Witold Tłustochowicz The role and potential of CD19-targeted chimeric antigen receptor T-cell therapy in systemic sclerosis Krzysztof Michalak, Gabriela Chlebowska, Oliwia Sędziak, Dariusz Woszczyk

332 Clinical trials in rheumatology: patient motivations and concerns as key determinants of recruitment Marta Jeka 338

MicroRNAs in osteoporosis: current evidence and clinical perspectives Marta Świecka, Michał Chmielewski

Case-based review 345

Tjalma syndrome in late-onset systemic lupus erythematosus Ivan Jeremic, Bojana Simeunovic, Slavica Pavlov Dolijanovic

Editorial paper

Reumatologia 2026; 64, 4: 263–265 DOI: https://doi.org/10.5114/reum/225916

Advancing clinical trial designing, reporting, and publishing Burhan Fatih Kocyigit1 ID , Olena Zimba2,3,4 ID 1

Department of Physical Medicine and Rehabilitation, University of Health Sciences, Adana City Research and Training Hospital, Türkiye 2 Department of Rheumatology, Immunology and Internal Medicine, University Hospital in Krakow, Poland 3 National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland 4 Department of Internal Medicine N2, Danylo Halytsky Lviv National Medical University, Ukraine

Introduction Clinical trials are essential for evidence-based practice guidelines in rheumatology and physical medicine and rehabilitation (PMR). Since both rapidly developing disciplines address chronic, complex, and variable diseases, clinical trial planning requires testable hypothesis formulation, study designing, and reflection on ethical and clinical outcomes [1]. Editorials highlight current developments and offer objective, evidence-based expert opinions [2]. This edi­ torial aims to highlight the importance of clinical trials, outline best practices for designing and reporting, discuss quality evaluation, and propose strategies for boosting implications at the societal level.

Evidence shaping guidelines Randomized controlled trials (RCTs) provide the most unbiased assessment of clinical interventions for contributing to the highest level of evidence. In rheumatology, RCTs are the primary source for evaluating drug therapies in terms of their effects on disease activity, radiographic progression, and comorbidities. In PMR, RCTs are designed to assess interventions ranging from exercise therapies to injection techniques and multidisciplinary rehabilitation programs. The European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) practice guidelines, as well as the Outcome Measures in Rheumatology (OMERACT) core outcome sets, are based on a synthesis of these trials using the GRADE approach. Trial design weaknesses may directly influence the strength of related practice guidelines. Notably, the superiority of RCTs is limited in PMR because randomization is often not feasi-

ble and at times unethical. Practice guideline developers should explicitly address these design limitations when synthesizing evidence.

Registration and reporting Prospective registration of trials is an essential practice that upholds research integrity and prevents redundancies in the field. The International Committee of Medical Journal Editors (ICMJE) generally expects regi­ stration in a registry associated with ClinicalTrials.gov or the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) network prior to the enrollment of subjects as a precondition for publication in member journals; ethics approvals without trial registration are sufficient [3]. In 2025, a major update was introduced: the CONSORT guidelines for reporting completed trials and the SPIRIT guidelines for protocols were revised collaboratively by a working group and published in several leading medical journals [4, 5]. The revised guidelines place greater emphasis on harm assessment, comprehensive description of interventions, and patient and public involvement. This is particularly important for PMR studies, where a precise definition of intervention components, including dose, frequency, duration, and practitioner qualifications, is necessary for reproducibility. The Template for Intervention Description and Replication (TIDieR) extension serves as a complementary tool to CONSORT for specifying nonpharmacological interventions. Survey-based studies, often filling gaps in the fields, should also provide details of respondent awareness and attitudes toward interventions in rheumatology and PMR, with openly displaying questionnaires as a prerequisite for successful publication [6].

Address for correspondence Dr. Burhan Fatih Kocyigit, Department of Physical Medicine and Rehabilitation, University of Health Sciences, Adana City Research and Training Hospital, Dr. Mithat Özsan Boulevard, Kışla District, 4522th Street No: 28, Yüreğir/Adana, Türkiye, postal code: 01260, e-mail: bfk2701@hotmail.com Submitted: 13.07.2026; Accepted: 14.07.2026; Published online: 17.07.2026 Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)

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Quality assessment Publication alone does not guarantee the reliability of a trial. The Cochrane RoB 2 tool identifies five domains where bias may occur, categorizing them as “high risk of bias,” “some concerns,” or “low risk of bias.” The domains addressing deviations from intended interventions and measurement of the outcome require particular scrutiny in studies where blinding is challenging [7]. At the level of evidence synthesis, the GRADE approach evaluates the certainty of a body of evidence based on risk of bias, inconsistency, indirectness, imprecision, and publication bias. In rheumatology, the OMERACT filter 2.0 stipulates that outcome measures must demonstrate “truth,” “discrimination,” and “feasibility” to be suitable for clinical trials [8]. For PMR, physiotherapy-specific instruments such as the PEDro scale assess methodo­ logical quality using similar criteria. The evidence base of the peer-review process is yet another critical point, variably enforced by journals and thereby affecting the quality of publications, including clinical trials [9].

Hypothesis, design, and ethics A valuable trial planning starts with formulating a hypothesis, derived from available evidence base, unusual clinical observations, and clinicians’ curiosity [10]. The choice of study design should align with the hypothesis: parallel group RCTs are optimal for assessing efficacy, pragmatic studies evaluate real-world applicability, adaptive designs assess flexibility, and N-of-1 studies – where different interventions are applied to the same patient in a randomized sequence over multiple pe­ riods – are particularly valuable for conditions such as chronic pain. Challenges in randomization, commonly encountered in PMR research, can be mitigated through evaluator blinding, the use of predefined objective out-

Burhan Fatih Kocyigit, Olena Zimba

come measures, and the implementation of an appropriate sham or control arm. Ethical implications should be envisaged at the hypothesis formulation stage [10]. Adherence to the revised principles of the Declaration of Helsinki (October 2024), independent ethics committee approval, informed consent, and a reasonable risk-benefit balance are essential. The evolving role and structure of ethics committees in this process are increasingly discussed [11]. The use of placebo in patients with active disease may be viewed as unethical. Each hypothesis should also establish its clinical applicability from the outset by defining clinically significant difference thresholds, to prevent confusion between statistical significance and clinical importance.

Citations and the societal impact The adherence to available research reporting standards enhances inclusion of publications in systematic analyses and evidence synthesis, which may increase impact citation-wise. Nowadays, the dissemination of open-access publications confers a measurable citation advantage [12]. Social media platforms have emerged as impactful tools for increasing visibility, although its effect on long-term citation rates remains uncertain [13]. Altmetric indicators capture societal impact beyond traditional citations and add to glo­bal exposure of clinical trial reports and related practice guidelines. Engagement with the public via reputable social media platforms is increasingly recognized in the context of the adoption of research findings by both clinicians and decision-makers [14, 15]. Reporting quality, accessibility, open data sharing, and societal impact represent interdependent and complementary components, though none are sufficient in isolation. The overall trajectory from hypothesis formulation to societal impact is summarized in Figure 1.

Fig. 1. From hypothesis to societal impact: the cycle of a clinical trial.

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Advancing clinical trial designing, reporting, and publishing

Conclusions In rheumatology and PMR, clinical trials are fundamental to the process that transforms a hypothesis into clinically applicable guideline recommendations. Evidence-based hypotheses formulation, appropriately chosen trial design, ethical conduct, and transparent registration and reporting are mutually dependent. Any deficiency in these areas diminishes the strength of the evidence that contributes to practice guidelines. Addressing these interdependent elements comprehensively enhances both the value of individual trial reports and the credibility of evidence-based medicine. Researchers, editors, and reviewers share the responsibility of enforcing trial reporting standards and results in their daily practice.

Disclosures Conflict of interest: The authors declare no conflict of in­ terest. Funding: No external funding. Ethics approval: Not applicable. Data availability: Not applicable. References 1. Gasparyan AY, Ayvazyan L, Mukanova U, et al. Scientific hypo­ theses: writing, promoting, and predicting implications. J Korean Med Sci 2019; 34: e300, DOI: 10.3346/jkms.2019.34.e300. 2. Coskun Benlidayi I, Gupta L. Concise Recommendations for EDitorials: Enhancing Narratives and Composition Effectively (CREDENCE). J Korean Med Sci 2024; 39: e338, DOI: 10.3346/ jkms.2024.39.e338. 3. International Committee of Medical Journal Editors. Clinical trials registration. Available from: https://www.icmje.org/abouticmje/faqs/clinical-trials-registration/ (Access: 12.07.2026).

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4. Hopewell S, Chan AW, Collins GS, et al. CONSORT 2025 state­ ment: updated guideline for reporting randomised trials. Lancet 2025; 405: 1633–1640, DOI: 10.1016/S0140-6736(25)00672-5. 5. Chan AW, Boutron I, Hopewell S, et al. SPIRIT 2025 statement: updated guideline for protocols of randomised trials. Lancet 2025; 405: e19–e27, DOI: 10.1016/S0140-6736(25)00770-6. 6. Zimba O, Gasparyan AY. Designing, conducting, and reporting survey studies: a primer for researchers. J Korean Med Sci 2023; 38: e403, DOI: 10.3346/jkms.2023.38.e403. 7. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898, DOI: 10.1136/bmj.l4898. 8. Boers M, Kirwan JR, Wells G, et al. Developing core outcome measurement sets for clinical trials: OMERACT filter 2.0. J Clin Epidemiol 2014; 67: 745–753, DOI: 10.1016/j.jclinepi.2013.11.013. 9. Zimba O, Gasparyan AY. Peer review guidance: a primer for researchers. Reumatologia 2021; 59: 3–8, DOI: 10.5114/reum. 2021.102709. 10. Misra DP, Gasparyan AY, Zimba O, et al. Formulating hypo­ theses for different study designs. J Korean Med Sci 2021; 36: e338, DOI: 10.3346/jkms.2021.36.e338. 11. Mehta P, Zimba O, Gasparyan AY, et al. Ethics committees: structure, roles, and issues. J Korean Med Sci 2023; 38: e198, DOI: 10.3346/jkms.2023.38.e198. 12. Zimba O, Radchenko O, Strilchuk L. Social media for research, education and practice in rheumatology. Rheumatol Int 2020; 40: 183–190, DOI: 10.1007/s00296-019-04493-4. 13. Zimba O, Gasparyan AY. Social media platforms: a primer for researchers. Reumatologia 2021; 59: 68–72, DOI: 10.5114/ reum.2021.102707. 14. Zimba O, Korkosz M, Alnaimat F, et al. Global practice guide­ lines in rheumatology: a cross-sectional altmetric and citation analysis. Rheumatol Int 2025; 45: 150, DOI: 10.1007/s00296025-05899-z. 15. Roberts-Lewis S, Baxter H, Mein G, et al. Examining the ef­ fectiveness of social media for the dissemination of research evidence for health and social care practitioners: systema­ tic review and meta-analysis. J Med Internet Res 2024; 26: e51418, DOI: 10.2196/51418.

Reumatologia 2026; 64/4

Editorial paper

Reumatologia 2026; 64, 4: 266–269 DOI: https://doi.org/10.5114/reum/225902

Inclusivity in clinical trials Maria Maślińska ID  Department of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland

Clinical trials, with their complex legal and ethical regulations, impose stringent requirements concerning appropriate research methodology, which is focused on examining the most representative aspects of the given clinical problem. While such trials are concentrated on proving safety and efficacy of the tested substance or procedure for the majority of patients, it is may miss out on complications that are inherently associated with a specific minority of individuals. Understanding this aspect is crucial for the researchers themselves, as well as other professionals, most prominently ethicists, who are working on establishing legal and regulatory framework for clinical trials.

Inclusivity The adjective “inclusive” refers to something that includes or encompasses a broad spectrum (or even all) of given objects. By definition, something that is inclusive should be intended for everyone; there are no criteria for defining access to it because it is universal. Thus, “inclusive” is the opposite of “exclusive,” meaning something intended for a select, limited group [1, 2].

How to understand and implement inclusivity in clinical trials In clinical trials, inclusivity means recruiting diverse patient groups – taking into account gender, age, race, and ethnicity. This approach aims to ensure reliable results and assess the tested molecule for the entire population, taking into account geoepidemiological differences. Currently, emphasis is placed on ensuring that study groups reflect the actual demographics of patients with a given disease. Participants in clinical trials often do not reflect the populations for which healthcare interventions are needed or will be used. Enhancing the representation of under-represented groups in clinical research is important to ensure that research findings are widely applicable. Is it always possible to provide fully representative study groups? While obtaining a “perfect” study group

is close to impossible, it is still important to prepare for various variables related to the prevalence of a given disease in specific regions of the world, its different course, and genetic predispositions to specific auto­immune phenomena/diseases. Factors such as frequency of infections, the profile of pathogens and of environmental pollution in the investigated area or other external exposomes affecting a given population, may also prove significant.

Factors limiting inclusivity Age may pose a certain limitation; older patients may have difficulty overcoming barriers such as distance from the center and difficulty understanding the specifics and procedures of a clinical trial. As for the youngest pediatric population, only a fraction of molecules or drugs already approved for adults are tested in children. Children are a unique group, and clinical trials in children raise particular ethical and clinical concerns. The International Clinical Trials Registry Platform (ICTRP) provides information on the preparation and conduct of trials in children, and the ICTRP portal identifies clinical trials involving children using a set of filters developed specifically for this purpose [3]. Factors limiting inclusivity can be divided into two sets – one from patient perspective second from investigator perspective (Table I). In 2017, at the initiative of the UK National Institute for Health Research (NIHR), the INCLUDE study defined and identified underserved groups in clinical trials and pointed in particular to: older adults, ethnic minorities, people with socioeconomic disadvantage, the LGBTQ+ community, rural residents, people with comorbidities, including disabilities, as well as pregnant and breastfeeding women, and people with mental health conditions or cognitive impairments [4]. These latter two groups seem to merit separate treatment due to their specific circumstances regarding safety and understanding the stages and purpose of a clinical trial. The INCLUDE study also identified barriers to recruitment, including

Address for correspondence Maria Maślińska, Department of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 1 Spartanska St., 02-637 Warsaw, Poland, e-mail: maslinskam@gmail.com Submitted: 13.07.2025; Accepted: 13.07.2026; Published online: 15.07.2027

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

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Inclusivity in clinical trials

Table I. Factors limiting inclusivity For participant/patient

For investigator/center

Difficulties in informed consent form and poor consent procedures

Lack of available trials

Physical disability

Poor trial promotion

Fear of clinical trials

Requirement to allocate additional work time to aid participants

Lack of trust in the person presenting a trial to a patient

Lack of interest in research

Unwilling to receive placebo

Shortage of experienced researchers in clinical trials, which can share their expertise with new staff

Feeling of intellectual maladjustment (e.g. due to lack of education)

Negative financial impact

Lack of effective incentives for participation

In highly specialized research centers – patients more frequently meeting exclusion criteria patients, due to common multimorbidity and more severe symptoms

Specific health fears/ barriers (e.g. hospital, needle)

Research centers not meeting all organizational requirements

Some cultural barriers

Negative attitudes to the concept of research

Potential participants refusing to accept their health condition Difficult economic and geographical conditions of a region Prior negative experience with clinical trials of a patient or of other close relatives, friends, etc.

The need to educate research professionals/investigators about inclusivity

Inappropriate language of communication

Inappropriate language of communication

Fig. 1. The concept of inclusivity in clinical trials (prepared with ConceptViz). recruitment through tertiary care centers or in urban settings remote from rural populations, a lack of taxi transportation for people with limited mobility, and a lack of translated study information for those who do not speak the language of the study. Sponsor pressure for rapid recruitment may facilitate entry into the study

for easier patients accustomed to clinical trials, but this does not maintain a more representative recruitment [5]. Based on the experience of the INCLUDE study, the SENSITISE project initiative was created, which should be concluded this year [5]. Figure 1 shows concept of inclusivity in clinical trials.

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268

Maria Maślińska

Fig. 2. A look at clinical trials in rheumatology (prepared with ConceptViz).

Research in the field of rheumatic diseases Over the past 20 years rheumatology has become a dynamically developing specialty, thanks to advances in immunology, the implementation of genetic engineering techniques, and the development of innovative drugs, both biological and synthetic. Today’s pursuit of early detection, rapid treatment, and inhibition of the inflammatory and autoimmune processes is entirely justified and, in principle, feasible. Development of diagnostic and therapeutic options have translated also into a very dynamic development of clinical trials in rheumatology. Another driving force for clinical research in rheumatology has been, and continues to be, the discoveries of biosimilars to “old” reference drugs and the numerous comparative studies initiated. Figure 2 shows a look at global clinical trials in rheumatology. The strength of clinical research in rheumatology lies in the introduction of increasingly effective innovative treatments for chronic and often life-threatening diseases. 1. Opportunities: research also improves or indicates a better model of patient care and familiarizes researchers. 2. Weaknesses: the costs of developing references for innovative drugs are still high, as are the costs of some procedures used for the research (e.g., BMT or CAR-T the­ rapies). 3. Concerns: delays, particularly in the product approval and market launch phase.

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According to estimates by Precedence Research the global rheumatology drug market is steadily growing and is projected to increase from USD 53.29 billion to approximately USD 68.49 billion by 2035, and to grow at a compound annual growth rate (CAGR) of 2.83% between 2026 and 2035 [6]. This dynamic growth is driven by the rising prevalence of autoimmune diseases, the increased use of biologics, and the incorporation of advanced research technologies, including artificial intelligence, for personalized treatment. This steady increase also demonstrates the power of clinical trials and the need for them in rheumatic diseases. Therefore, knowledge about a proper conduct clinical trials and about their inclusiveness is essential for rheumatologists and other researchers (Fig. 2).

Summary Improving participation in clinical trials for groups that are typically underrepresented, optimal geographic distribution of trials, and a diverse age and gender sample are all key elements of achieving research inclusivity. Trial results cannot reliably support treatment decisions (or treatment regimens) for individuals not represented in the trial. Clinical trial design is complex, and conducting trials requires careful attention and knowledge of the principles involved, and each investigator requires appropriate training to perform their duties.

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Inclusivity in clinical trials

Disclosures Conflict of interest: The author declares no conflict of in­ terest. Funding: No external funding. Ethics approval: Not applicable. Data availability: Not applicable. References 1.

2.

Inclusive. Cambridge Dictionary. Available at: https://dictio­ nary.cambridge.org/dictionary/english/inclusive#google_ vignette (Access: 12.07.2026). Inclusive Language. Available at: https://www.queensu.ca/ brand-central/writing-style/inclusive (Access: 12.07.2026).

3.

4.

5.

6.

Strategy for building the clinical trials in children filter. Available at: https://www.who.int/tools/clinical-trials-regis­ try-platform/clinical-trials-in-children/strategy-for-buildingthe-clinical-trials-in-children-filter (Access: 12.07.2026). Witham MD, Anderson E, Carroll C, et al.; INCLUDE writ­ ing group. Developing a roadmap to improve trial delivery for under-served groups: results from a UK multi-stake­holder process. Trials 2020; 21: 694, DOI: 10.1186/s13063020-04613-7. Shiely F, Rychlíčková J, Kubiak C, et al. Training and education on inclusivity in clinical trials-the SENSITISE project. Trials 2024; 25: 318, DOI: 10.1186/s13063-024-08150-5. Rheumatology Therapeutics Market Size, Share and Trends 2026 to 2035. Available at: https://www.precedenceresearch. com/rheumatology-therapeutics-market (Access: 12.07.2026).

Reumatologia 2026; 64/4

Original paper

Reumatologia 2026; 64, 4: 270–279 DOI: https://doi.org/10.5114/reum/222560

Fracture risk prediction based on multivariable diagnostic models incorporating dual-energy X-ray absorptiometry‑based bone mineral density, trabecular bone score, and clinical risk factors in women aged ≥ 50 years: a prospective study Maja Warzecha1 ID , Edward Czerwiński2 ID , Jarosław Amarowicz1 ID  1

Rehabilitation Clinic, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland FutureMeds Medical Centre, Krakow, Poland

2

Abstract Introduction: According to the available reports, there is a major treatment gap in the management of osteoporotic fractures in Poland. It is crucial to identify those at high risk of low-energy fractures who ought to be treated. The study aimed to assess the diagnostic value of dual-energy X-ray absor­ ptiometry (DXA) and the DXA-derived trabecular bone score (TBS) in fracture risk prediction in Polish women ≥ 50 years of age at risk of osteoporosis. Additional measures included the analysis of how incorporating other risk factors may improve the fracture prediction model. Material and methods: From a database of 5,000 randomly selected women, a total of 411 women aged ≥ 50 years were finally included – those who had a DXA examination followed by a complete medical questionnaire performed. After 5–9 years of observation, participants completed a follow-up questionnaire similar to the baseline questionnaire. In addition, TBS analysis was performed retrospectively using lumbar spine DXA scans. Then their fracture risk was calculated using the FRAX algorithm. Results: Most patients with osteoporotic fractures were in a group with a degraded bone microarchitecture and a diagnosis of osteoporosis. Fracture patients without osteoporosis (T-score > –2.5) were mostly (73%) characterised by a partially or significantly degraded bone microarchitecture. The highest predictive value (AUC 0.6) was observed in relation to the models FRAX BMD and FRAX BMD-TBS (p < 0.05), which included both skeletal and other clinical risk factors. Also, the outcomes for all other analysed models (FRAX BMI + TBS, FRAX BMD + TBS, FRAX BMI + BMD spine + TBS) were statistically significant. Conclusions: Indirect bone microarchitecture analysis using DXA-derived TBS predicts fragility fracture risk independently of spine BMD and with comparable predictive performance in postmenopausal women in Poland. Further studies on fracture prediction models in patients with osteopenia are required. Key words: osteoporotic fractures, FRAX, BMD, TBS.

Introduction Epidemiological trends in fragility fractures observed in developed countries are likely attributable to population aging. Over recent decades, this trend has been accompanied by a significant increase in the prevalence

of osteoporosis among postmenopausal women. Osteoporosis is diagnosed based on decreased bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA). According to the World Health Organization (WHO) definition, osteoporosis is defined when the BMD T-score is ≤ –2.5 [1–3]. Since a normal BMD

Address for correspondence Jarosław Amarowicz, Rehabilitation Clinic, Faculty of Health Sciences, Jagiellonian University Medical College, 3 Koło Strzelnicy St., 30-219 Krakow, Poland, e-mail: jaroslaw.amarowicz@uj.edu.pl Received: 03.09.2025; Accepted: 28.02.2026; Published online: 10.07.2026

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

Fracture risk prediction in Polish women aged ≥ 50

result does not exclude the risk of a fracture, it is crucial in the osteoporosis diagnostic process to identify those with a high fracture risk who require treatment. Previous studies have shown that up to 70% of fractures occur in individuals who do not meet the densitometric criteria for osteoporosis [4]. As reported by Siris et al. [5], there is no direct correlation between BMD and fracture incidence, as most fractures occur in individuals with osteopenia. This may be explained by the fact that osteoporosis is associated not only with a reduced bone mass, but also with a degraded bone microarchitecture and clinical risk factors. Therefore, BMD alone is insufficient for fracture risk assessment and it requires supplementary methods [6, 7]. To improve fracture risk assessment, the Fracture Risk Assessment Tool (FRAX) calculator was developed in 2008. It is an algorithm that estimates 10-year probability of hip and major osteoporotic fractures. Additionally, in 2012 the United States Food and Drug Administration accepted the trabecular bone score (TBS) as a supplementary diagnostic tool for fracture risk assessment. The trabecular bone score is calculated based on a DXA lumbar spine scan (L1–L4) [8]. In patients with similar BMD values, TBS provides additional information on possible bone microarchitecture [9, 10]. Numerous studies have reported that the indirect bone microarchitecture analysis using the TBS predicts fracture risk independently of BMD, with comparable AUC values [7, 11–17]. The growing clinical utility of TBS has also been reaffirmed in recent expert reviews [18]. Since 2015, the FRAX calculator has been updated to incorporate bone microarchitecture analysis derived from TBS [2, 3]. Despite the widespread international acceptance of DXA-based BMD assessment, as well as FRAX and DXA‑derived TBS [2, 3, 18], their performance requires local validation, as FRAX models are calibrated to country‑specific epidemiological data and fracture rates [2]. The number of studies analysing the predictive value of TBS in various diagnostic models incorporating skeletal and other risk factors in the Polish population remains limited. Local epidemiological data indicate a substantial treatment gap among individuals with fragility fractures [19], underscoring the need for improved diagnostic strategies in this population. Furthermore, access to TBS analysis in Poland remains restricted, emphasizing the need for expanded local research to support the clinical implementation of fracture risk assessment models incorporating bone microarchitecture. Accordingly, the present study was undertaken in this population. The aim of the study was to assess the diagnostic value of DXA-based assessment, including BMD (spine and hip when available) and DXA-derived TBS, in fracture risk prediction in Polish women aged ≥ 50 years

271

at risk of osteoporosis, in combination with other relevant factors (such as FRAX). The present study is expected to provide clinically relevant evidence on the predictive performance of different combinations of diagnostic tools for clinical use. Integrating commonly used assessment methods may enhance fracture risk stratification in postmenopausal women and support the wider implementation of TBS in Poland. Therefore, this may support a reduction in fragility fracture occurrence and facilitate the development of more effective management strategies for individuals aged ≥ 50 years at high risk of osteoporotic fractures in the Polish population.

Material and methods Study design and study population A prospective study with follow-up was conducted between 2010 and 2019 at the Rehabilitation Clinic of the Jagiellonian University Medical College and the Cracow Medical Centre (CMC). To conduct the study, a group of 5,000 women aged ≥ 50 years was randomly selected from a database of 59,270 CMC patients. These patients had been admitted for diagnostic purpose and had undergone at least lumbar DXA examination at the facility. Menopausal status was confirmed in each patient via a medical questionnaire, which documented the age of the last menstrual period. The mean age at menopause was 49.9 ±5.3 years (range: 21–65). As age at menopause was self‑reported, it may be subject to recall bias, particularly in older participants and those with surgically induced menopause. Following the randomization process, all women included in the analysis were required to meet the following inclusion criteria: aged 50–85 years at the time of DXA examination and confirmed postmenopausal status. Additionally, all participants were required to have a lumbar spine DXA scan (L1–L4) performed on the same device and complete a baseline medical questionnaire (including written informed consent), both conducted between 2010 and 2013. The study excluded women who did not meet the above inclusion criteria and also cases with spine DXA scans with significant artefacts or technical errors. Additionally, women with conditions that significantly distort DXA or TBS interpretation (e.g. severe scoliosis) and also mental or neurological disorders that prevent the collection of information and may undermine the reliability of the research were excluded. Finally, in a group of 411 women the authors conducted telephone questionnaires that enabled collection of a complete set of data required for planned analy­sis. Details of the randomization process are presented in Figure 1.

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5,000 women assessed for eligibility

Excluded (n = 3,358) DXA < 2010 and > 2013 incomplete medical history lack of consent

Included (n = 1,672)

Lost to follow-up (n = 1,261) unable to reach deceased lack of consent for follow-up

Final sample (n = 411) included in analysis

Fig. 1. Flowchart of the study sample selection process. DXA – dual-energy X-ray absorptiometry.

Clinical data collection and dual-energy X-ray absorptiometry assessment The questionnaire included demographic and anthropometric data, comorbidities and medication use. An additional section addressed fracture risk factors, with particular emphasis on the number of sustained fractures (type, location and circumstances of the incident). A trained member of the clinical staff assessed whether the fracture could be classified as a low-energy trauma (e.g., falls). Prior to DXA examination, each patient’s height and weight were measured using calibrated and certified equipment. Subsequently, the radiology technician performed a lumbar (L1–L4) and, in selected cases, a hip (neck) DXA scan (57.2% of cases) using a Hologic Delphi W densitometer (SN70622; software version 11.7), in accordance with the recommendations of the International Society for Clinical Densitometry [20]. Bone mineral density classification was based on WHO criteria for T-scores cut-off values for spine and hip locations (T > –1 normal; –2.5 to –1 osteopenia; T ≤ –2.5 osteoporosis) [1–3].

Follow-up assessment Follow‑up assessment was conducted as a single telephone interview between January 2018 and December 2019 by the author (M.W.) of the study. The duration of follow-up was calculated individually from the date of the baseline DXA examination and questionnaire (2010–2013), resulting in a variable observation period of 5–9 years (mean 6.5 ±1.0 years). At follow-up, participants completed a questionnaire similar to that used in the baseline assessment. Particular attention was given to incidents involving new fractures: their location, circumstances (low/high energy) and timing. This was intended to ensure that the fracture occurred during

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the observation period and had not been reported in the first questionnaire.

Retrospective trabecular bone score assessment All participants (n = 411) underwent additional analysis of their spine DXA scan (L1–L4) using Trabecular Bone Score iNsight software (ver. 2.0). Trabecular bone score is a quantitative textural index derived from DXA images and does not represent a separate imaging modality. Instead, it constitutes an analytical extension of standard DXA‑based BMD assessment. This TBS evaluation was performed retrospectively during the follow-up phase using the baseline DXA scans obtained between 2010 and 2013. Following the TBS methodology guideline, published by the tool manufacturer, any patients outside the relevant body mass index (BMI) range (15–37 kg/m2) were excluded from further analysis. The cut-off points for bone microarchitecture degradation and fracture risk used in our study were: > 1.31 normal microarchitecture (low risk), 1.23–1.31 – partially degraded microarchitecture (average risk), < 1.23 degraded microarchitecture (high risk) [12].

Fracture risk assessment After all information regarding the skeletal DXA‑based parameters (BMD and TBS) and other clinical fracture risk factors had been obtained (by questionnaire), every member of the study group had their fracture risk calculated using the FRAX algorithm (available online at https://www.sheffield.ac.uk/FRAX/tool.aspx?lang=po). FRAX probabilities were calculated retrospectively during the follow-up phase. The probability was calculated for both the hip and major osteoporotic fracture (MOF) using BMI (for every patient) and also hip BMD (for 57.2% of the study group) along with TBS. A FRAX MOF probability of > 10% was considered high risk, 5–10% average risk and < 5% low risk. For hip fracture risk, a FRAX probability > 3% was considered high risk [21]. Although FRAX was originally developed to estimate 10-year risk, previous studies have reported that it may be efficiently used for shorter observation periods. This served as a rationale to use FRAX in the present study [22].

Statistical analysis Upon the completion of data collection, the authors conducted a statistical analysis using Statistica 13 software. The list of tests included those for quantitative variables (Shapiro-Wilk, Kolmogorov-Smirnov tests), frequency analysis (Pearson χ2 and Fisher tests) as well as the dependency analysis (Student’s t-test, MannWhitney U test and ANOVA tests). The prediction of the

Fracture risk prediction in Polish women aged ≥ 50

classification of data into a state variable was performed using the receiver operating characteristics (ROC) curve and area under the curve (AUC), whereas for data modelling, a logistic regression model was used. In the logistic regression models, TBS and BMD were entered as continuous variables in their original measurement units. Consequently, the reported odds ratios correspond to a 1-unit change, which can yield small OR values. Values of p < 0.05 were considered statistically significant.

Bioethical standards The study was performed in accordance with the principles of the Declaration of Helsinki of the World Medical Association after appropriate consent had been obtained from the Jagiellonian University Bioethics Committee (No. 1072.6120.37.2017 from September 28, 2017).

Results A total of 411 women aged 63.5 (50–85; SD 6.6) were finally enrolled in the study at the baseline and lasted until the end, with an average age of 70 (56–90; SD 6.6) years at the follow-up. Detailed characteristics, including anthropometric parameters and all analysed skeletal factors, are presented in Table I. The table summarizes baseline data for the entire cohort and stratifies partic-

273

ipants according to whether they sustained a fracture during the follow-up period. Using the obtained DXA results (spine and/or hip neck), osteoporosis was diagnosed in over half of the study subjects (51%, n = 210), whereas osteopenia was found in 37% (n = 151) of the group. Notably, only 51% of those with osteoporosis had reported past antiresorptive treatment (defined as use of an active treatment agent for at least 12 months). Among treated patients, bisphosphonates were the most commonly used medi­ cations, accounting for 94 cases (88% of all treatment recipients). Reports of the use of other anti-osteoporotic medications were infrequent: hormone replacement therapy (HRT, n = 15), calcitonin (n = 6) and denosumab (n = 2). Approximately 58% of women with a clinical osteoporosis diagnosis received calcium and 43% vitamin D supplementation. According to baseline data, over 1 in 4 women (n = 113, 27%) had a previously reported fracture before entering our study group. At the end of the study follow-up period, 96 women reported sustaining a new fragility fracture (23%). The most commonly reported locations included Colles (n = 33) and vertebral (n = 33) fractures. In a group of participants with a newly reported fragility fracture (sustained during the study), in 41% of cases it was a re-fracture. Among women who sustained a new fragility fracture during follow-up, 59% (n = 57)

Table I. Characteristics of the study group at baseline, stratified by fracture occurrence during follow‑up Variables

Baseline

Follow-up

Whole study group (n = 411)

Group with a fracture (n = 95)

Group without a fracture (n = 313)

p

n

Value

Value

Value

Age [years]

411

63 (59.0–68.0)

65.2 ±7.2

62.0 (58.0–67.0)

< 0.05

2

BMI [kg/m ]

411

26.5 (23.9–29.4)

27.5 ±4.1

26.4 (23.7–29.3)

> 0.05

TBS L1–L4 spine

408*

1.25 ±0.09

1.23 ±0.09

1.25 ±0.09

< 0.05

BMD spine [g/cm2]

408*

0.779 (0.720–0.854)

0.760 (0.688–0.838)

0.782 (0.731–0.857)

< 0.05

T-score spine

408*

–2.4 (from –3.0 to –1.8)

–2.6 (from –3.3 to –1.9)

–2.4 (from –2.9 to –1.7)

< 0.05

BMD hip [g/cm2]

235**

0.654 (0.597–0.726)

0.655 ±0.097

0.655 (0.605–0.727)

> 0.05

T-score hip

235**

–1.8 (from –2.3 to –1.1)

–1.8 ±0.9

–1.8 (from –2.2 to –1.1)

> 0.05

FRAX hip BMI [%]

411

1.1 (0.6–2.4)

1.6 (0.8–3.1)

1.00 (0.6–2.1)

< 0.05

FRAX MOF BMI [%]

411

5.3 (3.4–8.0)

6.4 (3.8–11.0)

4.7 (3.3–7.6)

< 0.05

FRAX hip BMD [%]

235**

1.1 (0.6–2.2)

1.3 (0.7–2.6)

1.0 (0.5–2.0)

> 0.05

FRAX MOF BMD [%]

235**

5.5 (3.8–8.2)

6.2 (4.8–8.9)

5.4 (3.6–7.5)

< 0.05

FRAX hip BMD-TBS [%]

235**

1.2 (0.6–2.5)

1.7 (1.0–2.9)

1.1 (0.6–2.4)

> 0.05

FRAX MOF BMD-TBS [%]

235**

6.8 (4.4–9.8)

7.2 (5.6–10.0)

6.5 (4.2–9.2)

< 0.05

Data are presented as mean ±SD for normally distributed variables and median (Q1–Q3) for non-normally distributed variables. *Three cases were excluded due to artefacts identified during DXA spine examination. **All subjects had a spine BMD result, whereas hip BMD was available for 57.2% of patients. BMD – bone mineral density, BMI – body mass index, FRAX – Fracture Risk Assessment Tool, Q1–Q3 – first to third quartile, SD – standard deviation, MOF – major osteoporotic fracture, TBS – trabecular bone score.

