Accepted Manuscript The Comparative Safety of TNF Inhibitors in Rheumatoid Arthritis - A Meta-Analysis Update of 44 Randomized Controlled Trials Tzeyu L. Michaud, MHA Young Hee Rho, MD, PhD, MPH Tatyana Shamliyan, MD, MS Karen M. Kuntz, ScD Hyon K. Choi, MD, DrPH PII:
S0002-9343(14)00488-4
DOI:
10.1016/j.amjmed.2014.06.012
Reference:
AJM 12571
To appear in:
The American Journal of Medicine
Received Date: 18 November 2013 Revised Date:
22 May 2014
Accepted Date: 9 June 2014
Please cite this article as: Michaud TL, Rho YH, Shamliyan T, Kuntz KM, Choi HK, The Comparative Safety of TNF Inhibitors in Rheumatoid Arthritis - A Meta-Analysis Update of 44 Randomized Controlled Trials, The American Journal of Medicine (2014), doi: 10.1016/j.amjmed.2014.06.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The Comparative Safety of TNF Inhibitors in Rheumatoid Arthritis - A Meta-
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Analysis Update of 44 Randomized Controlled Trials
Tzeyu L. Michaud, MHA,a Young Hee Rho, MD, PhD, MPH,b Tatyana Shamliyan, MD, MS,c Karen M. Kuntz, ScD,a Hyon K. Choi, MD, DrPHb a
Division of Health Policy and Management, School of Public Health, University of Minnesota,
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Minneapolis, MN; bSection of Rheumatology and the Clinical Epidemiology Unit, Boston
Elsevier, Clinical Solutions, Philadelphia, PA.
Article type: Clinical Research Study.
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University School of Medicine, Boston, MA; cEvidence-Based Medicine Quality Assurance
Conflict of Interest: None.
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Funding: This research was supported by the National Institute of Health (RC1AR058601).
Authorship: All authors had access to the data, participated in the conception, design, writing, editing, and final approval of the manuscript.
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Requests for reprints should be addressed to Hyon K. Choi, MD, DrPH, Section of Rheumatology
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and the Clinical Epidemiology Unit, Boston University School of Medicine, 650 Albany Street, Suite 200, Boston, MA 02118. E-mail address: [email protected] Keywords: Rheumatoid arthritis; Meta-analysis; Safety; Adverse events; TNF inhibitors. Running Head: Meta-analysis for the safety of TNF inhibitors.
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ABSTRACT Objective. To evaluate and update the safety data from randomized controlled trials of TNF inhibitors (TNFis) in patients treated for rheumatoid arthritis.
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Methods. A systematic literature search was conducted from 1990 through May 2013. All studies included were randomized, double blind, controlled trials of patients with rheumatoid arthritis that evaluated adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab treatment. The
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serious adverse events and discontinuation rates were abstracted, and risk estimates were calculated by Peto odds ratios (ORs).
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Results. Forty-four randomized controlled trials involving 11,700 subjects receiving TNFis and 5,901 subjects receiving placebo and/or traditional disease-modifying anti-rheumatic drugs (DMARDs) were included. TNFi treatment as a group was associated with a higher risk of serious infection (OR, 1.42; 95% CI, 1.13-1.78) and treatment discontinuation due to adverse events (OR,
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1.23; 95% CI, 1.06-1.43) compared with placebo and/or traditional DMARD treatments. Specifically, patients on adalimumab, certolizumab pegol, and infliximab had an increased risk of serious infection (OR, 1.69, 1.98, and 1.63) and showed an increased risk of discontinuation due to
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adverse events (OR, 1.38, 1.67 and 2.04). In contrast, patients on etanercept had a decreased risk of discontinuation due to adverse events (OR, 0.72; 95% CI, 0.55-0.93). Although ORs for
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malignancy varied across the different TNFis, none reached a statistical significance. Conclusion. These meta-analysis updates of the comparative safety of TNFis suggest a higher risk of serious infection associated with adalimumab, certolizumab pegol, and infliximab, which appears to contribute to higher rates of discontinuation. In contrast, etanercept use showed a lower rate of discontinuation. These data may help guide clinical comparative decision making in the management of rheumatoid arthritis. 2
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INTRODUCTION Tumor necrosis factor inhibitors (TNFis) are the dominant first-line biologic therapy in the management of rheumatoid arthritis1, and up-to-date knowledge of their safety profiles remains
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critical in rheumatoid arthritis care. Furthermore, as TNFis show no detectable efficacy difference in rheumatoid arthritis, their safety profile is likely to be an important determinant for decision making in rheumatoid arthritis care.
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Since a meta-analysis of 9 randomized trials (n=3,493) reported an increased risk of
malignancy and serious infections among rheumatoid arthritis patients who received infliximab and
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adalimumab in 20062, subsequent meta-analyses have been published about various biologics, indications (rheumatoid arthritis only vs. inclusion of others), and safety outcomes.3-8 For example, a 2011 Cochrane review of the safety profile of biologics found a 55% increased risk of serious infection among users of biologics as a group in rheumatoid arthritis and only certolizumab pegol
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reached a significant association among individual agents, with an OR of 4.75 (for all indicated conditions).5 Another recent large randomized controlled trial meta-analysis focused on malignancy risk in rheumatoid arthritis patients concluded that biologic use (≥ 6 months) was not significantly
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associated with an increased risk of malignancy.5,7 As such, some of the initial meta-analysis findings2 have not been consistently replicated by subsequent studies and additional findings have
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emerged, underscoring the importance of updated comparative safety profiles of TNFis in the field. In this systematic review and meta-analysis, we aim to comparatively update the key relevant safety profiles (i.e. overall serious adverse events, malignancy, serious infection, and discontinuation due to adverse events) of all FDA-approved TNFis (i.e. infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab)9-11 in rheumatoid arthritis patients.
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MATERIALS AND METHODS Data Sources and Searches
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Study selection, assessment of eligibility criteria, data extraction, and statistical analysis were performed based on a predefined, peer-reviewed protocol according to the Cochrane Collaboration guidelines (http://www.cochrane.org/resources/handbook/index.html).
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We undertook a systematic literature search including randomized controlled trials
(randomized controlled trials) that selected adult patients with rheumatoid arthritis. We searched
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studies using MEDLINE® via OVID and PubMed®, the Cochrane databases, Google Scholar, clinicaltrials.gov, and manual searches of reference lists from systematic reviews and original publications and identified studies published in English from 1990 to May 2, 2013. PubMed Auto Alerts was set up to provide weekly updates of new literature until October 2013. In addition, we searched the FDA briefing documents, approval packages, and medical or statistical reviews to
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review the drug approval reports which provide eligible trials. The search terms included rheumatoid arthritis; etanercept; infliximab; adalimumab; certolizumab pegol; golimumab; Randomized Controlled Trial; adverse effects; infection; malignancy; English; All Adult (see
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Appendix I for detailed search strings).
Study selection
We pre-specified the target population, interventions, comparators, outcome measures of interest, timing, and settings (PICOTS) following the PICOTS framework.12 To be eligible, randomized controlled trials had to (1) compare the safety of any of the TNFis against placebo and/or traditional DMARDs; (2) include only patients with rheumatoid arthritis; (3) have a sample size greater than
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100; and (4) report a minimum of 12 weeks of the study duration. We excluded studies that were open-labeled. We defined the target population as 19 years of age or older (using a PubMed filter), with
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rheumatoid arthritis diagnosed according to the 1987 revised American College of Rheumatology criteria.13 Eligible interventions included all five currently available TNFis (adalimumab,
certolizumab pegol, etanercept, golimumab, and infliximab). Eligible comparators included placebo
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or traditional DMARDs.14 Eligible outcomes included 1) serious adverse events, which was any adverse event that resulted in death, was life threatening, resulted in hospitalization or prolongation
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of hospitalization, or caused persistent or substantial disability15; 2) serious infection, defined as an infection that requires antimicrobial therapy or hospitalization16; 3) malignancies, defined as each randomized controlled trial specified17; and 4) treatment discontinuation due to adverse events. Two investigators (TM and YR) independently determined the eligibility of the studies18 and discrepancy
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was resolved by consensus.
Data Extraction and Study Quality Assessment
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Two investigators (TM and YR) independently extracted baseline patient characteristics, drug doses and treatment duration, the number of subjects experiencing an event by outcomes in randomized
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groups, and the number of randomized patients for intention-to-treat analysis. Discrepancy was resolved by consensus.
We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for grading evidence.19-21 The ranks of the quality of evidence were based on the type of study design, the risk of bias in the body of evidence, the consistency of the results, and the precision of the overall estimate. For each outcome, the strength 5
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of the evidence was rated as high, moderate, low, or very low. We examined risk of bias in individual studies using the criteria from the Cochrane risk-of-bias tool.22 To appraise the risk of bias, we used predefined criteria, which included random sequence generation, allocation
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concealment, masking of the treatment status, masking of outcome assessment, selective outcome reporting, and intention-to-treat principles. Consistency was obtained based on the pooled statistical
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heterogeneity at the significant level α=0.1.
Data Synthesis and Statistical Analysis
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We compared each TNFi with placebo alone or in combination with traditional DMARDs. In addition, the subgroup analysis was presented to check whether TNFi mono-therapy or combination therapy with traditional DMARDs would substantially change the findings. We conducted meta-analyses wherever there was a consistent outcome measure.22 Both Peto odds ratios
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(ORs) and arcsine transformation risk differences (ASRDs) and their 95% confidence intervals (CIs) were calculated.
Although we report both measures of association, the Peto OR is preferred for uncommon
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events. Both the individual Peto ORs of studies and pooled Peto ORs were presented. The ASRDs
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were used to calculate the number needed to harm.23 The number needed to harm was defined as the reciprocal of the pooled ASRDs if the results from Peto ORs and ASRD were both significant.24 It is recommended that studies with zero events in both arms be excluded from meta-analyses of ORs.25 Furthermore, the Peto and ASRD method, which were used in the current study, effectively excludes those studies from the analysis by assigning them zero weight.22,26 No imputation or estimation methods were used for missing values during the study.
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To address the potential dose impact, we also compared the event rates according to TNFi dose (i.e., high dose vs normal dose), similar to a recent systematic review by Aaltonen et al.6 For this analysis, high dose referred to a higher than normal TNFi dose as per package insert of each
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TNFi as follows: infliximab 3 mg/kg/every 8 weeks, etanercept 50 mg/week (or 25 mg/twice per week), adalimumab 40 mg/every other week (or 20 mg/week), certolizumab pegol 400 mg/every 4 weeks, and golimumab 50 mg/every 4 weeks.
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We explored heterogeneity between the trials using the chi-square test for heterogeneity and a 10% level of significance. In addition, the I2 statistic was calculated from the results of the meta-
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analysis as I2 = 100%×(Q − df)/Q, where Q is Cochran’s heterogeneity statistic (chi-square) and df is the degrees of freedom, to quantify inconsistencies across studies, and results were complied with the recommendations put forward in the Cochrane Handbook.27 A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity.28 The study was
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considered heterogeneous when a p-value of chi-square statistics was less than 0.1 or the value of I2 was over 50%.29 All statistical tests and creation of forest plots were conducted with STATA 11 and
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Meta-Analyst software.30
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RESULTS Study Selection We identified a total of 268 titles and abstracts, from which 196 were excluded based on title and
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abstract review and 31 were excluded based on article review (Figure 1). Reasons for exclusion included no drug of interest, patients without rheumatoid arthritis, lack of randomization, blinding, or a control group, or a study duration of 1 year) did not appear to differ substantially (summary ORs, 1.37 vs 1.44
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for serious infection and 1.32 vs 1.20 for discontinuation due to adverse events, respectively).
Quality of Evidence for Our Analyses
Most of our comparison analyses reached a high level of quality of evidence (Table 2), while some
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were determined to be of a moderate level. The latter level was observed in the analyses comparing between: certolizumab pegol vs. placebo on all evaluated outcomes; etanercept plus DMARD vs.
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DMARD for overall serious adverse event (due to inconsistency); adalimumab vs. placebo/methotrexate controls for malignancy events (due to inconsistency); infliximab vs. methotrexate for serious infection events and discontinuation due to adverse events (due to
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imprecision).
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DISCUSSION Our objective was to systematically update major safety profiles reported in the randomized controlled trials of all approved TNFis to date to inform the field. Our findings indicate a higher
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risk of serious infection associated with adalimumab, certolizumab pegol, and infliximab, which appears to contribute to higher rates of discontinuation. A similar trend was observed with
golimumab plus methotrexate combination therapy, but not golimumab mono-therapy. In contrast,
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etanercept showed a lower rate of discontinuation with a tendency towards a lower rate of serious infection. Furthermore, we found no increased risk of malignancy associated with TNFi use. These
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comparative safety findings should inform clinical and policy decision making in the management of rheumatoid arthritis.
