The role of tumor necrosis factor α (TNF-α) proinflammatory cytokine in the pathogenesis of ulcerative colitis (UC) has been debated [1–5]. Inflammatory cascade involves activation of CD4+ T-lymphocytes into T helper (Th)-1 and Th-2 cells. Activation of Th-1 cells leads to secretion of interferon gamma (IFNγ), and interleukin (IL)-2, IL-12, and IL-18. In contrast, activation of Th-2 cells leads to secretion of IL-4, IL-5, IL-6, IL-10, and IL-13. TNF-α expression from macrophages and monocytes is stimulated by Th-1 response by the release of IFNγ.

The cytokine profile of UC has an atypical Th-2 pattern and reduced Th-1 response. CD4 natural-killing T cell in UC expresses intracellular IL-13; this is unique in UC and not found in Crohn’s disease [6]. While intestinal cytokine messenger ribonucleic acid (mRNA) analysis show increased levels of IL-1β, IL-4, IL-5, IL-8, IL-12p40, IFNγ, and TNF-α [7]. Despite this atypical pattern, elevated levels of TNF-α likely contributes to the effectiveness of anti-TNF-α therapy in UC.

TNF-α is produced as a 212-amino acid type II transmembrane protein in stable homotrimers or secreted 17-kDa form. The circulating soluble TNF-α is formed from cleavage of the transmembrane form by TNF-α converting enzyme (TACE). The circulating soluble TNF-α binds to two different TNF-α receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2) expressed in most tissues, leading to activation of other macrophages and augmenting T cell response with increased recruitment of neutrophils and induction of granuloma formation [8, 9].

Infliximab is a chimeric IgG1 monoclonal antibody of 149 kDa that binds and neutralizes TNF-α specifically. Binding of infliximab to the transmembrane TNF-α induces apoptosis of those cells in vitro. The binding of infliximab to soluble TNF-α prevents binding of TNF-α to TNFR. The Food and Drug Administration (FDA) approved infliximab in September 16, 2005 for use in moderate-to-severe UC that failed conventional therapy. The European Medicines Agency approved infliximab for ulcerative colitis, in 2006.

Infliximab showed a linear relationship between the dose administered and maximum serum concentration; it has an association constant of 10¹⁰ M⁻¹ to TNF-α. The volume of distribution at steady state was independent of dose and indicated that infliximab was distributed primarily within the vascular compartment. The median half-life of infliximab is 7.7–9.5 days [10].

The definition of efficacy of medical therapy in UC may be subject to varying interpretations. Efficacy may mean steroid-free clinical remission for some, or it may mean mucosal healing for others; both of these definitions are academic and may not have much relevance to patients as they do for their clinicians. Efficacy, for most patients, means maintaining a good quality of life, avoiding colectomy, and reducing risk of complications related to UC such as colorectal cancer. Prior to the biologics era, the probability of colectomy within the first 5 years of diagnosis ranges from 9 % in distal colitis to 35 % in pancolitis [11]. Several clinical trials have shown that infliximab is efficacious in induction and maintenance of remission and reduces colectomy rates in UC.

Initial small clinical trials showed conflicting results for infliximab for UC [12–16]. Rutgeerts et al. set forth to perform the much-needed multicenter randomized double blind, placebo-controlled efficacy trial for the use of infliximab in induction and maintenance of remission in UC [17]. Moderately to severely active UC patients (defined as full Mayo score of 6–12) despite the use of conventional therapy were enrolled and randomized to receive placebo, or infliximab 5 or 10 mg/kg at 0, 2, 6 weeks, and then every 8 weeks thereafter [18]. ACT 1 patients received treatment up to week 46 and were observed to week 54, and ACT 2 patients received treatment up to week 22 and were observed to week 30. The primary outcome was clinical response at week 8, defined by decrease from baseline total Mayo score of at least 3 points and at least 30 %, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or absolute subscore of 0 or 1. The ACT trials demonstrated that significantly higher proportion of patients achieved induction and maintenance of clinical response or remission at weeks 8, 30 and week 54 (in ACT 1) at either 5 or 10 mg/kg dosing, compared to placebo.

