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Purpose: To document the long-term visual outcomes in patients with Blau syndrome., Methods: A retrospective institutional cohort study was conducted, and 13 patients with genetically confirmed Blau syndrome were included. Demographic and clinical data were collected from standardised medical charts. Baseline was defined as the first detected uveitis and data were recorded onwards at intervals of 1, 3, 5, 10, 15 and 20 years., Results: Anterior uveitis was the most common classification at baseline (57.1%). Among patients with documented uveitis lasting 10 years or more, all of them developed panuveitis. Median logMAR visual acuity at baseline was 0 (range -0.5; 0.7), 0.19 (range 0; 1.5) at year 5, and 0.7 (range 0.1 - no perception of light) at year 20, as recorded in 13, 16, and 10 eyes, respectively. All patients received treatment with topical and oral steroids, and multiple systemic immunosuppressants including biologics. Disease control, defined as having cells <1+ in both eyes and using topical steroid eye drops less than twice daily, was achieved in 14.3% to 37.5% of patients at the different time points. Cataract surgery was performed in 12 eyes of 8 patients, 3 eyes of 3 patients necessitated glaucoma surgery, and 4 eyes of 4 patients required surgery for retinal detachment., Conclusion: Uveitis associated with Blau syndrome commonly leads to severe, chronic panuveitis, requiring long-term systemic immunosuppression. Early diagnosis and timely initiation of biologics may prevent significant visual impairment.

Objective: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a complex immune disorder consequence of somatic UBA1 variants. Most reported pathogenic UBA1 variants are missense or splice site mutations directly impairing the translational start site at p.Met41, with recent studies showing that these variants are frequent causes of recurrent inflammation in older individuals. Here we aimed to characterize a novel UBA1 variant found in two patients clinically presenting with VEXAS syndrome., Methods: Patients' data were collected from direct assessments and from their medical charts. Genomics analyses were undertaken by both Sanger and amplicon-based deep sequencing, and mRNA studies were undertaken by both cDNA subcloning and mRNA sequencing., Results: We report a novel, somatic variant in a canonical splice site of the UBA1 gene (c.346-2A>G), which was identified in two unrelated adult male patients with late-onset, unexplained inflammatory manifestations including recurrent fever, Sweet syndrome-like neutrophilic dermatosis, and lung inflammation responsive only to glucocorticoids. RNA analysis of the patients' samples indicated aberrant mRNA splicing leading to multiple in-frame transcripts, including a transcript retaining the full sequence of intron 4 and a different transcript with the deletion of the first 15 nucleotides of exon 5., Conclusion: Here we describe abnormal UBA1 transcription as a consequence of the novel c.346-2A>G variant, identified in two patients with clinical features compatible with VEXAS syndrome. Overall, these results further demonstrate the expanding spectrum of variants in UBA1 leading to pathology and provide support for a complete gene evaluation in those patients considered candidates for VEXAS syndrome., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Undiagnosed monogenic diseases represent a challenging group of human conditions highly suspicious to have a genetic origin, but without conclusive evidences about it. We identified two brothers born prematurely from a non-consanguineous healthy couple, with a neonatal-onset, chronic disease characterized by severe skin and bone inflammatory manifestations and a fatal outcome in infancy. We conducted DNA and mRNA analyses in the patients' healthy relatives to identify the genetic cause of the patients' disease. DNA analyses were performed by both Sanger and next-generation sequencing, which identified two novel heterozygous IL1RN variants: the intronic c.318 + 2T>G variant in the father and a ≈2,600-bp intragenic deletion in the mother. IL1RN mRNA production was markedly decreased in both progenitors when compared with healthy subjects. The mRNA sequencing performed in each parent identified two novel, truncated IL1RN transcripts. Additional experiments revealed a perfect intrafamilial phenotype-genotype segregation following an autosomal recessive inheritance pattern. The evidences shown here supported for the presence of two novel loss-of-function (LoF) IL1RN pathogenic variants in the analyzed family. Biallelic LoF variants at the IL1RN gene cause the deficiency of interleukin-1 receptor antagonist (DIRA), a monogenic autoinflammatory disease with marked similarities with the patients described here. Despite the non-availability of the patients' samples representing the main limitation of this study, the collected evidences strongly suggest that the patients described here suffered from a lethal form of DIRA likely due to a compound heterozygous genotype at IL1RN , thus providing a reliable genetic diagnosis based on the integration of old medical information with currently obtained genetic data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Urbaneja, Bonet, Solis-Moruno, Mensa-Vilaro, de Landazuri, Tormo, Lara, Plaza, Fabregat, Yagüe, Casals and Arostegui.)

Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory condition resulting from monoallelic NLRP3 variants that facilitate IL-1β production. Although these are gain-of-function variants characterized by hypersensitivity to cell priming, patients with CAPS and animal models of the disease may present inflammatory flares without identifiable external triggers. Here we find that CAPS-associated NLRP3 variants are forming constitutively active inflammasome, which induce increased basal cleavage of gasdermin D, IL-18 release and pyroptosis, with a concurrent basal pro-inflammatory gene expression signature, including the induction of nuclear receptors 4 A. The constitutively active NLRP3-inflammasome of CAPS is responsive to the selective NLRP3 inhibitor MCC950 and its activation is regulated by deubiquitination. Despite their preactivated state, the CAPS inflammasomes are responsive to activation of the NF-κB pathway. NLRP3-inflammasomes with CAPS-associated variants affect the immunometabolism of the myeloid compartment, leading to disruptions in lipids and amino acid pathways and impaired glycolysis, limiting IL-1β production. In summary, NLRP3 variants causing CAPS form a constitutively active inflammasome inducing pyroptosis and IL-18 release without cell priming, which enables the host's innate defence against pathogens while also limiting IL-1β-dependent inflammatory episodes through immunometabolism modulation., (© 2024. The Author(s).)

Importance: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management., Objective: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2., Evidence Review: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence., Findings: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined., Conclusions and Relevance: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS syndrome) is a recently described genetic disorder that gathers autoinflammatory symptoms and myeloid dysplasia. The first description was reported in 2020, and subsequently, a growing number of cases have been described worldwide. Herein, we describe a case of a 72-year-old male patient with VEXAS syndrome with p.Met41Val mutation of the UBA1 gene, prominent supraglottic larynx involvement, and costochondritis. To our knowledge, this is the first report of VEXAS syndrome in Colombia and South America. This disease could present features of relapsing polychondritis, polyarteritis nodosa, giant cell arteritis, and Sweet syndrome, associated with hematologic involvement, including cytopenias, myelodysplastic syndrome, or thromboembolic disease. Supraglottic larynx chondritis and costochondritis are atypical manifestations. These features were proposed previously to differentiate relapsing polychondritis from VEXAS syndrome but are not entirely reliable like in the case described. A diagnosis of VEXAS should be considered in male patients with incomplete or complete features of the previously described conditions, refractory to treatment, requiring high-dose glucocorticoids, and associated progressive hematologic abnormalities. Key Points • VEXAS syndrome is a recently described genetic (somatic mutations in UBA1 gene) disorder that gathers autoinflammatory and hematologic manifestations. • VEXAS syndrome should be considered in male patients with incomplete or complete features of relapsing polychondritis, polyarteritis nodosa, giant cell arteritis, and Sweet syndrome, refractory to treatment, associated with hematologic involvement, including cytopenias, myelodysplastic syndrome, or thromboembolic disease. • Glucocorticoids ameliorate symptoms effectively. However, other treatment options are limited due to a lack of evidence. Traditional immunosuppressants and biological therapy have been used empirically with limited efficacy and a transient effect. Bone marrow transplant offers a curative approach, but it has high morbidity and mortality., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Objective: Dominantly inherited PSTPIP1 mutations cause a spectrum of autoinflammatory manifestations epitomized by PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome.). The connections between PSTPIP1 and PAPA syndrome are poorly understood, although evidence suggests involvement of pyrin inflammasome activation. Interleukin-18 (IL-18) is an inflammasome-activated cytokine associated with susceptibility to macrophage activation syndrome (MAS). This study was undertaken to investigate an association of IL-18 with PAPA syndrome., Methods: Clinical and genetic data and serum samples were obtained from patients referred to institutions due to symptoms indicative of PAPA syndrome. Serum IL-18, IL-18 binding protein (IL-18BP), and CXCL9 levels were assessed by bead-based assay, and free IL-18 levels were assessed by enzyme-linked immunosorbent assay., Results: The symptoms of PSTPIP1-positive patients with PAPA syndrome overlapped with those of mutation-negative patients with PAPA-like conditions, but mutation-positive patients had earlier onset and a greater proportion had a history of arthritis. We found uniform elevation of total serum IL-18 in treated PAPA syndrome patients at levels nearly as high as those seen in NLRC4-associated autoinflammation with infantile enterocolitis patients, and well above levels found in most familial Mediterranean fever patients. Serum IL-18 elevation in PAPA syndrome patients persisted despite fluctuations in disease activity. Levels of the soluble IL-18 antagonist IL-18BP were modestly elevated, and PAPA syndrome patients had detectable free IL-18. PAPA syndrome was rarely associated with elevation of CXCL9, an indicator of interferon-γ activity, but no PAPA syndrome patients had a history of MAS., Conclusion: PAPA syndrome is a refractory and often disabling monogenic autoinflammatory disease associated with chronic and unopposed elevation of serum IL-18 levels but not with risk of MAS. These findings affect our understanding of the diseases in which IL-18 is overproduced and suggest a link between pyrin inflammasome activation, IL-18, and autoinflammation, without susceptibility to MAS., (© 2021, American College of Rheumatology.)

