Therapeutics
Review: Some TNF inhibitors increase adverse events in patients with rheumatoid arthritis Clinical impact ratings:
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Michaud TL, Rho YH, Shamliyan T, Kuntz KM, Choi HK. The comparative safety of tumor necrosis factor inhibitors in rheumatoid arthritis: a meta-analysis update of 44 trials. Am J Med. 2014;127:120832.
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Question
Conclusion
In patients with rheumatoid arthritis (RA), are some tumornecrosis factor (TNF) inhibitors safer than others?
In patients treated for rheumatoid arthritis, some tumor-necrosis factor inhibitors increase serious adverse events, serious infections, and treatment discontinuation due to adverse events, but not cancer, compared with control.
Review scope Included studies had durations ≥ 12 weeks and compared TNF inhibitors with placebo or traditional disease-modifying antirheumatic drugs (DMARDs) in adults ≥ 19 years of age with RA. Outcomes were serious adverse events (incidents that were lifethreatening; resulted in death, hospitalization, or prolongation of hospitalization; or caused substantial or persistent disability), serious infection requiring antimicrobial therapy or hospitalization, cancer, or treatment discontinuation due to adverse events.
Source of funding: National Institutes of Health. For correspondence: Dr. H.K. Choi, Harvard Medical School, Boston, MA, USA. E-mail [email protected].
Commentary Most RCTs are not large enough to provide good estimates of the rates of rare, but important, side effects. By combining data from multiple RCTs, meta-analyses are expected to provide a clearer answer. Unfortunately, when the event rates are zero or nearly zero, even meta-analyses can be imprecise, giving inconclusive results (1). Also, most methods, including those used in the review by Michaud and colleagues, give no weight to RCTs with zero events, which may bias the results.
Review methods MEDLINE, Cochrane databases, Google Scholar, www. ClinicalTrials.gov, and reference lists (1990 to May 2013) were searched for randomized controlled trials (RCTs) with > 100 patients. US Food and Drug Administration briefing documents, approval packages, and medical and statistical reviews were searched. PubMed Auto Alerts provided weekly updates until October 2013. Open-label RCTs were excluded. 38 RCTs (n = 17 601, mean age 47 to 61 y, 58% to 91% women) met the selection criteria. Duration ranged from 12 to 156 weeks. Adalimumab was assessed in 11 RCTs, etanercept in 8, golimumab in 7, infliximab in 7, and certolizumab pegol in 5. TNF inhibitors were compared with methotrexate in 26 trials, placebo in 8 trials, sulfasalazine plus hydroxychloroquine plus methotrexate in 2 trials, sulfasalazine in 1 trial, and DMARDs in 1 trial.
The finding of lower risks for some adverse events with etanercept is consistent with the results of an earlier review (2) and may be clinically relevant. However, the question of whether the risk for cancer is increased with TNF inhibitors still requires clarification. Although one of the earliest meta-analyses (3) found an increase in cancer, more recent studies (4), including this review, have found mainly nonsignificant increases. The review by Michaud and colleagues focuses on adverse events only in the context of treating RA, so the relevance of its findings on use of TNF inhibitors in other diseases is not explored in this review. Also, the assumption that all of the drugs are equally effective may not be entirely valid. For example, Launois and colleagues (5) found that, for some efficacy outcomes, certolizumab pegol was superior to other TNF inhibitors.
Main results Meta-analysis showed that TNF inhibitors overall did not increase serious adverse events compared with control (Table). Certolizumab pegol increased risk for serious adverse events (odds ratio [OR] 1.44, 95% CI 1.04 to 2.00); other individual TNF inhibitors did not. Neither TNF inhibitors overall (Table) nor any individual TNF inhibitors increased risk for cancer. TNF inhibitors overall (Table), adalimumab (OR 1.69, CI 1.12 to 2.54), and infliximab (OR 1.63, CI 1.07 to 2.47) increased risk for serious infections. TNF inhibitors overall (Table), adalimumab (OR 1.38, CI 1.00 to 1.89), certolizumab pegol (OR 1.67, CI 1.09 to 2.54), and infliximab (OR 2.04, CI 1.46 to 2.84) increased treatment discontinuation due to adverse events, whereas etanercept decreased treatment discontinuation due to adverse events (OR 0.72, CI 0.55 to 0.93).
