Cryopyrin-associated Periodic Syndrome Phenotypes Research Articles

Long-term safety and effectiveness of canakinumab therapy in patients with cryopyrin-associated periodic syndrome: results from the β-Confident Registry

ObjectiveTo report the long-term safety and effectiveness of canakinumab, a fully human anti-interleukin 1β monoclonal antibody, in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells...

Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today?

The cryopyrin-associated periodic syndromes (CAPS) are usually caused by heterozygous NLRP3 gene variants, resulting in excessive inflammasome activation with subsequent overproduction of interleukin (IL)-1β. The CAPS spectrum includes mild, moderate, and severe phenotypes. The mild phenotype is called familial cold autoinflammatory syndrome (FCAS), the moderate phenotype is also known as Muckle–Wells syndrome (MWS), and the neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous articular syndrome (CINCA) describes the severe phenotype. The CAPS phenotypes display unspecific and unique clinical signs. Dermatologic, musculoskeletal, ocular, otologic, and neurologic disease symptoms combined with chronic systemic inflammation are characteristic. Nevertheless, making the CAPS diagnosis is challenging as several patients show a heterogeneous multi-system clinical presentation and the spectrum of genetic variants is growing. Somatic mosaicisms and low-penetrance variants lead to atypical clinical symptoms and disease courses. To avoid morbidity and to reduce mortality, early diagnosis is crucial, and a targeted anti-IL-1 therapy should be started as soon as possible. Furthermore, continuous and precise monitoring of disease activity, organ damage, and health-related quality of life is important. This review summarizes the current evidence in diagnosis and management of patients with CAPS.

NLRP3 A439V Mutation in a Large Family with Cryopyrin-associated Periodic Syndrome: Description of Ophthalmologic Symptoms in Correlation with Other Organ Symptoms.

Cryopyrin-associated periodic syndrome (CAPS) is a group of inherited autoinflammatory disorders caused by mutations in the NLRP3 gene resulting in the overproduction of interleukin 1β. NLRP3 mutations cause a broad clinical phenotype of CAPS. The aims of the study were to evaluate clinical, laboratory, and genetic features of a 5-generation family with CAPS focusing in detail on ocular symptoms. In a retrospective observational cohort study, consecutive family members were screened for the presence of the NLRP3 mutation. Patients underwent standardized clinical, laboratory, and ophthalmological assessments. The genotype-specific risk of ophthalmological findings and other organ symptoms was determined. Twenty-nine patients were clinically affected. The A439V mutation encoded by exon 3 of the NLRP3 gene was found in 15 of 37 family members (41%). The most common clinical features were musculoskeletal symptoms, headaches, and ophthalmological symptoms. The mutation-positive patients were characterized by more frequent skin rashes, ocular symptoms, arthralgia, arthritis, and severe Muckle-Wells syndrome (MWS) Disease Activity Score. Rosacea was diagnosed in 8 patients. The NLRP3 mutation A439V is associated with a heterogeneous clinical spectrum of familial cold autoinflammatory syndrome/MWS-overlap syndrome. Skin rash and eye diseases, such as conjunctivitis and uveitis, were positively correlated with this mutation.

Real-life effectiveness of canakinumab in cryopyrin-associated periodic syndrome.

Cryopyrin-associated periodic syndrome (CAPS) is a heterogeneous group of diseases characterized by excessive IL-1β release resulting in severe systemic and organ inflammation. Canakinumab targets IL-1β and is approved at standard dose for children and adults with all CAPS phenotypes. Limited data are available for the real-life effectiveness of canakinumab in patients living with CAPS. Therefore the aim of the study was to evaluate the real-life dosing and effectiveness of canakinumab in CAPS. A multi-centre study of consecutive children and adults with CAPS treated with canakinumab was performed. Demographics, CAPS phenotype and disease activity, inflammatory markers and canakinumab treatment strategy were recorded. Treatment response was assessed using CAPS disease activity scores, CRP and/or serum amyloid A levels. Comparisons between age groups, CAPS phenotypes and centres were conducted. A total of 68 CAPS patients at nine centres were included. All CAPS phenotypes were represented. Thirty-seven (54%) patients were females, the median age was 25 years and 27 (40%) were children, and the median follow-up was 28 months. Overall, complete response (CR) was seen in 72% of CAPS patients, significantly less often in severe (14%) than in mild CAPS phenotypes (79%). Only 53% attained CR on standard dose canakinumab. Dose increase was more commonly required in children (56%) than in adults (22%). Centres with a treat-to-target approach had significantly higher CR rates (94 vs 50%). Real-life effectiveness of canakinumab in CAPS was significantly lower than in controlled trials. Treat-to-target strategies may improve the outcome of children and adults living with CAPS.