Generalized pustular psoriasis (GPP) represents the rarest form of psoriasis, which may be potentially fatal. In the last decade, (likely) pathogenic variants in the IL36RN, CARD14 and AP1S3 genes have been associated with monogenic GPP forms. Despite these advances, the genetic basis of most patients with GPP remains unidentified. Treatment of GPP patients is often difficult, with no consensus about the best available options to date. We report herein an infant with severe GPP in whom the disease started at the age of 2 months. Genetic investigations identified a heterozygous pathogenic variant in the IL36RN gene associated with a heterozygous variant of uncertain significance in the CARD14 gene. After previous treatment failures with acitretin, cyclosporin and anakinra, treatment with the interleukin-17 antagonist secukinumab resulted in a dramatic and prompt positive response that persisted at 12-month follow up. According to our experience, we believe secukinumab can be an effective and safe treatment for pediatric patients with GPP even before 1 year of age., (© 2021 Japanese Dermatological Association.)

An Addendum to this paper has been published: https://doi.org/10.1038/s41589-021-00741-6.

Objective: Deficiency of adenosine deaminase 2 (DADA2) is a potentially fatal monogenic syndrome characterized by variable manifestations of systemic vasculitis, bone marrow failure, and immunodeficiency. Most cases are diagnosed by pediatric care providers, given the typical early age of disease onset. This study was undertaken to describe the clinical phenotypes and treatment response both in adults and in children with DADA2 in India., Methods: A retrospective analysis of pediatric and adult patients with DADA2 diagnosed at various rheumatology centers across India was conducted. Clinical characteristics, diagnostic findings, and treatment responses were analyzed in all subjects., Results: In total, 33 cases of DADA2 were confirmed in this cohort between April 2017 and March 2020. Unlike previous studies, nearly one-half of the confirmed cases presented during adulthood. All symptomatic patients exhibited features of vasculitis, whereas constitutional symptoms and anemia were more common in pediatric patients. Cutaneous and neurologic involvement were common, and 18 subjects had experienced at least one stroke. In addition, the clinical spectrum of DADA2 was expanded by recognition of novel features in these patients, including pancreatic infarction, focal myocarditis, and diffuse alveolar hemorrhage. Treatment with tumor necrosis factor inhibitors (TNFi) was initiated in 25 patients. All of the identified disease manifestations showed marked improvement after initiation of TNFi, and disease remission was achieved in 19 patients. Two cases were complicated by tuberculosis infection, and 2 deaths were reported., Conclusion: This report presents the first case series of patients with DADA2 from India, diagnosed by adult and pediatric care providers. The findings raise awareness of this syndrome, particularly with regard to its presentation in adults., (© 2020, American College of Rheumatology.)

