Is Infliximab Effective for Induction of Remission in Patients with Ulcerative Colitis?

Crohn’s disease (CD) and ulcerative colitis (UC) constitute distinct yet somewhat similar idiopathic inflammatory disorders of the gastrointestinal tract. Manifestations of these diseases can be quite severe and often require treatment with long-term therapy mandating a variety of medications and/or surgery. Standard medical therapy is classically guided towards antiinflammatory treatment, antimicrobial treatment, and immune modulation. Laboratory-based research has helped identify many specific chemokine and cytokine-effector molecules that comprise the end effect of immune system activation resulting in the promotion of intestinal inflammation. These bench-based laboratory investigations have led to experimental clinical trials with specific cytokine agonists and antagonists. Inhibition of one such cytokine, tumor necrosis factor alpha (TNFα), with a monoclonal chimeric antibody, infliximab, has demonstrated significant clinical efficacy in the treatment of patients with CD. This observed clinical efficacy is consistent with scientific observations that suggest a central role for TNFα in the inflammatory cascade. TNFα is known to have biologic properties relating to inflammation, proliferation, differentiation, and cancer growth, and is also known to have a central role in shock resulting from sepsis and wasting syndromes subsequent to a variety of cancers. The inflammatory and proliferative effects of TNFα are important in inflammatory bowel disease (IBD). Macrophage activation, neutrophil priming, and increased epithelial permeability (1,–3) have all been documented to result from TNFα. TNFα is produced mainly from activated macrophages; however, lymphocytes and natural killer cells (1) also contribute to its production. Recent data has also illustrated that TNFα is also produced by mucosal mast cells in up to 60% of all lamina propria cells expressing TNFα (4). Immune-mediated tissue injury subsequently ensues and is a result of the induction of proteases, prostaglandins, leukotrienes, eicosanoids, and other products. However, some other agents such as prostaglandin E2 may also cause diarrhea by inducing mucosal secretion of chloride and potassium (5). Additionally, TNFα is involved in the recruitment of other immune cells (1,3). Many specific inflammatory and proliferative effects have been attributed to TNFα including: 1) induction of the expression of major histocompatability complex class II antigens on normal human colonic epithelium (in association with IFN-γ) (6); 2) inhibiting murine intestinal cell proliferation in response to various growth factors (7); 3) either stimulating (at low concentrations via binding of p75 cell surface TNFα receptors) or inhibiting (at high concentrations via binding of p55 cell surface TNFα receptors) proliferation of murine intestinal epithelial cells (7); 4) elaborating matrix metalloproteinases [these have been shown to contribute to tissue damage in experimentally inflamed fetal gastrointestinal cells (8,9)]; 5) increasing intestinal epithelial cellular secretion or gene expression of interleukin-8 as well as secretion of VCAM-1 and ICAM-1 by other epithelial cell lines (10,–12); 6) synergistically altering interferon-γ-dependent changes in the morphology and barrier properties (transepithelial resistance, paracellular flux, and short circuit current) of human intestinal cells (13); and 7) stimulating the in vitro production by intestinal epithelial cells of monocyte chemotactic protein 3 (MCP-3), a known chemoattractant of monocytes, T lymphocytes, eosinophils, and basophils. MCP-3 has previously been demonstrated to be upregulated in inflamed mucosa of patients with IBD (14). Additionally, there is data to suggest that TNFα plays a role in the inhibition of T lymphocyte apoptosis. The T cell is a central figure in the immunopathogenesis of CD, and recent evidence suggests that T lymphocytes isolated from patients with CD are resistant to apoptotic (programmed cell death) signals. This observation has been suggested to be due to an imbalance of cellular concentrations of Bcl-2 (an antiapoptotic protein) and BAX (a proapoptotic protein) (15). TNFα antagonism may specifically augment apoptosis of these long-living and proliferating T cells (16). In contrast, TNFα antagonism does not necessarily lead to apoptotic cell death in intestinal epithelial cells (13). Thus, it is obvious from the