Treatment of Ulcerative Colitis with Infliximab: Are We There Yet? (2004)

Recently, many new biologic agents have been developed to treat inflammatory bowel disease (IBD). These new agents have been developed as a consequence of the evolving understanding of the immunologic processes at play in the two major inflammatory bowel diseases, Crohn disease and ulcerative colitis (UC) (1). The understanding of Crohn disease has progressed more rapidly than the understanding of UC, and Crohn disease is now characterized as an IL-12–driven, IFN-γ/TNF-α process. With this model in mind, biologic agents have been fashioned to target this dysregulated immune pathway [reviewed in (2)]. Infliximab, a chimeric monoclonal antibody targeting tumor necrosis factor alpha (TNF-α), was one of the first biologic agents approved for the treatment of active Crohn disease. Infliximab produces significant endoscopic healing and improvement of both laboratory evaluations and quality of life scores. These findings, from an initial open-labeled trial (3), were subsequently repeated in a placebo-controlled trial that described healing of active disease in 65% of Crohn disease patients compared with a 17% placebo response (4). The response seen was rapid and often occurred within 1 to 2 weeks of the initial dosage. This earlier study established that a dose of 5 mg/kg appeared to be the most effective, with an overall response rate of 81%, whereas higher doses of 10–20 mg/kg were not superior in efficacy. In a subsequent placebo-controlled trial, evaluation of long-term clinical responses were analyzed (5). Patients who had maintained a positive response for greater than 8 weeks were re-randomized to receive either active drug or placebo every 2 months. Results from this trial showed that infliximab induced a clinical response in a most treated patients for more than 44 weeks. The sustained remission rate was 53% for patients receiving infliximab compared with 20% in placebo-treated patients. Further data gleaned from this study showed that the administration of infliximab plus another immunosuppressive agent such as 6 MP. At the end of the 44-week study, 75% of patients receiving concomitant 6-MP therapy had a sustained clinical response compared with 50% of patients on no additional immunosuppressive therapy. The mechanisms behind such a dramatic improvement have recently been elucidated. Studies by Ten Hove et al. have shown that clinical efficacy in humans correlates with the induced cell death (apoptosis) of activated T lymphocytes secreting inflammatory cytokines such as IFN-γ and TNF-α (6). In other reports by Lugering et al., infliximab induced apoptosis of antigen-presenting cells such as monocytes, which secrete TNF-α (7). These studies suggest that the clinical efficacy of infliximab is related not only to its ability to neutralize an inflammatory cytokine such as TNF-α directly but also to its ability to eliminate ongoing inflammation by inducing the cell death of effector cells secreting IFN-γ and TNF-α. Given the remarkable success of infliximab in the treatment of Crohn disease, the application of infliximab to the therapy treatment of UC appeared logical. Many previous treatment modalities for Crohn disease are also efficacious in UC. In this issue of The Journal of Pediatric Gastroenterology and Nutrition, Mamula et al. report on their experience with the administration of infliximab to 17 pediatric UC patients. These results are a follow-up to an earlier report in the Journal of Pediatric Gastroenterology and Nutrition on the administration of infliximab to 9 pediatric UC patients (8). In the initial report, 7 of 9 patients (78%) responded positively to an initial dose of infliximab. Responders were those who were able to avoid colectomy or the initiation of other therapies, specifically corticosteroids. In this subsequent report, an additional 8 patients have been added to the series. In this combined series, patients were treated in an open-labeled fashion and received infliximab infusions at a dose of 5 mg/kg on an as-needed basis determined by the individual gastroenterologist. Overall, short-term improvement was observed in 14 of 17 patients (82%), with a sustained clinical response in 10 of 16 patients (63%) during a 9 month follow-up. These results are quite similar to prior published reports concerning infliximab use in pediatric UC (9–11). As shown in Table 2 of the article by Mamula et al., an overall short-term response rate of 66% has been reported in these pediatric open-label trials. These results are also congruent with open-label trials performed in adult UC patients, in which an overall initial response rate of 58% has been reported (12–19). Placebo-controlled clinical trials evaluating the administration of infliximab in UC however, are very limited. In one study, a total of 11 patients were enrolled, with 8 of the 11 patients receiving infliximab infusions (12). Although the number of placebo-treated patients was small, the study demonstrated a clinical response (avoidance of colectomy) in 4 of the 8 infliximab-treated patients, with the remainder of the treatment group and the three placebo patients proceeding to colectomy after 6 weeks. Thus, these studies indicate that a clinical response in UC can be achieved with infliximab but only in highly selected group of patients after an initial infusion. What occurs during long-term follow-up? Many of these open-labeled studies have not had more than a 4–6 month follow-up after the initial infliximab infusion. According to the limited data available, the initial success achieved with infliximab may diminish over time. Great disparity is reported in these open label trials concerning long-term results. In one such study of 13 medically refractory adults, 10 of 13 (77%) responded to a single infusion of 5 mg/kg infliximab, and 90% of the responders maintained remission off steroids for a mean of 10.1 months (range, 5–12 months) (18). Mamula et al. report long-term improvement in 7 of their initial 9 pediatric patients (77%), with 6 of