Familial Cold Autoinflammatory Syndrome Research Articles

Clinical Characteristics of Cryopyrin-Associated Periodic Syndrome and Long-Term Real-World Efficacy and Tolerability of Canakinumab in Japan: Results of a Nationwide Survey.

We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)-unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti-tumor necrosis factor-α agents was effective for IBD- and CAPS-associated symptoms not resolved by canakinumab monotherapy. This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment.

Identification of a Novel NLRP12 Frameshift Mutation (Val730Glyfs∗41) by Whole-Exome Sequencing in Patients with Crohn’s Disease

NLRP12 encodes the nucleotide-binding leucine-rich repeat-containing receptor 12 protein and has been linked to familial cold autoinflammatory syndrome 2 (FCAS2). Previous studies have reported that NLRP12 protein can dampen inflammatory responses in DSS-induced mice colitis. To date, only four alterations in the NLRP12 gene have been associated with Crohn’s disease (CD). Here, we reported a novel heterozygous NLRP12 frameshift mutation (c.2188dupG, p.Val730Glyfs∗41) identified by whole-exome sequencing in the proband with CD. The Sanger sequencing confirmed that his sister and father also carried this NLRP12 mutation, which cosegregated well with the CD phenotype. In silico analysis predicted this mutation to be disease-causing. Patients heterozygous for this mutation exhibited decreased NLRP12 protein levels in the peripheral blood and colon. Functional assays showed that mutant NLRP12 plasmid-transfected HEK293T cells exhibited significantly lower NLRP12 mRNA and protein levels than wild-type plasmid-transfected cells. The nonsense-mediated decay inhibitor NMDI14 significantly increased NLRP12 mRNA and protein levels in mutant plasmid-transfected cells. Overall, our results demonstrated that this heterozygous NLRP12 mutation (c.2188dupG) resulted in decreased NLRP12 expression, which might contribute to the mechanism underlying CD.

A case of cryopyrin-associated periodic syndrome due to somatic mosaic mutation complicated with recurrent circinate erythematous psoriasis.

Cryopyrin-associated periotic syndrome (CAPS) is a rare autoinflammatory disease (AID) caused by genetic variants in innate immunity genes. AIDs, including CAPS, mediate proinflammatory cytokines such as interleukin (IL)-1 and IL-18 and result in severe systemic inflammation. A gain-of-function mutation in the NLRP3 gene, which encodes the protein cryopyrin, was identified to be responsible for CAPS in 2001, and since then several additional pathogenic mutations have been found. Moreover, other phenotypes have been identified based on severity and symptomatology, including familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID)/chronic neurologic cutaneous articular syndrome (CINCA). Prompt diagnosis of CAPS remains challenging, however, due to unspecific, extensive clinical signs, and delayed diagnosis and treatment targeting IL-1 lead to multiorgan damage. Another factor complicating diagnosis is the existence of somatic mosaic mutations in the NLRP3 gene in some cases, resulting in symptoms and clinical courses that are atypical. The frequency of somatic mosaic mutations in CAPS was estimated to be 19% in a systematic review. Psoriasis is a chronic inflammatory skin disease that affects about 3% of the global population. Although no reports have shown complication between CAPS and psoriasis, these diseases have several similarities and potential relationships, for instance activation of Th17 cells in the dermis and increased NLRP3 gene expression in psoriatic skin compared with normal skin. Here we report a case of CAPS due to a somatic mosaic mutation with recurrent circinate erythematous psoriasis.

NLRC4 gain-of-function variant is identified in a patient with systemic lupus erythematosus

NLRC4 gain-of-function variants are known to cause various autoinflammatory phenotypes, including familial cold autoinflammatory syndrome (FCAS4) and NLRC4 macrophage activation syndrome (NLRC4-MAS). However, to date, no study has linked NLRC4 gain-of-function variants to systemic lupus erythematosus (SLE). In this study, we identified a novel NLRC4 W655S variant in an SLE patient and her son, who had neonatal lupus complicated with macrophage activation syndrome. Our in vitro experiments demonstrated that the W655S NLRC4 increased ASC speck formation and mature IL-1β secretion compared to the wild-type NLRC4. In addition, the patient had elevated levels of IL-1β and IL-18 in both serum and PBMCs. RNA sequencing showed that NF-κB and interferon signaling pathways were significantly activated in the patient compared to healthy controls. Furthermore, gene set enrichment analysis revealed upregulation of NLRC4-related pathways in patient PBMCs. In conclusion, our study identified the NLRC4 W655S variant in a patient with SLE. This is the first report linking inflammasomopathy to monogenic SLE. Our findings suggest that inflammasome activation may be a critical driver in the pathogenicity of lupus, and autoinflammatory pathways may play important roles in the development of the disease.