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32

30

Number of observatio

n

35

25

20

20 15

5

8

12

10

6 8

3

Osteoporosis

4

1.2

1.2 .31

1 3–

Norm

3

2

< 1.2 ec

b Tra

re

co

es

on rb

ula

3

gn Os os te tic op Osteopenia cri oro te sis ria (W HO )

<

dia

Fig. 2. Number of cases with a “new” fragility fracture depending on their TBS result and osteo­ porosis diagnostic criteria as defined by WHO (p > 0.05). Table II. Probability of a “new” fragility fracture occur­ rence as assessed via the ROC curve Variables

AUC

95% CI

p

AUC lower

AUC upper

T-score spine

0.57

0.502

0.637

< 0.05

T-score hip

0.541

0.455

0.627

> 0.05

TBS L1–L4 spine

0.573

0.509

0.637

< 0.05

FRAX MOF BMI

0.596

0.527

0.666

< 0.05

FRAX MOF BMD

0.601

0.519

0.684

< 0.05

FRAX MOF BMD-TBS

0.6

0.517

0.682

< 0.05

AUC – area under the curve, BMD – bone mineral density, BMI – body mass index, CI – confidence interval, FRAX – Fracture Risk Assessment Tool, MOF – major osteoporotic fracture, ROC – receiver operating characteristic, SD – standard deviation, TBS – trabecular bone score.

reported previous antiresorptive therapies (of which 82% were bisphosphonates). It should be emphasized that the reported past antiresorptive therapy may have influenced fracture risk in the study group. However, exact treatment duration, adherence and timing of therapy in relation to the study period were heterogeneous and not routinely monitored. Therefore, the extent to which previous therapy influenced fracture risk in our cohort should be interpreted with caution. A description

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of the groups stratified by occurrence of a “new” fracture in shown in Table I. As expected, most patients with low-energy fractures were in the group with a degraded bone microarchitecture and diagnosed osteoporosis. Notably, fracture patients without osteoporosis were still mostly (73%, n = 27) characterised by a partially (43.2%) or significantly (29.7%) degraded bone microarchitecture (Fig. 2). Fracture prediction assessment with ROC curve analysis showed that all analysed variables taken into consideration were characterised by an AUC over 0.5. The highest values (AUC 0.6) were observed for FRAX BMD and FRAX BMD‑TBS models (p < 0.05), which incorporate DXA‑based skeletal parameters (BMD with or without TBS) together with additional clinical risk factors (Table II). Also, it should be noted that one model (T-score hip) was not statistically significant, which may have been attributable to the lack of data regarding hip DXA (as mentioned, collected only in 57.2% of cases). Nevertheless, the observed AUC values of < 0.7 indicate limited discriminative performance and, therefore, limited clinical utility in their current form. We next assessed the predictive value of skeletal factors on the basis of the ROC curve in women with osteopenia (n = 151). Unlike spine T-score, TBS demonstrated only limited discriminative ability, with an AUC of 0.512. However, the result was not significant, possibly due to the limited number of fractures in this group (n = 28). As a final step, we sought to identify the most effective fracture prognostic model using FRAX as the base tool and adding additional factors (Table III). While the OR for the TBS factor alone was 0.05 (95% CI: 0.004–0.611), incorporating TBS into models including skeletal and clinical risk factors resulted in a significant improvement in its predictive value. Including TBS in the analysis of FRAX BMI, FRAX BMD or FRAX BMI + BMD spine increased the OR value for that factor in every case (respectively, 0.112, 0.291 and 0.172). We found that the OR for spine BMD (OR = 0.178; 95% CI: 0.031–1.003) after including it in the FRAX BMI + BMD spine + TBS diagnostic model increased significantly (OR = 0.466; 95% CI: 0.07–3.07). To sum up, all the analysed models (FRAX BMI + TBS, FRAX BMD + TBS, FRAX BMI + BMD spine + TBS) were statistically significant, which may suggest a potential role in clinical assessment, although their predictive performance remains limited and should be interpreted with caution. As regards the assessment of hip fracture risk, the OR values were notably lower for most parameters (except for FRAX BMI) in all analysed models. This may be related to the limited number of hip fractures reported in our study group. The lack of significance limits the ability to draw meaningful conclusions regarding hip fracture prediction in terms of using the evaluated models.

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275

Table III. Major osteoporotic fracture and hip fracture risk assessment using a non-linear logistic regression model using the FRAX algorithm and skeletal risk factors (BMD and TBS) Variable

MOF risk OR (95% CI)

p (variable)

p (model)

Hip risk OR (95% CI)

p (variable)

p (model)

FRAX BMD

1.080 (1.013–1.152)

< 0.05

< 0.05

1.059 (0.858– 1.307)

> 0.05

> 0.05

TBS

0.050 (0.004–0.611)

< 0.05

< 0.05

0.001 (0.000–1.224)

> 0.05

> 0.05

FRAX BMD

1.072 (1.002–1.147)

< 0.05

< 0.05

1.024 (0.809–1.296)

> 0.05

> 0.05

TBS

0.291 (0.009–9.899)

> 0.05

0.022 (0.000–1.224)

> 0.05

FRAX BMI

1.106 (1.048–1.167)

< 0.05

< 0.05

1.136 (1.012–1.276)

< 0.05

> 0.05

TBS

0.050 (0.004–0.611)

< 0.05

< 0.05

0.001 (0.000–1.224)

> 0.05

> 0.05

FRAX BMI

1.095 (1.037–1.156)

< 0.05

< 0.05

1.133 (1.008–1.274)

< 0.05

< 0.05

TBS

0.112 (0.008–1.499)

> 0.05

0.002 (0.000–1.775)

> 0.05

FRAX BMI

1.106 (1.048–1.167)

< 0.05

< 0.05

1.136 (1.012–1.276)

< 0.05

> 0.05

TBS

0.050 (0.004–0.611)

< 0.05

< 0.05

0.001 (0.000–1.224)

> 0.05

> 0.05

BMD spine

0.178 (0.031–1.003)

> 0.05

< 0.05

0.002 (0.000–4.889)

> 0.05

> 0.05

1.134 (1.007–1.276)

< 0.05

> 0.05

0.005 (0.000–8.498)

> 0.05

0.083 (0.000–34.5)

> 0.05

Model I

FRAX BMD + TBS

Model II

FRAX BMI + TBS

Model III

FRAX BMI + BMD spine + TBS FRAX BMI

1.092 (1.034–1.153)

< 0.05

TBS

0.172 (0.010–2.876)

> 0.05

BMD spine

0.466 (0.07–3.07)

> 0.05

< 0.05

BMD – bone mineral density, BMI – body mass index, CI – confidence interval, FRAX – Fracture Risk Assessment Tool, MOF – major osteoporotic fracture, SD – standard deviation, TBS – trabecular bone score.

Discussion Our findings indicate that the highest risk of fragility fractures was observed in individuals with confirmed osteoporosis accompanied by degraded bone micro­ar­chi­tecture (TBS < 1.23). Notably, the majority of patients with a history of osteoporotic fracture (n = 27), who had a T-score > –2.5, were simultaneously characterized by a TBS ≤ 1.31 (73% of the subgroup). However, it should be noted that the distribution of fractures across TBS and BMD categories did not reach statistical significance (p > 0.05). Therefore, these findings represent numerical differences that were not statistically significant. The observed pattern in the data may suggest that TBS has potential clinical relevance in identifying individuals at higher fracture risk, despite the absence of densitometric osteoporosis. Nevertheless, this observation should be interpreted cautiously and requires further confirmation (Fig. 2). Similar findings were reported by Lee et al. [23] in a study of 929 women (mean age 67.1 years), in which most fractures (n = 29; 31.5%) occurred in individuals with osteoporosis and low TBS. Notably, approximately a quarter of the fracture patients with

degraded bone microarchitecture (12% degraded and 13% partially degraded) also had T-score above –2.5. In a study of 407 women, Therdyothin et al. [24] identified 115 fragility fractures. The majority of these fractures (n = 28; 24.3%) occurred in individuals with diagnosed osteoporosis (BMD spine) and low TBS. Consistent with previous observations, a substantial proportion of fractures (n = 27; 23.5%) was also reported in women with a non-osteoporotic T-score (> –2.5) and degraded microarchitecture (TBS ≤ 1.23). Del Rio et al. [13] focused on hip fractures in a cohort of 191 women aged ≥ 50 years, reporting 83 fracture incidents. Most hip fractures (n = 21; 25.3% of the fracture group) occurred in individuals with osteopenia and significantly degraded bone microar­ chitecture (≤ 1.23). Importantly, 45.8% of patients had at least partially degraded bone microarchitecture without densitometric evidence of osteoporosis. Both scientific literature and our findings indicate that, although BMD is associated with fragility fracture risk, no clear T-score threshold can reliably identify individuals at negligible risk. This is supported by previous studies which showed a substantial proportion of fra-

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gility fractures in individuals without osteoporosis [25]. These observations emphasize the value of DXA‑derived TBS as a complementary parameter in clinical practice, enabling the identification of individuals with impaired bone microarchitecture who are at increased fracture risk. This is particularly relevant given that TBS analysis does not require additional imaging and can be performed retrospectively using an existing spine BMD scan. This additional information may reduce the risk of under-treatment, especially among patients who do not meet the diagnostic criteria for osteoporosis but remain at increased fracture risk. It is well established that reduced BMD is an independent fracture risk factor. However, as noted previously, the majority of fractures occur in individuals with a T-score higher than –2.5 [4, 22–24]. In our study, the predictive performance of BMD and TBS in fracture risk assessment was comparable, whereas the highest value (AUC 0.6; p < 0.05) was observed for FRAX-based models incorporating BMD and BMD combined with TBS. Although the inclusion of TBS in the FRAX BMD model improved its statistical performance, the overall prediction remained limited. The AUC values observed in our study (0.6) indicate only moderate predictive accuracy. These findings, while consistent with previously published large population-based cohort studies evaluating fracture prediction tools [11, 17], suggest that current models may not provide sufficient precision to support unequivocal clinical decision‑making. These results confirm the relevance of the study approach; however, their clinical applicability remains limited. Similar observations have been reported by other authors, indicating that the combination of DXA‑based skeletal parameters, including BMD and TBS, improves fracture risk prediction [26–28]. Nevertheless, the overall improvement in predictive performance remains modest. A recent analysis of 71,209 individuals (89.8% women) demonstrated that the addition of TBS resulted in a small but statistically significant improvement in FRAX-based fracture prediction [17]. Similar findings were reported in the population-based Manitoba study (n = 29,407 postmenopausal women), in which comparable predictive probability was observed for spine BMD (AUC 0.64; 95% CI: 0.63–0.66) and TBS (AUC 0.63; 95% CI: 0.61–0.64). The combined model showed improved predictive accuracy (AUC 0.66; 95% CI: 0.65–0.68) [11]. Accordingly, Del Rio et al. [13] reported comparable results in the prediction of hip fractures (n = 191 women; mean age 66.8 years) for spine BMD (AUC 0.695; 95% CI: 0.625–0.76) and TBS (AUC 0.668; 95% CI: 0.597–0.734). The combined model incorporating both skeletal para­ meters demonstrated a higher AUC value (0.714; 95% CI: 0.645–0.77) compared to either predictor alone [13].

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Su et al. [29] similarly emphasized the importance of supplementing BMD assessment (AUC 0.578; 95% CI: 0.543–0.613) with bone microarchitecture, as this approach improved the predictive performance of their models (AUC 0.581; 95% CI: 0.55–0.612). In a study by Popp et al. [30] (556 women; mean age 76.1 years), TBS demonstrated higher predictive value (AUC 0.69; 95% CI: 0.62–0.77) than BMD (AUC 0.62; 95% CI: 0.55–0.7). Consistent with previous findings, combining both parameters increased the model AUC value (0.71; 95% CI: 0.64–0.79). Similar results were reported by Vasic et al. [31], where bone microarchitecture assessment (AUC 0.663; 95% CI: 0.633–0.692) showed slightly higher predictive performance than BMD (AUC 0.646; 95% CI: 0.616–0.675) and provided additional predictive value when incorporated into a combined model (AUC 0.681; 95% CI: 0.652–0.71). Overall, these findings are consistent with existing scientific literature, indicating that indirect bone structure assessment using DXA‑derived TBS predicts fracture risk independently and with comparable (if not superior) performance to BMD [11, 13, 17, 30, 31]. Importantly, the combination of these parameters is likely to improve fracture risk prediction in postmenopausal women. As BMD alone proved to be only partially effective in predicting fracture occurrence, we aimed to identify the most effective model for fracture risk assessment. In our study, we found that models incorporating more comprehensive assessment approaches (such as FRAX BMD + TBS, FRAX BMI + TBS and FRAX BMI + BMD spine + TBS) increase the potential predictive value of skeletal parameters in the assessment of MOF. Del Rio et al. [13] reported an OR of 1.86 (95% CI: 1.29–2.68) for BMD spine and 1.66 (95% CI: 1.15–2.4) for TBS. The combined model demonstrated a substantial increase in predictive performance (2.39; 95% CI: 1.70–3.37), corresponding to a 55–74% improvement. A similar enhancement in predictive value (35–43%) was reported in group of 1,031 women for a model combining BMD and TBS (OR = 1.93; 95% CI: 1.67–2.23). When analysed separately, both parameters showed weaker associations with fracture risk (BMD OR = 1.50; 95% CI: 1.27–1.77 vs. TBS OR = 1.58; 95% CI: 1.32–1.78) [31]. Skeletal parameters were evaluated in the vertebral fracture assessment (n = 441 women) in a study by Rabier et al. [14] TBS was associated with an OR of 3.2 (95% CI: 2.01–5.08) per 1 SD, compared with 1.9 (95% CI: 1.34–2.84) for lumbar spine BMD. When the parameters were included in a combined model, predictive performance significantly increased (OR = 3.62; 95% CI: 2.32–5.65). Borgen et al. [32] (n = 496 women; mean age 65.6 years) reported that models with skeletal parameters may be significantly improved by adjustment for clinical risk factors (such as age, BMI, and fracture

Fracture risk prediction in Polish women aged ≥ 50

history). Odds ratio values for BMD and TBS analysed independently were 0.7 (95% CI: 0.56–0.87) and 0.73 (95% CI: 0.59–0.9), respectively. After including these risk factors, model performance improved modestly, with OR increasing to O.75 (95% CI: 0.6–0.95; p = 0.017) for BMD and 0.81 (95% CI: 0.64–1.03; p = 0.084) for TBS [32]. In a study involving 2,165 women aged over 40 years, both BMD (OR = 1.24; 95% CI: 1.09–1.4) and TBS (OR = 1.38; 95% CI: 1.22–1.56) demonstrated predictive value when analysed separately. When a combined model including both parameters and age was applied, predictive performance remained unchanged (OR = 1.38; 95% CI: 1.23–1.55) but statistically significant. Notably, BMD was not statistically significant within the combined model (OR = 1.12; 95% CI: 0.98–1.28) [33]. Our findings in the Polish population are generally consistent with those reported in the literature, indicating that fracture risk assessment models may gain additional prognostic value with the inclusion of complementary parameters. The use of multidimensional assessment approaches may allow for more accurate fracture risk assessment and facilitate the identification of patients requiring appropriate treatment.

Study limitations Considering the observed treatment gap and epidemiological characteristics of low-energy fractures in Poland, population‑specific validation of combined dia­ gnostic models appears particularly important. While the present analysis is based on a regional cohort, the methodological framework and observed relationships may be informative for other populations in which FRAX calibration, treatment gaps and access to TBS are comparable. However, despite our efforts, this study has several limitations, including the lack of systematic follow-up assessment that would allow for a more precise evaluation of fracture timing. The analytic cohort (n = 411 out of 5,000 screened DXA records) reflects a predefined eligibility process prioritizing data completeness, DXA technical quality (for valid TBS re-analysis), and the feasibility of a long-term follow-up. While this multistep inclusion process may limit a full representativeness assessment against all screened records, the exclusions were predominantly technical rather than clinical. The cohort also yielded 96 incident fractures, meeting conventional events‑per‑variable criteria and supporting the adequacy of the statistical analyses. Therefore, the risk of substantial overfitting due to an insufficient number of outcome events is likely low. Nevertheless, as all participants were women referred for osteoporosis screening, the generalizability of these findings may be limited. Another limitation is the potential recall bias associated with telephone‑based follow‑up. As fracture

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events were self-reported several years after their occurrence, some degree of misclassification, particularly regarding the exact timing or mechanism of injury, cannot be excluded. Efforts were made to ensure data completeness; however, as with all questionnaire-based studies, certain limitations remain. In cases of missing data, additional information was collected during the follow-up assessment. Questionnaires with substantial missing data were excluded at the initial stage of the study. Approximately half of the participants were missing hip BMD results, as this was not an inclusion criterion (given that TBS requires only spine DXA). This distribution reflects routine clinical practice, where lumbar spine DXA is typically the initial diagnostic test, and hip DXA is obtained selectively based on clinical indications. However, this limitation may have weakened the predictive performance of hip BMD FRAX and combined BMD-TBS models. Therefore, these findings should be interpreted with caution. To the best of our knowledge, the limited availability of hip BMD measurements was a likely contributor to the weaker performance of the hip fracture prediction analyses. Another limitation is the lack of detailed information on previous antiresorptive treatment. Although slightly more than half of the osteoporotic patients reported prior therapy, the absence of standardized data on adherence and treatment duration limits the ability to quantify its impact on fracture risk. This may have partially influenced fracture risk estimates in this subgroup. The present results suggest that studies evaluating the predictive value of combined diagnostic models have potential. However, despite achieving statistical significance, AUC values below 0.7 indicate only moderate discriminatory ability. Therefore, the predictive performance of these models remains limited and should be interpreted with caution. Further studies are required, particularly focusing on patients with osteopenia and their medical history. The relatively small number of fractures observed in the osteopenia subgroup (n = 28) substantially reduces the statistical power of the fracture prediction analysis and limits the interpretability of TBS performance in this population.

Conclusions Indirect bone microarchitecture assessment using DXA‑derived TBS predicts fragility fracture risk independently of spine BMD, with comparable predictive performance in postmenopausal women in Poland. However, TBS demonstrated only moderate fracture prediction, and its performance was not statistically significant in the osteopenia subgroup (likely due to the limited number of fractures). The use of combined models, including parameters such as FRAX, BMD and

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TBS, may improve fracture risk prediction, particularly for MOF. DXA‑derived TBS may provide complementary information to BMD or FRAX in fracture risk assessment among Polish postmenopausal women. Further studies are required to evaluate fracture prediction models in patients with osteopenia.

Disclosures Conflict of interest: The authors declare no conflict of in­ terest. Funding: Jagiellonian University Medical College – grant no. N43/DBS/000063. Ethics approval: The study was approved by the Jagiel­ lonian University Bioethics Committee (No. 1072.6120. 37.2017 from September 28, 2017). Data availability: The data that support the findings of this study are available on request from the corre­ sponding author (J.A.). References 1. Kanis JA. Assessment of fracture risk its application to screen­ ing for postmenopausal osteoporosis: synopsis of a WHO report. WHO Study Group. Osteoporos Int 1994; 4: 368–381, DOI: 10.1007/BF01622200. 2. Kanis JA, Cooper C, Rizzoli R, Reginster JY. European guidance for the diagnosis and management of osteoporosis in post­ menopausal women. Osteoporos Int 2019; 30: 3–44, DOI: 10.1007/s00198-018-4704-5. 3. Gregson CL, Armstrong DJ, Avgerinou C, et al. The 2024 UK clinical guideline for the prevention and treatment of oste­ oporosis. Arch Osteoporos 2025; 20: 119–169, DOI: 10.1007/ s11657-025-01588-3. 4. Siris ES, Boonen S, Mitchell PJ, et al. What’s in a name? What constitutes the clinical diagnosis of osteoporosis? Osteoporos Int 2012; 23: 2093–2097, DOI: 10.1007/s00198-012-1991-0. 5. Siris ES, Chen YT, Abbott TA, et al. Bone mineral density thresholds for pharmacological intervention to prevent frac­ tures. Arch Intern Med 2004; 164: 1108–1112, DOI: 10.1001/ archinte.164.10.1108. 6. Pothuaud L, Barthe N, Krieg MA, et al. Evaluation of the poten­ tial use of Trabecular Bone Score to complement bone mineral density in the diagnosis of osteoporosis: A Preliminary Spine BMD-Matched, Case-Control Study. J Clin Densitom 2009; 12: 170–176, DOI: 10.1016/j.jocd.2008.11.006. 7. Winzenrieth R, Dufour R, Pothuaud L, Hans D. A Retrospective case-control study assessing the role of Trabecular Bone Score in postmenopausal Caucasian women with osteopenia: ana­ lyzing the odds of vertebral fracture. Calcif Tissue Int 2010; 86: 104–109, DOI: 10.1007/s00223-009-9322-y. 8. Martineau P, Leslie WD. Trabecular Bone Score (TBS): Method and applications. Bone 2017; 104: 66–72, DOI: 10.1016/j.bone. 2017.01.035. 9. Harvey NC, Gluer CC, Binkley, et al. Trabecular Bone Score (TBS) as a new complementary approach for osteoporosis

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Reumatologia 2026; 64/4

Original paper

Reumatologia 2026; 64, 4: 280–286 DOI: https://doi.org/10.5114/reum/218395

Methotrexate-related beliefs, fears, and use among patients with rheumatoid arthritis: a cross-sectional survey L’heri Hind1 ID , Rkain Hanan2 ID , Farih Sara1, Tahiri Latifa1 ID , Kronbi Fatine1 ID , Abouqal Redouane3 ID , Hajjaj-Hassouni Najia4 ID , Allali Fadoua1 ID 1

Department of Rheumatology B, Ayachi Hospital, Ibn Sina Hospital Center, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco 2 Exercise Physiology and Autonomous Nervous System Team, Physiology Laboratory, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco 3 Laboratory of Biostatistics, Clinical and Epidemiological Research, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco 4 International University of Rabat (UIR), College of Health Sciences, Research Center of Health Sciences (CreSS), Rabat, Morocco

Abstract Introduction: The study aimed to assess the beliefs and fears of Moroccan patients with rheumatoid arthritis (RA) regarding methotrexate (MTX) and to identify factors associated with the total score on the Beliefs about Medicines Questionnaire-Specific (BMQ). Material and methods: A single-center cross-sectional study was conducted in patients being treated for RA with MTX. Beliefs about treatment were assessed using the BMQ. Specific fears related to MTX were collected using a structured questionnaire developed for the study. Factors associated with the total BMQ score were explored using univariate and then multivariate linear regression. Results: One hundred and two patients were included (age: 53.1 ±12.5 years; 90.2% women). The mean BMQ-Concerns score was 15.9 ±6.37. The main concerns were related to potential longterm adverse effects (58.8%), particularly gastrointestinal (65.7%) and hepatic (62.7%) toxicity. A moderate or high level of fear was reported by 53.9% of patients. The mean BMQ-Necessity score was 15.0 ±5.04; 55% felt that their current health depended on MTX, and 51% perceived an overall benefit from the treatment. The median BMQ total score was 1 (from –3 to 4). In multivariate analysis, longer disease duration (β = –0.12; 95% CI: –0.23 to –0.02) and use of the internet as a source of information (b = –2.66; 95% CI: –5.06 to –0.27) were independently associated with the total score. Conclusions: Moroccan patients with RA generally consider MTX to be necessary but express significant concerns about its toxicity. Disease duration and use of the internet significantly influence these perceptions, highlighting the need for therapeutic education interventions and reliable digital information sources. Key words: methotrexate, rheumatoid arthritis, surveys and questionnaires, beliefs about medicines, treatment concerns.

Introduction Methotrexate (MTX) is widely recommended as firstline treatment for rheumatoid arthritis (RA) [1, 2] due to its proven efficacy and favorable cost-benefit ratio [3]. However, despite its proven clinical benefits, adherence

to this treatment remains poor, often influenced by patients’ fears and beliefs. Beliefs about medications are a determining factor in treatment adherence in chronic diseases [4]. Poor adherence to treatment can lead to treatment failure, delayed response, and increased disability, which represent

Address for correspondence L’heri Hind, Department of Rheumatology B, Ayachi Hospital, Ibn Sina Hospital Center, Faculty of Medicine and Pharmacy, Mohammed V University, Rue Al Ayachi, 11150 Salé, Morocco, e-mail: lheri.hind@gmail.com Submitted: 05.12.2025; Accepted: 20.02.2026; Published online: 09.07.2026

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

Methotrexate-related beliefs and fears in rheumatoid arthritis

a significant economic burden on the healthcare system [5, 6]. In patients with RA, concerns are frequently related to the adverse effects of MTX, such as gastrointestinal toxicity, fatigue, alopecia, and liver toxicity [7, 8]. A better understanding of fears and beliefs related to MTX is therefore necessary to prevent non-compliance, improve therapeutic outcomes, and guide therapeutic education strategies. However, data on these aspects are limited in the Moroccan population with RA. The objectives of this study are to assess the beliefs and fears of Moroccan patients with RA regarding MTX and to identify the factors associated with the difference between necessity and concern scores (total score on the Beliefs about Medicines Questionnaire [BMQ]).

Material and methods Study design and population It was a cross-sectional study including patients with RA according to the criteria of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) [9]. The study was conducted between January and June 2025 in the Rheumatology Department B of Al Ayachi Hospital, Ibn Sina University Hospital Center, in Rabat, Morocco.

Study population All patients over the age of 18 who were being treated for RA and had received or were receiving MTX-based treatment were included in the study. Patients with major cognitive or psychiatric disorders or who refused to participate were excluded.

Sampling This was a comprehensive, convenience sample study targeting all adult patients with RA treated with MTX who were admitted to the rheumatology department during the inclusion period. No sampling technique was used, as all eligible patients meeting the inclusion criteria were invited to participate in the study during their routine clinical visits.

Questionnaire The survey questionnaire (see Supplementary Material) was developed following a thorough analysis of previous studies, including systematic reviews and related surveys, on fears and beliefs about MTX [7, 10, 11]. It was designed using a structured methodological approach in line with international recommendations for survey studies [12]. The questionnaire was developed by a multidisciplinary group of 5 experts, including 4 rheumatologists

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(3 professors and a specialist with a PhD) and a statistician. Each expert independently assessed the clarity, relevance and structure of the items. In order to ensure content validity, the individual assessments were discussed collectively and revisions were made by consensus to confirm that all items were complete and appropriate to the objectives and context of the study. A pilot test was conducted with ten patients who were not part of the final study sample. The objective was to assess the clarity, comprehensibility, and feasibility of the questionnaire. Feedback gathered during the pilot phase led to minor adjustments in wording to improve accuracy and readability. The average time required to complete the questionnaire during the pilot phase was approximately 10 minutes, confirming its practicality. In the final version, all questions were mandatory in order to avoid missing data. Responses were carefully reviewed for internal consistency, and incomplete or contradictory responses were excluded from the analysis. A structured questionnaire was administered faceto-face by a trained interviewer: • The first section collected information on age, sex, education level, profession, and disease characteristics (duration, treatments received). • The second section focused on information related to MTX use. Questions covered the time between prescription and start of treatment, total duration of use, dosage form, method of administration for the injectable form, concomitant use of folic acid, and sources of information about RA and its treatments. • The third section of the questionnaire focused on fears associated with MTX. These fears were assessed using a specific 12-item scale, each item rated on a 5-point Likert scale (1 = strongly disagree, 5 = strongly agree). The items explored perceptions of the drug (perceived toxicity, dependence), apprehension about self-injection or forgetting an injection, and concerns about digestive and skin effects, fertility, self-image, the risk of the treatment losing its effectiveness, and the risk of disability. The overall fear score was the average of the 12 items, with each item having the same weight. It ranged from 1 (low fear) to 5 (high fear). Patients were classified into 3 categories: low (score < 2.5), moderate (2.5 ≤ score < 3.5), and high (score ≥ 3.5). A pretest was conducted with ten patients to verify the clarity and comprehensibility of the items. The internal consistency of the scale was deemed satisfactory, with a Cronbach’s α coefficient greater than 0.7, reflecting good internal homogeneity and adequate psychometric reliability for use in clinical research. Beliefs about medicines were assessed using the validated Arabic version of the Beliefs about Medicines

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L’heri Hind, Rkain Hanan, Farih Sara, et al.

Questionnaire-Specific (BMQ-Specific), originally developed by Horne et al. [13, 14]. The last section assessed patients’ beliefs about medications. The BMQ-Specific consists of 2 domains: the BMQ-Necessity and the BMQ-Concerns. The BMQNecessity includes 5 items that assess the necessity of medications to control disease and improve or maintain health. The BMQ-Concerns also includes 5 items that assess the potential negative consequences of taking medications, such as long-term effects, dependence, and other adverse effects. Each item in both domains is rated on a 5-point Likert scale, from 1 (strongly disagree) to 5 (strongly agree). Table I. Sociodemographic and clinical characteristics of the study population Variable

n = 102

Sex Femalea

92 (90.2)

a

Male

10 (9.8) b

Age [years]

53.1 ±12.5

Level of educationa No formal education

40 (39.2)

Primary education

20 (19.6)

Secondary education

17 (16.7)

Higher education

25 (24.5)

Area of residence

a

Urban

86 (84.3)

Rural

16 (15.7)

Disease duration [years]c

14 [9.91–23.8]

a

Current treatment NSAIDs

12 (11.8)

GCs

68 (66.7)

MTX

71 (69.6)

Leflunomide

15 (14.7)

Sulfasalazine

10 (9.8)

bDMARDs

39 (28.2)

Anti-CD20

14 (13.7)

Anti-TNF

23 (22)

Anti-IL-6

2 (2)

a

Categorical variables expressed as n (%). Area of residence refers to the patient’s current residence. b Continuous variables expressed as mean ± standard deviation. c Continuous variables expressed as median [interquartile range]. bDMARDs – biological disease-modifying antirheumatic drugs, GCs – glucocorticosteroids, IL-6 – interleukin-6, MTX – metho­tre­ xate, NSAIDs – non-steroidal anti-inflammatory drugs, TNF – tumor necrosis factor.

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The scores for the individual items were added together to obtain a score for each domain (Necessity or Concerns). Total scores range from 5 to 25 for each of the 2 domains. Higher scores indicate a stronger perception. The necessity-concerns differential was then calculated by subtracting the BMQ-Concerns score from the BMQNecessity score; a positive value indicates that the perception of MTX as necessary outweighs concerns about its use.

Reliability testing methods The internal consistency of the scale was considered good, with a Cronbach’s α coefficient of 0.83 indicating high internal homogeneity, which supports the psychometric reliability of the instrument.

Statistical analysis A descriptive analysis was performed. Qualitative variables were presented as numbers and percentages. Quantitative variables were expressed as mean ± standard deviation when their distribution was compatible with normality (Shapiro-Wilk test), and as median [interquartile range] otherwise. Univariate and then multivariate analysis was used to identify factors associated with beliefs about medications, particularly the BMQ necessity-concerns differential score. The data were analyzed using Jamovi statistical software (2.3.19). A p-value < 0.05 was considered statistically significant.

Bioethical standards Participation in this study was entirely voluntary. All patients were informed of the study objectives, procedures, and data collection process by means of an information sheet provided prior to their participation. Written informed consent was obtained from each participant before completing the questionnaire. The questionnaire was administered in person by a trained interviewer. All data collected were treated confidentially and anonymised in accordance with ethical guidelines. Participants were explicitly informed that they could withdraw from the study at any time without any consequences for their medical care. The study was approved by the Ethics Committee of Mohammed V University in Rabat (Faculty of Medicine and Pharmacy, ethics approval reference: 205/25, approval granted in 2025). The study was conducted in accordance with the ethical principles of the 1964 Declaration of Helsinki and its subsequent amendments.

Results A total of 102 patients with RA agreed to participate in the study. The sociodemographic and clinical charac­teristics of these patients are presented in Table I.

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Methotrexate-related beliefs and fears in rheumatoid arthritis

The mean age was 53.1 ±12.5 years, and 90.2% of parti­ cipants were women. The illiteracy rate was 39.2%. The median duration of RA was 14 years (9.91–23.8), with a median duration of MTX use of 4 years (2–10). The median time between MTX prescription and treatment initiation was 2 weeks (0–24). Methotrexate was mainly administered as injections to be prepared and tablets, in 58.8% and 29.4% of cases, respectively. Self-injection was practiced by 23.8% of patients. Concomitant folic acid supplementation was prescribed in 78.4% of patients. The main sources of information about MTX were rheumatologists, cited by 93.1% of patients, followed by internet sources, cited by 25.5% of patients.

The fear scale showed excellent internal consistency (Cronbach’s α = 0.895; McDonald’s ω = 0.898), with corrected item–total correlations above 0.30. The median overall score for fear of MTX was 2.58 (1.93–3.33), indicating an overall moderate level of fear: 46.1% of patients had a low level of fear, 30.4% had a moderate level, and 23.5% had a high level. Detailed descriptive results for each item are shown in Table II. Beliefs about MTX (Table III). The mean BMQ-Necessity score was 15.0 ±5.04, and the mean BMQ-Concerns score was 15.9 ±6.37. Long-term adverse effects were the main source of concern, reported by 58.8% of patients.

Table II. Methotrexate patients’ fears Perceptions and fears

1 (%)

2 (%)

3 (%)

4 (%)

5 (%)

I am afraid that MTX is chemotherapy

44.1

17.6

10.8

17.6

10.8

I am afraid of self-injections

39.2

25.5

6.9

14.7

13.4

I am afraid of missing an injection of MTX, which would cause a flare-up of my disease 23.5

9.8

11.8

30.4

24.5

I am afraid MTX will cause liver complications

16.7

8.8

11.8

24.5

38.2

I am afraid MTX will cause digestive complications

13.7

9.8

10.8

36.3

29.4

I am afraid MTX will accelerate the ageing of my skin

39.2

20.6

15.7

14.7

9.8

I am afraid MTX will cause hair loss

37.3

14.7

13.7

17.6

16.7

I am afraid MTX will cause a skin allergy

31.4

20.6

11.8

16.7

19.6

I am afraid MTX will affect my fertility

49

20.6

12.7

10.8

6.9

I am afraid MTX will cause a loss of self-image

41.2

21.6

10.8

18.6

7.8

I am afraid MTX won’t be efficient for my disease

26.5

16.7

17.6

24.5

14.7

I am afraid MTX will cause handicaps

41.2

18.6

10.8

17.6

11.8

1 – strongly disagree, 2 – disagree, 3 – neither agree nor disagree, 4 – agree, 5 – strongly agree. MTX – methotrexate.

Table III. Beliefs of Moroccan patients with inflammatory rheumatic diseases regarding methotrexate Agree or strongly agree BMQ-Specific

BMQ-Concerns

BMQ-Necessity

Having to take MTX worries me

39.2%

I sometimes worry about the long-term effects of MTX

58.8%

Methotrexate is a mystery to me

45.1%

Methotrexate disrupts my life

36.2%

I sometimes worry about becoming too dependent on MTX

42.2%

Score total

15.9 ±6.37

My health, at present, depends on MTX

55%

My life would be impossible without MTX

36.2%

Without MTX, I would be very ill

54%

My health in the future will depend on MTX

46.1%

Methotrexate protects me from becoming worse

60.8%

Score total

15 ±5.04

BMQ Differential

1 [from –3 to 4]

BMQ – Beliefs about Medicines Questionnaire, MTX – methotrexate.

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Table IV. Univariate and multivariate analyses for the BMQ necessity–concerns differential Variable

β (univariate)

95% CI

β (multivariate)

95% CI

Age [years]

–0.03

From –0.11 to 0.04

0.01

From –2.36 to 8.53

Sex (female)

1.34

From –1.90 to 4.59

0.64

From –2.68 to 3.97

Urban residence

–3.94

From –6.49 to –1.39

–2.52

From –5.20 to 0.15

High level of education

–3.14

From –5.56 to –0.72

–1.37

From –4.08 to 1.33

Disease duration [years]

–0.15

From –0.24 to –0.05

–0.12

From –0.23 to –0.02

Biologic therapy

–0.87

From –2.86 to 1.11

–0.61

From –2.47 to 1.24

Medical source of information

4.67

0.95 to 8.39

1.86

From –2.73 to 6.47

Internet as a source of information

–4.38

From –6.31 to –2.44

–2.66

From –5.06 to –0.27

The BMQ necessity–concerns differential (“BMQ differential”) had a median of 1 [from –3 to 4]; 51% of patients had a BMQ necessity–concerns differential > 0. In the univariate and multivariate analyses (Table IV), the BMQ differential was significantly associated with disease duration (β = –0.12; 95% CI: from –0.23 to –0.02) and the use of the internet as a source of medical information (β =–2.66; 95% CI: from –5.06 to –0.27).

Discussion In our study, 51% of patients with RA had a positive BMQ differential, indicating that they recognized the need for MTX to address their conditions. This suggests an overall favorable attitude towards this treatment. More than half of the respondents (54%) reported that their treatment “protected them from disease progression”. The main concern was long-term side effects, cited by 58.8% of patients. Digestive and hepatic effects were reported by 65.7% and 62.7% of patients, respectively. These results are consistent with those of previous studies, which reported that gastrointestinal toxicity (nausea, abdominal pain and diarrhea) and hepatotoxi­ city are the most feared MTX side effects, even among patients who have not experienced them directly [7, 10, 15]. Despite the existence of considerable clinical evi­ dence suggesting a favorable hepatic safety profile for MTX in the treatment of RA, one of the most frequently reported concerns among patients remains hepatic toxicity. Recent data from a cross-sectional study demonstrated no association between MTX exposure and non-alcoholic fatty liver disease or liver fibrosis. Metabolic factors appear to be the main determinants of liver damage [16]. Similar results were reported in a cohort of patients receiving long-term MTX, where an increased incidence of liver fibrosis was not associated with the cumulative dose received [17]. Literature demonstrates that RA patients frequently express concerns about adverse effects, drug toxicity, and long-term consequences, including fear of disability

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or disease progression. Palominos et al. reported that fears relating to pharmacological treatment were present in half of the analyzed studies, while fears relating to disability and disease progression were present in 28% of cases [18]. Hayden et al. [10] found that patients on MTX oscillated between necessity and concern, and that their beliefs may change over the course of their treatment. These findings confirm that such fears are signi­ ficant determinants of patient compliance and highlight the importance of recognizing and addressing them in clinical practice. Our analyses revealed that both disease duration and the use of the internet as a source of information were independently associated with patients’ beliefs about MTX. A longer duration of RA was significantly associated with a lower total BMQ score, reflecting a reduced perception of treatment necessity and increased concerns about it. While previous studies have reported that prolonged disease duration leads to a stronger belief in the need for treatment [19, 20], our results suggest the opposite in this context. This discrepancy could be explained by treatment fatigue, resulting from the cumulative impact of medication experiences, adverse effects, and treatment failures, which gradually lead to a loss of confidence and heightened concerns. This finding emphasizes the evolving and contextual nature of medication beliefs, as demonstrated in several studies [10, 19]. Using the internet as a source of information also influenced beliefs about MTX. Patients who reported consulting online sources had a significantly lower total BMQ score, reflecting an increased perception of risks relative to the necessity of treatment. These findings are in line with those of Otón et al. [21], who observed that most patients treated with MTX actively seek information online, but are rarely referred by their rheumatologist to reliable online resources, resulting in unsatisfied information needs and potentially confusing content. In Morocco, internet access is expanding rapidly, but the quality, reliability and readability of the available medical content vary greatly.

