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. 2016 Aug 29;2016(8):CD010227.
doi: 10.1002/14651858.CD010227.pub2.

Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis: A network meta-analysis

Glen S Hazlewood  1 , Cheryl Barnabe, George Tomlinson, Deborah Marshall, Daniel J A Devoe, Claire Bombardier
Affiliations

Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis: A network meta-analysis

Glen S Hazlewood et al. Cochrane Database Syst Rev. .

Abstract

Background: Methotrexate is considered the preferred disease-modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis, but controversy exists on the additional benefits and harms of combining methotrexate with other DMARDs.

Objectives: To compare methotrexate and methotrexate-based DMARD combinations for rheumatoid arthritis in patients naïve to or with an inadequate response (IR) to methotrexate.

Methods: We systematically identified all randomised controlled trials with methotrexate monotherapy or in combination with any currently used conventional synthetic DMARD , biologic DMARDs, or tofacitinib. Three major outcomes (ACR50 response, radiographic progression and withdrawals due to adverse events) and multiple minor outcomes were evaluated. Treatment effects were summarized using Bayesian random-effects network meta-analyses, separately for methotrexate-naïve and methotrexate-IR trials. Heterogeneity was explored through meta-regression and subgroup analyses. The risk of bias of each trial was assessed using the Cochrane risk of bias tool, and trials at high risk of bias were excluded from the main analysis. The quality of evidence was evaluated using the GRADE approach. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability that one treatment was superior.

Main results: 158 trials with over 37,000 patients were included. Methotrexate-naïve: Several treatment combinations with methotrexate were statistically superior to oral methotrexate for ACR50 response: methotrexate + sulfasalazine + hydroxychloroquine ("triple therapy"), methotrexate + several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%, moderate to high quality evidence), compared with 41% for methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression (moderate to high quality evidence) but the estimated mean change over one year with all treatments was less than the minimal clinically important difference of five units on the Sharp-van der Heijde scale. Methotrexate + azathioprine had statistically more withdrawals due to adverse events than oral methotrexate, and triple therapy had statistically fewer withdrawals due to adverse events than methotrexate + infliximab (rate ratio 0.26, 95% credible interval: 0.06 to 0.91). Methotrexate-inadequate response: In patients with an inadequate response to methotrexate, several treatments were statistically significantly superior to oral methotrexate for ACR50 response: triple therapy (moderate quality evidence), methotrexate + hydroxychloroquine (low quality evidence), methotrexate + leflunomide (moderate quality evidence), methotrexate + intramuscular gold (very low quality evidence), methotrexate + most biologics (moderate to high quality evidence), and methotrexate + tofacitinib (high quality evidence). There was a 61% probability of an ACR50 response with triple therapy, compared to a range of 27% to 64% for the combinations of methotrexate + biologic DMARDs that were statistically significantly superior to oral methotrexate. No treatment was statistically significantly superior to oral methotrexate for inhibiting radiographic progression. Methotrexate + cyclosporine and methotrexate + tocilizumab (8 mg/kg) had a statistically higher rate of withdrawals due to adverse events than oral methotrexate and methotrexate + abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments.

Authors' conclusions: We found moderate to high quality evidence that combination therapy with methotrexate + sulfasalazine+ hydroxychloroquine (triple therapy) or methotrexate + most biologic DMARDs or tofacitinib were similarly effective in controlling disease activity and generally well tolerated in methotrexate-naïve patients or after an inadequate response to methotrexate. Methotrexate + some biologic DMARDs were superior to methotrexate in preventing joint damage in methotrexate-naïve patients, but the magnitude of these effects was small over one year.

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Conflict of interest statement

GH ‐ GH received $1500 from Amgen as honorarium for an advisory board meeting, but the total amount was transferred without obligations to a non‐profit organization. This was discussed with the Funding Arbiters who agreed that the review could be published.

ChB ‐ Speaker fees: Abbott, BMS, Pfizer, UCB; Consultant: Abbott, Roche, UCB, Amgen; Educational Grant‐in‐Aid: Roche, Amgen/Pfizer; Unrestricted travel grant: Celgene

GT ‐ Chair of drug safety monitoring board for a clinical trial sponsored by Smith & Nephew.

