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Hal M Hoffman - One of the best experts on this subject based on the ideXlab platform.
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pediatric Recurrent Fever and autoinflammation from the perspective of an allergist immunologist
2020Co-Authors: Lori Broderick, Hal M HoffmanAbstract:Autoinflammatory diseases are monogenic and polygenic disorders due to dysregulation of the innate immune system. The inherited conditions have been clustered with primary immunodeficiencies in the latest practice parameters; however, these diseases have unique clinical presentations, genetics, and available therapies. Given the presentation of Fevers, rashes, and mucosal symptoms observed in many of these syndromes, patients are likely to present to an allergist/immunologist. Although there has been attention in the literature to diagnosis and treatment of rare, genetically defined autoinflammatory disorders, physicians are challenged by increasing numbers of patients with intermittent or periodic Fevers who face unnecessary morbidities due to a lack of a diagnosis. The broad differential of diseases presenting with Fever includes autoinflammatory syndromes, infections associated with immunodeficiency and/or allergies complicated by infection, and less commonly, autoimmune disorders or malignancy. To address this challenge, we review the history of the medical approach to Fever, current diagnostic paradigms, and controversies in management. We describe the spectrum of disorders referred to a Recurrent Fever disorders clinic established in an Allergy/Immunology division at a tertiary pediatric care center. Finally, we provide practical recommendations including historical features and initial laboratory investigations that can help clinicians appropriately manage these patients.
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canakinumab for the treatment of autoinflammatory Recurrent Fever syndromes
2018Co-Authors: Fabrizio De Benedetti, Marco Gattorno, Helen J Lachmann, I Konepaut, Jordi Anton, Eldad Benchetrit, Joost Frenkel, Hal M Hoffman, Seza OzenAbstract:BACKGROUND: Familial Mediterranean Fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by Recurrent Fever flares. METHODS: We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean Fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution of flare and no flare until week 16). In the subsequent phase up to week 40, patients who had a complete response underwent a second randomization to receive canakinumab or placebo every 8 weeks. Patients who underwent a second randomization and had a subsequent flare and all other patients received open-label canakinumab. RESULTS: At week 16, significantly more patients receiving canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with colchicine-resistant familial Mediterranean Fever (P<0.001), 35% versus 6% of those with mevalonate kinase deficiency (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006). The inclusion of patients whose dose was increased to 300 mg every 4 weeks yielded a complete response in 71% of those with colchicine-resistant familial Mediterranean Fever, 57% of those with mevalonate kinase deficiency, and 73% of those with TRAPS. After week 16, an extended dosing regimen (every 8 weeks) maintained disease control in 46% of patients with colchicine-resistant familial Mediterranean Fever, 23% of those with mevalonate kinase deficiency, and 53% of those with TRAPS. Among patients who received canakinumab, the most frequently reported adverse events were infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean Fever, those with mevalonate kinase deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years). CONCLUSIONS: In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean Fever, mevalonate kinase deficiency, and TRAPS. (Funded by Novartis; CLUSTER ClinicalTrials.gov number, NCT02059291 .).
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canakinumab for the treatment of autoinflammatory Recurrent Fever syndromes
2018Co-Authors: Fabrizio De Benedetti, Marco Gattorno, Helen J Lachmann, Koné-paut Isabelle, Jordi Anton, Joost Frenkel, Hal M Hoffman, Seza Ozen, Ben-chetrit Eldad, Anna SimonAbstract:Abstract Background Familial Mediterranean Fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor–associated periodic syn...
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pw03 009 genetics of pfapa syndrome
2013Co-Authors: Lori Broderick, Hal M Hoffman, Daniela Carvalho, Anthony E. Magit, Wen Jiang, Shelby C. Leuin, Marcella Bothwell, Donald B. Kearns, Seth M. PranskyAbstract:Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome is an autoinflammatory disorder of childhood and little is known about the underlying etiology. While mutations involving the IL-1 pathway have been identified in other Recurrent Fever disorders, including TNF-receptor associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndrome (CAPS), PFAPA syndrome is not traditionally considered to be a hereditary Fever disorder.
