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Infliximab vs Adalimumab for UC: Is There A Difference?

      Anti–tumor necrosis factor (anti-TNF) therapy has been transformational for the treatment of inflammatory bowel disease (IBD), beginning with Crohn’s disease (CD) in 1998
      • Targan S.R.
      • Hanauer S.B.
      • van Deventer S.J.
      • et al.
      A short term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease.
      and extending to ulcerative colitis (UC) in 2005.
      • Rutgeerts P.
      • Sandborn W.J.
      • Feagan B.G.
      • et al.
      Infliximab for induction and maintenance therapy for ulcerative colitis.
      Since their initial approval we have learned a great deal about these drugs for the treatment of IBD, some of which has differed from their use in other diseases. For instance, we have come to understand the value of induction therapy,
      • Hanauer S.B.
      • Feagan B.G.
      • Lichtenstein G.R.
      • et al.
      Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial.
      scheduled as opposed to episodic therapy,
      • Rutgeerts P.
      • Feagan B.G.
      • Lichtenstein G.R.
      • et al.
      Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease.
      combination therapy with immunomodulators,
      • Colombel J.-F.
      • Sandborn W.J.
      • Reinisch W.
      • et al.
      Infliximab, azathioprine, or combination therapy for Crohn’s disease.
      and therapeutic drug monitoring with a focus on the importance of drug concentration and immunogenicity and factors that influence both of these.
      • Colombel J.-F.
      • Feagan B.G.
      • Sandborn W.J.
      • et al.
      Therapeutic drug monitoring of biologics for inflammatory bowel disease.
      It has taken 20 years for our understanding of this class of medication to evolve, and as a result we might have given inadequate therapy to many patients who were treated with these agents in the earlier years. It is also unfortunate that our current understanding of these agents remains incomplete.
      Even though multiple anti-TNF drugs are currently approved for treatment of both CD and UC, it remains uncertain if a particular agent has any efficacy advantage over the other agents. There have been no randomized clinical trials performed to date to help answer this question, and it is unlikely that such a trial may ever occur, for a variety of reasons. There is a similar lack of prospective observational data in this space. Thus, the only data evaluating these issues are retrospective cohort studies and network meta-analyses, both of which have unique potential drawbacks. Retrospective cohort studies using administrative databases have the advantage of being large and generalizable but are subject to bias from lack of data on disease phenotype, disease duration, and disease activity, including endoscopic and biomarker data, drug concentrations, and antibody levels, as well as potential misclassification of exposure or outcome and residual confounding due to incomplete data on covariates, such as patient weight. Retrospective cohort studies derived from referral centers, which may have more complete data on disease-related factors, are often small and lack generalizability. Network meta-analyses utilize the phenomenon that these drugs have each been compared to similar other treatments (eg, placebo) and thus this is a method of indirect rather than direct comparison, and the results of such can vary depending which trials and patients are included and whether informative or noninformative prior distributions are used.
      In this month’s issue of Clinical Gastroenterology and Hepatology, Singh et al.
      • Singh S.
      • Andersen N.N.
      • Andersson M.
      • et al.
      Comparison of infliximab and adalimumab in biologic-naive patients with ulcerative colitis: a nationwide Danish cohort study.
      present the results of their retrospective cohort study comparing the effectiveness and safety of infliximab and adalimumab for the treatment of UC using a Danish national registration database. They matched 104 patients treated with adalimumab to 171 receiving infliximab during 2005–2014 using a propensity score that included demographic variables, disease activity, and use of UC-related medications. They found that new users of adalimumab had a significantly higher risk of all-cause hospitalization and among those receiving combination therapy, a higher risk of UC-related hospitalization, as compared with new users of infliximab. The risk of colectomy or need for new corticosteroids was not different between the groups. Additionally, the authors noted a significantly increased risk of hospitalized serious infection with adalimumab use. The strengths of this study are its population-based design and valiant attempt to match patients based on a fairly comprehensive propensity score. However, it is limited by its small sample size and low number of outcomes (especially for colectomy, new corticosteroid use, and serious infection), lack of adjustment for calendar year to account for differences in UC treatment before and after adalimumab became approved in 2012 (which was addressed in a post hoc sensitivity analysis in which the sample size became very small), and lacked endoscopic and laboratory data.
      The study by Singh et al.
      • Singh S.
      • Andersen N.N.