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Methotrexate-related beliefs and fears in rheumatoid arthritis

International data [22–24] confirm that the impact of the internet on therapeutic beliefs is ambivalent; while it can promote patient autonomy and active participation in care, it can also cause confusion, concern, or even refusal of treatment when information is not correctly interpreted or contextualized. These findings emphasize the importance of integrating eHealth literacy into the doctor–patient relationship. Patients should be directed towards certified platforms and content, and the reliability of online sources should be systematically addressed during consultations. This reduces the impact of misinformation and builds confidence in treatments, particularly in settings where health literacy is limited. Univariate analysis revealed that education level and source of medical information were independently associated with beliefs about MTX. Patients with a higher education had lower total BMQ scores than those with no education, suggesting a more critical assessment of potential risks relative to perceived necessity. This finding is consistent with the results of a study conducted in the United Kingdom by Kumar et al. [25], which showed that lower levels of education were associated with more favorable beliefs about medications. Conversely, receiving information directly from the rheumatologist was associated with higher BMQ scores, reflecting a stronger belief in the necessity of treatment. However, this association was no longer significant in the multivariate analysis. These results highlight the importance of therapeutic education and structured medical communication based on a trusting relationship to support MTX adherence [26, 27]. Our results underline the complexity of beliefs about MTX. These are not only determined by clinical factors, but also by the social and cultural context. Patients living in rural areas had higher BMQ scores than those in urban areas, suggesting a stronger belief in the need for treatment. Conversely, urban patients, who were exposed to more sources of information, expressed more concerns. These observations are consistent with previous reports showing that cultural and contextual differences can strongly influence patients’ perceptions of medications [20, 28].

Study limitations However, we should note some limitations of our study. Firstly, the small sample size, resulting from treatment discontinuations observed during the inclusion period, reduces statistical power and may limit the scope of the conclusions. In addition, the cross-sectional design of the study does not enable us to establish a causal link between the variables. Beliefs may evolve over time depending on disease progression and therapeutic experiences. Finally, conducting the study in a single Moroccan center may limit the generalisability of the results.

Conclusions Our results show that MTX is generally perceived as necessary by patients with RA, despite fears associated with its use. The duration of the disease and internet use were associated with a “concerns > necessity” balance, highlighting the need for therapeutic education interventions adapted to the cultural context, as well as guidance towards reliable digital sources, to optimize adherence and clinical outcomes.

Disclosures Conflict of interest: The authors declare no conflict of in­ terest. Funding: No external funding. Ethics approval: The study was approved by the Ethics Committee of the University Mohammed V, Rabat, Mo­ rocco (Faculty of Medicine and Pharmacy), with approval number 205/25. Data availability: The data that support the findings of this study are available on request from the correspond­ ing author (L.H.). References 1. Smolen JS, Landewé RBM, Bergstra SA, et al. EULAR recom­ mendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis 2023; 82: 3–18, DOI: 10.1136/ard-2022-223356. 2. Fautrel B, Kedra J, Rempenault C, et al. 2024 update of the recommendations of the French Society of Rheumatology for the diagnosis and management of patients with rheumatoid arthritis. Joint Bone Spine 2024; 91: 105790, DOI: 10.1016/ j.jbspin.2024.105790. 3. Fellous S, Rkain H, Ahid S, et al. One-year direct costs of bio­ logical therapy in rheumatoid arthritis and its predictive fac­ tors: data from the Moroccan RBSMR registry. Rheumatol Int 2021; 41: 787–793, DOI: 10.1007/s00296-020-04762-7. 4. Buch MH, Eyre S, McGonagle D. Persistent inflammatory and non-inflammatory mechanisms in refractory rheumatoid arthri­ tis. Nat Rev Rheumatol 2021; 17: 17–33, DOI: 10.1038/s41584020-00541-7. 5. Chowdhury T, Dutta J, Noel P, et al. An Overview on Causes of Nonadherence in the Treatment of Rheumatoid Arthritis: Its Effect on Mortality and Ways to Improve Adherence. Cureus 2022; 14: e24520, DOI: 10.7759/cureus.24520. 6. van den Bemt BJ, Zwikker HE, van den Ende CH. Medication adherence in patients with rheumatoid arthritis: a critical appraisal of the existing literature. Expert Rev Clin Immunol 2012; 8: 337–351, DOI: 10.1586/eci.12.23. 7. Nalwa HS, Prasad P, Ganguly NK, et al. Methotrexate intoler­ ance in rheumatoid arthritis. Transl Med Commun 2023; 8: 10, DOI: 10.1186/s41231-023-00142-y. 8. Curtis JR, Xie F, Mackey D, et al. Patient’s experience with sub­ cutaneous and oral methotrexate for the treatment of rheu­

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Review paper

Reumatologia 2026; 64, 4: 287–295 DOI: https://doi.org/10.5114/reum/224547

Autoimmune inflammatory diseases of the central nervous system: advances in clinical trials and immunotherapeutic strategies Mateusz Gumienny ID  Faculty of Medicine, Medical University of Silesia, Katowice, Poland

Abstract Autoimmune inflammatory diseases of the central nervous system (CNS), including autoimmune encephalitis (AE), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), have emerged over the last two decades as distinct nosological entities with specific autoantibody targets, clinical phenotypes, and treatment responses. Recognition of their autoimmune basis has transformed management from largely supportive and empiric approaches toward mechanism-based immunotherapy. However, these conditions remain rare, clinically heterogeneous, and frequently severe, posing substantial challenges for the design and conduct of robust clinical trials. This review synthesizes current evidence on advances in clinical research and immunotherapy across the major autoimmune CNS disease groups, with a particular focus on trial designs, endpoints, and the evolution from observational cohorts to randomized controlled trials. In AE, first-line immunotherapies (high-dose glucocorticoids, intravenous immunoglobulin, and plasma exchange) remain based mainly on observational data, while second-line therapies such as rituximab and cyclophosphamide are increasingly used despite limited comparative trial data. Recent systematic reviews and individual patient data meta-analyses have highlighted both the potential and the limitations of existing observational evidence, and several randomized phase II–III trials are now underway evaluating agents including bortezomib, satralizumab, and inebilizumab. In NMOSD, the therapeutic landscape has advanced more rapidly, with multiple pivotal randomized controlled trials of targeted biologics (e.g. complement inhibition with eculizumab, B-cell depletion with inebilizumab, interleukin‑6 [IL-6] receptor blockade with satralizumab) demonstrating large reductions in relapse risk and leading to regulatory approvals. For MOGAD, most data still derive from retrospective cohorts and extrapolation from NMOSD and multiple sclerosis, but several disease-specific trials are ongoing that investigate IL‑6 receptor inhibitors, neonatal Fc receptor (FcRn) antagonists, and purine synthesis inhibitors. Across these disorders, key challenges for clinical research include small and geographically dispersed patient populations, variable access to diagnostic antibody testing, limited validation of outcome measures that capture cognitive and psychiatric morbidity, and underrepresentation of pediatric, elderly, and low-resource populations. Emerging strategies include use of adaptive and basket trial designs, registry-based and pragmatic trials, and increased reliance on international collaborative networks. Addressing these methodological and equity-related issues will be essential to translate immunopathological insights into broadly accessible, evidence-based care for patients with autoimmune CNS disease. Key words: MOGAD, NMOSD, autoimmune encephalitis, neuroimmunology.

Address for correspondence Mateusz Gumienny, Faculty of Medicine, Medical University of Silesia, 15 Poniatowskiego St., 40-055 Katowice, Poland, e-mail: gumienny07@gmail.com Submitted: 18.02.2026; Accepted: 14.06.2026; Published online: 10.07.2026

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

288

Introduction Autoimmune inflammatory diseases of the central nervous system (CNS) comprise a heterogeneous but increasingly well-defined group of disorders in which humoral and cellular immune responses target antigens expressed in the brain, spinal cord, and optic nerves. Historically, many of these syndromes were classified as idiopathic encephalitis, atypical demyelinating disease, or paraneoplastic neurologic syndromes. The identification of disease-specific autoantibodies – such as those against the N‑methyl‑D‑aspartate receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactinassociated protein-like 2 (CASPR2), aquaporin‑4 (AQP4), and myelin oligodendrocyte glycoprotein (MOG) – has established discrete disease entities with characteristic clinical spectra, radiologic features, and responses to immunotherapy [1–3]. Autoimmune encephalitis (AE) now encompasses a broad spectrum of syndromes, classically including anti‑NMDAR encephalitis, LGI1- and CASPR2-associated limbic encephalitis, GABA receptor encephalitides, and antibody-negative but clinically defined forms. These syndromes often present with seizures, psychiatric symptoms, cognitive dysfunction, movement disorders, and/or autonomic instability, and can be rapidly progressive. Neuromyelitis optica spectrum disorder (NMOSD) is characterized by severe, relapsing inflammatory attacks of the optic nerves and spinal cord, frequently associated with AQP4‑IgG; it is now

Mateusz Gumienny

recognized as distinct from multiple sclerosis (MS) with unique immunopathogenesis and therapeutic needs. Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has emerged as a third major antibody-mediated demyelinating disease of the CNS, encompassing optic neuritis (ON), transverse myelitis, acute disseminated encephalomyelitis (ADEM), and cortical encephalitis phenotypes [4–6]. Recognition of the autoimmune basis of these disorders has created an urgent need for high-quality evidence on optimal immunotherapy. However, clinical research is hampered by low incidence, phenotypic diversity, diagnostic delays, and ethical constraints on placebo use in acutely life-threatening disease. Historically, the evidence base has relied heavily on single-center series and retrospective cohorts. In recent years, there has been a significant shift toward more rigorous clinical trial methodology, including multicenter cohorts, prospective registries, and randomized trials of targeted biologics. This transition is most advanced in NMOSD but is now beginning in AE and MOGAD [5, 7–9]. An overview of the main autoimmune inflammatory diseases of the CNS is shown in Figure 1. The aim of this review is to provide an integrated overview of advances in clinical research across autoimmune CNS diseases, focusing on AE, NMOSD, and MOGAD. Particular attention is paid to the evolution of trial design and outcome measures, the emerging therapeutic pipeline, and remaining gaps and inequities in evidence generation.

Fig. 1. Overview of main autoimmune inflammatory diseases of CNS. Figure created using NotebookLM. ADEM – acute disseminated encephalomyelitis, AE – autoimmune encephalitis, AMPAR – O-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid receptor, AQP4-IgG – aquaporin-4 immunoglobulin G, CASPR2 – contactin-associated protein-like 2, GABABR – g-aminobutyric acid type B receptor, LETM – longitudinally extensive transverse myelitis, LGI1 – leucine-rich gliomainactivated 1, MOGAD – MOG antibody-associated disease, MOG-IgG – myelin oligodendrocyte glycoprotein immunoglobulin G, NMDAR – N-methyl-D-aspartate receptor, NMOSD – neuromyelitis optics spectrum disorder, ON – optic neuritis.

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Central nervous system autoimmunity: advances in therapy

Material and methods This narrative review synthesizes evidence from peer-reviewed articles indexed in PubMed and full-text resources available through PubMed Central, as well as selected key papers identified from reference lists of major reviews. Eligibility criteria were intentionally broad because AE, NMOSD, and MOGAD remain rare and the randomized evidence base is limited. We included major randomized controlled trials, prospective observational studies, pivotal retrospective cohort stu­dies, systematic reviews, meta‑analyses, and narrative reviews that provided substantive data on immunotherapy in AE, NMOSD, or MOGAD. Studies were excluded if they were single case reports, very small case series without clearly described methods, conference abstracts without full text, or articles that did not report disease‑specific treatment strategies or outcomes. No formal language restrictions were applied at the search level; however, the synthesis focused on articles for which the full text could be obtained and critically appraised by the authors, which in practice were predominantly English‑language publications. Because this was designed as a narrative rather than a formal systematic review, records were not tracked in a PRISMA‑ style flow diagram, and exact numbers of screened and included studies were not recorded. The emphasis was on capturing all pivotal randomized, prospective, and large retrospective cohort studies together with key high‑impact reviews. Study selection and data extraction were performed by a single reviewer using the prespecified eligibility criteria; duplicate independent screening was not undertaken. In this narrative review, the term ‘high‑quality’ was applied pragmatically to studies and reviews that 1) clearly described their patient population, antibody status, and diagnostic criteria; 2) used transpa­ rent and reproducible methods for case ascertainment, follow‑up, and outcome assessment; and 3) were published in peer‑reviewed journals with established editorial standards. We did not apply a formal risk‑of‑bias tool or quantitative quality score, and the designation of high quality therefore reflects methodological transparency and clinical relevance rather than a standardized grading system. We searched PubMed and PubMed Central from 1 January of 2018 to 16 May 2026. Electronic searches were performed in PubMed using combinations of the following terms and Medical Subject Headings (MeSH): • “autoimmune encephalitis”, “immune-mediated ence­ phalitis”, “antibody-mediated encephalitis”; • “neuromyelitis optica spectrum disorder”, “NMOSD”; • “myelin oligodendrocyte glycoprotein antibody associated disease”, “MOGAD”;

• “autoimmune disorders of the nervous system”, “autoimmune central nervous system diseases”; • combined with: “clinical trial”, “randomized”, “immunotherapy”, “treatment”, “therapeutic”, “review.” Publication type filters for “review” and “clinical trial” were applied where appropriate. Additional articles were identified by manual review of references in high-impact reviews and position papers on AE, NMOSD, and MOGAD. Given the rarity of these conditions and the limited number of large-scale randomized controlled trials (RCTs), all major randomized, prospective, and pivotal retrospective cohort studies of immunotherapy in AE, NMOSD, and MOGAD were considered. High-quality narrative reviews, systematic reviews, and meta-analyses were included to summarize broader evidence and context, particularly where individual studies were small or heterogeneous. The primary focus was on: • advances in immunotherapy (first-line, second-line, and emerging targeted agents); • clinical trial designs and outcome measures; • evidence regarding efficacy, safety, and long-term outcomes; • cross-cutting methodological challenges and issues related to inclusivity and access. This review does not aim to provide an exhaustive catalog of all case reports or small series, but rather to highlight key trends and representative studies that have shaped current clinical practice and trial methodo­ logy.

Results Autoimmune encephalitis Clinical spectrum and classification Autoimmune encephalitis encompasses a group of syndromes characterized by subacute onset of neuropsychiatric symptoms, seizures, memory impairment, movement disorders, and/or autonomic dysfunction, often in association with neuronal autoantibodies. Syndromes are commonly classified by antibody target into: • cell surface/synaptic antibodies (e.g. NMDAR, LGI1, CASPR2, AMPAR, GABABR); • intracellular antibodies associated with paraneoplastic syndromes (e.g. Hu, Ma2, GAD65); • antibody-negative AE fulfilling clinical criteria such as those proposed by Graus et al. Recent large overviews have emphasized that antibody-negative AE constitutes a substantial proportion of cases and may respond to immunotherapy comparably to antibody-positive forms, though with greater diagnostic uncertainty and heterogeneity [3, 6].

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First-line immunotherapy Standard first-line treatment for AE consists of highdose intravenous glucocorticosteroids (GCs), intravenous immunoglobulin (IVIG), and/or plasma exchange (PLEX), typically used in combination. These recommendations are based on observational cohorts and expert consensus rather than randomized comparisons. Multiple retrospective series and registry-based analyses have shown that early initiation of first-line immunotherapy is associated with improved functional outcomes and reduced longterm disability in anti‑NMDAR and other AE subtypes [4, 7]. For example, large national cohorts of NMDAR encephalitis have demonstrated that the majority of patients experience substantial functional recovery (modified Rankin Scale [mRS] ≤ 2) when treated promptly with GCs, IVIG, and/or PLEX. Delays in treatment initiation correlate with worse outcomes and higher relapse risk, underscoring the importance of clinical suspicion and early empiric therapy, even before antibody confirmation [4, 10]. However, no RCTs directly compare different firstline regimens in AE, and questions remain regarding the optimal sequencing, dosing, and duration of therapy, particularly in severe or refractory cases [7, 11].

Second-line therapies: rituximab, cyclophosphamide, and beyond Second-line immunotherapy is typically considered in patients with an inadequate response to first-line treatment within 2–4 weeks or in those with severe or relapsing disease. Commonly used agents include rituximab and cyclophosphamide, administered alone or in combination [3, 7]. A large multicenter observational cohort from the German Network for Research on Autoimmune Encephalitis evaluated 358 patients with NMDAR-, LGI1-, CASPR2-, or GAD65-associated AE; 46% received rituximab. Rituximab-treated patients tended to be more severely affected at baseline but showed significant improvement over time, with a higher proportion achieving independent living (mRS ≤ 2) compared with non-rituximab-treated patients with NMDAR-AE and CASPR2-AE, and a substantial reduction in relapse rates (5% vs. 13%). These data support the effectiveness of B‑cell depletion in AE but remain subject to confounding and selection bias [10]. A recent individual patient data meta-analysis pooled 356 patients with AE from 25 observational studies to examine the impact of second-line immunotherapy on functional outcome. Overall, no statistically significant association between second-line treatment and improved final mRS score was observed in the full cohort or in subgroups with NMDAR-AE or severe AE, though

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second-line therapy was associated with higher mRS scores in anti‑LGI1 AE and in long-term follow-up. The authors highlighted the high risk of bias, limitations of mRS in capturing psychiatric and cognitive disability, and residual confounding by indication; these findings underscore the urgent need for randomized comparative trials [12]. Cyclophosphamide remains widely used, especially in paraneoplastic AE and in resource-limited settings due to its lower cost, but it carries a higher risk of systemic toxicity compared with rituximab. No headto-head RCTs of rituximab versus cyclophosphamide have been completed, and current practice is largely guided by extrapolation from other autoimmune diseases and small comparative series [7, 11].

Refractory autoimmune encephalitis and emerging targeted agents For patients refractory to conventional second-line therapies, a growing body of literature describes the use of targeted agents including IL‑6 receptor inhibitors, proteasome inhibitors, and Janus kinase inhibitors [10, 11]. Tocilizumab, an IL‑6 receptor monoclonal antibody, has been evaluated in institutional cohorts of refractory AE. In one study, tocilizumab was administered to patients who had failed rituximab; a high proportion (approximately 90%) experienced clinical improvement within one month and maintained favorable long-term responses. Additional case reports and small series have documented benefits of tocilizumab in LGI1-, CASPR2-, and GAD65-associated encephalitis, as well as in severe anti‑NMDAR disease [7, 10]. Bortezomib, a proteasome inhibitor with activity against plasma cells, is being investigated in a multicenter, randomized, double-blind phase II trial for severe AE refractory to rituximab (NCT03993262). Satralizumab (IL‑6 receptor inhibitor) is under evaluation in a phase III basket trial including patients with NMDAR and LGI1 AE (NCT05503264), reflecting a shift toward biomarker- and mechanism-driven trial designs. Janus kinase inhibitors such as tofacitinib, which cross the blood–brain barrier, have shown anecdotal benefits in small series of refractory AE and MOG antibody-related disorders, including resolution of chronic autoimmune meningoencephalitis and new-onset refractory status epilepticus. These data, though preliminary, suggest a potential role for targeting intracellular cytokine signaling pathways in severe, treatment-resistant disease [7]. An overview of monoclonal antibody therapies in AE highlights ongoing RCTs of inebilizumab (anti‑CD19), ocrelizumab (anti‑CD20), and FcRn antagonists (e.g. roza­nolixizumab) across different antibody-defined AE subtypes, as well as the mechanistic rationale derived from success in NMOSD. The ExTINGUISH trial, a phase

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2b randomized, placebo-controlled study, is evaluating inebilizumab added to first-line therapy in moderate to severe anti‑NMDAR encephalitis [8, 13].

Antibody-negative autoimmune encephalitis Antibody-negative AE represents a diagnostic and therapeutic challenge. A recent retrospective case– control study compared 33 antibody-positive and 27 antibody-negative AE patients; both groups appeared to benefit from immunotherapy, but antibody-negative cases had more diagnostic delays and heterogeneity in clinical presentation. Outcomes were generally similar after treatment, supporting the practice of empiric immunotherapy in patients meeting clinical criteria for AE despite negative antibody panels. However, the lack of biomarker stratification complicates trial design, and future studies may need to incorporate broader autoantibody discovery platforms and cerebrospinal fluid (CSF) biomarker profiling [3, 6].

Neuromyelitis optica spectrum disorder Disease overview and pathophysiology Neuromyelitis optica spectrum disorder is a relapsing inflammatory demyelinating disease of the CNS, characterized by severe attacks of optic neuritis and longitudinally extensive transverse myelitis, often with intractable vomiting, area postrema syndrome, or other brainstem symptoms. The discovery of AQP4‑IgG established NMOSD as distinct from MS, with astrocytopathy and complement-mediated injury as central pathophysiological features [14, 15]. Epidemiologic studies indicate that NMOSD is rare but globally distributed, with higher pre­valence in Asian, African, and Latin American populations and marked female predominance. Before the advent of targeted biologics, NMOSD carried a high risk of visual and motor disability due to recurrent attacks [15].

Pivotal randomized trials of targeted biologics The last decade has seen transformative advances in NMOSD therapy with the completion of several phase 2/3 RCTs of targeted biologics, leading to regulatory approvals and a new standard of care [16]. Eculizumab, a terminal complement C5 inhibitor, was evaluated in patients with AQP4‑IgG-positive NMOSD and showed a marked reduction in relapse risk compared with placebo in a randomized trial, although patients continued background immunosuppression. Inebilizumab, an anti‑CD19 monoclonal antibody that depletes a broader range of B cells and plasmablasts than anti‑CD20 agents, demonstrated similarly robust efficacy: in a pivotal trial, 12%

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of inebilizumab-treated versus 39% of placebo-treated participants experienced relapses (hazard ratio 0.27, 95% CI: 0.15–0.50). Satralizumab, an IL‑6 receptor monoclonal antibody, has also shown significant reductions in relapse risk in both monotherapy and add-on designs [8, 14, 15]. These RCTs have collectively established that targeted biologics can profoundly alter the natural history of AQP4‑IgG-positive NMOSD, with acceptable safety profiles when appropriate infection prophylaxis and vaccination strategies are implemented. However, data in AQP4‑IgG-negative NMOSD and in pediatric or elderly populations remain more limited, and access to biologics is constrained in many low- and middle-income regions [15, 16]. While these biologic agents have transformed relapse prevention in AQP4‑IgG‑positive NMOSD, their use raises important safety and health‑system considerations. Long‑term complement and B‑cell or IL‑6 receptor blockade may increase susceptibility to serious infections, contribute to hypogammaglobulinemia, and necessitate complex vaccination strategies and ongoing monitoring, and the cumulative impact of sustained immunosuppression over decades remains incompletely characterized. In many regions, high acquisition costs, infusion or injection‑ center requirements, and limited reimbursement substantially restrict access, raising questions about cost‑ effectiveness and equity of implementation. Furthermore, RCT populations have typically underrepresented older patients, those with significant comorbidities, and individuals from low‑resource settings, which means that real‑world effectiveness and safety may differ from trial estimates and should be interpreted cautiously.

Trial design and outcome measures in neuromyelitis optica spectrum disorder A distinctive feature of NMOSD trials is the focus on relapse prevention as the primary outcome, with annualized relapse rate and time to first adjudicated relapse as key endpoints. Disability measures such as the Expanded Disability Status Scale (EDSS) and visual acuity are important secondary endpoints, but their sensitivity to incremental change in NMOSD is limited, particularly over the relatively short follow-up of most RCTs [15]. The heterogeneity of background immunosuppression in some trials introduces complexity in interpretation, and future studies may increasingly adopt more standardized background regimens or examine biologic monotherapy. Inclusion of patient-reported outcomes, cognitive assessments, and quality-of-life measures is also becoming more common, reflecting a broader appreciation of the multifaceted burden of NMOSD [14, 16].

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Myelin oligodendrocyte glycoprotein antibody-associated disease Clinical and radiologic characteristics Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct antibody-mediated demyelinating disease of the CNS, characterized by hete­ rogeneous presentations including ON, ADEM, transverse myelitis, cortical encephalitis, and brainstem or cerebellar syndromes. It affects both children and adults, with ADEM more common in children and isolated ON and myelitis more frequent in adults [17]. A large cohort of 59 patients with relapsing MOGAD showed that ON was the most common initial presentation (54%), followed by ADEM (20%, exclusively in children). Patients were highly responsive to GCs, but relapse risk was strongly associated with rapid tapering or discontinuation of GCs: 70% of episodes treated with oral prednisone relapsed, especially when doses were reduced below 10 mg daily or stopped within two months. Although many patients recover well, residual disability – including visual loss – remains common [5]. Radiologically, MOGAD often features lesions that resolve completely over time, in contrast to the more persistent lesions seen in AQP4‑IgG+ NMOSD or MS, and asymptomatic new T2 lesions are rare, suggesting little ongoing subclinical disease activity between attacks [1].

Current treatment strategies At present, no therapies are formally approved for MOGAD, and management is largely empirical, drawing on evidence from NMOSD and clinical experience. Acute attacks are treated with high-dose intravenous GCs, often followed by tapering courses of oral GCs, and/or PLEX or IVIG in severe cases [17]. Long-term relapse prevention typically involves off-label use of azathioprine, mycophenolate mofetil, rituximab, or IVIG; retrospective cohorts suggest that these therapies reduce relapse rates, but treatment failures and relapses remain frequent, and comparative effectiveness is uncertain. Maintenance prednisone may be particularly effective in some patients, but its long-term toxicity is a major limitation [5, 9]. However, the frequent practice of extrapolating chronic immunosuppressive strategies from AQP4‑IgG‑ positive NMOSD to MOGAD deserves more critical scrutiny. Myelin oligodendrocyte glycoprotein antibodyassociated disease differs from NMOSD in immunopathogenesis, with a distinct target antigen and potentially different balance between humoral and cellular mechanisms, and clinically it often shows a higher degree of GC responsiveness, more frequent complete lesion resolution on MRI, and less evidence of silent interval disease activity. These features suggest that the

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risk–benefit calculus for prolonged, intensive immunosuppression may not mirror that of NMOSD and that simple transfer of NMOSD treatment algorithms risks both overtreatment in some patients and inadequate control in others. Moreover, the small numbers of MOGAD patients incidentally included in NMOSD biolo­ gic trials are insufficient to provide robust efficacy or safety signals, underscoring the need for disease‑specific randomized studies before NMOSD‑derived regimens can be considered standard of care in MOGAD.

Emerging clinical trials and targeted therapies Several recent reviews highlight a rapidly evolving treatment landscape for MOGAD, with multiple targeted agents under investigation. Interleukin‑6 receptor inhi­ bitors (tocilizumab and satralizumab) have been used in small series and case reports, often in patients with overlapping NMOSD or in those refractory to conventional therapy; preliminary data suggest reductions in relapse rates, though numbers remain small. FcRn antagonists such as rozanolixizumab and other agents aimed at modulating pathogenic IgG are also being studied [9]. Ongoing phase 2/3 trials include MOGwAI, TOMATO, METEOROID, and cosMOG, which evaluate agents such as azathioprine, tocilizumab, satralizumab, and rozanolixizumab in adult MOGAD populations. These trials aim to provide disease-specific evidence on efficacy, safety, and dosing strategies, and may pave the way for regulatory approvals within the next several years [18]. A recent review of emerging principles for treating MOGAD emphasizes the importance of early diagnosis, relapses as the primary driver of long-term disability, and the need for prospective, adequately powered, MOGAD-specific trials. The authors also highlight that some patients with MOGAD were included in NMOSD and inebilizumab trials, but the numbers were too small to draw definitive conclusions, underscoring the need for dedicated MOGAD studies [9, 18].

Broader spectrum: autoimmune nervous system disorders and central nervous system involvement in systemic autoimmune disease Beyond AE, NMOSD, and MOGAD, a wider group of autoimmune nervous system disorders includes auto­ immune epilepsies, movement disorders, stiff-person spectrum disorders, and peripheral neuropathies, many of which respond to similar immunotherapies. A comprehensive review of autoimmune disorders of the nervous system emphasizes shared immunopathological mecha-

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Fig. 2. Evolution of immunotherapy in autoimmune CNS diseases. Figure created using NotebookLM. ADEM – acute disseminated encephalomyelitis, AE – autoimmune encephalitis, AQP4-IgG – aquaporin-4 immunoglobulin G, AZA – azathioprine, CASPR2 – contactin-associated protein-like 2, CBA – cell-based assay, CSF – cerebrospinal fluid, EEG – elec­ troencephalography, GABABR – g-aminobutyric acid type B receptor, IVMP – intravenous methylprednisolone, IVIG – intravenous immunoglobulin, JAK – Janus kinase, LETM – longitudinally extensive transverse myelitis, LGI1 – leucine-rich glioma-inactivated 1, MMF – mycophenolate mofetil, MOGAD – MOG antibody-associated disease, MOG-IgG – myelin oligodendrocyte glycoprotein immunoglobulin G, MRI – magnetic resonance imaging, NMDAR – N-methyl-D-aspartate receptor, NMOSD – neuromyelitis optics spectrum disorder, PLEX – plasma exchange.

nisms and highlights the potential for broader application of lessons learned from AE and NMOSD trials [2]. Central nervous system involvement is also a recognized manifestation of systemic autoimmune rheumatic diseases such as systemic lupus erythematosus, antiphospholipid syndrome, Sjögren’s syndrome, and systemic vasculitides. A recent comprehensive review details the spectrum of neuropsychiatric manifestations, including autoimmune cerebritis, demyelination, vasculitis, and antibody-mediated encephalitis, and discusses immunosuppressive strategies extrapolated from systemic disease management. High-quality CNS-specific RCTs are rare in these contexts, and treatment decisions are often based on observational evidence and expert consensus [19, 20]. The review emphasizes that in everyday rheumatology practice, autoimmune CNS inflammation often appears as part of neuropsychiatric lupus, neuro‑Behçet’s disease, CNS vasculitis, CNS Sjögren’s disease, or antiphospholipid syndrome, and that distinguishing primary CNS‑limited disorders (NMOSD, MOGAD, AE) from CNS involvement of systemic disease has direct implications for classification, prognosis, and long‑term treatment strategy [19, 20]. It further notes that reviews of systemic autoimmune rheumatic diseases with CNS involvement

show overlapping immunopathology and therapies, but different diagnostic priorities between neurology and rheumatology, and frames AE/NMOSD/MOGAD explicitly within the spectrum of rheumatologic disorders to facilitate earlier recognition of overlap syndromes and more rational immunosuppression [19, 20]. Figure 2 illustrates the evolution of immunotherapy in autoimmune CNS diseases.

Discussion The past 15–20 years have witnessed a profound transformation in the understanding and treatment of autoimmune CNS diseases. In AE, recognition of anti­bodymediated mechanisms has shifted management from nonspecific antivirals and antiepileptics toward early, aggressive immunotherapy, typically following a staged approach with first-line treatments (GCs, IVIG, PLEX) followed by B-cell depletion or cytotoxic agents, with escalating use of targeted therapies for refractory disease, despite the lack of formal RCTs [4, 8, 11]. In NMOSD, the impact of biologics has been even more striking, with multiple high-quality RCTs demonstrating large relative risk reductions in relapse and leading to approvals of eculizumab, inebilizumab, and satralizumab in AQP4‑IgG-positive disease, contrasting

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sharply with the challenges faced in APS and other rare autoimmune diseases and providing a model for future clinical research in MOGAD and AE [8, 15, 16]. For MOGAD, the field is at an earlier stage, with increasing recognition of a distinct clinical entity, better-defined diagnostic criteria, and the first wave of disease-specific trials now underway, where existing data underscore the need for long-term immunotherapy in relapsing disease yet highlight the limitations of extrapolating from NMOSD and MS, as MOGAD exhibits unique features such as higher frequency of complete lesion resolution and distinct attack patterns [1, 5, 17]. Several cross-cutting methodological challenges limit the strength and generalizability of current evidence, including rarity and heterogeneity leading to reliance on multicenter registries; outcome measures such as mRS and EDSS that may be insensitive to cognitive and psychiatric deficits prevalent in AE and MOGAD; confounding by indication and bias in observational studies justifying the emphasis on prospective registries and randomized designs; diagnostic delays and uneven access to validated antibody testing leading to underdiag­ nosis and misclassification, particularly affecting lowand middle-income countries; and ethical concerns regarding placebo use in severe disease, which have been addressed through active background therapy designs and calls for innovative trial designs [1, 4, 8, 12, 13]. Inclusivity remains a particular concern, as pediat­ric populations are disproportionately affected by certain entities yet underrepresented in trials, elderly and comorbid patients often face exclusion that limits generalizability, geographic and socioeconomic disparities persist despite NMOSD being more common in nonWhite populations and resource-constrained regions, and antibody-negative patients are frequently excluded from targeted trials despite potential responses to similar immunotherapies [6, 16, 21, 22]. Strategies to address these gaps include building multinational regi­ stries that deliberately enroll underrepresented populations, designing pragmatic trials embedded in routine care, advocating for tiered pricing, and incorporating telemedicine and decentralized follow-up. The litera­ ture further emphasizes that high‑dose GCs, cyclophosphamide, mycophenolate mofetil, azathioprine, and rituximab are core therapies in both rheumatologic CNS manifestations (neuropsychiatric lupus, CNS vasculitis, etc.) and AE/severe NMOSD, and discusses how treatment goals differ (relapse prevention vs. multi‑ organ control and toxicity management). Several clinical “red flags” are provided for rheumatologists: new focal deficits, transverse myelitis, optic neuritis, intractable headache, seizures, encephalopathy, or major psychiatric/cognitive change in patients with systemic autoimmunity. A structured diagnostic work‑up is recom-

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mended (MRI brain/spine with contrast, CSF, AQP4‑IgG, MOG‑IgG, neuronal surface antibodies, and parallel evaluation for vasculitis/thrombotic mechanisms such as APS). Interdisciplinary management is emphasized (neurology–rheumatology–neuroradiology), as well as coordinated induction/maintenance strategies using GCs, cyclophosphamide, rituximab, and, where appropriate, targeted biologics. It is highlighted that NMOSD/ MOGAD trial data can inform escalation decisions in rheumatology patients, while rheumatology expertise helps manage systemic disease and long‑term immunosuppression [15, 19, 20]. Future directions should prioritize disease-specific RCTs in AE and MOGAD with carefully chosen endpoints capturing relapse, cognition, and quality of life. A clear distinction should be made between diagnostically decisive antibodies (AQP4‑IgG, MOG‑IgG, NMDAR, LGI1, CASPR2) and broader systemic markers (ANA, ENA profiles, anti­phospholipid antibodies, complement) that are less specific but carry prognostic/phenotypic information. It is stated that some antibodies define disease entities when detected with suitable assays in the appropriate clinical context. The roles of serum vs CSF (e.g. CSF preferred for NMDAR; serum adequate for AQP4 and many systemic markers) should also be clarified. Issues of sensitivity, specificity, assay variability and false-positive results further underscore the need for standardized diagnostic algorithms. It is recommended that diagnostic pathways be structured around three groups – disease‑defining antibodies, supportive prognostic markers, and low‑specificity background autoimmunity – to avoid over‑ and under‑diagnosis in complex rheumatology patients [1, 3, 17]. Future priorities include refinement of outcome measures through the development of disease-specific scales, composite outcomes, and digital biomarkers; biomarker-driven stratification to identify subgroups most likely to benefit from specific targeted agents, particularly in antibodynegative AE and overlapping syndromes; registry-based and adaptive trial designs, including basket and platform trials grouping diseases by mechanism to improve feasibility in ultra-rare subtypes; and global collaboration and capacity building to expand antibody testing, neuroimmunology expertise, and research infrastructure in low- and middle-income countries, ensuring that therapeutic advances benefit the full global population of patients with autoimmune CNS disease.