Musculoskeletal Symptoms in Patients With Cryopyrin‐Associated Periodic Syndromes: A Large Database Study

To determine the type and frequency of musculoskeletal symptoms at onset and during followup of cryopyrin-associated periodic syndromes (CAPS). We retrospectively recorded the articular and muscular symptoms of patients with CAPS followed up in French hospitals. Data were presented as frequencies or the median (range), and patient groups were compared using chi-square test, Fisher's exact test, and Mann-Whitney test. The study included 133 patients (33 children), 20 with familial cold autoinflammatory syndrome, 88 with Muckle-Wells syndrome, 22 with chronic infantile neurologic, cutaneous, articular syndrome, and 3 with unclassified CAPS. The median age was 35 years (range 0-78 years) at the time of the study, 1 year (range 0-41 years) at symptom onset, and 23 years (range 0-58 years) at diagnosis. The disease was sporadic in 17% of the patients. Cutaneous symptoms predominated at onset (77%), followed by articular symptoms (30%). The p.Thr348Met and p.Arg260Trp NLRP3 mutations were significantly associated with the presence and absence of articular symptoms at onset, respectively. During followup, 86% of the patients had musculoskeletal symptoms, 88% had arthralgia, and 58% had arthritis, but only 9% had joint destruction. Tendinopathies occurred in 21.5% of the patients, tender points in 16.5%, and myalgia in 33%. Only 3 patients had typical knee deformities. Radiographs were rarely obtained. Except for bone deformities, osteoarticular symptoms occurred at similar frequencies in the different CAPS phenotypes. Joint manifestations were frequent in all CAPS phenotypes. Bone deformities were rare. Musculoskeletal manifestations varied within given families but tended to worsen over time.

Safe and effective canakinumab-treatment of neonatal onset multisystem inflammatory disease (NOMID)/ chronic infantile neurologic cutaneous and articular (CINCA)

NOMID/CINCA is the most severe phenotype of cryopyrin-associated periodic syndrome (CAPS), characterized by persistence of inflammation-mediated symptoms and overproduction of interleukin (IL)-1β, associated with significant morbidity, if untreated. In CAPS-patients early initiation of anti-IL1β-treatment appears to prevent severe disease sequelae. However, canakinumab as a 1st-line treatment in young infants suffering from NOMID has been scarcely reported.

Canakinumab treat-to target strategies increase complete response rate in CAPS

Objective Cryopyrin-associated periodic syndrome (CAPS) is a heterogeneous group of diseases characterized by excessive Interleukin-1b (IL-1 b) release resulting in severe systemic and organ inflammation. Canakinumab targets IL-1b and is approved at standard dose for children and adults with all CAPS phenotypes. Limited data are available regarding real-life effectiveness of canakinumab in patients living with CAPS. Therefore the aim of the study was to evaluate the real-life dosing practice and effectiveness of canakinumab in CAPS.

Somatic NLRP3 mosaicism in Muckle-Wells syndrome

Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations. All these diseases are currently considered as different phenotypes of the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been recently detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this genetic mechanism in other CAPS phenotypes.

CAPS--pathogenesis, presentation and treatment of an autoinflammatory disease.