Clinical spectrum of Cryopyrin-associated Periodic Syndrome associated with a single nucleotide variant of the NLRP3 gene in a Puerto Rican family

Cryopyrin-associated Periodic Syndromes (CAPS) are a group of autoinflammatory disorders of varying degrees of severity that include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID, or as Chronic Infantile Neurological, Cutaneous, and Articular (CINCA). There is one case per one million inhabitants in the United States. Cryopyrinopathies arise from mutations in the NOD-like receptor protein 3 (NLRP3) gene, which assembles with the cysteine protease caspase-1 to form the NLP3 and releases several proinflammatory cytokines, including IL-1β. An autosomal dominant GOF mutation of the NLRP3 gene causes the overproduction of IL-1β, inducing excessive inflammation and even permanent organ damage. We describe a Puerto Rican family of three with Cryopyrin-associated Periodic Syndrome and varying degrees of severity that received Canakinumab. A 40-year-old mother and her two sons, ages 26 and 20, presented for an evaluation of cold-induced maculopapular rash, arthralgia, and lower extremity swelling. Their symptoms initially presented at birth and continued into their adulthood. The episodes started briefly after exposure to cool temperatures and lasted hours to days. High fevers and chills often accompany episodes. They all presented with chronic leukocytosis and high inflammatory laboratory values. The oldest son showed the most intense, enduring flares and severe complications. At age 1, he was diagnosed with neuroblastoma of the right adrenal gland and achieved remission with a combination of surgical resection, chemotherapy, and radiotherapy. He subsequently required multiple hospitalizations due to episodes of high fevers as a child. He also developed severe leptomeningeal inflammation at age 12 and underwent an exploratory craniotomy that yielded normal findings. The three family members underwent genetic testing two decades after the children were born, revealing a heterozygous missense mutation. They had a single nucleotide variant of the NPL3 gene c.913G>A (p. Asp305Asn) that has been linked to CAPS. Severe inflammatory neurologic symptoms and familial cold urticaria were the clues for the diagnostic suspicion of CAPS. IL-1β antagonists have been demonstrated to be effective in substantially reducing inflammatory markers and thus decreasing inflammation-related signs and symptoms. Residence in the tropics could have contributed to delayed diagnosis.Table 1General characteristics of the Cryopyrin-associated Periodic SyndromesFCASMWSNOMID/CINCAGenes and pattern of inheritanceNLRP3 gene ADNLRP3 gene ADNLRP3 gene ADEpidemiology Age of onset1:1 million.1Infancy1:1 million1Infancy1:1 million1Neonatal/early infancyCutaneous NeurologicUrticaria-like rash Headaches with fever after cold exposureUrticaria-like rash Headaches with fever during flares. Uncommon to have other CNS symptoms. 3Urticaria-like rash Headaches, fever, chronic aseptic meningitis, and high CNS pressure. Many develop mental or cognitive impairment.AuditoryMild hearing lossSensorineural hearing loss starting in adolescenceSensorineural hearing loss from infancy/childhoodOphthalmicConjunctivitis during flaresConjunctivitis during flaresPapilledema, uveitis, iritis, conjunctivitis, and vision lossLymphaticNot notedMay be notedMay have enlarged lymph nodesJointsArthralgiaArthralgia, stiffness, and swelling during flaresArthralgia, stiffness, and swelling during flaresLaboratory valuesHigh ESR, CRP, SAA, and leukocytosis with flaresHigh ESR, CRP, SAA, and leukocytosis with flaresChronically elevated ESR, CRP, SAA, and leukocytosisFCAS, Familial cold autoinflammatory syndrome; MWS Muckle Wells Syndrome; CINCA/NOMID, chronic infantile neurologic, cutaneous, and articular syndrome/neonatal-onset multisystem inflammatory disease.

