Efficacy and Safety of Combined Therapy With Synthetic Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis: Systematic Literature Review

Reumatol Clin (Engl Ed). 2020 Sep-Oct;16(5 Pt 1):324-332. doi: 10.1016/j.reuma.2018.07.016. Epub 2018 Sep 18.
[Article in English, Spanish]


Objective: 1) To systematically and critically review the evidence of combined therapy with synthetic disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA); 2) To design practical recommendations on their use.

Methods: A systematic literature review (SLR) was performed with a sensitive bibliographic search strategy in Medline, EMBASE and Cochrane Library. We selected randomized clinical trials that analyzed the efficacy and/or safety of 1) combined therapy of synthetic compared with sequential therapy of synthetic DMARD in early RA; and 2) combination of methotrexate+leflunomide or triple therapy with synthetic DMARD in established RA refractory to synthetic DMARD. Two reviewers made the first selection by title and abstract and 11 performed the selection after detailed review of the articles and data collection. The quality of the studies was evaluated with the Jadad scale. Based on the results, related recommendations were agreed upon in a nominal group meeting.

Results: Ultimately, no articles were included in the SLR. The analysis of the reviewed articles demonstrated the effectiveness of the treatment with synthetic DMARD following a "treat to target" strategy in early RA patients, and of combination therapy of synthetic DMARD in established RA refractory to synthetic DMARD. This resulted in 6 recommendations concerning combination therapy with synthetic DMARD.

Conclusions: These recommendations aim to facilitate decision-making with the use of combined therapy with DMARD in RA.

Keywords: Artritis reumatoide; Combined therapy; Disease-modifying antirheumatic drugs; Fármacos modificadores de la enfermedad; Revisión sistemática de la literatura; Rheumatoid arthritis; Systematic literature review; Terapia combinada.

Publication types

  • Systematic Review

MeSH terms

  • Antirheumatic Agents / administration & dosage*
  • Antirheumatic Agents / therapeutic use
  • Arthritis, Rheumatoid / drug therapy*
  • Drug Therapy, Combination
  • Humans
  • Leflunomide / administration & dosage
  • Leflunomide / therapeutic use
  • Methotrexate / administration & dosage
  • Methotrexate / therapeutic use
  • Treatment Outcome


  • Antirheumatic Agents
  • Leflunomide
  • Methotrexate