Methotrexate Reduces the Probability of Discontinuation of TNF Inhibitors in Seropositive Patients With Rheumatoid Arthritis. A Real-World Data Analysis

Abstract

Tumor necrosis factor inhibitors (TNFi) are widely used for the treatment of patients with rheumatoid arthritis (RA), however a considerable percentage of patients discontinued the therapy. The aim of this study is to explore real-world TNFi survival, stratified for seropositivity, and to determine the factors that may influence it. This is a retrospective, observational and longitudinal study, using real-world data of patients, who started their first TNFi therapy between 1999 and 2018 from the RA-PAZ cohort. Patients were considered seropositive if they showed positive serum levels of either RF, ACPA, or both. Treatment survival was analyzed using Kaplan-Meier curves, and Cox proportional hazards models were used to compare the risks of TNFi discontinuation for seronegative and seropositive patients. Of the included 250 patients, 213 (85%) were seropositive. Results showed that TNFi survival did not depend on seropositivity status. However, median survival time was significant longer for seropositive patients who received concomitant MTX compared to patients who did not receive it (median [95% CI]: 3.3 yr. [2.3–4.2] vs. 2.6 yr. [1.7–3.6], respectively; p = 0.008). Furthermore, seropositive patients who received concomitant MTX were 49% less likely to discontinue TNFi therapy than patients who did not receive it (HR: 0.51; 95% CI: 0.35–0.74). In addition, we found that in seropositive patients, the use of prednisone throughout the TNFi treatment was associated with a higher likelihood of therapy discontinuation (OR: 2.30; 95% CI: 1.01–5.23). In conclusion, these data provide evidence to support the use of concomitant MTX in seropositive patients to prolong the effectiveness and the survival of the TNFi therapy. Moreover, the co-administration of prednisone in seropositive patients receiving TNFi was highly associated with TNFi discontinuation.

Imbalance of Th17, Treg, and helper innate lymphoid cell in the peripheral blood of patients with rheumatoid arthritis

“…ACPA was measured using an anti-cyclic citrullinated peptide assay ELISA kit (Fuchunkexin, Shanghai, China) with an upper limit of normal of 25 IU/mL. ACPA > 25 IU/mL was considered positive (ACPA + ), and ACPA < 25 IU/mL was considered negative (ACPA − ) as previously described [ 15 ]. The C-reactive protein (CRP) and IgM-RF were measured using the Beckman Coulter IMMAGE800 (Beckman Coulter).…”

“…The C-reactive protein (CRP) and IgM-RF were measured using the Beckman Coulter IMMAGE800 (Beckman Coulter). RF > 20 IU/mL was considered positive (RF + ), whereas RF < 20 IU/mL was considered negative (RF − ) [ 15 ].…”

Clinical Phenotypes, Serological Biomarkers, and Synovial Features Defining Seropositive and Seronegative Rheumatoid Arthritis: A Literature Review

“…Differences in the response to treatment between seropositive and seronegative RA are also subject to debate. Methotrexate appears to be less effective in seronegative populations [67,68], but when analysing responses to biologic drugs, studies suggest that responses are similar between seronegative and seropositive RA patients [69,70]. A recent study by Jin et al [71] compared the effectiveness of biological DMARDs and JAK inhibitors between more than 4000 seronegative and more than 7000 seropositive patients.…”

When Autoantibodies Are Missing: The Challenge of Seronegative Rheumatoid Arthritis

“…However, several studies have shown that MTX is less effective in SNRA than in SPRA [94,95]. It has also been shown that MTX is not as effective in improving the retention rate of biologic drugs such as TNF inhibitors (TNFis) in SNRA compared with SPRA [96,97]. Since the enhanced action of biologics from combination therapy with MTX is attributed to the ability of MTX to inhibit the production of anti-drug antibodies (ADAs) by B lymphocytes [98], this evidence supports the hypothesis that adaptive immunity is less involved in SNRA than in SPRA.…”