Editorial

 

Infliximab in the treatment of severe ulcerative colitis

 

The treatment of ulcerative colitis shows a therapeutic window that is of great relevance for daily practice: the management of steroid-dependent patients who do not respond to mercaptopurine and that of steroid-refractory individuals. In a paper published in this issue, F. Bermejo et al. (1) manage these patients with infliximab (anti-TNF-α) in an attempt to solve this fortunately not-so-frequent difficulty.

TNF-α is synthesized by macrophages and to a lesser extent by T cells, NK cells, and mast cells within the colonic mucosa. The primary functions of this proinflammatory cytokine include: induction of class II major histocompatibility complex in association with IFN-γ in colonocytes, inhibition of enterocyte proliferation in the mouse, metalloproteinase synthesis stimulation, IL-8, VAN-1 and ICAM-1 synthesis activation synergically with IFN-γ, increased permeability of the mucosal barrier, MCP-3-mediated stimulation of chemotaxis in monocytes, neutrophils, eosinophils and basophils, and inhibition of T cell apoptosis (2-6).

In August 1998, the FDA approved infliximab for the treatment of fistulous inflammatory Crohn’s disease. This was the first chimeric antibody to neutralize TNF-α. The results of phase 3 treatment were so much brilliant in “healing” both gross and microscopic lesions that not more than 200 patients were ultimately needed, to which the drug’s orphan status contributed.

Crohn’s disease and ulcerative colitis are two distinct conditions that share a number of aspects, one of them being TNF-α as a key element in their inflammatory cascades, even though their intimate mechanisms differ. Evidence exists for the latter statement. On the one hand this cytokine is known to be highly concentrated in the lesions, circulation and feces of patients with colitis, and its levels correlate with inflammatory activity outbreaks (7-9). On the other hand anti-TNF-α therapy obtained positive results in ulcerative colitis animal models (10).

Research on the therapeutic role of infliximab in ulcerative colitis is and has been very poor. During the last 5-6 years a number of observational studies emerged on the treatment of ulcerative colitis with this anti-cytokine, and all of them supported a percentage of therapeutic response of 60-80%, similar to that seen for Crohn’s disease; however, they are based on hardly comparable, much too short, non-randomized series with no control groups and heterogeneous patient groups –including patients with pouchitis, indeterminate colitis, and both steroid-dependent and steroid-refractory severe colitis-as well as follow-up periods of 4 to 12 months in duration, much too wide relapse intervals, and scarce information on patients who keep their colon at follow-up endpoint (6,11-15). In 2003 the first extensive, randomized, controlled study in a group of steroid-refractory patients is reported, and no therapeutic effects are found with two 5 mg/kg doses at 0-2 weeks after a second infusion of infliximab (16).

The histologies and inflammatory models of ulcerative colitis and Crohn’s disease differ. Is the role of TNF-α within the inflammatory cascade also different in these two conditions? Do patients with ulcerative colitis make up a homogeneous group? Is there a reason to believe that steroid-refractory patients respond in a poorer way when compared to steroid-dependent patients? (15,16). In the article by F. Bermejo et al. (1), one patient did not respond but his/her refractory status is not specified; we would rather think this patient was refractory to steroids. Response to anti-TNF-α agents may not be accurately assessed until extensive randomized, controlled therapeutic trials are designed that include homogeneous patient groups, but the potential therapeutic niche of such drugs may be certainly delimited (17).

By using mesalazine, steroids and 6-mercaptopurine we may control ulcerative colitis in more than 90% of patients, but patients are either steroid-dependent or steroid-refractory in a percentage that is difficult to establish, and mercaptopurine is unable to solve this due to either prolonged therapeutic latency or intolerance; we then face a surgical indication that is pressing on occasion and leads to patient mutilation, with no assurance that the “disease” will be cured, and in association with pouchitis and significant morbidity and mortality.

Although suggested options include agents such as tacrolimus (FK506), intravenous 6-mercaptopurine, or lymphokine antagonists, well-researched data exist for cyclosporine (CyA) alone, a drug that inhibits IL-2 receptors on T cells and IL-2 secretion, as well as the secretion of IL-3, IL-4, and IFN-γ in a secondary manner.

Using 4-5 mg/kg/day intravenously, patients with UC exhibit blood levels ranging from 120 ng/mL to 483 ng/mL; by keeping concentrations in the high range end, patients manage to keep their colon at six months in a percentage oscillating between 33 and 80%, depending on whether medication is combined with mercaptopurine (18-21). These figures closely resemble those reported for infiximab.

There is seemingly no doubt that infliximab manages to nip severe ulcerative colitis flares in the proverbial bud, but its use is restricted to a marginal population of patients: those steroid-dependent individuals who do not respond to mercaptopurine. To steroid-refractory patients, too? How many infusions are needed to elicit response or otherwise consider a patient treatment-refractory? Are there any predictive factors for response? The one key question is whether this is more effective and less toxic when compared to CyA or tacrolimus followed by mercaptopurine, since it is certainly not cheaper.

J. Maté Jiménez

Gastroenterology Unit. Hospital de La Princesa. Madrid, Spain

 

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