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Recurrent Fever syndromes in patients after recovery from kawasaki syndrome
2011Co-Authors: Lori Broderick, Adriana H Tremoulet, Jane C Burns, John F Bastian, Hal M HoffmanAbstract:The recurrence of Fever in a child with a history of Kawasaki syndrome (KS) poses a dilemma for clinicians who must consider the possibility of Recurrent KS. In this report we present the cases of 4 patients who presented with classical symptoms of KS, were successfully treated with intravenous immunoglobulin, and later experienced a reappearance of inflammatory symptoms in a pattern consistent with a Recurrent Fever syndrome. The association of these syndromes within the same patient suggests that some patients may have a genetic propensity toward altered immune responses and autoinflammatory syndromes. We propose that these 2 syndromes exist within a family of febrile disorders related to innate immune dysregulation.
Anna Simon - One of the best experts on this subject based on the ideXlab platform.
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canakinumab for the treatment of autoinflammatory Recurrent Fever syndromes
2018Co-Authors: Fabrizio De Benedetti, Marco Gattorno, Helen J Lachmann, Koné-paut Isabelle, Jordi Anton, Joost Frenkel, Hal M Hoffman, Seza Ozen, Ben-chetrit Eldad, Anna SimonAbstract:Abstract Background Familial Mediterranean Fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor–associated periodic syn...
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validation of the auto inflammatory diseases activity index aidai for hereditary Recurrent Fever syndromes
2014Co-Authors: M Piram, Helen J Lachmann, Anna Simon, Joost Frenkel, Seza Ozen, Isabelle Konepaut, Jasmin B Kuemmerledeschner, Silvia Stojanov, Martina FinettiAbstract:Objectives To validate the Auto-Inflammatory Diseases Activity Index (AIDAI) in the four major hereditary Recurrent Fever syndromes (HRFs): familial Mediterranean Fever (FMF), mevalonate kinase deficiency (MKD), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndromes (CAPS). Methods In 2010, an international collaboration established the content of a disease activity tool for HRFs. Patients completed a 1-month prospective diary with 12 yes/no items before a clinical appointment during which their physician assessed their disease activity by a questionnaire. Eight international experts in auto-inflammatory diseases evaluated the patient9s disease activity by a blinded web evaluation and a nominal group technique consensus conference, with their consensus judgement considered the gold standard. Sensitivity/specificity/accuracy measures and the ability of the score to discriminate active from inactive patients via the best cut-off score were calculated by a receiver operating characteristic analysis. Results Consensus was achieved for 98/106 (92%) cases (39 FMF, 35 CAPS, 14 TRAPS and 10 MKD), with 26 patients declared as having inactive disease and 72 as having active disease. The median total AIDAI score was 14 (range=0–175). An AIDAI cut-off score ≥9 discriminated active from inactive patients, with sensitivity/specificity/accuracy of 89%/92%/90%, respectively, and an area under the curve of 98% (95% CI 96% to 100%). Conclusions The AIDAI score is a valid and simple tool for assessing disease activity in FMF/MKD/TRAPS/CAPS. This tool is easy to use in clinical practice and has the potential to be used as the standard efficacy measure in future clinical trials.
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Mevalonate kinase deficiency: Evidence for a phenotypic continuum
2004Co-Authors: Anna Simon, Hubertus P. H. Kremer, Ron A. Wevers, Hans Scheffer, J.g.n. De Jong, J.w.m. Van Der Meer, J.p.h. DrenthAbstract:Both mevalonic aciduria, characterized by psychomotor retardation, cerebellar ataxia, Recurrent Fever attacks, and death in early childhood, and hyper-immunoglobulin D (hyper-IgD) syndrome, with Recurrent Fever attacks without neurologic symptoms, are caused by a functional deficiency of mevalonate kinase. In a systematic review of known mevalonate kinase-deficient patients, the authors identified five adults with phenotypic overlap between these two syndromes, which argues for a continuous spectrum of disease. Mevalonate kinase deficiency should be considered in adult patients with fitting neurologic symptoms, with or without periodic Fever attacks.