A two-fold or higher risk of serious infection associated with adalimumab or infliximab were first reported by meta-analysis of randomized controlled trials in 20062 (Table 3). In 2009, a
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meta-analysis of 18 trials suggested that the increased risk associated with adalimumab or infliximab may be limited to the use of a higher than recommended dose.3 A subsequent metaanalysis found a >4-fold increased risk of serious infection among certolizumab pegol users, and a
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large Cochrane review of both randomized controlled trials and extension studies reported a 55% increased risk of serious infection among TNFi users in rheumatoid arthritis (no specific agent data
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in rheumatoid arthritis were reported) in 20115 (Table 3). The latest meta-analyses of randomized controlled trials also found effect estimates trending towards an increased risk among users of adalimumab, certolizumab pegol, and infliximab6, but not with etanercept.83 We found a 42% increased risk of serious infection associated with TNFi use as a group, and this was driven by adalimumab, certolizumab pegol, infliximab, and perhaps by golimumab. Etanercept was not associated with this risk and, if any, the point estimates were trending in an inverse direction. 13
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Furthermore, no significant risk difference was found among increased doses of TNFi treated patients and patients treated with normal doses in the included trials. Collectively, these findings allow conclusion that among available TNFis, etanercept stands out as a potentially safer option
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with regard to the risk of serious infection. Future research will likely confirm a statistically significant and clinically important increase in the risk of serious infections in patients with rheumatoid arthritis treated with TNFi.
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These differential risks of serious infection appear to drive those of adverse event-induced discontinuation. We found that this risk was also increased with TNFis as a group, which was
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driven by adalimumab, certolizumab pegol, and infliximab. In contrast, etanercept was associated with a 28% lower risk of adverse event-induced discontinuation. The increased risk of adverse event-induced discontinuation associated with adalimumab6,8,74, certolizumab pegol6,82, and infliximab6,8,73,74,80 has been reported by previous meta-analyses. In contrast, three previous meta-
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analyses reported that etanercept use is associated with a lower risk of adverse event-induced discontinuation (Table 3). These data, together with our findings, lead to the conclusion that among available TNFis, adverse events associated with adalimumab, certolizumab pegol, and infliximab
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(likely an increased risk of serious infection) lead to earlier termination of these agents, whereas etanercept use lasts longer with a better adverse event profile.6,74,83 The significant increased risk of
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discontinuation observed among golimumab plus methotrexate users (but not among golimumab mono-therapy users) is intriguing and calls for further examination. Despite these notably differential profiles on serious infection and adverse event-induced discontinuation among TNFis, our meta-analyses found no increased risk for overall serious adverse event among TNFis users as a group, except for certolizumab pegol use. This null conclusion has been consistently reported in all previous meta-analyses (Table 3), which may appear conflicting 14
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with the findings discussed above. Although the overall serious adverse event rates give a summary view of the overall "average" safety profile of TNFis as a class, it can mask important differences among TNFis, as demonstrated in our study. These comparative data among TNFis are indeed more
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relevant to the decision making of choosing one over the other to improve the net effectiveness of rheumatoid arthritis care.
With regard to the risk of malignancy, more than a 3-fold increased risk among users of
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adalimumab or infliximab was reported in the meta-analysis by Bongartz in 2006.2 Since then, no other meta-analyses3-5,7,8,73,74,80,82 have been able to replicate the findings (Table 3), including a
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very large recent meta-analysis for both TNFis alone and in combination with DMARDs in rheumatoid arthritis patients.7 Our findings also confirm no increased risk of malignancy associated with TNFis either as a group or individually. Furthermore, findings from observational studies as well as from a large long-term extension study of a randomized controlled trial have reported no
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increased risk of malignancy across all TNFis.7,84-86 Collectively, these data to date are reassuring with regards to malignancy risk among TNFi users. There are several limitations associated with systematic reviews in general, as well as that
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are specific to our study. Some safety data are not available in all finally selected articles and thus could not be included in our analysis. Similar to previous meta-analyses, we observed heterogeneity
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in our source trial data, including follow-up times and administered doses across included randomized controlled trials. We attempted to deal with these limitations in the original research by designing and applying stringent selection criteria so that our results are based on solid coherent evidence. Disease severity was not taken into account in our study, partly due to the difficulties associated with the different severity measures across the trials. Addressing this issue in future studies would be valuable. 15
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In conclusion, our meta-analysis of randomized controlled trials to date indicates potential important differences in the safety profile among all currently available TNFis. The risk of serious infection is increased among adalimumab-, certolizumab pegol-, or infliximab-treated patients. In
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turn, patients on these agents had an increased risk of discontinuation due to adverse events.
Etanercept-treated patients instead showed a decreased risk. Our null findings on malignancy risk together with multiple previous findings to date are reassuring. As available TNFis have shown no
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detectable differences in efficacy in rheumatoid arthritis, their safety profile could be an important determinant for patient and physician decision making. To that end, our findings should be relevant
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to clinical comparative effectiveness guidelines on treatment for rheumatoid arthritis patients.
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Table 1. Characteristic of Randomized Controlled Trials Included in the Analysis Treatment Group
33
Keystone
34
van de Putte
Miyasaka35
36
24
2004
52
2004
26
2008
24
Breedveld
2006
104
37
2007
24
2008
56
2003
24
Kim
Bejarano
38
39
Furst
40
Kavanaugh Detert
41
Moreland42
43
Bathon
16
Klareskog §
44
Combe †
RA with inadequate response to MTX RA with inadequate response to ≧1 DMARDs
RA with inadequate response to ≧ 1, DMARDs-, biologics- naïve
Female (%)
72
ADA 20mg qw
54
85
10.4
70
ADA 40mg qw
53
81
10
72
ADA 80mg qw
53
69
10.1
69
ADA 20mg eow
54
75
13.1
RA 12 weeks
↔ ↑ (CZP)
↔
↑ (overall) ↑ (ADA, CZP, INF)
9,862
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ADA, CZP, ETN, GLM, INF
Aaltonen, 20126
Malignancy
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73
Chen (NICE) , 2006
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2
Bongartz, 2006
Study Design
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Total Subjects 5,005
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ADA, INF
Included Studies, N 9
Interventions
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Author, Year
↔ NA ↔ (overall) ↑ (ADA, CZP, INF) ↓ (ETN, RR = 0.71 compared with control) NA ↓ (RR=0.53 for ETN + DMARDs vs. DMARD) ↑ (overall) ↑ (ADA, CZP, INF) ↓ (ETN, OR = 0.72)
Abbreviation: ADA, adalimumab; CZP, certolizumb pegol; ETN, etanercept; INF, infliximab; GLM, golimumab; ABT, abatacept; ANK, anakinra; RTX, rituximab; TCZ, tocilizumab; MTX, methotrexate; DMARD, disease-modifying antirheumatic drug; RR, relative risk; RD, risk difference; RCT, randomized controlled trial; CCT, controlled Clinical trial; OLE, open-label extension; SAE, serious adverse event; AEs, adverse events. NE, not estimable; NICE, National Institute for Clinical Excellence; CR, Cochrane Reviews. *The results are based on all indications of the 9 biologics invested in that study, unless marked otherwise. **ADA, CZP, ETN, GLM, INF, ABT, ANK, RTX and TCZ.
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Citations retrieved (n=285) Duplicate citations (n=17)
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Title and abstract review (n=268)
Excluded (n=196) No biologics of interest: 19 Patients without RA: 29 No randomization: 39 Sample size < 100: 19 Subanalysis of original data: 23 Review article: 14 Don’t evaluate adult: 6 No safety outcome: 47
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Citations identified from electronic database: MEDLINE: 261 The Cochrane Collaboration: 24
Article review (n=72)
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Excluded (n=31) Open-label trial: 15 No control group: 9 Study duration < 12 weeks: 5 Prior TNF inhibitor: 2
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PubMed Auto Alert after database search was completed (n=3)
Article eligible for extraction (n=44)
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Adalimumab n=11 (11 RCTs) Certolizumab Pegol n=5 (5 RCTs) Etanercept n=12 (8 RCTs) Golimumab n=7 (7 RCTs) Infliximab n=9 (7 RCTs)
Figure 1. Flow diagram for selection of studies included in the meta-analysis.
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Events, Treatment
Events, Control
0.71 0.76 0.81 1.15 1.45 1.18 1.17 0.47 0.93
(0.27, 1.91) (0.40, 1.45) (0.43, 1.52) (0.37, 3.59) (0.69, 3.04) (0.49, 2.82) (0.72, 1.91) (0.22, 0.99) (0.72, 1.19)
16/214 17/318 53/434 7/65 35/265 13/75 37/515 12/87 190/1973
7/70 22/318 16/110 6/63 8/87 11/73 32/517 22/85 124/1323
1.43 2.54 1.96 1.08 1.32 1.44
(0.80, 2.59) (0.76, 8.53) (0.88, 4.36) (0.58, 2.04) (0.60, 2.89) (1.04, 2.00)
63/783 8/111 36/494 52/851 16/124 175/2363
11/199 3/109 4/125 12/212 12/119 42/764
0.79 1.49 0.94 3.51 1.06 1.16
(0.47, 1.34) (0.78, 2.86) (0.57, 1.57) (1.63, 7.54) (0.58, 1.95) (0.89, 1.52)
44/454 23/266 33/274 50/204 35/244 185/1442
27/228 16/269 34/268 2/50 18/132 97/947
1.50 0.74 2.19 2.03 1.48 0.77 1.30
(0.39, 5.80) (0.34, 1.61) (0.84, 5.68) (0.70, 5.86) (0.18, 11.94) (0.12, 4.93) (0.82, 2.05)
12/137 25/474 18/311 20/513 3/173 3/203 81/1811
2/35 11/160 3/133 2/129 1/88 2/105 21/650
0.75 1.28 1.03 0.36 0.97 1.04
(0.40, 1.39) (0.85, 1.91) (0.64, 1.66) (0.05, 2.58) (0.46, 2.06) (0.80, 1.34)
57/342 103/749 55/721 1/87 19/165 235/2064
18/86 32/291 27/363 3/86 13/110 93/936
1.11 (0.97, 1.26)
866/9653
377/4620
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Adalimumab van de Putte 2003 Furst 2003 van de Putte 2004 Kim 2007 Miyasaka 2008 Bejarano 2008 Kavanaugh 2013 Detert 2013 Subtotal (I-squared = 0.0%, p = 0.458) . Certolizumab Pegol Keystone 2008 Fleischmann 2009 Smolen 2009 Weinblatt 2012 Choy 2012 Subtotal (I-squared = 0.0%, p = 0.687) . Etanercept Klareskog 2004 Weisman 2007 Emery 2008 Combe 2009 Moreland 2012 Subtotal (I-squared = 64.8%, p = 0.023) . Golimumab Kay 2008 Emery 2009 keystone 2009 Kremer 2010 Tanaka 2012 Takeuchi 2013 Subtotal (I-squared = 0.0%, p = 0.521) . Infliximab Lipsky 2000 St Clair 2004 Westhovens 2006 Zhang 2006 Schiff 2008 Subtotal (I-squared = 0.0%, p = 0.516) . Overall (I-squared = 15.3%, p = 0.234)
OR (95% CI)
1
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Year
SC
Author
10
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Figure 2. Effect of TNF inhibitors vs. control therapy on the occurrence of overall SAEs in patients with rheumatoid arthritis.
