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Jasmin B Kuemmerledeschner - One of the best experts on this subject based on the ideXlab platform.
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rapid and sustained long term efficacy and safety of canakinumab in patients with cryopyrin associated Periodic Syndrome ages five years and younger
Arthritis & Rheumatism, 2019Co-Authors: Paul Brogan, Jasmin B Kuemmerledeschner, Isabelle Konepaut, Michael Hofer, Joachim Roesler, Tilmann Kallinich, G Horneff, Inmaculada Calvo Penades, Belen Sevillaperez, L GoffinAbstract:Objective To assess long-term efficacy and safety of canakinumab and the response to vaccination in children ages ≤5 years with Cryopyrin-Associated Periodic Syndrome (CAPS). Methods CAPS patients (ages ≤5 years) received 2 mg/kg canakinumab subcutaneously every 8 weeks; patients with neonatal-onset multisystem inflammatory disease (NOMID) received a starting dose of 4 mg/kg in this open-label trial. Efficacy was evaluated using physician global assessment of disease activity and serum levels of C-reactive protein (CRP) and amyloid A (SAA). Adverse events (AEs) were recorded. Vaccination response was evaluated using postvaccination antibody titers at 4 and 8 weeks after immunization. Results Of the 17 patients enrolled, 12 (71%) had Muckle-Wells Syndrome, 4 (24%) had NOMID, and 1 (6%) had familial cold autoinflammatory Syndrome. All 17 patients had a complete response to canakinumab. Disease activity improved according to the physician global assessment, and for 65% of the patients autoinflammatory disease was characterized as "absent" at the end of the study. Median CRP levels decreased over time. No such change was evident in SAA levels. During the extension study, postvaccination antibody titers increased above protective levels in 16 (94%) of 17 assessable vaccinations. Ten of the patients (59%) had AEs suspected to be related to canakinumab; 8 (47%) experienced at least 1 serious AE (SAE). None of the AEs or SAEs required interruption of canakinumab therapy. Conclusion Our findings indicate that canakinumab effectively maintains efficacy through 152 weeks and appears to have no effect on the ability to produce antibodies against standard childhood non-live vaccines. The safety profile of canakinumab was consistent with previous studies, supporting long-term use of canakinumab for CAPS in children ≤5 years of age.
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diagnostic criteria for cryopyrin associated Periodic Syndrome caps
Annals of the Rheumatic Diseases, 2017Co-Authors: Jasmin B Kuemmerledeschner, Helen J Lachmann, Norbert Blank, Isabelle Konepaut, Hal M. Hoffman, Seza Ozen, Pascal N. Tyrrell, Raphaela Goldbachmansky, Elisabeth Weissbarthriedel, Boris HügleAbstract:Cryopyrin-Associated Periodic Syndrome (CAPS) is a rare, heterogeneous disease entity associated with NLRP3 gene mutations and increased interleukin-1 (IL-1) secretion. Early diagnosis and rapid initiation of IL-1 inhibition prevent organ damage. The aim of the study was to develop and validate diagnostic criteria for CAPS. An innovative process was followed including interdisciplinary team building, item generation: review of CAPS registries, systematic literature review, expert surveys, consensus conferences for item refinement, item reduction and weighting using 1000Minds decision software. Resulting CAPS criteria were tested in large cohorts of CAPS cases and controls using correspondence analysis. Diagnostic models were explored using sensitivity analyses. The international team included 16 experts. Systematic literature and registry review identified 33 CAPS-typical items; the consensus conferences reduced these to 14. 1000Minds exercises ranked variables based on importance for the diagnosis. Correspondence analysis determined variables consistently associated with the diagnosis of CAPS using 284 cases and 837 controls. Seven variables were significantly associated with CAPS (p<0.001). The best diagnosis model included: Raised inflammatory markers (C-reactive protein/serum amyloid A) plus ≥two of six CAPS-typical symptoms: urticaria-like rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis and skeletal abnormalities. Sensitivity was 81%, specificity 94%. It performed well for all CAPS subtypes and regardless of NLRP3 mutation. The novel approach integrated traditional methods of evidence synthesis with expert consensus, web-based decision tools and innovative statistical methods and may serve as model for other rare diseases. These criteria will enable a rapid diagnosis for children and adults with CAPS.
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nlrp3 a439v mutation in a large family with cryopyrin associated Periodic Syndrome description of ophthalmologic symptoms in correlation with other organ symptoms
The Journal of Rheumatology, 2016Co-Authors: Bianka Sobolewska, Christoph Deuter, Jasmin B Kuemmerledeschner, Eva Angermair, Deshka Doycheva, Manfred ZierhutAbstract:Objective. 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. Methods. 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. Results. 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. Conclusion. 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.
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real life effectiveness of canakinumab in cryopyrin associated Periodic Syndrome
Rheumatology, 2016Co-Authors: Jasmin B Kuemmerledeschner, Norbert Blank, Tilmann Kallinich, Ferdinand Hofer, T Endres, Birgit Kortusgoetze, Elisabeth Weisbarthriedel, Catharina Schuetz, Karoline Krause, Christoph RietschelAbstract:OBJECTIVE 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. METHODS 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. RESULTS 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%). CONCLUSION 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.