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology; Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Published by Elsevier Inc. All rights reserved.)

Autoinflammatory diseases (AIDs) were first described as clinical disorders characterized by recurrent episodes of seemingly unprovoked sterile inflammation. In the past few years, the identification of novel AIDs expanded their phenotypes toward more complex clinical pictures associating vasculopathy, autoimmunity, or immunodeficiency. Herein, we describe two unrelated patients suffering since the neonatal period from a complex disease mainly characterized by severe sterile inflammation, recurrent bacterial infections, and marked humoral immunodeficiency. Whole-exome sequencing detected a novel, de novo heterozygous PLCG2 variant in each patient (p.Ala708Pro and p.Leu845&#95;Leu848del). A clear enhanced PLCγ2 activity for both variants was demonstrated by both ex vivo calcium responses of the patient's B cells to IgM stimulation and in vitro assessment of PLC activity. These data supported the autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID) diagnosis in both patients. Immunological evaluation revealed a severe decrease of immunoglobulins and B cells, especially class-switched memory B cells, with normal T and NK cell counts. Analysis of bone marrow of one patient revealed a reduced immature B cell fraction compared with controls. Additional investigations showed that both PLCG2 variants activate the NLRP3-inflammasome through the alternative pathway instead of the canonical pathway. Collectively, the evidences here shown expand APLAID diversity toward more severe phenotypes than previously reported including dominantly inherited agammaglobulinemia, add novel data about its genetic basis, and implicate the alternative NLRP3-inflammasome activation pathway in the basis of sterile inflammation.

Autoinflammatory diseases comprise a wide range of syndromes caused by dysregulation of the innate immune response. They are difficult to diagnose due to their phenotypic heterogeneity and variable expressivity. Thus, the genetic origin of the disease remains undetermined for an important proportion of patients. We aim to identify causal genetic variants in patients with suspected autoinflammatory disease and to test the advantages and limitations of the clinical exome gene panels for molecular diagnosis. Twenty-two unrelated patients with clinical features of autoinflammatory diseases were analyzed using clinical exome sequencing (~4800 genes), followed by bioinformatic analyses to detect likely pathogenic variants. By integrating genetic and clinical information, we found a likely causative heterozygous genetic variant in NFKBIA (p.D31N) in a North-African patient with a clinical picture resembling the deficiency of interleukin-1 receptor antagonist, and a heterozygous variant in DNASE2 (p.G322D) in a Spanish patient with a suspected lupus-like monogenic disorder. We also found variants likely to increase the susceptibility to autoinflammatory diseases in three additional Spanish patients: one with an initial diagnosis of juvenile idiopathic arthritis who carries two heterozygous UNC13D variants (p.R727Q and p.A59T), and two with early-onset inflammatory bowel disease harbouring NOD2 variants (p.L221R and p.A728V respectively). Our results show a similar proportion of molecular diagnosis to other studies using whole exome or targeted resequencing in primary immunodeficiencies. Thus, despite its main limitation of not including all candidate genes, clinical exome targeted sequencing can be an appropriate approach to detect likely causative variants in autoinflammatory diseases., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Autoinflammation and phospholipase Cγ2-associated antibody deficiency and immune dysregulation (APLAID) is an exceedingly rare monogenic autoinflammatory disease. To date, only five cases have been reported with four distinct pathogenic mutations., Objectives: We present a novel case of APLAID, corroborated by molecular analysis, with newly described clinical findings including central nervous system vasculitis (CNSV); and distinctive histopathological characteristics that may expand our knowledge of this rare disease's phenotype., Methods: This is a case report presentation of a 3-year-old boy, seen at a reference paediatric hospital in Mexico. His parents authorized the use of his clinical information and photographs., Results: A 3-day-old boy presented to the emergency department with a vesiculo-pustular rash that resolved within 1 week. Two months later, he developed widespread papules and pseudovesicles that evolved into infiltrated plaques. He also had periodical flares of conjunctivitis, diarrhoea and erythematous blistering acral plaques triggered by upper respiratory infections. By the age of 10 months, he experienced seizures and CNSV. Laboratory work-up showed mild neutropenia, decreased serum levels of immunoglobulins and B-cell lymphopenia. A skin biopsy revealed a dense, perivascular and interstitial histiocytic and granulomatous infiltrate, with palisading granulomas, and leucocytoclastic vasculitis with karyorrhexis. APLAID syndrome was confirmed by Sanger sequencing of PLCG2 gene [heterozygous genotype LRG&#95;376t1:c.2543T>C or p.(Leu848Pro)]., Conclusions: Presence of CNSV has not been previously described in APLAID, however as the number of reported patients with APLAID is very small, it is possible that the overall spectrum of clinical manifestations has not been completely elucidated. The herein identified p.(Leu848Pro) variant was also documented in a Portuguese patient, suggesting that it could be a PLCG2 gene 'hot-spot'., (© 2019 European Academy of Dermatology and Venereology.)