A Case of Pneumocystis jirovecii Pneumonia in an Infant with Ataxia-Pancytopenia Syndrome

BackgroundAtaxia-pancytopenia syndrome (ATXPC), a rare autosomal dominant disorder caused by pathogenic variants in the SAMD9L gene, is characterized by variable onset and severity of cerebellar ataxia, hematologic cytopenias, and immunodeficiency of myeloid, B-, and NK-cells. ATXPC has been associated with viral and bacterial infections, but no cases of opportunistic PJP have been reported. CaseAt 6 weeks of age, the patient was admitted to the hospital for acute hypoxemic respiratory failure due to rhino/enterovirus bronchiolitis, requiring supplemental oxygen. The increased oxygen requirement later led to intubation. A chest x-ray showed diffuse bilateral opacities concerning for pediatric acute respiratory distress syndrome (PARDS). Bronchoalveolar lavage and silver stain revealed organisms morphologically suggestive of Pneumocystis jirovecii pneumonia (PJP), which was confirmed with a positive serum beta-glucan. Based on the diagnosis of PJP, the patient was started on steroids and Bactrim. Immunology was consulted for further evaluation for possible underlying immunodeficiency. The patient had a normal newborn screening. HIV PCR was negative. Repeated TRECs, CD3+, CD8+, CD19+, and immunoglobulin levels (IgG, IgE) were within normal limits, but modest reduction of CD45 RA/RO ratio and IgA were observed. Additionally, natural killer cell function was low. T-cell proliferation to mitogens were normal, but significantly decreased to candida and tetanus antigens. A significant reduction in the expression of HLA-ABC and HLA-DR was observed in the lymphocytes and monocytes of the patient compared to the control. Interestingly, HLA-DR expression on monocytes was particularly affected. A next-generation sequencing of primary immunodeficiency genes identified likely pathogenic, maternally inherited variants: a heterozygous SAMD9L variant (ataxia-pancytopenia syndrome) and NLRP12 variant (familial cold autoinflammatory syndrome 2). DiscussionATXPC has been associated with variable cellular immunodeficiencies. While prior studies have reported recurrent bacterial and viral infections in ATXPC patients, this case is the first to document a PJP opportunistic infection in an infant. It is possible that the NLRP12 variant found in this patient could have also contributed to this clinical presentation. Early diagnosis of ATXPC through clinical recognition and genetic testing may improve prognosis.

Molecular profile of patients with inborn errors of immunity from Nepal

Background and AimsInborn errors of immunity (IEIs) are increasingly being diagnosed in various regions of the world. There are significant challenges in the diagnosis and treatment of IEIs in resource-limited countries. With the availability of one immunologist and increasing awareness, IEIs are diagnosed with increasing frequency and accuracy in Nepal. IEIs are also being evaluated in children presenting with autoimmune manifestations. We describe the profile of patients diagnosed with IEIs in Nepal during 2020–2022. MethodsRecords of all patients with IEIs who were diagnosed and treated at our tertiary care center in Nepal from August 2020 to April 2022 were analysed. Lead author (DB) has examined and diagnosed all cases. IEIs were diagnosed based on the European Society for Immunodeficiencies (ESID) diagnostic criteria and genetic analysis. ResultsThirty-two patients with IEI (19 boys; 13 girls) and 801 children with autoimmune disorders were diagnosed during the study period. Genetic analysis was done on 18 patients. The diagnostic profile of the patients includes patients with chronic granulomatous disease, X-linked agammaglobulinemia, severe combined immunodeficiency, Job syndrome, selective IgA deficiency, specific antibody deficiency, Wiskott-Aldrich Syndrome, CTLA4 deficiency, IPEX syndrome, IFN-IL12 axis defect, hereditary angioedema, MonoMac syndrome, ARPC1B deficiency, leukocyte adhesion defect, PAPA syndrome, autoimmune lymphoproliferative syndrome, ADA2 deficiency, early-complement deficiency lupus, familial cold auto-inflammatory syndrome, A20 haploinsufficiency, and Blau syndrome. Some patients succumbed before the scope of diagnosis. HSCT is planned for 3 patients. ConclusionsOur is the first report of genetically proven IEIs in Nepal. Logistic constraints coupled with a lack of awareness of IEIs among laity and pediatrician accounted for a missed diagnosis, late diagnosis, and poor outcomes in resource-limited settings. Antimicrobial prophylaxis reduced the incidence of breakthrough infections. The lack of HSCT facilities precludes definitive treatment of many IEIs.