      • Andersson M.
      • et al.
      Comparison of infliximab and adalimumab in biologic-naive patients with ulcerative colitis: a nationwide Danish cohort study.
      adds to a small but growing body of literature comparing the effectiveness of infliximab to adalimumab for the treatment of patients with UC. So, to cut right to the chase: Which drug is better for UC? The answer is that we still don’t know, as they have not been compared head-to-head in a randomized controlled trial or even a good prospective observational cohort study. When examining the most robust data on each agent for UC (ie, the large randomized placebo-controlled Active Ulcerative Coitis Trial (ACT) 1 and 2 trials for infliximab
      • Rutgeerts P.
      • Sandborn W.J.
      • Feagan B.G.
      • et al.
      Infliximab for induction and maintenance therapy for ulcerative colitis.
      and Ulcerative Colitis Long-Term Remission and Maintenance with Adalimumab Treatment of Moderate to Severe Ulcerative colitis (ULTRA) 1 and 2 trials for adalimumab
      • Reinisch W.
      • Sandborn W.J.
      • Hommes D.
      • et al.
      Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial.
      • Sandborn W.J.
      • van Assche G.
      • Reinisch W.
      • et al.
      Adalimumab induces and maintains clinical remission in moderate-to-severe ulcerative colitis.
      ) at first glance it appears that these 2 drugs might not be the same. Although it is not valid to compare across trials, one can attempt to level the playing field by examining (1) only anti-TNF-naïve patients; (2) standard dosing (infliximab 5 mg/kg at weeks 0, 2, and 6, and then every 8 weeks; adalimumab 160 mg at week 0, 80 mg at week 2, and then 40 mg every other week); and (3) the difference in efficacy compared with placebo, rather than the absolute response rates (ie, calculate the number needed to treat). By doing this, raw week 8 induction rates of clinical remission, clinical response, and mucosal healing are approximately 16%, 18%, and 19%, respectively, higher for infliximab (ACT 1 and 2 trials combined) than adalimumab (ULTRA 1 and 2 trials combined), as compared with placebo; less dramatic differences favoring infliximab (approximately 9%, 13%, and 15%, respectively) are seen during maintenance at 1 year (ACT 1 trial week 54 vs ULTRA 2 trial week 52). Although the infliximab and adalimumab trials involved very different populations of patients at different times, they were similarly designed and these results are therefore difficult to ignore.
      With respect to retrospective cohort studies addressing this question, another population-based study by Singh et al.
      • Singh S.
      • Heien H.C.
      • Sanagaralingham L.R.
      • et al.
      Comparative effectiveness and safety of infliximab and adalimumab in patients with ulcerative colitis.
      using a different claims database did not find an increased risk of all-cause or UC-related hospitalization or serious infection with adalimumab but noted that adalimumab users may have a higher risk of corticosteroid use and lower rates of persistence on drug. Two non–population-based retrospective observational studies, 1 of which sampled gastroenterology practices across the United States and the other involved 2 tertiary care centers, showed no significant difference between infliximab and adalimumab across a variety of clinical outcomes in UC.
      • Sandborn W.J.
      • Sakuraba A.
      • Wang A.
      • et al.
      Comparison of real-world outcomes of adalimumab and infliximab for patients with ulcerative colitis in the United States.
      • Ananthakrishnan A.N.
      • Cagan A.
      • Cai T.
      • et al.
      Comparative effectiveness of infliximab and adalimumab in Crohn’s disease and ulcerative colitis.
      Of the 3 network meta-analyses on this topic,
      • Danese S.
      • Fiorino G.
      • Peyrin-Biroulet L.
      • et al.
      Biological agents for moderately to severely active ulcerative colitis.
      • Stidham R.W.
      • Lee T.C.H.
      • Higgins P.D.R.
      • et al.
      Systematic review with network meta-analysis: the efficacy of anti-tumour necrosis factor-alpha agents for the treatment of ulcerative colitis.
      • Thorlund K.
      • Druyts E.
      • Toor K.
      • et al.
      Comparative efficacy of golimumab, infliximab, and adalimumab for moderately to severely active ulcerative colitis: a network meta-analysis accounting for differences in trial designs.
      2 found that infliximab was superior to adalimumab as induction therapy using clinical and endoscopic outcomes
      • Danese S.
      • Fiorino G.
      • Peyrin-Biroulet L.