Background: Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA., Methods: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria., Results: The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98)., Conclusion: Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

NLRP3 (NOD-like receptor pyrin domain-containing protein 3) is an innate immune sensor that contributes to the development of different diseases, including monogenic autoinflammatory syndromes, gout, atherosclerosis, and Alzheimer's disease. The molecule sulfonylurea MCC950 is a NLRP3 inflammasome inhibitor with potential clinical utility. However, the mechanism of action of MCC950 remains unknown. Here, we characterize the mechanism of action of MCC950 in both wild-type and autoinflammatory-related NLRP3 mutants, and demonstrate that MCC950 closes the 'open' conformation of active NLRP3.

Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease with both autoimmune and autoinflammatory components. Recently, familial cases of systemic-onset JIA have been attributed to mutations in LACC1/FAMIN. We describe three affected siblings from a Moroccan consanguineous family with an early-onset chronic, symmetric and erosive arthritis previously diagnosed as rheumatoid factor (RF)-negative polyarticular JIA. Autozygosity mapping identified four homozygous regions shared by all patients, located in chromosomes 3, 6 (n:2) and 13, containing over 330 genes. Subsequent whole exome sequencing identified two potential candidate variants within these regions (in FARS2 and LACC1/FAMIN). Genotyping of a cohort of healthy Moroccan individuals (n: 352) and bioinformatics analyses finally supported the frameshift c.128&#95;129delGT mutation in the LACC1/FAMIN gene, leading to a truncated protein (p.Cys43Tyrfs*6), as the most probable causative gene defect. Additional targeted sequencing studies performed in patients with systemic-onset JIA (n:23) and RF-negative polyarticular JIA (n: 44) revealed no pathogenic LACC1/FAMIN mutations. Our findings support the homozygous genotype in the LACC1/FAMIN gene as the defect underlying the family here described with a recessively inherited severe inflammatory joint disease. Our evidences provide further support to the involvement of LACC1/FAMIN deficiency in different types of JIA in addition to the initially described systemic-onset JIA.

We report two unrelated infants in whom chronic urticaria was the first clinical manifestation of cryopyrin-associated periodic syndrome, which should be suspected in infants with early-onset chronic urticaria, especially if there is a neutrophil-rich infiltrate in the skin biopsy. Early diagnosis of cryopyrin-associated periodic syndrome may lead to early and successful treatment with anti-interleukin-1 medications., (© 2018 Wiley Periodicals, Inc.)

