Entwicklung von evidenzbasierten europäischen Therapieempfehlungen für Cryopyrin-assoziierte periodische Syndrome, eine seltene monogenetische autoinflammatorische Erkrankung

Cryopyrin-assoziierte periodische Syndrome (CAPS) ist eine seltene monogenetische autoinflammatorische Erkrankung. Es handelt sich um ein Erkrankungsspektrum, welches folgende drei Phänotypen beinhaltet: die mildeste Form familiäre Kälteurtikaria (Familial Cold Autoinflammatory Syndrome, FCAS), das stärker beeinträchtigende Muckle-Wells-Syndrom (MWS) und die schwerste Ausprägung Chronic Infantile Neurologic, Cutaneous and Articular (CINCA) Syndrom, auch bekannt als Neonatal-Onset Multisystem Inflammatory Disease (NOMID), sowie die überlappenden Krankheitsbilder FCAS-MWS und MWS-CINCA. Zugrunde liegt eine Mutation des Gens „cold- induced autoinflammatory syndrome 1“ (CIAS1), welche zu einer unkontrollierten Produktion von Interleukin-1β führt. Klinisch kann sich die Erkrankung mit Fieber, Urtikaria-ähnlichem Ausschlag, Arthralgie, Konjunktivitis und Fatigue präsentieren. Bei schwerer beeinträchtigten Patienten können als krankheitsbedingte Organschäden sensorineuraler Hörverlust und Amyloidose auftreten. Die schwerste Form CINCA/NOMID ist zudem charakterisiert durch Knochendeformitäten sowie Manifestationen im zentralen Nervensystem, wie beispielsweise eine aseptische Meningitis. Zur Therapie stehen aktuell die drei Interleukin-1-Inhibitoren Anakinra, Canakinumab und Rilonacept zur Verfügung. Bisher gab es keine einheitlichen Therapiestandards oder Therapieempfehlungen für die CAPS-Erkrankung in Deutschland, der EU oder weltweit. Diese werden im klinischen Alltag dringend benötigt, da die Therapieentscheidungen zumeist auf den durch die Seltenheit der Erkrankung oft limitierten Erfahrungen des behandelnden Arztes basieren und somit innerhalb Deutschlands und Europas erheblich differieren. Daher ist das Ziel der vorliegenden Arbeit, zum ersten Mal überhaupt, evidenzbasierte europäische Therapieempfehlungen für die CAPS-Erkrankung zu entwickeln. Am 20.06.2013 wurde eine systematische Literaturrecherche in den medizinischen Datenbanken Pubmed, EMBASE und Cochrane Library durchgeführt, welche insgesamt 1698 Artikel identifizierte. Davon wurden 160 Publikationen in die Volltextrecherche eingeschlossen. Es ergaben sich 25 100 Zusammenfassung relevante Publikationen mit dem Schwerpunkt „Behandlung“ und 33 mit dem Schwerpunkt „Symptome und Komplikationen“ von CAPS. Mittels eigens erstellter Bögen wurden diese von zwei unabhängigen CAPS-Experten hinsichtlich Validität und Evidenzklasse bewertet. Mit dem Schwerpunkt „Symptome und Komplikationen“ ergaben sich 29 valide Artikel, diese bildeten die Grundlage für die Entstehung von Diagnose-Kriterien für CAPS, welche nicht als Teil der vorliegenden Arbeit realisiert wurden. Mit dem Schwerpunkt „Behandlung“ resultierten 17 valide Artikel; diese bildeten die Grundlage für den Entwurf der evidenzbasierten Therapieempfehlungen. Parallel hierzu wurde ein CAPS-Expertenteam aus 21 international führenden Experten für pädiatrische oder adulte Rheumatologie, Immunologie, Innere Medizin und Nephrologie gegründet. Die Erkenntnisse aus der Literatur wurden im Rahmen von Onlineumfragen sowie während des Konsensustreffens am 19.03.2014 in Genua mittels Nominal Group Technique mit dem im CAPS-Expertenteam vorhandenen Expertenwissen zusammengeführt. Die vorgeschlagenen Empfehlungen wurden diskutiert, überarbeitet und final darüber abgestimmt. Empfehlungen wurden angenommen, wenn mehr als 80 % der Experten ihre Zustimmung ausdrückten. Zusammenfassend wurden, basierend auf der bestverfügbaren Evidenz, 15 finale Therapieempfehlungen für die CAPS- Erkrankung entwickelt. Es wurden vier Empfehlungen in der Kategorie „übergeordnete Grundsätze für CAPS“, fünf in der Kategorie „Behandlung von CAPS“ und sechs in der Kategorie „Monitoring-Untersuchungen von CAPS“ formuliert. Die aus dieser Arbeit resultierenden evidenzbasierten europäischen Therapieempfehlungen für CAPS wurden in einem renommierten internationalen Fachjournal veröffentlicht und sollen zur Verbesserung und Vereinheitlichung der Behandlung von CAPS-Patienten innerhalb Deutschlands und Europas beitragen

