Anti-cytokine therapy in Kawasaki syndrome: Current status and future directions Jane C. Burns, M.D. 　Administration of IVIG as a single 2 g/kg dose within the first 10 days after onset of fever in combination with high dose aspirin (ASA) reduces the risk of coronary artery damage to 3-5% by unknown mechanisms. However, IVIG therapy is expensive, is not available in all countries, and approximately 10-20% of KS patients fail to become afebrile after the first infusion. The risk of coronary artery aneurysms (CAA) is increased in these patients and no controlled clinical trials have established their optimal management. For KS patients with persistent or recrudescent fever after IVIG, current practice is to administer additional therapy, which may include one or more repeat doses of IVIG, high-dose pulse methylprednisolone, cyclophosphamide, methotrexate, ulinistatin (in Japan), cyclosporin A, or plasmapheresis. 　The vasculitis of KS is fueled by a wide range of pro-inflammatory cytokines, most notably interleukin (IL)-6, IL-1, and tumor necrosis factor (TNF)-α. The availability of biologic immunotherapeutic agents that specifically bind to these cytokines or interfere with their action is ushering in a new era in the therapy of inflammatory diseases. The growing list of these agents includes a monoclonal anti-IL-6 receptor, recombinant IL-1 receptor antagonist (anakinra), and numerous TNF-α antagonists. In the U.S., the TNF-α antagonists licensed for clinical use are a) etanercept (Enbrel, Immunex Corp., Seattle, WA), a dimer of the soluble TNF receptor II in which the extracellular domain of the p75 receptor is fused to the constant region of human IgG1, b) infliximab (Remicade, Centocor, Malvern, PA), a chimeric murine/human IgG1 monoclonal antibody that binds specifically to human TNF-α-1, and adalimumab, a humanized monoclonal antibody to TNF-α. Infliximab, which is administered intravenously, is effective in a broad spectrum of immunologic disorders in which inflammation is mediated by TNF-α. It has been approved in the U.S. for the treatment of rheumatoid arthritis and Crohn’s disease in adults and is under study in the U.S. for treatment of acute juvenile rheumatoid arthritis and Crohn's disease in children. In Japan, infliximab (Tanabe) is under study in clinical trials for adults with Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and ulcerative colitis. 　Serum levels of TNF-α are elevated in acute KS patients with the highest levels observed in patients who develop CAA. We postulated that TNF-α blockade might be effective in the control of inflammation in KS patients who fail to respond to IVIG. A review of a multicenter experience with infliximab (5mg/kg) for treatment of refractory KS patients suggested that this therapy was safe, well-tolerated, and effective with lysis of fever and clinical improvement in all 15 of the evaluable patients (1). In the 10 patients in whom pre- and post-infliximab C-reactive protein (CRP) levels were measured, a dramatic fall in CRP levels accompanied the favorable clinical response. In this small series of patients, no conclusions regarding coronary artery outcome could be made. As might be expected in this severely ill patient population, 12 patients had coronary artery abnormalities documented by echocardiogram prior to infliximab therapy: four had transient dilatation that resolved post-infliximab infusion, three had aneurysms, and five had ectasia. 　Encouraged by these preliminary results, we designed a randomized, prospective, Phase I clinical trial of infliximab (5mg/kg) vs. repeat IVIG infusion (2g/kg) for refractory KS. The trial is currently in progress at 6 clinical centers in the U.S. To date, 24 patients (9 infants and 15 children) have been enrolled. Eligible subjects were infants and children less than 18 years old with acute KS who had persistent or recrudescent fever (≥38.0℃ or 100.4℃ F orally or rectally)≥48 hours but ≤7 days after completing their initial IVIG infusion (2g/kg). Prior to the initial IVIG treatment, patients must have been febrile for ≥3 days and no longer than 14 days and have met 4/5 standard clinical criteria or have had fever and 3/5 clinical criteria with an echocardiogram demonstrating a z score of ≥2.5 for the internal diameter of either the right coronary artery or left anterior descending artery. Following parental informed consent, patients were randomized to receive either a 2nd IVIG infusion (2g/kg) or infliximab (5mg/kg). Patients who remained febrile (≥38.0℃ rectally or orally) at 24h post-completion of their first study treatment crossed over to receive the other study treatment (e.g. patients who failed to become afebrile following the 2nd IVIG infusion received infliximab and vice versa). To date, there have been no complications of infliximab infusion or any adverse reactions attributed to this study medication. Preliminary analysis of study findings will be presented. 　