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phenotypic and genotypic characteristics of cryopyrin associated Periodic Syndrome a series of 136 patients from the eurofever registry
Annals of the Rheumatic Diseases, 2015Co-Authors: Romain Levy, Helen J Lachmann, Jasmin B Kuemmerledeschner, Brigitte Badermeunier, Isabelle Konepaut, L Gerard, Luca Cantarini, P Woo, Aldo Naselli, Antonella InsalacoAbstract:Objective To evaluate genetic, demographic and clinical features in patients with Cryopyrin-Associated Periodic Syndrome (CAPS) from the Eurofever Registry, with a focus on genotype-phenotype correlations and predictive disease severity markers. Methods A web-based registry retrospectively collected data on patients with CAPS. Experts in the disease independently validated all cases. Patients carrying NLRP3 variants and germline-mutation-negative patients were included. Results 136 patients were analysed. The median age at disease onset was 9 months, and the median duration of follow-up was 15 years. Skin rash, musculoskeletal involvement and fever were the most prevalent features. Neurological involvement (including severe complications) was noted in 40% and 12% of the patients, respectively, with ophthalmological involvement in 71%, and neurosensory hearing loss in 42%. 133 patients carried a heterozygous, germline mutation, and 3 patients were mutation-negative (despite complete NLRP3 gene screening). Thirty-one different NLRP3 mutations were recorded; 7 accounted for 78% of the patients, whereas 24 rare variants were found in 27 cases. The latter were significantly associated with early disease onset, neurological complications (including severe complications) and severe musculoskeletal involvement. The T348M variant was associated with early disease onset, chronic course and hearing loss. Neurological involvement was less strongly associated with V198M, E311 K and A439 V alleles. Early onset was predictive of severe neurological complications and hearing loss. Conclusions Patients carrying rare NLRP3 variants are at risk of severe CAPS; onset before the age of 6 months is associated with more severe neurological involvement and hearing loss. These findings may have an impact on treatment decisions.
Toshio Heike - One of the best experts on this subject based on the ideXlab platform.
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live attenuated vaccines in a cryopyrin associated Periodic Syndrome patient receiving canakinumab treatment during infancy
Clinical Case Reports, 2017Co-Authors: Misa Watanabe, Ryuta Nishikomori, Toshio Heike, Yuki Fujimaki, Akira Ohara, Tsutomu SajiAbstract:Key Clinical Message We successfully immunized the neonatal-onset multisystem inflammatory disease (NOMID) patient with live-attenuated vaccines for measles, rubella, varicella, and mumps and achieved sufficient antibody titer under canakinumab therapy without complications.
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long term safety and efficacy of canakinumab in cryopyrin associated Periodic Syndrome results from an open label phase iii pivotal study in japanese patients
Clinical and Experimental Rheumatology, 2017Co-Authors: Shumpei Yokota, Ryuta Nishikomori, Toshio Heike, K Abrams, K Lheritier, Hidetoshi Takada, Tomoyuki Imagawa, Toshiro HaraAbstract:OBJECTIVES To assess the long-term safety and efficacy of canakinumab in Japanese patients with Cryopyrin-Associated Periodic Syndrome (CAPS). METHODS In this open-label phase 3 study, Japanese patients aged ≥2 years with CAPS received canakinumab 2-8 mg/kg subcutaneously every 8 weeks. The duration of the core treatment phase was 24 weeks followed by 22 months extension phase. The primary objective was the proportion of patients free of clinical and serologic relapse at week 24. RESULTS The study enrolled 19 Japanese patients (median age, 14 years; range, 2-48 years) with CAPS [MWS, 7 (36.8%); NOMID, 12 (63.2%)] for a median of 109 weeks. Fifteen patients (79%) achieved a complete response by day 15, 18 (94.7%) by week 24 and all by week 48. At the end of the study, 18 (95%) were free from relapse and 11 (57.9%) were assessed as having no disease activity by the PGA. Thirteen (68%) patients (MWS, 4; NOMID, 9) had their canakinumab dose increased during the trial. All patients experienced at least one adverse event (AE), the most common being infections (100%) and 5 (26.3%) reported serious AEs. No deaths were reported and the only patient who discontinued the study early withdrew consent. CONCLUSIONS Regular canakinumab treatment every 8 weeks at dose levels from 2-8 mg/kg, based on the clinical need, represents a successful strategy to induce rapid and complete response while maintain long-term disease control in Japanese patients with CAPS. The safety profile of canakinumab was consistent with that observed from previous studies.