To further assess if treatment with infliximab reduces colectomy rates, Sandborn et al. carried out an analysis of ACT data on the colectomy-sparing effect of infliximab therapy in UC [19]. Six hundred and thirty of 728 (87 %) randomized patients had complete colectomy follow-up data through 54 weeks. Eighty-two patients (36 from placebo, 28 and 18 from infliximab 5 and 10 mg/kg respectively) had colectomy within 54 weeks. The cumulative incidence of colectomy was significantly higher in placebo group than infliximab groups, with an absolute risk reduction of 7 % (95 % confidence interval of 0.01–0.12) and 41 % reduction in risk of colectomy for infliximab groups compared to placebo.

These studies demonstrate that infliximab is efficacious in the management of moderately to severely active UC.

Many questions remained regarding the optimal use of infliximab for the management of UC. The requirement of a concomitant immunosuppressant with infliximab was one of the most pressing issues.

Panaccione et al. set out to address this question by comparing efficacies of infliximab, purine antimetabolites, or combination of infliximab and purine antimetabolites. UC SUCCESS was a randomized, double blinded, double dummy efficacy trial, the primary outcome was proportion of patients in corticosteroid-free remission defined as total Mayo score of 2 points or less with no individual subscore greater than 1 point, and without use of corticosteroids at week 16 [20]. There was significantly higher proportion of patients in combination therapy (infliximab and azathioprine) achieving corticosteroid-free remission than azathioprine or infliximab alone at week 16, the difference was twofold. In light of these new evidence, the Toronto Consensus formulized guidelines for management of non-hospitalized UC addressing this specific issue by stating that combination therapy with thiopurine when initiating infliximab therapy is preferred [21]. Concomitant use of immunosuppression therapy has been shown to reduce the likelihood of anti-infliximab antibody formation. UC SUCCESS showed that less percentage of patients developed antibodies to infliximab at week 16 from the combination therapy group (infliximab and azathioprine) at 3 %, compared to infliximab monotherapy at 19% [20]. Armuzzi et al. demonstrated in a prospective observational trial that predictor for steroid-free clinical remission at 6 and 12 months were thiopurine-naïve status (hazard ratio (HR) of 2.5 and 2.8 respectively), and combination therapy (HR 2.1 and 2.2 respectively) [22]. Furthermore, a systematic review and meta-analysis of four controlled trials showed that clinical remission rate was significantly lower for infliximab monotherapy group than combination of infliximab and immunosuppressant therapy, with an odds ratio (OR) of 0.5 (95 % confidence interval of 0.34–0.73) [23].

The evidence for combination with methotrexate and infliximab is not as clear as that for thiopurine in the induction and maintenance of active UC. This may stem from the fact that the evidence for methotrexate in UC treatment has not been convincing [24–26]. The Cochrane systematic review included two randomized controlled trials comparing methotrexate with placebo in active UC [27]. The review included 101 patients and there was no statistical significant difference in clinical remission rate and complete withdrawal from steroid therapy, with a risk ratio of 0.96 (95 % confidence interval of 0.58–1.59). However, methotrexate used in combination with infliximab have been shown to reduced immunogenicity and increase infliximab trough levels in other conditions, such as Crohn’s disease, rheumatoid arthritis, and psoriasis. COMMIT is a trial to compare infliximab monotherapy to infliximab with methotrexate combination therapy in steroid-dependent Crohn’s disease [28]. The anti-infliximab antibody formation was 4 % in combination therapy compared to 20 % infliximab monotherapy, correlating to a higher trough level of 6.35 μg/mL in the combination group compared to 3.75 μg/mL in infliximab monotherapy group.

In patients with UC refractory to thiopurines or corticosteroids, TNF-α antagonist should be used for induction to complete corticosteroid-free remission. This has been shown in meta-analysis of randomized controlled trials to be efficacious in those who failed to respond to corticosteroids. Five trials showed that infliximab was superior to placebo in inducing endoscopic remission (Relative risk for no remission is 0.72 with 95 % confidence interval of 0.57–0.91).

For patients who responded to TNF-α antagonist therapy, it should be continued on as maintenance therapy.

Trough serum infliximab level is a predictor of clinical outcome for treatment in UC. A prospective observational trial by Seow et al. showed that detectable trough serum infliximab level after three induction doses followed by maintenance scheduled doses predicts clinical remission, endoscopic improvement, and lower risk of colectomy [31]. Adedokun et al. also showed that infliximab concentration and the infliximab antibodies influence response [32]. Infliximab concentration of approximately 41 μg/mL 2 weeks after induction is complete and an infliximab concentration of approximately 4 μg/mL during maintenance are desirable levels to achieve optimal outcomes.