Cryopyrin-associated Periodic Syndrome Patients Research Articles

HSP90β controls NLRP3 autoactivation.

Gain-of-function mutations in NLRP3 are linked to cryopyrin-associated periodic syndromes (CAPS). Although NLRP3 autoinflammasome assembly triggers inflammatory cytokine release, its activation mechanisms are not fully understood. Our study used a functional genetic approach to identify regulators of NLRP3 inflammasome formation. We identified the HSP90β-SGT1 chaperone complex as crucial for autoinflammasome activation in CAPS. A deficiency in HSP90β, but not in HSP90α, impaired the formation of ASC specks without affecting the priming and expression of inflammasome components. Conversely, activating NLRP3 with stimuli such as nigericin or alum bypassed the need for SGT1 and HSP90β, suggesting the existence of alternative inflammasome assembly pathways. The role of HSP90β was further demonstrated in PBMCs derived from CAPS patients. In these samples, the pathological constitutive secretion of IL-1β could be suppressed using a pharmacological inhibitor of HSP90β. This finding underscores the potential of SGT1-HSP90β modulation as a therapeutic strategy in CAPS while preserving NLRP3's physiological functions.

The discovery of NLRP3 and its function in cryopyrin-associated periodic syndromes and innate immunity.

From studies of individual families to global collaborative efforts, the NLRP3 inflammasome is now recognized to be a key regulator of innate immunity. Activated by a panoply of pathogen-associated and endogenous triggers, NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL-1 and IL-18. Initially discovered as the cause of the autoinflammatory spectrum of cryopyrin-associated periodic syndrome (CAPS), NLRP3 is now also known to play a role in more common diseases including cardiovascular disease, gout, and liver disease. We have seen cohesion in results from clinical studies in CAPS patients, exvivo studies of human cells and murine cells, and invivo murine models leading to our understanding of the downstream pathways, cytokine secretion, and cell death pathways that has solidified the role of autoinflammation in the pathogenesis of human disease. Recent advances in our understanding of the structure of the inflammasome have provided ways for us to visualize normal and mutant protein function and pharmacologic inhibition. The subsequent development of targeted therapies successfully used in the treatment of patients with CAPS completes the bench to bedside translational loop which has defined the study of this unique protein.

The genetic and clinical characteristics and effects of Canakinumab on cryopyrin-associated periodic syndrome: a large pediatric cohort study from China.

Cryopyrin-associated periodic syndrome (CAPS) comprises a group of disorders characterized by recurrent bouts of systemic inflammation related to overactivation of inflammasome. So far, neither large cases of the correlation between genotype and phenotype nor treatment strategies have been clearly stated in China. Here, we studied the clinical and genetic characteristics and their correlation from 30 CAPS patients in China. We identified the pathogenesis for novel mutations by activating NLRP3 inflammasome for peripheral cells with ATP plus LPS, compared characteristics with other case series, and analyzed treatment outcomes of these patients. The patients harbored 19 substitutions in NLRP3, and 8 of them were novel mutations. Among these novel mutations, percentages of severe musculoskeletal, ophthalmologic, and neurological symptoms were higher compared with other case serials. The correlation of phenotypes and their variants seemed different in our cases, such as T350M, S333G/I/R, and F311V (somatic mosaicism). Ten patients received Canakinumab treatment, which proved effective at alleviating musculoskeletal, neurological, auditory, visual manifestations, fever, and rash for 10-20 months follow-up. Patients treated with prednisolone or prednisolone plus thalidomide or methotrexate, tocilizumab, TNF inhibiting agents, and sirolimus achieved only partial remission. Importantly, we firstly identified somatic mosaicism mutation of F311V, which was severe. Our study extended the spectrum of genotype and phenotype and characteristics of their correlations and provided detailed responses to different treatment strategies. These data provide guidance for future diagnosis and management for CAPS.

