Shohei Ogata

Corticosteroid Pulse Combination Therapy for Refractory Kawasaki Disease: A Randomized Trial

Objective: This study examined the clinical efficacy and safety of intravenous methylprednisolone-pulse plus intravenous immunoglobulin (IVIG) combination therapy (IVMP+IVIG) for the initial treatment of patients predicted to have refractory Kawasaki disease (KD). Methods: One hundred twenty-two patients with KD were studied at Kitasato University. Refractory KD was predicted at diagnosis using the Egami score, and the patients were randomly divided to receive either IVMP+IVIG or IVIG alone. The Egami score is used to predict refractory KD patients before treatment using the patient’s age, days of illness, platelet count, C-reactive protein, and alanine aminotransferase level (cutoff: ≥3 points; 78% sensitivity and 76% specificity). Results: Forty-eight patients (39.3%) were predicted to have refractory KD on the basis of the Egami score. The predicted IVIG responders (n = 74) received the standard therapy. The 48 predicted refractory KD patients were randomly assigned to a single-IVIG group (n = 26) or an IVMP+IVIG group (n = 22). Nineteen of the 22 patients (86.4%) in the IVMP+IVIG group had a prompt defervescence compared with 6 of the 26 patients (23.1%) in the single-IVIG group. The number of patients who had a z score ≥2.5 at 1 month was significantly higher in the single-IVIG group than in the IVMP+IVIG group. No serious adverse events were observed in either treatment group. Conclusions: This study demonstrated that IVMP+IVIG therapy is safe and effective for KD patients predicted as refractory.

The strategy of immune globulin resistant Kawasaki disease: A comparative study of additional immune globulin and steroid pulse therapy

BACKGROUND We compared the clinical utility of additional intravenous immune globulin (IVIG) therapy with the clinical utility of steroid pulse therapy in patients with IVIG-resistant Kawasaki disease. METHODS We enrolled 164 patients with Kawasaki disease who were treated with a single dose of IVIG (2 g/kg) and aspirin (30 mg/kg per day). Twenty-seven of these patients (16%) were resistant to the initial IVIG treatment. We compared the effectiveness of treatment strategies for the initial IVIG-resistant 27 patients, 14 of these patients were treated with additional IVIG therapy, and the other 13 patients were treated with steroid pulse therapy (methylprednisolone 30 mg/kg per day for 3 days). RESULTS Three patients in the group receiving additional IVIG treatment had coronary artery aneurysms (21.4%), no patients had coronary artery aneurysm in the steroid pulse therapy group; the difference in the incidence of coronary artery aneurysm was not statistically significant. The duration of high fever after additional treatment in the steroid pulse therapy group (1 ± 1.3 days) was significantly shorter than that in the additional IVIG treatment group (3 ± 2.4 days; P < 0.05). The medical costs were significantly lower in the steroid pulse therapy group than in the additional IVIG treatment group. CONCLUSION Steroid pulse therapy was useful to reduce the fever duration and medical costs for patients with Kawasaki disease. Steroid pulse therapy and additional IVIG treatment were not significantly different in terms of preventing the development of coronary artery aneurysm.

Clinical score and transcript abundance patterns identify Kawasaki disease patients who may benefit from addition of methylprednisolone.

Intravenous immunoglobulin (IVIG) treatment-resistant patients are high risk of developing coronary artery lesions with Kawasaki disease. The IVIG-responsive (Group A; n = 6) and IVIG-resistant patients (Group B) were predicted before starting the initial treatment using the Egami scoring system and randomly allocated as a single-IVIG treatment group (group B1; n = 6) or as a IVIG-plus-methylprednisolone (IVMP) combined therapy group (group B2; n = 5). We investigated the transcript abundance in the leukocytes of those patients using a microarray analysis. Five patients in group A and one patient in group B1 responded to initial IVIG treatment. All group B2 patients responded to IVIG-plus-IVMP combined therapy. Before performing these treatments, those transcripts related to IVIG resistance and to the development of coronary artery lesions, such as IL1R, IL18R, oncostatin M, suppressor of cytokine signaling-3, S100A12 protein, carcinoembryonic antigen-related cell adhesion molecule-1, matrix metallopeptidase-9, and polycythemia rubra vera-1, were more abundant in group B patients in comparison with group A patients. Moreover, those transcripts in group B2 patients were more profoundly and broadly suppressed than group B1 patients after treatment. This study elucidated the molecular mechanism of the effectiveness of IVIG-plus-IVMP combined therapy.