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brief report late onset cryopyrin associated Periodic Syndrome due to myeloid restricted somatic nlrp3 mosaicism
Arthritis & Rheumatism, 2016Co-Authors: Anna Mensavilaro, María Teresa Bosque, Giuliana Magri, Yoshitaka Honda, Jordi Sintes, Helios Martinezbanaclocha, Marta Casorranberges, Eva Gonzalezroca, Estibaliz Ruizortiz, Toshio HeikeAbstract:Objective Gain-of-function NLRP3 mutations cause Cryopyrin-Associated Periodic Syndrome (CAPS), with gene mosaicism playing a relevant role in the pathogenesis. This study was undertaken to characterize the genetic cause underlying late-onset but otherwise typical CAPS. Methods We studied a 64-year-old patient who presented with recurrent episodes of urticaria-like rash, fever, conjunctivitis, and oligoarthritis at age 56 years. DNA was extracted from both unfractionated blood and isolated leukocyte and CD34+ subpopulations. Genetic studies were performed using both the Sanger method of DNA sequencing and next-generation sequencing (NGS) methods. In vitro and ex vivo analyses were performed to determine the consequences that the presence of the variant have in the normal structure or function of the protein of the detected variant. Results NGS analyses revealed the novel p.Gln636Glu NLRP3 variant in unfractionated blood, with an allele frequency (18.4%) compatible with gene mosaicism. Sanger sequence chromatograms revealed a small peak corresponding to the variant allele. Amplicon-based deep sequencing revealed somatic NLRP3 mosaicism restricted to myeloid cells (31.8% in monocytes, 24.6% in neutrophils, and 11.2% in circulating CD34+ common myeloid progenitor cells) and its complete absence in lymphoid cells. Functional analyses confirmed the gain-of-function behavior of the gene variant and hyperactivity of the NLRP3 inflammasome in the patient. Treatment with anakinra resulted in good control of the disease. Conclusion We identified the novel gain-of-function p.Gln636Glu NLRP3 mutation, which was detected as a somatic mutation restricted to myeloid cells, as the cause of late-onset but otherwise typical CAPS. Our results expand the diversity of CAPS toward milder phenotypes than previously reported, including those starting during adulthood.
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Late onset cryopyrin‐associated Periodic Syndrome due to myeloid‐restricted somatic NLRP3 mosaicism
Arthritis & rheumatology (Hoboken N.J.), 2016Co-Authors: Anna Mensa-vilaro, Eva González-roca, María Teresa Bosque, Giuliana Magri, Yoshitaka Honda, Helios Martínez-banaclocha, Marta Casorran-berges, Jordi Sintes, Estibaliz Ruiz-ortiz, Toshio HeikeAbstract:Objective Gain-of-function NLRP3 mutations cause Cryopyrin-Associated Periodic Syndrome (CAPS), with gene mosaicism playing a relevant role in the pathogenesis. This study was undertaken to characterize the genetic cause underlying late-onset but otherwise typical CAPS. Methods We studied a 64-year-old patient who presented with recurrent episodes of urticaria-like rash, fever, conjunctivitis, and oligoarthritis at age 56 years. DNA was extracted from both unfractionated blood and isolated leukocyte and CD34+ subpopulations. Genetic studies were performed using both the Sanger method of DNA sequencing and next-generation sequencing (NGS) methods. In vitro and ex vivo analyses were performed to determine the consequences that the presence of the variant have in the normal structure or function of the protein of the detected variant. Results NGS analyses revealed the novel p.Gln636Glu NLRP3 variant in unfractionated blood, with an allele frequency (18.4%) compatible with gene mosaicism. Sanger sequence chromatograms revealed a small peak corresponding to the variant allele. Amplicon-based deep sequencing revealed somatic NLRP3 mosaicism restricted to myeloid cells (31.8% in monocytes, 24.6% in neutrophils, and 11.2% in circulating CD34+ common myeloid progenitor cells) and its complete absence in lymphoid cells. Functional analyses confirmed the gain-of-function behavior of the gene variant and hyperactivity of the NLRP3 inflammasome in the patient. Treatment with anakinra resulted in good control of the disease. Conclusion We identified the novel gain-of-function p.Gln636Glu NLRP3 mutation, which was detected as a somatic mutation restricted to myeloid cells, as the cause of late-onset but otherwise typical CAPS. Our results expand the diversity of CAPS toward milder phenotypes than previously reported, including those starting during adulthood.
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successful resolution of stromal keratitis and uveitis using canakinumab in a patient with chronic infantile neurologic cutaneous and articular Syndrome a case study
Journal of Ophthalmic Inflammation and Infection, 2015Co-Authors: Masayuki Hirano, Ryuta Nishikomori, Toshio Heike, Jiro Seguchi, Masahiro Yamamura, Akiko Narita, Hirotaka Okanobu, Mio Hosokawa, Yuki Morizane, Fumio ShiragaAbstract:Background Cryopyrin-Associated Periodic Syndrome (CAPS) is a group of rare autoinflammatory diseases, and of these, chronic infantile neurologic, cutaneous, and articular/neonatal-onset multisystem inflammatory disease (CINCA/NOMID) Syndrome has the most severe phenotype. Canakinumab, a monoclonal antibody that targets interleukin-1β, has been shown to be an effective treatment for resolving systemic inflammation. However, its efficacy for treating ophthalmic symptoms of this disorder remains unclear.
Philip N. Hawkins - One of the best experts on this subject based on the ideXlab platform.
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Recognising and understanding Cryopyrin-Associated Periodic Syndrome in adults.
