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Background: We have reported that cyclosporin A (CsA) therapy may be a promising and safe option for patients with Kawasaki disease (KD) resistant to initial and additional intravenous immunoglobulin (IVIG). Up to now, it has been considered that CsA exerts effects on the intracellular phosphatase calcineurin, and subsequently inhibits activation of nuclear factor of activated T cells (NFAT). However, the functional mechanism of CsA therapy in KD patients has remained unclear. Methods: The KD patients enrolled in this study were treated with CsA between April 2012 and December 2013. In accordance with our treatment protocol, KD patients are initially treated with IVIG and aspirin. If there is no response, a further course of IVIG is given, and if there is no response to this additional IVIG, the patients are treated with CsA. Peripheral blood samples were obtained just before and after the initial course of IVIG, additional IVIG, and CsA therapy. To evaluate the NFAT pathway and activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, we examined the gene expression of cytokines and intracellular signal transducers using real-time RT-PCR and phospho-STAT3 (pSTAT3) and STAT5 (pSTAT5) using flow cytometry. Results: Thirty-six KD patients were divided into three groups: responsive to initial IVIG (n=19), responsive to additional IVIG (n=7), and treated with CsA group (n=10). In the CsA group, expression of mRNAs for interleukin (IL)-2, NFATc1 and NFATc2 was significantly increased, whereas the mean fluorescence intensity (MFI) of pSTAT3 (CD3+ T cell) and pSTAT3 (CD16b+ granulocyte) was decreased after CsA treatment. In the group responsive to initial IVIG, the expression of mRNAs for IL-2, IL-6, NFATc1 and NFATc2 was significantly increased, whereas that for STAT3, 5A, 5B was decreased after IVIG treatment; on the other hand, the MFI of pSTAT3 (CD3+ T cell) and pSTAT3 (CD16b+ granulocyte) was decreased, and that of pSTAT5 (CD16b+ granulocyte) was increased, after IVIG. Conclusion: In patients with refractory KD, CsA exerts effects on the activity of the NFAT and JAK-STAT pathways. However, our results suggest that in patients with immunoglobulin-resistant KD, CsA may act through a mechanism other than the NFAT pathway.

Background: About 10-20% of patients with Kawasaki Disease (KD) who fail to respond to IVIG, show a high prevalence of CAL. The new guideline (2012) has proposed several options for second- and third-line therapy for patients resistant to IVIG. However, there are still no definite treatment options for refractory KD. We have reported that cyclosporin A (CsA) is a well tolerated, safe and promising option for patients resistant to IVIG. However, certain subgroups of such patients may also be resistant to CsA. In this study, we examined if a third course IVIG might be effective for patients resistant to CsA. Patients and Methods: Between April 2008 and May 2014, 42 Japanese patients who met the diagnostic criteria for KD and received CsA treatment were enrolled as study subjects. All patients were resistant to both initial (2 g/kg for 24 hours) and additional IVIG, and were then administered CsA orally (Neoral[[Unable to Display Character: Ⓡ]], oral solution, Novartis Pharma Co. Ltd., Tokyo, Japan). The initial dose of CsA was 4mg/kg/day, and it was divided into two equal daily doses every 12 hours. The dose of CsA was adjusted to between 4 and 8 mg/kg/day to maintain a trough level of 60-200 ng/ml by reference to clinical and laboratory data such as body temperature and C-reactive protein level. After the start of CsA treatment, if patients remained febrile for more than 5 days, or if fever returned after an afebrile period within 5 days, CsA treatment was judged to be ineffective, and the patients were then given a third course of IVIG. We analyzed some laboratory data between CsA effective group and CsA resistant group. Results: CsA treatment was judged to be ineffective in 14 of 42 (33%) patients. Eleven of those 14 patients received a third IVIG, and then, 8 (72.7%) patients of them became afebrile within 24hours. The other three patients became afebrile after a fourth IVIG. The serum levels of AST and soluble interleukin-2 receptor before the start of CsA treatment were significantly lower in CsA effective group than in CsA resistant group. Conclusion: A third course of IVIG is an effective option for KD patients who are resistant to CsA .

Objectives: Optical coherence tomography (OCT) is an intracoronary arterial imaging modality employing near-infrared light to create images. OCT makes it possible to distinguish the three layers of the coronary arterial wall. However, few previous studies have used OCT to evaluate coronary arterial lesions (CAL) in Kawasaki disease (KD). Here we report the use of OCT to evaluate CALs in KD. Patients and Methods: Fifteen patients aged between 11 and 29 years were admitted to undergo coronary angiography (CAG) for follow-up of KD. The male : female ratio was 11:4. Their ages at disease onset and when OCT was performed were 1m - 10y11m (median; 1y2m), and 11y1m - 29y3m (median; 16y2m), respectively. The interval between disease onset and OCT examination was 5y1m - 24y4m (median; 13y2m). Repeated CAG was performed on the basis of the criteria stipulated in the guidelines for cardiovascular sequelae in KD (JCS 2008). At the time of the latest CAG, we performed not only regular CAG but also IVUS and OCT (C7 OCT imaging system, St Jude Medical, St. Paul, MN, USA) for coronary arteries between December 2012 and August 2014. Results: We demonstrated fresh thrombus, stenosis, fibrotic intimal thickening with lamellar calcification and partial disappearance of the tunica media in CAL. Fibrotic intimal thickening and disruption of the tunica media are demonstrated in all patients. In addition, OCT demonstrated intimal thickening and disruption of the tunica media in completely regressed lesions and even in regions where CAG had shown normal coronary arterial walls in the acute phase. Conclusions: Our data suggest that fibrotic intimal thickening and disruption of the tunica media may be basic changes of coronary arterial sequelae in KD. The use of OCT for evaluation of KD vasculitis may clarify the mechanisms responsible for coronary arterial sequelae and be useful for prognostication of CAL.

Kawasaki disease (KD; MIM611775) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD have suggested up-regulation of Ca2+/NFAT pathway as one of the main pathophysiological processes in KD. In this study, we focused on ORAI1, a gene for a channel involved in store operated Ca2+ entry located on 12q24 where positive linkage signal was seen in our previous sib pair study of KD, and conducted a genetic association study. By re-sequencing 17.4kb of ORAI1 region for 94 subjects, we identified 37 variants with minor allele frequencies larger than 0.05. After selecting 9 tagging SNPs which represent 37 variants we performed an association study using 730 KD cases and 1315 controls. As a result, one tagging SNP located within exon2 showed nominal association (rs3741596; OR = 1.19, 95%CI 1.02~1.40, P = 0.028). The same trend of association was observed in an independent case control panel (1813 KD cases and 1097 controls, OR=1.22, 95% CI 1.06-1.40, P = 0.0056) and a significant P value was observed in a meta-analysis (OR = 1.21, 95%CI 1.09~1.34, P = 0.00041). Furthermore, we also found a rare 6 base-pair insertion polymorphism which cause elongation of proline repeat within N-terminal cytoplasmic domain of the ORAI1 protein was overrepresented in KD cases (rs78448924; OR = 3.91, 95%CI 1.30~11.80, P=0.010). These data indicate altered ORAI1 function confers susceptibility of KD and further highlight importance of the Ca2+/NFAT pathway in the disease pathogenesis.