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Niacin-like Reaction to Infliximab Infusion in Systemic Juvenile Rheumatoid Arthritis To the Editor: Infliximab is a chimeric human/mouse monoclonal antibody that binds to tumor necrosis factor-a and has been used with success in pediatrics for ankylosing spondylitis, psoriatic arthritis, and sarcoid arthritis. The multicenter clinical trial for its juvenile rheumatoid arthritis (JRA) indication is currently under way. We and others have been using infliximab off-label for the treatment of refractory pediatric rheumatic diseases for the past few years. Adult clinical trials for infliximab have identified serious adverse reactions mainly associated with infection and hypersensitivity. In the ATTRACT study in which different regimens of infliximab plus methotrexate (MTX) were compared to MTX plus placebo, upper respiratory infections (34% vs 22%), sinusitis (17% vs 6%), and pharyngitis (11% vs 6%) were seen more frequently with infliximab1. In the MedWatch postmarketing surveillance report, disseminated tuberculosis was noted to be increased in patients with RA treated with infliximab2. In addition, acute infusion reactions including fever, chills, cardiopulmonary reactions, pruritis, and/or urticaria or anaphylaxis have consistently been reported3. Overall, however, the consensus is that the drug is safe. We describe 3 children we treated with infliximab for refractory systemic JRA who developed an initially drastic, yet ultimately benign, niacin-like effect, which may have been poorly recognized in pediatrics. Our infliximab protocol includes premedication with acetaminophen (10 mg/kg/dose) and diphenhydramine (1 mg/kg/dose) given 1 hour before infusion of the drug. Two patients with systemic arthritis who had received infliximab successfully, as well as one who had not, developed a previously undescribed side effect. They experienced cutaneous erythematous flushing over the face and chest and intense chest tightness during the first few minutes of the infusion. The vital signs remained stable thus no hypotension, tachycardia, or hypoxia was noted. Examination revealed no wheeze and no stridor. Upon discontinuation of the infusion, the flushing quickly resolved. For the first 2 patients, several premedications were added upon subsequent attempts, including dexamethasone, prednisone (on both the day previous and the day of medication), and albuterol nebulizer treatments. These interventions failed to prevent the reaction. A niacin-like reaction was suspected and ASA (10 mg/kg/dose with a maximum of 325 mg) was substituted for acetaminophen in the premedication protocol. After ASA was added, no further episodes were observed. We were able to slowly taper nearly all of the additional premedication drugs that were secondarily added without difficulty in Patients 1 and 2. Patient 3, who reacted at the first infusion, was immediately treated with ASA after the initial reaction and was rechallenged successfully after 30 minutes. Niacin, a water-soluble B vitamin, has been identified as a hypolipidemic agent, via reduction of triglyceride synthesis. Its use has been hindered by side effects, one of which is intense flushing. This dermatological effect is dose-related and is described as severe skin reddening, associated with warmth, mainly over the face, neck, and ears within 2 hours of ingesting the drug5. Studies have linked this effect to vasodilatation of cutaneous vessels from an endogenous release of prostaglandin D2 (PGD2)4. The skin has been shown to be a major site of PGD2 release after ingestion, although the specific cell from which PGD2 is released is unknown6. Pretreatment of patients receiving niacin with cyclooxygenase inhibitors has been shown to significantly lessen the cutaneous effects of this drug, most likely secondary to PGD2 inhibition7. A single dose of ASA 325 mg is the most effective in blocking this reaction. Our 3 patients exhibited symptoms similar to a previously described niacin-like effect not yet widely recognized with infliximab therapy. After treating these patients with 162–325 mg of ASA 1 hour prior to infusion, there was a dramatic improvement in their symptoms. Other investigators have reported a similar observation. A "red man syndrome" was described in a total of 5 patients with Crohn's disease treated with infliximab8,9. When the infusion rate was decreased or the drug stopped, the symptoms improved. It is intriguing that all our cases were patients with systemic JRA. This apparent association may be caused by more frequent use of infliximab in patients with the systemic subset. The finding of a similar adverse event among patients with Crohn's disease suggests a drug-related more than a disease-related effect. By changing the premedication protocol for infliximab when necessary to include ASA, we may enable the continuation of a successful therapy for patients with juvenile arthritis that is difficult to treat. MARA BECKER, MD, Pediatric Rheumatology Fellow; CARLOS D. ROSÉ, MD, CIP Professor of Pediatrics; GAIL McILVAIN-SIMPSON, MSN, RN, CSN, Division of Rheumatology, Department of Pediatrics, duPont Hospital for Children, Thomas Jefferson University, Wilmington, Delaware, USA REFERENCES 1. Lipsky PE, van der Heijde DMFM, St. Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000;343:1594-602. 2. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098-104. 3. Centocor, Inc. Infliximab package insert. Malvern, PA: Centocor, Inc. 4. Wilkin JK, Fortner G, Reinhardt LA, Flowers OV, Kilpatrick SJ, Streeter WC. Prostaglandins and nicotinate-provoked increase in cutaneous blood flow. Clin Pharmacol Ther 1985;38:273-7. 5. Wilkin, JK. Why is flushing limited to a mostly facial cutaneous distribution? J Am Acad Dermatol 1988;19:309-13. 6. Morrow JD, Awad JA, Oates JA, Roberts LJ. Identification of skin as a major site of prostaglandin D2 release following oral administration of niacin in humans. J Invest Dermatol 1992;98:812-5. 7. Gibbons LW, Gonzalez V, Gordon N, Grundy S. The prevalence of side effects with regular and sustained-release nicotinic acid. Am J Med 1995;99:378-85. 8. Lobel EZ, Korelitz BI, Warman JI. Red man syndrome and infliximab [letter]. J Clin Gastroenterol 2003;36:186. 9. Hyams JS, Markowitz J, Wyllie R. Use of infliximab in the treatment of Crohn's disease in children and adolescents. J Pediatr 2000;137:192-6.
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