Henry S. Sacks, PhD, MD Icahn School of Medicine at Mount Sinai New York, NY, USA References 1. Warren FC, Abrams KR, Sutton AJ. Hierarchical network meta-analysis models to address sparsity of events and differing treatment classifications with regard to adverse outcomes. Stat Med. 2014;33:2449-66. 2. Aaltonen KJ, Virkki LM, Malmivaara A, et al. Systematic review and metaanalysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS One. 2012;7:e30275. 3. Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies. JAMA. 2006;295:2275-85.
Tumor-necrosis factor (TNF) inhibitors vs control in rheumatoid arthritis* Outcomes
Weighted event rates TNF inhibitors
Control
At 12 to 156 wk RRI (95% CI)
4. Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, et al. Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA. 2012;308:898-908. 5. Launois RI, Avouac B, Berenbaum F, et al. Comparison of certolizumab pegol with other anticytokine agents for treatment of rheumatoid arthritis: a multiple-treatment Bayesian metaanalysis. J Rheumatol. 2011;38:835-45.
NNH (CI)
Serious adverse events
9.0%
8.2%
10% (⫺3 to 23)
Not significant
Cancer
0.7%
0.5%
29% (⫺15 to 96)
Not significant
Serious infection
2.8%
2.0%
41% (13 to 75)
123 (67 to 394)
Treatment discontinuation due to adverse events
6.1%
5.1%
22% (6 to 40)
92 (50 to 349)
*Abbreviations defined in Glossary. Weighted TNF inhibitor event rates, RRI, NNH, and CI calculated from control event rates and odds ratios in article.
姝 2015 American College of Physicians JC10 ACP Journal Club Downloaded From: http://annals.org/ by a Western Michigan University User on 05/06/2015
Annals of Internal Medicine
21 April 2015
Review: Some TNF inhibitors increase adverse events in patients with rheumatoid arthritis Clinical impact ratings:
多多多多多夞夞
多多多多多多夞
Michaud TL, Rho YH, Shamliyan T, Kuntz KM, Choi HK. The comparative safety of tumor necrosis factor inhibitors in rheumatoid arthritis: a meta-analysis update of 44 trials. Am J Med. 2014;127:120832.
多多多多多多夞
Question
Conclusion
In patients with rheumatoid arthritis (RA), are some tumornecrosis factor (TNF) inhibitors safer than others?
In patients treated for rheumatoid arthritis, some tumor-necrosis factor inhibitors increase serious adverse events, serious infections, and treatment discontinuation due to adverse events, but not cancer, compared with control.
Review scope Included studies had durations ≥ 12 weeks and compared TNF inhibitors with placebo or traditional disease-modifying antirheumatic drugs (DMARDs) in adults ≥ 19 years of age with RA. Outcomes were serious adverse events (incidents that were lifethreatening; resulted in death, hospitalization, or prolongation of hospitalization; or caused substantial or persistent disability), serious infection requiring antimicrobial therapy or hospitalization, cancer, or treatment discontinuation due to adverse events.
Source of funding: National Institutes of Health. For correspondence: Dr. H.K. Choi, Harvard Medical School, Boston, MA, USA. E-mail [email protected].
Commentary Most RCTs are not large enough to provide good estimates of the rates of rare, but important, side effects. By combining data from multiple RCTs, meta-analyses are expected to provide a clearer answer. Unfortunately, when the event rates are zero or nearly zero, even meta-analyses can be imprecise, giving inconclusive results (1). Also, most methods, including those used in the review by Michaud and colleagues, give no weight to RCTs with zero events, which may bias the results.