those 9 discontinuing steroids during follow-up (8). This is in contrast to other open-label trials of infliximab in UC, which have shown a diminishing effect during long-term follow-up. Other studies have been far less impressive, reporting sustained responses in less than 25% of patients, a rate not much better than that for placebo (19,20). The question remains: why the disparity among these studies? An even more important question is: why the difference in long-term response between UC and Crohn disease? To answer the latter question, we need to turn to the animal models of intestinal inflammation. A recent report by Heller et al. showed in a murine model of colitis that mimics many characteristics of UC that the inflammatory process was mediated by a Th2/IL-13 immunologic process (21). In these studies, the source of IL-13 was identified as natural killer T cells (NK T) which secreted the cytokine after activation by oxazolone, a chemical haptene reagent. The pathogenicity role of the NK T cells and IL-13 was proved by amelioration of colitis after administration of blocking antibodies to either NK T cells or IL-13. These experiments indicate that NK T cells, which were thought to be involved in regulation of innate immunity, may actually be involved in an autoimmune disease process. Natural killer T cells may have direct cytolytic potential as well as by secreting cytokines such as IL-13, a function that could have indirect toxic effects on the epithelial surface of the mouse intestine (22–24). If we extrapolate the findings of these studies to those in the clinical trials of infliximab, some of the disparities in the short and long-term clinical responses may become clearer. The remarkable efficacy of infliximab for the long-term treatment of Crohn disease understandably led to the use of this biologic agent in UC, as some therapeutic agents in the past have had similar efficacy in both diseases. However, as the immune studies that relate to human IBD show, although TNF-α appears to be an important cytokine in Crohn disease, it may not play as key a role in UC [reviewed in (25)]. Prior reports suggest that TNF-α is critical in the end-stage Th1 immunologic mediated disease process of Crohn disease (26). Conversely, although increased TNF-α levels are found in UC, the disease pathogenesis may rely on cell types other than conventional T lymphocytes (NK T cells) or other cytokines such as IL-13. If this is the case, the administration of infliximab might lead to the neutralization of circulating TNF-α, producing an acute improvement in clinical status; however, the driving factors of the disease process such as destruction of epithelium from NK T cells or epithelial effects from IL-13 may continue. An acute clinical response may be observed, but long-term remission may not be achieved because of the ongoing primarily dysregulated immune response. Other factors complicating the issue relate to the mechanisms involved in infliximab efficacy. As mentioned, the predominant effect of infliximab is induction of cell death (apoptosis) of activated effector lymphocytes or macrophage effector cells causing the inflammation. It is not known whether infliximab can induce apoptosis of NK T cells as it does with conventional T lymphocytes and/or macrophages. It is of interest that the patients having poorer response to infliximab were those with more chronic indolent disease and those who were deemed steroid refractory. These clinical findings suggest that patients with more acute disease secreting increased levels of TNF-α may be more responsive to therapy. In addition, factors such as induced cell death may also be decreased in these steroid refractory patients a factor that may curtail clinical responses. No doubt, disparity in response to infliximab exists between UC and Crohn disease. This brings us back to our first question: why the disparity? One undeniable problem in the existing clinical studies is that they have been uncontrolled and have involved nonhomogenous populations. Studies seem to indicate that the young and the elderly respond better to infliximab. Does age or disease duration possibly predict outcome? It is apparent that patients with more acute UC and who are not steroid refractory have a more favorable response to infliximab. This may be a clue to the difference in responsiveness. In the study by Chey et al. (14), for example, the patient population, although >60 years old, had had UC for less than 6 years, suggesting that disease duration and not age is a more important determinant of response. If this is the case, what is an appropriate timing for the introduction of infliximab therapy? In most of the open-label trials, infliximab was given at the discretion of the gastroenterologist with no uniform schedule of infusions. Thus, these studies cannot answer the important question of whether better clinical response occurs when the drug is used earlier or whether repetitive infusions will have a continuing impact on longstanding disease. No clearcut study populations nor clinical parameters have been identified to guide infusion schedules. Furthermore, although the long term side effects of infliximab are becoming known in CD, we still do not know whether there are long-term toxicities in UC on repetitive therapy. So far the results from initial trials would indicate that no serious side effects have occurred with administration; however, further placebo-controlled trials will be needed to be certain. In conclusion, infliximab has proved an effective drug in the treatment of one of the chronic inflammatory bowel diseases, namely Crohn disease. The results relative to UC show promise in selected groups of UC patients during the early treatment phase. However, many unanswered questions temper our view of these results, which can only be answered by further investigation. We await the results of double-blinded placebo-controlled trials to confirm whether infliximab will be as efficacious in long-term therapy of UC as it appears to be in the more acute setting and in Crohn disease.