Infliximab was approved for moderate-to-severe Crohn’s disease in 1998, after which it remained the only available biologic treatment for nearly a decade. Several other biologic therapies for inflammatory bowel disease [IBD] have subsequently been approved, including other anti-tumour necrosis factor-alpha [TNF] agents [adalimumab, certolizumab pegol, and golimumab] and non anti-TNF biologic agents [natalizumab, vedolizumab, and ustekinumab], and there are several novel small-molecule compounds and dozens of other therapies currently in clinical development.1–4 With more therapies available, patients and clinicians can anticipate better overall outcomes; however, there is a dearth of appropriately powered clinical trials comparing the efficacy of one treatment relative to another. Thus, there are no evidence-based guidelines to support the relative positioning of one therapeutic agent or class relative to another and instead, determination of the index biologic treatment and the introduction of subsequent therapies are largely left to the discretion of the treating physician, patient preferences, and payer guidelines. Therapeutic drug monitoring may help guide decision making about switching within-class vs out-of-class after failure of initial anti-TNF therapy, but this approach has yet to be validated in prospective comparative trials. In this issue of the Journal of Crohn’s and Colitis, Singh et al.5 aim to address the question of comparative efficacy by performing a meta-analysis to estimate the response to a second biologic agent following exposure to anti-TNF therapy for at least 14 days. The primary outcome was the proportion of patients achieving clinical remission, based on reason for discontinuation of the index anti-TNF agent. They evaluated phase II or III randomised control trials [RCTs] of adults with moderate-to-severe ulcerative colitis [UC] or Crohn’s disease [CD] based on Mayo Clinical Score [MCS] 6–12 or Crohn’s Disease Activity Index [CDAI] >220 but <450, and a total of eight studies were included in the analysis. In addition, sub-group analyses were performed based on trial design, disease type, and class of second-line agent. The relative risk [RR] of achieving clinical remission with the second-line agent was calculated in patients who discontinued previous anti-TNF due to primary non-response [PNR] compared with intolerance, PNR relative to loss of response [LOR], and LOR compared with intolerance. PNR was defined as a lack of initial clinical response to the index anti-TNF agent, secondary LOR was defined as a loss of response in patients with initial disease improvement to an anti-TNF agent, and intolerance was defined as unacceptable side effects due to the index anti-TNF agent, warranting discontinuation of therapy. PNR was reported in median 43.1% patients with previous anti-TNF exposure, and a median 64.7% of patients were classified as having secondary LOR, with a noted higher proportion in ustekinumab trials as compared with participants in vedolizumab trials. Intolerance was reported in a median 35.4% of participants across trials. Their findings showed that patients with PNR to an initial anti-TNF were 24% less likely to achieve clinical remission with any second-line biologic agent as compared with patients who discontinued the initial anti-TNF due to intolerance [RR 0.76, 95% CI 0.61–0.96]. In comparing PNR with secondary LOR to the initial anti-TNF agent, there was no significant difference in response to second-line non-TNF biologic in participants. In patients specifically treated with ustekinumab as a second-line agent after PNR to an initial anti-TNF, there was a lower likelihood [RR 0.53, 95% CI 0.39–0.71] of achieving remission when compared with LOR as the reason for discontinuing the initial anti-TNF agent. In patients treated with vedolizumab as a second-line agent, there was no difference in response based on previous PNR vs secondary LOR to the initial anti-TNF agent. Finally, when comparing those who discontinued anti-TNF therapy due to secondary LOR vs intolerance, there was no overall difference in response to second-line biologic agent. The article uses meta-analysis to address the clinical question of whether the likelihood of response to second-line treatment [with another biologic agent] can be predicted by the clinical reason for discontinuation of initial anti-TNF agent, with the noted absence of an objective measure and practice guidelines to help inform the reason for anti-TNF failure. The findings, however, are limited by the small number of eligible studies, which lead the authors to combine CD and UC studies, and which