Current Evidence on Vaccinations in Pediatric and Adult Patients with Systemic Autoinflammatory Diseases

Systemic autoinflammatory diseases (SAIDs) are defined by recurrent febrile attacks associated with protean manifestations involving joints, the gastrointestinal tract, skin, and the central nervous system, combined with elevated inflammatory markers, and are caused by a dysregulation of the innate immune system. From a clinical standpoint, the most known SAIDs are familial Mediterranean fever (FMF); cryopyrin-associated periodic syndrome (CAPS); mevalonate kinase deficiency (MKD); and periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) syndrome. Current guidelines recommend the regular sequential administration of vaccines for all individuals with SAIDs. However, these patients have a much lower vaccination coverage rates in 'real-world' epidemiological studies than the general population. The main purpose of this review was to evaluate the scientific evidence available on both the efficacy and safety of vaccines in patients with SAIDs. From this analysis, neither serious adverse effects nor poorer antibody responses have been observed after vaccination in patients with SAIDs on treatment with biologic agents. More specifically, no new-onset immune-mediated complications have been observed following immunizations. Post-vaccination acute flares were significantly less frequent in FMF patients treated with colchicine alone than in those treated with both colchicine and canakinumab. Conversely, a decreased risk of SARS-CoV-2 infection has been proved for patients with FMF after vaccination with the mRNA-based BNT162b2 vaccine. Canakinumab did not appear to affect the ability to produce antibodies against non-live vaccines in patients with CAPS, especially if administered with a time lag from the vaccination. On the other hand, our analysis has shown that immunization against Streptococcus pneumoniae, specifically with the pneumococcal polysaccharide vaccine, was associated with a higher incidence of adverse reactions in CAPS patients. In addition, disease flares might be elicited by vaccinations in children with MKD, though no adverse events have been noted despite concurrent treatment with either anakinra or canakinumab. PFAPA patients seem to be less responsive to measles, mumps, and rubella-vaccine, but have shown higher antibody response than healthy controls following vaccination against hepatitis A. In consideration of the clinical frailty of both children and adults with SAIDs, all vaccinations remain 'highly' recommended in this category of patients despite the paucity of data available.

NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies.

The NLRP3 inflammasome is one of the NOD-like receptor family members with the most functional characterization and acts as a key player in innate immune system, participating in several physiological processes including, among others, the modulation of the immune system response and the coordination of host defences. Activation of the inflammasome is a crucial signaling mechanism that promotes both an acute and a chronic inflammatory response, which can accelerate the production of pro-inflammatory cytokines, mainly Interleukin (IL)-1β and IL-18, leading to an exacerbated inflammatory network. Cryopyrin associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disorder, clinically characterized by cutaneous and systemic, musculoskeletal, and central nervous system inflammation. Gain-of-function mutations in NLRP3 gene are causative of signs and inflammatory symptoms in CAPS patients, in which an abnormal activation of the NLRP3 inflammasome, resulting in an inappropriate release of IL-1β and gasdermin-D-dependent pyroptosis, has been demonstrated both in in vitro and in ex vivo studies. During recent years, two new hereditary NLRP3-related disorders have been described, deafness autosomal dominant 34 (DFN34) and keratitis fugax hereditaria (KFH), with an exclusive cochlear- and anterior eye- restricted autoinflammation, respectively, and caused by mutations in NLRP3 gene, thus expanding the clinical and genetic spectrum of NLRP3-associated autoinflammatory diseases. Several crucial mechanisms involved in the control of activation and regulation of the NLRP3 inflammasome have been identified and researchers took advantage of this to develop novel target therapies with a significant improvement of clinical signs and symptoms of NLRP3-associated diseases. This review provides a broad overview of NLRP3 inflammasome biology with particular emphasis on CAPS, whose clinical, genetic, and therapeutic aspects will be explored in depth. The latest evidence on two “new” diseases, DFN34 and KFH, caused by mutations in NLRP3 is also described.

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.

Galectin-3: a new biomarker for differentiating periodic fever, adenitis, pharyngitis, aphthous stomatitis (PFAPA) syndrome from familial Mediterranean fever?