Marco Gattorno - One of the best experts on this subject based on the ideXlab platform.
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syndrome of undifferentiated Recurrent Fever surf an emerging group of autoinflammatory Recurrent Fevers
2021Co-Authors: Riccardo Papa, Roberta Caorsi, Federica Penco, Stefano Volpi, Diana Sutera, Marco GattornoAbstract:Syndrome of undifferentiated Recurrent Fever (SURF) is a heterogeneous group of autoinflammatory diseases (AID) characterized by self-limiting episodes of systemic inflammation without a confirmed molecular diagnosis, not fulfilling the criteria for periodic Fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome. In this review, we focused on the studies enrolling patients suspected of AID and genotyped them with next generation sequencing technologies in order to describe the clinical manifestations and treatment response of published cohorts of patients with SURF. We also propose a preliminary set of indications for the clinical suspicion of SURF that could help in everyday clinical practice.
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canakinumab for the treatment of autoinflammatory Recurrent Fever syndromes
2018Co-Authors: Fabrizio De Benedetti, Marco Gattorno, Helen J Lachmann, I Konepaut, Jordi Anton, Eldad Benchetrit, Joost Frenkel, Hal M Hoffman, Seza OzenAbstract:BACKGROUND: Familial Mediterranean Fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by Recurrent Fever flares. METHODS: We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean Fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution of flare and no flare until week 16). In the subsequent phase up to week 40, patients who had a complete response underwent a second randomization to receive canakinumab or placebo every 8 weeks. Patients who underwent a second randomization and had a subsequent flare and all other patients received open-label canakinumab. RESULTS: At week 16, significantly more patients receiving canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with colchicine-resistant familial Mediterranean Fever (P<0.001), 35% versus 6% of those with mevalonate kinase deficiency (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006). The inclusion of patients whose dose was increased to 300 mg every 4 weeks yielded a complete response in 71% of those with colchicine-resistant familial Mediterranean Fever, 57% of those with mevalonate kinase deficiency, and 73% of those with TRAPS. After week 16, an extended dosing regimen (every 8 weeks) maintained disease control in 46% of patients with colchicine-resistant familial Mediterranean Fever, 23% of those with mevalonate kinase deficiency, and 53% of those with TRAPS. Among patients who received canakinumab, the most frequently reported adverse events were infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean Fever, those with mevalonate kinase deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years). CONCLUSIONS: In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean Fever, mevalonate kinase deficiency, and TRAPS. (Funded by Novartis; CLUSTER ClinicalTrials.gov number, NCT02059291 .).
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canakinumab for the treatment of autoinflammatory Recurrent Fever syndromes
2018Co-Authors: Fabrizio De Benedetti, Marco Gattorno, Helen J Lachmann, Koné-paut Isabelle, Jordi Anton, Joost Frenkel, Hal M Hoffman, Seza Ozen, Ben-chetrit Eldad, Anna SimonAbstract:Abstract Background Familial Mediterranean Fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor–associated periodic syn...
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unexplained Recurrent Fever when is autoinflammation the explanation
2013Co-Authors: Tilmann Kallinich, Marco Gattorno, Clive Grattan, H D De Koning, Claudia Traidlhoffmann, Eugen Feist, Karoline Krause, Dan Lipsker, Alexander A Navarini, Marcus MaurerAbstract:Recurrent Fever can be the sole or leading manifestation of a variety of diseases including malignancies, autoimmune diseases and infections. Because the differential diagnoses are manifold, no formal guidelines for the approach of patients with Recurrent Fever exists. The newly recognized group of autoinflammatory diseases are often accompanied by repetitive Fever attacks. As these episodes are frequently associated by a variety of divergent presentations, the differentiation of other causes for febrile illnesses can be difficult. In this article, we first review disease entities, which frequently present with the symptom of Recurrent Fever. In a next step, we summarize their characteristic pattern of disease presentation. Finally, we analyse key features of autoinflammatory diseases, which are helpful to distinguish this group of diseases from the other causes of Recurrent Fever. Recognizing these symptom patterns can provide the crucial clues and, thus, lead to the initiation of targeted specific diagnostic tests and therapies.