Lifting the Lid on CAPS: Uncovering Genetic Anticipation in Cryopyrin-Associated Periodic Syndrome

Cryopyrin-associated periodic syndrome (CAPS) is a spectrum of autoinflammatory conditions comprising three subtypes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID).1 Symptoms include urticaria, fever, arthralgias, conjunctival injection, and headaches, which can occur spontaneously or during periods of cold/stress.2 Complications include permanent sensorineural hearing loss (SNHL), chronic aseptic meningitis, systemic amyloidosis, developmental delay, seizures, and chronic arthropathy.3 CAPS is treated with inhibition of interleukin (IL)-1 which can reduce symptoms and prevent progression of complications including hearing loss, CNS inflammation, and renal disease from amyloidosis.3,4.Here, we present a five-year-old boy who developed unexplained arthralgias, SNHL, increased intracranial pressure, atrophic retinal nerve fiber layer, and painful urticaria. Laboratory testing showed elevated inflammatory markers and neutrophil count. Genetic testing showed a heterozygous variant in the NLRP3 gene that was previously reported in a patient with NOMID. Interestingly, his mother had similar history of arthralgia, aseptic meningitis, SNHL, and recurrent aphthous ulcers, while his maternal grandmother had a history of SNHL and arthralgia. The mother and grandmother had similar elevations in inflammatory markers and neutrophils. Both were found to have the same variant in NLRP3 as the index patient and were diagnosed with CAPS/NOMID. The histories suggested a degree of genetic anticipation, for the child’s symptoms were most severe, while his mother had moderate symptoms and his grandmother was relatively mildly affected. Notably, neither the mother nor grandmother had signs of kidney disease to suggest amyloidosis. All three family members were started on canakinumab injections. The child’s arthralgias and mother’s symptoms improved, and flares have decreased in frequency. The grandmother has not yet received therapy long enough to assess for improved symptoms.CAPS is a group of autoinflammatory disorders with autosomal dominant inheritance, quality-of-life-limiting symptoms, and potential life-long complications. CAPS should be suspected and screened for in relatives of affected individuals. This familial case demonstrates a pattern of increased severity of CAPS symptoms with each subsequent generation from grandmother to grandchild suggestive of genetic anticipation. Early diagnosis and initiation of anti-IL-1 therapy is important to prevent progression and complications.

Autoinflammatory Conditions May Increase Risk of Adverse Drug Reactions

In this case report, we will describe a patient who has been diagnosed with cryopyrin associated autoinflammatory syndrome (CAPS), with a history consistent with familial cold autoinflammatory syndrome (FCAS). The patient experienced drug reactions to multiple treatments highlighting how autoinflammatory conditions may increase the risk of drug reactions in patients.CAPS is a rare genetic autoinflammatory condition caused by gain of function mutation in NLRP3 leading to the activation of the cryopyrin inflammasome which causes release of many cytokines including IL-1β. Patients experience systemic symptoms involving the musculoskeletal, nervous system, and cutaneous systems. This patient is a 32-year-old female with no past medical history who presented with symptoms of recurrent cold urticaria, arthralgias, and frequent conjunctivitis since she was 15 years old. Her father and brother also experienced similar symptoms. Patient’s genetic testing revealed a pathogenic variant in the NLRP3 gene (Variant c1322C>T (p.Ala441Val)) consistent with CAPS. The patient was initially treated with canakinumab, a monoclonal antibody to IL-β, the cytokine implicated in CAPS. During the three months of therapy, the patient’s symptoms abated, however, she experienced increased bruising and heavier menstrual cycles. Her laboratory testing at the time revealed a stable platelet count of 157 000 µL (106 000 µL prior to treatment) and stable hemoglobin level of 11.6 g/dL (10.9 g/dL prior to treatment). Due to her significant symptoms, canakinumab was discontinued and she was trialed on Anakinra, an IL-1 receptor antagonist. After a week of daily injections, the patient developed bullous urticaria at the injection site. Skin biopsy of the lesions confirmed the presence of eosinophils within the dermis consistent with a drug eruption to Anakinra. Currently, the patient is trialing Rilocept, a dimeric fusion protein that prevents IL-β signaling, with close monitoring for any adverse effects.The immune modulation which occurs in patients with autoinflammatory conditions may predispose them to various adverse drug effects. This could be explained by the cytokine up-regulation which causes increased sensitization to various other inflammatory pathways including histamine and coagulopathy pathways. This case highlights the need for further research about drug reactions in autoinflammatory conditions.