Differentiating PFAPA (periodic fever, aphthosis, pharyngitis, and adenitis) syndrome from familial Mediterranean fever (FMF) could be challenging in some cases. Galectin-3 is a lectin with regulatory functions in apoptosis and inflammation. We aimed to test whether galectin-3 could be a biomarker for differentiating PFAPA syndrome from FMF. Patients with PFAPA syndrome, FMF, cryopyrin-associated periodic syndrome (CAPS), and streptococcal pharyngitis, and healthy controls were included in this study. Serum galectin-3 levels were measured using enzyme-linked immunosorbent assay. Eighty-seven patients (36 with PFAPA, 39 with FMF, 8 with CAPS, 4 with streptococcal pharyngitis), and 17 healthy controls were included. Blood samples were drawn during attacks from 20 PFAPA and 7 FMF patients and attack-free periods from 22 PFAPA, 35 FMF, and 8 CAPS patients. The median serum galectin-3 level in the PFAPA-attack group (1.025ng/ml) was significantly lower than the levels in healthy control (2.367ng/ml), streptococcal pharyngitis (3.021ng/ml), FMF attack (2.402ng/ml), and FMF-attack-free groups (2.797ng/ml) (p = 0.006, 0.03, 0.01, and < 0.001, respectively). PFAPA-attack-free group had lower galectin-3 levels than the FMF-attack-free group (1.794 vs. 2.797ng/ml, respectively; p = 0.01). Galectin-3 levels did not differ significantly between CAPS and attack-free PFAPA patients (1.439ng/ml vs. 1.794ng/ml, respectively; p = 0.63). In our study, for the first time, we defined galectin-3 as a promising biomarker that differs between PFAPA and FMF patients during both disease flares and attack-free periods. Further studies with high number of patients could validate its role as a biomarker.

The NLRP3 inhibitor MCC950 inhibits IL-1β production in PBMC from 19 patients with Cryopyrin-Associated Periodic Syndrome and in 2 patients with Schnitzler’s Syndrome

Background: The cryopyrin-associated periodic syndromes (CAPS) are a group of inherited disorders associated with systemic auto-inflammation. CAPS result from gain-of-function mutations in NLRP3, which result in formation of an intracellular protein complex known as the NLRP3 inflammasome. This leads to overproduction of IL-1β and other pro-inflammatory signals, resulting in inflammatory symptoms. Treatments for NLRP3-related diseases are biologic agents that directly target IL-1β. We sought to determine if the orally available small molecule NLRP3 inhibitor MCC950 could inhibit IL-1β ex vivo in a cohort of patients with autoinflammatory disease. Methods: Patients were recruited to donate blood, from which PBMCs were isolated and assayed in the presence of MCC950 to determine inhibitory efficacy. Results: We found that apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and mature IL-1β was higher in ex vivo PBMCs from CAPS patients than healthy donors. MCC950 inhibited production of mature IL-1β in PBMC from CAPS patients with a range of mutations and blocked NLRP3 activity in an in vitro mutation reconstitution assay. Similar results were observed with PBMC from two patients with Schnitzler’s Syndrome, another auto-inflammatory disease. Conclusions: The NLRP3 inflammasome inhibitor MCC950 blocked constitutive activation of NLRP3 observed in the PBMCs of CAPS patients. This study highlights the potential utility of NLRP3 inhibition by a small molecule for rare autoinflammatory diseases that are driven by NLRP3.

Autoinflammatory Eye Disease Due to NLRP3 Inflammasome-Associated Mutations and Excessive IL-1β Responses may be Driven by Ocular Exposure to Commensals

Abstract In previous studies we have shown that the healthy murine ocular surface is colonized by a commensal, Corynebacterium mastitidis, that elicits IL-17 from γδ T cells and promotes local host defense. Based on that, we hypothesized that ocular inflammation in patients with NLRP3-associated mutations, including those with Cryopyrin Associated Periodic Syndrome (CAPS), may be triggered by an overactive response to their own eye surface commensals. We found that, unlike wild type mice, mice with a CAPS mutant NLRP3 gene and increased IL-1β and IL-17 responses, develop conjunctival neutrophilia and ocular inflammation following ocular exposure to C. mast. Single cell transcriptomics confirmed that conjunctival γδ T cells were the major source of IL-17 and identified increased amounts of ccr2 and s100a8 mRNA, accounting for the neutrophil infiltration. In parallel studies of patients with inflammasome-associated mutations (NLRP3 or CARD8 mutations) we found that patient PBMCs cultured with C. mast produced increased amounts of IL-17A compared to healthy controls (C. mast. status of subjects: unknown). Patient immune cells (conjunctival and PBMC) showed upregulation of RORC, BATF and STAT3 as well as interferon-related genes (IRF1, STAT1). However, unlike in mice, IL-17-related genes appeared to be more upregulated in αβ than in γδ T cells, suggesting that in patients this response may be mediated by other cells, and/or that other commensals than in mice may be the stimulus. Thus, commensals can elicit an exaggerated immune response in humans and mice with NLRP3-related autoinflammatory disease. If indeed the conjunctivitis in CAPS patients reflects a response to their own commensals, adjunct antimicrobial therapy may be considered.

