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Systematic review and network meta-analysis of the efficacy and safety of tumour necrosis factor inhibitor–methotrexate combination therapy versus triple therapy in rheumatoid arthritis

Objective Clinical trials have not consistently demonstrated differences between tumour necrosis factor inhibitor (TNFi) plus methotrexate and triple therapy (methotrexate plus hydroxychloroquine plus sulfasalazine) in rheumatoid arthritis (RA). The study objective was to estimate the efficacy, radiographic benefits, safety and patient-reported outcomes of TNFi–methotrexate versus triple therapy in patients with RA. Methods A systematic review and network meta-analysis (NMA) of randomised controlled trials of TNFi–methotrexate or triple therapy as one of the treatment arms in patients with an inadequate response to or who were naive to methotrexate was conducted. American College of Rheumatology 70% response criteria (ACR70) at 6 months was the prespecified primary endpoint to evaluate depth of response. Data from direct and indirect comparisons between TNFi–methotrexate and triple therapy were pooled and quantitatively analysed using fixed-effects and random-effects Bayesian models. Results We analysed 33 studies in patients with inadequate response to methotrexate and 19 in patients naive to methotrexate. In inadequate responders, triple therapy was associated with lower odds of achieving ACR70 at 6 months compared with TNFi–methotrexate (OR 0.35, 95% credible interval (CrI) 0.19 to 0.64). Most secondary endpoints tended to favour TNFi–methotrexate in terms of OR direction; however, no clear increased likelihood of achieving these endpoints was observed for either therapy. The odds of infection were lower with triple therapy than with TNFi−methotrexate (OR 0.08, 95% CrI 0.00 to 0.57). There were no differences observed between the two regimens in patients naive to methotrexate. Conclusions In this NMA, triple therapy was associated with 65% lower odds of achieving ACR70 at 6 months compared with TNFi–methotrexate in patients with inadequate response to methotrexate. Although secondary endpoints numerically favoured TNFi–methotrexate, no clear differences were observed. The odds of infection were greater with TNFi–methotrexate. No differences were observed for patients naive to methotrexate. These results may help inform care of patients who fail methotrexate first-line therapy.


Source
No.

Risk of Bias Assessment
One reviewer individually extracted data and assessed study quality (using the Cochrane Collaboration Risk of Bias tool for RCTs). See Table 2 below for summarizing study-level risk of bias across domains and the criteria used to judge risk of bias. Describe all measures used, if any, to blind study participants and personnel from knowledge of which intervention a participant received; provide any information relating to whether the intended blinding was effective Was knowledge of the allocated intervention adequately prevented during the study?

Review Authors' Judgment
Incomplete outcome data; assessments should be made for each main outcome (or class of outcomes) Describe the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis; state whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomized participants), reasons for attrition/exclusions where reported, and any reinclusions in analyses performed by the review authors frequentist approaches and provides greater confidence when a statistical difference is found.
Fixed-and random-effects models were fitted with preferred model fit determined by the deviance information criterion (DIC). A model with a lower DIC score was considered a better fit.
Model fit was also assessed by comparing the residual deviance with the total number of data points. A model with a residual deviance closer to the number of data points was considered a better fit. [3,4] Simulation convergence was evaluated by visual inspection of trace from a burn-in of 40

Characteristics of studies included in the analysis
The search yielded a total of 6560 abstracts and citations from EMBASE, MEDLINE, and In addition to the database searches, a manual bibliography search was performed using identified relevant systematic reviews, Cochrane reviews, and meta-analysis [6][7][8][9][10][11][12][13][14][15][16][17][18]. One study was identified and included through this process. [19] In summary, 136 records were included from all sources as described above. After grouping the publications from the same primary studies together, there were 60 primary clinical studies included in this review. Of the 60 studies, 39  studies were in MTX-inadequate response (IR) patients, and the remaining 21  were in methotrexate (MTX)-naive patients. Table 3 shows the patient characteristics for each study considered for the analysis.   Figures 1-14). Overall, there were no clinically meaningful differences seen in treatment cohorts across the studies as determined by coauthors who are practicing rheumatologists.  ranged from 43% to 100%. Three trials included a higher proportion of women; an ADA study enrolled 95% women, and two IFX studies enrolled more than 95% women. ADA=adalimumab;
Numbers represent dose in mg.  Mean disease duration varied across trials; on average participants had RA for more than 5 years. Duration of disease ranged from <1 year to 14 years. Greatest variation in disease duration was observed within ADA and IFX trials. ADA=adalimumab; CZP=certolizumab; ETN=etanercept; GOL=golimumab; IFX=infliximab; RA=rheumatoid arthritis; TT=triple therapy.
Numbers represent dose in mg. NSAID=nonsteroidal anti-inflammatory drug.

