Objective To report a chronic recurrent multifocal osteomyelitis (CRMO)-like clinical phenotype with multisystem inflammation associated with a novel gene variant in the spectrum of IL-1-mediated diseases. Methods A 3-year-old boy presented with recurrent episodes of fever, serositis, pancreatitis and high inflammatory markers with onset at age 13 months. At age 3 years, he started limping. Imaging revealed multifocal pelvic bone inflammation suggestive of CRMO. Autoinflammation panel testing was non-contributory. Whole exome sequencing (WES) and advanced IL-1 pathway analysis was conducted. Results WES identified a novel homozygous interleukin receptor 1 (IL1RN) variant (c.62C>G; p. Ser21*) (NM_173842.2). Functional analysis of IL1RN mRNA and IL-1 receptor antagonist (IL-1RA) protein confirmed the diagnosis of a deficiency of the IL-1 receptor antagonist (DIRA). Treatment with the nonselective IL-1 inhibitor anakinra resulting in rapid remission; switch to the selective IL-1β antagonist canakinumab led to a flare within 6 weeks. Re-start of anakinra recaptured remission, last documented at the recent 19-month follow-up. Conclusion This is the first report of a novel late-onset DIRA confirmed by advanced diagnostic testing. In patients with systemic inflammation and CRMO-like bone lesions, IL1RN testing should be considered; even in the absence of skin manifestations. Non-selective IL-1 inhibition is an effective therapy.

Objective. The diagnosis of Muckle-Wells syndrome (MWS) remains challenging due to the clinical heterogeneity and lack of diagnostic criteria. The aims of this study were to describe key elements of the diagnostic evaluation process in MWS and compare identified variables between patients diagnosed in childhood and adulthood. Methods. A cohort study of consecutive patients with a clinical and genetic diagnosis of MWS was conducted at 2 reference centers for autoinflammatory diseases. Demographic information, clinical presentation, access to care, and preclinical evaluation variables were captured. Presenting symptoms were compared between groups of patients diagnosed in childhood and adulthood. Prediction analysis explored variables associated with late diagnosis. Correspondence analysis identified clinical phenotypes. Results. A total of 34 MWS patients were included (16 males, 18 females) and median age at diagnosis was 31.5 years (range 0.5-75 years). Patients diagnosed during childhood reported musculoskeletal symptoms (62%), rash (62%), fever (54%), and abdominal pain (31%). Those diagnosed as adults described musculoskeletal symptoms (86%), rash (67%), hearing loss (52%), and fatigue (29%). Hearing loss was associated with late diagnosis, while access-to-care variables were not predictive. Correspondence analysis identified distinct clinical phenotypes as follows: an "inflammatory phenotype" (most commonly seen in patients diagnosed in childhood and characterized by relapsing fever and abdominal pain), an intermediate phenotype, and an "organ-disease" phenotype in patients diagnosed during adulthood and characterized by fatigue and hearing loss. Conclusion. Distinct clinical phenotypes were identified in patients with MWS. These are closely related to age at diagnosis. The presence of these phenotypes has to be considered when developing diagnostic criteria for MWS.

COVID-19 disease increases interleukin (IL)-1β release. Anti-IL-1-treatment is effective in IL-1-mediated autoinflammatory diseases (AID). This case series presents COVID-19 in patients with IL-1-mediated and unclassified AID with immunosuppressive therapy (IT). Patient 1 is a 34-year-old woman with an unclassified AID and methotrexate. Patients 2 and 3 (14-year-old girl and 12-year-old boy, respectively) have a Cryopyrin-Associated Periodic Syndrome (NLRP3 p.Q703K heterozygous, CAPS) treated with canakinumab 150 mg/month since three and five years, respectively. Patient 4 is a 15-year-old girl who has had familial Mediterranean fever (MEFV p.M694V homozygous) for 3 years treated with canakinumab 150 mg/month and colchicine. All patients had a mild acute COVID-19 course, particularly the adolescent patients. A few weeks after COVID-19 recovery, both CAPS patients developed increased AID activity, necessitating anti-IL-1-treatment intensification in one patient. At day 100, one out of four patients (25%) showed positive antibody response to SARS-CoV-2. This is one of the first reports providing follow-up data about COVID-19 in AID. The risk for severe acute COVID-19 disease was mild/moderate, but increased AID activity post-COVID-19 was detected. Follow-up data and data combination are needed to expand understanding of COVID-19 and SARS-CoV-2 immunity in AID and the role of IT.

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