Neonatal-onset multisystem inflammatory disease (NOMID) is a rare and severe autoinflammatory disease caused by mutations of the NLRP3 gene and is characterized by a skin rash, fever, arthropathy, and neurologic manifestations. We herein report a neonatal case with recurrent rash, fever, and meningitis from 12 h after birth, and NOMID was diagnosed during the neonatal period. We also reviewed the clinical characteristics and genetic mutations of previously reported Chinese neonates with NOMID.
NOMID is rare in China, and there have been over 100 cases uncovered thus far, including ours. The patient we reported here was the youngest among the confirmed Chinese cases and had the de novo mutation c.1210G>C (p.V404L) in exon 4 of the NLRP3 gene, which has not been reported previously. All 25 patients manifested recurrent urticaria-like rash, and 24 were febrile. Of the 23 patients with genetic data available, all had NLRP3 mutations. The primary treatment of these patients entailed glucocorticoids and immunosuppressants; however, the IL-1 inhibitor was rarely used due to its current unavailability in China. One patient was cured by umbilical cord blood stem cell transplantation (UCBT), which provided an alternative treatment.
We recommend that NOMID be considered for neonates with recurrent rash, fever, and aseptic meningitis. However, further research on underlying mechanisms and therapeutic regimens in China is necessary to provide improved management.

Background: Cryopyrin-associated periodic syndromes (CAPS) is a group of rare autoinflammatory diseases. Little is known about the burden of disease, patients\' views on treatment, and adverse events (AEs) with current therapy. Objectives: The main study objective was to quantify the patients\' burden of disease in terms of flares and resource use and to characterize patient symptomatology and tolerability of treatment with anakinra. A secondary objective included comparing chart review and patient recall of symptoms and AEs. Methods: A retrospective medical chart review and concurrent online patient survey was conducted in four European countries. Data 12 months prior to initiation of/during anakinra treatment were entered into web-based case report forms by study groups. Results: Forty-two patients received/were receiving anakinra as primary treatment for at least 12 months. Patients experienced a 79.5% reduction in flares after commencing anakinra treatment. During the past 12 months on anakinra, four of five (80%) patients who recalled experiencing flares reported cancelling social activities and staying home as the most common courses of action. Most common AEs were injection site pain upon treatment initiation and weight gain. According to patient recall, 12 of 21 patients (57.1%) discontinued anakinra to enter another clinical trial; of the 12, eight (38%) specifically discontinued anakinra only for that reason, and four patients cited entering a clinical trial as one of many reasons for discontinuing anakinra. Conclusions: To our knowledge, this is the most comprehensive survey of patient experience with CAPS. Although improved, CAPS treatment remains suboptimal and a significant burden is placed upon patients, caregivers, and the healthcare system. With new agents available, it will be important to compare outcomes in patients using all therapeutic options.

BACKGROUND: Cryopyrin-associated periodic syndrome (CAPS), a rare genetic autoimmune disease, is composed of familial cold autoinflammatory syndrome (FCAs), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID). MWS is caused by dominantly inherited or de novo gain-of-function mutations in the NOD-like receptor 3 (NLRP3) gene. At present, there is no report about the variation of R262W in China.
METHODS: We reported a 3-year-old Chinese boy who had recurrent fever without obvious inducement, bilateral conjunctival congestion, and urticarial-like rash. Laboratory examination showed elevation in leukocyte count, neutrophil count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) and serum amyloid protein (SAA) levels. Whole exome sequencing identified a missense variation c.784-786delinsTGG (p.R262W) in the coding region of the NLRP3 gene.
CONCLUSIONS: A classical variant of the NLRP3 gene in a patient with MWS was first reported in China.

