What question did this study set out to answer?

The study aims to identify factors associated with difficult-to-treat rheumatoid arthritis (D2T-RA).

February 2, 2026Open Access

Factors Associated with Difficult-to-Treat Rheumatoid Arthritis (D2T-RA): Real-World Evidence from a Single-Center Cross-Sectional Study

Puntos clave

The study aims to identify factors associated with difficult-to-treat rheumatoid arthritis (D2T-RA).
Retrospective evaluation of 344 patients with established rheumatoid arthritis.
Classification into D2T group (164 patients) and NO-D2T group (180 patients) based on EULAR criteria.
Analysis of clinical, laboratory, and therapeutic data including demographics, disease markers, and treatment history.
Female sex, longer disease duration, and higher RF and ACPA titers were significantly associated with D2T-RA.
Glucocorticoid therapy and a greater number of failed advanced therapies were also linked to D2T-RA.
JAK inhibitors, especially Filgotinib and Upadacitinib, were more common in the D2T cohort and associated with clinical stabilization.

Resumen

Background: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Despite the implementation of the treat-to-target (T2T) strategy and the introduction of several classes of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), a considerable proportion of patients continues to exhibit active, refractory disease. In 2021, the European Alliance of Associations for Rheumatology (EULAR) defined this condition as Difficult-to-Treat Rheumatoid Arthritis (D2T-RA). This study aimed to identify clinical, laboratory, and therapeutic factors associated with D2T-RA. Methods: A total of 344 patients with established RA were retrospectively evaluated. Among them, 164 fulfilled the 2021 EULAR criteria for D2T-RA (D2T group), while 180 did not (NO-D2T group). Clinical (age, sex, disease duration, BMI, smoking, comorbidities), laboratory (RF, ACPA, ESR, CRP), clinimetric (DAS28, CDAI, PhGA, PGA, HAQ), and therapeutic data (glucocorticoid use, methotrexate treatment and dose, monotherapy, advanced therapy exposure, number of failed advanced therapies, current DMARD regimen) were analyzed. Results: Factors significantly associated with D2T-RA included female sex, longer disease duration, higher RF and ACPA titers, elevated ESR levels, glucocorticoid therapy, and a greater number of failed advanced therapies. Although both groups achieved low disease activity or remission by DAS28 and CDAI, JAK inhibitors—particularly Filgotinib and Upadacitinib—were significantly more common in the D2T cohort and appeared associated with clinical stabilization. Conclusions: This study strengthens the understanding of the predictive profile of D2T-RA, confirming the role of disease chronicity and persistent inflammation in the development of treatment resistance. Importantly, the observed trend toward clinical stabilization achieved under JAK inhibitor therapy reinforces their potential to address unmet therapeutic needs in D2T-RA, providing a mechanistically grounded strategy for patients refractory to conventional and biologic DMARDs.

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