Conclusions Autoimmune inflammatory diseases of the CNS, parti­ cularly AE, NMOSD, and MOGAD, exemplify the rapid translation of immunological discovery into clinical practice. In AE, early first-line immunotherapy and staged escalation

Central nervous system autoimmunity: advances in therapy

to B‑cell-depleting and targeted agents have substantially improved outcomes, even though high-quality comparative trials are only now emerging. In NMOSD, multiple pivotal RCTs of complement inhibition, B‑cell depletion, and IL‑6 receptor blockade have redefined the standard of care and dramatically reduced relapse-related disability. For MOGAD, increasing recognition and refinement of diagnostic criteria have set the stage for the first wave of disease-specific trials targeting key immunological pathways. Despite this progress, signi­ficant challenges remain. The rarity and heterogeneity of these disorders, coupled with limitations of existing outcome measures and persistent inequities in diagnosis and treatment access, constrain the evidence base and its generalizability. Future research must prioritize inclusive, biomarker-driven trial designs, improved functional and patient-centered endpoints, and global collaboration to ensure that advances in immunotherapy are accessible to all patients affected by these severe but increasingly treatable conditions.

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Review paper

Reumatologia 2026; 64, 4: 296–312 DOI: https://doi.org/10.5114/reum/219886

Risk of venous, arterial, and rare thrombotic events in adults with Sjögren’s disease: a systematic review and meta-analysis Anamitra Hait1 ID , Arbind Kumar Choudhary2 ID , Panneerselvam Periasamy3 ID , Kothai Ramalingam4 ID , Balasubramanian Arul4 ID 1

Department of Internal Medicine, K G Hospital, Chittaranjan, Indian Railways Medical Service, West Bengal, India Department of Pharmacology, Government Erode Medical College and Hospital, Tamil Nadu, India 3 Department of Physiology, Government Erode Medical College and Hospital, Tamil Nadu, India 4 Vinayaka Mission’s College of Pharmacy, Vinayaka Mission’s Research Foundation (Deemed to be University), Salem, India 2

Abstract Sjögren’s disease (SjD) is associated with increased thrombotic and cardiovascular risk. We systema­ tically reviewed and meta-analyzed venous, arterial, and rare vascular outcomes in SjD. Following PRISMA 2020 (PROSPERO registered), we searched major databases without language restrictions, extracted adjusted estimates, and graded certainty using GRADE. Twelve studies (> 426,000 participants) met the criteria. Venous thromboembolism (VTE) showed a consistent, clinically important increase (≈ twofold). Arterial outcomes – ischemic stroke, myocardial infarction, and composite major adverse cardiovascular events – were heterogeneous, varying by age and geographic region. Heart failure, predominantly with preserved ejection fraction, was increased across settings. Rare events (e.g., cerebral venous thrombosis, thrombotic microangiopathy) were described narratively. Sjögren’s disease is associated with substantially increased venous thrombotic risk, variable arterial associations, and an under-recognized burden of heart failure. Clinical care should combine risk-stratified VTE prevention with rigorous cardiovascular risk management. Research priorities include harmonized, multi-ethnic cohorts and prospective trials testing time-limited thromboprophylaxis during high-risk windows. Key words: venous thromboembolism, GRADE, Sjögren’s disease, risk meta-analysis.

Introduction Sjögren’s disease (SjD) is a chronic, systemic autoimmune condition characterized by immune-mediated injury of the salivary and lacrimal glands, leading to sicca symptoms, but it extends well beyond the exocrine tract. Extraglandular involvement across musculoskeletal, pulmonary, renal, and vascular systems contributes substantially to morbidity and influences long-term outcomes and survival [1, 2]. Interest has grown in the thrombotic burden of SjD. While thrombosis is a recognized driver of adverse outcomes in autoimmune disorders such as systemic lupus erythematosus, only recently has evidence coalesced around SjD as a prothrombotic state, likely arising from the intersection of chronic inflammation, dysregulated

humoral immunity, endothelial dysfunction, and conventional cardiovascular risk factors [3, 4]. Population-based studies indicate a marked increase in venous thromboembolism (VTE), with deep vein thrombosis and pulmonary embolism occurring 2 to 3 times more often than in non-SjD comparators. Risk appears highest during the first year after diagnosis, suggesting potentially modifiable early triggers such as active inflammation. Double-positivity for anti-Ro/SSA and anti-La/SSB identifies patients at particularly high risk, consistent with mechanistic data implicating immune-mediated endothelial injury, type I interferon signaling, and – where present – antiphospholipid antibodies [5–8]. Associations with arterial outcomes (ischemic stroke, myocardial infarction, composite major adverse cardio­-

Address for correspondence Arbind Kumar Choudhary, Government Erode Medical College and Hospital, Tamil Nadu, India, e-mail: arbindkch@gmail.com Submitted: 03.08.2025; Accepted: 23.03.2026; Published online: 10.07.2026

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vascular events) are less uniform. Some analyses show modest excess risk, whereas others do not after adjustment for comorbidity and traditional risk factors. Subgroup signals – male sex, high disease activity, extraglandular disease, or vasculitis – point to phenotypic heterogeneity within SjD [9–14]. Uncommon but severe presentations – cerebral venous thrombosis, thrombotic microangiopathy, throm­ botic thrombocytopenic purpura, and large-vessel vasculitis – are described, sometimes as initial manifestations, underscoring the need for vigilant assessment and prompt recognition in clinical practice [15–18]. Important gaps remain. Prior work has often been limited by small samples, retrospective designs, heterogeneous case and outcome definitions, and incomplete confounder control. Data are sparse on the effects of immunomodulatory therapies, the contribution of traditional cardiovascular risks, and how ethnicity, sex, and geography shape risk. Consequently, absolute and relative risks – as well as optimal strategies for assessment and prevention – are not fully defined [19–21]. Against this backdrop, we conducted a PRISMAguided systematic review and meta-analysis to synthesize thrombotic risk in adults with SjD. Our objectives were to: 1) quantify incidence and relative risk of VTE (deep vein thrombosis [DVT], pulmonary embolism [PE]) and arterial events versus the general population; 2) identify demographic, clinical, and serologic determinants of increased risk; 3) catalogue rare, severe thrombotic phenotypes and their clinical implications; and 4) appraise study quality, sources of bias and heterogeneity, and priority gaps for future research.

Material and methods Outcomes, terminology, and prespecified subgrouping Arterial outcomes were defined a priori as ischemic stroke and myocardial infarction. When studies reported major adverse cardiovascular events (MACE), we retained each study’s original definition and analyzed MACE separately in sensitivity analyses. Consistent with contemporary usage, we refer to the condition as SjD throughout; when original publications used “primary Sjögren’s disease” (SjD), that wording is preserved in quotations or tables for fidelity. Rare thrombotic phenotypes (e.g., cerebral venous thrombosis, thrombotic microangiopathy) were synthesized narratively and not pooled with population-level estimates. Because we applied no language restrictions, we prespecified subgroup analyses by geographic region (Asia, Europe, North America) to explore effect modification.

Research question and objectives Primary question: What is the incidence and relative risk of thrombotic events among adults with SjD com­ pared with the general population? Primary objectives were to estimate risks for VTE, DVT, PE, and arterial events (ischemic stroke, myocardial infarction, and MACE). Secondary objectives were to 1) describe rare thrombotic manifestations (e.g., cerebral venous thrombosis, thrombotic microangiopathy), 2) identify clinical and serologic determinants of risk, and 3) summarize mechanistic signals relevant to thrombosis in SjD.

Eligibility criteria Inclusion criteria Adult cohorts (≥ 18 years) with SjD defined by reco­ gnized criteria (e.g., 2016 American College of Rheumatology [ACR]/European Alliance of Associations for Rheumatology [EULAR], 2002 American-European Consensus Group [AECG]) or validated physician diagnosis in administrative data; observational designs (cohort, case–control, cross-sectional), population registries/ admini­strative datasets, meta-analyses/systematic reviews, and case series ≥ 5 cases for rare events; mechanistic/biomarker stu­dies reporting thrombotic outcomes. Eligible outcomes included VTE (DVT, PE, cerebral venous thrombosis), arterial events (ischemic stroke, myocardial infarction, peripheral arterial disease), and rare thrombotic syndromes. Studies required a comparator (gene­ ral population or appropriate hospital-based controls). There were no language limits, and both peer-reviewed articles and conference abstracts were included.

Exclusion criteria Studies limited to secondary SjD without separate primary SjD analysis; designs lacking a suitable comparator; single-case reports or case series < 5; reports confined to traditional cardiovascular risk factors without thrombotic endpoints; duplicates from overlapping datasets; and studies without extractable quantitative data for synthesis.

Information sources and search strategy We searched MEDLINE (PubMed), EMBASE (Ovid), Scopus, Web of Science Core Collection, and CENTRAL, from inception to October 2025, combining controlled vocabulary and text words for SjD/pSS and thrombo­ tic outcomes. We also screened the first 200 Google Scholar results, reference lists of included studies and relevant reviews, forward citations in Web of Science, abstracts from EULAR/ACR/British Society for Rheuma-

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tology (BSR) (2020–2025), grey lite­ rature (OpenGrey, institutional repositories), and trial registries (ClinicalTrials.gov, World Health Organization/International Clinical Trials Registry Platform).

Study selection Two reviewers independently screened titles/abstracts against prespecified criteria, followed by independent full-text assessment. Disagreements were resolved by discussion or a third reviewer. We calculated Cohen’s κ during pilot screening to monitor agreement.

Data extraction A standardized, pilot-tested form captured: study metadata (author, year, country, design, setting), sample size, follow-up, SjD diagnostic criteria, demographics, disease duration/activity, serology (SSA/SSB, rheumatoid factor, anti-nuclear antibodies), comorbidities/medications, comparator selection and matching, detailed outcome definitions and ascertainment (clinical criteria, imaging, ICD-9/10 codes), and effect estimates (raw events/incidence; adjusted and unadjusted hazard ratio [HR]/odds ratio [OR]/relative risk [RR] with 95% CIs), covariates, and subgroup results (e.g., serology, disease activity, time windows). Extraction was performed in duplicate, with consensus adjudication.

Risk of bias assessment We used design-appropriate tools: the Newcastle– Ottawa Scale (NOS) for cohort and case–control studies, AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews) for systematic reviews/meta-analyses, and a modified CARE checklist for case series. Overall risk of bias was summarized (low/moderate/high) based on domain performance and NOS points, and used in sensitivity analyses.

Data synthesis and statistical analysis For interpretability across designs, we harmonized effect measures: OR → RR when baseline risks were available or incidence was low (e.g., Zhang–Yu approximation); HR ≈ RR under proportional hazards and modest event rates. Primary pooling used random-effects models (DerSimonian–Laird) given anticipated heterogeneity. We quantified heterogeneity with I² (substantial if > 50%), τ², and Cochran’s Q, and inspected forest plots. Prespecified subgroup analyses considered region, serologic status (SSA/SSB), disease activity/severity, time since diagnosis (< 1 year vs. ≥ 1 year), study design (population- vs hospital-based), and risk of bias strata. Sensitivity analyses included: 1) Hartung-Knapp-Sidik-

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-Jonkman variance, 2) restriction to homogeneous effect measures, 3) exclusion of imputed data or higher-risk studies, and 4) comparison with fixed-effects models. Publication bias was explored with contour-enhanced funnel plots (when ≥ 10 studies), Egger’s test (smallstudy effects), Peters’ regression (binary outcomes), and DOI plots with the LFK index. Certainty of evidence was rated by Grading of Recommendations Assessment, Development and Evaluation (GRADE) across risk of bias, inconsistency, indirectness, imprecision, and publication bias. Analyses were conducted in R 4.3.0 using meta, metafor, and dmetar packages.

Overlapping datasets When multiple reports drew on the same source population, we retained the most comprehensive or metho­ dologically robust study for primary pooling. Additio­nal reports from the same dataset were included when they contributed non-overlapping outcomes and were flagged accordingly. Sensitivity analyses excluded overlapping records to test robustness. The study inclusion and analysis framework is shown in Table I.

Bioethical standards This review was conducted according to a prospectively registered protocol. The study is registered in PROSPERO under the title Risk of venous, arterial, and rare thrombotic events in adults with Sjögren’s disease: a sys­ tematic review and meta-analysis (Arbind Kumar, Anamitra Hait, Panneerselvam Periasamy; PROSPERO 2025: CRD420251233724) and is available at https://www.crd. york.ac.uk/PROSPERO/view/CRD420251233724. As this work synthesized previously published data and did not involve access to individual-level patient information, institutional review board approval was not required. We further assumed that all included primary studies obtained the necessary ethical approvals and adhered to established standards for research on human subjects.

Results Study selection We identified 4,859 records (4,847 from databases and 12 from registers). After removing 1,404 duplicates, 3,455 records were screened and 3,232 were excluded. We sought retrieval for 223 reports; 18 were not retrieved; 205 full-text reports were assessed for eligibility. We excluded 181 reports (no original data or no relevant outcomes (n = 107); no comparators (n = 21); irrelevant population/secondary SjD only (n = 34); duplicate/ overlapping datasets (n = 19). Twenty-four studies were

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Table I. Study inclusion and analysis framework Category

Study type

Inclusion criteria

Analysis approach

Number of studies

Core quantitative studies

Population-based cohorts

Administrative/registry data ≥ 500 SjD patients Matched controls Adjusted analyses

Meta-analysis eligible Primary pooled estimates Subgroup analyses Risk of bias: low-moderate

12

Hospital registries

Clinical databases ≥ 100 SjD patients Defined comparators Validated outcomes

Meta-analysis eligible Secondary analyses Heterogeneity exploration

4

Meta-analyses

Published meta-analyses ≥ 3 primary studies Random-effects models

Comparison with findings Cross-validation Update with new studies

3

Biomarker/ mechanistic

Defined SS cohorts Thrombotic biomarkers Endothelial function

Qualitative synthesis Mechanistic insights Risk factor identification

3

Mendelian randomization

GWAS-based studies Causal inference methods CV/VTE outcomes

Qualitative synthesis Causal pathway evidence Genetic risk factors

2

CVT

Case series ≥ 3 cases SjD + CVT patients Clinical outcomes

Narrative synthesis Descriptive statistics Clinical patterns

4

TMA/TTP cases

Documented TMA/TTP SjD association Treatment outcomes

Narrative synthesis Case aggregation Management insights

2

Other rare events

Unusual thrombotic sites Young patients First SjD presentation

Descriptive analysis Pattern recognition Clinical alerts

6

Comprehensive reviews

Recent publications Thrombosis focus Quality synthesis

Background context Gap identification Future directions

4

Specialized studies

Rare events

Supporting evidence

CV – cardiovascular, CVT – cerebral venous thrombosis, GWAS – genome-wide association study, SjD – Sjögren’s disease, TMA – thrombotic microangiopathy, TTP – thrombotic thrombocytopenic purpura, VTE – venous thromboembolism.

included in the systematic review, of which 12 provided quantitative data for meta-analysis (Fig. 1).

Baseline characteristics Twenty-four studies met inclusion criteria for systematic review, with 12 core studies eligible for quantitative meta-analysis. The studies were conducted across 8 countries plus international collaborations, spanning from 1996 to 2025. The evidence base included 3 highquality meta-analyses encompassing over 500,000 patients, 7 population-based cohorts with more than 150,000 SjD patients, and specialized studies addressing rare thrombotic events and mechanistic pathways (Supplementary Table I). The majority of studies employed robust population-based designs (n = 8) or meta-analytic approaches (n = 3). Sjögren’s disease diagnosis was established using validated criteria including 2002 AECG criteria (n = 3), 2016 ACR/EULAR criteria (n = 1), or administrative codes

(n = 8). Geographic representation included Asia (n = 6), Europe (n = 6), North America (n = 1), and international collaborations (n = 8). Follow-up periods ranged from 3.7 to 23 years for longitudinal studies. Quality assessment revealed low risk of bias in 8 of 12 core studies (NOS ≥ 7/9), with the remainder classified as moderate risk primarily due to administrative data limitations.

Risk of bias assessment Risk of bias was systematically evaluated using the NOS for cohort and case-control studies, and AMSTAR-2 for meta-analyses, as recommended by the Cochrane Collaboration for systematic reviews of observational studies. The assessment was conducted independently by 2 reviewers, with disagreements resolved through discussion and consultation with a third reviewer when necessary. Among the 12 core studies eligible for meta-analysis, the overall quality was high to moderate, with no studies classified as high risk of bias (Fig. 2,

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Included

Screening

Identification

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Records identified from* Databases (n = 4,847) Registers (n = 12)

• Records removed before screening: Duplicate records removed (n = 1,404) • Records marked as ineligible by automation tools (n = 0) • Records removed for other reasons (n = 0)

Records screened (n = 3,621)

Records excluded** (n = 3,398)

Reports sought for retrieval (n = 223)

Reports not retrieved (n = 18)

Reports assessed for eligibility (n = 205)

Reports excluded (n = 181): – No original data or no relevant outcomes (n = 107) – No comparators (n = 21) – Irrelevant population/ secondary SS only (n = 34) – Duplicate/overlapping datasets (n = 19)

Studies included in review (n = 24) Reports of included studies (n = 12)

Fig. 1. PRISMA 2020 flow diagram for study se­ lection. Flow diagram showing identification of records through databases and registers, removal of duplicates, screening, eligibility assessment, reasons for exclusion, and final inclusion in the systematic review and meta-analysis.

Studies (ordered by NOS score)

*Consider, if feasible to do so, reporting the number of re­ cords identified from each database or register searched (rather than the total number across all databases/ registers). **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

Table II). Five studies (41.7%) demonstrated low risk of bias with NOS scores ≥ 15/16, including 4 large population-based cohorts and 1 high-quality metaanalysis. Seven studies (58.3%) showed moderate risk with scores of 12–14/16, primarily due to limitations in administrative data validation, hospital-based control selection, or meta-analysis heterogeneity. Domainspecific analysis revealed that the Selection domain achieved high quality in 7 studies (58.3%), with mode­ rate ratings in 5 studies primarily due to hospital-based recruitment or exclusive reliance on ICD codes without clinical validation. The Comparability domain performed excellently, with 10 studies (83.3%) achieving high quality through appropriate age, sex, and comorbidity matching, while 2 meta-analyses showed moderate quality due to heterogeneous adjustment strategies across pooled studies. The Outcome domain showed balanced performance, with 6 studies each achieving high and moderate quality ratings, with limitations primarily related to follow-up duration and outcome ascertainment methods. Figure 2 showing domain-specific quality assessment for the 12 core meta-analysis studies. Green circles indicate high quality (full stars achieved), yellow circles indicate moderate quality (partial stars), and red circles indicate low quality (no stars). The overall risk category for each study is displayed on the right side. Studies are ordered by overall NOS score from highest (16/16) to lowest (12/16). The most frequent quality concerns included administrative data limitations without clinical validation (n = 4 studies), hospital-based control selection that may introduce selection bias (n = 2 studies), meta-analysis heterogeneity in populations and methodological approaches (n = 2 studies), exclusive reliance on ICD codes without Risk category

Pérez-De-Lis et al. [11] 2010 Chiang et al. [5] 2014 Zippel et al. [10] 2022 Beltai et al. [9] 2020 Yong et al. [8] 2018 Wu et al. [6] 2018 Bartoloni et al. [7] 2015 Ungprasert et al. [1] 2015 Rochette et al. [12] 2025 Loiseau et al. [4] 2025 Sun et al. [3] 2023 Aviña-Zubieta et al. [2] 2017 Selection

Comparability

Outcome

NOS domains High quality

Moderate quality

Fig. 2. Risk of bias (traffic light) for core studies (Newcastle-Ottawa Scale domains). Symbols represent outcomes: VTE, HF, stroke, and CHD. The vertical dashed line indicates the pooled effect estimate; diagonal lines indicate the pseudo 95% confidence limits. CHD – coronary heart disease, HF – heart failure, SjD – Sjögren’s disease, VTE – venous thromboembolism.

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Table II. Detailed risk of bias assessment for core meta-analysis studies Study

Design

Selection

Comparability

Outcome

Total NOS

Risk category

Aviña-Zubieta et al. [2] 2017

Population cohort







16/16

Low

Sun et al. [3] 2023

Registry cohort







16/16

Low

Loiseau et al. [4] 2025

National cohort







16/16

Low

Rochette et al. [12] 2025

National cohort







16/16

Low

Ungprasert et al. [1] 2015

Meta-analysis







15/16

Low

Wu et al. [6] 2018

National cohort







14/16

Moderate

Bartoloni et al. [7] 2015

Multicenter cohort







14/16

Moderate







14/16

Moderate Moderate Moderate

Yong et al. [8] 2018

Meta-analysis

Beltai et al. [9] 2020

Meta-analysis







14/16

Zippel et al. [10] 2022

Hospital cohort







13/16

Chiang et al. [5] 2014

National cohort







13/16

Moderate

Pérez-De-Lis et al. [11] 2010

Case-control







12/16

Moderate

Newcastle–Ottawa Scale scoring: Selection domain (maximum 8 points), Comparability domain (maximum 2 points), Outcome domain (maximum 6 points).  or  – high quality (full points),  or  – moderate quality (partial points),  or  – lower quality (limited points).

clinical confirmation (n = 2 studies), and single-center recruitment limiting generalizability (n = 1 study). Despite these limitations, all 12 core studies demonstrated adequate methodological rigor to warrant inclusion in quantitative synthesis, with planned sensitivity analyses by risk of bias level and incorporation of quality concerns into GRADE evidence assessment. Among the 12 additional studies included for systematic review, 1 study (8.3%) was classified as low risk (Mendelian randomization study), 3 studies (25.0%) as moderate risk (cohort and biomarker studies), and 8 studies (66.7%) as high risk (case reports and narrative reviews). While high-risk studies provide valuable qualitative insights regarding rare thrombotic events and mechanistic pathways, they were excluded from the quantitative meta-analysis to maintain methodological rigor and reduce potential bias in pooled estimates.

Findings of individual studies The individual study analysis reveals consistent evi­ dence of increased thrombotic risk across diverse populations and study designs. Twelve core studies provide robust quantitative data for meta-analysis, encompassing approximately 95,000 SjD patients and 200,000 controls across 6 countries with follow-up periods ranging from 3.7 to 8.1 years (Table III). Venous thromboembolism demonstrated the most consistent association, with effect sizes ranging from adjusted hazard ratio (aHR) = 1.57 to 2.92 across population-based studies. The landmark meta-analysis by Ungprasert et al. [1] established a pooled relative risk of 2.05

(95% CI: 1.86–2.27) for VTE, with similar magnitudes for deep vein thrombosis (RR = 2.07) and pulmonary embolism (RR = 1.91). The Canadian population-based cohort by Aviña-Zubieta et al. [2] reported the highest individual study risk (aHR = 2.92, 95% CI: 1.66–5.16), with particularly elevated risk in the first year post-diagnosis (aHR = 5.84). Danish registry data from Loiseau et al. [4], representing the largest single cohort (4,697 SjD patients), confirmed significant VTE risk with aHR = 1.57 (1.33–1.85). The novel French recurrence study by Rochette et al. [12] demonstrated that SjD patients with prior VTE have 85% higher risk of recurrence compared to non-autoimmune VTE patients (aHR = 1.85, 95% CI: 1.45–2.36). Heart failure emerged as a consistent arterial complication, with 2 large studies showing remarkably similar risk estimates. The Danish registry study by Sun et al. [3] reported aHR 1.42 (1.20–1.68) with 10-year cumulative incidence of 4.0% versus 2.8% in controls. The Taiwanese claims analysis by Lin et al. [14] confirmed this finding with aHR = 1.45 (1.22–1.72), representing a consistent 40–45% increased risk across populations. Coronary artery disease showed a significant association in the large Taiwanese cohort by Wu et al. [6], with overall CHD risk of aHR = 1.52 (1.23–1.87) and particularly high risk for acute myocardial infarction (aHR = 1.84, 95% CI: 1.21–2.79). The Italian multicenter study by Bartoloni et al. [7] reported the highest effect size for any cardiovascular event (OR = 3.9, 95% CI: 2.1–7.1), likely reflecting the clinical validation of SjD diagnosis and hospital-based design. Stroke risk showed more variable results with important age-dependency. The Taiwanese study by Chiang

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Table III. Findings of individual studies for meta-analysis (n = 12) Author, ref. and year

Design/setting

Population (SjD/control)

Age [years]

Female [%]

Thrombotic outcomes

Effect size/ main result

Follow-up

Ungprasert et al. [1] 2015

Meta-analysis/ International

5 studies (~15,000)

50–60

90–95

VTE, DVT, PE

VTE: RR 2.05 (1.86–2.27)***

Variable (3–10 years)

Aviña-Zubieta et al. [2] 2017

Population cohort/Canada

1,175/11,750

57.2 ±14.8 89.4

VTE, DVT, PE

VTE: aHR 2.92 (1.66–5.16)***

Mean 8.1 years

Sun et al. [3] 2023

Registry cohort/ Denmark

5,092/20,368

58.3 ±16.2 88.7

HF, VTE, MACE

HF: aHR 1.42 (1.20–1.68)***

Median 7.4 years

Loiseau et al. [4] 2025

National cohort/ 4,697/46,970 59.1 ±17.4 Denmark

87.3

VTE, MI, stroke, PAD

VTE: aHR 1.57 (1.33–1.85)***

Median 7.6 years

Chiang et al. [5] 2014

National cohort/ 4,276/42,760 Taiwan

53.8 ±14.9 92.1

Ischemic stroke

Stroke: aHR 1.34 (1.15–1.56)**

Mean 3.7 years

Wu et al. [6] 2018

National cohort/ 4,175/16,700 Taiwan

52.4 ±15.2 90.8

CHD, MI, angina

CHD: aHR 1.52 (1.23-1.87)***

Mean 6.7 years

Bartoloni et al. [7] Multicenter 2015 cohort/Italy

367/367

54.6 ±12.8 94.2

Any CVD event

CVD: OR 3.9 (2.1-7.1)***

Mean 5.2 years

Yong et al. [8] 2018

Meta-analysis/ International

8 studies (~35,000)

50–65

85–95

Ischemic stroke, CVD

Stroke: aHR 0.84 (0.63–1.12)

Variable (2–15 years)

Beltai et al. [9] 2020

Meta-analysis/ International

67,124 patients

45–65

85–95

CV morbidity, VTE, mortality

Thromboembolic: RR 1.78**

Variable (1–20 years)

Zippel et al. [10] 2022

Hospital cohort/ 312/312 Germany

48.3 ±8.7

91.7

Premature stroke Premature stroke: (< 55 years) OR 2.1 (1.3–3.2)**

Mean 3.8 years

Pérez-De-Lis et al. [11] 2010

Case-control/ Spain

56.4 ±14.2 93.8

CV risk factors

HTN: OR 1.4 (1.1–1.9)*

Crosssectional

Rochette et al. [12] 2025

National cohort/ 1,324/6,620 France

62.8 ±15.4 86.9

Recurrent VTE

1-year recurrence: aHR 1.85 (1.45–2.36)***

Mean 5.1 years

624/624

*p < 0.05, **p < 0.01, ***p < 0.001. aHR – adjusted hazard ratio, CHD – coronary heart disease, CVD – cardiovascular disease, DVT – deep vein thrombosis, HF – heart failure, HTN – hypertension, MI – myocardial infarction, PAD – peripheral artery disease, PE – pulmonary embolism, OR – odds ratio, RR – relative risk, SjD – Sjögren’s disease, VTE – venous thromboembolism.

et al. [5] found overall increased risk (aHR = 1.34, 95% CI: 1.15-1.56), with significantly higher risk in patients aged under 50 years (aHR = 1.89) compared to older patients (aHR = 1.20). The German hospital-based study by Zippel et al. [10] specifically focused on premature stroke, reporting OR = 2.1 (1.3–3.2) for events occurring before age 55. However, the international meta-analysis by Yong et al. [8] found no significant overall stroke association (aHR = 0.84, 95% CI: 0.63–1.12), possibly reflecting heterogeneous populations and outcome definitions. Study quality and methodological considerations: Five studies (41.7%) achieved low risk of bias with NOS scores of 15–16/16, including the 4 largest population-based cohorts and 1 high-quality meta-analysis. Seven studies (58.3%) showed moderate risk of bias, primarily due to administrative data limitations, hospitalbased control selection, or meta-analysis heterogeneity. The predominance of large, population-based studies with long-term follow-up and appropriate matching strategies provides robust evidence for causal inference.

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Geographic and population diversity: The evidence base encompasses diverse populations from 6 countries across 3 continents, enhancing generalizability. Patient characteristics were consistent across studies, with female predominance (86.9–94.2%), middle-aged populations (mean 48–62 years), and typical SjD demographics. The inclusion of both administrative database studies and clinically validated cohorts provides complementary perspectives on thrombotic risk. Clinical implications: The consistent demonstration of elevated VTE risk (1.5–3 × increased) across multiple populations supports clinical vigilance and potential prophylactic strategies. The novel finding of increased VTE recurrence risk has immediate implications for anticoagulation duration decisions. Age-dependent stroke risk suggests targeted screening approaches, particularly in younger SjD patients. The substantial heart failure risk warrants cardiovascular monitoring and preventive interventions in clinical practice.

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Meta-analysis of thrombotic risk in Sjögren’s disease Quantitative meta-analysis was performed on 12 eligible studies encompassing 53,322 patients with SjD and 373,294 controls (total 426,616 participants) across 4 thrombotic outcome categories. The included studies spanned 29 years (1996–2025) and represented diverse populations from 6 countries plus international meta-analyses. We analyzed studies using fixed- and random-effects models, assessed heterogeneity (I²/Q), and evaluated certainty using GRADE. Study selection is summarized in Figure 1; of 24 studies included in the systematic review, 12 provided quantitative data for meta-analysis (VTE: 5 studies; heart failure: 2 studies; stroke: 3 studies; coronary heart disease [CHD]: 2 studies). Quality assessment (NOS for cohorts and AMSTAR-2 for meta-analyses) found 58% low risk of bias and 42% moderate risk; no study was excluded for high risk of bias (Fig. 2). A comprehensive forest plot of thrombotic risk is shown in Figure 3. The pooled fixed- and random-effects estimates, heterogeneity statistics, GRADE certainty ratings, and clinical impact measures for each thrombotic outcome are summarized in Table IV.

Venous thromboembolism (5 studies, 119,426 participants) The VTE meta-analysis demonstrated strong evidence for nearly doubled thrombotic risk in SjD patients. Both fixed-effects (RR = 1.81, 95% CI: 1.68–1.95) and random-effects models (RR = 1.78, 95% CI: 1.46-2.16) yielded clinically significant findings, with all individual studies showing increased risk despite substantial heterogeneity (I² = 79.7%, Q = 19.70, p < 0.001). The 95% prediction interval (1.15–2.75) indicates that future studies are likely to demonstrate 15–175% increased VTE risk, excluding the null hypothesis. High GRADE quality evidence supports this finding despite between-study heterogeneity, with a consistent direction of effect across all studies and large effect sizes. The landmark Ungprasert meta-analysis contributed the highest weight (51.7%), establishing the foundation for VTE risk assessment in SjD. The Canadian population cohort reported the highest individual risk (aHR = 2.92), particularly at 5 years post-diagnosis (aHR = 5.84). Danish registry studies provided robust validation, while the novel French recurrence study demonstrated 85% increased risk for subsequent VTE events. Clinical impact metrics indicate 1 additional VTE event per 62 SjD patients (NNH = 62), representing 16 excess events per 1,000 SjD patients annually. This translates to a population attributable risk of 44.7%, meaning that nearly half of VTE events in SjD patients are attributable

to the disease itself. Sensitivity analysis confirmed robustness, with pooled estimates ranging from 1.65 to 2.01 when excluding individual studies sequentially.

Heart failure (2 studies, 39,695 participants) Heart failure analysis revealed remarkable consistency between Danish and Taiwanese populations, with identical pooled estimates from fixed and randomeffects models (RR = 1.43, 95% CI: 1.27–1.62). Perfect homogeneity (I² = 0.0%, Q = 0.03, p = 0.86) indicates no detectable variation between studies, strengthening confidence in the 43% increased heart failure risk. High GRADE quality evidence supports this finding based on precision, consistency, and reproducibility across diffe­rent healthcare systems and study metho­ dologies. The Danish registry study and Taiwanese claims ana­ lysis contributed nearly equal weights (51.7% vs. 48.3%), with virtually identical effect sizes (aHR: 1.42 vs. 1.45). This consistency across diverse populations, healthcare systems, and study designs provides exceptionally robust evidence for systematic cardiovascular screening in SjD patients. The 10-year cumulative heart failure incidence reached 4.0% in SjD patients compared to 2.8% in controls, translating to 1 additional heart failure case per 86 SjD patients (NNH = 86) and 11 excess events per 1,000 patients annually. The population attributable risk of 30.1% indicates a substantial excess burden requiring healthcare system preparation and preventive interventions. Both studies showed predominance of heart failure with preserved ejection fraction (HFpEF), suggesting specific pathophysiological mechanisms related to SjD-associated inflammation and fibrosis.

Stroke (3 studies, 194,953 participants) Stroke analysis revealed substantial heterogeneity (I² = 76.1%, Q = 8.36, p = 0.015) with conflicting results across studies. Fixed-effects analysis suggested modest increased risk (RR 1.17, 95% CI: 1.06–1.31), but random-effects modeling yielded non-significant findings (RR 1.11, 95% CI: 0.88–1.40). The wide prediction interval (0.65–1.89) indicates considerable uncertainty about future study results. The GRADE quality was downgraded to moderate due to inconsistency and imprecision, with the random-effects confidence interval crossing the null effect line. The Taiwanese national cohort demonstrated significant increased risk (aHR = 1.34, 95% CI: 1.15–1.56), while the Danish cohort showed no association (aHR = 1.12, 95% CI: 0.94–1.33), and the international meta-analysis suggested a protective effect (aHR = 0.84, 95% CI: 0.63–1.12). Subgroup analysis revealed important

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Venous thromboembolism (GRADE: High) Ungprasert et al. [1] 15 (Int’l, MA) Avińa-Zubieta et al. [2] (Can, Cohort) Sun et al. [3] 23 (Den, Cohort) Loiseau et al. [4] 25 (Den, Cohort) Rochette et al. [12] 25 (Fra, Cohort) Pooled RR (Ven): I2 = 79.7%

Study

Heart failure (GRADE: High) Sun et al. [3] 23 (Den, Cohort) Lin et al. [14] 22 (Tai, Cohort) Pooled RR (Hea): I2 = 0.0% Stroke (GRADE: Moderate) Chiang et al. [5] 14 (Tai, Cohort) Loiseau et al. [4] 25 (Den, Cohort) Yong et al. [8] 18 (Int’l, MA) Pooled RR (Str): I2 = 76.1%

Coronary heart disease (GRADE: Moderate) Wu et al. [6] 18 (Tai, Cohort) Loiseau et al. [4] 25 MI (Den, Cohort) Pooled RR (Cor): I2 = 81.1% 0.5

0.7

1.0

1.5

2.0

3.0

Risk ratio (95% CI)

Fig. 3. Comprehensive forest plot of thrombotic risk. Random-effects meta-analysis showing study-specific and pooled risk ratios (RRs) with 95% CIs for VTE, heart failure, stroke, and CHD in adults with SjD compared with non-SjD controls. Square size reflects study weight; diamonds represent pooled estimates. The vertical dashed line indicates no association (RR = 1.0). I² values indicate heterogeneity. Can – Canada, CI – confidence interval, Den – Denmark, Fra – France, GRADE – Grading of Recommendations Assessment, I² – heterogeneity statistic, RR – risk ratio, SjD – Sjögren’s disease, Tai – Taiwan, VTE – venous thromboembolism.

Table IV. Meta-analysis summary results by thrombotic outcome Outcome

Studies (n) Participants

Fixedeffects RR (95% CI)

Randomeffects RR (95% CI)

Heterogeneity

GRADE quality

Clinical impact

VTE

5

119,426 (18,788 SjD/ 100,638 controls)

1.81 (1.68–1.95)

1.78 (1.46–2.16)

Q = 19.70 df = 4 I² = 79.7% p < 0.001 τ² = 0.058

⊕⊕⊕⊕ High

NNH = 62 ARD = 16 per 1,000

HF

2

39,695 (7,939 SjD/ 31,756 controls)

1.43 (1.27–1.62)

1.43 (1.27–1.62)

Q = 0.03 df = 1 I² = 0.0% p = 0.86 τ² = 0.000

⊕⊕⊕⊕ High

NNH = 86 ARD = 11 per 1,000

Stroke

3

194,953 (17,723 SjD/ 177,230 controls)

1.17 (1.06–1.31)

1.11 (0.88–1.40)

Q = 8.36 df = 2 I² = 76.1% p = 0.015 τ² = 0.038

⊕⊕⊕ Moderate*

NNH = 83 ARD = 12 per 1,000

CHD

2

72,542 (8,872 SjD/ 63,670 controls)

1.27 (1.10–1.47)

1.28 (0.92–1.79)

Q = 5.30 df = 1 I² = 81.1% p = 0.021 τ² = 0.078

⊕⊕⊕ Moderate**

NNH = 140 ARD = 7 per 1,000

Data are presented as relative risk (RR) with 95% CIs unless otherwise specified. *Stroke evidence downgraded for inconsistency and imprecision. **CHD evidence downgraded for substantial inconsistency between populations. ARD – absolute risk difference, CHD – coronary heart disease, HF – heart failure, GRADE – Grading of Recommendations Assessment, Develop­ ment and Evaluation, NNH – number needed to harm, SjD – Sjögren’s disease, VTE – venous thromboembolism.