There are many paths by which infliximab may improve the outcome for patients with KS. One potential benefit for patients with KS may be the improvement in endothelial cell function following infliximab treatment that has been documented in two different patient populations. In adults with rheumatoid arthritis, infliximab improved endothelial cell function as assessed by eNOS-dependent vasodilatation in response to acetylcholine (2). In a study of adults with anti-neutrophil cytoplasmic antibody-associated systemic vasculitis, treatment with infliximab improved both clinical indicators of inflammation and endothelial cell vasomotor function as measured by forearm blood flow response to intra-arterial infusion of acetylcholine (3). Thus, anti-TNF-α therapy not only reduced inflammation in these patient populations, but also improved endothelial cell function. 　The safety profile of infliximab deserves further consideration. In adults the most common minor side effects are headache, nausea, and upper respiratory infections(4). Infusion reactions, ranging from flushing and dyspnea to anaphylaxis, are thought to be related to formation of antibodies directed against infliximab in patients receiving repeated doses for chronic diseases. Such reactions are associated with 4-13% of infusions in adults and adolescents receiving chronic therapy but have not been observed following the first infusion. No data are available regarding the rate of infusion reactions or other side effects in infants and young children. Other complications of infliximab administration are related to immunosuppression and include re-activation of latent tuberculosis, histoplasmosis, and coccidiomycosis, increased risk of bacterial sepsis, increased risk of lymphoma, and development of IgM and IgA anti-nuclear antibodies. Many patients who receive infliximab are on other immunosuppressive agents so the contribution of TNF-α suppression to their infectious complication is difficult to assess. In assessing the safety of TNF-α blockade in children with KS, a population of patients with depressed myocardial contractility, it is important to consider the occurrence of new-onset heart failure in ten young adults (age 19-48 yrs.) following anti-TNF therapy for rheumatoid arthritis or Crohn's disease (5). Whether or not a causal relationship exists between TNF-α blockade and the occurrence of heart failure is complicated by the fact that heart failure is a known complication of rheumatoid arthritis. Indeed, a retrospective review of over 13,000 patients with rheumatoid arthritis found a 3.9% incidence of heart failure and a significant protective effect of anti-TNF therapy among the 5,800 patients receiving this therapy. Conversely, clinical trials designed to test the hypothesis that TNF-α blockade might be beneficial in adults with ischemic heart failure were terminated prematurely because of either no benefit of anti-TNF therapy or worsening heart failure and death. Although virtually all patients with KS have subclinical myocarditis, no adverse effect on myocardial contractility was observed in our small series of patients. 　Numerous recent studies have developed scoring systems based on clinical criteria in an attempt to identify patients who will be refractory to IVIG infusion and require further therapy. In an attempt to identify polymorphisms that influence response to IVIG, we are currently analyzing 144 loci in KS trios (KS patient, biologic mother and father) who responded or were refractory to IVIG infusion. This type of investigation may identify polymorphisms that confer increased risk of IVIG failure. The future of therapy for children with KS will include predictive testing based on both clinical parameters and genotyping that will identify both the subset of patients likely to fail initial IVIG therapy as well as the subset of patients at highest risk for developing coronary artery aneurysms. Once identified, these patients will be candidates for more aggressive therapy that may include a cocktail of agents that block the action of pro-inflammatory cytokines. References 1. Burns JC, Mason WH, Hauger SB, Janai H, Bastian JF, Wohrley JD, et al. Infliximab treatment for refractory Kawasaki syndrome. J Pediatr 2005;146(5):662-7. 2. Hurlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 2002;106(17):2184-7. 3. Booth AD, Jayne DR, Kharbanda RK, McEniery CM, Mackenzie IS, Brown J, et al. Infliximab improves endothelial dysfunction in systemic vasculitis: a model of vascular inflammation. Circulation 2004;109(14):1718-23. 4. Markham A, Lamb HM. Infliximab: a review of its use in the management of rheumatoid arthritis. Drugs 2000;59(6):1341-59. 5. Kwon HJ, Cote TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med 2003;138(10):807-11.