Treatment Of Cryopyrin-associated Periodic Syndromes Research Articles

Long-term safety and effectiveness of canakinumab in patients with monogenic autoinflammatory diseases: results from the interim analysis of the RELIANCE registry

ObjectiveInterim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS),...

Antisense Oligonucleotide Therapy Decreases IL-1β Expression and Prolongs Survival in Mutant Nlrp3 Mice.

Antisense oligonucleotides (ASOs) are a novel therapeutic strategy that targets a specific gene and suppresses its expression. The cryopyrin-associated periodic syndromes (CAPS) are a spectrum of autoinflammatory diseases characterized by systemic and tissue inflammation that is caused by heterozygous gain-of-function mutations in the nucleotide-binding and oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) gene. The aim of this study was to investigate the efficacy of an Nlrp3-specific ASO treatment in CAPS. An Nlrp3-specific ASO was designed and tested in murine cell lines and bone marrow-derived macrophages (BMDMs) from wild-type and CAPS mouse models. Nlrp3 knock-in mice were treated invivo with Nlrp3-specific ASO, survival was monitored, and expression of organ-specific Nlrp3 and IL-1β was measured. Nlrp3-specific ASO treatment of murine cell lines and BMDMs showed a significant downregulation of Nlrp3 and mature IL-1β protein expression. Ex vivo treatment of Nlrp3 mutant mouse-derived BMDMs with Nlrp3-specific ASO demonstrated significantly reduced IL-1β release. In vivo, Nlrp3-specific ASO treatment of Nlrp3 mutant mice prolonged survival, reduced systemic inflammation, and decreased tissue-specific expression of Nlrp3 and mature IL-1β protein. The results of this study demonstrate that Nlrp3-specific ASO treatment downregulates Nlrp3 expression and IL-1β release in CAPS models, suggesting ASO therapy as a potential treatment of CAPS and other NLRP3-mediated diseases.

Systematic literature review of efficacy/effectiveness and safety of current therapies for the treatment of cryopyrin-associated periodic syndrome, hyperimmunoglobulin D syndrome and tumour necrosis factor receptor-associated periodic syndrome

ObjectivesSeveral therapies are used for the treatment of rareautoinflammatory conditions like cryopyrin-associated periodic fever syndromes (CAPS), hyperimmunoglobulin Dsyndrome (HIDS)/mevalonate kinase deficiency (MKD) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS)....

MCC950/CRID3 potently targets the NACHT domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition.

The nucleotide-binding-domain (NBD)–and leucine-rich repeat (LRR)–containing (NLR) family, pyrin-domain–containing 3 (NLRP3) inflammasome drives pathological inflammation in a suite of autoimmune, metabolic, malignant, and neurodegenerative diseases. Additionally, NLRP3 gain-of-function point mutations cause systemic periodic fever syndromes that are collectively known as cryopyrin-associated periodic syndrome (CAPS). There is significant interest in the discovery and development of diarylsulfonylurea Cytokine Release Inhibitory Drugs (CRIDs) such as MCC950/CRID3, a potent and selective inhibitor of the NLRP3 inflammasome pathway, for the treatment of CAPS and other diseases. However, drug discovery efforts have been constrained by the lack of insight into the molecular target and mechanism by which these CRIDs inhibit the NLRP3 inflammasome pathway. Here, we show that the NAIP, CIITA, HET-E, and TP1 (NACHT) domain of NLRP3 is the molecular target of diarylsulfonylurea inhibitors. Interestingly, we find photoaffinity labeling (PAL) of the NACHT domain requires an intact (d)ATP-binding pocket and is substantially reduced for most CAPS-associated NLRP3 mutants. In concordance with this finding, MCC950/CRID3 failed to inhibit NLRP3-driven inflammatory pathology in two mouse models of CAPS. Moreover, it abolished circulating levels of interleukin (IL)-1β and IL-18 in lipopolysaccharide (LPS)-challenged wild-type mice but not in Nlrp3L351P knock-in mice and ex vivo-stimulated mutant macrophages. These results identify wild-type NLRP3 as the molecular target of MCC950/CRID3 and show that CAPS-related NLRP3 mutants escape efficient MCC950/CRID3 inhibition. Collectively, this work suggests that MCC950/CRID3-based therapies may effectively treat inflammation driven by wild-type NLRP3 but not CAPS-associated mutants.

A Clinical Study of Tranilast in the Treatment of Cryopyrin-Associated Periodic Syndrome (CAPS)

A Clinical Study of Tranilast in the Treatment of Cryopyrin-Associated Periodic Syndrome (CAPS)

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.

