Background/Purpose: Despite several randomized controlled trials showing comparable clinical outcomes with triple therapy (Triple; MTX, SSZ, HCQ) versus combination therapy with MTX+TNFi (TNFi Combo), the real-world experience comparing these two strategies may differ.

Methods: We identified new users of Triple vs. TNFi Combo amongst RA patients in the Corrona registry. Initiation of these therapies could have been simultaneous or sequential, but patients had to receive all therapies simultaneously and could not have ever received Triple or TNFi Combo treatment previously. Patients must have had moderate/high disease activity (CDAI >10) at baseline and have >=1 follow-up visit.

Treatment failure was defined as starting/adding a new biologic/JAKi, csDMARD, or discontinuation of any of the medications in Triple or TNFi Combo exposures. Patients were censored if they attained low disease activity (CDAI< 10). Propensity score (PS) matching (1:3, and 1:1 as part of a sensitivity analysis) was used to balance exposure groups (8-1 digit Greedy Match), with caliper widening if required for higher order matches. Treatment failure was evaluated using KM curves. Cox models were used to control for residual imbalance in baseline factors and account for clustering of the matched PS pairs. An additional sensitivity analysis evaluated adjusted treatment failure in the entire unmatched sample, controlling for baseline factors and excluding patients in the non-overlapping tails of the PS.

Results: A total of 2156 TNFi Combo and 105 Triple patients were eligible for analysis. Before PS matching, numerous factors were imbalanced between the two groups, with Triple patients being older (mean age: 62 vs. 56yrs), having longer RA disease duration (9 vs. 6yrs), and a higher proportion with history of malignancy, diabetes, and serious infections. They also had lower baseline disease activity (mean Triple: 21.2 vs. TNFi Combo: 26.6).

After 1:3 PS matching (n=103 in Triple, n=309 in TNFi Combo in each group), balance was improved but some residual differences remained. Treatment failure was more likely in the Triple group (Figure). After multivariable adjustment, treatment failure was more likely in the Triple group compared to the TNFi combo group (adjusted hazard ratio [aHR]=1.38, 95% CI 1.02-1.88). Results from both sensitivity analyses (n=2240 patients in entire sample, n=204 in matched sample) were similar (HR=1.45, 95% CI 1.10 to 1.92; aHR=1.64, 95% CI=1.12-2.38 matched, respectively).

Conclusion: Based on real world evidence from a large U.S. RA registry, use of Triple is uncommon, and outcomes associated with Triple are less favorable compared to combination therapy with TNFi+MTX.

Figure: Treatment Failure associated with Triple Therapy (n=103) versus Combination TNFi+MTX (n=309)