Background/Purpose: Long-term observational data from national registries in rheumatoid arthritis allow the examination of TNF drug survival rates. Despite a good initial response to a TNF inhibitor, efficacy can wane over time. Secondary failure may result from the formation of antidrug antibodies (ADA). Concomitant immunosuppression with methotrexate increases TNF inhibitor concentrations via the suppression of ADAs, prolonging TNF drug survival [1]. It is plausible that the production of ADA is less robust in elderly adults, as the aging immune system undergoes a gradual process of decline, termed immunosenescence. This may eliminate the need for concomitant immunosuppression with methotrexate. The objective of this study was to evaluate drug survival with TNF monotherapy compared to combination therapy with methotrexate in rheumatoid arthritis older adults (≥75 years).

Methods: Patients from the British Society for Rheumatology Biologics Register (BSRBR-RA), a prospective observational cohort study, who were biologic naïve and commencing their first TNF inhibitors were included in the analysis. The cohort was stratified according to age at registration: < 75 and ≥75 years. Cox proportional hazards were generated to compare the risk of TNF discontinuation between patients prescribed TNF monotherapy compared to TNF-methotrexate combination. Three models were developed evaluating treatment discontinuation; 1) any cause 2) inefficacy and 3) adverse events. Propensity score models were used to address confounding by indication.

Results: The analysis included 15,700 patients, of which 14, 932 (95%) were < 75 years old. Comorbidity burden and RA disease activity were higher in the ≥75 cohort. Fifty two percent of patients discontinued TNF therapy during the follow up period. Persistence with therapy was higher in the < 75 cohort. Patients receiving TNF monotherapy were more likely to discontinue compared to patients receiving concomitant methotrexate [hazard rate (HR) 1.12 (1.06-1.18) p=< 0.001]. This finding only held true in patients in the < 75 cohort. Examining TNF discontinuation by cause revealed patients ≥75 receiving TNF monotherapy were less likely to discontinue TNF due to inefficacy [HR 0.66 (0.43-0.99) p=0.04] and more likely to discontinue therapy from adverse events [HR 1.21 (1.11-1.32) p< 0.001] (figure 1). These results were supported by the propensity score analyses.

Conclusion: TNF monotherapy is associated with an increase in treatment failure. In the older adults the disadvantage of TNF monotherapy on drug survival is no longer seen. Patients over 75 have fewer discontinuations due to inefficacy compared to younger patients. We speculate that this may reflect a decline in immunogenicity associated with immunosenescence. 

1. Kalden JR, Schulze-Koops H. Immunogenicity and loss of response to TNF inhibitors: implications for rheumatoid arthritis treatment. Nature reviews Rheumatology. 2017;13(12):707-718.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/is-background-methotrexate-still-advantageous-in-extending-tnf-drug-survival-in-the-elderly-an-analysis-of-the-british-society-for-rheumatology-biologics-register-rheumatoid-arthritis/