      • et al.
      Biological agents for moderately to severely active ulcerative colitis.
      • Thorlund K.
      • Druyts E.
      • Toor K.
      • et al.
      Comparative efficacy of golimumab, infliximab, and adalimumab for moderately to severely active ulcerative colitis: a network meta-analysis accounting for differences in trial designs.
      while 2 suggested possible superiority of infliximab for maintenance.
      • Stidham R.W.
      • Lee T.C.H.
      • Higgins P.D.R.
      • et al.
      Systematic review with network meta-analysis: the efficacy of anti-tumour necrosis factor-alpha agents for the treatment of ulcerative colitis.
      • Thorlund K.
      • Druyts E.
      • Toor K.
      • et al.
      Comparative efficacy of golimumab, infliximab, and adalimumab for moderately to severely active ulcerative colitis: a network meta-analysis accounting for differences in trial designs.
      Is there a difference between these 2 drugs? For severe UC, the answer is likely yes and due to dosing. Infliximab has been shown to be noninferior to cyclosporine for the treatment of hospitalized severe UC.
      • Laharie D.
      • Bourreille A.
      • Branche J.
      • et al.
      Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial.
      However, in this setting, infliximab at standard dosing may be inadequate and some patients require accelerated dosing.
      • Gibson D.J.
      • Heetun Z.S.
      • Redmond C.E.
      • et al.
      An accelerated infliximab induction regimen reduces the need for early colectomy in patients with acute severe ulcerative colitis.
      In fact, in a recent survey of IBD specialists, 76% reported that they used more frequent or higher doses of infliximab for the treatment of severe UC.
      • Herfarth H.H.
      • Rogler G.
      • Higgins P.D.R.
      Pushing the pedal to the metal: should we accelerate infliximab therapy for patients with severe ulcerative colitis.
      The reason for this is likely that a severely inflamed colon, which can lead to large fecal losses of infliximab,
      • Brandse J.F.
      • van den Brink G.R.
      • Wildenberg M.E.
      • et al.
      Loss of infliximab into feces is associated with lack of response to therapy in patients with severe ulcerative colitis.
      coupled with a low serum albumin level leads to lower serum infliximab levels as compared with patients with moderate UC.
      • Ungar B.
      • Mazor Y.
      • Yanai H.
      • et al.
      Induction infliximab levels among patients with acute severe ulcerative colitis compared to patients with moderately severe ulcerative colitis.
      At its current fixed non–weight-based dosing, adalimumab is unlikely to compete with infliximab in this realm. However, for moderate UC it is possible that the drugs perform similarly, although data stratified by disease activity are lacking. The discrepant results in various studies comparing these drugs in UC could be partly due to different admixtures of disease activity in the patients included. Also, heavier adalimumab-treated patients may have been underdosed, leading to decreased effect. Even for CD, in which these drugs seem to perform comparably in clinical practice, studies have reported conflicting results, with some observing infliximab to be superior overall or in certain subpopulations and others reporting no difference.
      • Osterman M.T.
      • Haynes K.
      • Delzell
      • et al.
      Comparative effectiveness of infliximab and adalimumab for Crohn’s disease.
      • Hazlewood G.S.
      • Rezaie A.
      • Borman M.
      • et al.
      Comparative effectiveness of immunosuppressants and biologics for inducing and maintaining remission in Crohn’s disease: a network meta-analysis.
      • Singh S.
      • Heien H.C.
      • Sangaralingham L.
      • et al.
      Comparative effectiveness and safety of anti-tumor necrosis factor agents in biologic-naïve patients with Crohn’s disease.
      All of this uncertainty about the comparative effectiveness of available anti-TNF agents in IBD underscores the need for future prospective and preferably randomized comparative effectiveness studies. As more drugs become approved for the treatment of IBD, these types of studies will become even more important, to compare drugs both within class and out of class. The era of comparative effectiveness has arrived. Clinically, after establishing that a drug is efficacious and safe (a function handled by the Food and Drug Administration regulatory approval process), most of the important questions posed concern drugs comparative effectiveness (ie, deciding which drug to choose). Several important questions may be posed: (1) Does it work better than an alternative agent? (2) Is it faster? (3) Does the effect occur in all patients or only in a subset of patients? and (4) Is there a cost advantage when using this agent? These and many other questions represent important issues that enable clinicians to deliver top-quality care to their patients.

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