The genetics underlying severe COVID-19: The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science , this issue p. eabd4570 , p. eabd4585 ; see also p. 404

Objectives To validate the previously proposed classification criteria for Henoch–Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA). Methods Step 1: retrospective/prospective web-data collection for children with HSP, c-PAN, c-WG and c-TA with age at diagnosis ≤18 years. Step 2: blinded classification by consensus panel of a representative sample of 280 cases. Step 3: statistical (sensitivity, specificity, area under the curve and κ-agreement) and nominal group technique consensus evaluations. Results 827 patients with HSP, 150 with c-PAN, 60 with c-WG, 87 with c-TA and 52 with c-other were compared with each other. A patient was classified as HSP in the presence of purpura or petechiae (mandatory) with lower limb predominance plus one of four criteria: (1) abdominal pain; (2) histopathology (IgA); (3) arthritis or arthralgia; (4) renal involvement. Classification of c-PAN required a systemic inflammatory disease with evidence of necrotising vasculitis OR angiographic abnormalities of medium-/small-sized arteries (mandatory criterion) plus one of five criteria: (1) skin involvement; (2) myalgia/muscle tenderness; (3) hypertension; (4) peripheral neuropathy; (5) renal involvement. Classification of c-WG required three of six criteria: (1) histopathological evidence of granulomatous inflammation; (2) upper airway involvement; (3) laryngo-tracheo-bronchial involvement; (4) pulmonary involvement (x-ray/CT); (5) antineutrophilic cytoplasmic antibody positivity; (6) renal involvement. Classification of c-TA required typical angiographic abnormalities of the aorta or its main branches and pulmonary arteries (mandatory criterion) plus one of five criteria: (1) pulse deficit or claudication; (2) blood pressure discrepancy in any limb; (3) bruits; (4) hypertension; (5) elevated acute phase reactant. Conclusion European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society propose validated classification criteria for HSP, c-PAN, c-WG and c-TA with high sensitivity/specificity.

Type I interferons (IFNs) are essential mediators of antiviral responses. These cytokines have been implicated in the pathogenesis of autoimmunity, most notably systemic lupus erythematosus (SLE), diabetes mellitus, and dermatomyositis, as well as monogenic type I interferonopathies. Despite a fundamental role in health and disease, the direct quantification of type I IFNs has been challenging. Using single-molecule array (Simoa) digital ELISA technology, we recorded attomolar concentrations of IFNα in healthy donors, viral infection, and complex and monogenic interferonopathies. IFNα protein correlated well with functional activity and IFN-stimulated gene expression. High circulating IFNα levels were associated with increased clinical severity in SLE patients, and a study of the cellular source of IFNα protein indicated disease-specific mechanisms. Measurement of IFNα attomolar concentrations by digital ELISA will enhance our understanding of IFN biology and potentially improve the diagnosis and stratification of pathologies associated with IFN dysregulation.

Children account for only 1% to 2% of hospitalized patients with coronavirus disease 2019 (COVID-19).¹ However, in April 2020, severe systemic hyperinflammatory disease was reported in children in Europe and the United States, occurring 2 to 4 weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.^2-6 This novel entity, named multisystem inflammatory syndrome in children (MIS-C)⁷ or pediatric multisystem inflammatory syndrome temporally associated with COVID-19,⁸ is associated with a wide range of clinical features including persistent fever, digestive symptoms, rash, bilateral nonpurulent conjunctivitis, mucocutaneous inflammation signs, and frequent cardiovascular involvement.^2,4-6,9 MIS-C is often associated with hemodynamic failure, with acute cardiac dysfunction requiring hemodynamic support in 60% to 75% of cases,^5,6 sometimes associated with death.^2-6

Systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD) are considered the same disease, but a common approach for diagnosis and management is still missing. Methods In May 2022, EULAR and PReS endorsed a proposal for a joint task force (TF) to develop recommendations for the diagnosis and management of sJIA and AOSD. The TF agreed during a first meeting to address four topics: similarity between sJIA and AOSD, diagnostic biomarkers, therapeutic targets and strategies and complications including macrophage activation syndrome (MAS). Systematic literature reviews were conducted accordingly. Results The TF based their recommendations on four overarching principles, highlighting notably that sJIA and AOSD are one disease, to be designated by one name, Still’s disease. Fourteen specific recommendations were issued. Two therapeutic targets were defined: clinically inactive disease (CID) and remission, that is, CID maintained for at least 6 months. The optimal therapeutic strategy relies on early use of interleukin (IL-1 or IL-6 inhibitors associated to short duration glucocorticoid (GC). MAS treatment should rely on high-dose GCs, IL-1 inhibitors, ciclosporin and interferon-γ inhibitors. A specific concern rose recently with cases of severe lung disease in children with Still’s disease, for which T cell directed immunosuppressant are suggested. The recommendations emphasised the key role of expert centres for difficult-to-treat patients. All overarching principles and recommendations were agreed by over 80% of the TF experts with a high level of agreement. Conclusion These recommendations are the first consensus for the diagnosis and management of children and adults with Still’s disease.