Early-onset recurrent panniculitis as a phenotype of NLRC4-associated autoinflammatory syndrome: Characterization of pathogenicity of the p.Ser445Pro NLRC4 variant.

Monoallelic NLRC4 gain-of-function variants cause an inflammasomopathy with diverse clinical forms including infantile enterocolitis, recurrent macrophage activation syndrome, cold-induced urticaria-like lesions (or familial-cold autoinflammatory syndrome, FCAS4), and painful subcutaneous nodules. Here, we identified a large family with six consecutive generations affected. Genetic analyses detected the heterozygous p.Ser445Pro NLRC4 variant in three patients, which has been previously reported in a Dutch family with FCAS4. We aimed to describe the clinicopathological features and the functional consequences of the detected NLRC4 variant. Patients presented an early-onset (3months-6 years) inflammatory disease characterized by recurrent panniculitis, fever and arthralgia. Histopathological examination showed perivascular and interstitial lymphohistiocytic infiltrates in the dermis and mixed panniculitis. Functional analysis supported the conclusion that the p.Ser445Pro NLRC4 variant leads to a constitutive activation of NLRC4-inflammasome and increased plasma levels of IL-18. Prompt recognition of early-onset panniculitis through clinicopathological examination and laboratory biomarkers may allow targeted therapies.

Identification of a variant in NLRP3 gene in a patient with Muckle-Wells syndrome: a case report and review of literature

BackgroundCryopyrin-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.Case presentationWe 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.ConclusionA classical variant of the NLRP3 gene in a patient with MWS was first reported in China.

Assessment of the Frequency of Variants of Undetermined Significance (VUS) in Adult Patients with Chronic Idiopathic Neutropenia Studied for Myeloid Gene Mutations By Next Generation Sequencing

Background: Chronic Idiopathic Neutropenia (CIN) is a neutrophil disorder characterized by the persistent and unexplained reduction in the number of peripheral blood (PB) neutrophils. The diagnosis of CIN is based on exclusion criteria, namely the absence of clinical/laboratory evidence of any underlying disease or use of drugs that might be associated with neutropenia, absence of history of exposure to irradiation or use of chemical compounds, negative antineutrophil antibodies, and normal bone marrow (BM) morphology and karyotype. We have previously performed next generation sequencing (NGS) analysis of genes recurrently mutated in myeloid malignancies in a cohort of CIN patients and we found that 11.35% of the patients display clonal hematopoiesis in term of presence of pathogenic/likely pathogenic variants with VAF higher than 2%. Variants of undetermined significance (VUS) were ruled out from the analysis and their potential significance was not assessed. Aims: In the current study we have assessed the presence, frequency and potential clinical significance of VUS detected in our cohort of CIN patients previously studied for clonal hematopoiesis. Methods: Genomic DNA was extracted from CIN patients' BM or PB samples, sequencing libraries were prepared and subjected to targeted NGS on an Ion S5 Prime Sequencer (Thermo Fisher Scientific) using a panel of 38 genes recurrently mutated in myeloid malignancies (Tsaknakis G et al. Blood. 2021;138:1249-1257). Results: NGS analysis of myeloid genes has been performed in 139 CIN patients (106 female subjects and 33 male subjects, aged 21 to 89 years with a median age of 59 years). Re-analysis of patients' NGS data and assessment of VUS revealed that 35 out of 139 patients (25.18%) carried one or more VUS (a total of 39 VUS were detected, all with an allelic frequency of 50% and all missense variants). Genetic variants were evaluated according to the ACMG guidelines and classified as VUS. The majority of VUSs were observed in ATM (n=7) and SETBP1 (n=6) genes followed by TET2, NOTCH1 (4 occurrences respectively) and PLCG2 (n=3). Two different patients shared the same variant in TET2 gene whereas two siblings shared the same variant in SETBP1 gene. Pathogenicity score calculation based on the combined evidence from multiple other in-silico predictors identified 3 variants in 3 different genes as having the highest probability to be pathogenic. Namely these were PLCG2K456E,CXCR4R235C and SF3B1T56I. PLCG2 variants have been implicated in familial cold autoinflammatory syndrome 3 (PLCG2 associated antibody deficiency and immune dysregulation, PLAID) and in autoinflammation, antibody deficiency, and immune dysregulation syndrome (APLAID) whereas CXCR4 variants are known to be associated with Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome. SF3B1 mutations have not yet been shown to be involved in hereditary disease. Conclusions: Our study of VUS assessment in a cohort of 139 well characterized adult CIN patients identified 39 VUS, all heterozygous, in a total of 35 patients. Further steps include paired analysis with constitutional reference tissue to determine the germline nature of the mutations. Moreover, these variants should be functionally tested and integrated with functional results and clinical phenotypes to more accurately interpret their potential contribution to disease onset. This study of VUS analysis in CIN patients is anticipated to contribute to the better understanding of the pathogenetic causes of this rare disease.