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Year
Adalimumab Furst 2003 Weinblatt 2003 van de Putte 2004 Keystone 2004 Breedveld 2006 Miyasaka 2008 Kavanaugh 2013 Detert 2013 van de Putte 2003 Kim 2007 Bejarano 2008 Subtotal (I-squared = 47.9%, p = 0.062) . Certolizumab Pegol Keystone 2008 Smolen 2009 Fleischmann 2009 Weinblatt 2012 Choy 2012 Subtotal (I-squared = 0.0%, p = 0.332) . Etanercept Bathon 2000 van der Heijde 2006 Weisman 2007 Emery 2008 Combe 2009 Moreland 2012 Hu 2009 Subtotal (I-squared = 0.0%, p = 0.853) . Golimumab Kay 2008 Emery 2009 keystone 2009 Tanaka 2012 Takeuchi 2013 Subtotal (I-squared = 8.5%, p = 0.335) . Infliximab Lipsky 2000 St Clair 2004 Westhovens 2006 Schiff 2008 Subtotal (I-squared = 0.0%, p = 0.849) . Overall (I-squared = 0.9%, p = 0.449)
OR (95% CI)
Events, Treatment
Events, Control
7.39 (0.15, 3.66 (0.03, 1.01 (0.11, 4.41 (0.54, 0.70 (0.18, 0.02 (0.00, 7.42 (0.15, 0.13 (0.01, (Excluded) (Excluded) (Excluded) 0.80 (0.35,
1/318 1/209 4/434 4/419 6/542 0/265 1/515 0/87 0/214 0/65 0/75 17/3143
0/318 0/62 1/110 0/200 4/257 2/87 0/517 3/85 0/70 0/63 0/73 10/1842
11/783 2/494 0/111 0/851 0/124 13/2363
1/199 1/125 0/109 0/212 0/119 2/764
372.38) 388.65) 9.06) 36.06) 2.64) 0.43) 373.84) 1.26)
1.82)
SC
2.11 (0.51, 8.69) 0.44 (0.03, 7.43) (Excluded) (Excluded) (Excluded) 1.54 (0.43, 5.46)
RI PT
Author
6.21) 7.21) 3.93) 3.95) 114.72) 12.28) 2.78)
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1.29 (0.27, 2.15 (0.64, 0.68 (0.12, 0.98 (0.24, 3.49 (0.11, 2.27 (0.42, (Excluded) 1.45 (0.76,
0/35 2/160 0/133 0/88 0/105 2/521
111.66) 2.57) 300.81) 4.52)
2/137 2/474 1/311 0/173 0/203 5/1298
3.54 4.03 1.46 1.32 2.29
31.85) 35.83) 11.69) 13.44) 6.86)
5/342 4/749 3/721 2/165 14/1977
0/86 0/291 1/361 1/110 2/848
77/10756
28/5259
(0.39, (0.45, (0.18, (0.13, (0.77,
10
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1
2/217 2/228 3/269 4/268 0/50 1/132 0/120 12/1284
3.54 (0.11, 0.27 (0.03, 4.17 (0.06, (Excluded) (Excluded) 0.80 (0.14,
1.29 (0.85, 1.97)
.1
5/415 10/454 2/266 4/274 2/204 5/244 0/118 28/1975
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Figure 3. Effect of TNF inhibitors vs. control therapy on the occurrence of one or more malignancies in patients with rheumatoid arthritis.
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Events, Control
3.82 0.67 3.67 3.58 3.46 0.80 2.67 1.47 2.13 0.73 1.69
(0.39, (0.19, (0.13, (0.75, (1.23, (0.30, (0.77, (0.25, (0.86, (0.16, (1.12,
37.62) 2.32) 100.18) 16.96) 9.68) 2.13) 9.19) 8.68) 5.27) 3.28) 2.54)
4/214 4/318 2/209 10/434 16/419 12/542 13/265 3/75 13/515 3/87 80/3078
0/70 6/318 0/62 0/110 1/200 7/257 1/87 2/73 6/517 4/85 27/1779
7.32 3.60 1.34 1.44 1.98
(0.46, (0.96, (0.51, (0.25, (0.99,
117.84) 13.45) 3.55) 8.44) 3.96)
2/111 14/494 22/851 3/124 41/1580
0/109 0/125 4/212 2/119 6/565
3.49 0.80 0.52 0.61 1.22 0.73
(0.11, (0.31, (0.21, (0.20, (0.38, (0.45,
114.72) 2.06) 1.24) 1.83) 3.87) 1.20)
1
2/204 8/266 21/416 5/274 9/244 45/1404
0/50 10/269 10/115 8/268 4/132 32/834
0.75 1.23 2.50 2.01 4.52 0.49 1.55
(0.06, (0.36, (0.59, (0.45, (0.07, (0.03, (0.76,
8.70) 4.16) 10.53) 8.87) 285.61) 9.19) 3.17)
3/137 11/474 8/311 10/513 1/173 1/203 34/1811
1/35 3/160 1/133 1/129 0/88 1/105 7/650
3.23 0.72 2.17 1.86 1.54 1.63
(0.06, (0.28, (1.12, (0.86, (0.43, (1.07,
181.94) 1.88) 4.19) 4.02) 5.57) 2.47)
2/87 21/342 40/749 24/721 7/165 94/2064
0/14 7/86 6/291 6/363 3/110 22/864
294/9937
94/4692
1.42 (1.13, 1.78)
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Events, Treatment
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Adalimumab van de Putte 2003 Furst 2003 Weinblatt 2003 van de Putte 2004 Keystone 2004 Breedveld 2006 Miyasaka 2008 Bejarano 2008 Kavanaugh 2013 Detert 2013 Subtotal (I-squared = 8.4%, p = 0.365) . Certolizumab Pegol Fleischmann 2009 Smolen 2009 Weinblatt 2012 Choy 2012 Subtotal (I-squared = 0.0%, p = 0.497) . Etanercept Combe 2006 Weisman 2007 van der Heijde 2007 Emery 2008 Moreland 2012 Subtotal (I-squared = 0.0%, p = 0.687) . Golimumab Kay 2008 Emery 2009 keystone 2009 Kremer 2010 Tanaka 2012 Takeuchi 2013 Subtotal (I-squared = 0.0%, p = 0.868) . Infliximab Maini 1998 Lipsky 2000 St Clair 2004 Westhovens 2006 Schiff 2008 Subtotal (I-squared = 0.0%, p = 0.440) . Overall (I-squared = 0.0%, p = 0.467)
OR (95% CI)
RI PT
Year
SC
Author
10
AC C
EP
Figure 4. Effect of TNF inhibitors vs. control therapy on the occurrence of serious infections in patients with rheumatoid arthritis.
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Events, Control
1.55 0.72 1.13 2.50 1.54 0.97 1.59 1.94 1.33 0.49 1.38
(0.24, (0.12, (0.43, (0.75, (0.85, (0.23, (0.61, (0.38, (0.69, (0.10, (1.00,
10.08) 4.28) 2.96) 8.31) 2.79) 4.03) 4.15) 9.88) 2.56) 2.49) 1.89)
5/214 5/209 9/318 16/434 42/419 4/65 20/265 4/75 21/515 2/87 128/2601
1/70 2/62 8/318 1/110 13/200 4/63 4/87 2/73 16/517 4/85 55/1585
2.39 2.37 1.98 1.24 1.13 1.67
(1.08, (0.53, (0.67, (0.60, (0.37, (1.09,
5.26) 10.64) 5.85) 2.56) 3.44) 2.54)
39/407 5/111 19/494 40/851 7/124 110/1987
3/101 2/109 2/125 8/212 6/119 21/666
1.21 0.45 0.71 0.78 0.90 0.99 0.72
(0.32, (0.24, (0.46, (0.46, (0.38, (0.36, (0.55,
4.60) 0.84) 1.08) 1.33) 2.15) 2.74) 0.93)
7/154 23/415 71/454 28/274 30/204 11/244 170/1745
3/80 24/217 47/228 34/268 8/50 6/132 122/975
1.27 1.85 0.73 3.00 1.42 0.49 1.43
(0.30, (0.84, (0.20, (0.79, (0.36, (0.09, (0.88,
5.45) 4.04) 2.70) 11.40) 5.69) 2.67) 2.35)
10/137 30/474 7/311 9/173 9/395 3/203 68/1693
2/35 5/160 4/133 1/88 2/129 3/105 17/650
3.39 0.93 2.45 2.13 1.51 3.46 2.04
(0.32, (0.38, (1.47, (1.14, (0.42, (0.89, (1.46,
36.52) 2.25) 4.08) 3.97) 5.38) 13.38) 2.84)
6/87 26/342 69/751 38/721 6/87 8/165 153/2153
0/14 7/86 9/298 8/363 4/86 1/110 29/957
629/10179
244/4833
1.23 (1.06, 1.43)
1
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.1
Events, Treatment
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Adalimumab van de Putte 2003 Weinblatt 2003 Furst 2003 van de Putte 2004 Keystone 2004 Kim 2007 Miyasaka 2008 Bejarano 2008 Kavanaugh 2013 Detert 2013 Subtotal (I-squared = 0.0%, p = 0.922) . Certolizumab Pegol Keystone 2008 Fleischmann 2009 Smolen 2009 Weinblatt 2012 Choy 2012 Subtotal (I-squared = 0.0%, p = 0.695) . Etanercept Moreland 1999 Bathon 2000 van der Heijde 2006 Emery 2008 Combe 2009 Moreland 2012 Subtotal (I-squared = 0.0%, p = 0.619) . Golimumab Kay 2008 Emery 2009 keystone 2009 Tanaka 2012 Weinblatt 2013 Takeuchi 2013 Subtotal (I-squared = 0.0%, p = 0.525) . Infliximab Maini 1998 Lipsky 2000 St Clair 2004 Westhovens 2006 Zhang 2006 Schiff 2008 Subtotal (I-squared = 0.0%, p = 0.476) . Overall (I-squared = 31.1%, p = 0.047)
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Figure 5. Effect of TNF inhibitors vs. control therapy on the occurrence of discontinuation due to AEs in patients with rheumatoid arthritis.
ACCEPTED MANUSCRIPT Appendix I: Exact Strings Title of database searched: PubMed, and the Cochrane Library. Date search was run (month, day, and year): May 2, 2013. Years covered by the search: from 1990 until May 2, 2013. Language restrictions, all other possible restrictions: randomized controlled trials published in English and adults. Time, Database
#1
Search (etanercept OR infliximab OR adalimumab OR certolizumab pegol OR golimumab)
PubMed, 05/02/2013
12642
#2
Search malignancy
PubMed, 05/02/2013
2491138
#3
Search infection
PubMed, 05/02/2013
1196618
#4
Search adverse effects
PubMed, 05/02/2013
1711984
#5
Search rheumatoid arthritis
PubMed, 05/02/2013
117172
#6
Search (((etanercept OR infliximab OR adalimumab OR certolizumab pegol OR golimumab))) AND rheumatoid arthritis
PubMed, 05/02/2013
4300
#7
Search (((etanercept OR infliximab OR adalimumab OR certolizumab pegol OR golimumab))) AND rheumatoid arthritis Filters: Randomized Controlled Trial; English; Adult: 19+ years
PubMed, 05/02/2013
245
#8
Search (#5 AND #1) AND ((#2 or #3 or #4) Filters: Journal Article; English
PubMed, 05/02/2013
1288
#9
Search (#5 AND #1) AND ((#2 or #3 or #4) Filters: Randomized Controlled Trial; English
PubMed, 05/02/2013
103
#10
Search (#5 AND #1) AND (#2 or #3 or #5) Filters: Journal Article; English
PubMed, 05/02/2013
3252
#11
Search (#5 AND #1) AND ((#2 or #3 or #4) Filters: Journal Article; English; Adult: 19+ years
PubMed, 05/02/2013
848
#12
Search The Surveillance, Epidemiology and End Results Filters: Journal Article; English; Adult: 19+ years
PubMed, 05/02/2013
21503
#13
Search ((((#5 AND #1) AND ((#2 or #3 or #4)) AND Journal Article[ptyp] AND English[lang] AND adult[MeSH])) AND (The Surveillance, Epidemiology and End Results AND Journal Article[ptyp] AND English[lang] AND adult[MeSH]) Filters: Journal Article; English; Adult: 19+ years
PubMed, 05/02/2013
8
#14
Search ((((#5 AND #1) AND ((#2 or #3 or #4)) AND Journal Article[ptyp] AND English[lang] AND adult[MeSH])) AND Medicare Filters: Journal Article; English; Adult: 19+ years
PubMed, 05/02/2013
6
#15
Search (Drug Monitoring"[Mesh]) OR Pharmacovigilance Filters: Journal Article; English; Adult: 19+ years
PubMed, 05/02/2013
619
#16
Search #19 and #23 Filters: Journal Article; English; Adult: 19+ years
PubMed, 05/02/2013
9
#17
Search #1 Filters: Journal Article; Randomized Controlled Trial; English; Adult: 19+ years
PubMed, 05/02/2013
4735
#18
Search #1 Filters: Randomized Controlled Trial; English
PubMed, 05/02/2013
760
#19
Search rheumatoid arthritis Filters: Randomized Controlled Trial; English
PubMed, 05/02/2013
2634
#20
Search (etanercept OR infliximab OR adalimumab OR certolizumab pegol OR golimumab)and rheumatoid arthritis Filters: Randomized Controlled Trial; English; Adult: 19+ years
PubMed, 05/02/2013
261
#21
Arthritis, Rheumatoid and etanercept OR infliximab OR adalimumab OR certolizumab pegol OR golimumab
Cochrane Library, 05/02/2013
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ACCEPTED MANUSCRIPT Appendix II: excluded references
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31. Criswell LA, Lum RF, Turner KN, Woehl B, Zhu Y, Wang J, et al. The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis & Rheumatism; 2004:2750-6. 32. Cuomo G, Molinaro G, La Montagna G, Migliaresi S, Valentini G. [A comparison between the Simplified Disease Activity Index (SDAI) and the Disease Activity Score (DAS28) as measure of response to treatment in patients undergoing different therapeutic regimens]. Reumatismo; 2006:225. 33. Curtis JR, Luijtens K, Kavanaugh A. Predicting future response to certolizumab pegol in rheumatoid arthritis patients: features at 12 weeks associated with low disease activity at 1 year. Arthritis Care Res (Hoboken). 2012;64(5):658-67. 34. Davis JC, Jr., Van Der Heijde D, Braun J, Dougados M, Cush J, Clegg DO, et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum. 2003;48(11):3230-6. 35. Davis JC, Van Der Heijde D, Braun J, Dougados M, Cush J, Clegg DO, et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis and rheumatism; 2003:3230-6. 36. De Filippis L, Caliri A, Anghelone S, Scibilia G, Lo Gullo R, Bagnato G. Improving outcomes in tumour necrosis factor a treatment: comparison of the efficacy of the tumour necrosis factor a blocking agents etanercept and infliximab in patients with active rheumatoid arthritis. Panminerva Med. 2006;48(2):129-35. 37. De Stefano R, Frati E, Nargi F, Baldi C, Menza L, Hammoud M, et al. Comparison of combination therapies in the treatment of rheumatoid arthritis: leflunomide-anti-TNF-alpha versus methotrexateanti-TNF-alpha. Clin Rheumatol. 2010;29(5):517-24. 38. de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Verpoort KN, Schreuder GM, Ewals JA, Terwiel JP, et al. Progression of joint damage in early rheumatoid arthritis: association with HLA-DRB1, rheumatoid factor, and anti-citrullinated protein antibodies in relation to different treatment strategies. Arthritis Rheum. 2008;58(5):1293-8. 39. Delabaye I, De Keyser F. 74-week follow-up of safety of infliximab in patients with refractory rheumatoid arthritis. Arthritis Res Ther. 2010;12(3):R121. 40. den Broeder A, van de Putte L, Rau R, Schattenkirchner M, Van Riel P, Sander O, et al. A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis. J Rheumatol. 2002;29(11):2288-98. 41. Dias EM, Lukas C, Landewé R, Fatenejad S, van der Heijde D. Reliability and sensitivity to change of the Simple Erosion Narrowing Score compared with the Sharp-van der Heijde method for scoring radiographs in rheumatoid arthritis. Annals of the rheumatic diseases; 2008:375-9. 42. Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, et al. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum. 2007;56(12):3919-27. 43. Durez P, Nzeusseu Toukap A, Lauwerys BR, Manicourt DH, Verschueren P, Westhovens R, et al. A randomised comparative study of the short term clinical and biological effects of intravenous pulse methylprednisolone and infliximab in patients with active rheumatoid arthritis despite methotrexate treatment. Ann Rheum Dis. 2004;63(9):1069-74. 44. Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, et al. Randomised doubleblind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet. 1994;344(8930):1105-10.