Magnetic resonance imaging findings in a patient with cryopyrin-associated periodic syndrome: A rare hereditary multi-system inflammatory disorder

Cryopyrin-associated periodic syndrome is a hereditary inflammatory disorder encompassing a wide spectrum of clinical phenotypes. This disorder has been associated with mutation of the NLRP3 gene coding for cryopyrin, which leads to overproduction of interleukin-1. The condition causes relapsing bouts of inflammation involving multiple organ systems, including the central nervous system, and, if untreated, can lead to long-term debilitating effects. A literature review revealed only a few brief descriptions of magnetic resonance imaging findings in cryopyrin-associated periodic syndrome patients. We describe serial magnetic resonance imaging findings in an 11-year-old female with clinically diagnosed cryopyrin-associated periodic syndrome who presented with intermittent headaches, progressive sensorineural hearing loss, fevers, and abdominal pain. The magnetic resonance imaging showed progressively worsening low T2 signal in the cochlea, cochlear enhancement, and leptomeningeal enhancement. We also describe some previously unreported findings in this syndrome, including cranial nerve and cauda equina enhancement.

Commensal microbiota as possible pathobiont in autoinflammatory disease

Abstract The ocular surface has an associated microbiome that contributes to maintenance of local immune homeostasis and protects the ocular surface from fungal and bacterial infections. However, in individuals with a dysregulated immune response, commensal flora could cause pathology. In this study, we seek to understand how an ocular commensal colonizing humans and mice, C. mastitidis (C. mast), stimulates immunity in the immunologically perturbed host. Cryopyrin Associated Periodic Syndrome (CAPS) patients suffer from systemic and ocular autoinflammatory disease caused by a hyperactive NLRP3 inflammasome. Knock-in mice bearing a mutated NLRP3 gene cloned from a CAPS patient responded to ocular colonization with C. mast by increased conjunctival neutrophilia, which progressed to overt ocular surface disease. Compared to wild type (WT) controls, their BM dendritic cells produced elevated IL-1 in response to C. mast. Additionally, gd T cells, which were primarily the Vg4 subset, isolated from eye-draining lymph nodes of C. mast-associated mutant mice were more activated and produced more IL-17, suggesting a qualitatively analogous but quantitatively amplified response compared to WT. Importantly, the same commensal elicited strongly elevated IL-17 production from leukocytes of inflammasome disease patients when compared with healthy controls. Our results suggest that C. mast induces an abnormal immune response in the NLRP3 mutant and acts as a pathobiont, in contrast to its behavior in the immunologically normal host. Based on these data, we hypothesize that the recurrent non-infectious conjunctivitis observed in CAPS patients may be driven by a hyperactive immune response to their own ocular surface bacteria.

CAPS and NLRP3.

Cryopyrin-associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disorder characterized by systemic, cutaneous, musculoskeletal, and central nervous system inflammation. Gain-of-function mutations in NLRP3 in CAPS patients lead to activation of the cryopyrin inflammasome, resulting in the inappropriate release of inflammatory cytokines including IL-1β and CAPS-related inflammatory symptoms. Several mechanisms have been identified that are important for the normal regulation of the cryopyrin inflammasome in order to prevent uncontrolled inflammation. Investigators have taken advantage of some of these pathways to develop and apply novel targeted therapies, which have resulted in improved quality of life for patients with this orphan disease.

Development and effect of antibodies to anakinra during treatment of severe CAPS: sub-analysis of a long-term safety and efficacy study

