Added value of combining methotrexate with a biological agent compared to biological monotherapy in rheumatoid arthritis patients: A systematic review and meta-analysis of randomised trials

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Background Methotrexate (MTX) is considered the anchor drug in rheumatoid arthritis (RA) treatment, based on efficacy, safety, and its ability to increase the efficacy of biologic agents when used in combination. Both the “American College of Rheumatology” (ACR) and the “European League Against Rheumatism” (EULAR) recommend the use of biologic agents with concomitant MTX in RA. However, analyses from health care claims suggest that the MTX prescribed in conjunction with a biologic disease-modifying antirheumatic drug (bDMARD), is not collected at the pharmacy by more than half of the patients. Despite claims from pivotal trial data, the empirical evidence supporting combination MTX plus bDMARD in terms of the actual benefit-harm has not been evaluated extensively.

Objectives To review the evidence for benefit and harm associated with combining MTX with a biologic agent in RA patients.

Methods A systematic review and meta-analysis of randomised controlled trials (RCTs) was performed to identify all trials relating treatment of RA with MTX in combination with bDMARD compared to a bDMARD in monotherapy. Random-effects models were applied for meta-analyses with risk ratio and 95% confidence intervals (RR, 95%CI) and inconsistency (I2, %) estimated using Review Manager. According to the protocol the major outcomes were ACR50 for benefit and withdrawals due to adverse events (AEs) for harm (PROSPERO: CRD42014014633).

Results From the 4,405 identified references, 14 trials were eligible for inclusion in the meta-analysis. The overall likelihood of responding to therapy (ie, RR according to ACR50) was 1.36 [1.24 to 1.49] – with a low degree of inconsistency (28%) – in favour of concomitant use of MTX when treating with a biologic (P<0.001). There was no reason to suspect that added value of MTX varied with the choice of bDMARD (Test for subgroup differences P=0.38): abatacept 1.27 [0.97 to 1.67], adalimumab 1.42 [1.24 to 1.61], etanercept 1.44 [1.22 to 1.69], golimumab 1.60 [1.13 to 2.27], infliximab 3.54 [1.38 to 9.08], rituximab 1.31 [0.74 to 2.32], and tocilizumab 1.24 [1.03 to 1.51]. The overall estimate of discontinuing therapy due to AEs from concomitant use of MTX was 1.17 [0.94 to 1.44] (P=0.16) compared to bDMARD in monotherapy – corresponding to a possible 17% increased risk.

Conclusions This systematic review and meta-analysis of RCTs provides empirical evidence about the clinical value of combining the prescribed bDMARD with the recommended concomitant use of MTX. Combination therapy increases the probability of achieving treatment success at the level of ACR50 by approximately 40% compared to patients using biologics in monotherapy. Although the precision around the estimate of concomitant MTX use does not rule out an increased risk of clinically important harms, these findings justify the recommendation that all patients prescribed biologics should be encouraged to continue MTX therapy.

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