Socio-professional impact and quality of life of cryopyrin-associated periodic syndromes in 54 patients in adulthood.

Cryopyrin-associated periodic syndromes (CAPS) belongs to the group of hereditary recurrent fever disorders characterised by interleukin1β-mediated systemic inflammation. Specific treatment by IL-1 targeting drugs has significantly modified the disease evolution. We aimed to evaluate the socio-professional impact of CAPS in the long term and the influence of genetic variants in the phenotype. We made a multicentre, observational and descriptive study and collected retrospective data from childhood to adulthood, and until the last year of follow-up. We assessed the quality of life (QoL) of the patients by phone interviews. We also used the SF36 questionnaire including 8 domains: physical function, physical role, body pain, general health, vitality, social function, emotional role and mental health. A high score means a better QoL. Fifty-four patients were evaluated (14 familial cold autoinflammatory syndrome, 27 Muckle-Wells syndrome, 7 chronic infantileneurological cutaneous and articular syndrome. The study showed improvement in symptoms in adulthood and good QoL in all domains apart from school (87%) and work (61%) absenteeism. The MWS group is intermediate in terms of symptoms but seems to describe a better QoL compared to the other groups. The genetic variant alone does not determine the expression of the disease. Our study shows that CAPS patients have an improvement of symptoms in adulthood and a satisfactory QoL for most of them. Anti-IL1 treatment is the main factor linked to this improvement and therefore early initiation should be encouraged.

Equally potent: Nlrp3 mutation in macrophages or neutrophils is sufficient to drive autoinflammation.

Gain-of-function mutation in NLRP3 is associated with a spectrum of autoinflammatory disorders including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal onset multisystem inflammatory disease, collectively known as cryopyrin-associated periodic syndrome (CAPS). However, the cell types mediating the pathogenesis of CAPS are not completely understood. Two studies in EMBO Reports now demonstrate that gain-of-function Nlrp3 mutation in either macrophages or neutrophils alone is sufficient to trigger systemic autoinflammation and lethality in mice.

Real-world safety and effectiveness of canakinumab in patients with cryopyrin-associated periodic fever syndrome: a long-term observational study in Japan.

A post-marketing all-patient surveillance program was conducted to evaluate the safety and effectiveness of canakinumab, a monoclonal anti-interleukin-1β antibody, in patients in Japan with cryopyrin-associated periodic fever syndrome (CAPS), including familial cold auto-inflammatory syndrome, Muckle-Wells syndrome, and neonatal onset multisystem inflammatory disease. All patients with CAPS who received canakinumab treatment after drug approval in Japan were registered in this non-interventional, observational study. The observation period per patient was two years. Patients newly treated with canakinumab (New patients; NP) and those continuously treated with canakinumab following clinical trials (Roll-over patients; RP) were included. Data collection of clinical symptoms affecting physical function and prognosis was not mandated but assessed where available. Here, the interim results are reported. Of 87 patients in the safety set, the proportion of patients with any adverse drug reactions (ADRs) and any serious ADRs was 31.03% and 3.45%, respectively. The most common ADRs reported under system organ class were infections and infestations (20.69%). Of 84 patients in the effectiveness set, 75.76% and 83.33% of NP and RP, respectively, were responders at Week 24, achieving complete response without relapse. Responder rates were maintained up to Week 104. Clinical symptoms affecting physical function and prognosis remained unchanged in over half of those patients. Interim results provided the safety profile of canakinumab in a real-world setting, and identified no new safety concerns. Treatment with canakinumab has suggested sustained remission in the majority of patients in the real-world setting.

