When should drug combination therapy be considered for the treatment of rheumatoid arthritis (RA)?

Updated: Mar 05, 2021
  • Author: Howard R Smith, MD; Chief Editor: Herbert S Diamond, MD  more...
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Combination therapy appears to be helpful in patients whose disease partly or completely fails to respond to DMARD monotherapy. One study found that in patients with early, active RA, combination DMARD therapy with downward titration or intensive triple-DMARD combination therapy is more cost-effective than DMARD monotherapy. [119] Several combinations have proved successful without posing unexpected added risks; most include MTX (eg, MTX plus SSZ plus HCQ, MTX plus leflunomide, or MTX plus biologic DMARDs).

MTX combined with infliximab [120] or rituximab [121] yields a better response than monotherapy does. MTX combined with etanercept provides a higher rate of meaningful clinical response. MTX combined with cyclosporine, though not a commonly used combination, results in greater clinical improvement than MTX alone. Triple therapy with MTX, SSZ, and HCQ may provide substantially greater clinical improvement than either MTX alone or SSZ plus HCQ. [122]

In new-onset early RA, the use of MTX in combination with biologic DMARDs—mainly, TNF inhibitors—has not shown sufficient superiority to MTX with or without additional conventional synthetic DMARDs to justify first-line use. In the VEDERA (Very Early Versus Delayed Etanercept in Patients With RA) trial, remission rates with etanercept plus MTX versus treat-to-target MTX (with etanercept added in patients not in remission at 24 weeks) were 38% vs 33% at week 24 and 52% vs 38% at week 48, respectively (odds ratios 1.6, 95% CI 0.8-3.5, P=0.211). The study data suggested that delaying etanercept until failure of methotrexate was linked to poorer response to etanercept; that finding requires validation. [123]

The VEDERA results failed to confirm the large effect size (30%) suggested in previous exploratory analysis of first-line TNF inhibitor plus MTX compared with treat-to-target MTX. This highlights the fact that even when clinicians incorporate all the recommended treat-to-target strategies in treatment-naïve patients with early RA (ie, symptoms for ≤12 months), a ceiling effect exists. [123]

The toxicities of these drug combinations are rarely more significant than those occurring with any of the individual agents used alone, though liver and bone marrow toxicity may be increased if MTX and leflunomide are combined.

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