Calcineurin inhibitor treatment of intravenous immunoglobulin-resistant Kawasaki disease.

OBJECTIVE To describe the clinical course and outcome of 10 patients with Kawasaki disease (KD) treated with a calcineurin inhibitor after failing to respond to multiple therapies. STUDY DESIGN Demographic and clinical data were prospectively collected using standardized case report forms. T-cell phenotypes were determined by flow cytometry, and KD risk alleles in ITPKC (rs28493229), CASP3 (rs72689236), and FCGR2A (rs1801274) were genotyped. RESULTS Intravenous followed by oral therapy with cyclosporine (CSA) or oral tacrolimus was well tolerated and resulted in defervescence and resolution of inflammation in all 10 patients. There were no serious adverse events, and a standardized treatment protocol was developed based on our experiences with this patient population. Analysis of T-cell phenotype by flow cytometry in 2 subjects showed a decrease in circulating activated CD8(+) and CD4(+) T effector memory cells after treatment with CSA. However, suppression of regulatory T-cells was not seen, suggesting targeting of specific, proinflammatory T-cell compartments by CSA. CONCLUSION Treatment of refractory KD with a calcineurin inhibitor appears to be a safe and effective approach that achieves rapid control of inflammation associated with clinical improvement.

[1]  F. Macian,et al.  NFAT proteins: key regulators of T-cell development and function , 2005, Nature Reviews Immunology.

[2]  Walter R Wilson,et al.  Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Statement for Health Professionals From the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association , 2004, Pediatrics.

[3]  Tien Yin Wong,et al.  Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease , 2011, Nature Genetics.

[4]  C. G. Egan,et al.  Bioavailability of Sandimmun® versus Sandimmun Neoral®: A Meta-Analysis of Published Studies , 2010, International journal of immunopathology and pharmacology.

[5]  M. Fishbein,et al.  Involvement of Innate and Adaptive Immunity in a Murine Model of Coronary Arteritis Mimicking Kawasaki Disease1 , 2009, The Journal of Immunology.

[6]  J. Newburger,et al.  Resistance to intravenous immunoglobulin in children with Kawasaki disease. , 2008, The Journal of pediatrics.

[7]  A. Hata,et al.  Cyclosporin A Treatment for Kawasaki Disease Refractory to Initial and Additional Intravenous Immunoglobulin , 2011, The Pediatric infectious disease journal.

[8]  J. Barkun,et al.  Comparison of neoral dose monitoring with cyclosporine through levels versus 2-hr postdose levels in stable liver transplant patients. , 1998, Transplantation.

[9]  P. Bruhns,et al.  Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. , 2009, Blood.

[10]  J. Newburger,et al.  Intravenous gamma-globulin treatment and retreatment in Kawasaki disease. US/Canadian Kawasaki Syndrome Study Group. , 1998, The Pediatric infectious disease journal.

[11]  F. Citterio.  Evolution of the therapeutic drug monitoring of cyclosporine. , 2004, Transplantation proceedings.

[12]  J. Burns,et al.  Memory T-cells and characterization of peripheral T-cell clones in acute Kawasaki disease , 2010, Autoimmunity.

[13]  C. Hack,et al.  Longstanding obliterative panarteritis in Kawasaki disease: lack of cyclosporin A effect. , 2003, Pediatrics.

[14]  Yusuke Nakamura,et al.  ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms , 2008, Nature Genetics.

[15]  A. Freeman,et al.  Refractory Kawasaki Disease , 2004, The Pediatric infectious disease journal.

[16]  T. Chatila,et al.  Response of refractory Kawasaki disease to pulse steroid and cyclosporin A therapy. , 2001, The Pediatric infectious disease journal.

[17]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[18]  Yusuke Nakamura,et al.  A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population , 2009, Nature Genetics.

[19]  O. Ramilo,et al.  Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease. , 2008, The Journal of pediatrics.

[20]  E. Silverman,et al.  Superantigenic activity is responsible for induction of coronary arteritis in mice: an animal model of Kawasaki disease. , 2003, International immunology.

[21]  W. Daniel,et al.  Activated myeloid dendritic cells accumulate and co-localize with CD3+ T cells in coronary artery lesions in patients with Kawasaki disease. , 2007, Experimental and molecular pathology.

[22]  Kazuo Suzuki,et al.  Mizoribine provides effective treatment of sequential histological change of arteritis and reduction of inflammatory cytokines and chemokines in an animal model of Kawasaki disease , 2011, Pediatric Rheumatology Online Journal.

[23]  Anbupalam Thalamuthu,et al.  A Genome-Wide Association Study Identifies Novel and Functionally Related Susceptibility Loci for Kawasaki Disease , 2009, PLoS genetics.

[24]  K. Welte,et al.  Pharmacokinetic monitoring of intravenous cyclosporine A in pediatric stem‐cell transplant recipients. The trough level is not enough , 2009, Pediatric transplantation.

[25]  Yusuke Nakamura,et al.  Common variants in CASP3 confer susceptibility to Kawasaki disease. , 2010, Human molecular genetics.

[26]  B. McCrindle,et al.  Improved Classification of Coronary Artery Abnormalities Based Only on Coronary Artery z-Scores After Kawasaki Disease , 2010, Pediatric Cardiology.

[27]  G. Koren,et al.  Difficulty in achieving therapeutic serum concentrations of salicylate in Kawasaki disease. , 1984, The Journal of pediatrics.

[28]  R. Holman,et al.  Analysis of Potential Risk Factors Associated With Nonresponse to Initial Intravenous Immunoglobulin Treatment Among Kawasaki Disease Patients in Japan , 2008, The Pediatric infectious disease journal.

[29]  Ravi S. Misra,et al.  Proteolytic Regulation of Nuclear Factor of Activated T (NFAT) c2 Cells and NFAT Activity by Caspase-3* , 2006, Journal of Biological Chemistry.

[30]  B. Nashan,et al.  Monitoring of Nuclear Factor of Activated T-Cell-Regulated Gene Expression in De Novo and Long-Term Liver Transplant Recipients Treated With Cyclosporine A , 2011, Therapeutic drug monitoring.

[31]  Chien-Fu Huang,et al.  CASP3 gene single-nucleotide polymorphism (rs72689236) and Kawasaki disease in Taiwanese children , 2011, Journal of Human Genetics.

[32]  T Tanaka,et al.  ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease , 2011, The Pharmacogenomics Journal.

[33]  M Takahashi,et al.  A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. , 1991, The New England journal of medicine.

[34]  J. Newburger,et al.  Treatment of immune globulin-resistant Kawasaki disease with pulsed doses of corticosteroids. , 1996, The Journal of pediatrics.

[35]  Tomio Kobayashi,et al.  Risk Stratification in the Decision to Include Prednisolone With Intravenous Immunoglobulin in Primary Therapy of Kawasaki Disease , 2009, The Pediatric infectious disease journal.