An Immunological Axis Involving Interleukin 1ß and Leucine-Rich-α2-Glycoprotein Reflects Therapeutic Response of Children with Kawasaki Disease: Implications from the KAWAKINRA Trial.

PURPOSE: A recent phase II open-label study of the interleukin 1 (IL-1) receptor antagonist (IL-1Ra) anakinra in treating IVIG-resistant Kawasaki disease (KD) patients reported promising results. Here, we aimed to characterize the immunological impact of IL-1 blockade in this unique study population. METHODS: Patients' and control sera and supernatants of cells (whole blood, neutrophils, coronary artery endothelial cells) stimulated with recombinant IL-1ß were analyzed for single or multiple marker (n = 22) expression by ELISA or multiplexed bead array assay. Data were analyzed using unsupervised hierarchical clustering, multiple correlation, and multi-comparison statistics and were compared to retrospective analyses of KD transcriptomics. RESULTS: Inflammation in IVIG-resistant KD (n = 16) is hallmarked by over-expression of innate immune mediators (particularly IL-6 > CXCL10 > S100A12 > IL-1Ra). Those as well as levels of immune or endothelial cell activation markers (sICAM-1, sVCAM-1) declined most significantly in course of anakinra treatment. Prior as well as following IL-1R blockade, over-expression of leucine-rich-α2-glycoprotein 1 (LRG1) associated best with remnant inflammatory activity and the necessity to escalate anakinra dosage and separated inflammatory KD patients from sJIA-MAS (n = 13) and MIS-C (n = 4). Protein as well as retrospective gene expression analyses indicated tight association of LRG1 with IL-1ß signaling and neutrophilia, while particularly neutrophil stimulation with recombinant IL-1ß resulted in concentration-dependent LRG1 release. CONCLUSION: Our study identifies LRG1 as known trigger of endothelial activation and cardiac re-modeling to associate with IL-1ß signaling in KD. Besides a potential patho-mechanistic implication of these findings, our data suggest blood leukocyte and neutrophil counts to best predict response to IL-1Ra treatment in IVIG-resistant KD.

Phase II Open Label Study of Anakinra in Intravenous Immunoglobulin-Resistant Kawasaki Disease.

OBJECTIVE: Anakinra has been shown to be successful in preventing and treating cardiovascular lesions both in experimental murine models of Kawasaki disease (KD) and in several studies on intravenous immunoglobulin (IVIG)- and steroid-resistant patients with KD. This study was undertaken to determine the safety of blocking interleukin-1 in patients with IVIG-resistant KD. METHODS: Sixteen patients were included in the present study. Patients with KD who were not responsive to 1 or more courses of 2 mg/kg of IVIG received anakinra by subcutaneous daily injections. Starting doses were 2 mg/kg of IVIG (4 mg/kg in patients who were age <8 months and who weighed ≥5 kilograms), and the dose was increased up to 6 mg/kg every 24 hours if the patient's body temperature remained >38°C, indicative of a fever. Treatment duration was 14 days. The last visit was on day 45. Primary outcome was abatement of fever. Secondary measures included disease activity, coronary artery Z score, and C-reactive protein (CRP) levels. RESULTS: Seventy-five percent of patients in the intention-to-treat group and 87.5% in the per-protocol group became afebrile within 48 hours of the last escalation dose of anakinra. Reduction of disease activity by 50% was indicated on 93.3% (95% confidence interval [95% CI] 68.1-99.8%) of physician evaluations and on 100% (95% CI 73.5-100%) of parent evaluations. CRP values normalized by day 30. At the initial screening, 12 of 16 patients had a maximum coronary artery Z score of >2, and 10 of 16 patients had a maximum Z score of >2.5. At day 45, 5 of 10 patients (50% [95% CI 18.7-81.3%]) and 6 of 12 patients (50% [95% CI 21.1-78.9%]) had achieved coronary artery Z scores of <2.5 and <2, respectively. Five serious adverse events were observed in 3 patients, but no serious infections or deaths occurred. CONCLUSION: Anakinra was well tolerated in the study patients and may have some efficacy in reducing fever, markers of systemic inflammation, and coronary artery dilatation in individuals with IVIG-refractory KD.