Background: Hereditary recurrent fevers (HRFs) are rare inflammatory diseases sharing similar clinical symptoms and effectively treated with anti-inflammatory biological drugs. Accurate diagnosis of HRF relies heavily on genetic testing., Objectives: This study aimed to obtain an experts' consensus on the clinical significance of gene variants in four well-known HRF genes: MEFV , TNFRSF1A , NLRP3 and MVK ., Methods: We configured a MOLGENIS web platform to share and analyse pathogenicity classifications of the variants and to manage a consensus-based classification process. Four experts in HRF genetics submitted independent classifications of 858 variants. Classifications were driven to consensus by recruiting four more expert opinions and by targeting discordant classifications in five iterative rounds., Results: Consensus classification was reached for 804/858 variants (94%). None of the unsolved variants (6%) remained with opposite classifications (eg, pathogenic vs benign). New mutational hotspots were found in all genes. We noted a lower pathogenic variant load and a higher fraction of variants with unknown or unsolved clinical significance in the MEFV gene., Conclusion: Applying a consensus-driven process on the pathogenicity assessment of experts yielded rapid classification of almost all variants of four HRF genes. The high-throughput database will profoundly assist clinicians and geneticists in the diagnosis of HRFs. The configured MOLGENIS platform and consensus evolution protocol are usable for assembly of other variant pathogenicity databases. The MOLGENIS software is available for reuse at http://github.com/molgenis/molgenis; the specific HRF configuration is available at http://molgenis.org/said/. The HRF pathogenicity classifications will be published on the INFEVERS database at https://fmf.igh.cnrs.fr/ISSAID/infevers/., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: Provide baseline and preliminary follow-up results in a 5-year longitudinal study of Blau syndrome., Design: Multicenter, prospective interventional case series., Methods: Baseline data from 50 patients from 25 centers worldwide, and follow-up data for patients followed 1, 2, or 3 years at the end of study enrollment. Ophthalmic data were collected at baseline and yearly visits by means of a standardized collection form., Results: Median age at onset of eye disease was 60 months and duration of eye disease at baseline 145 months. At baseline 38 patients (78%) had uveitis, which was bilateral in 37 (97%). Eight patients (21%) had moderate to severe visual impairment. Panuveitis was found in 38 eyes (51%), with characteristic multifocal choroidal infiltrates in 29 eyes (39%). Optic disc pallor in 9 eyes (12%) and peripapillary nodules in 9 eyes (12%) were the commonest signs of optic nerve involvement. Active anterior chamber inflammation was noted in 30 eyes (40%) at baseline and in 16 (34%), 17 (57%), and 11 (61%) eyes at 1, 2, and 3 years, respectively. Panuveitis was associated with longer disease duration. At baseline, 56 eyes (75%) were on topical corticosteroids. Twenty-six patients (68%) received a combination of systemic corticosteroids and immunomodulatory therapy., Conclusions: Blau uveitis is characterized by progressive panuveitis with multifocal choroiditis, resulting in severe ocular morbidity despite continuous systemic and local immunomodulatory therapy. The frequency and severity of Blau uveitis highlight the need for close ophthalmologic surveillance as well as a search for more effective therapies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

To date, the pathogenic mechanisms underlying Schnitzler syndrome remain obscure, in particular, the interplay between the monoclonal protein and increased interleukin-1β (IL-1β) production, although interest in the contribution of genetic factors has been fueled by detection of somatic NLRP3 mosaicism in 2 patients with the variant-type Schnitzler syndrome. At 2 specialist UK centers, we have identified 21 patients who fulfilled diagnostic criteria for Schnitzler syndrome with urticarial rash, fever, arthralgia, and bone pain; 47% reported weight loss, 40% fatigue, and 21% lymphadenopathy. An immunoglobulin M (IgM) κ paraprotein was detected in 86%; the remainder had IgM λ or IgG κ. Patients underwent searches for germ line and somatic mutations using next-generation sequencing technology. Moreover, we designed a panel consisting of 32 autoinflammatory genes to explore genetic susceptibility factor(s) to Schnitzler syndrome. Genetic analysis revealed neither germ line nor somatic NLRP3 , TNFRSF1A , NLRC4 , or NOD2 mutations, apart from 1 patient with a germ line NLRP3 p.V198M substitution. The proinflammatory cytokines and extracellular apoptosis-associated speck-like protein with caspase recruitment domain (ASC) measured in the serum of Schnitzler syndrome patients during active disease were significantly higher than healthy controls. Ninety-five percent of our cohort achieved a complete response to recombinant IL-1 receptor antagonist (anakinra). Our findings do not support a role for somatic NLRP3 mosaicism in disease pathogenesis; although elevated levels of ASC, IL-6, and IL-18 in patients' serum, and the response to anakinra, suggest that Schnitzler syndrome is associated with upregulated inflammasome activation. Despite its rarity, Schnitzler syndrome is an important diagnosis as treatment with IL-1 antagonists dramatically improves quality of life for patients., (© 2018 by The American Society of Hematology.)