Recommendations for the management of autoinflammatory diseases.

Autoinflammatory diseases are characterised by fever and systemic inflammation, with potentially serious complications. Owing to the rarity of these diseases, evidence-based guidelines are lacking. In 2012, the European project Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate regimens for the management of children and young adults with rheumatic diseases, facilitating the clinical practice of paediatricians and (paediatric) rheumatologists. One of the aims of SHARE was to provide evidence-based recommendations for the management of the autoinflammatory diseases cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). These recommendations were developed using the European League Against Rheumatism standard operating procedure. An expert committee of paediatric and adult rheumatologists was convened. Recommendations derived from the systematic literature review were evaluated by an online survey and subsequently discussed at a consensus meeting using Nominal Group Technique. Recommendations were accepted if more than 80% agreement was reached. In total, four overarching principles, 20 recommendations on therapy and 14 recommendations on monitoring were accepted with ≥ 80% agreement among the experts. Topics included (but were not limited to) validated disease activity scores, therapy and items to assess in monitoring of a patient. By developing these recommendations, we aim to optimise the management of patients with CAPS, TRAPS and MKD

Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS)

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

Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS)

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

Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS)

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= 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

Evidence Based Recommendations For Diagnosis And Treatment Of Cryopyrin-Associated Periodic Syndromes (Caps)

PubMe

Recommendations for the management of autoinflammatory diseases

: Autoinflammatory diseases are characterised by fever and systemic inflammation, with potentially serious complications. Owing to the rarity of these diseases, evidence-based guidelines are lacking. In 2012, the European project Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate regimens for the management of children and young adults with rheumatic diseases, facilitating the clinical practice of paediatricians and (paediatric) rheumatologists. One of the aims of SHARE was to provide evidence-based recommendations for the management of the autoinflammatory diseases cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). These recommendations were developed using the European League Against Rheumatism standard operating procedure. An expert committee of paediatric and adult rheumatologists was convened. Recommendations derived from the systematic literature review were evaluated by an online survey and subsequently discussed at a consensus meeting using Nominal Group Technique. Recommendations were accepted if more than 80% agreement was reached. In total, four overarching principles, 20 recommendations on therapy and 14 recommendations on monitoring were accepted with ≥80% agreement among the experts. Topics included (but were not limited to) validated disease activity scores, therapy and items to assess in monitoring of a patient. By developing these recommendations, we aim to optimise the management of patients with CAPS, TRAPS and MKD.status: publishe

Recommendations for the management of autoinflammatory diseases

Autoinflammatory diseases are characterised by fever and systemic inflammation, with potentially serious complications. Owing to the rarity of these diseases, evidence-based guidelines are lacking. In 2012, the European project Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate regimens for the management of children and young adults with rheumatic diseases, facilitating the clinical practice of paediatricians and (paediatric) rheumatologists. One of the aims of SHARE was to provide evidence-based recommendations for the management of the autoinflammatory diseases cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). These recommendations were developed using the European League Against Rheumatism standard operating procedure. An expert committee of paediatric and adult rheumatologists was convened. Recommendations derived from the systematic literature review were evaluated by an online survey and subsequently discussed at a consensus meeting using Nominal Group Technique. Recommendations were accepted if more than 80% agreement was reached. In total, four overarching principles, 20 recommendations on therapy and 14 recommendations on monitoring were accepted with >= 80% agreement among the experts. Topics included (but were not limited to) validated disease activity scores, therapy and items to assess in monitoring of a patient. By developing these recommendations, we aim to optimise the management of patients with CAPS, TRAPS and MKD