Anakinra is an effective, well-tolerated, long-term anti-inflammatory treatment for cryopyrin-associated periodic syndromes (CAPS), yet evidence shows that it can induce the development of anti-drug antibodies (ADA). This analysis aims to determine ADA occurrence in CAPS patients and elucidate their effects on anakinra dosing and drug efficacy. A post hoc analysis was performed on data from a long-term safety and efficacy study in patients with severe CAPS. Patients were initiated on an anakinra dose of 1.0–2.4 mg/kg once daily subcutaneously, which was increased (in 0.5–1.0 mg/kg increments) to 2.0–5.0 mg/kg/day according to clinical need (median 3.1 mg/kg/day). ADA, serum amyloid A (SAA), and C-reactive protein (CRP) levels were measured at various time points, and pharmacokinetic (PK) parameters at 1 and 3 months. Efficacy was evaluated using a diary symptom sum score (DSSS), and SAA and CRP levels were evaluated as proxies of efficacy. Safety was evaluated by an analysis of adverse events (AEs). Anakinra dose levels were unrelated to ADA status. A high proportion of patients with at least one post-baseline assessment developed ADA (83%), the majority (79%) within 3 months. However, anakinra treatment markedly improved symptoms and was effective regardless of the presence of ADA; the annual rates of AEs were comparable between ADA-negative and ADA-positive patients. While ADA are likely to occur in CAPS patients treated with anakinra, our evidence shows that chronic daily subcutaneous treatment with anakinra is safe and effective regardless of the development and presence of ADA.

Gene mutations and clinical phenotypes in 15 Chinese children with cryopyrin-associated periodic syndrome (CAPS).

The aim of our study is to explore the features of clinical manifestations and genetic mutations in Chinese CAPS patients. Fifteen confirmed patients with CAPS were enrolled. The onset time ranges from 2 days after birth to 6 years and 1 month. Recurrent urticaria rash (93.3%) with fever (100%) were two dominant characteristics of these patients that were presented as either acute or chronic process. Systemic involvements were found in all patients except for one with only rash and fever. The top three symptoms were fever (100%), rash (93.3%) and myalgia (76%). Other clinical manifestations include arthritis (11 cases), lung involvement (seven cases), optical dysfunction (seven cases), nerve deafness (six cases), nervous system involvement (five cases), hepatomegaly, splenomegaly and lymphadenectasis (five cases). Also, four patients had heart involvement and one patient suffered kidney involvement. The laboratory inflammation index such as leukocyte counts, platelet counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum amyloid A (SAA) and fibrinogen (FIB) increased significantly at initial stage, but decreased after therapy. As for gene mutation detection, Twelve out of 15 patients were confirmed with mutation in NLRP3, including 11 mutant site: c1789A<G, c.1703T<A, c.913G<A, c.1710G<C, c.1057G<T, c.2335C<T, c.932TvC, c.296G<C, c.663C<T, t.1702T<A, 299G<A. Mutation sites c.1703T<A, c.2335C<T, c.296G<C, c.663C<T, and 299G<A were newly identified. The association between gene mutation and clinical manifestation shows that D305N was highly associated with severe organs involvements, and therefore, the time of therapy and regimen were critical for the prognosis of disease. As the largest cohort study of Chinese CAPS patients, we confirmed that all patients presented typical clinical manifestations, identified five new mutation sites on NLRP3 and analyzed the correlation between the genotypes and phenotypes. We also raise concerns for one case with serious conditions that only had two nonsense mutations (c.663C<T and t.1702T<A) detected.

Confounding role of tumor necrosis factor in cryopyrin-associated periodic syndromes.

The NLRP3 inflammasome is a critical component of the innate immune system and can be activated in response to microbial and endogenous danger signals. Activation of the NLRP3 inflammasome results in caspase-1-dependent secretion of the proinflammatory cytokines IL-1β and IL-18. Gain-of-function missense mutations in NLRP3 result in a group of autoinflammatory diseases collectively known as the cryopyrin-associated periodic syndromes (CAPS). CAPS patients have traditionally been successfully treated with therapeutics targeting the IL-1 pathway; however, there are a number of identified CAPS patients who show only a partial response to IL-1 blockade. In this issue of the JCI, McGeough et al. demonstrated that TNF-α, in addition to IL-1β, plays an important role in promoting NLRP3 inflammasomopathies.

TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies.