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45. Emery P, Fleischmann R, van der Heijde D, Keystone EC, Genovese MC, Conaghan PG, et al. The effects of golimumab on radiographic progression in rheumatoid arthritis: results of randomized controlled studies of golimumab before methotrexate therapy and golimumab after methotrexate therapy. Arthritis Rheum. 2011;63(5):1200-10. 46. Emery P, Genovese MC, van Vollenhoven R, Sharp JT, Patra K, Sasso EH. Less radiographic progression with adalimumab plus methotrexate versus methotrexate monotherapy across the spectrum of clinical response in early rheumatoid arthritis. J Rheumatol. 2009;36(7):1429-41. 47. Emery P, van der Heijde D, Ostergaard M, Conaghan PG, Genovese MC, Keystone EC, et al. Exploratory analyses of the association of MRI with clinical, laboratory and radiographic findings in patients with rheumatoid arthritis. Ann Rheum Dis. 2011;70(12):2126-30. 48. Englbrecht M, Wang Y, Ronneberger M, Manger B, Vastesaeger N, Veale DJ, et al. Measuring joint involvement in polyarticular psoriatic arthritis: an introduction of alternatives. Arthritis care & research; 2010:977-83. 49. Engvall IL, Tengstrand B, Brismar K, Hafstrom I. Infliximab therapy increases body fat mass in early rheumatoid arthritis independently of changes in disease activity and levels of leptin and adiponectin: a randomised study over 21 months. Arthritis Res Ther. 2010;12(5):R197. 50. Farahani P, Levine M GR. A comparison between integrating clinical practice setting and randomized controlled trial setting into economic evaluation models of therapeutics. Journal of Evaluation in Clinical Practice; 2006:463-70. 51. Fasanmade AA, Adedokun OJ, Ford J, Hernandez D, Johanns J, Hu C, et al. Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. Eur J Clin Pharmacol. 2009;65(12):1211-28. 52. Fernandez-Lopez C, Blanco FJ. [ATTAIN study: Efficacy of abatacept in patients with rheumatoid arthritis and inadequate response to anti-TNF-alpha]. Reumatologia Clinica Suplementos; 2006:3443. 53. Flint-Wagner HG, Lisse J, Lohman TG, Going SB, Guido T, Cussler E, et al. Assessment of a sixteen-week training program on strength, pain, and function in rheumatoid arthritis patients. J Clin Rheumatol. 2009;15(4):165-71. 54. FSmolen JS, Han C, van der Heijde DM, Emery P, Bathon JM, Keystone E, et al. Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade. Ann Rheum Dis. 2009;68(6):823-7. 55. Furst DE, Gaylis N, Bray V, Olech E, Yocum D, Ritter J, et al. Open-label, pilot protocol of patients with rheumatoid arthritis who switch to infliximab after an incomplete response to etanercept: the opposite study. Ann Rheum Dis. 2007;66(7):893-9. 56. Garnero P, Gineyts E, Christgau S, Finck B, Delmas PD. Association of baseline levels of urinary glucosyl-galactosyl-pyridinoline and type II collagen C-telopeptide with progression of joint destruction in patients with early rheumatoid arthritis. Arthritis Rheum. 2002;46(1):21-30. 57. Genovese MC, Bathon JM, Fleischmann RM, Moreland LW, Martin RW, Whitmore JB, et al. Longterm safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis. J Rheumatol. 2005;32(7):1232-42. 58. Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum. 2002;46(6):1443-50.
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59. Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor a inhibition. New England Journal of Medicine; 2005:1114-23. 60. Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 2004;50(5):1412-9. 61. Genovese MC, Han C, Keystone EC, Hsia EC, Buchanan J, Gathany T, et al. Effect of golimumab on patient-reported outcomes in rheumatoid arthritis: results from the GO-FORWARD study. J Rheumatol. 2012;39(6):1185-91. 62. Gerlag DM, Hollis S, Layton M, Vencovský J, Szekanecz Z, Braddock M, et al. Preclinical and clinical investigation of a CCR5 antagonist, AZD5672, in patients with rheumatoid arthritis receiving methotrexate. Arthritis and rheumatism; 2010:3154-60. 63. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, Kerstens PJ, Grillet BA, de Jager MH, et al. Patient preferences for treatment: report from a randomised comparison of treatment strategies in early rheumatoid arthritis (BeSt trial). Ann Rheum Dis. 2007;66(9):1227-32. 64. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Annals of internal medicine; 2007:406-15. 65. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 2005;52(11):3381-90. 66. Goldman JA, Xia HA, White B, Paulus H. Evaluation of a modified ACR20 scoring system in patients with rheumatoid arthritis receiving treatment with etanercept. Ann Rheum Dis. 2006;65(12):1649-52. 67. Guler-Yuksel M, Allaart CF, Watt I, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, van Schaardenburg D, et al. Treatment with TNF-alpha inhibitor infliximab might reduce hand osteoarthritis in patients with rheumatoid arthritis. Osteoarthritis Cartilage. 2010;18(10):1256-62. 68. Guler-Yuksel M, Bijsterbosch J, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Hulsmans HM, de Beus WM, et al. Changes in bone mineral density in patients with recent onset, active rheumatoid arthritis. Ann Rheum Dis. 2008;67(6):823-8. 69. Guler-Yuksel M, Klarenbeek NB, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, van der Kooij SM, Gerards AH, et al. Accelerated hand bone mineral density loss is associated with progressive joint damage in hands and feet in recent-onset rheumatoid arthritis. Arthritis Res Ther. 2010;12(3):R96. 70. Han C, Rahman MU, Doyle MK, Bathon JM, Smolen J, Kavanaugh A, et al. Association of anemia and physical disability among patients with rheumatoid arthritis. J Rheumatol. 2007;34(11):2177-82. 71. Han C, Smolen J, Kavanaugh A, St Clair EW, Baker D, Bala M. Comparison of employability outcomes among patients with early or long-standing rheumatoid arthritis. Arthritis Rheum. 2008;59(4):510-4. 72. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet; 2002:1541-9. 73. Hasan U. Tumour necrosis factor inhibitors--what we need to know. N Z Med J. 2006;119(1246):U2336. 74. Haugeberg G, Conaghan PG, Quinn M, Emery P. Bone loss in patients with active early rheumatoid arthritis: infliximab and methotrexate compared with methotrexate treatment alone. Explorative
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disease activity at 1 year in rheumatoid arthritis patients treated with certolizumab pegol: a post-hoc analysis of the RAPID 1 trial. J Rheumatol. 2012;39(7):1326-33. van der Heijde D, Klareskog L, Boers M, Landewe R, Codreanu C, Bolosiu HD, et al. Comparison of different definitions to classify remission and sustained remission: 1 year TEMPO results. Ann Rheum Dis. 2005;64(11):1582-7. van der Heijde D, Klareskog L, Singh A, Tornero J, Melo-Gomes J, Codreanu C, et al. Patient reported outcomes in a trial of combination therapy with etanercept and methotrexate for rheumatoid arthritis: the TEMPO trial. Ann Rheum Dis. 2006;65(3):328-34. van der Heijde D, Landewe R, Einstein S, Ory P, Vosse D, Ni L, et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum. 2008;58(5):1324-31. van der Heijde D, Landewe R, Klareskog L, Rodriguez-Valverde V, Settas L, Pedersen R, et al. Presentation and analysis of data on radiographic outcome in clinical trials: experience from the TEMPO study. Arthritis Rheum. 2005;52(1):49-60. van der Heijde D, Landewé R, van Vollenhoven R, Fatenejad S, Klareskog L. Level of radiographic damage and radiographic progression are determinants of physical function: a longitudinal analysis of the TEMPO trial. Annals of the rheumatic diseases; 2008:1267-70. van der Kooij SM, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Ewals JA, Han KH, Hazes JM, et al. Patient-reported outcomes in a randomized trial comparing four different treatment strategies in recent-onset rheumatoid arthritis. Arthritis Rheum. 2009;61(1):4-12. van der Kooij SM, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, van Zeben D, Kerstens PJ, Gerards AH, et al. Limited efficacy of conventional DMARDs after initial methotrexate failure in patients with recent onset rheumatoid arthritis treated according to the disease activity score. Ann Rheum Dis. 2007;66(10):1356-62. van der Kooij SM, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Guler-Yuksel M, Zwinderman AH, Kerstens PJ, et al. Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis. Ann Rheum Dis. 2009;68(6):914-21. van der Kooij SM, le Cessie S, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, van Zeben D, Kerstens PJ, et al. Clinical and radiological efficacy of initial vs delayed treatment with infliximab plus methotrexate in patients with early rheumatoid arthritis. Ann Rheum Dis. 2009;68(7):1153-8. van Riel PL, Freundlich B, MacPeek D, Pedersen R, Foehl JR, Singh A, et al. Patient-reported health outcomes in a trial of etanercept monotherapy versus combination therapy with etanercept and methotrexate for rheumatoid arthritis: the ADORE trial. Annals of the rheumatic diseases; 2008:1104-10. van Riel PL, Taggart AJ, Sany J, Gaubitz M, Nab HW, Pedersen R, et al. Efficacy and safety of combination etanercept and methotrexate versus etanercept alone in patients with rheumatoid arthritis with an inadequate response to methotrexate: the ADORE study. Ann Rheum Dis. 2006;65(11):1478-83. van Vollenhoven RF, Cifaldi MA, Ray S, Chen N, Weisman MH. Improvement in work place and household productivity for patients with early rheumatoid arthritis treated with adalimumab plus methotrexate: work outcomes and their correlations with clinical and radiographic measures from a randomized controlled trial companion study. Arthritis Care Res (Hoboken). 2010;62(2):226-34. van Vollenhoven RF, Felson D, Strand V, Weinblatt ME, Luijtens K, Keystone EC. American College of Rheumatology hybrid analysis of certolizumab pegol plus methotrexate in patients with
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active rheumatoid arthritis: data from a 52-week phase III trial. Arthritis Care Res (Hoboken). 2011;63(1):128-34. van Vollenhoven RF, Kinnman N, Vincent E, Wax S, Bathon J. Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase II, randomized, placebo-controlled trial. Arthritis Rheum. 2011;63(7):1782-92. Vastesaeger N, Xu S, Aletaha D, St Clair EW, Smolen JS. A pilot risk model for the prediction of rapid radiographic progression in rheumatoid arthritis. Rheumatology (Oxford). 2009;48(9):1114-21. Vgontzas AN, Zoumakis E, Lin HM, Bixler EO, Trakada G, Chrousos GP. Marked decrease in sleepiness in patients with sleep apnea by etanercept, a tumor necrosis factor-A antagonist. Journal of Clinical Endocrinology & Metabolism; 2004:4409-13. Visser K, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Ronday HK, Seys PE, Kerstens PJ, et al. A matrix risk model for the prediction of rapid radiographic progression in patients with rheumatoid arthritis receiving different dynamic treatment strategies: post hoc analyses from the BeSt study. Ann Rheum Dis. 2010;69(7):1333-7. Visvanathan S, Keenan GF, Baker DG, Levinson AI, Wagner CL. Response to pneumococcal vaccine in patients with early rheumatoid arthritis receiving infliximab plus methotrexate or methotrexate alone. J Rheumatol. 2007;34(5):952-7. Visvanathan S, Marini JC, Smolen JS, Clair EW, Pritchard C, Shergy W, et al. Changes in biomarkers of inflammation and bone turnover and associations with clinical efficacy following infliximab plus methotrexate therapy in patients with early rheumatoid arthritis. J Rheumatol. 2007;34(7):1465-74. Visvanathan S, Wagner C, Rojas J, Kay J, Dasgupta B, Matteson EL, et al. E-selectin, interleukin 18, serum amyloid a, and matrix metalloproteinase 9 are associated with clinical response to golimumab plus methotrexate in patients with active rheumatoid arthritis despite methotrexate therapy. J Rheumatol. 2009;36(7):1371-9. Visvanathan S, Wagner C, Smolen J, St, Clair EW, Hegedus R, et al. IgG and IgM anticardiolipin antibodies following treatment with infliximab plus methotrexate in patients with early rheumatoid arthritis. Arthritis and Rheumatism; 2006:2840-4. Wang SY, Liu YY, Ye H, Guo JP, Li R, Liu X, et al. Circulating Dickkopf-1 is correlated with bone erosion and inflammation in rheumatoid arthritis. J Rheumatol. 2011;38(5):821-7. Weinblatt M, Schiff M, Goldman A, Kremer J, Luggen M, Li T, et al. Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial. Ann Rheum Dis. 2007;66(2):228-34. Weinblatt ME, Keystone EC, Furst DE, Kavanaugh AF, Chartash EK, Segurado OG. Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis: ARMADA 4 year extended study. Ann Rheum Dis. 2006;65(6):753-9. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340(4):253-9. Weinblatt ME, Schiff MH, Ruderman EM, Bingham CO, 3rd, Li J, Louie J, et al. Efficacy and safety of etanercept 50 mg twice a week in patients with rheumatoid arthritis who had a suboptimal response to etanercept 50 mg once a week: results of a multicenter, randomized, double-blind, active drug-controlled study. Arthritis Rheum. 2008;58(7):1921-30. Weisman MH, Moreland LW, Furst DE, Weinblatt ME, Keystone EC, Paulus HE, et al. Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-
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Adalimumab, certolizumab pegol, and infliximab are associated with a higher risk of serious infection, which appears to contribute to higher rates of discontinuation. In contrast, etanercept showed a lower rate of discontinuation with a tendency
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towards a lower rate of serious infection.