British Journal of Nursing, 2019Co-Authors: Rene Williams, Philip N. Hawkins, Thirusha LaneAbstract:Cryopyrin-Associated Periodic Syndrome (CAPS) is a group of rare hereditary autoinflammatory diseases characterised by recurrent flares of mild to severe systemic inflammation and fever. CAPS is th...
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Recognising and understanding Cryopyrin-Associated Periodic Syndrome in adults.
British journal of nursing (Mark Allen Publishing), 2019Co-Authors: Rene Williams, Philip N. Hawkins, Thirusha LaneAbstract:Cryopyrin-Associated Periodic Syndrome (CAPS) is a group of rare hereditary autoinflammatory diseases characterised by recurrent flares of mild to severe systemic inflammation and fever. CAPS is the umbrella term for a spectrum of individual conditions, namely familial cold autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic, cutaneous and articular (CINCA) Syndrome. The flare symptoms include fever, fatigue, rashes, headaches, arthralgia and myalgia that can last for a few hours or for several days. These symptoms are debilitating, contributing to poor quality of life for patients if left untreated. Serious life-changing complications such as hearing loss, blindness and AA amyloidosis resulting in kidney failure can occur. Until recently, treatment of the disease was symptomatic using non-steroidal anti-inflammatory and immunosuppressant drugs with limited success. In contrast, biological treatments targeting interleukin 1 (IL-1) have proved remarkably effective, often associated with complete and sustained disease remission, vastly improved quality of life and avoidance of serious long-term complications.
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retrospective case series describing the efficacy safety and cost effectiveness of a vial sharing programme for canakinumab treatment for paediatric patients with cryopyrin associated Periodic Syndrome
Pediatric Rheumatology, 2019Co-Authors: Abdulkadir A Elmi, Helen J Lachmann, Philip N. Hawkins, Karen Wynne, Iek Cheng, Despina Eleftheriou, Paul BroganAbstract:Cryopyrin-Associated Periodic Syndrome (CAPS) is a rare autoinflammatory disease, caused by gain of function mutation in NLRP3 resulting in excess production of interleukin-1 (IL-1). Canakinumab is a human monoclonal antibody against Interleukin-1 beta (IL-1β), licensed for the treatment of CAPS. The objective of the study was to describe the feasibility and cost-effectiveness of a canakinumab vial-sharing programme for paediatric patients with CAPS. Retrospective case series and clinical service description of a national specially commissioned CAPS clinic at Great Ormond Street Hospital (GOSH). Effectiveness was assessed using a CAPS disease activity score (DAS) and serum amyloid A protein (SAA). Adverse events were collected to determine safety. The number of canakinumab vials saved was considered when investigating the cost-effectiveness of vial-sharing. Nineteen/20 (95%) of our paediatric patients achieved minimally active clinical disease activity with canakinumab monotherapy; and 75% achieved both minimally active clinical disease and serological remission using a pre-specified definition based on the CAPS DAS and SAA level. Canakinumab was well tolerated, with only one child developing an infection requiring hospitalisation during the study. Canakinumab vial sharing resulted in 117 vials of canakinumab saved over a 24-month period, equating to a direct drug-related cost saving of £1,385,821, and a conservative estimated 5-year cost-saving of £3,464,552.50. We provide further evidence for the effectiveness and safety of canakinumab in children with CAPS, and highlight the cost-effectiveness of a vial-sharing programme for this high cost medicine. We suggest that this could have important implications for the delivery of other high cost medicines used in paediatric practice.
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sat0524 evaluation of long term safety and effectiveness of canakinumab therapy in patients with cryopyrin associated Periodic Syndrome results from beta confident registry
Annals of the Rheumatic Diseases, 2015Co-Authors: J Kuemmerledeschner, Philip N. Hawkins, Tom Van Der Poll, Ulrich A Walker, H Hoffman, A Speziale, Hugh H TilsonAbstract:Background Cryopyrin-Associated Periodic Syndrome (CAPS), a rare hereditary autoinflammatory disorder consists of three groups/phenotypes: familial cold auto-inflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS), and chronic infantile neurologic cutaneous and articular Syndrome/neonatal onset multisystem inflammatory disease (CINCA/NOMID).1 Here we evaluate the final interim data of canakinumab (CAN), a selective, human anti-IL-1β monoclonal antibody, use in CAPS patients in clinical practice from the multicentre, observational β–Confident Registry. Objectives The primary objective is to monitor and explore the overall safety of CAN with a focus on serious adverse events (SAEs) including serious infections, vertigo, malignancies and hypersensitivity reactions. The secondary objective is to measure efficacy using physician global assessments (PGA). Methods β–Confident Registry protocol does not mandate any visits or procedures, but records all observed and reported adverse events (AEs) and serious AE (SAEs) or AEs potentially related to treatment with CAN. Cumulative safety data are reported as incidence rate (number of events) per 100 patient-years (IR/100 pyr) from the date of first patient enrollment (19 November 2009) until the current data cut-off date (31 December, 2014). Additional safety data will be updated, as available, at the time of the presentation. Results 