SAN FRANCISCO – Valid diagnostic criteria for cryopyrin-associated periodic syndromes are sorely needed, and a new model of CAPS diagnostic criteria enables rapid diagnosis of this rare, heterogeneous, inflammatory disease that can have devastating consequences if left undiagnosed and untreated.
“Our novel, unique approach integrated traditional methods of evidence synthesis with expert consensus, web-based decision tools, and innovative statistical methods. We hope this model can be of benefit in the diagnosis of other rare diseases,” said Dr. Jasmin B. Kümmerle-Deschner of the department of pediatrics at the University of Tübingen (Germany). She noted that the panel wanted to develop diagnostic criteria that could be used prior to genetic testing or in cases where no genetic mutation is identified.
Alice Goodman/Frontline Medical News
Dr. Jasmin B. Kümmerle-Deschner
Dr. Kümmerle-Deschner, who was on the multinational panel that developed the new diagnostic criteria, reviewed the process and presented the new criteria at the annual meeting of the American College of Rheumatology.
Cryopyrin-associated periodic syndromes (CAPS) comprise a rare, clinically heterogeneous group of devastating inflammatory diseases characterized by variable, severe system and organ inflammation resulting in permanent organ damage. The disease can manifest right after birth or later in life, and it can be associated with a mutation in the NLRP3 gene. Because the pathogenesis involves continually increased IL-1 secretion, early diagnosis and rapid initiation of IL-1 inhibition can control inflammation and prevent organ damage in children and adults with CAPS.
The lengthy process for developing the diagnostic criteria involved building an 18-member team of pediatric and adult subspecialists and experts in methods for rare disease. They generated 32 CAPS-typical items from a systematic literature review of 33 papers that described symptoms of CAPS and then reviewed the items in CAPS registries, weighting them via decision analysis software. Next, the panel refined these to 14 items plus the NLRP3 mutation. 1000Minds decision-making software ranked these 14 variables based on importance for the diagnosis of CAPS, with excellent correlation among experts.
Then a correspondence analysis determined variables consistently associated with the diagnosis of CAPS based on 284 cases and 873 controls; this process removed infrequently observed variables, such as “amyloidosis.” The remaining seven variables were found to be significantly associated with a diagnosis of CAPS (P less than .001 for all).
The final CAPS diagnosis model includes raised inflammatory markers (C-reactive protein/serum amyloid A) as a mandatory criterion, plus at least two of six different typical signs and symptoms of CAPS: urticaria-like rash, cold-stress triggered episodes, sensorineural hearing loss, musculoskeletal symptoms such as arthralgia, arthritis, and myalgia, chronic aseptic meningitis, and skeletal abnormalities such as epiphyseal overgrowth/frontal bossing. This model had a sensitivity of 81% and a specificity of 94%, performing well in all CAPS subtypes as well as in subgroups with or without evidence of germline NLRP3 mutations.
Dr. Kümmerle-Deschner opened her talk with a case description of an 81-year-old man who presented with a baffling disease. It turned out that his granddaughter was diagnosed with CAPS and 16 other family members were affected. She closed the talk by showing how this man could have been rapidly diagnosed by the new CAPS criteria. He presented with urticaria-like rash, arthralgia, arthritis, and cold-triggered episodes in the context of raised inflammatory markers.
“Early diagnosis enabling rapid treatment is possible,” she stated.
Dr. Kümmerle-Deschner disclosed financial ties with Novartis.