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making in the management of rheumatoid arthritis.
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These comparative safety findings should inform clinical and policy decision
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S0002-9343(14)00488-4
DOI:
10.1016/j.amjmed.2014.06.012
Reference:
AJM 12571
To appear in:
The American Journal of Medicine
Received Date: 18 November 2013 Revised Date:
22 May 2014
Accepted Date: 9 June 2014
Please cite this article as: Michaud TL, Rho YH, Shamliyan T, Kuntz KM, Choi HK, The Comparative Safety of TNF Inhibitors in Rheumatoid Arthritis - A Meta-Analysis Update of 44 Randomized Controlled Trials, The American Journal of Medicine (2014), doi: 10.1016/j.amjmed.2014.06.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The Comparative Safety of TNF Inhibitors in Rheumatoid Arthritis - A Meta-
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Analysis Update of 44 Randomized Controlled Trials
Tzeyu L. Michaud, MHA,a Young Hee Rho, MD, PhD, MPH,b Tatyana Shamliyan, MD, MS,c Karen M. Kuntz, ScD,a Hyon K. Choi, MD, DrPHb a
Division of Health Policy and Management, School of Public Health, University of Minnesota,
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Minneapolis, MN; bSection of Rheumatology and the Clinical Epidemiology Unit, Boston
Elsevier, Clinical Solutions, Philadelphia, PA.
Article type: Clinical Research Study.
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University School of Medicine, Boston, MA; cEvidence-Based Medicine Quality Assurance
Conflict of Interest: None.
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Funding: This research was supported by the National Institute of Health (RC1AR058601).
Authorship: All authors had access to the data, participated in the conception, design, writing, editing, and final approval of the manuscript.
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Requests for reprints should be addressed to Hyon K. Choi, MD, DrPH, Section of Rheumatology
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and the Clinical Epidemiology Unit, Boston University School of Medicine, 650 Albany Street, Suite 200, Boston, MA 02118. E-mail address: [email protected] Keywords: Rheumatoid arthritis; Meta-analysis; Safety; Adverse events; TNF inhibitors. Running Head: Meta-analysis for the safety of TNF inhibitors.
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ABSTRACT Objective. To evaluate and update the safety data from randomized controlled trials of TNF inhibitors (TNFis) in patients treated for rheumatoid arthritis.
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Methods. A systematic literature search was conducted from 1990 through May 2013. All studies included were randomized, double blind, controlled trials of patients with rheumatoid arthritis that evaluated adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab treatment. The
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serious adverse events and discontinuation rates were abstracted, and risk estimates were calculated by Peto odds ratios (ORs).
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Results. Forty-four randomized controlled trials involving 11,700 subjects receiving TNFis and 5,901 subjects receiving placebo and/or traditional disease-modifying anti-rheumatic drugs (DMARDs) were included. TNFi treatment as a group was associated with a higher risk of serious infection (OR, 1.42; 95% CI, 1.13-1.78) and treatment discontinuation due to adverse events (OR,
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1.23; 95% CI, 1.06-1.43) compared with placebo and/or traditional DMARD treatments. Specifically, patients on adalimumab, certolizumab pegol, and infliximab had an increased risk of serious infection (OR, 1.69, 1.98, and 1.63) and showed an increased risk of discontinuation due to
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adverse events (OR, 1.38, 1.67 and 2.04). In contrast, patients on etanercept had a decreased risk of discontinuation due to adverse events (OR, 0.72; 95% CI, 0.55-0.93). Although ORs for
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malignancy varied across the different TNFis, none reached a statistical significance. Conclusion. These meta-analysis updates of the comparative safety of TNFis suggest a higher risk of serious infection associated with adalimumab, certolizumab pegol, and infliximab, which appears to contribute to higher rates of discontinuation. In contrast, etanercept use showed a lower rate of discontinuation. These data may help guide clinical comparative decision making in the management of rheumatoid arthritis. 2
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INTRODUCTION Tumor necrosis factor inhibitors (TNFis) are the dominant first-line biologic therapy in the management of rheumatoid arthritis1, and up-to-date knowledge of their safety profiles remains
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critical in rheumatoid arthritis care. Furthermore, as TNFis show no detectable efficacy difference in rheumatoid arthritis, their safety profile is likely to be an important determinant for decision making in rheumatoid arthritis care.
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Since a meta-analysis of 9 randomized trials (n=3,493) reported an increased risk of
malignancy and serious infections among rheumatoid arthritis patients who received infliximab and
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adalimumab in 20062, subsequent meta-analyses have been published about various biologics, indications (rheumatoid arthritis only vs. inclusion of others), and safety outcomes.3-8 For example, a 2011 Cochrane review of the safety profile of biologics found a 55% increased risk of serious infection among users of biologics as a group in rheumatoid arthritis and only certolizumab pegol
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reached a significant association among individual agents, with an OR of 4.75 (for all indicated conditions).5 Another recent large randomized controlled trial meta-analysis focused on malignancy risk in rheumatoid arthritis patients concluded that biologic use (≥ 6 months) was not significantly
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associated with an increased risk of malignancy.5,7 As such, some of the initial meta-analysis findings2 have not been consistently replicated by subsequent studies and additional findings have
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emerged, underscoring the importance of updated comparative safety profiles of TNFis in the field. In this systematic review and meta-analysis, we aim to comparatively update the key relevant safety profiles (i.e. overall serious adverse events, malignancy, serious infection, and discontinuation due to adverse events) of all FDA-approved TNFis (i.e. infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab)9-11 in rheumatoid arthritis patients.
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MATERIALS AND METHODS Data Sources and Searches
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Study selection, assessment of eligibility criteria, data extraction, and statistical analysis were performed based on a predefined, peer-reviewed protocol according to the Cochrane Collaboration guidelines (http://www.cochrane.org/resources/handbook/index.html).
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We undertook a systematic literature search including randomized controlled trials
(randomized controlled trials) that selected adult patients with rheumatoid arthritis. We searched
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studies using MEDLINE® via OVID and PubMed®, the Cochrane databases, Google Scholar, clinicaltrials.gov, and manual searches of reference lists from systematic reviews and original publications and identified studies published in English from 1990 to May 2, 2013. PubMed Auto Alerts was set up to provide weekly updates of new literature until October 2013. In addition, we searched the FDA briefing documents, approval packages, and medical or statistical reviews to
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review the drug approval reports which provide eligible trials. The search terms included rheumatoid arthritis; etanercept; infliximab; adalimumab; certolizumab pegol; golimumab; Randomized Controlled Trial; adverse effects; infection; malignancy; English; All Adult (see
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Appendix I for detailed search strings).
Study selection
We pre-specified the target population, interventions, comparators, outcome measures of interest, timing, and settings (PICOTS) following the PICOTS framework.12 To be eligible, randomized controlled trials had to (1) compare the safety of any of the TNFis against placebo and/or traditional DMARDs; (2) include only patients with rheumatoid arthritis; (3) have a sample size greater than
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100; and (4) report a minimum of 12 weeks of the study duration. We excluded studies that were open-labeled. We defined the target population as 19 years of age or older (using a PubMed filter), with
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rheumatoid arthritis diagnosed according to the 1987 revised American College of Rheumatology criteria.13 Eligible interventions included all five currently available TNFis (adalimumab,
certolizumab pegol, etanercept, golimumab, and infliximab). Eligible comparators included placebo
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or traditional DMARDs.14 Eligible outcomes included 1) serious adverse events, which was any adverse event that resulted in death, was life threatening, resulted in hospitalization or prolongation
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of hospitalization, or caused persistent or substantial disability15; 2) serious infection, defined as an infection that requires antimicrobial therapy or hospitalization16; 3) malignancies, defined as each randomized controlled trial specified17; and 4) treatment discontinuation due to adverse events. Two investigators (TM and YR) independently determined the eligibility of the studies18 and discrepancy
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was resolved by consensus.
Data Extraction and Study Quality Assessment
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Two investigators (TM and YR) independently extracted baseline patient characteristics, drug doses and treatment duration, the number of subjects experiencing an event by outcomes in randomized
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groups, and the number of randomized patients for intention-to-treat analysis. Discrepancy was resolved by consensus.
We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for grading evidence.19-21 The ranks of the quality of evidence were based on the type of study design, the risk of bias in the body of evidence, the consistency of the results, and the precision of the overall estimate. For each outcome, the strength 5
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of the evidence was rated as high, moderate, low, or very low. We examined risk of bias in individual studies using the criteria from the Cochrane risk-of-bias tool.22 To appraise the risk of bias, we used predefined criteria, which included random sequence generation, allocation
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concealment, masking of the treatment status, masking of outcome assessment, selective outcome reporting, and intention-to-treat principles. Consistency was obtained based on the pooled statistical
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heterogeneity at the significant level α=0.1.
Data Synthesis and Statistical Analysis
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We compared each TNFi with placebo alone or in combination with traditional DMARDs. In addition, the subgroup analysis was presented to check whether TNFi mono-therapy or combination therapy with traditional DMARDs would substantially change the findings. We conducted meta-analyses wherever there was a consistent outcome measure.22 Both Peto odds ratios
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(ORs) and arcsine transformation risk differences (ASRDs) and their 95% confidence intervals (CIs) were calculated.
Although we report both measures of association, the Peto OR is preferred for uncommon
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events. Both the individual Peto ORs of studies and pooled Peto ORs were presented. The ASRDs
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were used to calculate the number needed to harm.23 The number needed to harm was defined as the reciprocal of the pooled ASRDs if the results from Peto ORs and ASRD were both significant.24 It is recommended that studies with zero events in both arms be excluded from meta-analyses of ORs.25 Furthermore, the Peto and ASRD method, which were used in the current study, effectively excludes those studies from the analysis by assigning them zero weight.22,26 No imputation or estimation methods were used for missing values during the study.