American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) 2015 Meeting Highlights: New Data on Canakinumab

Interleukin (IL)-1 is a messenger for the regulation of inflammatory responses, but it can be harmful when in excess, such as in the inflammation observed in patients with autoinflammatory disease. Cryopyrinassociated periodic syndromes (CAPS) are a group of rare autoinflammatory diseases with an estimated population frequency ranging from 1–3 people per million.>1 These hereditary cytokine dysregulation syndromes encompass a spectrum of three cryopyrinopathies, including familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and neonatal-onset multisystemic inflammatory disease. In such genotypes, the NLRP3 gene that encodes cryopyrin, an inflammation mediator involved in IL-1β processing, is mutated. Canakinumab (CAN) is a humanised monoclonal antibody, which is administered subcutaneously and acts as an IL-β inhibitor drug, with a long plasma half-life (21–28 days) and an activity in the picomolar range. In the USA, CAN is indicated for the treatment of CAPS, including FCAS and MWS in adults and children. CAN was subsequently approved in 2013 for the treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients aged ≥2.2-4 The European Medicines Agency (EMA) approved CAN for the management of CAPS, gouty arthritis (GA), and SJIA in October 2009.5 New data on CAN use in CAPS is still emerging and CAN is also currently being evaluated in the treatment of other autoinflammatory diseases, including SJIA, as well as hereditary periodic fever syndromes and a range of other conditions, such as GA.6-8 This article reviews the new preclinical and clinical evidence on CAN presented at the American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) meeting held in San Francisco, California, USA from 6th–11th November 2015.

Canakinumab for the treatment of cryopyrin-associated periodic syndromes.

Familial cold-induced autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease make up cryopyrin-associated periodic syndromes (CAPS). These are autoinflammatory inherited disorders caused by autosomal dominant gain-of-function mutations in the NLRP3 gene, located on chromosome 1q44. Cryopyrin/NALP3/NLRP3 is an essential component of intracellular inflammasomes that activate caspase-1, which in turn converts interleukin-1beta (IL-1beta) to its active form. IL-1beta is a potent cytokine that activates diverse elements of the immune and inflammatory systems leading to the pathogenic changes characteristic of CAPS. There is therefore much interest in the development of IL-1beta blocking agents as novel biologic treatments for these conditions. Canakinumab (ACZ-885; Ilaris, Novartis Pharma) is a fully humanized monoclonal antibody (mAb) specific for IL-1beta and is indicated for a wide range of inflammatory disorders including CAPS. This review will assess the utility of canakinumab as a treatment for CAPS.

Efficacy, safety, and post-vaccination antibody titer data in children with CAPS treated with Canakinumab

Background Canakinumab (CAN) is indicated for the treatment of cryopyrin-associated periodic syndrome (CAPS) in patients ≥2 years of age [1]. However, patients may require treatment in infancy where CAN has not yet been studied. IL-1 inhibition has not affected antibody production after vaccination in healthy volunteers [2], but no data in patients receiving standard childhood vaccines are available.

How to Diagnose and Manage Systemic Autoinflammatory Diseases in Childhood

Systemic autoinflammatory diseases (sAIDs) are severe disabling conditions associated with a significant morbidity and limited awareness. Cryopyrin-associated periodic syndrome (CAPS) and systemic juvenile idiopathic arthritis (sJIA) are two prototype sAIDs that present with chronic urticarial or maculo-papular rash in early childhood. A diagnosis of sAID relies on combined clinical symptoms, a positive family history, where applicable, and typical laboratory results. Treatment with anti-cytokine blockers targeting interleukin-1 (IL-1) or IL-6 is effective in reducing clinical symptoms and inflammatory markers and approved for the treatment of CAPS and/or sJIA. In order to prevent severe complications such as amyloidosis, destructive arthropathy or macrophage activation syndrome (MAS), it is important to diagnose patients early and to initiate anti-IL-1 blockade in symptomatic CAPS patients and anti-IL-1 or anti-IL-6 blockade in therapy-refractive sJIA patients without delay.

Canakinumab: new treatment choice for systemic juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and systemic juvenile idiopathic arthritis (sJIA) accounts for 6–15% of the patients. It was found that there was spontaneous expression of IL-1β in patients with sJIA. Canakinumab (ACZ885, Canakinumab) is a human anti-IL-1β monoclonal antibody. Its mode of action is based on the neutralization of IL-1β signaling which may result in the suppression of inflammation process in patients with disorders of autoinflammatory origin including sJIA. In addition to its use in the treatment of CAPS (cryopyrin-associated periodic syndromes) and acute gouty arthritis flares in many countries, the drug provides significant advantages over existing competitive therapies, including monthly SC administration and favorable safety profile.