288 patients (FCAS, n=40; MWS, n=167; NOMID, n=33; others, n=37) were enrolled with a mean ± SD duration of 193±72 weeks in the registry. Of these, 21 (7.3%) patients discontinued CAN: 5 each due to AE, poor efficacy, and patient preference; and 6 due to unknown reasons. The IR/100 pyr of overall AEs was 100.0. Patients with FCAS, the least severe phenotype, had the lowest AE IR/100 pyr (60.9) as compared with patients with MWS (IR/100 pyr 107.2) and NOMID (IR/100 pyr 120.3), the more severe phenotypes. The most common types of AEs were infections and infestations with an IR/100 pyr of 36.7. Vertigo was reported by 19 patients (IR/100 pyr 3.7). A total of 117 SAEs was reported by 62 patients resulting in an IR/100 pyr of 15.0 SAEs. The most common type of SAE was infection (IR/100 pyr 4.1). One death in a 76 yr old MWS patient with metastatic rectal adenocarcinoma was reported. Of 18 patients that received pneumococcal vaccination (PPV), 13 reported a local post-PPV injection site reaction; of which 4 were considered as serious. Based on PGA, nearly half the patients had no disease activity while most others had mild/moderate disease activity, at the current data cut-off. Similarly, disease activity was mostly absent in NLRP3 mutation negative CAPS patients (n=14) treated with CAN. There was no evidence of loss of effect with time. Conclusions Long-term safety and effectiveness observed with the use of canakinumab in CAPS registry is consistent with that observed in the clinical trial program. Canakinumab therapy is also effective in NLRP3 mutation negative CAPS patients. References 1. Kuemmerle-Deschner JB, et al. Arthritis Res Ther. 2011;13(1):R34. Disclosure of Interest J. Kuemmerle-Deschner Grant/research support from: Novartis, Consultant for: Novartis, H. Hoffman Consultant for: Novartis, Speakers bureau: Novartis, P. Hawkins: None declared, T. van der Poll: None declared, U. Walker Consultant for: Novartis, A. Speziale Employee of: Novartis, H. Tilson Consultant for: Novartis
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op0114 interim safety and efficacy results of patients with cryopyrin associated Periodic Syndrome participating in the β confident registry
Annals of the Rheumatic Diseases, 2014Co-Authors: J Kuemmerledeschner, Philip N. Hawkins, K Abrams, Hugh H Tilson, Tom Van Der Poll, Ulrich A Walker, Hal M. HoffmanAbstract:Background Cryopyrin-Associated Periodic Syndrome (CAPS) is a continuum of rare hereditary disorders that includes three phenotypes, in the order of severity: familial cold auto-inflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS), and chronic infantile neurologic cutaneous and articular Syndrome/neonatal onset multisystem inflammatory disease (CINCA/NOMID).1 Here we present the current safety data of canakinumab (CAN) use in CAPS patients (pts) in clinical practice from the on-going observational β-Confident Registry, involving 40 sites in 13 countries in EU region and US. Objectives To monitor and explore the overall safety of CAN with a focus on serious adverse events (SAEs), including serious infections, vertigo, malignancies and hypersensitivity reactions. The secondary objective is to measure efficacy using physician9s global assessments (PGA). Methods β–Confident Registry protocol does not mandate any visits or procedures, but records all observed and reported adverse events (AEs) and SAEs or AEs potentially related to treatment with CAN. Cumulative safety data are reported as incidence rate (number of events) per 100 patient-years (IR/100 pyr) from the date of first pt enrollment (19 November 2009) until the current data cut-off date (31 December 2013). Additional safety data will be updated, as available, at the time of the conference. Results 270 pts were enrolled with a mean duration of 154 weeks (2-233 weeks) in the registry. In total 4 (1.5%) pts discontinued CAN due to an AE and 5 (1.9%) due to poor efficacy. The most common types of AEs (IR >2/100 pyr) are reported in the table below. Pts with FCAS, the least severe phenotype, had the lowest AE incidence rate (44/100 pyr) as compared with pts with MWS (112/100 pyr) and NOMID (140/100 pyr), the more severe phenotypes. No hypersensitivity to CAN was reported as AEs. A total of 71 SAEs were reported by 42 pts (13.2 SAEs/100 pyr). The most common type of SAE was infection (3.2/100 pyr). One death in 76 yr MWS pt with metastatic rectal adenocarcinoma was reported. Of 8 (2.9%) pts that received pneumococcal vaccination (PPV), 7 reported a local post-PPV injection site reaction, 3 of which were considered serious. At the end of current data cut-off, based on PGA assessment, nearly half the pts had no disease activity while most others had mild/moderate disease activity. There was no evidence of loss of effect with time. Conclusions The safety profile observed in the canakinumab CAPS registry is consistent with that observed in the clinical trial program. Response rates were as expected based on clinical trial experience with no evidence of loss of efficacy. References Farasat S et al. Arch Dermatol. 2008;144:392-402 Disclosure of Interest J. Kuemmerle-Deschner Grant/research support: Novartis, Consultant for: Novartis, H. Tilson Consultant for: Novartis on the Beta-Confident Registry (Chair) and 2 other Registry projects, P. Hawkins: None declared, T. van der Poll: None declared, U. Walker Consultant for: Novartis, K. Abrams Shareholder of: Novartis, Employee of: Novartis, H. Hoffman Consultant for: Novartis. Also on an international registry committee for Novartis DOI 10.1136/annrheumdis-2014-eular.3512
Isabelle Konepaut - One of the best experts on this subject based on the ideXlab platform.
