Infliximab Reduces the Cytokine-Mediated Inflammation but Does Not Suppress Cellular Infiltration of the Vessel Wall in Refractory Kawasaki Disease

Abstract

ABSTRACT:The aim of our study was to evaluate the efficacy of infliximab for the treatment of patients with refractory Kawasaki disease (KD) and investigate the dynamic changes of cytokines during infliximab treatment. We have performed a study of cytokine and proinflammatory molecule levels in 43 KD patients including 18 responders to IVIG, 14 nonresponders, and 11 patients treated with infliximab. We determined serum levels of soluble TNF receptor I (sTNFR I) and IL-6, as well as VEGF, damage associated molecular pattern (DAMP) molecules; myeloid-related protein (MRP)8/MRP14 and S100A12 sequentially. In eight patients, fever subsided immediately upon infliximab treatment. Four patients, who started infliximab after 12 d of illness, developed coronary artery lesions. Each of the cytokines was elevated before infliximab treatment in all patients. Although serum levels of proinflammatory cytokines decreased dramatically after infliximab treatment, DAMP molecules and VEGF and markers of local tissue damage were not suppressed. In contrast, in IVIG responders all cytokines decreased markedly after IVIG treatment. We show that infliximab is one of the adoptive therapies in refractory KD patients. Different behaviors of proinflammatory cytokines and DAMP molecules and VEGF after infliximab treatment suggest that infliximab is effective for suppression of cytokinemediated inflammation, but could not completely block local vasculitis. (Pediatr Res 65: 696-701, 2009) K awasaki disease (KD) is the most common systemic vasculitis syndrome primarily affecting small and medium-sized arteries, particularly the coronary artery. Although timely treatment with high-dose i.v. immune globulin (IVIG) is now accepted as reducing the incidence of coronary artery lesions (CAL), approximately 15% of the patients do not respond to IVIG treatment and have persistent fever as a manifestation of ongoing inflammation. These patients are at highest risk for development of CAL (1). The current practice for patients with KD and persistent or recrudescent fever after IVIG is to institute additional therapies, which may include one or more repeat doses of IVIG, high-dose pulse methylprednisoline, cyclophosphamide, methotrexate, ulinastatin, cyclosporine A (CyA), or plasmapheresis (2,3). Recently, potential new therapeutic approaches with infliximab (Remicade), a chimeric mouse-human MAb against tumor necrosis factor (TNF)-␣, have been reported in refractory KD patients (4).During the acute phase of KD, serum levels of proinflammatory cytokines such as TNF-␣ are elevated (5). In experimental studies of this syndrome, characterized by vasculitis resulting in coronary, as well as extracoronary, aneurysms, and stenosis, the attenuation of cytokine responses, especially IL-6, after infusions of IVIG may play an integral role in the rapid resolution of most of the symptoms in children with KD (6). In addition to these proinflammatory cytokines, VEGF, and markers of local inflammation of the family of damageassociated molecular pattern molecules (DAMP...

Transcriptional regulation by infliximab therapy in kawasaki disease patients with immunoglobulin resistance

“…The increased transcript abundance of several genes in the IL-1 pathway has been confirmed among IVIG-resistant KD subjects (13). Meanwhile, another study reported that the serum levels of soluble TNF receptor 1 and IL-6 are dramatically decreased after IFX therapy in refractory KD subjects (9). In this study, IFX therapy greatly suppressed the expression levels of transcripts, which are involved in the main pathways of cytokine signaling related to KD vasculitis.…”

“…Recently, the use of IFX has been attempted as a novel therapy for refractory KD (6)(7)(8)(9). In a randomized study of additional IVIG vs. IFX infusion in KD patients with fever following initial treatment with IVIG, IFX infusion was found to be safe and well tolerated in KD patients, with no serious adverse reactions attributed to either therapy.…”

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association

“…Proinflammatory cytokine levels fell after infliximab treatment, but markers of vasculitis, including vascular endothelial growth factor and the S100 proteins, remained elevated. 196 This suggested the possibility that infliximab was effective in reducing systemic levels of inflammation but not in suppressing the vasculitis.…”

The IgG molecule as a biological immune response modifier: Mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders

“…The immune-suppressing effects of IVIG in patients with Kawasaki disease and, more importantly, its ability to prevent the development of coronary artery aneurysms might relate to the neutralizing antibody activity in IVIG against these bacterial enterotoxins 26 and proinflammatory cytokines. 29 It was also shown in patients with Kawasaki disease that IVIG therapy could modify the production of cytokines by mononuclear cells. IVIG inhibits the production of IL-1, TNF-a, TNF-b, and IFN-g by PBMCs stimulated with bacterial superantigens or LPS while increasing the production of IL-1 receptor antagonist, an anti-inflammatory cytokine that counteracts the effects of IL-1.…”