Infliximab as First-Line Therapy for Crohn's Disease Is Premature

The clinical course of Crohn's disease (CD) is characterized by remissions and recurrences that vary considerably among patients. Because no therapy for CD, medical or surgical, is curative, treatment objectives are directed towards optimizing quality of life by inducing and then sustaining remissions with a minimum of adverse events. For several decades, the conventional steroids prednisone and prednisolone have been a cornerstone first-line drug therapy for active CD. That the introduction of infliximab has been a major advance in the therapeutic armamentarium for the treatment of CD would find few dissenters. However, the notion that infliximab should supplant corticosteroids as first-line therapy for CD seems premature. Population-based studies indicate that only about 43% of patients with CD will ever require corticosteroid therapy (1), underscoring the importance of tempering enthusiasm for administering potent therapeutic agents, old or new, and ensuring that indications are appropriate. Recognizing that there are no clinical trials directly comparing prednisone and infliximab, are the expectations for clinical outcome from the two therapies appreciably different? For the treatment of moderate-to-severely active CD, evidence provided from large multicenter randomized trials attest to the efficacy of conventional corticosteroids. Clinical remission is achieved in 60–80% of patients treated with tapering doses of prednisone over 2–4 months (2,3). Only 16–20% of patients are refractory to treatment (1,4). Symptomatic improvement is rapid, although complete endoscopic healing is less consistent and occurs in about 30% of patients (5). One year after initiation and withdrawal of corticosteroid therapy, approximately 33% of patients show a sustained response, and generally without immunosuppressive (azathioprine, methotrexate) drugs (1). From a pivotal multicenter dose-ranging study, we have learned that for active CD, a single infusion of infliximab at an optimal dose of 5 mg/kg also provides rapid clinical improvement usually within 2 weeks (6). Although a clinical response is observed in 65% of patients, approximately 33% of patients achieve a clinical remission at 4 weeks (6), a rate that may be somewhat improved on by incorporating a three-dose induction regimen of 5 mg/kg at 0, 2, and 6 weeks (7). In contrast to prednisone therapy, endoscopic healing is observed in a majority of patients who have received infliximab; however, with clinical relapse ulceration does recur at the same site (8). Thus, en face, on clinical grounds alone for induction of remission in patients with active CD, prednisone appears to be at least as effective as anti-tumor necrosis factor (TNF) therapy. A compelling difference, however, lies in the observation that in the study of Targan et al. (6) treatment effects of infliximab were consistent regardless of concurrent drug therapy, and 53% of patients were receiving corticosteroids. Thus, infliximab provides benefit for active patients who have failed prednisone, which is clearly an important advance. However, the proportion of patients in this subgroup who achieve remission and ultimately discontinue steroids has only recently been addressed in a large, multicenter trial (7). The final analysis, including the magnitude of the steroid-sparing capabilities of infliximab, will be of substantial interest. Infliximab is the only drug that has been shown in a multicenter trial (9) to improve outcome in patients with active fistulizing, perianal disease; corticosteroids are not effective and indeed may accelerate activity. The spectrum of adverse events associated with conventional corticosteroids is well recognized (10) and provides the most cogent argument for seeking alternative therapies. Cosmetic and psychological complications of prednisone become an important albeit reversible issue, particularly in young adults. Reduction in bone mineral density is a frequently cited side effect associated with corticosteroid therapy, but in CD the pathogenesis of osteopenia is complex with genetic predisposition and disease activity also likely playing important roles. One of the new steroids that has emerged as a treatment option for active CD is budesonide, formulated as an oral delayed-release ileal preparation. For the treatment of moderately active ileocecal CD, oral budesonide is more effective than placebo (11), superior to mesalamine, and is only marginally less effective than prednisolone (12). The corticosteroid-associated adverse event profile after budesonide treatment is no different than placebo (11). However, the available formulations of budesonide are only beneficial for patients with active disease limited to the ileum and right colon and not patients with extensive colonic disease. Similar to conventional corticosteroids, budesonide also is not effective for long-term maintenance of remission (13). In the treatment of CD, experience with infliximab is more limited; however, as with corticosteroids, there is an adverse events profile. Infusion reactions are observed in up to 16% of treated patients, and delayed hypersensitivity reactions may occur when the infusion interval exceeds 1 year. Development of antinuclear antibodies and the presence of double-stranded DNA are well documented (14); the long-term significance of these observations remains unclear, although a lupus-like syndrome appears to be an uncommon event (14). Human antichimeric antibody formation has been reported in up to 36% of patients, which has been related to loss of treatment response and to an increased risk of infusion reactions (15). Initial reports that infliximab may be associated with the development of lymphoma seem to be allied as experience becomes more extensive, but requires continued monitoring. The emergence of cases of tuberculosis is of concern and emphasizes the importance of careful screening prior to therapy. Similar to prednisone, death has been reported due to intestinal sepsis associated with active CD. In CD, studies evaluating the long-term outcome and safety of infliximab are limited. Infliximab infused at 8-week intervals maintains remission in 53% of patients, compared with 20% receiving placebo followed for 48 weeks (16). Thus, although infliximab is effective for maintaining remission, these initial prospective data coupled with clinical experience suggest that a proportion of treated patients become infliximab dependent. Whether azathioprine or methotrexate reduces this requirement for anti-TNF therapy, as in patients with steroid dependence (17,18), has not been established and requires prospective evaluation. Moreover, the long-term outcome in CD including the propensity for relapse and safety beyond 1 year is unknown. Lastly, further reflection on the question “corticosteroids or infliximab” might more appropriately be phrased “corticosteroids or infliximab plus...” Experimental evidence obtained from genetically susceptible animal models demonstrate the important contribution of commensal enteric flora to the development of intestinal inflammation, particularly in the colon. Although antibiotics do not appear to be effective for patients with CD of the ileum (19), observations from clinical trials are consistent in that patients with involvement of the colon do appear to derive benefit from antibiotics alone (20) or in combination with an immune modulator (19); however, the number of patients studied were inadequate to achieve statistical significance. The role of antibiotics alone or in combination with an immune modulator for the treatment of patients with Crohn's colitis and with major involvement of the colon also remains an area for prospective evaluation. Thus, in the absence of prednisone failure or perianal fistulizing disease, there are no compelling reasons to consider infliximab as first-line therapy. Indeed, the cost of treating all CD patients with infliximab could be prohibitive in many countries. Although long-term prospective trials may eventually establish that infliximab does alter the natural history of CD by reducing complications and the requirement for surgery, with an acceptable adverse event profile, to replace current therapeutic options including corticosteroids seems premature.

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