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rapid and sustained long term efficacy and safety of canakinumab in patients with cryopyrin associated Periodic Syndrome ages five years and younger
Arthritis & Rheumatism, 2019Co-Authors: Paul Brogan, Jasmin B Kuemmerledeschner, Isabelle Konepaut, Michael Hofer, Joachim Roesler, Tilmann Kallinich, G Horneff, Inmaculada Calvo Penades, Belen Sevillaperez, L GoffinAbstract:Objective To assess long-term efficacy and safety of canakinumab and the response to vaccination in children ages ≤5 years with Cryopyrin-Associated Periodic Syndrome (CAPS). Methods CAPS patients (ages ≤5 years) received 2 mg/kg canakinumab subcutaneously every 8 weeks; patients with neonatal-onset multisystem inflammatory disease (NOMID) received a starting dose of 4 mg/kg in this open-label trial. Efficacy was evaluated using physician global assessment of disease activity and serum levels of C-reactive protein (CRP) and amyloid A (SAA). Adverse events (AEs) were recorded. Vaccination response was evaluated using postvaccination antibody titers at 4 and 8 weeks after immunization. Results Of the 17 patients enrolled, 12 (71%) had Muckle-Wells Syndrome, 4 (24%) had NOMID, and 1 (6%) had familial cold autoinflammatory Syndrome. All 17 patients had a complete response to canakinumab. Disease activity improved according to the physician global assessment, and for 65% of the patients autoinflammatory disease was characterized as "absent" at the end of the study. Median CRP levels decreased over time. No such change was evident in SAA levels. During the extension study, postvaccination antibody titers increased above protective levels in 16 (94%) of 17 assessable vaccinations. Ten of the patients (59%) had AEs suspected to be related to canakinumab; 8 (47%) experienced at least 1 serious AE (SAE). None of the AEs or SAEs required interruption of canakinumab therapy. Conclusion Our findings indicate that canakinumab effectively maintains efficacy through 152 weeks and appears to have no effect on the ability to produce antibodies against standard childhood non-live vaccines. The safety profile of canakinumab was consistent with previous studies, supporting long-term use of canakinumab for CAPS in children ≤5 years of age.
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real world experience and impact of canakinumab in cryopyrin associated Periodic Syndrome results from a french observational study
Arthritis Care and Research, 2017Co-Authors: Isabelle Konepaut, Pierre Quartier, O. Fain, G. Grateau, P. Pillet, F. Bonnet, V. Despert, Le P Blay, K Stankovicstojanovic, L. WilleminAbstract:Objective 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. Methods 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. Results 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 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). Conclusion 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.
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diagnostic criteria for cryopyrin associated Periodic Syndrome caps
Annals of the Rheumatic Diseases, 2017Co-Authors: Jasmin B Kuemmerledeschner, Helen J Lachmann, Norbert Blank, Isabelle Konepaut, Hal M. Hoffman, Seza Ozen, Pascal N. Tyrrell, Raphaela Goldbachmansky, Elisabeth Weissbarthriedel, Boris HügleAbstract:Cryopyrin-Associated Periodic Syndrome (CAPS) is a rare, heterogeneous disease entity associated with NLRP3 gene mutations and increased interleukin-1 (IL-1) secretion. Early diagnosis and rapid initiation of IL-1 inhibition prevent organ damage. The aim of the study was to develop and validate diagnostic criteria for CAPS. An innovative process was followed including interdisciplinary team building, item generation: review of CAPS registries, systematic literature review, expert surveys, consensus conferences for item refinement, item reduction and weighting using 1000Minds decision software. Resulting CAPS criteria were tested in large cohorts of CAPS cases and controls using correspondence analysis. Diagnostic models were explored using sensitivity analyses. The international team included 16 experts. Systematic literature and registry review identified 33 CAPS-typical items; the consensus conferences reduced these to 14. 1000Minds exercises ranked variables based on importance for the diagnosis. Correspondence analysis determined variables consistently associated with the diagnosis of CAPS using 284 cases and 837 controls. Seven variables were significantly associated with CAPS (p<0.001). The best diagnosis model included: Raised inflammatory markers (C-reactive protein/serum amyloid A) plus ≥two of six CAPS-typical symptoms: urticaria-like rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis and skeletal abnormalities. Sensitivity was 81%, specificity 94%. It performed well for all CAPS subtypes and regardless of NLRP3 mutation. The novel approach integrated traditional methods of evidence synthesis with expert consensus, web-based decision tools and innovative statistical methods and may serve as model for other rare diseases. These criteria will enable a rapid diagnosis for children and adults with CAPS.