The NLRP3 inflammasome is a protein complex responsible for caspase-1-dependent maturation of the proinflammatory cytokines IL-1β and IL-18. Gain-of-function missense mutations in NLRP3 cause the disease spectrum known as the cryopyrin-associated periodic syndromes (CAPS). In this study, we generated Nlrp3-knockin mice on various KO backgrounds including Il1b/Il18-, caspase-1-, caspase-11- (Casp1/11-), and Tnf-deficient strains. The Nlrp3L351P Il1b-/- Il18-/- mutant mice survived and grew normally until adulthood and, at 6 months of age, exhibited marked splenomegaly and leukophilia. Injection of these mice with low-dose LPS resulted in elevated serum TNF levels compared with Nlrp3L351P Casp1/11-/- mice and Il1b-/- Il18-/- littermates. Treatment of Nlrp3A350V mice with the TNF inhibitor etanercept resulted in all pups surviving to adulthood, with normal body and spleen/body weight ratios. Nlrp3A350V Tnf-/- mice showed a similar phenotypic rescue, with marked reductions in serum IL-1β and IL-18, reduced myeloid inflammatory infiltrate in the skin and spleen, and substantial decreases in splenic mRNA expression of both inflammasome components (Nlrp3, Pycard, pro-Casp1) and pro-cytokines (Il1b, Il18). Likewise, we observed a reduction in the expression of both pro-Casp1 and pro-Il1b in cultured Nlrp3A350V Tnf-/- BM-derived DCs. Our data show that TNF is an important transcriptional regulator of NLRP3 inflammasome components in murine inflammasomopathies. Moreover, these results may have therapeutic implications for CAPS patients with partial responses to IL-1-targeted therapies.

Late-Onset Cryopyrin-Associated Periodic Syndromes Caused by Somatic NLRP3 Mosaicism-UK Single Center Experience.

Cryopyrin-associated periodic syndrome (CAPS) is caused by gain-of-function NLRP3 mutations. Recently, somatic NLRP3 mosaicism has been reported in some CAPS patients who were previously classified as “mutation-negative.” We describe here the clinical and laboratory findings in eight British adult patients who presented with symptoms typical of CAPS other than an onset in mid-late adulthood. All patients underwent comprehensive clinical and laboratory investigations, including analysis of the NLRP3 gene using Sanger and amplicon-based deep sequencing (ADS) along with measurements of extracellular apoptosis-associated speck-like protein with CARD domain (ASC) aggregates. The clinical phenotype in all subjects was consistent with mid-spectrum CAPS, except a median age at disease onset of 50 years. Sanger sequencing of NLRP3 was non-diagnostic but ADS detected a somatic NLRP3 mutation in each case. In one patient, DNA isolated from blood demonstrated an increase in the mutant allele from 5 to 45% over 12 years. ASC aggregates in patients’ serum measured during active disease were significantly higher than healthy controls. This series represents 8% of CAPS patients diagnosed in a single center, suggesting that acquired NLRP3 mutations may not be an uncommon cause of the syndrome and should be sought in all patients with late-onset symptoms otherwise compatible with CAPS. Steadily worsening CAPS symptoms in one patient were associated with clonal expansion of the mutant allele predominantly affecting myeloid cells. Two patients developed AA amyloidosis, which previously has only been reported in CAPS in association with life-long germline NLRP3 mutations.

Efficacy and safety analysis of off-label treatment with biologics in autoinflammatory diseases : Experiences from aGerman registry(GRAID2)

To evaluate the safety and efficacy of therapy with biologics in patients with autoinflammatory diseases (AIF) or macrophage activating syndrome (MAS) in areal-life setting in Germany. The German Register of Autoimmune Diseases2 (GRAID2) is aretrospective, non-interventional, multicenter registry collecting data from all patients with inflammatory rheumatic diseases refractory to conventional therapy and treated with initial off-label biologics between August 2006 and December 2013. Patients with MAS could be included without prior treatment with abiologic agent. Data from 26patients with AIF and 5with MAS were collected. Of the AIF patients 13(50%) were diagnosed with adult onset Still's disease (AOSD), 6(23%) with familial Mediterranean fever (FMF), 4(15.4%) with tumor necrosis factor-associated periodic syndrome (TRAPS), 1(3.8%) patient with cryopyrin-associated periodic syndrome (CAPS) and 2(8%) with undifferentiated fever syndromes. The 5MAS patients suffered from rheumatoid arthritis (RA) with chronic myeloid leukemia, systemic lupus erythematosus and in 2cases AOSD. In 1patient achronic neurological disease was documented without further differentiaton. All patients with TRAPS were primarily treated with etanercept and all CAPS patients with canakinumab. The AOSD and FMF patients were treated with anakinra as the first line off-label biologic in 6 out of 13 and 5 out of 6cases, respectively. The MAS patients responded very well or well to therapy in 40% and 60% had amoderate response. There were no non-responders. Within the group of AIF patients the physicians documented avery effective or effective treatment in 38.5%, amoderate response in 30.8% and no response in 30.7%. The tolerance was very good in 5 out of 5of the MAS and in 92% of the AIF patients. The data of this retrospective register provide indications for an effective and safe treatment with off-label biologic medication in patients with AIF and MAS in daily practice.