may impact on the clinical application of the results, as other studies have shown differences in response rates to a second-line agent when data are pooled rather than separated based on disease type.6 Furthermore, limitations in the studies used for the final analysis include the lack of therapeutic drug monitoring to guide changes in therapy, which may have helped elucidate mechanisms for LOR, and whether the initial therapy could have been optimised rather than discontinued.7,8 The analysis did not include endoscopic and histopathological confirmation of active disease likely to respond to medical therapy, which may have helped determine non-inflammatory aetiologies such as fibrostenotic strictures that would be unlikely to respond to any subsequent medical treatment. In addition, the clinical trial patient population may not be generalisable and may be potentially biased toward those with more refractory disease. Finally, the reason for initial anti-TNF discontinuation relied on patient recall in some of the included trials; however, the authors tried to adjust for this limitation by including those patients in multiple categories. Despite these limitations, the authors sought to rigorously address the clinical approach to the positioning of second-line biologic therapies in IBD after initial anti-TNF discontinuation. If restrictions did not exist, including insurance coverage constraints, can we predict which drug is most likely to benefit the patient in front of us? From this study, it seems those with PNR to anti-TNF are less likely to improve with any subsequent agent. However, we ideally need prospective head-to-head comparisons of various treatment strategies that incorporate therapeutic drug monitoring and endoscopic confirmation of disease activity. Until then, comparative effectiveness studies such as the current one can help guide clinical care. Although this meta-analysis does not clearly inform the choice of a second-line agent, it serves as an important reminder for clinicians and researchers that the reason for discontinuation of an initial anti-TNF agent is an important factor when considering the most appropriate next drug. Conflicts of Interest GYM: consultant Abbvie, Celgene, Genentech, Jannsen, Medtronic, Pfizer, Samsung Bioepis, Takeda, UCB; research funding from Pfizer, Prometheus. Author Contributions SQA: design, wrote first draft, revisions, and editing. GYM: design, important revisions to draft, and guarantor. References: 1. McLean MH , Neurath MF , Durum SK . Targeting interleukins for the treatment of inflammatory bowel disease – what lies beyond anti-TNF therapy ? Inflamm Bowel Dis 2014 ; 20 : 389 – 97 . Google Scholar CrossRef Search ADS PubMed 2. Sandborn WJ , Su C , Sands BE et al. ; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain Investigators . Tofacitinib as induction and maintenance therapy for ulcerative colitis . N Engl J Med 2017 ; 376 : 1723 – 36 . Google Scholar CrossRef Search ADS PubMed 3. Nielsen OH , Ainsworth MA . Tumor necrosis factor inhibitors for inflammatory bowel disease . N Engl J Med 2013 ; 369 : 754 – 62 . Google Scholar CrossRef Search ADS PubMed 4. Cohen LB , Nanau RM , Delzor F , Neuman MG . Biologic therapies in inflammatory bowel disease . Transl Res 2014 ; 163 : 533 – 56 . Google Scholar CrossRef Search ADS PubMed 5. Singh S , George J , Boland BS et al. Primary non-response to tumor necrosis factor antagonists is associated with inferior response to second-line biologics in patients with inflammatory bowel diseases: a systematic review and meta-analysis . J Crohns Colitis 2018 ;635–43 6. Gisbert JP , Marín AC , McNicholl AG , Chaparro M . Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous anti-TNF treatment has failed . Aliment Pharmacol Ther 2015 ; 41 : 613 – 23 . Google Scholar CrossRef Search ADS PubMed 7. Yarur AJ , Rubin DT . Therapeutic drug monitoring of anti-tumor necrosis factor agents in patients with inflammatory bowel diseases . Inflamm Bowel Dis 2015 ; 21 : 1709 – 18 . Google Scholar CrossRef Search ADS PubMed 8. Vande Casteele N , Herfarth H , Katz J , Falck-Ytter Y , Singh S . American Gastroenterological Association Institute technical review on the role of therapeutic drug monitoring in the management of inflammatory bowel diseases . Gastroenterology 2017 ; 153 : 835 – 57 .e6. Google Scholar CrossRef Search ADS PubMed Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: firstname.lastname@example.org This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Journal of Crohn's and Colitis – Oxford University Press
Published: Apr 26, 2018
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