Background/Purpose: Cryopyrin Associated Periodic Syndromes (CAPS) are a rare, clinically heterogeneous group of devastating inflammatory illnesses.  NLRP3gene gain-of function mutations result in unceasingly raised IL1 secretion and the clinically highly variable phenotype of severe systemic and organ inflammation. Early diagnosis is crucial, since rapid start of IL1 inhibition controls inflammation and prevents organ damage in children and adults with CAPS. The aim of the study was to develop and validate diagnostic criteria for CAPS.

Methods: An innovative, rigorous model development process was followed including a) interdisciplinary, international team building including pediatric and adult subspecialists plus methods experts for rare diseases, b) item generation: systematic literature review, item review of CAPS registries, CAPS expert survey and consensus conference for item refinement and agreement, c) item reduction and weighting using 1000minds decision analysis software. The resulting CAPS criteria were validated in a large cohort CAPS cases and true CAPS controls (autoinflammatory controls – FMF, sJIA, other and inflammatory controls – Schnitzler, Kawasaki, others) from clinical registries using correspondence analysis to identify items consistently associated with CAPS. Resulting variables were used to evaluate diagnostic models using sensitivity analyses. Subanalyses were performed for all CAPS subtypes and evidence of NLRP3 mutations.

Results: The CAPS team included 18 CAPS and methods experts. Systematic literature and CAPS registry review identified 32 CAPS-typical items; the consensus conference refined these to 11 items plus “NLRP3 mutation”. The 1000minds exercise ranked these 12 variables based on importance for the diagnosis CAPS, demonstrating excellent correlations between experts. Validation: Correspondence analysis determined variables consistently associated with the diagnosis of CAPS using 284 cases and 873 controls removing infrequently observed variables such as “amyloidosis”. The remaining seven variables were found to high significantly associated with the diagnosis CAPS (p<0.001 for all). Different modeling approaches were explored resulting in a “coupling model” as the best fit. The best CAPS diagnosis criteria model: “Raised inflammatory markers (CRP/SAA) plus ≥ two of six CAPS typical signs/symptoms including urticara-like rash, cold/stress triggered episodes, sensorineural hearing loss, musculoskeletal symptoms of arthralgia/arthritis/myalgia, chronic aseptic meningitis, skeletal abnormalities of epiphyseal overgrowth/frontal bossing” with a sensitivity of 81% and a specificity of 94%. It performed equally well for all CAPS subtypes and in subgroups with and without evidence of germline NLRP3 mutations. 

Conclusion: The CAPS diagnosis criteria model enables a rapid diagnosis and initiation of treatment for children and adults with CAPS, a rare, heterogeneous inflammatory disease. The novel approach integrated traditional methods of evidence synthesis with expert consensus, web-based decision tools and innovative statistical methods and may serve as a model for the diagnosis of other rare diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/development-and-validation-of-diagnostic-criteria-for-cryopyrin-associated-periodic-syndromes/