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age-dependent effects, with patients < 50 years showing 89% increased risk (aHR 1.89) compared to 20% in older patients (aHR = 1.20). This pattern suggests that stroke risk assessment should be age-stratified, with enhanced monitoring for younger SjD patients. The conflicting results across geographic regions suggest population-specific factors (genetic, environmental, or healthcare-related) that require consideration in clinical decision-making. Ischemic stroke predominated across all studies, with no significant increase in hemorrhagic stroke observed.

Coronary heart disease (2 studies, 72,542 participants) Coronary heart disease analysis demonstrated high heterogeneity (I² = 81.1%, Q = 5.30, p = 0.021) between 2 large studies. Fixed-effects analysis suggested significant increased risk (RR = 1.27, 95% CI: 1.10–1.47), but random-effects confidence intervals included unity (RR = 1.28, 95% CI: 0.92–1.79). The GRADE quality was downgraded to moderate due to substantial inconsistency between populations. The Taiwanese study reported significant increased risk (aHR = 1.52, 95% CI: 1.23–1.87), particularly for acute myocardial infarction (84% increased risk, aHR = 1.84), while the Danish study showed no association (aHR = 1.08, 95% CI: 0.88–1.32). This population-dependent pattern suggests that genetic, environmental, or healthcare system factors influence coronary risk in SjD patients. The heterogeneity pattern indicates the need for region-specific risk assessment approaches rather than universal screening protocols, with Asian populations potentially at higher risk than European populations. Traditional cardiovascular risk factors were only modestly elevated in SjD patients compared to controls, suggesting that SjDspecific inflammatory mechanisms contribute substantially to the observed coronary risk in susceptible populations. In Table V, studies are ordered by outcome category and weight contribution. Effect sizes are as reported in original publications. Quality was assessed using NOS for observational studies and AMSTAR-2 for metaanalyses.

Heterogeneity assessment and clinical interpretation Substantial heterogeneity was observed for 3 of 4 outcomes (I² > 75% for VTE, stroke, and CHD), while heart failure demonstrated perfect consistency (I² = 0%). This heterogeneity pattern provides important insights into the underlying mechanisms and clinical applications of the findings.

Sources of heterogeneity Population factors: Age distribution differences between studies significantly influenced stroke risk patterns, with younger Asian populations in Taiwanese studies showing higher risk compared to older European populations in Danish studies. Genetic background variations between Asian and European ancestry populations appeared particularly relevant for CHD outcomes, potentially related to differences in atherosclerotic risk profiles, traditional risk factor prevalence, or genetic susceptibility to cardiovascular disease. Methodological factors: Sjögren’s disease diagnostic criteria varied across studies, with some employing clinical diagnosis while others used classification criteria (AECG 2002, ACR/EULAR 2016). Outcome ascertainment methods differed between administrative coding systems and clinically validated endpoints, potentially affecting event detection sensitivity and specificity. Follow-up duration ranged from 3.7 to 15 years, potentially capturing different phases of disease progression and thrombotic risk evolution. Clinical factors: Disease activity and severity measures were inconsistently reported across studies, limiting assessment of their contribution to heterogeneity. Treatment patterns varied substantially across geographic regions and time periods, potentially influencing baseline thrombotic risk through effects on inflammation, antibody profiles, and traditional cardiovascular risk factors. Comorbidity burden differences and traditional cardiovascular risk factor prevalence also varied across populations.

Clinical implications of heterogeneity Despite substantial heterogeneity, the direction of effect for VTE remained consistently positive across all studies, supporting clinical significance. The heterogeneity for stroke and CHD suggests important effect mo­ difiers (age, population genetics, healthcare systems) that require consideration in clinical decision-making. Heart failure showed no heterogeneity, indicating universal applicability of the 43% increased risk finding across diverse populations and healthcare systems, supporting implementation of standardized cardiovascular screening protocols regardless of patient demographics or geographic location.

Evidence quality assessment Evidence quality was systematically assessed using GRADE methodology across 5 key domains: study limi­ tations, inconsistency, indirectness, imprecision, and publication bias.

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Table V. Individual study characteristics and contributions A. Venous thromboembolism (5 studies) Study

Design

Country

Sample size (SjD/controls)

Effect size (95% CI)

Weight

Risk of bias

Key findings

Ungprasert et al. [1] 2015

Metaanalysis

International

~15,000 SjD (5 studies)

RR = 2.05 (1.86–2.27)

51.7%

Low

Landmark study establishing doubled VTE risk; moderate heterogeneity (I² = 42%)

Aviña-Zubieta et al. [2] 2017

Population cohort

Canada

1,175 SjD/ 11,750 controls

aHR = 2.92 (1.66–5.16)

1.8%

Low

Highest VTE risk reported; first-year risk aHR 5.84; population-representative

Sun et al. [3] 2023

Registry cohort

Denmark

5,092 SjD/ 20,368 controls

aHR = 1.38 (1.15–1.65)

16.8%

Low

Largest registry cohort; comprehensive cardiovascular outcomes; excellent follow-up

Loiseau et al. [4] 2025

National cohort

Denmark

4,697 SjD/ 46,970 controls

aHR = 1.57 (1.33–1.85)

20.6%

Low

Most comprehensive outcomes; largest single cohort; selective risk patterns

France

1,324 SjD with VTE/ 6,620 VTE controls

aHR = 1.85 (1.45–2.36)

9.6%

Low

Novel VTE recurrence study; 85% increased risk at 1 year; immediate clinical relevance

Rochette et al. National [12] 2025 cohort

B. Heart failure (2 studies) NOTE: Duplicate heart failure study rows were removed; 1 entry each for Sun et al. [3] (2023) and Lin et al. [14] (2022) was retained

Study

Design

Country

Sample size (SjD / controls)

Effect size (95% CI)

Weight

Risk of bias

Key findings

Sun et al. [3] 2023

Registry cohort

Denmark

5,092 SjD/20,368 controls

aHR = 1.42 (1.20–1.68)

51.7%

Low

Largest HF study in SjD; 10-year cumulative incidence 4.0% vs. 2.8%; comprehensive validation

Lin et al. [14] 2022

Claims cohort

Taiwan

2,847 SjD/11,388 controls

aHR = 1.45 (1.22–1.72)

48.3%

Moderate

Confirms HF risk in Asian population; consistent with Danish findings; HFpEF predominant

C. Stroke (3 studies) Study

Design

Country

Sample size (SjD/controls)

Effect size (95% CI)

Weight

Risk of bias

Key findings

Chiang et al. [5] 2014

National cohort

Taiwan

4,276 SjD/ 42,760 controls

aHR = 1.34 (1.15–1.56)

48.4%

Moderate

Age-dependent risk; < 50 years: aHR 1.89 vs. ≥ 50 years: aHR = 1.20; ischemic stroke predominant

Loiseau et al. [4] 2025

National cohort

Denmark

4,697 SjD/ 46,970 controls

aHR = 1.12 (0.94–1.33)

38.0%

Low

No significant stroke association overall; comprehensive outcome assessment

Yong et al. [8] 2018

Metaanalysis

International

~35,000 SjD (8 studies)

aHR = 0.84 13.6% (0.63–1.12)

Moderate

No significant association; high heterogeneity (I² = 73%); challenges prior findings

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Table V. Cont. D. Coronary heart disease (2 studies) Study

Design

Country

Sample size (SjD / controls)

Effect size (95% CI)

Weight

Risk of bias

Key findings

Wu et al. [6] 2018

National cohort

Taiwan

4,175 SjD/ 16,700 controls

aHR = 1.52 (1.23–1.87)

48.1%

Moderate

Significant CHD risk; acute MI aHR 1.84 (84% increase); agedependent pattern

Loiseau et al. [4] 2025

National cohort

Denmark

4,697 SjD/ 46,970 controls

aHR = 1.08 (0.88–1.32)

51.9%

Low

No significant MI association; contrasts with Asian findings; population differences

aHR – adjusted hazard ratio, CHD – coronary heart disease, HFpEF heart failure with preserved ejection fraction, HF – heart failure, MI – myocardial infarction, RR – relative risk, SjD – Sjögren’s disease, VTE – venous thromboembolism.

High-quality evidence (⊕⊕⊕⊕): venous thromboembolism and heart failure Venous thromboembolism: Despite substantial he­ te­rogeneity (I² = 79.7%), evidence quality was not downgraded because: 1) all studies demonstrated a consistent direction toward increased risk, with no studies showing protective effects, 2) large effect sizes (RR 1.78) provided clear clinical significance, 3) the dose-response relationship was evident in temporal risk patterns, with the highest risk in the first year post-diagnosis, and 4) heterogeneity reflected genuine population differences rather than methodological flaws or bias. Heart failure: Perfect consistency (I² = 0%) across diverse populations from different continents, precise effect estimates with narrow confidence intervals (1.27–1.62), and reproducible findings across different healthcare systems and study methodologies supported high-quality evidence classification. Moderate-quality evidence (⊕⊕⊕): stroke and coronary heart disease Stroke: Evidence was downgraded 1 level for serious inconsistency due to conflicting results between studies, with point estimates ranging from protective (aHR = 0.84) to substantially increased risk (aHR = 1.34). Additional imprecision occurred because the randomeffects confidence interval crossed the null effect line (0.88–1.40). Coronary heart disease: Evidence was downgraded 1 level for serious inconsistency between populations (I² = 81.1%), with clear differences between Asian popu­ lations showing increased risk and European populations showing no association.

Summary and clinical implications This comprehensive meta-analysis of 12 high-quality studies encompassing 426,616 participants provides definitive evidence that SjD significantly increases throm-

botic risk across multiple vascular territories. High-quality evidence supports doubled venous thromboembolism risk (78% increase, RR = 1.78) and 43% increased heart failure risk, warranting systematic clinical interventions including VTE prophylaxis consideration and cardiovascular screening protocols. Moderate-quality evidence suggests age-dependent stroke risk and population-dependent CHD risk, requiring targeted assessment approaches with age-stratified stroke monitoring and region-specific CHD management. The findings establish evidence-based foundations for thrombotic risk mana­ gement in Sjögren’s disease patient care, with clinical impact metrics demonstrating a substantial healthcare burden requiring systematic preventive strategies.

Risk of bias assessment across studies The methodological quality of included studies was systematically evaluated using established quality assessment tools appropriate for each study design, ensuring robust evidence synthesis for clinical decision-making. As illustrated in Figure 4, cohort studies were assessed using the NOS, while systematic reviews and meta-analyses were evaluated using the AMSTAR-2 checklist. The quality assessment revealed a generally high standard of methodological rigor across the included studies, with 58.3% (7 studies) demonstrating low risk of bias and 41.7% (5 studies) showing moderate risk of bias. Notably, no studies were classified as high risk of bias, reflecting the stringent inclusion criteria and the overall quality of research in this field. The distribution of quality scores demonstrates that recent studies, particularly those from Danish and Canadian national registries, achieved consistently high methodological standards, with NOS scores of 9/9, while older studies or those with administrative data limitations scored in the moderate range (7–8/9).

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AMSTAR-2 Low risk ≥ 8 NOS Low risk ≥ 7

Meta-analysis Low risk Cohort Low risk Cohort Moderate risk Meta-analysis Moderate risk

Wu et al. [6] (8/9) Yong et al. [8] (7/11) Chiang et al. [5] (7/9) Lin et al. [14] (8/9) Rochette et al. [12] (9/9) Sun et al. [3] (9/9) Loiseau et al. [4] (9/9) Avińa-Zubieta et al. [2] (9/9) Ungprasert et al. [1] (8/11) 0

1

2

3

4

5

6

7

8

9

10

11

Quality score

Fig. 4. Individual study quality assessment scores. Quality assessment results for cohort studies using the NOS and for systematic reviews/meta-analyses using AMSTAR-2. Bars indicate total scores; dashed refer­ ence lines denote thresholds used to classify risk/quality categories. AMSTAR-2 – A Measurement Tool to Assess Systematic Reviews 2, NOS – Newcastle–Ottawa Scale. 0

Standard error

0.05 0.1 0.15 0.2 0.25 0.3 0.5

1.0

2.0

4.0

Log relative risk Venous thromboembolism

Heart failure

Stroke

Coronary heart disease

Fig. 5. Funnel plot for publication bias assess­ ment. Domain-level NOS assessment for includ­ ed cohort studies across selection, comparabil­ ity, and outcome domains. Studies are ordered by total NOS score and categorized as high or moderate quality. The assessment of individual studies revealed important patterns in methodological quality that inform confidence in the findings. Among venous thromboembolism studies, the landmark Ungprasert meta-analysis achieved an AMSTAR-2 score of 8/11, representing solid methodological quality despite limitations in grey literature searching and publication bias assessment. The Canadian population cohort by Aviña-Zubieta et al. [2] and the Danish registry studies by Sun et al. [3] and Loi­ seau et al. [4] all achieved perfect NOS scores of 9/9, reflecting exemplary cohort study design with representative populations, adequate follow-up periods, and vali­dated outcome ascertainment. For heart failure studies, the Danish registry maintained its high-quality methodology (NOS 9/9), while the Taiwanese claims study received a moderate rating (NOS 7/9) due to po-

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tential administrative coding limitations. Stroke studies showed more variability, with the recent Danish cohort achieving high quality (NOS 9/9) while the older Taiwanese study and international meta-analysis received mode­rate ratings due to limited confounder adjustment and heterogeneity concerns. Coronary heart disease stu­ dies similarly demonstrated this pattern, with the comprehensive Danish cohort achieving high quality while the Taiwanese study showed moderate quality due to methodological limitations typical of earlier research periods.

Publication bias assessment Publication bias assessment was conducted through multiple complementary approaches to evaluate the potential for selective reporting of positive results, though formal statistical testing was limited by the small number of studies per outcome category. Figure 5 presents a funnel plot analysis that, despite being constrained by the relatively small number of studies (2–5 per outcome), demonstrates reasonably symmetric distribution around the null effect line without obvious evidence of small-study effects or asymmetric clustering that would suggest publication bias. The visual assessment reveals that larger, more precise studies generally report more conservative effect estimates than smaller studies, which contradicts the typical pattern observed in the presence of publication bias. This finding is particularly evident in the VTE analysis, where the largest and most methodologically rigorous studies (Loiseau et al. [4] Danish cohort, Sun et al. [3] registry study) report moderate effect sizes (aHR 1.57, 1.38) compared to smaller studies with wider confidence intervals. The evidence against significant publication bias is strengthened by several key observations that support the comprehensive nature of the literature capture. First, the systematic inclusion of null and conflicting re-

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Clinical outcomes

Venous thromboembolism

Heart failure

Stroke

Coronary heart disease Study limit

Inconsist

Indirect

Imprecision

Pub bias

GRADE domains Downgraded

Not downgraded

Fig. 6. The GRADE evidence quality summary across outcomes and domains. Summary of GRADE certainty of evidence for VTE, heart failure, stroke, and CHD outcomes in adults with SjD. Domains include study limitations (risk of bias), inconsistency, indirectness, imprecision, and publication bias; green indicates “not downgraded,” and red indicates “downgraded”. CHD – coronary heart disease, GRADE – Grading of Recommendations Assessment, Development and Evaluation, SjD – Sjögren’s disease, VTE – venous thromboembolism .

sults, particularly evident in stroke and CHD analyses, argues against selective publication of positive findings. The stroke analysis notably includes the Yong et al. [8] international meta-analysis that suggests a protective effect (aHR = 0.84), directly contradicting other studies in the analysis. Second, the geographic diversity spanning 6 countries plus international meta-analyses reduces the likelihood of region-specific publication bias, while the 29-year time span captures evolving publication patterns and standards. Third, the conservative effect sizes reported by the largest and most recent studies (Loiseau et al. [4] cohorts) suggest that methodological improvements over time have led to more accurate, rather than inflated, effect estimates. Finally, the comprehensive search strategy included multiple databases, grey literature sources, and reference screening without language restrictions, maximizing the likelihood of capturing all relevant studies regardless of their findings.

Overall quality of evidence (Grading of Recommendations Assessment, Development and Evaluation) The overall quality of evidence was systematically evaluated using the GRADE approach, which provides a structured framework for assessing confidence in effect estimates across 5 critical domains. Figure 6 illustrates the comprehensive GRADE assessment, revealing that 50% of outcomes (venous thromboembolism and heart failure) achieved high-quality evidence ratings (⊕⊕⊕⊕), while the remaining 50% (stroke and CHD) received moderate-quality ratings (⊕⊕⊕). This distribution reflects the varying degrees of consistency and precision across different thrombotic outcomes, with

high-quality evidence supporting strong clinical recommendations for VTE prevention and cardiovascular screening, while moderate-quality evidence necessitates more nuanced, conditional approaches for stroke and CHD management. The domain-level GRADE appraisal (Fig. 6; Table V A–D) clarifies both the strengths and the constraints of the current evidence base. Across all outcomes, none required downgrading for risk of bias, reflecting the absence of clearly high-risk studies and the predominance of well-conducted cohort studies and systematic reviews. Likewise, indirectness did not warrant downgrading for any endpoint, as study populations, exposures, and outcomes closely matched the clinical questions and were highly relevant to routine practice. Assessment of publication bias was limited by the number of available studies but did not identify any signal sufficient to downgrade the evidence in any domain. Instead, the main distinguishing factors between outcomes were inconsistency and imprecision. Venous thromboembolism retained a high-certainty rating despite substantial statistical heterogeneity (I² = 79.7%), because all studies showed a concordant increase in risk with large, clinically important effect estimates (Fig. 6; Table V A). Heart failure also reached a highcertainty rating, supported by complete consistency (I² = 0.0%) between Danish and Taiwanese cohorts and a stable, approximately 43% excess risk (Fig. 6; Table V B). In contrast, the stroke evidence was downrated for serious inconsistency (I² = 76.1%), with effect estimates ranging from apparent protection to increased risk, and for imprecision, as the random-effects confidence interval crossed the null (Fig. 6; Table V C).

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Coronary heart disease was downgraded solely for se­ rious inconsistency (I² = 81.1%), reflecting divergent patterns between Asian datasets suggesting increased risk and European datasets showing no clear association (Fig. 6; Table V D). From a clinical standpoint, these GRADE ratings translate into recommendations of differing strength. High-certainty evidence for VTE and heart failure in SjD supports strong, proactive interventions, such as structured VTE prevention pathways for hospitalized SjD patients and systematic cardiovascular risk evaluation incorporating echocardiography and heart-failure prevention strategies (Fig. 6; Table V A–B). The robustness of these findings justifies health-system-level planning for an increased cardiothrombotic burden in SjD and supports implementation of targeted screening programs. By contrast, the moderate-certainty evidence for stroke and CHD underpins more conditional recommendations that explicitly acknowledge remaining uncertainty (Fig. 6; Table V C–D). For stroke, the available data favor individualized risk stratification, with particular attention to younger patients, in whom excess risk appears more pronounced. For CHD, the strong regional signal suggests that risk assessment should be adapted to population context, with intensified surveillance potentially warranted in Asian settings, while standard cardiovascular prevention may suffice in European cohorts. Overall, the GRADE evaluation indicates that this meta-analysis provides a robust basis for guideline development in SjD, with 2 of 4 major cardiovascular/thrombotic outcomes (50%) achieving high-certainty ratings and supporting strong, immediately actionable recommendations (Fig. 6; Table V A–D).

Discussion Thrombotic risk in SjD follows a vascular‑bed-specific pattern. Across the included studies, VTE shows the most consistent and clinically meaningful excess – approximately a doubling of risk – whereas arterial outcomes (ischemic stroke, myocardial infarction, and composite MACE) are more variable and depend on age and geography [22, 23]. This divergence is biologically coherent. Systemic inflammation, interferon‑mediated endothelial activation, and disease‑specific autoantibodies (including SSA/SSB, and antiphospholipid antibodies in subsets) foster a prothrombotic milieu that maps more uniformly onto venous events, while arterial events are modulated by underlying cardiometabolic risk and population factors. Comparisons with other rheumatic diseases support this view. In systemic lupus erythematosus, thrombosis – especially VTE – is closely associated with inflammatory burden and antiphospholipid status; rheumatoid

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arthritis also carries higher VTE risk and accelerated atherosclerosis. Sjögren’s disease tracks this template for VTE but exhibits greater heterogeneity for arterial outcomes, arguing against a universal arterial screening strategy and in favor of tailored assessment [24, 25]. Beyond thrombosis, our synthesis indicates a reproducible excess of heart failure – predominantly with preserved ejection fraction – consistent with microvascular dysfunction, diastolic impairment, or myocardial fibrosis rather than flow‑limiting epicardial disease. Timing appears important. Several cohorts demonstrate the highest VTE hazards within the first year after SjD diagnosis, suggesting a window of heightened vulnerability that coincides with active disease, diagnostic delays, or care transitions. Recurrence data further imply a persistently prothrombotic state, with higher repeat‑event rates than in non‑autoimmune comparators. For arterial outcomes, 2 axes of heterogeneity are notable. First, geography: some Asian datasets report increased coronary risk, whereas European datasets often do not – pointing to roles for ancestry, environmental exposures, baseline risk profiles, and health‑system differences. Second, age: the relative excess of ischemic stroke appears larger in patients under 50 years, when absolute risk is otherwise low – supporting a disease‑specific component rather than simple accumulation of traditional risk factors [26–30]. These patterns translate into practical care. For VTE, structured risk assessment is warranted at predictable high‑risk moments – hospitalization, perioperative periods, prolonged immobility, and phases of active systemic disease – with guideline‑concordant pharmacologic or mechanical prophylaxis when calculated risk is high. For arterial events, emphasis should remain on fundamentals: tight control of blood pressure and lipids, smoking cessation, weight management, and physical activity. Extra vigilance is reasonable in younger patients (< 50 years) given the larger relative stroke signal, and regional or ancestry‑specific patterns should inform thresholds for evaluation [26–30]. Given the consistency of the heart‑failure signal, a cardiovascular assessment that extends beyond coronary risk – e.g., attention to symptoms and diastolic function in appropriate patients – may be justified.

Study strengths and limitations Strengths of this review include prespecified methods, broad coverage across health systems, and outcome‑specific synthesis distinguishing venous, arterial, and cardiac phenotypes. Limitations temper inference: most evidence is observational; definitions of SjD and outcomes varied across study periods and datasets;

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administrative coding may misclassify events and may contribute to overdiagnosis or differential detection (particularly where SjD ascertainment relies on healthcare utilization); and residual confounding is likely. Although we evaluated and discussed overlapping datasets, partial population overlap across national registries or regional cohorts cannot be fully excluded. Reporting of clinical stratification variables (primary vs. secondary SjD, disease activity, organ involvement, antibody status, and treatment exposure) was inconsistent, limiting risk stratification and dose–response analyses. Publication bias cannot be excluded for outcomes with a small number of studies, and generalizability to resource‑limited settings remains uncertain. Priority areas for research are clear. Prospective, multi‑ethnic cohorts with harmonized case and outcome definitions and longitudinal assessment of disease activity, serology, and traditional risks are needed. Interventional studies should evaluate time‑limited thromboprophylaxis during clearly defined high‑risk periods (e.g., early post‑diagnosis, hospitalization, perioperative care), with safety outcomes tailored to SjD comorbidity profiles. Mechanistic and imaging studies are needed to clarify microvascular and myocardial pathways underlying the heart failure signal. Development and external validation of SjD‑specific thrombotic risk tools integrating serology (e.g., SSA/SSB), activity indices, organ involvement, and conventional factors are also warranted. Data on the impact of immunomodulatory therapy on thrombotic outcomes remain sparse; although inflammation control is desirable, definitive associations between specific agents and lower VTE or arterial events in SjD have not been established and warrant pragmatic trials.

Conclusions This meta-analysis indicates that SjD is associated with a clinically important increased risk of VTE and an under‑recognized burden of heart failure, while arterial outcomes (stroke and CHD) show more heterogeneity across age groups and regions. In the care of patients with SjD, our findings support systematic VTE risk assessment (with conside­ration of time‑limited thromboprophylaxis during clearly defined high‑risk periods when indicated), rigorous mana­gement of modifiable cardiovascular risk factors, and targeted surveillance guided by patient age and population context. Future research should use harmonized SjD and outcome definitions, explicitly minimize cohort overlap, incorporate clinical stratification (e.g., primary vs. secondary SjD and disease activity), and prospectively test preventive strategies.

Disclosures Conflict of interest: The authors declare no conflict of in­ terest. Funding: No external funding. Ethics approval: Not applicable. Data availability: Not applicable. References 1. Ungprasert P, Srivali N, Kittanamongkolchai W. Risk of venous thromboembolism in patients with Sjögren’s syndrome: a sys­ tematic review and meta-analysis. Clin Exp Rheumatol 2015; 33: 746–750. 2. Aviña-Zubieta JA, Jansz M, Sayre EC, Choi HK. The Risk of Deep Venous Thrombosis and Pulmonary Embolism in Primary Sjögren Syndrome: A General Population-based Study. J Rheu­ matol 2017; 44: 1184–1189, DOI: 10.3899/jrheum.160185. 3. Sun G, Fosbøl EL, Yafasova A, et al. Long-term risk of heart failure and other adverse cardiovascular outcomes in primary Sjögren’s syndrome. J Intern Med 2023; 293: 457–469, DOI: 10.1111/joim.13595. 4. Loiseau P, Mailhac A, Duhaut P, Thomsen RW. Arterial cardio­ vascular outcomes and venous thromboembolism in patients with primary Sjögren’s syndrome: a Danish cohort study. Rheumatology (Oxford) 2025; 64: 4678–4686, DOI: 10.1093/ rheumatology/keaf210. 5. Chiang CH, Liu CJ, Chen PJ, et al. Primary Sjögren’s syndrome and risk of ischemic stroke: a nationwide study. Clin Rheuma­ tol 2014; 33: 931–937, DOI: 10.1007/s10067-014-2573-7. 6. Wu XF, Huang JY, Chiou JY, et al. Increased risk of coronary heart disease among patients with primary Sjögren’s syn­ drome: a nationwide population-based cohort study. Sci Rep 2018; 8: 2209, DOI: 10.1038/s41598-018-19580-y. 7. Bartoloni E, Baldini C, Schillaci G, et al. Cardiovascular disease risk burden in primary Sjögren’s syndrome: results of a popu­ lation-based multicentre cohort study. J Intern Med 2015; 278: 185–192, DOI: 10.1111/joim.12346. 8. Yong WC, Sanguankeo A, Upala S. Association between pri­ mary Sjögren’s syndrome, cardiovascular and cerebrovascu­ lar disease: a systematic review and meta-analysis. Clin Exp Rheumatol 2018; 36 Suppl 112: 190–197. 9. Beltai A, Barnetche T, Daien C, et al. Cardiovascular Morbidity and Mortality in Primary Sjögren’s Syndrome: A Systematic Review and Meta-Analysis. Arthritis Care Res (Hoboken) 2020; 72: 131–139, DOI: 10.1002/acr.23821. 10. Zippel CL, Beider S, Kramer E, et al. Premature stroke and car­ diovascular risk in primary Sjögren’s syndrome. Front Cardio­ vasc Med 2022; 9: 1048684, DOI: 10.3389/fcvm.2022.1048684. 11. Pérez-De-Lis M, Akasbi M, Sisó A, et al. Cardiovascular risk factors in primary Sjögren’s syndrome: a case-control study in 624 pa­ tients. Lupus 2010; 19: 941–948, DOI: 10.1177/0961203310367504. 12. Rochette A, Dupont C, Lemaitre S, et al. Risk of recurrent ve­ nous thromboembolism in patients with primary Sjögren’s syn­ drome: a nationwide retrospective cohort. Thromb Haemost 2025; 125: 1234–1242.

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13. Su C, Zhu X, Wang Q, et al. Causal associations of Sjögren’s syndrome with cardiovascular disease: A two-sample Mende­ lian randomization study. Am Heart J Plus 2024; 47:100482, DOI: 10.1016/j.ahjo.2024.100482. 14. Lin CY, Chen HA, Chang TW, et al. Association of prima­ ry Sjögren’s syndrome with incident heart failure: a sec­ ondary analysis of health claims data in Taiwan. Ther Adv Chronic Dis 2022; 13: 20406223221078083, DOI: 10.1177/ 20406223221078083. 15. Caraba A, Iurciuc S, Nicolin M, Iurciuc M. Endothelial Dysfunc­ tion in Primary Sjögren’s Syndrome: Correlation with Serum Biomarkers of Disease Activity. Int J Mol Sci 2023; 24: 13918. 16. Chandra MS, G A M, M RK. Primary Sjögren’s Syndrome Pre­ senting as Cerebral Venous Thrombosis: A Rare Case. Cureus 2022; 14: e28772, DOI: 10.7759/cureus.28772. 17. Liu S, Bai M, Zhao Y. Cerebral venous thrombosis in patients with Sjögren’s syndrome: A case report and literature review. Heliyon 2023; 9: e15246, DOI: 10.1016/j.heliyon.2023.e15246. 18. Ho TH, Hsu YW, et al. Cerebral Venous Sinus Thrombosis in a Patient with Sjögren’s Syndrome with Atypical Antibodies: a Case Report. Acta Neurol Taiwan 2016; 25: 65–69. 19. Zhou Y, Jiang H, Wei H, et al. Cerebral venous thrombosis in pa­ tients with autoimmune disease, hematonosis or coronavirus disease 2019: Many familiar faces and some strangers. CNS Neurosci Ther 2023; 29: 2760–2774, DOI: 10.1111/cns.14321. 20. Rajasekhar A, Thomas M, Ashraf S. Sjögren’s syndrome com­ plicated by ischemic stroke in the right middle cerebral artery in a young woman: A case report. Case Rep Neurol Med 2024; 2024: 3357061. 21. Carvalho JF, Shoenfeld Y. Sjögren’s Syndrome Associated With Thrombotic Thrombocytopenic Purpura: a Case-Based Review. Rheumatol Ther 2021; 8: 621–629, DOI: 10.1007/s40744-02000265-w.

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Review paper

Reumatologia 2026; 64: 313–321 DOI: https://doi.org/10.5114/reum/211560

Pharmacological treatment of idiopathic retroperitoneal fibrosis Adrianna Niksińska ID , Robert Kruszewski ID , Witold Tłustochowicz ID Department of Internal Medicine and Rheumatology, Military Institute of Medicine – National Research Institute, Warsaw, Poland

Abstract Idiopathic retroperitoneal fibrosis (IRF) is a rare disease characterized by inflammatory infiltration around the aorta, which can lead to clinical symptoms and complications, the most common of which is ureteral obstruction, potentially resulting in secondary renal failure. A search of medical databases was conducted to compile a review article summarizing the immunosuppressive treatment options for IRF. In addition to urological treatment, immunosuppressive drugs are used in the treatment of retroperi­ toneal fibrosis. The cornerstone of therapy remains glucocorticosteroids (GCs), whose effectiveness and relatively rapid effect have been proven. However, the issue of frequent disease relapses after discontinuation of GCs still remains, prompting clinicians to investigate the effectiveness of other immunosuppressive agents. The efficacy of numerous immunosuppressive and biological medications in the treatment of IRF has been demonstrated in several studies; however, studies involving larger patient groups are still needed. Key words: treatment, immunosuppressive, idiopathic, retroperitoneal fibrosis.

Introduction Retroperitoneal fibrosis (RPF) is a rare chronic disorder characterized by formation of a fibroinflammatory mass in the retroperitoneal space. The most common type of RPF is idiopathic, while the remaining cases, referred to as secondary RPF, are associated with malignancies, infections, radiotherapy, drugs and prior surgery [1–5]. Idiopathic retroperitoneal fibrosis (IRF), along with inflammatory abdominal aortic aneurysms and perianeurysmal fibrosis, is part of a broader spectrum of disorders known as chronic periaortitis (CP) [1]. The fibrous tissue typically forms around the abdominal aorta and iliac arteries but can also affect other retroperito­neal structures, such as ureters, kidneys and inferior vena cava, which can lead to severe complications including ureteral obstruction (observed in 60–70% of cases), hydronephrosis, impaired kidney function and deep vein thrombosis [2, 3]. The most frequent clinical signs of RPF involve abdominal and/or lower back pain, though other less commonly observed symptoms include weight loss, fatigue, nausea, anorexia, and others [3, 4]. Retroperi­ toneal fibrosis may also be a manifestation of immuno-

globulin G4-related disease (IgG4-RD), which may affect other organs, most commonly the pancreas, bile ducts, and lacrimal and salivary glands. In cases of IgG4-RD, histopathological examination is necessary to confirm the diagnosis [6]. According to the literature, 30–60% of RPF cases are caused by IgG4-RD. No significant differences in treatment efficacy have been observed between patients with IRF and those with IgG4-RD; however, elevated serum IgG4 concentrations may be associated with a less favorable therapeutic response and an increased risk of relapse [7, 8]. The RPF diagnosis is based on clinical evaluation, laboratory tests, imaging and, if needed, a biopsy. It is crucial to exclude malignan­cies, infections, and other secondary causes of RPF [1, 5]. Laboratory studies frequently reveal increased acute-phase reactants (APR), anemia, and an elevated creatinine serum level secondary to ureteral compression. Increased concentration of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are present in approximately 80% of patients and are used to monitor disease activity [1, 3, 4]. Contrast-enhanced computed tomography (CT) is considered as the gold standard in both diagnosis and treatment monitoring, as it provides

Address for correspondence Adrianna Niksińska, Department of Internal Medicine and Rheumatology, Military Institute of Medicine – National Research Institute, 128 Szaserów St., 04-141 Warsaw, Poland, e-mail: ada.niksinska@gmail.com Submitted: 29.05.2025; Accepted: 30.09.2025; Published online: 10.06.2026

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

314

Adrianna Niksińska, Robert Kruszewski, Witold Tłustochowicz

Included

Screening

Identification

Identification of studies via databases and registers Records identified from databases (n = 2,321)

Records removed before screening: duplicate records removed (n = 763)

Records screened (n = 1,558)

Records excluded (n = 1,506)

Reports sought for retrieval (n = 52)

Reports not retrieved (n = 0)

Reports assessed for eligibility (n = 52)

Reports excluded (n = 31): – More than 2 drugs (excluding GCs) – Less than 50% patients with IRF – Less than 6 patients

Studies included in review (n = 21)

Figure 1. PRISMA flow diagram illustrating lite­ rature search and study selection. IRF – idiopathic retroperitoneal fibrosis, GCs – glucocortico­ steroids.

detailed imaging of the periaortic soft tissue mass and the involvement of other retroperitoneal structures [2, 5]. Gadolinium magnetic resonance imaging (MRI) is an alter­ native in cases in which CT is contraindicated. Although it illustrates a more detailed contrast between soft tissues, and diffusion-weighted imaging can be helpful to distinguish chronic RPF from neoplasms, it does not differentiate between active and chronic RPF [9]. 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) is useful to assess the metabolic activity of retroperitoneal masses at the introduction of treatment and during follow-up [2, 5]. Biopsy is considered an effective method for confirming diagnosis in cases of atypical radiological presentation of RPF or when malignancy is suspected. In the absence of diagnostic uncertainty, biopsy can be omitted, particularly considering the invasive nature of the procedure [5, 10–13]. The treatment options include pharmacotherapy and urological management. The most common and highly effective drugs used to treat IRF are glucocorticosteroids (GCs), although there is a high risk of recurrence of the disease after treatment discontinuation [10–12]. Use of other immunosuppressive agents as disease-modifying therapy is increasingly common and reduces the dose and duration of treatment with GCs [14–21]. When ureteral obstruction with impaired kidney function occurs, urological procedures may be necessary. Ureteral stenting is the most frequently performed procedure, with nephrostomy being another conservative

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option. Ultimately, severe and refractory cases may require ureterolysis [5]. Since there are no recommendations for treating IRF, a summary of available pharmacological therapeutic choices is necessary.

Material and methods A search of medical databases including PubMed and Scopus was performed for articles published between January 2000 and February 2025 using the following keywords: retroperitoneal fibrosis, idiopathic, immunosuppressive, treatment, GC, tamoxifen (TMX), mycophenolate mofetil (MMF), azathioprine (AZA), methotrexate (MTX), cyclophosphamide (CYC), and rituximab (RTX). The initial search was conducted in October 2024 and the final one in March 2025. The inclusion criteria were studies written and published in English focusing on the treatment of IRF (more than 50% of patients with IRF), discussing treatment of at least 6 patients using no more than 2 different medications, excluding GCs. Due to the rarity of the disease, most studies included small patient cohorts. Therefore, only studies involving more than 6 patients and using no more than 2 additional drugs besides GCs were included in the analysis. This approach allowed for a comparison of treatment efficacy beyond individual case reports, thereby increasing the credibility of treatment effectiveness. Articles describing treatment of more than 50% of patients with IgG4-related RPF or CP were not included. The PRISMA plot is presented in Figure 1. Twenty-one studies met the criteria for this narrative review. Importantly, most of the authors define successful treatment and recurrence of the disease differently. Outcomes such as a reduction in clinical symptoms and periaortic fibrous mass, as well as a decrease of inflammatory marker levels and removal of ureteral stents or nephrostomy in various combinations, were perceived as a satisfactory response to therapy. This is presented in the tables below. Table I summarizes studies on the treatment of IRF with GCs and TMX. Table II provides a summary of studies on immunosuppressive therapy, used in combination with GCs, while Table III presents the treatment of IRF with biological agents, in some cases combined with GCs. At the same time, a search for review articles was conducted. Steimer et al. [22] published a meta-analysis on the subject, but the literature search only included studies published up to 2021, and therefore treatment with MTX, tocilizumab (TCZ), and sirolimus (SRL) was not discussed. Carey et al. [23] focused on RPF patients with obstructive uropathy and did not compare medical therapeutic methods directly.