Rare mutations in NLRP3 and NLRP12 associated with familial cold autoinflammatory syndrome: two Chinese pedigrees.

Familial cold autoinflammatory syndrome (FCAS) is the mildest subtype of cryopyrin-associated periodic syndrome (CAPS) and is a rare inherited systemic autoinflammatory disease (SAID). CAPS is the consequence of a rare group of genetic disorders that are mostly reported in European and American populations, but scarcely reported in Chinese populations. NLRP3, NLRP12, PLCG2, and NLRC4 are known pathogenic genes associated with FCAS, and the aim of this study was to identify pathogenic mutations in two intact pedigrees of Chinese FCAS. We performed Sanger sequencing of genomic DNA samples from 25 affected and 32 unaffected members of the two intact pedigrees and analyzed the pathogenic mutations for their conservativeness using multiple sequence alignment tools. In addition, we reviewed previously reported pathogenic genes of FCAS and their pathogenicity classification and summarized the characteristics of different genotypes and phenotypes of FCAS. This study reported two intact FCAS pedigrees with different genotypes and phenotypes, the heterozygous mutation (p.V72M) in NLRP3 in pedigree 1 and the heterozygous mutation (p.R754H) in NLRP12 in pedigree 2. There are no reports targeting p.V72M in NLRP3 in FCAS1, and there are relatively few relevant phenotypic data on the clinical manifestations identified in previous pedigrees. Multiple sequence comparisons of NLRP3 indicate that the p.V72M mutation is highly conserved during evolution. Our study has enriched the understanding of the pathogenesis of FCAS, a rare disease especially in Asian populations. KEY POINTS: •The NLRP3 (p.V72M) variant was first discovered in the Chinese pedigree of FCAS1 •NLRP12 (p.R754H) variants are not conserved in multiple sequence alignments, but they are still co-segregated and expressed in the big Chinese diseased pedigree.

Cryo-sensitive aggregation triggers NLRP3 inflammasome assembly in cryopyrin-associated periodic syndrome.

Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory syndrome caused by mutations of NLRP3 gene encoding cryopyrin. Familial cold autoinflammatory syndrome, the mildest form of CAPS, is characterized by cold-induced inflammation induced by the overproduction of IL-1β. However, the molecular mechanism of how mutated NLRP3 causes inflammasome activation in CAPS remains unclear. Here, we found that CAPS-associated NLRP3 mutants form cryo-sensitive aggregates that function as a scaffold for inflammasome activation. Cold exposure promoted inflammasome assembly and subsequent IL-1β release triggered by mutated NLRP3. While K+ efflux was dispensable, Ca2+ was necessary for mutated NLRP3-mediated inflammasome assembly. Notably, Ca2+ influx was induced during mutated NLRP3-mediated inflammasome assembly. Furthermore, caspase-1 inhibition prevented Ca2+ influx and inflammasome assembly induced by the mutated NLRP3, suggesting a feed-forward Ca2+ influx loop triggered by mutated NLRP3. Thus, the mutated NLRP3 forms cryo-sensitive aggregates to promote inflammasome assembly distinct from canonical NLRP3 inflammasome activation.

Familial cold autoinflammatory syndrome and multiple sclerosis

AbstractBackgroundCryopyrin‐associated periodic syndrome (CAPS) is an autoinflammatory disorder with a spectrum ranging from the milder familial cold auto‐inflammatory syndrome (FCAS) phenotype to the more severe Muckle–Wells Syndrome. Although headaches are the most common neurological symptoms, neuroinflammatory diseases such as multiple sclerosis (MS) have only been reported in the more severe phenotypes.Case PresentationWe describe a 43‐year‐old male diagnosed with relapse‐remitting MS who developed cold‐induced arthralgias and urticaria. He initially presented with facial numbness and arthralgias in his late teenage years, and brain magnetic resonance imaging (MRI) demonstrated multiple lesions with periventricular white matter extension. Oligoclonal bands were detected in the cerebrospinal fluid (CSF). Symptoms gradually improved, and a decade later he presented with numbness at upper limbs and tongue. Brain and spine MRI showed new lesions, but CSF was unremarkable. He was started on interferon β‐1a with symptomatic improvement until another flare around 13 years later. Treatment was changed to dimethyl fumarate. During this hospitalization, urticaria was problematic and particularly associated with cold temperatures. This raised suspicion for possible CAPS and subsequently confirmed with an A439V mutation in the NLRP3 gene, consistent with FCAS. Anakinra was started but was not tolerated because of localized reactions despite desensitization. His serum amyloid A was mildly elevated at 9 mg/L (reference range 0–6). He remains stable from a neurological perspective, including imaging, and continues dimethyl fumarate.ConclusionsTo date, FCAS and possible association with MS has not been described. The case raises challenges in the diagnosis of concurrent disease processes. It also highlights that neurological sequelae should be considered in all spectrums of CAPS, and distinctions with MS should be made where possible.

