Anti-TNF Therapies Have Eliminated the Need for Steroids in Pediatric Crohn's Disease: Con. Why Use a Drug with an Unknown Long-Term Safety Profile if More Established Therapies Will Be Effective?

The advent of biological therapies such as infliximab, which are rapidly effective in the settings of fistulizing disease and acute inflammatory disease even among corticosteroid-refractory or corticosteroid-dependent patients, is a significant therapeutic advance (1,–3). The question we debate in this forum and in clinical practice is how and when to use infliximab in children with Crohn's disease (CD). Recently published evidence-based guidelines, written by adult gastroenterologists concerning the use of infliximab in CD, recommend its use in inflammatory disease, not as first-line therapy, but among patients who demonstrate continuing symptoms despite optimal use of corticosteroids and conventional immunomodulatory therapies (4). More frequent, more aggressive use that eliminates the need for corticosteroid therapy among pediatric patients is unjustified and cavalier. Pediatric gastroenterologists are under no delusions concerning the efficacy of corticosteroids in the treatment of CD. They do not induce mucosal healing (5,6). They do alleviate symptoms, and induce clinical remission, as defined by multi-item measures of disease activity, in up to 90% of young patients in the controlled trial setting of acute disease (7,8). Serious toxicity with short-term prednisone use is uncommon; cosmetic side effects can be reduced by attention to the limited dose-ranging data in acute inflammatory bowel disease (IBD), which suggest that moderate dosage is as effective as high dosage in most patients (9). For children or adolescents with mild-to-moderate disease, 5-aminosalicylic acid, antibiotics, enteral nutrition, or controlled ileal-release budesonide may obviate systemic steroid use. Neither conventional steroids nor controlled ileal release budesonide have a role in relapse prevention (10,11). Former pediatric practice of routinely continuing alternate day prednisone to maintain clinical remission following successful treatment of acute disease has, therefore, been abandoned. In contrast, 6-mercaptopurine (6-MP) or its prodrug azathioprine (AZA) have been established in the controlled trial setting among adults and recently among children as relapse-preventing medications (8,12). Recent studies measuring metabolite levels suggest a means of dose optimization to further enhance efficacy (13,14). Data concerning long-term safety among patients with IBD are reassuring (15,16). Clinical response may well be associated with mucosal healing; that has not been examined. Pediatric gastroenterologists increasingly institute immunomodulatory therapy early, thereby reducing subsequent clinical relapses and corticosteroid requirements (8). Although there are no directly comparative data, in clinical practice, as reported by Mack et al., a proportion of children intolerant of or refractory to AZA/6-MP respond to methotrexate (MT) (17,–19). If corticosteroids can dampen the symptoms associated with acute disease, while allowing immunomodulatory drugs with acceptable long-term safety to achieve and maintain control, what would be gained by substituting infliximab in the acute treatment phase? In the first placebo-controlled study among adults with treatment-resistant CD, the 4-week clinical remission rate with all dosages of infliximab combined was 33% (1). The 10-week “response” rate to a single infusion of infliximab in the recently reported Accent 1 trial involving a total over 500 patients was 53% (20). There are no data available to allow direct comparison of corticosteroids versus infliximab in the initial treatment of first or subsequent acute exacerbations of CD. Would rates of remission, which should be the goal rather than “response,” be higher in these circumstances than when infliximab has been used in clinical trials among corticosteroid-dependent or refractory patients? Is there a treatment benefit for infliximab versus corticosteroids as de novo therapy? Efficacy data concerning infliximab have been accrued predominantly among patients still receiving corticosteroids and/or immune-modulating drugs, raising the possibility of adjuvant effects. In the maintenance phase of the Accent I trial, only 30% of adult patients treated with infliximab (5 mg/kg) at 8-week intervals were in clinical remission off steroids at 30 weeks (20). Induction of remission with infliximab does not eliminate the need for maintenance immunomodulatory therapy. The responses to infliximab therapy in clinical trials have been of short duration, with gradual loss of response typically observed between 4 and 12 weeks following an infusion (1,21). The observation of prolonged duration of response in early pediatric CD is based on a very small number of patients (22), and seems contrary to what we understand about the mechanism of action. Nikolaus et al. have demonstrated that reactivation of clinical symptoms is predictably preceded by an increase in circulating levels of tumor necrosis factor-α (TNF-α) and mucosal nuclear NFκB (21), so that repeated reinfusion would be essential were remission to be maintained with infliximab alone. Moreover, a randomized controlled trial of repeated infliximab infusions in rheumatoid arthritis demonstrated a benefit to concomitant administration of MT in reducing antibody formation and sustaining responsiveness to infliximab (23). By analogy, concomitant use of AZA/6-MP or MT is recommended for patients with CD. Conservatism in the use of infliximab in children is required in the absence of data concerning potential long-term toxicity. “Might the devil you know be better than the devil you don't know?” Certainly the toxic effects of steroids are not to be denied, although some adverse events in CD historically attributed to steroids, such as osteoporosis, osteonecrosis, and growth impairment, are now recognized to be in part effects of the chronic inflammatory process itself (24,–26). We are still acquiring knowledge concerning risk of malignancy, infection, and autoimmunity potentially associated with infliximab therapy, given that TNF-α is a key cytokine in immune surveillance (27,28). The number of lymphoid and nonlymphoid cancers reported in CD patients treated with infliximab does not appear to be greater than expected based on the inherent risk, but follow-up duration of all treated patients is still short (28). Questions concerning optimal and acceptable dosing intervals remain, in the light of early observations that serum sickness-like reactions were more common among patients reinfused after a long hiatus. The effects of repeated infusions on the natural history of CD are also unknown, and give some cause for concern given the potential to heal with stricture formation. Until a broader and longer experience with its use exists, infliximab should not be used in clinical practice to treat inflammatory disease in children who would respond acutely to corticosteroids and be well controlled with traditional immune modulators. The spectrum of pediatric CD includes, however, children and adolescents, who will not attain a satisfactory remission, despite corticosteroid treatment and optimal use of AZA/6-MP or MT and nutritional support, but who do not have a clear indication for surgical treatment (29). Persistent chronic inflammation in children with CD carries the additional burden of impaired growth and pubertal development (29,30). Proinflammatory cytokines, including interleukin-6 and TNF-α, impair appetite and directly impede linear bone growth and bone mineralization (26,31,32). Whereas normal growth is a marker of success of therapy, growth impairment is a sign of ineffectively controlled inflammation and associated chronic undernutrition. Despite decades of recognition and treatment of the spectrum of pediatric CD, there are no identified predictors of a chronically active inflammatory course versus a sustained remission following initial treatment. As we continue to grapple with the questions of when to use what therapies in the era of new biological agents, more progress would be made if children with disease well characterized at presentation were treated and followed in the context of well-designed protocols. Infliximab is a significant addition to the therapeutic armamentarium of inflammatory CD, to be employed among otherwise treatment-refractory young patients, but earlier use in clinical practice should await additional data concerning sustained efficacy and safety.

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