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Mevalonate kinase deficiency (hyper IgD syndrome with periodic Fever)--different faces with separate treatments: two cases and review of the literature.
2012Co-Authors: Pinar Gencpinar, Marco Gattorno, Balahan Makay, Francesco Caroli, Erbil UnsalAbstract:The hyperimmunoglobulinemia D syndrome (HIDS), so-called mevalonate kinase deficiency, is caused by recessive mutations in the gene encoding mevalonate kinase enzyme. HIDS is characterized by Recurrent Fever attacks of 3-7 days that begin in infancy and recur every 4-6 weeks. The febrile period is accompanied by lymphadenopathy, arthralgia, abdominal pain, diarrhea, aphthous ulcers, and varying degree of skin involvement. The course and severity of the disease may be quite different. There is no effective or proven therapy for HIDS. We report two cases with HIDS, which had separate clinical findings and treatment strategies.
Helen J Lachmann - One of the best experts on this subject based on the ideXlab platform.
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op0254 canakinumab improves patient reported outcomes in patients with Recurrent Fever syndromes results from a phase 3 trial cluster
2019Co-Authors: Helen J Lachmann, Tilmann Kallinich, Bernard Lauwerys, Paivi Miettunen, Gerd Horneff, Riva Brik, Rafaelle Manna, Sara Murias, Sinisa Savic, Serge J SmeetsAbstract:Background Recurrent Fever syndromes have a significant impact on health-related quality of life (HRQoL).1 Canakinumab (CAN) has demonstrated efficacy and safety in patients with colchicine-resistant familial Mediterranean Fever (crFMF), hyper-immunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS) in the pivotal, Phase 3, CLUSTER trial (NCT02059291),2 but there are limited published data on the impact of CAN on the HRQoL, work/school and social life of these patients. Objectives To evaluate effect of CAN on HRQoL, work/school and social life of patients in the 3 disease cohorts (crFMF, HIDS/MKD, and TRAPS) in a double blinded randomised study. Methods The detailed study design was reported previously.2 The HRQoL of patients treated with CAN was assessed at Baseline (BL), Week 17 (Wk17) and Week 41 (Wk41) in patients who fully responded (absence of flares), either to 150 mg q4w CAN, or to 300 mg q4w CAN after up dosing. Methods used were the Child Health Questionnaire (CHQ)-PF50 physical (PhS) and psychosocial (PsS) summary scores (children >5– Results Patients showed a high impairment of HRQoL at baseline in all 3 cohorts (crFMF n=31, HIDS/MKD n=37 and TRAPS n=22). At Wk17, a moderate to large treatment effect, either with 150 mg or 300 mg q4w CAN, was observed by an improvement in the CHQ-PF50 PhS and PsS (increased >5), SF-12 PCS (increased >5) and SDS scores (decreased below 2). At Wk41, the number of patients on CAN was limited (crFMF n=9, HIDS/MKD n=6 and TRAPS n=4) due to the design of the trial (randomised withdrawal part). For the patients who remained on CAN, the improvement in HRQoL, work/school and social life was sustained. Conclusion Treatment with CAN led to sustained improvement of HRQoL, work/school and social life in patients with crFMF, HIDS/MKD and TRAPS. References [1] Sahin, et al. Eur Rev Med Pharmacol Sci. 2013;17:958–963. [2] De Benedetti, et al. NEJM 2018;378:1908–1990. Disclosure of Interests Helen J. Lachmann Grant/research support from: SOBI, Novartis, Consultant for: Novartis, Takeda, Speakers bureau: SOBI. Novartis, Bernard Lauwerys: None declared, Paivi Miettunen: None declared, Tilmann Kallinich Grant/research support from: Novartis, Speakers bureau: Sobi, Roche, Novartis, CLB, Gerd Horneff: None declared, Riva Brik: None declared, Rafaelle Manna: None declared, Sara Murias: None declared, Sinisa Savic Grant/research support from: Novartis and Sobi, Serge Smeets Employee of: Novartis, Fabrizio De Benedetti Grant/research support from: Abbvie, SOBI, Novimmune, Roche, Novartis, Sanofi, Pfizer, Anna Simon: None declared
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canakinumab for the treatment of autoinflammatory Recurrent Fever syndromes