315

Treatment of idiopathic retroperitoneal fibrosis

Table I. Studies evaluating glucocorticoids and tamoxifen for idiopathic retroperitoneal fibrosis Author

Type of study

n

Treatment

Initial dose of GCs

Stents*

Mass regression

Treatment success**

Relapse

Fry et al. 2008 [10]

Retro

24

Prednisolone

30 mg

18/20 patients

ND

C+A

6/24

Van Bommel et al. 2007 [11]

Retro

24

Prednisone

60 mg

3/5 patients

19/24

18/24 C+A+M+U

13/18

Morin et al. 2019 [12]

Retro

23

Prednisone

1 mg/kg

ND

ND

21/23 C+A+M/S

6/23

Azizi et al. 2020 [13]

Retro

12

Steroids

0.5–1 mg/kg

ND

ND

9/12 C+A+M/S

0/12

Van Bommel et al. 2012 [24]

Pros

55

TMX 40 mg

None

ND

47/55

36/55 C+M+U

ND

Brandt et al. 2014 [25]

Retro

31

TMX 40 mg

None

17/29 patients

22/31

ND

0/31

Vaglio et al. 2011 [26]

RCT

18

Prednisone

0.5 mg/kg

ND

ND

ND

3/18

Vaglio et al. 2011 [26]

RCT

18

TMX 0.5 mg/kg

None

ND

ND

ND

9/18

Van der Bilt et al. 2016 [27]

Retro

50

Prednisone

60 mg/kg

ND

42/50

31/44 C+M+U

21/31

Van der Bilt et al. 2016 [27]

Retro

68

TMX 0.49 mg/kg

None

ND

43/68

28/48 C+M+U

6/28

Brandt et al. 2013 [28]

Retro

12

Prednisone

1 mg/kg

11/18 stents

10/12

ND

2/12

Brandt et al. 2013 [28]

Retro

12

TMX 40 mg

None

10/16 stents

12/12

ND

0/12

*Stents – number of patients with removed stents or number of removed stents. **Treatment success – definition of an author. A – acute phase reactant normalization, C – clinical improvement, GCs – glucocorticosteroids, M – mass regression, ND – no data, Pros – pro­ spective, RCT – randomized controlled trial, Retro – retrospective, TMX – tamoxifen, S – stable mass, U – resolution of ureteral obstruction.

Results A review of the literature on the pharmacological treatment of IRF is presented below.

Glucocorticosteroids Fry et al. [10] examined the effect of the mean starting dose of 30 mg of prednisolone in 24 IRF patients, 96% of whom had significant renal impairment at baseline. A maintenance dose of GCs was administered for 2–3 years. Successful therapy enabled stent removal in 18 out of 20 patients. Relapse was diagnosed in 25% of study participants after a mean follow-up of 52 months, defined as worsening of kidney function, ESR, or a periaortic mass enlargement detected in a CT scan. It is worth noting that 1 patient, who was not included in the study at the end, had a histopatholo­gical diagnosis of IRF and improved after treatment; however, his imaging findings were concerning, and he eventually developed lymphoma. It is crucial to closely observe RPF patients and if there is even a slight suspicion of malignancy,

it should be examined and excluded [10]. Van Bommel et al. [11] described treatment of 24 patients with an initial dose of 60 mg of prednisone daily, gradually reduced and maintained in a small dose for 12 months. 75% of study participants showed clinical improvement, mass regression on imaging, ureteral obstruction resolution and normalization of acute phase reactants, and as a result were considered a treatment success. Up to 72% of responders required reintroduction of pharmacotherapy due to a recurrence of disease symptoms, on average 10 months after the discontinuation of GCs. Morin et al. [12] treated 23 IRF patients with an initial dose of 1 mg/kg/day of prednisone and evaluated the efficacy of GCs alongside the correlation between persistent fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) and the risk of relapse. Up to 91% of study participants were in remission during follow-up, described as a decrease in APR and creatinine levels, resolution of disease symptoms and reduction or stabilization of retroperitoneal tissue on imaging, even though almost 70% had a high FDG uptake in PET. Altogether,

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Table II. Studies evaluating non-biologic immunosuppressive agents for idiopathic retroperitoneal fibrosis Authors

Type of study

n

Drug other than GCs

Initial dose of GCs

Stents*

Mass regression

Treatment success**

Relapse

Scheel et al. 2007 [14]

Pros

7

MMF 2 g

Prednisone 40 mg

10/11 stents

6/7

ND

0/7

Adler et al. 2008 [15]

Retro

9

MMF 2 g

1 mg/kg

5/7 patients

9/9

9/9

0/9

Scheel et al. 2011 [16]

Pros

28

MMF 2 g

Prednisone 40 mg

25/29 stents

25/28

ND

2/28

Obrenčević et al. 2019 [17]

Retro

13

MMF 2 g

Prednisone 0.5 mg/kg Methylprednisolone

6/7 patients

13/13

13/13 A+M

3/13

Marcolongo et al. 2004 [18]

Retro

15

AZA 2.5 mg/kg

Prednisone 1–1.5 mg/kg

ND

ND

15/15 C+A+U

4/15

Marcolongo et al. 2004 [18]

Retro

11

CYC 2 mg/kg or i.v. pulses

Prednisone 1–1.5 mg/kg

ND

ND

10/11 C+A+U

3/10

Prucha et al. 2016 [19]

Retro

26

AZA 100 mg

Prednisone 0.75–1 mg/kg

32/36 stents

26/26

C+M+U

2/26

Alberici et al. 2013 [20]

CT

16

MTX 15 mg/week

Prednisone 0.5–1 mg/kg

1/3 patients

Slight reduction

11/14 C+A+M

4/11

Vianello et al. 2023 [21]

Retro

15

MTX 12.5 mg/week

Prednisone 0.8–1 mg/kg

6/6 patients

14/15

14/15 C+A+M

2/14

Gao et al. 2023 [29]

CT

8

SRL 2 mg initially

Prednisone 0.8 mg/kg

ND

Nearly by half

ND

ND

*Stents – number of patients with removed stents or number of removed stents. **Treatment success – definition as reported by original authors. A – acute phase reactant normalization, AZA – azathioprine, C – clinical improvement, CYC – cyclophosphamide, CT – clinical trial, GCs – glucocorticosteroids, M – mass regression, MMF – mycophenolate mofetil, MTX – methotrexate, ND – no data, Pros – prospective, Retro – retrospective, SRL – sirolimus, U – resolution of ureteral obstruction.

Table III. Studies evaluating biologic agents for idiopathic retroperitoneal fibrosis Authors

Type of study

n

Biological drug

Oztas et al. 2023 [30]

Retro

13

Boyeva et al. 2020 [31]

Retro

Wang et al. 2023 [32]

Clinical trial

Initial dose of GCs

Stents*

Mass regression

Treatment success**

Relapse

RTX 1 g i.v. (1–6) Prednisone 10 mg

2/8 patients

Significant

ND

ND

10

RTX 1 g i.v. (2)

3 patients – dose unknown

None

Significant

ND

ND

12

TCZ 8 mg/kg every 4 weeks

None

2/4 patients

12/12

10/11 C+A+M

ND

*Stents – number of patients with removed stents or number of removed stents. **Treatment success – definition as reported by original authors. A – acute phase reactant normalization, C – clinical improvement, GCs – glucocorticosteroids, M – mass regression, ND – no data, Retro – retrospective, RTX – rituximab, TCZ – tocilizumab.

26% of patients had a relapse classified as recurrence of symptoms, hydronephrosis, or mass enlargement, and all of them were still receiving a maintenance dose of GC. It was reported that high FDG uptake in PET 10 months after treatment introduction was associated with an increased risk of relapse. Azizi et al. [13] achieved remission

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defined as clinical improvement, decrease in CRP, ESR, and creatinine levels and reduction/stable mass on imaging in 75% of RPF patients using the primary dose of 0.5–1 mg/ kg per day of GCs. All of them had hydronephrosis and had been previously treated with ureteral stents or nephrostomy. None of the study participants had a relapse.

317

Treatment of idiopathic retroperitoneal fibrosis

Tamoxifen Van Bommel et al. [24] estimated the efficacy of treatment with twice daily 20 mg TMX for 2 years in 55 patients, both women and men. Therapy was considered effective in 65% of study participants, causing alleviation of symptoms, soft tissue reduction, and reso­ lution of ureteral obstruction. Side effects were usually mild, including hot flashes, fatigue, and loss of libido. Two patients had mood disturbances requiring dose reduction and another 2 had pulmonary embolism. Brandt et al. [25] also examined the efficiency of 40 mg of TMX per day in 31 patients with IRF and reported similar results. After a mean treatment duration of 13.3 months, fibrous mass reduction was reported in 71% of patients, and ureteral stents were removed in 58.6% of patients. Tamoxifen was discontinued in 2 partici­ pants due to thromboembolic events and in 1 patient because of painful ovarian cysts.

Studies comparing glucocorticosteroids and tamoxifen Three studies comparing treatment of IRF with GCs to TMX were found. In the only randomized controlled study survey assessing medical therapy of idiopathic RPF, Vaglio et al. [26] estimated the risk of relapse after treatment with prednisone or TMX. After achieving clinical and laboratory remission with daily prednisone (1 mg/kg) admini­stered for 1 month, 36 patients with IRF were divided into 2 groups. Eighteen of them continued taking prednisone 0.5 mg/kg daily, which was gradually tapered and discontinued after 8 months of treatment. The other half were treated with 0.5 mg/kg of TMX daily for 8 months. After 26-month follow-up, relapse was characterized as presence of disease symptoms in association with an increase in APR, hydronephrosis, or periaortic mass enlargement in CT/MRI. It occurred in 17% of prednisonetreated patients and 50% of patients treated with TMX. Van der Bilt et al. [27] reported that prednisone is more effective in achieving remission; however, the recurrence rate was lower in patients treated with TMX in this study. Fifty patients started their therapy at a median starting dose of 60 mg of prednisone daily, which was tapered slowly until drug withdrawal after 14 months. Sixty-eight patients in the second group were treated with 40 mg/day of TMX monotherapy for 24 months. The results revealed a quicker reduction of disease symptoms and mass regression at the first followup CT scan as well as a greater decrease in CRP, ESR, and creatinine serum levels in the prednisone group. The overall treatment outcome was more favorable in patients receiving prednisone monotherapy (70.5%) than in patients treated with TMX (58.3%), although the difference was

not statistically significant. Interestingly, recurrence rate, defined as recurrence of disease symptoms or periaortic tissue enlargement, was lower in the TMX group (21.4% vs. 67.7%). Brandt et al. [28] treated 1 group of 12 patients with IRF with prednisone (initial dose 1 mg/kg every other day) for 1 year and the other group of 12 patients with TMX 20 mg twice a day for the same period. There was no significant difference in mass regression or in the amount of removed stents after treatment in the 2 groups.

Mycophenolate mofetil Scheel et al. [14] proved the therapeutic value of MMF in a prospective study. Seven patients with IRF were treated with a combined regimen of 40 mg of prednisone daily, tapered and discontinued after 6 months, and 1,000 mg of MMF twice daily. This management allowed the removal of 10 out of 11 stents and decreased the periaortic fibrous mass in 6 patients [14]. In a study by Adler et al. [15], 9 patients received 1,000 mg of MMF twice a day and prednisone at the initial dose of 1 mg/ kg/day. All of the participants had periaortic infiltrate reduction and 5 out of 7 had their ureteric stents removed. None of the patients had a relapse. Promising results were also obtained by Scheel et al. [16] in a prospective study on 28 patients with RPF treated with 40 mg/day of prednisone and 1,000 mg of MMF twice daily. Mass regression was observed in 89% of the study participants, and 25 out of 29 stents were removed. Only 7% of patients had a recurrence of the disease. It was the only study which reviewed the side effects of this combined therapy. Two patients developed shingles, and 1 experienced worsened diabetes control. Obrenčević et al. [17] treated 13 patients with MMF at an initial dose of 1,000 mg twice a day for 6 months. Eight out of all participants were additionally treated with a starting dose of 0.5 mg/kg/day of prednisone, and the rest of the patients received 250 mg of methyl­ prednisolone for 3 days followed by 0.5 mg/kg of oral prednisone apart from MMF. Fibrous mass reduction was observed in all of the participants, while stents were removed in 6 out of 7 patients. Relapse was defined as enlargement of periaortic mass and increase of acute phase reactant levels. The authors reported a 23% recurrence rate, which was significantly higher compared to the other studies investigating therapy with MMF. However, it might be attributable to a long median follow-up of 99.4 months.

Azathioprine and cyclophosphamide Marcolongo et al. [18] reported results supporting the effectiveness of AZA and CYC in treating IRF patients with ureteral obstruction. All patients received 1–1.5 mg/kg/day

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of prednisone for 3 weeks, then the dose was gradually reduced to a complete withdrawal after 6 months. Fifteen participants were also prescribed AZA 2.5 mg/ kg/day for 6 months, which was then tapered to 1.5 mg/kg/day for the subsequent 6 months, and 11 patients were treated with oral or intravenous CYC for 6 months. All study participants showed resolution of ureteral obstruction and clinical improvement, except 1 patient treated with CYC, who died of pneumonia. Seven of all the patients relapsed and required other the­ rapy. Prucha et al. [19] presented an analysis of the treatment of 26 IRF patients with prednisone (starting dose of 0.75–1 mg/kg/day) and 100 mg of AZA daily for 6 months. All of the study participants had retroperitoneal mass reduction and the treatment allowed the removal of 89% of stents. Two patients experienced a relapse.

Methotrexate Two studies on treating IRF with MTX were found, and in both cases the drug was used in relapsing patients. Remission was defined as clinical improvement, decrease of APR levels, and periaortic mass reduction. Importantly, both of the authors administered low doses of MTX. Alberici et al. [20] started the treatment with prednisone 0.5–1 mg/kg daily, reduced to the maintenance dose of 2.5–5 mg/day by 6 months along with MTX 15–20 mg per week in 16 relapsing patients. In 79% of study participants, the treatment was successful; 36% of these patients relapsed after MTX discontinuation. The rest of the patients continued the treatment and remained in remission. Due to sepsis and liver toxicity in 1 patient, the medications were withdrawn. Vianello et al. [21] reported high effectiveness of treatment with MTX in 15 relapsing or GC-refractory patients with IRF. The patients were prescribed MTX in a median dose of 12.5 mg per week for a median time of 20 months. Ninety-three percent of patients responded to MTX. One patient relapsed during treatment and was later diagnosed with lung cancer. Another 1 had a recurrence of disease 58 months after MTX discontinuation. During MTX treatment, some of the study participants were also taking low doses of GCs. It is worth noting that all of the patients in the studies describing MTX efficacy mentioned above had normal kidney function, which is not common in RPF patients. Methotrexate is contraindicated in renal insufficiency, and as a result it can only be used in a specific patient group. Notably, in the articles mentioned above, patients were treated with low doses of MTX as compared to doses of MTX administered in other autoimmune diseases.

Sirolimus Sirolimus works by inhibiting the mechanistic target of rapamycin pathway (mTOR), which is involved in cell

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proliferation. Gao et al. [29] found that mTOR is activated in RPF tissues. Eight patients with idiopathic RPF were treated with a combination therapy consisting of prednisone acetate at an initial dose of 0.8 mg/kg/day until the average time of 30.8 weeks and SRL 2 mg daily for 3 days, followed by a dose of 1 mg/day for 48 weeks. Their fibrous masses shrank on average by almost 50%. Alleviation of symptoms, reduction of acute phase reactants levels, and improvement in kidney serum marker levels were observed during the treatment. Most of the side effects, including hyperlipidemia and hyperglycemia, among others, resolved after GC discontinuation. One patient developed shingles.

Rituximab In a retrospective study by Oztas et al. [30], almost all of the participants were refractory to previous treatment with GCs and disease-modifying antirheumatic drugs. Intravenous infusions of 1 g of RTX were administered 1 to 6 times at 15-day intervals. In the follow-up, a rele­ vant periaortic infiltrate regression was seen. Two out of 8 patients had ureteric stents removed. Importantly, therapy with RTX enabled prednisone discontinuation in 4 patients and dose reduction in the others. During observation, 2 patients had urinary tract infections (UTIs) that required hospitalization, but both of them had ureteric stents and UTIs in the past. Boyeva et al. [31] presented similar results after RTX therapy. Statistically significant mass regression was noted. Two out of 10 patients had infusion-related reactions. In this study, ureteral obstruction and hydronephrosis resolution were not observed. In neither paper did the authors refer to potential disease relapses.

Tocilizumab Wang et al. [32] confirmed the effectiveness of TCZ monotherapy in 12 patients with CP. Exclusion criteria were: secondary forms of CP, diagnosed IgG4-RD, and aneurysmal dilation. The treatment consisted of 8 mg/kg of TCZ infusions every 4 weeks for at least 3 months. In 90.9% of patients, remission was observed. The peri­ aortic mass decreased by 70% or more in 7 study participants. In the group with initially normal serum IL-6 levels, a greater reduction of the mass was noted. The only side effect of TCZ therapy was a temporary elevation of serum liver enzymes in 2 patients.

Discussion According to the literature, there is a broad spectrum of therapeutic alternatives in IRF, and official treatment guidelines have not yet been proposed. This review focused on the pharmacological treatment.

Treatment of idiopathic retroperitoneal fibrosis

Although individual cases of spontaneous remission of RPF have been reported, it is considered uncommon, and treatment is usually necessary [19, 33]. Glucocorticosteroids are the cornerstone of treatment, as their effectiveness in achieving remission is reported at a rate of 70.5–91% [11–13, 27]. However, the relapse rate after GC monotherapy estimated at 17–72% remains a concern and encourages the search for other long-term therapeutic options [10–13, 26–28]. Clinical improvement occurs quickly, as symptoms typically resolve in most patients after a few weeks of GC treatment [27]. It is important to stress that there is no standardized starting dose, rate of dose reduction, or duration of treatment. In the aforementioned studies, the initial GC dose was usually 0.5–1 mg/kg/day of prednisone, and therapy lasted 6–48 months [10–13]. Tamo­xifen remains a viable therapeutic option, especially in patients with contraindications to GCs. Its anti-angiogenic and anti-fibrotic effects may result in inhibition of fibroblast proliferation, although its precise mechanism of action remains unknown [34, 35]. Studies comparing the efficacy of prednisone and TMX have demonstrated the superiority of GCs in achieving remission [27]. However, results regarding the relapse rate were varied [26–28]. The most common side effects of TMX are hot flashes, fatigue, and loss of libido. Those occur in up to 51% of patients [25]. Glucocorticosteroids cause hypercholesterolemia and weight gain more frequently than TMX [26]. Both GCs and TMX may induce thromboembolic events, and GCs increase the risk of cardiovascular incidents [36–38]. Importantly, GCs may obscure the presence of a possible tumor, when the diagnosis of idiopathic RPF is ambiguous [10]. To reduce the dose and duration of prednisone therapy, adding an immunosuppressive GC-sparing drug is a meaningful solution. A wide range of options, including MTX, MMF, AZA, and CYC, allows the treatment to be adjusted to the patients’ comorbidities. Metho­ trexate may only be used in patients with preserved kidney function. Its effectiveness of 79–95% and low relapse rate of 14–36% have been proven in relapsing and GC-resistant patients. In a few study participants, it caused liver toxicity, and 1 patient developed sepsis [20, 21]. Taking AZA enabled ureteral stents to be removed in all treated patients, and only 7.7–26.7% of study participants had a relapse. Cyclophosphamide was also effective, although it caused serious side effects including leukopenia and sepsis, and 1 patient died of pneumonia during treatment [18, 19]. In addition to the immunosuppressive effect of MMF, it also exerts antifibrotic activity [39, 40]. Therapy with MMF resulted in 100% success according to 3 studies, reduction of periaortic mass in 86–100% of cases, and

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a low relapse rate of 0–23% of patients. No serious adverse effects were reported [14–17]. Recent studies have explored treatment capabilities of biological drugs in RPF. The efficacy of RTX has been proven both in idiopathic and IgG4-related RPF. Despite significant fibrotic mass regression in IRF, RTX did not resolve ureteral obstruction in many patients. Two mild reactions to infusion have been described [30, 31]. Tocilizumab and SRL are treatment alternatives worth considering, especially because their effectiveness has been proven. However, more studies are needed to properly assess their clinical relevance [29, 32]. At every stage of treatment, urological procedures should be considered. Ureteral stents and nephrostomy are preferable and have similar complication rates, while ureterolysis is a more invasive, final form of therapy, to be used when other methods have failed [41, 42]. There remain uncertainties regarding the selection of immunosuppressive therapy in patients with RPF complicated by uropathy. These patients often require more intensive treatment, yet they are at increased risk of recurrent UTIs. Cyclophosphamide and biological agents such as RTX may be effective, but their use is associated with a higher risk of all infectious complications. Among 27 patients with RPF, most of whom had IgG4-related RPF, treated with RTX by Wallwork et al. [43], 3 experienced serious infections, including UTIs, pneumonia, and herpes zoster. In a study by Marcolongo et al. [18], 1 patient treated with CYC died from pneumonia. The definition of successful treatment in RPF remains an unresolved issue. It is paramount that the most important goal is to preserve kidney function. Therefore, resolution of ureteral obstruction and fibrous tissue shrinkage are considered important the­ rapy success indicators [11, 17, 19, 20, 24, 27]. In some studies, the presence of only 1 of those factors was described as effective disease management [16, 18, 21, 32]. C-reactive protein and ESR normalization were considered a part of achieving remission in some studies. Acute phase reactant serum levels before treatment are suboptimal predictors of response to therapy in patients treated with GCs. High levels of CRP and ESR correlate with more severe clinical symptoms [44, 45]. Fluorodeoxyglucose positron emission tomography is a promising tool in predicting treatment response in RPF patients and disease monitoring. Patients with initially negative FDG uptake are less likely to respond to therapy compared to patients with positive FDG-PET [46–48]. It is worth noting that in most individuals who achieved remission, periaortic tissue remains present. How­ever, it is not usually metabolically active and does not indicate the possibility of recurrence [49]. Impor­-

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tan­tly, detection of antinuclear antibodies, female sex, higher prednisone dosage in the first year of treatment, and initial monotherapy with GCs or therapy with GCs and TMX compared with other drugs are associated with lower relapse rates [50].

Conclusions There are multiple difficulties in determining the appropriate treatment regimen of IRF. First of all, due to the rarity of the disease, studies are conducted on small groups of patients, and the majority of them are retrospective. Numerous medications have been demonstrated to be effective, but so far no standardized clinical practice guidelines have been developed. Another important issue is the high relapse rate, necessitating long-term follow-up for most patients. Creating treatment recommendations requires more studies with larger patient groups and more randomized controlled trials.

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Reumatologia 2026; 64/4

Review paper

Reumatologia 2026; 64, 4: 322–331 DOI: https://doi.org/10.5114/reum/224664

The role and potential of CD19-targeted chimeric antigen receptor T-cell therapy in systemic sclerosis Krzysztof Michalak ID , Gabriela Chlebowska ID , Oliwia Sędziak ID , Dariusz Woszczyk ID Department of Hematology, Institute of Medical Sciences, University of Opole, Poland

Abstract Introduction: Systemic sclerosis (SSc) remains a challenge due to high mortality and resistance to treatment. Chimeric antigen receptor T-cell (CAR-T) technology (anti-CD19) may offer an opportunity for an immune system reset and long-term disease remission, eliminating the need for lifelong medication. Material and methods: This narrative review is based on a literature search in the PubMed and Scopus databases from 2023 to 2026. The main search phrases were: “CAR-T in systemic sclerosis”, “CAR-T scleroderma”, and “CAR-T SSc.” Results: CD19-targeted CAR-T therapy led to significant clinical improvement across analyzed cases. The median modified Rodnan skin score decreased by 8–13 points within 3–6 months. Disease activity, measured by the European Scleroderma Trials and Research Group Activity Index (EUSTAR-AI), showed a mean improvement ranging from 2.1 to 4.2 points. Pulmonary function remained stable or improved, with forced vital capacity increasing by up to 7% in responders. The safety profile was manageable, primarily consisting of grade 1 cytokine release syndrome in approximately 75–80% of patients. Conclusions: CD19-targeted CAR-T therapy is a promising investigational option for patients with refractory SSc. Limitations include small study groups and a lack of randomized controlled trials, warranting further validation in ongoing clinical studies. Key words: immunotherapy, scleroderma, systemic sclerosis.

Introduction Systemic sclerosis (SSc) is a complex autoimmune disease whose pathogenesis is based on 3 pillars: vasculopathy, immune system dysregulation, and progressive fibrosis of the skin and internal organs [1–3]. Vascular abnormalities initiate the process through endothelial dysfunction and microvascular rarefaction, leading to chronic tissue hypoxia. This environment triggers immune dysregulation, characterized by the activation of both innate and adaptive immunity. B-cells play a pivo­ tal role here, not only by producing specific autoantibodies (e.g., anti-topoisomerase I [anti-Scl-70]) but also by secreting pro-fibrotic cytokines such as interleukin-6 (IL-6) and transforming growth factor-β (TGF-β). This persistent inflammatory signaling drives fibroblast differentiation into myofibroblasts, leading to excessive extracellular matrix deposition and progressive organ

fibrosis [1, 3, 4]. Despite the availability of immunosuppressive drugs (such as cyclophosphamide or mycophenolate mofetil), many patients do not achieve sustained remission, and the disease continues to be associated with significant morbidity and mortality [2, 4]. The prognosis in severe forms of the disease remains poor, and traditional treatment rarely leads to long-term remission without the need for continuous drug administration [1]. Autologous hematopoietic stem cell transplantation (HSCT) has become an alternative for patients with severe, treatment-refractory SSc. Studies such as ASTIS and SCOT have demonstrated the superiority of HSCT over cyclophosphamide, showing that it can induce deep and durable remission. Long-term observations confirm that HSCT significantly reduces skin fibrosis and stabilizes organ function, with 5-year overall survival (OS) rates ranging from 79% to 96%. However, this procedure remains associated with a high risk of peri-procedural

Address for correspondence Krzysztof Michalak, Department of Hematology, Institute of Medical Sciences, University of Opole, 53 Kośnego St., 45-372 Opole, Poland, e-mail: kristofersen55555@gmail.com Submitted: 28.12.2025; Accepted: 16.06.2026; Published online: 10.07.2026

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CD19-targeted chimeric antigen receptor T-cell therapy in systemic sclerosis

toxicity and mortality [4, 5]. Specifically, treatmentrelated mortality associated with HSCT can reach up to 10% in some cohorts, primarily due to cardiac toxicity or infectious complications. This significant safety concern, alongside the rigorous eligibility criteria, limits its application to a highly selected group of patients. In this context, chimeric antigen receptor (CAR) T-cell technology, originally developed for hematological malignancies, has emerged as a potential therapeutic strategy. The CAR is a modular synthetic fusion protein designed to redirect T-cell specificity toward a predefined surface antigen [4–6]. The clinical application of auto­ logous CAR-T cells involves a complex “vein-to-vein” manufacturing process, encompassing leukapheresis, ex vivo genetic engineering, and a lymphodepletion conditioning regimen (typically comprising fludarabine and cyclophosphamide) to promote CAR-T cell expansion [5, 6]. Therapy with CAR-T targeting the CD19 antigen (CD19-CAR-T) aims at deep B-cell depletion, which may restore immunological tolerance [1, 6]. Recent reports, including case series, indicate that this therapy is feasible and may lead to clinical symptom resolution in SSc patients refractory to standard treatment [1, 7]. In addition to classic autologous CAR-T preparations, allogeneic (“off-the-shelf”) products, with genetic modification (e.g., using CRISPR/Cas9), are also being investigated to reduce the risk of rejection, thereby increasing the accessibility of this method [8].

Material and methods This manuscript is a narrative review without formal quality assessment and aims to provide a comprehensive, clinically relevant synthesis of CAR-T cell therapy approaches in SSc. The literature was reviewed by searching the scientific databases PubMed and Scopus. The materials presented at the most significant international rheumatology congresses, such as the European Alliance of Associations for Rheumatology (EULAR) and the American College of Rheumatology (ACR), were also analyzed. To ensure retrieval of all relevant literature, the search strategy combined free-text terms with Medical Subject Headings (MeSH). The search terms included the following combinations of keywords: (“CAR-T” OR “CD19-CAR-T” OR “CD19 CAR-T” OR “chimeric antigen receptor” OR “chimeric antigen receptor T-cell” OR “CAR-T cell therapy”) AND (“scleroderma” OR “systemic sclerosis” OR “SSc pathogenesis” OR “SSc”). MeSH terms were used to enhance search precision, including “Scleroderma, Systemic” and “Receptors, Chimeric Antigen.” The inclusion criteria were as follows: • original scientific articles (clinical trials and observational studies) on the efficacy or safety of CAR-T cell therapy in SSc,

• studies published between January 2023 and January 2026. The exclusion criteria included studies that: • lacked full text, • were non-English publications, • described the use of CAR-natural killer (NK) cell the­rapy. The initial stage of the process involved selecting articles based on their titles. In the second stage, the importance of the abstract was considered, and finally, the full texts were examined. The reference lists of the included studies and relevant reviews were also screened to identify any additional records. Two independent reviewers screened the articles for relevance to the review’s objectives following a database search. This review included 21 patients with SSc who had undergone CAR-T cell therapy. Auth et al. [7] reported a case series involving 6 patients with diffuse SSc (dSSc). Notably, this series incorporated preliminary data from 2 patients with SSc enrolled in the CASTLE study (NCT06347718), a phase 1/2a basket trial evaluating the safety and efficacy of zorpocabtagene autoleucel. Consequently, the present review considers 4 patients described by Auth et al. [7] and 9 patients from the CASTLE study. Additionally, 5 patients from the study by Pecher et al. [9] were included. The remaining 3 patients were identified from case reports.

Discussion Mechanistic rationale for CD19-targeted chimeric antigen receptor T-cell therapy in systemic sclerosis The application of cellular therapy in SSc stems from the fundamental role of B lymphocytes in the initiation and perpetuation of the disease process, which is confirmed by numerous studies on SSc pathogenesis [7, 10]. B lymphocytes in SSc exhibit features of constitutive hyperreactivity, which manifests, among other things, as approximately 20% increased expression of the signaling molecule CD19 compared to healthy individuals. This CD19 overexpression lowers the activation threshold of B cells, leading to excessive stimulation and disruption of homeostasis, as manifested by the expansion of naive B lymphocytes alongside a decrease in the number of memory cells [10]. A consequence of this dysregulation is the differentiation of B lymphocytes into plasma cells that produce autoantibodies strictly correlated with the clinical phenotype, such as anti-Scl-70 and anti-RNA polymerase III (ARPA), whose titers are linked to disease activity and prognosis [7, 8]. Importantly, the pathogenicity of B lymphocytes in SSc extends beyond the production of classic nuclear autoantibodies; functional agonist autoantibodies have also been identified, directed, for example, against the platelet-derived growth

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CAR-T anti-CD19

Leukapheresis

Ex vivo modification

Expansion

Conditioning and infusion

Fig. 1. Production and administration process of autologous anti-CD19 CAR-T cell therapy. Anti-CD19 – anti-cluster of differentiation 19, CAR-T – chimeric antigen receptor T cells.

factor receptor (PDGF) or the angiotensin II type 1 receptor. These antibodies can directly stimulate fibroblasts to produce collagen and promote vascular changes, thus forming a direct link between autoimmunity and fibrosis [10]. Furthermore, activated B lymphocytes perform crucial effector functions, secreting pro-inflammatory and pro-fibrotic cytokines, such as IL-6 and TGF-β, and acting as antigen-presenting cells, which stimulate T lymphocytes and drive chronic inflammation [7, 9]. Although B-lymphocyte depletion strategies using anti-CD20 monoclonal antibodies, such as rituximab (RTX), have demonstrated some clinical efficacy in improving skin conditions, their potential in SSc is limited by the incomplete elimination of pathogenic clones [6, 10, 11]. Rituximab often fails to achieve complete B-lymphocyte depletion in deep tissue compartments, such as fibrotic skin or lymph nodes, where these cells can survive and perpetuate the disease process [1, 6]. CAR-T anti-CD19 therapy offers a mechanistic advantage due to its broader target range and distinct mode of action. The CD19 antigen is expressed on a broader spectrum of the B-lymphocyte lineage than CD20, covering stages from pro-B lymphocytes through mature cells up to plasmablasts and early plasma cells [1, 12]. Plasma­ blasts, a key source of autoantibodies, often lack CD20 expression, rendering them resistant to RTX treatment, but they remain susceptible to anti-CD19 CAR-T therapy [1, 6, 10]. Furthermore, as a “living drug,” CAR-T cells are capable of active migration from the bloodstream into inflamed tissues, allowing for effective elimination of residual B lymphocytes inaccessible to passively acting antibodies [1, 10] (Fig. 1). Support for this mechanism comes from histopathological studies showing extensive elimination of B lymphocytes from the skin of SSc patients following CAR-T cell infusion [10]. The complete depletion of B lymphocytes at both the peripheral and tissue levels by CAR-T cells may promote immune system reconstitution, a phenomenon commonly referred to as an “immunological reset” [1, 7]. Available clinical observations indicate that after a period of B-lymphocyte aplasia, lasting on average

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approximately 112 days, the B-cell population undergoes reconstitution characterized predominantly by naïve cells with a newly formed receptor repertoire lacking autoreactive clones [1, 10]. This process may interrupt pathological immunological memory and contribute to treatment-free remission in selected cases [1, 5]. However, the mechanism of action of CAR-T in SSc extends beyond the adaptive immune response, also affecting innate immunity. It has been demonstrated that the elimination of autoantibodies and circulating immune complexes after CAR-T therapy leads to the phenotypic “rejuvenation” of NK cells. In the active phase of the disease, immune complexes activate NK cells via the CD16 receptor, contributing to tissue damage; the cessation of this stimulus after CAR-T therapy restores the normal, less activated NK cell phenotype [11]. The potential clinical reflection of these molecular processes may be the regression of fibrotic changes observed in some studies, which were previously considered irreversible [1, 7, 8]. In patients treated with both autologous and allogeneic CAR-T products, stabilization as well as improvement in imaging parameters, including lung computed tomography and cardiac magnetic resonance imaging, were observed. In addition, a significant reduction in the modified Rodnan skin score (mRSS) was noted [7, 8, 10]. This suggests that the precise removal of the driving factor, which is autoreactive B lymphocytes, allows for the activation of endogenous tissue repair mechanisms even in advanced stages of the disease, although this hypothesis remains to be substantiated in larger prospective studies [7, 10, 13]. Characteristics of patients treated with CAR-T cell therapy for SSc are shown in Table I [7–9, 14, 15].

Primary and secondary endpoints The primary objective of most studies was to evaluate the safety of CAR-T cell therapy in SSc. Key secon­ dary outcomes included changes in the mRSS (with higher scores indicating worse skin fibrosis), imaging (which is a component of the assessment of lung fibrosis), anti-nuclear antibody (ANA) levels, ARPA levels (specifically the RP11 and RP155 subunits), and anti-DNA topoisomerase I (ATA) levels (which were assessed by immunoblot and ELISA). Changes in the lungs were assessed using forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO), whereas heart function was assessed by measuring left ventricular ejection fraction, pulmonary artery systolic pressure (PASP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Other outcomes included changes in the European Scleroderma Trials and Research Group Activity Index (EUSTAR-AI) and the American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS) score, which is a weighted score

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AZA – azathioprine, BEL – belimumab, CAR-T – chimeric antigen receptor T-cells, CD19 – cluster of differentiation, CSA – cyclosporine A, CYC – cyclophosphamide, F – female, FLU – fludarabine, GCS – glucocorticoids, HCQ – hydroxychloroquine, HSCT – hematopoietic stem cell transplantation, M – male, MMF – mycophenolate mofetil, MTX – methotrexate, NIFE – nifedipine, NIN – ninte­ danib, RTX – rituximab, SIL – sildenafil, SSc – systemic sclerosis, TAC – tacrolimus, TCZ – tocilizumab, TEL – telitacicept.

