New choices, new challenges: Anti-TNF versus anti-integrin molecule therapy in IBD.

Abstract

The arrival of vedolizumab for the treatment of inflammatory bowel disease (IBD) provides a welcome opportunity to apply a novel mechanism of action to many patients who warrant biologic treatment. Whilst, in the past two decades, anti-tumor necrosis factor (TNF) therapies (locally infliximab and adalimumab) have revolutionized the management of IBD, it is increasingly clear that a significant proportion of patients are either primary non-responders, have secondary loss of response, are intolerant, or have had serious adverse reactions (including infusion-related, paradoxical immune-inflammatory reactions, cardiac failure, demyelinating, and/or infective complications) to these agents.1, 2 In addition, there are an increasing number of patients with IBD who are at higher risk of anti-TNF exposure given the pleiotropic role of the cytokine TNF in both regulatory and pathological processes in humans, which remain only superficially understood. These risks include those relatively immunosuppressed, those with prior skin, solid and lymphatic malignancies, and other comorbidities. Hence, the challenge for the clinician is positioning vedolizimub in the treatment algorithm for IBD. There are limited data to definitively support vedolizumab as a first-line biologic in place of anti-TNF therapies or for when and how to introduce vedolizumab as a second-line biologic post anti-TNF. It is unclear whether head-to-head trials of anti-integrin and anti-TNF therapies will occur, but it would be imprudent to compare the registration trials of these agents given the multiple confounders of patient selection, prior treatment exposure (non-response), study duration, and variation in endpoints measured between studies. Multiple Bayesian network meta-analyses have attempted to address the issue of comparing these agents, but results are conflicting,3 as the only trials available for meta-analysis are the GEMINI registration trials, which lack long-term data on vedolizumab.4 Nevertheless, it is interesting that as in Fig. 1, in Crohn's disease (CD) for example, clinical remission rates at 1 year (approximately) are virtually identical in the registration trials of infliximab, adalimumab, and vedolizumab. Hence, if one assumes similar efficacy between the classes, the most obvious factor favoring vedolizumab over anti-TNF therapies is its apparent excellent tolerability and safety demonstrated in the GEMINI studies,4 along with recent real-world data.5 Given its gut-specific effect on the α4β7 integrin subunits, systemic complications are theoretically rare. In the Cochrane review by Bickston et al., the placebo group had a slight higher proportion of one or more adverse effects compared with the vedolizumab group (90% vs 89%),6 and according to a meta-analyses, vedolizumab was found to have fewer treatment withdrawals in the GEMINI trials than reported in landmark studies of other drugs such as azathioprine, methotrexate, and infliximab in CD.7 It follows that there are a number of patient subgroups where safety and tolerability are paramount, even if at a small cost of efficacy (or lack of evidence thereof), and thus, vedolizumab should be considered as a first-line option. This includes the elderly patient with IBD, where at least one study showed that anti-TNF use in a rather sick, elderly group culminated in 11% having serious infections, 3% developing malignancies, and 10% dying within the follow-up period.8 Patients with pediatric-onset IBD, consigned to long-term immunosuppression, and at higher risk of potentially fatal systemic complications such as T-cell lymphomas, might also be considered for vedolizumab first line. Additionally those with a history of solid organ or skin (e.g. melanoma) malignancy may also be candidates for a gut-specific therapy like vedolizumab given the uncertain impact of anti-TNF therapies on cancer recurrence and survival.9 A targeted agent like vedolizumab in a patient with no systemic or extra-intestinal manifestations of IBD and in settings of limited yet highly symptomatic disease such as those perhaps with ulcerative proctitis, segmental colitis, or limited ileal CD could also be considered. Yet, there are no robust data to support these assumptions currently. Conversely, the use of anti-TNF therapies as first line compared with vedolizumab is supported by data in many patient subgroups, including perianal fistulizing disease, extra-intestinal manifestations, mitigation of postoperative recurrence in CD and acute severe colitis. Quality, sensible use of these expensive agents would, for instance, in the setting of loss of response to a first anti-TNF agent, first attempt to regain response to this agent (e.g. with dose intensification) before moving to the alternative anti-TNF agent and only then if this fails switch out of class to vedolizumab (and vice versa). However, one must also be mindful of the ‘law of diminishing returns’ in that for every new trial of treatment, it generally holds that a lower potential response rate can be expected.10 In conclusion, the IBD clinician not only can celebrate the availability of vedolizumab, but also ponder the added complexity this choice provides day-to-day clinical decision-making. Perhaps, the most important factor influencing the use of vedolizumab is the comparative importance of safety versus efficacy for the individual patient.