(Vienna, 11 August 2026) Despite remarkable advances in the treatment of rheumatoid arthritis (RA), a substantial proportion of patients continue to experience persistent symptoms despite multiple therapies. These patients are classified as having difficult-to-treat rheumatoid arthritis (D2T RA), a complex condition for which clinical decision-making remains challenging. In a new systematic literature review published in RMD Open, researchers from the Division of Rheumatology at the Medical University of Vienna, together with international collaborators from the STRATA-FIT consortium, provide a comprehensive overview of the available evidence on therapeutic strategies for D2T RA.
The review synthesizes evidence from 131 studies and highlights both promising treatment approaches and major evidence gaps that continue to limit optimal care for this patient population.
Building the evidence for difficult-to-treat RA
The study was led by Golnaz Shams and Paul Studenic at the Division of Rheumatology, Medical University of Vienna, and conducted within the European STRATA-FIT consortium, the first Horizon Europe-funded initiative dedicated to difficult-to-treat RA.
“Patients with difficult-to-treat rheumatoid arthritis represent one of the greatest unmet needs in rheumatology,” explains first author Golnaz Shams. “By systematically reviewing the available evidence, we wanted to identify which treatment strategies are supported by data, and where important knowledge gaps remain.”
“This review provides an essential evidence base for more personalized treatment decisions,” adds senior author Paul Studenic. “At the same time, it clearly shows that we need better-designed studies focusing specifically on patients with difficult-to-treat disease rather than relying on indirect evidence.”
Supporting treatment decisions in complex patients
The review examined three common clinical scenarios encountered in D2T RA:
- Patients whose treatment options are limited by comorbidities or contraindications.
- Patients with persistent active disease with failure of at least two biologic or targeted synthetic therapies.
- Patients with ongoing symptoms and impaired quality of life despite low levels of measurable inflammation.
Across these scenarios, the authors found that disease-modifying antirheumatic drugs (DMARDs) generally remain effective even in complex patient populations, although treatment selection must carefully balance efficacy with individual safety considerations.
Balancing efficacy and safety
Among patients with multiple previous treatment failures, Janus kinase (JAK) inhibitors continued to demonstrate clinical efficacy, even after several biologic therapies had failed. However, the review also confirms the importance of carefully considering cardiovascular and malignancy risks when selecting these therapies.
The authors further identified a striking lack of high-quality evidence for non-pharmacological interventions, despite their potential importance for patients whose symptoms are driven by pain, fatigue, or reduced quality of life rather than active inflammation.
Building the foundation for personalized care
The review forms an important scientific cornerstone of the STRATA-FIT project, which aims to develop personalized treatment strategies for patients with difficult-to-treat RA. The evidence generated will inform the consortium's upcoming prospective interventional studies and contribute to future clinical recommendations.
By identifying both what is known and what remains unknown, the study provides an important roadmap for future research and for improving the care of one of the most challenging patient groups in rheumatology.
Publication: RMD Open
Therapeutic approaches for difficult-to-treat rheumatoid arthritis: a systematic literature review of current evidence
Golnaz Shams, András Miklós Dorgó, Chiara Ripepi, Emma Wettersand, et al.
Senior author: Paul Studenic
https://doi.org/10.1136/rmdopen-2026-006860