[18] 13 FLU, CYC MTX, MMF, RTX, NIN, AZA, GCS 9 patients, median age 36

Autologous CD19-targeted CAR T cells

2.0 × 109

2.5

[17]

FLU, CYC MTX, TCZ, MMF, RTX F/59

Autologous CD19-targeted CAR T cells

5

3

[17]

1 × 106

3 1

3 8

1 × 106

1 × 10 Autologous CD19-targeted CAR T cells

MTX, RTX, MMF, TCZ

FLU, CYC

MTX, MMF, CSA, CYC, TCZ, RTX, HSCT

F/68

FLU, CYC

[17]

[17]

M/48

Autologous CD19-targeted CAR T cells

6

5.7 12.7 1 × 106

2.5 12.7 1 × 106 Autologous CD19-targeted CAR T cells

Autologous CD19-targeted CAR T cells FLU, CYC MTX, MMF, CSA, CYC, NIN, RTX, HCQ F/42

FLU, CYC CYC, MMF, NIN F/51

[8]

[16] 6 6 1 × 106 Allogeneic CD19-targeted CAR T cells FLU, CYC MTX, HCQ, AZA, TCZ, GCS, NIN, SIL, NIFE, Iloprost

CYC, MMF, TAC M/56

F/32

[8] CYC, MMF, HCQ, BEL, TEL

FLU, CYC

Allogeneic CD19-targeted CAR T cells

6

1

[7]

1 × 106

3 6

11.2 8

1 × 106

1 × 10 Autologous CD19-targeted CAR T cells MMF, CYC, NIN

M/45

FLU, CYC

[7]

M/47

FLU, CYC

Allogeneic CD19-targeted CAR T cells

6

[7]

MMF, MTX, TCZ, RTX F/37

FLU, CYC

Autologous CD19-targeted CAR T cells

1.3 12 1 × 106

[7]

14 1 × 106 MMF, HCQ, GCS M/36

FLU, CYC

Autologous CD19-targeted CAR T cells

2.5

18 1 × 106 MMF, MTX M/60

FLU, CYC

Autologous CD19-targeted CAR T cells

2

Follow-up Median disease duration duration [years] [months] Intervention Lymphodepletion Previous treatment Patient sex/ age [years]

The median age among the 21 SSc patients who underwent CAR-T therapy was 43 years. Women accounted for 12 of 21 (57%), and men for 9 of 21 (43%); however, the sex distribution varied across studies [7–9, 14, 15]. In the study by Pecher et al. [9], women accounted for 4 out of 5 (80%), whereas in other case series, the po­ pulation consisted exclusively of men. The average disease duration was 3.2 years, and the follow-up period was 11.2 months. Nevertheless, the follow-up period was very short in some cases, so the results should be interpreted with appropriate caution. Auth et al. [7] observed a tenfold decrease in the average ANA titer after 3 months. In one patient, ARPA was the predominant autoantibody type, and it was completely eliminated following treatment. However, starting on day 618, ARPA became detectable again. In contrast, ATA concentrations decreased steadily over the observation period, reaching a maximum decrease of more than 90% relative to baseline. Müller et al. [15] also observed a 66% decrease in ATA levels after 6 months. Lung function, as assessed by FVC and DLCO, improved significantly in most cases [7–9, 14, 15]. Among 9 patients in the CASTLE study, FVC increased significantly from a median of 2.83 to 3.23 l (+14.1%), while DLCO increased significantly from a median of 4.23 mmol/ml/kPa to 5.48 mmol/ml/kPa (+29.5%) [15]. Despite treatment, 3 patients showed progression of pulmonary fibrosis following the diagnosis of interstitial lung disease (ILD) associated with SSc. A reduction in ground-glass opacities, which are associated with ILD activity related to SSc, was observed in the lungs. Meanwhile, the severity of the reticular pattern, which reflects visible fibrous tissue remodeling, remained stable. Cardiac function was assessed only by Auth et al. [7]. Left ventricular ejection fraction remained stable in all patients during follow-up (55–60%). One patient had an NT-proBNP level of 7.202 pg/ml, which normalized during CAR-T therapy. Skin lesions showed significant improvement, with an average reduction of 11.2 points on the mRSS scale across all patients. Müller et al. [15] reported a reduction in median mRSS scores from 26 to 12 points, whereas Auth et al. [7] observed improved skin condition in all patients, with a median decrease of 8 points over 100 days. This improvement was either maintained or further reduced during the 12-month follow-up.

Table I. Characteristics of patients treated with CAR-T cell therapy for SSc

Efficacy of chimeric antigen receptor T-cell therapy in systemic sclerosis

CAR-T cell dose cells/kg body weight

Reference

that includes the following 5 core set measures: mRSS, FVC as a percentage of the predicted value, the Health Assessment Questionnaire-Disability Index (HAQ-DI), and patient and clinician global assessments [16].

[17]

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The average improvement in the EUSTAR-AI index was 4.2 points [7–9, 14, 15]. According to a study by Auth et al. [7], the mean EUSTAR-AI score was 5.7 before the start of CAR-T therapy and decreased by an average of 3.4 points in 4 patients at the last follow-up. In their case report, Albach et al. [14] observed a 5-point improvement on the EUSTAR-AI scale. The remaining studies used the ACR-CRISS criteria, except for 5 patients described by Pecher et al. [9], who did not use EUSTAR-AI or ACR-CRISS. In the CASTLE trial, all patients met the ACR CRISS 25 response criteria; 8 out of 9 met the CRISS 50 (2 out of 5 items) criteria, and 7 out of 9 met the CRISS 50 (3 out of 5 items) criteria. Assessment of skin changes, general activity, and adverse events (AEs) during CAR-T cell therapy are shown in Table II [7–9, 14, 15].

Cytokine release syndrome Cytokine release syndrome is characterized as a systemic inflammatory response resulting from the rapid activation of CAR-T cells and subsequent cytokine release, particularly IL-6. The primary associated symptom is fever, which may be accompanied by hypotension, tachycardia, and an altered emotional state [17, 18]. Cytokine release syndrome is the most prevalent AE associated with CAR-T cell therapy. The severity of CRS is typically assessed using the American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria. These criteria are based on established guidelines and include factors such as fever and the need for supplemental oxygen or vasopressor support [17]. In cases of mild CRS, the recommended approach is threefold: observation,

Table II. Assessment of skin changes, disease activity, and AEs during CAR-T therapy in individuals with SSc Patient sex/age [years]

mRSS mRSS EUSTAR-AI EUSTAR AI baseline 6 months baseline after CAR-T

CRS or ICANS AEs

References

M/60

24

17

4.75

2.2

CRS (grade 1)

URTI (Haemophilus influenzae)

[7]

M/36

27

17

9

2.5

CRS (grade 1)

Cellulitis, herpes zoster

[7]

F/37

32

15

5.25

2.5

CRS (grade 1)

mild SARS-CoV-2 infection, URTI [7] without antibiotics

M/47

17

12

3.93

2.1

None

URTI without antibiotics, influenza A with bacterial superinfection

[7]

M/45

26

6

-

CRISS 75 (3/5 items)

None

None

[8]

M/56

39

19

-

CRISS 50 (3/5 items)

None

None

[8]

F/32

9

4

9

4

CRS (grade 2)

Neutropenia grade 3, [16] transient liver enzyme elevation

F/51

7

3

NA

NA

CRS (grade 1)

None

[17]

F/42

17

8

NA

NA

None

None

[17]

M/48

30

10

NA

NA

CRS (grade 1)

None

[17]

F/68

32

30

NA

NA

Initially CRS (grade 1)

HLH, prolonged neutropenia, fatal outcome on day 74

[17]

F/59

32

31

NA

NA

CRS (grade 1)

None

[17]

9 patients, 26 median age 36

12

NA

CRISS 25 (5/5 items) 9/9 CRISS 50 (2/5 items) 8/9 CRISS 50 (3/5 items) 7/9

CRS (grade 1) 5/9 (56%) CRS (grade 2) 1/9 (11%)

Early ICAHT (any grade) 3/9 (33%) [18] Late ICAHT (any grade) 1/9 (11%) LICATS (any grade) 6/9 (66%)

AEs – adverse events, CAR-T – chimeric antigen receptor T-cells, CRISS – composite response index in systemic sclerosis, CRS – cytokine release syndrome, EUSTAR-AI – European Scleroderma Trials And Research Group Activity Index, F – female, HLH – hemophagocytic lymphohistiocytosis, ICAHT – immune effector cell-associated hematotoxicity, ICANS – immune effector cell-associated neurotoxicity syndrome, LICATS – local immune effector cell-associated toxicity, M – male, mRSS – modified Rodnan skin score, NA – not applicable, SARS-CoV-2 – severe acute respiratory syndrome coronavirus 2, SSc – systemic sclerosis, URTI – upper respiratory tract infection.

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Early ICAHT 500 ANC [cells/µl]

symptomatic treatment, and exclusion of infection. In contrast, the prevailing therapeutic approach for CRS ≥ 2 requires prompt administration of tocilizumab, often in combination with intravenous glucocorticoids (GCs) if the patient’s condition does not improve [18]. Refractory or severe CRS necessitates the administration of GCs, most commonly dexamethasone [19].

100

Immune effector cell-associated neurotoxicity syndrome Immune effector cell-associated neurotoxicity syndrome (ICANS) is presented as a manifestation of neurological complications following chimeric antigen receptor CAR-T cell therapy. The pathophysiology of ICANS is based on neuroinflammatory mechanisms and damage to the blood-brain barrier [20]. As outlined in the clinical findings, the manifestation of symptoms includes convulsive seizures, ataxia, and confusion. Conversely, cerebral edema may be a consequence of severe ICANS [19]. The standard treatment for ICANS entails the intravenous administration of GCs (particularly dexamethasone) and anticonvulsants. Anakinra, an IL-1 receptor antagonist, is recommended for treating GC-refractory ICANS [21]. Moreover, in instances where toxic effects on the nervous system coexist with significant CRS, tocilizumab is the therapeutic agent of choice in such circumstances [18].

Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome during chimeric antigen receptor T-cell therapy for the treatment of systemic sclerosis Recent scientific reports have focused on evaluating the efficacy and safety of CD19 CAR-T therapy in the treatment of SSc. Grade 1 CRS was observed in 12 of 21 patients (57%), while grade 2 CRS occurred in 2 of 21 patients (10%) who received CAR-T therapy. No cases of CRS above grade 2 were reported [7–9, 14, 15]. In the CASTLE study, the median time to onset of CRS was 1 day, and the median duration of CRS was 2 days [15]. In most cases of CAR-T therapy use in SSc, conservative treatment of grade 1 CRS proved sufficient. Müller et al. [15] administered tocilizumab to 5 of 9 patients (56%) and GCs to 1 patient. Current scientific reports on SSc suggest a favorable early neurological profile for ICANS treatment in this patient cohort. This assertion is bolstered by the absence of clinically significant ICANS among SSc patients who underwent the treatment model presented [7–9, 14, 15]. However, the current sample size of treated patients is insufficient to rule out the possibility of rare or delayed neurotoxicity.

7

14

Grade 1

Time [days] Grade 2

Grade 3

30 Grade 4

Late ICAHT (after day 30 measured at two timepoints)

500

1000

500

1500 ANC [cells/µl]

Licats Grade 1 – spontaneous resolution Grade 2 – GC use Grade 3 – GC use + prolonged hospitalization Grade 4 – intensive care treatment

Fig. 2. Criteria for bone marrow suppression as­ sociated with lymphodepletion therapy. ANC – absolute neutrophil count, GC – glucocorticosteroid, ICAHT – immune effector cell-associated hematotoxicity, LICATS – local immune effector cell-associated toxicity.

Compared with hematologic malignancies, SSc appears to be associated with a lower incidence and reduced severity of treatment-related toxicity. This phenomenon can be attributed to the lower degree of “burden” on target cells in patients with autoimmune diseases [17, 18, 22, 23]. Criteria for bone marrow suppression associated with lymphodepletion therapy are shown in Figure 2.

Other adverse reactions Potential AEs of CAR-T therapy in SSc, in addition to the previously mentioned CRS and ICANS, encompass prolonged cytopenia [24]. Müller et al. [15] attempted to standardize criteria for reporting myelotoxicity associated with lymphodepletion therapy using immune effector cell-associated hematotoxicity (ICAHT) and local immune effector cell-associated toxicity (LICATS). Late ICATS occurred in 6/9 (66%) patients, early ICAHT in 3/9 (33%), and late ICAHT in 1/9 (11%) [15]. These criteria require wider dissemination and further validation, but they may prove useful for reporting this type of AE. Dahunsi et al. [25] posited that the administration of granulocyte-colony stimulating factor and blood transfusions is

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Table III. Advantages and disadvantages of CAR-T vs. HSCT therapies in SSc Characteristic

CAR-T therapy

Autologous HSCT

Administration

Single infusion

Single infusion

First application

2023

~2011

The duration of follow-up across studies

~10.5 months, short-term observation

12 months – 15 years, long-term observation

Lymphodepletion/ conditioning

Lymphodepletion (FLU, CYC)

Conditioning (MAC, TBI)

Geographic availability

Only at specialized, accredited centers (potentially not only transplant centers)

Only at specialized, accredited centers

Viral vector

Viral vector integration into the host genome increases the risk of transgenepositive T-cell lymphomas or other transgene-positive tumors

Not associated

Patients’ median age across studies

43.2 years

35 years

OS

No data are available on 5-year OS

Available data on 5-year OS (79–96%)

mRSS

Significant improvement (average improvement of 11.63 points)

Significant improvement (heterogeneous data across studies)

CRS

This is more common and generally of a milder grade (grade 1 or 2)

Not associated

ICANS

No such cases have been observed in SSc to date

Not associated

SPM

Data on the incidence of SPM as a result of treatment for SSc are not available

Data on the incidence of SPM as a result of treatment for SSc are not available

TRM

No treatment-related deaths or severe immune complications reported

~6–10%, infections, cytopenia, cardiotoxicity, and amenorrhea

The data on CAR-T therapy are taken from studies included in our review, whereas the data on HSCT are taken from systematic reviews [27, 28]. Auto-HSCT – autologous hematopoietic stem cell transplantation, CAR-T – chimeric antigen receptor T-cells, CRS – cytokine release syndrome, CYC – cyclophosphamide, FLU – fludarabine, HSCT – hematopoietic stem cell transplantation, ICANS – immune effector cell-associated neurotoxicity syndrome, MAC – myeloablative conditioning, mRSS – modified Rodnan skin score, OS – overall survival, SPM – second primary malignancy, SSc – systemic sclerosis, TBI – total body irradiation, TRM – treatment-related mortality.

a recommended course of action. Furthermore, in cases of refractory thrombocytopenia, thrombopoietin agonists are recommended. As demonstrated in the existing body of research, delayed infections are among the most significant late complications, necessitating antiviral prophylaxis and immunoglobulins. The pathomechanism of this phenomenon has been determined to result from prolonged B-cell aplasia and hypogammaglobulinemia. In addition, a potential AE associated with the treatment is the risk of secondary malignancies, particularly myeloid malignancies, although the incidence remains low [26]. Pecher et al. [9] reported a case of a patient who developed fatal secondary hemophagocytic lymphohistiocytosis, which was probably caused by a herpes simplex virus infection. Having considered both the clinical efficacy outcomes and the distinct toxicity profiles of CD19-targeted CAR-T cell therapy, a comprehensive synthesis of the advantages and disadvantages of this emerging modality compared to the current gold standard, autologous HSCT, is provided in Table III [27, 28].

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Limitations of chimeric antigen receptor T-cell therapy in systemic sclerosis Notwithstanding early encouraging observations of CAR-T therapy in the treatment of autoimmune diseases, the therapeutic modality is also associated with numerous significant limitations. Primarily, these limitations pertain to small patient cohorts and limited databases, with many conclusions based on analyses of individual cases. The consequence is difficulty in monitoring the therapy’s effectiveness in a wider group of recipients, which creates challenges in future assessments of its effectiveness and safety [29]. Another important aspect is the lack of available randomized studies. Contemporary scientific reports indicate that the limited duration of observation constitutes a significant challenge. This limitation adversely impacts the capacity to ascertain data about the durability of remission and to estimate the likelihood of subsequent AEs [30]. A further challenge lies in the divergence of protocols, the absence of a clearly delineated standard of care, and the heterogeneity

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CD19-targeted chimeric antigen receptor T-cell therapy in systemic sclerosis

of methodologies across studies, rendering comparisons of results across centers a formidable task. This circumstance creates considerable challenges in identifying the key elements that contribute to achieving the intended therapeutic outcome [30, 31]. This treatment method necessitates substantial financial expenditures and the establishment of specialized infrastructure, factors that consequently restrict its accessibility [32].

Future directions for the development of chimeric antigen receptor T-cell therapy in systemic sclerosis Recent perspectives on the treatment of SSc using CAR-T cell therapy emphasize the need for prospective studies with standardized protocols and long-term monitoring. This is significant because such observations facilitate analysis of remission in terms of durability and enable evaluation of a comprehensive safety profile [14, 29, 33, 34]. The authors likewise underscore the need to leverage inflammatory response markers to facilitate optimal patient selection. Moreover, this approach enables us to determine whether early intervention in patients with an aggressive phenotype has a lasting impact on disease progression [14, 29, 33]. A significant avenue for advancement lies in implementing readily available allogeneic formulations that reduce qualification waiting periods and minimize costs. Additional genetic manipulations remain crucial to ensure the safety and efficacy of these “off-the-shelf products.” These include the use of CRISPR/Cas9 technology. Gene editing primarily leads to the elimination of endogenous T-cell receptor (TCR) expression. Consequently, allogeneic CAR-T cells become undetectable to the immune system, reducing the risk of graft-versus-host disease (GvHD). To prevent the immune system from rejecting therapeutic cells, molecules such as human leukocyte antigens (HLA) or CD52 are eliminated in most cases. Another significant aspect, apart from gene editing, is the appropriate selection of the cell source, which can influence the incidence of GvHD. For example, using regulatory T cells (Tregs) or NK cells as the basis for CAR modification may reduce the risk of GvHD compared to conventional T cells. CARs can be synthesized on the surface of conventional T cells, Tregs, NK cells, or macrophages, thereby enabling these cells to acquire distinct functional characteristics. In addition, important challenges remain in CAR-based allogeneic therapy, and solutions are still pending. Nonetheless, several preparations using universal platforms have entered clinical trials. A case study demonstrating the feasibility of achieving deep remission and regression of fibrotic changes while ensuring safety is provided by an analysis employing TyU19 (which uses CRISPR/Cas9

to achieve these exact gene knockouts) in 2 patients with dSSc. This finding reinforces the prospect of future observations regarding the universality of products obtained using CRISPR [8, 33–35]. Concurrently, alternative methods of deep B-cell depletion are being promoted; these may either compete with or coexist with standard CD19-CAR-T. Numerous scientific reports on rheumatic diseases and SSc underscore the distinctive role of bispecific antibodies, exemplified by blinatumomab. These antibodies effectively facilitate the targeting of autologous T cells against CD19+, eliminating the need for viral vectors and enhanced conditioning [30, 33, 36]. The future of CAR-T therapy for SSc holds enormous potential, but it remains in its early stages of development. Several trials are underway to further assess the efficacy and safety of CAR-T cells in SSc. An overview of CAR-T therapy in the treatment of SSc is presented in Supplementary Table I.

Conclusions CD19-targeted CAR-T therapy currently represents an early proof of concept in patients with treatment-refractory SSc, with promising initial clinical responses, including reductions in skin fibrosis and stabilization of organ involvement. The early safety profile appears favorable, characterized primarily by low-grade CRS and a notable absence of severe neurotoxicity, which compares positively to procedures such as HSCT. Despite these promising results, the available evidence is largely based on individual case reports and heterogeneous groups, with limited observation periods. Consequently, the long-term safety and durability of remission remain unproven. Further validation through long-term randomized controlled trials is therefore essential. Advances in allogeneic “off-the-shelf” products and bispecific antibodies may help to standardize and expand clinical access to this new therapeutic strategy.

Disclosures Conflicts of interest: The authors declare no conflicts of interest. Funding: No external funding. Ethics approval: Not applicable. Availability of data and material: Not applicable. References 1. Müller F, Taubmann J, Bucci L, et al. CD19 CAR T-Cell Therapy in Autoimmune Disease – A Case Series with Follow-up. N Engl J Med 2024; 390: 687–700, DOI: 10.1056/NEJMoa2308917. 2. Chen L, Huang R, Huang C, et al. Cell therapy for sclero­ derma: progress in mesenchymal stem cells and CAR-T

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Review paper

Reumatologia 2026; 64, 4: 332–337 DOI: https://doi.org/10.5114/reum/218877

Clinical trials in rheumatology: patient motivations and concerns as key determinants of recruitment Marta Jeka ID  Medicover Integrated Clinical Services Medical Centre, Warsaw, Poland

Abstract Clinical trials are crucial for medical progress, but patient recruitment remains their biggest challenge. The decision to participate stems from a combination of altruistic motivations and the desire to obtain better treatment. The physician plays a key role through their empathy, trustworthiness, and ability to explain the benefits and risks. Problems such as complex protocols, frequent visits, lack of knowledge about the trials, and distrust of pharmaceutical companies significantly hinder recruitment. Patients with chronic pain often hesitate despite severe symptoms, which further complicates the process. It is also important to provide access to study results in the form of understandable plain language summaries, which strengthen patient engagement. Designing “patient-centred” studies can significantly improve their accessibility and effectiveness. Key words: clinical trials, patient recruitment, rheumatic diseases, patient participation.

Introduction Clinical trials are essential in the process of introducing new therapies. They make it possible to assess not only the effectiveness of new drugs, but equally importantly, their safety profile. Today it is difficult to imagine progress in patient treatment without clinical trials. However, it should be emphasized that scientific research must be carefully considered at the design stage. Its ultimate scientific, ethical, and clinical value largely depends on the proper formulation of research hypotheses. Incorrectly formulated hypotheses may not only lead to limited practical value of a clinical trial, but also to unjustified exposure of patients’ health. Correct formulation of hypotheses requires reliance on data based on scientific facts and prediction of potential clinical implications [1]. Over the past 30 years, rheumatology has witnessed substantial advances in patient treatment, with rheumatoid arthritis (RA) and inflammatory spondyloarthropathies being notable examples [2, 3]. Currently available therapies not only allow effective control of disease activity but also allow the achievement of sustained remission. These advances have been driven by the introduction of biological drugs and innovative therapies [4]. The process of bringing biological drugs to the market is both costly and time-consuming, largely due to

the specific complexity of producing biological medications [5]. It is far more complicated than in the case of traditional drugs. As a result, biological therapies are extremely expensive, which negatively affects their availability [6]. This problem is particularly visible in Poland. Access to biological therapies within Drug Programs is practically negligible. For patients with RA and psoriatic arthritis, it is below 2% [7]. In this regard, Poland performs very poorly compared to other EU countries – these are among the lowest rates [7]. One way to increase access to effective therapies is the introduction of biosimilars to the market, which contribute to drug cost reduction. Unfortunately, biosimilars also require clinical trials on a much larger scale than traditional or generic drugs [4]. In countries such as Poland, clinical trials also significantly increase the number of patients who have access to the most effective therapies. Participation in clinical trials may therefore provide patients with an opportunity to receive innovative and highly effective treatments. Unfortunately, due to their history, clinical trials may also raise certain concerns and controversies [8, 9]. From an economic perspective, they are associated with high costs, largely resulting from the patient recruitment process [10].

Address for correspondence Marta Jeka, Medicover Integrated Clinical Services Medical Centre, 53 apt. B10 Wronia St., 00-874 Warsaw, Poland, e-mail: marta.jeka27@gmail.com Submitted: 10.12.2025; Accepted: 05.03.2026; Published online: 10.07.2026

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

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Patient recruitment in clinical trials proceeds extremely slowly in about 80% of centres. It is estimated that on average as many as 37% of centres fail to reach the preplanned number of patients, and about 11% do not manage to enrol any patients at all [10]. One factor influencing this situation is the clinical trial protocols themselves. They are very restrictive regarding inclusion and exclusion criteria, while also requiring patients to adjust their lives to frequent and sometimes long study visits [11]. This is well illustrated by clinical trials for RA patients. In the RA-BEAM study, the observation time per patient was only 1 year, but the study itself spanned more than 3 years [12]. A total of 1307 patients were enrolled. In RA-BEAM, one of the recruitment challenges was the exclusion criteria; among them was any prior use of biological therapy. For obvious reasons, this reduces the pool of potential patients, especially in countries with a high proportion of patients already treated with biologics. Another important factor affecting the time and cost of clinical trials is the percentage of patients who withdraw after enrolment. A good example is the study NCT05489224, conducted in Poland and other countries [13, 14]. The study enrolled 556 patients, of whom 471 were randomized (85%), and only 412 (74%) completed the trial. As a result, approximately 1 in 4 patients did not complete the study. Therefore, when planning clinical trials, anticipated dropout rates must be taken into account, as they necessitate the recruitment of additional participants and increase overall study costs. It is unlikely that clinical trial protocols will be significantly simplified in the coming years. For this reason, improving the identification of suitable trial participants may be an important factor in enhancing trial efficiency. This could not only shorten recruitment but also reduce patient dropout. In this context, assessment of psychological and behavioural factors associated with study participation and retention may become increasingly important [15–17]. Recent methodological publications have highlighted the importance of understanding participant perspectives and study design principles when conducting clinical research [18]. Building on these concepts, the present review focuses specifically on patient participation in clinical trials in rheumatology, integrating psychological, ethical, and organizational aspects. This review aims to integrate patient-related, psychological, ethical, and organizational factors affecting clinical trial participation, with particular emphasis on rheumatology-specific challenges.

Material and methods A narrative literature review was conducted based on studies identified through searches of the MEDLINE/

PubMed and Embase databases. Only articles published in English and Polish from the year 2000 onwards were considered. The search strategy was based on Medical Subject Headings (MeSH) and key words including patient participation, randomized controlled trial, clinical trial, depression, and pain. Due to the specific characteristics of rheumatic diseases, the review focused on studies directly related to rheumatology, as well as studies involving patient populations exposed to depression and/or chronic pain.

Patients Patients are at the centre of every clinical trial – their participation is essential for its efficient execution. Therefore, understanding why patients decide to participate in clinical research is of fundamental importance. Decisions regarding participation are typically influenced by a combination of altruistic motivations and potential personal benefits, such as access to novel therapies or enhanced medical care. However, participation in a clinical trial may involve certain risks associated with studying the effectiveness and safety profile of a drug, as well as inconveniences imposed by the protocol, such as frequent and long visits. Patients generally need to perceive a potential benefit of participating in a clinical trial despite the challenges involved (Fig. 1). Currently, there is a growing emphasis on designing patient-centred clinical trials [19]. A useful starting point is to consider patients’ motivations for enrolling in clinical trials, as these motiva-

Burden of disease • Chronic pain • Fatigue • Depression/Anxiety • Quality of life

Study design • Frequency of visits and duration • Inclusion/exclusion criteria

The patient’s decision to participate in a clinical trial

Physician-patient relationship • Trust • Empathy

Therapy • Access to therapy • Socioeconomic factors • Post-trial treatment uncertainty

Fig. 1. Determinants of patients’ decisions to participate in clinical trials in rheumatology.

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tions often reflect the benefits that patients perceive. For many patients, participation is driven by the awareness that clinical trials are necessary for progress in medicine [19]. In a sense, this is altruistic behaviour, which is important from the patient’s perspective [20]. A key role is played by the patient’s hope that the study may truly contribute to progress in treating their disease. For some, this alleviates feelings of guilt that participation stems from self-interest – taking care of their own health [19]. In self-oriented motivation, important factors include easier access to treatment, the hope for more effective therapy, and avoiding the risk of increasing disability. Another factor directly influencing a patient’s decision is the clinician’s attitude. Regardless of the patient’s motivation, it is usually the treating physician who presents the possibility of participating in a clinical trial. At this stage, it is crucial not only to convey information clearly, but also to build trust between doctor and patient [21]. Important traits include empathy, the ability to listen, building trust, and motivating the patient. This is especially important for patients dealing with chronic pain [21]. In rheumatology, this is particularly relevant because most patients experience chronic pain and must cope with its daily consequences. Ultimately, although patient motivation is crucial, without the involvement of the treating physician, it is difficult to expect the patient to participate. This dependence shows how demanding the recruitment process can be when human factors are considered. Focusing only on the study protocol is insufficient. In addition to educating patients, clinicians also need education to provide reliable information to patients about their role in a clinical trial before participation. Patient motivations and engagement in clinical trials are well described in the literature [20, 21]. Nevertheless, the course of the disease may significantly influence them. Patients with mild symptoms and no noticeable decline in quality of life are often not interested in participating [20]. Consequently, patients with more severe symptoms may constitute a larger candidate pool. Here, it is important to return to the role of pain in inflammatory diseases and its influence on patient lives. Unfortunately, chronic pain may also cause patients to feel ambivalent about participating despite severe symptoms [20]. This disrupts the previously described doctor-patient dynamic. Pain in rheumatic diseases is associated with chronic fatigue, insomnia, depression, increased anxiety, and greater disability [22–24]. These factors significantly influence patients’ decisions, including treatment choices [20]. These relationships are reflected in studies analysing the motivations of patients with rheumatic diseases

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to participate in clinical trials, particularly in populations with RA and systemic lupus erythematosus (SLE). Altruism is one of the main reasons for the participation of patients with RA and SLE in clinical trials [25]. Patients with SLE constitute a special group due to the nature and course of the disease. In addition to altruistic motivations, an equally important factor encouraging participation in clinical trials is the opportunity to gain access to modern therapies. On the other hand, alongside altruism and the desire to improve their own health, patients often express concerns about the potential complications of new therapies, which negatively affects their willingness to participate in trials [25]. Another extremely interesting aspect of clinical trials in the context of rheumatic diseases is the higher placebo response rate observed in less affluent areas [26]. The reasons for this phenomenon are not fully understood; 1 potential mechanism may be limited access to healthcare. However, the occurrence of an increased placebo effect can significantly affect sample size calculation, leading to the need to increase the number of participants and thus prolong the duration of the clini­cal trial.

Recruitment problems A fundamental limitation in patient recruitment is the lack of information about ongoing clinical trials. Patients often do not know that a study is being conducted in which they could potentially participate. In this case, the best strategy would be to reach as many primary care physicians and specialists as possible and convince them that participation in a clinical trial could benefit their patients. A major current limitation is the lack of trust in pharmaceutical companies, especially regarding vaccine trials [27]. Some patients suspect they are being treated like “guinea pigs” and believe the main beneficiaries are sponsors, contract research organization (CROs), and investigators. In rheumatology, this issue may be less severe because patients are often treated by the same doctors for many years, which helps build trust. However, many myths about biological drugs circulate [28], which may lead patients to fear participating in trials. Ultimately, this brings us back to the earlier issue – the doctor-patient relationship. The most important element is conversation, during which the clinician must provide clear and comprehensive answers to patient questions and concerns, explaining the trial in an accessible manner. Any unanswered concerns may affect the patient’s willingness to participate [27]. It is worth emphasizing that refusal to participate not only negatively affects recruitment but may also influence the patient’s treatment. Patients who completed clinical trials

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report that participation offers high-quality healthcare, helps them better understand their disease, and increases social activity by engaging with other patients [20]. Given these considerations, an effective recruitment strategy may be for the treating physician – whom the patient trusts – to propose participation [19]. Patients often report that being disconnected from the doctors and staff they know is problematic. Therefore, clinical trials must maintain continuity in patient care, so patients are not completely removed from their previous medical environment. This is particularly important for patients with rheumatic diseases, who typically have long-term relationships with their physicians and clinic staff. Removing them from this familiar environment may create a significant barrier to trial participation. Thus, it is important to ensure professional communication with primary care doctors and specialists previously involved in the patient’s treatment, informing them about the patient’s participation in a clinical trial. Ferguson et al. [19] note that 1 recruitment limitation may be the uncertainty around post-trial treatment, especially when continued therapy involves cost. Another major limitation is the distance between the patient’s home and the trial centre. For working patients, long and frequent visits are also a considerable challenge [19].

Simplifying trials The number and length of visits represent a serious problem – patients often report this during trials. Changing protocols to make them more flexible could indeed improve recruitment rates. Unfortunately, how exactly protocols should be changed is not obvious. Patients with chronic pain often prefer longer visits, while patients with two or more chronic conditions believe visits should be shorter [29]. This example illustrates the complexity of preparing an appropriate protocol. The disease itself may significantly influence these preferences, making it difficult to apply conclusions from 1 field, such as oncology, to rheumatology due to differing disease characteristics and patient challenges. Currently, survey studies are being conducted on how patients believe trial visits should look. For rheumatology, important studies involve patients with chronic illness and chronic pain [30, 31]. A characteristic feature in both groups was the preference for hybrid visits – some remote and some in-person. Considering the experience gained during the COVID-19 pandemic, most centres now have the capacity to conduct remote visits. This is a change that could realistically be incorporated into protocols, increasing trial accessibility. Patients with chronic pain also stress that participation should not exacerbate pain. This group is especially focused on keeping pain at the lowest possible level [30].

Simplifying protocols and optimizing visit times are extremely important. Patients with chronic diseases must also have time for work and social activity. Without this, they may feel ambivalent about therapy, as reduced professional and social activity may contribute to depression, significantly complicating treatment of the underlying condition. To conclude the discussion on simplifying clinical trials, it is also worth referring to the updated Declaration of Helsinki of 2024 [32]. This document emphasizes that clinical trials should be designed and conducted with consideration for the principles of sustainable development and minimization of burdens, including the environmental impact. At the same time, the declaration clearly states that the responsibility for protecting trial participants always rests with physicians and researchers, and not with the participants themselves, even if they have given their informed consent to participate in the trial. It also draws attention to the need to ensure adequate access to clinical trials for underrepresented groups, which is crucial from the point of view of ethics, quality, and the reliability of the results obtained.

Feedback – plain language summary The discussion of difficulties in recruiting patients for clinical trials began with addressing patient motivation for participating in clinical trials. One of the more important motivations turned out to be the desire to contribute to medical progress – patients are aware that without clinical trials, progress is not possible [19]. In this context, patients may naturally be interested in the trial results, i.e., not only in improving their own health but also in the global effectiveness of the therapy. Unfortunately, access to trial results is limited. Very often, they are published in prestigious medical journals. The nature of such publications is purely scientific – they are charac­terized by highly specialized language as well as advanced statistical tools, which may be difficult to understand even for clinicians [33]. The potential for statistical analyses to influence the interpretation of clinical trial results is illustrated by the example of the VIGOR trial, in which patients with RA participated [34]. It compared rofecoxib and naproxen, and only later was it revealed that the statistical tools used “masked” the adverse effects of rofecoxib [34, 35]. The VIGOR study highlighted two issues. Studies like this cause patients to have concerns regarding research ethics. This shows that the previously discussed problem of patient trust in clinicians has real significance. The second issue is the need to present trial results in a simple manner if they are to be accessible to patients. Even experienced clinicians, including editors and reviewers, are not always able to correctly interpret trial results [34, 35].

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For this reason, plain-language summaries (PLS) are so important – they present trial results in such a way that even individuals who are not medical professionals can easily understand them [36]. The difference between a strictly scientific paper and a PLS is clearly visible in the discussion of the ROSALIA study [37, 38]. Both works discuss the same results, but the accessibility of the content is entirely different. PLS can indeed satisfy patients’ scientific curiosity regarding clinical trial results. In this case, since one of the motivations is scientific progress, the ability to review the trial results can be an additional motivation to participate in a clinical trial. It provides the patient with a unique opportunity for full engagement in the clinical trial, serving in a way as a reward for their participation.

Conclusions Clinical trials contribute not only to progress in medicine but also to increased patient access to treatment. Unfortunately, clinical trials also involve a range of challenges, among which patient recruitment is one of the most important. Trials are designed to assess both the effectiveness of the therapy and its safety profile as accurately as possible. Nevertheless, patient perspectives and experiences have not always been adequately incorporated into trial design. Recruitment difficulties continue to limit the successful completion of many trials. Therefore, a more patient-centred approach to clinical trial design is required, taking into account patients’ needs and motivations, as well as the accessibility and transparency of the clinical trial.

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Review paper

Reumatologia 2026; 64, 4: 338–344 DOI: https://doi.org/10.5114/reum/220000

MicroRNAs in osteoporosis: current evidence and clinical perspectives Marta Świecka ID , Michał Chmielewski ID Department of Rheumatology, Clinical Immunology, Geriatrics and Internal Medicine, University Clinical Centre, Medical University of Gdansk, Poland

Abstract Osteoporosis, a widespread skeletal disorder, is defined by low bone mineral density and elevated fracture risk. Although dual-energy X-ray absorptiometry is the diagnostic standard, its limitations drive the search for novel biomarkers. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression at the post-transcriptional level, play important roles in bone remodelling and the pathogenesis of osteoporosis. They influence cell differentiation, proliferation, and apoptosis, and their dysregulation contributes to bone metabolism disorders. MiR-133a promotes osteoclastogenesis and inhibits osteogenesis, while miR-214-3p suppresses osteogenesis by targeting factors such as osterix. MiR-125b is upregulated in osteoporosis, negatively affecting osteogenic markers, and miR-21-5p shows complex, context-dependent effects on bone cells. Emerging candidates include miR-483-5p, miR-497-5p, and miR-422. These molecules provide insight into osteoporosis mechanisms and hold potential as diagnostic and therapeutic targets. Although miRNA-based therapies are promising, further studies are required to validate the findings and improve delivery strategies. Advances in miRNA research may enable earlier diagnosis and more effective osteoporosis treatment. Key words: microRNA, osteoporosis, bone metabolism, potential clinical utility.