Figure 13
Distribution of mean (SD) proportion of participants who received concomitant prednisone at baseline. Percentage of patients taking prednisone upon study enrollment ranged from 0% to 89% prednisone use. On average, the proportion of patients who used prednisone during each trial was 50% to 70%. ADA=adalimumab; CZP=certolizumab; ETN=etanercept; GOL=golimumab; IFX=infliximab; TT=triple therapy. Numbers represent dose in mg.

MTX-Naive
The   IFX=infliximab; TT=triple therapy. Numbers represent dose in mg. Figure 17. Distribution of mean proportion of participants enrolled at baseline who were RF+ (ranged from 70% to 85%). One study enrolled as low as 49% RF+ participants, whereas another study enrolled as high as 100% RF+ participants. ADA=adalimumab; ETN=etanercept; RF+=rheumatoid factor-positive; GOL=golimumab; IFX=infliximab; TT=triple therapy. Numbers represent dose in mg. Numbers represent dose in mg.

MTX-Naive Patients
The networks used for the NMA of the primary endpoint for methotrexate naive patients is shown in Figure 28.    Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

Protocol and registration 5
Indicate if a review protocol exists, if and where it can be accessed (eg, web address), and, if available, provide registration information including registration number.

Yes
Eligibility criteria 6 Specify study characteristics (eg, PICOS, length of follow-up) and report characteristics (eg, years considered, language, publication status) used as criteria for eligibility, giving rationale.

Yes
Information sources 7 Describe all information sources (eg, databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

Search 8
Present full electronic search strategy for at least 1 database, including any limits used, such that it could be repeated.

Yes
Study selection 9 State the process for selecting studies (ie, screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

Yes
Data collection process 10 Describe method of data extraction from reports (eg, piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

Data items 11
List and define all variables for which data were sought (eg, PICOS, funding sources) and any assumptions and simplifications made.

Yes
Risk of bias in individual studies

12
Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

Summary measures 13
State the principal summary measures (eg, risk ratio, difference in means).

Synthesis of results 14
Describe the methods of handling data and combining results of studies, if done, including measures of consistency (eg, I 2 for each meta-analysis).

Risk of bias across studies 15
Specify any assessment of risk of bias that may affect the cumulative evidence (eg, publication bias, selective reporting within studies).

Additional analyses 16
Describe methods of additional analyses (eg, sensitivity or subgroup analyses, meta-regression), if done, indicating which were prespecified.

Study selection 17
Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

Study characteristics 18
For each study, present characteristics for which data were extracted (eg, study size, PICOS, follow-up period) and provide the citations.

Risk of bias within studies 19
Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).

Results of individual studies 20
For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

Synthesis of results 21
Present results of each meta-analysis, including confidence intervals and measures of consistency.

Risk of bias across studies 22
Present results of any assessment of risk of bias across studies (see item 15).

Additional analysis 23
Give results of additional analyses, if done (eg, sensitivity or subgroup analyses, meta-regression [see item 16]).

Summary of evidence 24
Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (eg, healthcare providers, users, and policy makers).

Limitations 25
Discuss limitations at study and outcome level (eg, risk of bias), and at review level (eg, incomplete retrieval of identified research, reporting bias).

Conclusions 26
Provide a general interpretation of the results in the context of other evidence and implications for future research.

Funding 27
Describe sources of funding for the systematic review and other support (eg, supply of data); role of funders for the systematic review.

Yes
PRISMA=Preferred Reporting Items for Systematic Reviews and Meta-Analyses