The cytokine interleukin (IL)-1 plays a pivotal role in immune-mediated disorders, particularly in autoinflammatory diseases. Targeting this cytokine proved to be efficacious in treating numerous IL-1-mediated pathologies. Currently, three IL-1 blockers are approved, namely anakinra, canakinumab and rilonacept, and two additional ones are expected to receive approval, namely gevokizumab and bermekimab. However, there is no systematic review on the safety and efficacy of these biologics in treating immune-mediated diseases.
To evaluate safety and efficacy of anakinra, canakinumab, rilonacept, gevokizumab, and bermekimab for the treatment of immune-mediated disorders compared to placebo, standard-of-care treatment or other biologics.
The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 1 January 1984 and 31 December 2020 focusing on immune-mediated disorders. Our PubMed literature search identified 7363 articles. After screening titles and abstracts for the inclusion and exclusion criteria and assessing full texts, 75 articles were included in a narrative synthesis.
Anakinra was both efficacious and safe in treating cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), gout, macrophage activation syndrome, recurrent pericarditis, rheumatoid arthritis (RA), and systemic juvenile idiopathic arthritis (sJIA). Conversely, anakinra failed to show efficacy in graft-versus-host disease, Sjögren\'s syndrome, and type 1 diabetes mellitus (T1DM). Canakinumab showed efficacy in treating CAPS, FMF, gout, hyper-IgD syndrome, RA, Schnitzler\'s syndrome, sJIA, and TNF receptor-associated periodic syndrome. However, use of canakinumab in the treatment of adult-onset Still\'s disease and T1DM revealed negative results. Rilonacept was efficacious and safe for the treatment of CAPS, FMF, recurrent pericarditis, and sJIA. Contrarily, Rilonacept did not reach superiority compared to placebo in the treatment of T1DM. Gevokizumab showed mixed results in treating Behçet\'s disease-associated uveitis and no benefit when assessed in T1DM. Bermekimab achieved promising results in the treatment of hidradenitis suppurativa.
This systematic review of IL-1-targeting biologics summarizes the current state of research, safety, and clinical efficacy of anakinra, bermekimab, canakinumab, gevokizumab, and rilonacept in treating immune-mediated disorders.
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021228547.

Cryopyrin-associated periodic syndrome (CAPS) is a rare but treatable inherited autoinflammatory condition including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurologic cutaneous articular syndrome (CINCA). Our objective was to describe the main features of CAPS AA amyloidosis (AA-CAPS) associated and the efficacy of IL-1 inhibitors in this indication.
Retrospective study in France associated with a systematic literature review.
Eighty-six patients were identified: 23 new French cases and 63 from the literature, with a median age at amyloidosis diagnosis of 39 years old. CAPS subtypes were MWS (n = 62), FCAS (n = 9), frontier forms between MWS and FCAS (n = 12) and between CINCA and MWS (n = 3). NLRP3 had been sequenced in 60 patients (70%) and the most frequent mutation was R260W (60%). Three AA-CAPS patients displayed somatic NLRP3 mutations. Death occurred in 35 patients (41%), none of whom having ever received IL-1 inhibitors. Twenty-eight patients (33%) received IL-1 inhibitors, with a >50% decrease in proteinuria in 89% of cases.
AA amyloidosis can occur in nearly all CAPS subtypes. IL-1 inhibitors are effective, underlining the necessity of an early diagnosis of CAPS in order to start this treatment as soon as possible among AA-CAPS patients.

BACKGROUND: Cryopyrin-associated periodic syndrome (CAPS) is a life-long, autoinflammatory disease associated with a gain-of-function mutation in the nucleotide-binding domain, leucine-rich repeat family, pyrin domain containing 3 (NLRP3) gene, which result in uncontrolled production of IL-1β and chronic inflammation. Chronic infantile neurologic cutaneous and articular (CINCA) syndrome/neonatal-Onset multisystem inflammatory disease (NOMID) is the most severe form of CAPS. Although the first symptoms may be presented at birth, there are few reports on the involvement of the placenta and umbilical cord in the disease. Therefore, we present herein a preterm case of CINCA/NOMID syndrome and confirms intrauterine-onset inflammation with conclusive evidence by using fetal and placental histopathological examination.
METHODS: The female patient was born at 33weeks of gestation by emergency caesarean section and weighted at 1,514 g. The most common manifestations of CINCA/NOMID syndrome including recurrent fever, urticarial rash, and ventriculomegaly due to aseptic meningitis were presented. She also exhibited atypical symptoms such as severe hepatosplenomegaly with cholestasis. The genetic analysis of NLRP3 revealed a heterozygous c.1698 C > G (p.Phe566Leu) mutation, and she was diagnosed with CINCA/NOMID syndrome. Further, a histopathological examination revealed necrotizing funisitis, mainly inflammation of the umbilical artery, along with focal neutrophilic and lymphocytic villitis.
CONCLUSIONS: The necrotizing funisitis, which only involved the artery, was an unusual observation for chorioamnionitis. These evidences suggest that foetal inflammation, probably due to overproduction of IL-1β, caused tissue damage in utero, and the first symptom of a newborn with CINCA/NOMID.