Real-World Experience and Impact of Canakinumab in Cryopyrin-Associated Periodic Syndrome: Results From a French Observational Study.

The ENVOL study was designed to assess the psychosocial impact of disease and therapy in a French cohort of cryopyrin-associated periodic syndromes (CAPS) patients (and caregivers) treated with canakinumab. The ENVOL study was a multicenter, observational study of CAPS patients given ≥1 canakinumab dose. Data were collected before treatment, at 6 and 12 months afterward, and at the last visit. Patients and caregivers completed questionnaires assessing changes from the 12 months of pretreatment to 12 months prior to interview. Data were analyzed retrospectively. The study included 10 physicians and 68 patients (53 adults, 15 children). Sixty-five patients (95.6%) were still receiving canakinumab at the last visit (median 5 years after starting therapy). The mean ± SD score for patient-reported general health increased from 7 ± 2.9 before canakinumab to 2.7 ± 2.7 after treatment (P < 0.001). Physical and emotional symptoms resolved or improved in a substantial proportion of patients, including bodily pain (38 of 46 patients), fever (32 of 39), skin disease (35 of 41), fatigue (31 of 47), self-confidence (29 of 46), and energy (34 of 47). Social activity, relationships, sexuality, and energy measures improved in >40% of respondents. Caregivers spent a median of 3 versus 0.5 hours/week on care in the 12 months of pretreatment versus 12 months prior to interview (P < 0.001). Following treatment, patients required fewer consultations with general practitioners (mean ± SD per patient per year: 5.2 ± 7.4 versus 8.5 ± 7.2 pretreatment), internists/rheumatologists/dermatologists (2.0 ± 2.1 versus 3.7 ± 3.9), and pediatricians (1.8 ± 1.5 versus 4.4 ± 4.2). Long-term treatment with canakinumab achieves a highly relevant improvement in the physical, emotional, and social lives of patients with CAPS, accompanied by a marked reduction in support required from caregivers and in health care consultations.

Safety of vaccinations in patients with cryopyrin-associated periodic syndromes: a prospective registry based study.

Pneumococcal, tetanus and influenza vaccinations are recommended for patients with cryopyrin-associated periodic syndromes (CAPS) when treated with immunosuppressive medication. The aim of this publication is to report the safety of pneumococcal and other vaccinations in CAPS patients. All CAPS patients followed in the β-CONFIDENT (Clinical Outcomes and Safety Registry study of Ilaris patients) registry were analysed if they had received a vaccination. The β-CONFIDENT registry is a global, long-term, prospective, observational registry, capturing and monitoring patients treated with canakinumab. Sixty-eight CAPS patients had received a total of 159 vaccine injections, 107 injections against influenza, 19 pneumococcal vaccinations, 12 against tetanus/diphtheria antigens and 21 other vaccinations. Fourteen per cent of injections had elicited at least one vaccine reaction. All five vaccine-related serious adverse events were associated with pneumococcal vaccination. Vaccine reactions were observed in 70% of pneumococcal vaccinations, compared with 7% in influenza and 17% in tetanus/diphtheria vaccinations. The odds ratios to react to the pneumococcal vaccines compared with influenza and tetanus/diphtheria vaccines were 31.0 (95% CI: 8, 119) and 10.8 (95% CI: 2, 74). Vaccine reactions after pneumococcal vaccinations were more severe and lasted significantly longer (up to 3 weeks) compared with other vaccinations. In two patients, pneumococcal vaccination also elicited symptoms consistent with systemic inflammation due to CAPS reactivation. Pneumococcal vaccines, unlike other vaccines, frequently trigger severe local and systemic inflammation in CAPS patients. Clinicians must balance potential benefits of pneumococcal immunization against safety concerns. The 13-valent pneumococcal conjugate vaccine might be favourable over the polysaccharide vaccine in CAPS patients.