2018Co-Authors: Fabrizio De Benedetti, Marco Gattorno, Helen J Lachmann, I Konepaut, Jordi Anton, Eldad Benchetrit, Joost Frenkel, Hal M Hoffman, Seza OzenAbstract:BACKGROUND: Familial Mediterranean Fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by Recurrent Fever flares. METHODS: We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean Fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution of flare and no flare until week 16). In the subsequent phase up to week 40, patients who had a complete response underwent a second randomization to receive canakinumab or placebo every 8 weeks. Patients who underwent a second randomization and had a subsequent flare and all other patients received open-label canakinumab. RESULTS: At week 16, significantly more patients receiving canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with colchicine-resistant familial Mediterranean Fever (P<0.001), 35% versus 6% of those with mevalonate kinase deficiency (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006). The inclusion of patients whose dose was increased to 300 mg every 4 weeks yielded a complete response in 71% of those with colchicine-resistant familial Mediterranean Fever, 57% of those with mevalonate kinase deficiency, and 73% of those with TRAPS. After week 16, an extended dosing regimen (every 8 weeks) maintained disease control in 46% of patients with colchicine-resistant familial Mediterranean Fever, 23% of those with mevalonate kinase deficiency, and 53% of those with TRAPS. Among patients who received canakinumab, the most frequently reported adverse events were infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean Fever, those with mevalonate kinase deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years). CONCLUSIONS: In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean Fever, mevalonate kinase deficiency, and TRAPS. (Funded by Novartis; CLUSTER ClinicalTrials.gov number, NCT02059291 .).
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canakinumab for the treatment of autoinflammatory Recurrent Fever syndromes
2018Co-Authors: Fabrizio De Benedetti, Marco Gattorno, Helen J Lachmann, Koné-paut Isabelle, Jordi Anton, Joost Frenkel, Hal M Hoffman, Seza Ozen, Ben-chetrit Eldad, Anna SimonAbstract:Abstract Background Familial Mediterranean Fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor–associated periodic syn...
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validation of the auto inflammatory diseases activity index aidai for hereditary Recurrent Fever syndromes
2014Co-Authors: M Piram, Helen J Lachmann, Anna Simon, Joost Frenkel, Seza Ozen, Isabelle Konepaut, Jasmin B Kuemmerledeschner, Silvia Stojanov, Martina FinettiAbstract:Objectives To validate the Auto-Inflammatory Diseases Activity Index (AIDAI) in the four major hereditary Recurrent Fever syndromes (HRFs): familial Mediterranean Fever (FMF), mevalonate kinase deficiency (MKD), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndromes (CAPS). Methods In 2010, an international collaboration established the content of a disease activity tool for HRFs. Patients completed a 1-month prospective diary with 12 yes/no items before a clinical appointment during which their physician assessed their disease activity by a questionnaire. Eight international experts in auto-inflammatory diseases evaluated the patient9s disease activity by a blinded web evaluation and a nominal group technique consensus conference, with their consensus judgement considered the gold standard. Sensitivity/specificity/accuracy measures and the ability of the score to discriminate active from inactive patients via the best cut-off score were calculated by a receiver operating characteristic analysis. Results Consensus was achieved for 98/106 (92%) cases (39 FMF, 35 CAPS, 14 TRAPS and 10 MKD), with 26 patients declared as having inactive disease and 72 as having active disease. The median total AIDAI score was 14 (range=0–175). An AIDAI cut-off score ≥9 discriminated active from inactive patients, with sensitivity/specificity/accuracy of 89%/92%/90%, respectively, and an area under the curve of 98% (95% CI 96% to 100%). Conclusions The AIDAI score is a valid and simple tool for assessing disease activity in FMF/MKD/TRAPS/CAPS. This tool is easy to use in clinical practice and has the potential to be used as the standard efficacy measure in future clinical trials.
