Real‐World Outcomes Associated With Methotrexate, Sulfasalazine, and Hydroxychloroquine Triple Therapy Versus Tumor Necrosis Factor Inhibitor/Methotrexate Combination Therapy in Patients With Rheumatoid Arthritis

Abstract

Objective. Though randomized controlled trials have demonstrated relatively comparable clinical outcomes with triple therapy (methotrexate [MTX], sulfasalazine [SSZ], and hydroxychloroquine [HCQ]) compared to combination therapy (tumor necrosis factor inhibitor [TNFi] and MTX), real-world experiences comparing these strategies have not been well studied.Methods. We evaluated the clinical effectiveness and effects of medication discontinuation of triple therapy with MTX/SSZ/HCQ versus combination therapy with TNFi/MTX in rheumatoid arthritis (RA) patients enrolled in the Corrona RA Drug Safety & Effectiveness Registry. Propensity score matching was used to match patients up to a ratio of 1:3 to adjust for imbalances between treatment groups, with stratification performed according to biologics-naive or biologics-exposed status of study participants.Results. Patients eligible for analysis in this study included biologics-naive RA patients (3,926 who received combination therapy with TNFi/MTX and 262 who received triple therapy with MTX/SSZ/HCQ) and biologics-exposed RA patients (3,365 who received combination therapy with TNFi/MTX and 130 patients who received triple therapy with MTX/SSZ/HCQ). Before propensity score matching, numerous factors were imbalanced between the treatment groups, with triple therapy patients generally being older, having a longer disease duration of RA and lower RA disease activity, and more likely having a history of malignancy and other comorbidities. After matching, almost all (93-98%) triple therapy patients could be matched to TNFi/MTX therapy patients, and cohort characteristics were generally well balanced. Discontinuation of medication was greater in triple therapy patients referent to TNFi/MTX therapy patients (adjusted hazard ratio [HR] of 2.17 [95% confidence interval 1.63-2.88] in the biologics-naive group; adjusted HR of 1.51 [95% confidence interval 1.06-2.15] in the biologics-exposed group). At 6 months, the proportion of biologics-naive patients attaining low disease activity was significantly greater in the TNFi/MTX treatment group (49.2% in TNFi/MTX therapy patients versus 33.3% in triple therapy patients), as was the mean change in Clinical Disease Activity Index scores (-9.3 units versus -5.5 [95% confidence interval -1.5, -6.1]). Corresponding results in the biologics-exposed patients numerically favored TNFi/MTX therapy compared to triple therapy but did not reach statistical significance.Conclusion. Few patients receive triple therapy with MTX/SSZ/HCQ in the US. In the present study, drug persistence and clinical effectiveness outcomes were less favorable in triple therapy patients compared to TNFi/MTX therapy patients.

Real-world effectiveness of a single conventional disease-modifying anti-rheumatic drug (cDMARD) plus an anti-TNF agent versus multiple cDMARDs in rheumatoid arthritis: a prospective observational study

“…As shown in our study, bDMARD-containing regimens were associated with several better outcomes than multiple cDMARD therapy in these studies [9,10]. In one study, treatment with anti-TNF agent plus methotrexate was associated with significantly higher rates of attaining low disease activity, greater improvements in CDAI scores, and lower rates of mediation discontinuation at 6 months than triple cDMARD therapy in patients who had not previously been exposed to a bDMARD [9]. In the other study, DAS responses at 6 and 12 months were significantly better when patients were switched to a regimen containing a bDMARD than when they were switched to a regimen containing cDMARD(s) with or without corticosteroids [10].…”

“…In contrast, large real-world studies [ 10 , 11 ] support the ACR’s conditional recommendation to switch to cDMARD plus bDMARD or tsDMARD therapy when initial methotrexate therapy had failed [ 3 ]. As shown in our study, bDMARD-containing regimens were associated with several better outcomes than multiple cDMARD therapy in these studies [ 9 , 10 ]. In one study, treatment with anti-TNF agent plus methotrexate was associated with significantly higher rates of attaining low disease activity, greater improvements in CDAI scores, and lower rates of mediation discontinuation at 6 months than triple cDMARD therapy in patients who had not previously been exposed to a bDMARD [ 9 ].…”

Combined Conventional Synthetic Disease Modifying Therapy vs. Infliximab for Rheumatoid Arthritis: Emulating a Randomized Trial in Observational Data

“…The fact that this emulation managed to obtain similar results to its target trial is not a guarantee for observational studies in general. Nevertheless, previous observational studies comparing similar treatment strategies but not emulating SWEFOT obtained results with similar qualitative interpretation (despite some heterogeneity in treatments, outcome measures and effect estimates) 22–24 . The current study shows that close emulation of a trial protocol using similar data can also produce quantitatively similar results.…”

“…The fact that this emulation managed to obtain similar results to its target trial is not a guarantee for observational studies in gen-Nevertheless, previous observational studies comparing similar treatment strategies but not emulating SWEFOT obtained results with similar qualitative interpretation (despite some heterogeneity in treatments, outcome measures and effect estimates). [22][23][24] The current study shows that close emulation of a trial protocol using similar data can also produce quantitatively similar results. This holds promise for conducting in parallel pragmatic trials and observational trial emulations in large healthcare registries in order to broaden the scope of evidence to the entire population requiring treatment in real-world clinical practice.…”

“…Several other observational studies also found combinations of TNFi 22,23 or other bDMARDs 24 with MTX superior to the SSZ + HCQ + MTX at 6 months and 1 year. One of the studies used data from the SRQ within a time period overlapping with SWEFOT, but substituted infliximab for a wider bDMARD group, defined different outcomes and identified the SSZ + HCQ + MTX group using a different algorithm and data source than in our study 24 .…”