A Novel Strategy for Hemolytic Uremic Syndrome: Successful Treatment With Thrombomodulin α

Hemolytic uremic syndrome (HUS) is a life-threatening infectious disease in childhood for which there is no confirmed therapeutic strategy. Endothelial inflammation leading to microthrombosis formation via complement activation is the main pathology of HUS. Thrombomodulin is an endothelial membrane protein that has anticoagulation and anti-inflammatory effects, including the suppression of complement activity. Recombinant human soluble thrombomodulin (rTM) is a novel therapeutic medicine for disseminated intravascular coagulation. We administered rTM to 3 patients with HUS for 7 days and investigated the outcomes in view of the patients’ prognoses, changes in biochemical markers, complications, and adverse effects of rTM. Symptoms and laboratory data improved after initiation of rTM in all 3 patients. Abnormal activation of complements was also dramatically suppressed in 1 patient. The patients recovered without any complications or adverse effects of rTM. They were discharged having normal neurologic status and with no renal dysfunction. To our knowledge, this is the first report of rTM being used to treat HUS. These case reports show the positive effect of rTM in patients with HUS. Randomized controlled studies should be performed to assess the efficacy and safety of rTM for children with HUS.

Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome

Background Autoimmune diseases in children are rare and can be difficult to diagnose. Autoimmune lymphoproliferative syndrome (ALPS) is a well‐characterized pediatric autoimmune disease caused by mutations in genes associated with the FAS‐dependent apoptosis pathway. In addition, various genetic alterations are associated with the ALPS‐like phenotype. Objective The aim of the present study was to elucidate the genetic cause of the ALPS‐like phenotype. Methods Candidate genes associated with the ALPS‐like phenotype were screened by using whole‐exome sequencing. The functional effect of the identified mutations was examined by analyzing the activity of related signaling pathways. Results A de novo heterozygous frameshift mutation of TNF‐&agr;–induced protein 3 (TNFAIP3, A20), a negative regulator of the nuclear factor &kgr;B pathway, was identified in one of the patients exhibiting the ALPS‐like phenotype. Increased activity of the nuclear factor &kgr;B pathway was associated with haploinsufficiency of TNFAIP3 (A20). Conclusion Haploinsufficiency of TNFAIP3 (A20) by a germline heterozygous mutation leads to the ALPS phenotype.

Transcriptional regulation by infliximab therapy in Kawasaki disease patients with immunoglobulin resistance.

Background:Infliximab (IFX), a known monoclonal antibody against tumor necrosis factor-α (TNF-α), is used to treat Kawasaki disease (KD) patients with intravenous immunoglobulin (IVIG) resistance. The transcriptional modulation of inflammation following IFX therapy has not been reported in KD patients.Methods:We investigated the transcript abundance profiles in whole blood obtained from eight IVIG-resistant KD subjects treated with IFX therapy using microarray platforms and compared them with those in initially IVIG-responsive subjects. A pathway analysis was performed using WikiPathways to search for the biological pathways of the transcript profiles. Four transcripts changed by IFX therapy were subsequently validated using quantitative real-time polymerase chain reaction.Results:The pathway analysis showed the reduced abundance of transcripts in the nucleotide-binding oligomerization domain, matrix metalloproteinase (MMP), and inflammatory cytokine pathways and the increased abundance of transcripts in the T-cell receptor, apoptosis, TGF-β, and interleukin-2 pathways. Additionally, the levels of four transcripts (peptidase inhibitor-3, MMP-8, chemokine receptor-2, and pentraxin-3) related to KD vasculitis and IVIG resistance decreased after IFX therapy.Conclusion:The administration of IFX was associated with both the signaling pathways of KD inflammation and several transcripts related to IVIG resistance factors. These findings provide strong theoretical support for the use of IFX in KD patients with IVIG resistance.Pediatric Research (2014); 76 3, 287–293. doi:10.1038/pr.2014.92

Kikuchi-Fujimoto disease developed into autoimmune disease : a report of two cases

We report herein the pathological findings and clinical courses of two cases of Kikuchi–Fujimoto disease (KFD) that developed into autoimmune diseases. The patients are currently undergoing treatment for a disease similar to Sjogren’s syndrome and systemic lupus erythematosus/mixed connective tissue disease. KFD is not an independent condition and most likely develops due to an autoimmune mechanism. Pediatricians should pay careful attention to KFD and encourage long-term follow-up in patients with this condition.