Seza Ozen - One of the best experts on this subject based on the ideXlab platform.
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canakinumab for the treatment of autoinflammatory Recurrent Fever syndromes
2018Co-Authors: Fabrizio De Benedetti, Marco Gattorno, Helen J Lachmann, I Konepaut, Jordi Anton, Eldad Benchetrit, Joost Frenkel, Hal M Hoffman, Seza OzenAbstract:BACKGROUND: Familial Mediterranean Fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by Recurrent Fever flares. METHODS: We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean Fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution of flare and no flare until week 16). In the subsequent phase up to week 40, patients who had a complete response underwent a second randomization to receive canakinumab or placebo every 8 weeks. Patients who underwent a second randomization and had a subsequent flare and all other patients received open-label canakinumab. RESULTS: At week 16, significantly more patients receiving canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with colchicine-resistant familial Mediterranean Fever (P<0.001), 35% versus 6% of those with mevalonate kinase deficiency (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006). The inclusion of patients whose dose was increased to 300 mg every 4 weeks yielded a complete response in 71% of those with colchicine-resistant familial Mediterranean Fever, 57% of those with mevalonate kinase deficiency, and 73% of those with TRAPS. After week 16, an extended dosing regimen (every 8 weeks) maintained disease control in 46% of patients with colchicine-resistant familial Mediterranean Fever, 23% of those with mevalonate kinase deficiency, and 53% of those with TRAPS. Among patients who received canakinumab, the most frequently reported adverse events were infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean Fever, those with mevalonate kinase deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years). CONCLUSIONS: In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean Fever, mevalonate kinase deficiency, and TRAPS. (Funded by Novartis; CLUSTER ClinicalTrials.gov number, NCT02059291 .).
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canakinumab for the treatment of autoinflammatory Recurrent Fever syndromes
2018Co-Authors: Fabrizio De Benedetti, Marco Gattorno, Helen J Lachmann, Koné-paut Isabelle, Jordi Anton, Joost Frenkel, Hal M Hoffman, Seza Ozen, Ben-chetrit Eldad, Anna SimonAbstract:Abstract Background Familial Mediterranean Fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor–associated periodic syn...
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validation of the auto inflammatory diseases activity index aidai for hereditary Recurrent Fever syndromes
2014Co-Authors: M Piram, Helen J Lachmann, Anna Simon, Joost Frenkel, Seza Ozen, Isabelle Konepaut, Jasmin B Kuemmerledeschner, Silvia Stojanov, Martina FinettiAbstract:Objectives To validate the Auto-Inflammatory Diseases Activity Index (AIDAI) in the four major hereditary Recurrent Fever syndromes (HRFs): familial Mediterranean Fever (FMF), mevalonate kinase deficiency (MKD), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndromes (CAPS). Methods In 2010, an international collaboration established the content of a disease activity tool for HRFs. Patients completed a 1-month prospective diary with 12 yes/no items before a clinical appointment during which their physician assessed their disease activity by a questionnaire. Eight international experts in auto-inflammatory diseases evaluated the patient9s disease activity by a blinded web evaluation and a nominal group technique consensus conference, with their consensus judgement considered the gold standard. Sensitivity/specificity/accuracy measures and the ability of the score to discriminate active from inactive patients via the best cut-off score were calculated by a receiver operating characteristic analysis. Results Consensus was achieved for 98/106 (92%) cases (39 FMF, 35 CAPS, 14 TRAPS and 10 MKD), with 26 patients declared as having inactive disease and 72 as having active disease. The median total AIDAI score was 14 (range=0–175). An AIDAI cut-off score ≥9 discriminated active from inactive patients, with sensitivity/specificity/accuracy of 89%/92%/90%, respectively, and an area under the curve of 98% (95% CI 96% to 100%). Conclusions The AIDAI score is a valid and simple tool for assessing disease activity in FMF/MKD/TRAPS/CAPS. This tool is easy to use in clinical practice and has the potential to be used as the standard efficacy measure in future clinical trials.