Background Multisystem inflammatory syndrome in children (MIS-C) is a potentially life-threatening hyperinflammatory syndrome that occurs after primary SARS-CoV-2 infection. The pathogenesis of MIS-C remains undefined, and whether specific inflammatory biomarker patterns can distinguish MIS-C from other hyperinflammatory syndromes, including Kawasaki disease and macrophage activation syndrome (MAS), is unknown. Therefore, we aimed to investigate whether inflammatory biomarkers could be used to distinguish between these conditions. Methods We studied a prospective cohort of patients with MIS-C and Kawasaki disease and an established cohort of patients with new-onset systemic juvenile idiopathic arthritis (JIA) and MAS associated with systemic JIA (JIA-MAS), diagnosed according to established guidelines. The study was done at Cincinnati Children's Hospital Medical Center (Cincinnati, OH, USA). Clinical and laboratory features as well as S100A8/A9, S100A12, interleukin (IL)-18, chemokine (C-X-C motif) ligand 9 (CXCL9), and IL-6 concentrations were assessed by ELISA and compared using parametric and non-parametric tests and receiver operating characteristic curve analysis. Findings Between April 30, 2019, and Dec 14, 2020, we enrolled 19 patients with MIS-C (median age 9·0 years [IQR 4·5–15·0]; eight [42%] girls and 11 [58%] boys) and nine patients with Kawasaki disease (median age 2·0 years [2·0–4·0]); seven [78%] girls and two [22%] boys). Patients with MIS-C and Kawasaki disease had similar S100 proteins and IL-18 concentrations but patients with MIS-C were distinguished by significantly higher median concentrations of the IFNγ-induced CXCL9 (1730 pg/mL [IQR 604–6300] vs 278 pg/mL [54–477]; p=0·038). Stratifying patients with MIS-C by CXCL9 concentrations (high vs low) revealed differential severity of clinical and laboratory presentation. Compared with patients with MIS-C and low CXCL9 concentrations, more patients with high CXCL9 concentrations had acute kidney injury (six [60%] of ten vs none [0%] of five), altered mental status (four [40%] of ten vs none [0%] of five), shock (nine [90%] of ten vs two [40%] of five), and myocardial dysfunction (five [50%] of ten vs one [20%] of five); these patients also had higher concentrations of systemic inflammatory markers and increased severity of cytopenia and coagulopathy. By contrast, patients with MIS-C and low CXCL9 concentrations resembled patients with Kawasaki disease, including the frequency of coronary involvement. Elevated concentrations of S100A8/A9, S100A12, and IL-18 were also useful in distinguishing systemic JIA from Kawasaki disease with high sensitivity and specificity. Interpretation Our findings show MIS-C is distinguishable from Kawasaki disease primarily by elevated CXCL9 concentrations....

Objective. Kawasaki disease (KD) is an acute vasculitis of childhood, predominantly affecting the coronary arteries. S100A12, a granulocyte-derived agonist of both the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR-4), is strongly up-regulated in KD. This study was undertaken to investigate the potential contributions of S100A12 to the pathogenesis of KD.Methods. Serum samples from patients with KD (n = 30) at different stages pre-and post-intravenous immunoglobulin (IVIG) treatment were analyzed for the expression of S100A12, cytokines, chemokines, and soluble markers of endothelial cell activation. Primary human coronary artery endothelial cells (HCAECs) were analyzed for responsiveness to direct stimulation with S100A12 or lipopolysaccharide (LPS), as assessed by real-time quantitative reverse transcription-polymerase chain reaction analysis of cytokine and endothelial cell adhesion molecule messenger RNA expression. Alternatively, HCAECs were cultured in conditioned medium obtained from primary human monocytes that were stimulated with LPS or S100A12 in the absence or presence of IVIG or cytokine antagonists.Results. In the serum of patients with KD, pretreatment S100A12 levels were associated with soluble vascular cell adhesion molecule 1 titers in the course of IVIG therapy (r s = −0.6, P = 0.0003). Yet, HCAECs were not responsive to direct S100A12 stimulation, despite the presence of appropriate receptors (RAGE, TLR-4). HCAECs did, however, respond to supernatants obtained from S100A12-stimulated primary human monocytes, as evidenced by the gene expression of inflammatory cytokines and adhesion molecules. This response was strictly dependent on interleukin-1β (IL-1β) signaling (P < 0.001).Conclusion. In its role as a highly expressed mediator of sterile inflammation in KD, S100A12 appears to activate HCAECs in an IL-1β-dependent manner. These data provide new mechanistic insights into the contributions of S100A12 and IL-1β to disease pathogenesis, and may therefore support current IL-1-targeting studies in the treatment of patients with KD.

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Systemic juvenile idiopathic arthritis (SJIA) is distinguished from other forms of JIA by the prevalence of severe, life-threatening complications macrophage activation syndrome (SJIA-MAS) and lung disease (SJIA-LD). Alternative therapeutics are urgently needed, as disease pathogenesis diverges from what is observed in SJIA, and currently available biologics are insufficient. SJIA-MAS, defined by a cytokine storm and dysregulated proliferation of T-lymphocytes, and SJIA-LD which presents with lymphocytic interstitial inflammation and pulmonary alveolar proteinosis, are both thought to be driven by interferons, in particular type II interferon (IFN-y). Involvement of IFNs and a possible crosstalk of type I IFNs with existing biologics indicate a distinct role for the JAK-STAT signaling pathway in the pathogenesis of SJIA-MAS and SJIA-LD. Here, we review this role of JAK-STATs and interferons in SJIA complications and discuss how new insights of ongoing research are shaping future therapeutic advances in the form of JAK inhibitors and antibodies targeting IFNs.

Itch lasting for longer than 6 weeks (chronic pruritus) is one of the main symptoms in dermatology and can appear not only in dermatological disorders, but also in systemic, neurological and psychological diseases. Chronic pruritus is often difficult to treat and has a high level of impact on a patient's quality of life. There are only a few validated standard measurement instruments available for the evaluation of chronic pruritus, which makes it difficult to assess this symptom objectively. This study validated the Chronic Pruritus Tools Questionnaire PRURITOOLS, which assembles a set of tools for the assessment of pruritus and can now be used in routine care or in clinical trials.Few studies have validated standard measurement instruments for evaluation of chronic pruritus. The Chronic Pruritus Tools Questionnaire PRURITOOLS assembles a set of instruments for the assessment of pruritus, such as the visual analogue scale (horizontal 100-mm line), numerical rating scale (0-10), verbal rating scale, and information on pruritus quality and improvement during therapy. This study, with 40 subjects, analysed PRURITOOLS regarding convergent validity and test-retest reliability (60 min), followed by a feasibility questionnaire. Test-retest reliability for PRURITOOLS items was excellent (intraclass correlation coefficient 0.84-1). Strong to very strong correlations between the pruritus intensity scales indicated convergent validity. The feasibility questionnaire showed an overall acceptance of PRURITOOLS, and the majority of subjects (82.5%) considered it an appropriate questionnaire to measure pruritus. In conclusion, PRURITOOLS offers validated tools for rapid pruritus assessment in routine care or endpoints of clinical trials.