Acute generalised exanthematous pustulosis (AGEP) is a rare toxicoderma characterised by an acute onset rash, with many sterile pustules on the surface, high fever and increased acute phase reactants. We report the case of a patient who presented to the dermatology department with an AGEP and polyarthritis, in which a novel CARD14 mutation was identified. The pathophysiological mechanism of AGEP remains unclear, although mutations in the IL36RN gene have been identified in a small subset of AGEP patients. Similarly, mutations in the CARD14 gene have been linked to pustular types of psoriasis and familiar cases of pityriasis rubra pilaris; however, there are no reports associating mutations in the CARD14 gene with AGEP., (© 2017 The Australasian College of Dermatologists.)

Objective: Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND) is a recently described monogenic autoinflammatory disease. The causal p.S242R MEFV mutation disrupts a binding motif of the regulatory 14-3-3 proteins within pyrin. Here, we investigate a family with clinical features consistent with PAAND in whom the novel p.E244K MEFV mutation, located in the +2 site of the 14-3-3 binding motif in pyrin, has been found., Methods: Multiplex cytokine analyses were performed on p.E244K patient and control serum. Peripheral blood mononuclear cells were stimulated ex vivo with lipopolysaccharide (LPS). In vitro, inflammasome complex formation was evaluated by flow cytometry of Apoptosis-associated Speck-like protein containing a Caspase recruitment domain (ASC) specks. Interleukin-1β (IL-1β) and IL-18 production was quantified by ELISA. The ability of the p.E244K pyrin mutation to interact with 14-3-3 was assessed by immunoprecipitation., Results: PAAND p.E244K patient serum displayed a different cytokine profile compared with patients with Familial Mediterranean Fever (FMF). In overexpression models, p.E244K pyrin was associated with decreased 14-3-3 binding and increased ASC speck formation. THP-1 monocytes expressing PAAND pyrin mutations demonstrated spontaneous caspase-1-dependent IL-1β and IL-18 secretion, as well as cell death, which were significantly greater than those of wild-type and the FMF-associated mutation p.M694V., Conclusion: In PAAND, disruption of the +2 position of a 14-3-3 binding motif in pyrin results in its constitutive activation, with spontaneous production of IL-1β and IL-18, associated with inflammatory cell death. The altered serum cytokine profile may explain the different clinical features exhibited by PAAND patients compared with those with FMF., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To evaluate the rate of somatic NLRP3 mosaicism in an Italian cohort of mutation-negative patients with cryopyrin-associated periodic syndrome (CAPS)., Methods: The study enrolled 14 patients with a clinical phenotype consistent with CAPS in whom Sanger sequencing of the NLRP3 gene yielded negative results. Patients' DNA were subjected to amplicon-based NLRP3 deep sequencing., Results: Low-level somatic NLRP3 mosaicism has been detected in 4 patients, 3 affected with chronic infantile neurological cutaneous and articular syndrome and 1 with Muckle-Wells syndrome. Identified nucleotide substitutions encode for 4 different amino acid exchanges, with 2 of them being novel (p.Y563C and p.G564S). In vitro functional studies confirmed the deleterious behavior of the 4 somatic NLRP3 mutations. Among the different neurological manifestations detected, 1 patient displayed mild loss of white matter volume on brain magnetic resonance imaging., Conclusion: The allele frequency of somatic NLRP3 mutations occurs generally under 15%, considered the threshold of detectability using the Sanger method of DNA sequencing. Consequently, routine genetic diagnostic of CAPS should be currently performed by next-generation techniques ensuring high coverage to identify also low-level mosaicism, whose actual frequency is yet unknown and probably underestimated.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a dominantly inherited autoinflammatory disease caused by TNFRSF1A mutations. Patients with TRAPS suffer from recurrent, long episodes with fever, arthralgia/arthritis, migratory myalgias, abdominal pain, serositis, conjunctivitis and migratory erythematous skin rash. More than 70 different TNFRSF1A mutations have been reported to date, and as consequence of its genetic heterogeneity, TRAPS shows a variable phenotypic expression. Among TNFRSF1A variants, the low-penetrance p.Arg92Gln variant represents the most commonly detected, and is typically associated with mild and short episodes, with a higher tendency to spontaneous resolution, and less familial association than the structural TNFRSF1A mutations. Pericardial involvement is rare but a well-known clinical feature of TRAPS, with a significant increased rate in those adult patients in whom the onset of the disease occurred during adulthood. Moreover, idiopathic recurrent acute pericarditis has also been occasionally described as a clinical presentation of TRAPS. However, cardiac tamponade is an unusual initial manifestation of the disease. Herein, we present a brief review based on the description of the exceptional case of a 35-year-old female patient who presented with recurrent pericardial effusions and cardiac tamponade. TNFRSF1A analyses showed a heterozygous genotype for the low-penetrance p.Arg92Gln variant. Due to disease severity, the patient was treated with the anti-interleukin-1 drug anakinra, showing a prompt resolution of her clinical manifestations., (© 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Chronic obstructive pulmonary disease (COPD) is characterised by pulmonary and systemic inflammation that bursts during exacerbations of the disease (ECOPD). The NLRP3 inflammasome is a key regulatory molecule of the inflammatory response. Its role in COPD is unclear. We investigated the NLRP3 inflammasome status in: 1) lung tissue samples from 38 patients with stable COPD, 15 smokers with normal spirometry and 14 never-smokers; and 2) sputum and plasma samples from 56 ECOPD patients, of whom 41 could be reassessed at clinical recovery. We observed that: 1) in lung tissue samples of stable COPD patients, NLRP3 and interleukin (IL)-1β mRNA were upregulated, but both caspase-1 and ASC were mostly in inactive form, and 2) during infectious ECOPD, caspase-1, oligomeric ASC and associated cytokines (IL-1β, IL-18) were significantly increased in sputum compared with clinical recovery. The NLRP3 inflammasome is primed, but not activated, in the lungs of clinically stable COPD patients. Inflammasome activation occurs during infectious ECOPD. The results of this study suggest that the inflammasome participates in the inflammatory burst of infectious ECOPD., Competing Interests: can be found alongside this article at openres.ersjournals.com