laboratory-based data presented that TNFα occupies a central and important position and plays a significant role in the regulation of inflammation within the intestinal tract. The inhibition of TNFα on theoretical grounds thus seems likely to be clinically beneficial in IBD. On the other hand, there is important clinical data derived from the use of infliximab. Infliximab, a chimeric monoclonal antibody directed against TNFα, which has a high affinity and specificity for TNFα, has been demonstrated to be effective for the treatment of patients with CD. Several well-designed clinical trials have been performed demonstrating remarkable efficacy of infliximab in the treatment of patients with CD (17,–19). Infliximab is FDA-approved for the treatment of inflammatory and fistulizing CD. In concert with the success of infliximab, there exist several other TNFα antagonists in various phases of investigation for patients with CD including the chimeric monoclonal antibody CDP 571, the fusion peptide Etanercept, the phosphodiesterase inhibitor oxpentifylline, and thalidomide. With the initial tremendous success of infliximab in CD, the authors in this study elected to proceed to evaluate the efficacy of infliximab in patients with UC who had severe steroid-refractory disease. Their decision to proceed with this investigation was supported from other data as well. TNFα is not only thought to be important in CD, but there currently exists substantial evidence highlighting the importance of TNFα in ulcerative colitis. In addition to the pathogenic plausibility, there are two lines of preclinical evidence for the potential efficacy of anti-TNFα therapy in the treatment of UC. The first line of evidence is the descriptive characterization of high levels of TNFα production on either the local or systemic level. This includes the demonstration of an increased production of this cytokine in colonic mucosa, stools, rectal dialysate (less convincing), or plasma from patients with active UC, and the increased concentration correlates with disease severity, both clinically and endoscopically (20,–25). There is also an increased concentration of soluble TNFα receptors (p55 and p75) in the urine of patients with UC, and the increased concentrations correlated with disease activity (26). This line of evidence is very descriptive and does not provide any collaborating evidence for a role of TNFα in disease. There is abundant literature on these types of descriptive studies. In addition, there is also in vitro evidence that in UC, TNFα contributes to cellular injury in colonic epithelium by increasing antibody-dependent cellular cytotoxicity (27). The second line of evidence comes from animal data. Evidence of an anti-TNFα treatment effect has also been demonstrated in the cotton-top tamarin, an animal model of idiopathic UC (28). These animals present with chronic diarrhea and weight loss and possible death unless treated with 5-aminosalicylic acid compounds or corticosteroids. The pathology and response to medical therapy are similar to that of UC in humans. Additionally, they develop secondary complications such as colorectal adenocarcinoma and sclerosing cholangitis. Fecal concentrations of TNFα are increased in these cotton-top tamarins (29), and treatment of six cotton-top tamarins with chimeric monoclonal anti-TNFα antibodies (CDP 571) led to increased weight and improved histologic evidence of mucosal inflammation (28). Additionally, with use of CDP 571, a chimeric monoclonal antibody directed against TNFα, there was a clinical trial performed and reported in 1997 in patients with mildly to moderately active UC, some of whom were refractory to medical therapy (30). Fifteen patients were enrolled and received a single dose of CDP 571 at 5 mg/kg and were followed for 8 weeks. The primary endpoint was a decrease in the Powell-Tuck score over the course of the investigation. Assessment of disease activity consisted of subjective symptom reporting, a visual analogue disease activity score, subjective scoring on flexible sigmoidoscopy, and the Powell-Tuck score—all measured at weeks 0, 1, 2, 4, and 8. Enrollment criteria specified that maintenance therapy had been unchanged for at least 1 month prior to enrollment with the exception of azathioprine. Azathioprine therapy was unchanged for at least 3 months prior to enrollment. Nine of the 15 patients were not receiving corticosteroids at study entry. The remaining six were refractory to prednisone at a dose