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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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Tarp S1, Jørgensen TS2, Furst DE3, Dossing A2, Taylor PC4, Choy EH5, Suarez-Almazor ME6, Lyddiatt A7, Kristensen LE2, Bliddal H2, Christensen R2. Semin Arthritis Rheum. 2018 Oct 9. pii: S0049-0172(18)30093-3. doi: 10.1016/j.semarthrit.2018.10.002. [Epub ahead of print]

Abstract

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1 Musculoskeletal Statistics Unit, The Parker Institute, Bispebjerg and Frederiksberg Hospital, Nordre Fasanvej 57, 2000 Copenhagen, Denmark. Electronic address: simon.tarp@regionh.dk.

2 Musculoskeletal Statistics Unit, The Parker Institute, Bispebjerg and Frederiksberg Hospital, Nordre Fasanvej 57, 2000 Copenhagen, Denmark.

3 Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.

4 Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Headington, Oxford, UK.

5 Section of Rheumatology, Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK; CREATE Centre, Division of Infection and Immunity, Cardiff University, Cardiff, UK.

6 Section of Rheumatology and Clinical Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

7 Musculoskeletal Group, Cochrane Collaboration, Ottawa, ON K1H 8L6, Canada.

Abstract

OBJECTIVES: To assess the efficacy and safety of methotrexate (MTX) in combination with an approved biological agent compared to biological monotherapy, in the management of patients with rheumatoid arthritis (RA).

METHODS: MEDLINE, EMBASE, CENTRAL and other sources were searched for randomised trials evaluating a biological agent plus MTX versus the same biological agent in monotherapy. Co-primary outcomes were ACR50 and the number of patients who discontinued due to adverse events (AEs). Random-effects models were applied for meta-analyses with risk ratio and 95% confidence intervals and the GRADE approach was used to assess confidence in the estimates.

RESULTS: The analysis comprised 16 trials (4965 patients), including all biological agents approved for RA except anakinra and certolizumab. The overall likelihood of responding to therapy (i.e. ACR50) after 6 months was 32% better when MTX was given concomitantly with biological agents (1.32 [1.20-1.45]; P < 0.001) corresponding to 11 more out of 100 patients (7-16 more); Moderate Quality Evidence. Discontinuing due to AEs from concomitant use of MTX was potentially 20% increased (1.21 [0.97-1.50]; P = 0.09) compared to biological monotherapy corresponding to 1 more out of 100 patients (0-3 more); Moderate Quality Evidence.

CONCLUSIONS: Randomised trials provide Moderate Quality Evidence for a favourable benefit-harm balance supporting concomitant use of MTX rather than monotherapy when prescribing a biological agent in patients with RA although in absolute terms only 7-16 more out of 100 patients will achieve an ACR50 response after 6 months of this combination therapy.