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To address the potential dose impact, we also compared the event rates according to TNFi dose (i.e., high dose vs normal dose), similar to a recent systematic review by Aaltonen et al.6 For this analysis, high dose referred to a higher than normal TNFi dose as per package insert of each
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TNFi as follows: infliximab 3 mg/kg/every 8 weeks, etanercept 50 mg/week (or 25 mg/twice per week), adalimumab 40 mg/every other week (or 20 mg/week), certolizumab pegol 400 mg/every 4 weeks, and golimumab 50 mg/every 4 weeks.
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We explored heterogeneity between the trials using the chi-square test for heterogeneity and a 10% level of significance. In addition, the I2 statistic was calculated from the results of the meta-
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analysis as I2 = 100%×(Q − df)/Q, where Q is Cochran’s heterogeneity statistic (chi-square) and df is the degrees of freedom, to quantify inconsistencies across studies, and results were complied with the recommendations put forward in the Cochrane Handbook.27 A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity.28 The study was
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considered heterogeneous when a p-value of chi-square statistics was less than 0.1 or the value of I2 was over 50%.29 All statistical tests and creation of forest plots were conducted with STATA 11 and
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Meta-Analyst software.30
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RESULTS Study Selection We identified a total of 268 titles and abstracts, from which 196 were excluded based on title and
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abstract review and 31 were excluded based on article review (Figure 1). Reasons for exclusion included no drug of interest, patients without rheumatoid arthritis, lack of randomization, blinding, or a control group, or a study duration of 1 year) did not appear to differ substantially (summary ORs, 1.37 vs 1.44
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for serious infection and 1.32 vs 1.20 for discontinuation due to adverse events, respectively).
Quality of Evidence for Our Analyses
Most of our comparison analyses reached a high level of quality of evidence (Table 2), while some
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were determined to be of a moderate level. The latter level was observed in the analyses comparing between: certolizumab pegol vs. placebo on all evaluated outcomes; etanercept plus DMARD vs.
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DMARD for overall serious adverse event (due to inconsistency); adalimumab vs. placebo/methotrexate controls for malignancy events (due to inconsistency); infliximab vs. methotrexate for serious infection events and discontinuation due to adverse events (due to
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imprecision).
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DISCUSSION Our objective was to systematically update major safety profiles reported in the randomized controlled trials of all approved TNFis to date to inform the field. Our findings indicate a higher
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risk of serious infection associated with adalimumab, certolizumab pegol, and infliximab, which appears to contribute to higher rates of discontinuation. A similar trend was observed with
golimumab plus methotrexate combination therapy, but not golimumab mono-therapy. In contrast,
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etanercept showed a lower rate of discontinuation with a tendency towards a lower rate of serious infection. Furthermore, we found no increased risk of malignancy associated with TNFi use. These
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comparative safety findings should inform clinical and policy decision making in the management of rheumatoid arthritis.
A two-fold or higher risk of serious infection associated with adalimumab or infliximab were first reported by meta-analysis of randomized controlled trials in 20062 (Table 3). In 2009, a
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meta-analysis of 18 trials suggested that the increased risk associated with adalimumab or infliximab may be limited to the use of a higher than recommended dose.3 A subsequent metaanalysis found a >4-fold increased risk of serious infection among certolizumab pegol users, and a
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large Cochrane review of both randomized controlled trials and extension studies reported a 55% increased risk of serious infection among TNFi users in rheumatoid arthritis (no specific agent data
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in rheumatoid arthritis were reported) in 20115 (Table 3). The latest meta-analyses of randomized controlled trials also found effect estimates trending towards an increased risk among users of adalimumab, certolizumab pegol, and infliximab6, but not with etanercept.83 We found a 42% increased risk of serious infection associated with TNFi use as a group, and this was driven by adalimumab, certolizumab pegol, infliximab, and perhaps by golimumab. Etanercept was not associated with this risk and, if any, the point estimates were trending in an inverse direction. 13
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Furthermore, no significant risk difference was found among increased doses of TNFi treated patients and patients treated with normal doses in the included trials. Collectively, these findings allow conclusion that among available TNFis, etanercept stands out as a potentially safer option
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with regard to the risk of serious infection. Future research will likely confirm a statistically significant and clinically important increase in the risk of serious infections in patients with rheumatoid arthritis treated with TNFi.
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These differential risks of serious infection appear to drive those of adverse event-induced discontinuation. We found that this risk was also increased with TNFis as a group, which was
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driven by adalimumab, certolizumab pegol, and infliximab. In contrast, etanercept was associated with a 28% lower risk of adverse event-induced discontinuation. The increased risk of adverse event-induced discontinuation associated with adalimumab6,8,74, certolizumab pegol6,82, and infliximab6,8,73,74,80 has been reported by previous meta-analyses. In contrast, three previous meta-
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analyses reported that etanercept use is associated with a lower risk of adverse event-induced discontinuation (Table 3). These data, together with our findings, lead to the conclusion that among available TNFis, adverse events associated with adalimumab, certolizumab pegol, and infliximab
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(likely an increased risk of serious infection) lead to earlier termination of these agents, whereas etanercept use lasts longer with a better adverse event profile.6,74,83 The significant increased risk of
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discontinuation observed among golimumab plus methotrexate users (but not among golimumab mono-therapy users) is intriguing and calls for further examination. Despite these notably differential profiles on serious infection and adverse event-induced discontinuation among TNFis, our meta-analyses found no increased risk for overall serious adverse event among TNFis users as a group, except for certolizumab pegol use. This null conclusion has been consistently reported in all previous meta-analyses (Table 3), which may appear conflicting 14
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with the findings discussed above. Although the overall serious adverse event rates give a summary view of the overall "average" safety profile of TNFis as a class, it can mask important differences among TNFis, as demonstrated in our study. These comparative data among TNFis are indeed more
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relevant to the decision making of choosing one over the other to improve the net effectiveness of rheumatoid arthritis care.
With regard to the risk of malignancy, more than a 3-fold increased risk among users of
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adalimumab or infliximab was reported in the meta-analysis by Bongartz in 2006.2 Since then, no other meta-analyses3-5,7,8,73,74,80,82 have been able to replicate the findings (Table 3), including a
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very large recent meta-analysis for both TNFis alone and in combination with DMARDs in rheumatoid arthritis patients.7 Our findings also confirm no increased risk of malignancy associated with TNFis either as a group or individually. Furthermore, findings from observational studies as well as from a large long-term extension study of a randomized controlled trial have reported no
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increased risk of malignancy across all TNFis.7,84-86 Collectively, these data to date are reassuring with regards to malignancy risk among TNFi users. There are several limitations associated with systematic reviews in general, as well as that
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are specific to our study. Some safety data are not available in all finally selected articles and thus could not be included in our analysis. Similar to previous meta-analyses, we observed heterogeneity
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in our source trial data, including follow-up times and administered doses across included randomized controlled trials. We attempted to deal with these limitations in the original research by designing and applying stringent selection criteria so that our results are based on solid coherent evidence. Disease severity was not taken into account in our study, partly due to the difficulties associated with the different severity measures across the trials. Addressing this issue in future studies would be valuable. 15
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In conclusion, our meta-analysis of randomized controlled trials to date indicates potential important differences in the safety profile among all currently available TNFis. The risk of serious infection is increased among adalimumab-, certolizumab pegol-, or infliximab-treated patients. In
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turn, patients on these agents had an increased risk of discontinuation due to adverse events.
Etanercept-treated patients instead showed a decreased risk. Our null findings on malignancy risk together with multiple previous findings to date are reassuring. As available TNFis have shown no
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detectable differences in efficacy in rheumatoid arthritis, their safety profile could be an important determinant for patient and physician decision making. To that end, our findings should be relevant
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to clinical comparative effectiveness guidelines on treatment for rheumatoid arthritis patients.
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Table 1. Characteristic of Randomized Controlled Trials Included in the Analysis Treatment Group
33
Keystone
34
van de Putte
Miyasaka35
36
24
2004
52
2004
26
2008
24
Breedveld
2006
104
37
2007
24
2008
56
2003
24
Kim
Bejarano
38
39
Furst
40
Kavanaugh Detert
41
Moreland42
43
Bathon
16
Klareskog §
44
Combe †
RA with inadequate response to MTX RA with inadequate response to ≧1 DMARDs
RA with inadequate response to ≧ 1, DMARDs-, biologics- naïve
Female (%)
72
ADA 20mg qw
54
85
10.4
70
ADA 40mg qw
53
81
10
72
ADA 80mg qw
53
69
10.1
69
ADA 20mg eow
54
75
13.1
RA 12 weeks
↔ ↑ (CZP)
↔
↑ (overall) ↑ (ADA, CZP, INF)
9,862
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ADA, CZP, ETN, GLM, INF
Aaltonen, 20126
Malignancy
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73
Chen (NICE) , 2006
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2
Bongartz, 2006
Study Design
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Total Subjects 5,005
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ADA, INF
Included Studies, N 9
Interventions
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Author, Year
↔ NA ↔ (overall) ↑ (ADA, CZP, INF) ↓ (ETN, RR = 0.71 compared with control) NA ↓ (RR=0.53 for ETN + DMARDs vs. DMARD) ↑ (overall) ↑ (ADA, CZP, INF) ↓ (ETN, OR = 0.72)
Abbreviation: ADA, adalimumab; CZP, certolizumb pegol; ETN, etanercept; INF, infliximab; GLM, golimumab; ABT, abatacept; ANK, anakinra; RTX, rituximab; TCZ, tocilizumab; MTX, methotrexate; DMARD, disease-modifying antirheumatic drug; RR, relative risk; RD, risk difference; RCT, randomized controlled trial; CCT, controlled Clinical trial; OLE, open-label extension; SAE, serious adverse event; AEs, adverse events. NE, not estimable; NICE, National Institute for Clinical Excellence; CR, Cochrane Reviews. *The results are based on all indications of the 9 biologics invested in that study, unless marked otherwise. **ADA, CZP, ETN, GLM, INF, ABT, ANK, RTX and TCZ.
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Citations retrieved (n=285) Duplicate citations (n=17)
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Title and abstract review (n=268)
Excluded (n=196) No biologics of interest: 19 Patients without RA: 29 No randomization: 39 Sample size < 100: 19 Subanalysis of original data: 23 Review article: 14 Don’t evaluate adult: 6 No safety outcome: 47
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Citations identified from electronic database: MEDLINE: 261 The Cochrane Collaboration: 24
Article review (n=72)
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Excluded (n=31) Open-label trial: 15 No control group: 9 Study duration < 12 weeks: 5 Prior TNF inhibitor: 2
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PubMed Auto Alert after database search was completed (n=3)
Article eligible for extraction (n=44)
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Adalimumab n=11 (11 RCTs) Certolizumab Pegol n=5 (5 RCTs) Etanercept n=12 (8 RCTs) Golimumab n=7 (7 RCTs) Infliximab n=9 (7 RCTs)
Figure 1. Flow diagram for selection of studies included in the meta-analysis.
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Events, Treatment
Events, Control
0.71 0.76 0.81 1.15 1.45 1.18 1.17 0.47 0.93
(0.27, 1.91) (0.40, 1.45) (0.43, 1.52) (0.37, 3.59) (0.69, 3.04) (0.49, 2.82) (0.72, 1.91) (0.22, 0.99) (0.72, 1.19)
16/214 17/318 53/434 7/65 35/265 13/75 37/515 12/87 190/1973
7/70 22/318 16/110 6/63 8/87 11/73 32/517 22/85 124/1323
1.43 2.54 1.96 1.08 1.32 1.44
(0.80, 2.59) (0.76, 8.53) (0.88, 4.36) (0.58, 2.04) (0.60, 2.89) (1.04, 2.00)
63/783 8/111 36/494 52/851 16/124 175/2363
11/199 3/109 4/125 12/212 12/119 42/764
0.79 1.49 0.94 3.51 1.06 1.16
(0.47, 1.34) (0.78, 2.86) (0.57, 1.57) (1.63, 7.54) (0.58, 1.95) (0.89, 1.52)
44/454 23/266 33/274 50/204 35/244 185/1442
27/228 16/269 34/268 2/50 18/132 97/947
1.50 0.74 2.19 2.03 1.48 0.77 1.30
(0.39, 5.80) (0.34, 1.61) (0.84, 5.68) (0.70, 5.86) (0.18, 11.94) (0.12, 4.93) (0.82, 2.05)
12/137 25/474 18/311 20/513 3/173 3/203 81/1811
2/35 11/160 3/133 2/129 1/88 2/105 21/650
0.75 1.28 1.03 0.36 0.97 1.04
(0.40, 1.39) (0.85, 1.91) (0.64, 1.66) (0.05, 2.58) (0.46, 2.06) (0.80, 1.34)
57/342 103/749 55/721 1/87 19/165 235/2064
18/86 32/291 27/363 3/86 13/110 93/936
1.11 (0.97, 1.26)
866/9653
377/4620
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Adalimumab van de Putte 2003 Furst 2003 van de Putte 2004 Kim 2007 Miyasaka 2008 Bejarano 2008 Kavanaugh 2013 Detert 2013 Subtotal (I-squared = 0.0%, p = 0.458) . Certolizumab Pegol Keystone 2008 Fleischmann 2009 Smolen 2009 Weinblatt 2012 Choy 2012 Subtotal (I-squared = 0.0%, p = 0.687) . Etanercept Klareskog 2004 Weisman 2007 Emery 2008 Combe 2009 Moreland 2012 Subtotal (I-squared = 64.8%, p = 0.023) . Golimumab Kay 2008 Emery 2009 keystone 2009 Kremer 2010 Tanaka 2012 Takeuchi 2013 Subtotal (I-squared = 0.0%, p = 0.521) . Infliximab Lipsky 2000 St Clair 2004 Westhovens 2006 Zhang 2006 Schiff 2008 Subtotal (I-squared = 0.0%, p = 0.516) . Overall (I-squared = 15.3%, p = 0.234)
OR (95% CI)
1
RI PT
Year
SC
Author
10
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Figure 2. Effect of TNF inhibitors vs. control therapy on the occurrence of overall SAEs in patients with rheumatoid arthritis.
