Is Background Methotrexate Advantageous in Extending TNF Inhibitor Drug Survival in Elderly Patients with Rheumatoid Arthritis?

Objective: To evaluate drug survival with monotherapy compared to combination therapy with methotrexate in rheumatoid arthritis older adults. Methods: Patients from the British Society for Rheumatology Biologics Register, a prospective observational cohort, who were biologic naïve and commencing their first TNF inhibitors (TNFi) were included. The cohort was stratified according to age: <75 and ≥75. Cox-proportional hazards models compared the risk of TNFi discontinuation from i) any-cause ii) inefficacy and iii) adverse events, between patients prescribed TNFi-monotherapy compared to TNFi-methotrexate combination. Findings: The analysis included 15,700 patients. Ninety five percent were <75 years-old. Comorbidity burden and disease activity were higher in the ≥75 cohort. Fifty-two percent of patients discontinued TNFi therapy during the follow up period. Persistence with therapy was higher in the <75 cohort. Patients receiving TNFi monotherapy were more likely to discontinue compared to patients receiving concomitant methotrexate [hazard rate 1·12 (1·06-1·18) p<0.001]. This finding only held true in patients <75 [HR 1·11 (1·05-1·17) versus ≥75 [HR 1.13 (0.90-1.41)]. Examining TNFi discontinuation by cause revealed patients ≥75 receiving TNFi monotherapy were less likely to discontinue TNFi due to inefficacy [HR 0·66(0·43-0·99)p=0·04] and more likely to discontinue therapy from adverse events [HR 1·41(1·02-1·96)p=0·04]. These results were supported by the multivariate adjustment in complete case and imputed analyses. Interpretation: TNFi monotherapy is associated with increased treatment failure. In older adults the disadvantage of TNFi monotherapy on drug survival is no longer seen. Patients ≥75 have fewer discontinuations due to inefficacy than adverse events compared to younger patients. This likely reflects greater disposition to toxicity but perhaps also a decline in immunogenicity associated with immunosenescence.