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Risk of Infection with Methotrexate Therapy in Inflammatory Diseases: A Systematic Review and Meta-Analysis.

ABSTRACT: The aim of this study was to determine the risk of infection in adults with inflammatory rheumatic diseases (IRDs) treated with methotrexate. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing methotrexate versus placebo in adults using MEDLINE, EMBASE, and CENTRAL databases from 1980 to August 2017. The primary outcome was the risk of infection associated with methotrexate therapy. We chose a random effect model to summarize adverse event outcomes as risk ratios (RRs) and related 95% confidence intervals (95% CI). Twelve RCTs (total patients 1146) met the inclusion criteria for our main analysis, and ten for risk of serious infection (total patients 906). Overall, methotrexate was associated with increased risk of infection in rheumatoid arthritis (RA) (RR: 1.25; 95% CI, 1.01?1.56; p = 0.04; I² = 0%), but not in other non-RA IRD populations. There was no increased risk of total infections (RR: 1.14; 95% CI, 0.98?1.34; p = 0.10; I² = 0%) or serious infections (RR: 0.76; 95% CI, 0.11?5.15; p = 0.78; I² = 0%) in all included IRDs. Conclusively, methotrexate use in IRDs is associated with a higher risk of all infections in RA, but not in other non-RA (IRD) populations. There is no increased risk of serious infections.

SUBMITTER: Ibrahim A

PROVIDER: S-EPMC6352130 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

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Risk of Infection with Methotrexate Therapy in Inflammatory Diseases: A Systematic Review and Meta-Analysis.

Ibrahim Ammar A Ahmed Mohammed M Conway Richard R Carey John J JJ

Journal of clinical medicine 20181221 1

The aim of this study was to determine the risk of infection in adults with inflammatory rheumatic diseases (IRDs) treated with methotrexate. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing methotrexate versus placebo in adults using MEDLINE, EMBASE, and CENTRAL databases from 1980 to August 2017. The primary outcome was the risk of infection associated with methotrexate therapy. We chose a random effect model to summarize adverse event outcome ...[more]

PMID: 30583473

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Project description:ImportanceBiologic therapies are widely prescribed immunomodulatory agents. There are concerns that compared with treatment with conventional systemic therapy, long-term biologic treatment for common immune-mediated inflammatory diseases, namely inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and psoriasis, may be associated with increased risk of melanoma.ObjectiveTo examine whether biologic treatment of IBD, RA, or psoriasis is associated with an increased risk of melanoma compared with conventional systemic therapy.Data sourcesEmbase, MEDLINE, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for articles published from January 1, 1995, to February 7, 2019, for eligible studies.Study selectionRandomized clinical trials, cohort studies, and nested case-control studies quantifying the risk of melanoma in biologic-treated patients with IBD, RA, and psoriasis compared with patients treated with conventional systemic therapy were included.Data extraction and synthesisTwo reviewers independently extracted key study characteristics and outcomes. Study-specific risk estimates were pooled, and random- and fixed-effects model meta-analyses were conducted. Heterogeneity was assessed using the I2 statistic. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines were followed.Main outcomes and measuresThe pooled relative risk (pRR) of melanoma in biologic-treated patients with IBD, RA, and psoriasis compared with biologic-naive patients treated with conventional systemic therapy.ResultsSeven cohort studies comprising 34 029 biologic-treated patients and 135 370 biologic-naive patients treated with conventional systemic therapy were eligible for inclusion. Biologic treatment was positively associated with melanoma in patients with IBD (pRR, 1.20; 95% CI, 0.60-2.40), RA (pRR, 1.20; 95% CI, 0.83-1.74), or psoriasis (hazard ratio, 1.57; 95% CI, 0.61-4.09) compared with those who received conventional systemic therapy, but the differences were not statistically significant. Adjustment for other risk factors was absent from most studies.Conclusions and relevanceThe findings suggest that clinically important increases in melanoma risk in patients treated with biologic therapy for common inflammatory diseases cannot be ruled out based on current evidence. However, further studies with large patient numbers that adjust for key risk factors are needed to resolve the issue of long-term safety of biologic therapy.

Project description:Background & aimsWe performed a systematic review and meta-analysis to evaluate the comparative risk of serious infections with tumor necrosis factor (TNF) antagonists, non-TNF targeted biologics, tofacitinib, and immunosuppressive agents in patients with inflammatory bowel diseases (IBDs).MethodsIn a systematic search of publications, through March 18, 2018, we identified 15 observational studies (>500 person-years) of patients with IBD treated with TNF antagonists, non-TNF targeted biologics, tofacitinib, and/or immunosuppressive agents (thiopurines, methotrexate) that reported risk of serious infections. Only studies with active comparators were included, to allow appropriate comparative synthesis. We performed random-effects meta-analysis and estimated relative risk (RR) and 95% CIs.ResultsCompared with anti-TNF monotherapy, risk of serious infection increased with the combination of anti-TNF and an immunosuppressive agent (in 6 cohorts: RR, 1.19; 95% CI, 1.03-1.37), with anti-TNF and a corticosteroid (in 4 cohorts: RR, 1.64; 95% CI, 1.33-2.03), or with all 3 drugs (in 2 cohorts: RR, 1.35; 95% CI, 1.04-1.77); there was minimal heterogeneity among studies. In contrast, monotherapy with an immunosuppressive agent was associated with a lower risk of serious infections than monotherapy with a TNF antagonist (7 cohorts: RR, 0.61; 95% CI 0.44-0.84) or a TNF antagonist with an immunosuppressive agent (2 cohorts: RR, 0.56; 95% CI, 0.39-0.81). Infliximab-based therapy was associated with a lower risk of serious infections compared with adalimumab-based therapy in patients with ulcerative colitis (4 cohorts: RR, 0.57; 95% CI, 0.33-0.97), but not Crohn's disease (4 cohorts: RR, 0.91; 95% CI, 0.49-1.70). Few data were available on the comparative safety of biologic agents that do not inhibit TNF and tofacitinib.ConclusionsCombination therapies for IBD that include TNF antagonists, especially with corticosteroids, are associated with a higher risk of serious infection, whereas monotherapy with an immunosuppressive agent is associated with a lower risk, compared with monotherapy with a TNF antagonist. Studies are needed to evaluate the comparative safety of non-TNF targeted biologics and small molecules for treatment of IBD.

Dataset Information

Risk of Infection with Methotrexate Therapy in Inflammatory Diseases: A Systematic Review and Meta-Analysis.

Publications

Risk of Infection with Methotrexate Therapy in Inflammatory Diseases: A Systematic Review and Meta-Analysis.

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