ACCEPTED MANUSCRIPT
Year
Adalimumab Furst 2003 Weinblatt 2003 van de Putte 2004 Keystone 2004 Breedveld 2006 Miyasaka 2008 Kavanaugh 2013 Detert 2013 van de Putte 2003 Kim 2007 Bejarano 2008 Subtotal (I-squared = 47.9%, p = 0.062) . Certolizumab Pegol Keystone 2008 Smolen 2009 Fleischmann 2009 Weinblatt 2012 Choy 2012 Subtotal (I-squared = 0.0%, p = 0.332) . Etanercept Bathon 2000 van der Heijde 2006 Weisman 2007 Emery 2008 Combe 2009 Moreland 2012 Hu 2009 Subtotal (I-squared = 0.0%, p = 0.853) . Golimumab Kay 2008 Emery 2009 keystone 2009 Tanaka 2012 Takeuchi 2013 Subtotal (I-squared = 8.5%, p = 0.335) . Infliximab Lipsky 2000 St Clair 2004 Westhovens 2006 Schiff 2008 Subtotal (I-squared = 0.0%, p = 0.849) . Overall (I-squared = 0.9%, p = 0.449)
OR (95% CI)
Events, Treatment
Events, Control
7.39 (0.15, 3.66 (0.03, 1.01 (0.11, 4.41 (0.54, 0.70 (0.18, 0.02 (0.00, 7.42 (0.15, 0.13 (0.01, (Excluded) (Excluded) (Excluded) 0.80 (0.35,
1/318 1/209 4/434 4/419 6/542 0/265 1/515 0/87 0/214 0/65 0/75 17/3143
0/318 0/62 1/110 0/200 4/257 2/87 0/517 3/85 0/70 0/63 0/73 10/1842
11/783 2/494 0/111 0/851 0/124 13/2363
1/199 1/125 0/109 0/212 0/119 2/764
372.38) 388.65) 9.06) 36.06) 2.64) 0.43) 373.84) 1.26)
1.82)
SC
2.11 (0.51, 8.69) 0.44 (0.03, 7.43) (Excluded) (Excluded) (Excluded) 1.54 (0.43, 5.46)
RI PT
Author
6.21) 7.21) 3.93) 3.95) 114.72) 12.28) 2.78)
M AN U
1.29 (0.27, 2.15 (0.64, 0.68 (0.12, 0.98 (0.24, 3.49 (0.11, 2.27 (0.42, (Excluded) 1.45 (0.76,
0/35 2/160 0/133 0/88 0/105 2/521
111.66) 2.57) 300.81) 4.52)
2/137 2/474 1/311 0/173 0/203 5/1298
3.54 4.03 1.46 1.32 2.29
31.85) 35.83) 11.69) 13.44) 6.86)
5/342 4/749 3/721 2/165 14/1977
0/86 0/291 1/361 1/110 2/848
77/10756
28/5259
(0.39, (0.45, (0.18, (0.13, (0.77,
10
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1
2/217 2/228 3/269 4/268 0/50 1/132 0/120 12/1284
3.54 (0.11, 0.27 (0.03, 4.17 (0.06, (Excluded) (Excluded) 0.80 (0.14,
1.29 (0.85, 1.97)
.1
5/415 10/454 2/266 4/274 2/204 5/244 0/118 28/1975
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Figure 3. Effect of TNF inhibitors vs. control therapy on the occurrence of one or more malignancies in patients with rheumatoid arthritis.
ACCEPTED MANUSCRIPT
Events, Control
3.82 0.67 3.67 3.58 3.46 0.80 2.67 1.47 2.13 0.73 1.69
(0.39, (0.19, (0.13, (0.75, (1.23, (0.30, (0.77, (0.25, (0.86, (0.16, (1.12,
37.62) 2.32) 100.18) 16.96) 9.68) 2.13) 9.19) 8.68) 5.27) 3.28) 2.54)
4/214 4/318 2/209 10/434 16/419 12/542 13/265 3/75 13/515 3/87 80/3078
0/70 6/318 0/62 0/110 1/200 7/257 1/87 2/73 6/517 4/85 27/1779
7.32 3.60 1.34 1.44 1.98
(0.46, (0.96, (0.51, (0.25, (0.99,
117.84) 13.45) 3.55) 8.44) 3.96)
2/111 14/494 22/851 3/124 41/1580
0/109 0/125 4/212 2/119 6/565
3.49 0.80 0.52 0.61 1.22 0.73
(0.11, (0.31, (0.21, (0.20, (0.38, (0.45,
114.72) 2.06) 1.24) 1.83) 3.87) 1.20)
1
2/204 8/266 21/416 5/274 9/244 45/1404
0/50 10/269 10/115 8/268 4/132 32/834
0.75 1.23 2.50 2.01 4.52 0.49 1.55
(0.06, (0.36, (0.59, (0.45, (0.07, (0.03, (0.76,
8.70) 4.16) 10.53) 8.87) 285.61) 9.19) 3.17)
3/137 11/474 8/311 10/513 1/173 1/203 34/1811
1/35 3/160 1/133 1/129 0/88 1/105 7/650
3.23 0.72 2.17 1.86 1.54 1.63
(0.06, (0.28, (1.12, (0.86, (0.43, (1.07,
181.94) 1.88) 4.19) 4.02) 5.57) 2.47)
2/87 21/342 40/749 24/721 7/165 94/2064
0/14 7/86 6/291 6/363 3/110 22/864
294/9937
94/4692
1.42 (1.13, 1.78)
TE D .1
Events, Treatment
M AN U
Adalimumab van de Putte 2003 Furst 2003 Weinblatt 2003 van de Putte 2004 Keystone 2004 Breedveld 2006 Miyasaka 2008 Bejarano 2008 Kavanaugh 2013 Detert 2013 Subtotal (I-squared = 8.4%, p = 0.365) . Certolizumab Pegol Fleischmann 2009 Smolen 2009 Weinblatt 2012 Choy 2012 Subtotal (I-squared = 0.0%, p = 0.497) . Etanercept Combe 2006 Weisman 2007 van der Heijde 2007 Emery 2008 Moreland 2012 Subtotal (I-squared = 0.0%, p = 0.687) . Golimumab Kay 2008 Emery 2009 keystone 2009 Kremer 2010 Tanaka 2012 Takeuchi 2013 Subtotal (I-squared = 0.0%, p = 0.868) . Infliximab Maini 1998 Lipsky 2000 St Clair 2004 Westhovens 2006 Schiff 2008 Subtotal (I-squared = 0.0%, p = 0.440) . Overall (I-squared = 0.0%, p = 0.467)
OR (95% CI)
RI PT
Year
SC
Author
10
AC C
EP
Figure 4. Effect of TNF inhibitors vs. control therapy on the occurrence of serious infections in patients with rheumatoid arthritis.
ACCEPTED MANUSCRIPT
Events, Control
1.55 0.72 1.13 2.50 1.54 0.97 1.59 1.94 1.33 0.49 1.38
(0.24, (0.12, (0.43, (0.75, (0.85, (0.23, (0.61, (0.38, (0.69, (0.10, (1.00,
10.08) 4.28) 2.96) 8.31) 2.79) 4.03) 4.15) 9.88) 2.56) 2.49) 1.89)
5/214 5/209 9/318 16/434 42/419 4/65 20/265 4/75 21/515 2/87 128/2601
1/70 2/62 8/318 1/110 13/200 4/63 4/87 2/73 16/517 4/85 55/1585
2.39 2.37 1.98 1.24 1.13 1.67
(1.08, (0.53, (0.67, (0.60, (0.37, (1.09,
5.26) 10.64) 5.85) 2.56) 3.44) 2.54)
39/407 5/111 19/494 40/851 7/124 110/1987
3/101 2/109 2/125 8/212 6/119 21/666
1.21 0.45 0.71 0.78 0.90 0.99 0.72
(0.32, (0.24, (0.46, (0.46, (0.38, (0.36, (0.55,
4.60) 0.84) 1.08) 1.33) 2.15) 2.74) 0.93)
7/154 23/415 71/454 28/274 30/204 11/244 170/1745
3/80 24/217 47/228 34/268 8/50 6/132 122/975
1.27 1.85 0.73 3.00 1.42 0.49 1.43
(0.30, (0.84, (0.20, (0.79, (0.36, (0.09, (0.88,
5.45) 4.04) 2.70) 11.40) 5.69) 2.67) 2.35)
10/137 30/474 7/311 9/173 9/395 3/203 68/1693
2/35 5/160 4/133 1/88 2/129 3/105 17/650
3.39 0.93 2.45 2.13 1.51 3.46 2.04
(0.32, (0.38, (1.47, (1.14, (0.42, (0.89, (1.46,
36.52) 2.25) 4.08) 3.97) 5.38) 13.38) 2.84)
6/87 26/342 69/751 38/721 6/87 8/165 153/2153
0/14 7/86 9/298 8/363 4/86 1/110 29/957
629/10179
244/4833
1.23 (1.06, 1.43)
1
TE D
.1
Events, Treatment
M AN U
Adalimumab van de Putte 2003 Weinblatt 2003 Furst 2003 van de Putte 2004 Keystone 2004 Kim 2007 Miyasaka 2008 Bejarano 2008 Kavanaugh 2013 Detert 2013 Subtotal (I-squared = 0.0%, p = 0.922) . Certolizumab Pegol Keystone 2008 Fleischmann 2009 Smolen 2009 Weinblatt 2012 Choy 2012 Subtotal (I-squared = 0.0%, p = 0.695) . Etanercept Moreland 1999 Bathon 2000 van der Heijde 2006 Emery 2008 Combe 2009 Moreland 2012 Subtotal (I-squared = 0.0%, p = 0.619) . Golimumab Kay 2008 Emery 2009 keystone 2009 Tanaka 2012 Weinblatt 2013 Takeuchi 2013 Subtotal (I-squared = 0.0%, p = 0.525) . Infliximab Maini 1998 Lipsky 2000 St Clair 2004 Westhovens 2006 Zhang 2006 Schiff 2008 Subtotal (I-squared = 0.0%, p = 0.476) . Overall (I-squared = 31.1%, p = 0.047)
OR (95% CI)
RI PT
Year
SC
Author
10
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Figure 5. Effect of TNF inhibitors vs. control therapy on the occurrence of discontinuation due to AEs in patients with rheumatoid arthritis.