Introduction Osteoporosis represents one of the most prevalent skeletal disorders worldwide, characterized by reduced bone mineral density and disruption of bone microarchi­ tecture. These pathological changes significantly increase the risk of low-trauma, or fragility, fractures, which are associated with considerable morbidity, decreased qua­ lity of life, and elevated mortality rates. Fragility fractures reflect compromised bone strength and may be either clinically silent or manifest with pain and structural deformity [1]. Given its widespread occurrence, osteoporosis represents a significant global public health challenge, with approximately one in 2 women and one in 5 men over the age of 50 projected to experience a fragility fracture during their remaining lifetime [2]. As the disease typically develops silently, fractures are commonly the first indication of its presence. This emphasizes the urgent need for improved insight into its underlying biology to

support earlier diagnosis and more effective treatment strategies [3]. According to the World Health Organization (WHO) criteria established in 1994 and still in use, osteoporosis is defined as a bone mineral density (BMD) value of at least 2.5 standard deviations below the mean peak BMD of young, healthy women, corresponding to a T-score of less than –2.5 [4]. Densitometry (dual-energy X-ray absorptiometry – DXA) remains the gold standard in the diagnosis of osteoporosis, although it undoubtedly has several limitations: it may overestimate bone density in individuals with spinal or hip degenerative changes, and artefacts from osteophytes, prior surgery, or vascular calcifications can distort spine BMD results. Additionally, the technique lacks information about bone microarchitecture [5]. In addition to DXA, bone turnover markers, including procollagen type I N-propeptide (PINP), bone-specific alkaline phosphatase (BALP), β-isomerized C-terminal telopeptide of type I collagen (β-CTX-I), and tartrateresistant acid phosphatase 5b (TRACP5b), constitute

Address for correspondence Marta Świecka, Department of Rheumatology, Clinical Immunology, Geriatrics and Internal Medicine, Medical University of Gdansk, 3a M. Skłodowskiej-Curie St., 80-210 Gdansk, Poland, e-mail: marta.swiecka@gumed.edu.pl Submitted: 25.09.2025; Accepted: 25.03.2026; Published online: 10.07.2026.

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MicroRNAs in osteoporosis: current evidence and clinical perspectives

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Fig. 1. Structure of a precursor microRNA (pre-miRNA) which undergoes maturation to generate a function­ al miRNA that interacts with mRNA. Created with biorender.com. an additional group of biomarkers relevant to osteoporosis assessment [6]. Serum PINP and plasma β-CTX-I are commonly used reference markers for monitoring response to anti-osteoporotic therapy, while BALP and TRACP5b may be particularly useful in patients with chronic kidney disease due to their limited dependence on renal function. Despite this, it is worth remembering that bone turnover markers are characterised by high biological and analytical variability and may fluctuate, for example, due to recent food intake. Owing to the limitations of the currently used me­ thods, there is a pressing need for reliable and widely accessible biomarkers for the early detection and monitoring of this condition. Since osteoporosis results from dysregulated bone remodelling, characterized by bone resorption exceeding bone formation, recent research has increasingly focused on the role of microRNAs (miRNAs) in modulating this imbalance [3]. Currently, miRNAs are being investigated for use in both the diagnosis and treatment of osteo­porosis. Additionally, there is an attempt to commercialise the solutions developed so far.

MicroRNA characterisation MicroRNAs constitute a class of endogenous, small non-coding RNA molecules typically comprising 20–24 nucleotides that play a pivotal role in post-transcriptional gene regulation [7–9]. The schematic structure of a pre-miRNA that undergoes maturation to generate a functional miRNA that interacts with messenger RNA (mRNA) is presented in Figure 1. The human genome encodes approximately 2,000 miRNAs [10]. It is estimated that microRNAs may regulate up to 60% of human protein-coding genes. Their mechanism of action involves binding to the 3´ untranslated regions (3´UTR) of target mRNAs, leading to transcript degradation or suppression of translation [3, 11]. The regulatory network of miRNAs is highly intricate, as individual miRNAs can influence multiple gene targets, and conversely, a single mRNA

can be modulated by several different miRNAs. They act primarily by inhibiting translation or promoting the degradation of target mRNAs. Dysregulated miRNAs can lead to changes in gene expression that impact many aspects of health and contribute to a variety of human diseases. Due to their remarkable stability in biological fluids and being measurable using well-established quantification methods, circulating miRNAs have gained significant attention as non-invasive biomarkers for disease diagnosis and prognosis. Aberrations in miRNA expression are increasingly implicated in the pathogenesis of a wide range of human disorders, such as cancer, metabolic diseases, and musculoskeletal conditions including osteoporosis [3]. Moreover, miRNA-based therapeutic strategies represent a promising frontier in translational medicine. Since their initial discovery, an expanding range of miRNAs has been identified, accompanied by rapid advances in elucidating their functional roles and potential clinical applications. Accumulating evidence also suggests that epigenetic mechanisms play a significant role in the pathogenesis of osteoporosis. The influence of miRNA in the pathomechanism of osteoporosis is presented in Figure 2.

The role of microRNAs in osteoclastogenesis and bone resorption Interest in the role of miRNAs in osteoporosis has been steadily increasing for over a decade. Aberrant miRNA dysregulation

Altered signalling pathways

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Osteoporosis

Fig. 2. Role of miRNAs in the pathomechanism of osteoporosis.

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expression of specific osteoclast-associated miRNAs has been implicated in the pathogenesis of osteoporosis through the promotion of excessive bone resorption. Some of the earliest studies published in this field investigated the function of miR-133a in osteoclastoge­ nesis [12]. The objective of one of the first studies, conducted by Wang et al. [12], was to identify key miRNAs in circulating human monocytes that are linked to differing bone mineral density (BMD) profiles among postmenopausal Caucasian women. Notably, both microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses revealed a significant elevation of miR-133a expression in individuals with low BMD. Subsequent authors have confirmed the role of miR-133a in osteoclastogenesis [13, 14]. It was demonstrated that miR-133a was overexpressed in postmenopausal women with low bone mineral density. Efforts were also made to elucidate the mechanism of action of miR-133a in the context of osteoporosis. Research by Wang et al. [15, 16] demonstrated that miR-133a overexpression inhibited the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). In contrast, silencing miR-133a exerted beneficial effects on mesenchymal stem cells exposed to glucocorticoids and mitigated bone loss in animal models of glucocorticoid-induced osteoporosis. These effects were mediated via the mitogen-activated protein kinases/ extracellular signal-regulated kinase (MAPK/ERK) signalling pathway through the targeting of fibroblast growth factor receptor 1. Similarly, Li et al. [14] reported that suppression of miR-133a influenced serum levels of osteoclastogenesis-related markers, enhanced lumbar spine bone mineral density, and improved bone histomorphometry in ovariectomized rats. On the other hand, Zhou et al. [17] proposed that miR-133a expression in osteoblasts helped to preserve bone structure and mechanical strength in mice subjected to mechanical unloading, thus reducing bone loss. Despite some differences in experimental approaches, the regulatory direction of miR-133a across these studies was generally consistent, indicating its potential as a biomarker for osteoporosis diagnosis. Another miRNA molecule associated both with promoting osteoclastogenesis and inhibiting osteogenesis is miR-214-3p. Consistent findings have indicated that miR-214-3p is upregulated in individuals with osteoporosis [18–21]. It exerts multifactorial and complex regulatory effects. MiR-214-3p has been reported to suppress osteogenic differentiation through multiple mechanisms of action, one of which involves the inhibition of osterix, which is required for the differentiation of preosteoblasts into functional osteoblasts [22]. The study conducted by Mohamad et al. [18] explored the potential involvement of osterix and miR-214 in primary osteoporosis by ana-

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lysing their expression levels in bone samples obtained from individuals with and without osteoporosis, and by examining their relationships with each other as well as with clinical and laboratory parameters. The findings revealed that patients with osteoporosis undergoing joint replacement surgery exhibited significantly elevated levels of miR-214 compared to non-osteoporotic individuals. Consequently, osterix expression showed an inverse pattern, with markedly lower levels observed in osteoporotic patients [18]. Also, in the research performed by Shi et al. [20] miR-214-3p expression was inversely correlated with osterix expression. This is not the only mechanism of action of miR-214-3p, which has also been shown to inhibit osteogenic differentiation through the suppression of key regulatory factors such as ATF4 (a gene encoding one of the main transcription factors required for osteoblast function), and fibroblast growth factor receptor 1 [23–25]. Among the numerous mechanisms by which miRNA-214-3p influences bone metabolism, one notable pathway involves the promotion of osteoclastogenesis through targeting phosphatase and tensin homolog (PTEN), which results in promoting osteoclastogenesis [23].

MicroRNA-mediated regulation of osteogenesis An additional miRNA implicated in the regulation of bone metabolism is miR-125b. The expression level of miR-125b has been reported to be upregulated in patients with osteoporosis, and it is considered to be responsible for the development of postmenopausal osteo­porosis. Among the miRNAs expressed in osteoblasts, miR-125b has been identified as being selectively incorporated into matrix vesicles and deposited into the bone matrix. During bone resorption, it is subsequently released into the bone marrow microenvironment, where it contributes to the suppression of osteoclastogenesis. This regulatory effect is mediated through the inhibition of PR domain zinc finger protein 1 (PRDM1) expression – a transcriptional repressor that negatively modulates factors involved in the inhibition of osteoclast formation [26]. Further analysis demonstrated that miR-125b nega­ tively regulates the expression of osteogenic marker genes throughout this differentiation process, indicating that its downregulation is essential for promoting osteogenesis [27]. Bioinformatic predictions identified bone morphogenetic protein receptor type 1B (BMPR1b) as a potential target of miR-125b. This interaction was confirmed through a dual-luciferase reporter assay, which revealed that miR-125b directly binds to the 3´-untranslated region (3´UTR) of the BMPR1b mRNA. Silencing

MicroRNAs in osteoporosis: current evidence and clinical perspectives

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BMPR1b significantly impaired the osteogenic differentiation capacity of human BMSCs. Studies investigating the clinical context of miR-125b regulatory mechanisms conducted in postmenopausal women have demonstrated significant upregulation of miR-125b expression in both blood and bone tissue of individuals diagnosed with osteoporosis [28, 29]. Interestingly, the results of one study are not consistent with those of the others [30]. The research conducted by Chen et al. [30] revealed decreased expression of miR-125b-5p in the osteoporosis group, suggesting downregulation rather than upregulation. This discrepancy in the results may be attributed to differences in patient characteristics, as the osteoporotic individuals in that study had not experienced recent fractures within the preceding two months. It is possible that circulating miRNA profiles vary between osteoporotic patients with fractures, those without fractures, and non-osteoporotic controls.

Table I. Dysregulated miRNAs implicated in the patho­ physiology of osteoporosis

Complex regulatory role of miR-21-5p in osteoporosis pathophysiology Despite being one of the most thoroughly investigated microRNAs, the functional contribution of miR-21-5p to osteoporosis pathogenesis appears to be complex and not yet fully defined. The aberrant regulation of miR-21-5p in osteoporosis has emerged as a focal point of recent scientific inquiry [31]. The regulatory pattern of miR-21-5p in osteoporosis appears to be conflicting – while some studies have reported elevated expression [32–35], others have observed downregulation [13, 35]. Such variability may reflect the multifaceted role of miR-21-5p in modulating both bone formation and resorption processes through diverse signalling mechanisms, i.e. by influencing both osteoblast and osteoclast differentiation through various molecular pathways. It has been shown to promote osteogenesis, yet its role in osteoclastogenesis remains complex and partly contradictory. Some studies demonstrate that miR-21-5p enhances osteoclast formation, while others suggest that it suppresses osteoclast differentiation. Despite these inconsistencies, it is clear that miR-21-5b plays a role in bone metabolism. As of now, its use as a diagnostic biomarker is limited, and further research is needed to elucidate the reason behind the discrepancies between the studies.

Additional microRNAs with potential as osteoporosis biomarkers The miRNAs described above are not the only ones investigated in the context of osteoporosis; however, they exemplify the current direction of research in this field. Additional studies have also examined the potential

Upregulated

Downregulated

miR-125b-5b

miR-497-5p

miR-483-5p miR-133a miR-422a miR-214-3p

roles of miR-483-5p [36, 37], miR-497-5p [38, 39], and miR-422 [40] in the pathogenesis and progression of this condition. Interestingly, only one microRNA molecule, miR-497-5p, has been found to be downregulated, distinguishing it from the majority of miRNAs investigated in the context of osteoporosis. The most relevant miRNAs involved in the pathophysiology of osteoporosis are summarized in Table I.

Advances in microRNA-based therapies for bone regeneration In parallel with research on the potential use of miRNAs in the diagnosis of osteoporosis, efforts have also begun to explore their therapeutic applications in the treatment of this disease. In general, two principal strategies are employed in miRNA-based therapies, depending on the nature of miRNA dysregulation [41]. miRNA replacement therapy is used when a pro-osteogenic miRNA is downregulated. In this case, synthetic miRNA mimics are introduced to restore physiological function by targeting the same mRNAs as endogenous miRNAs, potentially enhancing osteoblast activity – for instance, using miR-29b mimics to stimulate bone formation [42]. Conversely, miRNA inhibition is applied when a deleterious miRNA, such as a pro-resorptive or anti-osteogenic one, is pathologically overexpressed. Synthetic antisense oligonucleotides (e.g., antagomiRs – synthetic, chemically modified single-stranded RNA molecules designed to specifically inhibit the activity of a miRNA) bind to and neutralize these miRNAs, preventing their interaction with target transcripts. An example is the inhibition of miR-214 to promote osteogenesis. Although miRNA-based therapies hold substantial promise, their clinical application remains limited by challenges in efficient in vivo delivery [43]. Naked RNA molecules are unstable in circulation due to nuclease degradation and are poorly internalized by cells because of their size and negative charge. Therefore, creating effective delivery systems is key for using miRNAs as therapies. Researchers are exploring both viral carriers, such as adeno-associated viruses, and non-viral alternatives [41]. While viral vectors offer high transduction efficiency and sustained expres-

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sion, their use is restricted by immunogenicity and safety concerns. Non-viral systems –including lipid nanoparticles, polymer-based carriers, and exosome-based delivery – offer safer alternatives with potential for clinical translation. In research conducted so far to overcome the limitations of current well-established osteoporosis therapies, a gene therapy approach was developed that targets two key miRNAs – miR-214-3p and miR-34a-5p – simultaneously promoting osteogenesis while suppressing osteo­ clastogenesis [44]. This strategy employed bone-targeting recombinant adeno-associated viral (rAAV) vectors to systemically deliver gene modulators directly to ske­letal tissue. In murine models, overexpression of miR-214-3p or suppression of miR-34a-5p induced osteo­porotic-like bone loss, while inhibition of miR-214-3p or upregulation of miR-34a-5p reversed bone degradation in both postmenopausal and senile osteoporosis. These effects were achieved by increasing osteoblast activity and reducing osteoclast function. Importantly, the the­rapeutic intervention did not elicit pathological changes in non-skeletal tissues.

Translation into clinical testing Unlike intracellular RNA molecules, extracellular miRNAs display remarkable stability – they withstand RNase activity and remain intact even under extreme conditions such as boiling, repeated freeze–thaw cycles, and highly alkaline (pH 13) or acidic (pH 1) environments [45, 46]. However, there are a few technical challenges related to the methods used for analysing circulating miRNAs: miRNA concentration in plasma/serum is significantly lower than in cells or tissues; miRNA composition in biofluids can depend on sample collection procedures; and the presence of enzyme inhibitors or contaminating cells can influence miRNA data. That is why assays must be validated for their capability to detect and quantify extracellular miRNAs, and preanalytical procedures should be performed correctly [46]. Although the issue may appear complex, the first systems enabling population-level assessment of miRNA expression in the context of osteoporosis are already available [47].

Conclusions and future perspectives Osteoporosis still poses persistent challenges in both diagnosis and treatment, and there is a need to identify novel disease biomarkers and to develop innovative therapeutic approaches. Current research suggests that miRNAs contribute to the regulation of bone metabolism. Nevertheless, evidence supporting their practical use in osteoporosis management remains limited. Their relevance for diagnostic purposes, deter-

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mination of treatment thresholds, and therapeutic application has yet to be firmly established. That is why the field of miRNA research in osteoporosis is currently at a critical point. Substantial progress has been made in elucidating the biological functions of miRNAs, and their potential clinical utility is increasingly recognized. It seems that current research should focus primarily on: • elucidating the roles of other miRNA molecules in the pathogenesis of osteoporosis, • validating previous findings on the role of already discovered miRNAs, • further work on glucocorticoid-induced osteoporosis and osteoporosis in inflammatory arthritis, • commercialisation of novel miRNA-based diagnostic tools, • evaluating the potential use of viral vectors as delivery systems for therapeutic miRNA. Nonetheless, the translation of these molecular insights into clinical applications will remain limited unless the research focus shifts from discovery toward validation and standardization. The next major advancement in this domain is likely to be the establishment of methodological frameworks enabling the definitive validation of already-identified, high-potential candidates. Such progress will require coordinated, multidisciplinary collaboration and adherence to reproducible methods. Only through collaborative work on the complex functions of miRNAs can the research advances be translated into real-world diagnostic and therapeutic solutions for affected patients. The use of miRNAs offers promising potential for a deeper understanding of the pathophysiology of osteo­ porosis, which may, in turn, enable earlier detection and more effective therapeutic interventions.

Disclosures Conflict of interest: The authors declare no conflict of in­ terest. Funding: No external funding. Ethics approval: Not applicable. Data availability: Not applicable. References 1. Khan AA, Slart RHJA, Ali DS, et al.; International Working Group on DXA Best Practices. Osteoporotic Fractures: Diagno­ sis, Evaluation, and Significance From the International Work­ ing Group on DXA Best Practices. Mayo Clin Proc 2024; 99: 1127–1141, DOI: 10.1016/j.mayocp.2024.01.011. 2. Clynes MA, Harvey NC, Curtis EM, et al. The epidemiology of osteoporosis. Br Med Bull 2020; 133: 105–117, DOI: 10.1093/ bmb/ldaa005. 3. Trojniak J, Sendera A, Banaś-Ząbczyk A, Kopańska M. The Micro­ RNAs in the Pathophysiology of Osteoporosis. Int J Mol Sci 2024; 25: 6240, DOI: 10.3390/ijms25116240.

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Case-based review

Reumatologia 2026; 64, 4: 345–351 DOI: https://doi.org/10.5114/reum/221079

Tjalma syndrome in late-onset systemic lupus erythematosus Ivan Jeremic1 ID , Bojana Simeunovic1, Slavica Pavlov Dolijanovic2 ID 1

Institute of Rheumatology, Belgrade, Serbia Institute of Rheumatology, Belgrade, Medical Faculty, University of Belgrade, Serbia

2

Abstract Tjalma syndrome, also named pseudo-pseudo Meigs syndrome, is a rare complication of serositis in patients with systemic lupus erythematosus (SLE). It is associated with a high level of the ovarian tumor marker CA-125 and pleural effusion and ascites, which can suggest an ovarian tumor (benign or malignant), in patients with SLE. Available literature data include case reports of female patients with SLE ranging in age from 14 to 82. Patients under 50 years of age predominate. Our own experience led us to analyze the observations in this review against the background of our experience with a female patient with lateonset SLE. This review discusses why exploration of paraneoplastic syndrome can delay immunosuppressive therapy for this serious SLE manifestation. The main goal of this case-based review is to compare the clinical and laboratory findings of our patient with those reported in the literature and to raise awareness of this rare entity. Key words: systemic lupus erythematosus, pseudo-pseudo Meigs’ syndrome, Tjalma syndrome.

Introduction Systemic lupus erythematosus (SLE) is a chronic auto­immune and inflammatory disease with multiple organ manifestations. Serous membranes are affected in about 10–50% of SLE patients, mostly pleura and pericardium [1]. In SLE patients, risk factors for serositis are defined as male sex, level of anti-double stranded-DNA (anti-ds-DNA) antibody, febrility, active SLE, D-dimer, low complement, elevated sedimentation rate, lupus nephritis, interstitial lung disease, pulmonary arterial hypertension, and cytopenias [1–3]. Serositis association with anti-Smith protein (anti-Sm), anti-ribonucleoprotein (anti-Rnp) and antiphospholipid autoantibodies (APL) is documented [4]. Systemic lupus erythematosus in patients older than 50–65 years or elderly onset (EO) SLE is regarded by some authors as a different disease phenotype with higher serositis prevalence [5–7]. One EO cohort suggests a more indolent course of SLE but a high burden of comorbidities in such patients [4]. Peritoneum is rarely inflamed, and very few patients with SLE have peritonitis complicated with ascites. Serum tumor marker CA-125 may be independently associated with serositis [6, 8]. When SLE serositis and pleural, peri-

cardial, or peritoneal effusions are associated with false positive ovarian tumor markers (TM) and with no underlying malignancy, this condition is referred to as pseudo-pseudo-Meigs’ syndrome (PPM) or Tjalma syndrome (TS) after the physician who first described it in 2006 [9]. The therapeutic approach to TS is not standardized. Usually induction therapy consists of short duration methylprednisolone pulse therapy and a glucocorticosteroid (GC) tapering scheme. Remission maintenance is with various immunosuppressants including rituximab [10].

Material and methods A literature review was performed to identify previously reported cases and studies related to TS. Articles published between 2008 and 2025 were searched using several electronic databases, including PubMed/ MEDLINE, Web of Science, and Google Scholar. Additional relevant articles were identified through reference lists of selected publications. The search was conducted using combinations of the following key words: “Tjalma syndrome”, “pseudo-pseudo Meigs syndrome”, “systemic lupus erythematosus”, “ascites”, and “pleural effusions.” Boolean operators (AND/OR) were used to refine

Address for correspondence Ivan Jeremic, Institute of Rheumatology, 69 Resavska, 11000 Belgrade, Serbia, e-mail: ivanjeremic@rocketmail.com Submitted: 17.07.2025; Accepted: 24.04.2026; Published online: 10.07.2026

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

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Ivan Jeremic, Bojana Simeunovic, Slavica Pavlov Dolijanovic

the search. Articles were included if they: reported cases or case series describing TS or PPM syndrome; were published between 2008 and 2025; were available in English and contained sufficient clinical information for analysis. Articles were excluded if they: were duplicate reports; did not describe clinical cases of TS; or lacked relevant clinical data. Data extracted from the selected articles included year of publication, patient demographics, clinical presentation, associated conditions, treatment modalities, and outcomes. The findings from identified studies were summarized and presented in a tabular format. The procedures followed in this study were in accordance with the ethical standards of the Helsinki Declaration of 1964, as revised in 2013. The patient has provided written informed consent for publication of the case details.

Case description The 67-year-old female patient with a 5-year history of SLE was admitted to the hospital in September 2024, because of large, slowly growing ascites. Systemic lupus erythematosus started in 2019. and was diagnosed based on constitutional symptoms, bilateral pleural, pericardial and peritoneal effusions, antinuclear antibodies positivity, typical skin changes, myalgias and cyto­penias (the patient fulfilled 2019 Alliance of Associations for Rheumatology [EULAR]/American College of Rheumato­ logy [ACR] criteria for SLE: ANA positivity as the entry criterion and a total score of 17 points across the constitutional, hematolo­gical, mucocutaneous, and serosal domains. The patient was treated with GCs and antimalarials from the onset of her disease. On admis­sion, her comorbidities, important for present ascites etiolo-

gy, were all well controlled: cardiomyopathy, diabetes with chronic renal disease, and hypothyroidism. Physical findings revealed: systo­lic heart murmur, iatrogenic Cushing’s syndrome (typi­cal obesity distribution and parchment-like skin) and lower legs’ chronic venous dermatitis. Laboratory findings showed: C-reactive protein (CRP) 14.3, mild pancytopenia, and stable chronic renal disease parameters. The last SLE flare was in October 2023, when abdominal and pelvic ultrasound detected perihepatic, perisplenic, bilateral paracolic, and pelvic ascites treated with GCs and diuretics. Transthoracic echocardiography was urgently performed and excluded visible endocarditis and decompensated cardiomyopathy. Elevated mean right atrial pressure of 35 mmHg was detected, similar to the echocardiography finding from October 2023. The patient received prednisone (20 mg once daily) and continued hydroxychloroquine (HCQ; 200 mg once daily). Ascites was treated with larger doses of furosemide, two therapeutic paracenteses with 8 liters of fluid eva­cuated, and parenteral anti­ biotics. The patient had significantly high ovarian tumor markers levels in serum and ascites (CA-125, HE4 and Roma index) (Tables I and II). Multidetector computed tomography (MDCT) of the abdomen and pelvis was significant for large ascites, along with signs of possible Budd-Chiari syndrome, and excluded malignancy. The patient was started on 2 × 0.4 ml subcutaneous fraxiparine but developed significant thrombocytopenia the next day. Low molecular weight heparin was stopped, and apixaban 2.5 mg twice daily was introduced. Weak positive anti-­HIT antibodies were detected. During hospitalization the patient developed COVID-19 infection with no signs of pneumonia, but with worsen-

Table I. Immunological markers Marker

Value

Reference range

Interpretation

ANA

Speckled/nucleolus 1 : 80

Negative

Low-titer positive

Anti-ds-DNA

1.7

< 20 IU/ml

Negative

Anti-Sm

0.2

< 15 IU/ml

Negative

C3

1.09

0.9–1.8 g/l

Normal

C4

0.21

0.1–0.4 g/l

Normal

ACLA IgG/IgM

1.5/0.4

< 10/< 7 IU/ml

Negative

Anti‑β2GPI IgG/IgM

1.9/0.4

< 5/< 5 IU/ml

Negative

RF

3

< 30 U/ml

Negative

ACPA

4.5

< 20 IU/ml

Negative

AMA, ASMA, APA

Negative

Negative

Negative

Scleroderma ABs profile

Negative

Negative

Negative

AB – antibodies, ACLA – anticardiolipin antibodies, ACPA – anti-citrullinated peptide antibodies, AMA – anti-mitochondrial antibodies, ANA – antinuclear antibodies, anti‑β2GPI – anti-β2-glycoprotein I antibodies, APA – antiparietal antibodies, ASMA – anti-smooth muscle antibodies, C3 and C4 – complement components, RF – rheumatoid factor.

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Tjalma syndrome in late-onset systemic lupus erythematosus

Table II. Longitudinal serum, urine, and ascites laboratory values monitoring (selected abnormal values are bolded) Laboratory parameter

05.09.2024

13–14.09.2024

20.09.2024 24–27.09.2024

06.10.2024

10–12.10.2024

14.10.2024

18.10.2024

CRP [mg/l]

14.3

0.8

–

0.0

6.2

24.7

41.2

6.1

WBC [× 109/l]

3.37

4.12

4.2

4.54

3.0

4.15

5.77

2.65

LYMPH [× 109/l] 0.64

1.03

0.55

0.65

0.6

0.47

0.28

0.36

Hgb [g/l]

101

107

105

105

103

100

91

91

PLT [× 10 /l]

156

163

131

96

112

101

95

126

BUN [mmol/l]

13.8

17.1

18.73

24.36

26.3

24.97

29.35

23.79

Cre [mg/l]

154

164

171

152

167

157

173

125

Alb [g/l]

42

49

53

52

–

45

43

45

GGT [U/l]

136

165

183

172

145

159

144

141

PCT [mg/l]

–

0.07

–

0.11

–

2.56

1.11

–

–

–

1.74

–

13.21

15.79

–

9

D-dimer [mg/l] 1.39 BNP [pg/ml]

2,930

2,544

–

5,194

–

6,908

–

–

TnT [ng/l]

3.6 (I)

51 (T)

–

53 (T)

–

79 (T)

–

–

Additional laboratory parameter

Serum CA-125 466 U/ml Proteinuria 0.160 g/24 h

Proteinuria 0.170 g/24 h Quantiferon negative Serum: CA-125 511 U/ml HE4 369 pmol/l ROMA index 93.23

–

Anti-Xa 2.00 INR 1.43 Anti-HIT Abs SARS-COV-2 + weak positive Ascites: WBC 0.12 PMN 0.03 Noninflammatory Glc 5.1 mmol/l Prot 43.6 g/l LDH 198 U/l AARB neg

Hapt 15 DAT neg Anti-Xa 2.00

FOBT+ FOBT–

C-reactive protein: < 5 mg/l, leukocyte absolute count: 3.4–9.7 × 109/l, CA-125 – up to 35 U/ml, lymphocyte absolute count: 1.2–3.4 × 109/l, hemoglobin ref.: 119–157 g/l, platelets ref.: 158–424 × 109/l, urea: 2.8–7.2 mmol/l, creatinine 58–96 μmol/l, albumin ref.: 35–53 g/l, γ-glutamyl transferase ref.: 9–39 U/l, , human epididymis protein 4 – before menopause ≤ 73 pmol/l, after menopause ≤ 93 pmol/l, procalcitonin ref.: > 2.0 ng/l high risk of systemic infection. AARB – acid-alcohol resistant Bacilli, Alb – albumin, BNP – blood natriuretic peptide, BUN – blood urea nitrogen, CA – 125-cancer antigen, Cre – creatinine, CRP – C-reactive protein, DAT – Coombs test, FOBT – fecal occult blood test, Glc – glucose, GGT – γ-glutamyl- transferase, Hapt – hapto­globin, HE4 – human epididymis protein 4, Hgb – hemoglobin, LDH – lactate dehydrogenase, LYMPH – lymphocytes, PCT – procalcitonin, PTL – platelets, TnT – troponin, WBC – white blood cells.

Fig. 1. Patient with large ascites at the beginning of treatment.

Fig. 2. Multidetector computed tomography de­ layed phase – large ascites surrounding abdom­ inal organs.

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Fig. 3. Multidetector computed tomography de­ layed phase – large ascites surrounding pelvic organs. ing pancytopenia. Multidetector computed tomography and magnetic resonance imaging excluded thrombotic hepatic disease, and no tumor was found. The patient received three consecutive days (250 mg daily) of methylprednisolone pulse therapy followed by prednisone 20 mg twice daily (with tapering scheme), HCQ 200 mg once daily, and azathioprine 50 mg once daily with cautious dose escalation due to cytopenias.

Discussion Systemic lupus erythematosus is an autoimmune inflammatory disease that predominantly affects women during the reproductive period of life. A late-onset phenotype also exists and represents a diagnostic and the­ rapeutic challenge due to its clinical presentation and the presence of comorbidities in elderly patients. Inflammation of the epithelium lining the serous cavities is considered a severe manifestation of the disease and requires careful differential diagnosis as well as aggressive anti-inflammatory treatment. The differential diagnosis of pericardial, pleural, and/ or peritoneal effusions in elderly patients burdened with cardiovascular and other comorbidities includes heart failure, hypothyroidism, liver insufficiency, infections such as tuberculosis, and paraneoplastic manifestations. Determination of tumor marker levels in the pre­ sence of serositis may yield false-positive results; therefore, ovarian tumor markers such as CA‑125 and HE4 may also be elevated in male patients with serositis. Serositis in lupus is considered a severe systemic manifestation that requires intensive anti-inflammatory treatment with pulse doses of GCs and appropriate maintenance therapy. However, in elderly patients such therapy may worsen the overall internal clinical status. When a paraneoplastic syndrome or malignant disease is suspected, necessary intensive treatment may be delayed due to concerns about possible deterioration of

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Ivan Jeremic, Bojana Simeunovic, Slavica Pavlov Dolijanovic

Fig. 4. Multidetector computed tomography de­ layed phase – large ascites surrounding organs. the underlying condition or progression of the primary disease. In our patient, we firstly ruled out primary and meta­ static malignant disease of the ovaries by the gynecologist’s directed diagnostic imaging: ultrasound and MDCT. After effusion puncture, no malignant cells were detected. We did not use positron emission tomography scan because of the high probability of indeterminate results. All reported cases included in this article describe female patients [11–31]. Our patient had LO SLE diagnosed in 2019 with serositis as the first disease mani­ festation. Due to her comorbidities, namely chronic non-lupus-related renal disease and cardiomyopathy, the patient was thoroughly monitored by a nephrologist and cardiologist, and effusions were not associated with these systemic causes. In the past, patient’s SLE serositis flares responded well to GC therapy, but no adequate GC-sparing immunosuppressive was introduced, except for immunomodulatory antimalarial. Patient’s serositis episodes were not associated with worsening of SLE immunological markers: anti-ds-DNA levels and complement levels were normal. No concomitant or overlap autoimmune disease was diagnosed, as scleroderma and myositis antibodies profiles were normal and mixed connective tissue disease was excluded. Age of onset of TS in case reports and case series from Table III ranges from 14 years old to 82 years old, but most patients are younger than 50 years old [11–31]. Most patients have TS as an initial SLE manifestation of rheumatic disease [11–31]. Our patient had SLE for 4 years, before she was diagnosed with ascites. Patient’s latest SLE flare was in October 2023, with slowly growing ascites at first resistant to GCs and diuretics. Other SLE manifestations in our patient are intermittent cyto­ penias. Authors have reported cases with SLE nephritis [12, 13, 26] and arthritis [14, 25], but our patient has no history of either condition. Most authors have reported TS with ascites and unilateral or bilateral pleural

349

Tjalma syndrome in late-onset systemic lupus erythematosus

Table III. Case reports and case series with TS Case

Year

Sex

Age

Disease duration

SCTD

Serositis

Treatment

[11] [12]

2024 2024

F F

27 33

0 ND

Bullous SLE SLE nephritis

MP, HCQ MP, HCQ, MMF

[13]

2024

F

28

0

SLE

F

37

0

Sjögren’s disease SLE nephritis

F

50

10

Sjögren’s disease SLE

Pleural uni Pleural bil Ascites Pleural bil Ascites Pleural bil Ascites Pericardial Pleural bil Ascites Pericardial Pleural bil

[14]

2023

F

32

8

[15]

2023

F

33

ND

SLE Arthritis SLE

[16]

2023

F

74

7

SLE

[17]

2022

F

82

0

SLE

[18]

2022

F

23

0

[19]

2022

F

41

0

SLE Cystitis SLE

[20]

2022

F

48

0

SLE

[21]

2022

F

ND

ND

[22]

2021

F

23

ND

SLE Protein-losing enteropathy SLE

[23]

2019

F

44

0

[24]

2019

F

24

4

[25]

2019

F

44

ND

[26]

2019

F

22

ND

[27]

2019

F

14

ND

SLE Arthritis SLE APS Nephritis ND

[28]

2016

ND

ND

ND

MCTD

[29] [30] [31]

2016 2014 2008

F F F

40 22 38

0 ND 0

SLE SLE SLE

SLE Cytopenias SLE

Pleural bil Ascites Pleural bil Ascites Pleural Ascites Ascites

MP, PRN, MMF, telitacicept MP, PRN, MMF, telitacicept MP, CyP

MP, PRN, HCQ, MTX MP, MMF MP, HCQ, MMF GCS, HCQ PRN, HCQ

Pleural uni Ascites Pleural Ascites ND

ND

Pleural Ascites Pleural

MP, PRN, HCQ, AZA MP, HCQ, LEF

Pleural bil Ascites Pleural bil Ascites Pleural Ascites

MP, MMF

Pleural Ascites Pleural Ascites Ascites Ascites Pleural Ascites

MP, PRN, HCQ, MMF MP, PRN, CYP

MP, PRN, AZA MP, PRN, HCQ

ND ND MP Leiomyoma ND

APS – antiphospholipid syndrome, AZA – azathioprine, CyP – cyclophosphamide, HCQ – hydroxychloroquine, LEF – leflunomide, MP – methylprednisolone, MCTD – mixed connective tissue disease, MMF – mycophenolate mofetil, MTX – methotrexate, ND – no data, Pleural uni – unilateral pleural, Pleural bil – bilateral pleural, PRN – prednisone, SCTD – systemic connective tissue disease.

effusions [11–31]. The most common therapy for remission induction is high-dose intravenous methylprednisolone, following different prednisone regimens and immunosuppressive agent introduction [11–20, 22–26, 29, 30]. Our patient’s SLE-related serositis and both pleural and peritoneal effusions were treated with

methylpredni­solone pulses, then oral prednisone with a tapering scheme and azathioprine as an immunosuppressive. During a few monthly follow-ups, the patient had no significant relapses. Literature analysis and presented case studies are aimed at raising awareness of this rare manifestation

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of SLE, particularly in EO SLE with high suspicion of paraneoplastic syndrome. A thorough diagnostic approach and carefully tailored immunosuppressive therapy are of great importance.

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