of 40 mg/day for at least 2 weeks prior to entry. The mean Powell-Tuck score fell from 6.7 at baseline to 4.6 at week 1 (p = 0.023) and to 5.5 at week 2 (p = 0.218). The mean visual analogue disease activity score fell from 6.6 at baseline to 5.9 at week 1 and to 5.3 at week 2, although none of these changes were statistically significant. The mean sigmoidoscopic score fell from 2.3 at baseline to 1.2 at week 2 and to 1.4 at week 4, although none of these changes were statistically significant. Mean Powell-Tuck, sigmoidoscopic, and visual analogue disease activity scores were not provided past week 4. Although disease activity initially decreased in 10 patients, persistent improvements beyond 2 weeks postinfusion were not clearly demonstrated. This data suggested a short-term response benefit from 5 mg/kg CDP 571 in patients with mildly to moderately active UC. The optimal dose and dosing regimen still remain undefined. In a similar fashion, thalidomide has been used for patients with CD refractory to conventional medical therapies. Thalidomide is known to inhibit TNFα production by monocytes in vitro, and has been found to have effects on other cytokines. Thalidomide has several mechanisms of action including inhibition of TNFα expression by destabilizing messenger RNA (preventing either expression on the cell surface or release into the interstitial fluid or serum), decreased expression of interleukin-12, down-regulation of integrins, diminished leukocyte migration by inhibition of protein kinase C, and impaired angiogenesis. In light of its activity against TNFα (and other actions), it has been used in two pilot trials for the treatment of CD (31,32). Additionally, Kam et al. (33) have treated seven patients with refractory UC with orally administered thalidomide in doses of 50–100 mg/day. Entry criteria specified a modified Truelove and Witts scale between 10–16 (consistent with moderately active disease) and either resistance or intolerance to high-dose 5-aminosalicylic acid (5-ASA), steroids (with daily prednisone dose of between 10–40 mg), and immunomodulator therapy. Clinical response was defined as a decrease in the end-point assessments consisting of modified Truelove and Witts scale, steroid dose, and the Inflammatory Bowel Disease Questionnaire (a validated quality-of-life instrument specific to IBD) at both 4 and 12 weeks. Clinical remission was defined as a modified Truelove and Witts scale of 3 or less. Overall, response was observed in 43% of patients at 4 weeks but in only 29% of patients at 12 weeks. Likewise, remission was observed in 29% of patients at 4 weeks but in only 29% of patients at 12 weeks. Of note, 29% of patients were no longer receiving prednisone by week 12. Quality-of -life improvements paralleled clinical response and remission. In this issue of Inflammatory Bowel Diseases ®, Sands et al. report on the efficacy of single-dose infliximab on severe UC. Patients with refractory UC remain an important focus for new medications, as has been the target of some of the aforementioned studies. More importantly, however, are patients with steroid-refractory UC who have severely active disease. These patients historically had resorted to colectomy prior to the advent of cyclosporine A. With the use of cyclosporine A, an 82% acute response to therapy within a mean time of 7.1 days has been documented (34). Without the concurrent use of azathioprine or 6-mercaptopurine, some initial reports suggested that up to 70% of patients will require colectomy within a short time period. With use of azathioprine after cyclosporine salvage to corticosteroid-resistant patients, several papers have been published documenting excellent responses: 90% remission in one series (35) and 65% complete and 24% partial response in another series (36). Another study estimated life table analysis of noncolectomy survival at 5.5 years as 58% of all patients, 70% of initial cyclosporine A responders, and 71% of cyclosporine A responders receiving 6-mercaptopurine or azathioprine. Of importance is that all colectomies occurred within 18 months of cyclosporine A initiation (37). These data on efficacy are impressive; however, data regarding toxicity are of significantly concern with one report documenting a 3% incidence of colonic perforation and a 3% postoperative death rate in 32 patients who received cyclosporine A after failing i.v. corticosteroids (38,39). In another series that evaluated 22 patients, 6 (27%) had headaches, 4 (18%) had paresthesias or tremors, 4 (18%) had hypertension, and 2 (9%) had reversible renal impairment. Cyclosporine was not discontinued due to adverse events. Another series evaluating 42 patients noted complications resulting in cyclosporine A discontinuation in six patients. All adverse events were reversible with complete recovery noted (37). The current paper examines the role of infliximab serving as a new therapy for treatment of patients with severe steroid-refractory UC. The study performed is a pilot study that was terminated early due to an inability to adequately recruit patients into the study. The authors planned the initial study with the intent of recruiting 60 patients; however, the study was terminated after they recruited only 11 patients. All patients in this trial were treated with at least 7 days of corticosteroids with at least 5 days of parenteral corticosteroids at a dose equivalent of ≥ 40 mg and ≤ 60 mg daily. The patients’ erythrocyte sedimentation rate, C-reactive protein, serum TNFα levels, and serum interleukin-6 assessments were measured initially and at various times after administration of medication or placebo, and sigmoidoscopy with biopsy was performed within 7 days of medication infusion and at 2 and 6 weeks postinfusion. Patients received either placebo, infliximab at 5 mg/kg, infliximab at 10 mg/kg, or infliximab at 20 mg/kg. Clinical response was assessed prior to medication infusion, at 72 hours 1, 2, 4, 6, and 12 weeks after infusion, or until treatment failure was observed. Treatment failure was defined as 1) unachieved clinical response as defined by a modified Truelove and Witts severity score, 2) increase in corticosteroid dosage, 3) addition of immunosuppressants, 4) colectomy, or 5) death. The study demonstrated that 50% (four of eight) of patients who received infliximab were considered treatment successes at 2 weeks, in comparison with none of the three who received placebo. In patients who received infliximab, improvement in erythrocyte sedimentation rate, C-reactive protein, and interluekin-6 correlated with clinical response. Five of eight infliximab-treated patients demonstrated decreases in modified Truelove and Witts disease severity scores, and five of six infliximab-treated patients who underwent sigmoidoscopic evaluations demonstrated improvement. There were no significant adverse events from infliximab. These results from the study reported by Sands et al. in this issue are of utmost importance; however, several important questions still remain unanswered: It is often customary to treat patients with the equivalent dose of 300 mg of intravenous hydrocortisone (i.e., 60 mg daily of methylprednisolone or 75 mg of prednisone); it is uncertain why the authors chose a lower dose than had been used by other trials. Additionally, they chose a shorter minimal duration of therapy. Other trials have notably chosen 7–10 days of parenteral treatment with corticosteroids as the minimum duration of treatment time prior to stating that a patient has not responded to medical therapy. What effect did treatment have on intestinal mucosa? Was healing achieved as has been the case with patients who have Crohn’s disease and receive infliximab? How may patients had previous therapy with cyclosporine A? We are informed that cyclosporine A was not permitted within 3 months of enrollment. Did any individuals who received cyclosporine A previously with no response respond to infliximab? Also, did any patients who did not respond to infliximab respond to cyclosporine A? What is the long-term follow-up on these patients? How long did the responses last in the patients who responded to these single infusions of infliximab, and did they receive subsequent infusions of infliximab? If so, what occurred with these patients on subsequent repeat dosing? What will be the best dose of infliximab in patients with ulcerative colitis? Despite the shortcomings in this study, the results obtained do suggest that infliximab administered at 5, 10, or 20 mg/kg daily was well tolerated and may provide clinical benefit to patients with severe, steroid-refractory UC. The small number of patients in this study preclude us from making a definitive statement about clinical response to infliximab; however, these results do set the groundwork and suggest that a larger controlled trial is indicated to confirm the impression of benefit and to define the magnitude of response and remission to infliximab in patients with UC.