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Therapeutic options for patients with rare rheumatic diseases: a systematic review and meta-analysis


Orphanet J Rare Dis. 2020 Oct 31;15(1):308. doi: 10.1186/s13023-020-01576-5.

Tim T A Bender 1Judith Leyens 2Julia Sellin 1Dmitrij Kravchenko 3Rupert Conrad 4Martin Mücke 5Matthias F Seidel 6

Author Information

1 Center for Rare Diseases Bonn, University Hospital of Bonn, Bonn, Germany.

2 Children's University Hospital of Bonn, Bonn, Germany.

3 Radiological Department, University Hospital of Bonn, Bonn, Germany.

4 Department of Psychosomatic Medicine and Psychotherapy, University Hospital Bonn, Bonn, Germany. rupert.conrad@ukbonn.de.

5 Center for Rare Diseases Bonn, University Hospital of Bonn, Bonn, Germany. martin.muecke@ukbonn.de.

6 Department of Rheumatology, Hospital Centre Biel-Bienne, Biel, Switzerland. matthias.seidel@szb-chb.ch.


Background: Rare diseases (RDs) in rheumatology as a group have a high prevalence, but randomized controlled trials are hampered by their heterogeneity and low individual prevalence. To survey the current evidence of pharmacotherapies for rare rheumatic diseases, we conducted a systematic review and meta-analysis. Randomized controlled trials (RCTs) of RDs in rheumatology for different pharmaco-interventions were included into this meta-analysis if there were two or more trials investigating the same RD and using the same assessment tools or outcome parameters. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PUBMED were searched up to April 2nd 2020. The overall objective of this study was to identify RCTs of RDs in rheumatology, evaluate the overall quality of these studies, outline the evidence of pharmacotherapy, and summarize recommended therapeutic regimens.

Results: We screened 187 publications, and 50 RCTs met our inclusion criteria. In total, we analyzed data of 13 different RDs. We identified several sources of potential bias, such as a lack of description of blinding methods and allocation concealment, as well as small size of the study population. Meta-analysis was possible for 26 studies covering six RDs: Hunter disease, Behçet's disease, giant cell arteritis, ANCA-associated vasculitis, reactive arthritis, and systemic sclerosis. The pharmacotherapies tested in these studies consisted of immunosuppressants, such as corticosteroids, methotrexate and azathioprine, or biologicals. We found solid evidence for idursulfase as a treatment for Hunter syndrome. In Behçet's disease, apremilast and IF-α showed promising results with regard to total and partial remission, and Tocilizumab with regard to relapse-free remission in giant cell arteritis. Rituximab, cyclophosphamide, and azathioprine were equally effective in ANCA-associated vasculitis, while mepolizumab improved the efficacy of glucocorticoids. The combination of rifampicin and azithromycin showed promising results in reactive arthritis, while there was no convincing evidence for the efficacy of pharmacotherapy in systemic sclerosis.

Conclusion: For some diseases such as systemic sclerosis, ANCA-associated vasculitis, or Behcet's disease, higher quality trials were available. These RCTs showed satisfactory efficacies for immunosuppressants or biological drugs, except for systemic sclerosis. More high quality RCTs are urgently warranted for a wide spectrum of RDs in rheumatology.