How should complex perianal Crohn's disease be treated in the Remicade era.

Perhaps one of the most difficult aspects of treat­ ing Crohn's disease (CD) is the management of complex perianal disease. Perianal fistulas occur in 17%-43% of patients with CD and are more com­ monly associated with colonic CD than small bowel CD. Almost 100% of patients with rectal CD have perianal fistulas at some point. Perianal fistulas in CD can be broken down into two categories: simple or low and complex or high fistulas. The treatment for the two categories is dif­ ferent, and this review will concentrate on complex or high fistulas. This group includes high trans­ sphincteric, suprasphincteric, and extrasphincteric fistulas; multiple fistulas; fistulas with multiple exter­ nal openings; rectovaginal fistulas; and any perianal fistula in the presence of active rectal disease. Remicade is a genetically constructed IgG1 mu­ rine-human chimeric molecule (75% human) that binds both soluble and bound TNFa. In 1999, Pres­ ent et al. I performed a randomized double-blinded placebo controlled trial of Remicade for fistulizing CD. Fifty-five percent of the fistulas (of which 90% were perianal) treated with 5 mg/kg Remicade at 0,2, and 6 weeks were reported as closed. Closure was defined as no drainage despite gentle compres­ sion. The median length of closure was 3 months. Sixty percent of patients reported adverse events, in­ cluding 11 % abscess formation. Based on this study and subsequent studies, the standard dosing regimen of Remicade for perianal fistulas is 5 mg/kg given at 0, 2, and 6 weeks. Maintenance therapy, when indi­ cated is 5 mg/kg every 8 weeks. Premedication with Tylenol, Benadryl, or corticosteroids is given as needed. Subsequent studies have shown a complete peria­ nal fistula closure rate between 25% and 67% and a rectovaginal fistula closure rate of 0%-13%. The Accent II trial randomized patients with fistulizing CD to initial therapy at 0, 2, and 6 weeks with either 5 mg/kg of Remicade or placebo. Sixty-nine percent of patients in the Remicade group responded. Those 69% were then randomized to maintenance therapy with either Remicade at 5 mg/kg or placebo every 8 weeks for 54 weeks. Of those patients on Remicade maintenance, 42% lost the effect of the medication by 54 weeks. Infusion reactions are seen in about 20%-30% of patients, and especially in those patients with subse­ quent doses. The majority of reactions are minor and include low-grade fever, rash, and tachycardia. Symptoms usually resolve with decreasing the infu­ sion rate or cessation of the infusion. Pretreatment with Tylenol and Benadryl, and sometimes cortico­ steroids, usually permits subsequent administration of Remicade. Approximately 2 % of patients have a severe infusion reaction consisting of anaphylaxis, dyspnea, and/or hypotension. In these patients, further treatment with Remicade is contraindicated. Infusion reactions are thought to occur due to the development of human antichimeric antibodies. Infectious complications are not uncommon with Remicade treatment. Abscesses develop in about 10%-35% of patients due to healing of the external opening prior to healing of the fistula tract. This can usually be prevented in perianal fistulas by the place­ ment of setons. Upper respiratory infections, includ­ ing bacterial pneumonia and Pneumocystis carinii, develop in up to 16% of patients. Tuberculosis has been reported in over 70 patients, as have other op­ portunistic infections. Also reported is the possible increased risk of lymphoma and development of lupuslike reactions. Resolution of clinical signs of the fistula such as drainage and closure of the external opening does not mean that the fistula tract has healed. Several studies using endoanal ultrasound and magnetic res­ onance imaging have shown that the fistula tract persists despite cessation of drainage and apparent