Spondylitis : A Systematic Review and Bayesian Network Metaanalysis Inhibitors in Ankylosing α Comparative Efficacy of Tumor Necrosis Factor -

Objective. To compare the efficacy of 6 tumor necrosis factor–α inhibitors (TNFi) in treatment of ankylosing spondylitis (AS) at 12 weeks and 24 weeks. Methods. We performed a systematic literature review of randomized controlled trials of TNFi in patients with active AS. We included trials that reported efficacy at 10 to 14 weeks (12–week analysis) and at 24 to 30 weeks (24-week analysis). We used Bayesian network metaanalysis (NMA) to compare their relative efficacy to improve the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and C-reactive protein (CRP) level. Results. We included 20 trials of 6 TNFi, with 43 treatment arms and 3220 participants. All TNFi were significantly better than placebo in reducing BASDAI and BASFI at 12 weeks and 24 weeks; all but certolizumab pegol (CZP) were statistically better than placebo in reducing CRP at 12 weeks; all but CZP and infliximab-dyyb (IFX biosimilar) were significantly better than placebo in reducing CRP at 24 weeks. IFX was superior to the other TNFi in decreasing BASDAI at 12 weeks, but not at 24 weeks. Excluding 1 open-label trial, there were no differences among TNFi. Conclusion. Based on this NMA of clinical trials, IFX was superior to other TNFi in reducing BASDAI at 12 weeks, but sensitive to inclusion of an open-label trial, and its efficacy was diminished at 24 weeks. The analysis was limited by few direct comparison trials. Further study of relative safety and longterm effectiveness will help inform the choice of TNFi in treating active AS. (First Release January 15 2018; J Rheumatol 2018;45:481–90; doi:10.3899/jrheum.170224) Key Indexing Terms: ANKYLOSING SPONDYLITIS TUMOR NECROSIS FACTOR-Α COMPARATIVE EFFECTIVENESS RESEARCH NETWORK METAANALYSIS From Columbia University Medical Center, New York; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland, USA. Funding provided by Intramural Research Program, NIAMS, and NIH. RW is a recipient of the Rheumatology Research Foundation Scientist Development Award. The content is the responsibility of the authors and does not necessarily represent the official views of the NIH. Portions of the data were obtained from the Pfizer Clinical Data Set through a data-use agreement, and from Amgen Inc. through a data-sharing agreement. In addition, the study, carried out under YODA Project #2014-0291, used data obtained from the Yale University Open Data Access Project, which has an agreement with Janssen Research & Development LLC. The interpretation and reporting of research using these data are solely the responsibility of the authors and do not necessarily represent the official views of the Yale University Open Data Access Project or Janssen Research & Development LLC. Amgen Inc., Pfizer Inc., and the Yale Open Data Access Project were provided copies of the manuscript before submission. R. Wang, MD, MHS, Division of Rheumatology, Columbia University Medical Center; A. Dasgupta, PhD, Intramural Research Program, NIAMS, NIH; M.M. Ward, MD, MPH, Intramural Research Program, NIAMS. Address correspondence to Dr. R. Wang, MD, MHS, Division of Rheumatology, Columbia University Medical Center, P & S 10-445, 630 W. 168th St., New York, New York 10032, USA. E-mail: rw2646@cumc.columbia.edu Accepted for publication September 29, 2017. Tumor necrosis factor-α inhibitors (TNFi) have been widely used as a second-line therapy when patients with ankylosing spondylitis (AS) have persistent symptoms despite treatment with nonsteroidal antiinflammatory drugs (NSAID)1. Six different TNFi have been approved for the treatment of AS, including adalimumab (ADA), certolizumab pegol (CZP), etanercept (ETN), golimumab (GOL), infliximab (IFX), and IFX-dyyb (IFX biosimilar). Although they share the same mechanism of action, they are structurally different and have varying efficacy in other conditions in the spondyloarthritis family, including uveitis and inflammatory bowel disease2. It remains unclear whether all TNFi are equally efficacious in relieving the symptoms and signs of active AS. In clinical practice, physicians and patients may favor a particular TNFi over others based on convenience, comorbidities, or cost, rather than a comparison of relative efficacy. To date, only 2 head-to-head trials of TNFi in AS have been conducted: 1 of ETN versus IFX, and the other of IFX versus IFX-dyyb3,4. In the absence of direct comparisons, indirect comparisons of ≥ 2 medications can be made through a common comparator using network metaanalysis (NMA). Rheumatology The Journal of on April 7, 2018 Published by www.jrheum.org Downloaded from Previous NMA that used the Assessments in Ankylosing Spondylitis 20% response criteria (ASAS20) as the outcome did not detect any difference in efficacy among TNFi5,6,7,8. However, dichotomous measures such as the ASAS20 are less sensitive