The cryopyrin-associated periodic syndrome (CAPS) is a severity spectrum of rare diseases. CAPS comprises the three conditions previously described as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID), also known as chronic infantile neurologic, cutaneous, and articular (CINCA) syndrome. The clinical phenotype of CAPS is characterized by systemic inflammation. General symptoms are fatigue and fever. Local manifestations affect multiple tissues such as skin, joints, muscles, eyes, and the central nervous system. Distinct clinical features are characteristic for each subphenotype. In FCAS, these are cold-induced urticaria and fever, in MWS systemic amyloidosis and hearing loss and in NOMID/CINCA central nervous system inflammation and bone deformities. CAPS is caused by single heterozygous germline or somatic gain of function mutations in the NLRP3 gene encoding the protein cryopyrin. Cryopyrin nucleates an NLRP3 inflammasome, which regulates the activation and cleavage of caspase-1 that cleaves the pro-inflammatory cytokines, IL-1β and IL-18. IL-1β plays the key role in the induction of inflammation in CAPS. This has been confirmed by the application of IL-1 blocking agents, which lead not only to a rapid and sustained reversal of daily symptoms but also to some extent of long-term disease sequelae. To prevent CAPS-induced organ damage, early diagnosis and swift initiation of effective treatment are mandatory.

Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes

: Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes. To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative. NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. A variable degree (5.5-34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses. We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tools.

PReS-FINAL-2199: A novel mutation in the CIAS1/NLRP3 gene associated with an unusual phenotype of CAPS

Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory syndrome caused by heterozygous mutations of CIAS1/NLRP3 gene. Affected patients may present three different phenotypes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome and CINCA syndrome. Common symptoms include sporadic or cold-induced non pruritic urticarial rash and fever. Severe cases suffers from deafness, meningitis, articular contracture and secondary amyloidosis.

Clinical characteristics in subjects with NLRP3 V198M diagnosed at a single UK center and a review of the literature

IntroductionMutations in the NLRP3 gene are associated with the dominantly inherited cryopyrin-associated periodic syndrome (CAPS). The significance of the V198M variant is unclear; it has been reported in association with various CAPS phenotypes and as a variant of uncertain consequence. The aim of this study was to characterize the clinical phenotypes and treatments in individuals with V198M assessed in a single UK center.MethodsDNA samples from 830 subjects with fever syndromes or a family history of CAPS were screened for mutations in the NLRP3 gene with polymerase chain reaction (PCR) and sequencing. A detailed medical history was available in all cases. Inflammatory disease activity was monitored monthly with measurements of serum amyloid A protein (SAA) and C-reactive protein (CRP) in symptomatic individuals.ResultsNLRP3 V198M was identified in 19 subjects. It was found in association with CAPS in five cases, in one patient with Schnitzler syndrome, in three patients who also had a nucleotide alteration in another fever gene, and in three other patients with evidence of an autoinflammatory phenotype. Seven asymptomatic individuals were detected during screening of family members.ConclusionsThe NLRP3 V198M variant shows variable expressivity and reduced penetrance. It may be associated with classical inherited or apparently sporadic CAPS and with atypical autoinflammatory disease of varying severity, intriguingly including Schnitzler syndrome. The factors that influence the pathogenic consequences of this variant remain unknown. However, the remarkable response to interleukin 1 (IL-1) blockade in all but one individual in our series confirms that their clinical features are indeed mediated by IL-1.

Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes

ObjectiveLonger-term effects of prolonged selective interleukin-1β blockade with canakinumab were evaluated in the largest cohort of cryopyrin-associated periodic syndrome (CAPS) patients studied to date.MethodsAdult and paediatric CAPS patients (n=166, including...

Cryopyrin-Associated Periodic Syndrome: An Update on Diagnosis and Treatment Response

Cryopyrin-associated periodic syndrome (CAPS) is a rare hereditary inflammatory disorder encompassing a continuum of three phenotypes: familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease. Distinguishing features include cutaneous, neurological, ophthalmologic, and rheumatologic manifestations. CAPS results from a gain-of-function mutation of the NLRP3 gene coding for cryopyrin, which forms intracellular protein complexes known as inflammasomes. Defects of the inflammasomes lead to overproduction of interleukin-1, resulting in inflammatory symptoms seen in CAPS. Diagnosis is often delayed and requires a thorough review of clinical symptoms. Remarkable advances in our understanding of the genetics and the molecular pathway that is responsible for the clinical phenotype of CAPS has led to the development of effective treatments. It also has become clear that the NLRP3 inflammasome plays a critical role in innate immune defense and therefore has wider implications for other inflammatory disease states.