ACCEPTED MANUSCRIPT Appendix I: Exact Strings Title of database searched: PubMed, and the Cochrane Library. Date search was run (month, day, and year): May 2, 2013. Years covered by the search: from 1990 until May 2, 2013. Language restrictions, all other possible restrictions: randomized controlled trials published in English and adults. Time, Database
#1
Search (etanercept OR infliximab OR adalimumab OR certolizumab pegol OR golimumab)
PubMed, 05/02/2013
12642
#2
Search malignancy
PubMed, 05/02/2013
2491138
#3
Search infection
PubMed, 05/02/2013
1196618
#4
Search adverse effects
PubMed, 05/02/2013
1711984
#5
Search rheumatoid arthritis
PubMed, 05/02/2013
117172
#6
Search (((etanercept OR infliximab OR adalimumab OR certolizumab pegol OR golimumab))) AND rheumatoid arthritis
PubMed, 05/02/2013
4300
#7
Search (((etanercept OR infliximab OR adalimumab OR certolizumab pegol OR golimumab))) AND rheumatoid arthritis Filters: Randomized Controlled Trial; English; Adult: 19+ years
PubMed, 05/02/2013
245
#8
Search (#5 AND #1) AND ((#2 or #3 or #4) Filters: Journal Article; English
PubMed, 05/02/2013
1288
#9
Search (#5 AND #1) AND ((#2 or #3 or #4) Filters: Randomized Controlled Trial; English
PubMed, 05/02/2013
103
#10
Search (#5 AND #1) AND (#2 or #3 or #5) Filters: Journal Article; English
PubMed, 05/02/2013
3252
#11
Search (#5 AND #1) AND ((#2 or #3 or #4) Filters: Journal Article; English; Adult: 19+ years
PubMed, 05/02/2013
848
#12
Search The Surveillance, Epidemiology and End Results Filters: Journal Article; English; Adult: 19+ years
PubMed, 05/02/2013
21503
#13
Search ((((#5 AND #1) AND ((#2 or #3 or #4)) AND Journal Article[ptyp] AND English[lang] AND adult[MeSH])) AND (The Surveillance, Epidemiology and End Results AND Journal Article[ptyp] AND English[lang] AND adult[MeSH]) Filters: Journal Article; English; Adult: 19+ years
PubMed, 05/02/2013
8
#14
Search ((((#5 AND #1) AND ((#2 or #3 or #4)) AND Journal Article[ptyp] AND English[lang] AND adult[MeSH])) AND Medicare Filters: Journal Article; English; Adult: 19+ years
PubMed, 05/02/2013
6
#15
Search (Drug Monitoring"[Mesh]) OR Pharmacovigilance Filters: Journal Article; English; Adult: 19+ years
PubMed, 05/02/2013
619
#16
Search #19 and #23 Filters: Journal Article; English; Adult: 19+ years
PubMed, 05/02/2013
9
#17
Search #1 Filters: Journal Article; Randomized Controlled Trial; English; Adult: 19+ years
PubMed, 05/02/2013
4735
#18
Search #1 Filters: Randomized Controlled Trial; English
PubMed, 05/02/2013
760
#19
Search rheumatoid arthritis Filters: Randomized Controlled Trial; English
PubMed, 05/02/2013
2634
#20
Search (etanercept OR infliximab OR adalimumab OR certolizumab pegol OR golimumab)and rheumatoid arthritis Filters: Randomized Controlled Trial; English; Adult: 19+ years
PubMed, 05/02/2013
261
#21
Arthritis, Rheumatoid and etanercept OR infliximab OR adalimumab OR certolizumab pegol OR golimumab
Cochrane Library, 05/02/2013
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Literature string
# Retrieved Articles
24
ACCEPTED MANUSCRIPT Appendix II: excluded references
6.
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9.
10. 11.
12.
13.
14.
15.
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Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, et al. A multicenter, doubleblind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37-44. Abrahamyan L, Beyene J, Feng J, Chon Y, Willan AR, Schmeling H, et al. Response times follow lognormal or gamma distribution in arthritis patients. J Clin Epidemiol. 2010;63(12):1363-9. Aletaha D, Funovits J, Breedveld FC, Sharp J, Segurado O, Smolen JS. Rheumatoid arthritis joint progression in sustained remission is determined by disease activity levels preceding the period of radiographic assessment. Arthritis and rheumatism; 2009:1242-9. Allaart CF, Breedveld FC, Dijkmans BA. Treatment of recent-onset rheumatoid arthritis: lessons from the BeSt study. The Journal of rheumatology. Supplement; 2007:25-33. Allaart CF, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Breedveld FC, Dijkmans BA. Aiming at low disease activity in rheumatoid arthritis with initial combination therapy or initial monotherapy strategies: the BeSt study. Clin Exp Rheumatol. 2006;24(6 Suppl 43):S-77-82. Anis A, Zhang W, Emery P, Sun H, Singh A, Freundlich B, et al. The effect of etanercept on work productivity in patients with early active rheumatoid arthritis: results from the COMET study. Rheumatology (Oxford). 2009;48(10):1283-9. Antoni C, Kalden JR. Combination therapy of the chimeric monoclonal anti-tumor necrosis factor alpha antibody (infliximab) with methotrexate in patients with rheumatoid arthritis. Clinical and experimental rheumatology; 1999:S73-7. Antoni CE, Kavanaugh A, Kirkham B, Tutuncu Z, Burmester GR, Schneider U, et al. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum. 2005;52(4):1227-36. Baker JF, Baker DG, Toedter G, Shults J, Von Feldt JM, Leonard MB. Associations between vitamin D, disease activity, and clinical response to therapy in rheumatoid arthritis. Clin Exp Rheumatol. 2012;30(5):658-64. Bankhurst AD. Etanercept and methotrexate combination therapy. Clin Exp Rheumatol. 1999;17(6 Suppl 18):S69-72. Bathon JM, Fleischmann RM, Van der Heijde D, Tesser JR, Peloso PM, Chon Y, et al. Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis. J Rheumatol. 2006;33(2):234-43. Baumgartner SW, Fleischmann RM, Moreland LW, Schiff MH, Markenson J, Whitmore JB. Etanercept (Enbrel) in patients with rheumatoid arthritis with recent onset versus established disease: improvement in disability. J Rheumatol. 2004;31(8):1532-7. Bejarano V, Conaghan PG, Quinn MA, Saleem B, Emery P. Benefits 8 years after a remission induction regime with an infliximab and methotrexate combination in early rheumatoid arthritis. Rheumatology (Oxford). 2010;49(10):1971-4. Bendtzen K, Geborek P, Svenson M, Larsson L, Kapetanovic MC, Saxne T. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum. 2006;54(12):3782-9. Benucci M, Saviola G, Baiardi P, Manfredi M, Sarzi-Puttini P, Atzeni F. Efficacy and safety of leflunomide or methotrexate plus subcutaneous tumour necrosis factor-alpha blocking agents in rheumatoid arthritis. Int J Immunopathol Pharmacol. 2011;24(1):269-74.
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16. Billiau AD, Loop M, Le PQ, Berthet F, Philippet P, Kasran A, et al. Etanercept improves linear growth and bone mass acquisition in MTX-resistant polyarticular-course juvenile idiopathic arthritis. Rheumatology (Oxford, England); 2010:1550-8. 17. Bliddal H, Terslev L, Qvistgaard E, Konig M, Holm CC, Rogind H, et al. A randomized, controlled study of a single intra-articular injection of etanercept or glucocorticosteroids in patients with rheumatoid arthritis. Scand J Rheumatol. 2006;35(5):341-5. 18. Blumenauer Barbara BTB, Cranney A, Burls A, Coyle D, Hochberg Marc C, Tugwell P, et al. Etanercept for the treatment of rheumatoid arthritis. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2003. 19. Blumenauer Barbara BTB, Judd M, Wells George A, Burls A, Cranney A, Hochberg Marc C, et al. Infliximab for the treatment of rheumatoid arthritis. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2002. 20. Boesen M, Boesen L, Jensen KE, Cimmino MA, Torp-Pedersen S, Terslev L, et al. Clinical outcome and imaging changes after intraarticular (IA) application of etanercept or methylprednisolone in rheumatoid arthritis: magnetic resonance imaging and ultrasound-Doppler show no effect of IA injections in the wrist after 4 weeks. J Rheumatol. 2008;35(4):584-91. 21. Breedveld FC, Emery P, Keystone E, Patel K, Furst DE, Kalden JR, et al. Infliximab in active early rheumatoid arthritis. Ann Rheum Dis. 2004;63(2):149-55. 22. Breedveld FC, Han C, Bala M, van der Heijde D, Baker D, Kavanaugh AF, et al. Association between baseline radiographic damage and improvement in physical function after treatment of patients with rheumatoid arthritis. Annals of the rheumatic diseases; 2005:52-5. 23. Brunner HI, Lovell DJ, Finck BK, Giannini EH. Preliminary definition of disease flare in juvenile rheumatoid arthritis. The Journal of rheumatology; 2002:1058-64. 24. Capsoni F, Sarzi-Puttini P, Atzeni F, Minonzio F, Bonara P, Doria A, et al. Effect of adalimumab on neutrophil function in patients with rheumatoid arthritis. Arthritis Res Ther. 2005;7(2):R250-5. 25. Chang J, Girgis L. Clinical use of anti-TNF-alpha biological agents--a guide for GPs. Aust Fam Physician. 2007;36(12):1035-8. 26. Chen DY, Chou SJ, Hsieh TY, Chen YH, Chen HH, Hsieh CW, et al. Randomized, double-blind, placebo-controlled, comparative study of human anti-TNF antibody adalimumab in combination with methotrexate and methotrexate alone in Taiwanese patients with active rheumatoid arthritis. J Formos Med Assoc. 2009;108(4):310-9. 27. Chen HA, Lin KC, Chen CH, Liao HT, Wang HP, Chang HN, et al. The effect of etanercept on anticyclic citrullinated peptide antibodies and rheumatoid factor in patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65(1):35-9. 28. Choy EH, Hazleman B, Smith M, Moss K, Lisi L, Scott DG, et al. Efficacy of a novel PEGylated humanized anti-TNF fragment (CDP870) in patients with rheumatoid arthritis: a phase II doubleblinded, randomized, dose-escalating trial. Rheumatology (Oxford). 2002;41(10):1133-7. 29. Clark W, Jobanputra P, Barton P, Burls A. The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: a systematic review and economic analysis. Health Technol Assess. 2004;8(18):iii-iv, ix-x, 1-105. 30. Conaghan PG, Emery P, Ostergaard M, Keystone EC, Genovese MC, Hsia EC, et al. Assessment by MRI of inflammation and damage in rheumatoid arthritis patients with methotrexate inadequate response receiving golimumab: results of the GO-FORWARD trial. Ann Rheum Dis. 2011;70(11):1968-74.
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31. Criswell LA, Lum RF, Turner KN, Woehl B, Zhu Y, Wang J, et al. The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis & Rheumatism; 2004:2750-6. 32. Cuomo G, Molinaro G, La Montagna G, Migliaresi S, Valentini G. [A comparison between the Simplified Disease Activity Index (SDAI) and the Disease Activity Score (DAS28) as measure of response to treatment in patients undergoing different therapeutic regimens]. Reumatismo; 2006:225. 33. Curtis JR, Luijtens K, Kavanaugh A. Predicting future response to certolizumab pegol in rheumatoid arthritis patients: features at 12 weeks associated with low disease activity at 1 year. Arthritis Care Res (Hoboken). 2012;64(5):658-67. 34. Davis JC, Jr., Van Der Heijde D, Braun J, Dougados M, Cush J, Clegg DO, et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum. 2003;48(11):3230-6. 35. Davis JC, Van Der Heijde D, Braun J, Dougados M, Cush J, Clegg DO, et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis and rheumatism; 2003:3230-6. 36. De Filippis L, Caliri A, Anghelone S, Scibilia G, Lo Gullo R, Bagnato G. Improving outcomes in tumour necrosis factor a treatment: comparison of the efficacy of the tumour necrosis factor a blocking agents etanercept and infliximab in patients with active rheumatoid arthritis. Panminerva Med. 2006;48(2):129-35. 37. De Stefano R, Frati E, Nargi F, Baldi C, Menza L, Hammoud M, et al. Comparison of combination therapies in the treatment of rheumatoid arthritis: leflunomide-anti-TNF-alpha versus methotrexateanti-TNF-alpha. Clin Rheumatol. 2010;29(5):517-24. 38. de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Verpoort KN, Schreuder GM, Ewals JA, Terwiel JP, et al. Progression of joint damage in early rheumatoid arthritis: association with HLA-DRB1, rheumatoid factor, and anti-citrullinated protein antibodies in relation to different treatment strategies. Arthritis Rheum. 2008;58(5):1293-8. 39. Delabaye I, De Keyser F. 74-week follow-up of safety of infliximab in patients with refractory rheumatoid arthritis. Arthritis Res Ther. 2010;12(3):R121. 40. den Broeder A, van de Putte L, Rau R, Schattenkirchner M, Van Riel P, Sander O, et al. A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis. J Rheumatol. 2002;29(11):2288-98. 41. Dias EM, Lukas C, Landewé R, Fatenejad S, van der Heijde D. Reliability and sensitivity to change of the Simple Erosion Narrowing Score compared with the Sharp-van der Heijde method for scoring radiographs in rheumatoid arthritis. Annals of the rheumatic diseases; 2008:375-9. 42. Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, et al. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum. 2007;56(12):3919-27. 43. Durez P, Nzeusseu Toukap A, Lauwerys BR, Manicourt DH, Verschueren P, Westhovens R, et al. A randomised comparative study of the short term clinical and biological effects of intravenous pulse methylprednisolone and infliximab in patients with active rheumatoid arthritis despite methotrexate treatment. Ann Rheum Dis. 2004;63(9):1069-74. 44. Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, et al. Randomised doubleblind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet. 1994;344(8930):1105-10.
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Adalimumab, certolizumab pegol, and infliximab are associated with a higher risk of serious infection, which appears to contribute to higher rates of discontinuation. In contrast, etanercept showed a lower rate of discontinuation with a tendency
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towards a lower rate of serious infection.
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making in the management of rheumatoid arthritis.
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These comparative safety findings should inform clinical and policy decision
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