Validation of the new classification criteria for hereditary recurrent fever in an independent cohort: experience from the JIR Cohort Database

Abstract

Objective The new classification criteria for the hereditary recurrent fever (HRF) syndrome [cryopyrin-associated periodic syndrome (CAPS), TNF-α receptor-associated periodic syndrome (TRAPS), FMF and mevalonate kinase deficiency] have been published recently. These criteria define two core sets of criteria for each HRF: mixed criteria, including genetic and clinical variables, and clinical criteria, relying on clinical variables only. Our aim was to validate the criteria for HRF in an independent cohort, the JIR Cohort database, an international repository of systemic inflammatory diseases. Methods We enrolled patients with HRF, periodic fever, adenitis, pharyngitis and aphthous stomatitis syndrome (PFAPA) and syndrome of undefined recurrent fever (SURF). A score ranging from zero to two was attributed to their respective genotypes: zero (no mutation), one (non-confirmatory genotype) or two (confirmatory genotype). The criteria were applied to all patients based on genotype scoring. The treating physician’s diagnosis served as the gold standard for the determination of specificity. Results We included 455 patients. The classification criteria showed excellent specificity for CAPS and TRAPS (98% specificity each), fair specificity for FMF (88%), but poor specificity for mevalonate kinase deficiency (58%). Sub-analysis showed excellent accuracy of the mixed criteria for all four HRFs. Misclassification was mainly attributable to clinical criteria sets, with false-positive patients in all four HRF clinical criteria sets. Conclusion This study represents the final validation step of the HRF classification criteria as recommended by the ACR. Genetic data appear to be necessary to classify patients with HRF correctly.

Contrasting role of NLRP12 in autoinflammation: evidence from a case report and mouse models

“…Recently, a new classification (including genetic data) of the these defects, also called hereditary recurrent fever syndromes, has been published. 2 Among these diseases, inflammasomopathies are the most common. 3 Inflammasomes are intracellular multiprotein complexes involved in sensing and responding to both extracellular and intracellular factors, leading to the maturation and release of bioactive interleukin (IL)-1β which is necessary for appropriate responses against various pathogens.…”

The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist

“…Overarching principle B outlines the need to initiate a clinical workup that assesses the extent of the inflammatory organ involvement and screens for treatment-related comorbidities, a process that often requires a multidisciplinary team of subspecialists 24 25 47. The third goal (overarching principle C) highlights the need for an accurate genetic diagnosis, which in many countries may be required to access the IL-1 blocking biological agents that prevent life-threatening complications,47 51 52 and facilitate access to supportive care 24 25 47…”

“…Suggestive clinical features should trigger a genetic investigation, as genetic testing is a crucial component of an accurate diagnosis of CAPS, TRAPS, MKD and DIRA 41 65. Next-generation sequencing (NGS) platforms are now widely used and are replacing the Sanger sequencing “gene by gene” approach 51 52 66–68. NGS is therefore generally recommended 52 63 66 69 70.…”

“…In CAPS, de novo mutations are most frequently found in patients with severe phenotypes 7. Somatic mutations in these patients may be undetected by standard coverage of NGS and may require deep sequencing, though this analysis may not be available to all providers 51 74–77. In contrast, MKD and DIRA are caused by recessive loss-of-function mutations in MVK 78 79 and IL1RN 2 genes, respectively.…”

The 2021 EULAR/American College of Rheumatology Points to Consider for Diagnosis, Management and Monitoring of the Interleukin‐1 Mediated Autoinflammatory Diseases: Cryopyrin‐Associated Periodic Syndromes, Tumour Necrosis Factor Receptor‐Associated Periodic Syndrome, Mevalonate Kinase Deficiency, and Deficiency of the Interleukin‐1 Receptor Antagonist

“…TRAPS, MKD and DIRA (41,65). Next-generation sequencing (NGS) platforms are now widely used and are replacing the Sanger sequencing "gene by gene" approach (51,52,(66)(67)(68). NGS is therefore generally recommended (52,63,66,69,70).…”