The interleukin 1 inhibitor canakinumab in the treatment of cryopyrin-associated periodic syndromes (CAPS): clinical experience

Interleukin (IL) 1β is a major mediator of cryopyrin-associated periodic syndrome (CAPS). In this connection, the experience with IL-1 inhibitors used in patents with CAPS is being accumulated worldwide. Canakinumab was approved by FDA and EMEA in 2009 to treat CAPS and registered in the Russian Federation for this in 2011. The drug has been shown to be highly effective and well tolerated by patients with CAPS. Objective : to present Russia's experience in using the IL-1 inhibitor canakinumab in children with CAPS. Subjects and methods. The trial enrolled 6 CAPS patients, including 4 with Muckle-Wells Syndrome (MWS) and 4 with chronic infantile onset neurologic cutaneous articular/neonatal onset multisystem inflammatory disease (CINCA/NOMID), among whom there were 5 female patients aged 3.5 to 40 years and 1 male patient aged 17 years. Two patients (a 17-year-old daughter and her 40-year-old mother) were stated to have a familial MWS case. The duration of the disease was 3.5 to 33 years. All the patients underwent a molecular genetic analysis for mutations in the NLRP3 (CIAS1) gene. Four patients with MWS were found to have Thr436Ile and Thr438Ile mutations; the mother and her daughter had Thr350Met mutations; no mutations were detected in 2 patients with CINCA/NOMID. At the study, one female patient with MWS took gluco-corticoids (GC) in a dose of 0.1 mg/kg; the others received symptomatic therapy with nonsteroidal antiinflammatory drugs. Canakinumab was injected subcutaneously every 8 weeks in a dose of 4 mg/kg for patients with a body weight of <15 kg and in a dose of 2 mg/kg for those with a body weight of >15 kg. By now, 2 patients with MWS received 7 injections of the drug (a 48-week follow-up); 2 patients with CINCA/NOMID had its 6 injections (a 40-week follow-up) and 2 patients with MWS had 2 injections (a 10-week follow-up). Results . All the patients showed a significant clinical improvement: recovery; elimination of fever, rash, and eye symptoms; and a reduction in the levels of acute-phase markers. The effect retained throughout the follow-up. GC could be completely discontinued in the female patient with MWS. No adverse events were observed in any case. Conclusion . The experience in using canakinumab in the patients with CAPS showed the high efficacy and good tolerability of the drug. The decrease in acute-phase markers was slower in the patients with CINCA/NOMID, the most severe form of CAPS.

Evidence based recommendations for diagnosis and treatment of cryopyrin-associated periodic syndromes (CAPS)

Cryopyrin-associated periodic syndromes (CAPS) is a group of rare monogenetic autoinflammatory disorders. Evidence-based guidelines are lacking and management is mostly based on physician’s experience. Consequently, treatment regimens differ throughout Europe. In 2012, a European initiative called SHARE (Single Hub and Access point for pediatric Rheumatology in Europe) was launched to optimize and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases.

Canakinumab for the treatment of different refractory autoinflammatory disorders

Interleukin-1β (IL-1β) is a powerful pro-inflammatory cytokine synthesized in the inflammasome complex of immune cells in response to injury and infection. The excess activity of this cytokine plays a fundamental role in the pathogenesis of the autoinflammatory disorders. An emphasis on pediatric rheumatology is given to systemic-onset juvenile idiopathic arthritis (SoJIA) and periodic fever syndromes. Until the last decade, there wasnt an efficient alternative for the treatment of autoinflammatory syndromes refractory for convencional therapies. This scenery was modified with the introduction of biological agents, especially the IL-1 antagonist group (Anakinra, Rilonacept and Canakinumab). Canakinumab, a fully human anti-IL-1β monoclonal antibody, selectively binds to IL-1β, and intercepts the spread of inflammation. This medication was approved for treatment of cryopyrin-associated periodic syndrome (CAPS) in 2009, and SoJIA in 2013, and has shown to be an excellent tool for controlling these disorders.

An experience of use of canakinumab IL-1 inhibitor in children with cryopyrin-associated periodic syndromes (CAPS)

Interleukin-1β (IL-1β) is a basic mediator of cryopyrin-associated periodic syndromes (CAPS). In this respect an experience of the use of IL-1 inhibitors has been gained in patients with CAPS. Canakinumab was approved by FDA and EMEA in 2009 and registered in the Russian Federation in 2011 for treatment of CAPS. Canakinumab is shown to have high efficiency and good tolerability in patients with CAPS.

THU0394 Long-Term Therapy with Canakinumab in Two Patients with Refractory Chronic Autoinflammatory Arthritis

BackgroundCanakinumab, a human anti-IL-1β monoclonal antibody, has been licensed for the treatment of cryopyrin-associated periodic syndrome (CAPS), while few reports have shown benefit in patients with refractory familial Mediterranean fever...