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phenotypic and genotypic characteristics of cryopyrin associated Periodic Syndrome a series of 136 patients from the eurofever registry
Annals of the Rheumatic Diseases, 2015Co-Authors: Romain Levy, Helen J Lachmann, Jasmin B Kuemmerledeschner, Brigitte Badermeunier, Isabelle Konepaut, L Gerard, Luca Cantarini, P Woo, Aldo Naselli, Antonella InsalacoAbstract:Objective To evaluate genetic, demographic and clinical features in patients with Cryopyrin-Associated Periodic Syndrome (CAPS) from the Eurofever Registry, with a focus on genotype-phenotype correlations and predictive disease severity markers. Methods A web-based registry retrospectively collected data on patients with CAPS. Experts in the disease independently validated all cases. Patients carrying NLRP3 variants and germline-mutation-negative patients were included. Results 136 patients were analysed. The median age at disease onset was 9 months, and the median duration of follow-up was 15 years. Skin rash, musculoskeletal involvement and fever were the most prevalent features. Neurological involvement (including severe complications) was noted in 40% and 12% of the patients, respectively, with ophthalmological involvement in 71%, and neurosensory hearing loss in 42%. 133 patients carried a heterozygous, germline mutation, and 3 patients were mutation-negative (despite complete NLRP3 gene screening). Thirty-one different NLRP3 mutations were recorded; 7 accounted for 78% of the patients, whereas 24 rare variants were found in 27 cases. The latter were significantly associated with early disease onset, neurological complications (including severe complications) and severe musculoskeletal involvement. The T348M variant was associated with early disease onset, chronic course and hearing loss. Neurological involvement was less strongly associated with V198M, E311 K and A439 V alleles. Early onset was predictive of severe neurological complications and hearing loss. Conclusions Patients carrying rare NLRP3 variants are at risk of severe CAPS; onset before the age of 6 months is associated with more severe neurological involvement and hearing loss. These findings may have an impact on treatment decisions.
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longterm followup of quality of life in patients with cryopyrin associated Periodic Syndrome treated with canakinumab an anti interleukin 1β monoclonal antibody
The Journal of Rheumatology, 2014Co-Authors: Celine Marsaud, Isabelle Marie, Isabelle KonepautAbstract:To the Editor: Cryopyrin-Associated Periodic Syndrome (CAPS) is an inherited autoinflammatory disorder that comprises a clinical spectrum of 3 distinct phenotypes increasing in severity: familial cold autoinflammatory Syndrome, Muckle-Wells Syndrome (MWS), and chronic infantile neurological cutaneous and articular Syndrome (CINCA). Urticarial rash, fever, arthralgia, and intense fatigue are the main clinical signs1. CINCA is the most severe form, with mental and physical disability. Some patients are difficult to classify because they present intermediate phenotypes. The effect of CAPS on quality of life is significant in all phenotypes, with limitation in ability to work (78%) and in participation in outdoor activities (95%)2. The NOD-like receptor 3 (NLPR3) gene mutation is responsible for overproduction of interleukin 1β (IL-1β)3. Three IL-1 inhibitors have shown efficacy in CAPS: anakinra, rilonacept, and canakinumab4. The approval of canakinumab by the US Food and Drug Administration was based on a 48-week, double-blinded study showing rapid and sustained remission of symptoms under treatment5. Our objective with this monocentric longitudinal study was to evaluate quality of life and socioprofessional effects of … Address correspondence to Dr. C. Marsaud, Department of Pediatrics and Pediatric Rheumatology, Bicetre University Hospital, Paris XI University, 78 rue du General Leclerc, 94270 Le Kremlin Bicetre, Paris, France. E-mail: celine.marsaud{at}bct.aphp.fr
Ryuta Nishikomori - One of the best experts on this subject based on the ideXlab platform.
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Necrotizing Funisitis As an Intrauterine Manifestation of Cryopyrin-Associated Periodic Syndrome: A Case Report and Review of The Literature
2020Co-Authors: Kyoko Yokoi, Yoshitaka Honda, Sachiko Minamiguchi, Mizuho Kobayashi, Satoru Kobayashi, Ryuta NishikomoriAbstract:Abstract Background: Cryopyrin-Associated Periodic Syndrome (CAPS) is a life-long, autoinflammatory disease associated with a gain-of-function mutation in the nucleotide-binding domain, leucine-rich repeat family, pyrin domain containing 3 (NLRP3) gene, which result in uncontrolled production of IL-1β and chronic inflammation. Chronic infantile neurologic cutaneous and articular (CINCA) Syndrome/neonatal-Onset multisystem inflammatory disease (NOMID) is the most severe form of CAPS. Although the first symptoms may be presented at birth, there are few reports on the involvement of the placenta and umbilical cord in the disease. Therefore, we present herein a preterm case of CINCA/NOMID Syndrome and confirms intrauterine-onset inflammation with conclusive evidence by using fetal and placental histopathological examination. Case presentation: The female patient was born at 33weeks of gestation by emergency caesarean section and weighted at 1,514 g. The most common manifestations of CINCA/NOMID Syndrome including recurrent fever, urticarial rash, and ventriculomegaly due to aseptic meningitis were presented. She also exhibited atypical symptoms such as severe hepatosplenomegaly with cholestasis. The genetic analysis of NLRP3 revealed a heterozygous c.1698C>A (p.Phe566Leu) mutation, and she was diagnosed with CINCA/NOMID Syndrome. Further, a histopathological examination revealed necrotizing funisitis, mainly inflammation of the umbilical artery, along with focal neutrophilic and lymphocytic villitis. Conclusion: The necrotizing funisitis, which only involved the artery, was an unusual observation for chorioamnionitis. These evidences suggest that foetal inflammation, probably due to overproduction of IL-1β, caused tissue damage in utero, and the first symptom of a newborn with CINCA/NOMID.