Inflammation and immune-mediated processes are pivotal to the pathogenic progression of age-related macular degeneration (AMD). Although plasma levels of C-reactive protein (CRP) have been shown to be associated with an increased risk for AMD, the pathophysiological importance of the prototypical acute-phase reactant in the etiology of the disease is unknown, and data regarding the exact role of CRP in ocular inflammation are limited. In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the "risk" His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained.

Objectives: Cryopyrin-associated periodic syndromes (CAPS) are dominantly-inherited autoinflammatory diseases. The uncontrolled IL-1β overproduction observed in these patients is the rational basis to treat them with anti-IL-1 drugs. The objective of this study was to evaluate the efficacy and safety of treatment with the long-lasting fully humanised anti-IL-1β monoclonal antibody canakinumab in a Spanish cohort of patients with CAPS., Methods: Clinical and laboratory data of CAPS patients carrying a heterozygous germline NLRP3 mutation were obtained. The initial treatment scheme with canakinumab was 150 mg/8 weeks administered subcutaneously in adult patients and 2 mg/kg/8 weeks in paediatric patients., Results: Eight unrelated patients were enrolled. Canakinumab was the first anti-IL-1 drug used in three of them; five were already receiving anakinra. The clinical response to the initial canakinumab scheme was positive in all patients, and was quickly observed in the first 24-72 hours. Four required increasing the frequency and/or dose of canakinumab. A limited or no efficacy in those symptoms related to consequence of the deforming arthropathy and neurosensorial deafness was observed. The adverse side effects were restricted to infectious complications in a small percentage of patients. The treatment was well tolerated by all patients, with no reactions at drug site injections., Conclusions: Canakinumab caused fast and sustained remissions in most clinical and biochemical manifestations in all enrolled patients, with a limited efficacy in the structural lesions. Dose adjustments seem to be necessary for children and/or for patients with the most severe CAPS phenotypes. Treatment was well tolerated with a low incidence of adverse effects.