A2: Rapid and Sustained Response in Patients Suffering From Severe Cryopyrin‐Associated Periodic Syndromes Treated With Anakinra (Kineret®)

Background/Purpose:Cryopyrin‐Associated Periodic Syndromes (CAPS) are a group of rare inherited autoinflammatory diseases consisting of a spectrum of three conditions: FCAS, Muckle‐Wells Syndrome and the most severe form, NOMID. Anakinra was recently approved in the US for treatment of NOMID and in the European Union for treatment of CAPS. The objective of the present analysis is to assess the response rate to anakinra treatment and time to changes in symptom severity after initiation, withdrawal and re‐institution of the treatment in patients with severe CAPS.Methods:A prospective, open‐label withdrawal design study of anakinra treatment with long‐term extension including 43 patients was conducted at the National Institutes of Health (Goldbach‐Mansky et al 2006, Sibley et al 2012). The primary efficacy endpoint, the Diary Symptom Sum Score (DSSS) collected daily up to 60 months included 5 symptoms (fever, rash, joint pain, vomiting, headache); each scored from 0 (no symptoms) to 4 (severe symptoms). Earlier data demonstrated that rash and conjunctivitis disappeared in 3 days in all patients, the DSSS was decreased at 3 months and all patients except one met the criteria of a flare during the 7‐day withdrawal phase (Goldbach‐Mansky et al 2006). In the present analysis, we defined the response as at least 50% improvement from baseline in the weekly average DSSS. The mean changes in DSSS were estimated with Mixed Model for Repeated Measures (MMRM).Results:Twenty nine out of the 43 enrolled patients provided valid DSSS data for the analysis. A majority of the patients were children (17% <2 years, 55% 2–11 years, 7% 12–17 years, 21% 18 years or more). All 29 patients responded to the treatment during the first 10 days based on DSSS. The average DSSS decreased from 4.5 to 0.8 in 2 days. This response was maintained throughout the study up to 60 months and at each post‐baseline visit >80% of the patients met the response criteria. Eleven consecutive patients participated in the withdrawal phase at 3 months of treatment. After treatment withdrawal the average DSSS increased from 0.6 to 5.2 (p<0.0001 compared to continuously treated patients). After re‐institution of treatment the DSSS returned to pre‐withdrawal levels within 3 days.Conclusion:All patients experienced a rapid response to the anakinra treatment, both initially and after a flare caused by the withdrawal phase. The response was maintained up to 60 months.

IL-1 Blockade in Autoinflammatory Syndromes

Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. Pathogenic variants in two interleukin-1 (IL-1)-regulating genes, NLRP3 and IL1RN, cause two severe and early-onset autoinflammatory syndromes, CAPS (cryopyrin associated periodic syndromes) and DIRA (deficiency of IL-1 receptor antagonist). The discovery of the mutations that cause CAPS and DIRA led to clinical and basic research that uncovered the key role of IL-1 in an extended spectrum of immune dysregulatory conditions. NLRP3 encodes cryopyrin, an intracellular "molecular sensor" that forms a multimolecular platform, the NLRP3 inflammasome, which links "danger recognition" to the activation of the proinflammatory cytokine IL-1β. The success and safety profile of drugs targeting IL -1 in the treatment of CAPS and DIRA have encouraged their wider use in other autoinflammatory syndromes including the classic hereditary periodic fever syndromes (familial Mediterranean fever, TNF receptor-associated periodic syndrome, and hyperimmunoglobulinemia D with periodic fever syndrome) and additional immune dysregulatory conditions that are not genetically well defined, including Still's, Behcet's, and Schnitzler diseases. The fact that the accumulation of metabolic substrates such as monosodium urate, ceramide, cholesterol, and glucose can trigger the NLRP3 inflammasome connects metabolic stress to IL-1β-mediated inflammation and provides a rationale for therapeutically targeting IL-1 in prevalent diseases such as gout, diabetes mellitus, and coronary artery disease.

THU0392 Beta-confident-registry: Efficacy and safety of canakinumab in cryopyrin associated periodic syndrome - 18 month follow-up

BackgroundCanakinumab (CAN, Ilaris®), a fully human anti-IL-1β monoclonal antibody, selectively inhibits IL-1β and has been approved for the treatment of cryopyrin-associated periodic syndrome (CAPS), an extremely rare inherited inflammatory disorder.ObjectivesThe...

OP0061 Kineret® (Anakinra) Controls Disease Symptoms in Patients with Severe Cryopyrin-Associated Periodic Syndromes (CAPS): Up to 5-Year Follow-Up Data

BackgroundIn severe forms of the rare monogenic autoinflammatory syndrome CAPS (NOMID, also denoted CINCA), persistent systemic and organ specific inflammation includes rash, central nervous system, and eye and cochlear inflammation...