DM ‐ Health economics and outcomes research consultant through OptumInsight.

ClB ‐ Consultant: Abbott, AstraZeneca, Bristol‐Myers Squibb Canada, Janssen, Pfizer, UCB Canada; Advisory board: Janssen, Pfizer, Takeda Canada Inc; Research funding: Abbott, Amgen, Bristol‐Myers Squibb Canada, Janssen, Hoffman La‐Roche, Pfizer, UCB Canada Inb

DD ‐ None

Figures

1
1
Search flow chart
2
2
Networks of included studies for methotrexate‐naïve (A) and methotrexate‐inadequate response populations (B). Each line represents a direct comparison between two treatments from one or more trials. The line thickness is directly proportional to the total sample size of all trials for that comparison (line length has no meaning). Biologic/targeted synthetic DMARDs are shown on the left of each network and conventional synthetic DMARDs on the right. Treatments on the innermost circle (green hashed line) are treatments of interest, whereas treatments on the outermost circle (red hashed line) are other treatments that form links between treatments of interest. Comparisons to methotrexate are shown in blue. Two trials were included in both analyses. Abbreviations: ABAT, abatacept; ADA, adalimumab; AZA, azathioprine; CTZ, certolizumab; CQ, chloroquine; CyA, cyclosporine; ETN, etanercept; GOL, golimumab; HCQ, hydroxychloroquine; IFX, infliximab; IM, intra‐muscular; IV, intravenous; LEF, leflunomide; , methotrexate; RTX, rituximab; sc, subcutaneous; SSZ, sulphasalazine; TCZ, tocilizumab; TOFA, tofacitinib
3
3
4
4
Selected meta‐regression and sensitivity analyses for ACR50 response in methotrexate‐naïve trials Abbreviations: ABAT, abatacept; ADA, adalimumab; CQ, chloroquine; CyA, cyclosporine; ETN, etanercept; GOL, golimumab; HCQ, hydroxychloroquine; IFX, infliximab; IM, intra‐muscular; IV, intravenous; LEF, leflunomide; MTX, methotrexate; RTX, rituximab; sc, subcutaneous; SSZ, sulphasalazine; TCZ, tocilizumab
5
5
Selected meta‐regression and sensitivity analyses for ACR50 response in methotrexate‐inadequate response trials Abbreviations: ABAT, abatacept; ADA, adalimumab; CTZ, certolizumab; CQ, chloroquine; ETN, etanercept; GOL, golimumab; HCQ, hydroxychloroquine; IFX, infliximab; IA, IM, intra‐muscular; IV, intravenous; LEF, leflunomide; MTX, methotrexate; RTX, rituximab; sc, subcutaneous; SSZ, sulphasalazine; TCZ, tocilizumab; TOFA, tofacitinib
6
6
MTXSensitivity analyses for ACR50 response in methotrexate‐naïve trials for different time‐points of outcome assessment Abbreviations: ABAT, abatacept; ADA, adalimumab; AZA, azathioprine; CQ, chloroquine; CyA, cyclosporine; ETN, etanercept; GOL, golimumab; HCQ, hydroxychloroquine; IFX, infliximab; IA, IM, intra‐muscular; IV, intravenous; MTX, methotrexate; RTX, rituximab; sc, subcutaneous; SSZ, sulphasalazine; TCZ, tocilizumab
7
7
Sensitivity analyses for ACR50 response in methotrexate‐inadequate response trials for different time‐points of outcome assessment Abbreviations: ABAT, abatacept; ADA, adalimumab; CTZ, certolizumab; CQ, chloroquine; ETN, etanercept; GOL, golimumab; HCQ, hydroxychloroquine; IFX, infliximab; IA, IM, intra‐muscular; IV, intravenous; LEF, leflunomide; MTX, methotrexate; RTX, rituximab; sc, subcutaneous; SSZ, sulfasalazine; TCZ, tocilizumab; TOFA, tofacitinib
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