than continuous measures in detecting a difference among medications, in part because such measures ignore any differences in efficacy beyond the ASAS20 threshold9. In our study, we used 3 continuous measures: Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)10, Bath Ankylosing Spondylitis Functional Index (BASFI)11, and C-reactive protein (CRP) level as primary outcomes to compare the relative efficacy of 6 TNFi in treatment of active AS. MATERIALS AND METHODS Literature search. The study protocol was registered at PROSPERO (registration number CRD42014014228). We searched PubMed, EMBASE, Scopus, and the Cochrane Database for published randomized controlled trials (RCT) of TNFi in AS through March 31, 2016, in all languages. Searches were performed by a medical informatician, and search terms are summarized in Supplementary Table 1 (available with the online version of this article). We further manually searched reference lists of review articles. Two authors (RW and MMW) reviewed the search results for eligible studies based on selection criteria. Disagreement was resolved by discussion. Our study was exempted from ethics review by the US National Institutes of Health Office of Human Subjects Research. Selection criteria. We included RCT that evaluated the efficacy of TNFi in adult patients with AS, compared to placebo or to a different TNFi, at 10 to 16 weeks, or at 24 to 30 weeks. AS was defined in the trials by the modified New York criteria12. To enhance homogeneity, we excluded studies of axial spondyloarthritis, unless a subgroup analysis of patients with AS was reported. TNFi include ADA, CZP, ETN, GOL, IFX, and IFX-dyyb. We included studies irrespective of whether they allowed concomitant use of NSAID, corticosteroids, and disease-modifying antirheumatic drugs (DMARD). We excluded studies that were reported only as an abstract. Data extraction and assessment of bias. Data extraction was performed independently by 2 reviewers (RW and MMW). Any discrepancies were resolved by discussion. We extracted features of the study design, characteristics of participants, and relevant outcome measures. The primary efficacy measures were changes from baseline in the BASDAI, BASFI, and CRP. We extracted the mean change score and its SD, or calculated the change from baseline and final scores. When only medians and ranges were reported, we imputed means and SD using standard methods13. Authors of the original articles or study sponsors were contacted for additional data when needed. Missing SD were imputed using SD of other included studies13. Intention-to-treat data were collected whenever available. To assess study quality, we used the Cochrane Collaboration tool for assessment of risk of bias13. Each study was evaluated on 6 domains (i.e., sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other sources of bias), and rated as low, unclear, or high risk. Statistical analysis. We performed Bayesian NMA to quantify the relative efficacy of each drug using a random effects model under the assumption of consistency. Bayesian NMA allows the indirect comparison of 2 drugs based on the observed direct effects. For example, the relative effect of drug A and B is the difference of the relative effects of drug A and C and the relative effects of drug B and C, if these direct comparisons are available. We grouped studies that reported outcomes at 10 to 16 weeks for the 12-week analysis, and studies that reported outcomes at 24 to 30 weeks for the 24-week analysis. Bayesian NMA was performed for each outcome at these 2 timepoints. The relative effect size was presented as the mean difference (MD) with 95% credible intervals (CrI). Outcomes of open-label trials may differ from those of blinded trials; on the other hand, open-label trials closely mimic the real-life experience. Therefore, we performed 2 analyses: the first included a single open-label study, and a second analysis excluded this single open-label study. We assessed the absolute model fit by the overall residual deviance (Dbar)14. Dbar of each drug should approximate the total number of trial arms included in the metaanalysis when the model fits the data well. We assessed heterogeneity among the trial results using Higgins I2, which measures the percent of variability in effect estimates that is a result of heterogeneity rather than sampling error15. Lower I2 indicates less heterogeneity. To estimate the effect of heterogeneity as a result of differences in initial AS activity among trial participants, we performed metaregression that adjusted for the weighted mean baseline value of each outcome; the BASDAI and BASFI analyses were also adjusted for mean baseline CRP. Because TNFi trials were performed over a span of 15 years, we examined whether there was a drift in placebo responses over time (owing to possibly greater expectations of benefit in later trials), which could affect the direct and indirect comparisons among TN