Analysis of clinical characteristics of 35 inflammasomopathies cases

Objective: To summarize the clinical characteristics of inflammasomopathies, enhance the recognition of those diseases, and help to establish the early diagnosis. Methods: The clinical manifestations including fever, rash, systems involvement as well as laboratory results and genotypic characteristics of 35 children with inflammasomopathies diagnosed by the Department of Pediatrics, Peking Union Medical College Hospital, from January 1, 2008 to December 31, 2020 were analyzed retrospectively. Results: A total of 35 cases of inflammasomopathies were diagnosed, and 20 of them were boys while 15 were girls. Inflammasomopathies patients have early onset, the age of onset as well as diagnostic age were 1 (0,7) and 7 (3,12), respectively. Among those patients, 10 had familial mediterranean fever, 3 had mevalonate kinase deficiency, 15 cases had NLRP3 gene associated autoinflammatory disease, 4 cases had NLRP12-associated autoinflammatory disease, 2 cases had familial cold autoinflammatory syndrome 3, and 1 case had familial cold autoinflammatory syndrome 4. A total of 34 cases (97%) showed recurrent fever, 27 cases (77%) had skin rashes, while 11 cases (31%), 10 cases (29%), and 8 cases (23%) were presented with lymphadenopathy, hepatosplenomegaly and growth retardation, respectively. In terms of systemic involvement, there were 18 cases (51%), 12 cases (34%), 8 cases (23%), and 5 cases (14%) with skeletal, neurological, auditory, and renal involvement, respectively. Central nervous system involvement was seen only in NLRP3 gene associtated autoinflammatory diseases (12 cases), sensorineural deafness was seen in NLRP3 gene associtated autoinflammatory diseases (6 cases) and NLRP12 gene associated autoinflammatory diseases (2 cases), and abdominal pain was observed in familial Mediterranean fever (5 cases), mevalonate kinase deficiency (1 case) and NLRP12 gene related autoinflammatory diseases (1 case). In the acute inflammatory phase, the acute phase reactants (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) of 35 cases (100%) were significantly increased. There were 21 cases received ferritin examination, and only 4 cases (19%) showed an increase of it. In terms of autoantibodies, among all 35 patients, 4 cases (11%) were positive for antinuclear antibodies (ANA). Conclusions: Fever, skin rash, and skeletal manifestations are the most common clinical features, accompanied with increased CRP and ESR, and negative results of autoantibodies such as ANA. The clinical manifestations of those diseases are complex and diverse, and it is prone to delayed diagnosis and treatment.

HSC70 as a sensor of low temperature: role in cold-triggered autoinflammatory disorders.

Familial cold autoinflammatory syndrome (FCAS) is a subset of heritable autoinflammatory disorders wherein inflammatory symptoms aggravate upon exposure of the individual to subnormal temperature. In the past two decades, several mutations in various genes such as NLRP3, NLRP12, PLCG2 and NLRC4 have been identified that cause cold-triggered inflammation. However, our understanding of the mechanisms by which cells perceive subnormal temperature, and what keeps the inflammation under check until exposure to low temperature, is very limited. We hypothesise that recognition of FCAS-associated mutants as misfolded polypeptides by temperature-sensitive HSC70 (HSPA8) chaperone determines the FCAS phenotype. At 37 °C, HSC70 would interact with the mutant proteins, keeping them almost inactive, and loss of interaction at low temperature due to a conformational change in HSC70 would lead to their activation. The proposed mechanism of low temperature sensing in the context of FCAS may have wider implications for HSC70 as a cold temperature sensor in various pathological conditions where symptoms get aggravated upon exposure to low temperature.