Editorial: tofacitinib and biologics for moderate‐to‐severe ulcerative colitis—what is best in class?

Abstract

Double-blind placebo controlled clinical trials remain the most important method of evaluating the safety and efficacy of a drug.However, these are very costly to run and drug license holders do their major trials largely for regulatory bodies. With the proliferation of biologic therapies for the treatment of inflammatory bowel diseases, it is reasonable to ask which drug is the most effective for a particular clinical problem. Prospective double-blind head-to-head clinical trials are the best ways to resolve this question but are unlikely to take place in view of the prohibitive costs and the large numbers of subjects required to avoid type II errors (false negatives). Hence, network meta-analyses have evolved to try to elucidate relative efficacy of various drugs using available published data.To perform a network meta-analysis well requires rigorous discipline and honesty. There must be a common comparator and the disease must be homogenous across populations and the endpoints clear and objective. Unfortunately, for inflammatory bowel diseases, the latter two criteria are not easily met. In AP&T, Bonovas et al have attempted the task for ulcerative colitis, comparing tofacitinib and biological therapies for moderate-to-severe ulcerative colitis.1 Fortunately, all the trials included have a common comparator: the placebo arm and a pleasing homogeneity in patient selection process (moderate-to-severe based on Mayo scores). However, these trials took place in many diverse countries, from North America, Japan, Europe etc. Mayo scores depend considerably on the subjective input from the patient (a symptom score) and a "global physician assessment", which is equally subjective and may differ culturally. The only relatively objective measure is "mucosal healing" score, which the authors have also extracted from the data. Mucosal healing is a good predictor of favourable outcome and is gaining support as a target for treatments. 2The key conclusions of the study are as follows: It is evident that all these drugs do work when compared to placebo. However, indirect evidence suggests that infliximab performs better than adalimumab and golimumab. While the efficacy of tofacitinib could not be shown to be different than that of biologic therapies, it appears to be just slightly sub-par to the index infliximab study in both clinical scores and mucosal healing data sets, though not reaching sta- Performed well, network meta-analysis is a useful tool in teasing out the last bits of useful information from regulatory trials in the absence of head-to-head studies. This study is certainly in concordance with previously published meta-analyses. 3,4 Their conclusions seem very reasonable, and with an orally active drug standing up well in comparison to parenteral rivals, it certainly bodes well for tofacitinib. This study would also aid phamaco-economic modelling of these expensive drugs so that health care payers can get the most cost-effective treatment of this disabling condition. ACKNOWLEDG EMENTS

<p>Inflammation in gastrointestinal disorders: prevalent socioeconomic factors</p>

“…On the other hand, the search for inflammatory markers in colonic disorders can easily raise concerns regarding doctor–patient relationship. For instance, prescription of the anti-inflammatory aminosalycilic acid (5-ASA) can make an IBS patient believe that the diagnosis of full-blown IBD had been originally missed; moreover, UC patients, if offered to participate in a trial with the anti-STAT molecule tofacitinib,57 may suspect being offered a modern expensive version of a cortisone drug.…”

Editorial: tofacitinib and biologics for moderate‐to‐severe ulcerative colitis—what is best in class? Authors’ reply

“…Tofacitinib is a novel treatment option for UC, pending review by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and other international regulators . It is very interesting in our study results that the efficacy of tofacitinib could not be shown to be different than that of approved biologic therapies, though—as correctly Dr. Tsai points out—tofacitinib appears to be “slightly sub‐par” to infliximab and vedolizumab in all efficacy comparisons. Nevertheless, given that its oral administration may increase treatment adherence and improve quality of life in patients distressed by the long‐term need for injections or infusions, tofacitinib could be well integrated into clinical practice …”

“…We thank Dr. Tsai for his editorial on our publication . We conducted a systematic review of randomised controlled trials assessing tofacitinib and approved biologics (infliximab, adalimumab, golimumab, vedolizumab) as induction and/or maintenance therapies for adult patients with moderate‐to‐severe ulcerative colitis (UC), who were not previously exposed to tumour necrosis factor antagonists.…”

Inflammatory Bowel Disease 2018: Consistency and Controversy

“…The undecapeptide Cyclosporin [18] and the anti-TNF monoclonals [19] represent the new remedies for the acute IBD presentations. The very new strategy designed to inhibit the bulk of the immune responses promoted by activation of the Janus Kinases, is the design that pivots on the molecule "Tofacitinib", a JAK inhibitor that is active on a number of pro-inflammatory cytokines [20].…”