Haploinsufficiency of A20 causes autoinflammatory and autoimmune disorders

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The Clinical Utility and Safety of a New Strategy for the Treatment of Refractory Kawasaki Disease

Objective To assess the clinical utility and safety of a strategy for refractory Kawasaki disease, defined by Egami score ≥3. Study design First‐line treatment was with intravenous methylprednisolone (30 mg/kg, 2 hours, 1 dose) plus intravenous immunoglobulin (2 g/kg, 24 hours) treatment. Patients resistant to first‐line treatment received additional intravenous immunoglobulin as a second‐line treatment. Patients resistant to second‐line treatment who had received Bacillus Calmette‐Guérin vaccination 6 months earlier were treated with infliximab; otherwise, plasma exchange was performed. A total of 71 refractory patients with Kawasaki disease (median age: 2.4 years) of 365 patients with Kawasaki disease were treated according to our strategy from April 2007 to April 2016. Treatment resistance was defined as a persistent fever at 36 hours after treatment. We evaluated coronary artery lesions at the time of the diagnosis, at 1 month, and at 1 year after the diagnosis in accordance with the American Heart Association guidelines and the criteria of the Japanese Ministry of Health, Labour, and Welfare. Results First‐line therapy was effective for 58 of 71 patients (81.6%), and second‐line therapy was effective for 9 of 13 patients (69.2%). At third line, 3 patients were treated by infliximab, and 1 was treated with plasma exchange. Of the 18 patients with coronary artery abnormalities at diagnosis, 13 patients at 1 month and 6 patients at 1 year had coronary artery dilatation (median z score 3.0, 2.6, and 1.4, respectively). There were no patients with coronary artery aneurysm (CAA). Conclusions Our strategy for refractory Kawasaki disease was safe and effective in preventing CAA.

Association of Severity of Coronary Artery Aneurysms in Patients With Kawasaki Disease and Risk of Later Coronary Events

Importance Few studies with sufficient statistical power have shown the association of the z score of the coronary arterial internal diameter with coronary events (CE) in patients with Kawasaki disease (KD) with coronary artery aneurysms (CAA). Objective To clarify the association of the z score with time-dependent CE occurrence in patients with KD with CAA. Design, Setting, and Participants This multicenter, collaborative retrospective cohort study of 44 participating institutions included 1006 patients with KD younger than 19 years who received a coronary angiography between 1992 and 2011. Main Outcomes and Measures The time-dependent occurrence of CE, including thrombosis, stenosis, obstruction, acute ischemic events, and coronary interventions, was analyzed for small (z score, <5), medium (z score, ≥5 to <10; actual internal diameter, <8 mm), and large (z score, ≥10 or ≥8 mm) CAA by the Kaplan-Meier method. The Cox proportional hazard regression model was used to identify risk factors for CE after adjusting for age, sex, size, morphology, number of CAA, resistance to initial intravenous immunoglobulin (IVIG) therapy, and antithrombotic medications. Results Of 1006 patients, 714 (71%) were male, 341 (34%) received a diagnosis before age 1 year, 501 (50%) received a diagnosis between age 1 and 5 years, and 157 (16%) received a diagnosis at age 5 years or older. The 10-year event-free survival rate for CE was 100%, 94%, and 52% in men (P < .001) and 100%, 100%, and 75% in women (P < .001) for small, medium, and large CAA, respectively. The CE-free rate was 100%, 96%, and 79% in patients who were not resistant to IVIG therapy (P < .001) and 100%, 96%, and 51% in patients who were resistant to IVIG therapy (P < .001), respectively. Cox regression analysis revealed that large CAA (hazard ratio, 8.9; 95% CI, 5.1–15.4), male sex (hazard ratio, 2.8; 95% CI, 1.7–4.8), and resistance to IVIG therapy (hazard ratio, 2.2; 95% CI, 1.4–3.6) were significantly associated with CE. Conclusions and Relevance Classification using the internal diameter z score is useful for assessing the severity of CAA in relation to the time-dependent occurrence of CE and associated factors in patients with KD. Careful management of CE is necessary for all patients with KD with CAA, especially men and IVIG-resistant patients with a large CAA.