Review methods MEDLINE, Cochrane databases, Google Scholar, www. ClinicalTrials.gov, and reference lists (1990 to May 2013) were searched for randomized controlled trials (RCTs) with > 100 patients. US Food and Drug Administration briefing documents, approval packages, and medical and statistical reviews were searched. PubMed Auto Alerts provided weekly updates until October 2013. Open-label RCTs were excluded. 38 RCTs (n = 17 601, mean age 47 to 61 y, 58% to 91% women) met the selection criteria. Duration ranged from 12 to 156 weeks. Adalimumab was assessed in 11 RCTs, etanercept in 8, golimumab in 7, infliximab in 7, and certolizumab pegol in 5. TNF inhibitors were compared with methotrexate in 26 trials, placebo in 8 trials, sulfasalazine plus hydroxychloroquine plus methotrexate in 2 trials, sulfasalazine in 1 trial, and DMARDs in 1 trial.
The finding of lower risks for some adverse events with etanercept is consistent with the results of an earlier review (2) and may be clinically relevant. However, the question of whether the risk for cancer is increased with TNF inhibitors still requires clarification. Although one of the earliest meta-analyses (3) found an increase in cancer, more recent studies (4), including this review, have found mainly nonsignificant increases. The review by Michaud and colleagues focuses on adverse events only in the context of treating RA, so the relevance of its findings on use of TNF inhibitors in other diseases is not explored in this review. Also, the assumption that all of the drugs are equally effective may not be entirely valid. For example, Launois and colleagues (5) found that, for some efficacy outcomes, certolizumab pegol was superior to other TNF inhibitors.
Main results Meta-analysis showed that TNF inhibitors overall did not increase serious adverse events compared with control (Table). Certolizumab pegol increased risk for serious adverse events (odds ratio [OR] 1.44, 95% CI 1.04 to 2.00); other individual TNF inhibitors did not. Neither TNF inhibitors overall (Table) nor any individual TNF inhibitors increased risk for cancer. TNF inhibitors overall (Table), adalimumab (OR 1.69, CI 1.12 to 2.54), and infliximab (OR 1.63, CI 1.07 to 2.47) increased risk for serious infections. TNF inhibitors overall (Table), adalimumab (OR 1.38, CI 1.00 to 1.89), certolizumab pegol (OR 1.67, CI 1.09 to 2.54), and infliximab (OR 2.04, CI 1.46 to 2.84) increased treatment discontinuation due to adverse events, whereas etanercept decreased treatment discontinuation due to adverse events (OR 0.72, CI 0.55 to 0.93).
Henry S. Sacks, PhD, MD Icahn School of Medicine at Mount Sinai New York, NY, USA References 1. Warren FC, Abrams KR, Sutton AJ. Hierarchical network meta-analysis models to address sparsity of events and differing treatment classifications with regard to adverse outcomes. Stat Med. 2014;33:2449-66. 2. Aaltonen KJ, Virkki LM, Malmivaara A, et al. Systematic review and metaanalysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS One. 2012;7:e30275. 3. Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies. JAMA. 2006;295:2275-85.
Tumor-necrosis factor (TNF) inhibitors vs control in rheumatoid arthritis* Outcomes
Weighted event rates TNF inhibitors
Control
At 12 to 156 wk RRI (95% CI)
4. Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, et al. Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA. 2012;308:898-908. 5. Launois RI, Avouac B, Berenbaum F, et al. Comparison of certolizumab pegol with other anticytokine agents for treatment of rheumatoid arthritis: a multiple-treatment Bayesian metaanalysis. J Rheumatol. 2011;38:835-45.
NNH (CI)
Serious adverse events
9.0%
8.2%
10% (⫺3 to 23)
Not significant
Cancer
0.7%
0.5%
29% (⫺15 to 96)
Not significant
Serious infection
2.8%
2.0%
41% (13 to 75)
123 (67 to 394)
Treatment discontinuation due to adverse events
6.1%
5.1%
22% (6 to 40)
92 (50 to 349)
*Abbreviations defined in Glossary. Weighted TNF inhibitor event rates, RRI, NNH, and CI calculated from control event rates and odds ratios in article.
姝 2015 American College of Physicians JC10 ACP Journal Club Downloaded From: http://annals.org/ by a Western Michigan University User on 05/06/2015
Annals of Internal Medicine
21 April 2015