Several therapies are used for the treatment of rareautoinflammatory conditions like cryopyrin-associated periodic fever syndromes (CAPS), hyperimmunoglobulin Dsyndrome (HIDS)/mevalonate kinase deficiency (MKD) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS). However, reviews reporting on treatment outcomes of these therapies are lacking.
A systematic literature review was conducted using Embase, MEDLINE, MEDLINE-In Process and Cochrane databases to identify the randomised/non-randomised controlled trials (RCTs/non-RCTs) and real-world observational studies of CAPS, HIDS/MKD and TRAPS published as full-texts (January 2000-September 2017) or conference abstracts (January 2014-September 2017). Studies with data for ≥1 biologic were included. Studies with <5 patients were excluded.
Of the 3 342 retrieved publications, 72 studies were included (CAPS, n=43; HIDS/MKD, n=9; TRAPS, n=7; studies with ≥2 cohorts, n=13). Most studies were full-text (n=56), published after 2010 (n=56) and real-world observational studies (n=58). Among included studies, four were RCTs (canakinumab, n=2 (CAPS, n=1; HIDS/MKD and TRAPS, n=1); rilonacept, n=1 (in CAPS); simvastatin, n=1 (in HIDS/MKD)). Canakinumab and anakinra were the most commonly used therapies for CAPS and HIDS/MKD, whereas etanercept, canakinumab and anakinra were the most common for TRAPS. The available evidence suggested the efficacy or effectiveness of canakinumab and anakinra in CAPS, HIDS/MKD and TRAPS, and of etanercept in TRAPS; asingle RCT demonstrated the efficacy of rilonacept in CAPS.
Canakinumab, anakinra, etanercept and rilonacept were reported to be well tolerated; however, injection-site reactions were observed frequently with anakinra, rilonacept and etanercept. Data on the use of tocilizumab, infliximab and adalimumab in these conditions were limited; thus, further research is warranted.

Cryopyrin-associated periodic fever syndrome (CAPS) represents an increasingly recognized disease group entity, with varied presentations. CAPS includes 3 clinical entities, namely, familial cold-induced autoinflammatory syndrome (FCAS; MIM #120100), Muckle-Wells syndrome (MWS; MIM #191900) and chronic inflammatory neurologic cutaneous and articular syndrome (CINCA; MIM #607115); which share several overlapping clinical features. These patients often present with early-onset episodes of fever and rash, and variable systemic signs and symptoms, making it a great mimicker of other systemic autoimmune diseases. The episodes are transient and related to exposure to cold temperature and worsen in the winter season. We hereby present a case presenting with recurrent seasonal fever and rash, diagnosed as FCAS/ MWS overlap based on clinical signs and symptoms and positive testing for NLRP3 gene mutation. We also discuss the clinical presentation and complications of CAPS, chiefly FCAS and MWS, along with the previously described pediatric cases of CAPS. We tried to review the complexities of management of such patients, including the genetic diagnosis and the role of biological therapy. Based on the review of the literature, given the evident broad spectrum of symptoms and signs, use of next-generation sequencing can help in prompt diagnosis and early initiation of biological agents, which may play a great role in reducing the complications that these patients may experience in the long run.

Infant-onset bilateral sensorineural hearing loss is a key presenting symptom of the autoinflammatory cryopyrin-associated periodic syndrome. Other symptoms include periodic fever, cold-induced urticaria-like rash, chronic aseptic meningitis, polyarticular arthralgias, and renal AA amyloidosis. Early recognition and treatment with interleukin-1 blockade are critical for preventing disabling or fatal complications. We describe a patient with severe cryopyrin-associated periodic syndrome who presented at age 18 months with macrocephaly and moderate sensorineural hearing loss, later developing systemic sequelae. The pathogenic nature of the de novo NLRP3 gene variant identified was supported by a markedly elevated serum amyloid A level and sustained clinical response to anti-IL-1 therapy.

Neutrophilic urticarial dermatosis (NUD) is a rare form of dermatosis. In clinical terms, it consists of a chronic or recurrent eruption comprising slightly elevated, pink to reddish plaques or macules. The elementary lesion lasts 24 to 48hours and resolves without leaving any residual pigmentation. Extra-cutaneous signs are common, particularly fever or arthralgia. At histopathology, the dermis contains dense neutrophilic interstitial infiltrate with leukocytoclasis, but without fibrinoid necrosis of vessel walls. NUD often occurs in a setting of underlying systemic disease. The most commonly associated diseases are adult-onset Still\'s disease, Schnitzler syndrome, lupus erythematosus and cryopyrin-associated periodic syndromes. Treatment of NUD depends on the clinical context. Dapsone and colchicine are often effective.