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a rare case of cryopyrin associated Periodic Syndrome in an elderly woman with nlrp3 and mefv mutations
Internal Medicine, 2019Co-Authors: Seiko Nakamichi, Ryuta Nishikomori, Tomoki Origuchi, Shoichi Fukui, Aya Yoda, Hiroshi Matsubara, Yuki Nagaura, Kiyoshi Migita, Noriho Sakamoto, Atsushi KawakamiAbstract:We herein report a case of a 75-year-old woman who presented with a low-grade fever, repeated cold-induced urticaria, and painful leg edemas with neutrocytosis. Because her mother also had cold-induced urticaria and her skin lesions histologically showed neutrophilic dermatitis, we suspected that she had familial cold autoinflammatory Syndrome, a subtype of Cryopyrin-Associated Periodic Syndromes. Sequencing of the NLRP3 and MEFV genes revealed that she carried both the p.A439V missense mutation and p.E148Q homozygous mutation, which is commonly detected in familial Mediterranean fever patients. The administration of colchicine reduced the frequency and severity of her skin rash and leg edema.
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live attenuated vaccines in a cryopyrin associated Periodic Syndrome patient receiving canakinumab treatment during infancy
Clinical Case Reports, 2017Co-Authors: Misa Watanabe, Ryuta Nishikomori, Toshio Heike, Yuki Fujimaki, Akira Ohara, Tsutomu SajiAbstract:Key Clinical Message We successfully immunized the neonatal-onset multisystem inflammatory disease (NOMID) patient with live-attenuated vaccines for measles, rubella, varicella, and mumps and achieved sufficient antibody titer under canakinumab therapy without complications.
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long term safety and efficacy of canakinumab in cryopyrin associated Periodic Syndrome results from an open label phase iii pivotal study in japanese patients
Clinical and Experimental Rheumatology, 2017Co-Authors: Shumpei Yokota, Ryuta Nishikomori, Toshio Heike, K Abrams, K Lheritier, Hidetoshi Takada, Tomoyuki Imagawa, Toshiro HaraAbstract:OBJECTIVES To assess the long-term safety and efficacy of canakinumab in Japanese patients with Cryopyrin-Associated Periodic Syndrome (CAPS). METHODS In this open-label phase 3 study, Japanese patients aged ≥2 years with CAPS received canakinumab 2-8 mg/kg subcutaneously every 8 weeks. The duration of the core treatment phase was 24 weeks followed by 22 months extension phase. The primary objective was the proportion of patients free of clinical and serologic relapse at week 24. RESULTS The study enrolled 19 Japanese patients (median age, 14 years; range, 2-48 years) with CAPS [MWS, 7 (36.8%); NOMID, 12 (63.2%)] for a median of 109 weeks. Fifteen patients (79%) achieved a complete response by day 15, 18 (94.7%) by week 24 and all by week 48. At the end of the study, 18 (95%) were free from relapse and 11 (57.9%) were assessed as having no disease activity by the PGA. Thirteen (68%) patients (MWS, 4; NOMID, 9) had their canakinumab dose increased during the trial. All patients experienced at least one adverse event (AE), the most common being infections (100%) and 5 (26.3%) reported serious AEs. No deaths were reported and the only patient who discontinued the study early withdrew consent. CONCLUSIONS Regular canakinumab treatment every 8 weeks at dose levels from 2-8 mg/kg, based on the clinical need, represents a successful strategy to induce rapid and complete response while maintain long-term disease control in Japanese patients with CAPS. The safety profile of canakinumab was consistent with that observed from previous studies.
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successful resolution of stromal keratitis and uveitis using canakinumab in a patient with chronic infantile neurologic cutaneous and articular Syndrome a case study
Journal of Ophthalmic Inflammation and Infection, 2015Co-Authors: Masayuki Hirano, Ryuta Nishikomori, Toshio Heike, Jiro Seguchi, Masahiro Yamamura, Akiko Narita, Hirotaka Okanobu, Mio Hosokawa, Yuki Morizane, Fumio ShiragaAbstract:Background Cryopyrin-Associated Periodic Syndrome (CAPS) is a group of rare autoinflammatory diseases, and of these, chronic infantile neurologic, cutaneous, and articular/neonatal-onset multisystem inflammatory disease (CINCA/NOMID) Syndrome has the most severe phenotype. Canakinumab, a monoclonal antibody that targets interleukin-1β, has been shown to be an effective treatment for resolving systemic inflammation. However, its efficacy for treating ophthalmic symptoms of this disorder remains unclear.