CAPS: Improving Our Understanding of a Rare Inflammatory Disease Caused by a Partial NLRP3 Gene Mutation

Summary by: Dr Yixiang Yves-Jean Zhu

First author: Bonet N.

Journal: Journal of Clinical Immunology

Reference: J Clin Immunol. 2025 Sep 30;45(1):134. doi: 10.1007/s10875-025-01922-x

Link to PubMed: https://pubmed.ncbi.nlm.nih.gov/41026232/

Introduction:

Cryopyrin-associated periodic syndrome (CAPS) is a rare monogenic autoinflammatory disease associated with gain‑of‑function variants in the NLRP3 gene. These variants lead to constitutive activation of the corresponding inflammasome and excessive production of IL‑1β. The classic manifestations combine a urticaria‑like rash, arthralgia, recurrent fever, neurologic involvement, and sensorineural hearing loss, in a context of biological inflammation (elevated CRP). Within the clinical spectrum of CAPS, Neonatal Onset Multisystem Inflammatory Disease (NOMID) stands out because of its particular severity. Current treatment relies on IL‑1β‑blocking agents, and specific *NLRP3* inflammasome inhibitors such as MCC950 are under investigation. Transmission is usually autosomal dominant, but some cases result from post‑zygotic mutations leading to mosaicism, a phenomenon that remains poorly documented. This retrospective Spanish study reports the largest cohort to date of CAPS patients with NLRP3 mosaicism, providing clinical, genetic, and functional analyses of 17 patients.

Main results:

-Clinical characteristics: Seventeen individuals (7 men, 10 women) were included. Four had a NOMID phenotype, 14 had a CAPS phenotype other than NOMID, and one individual was asymptomatic. The mean age at onset was 26 years (range 0.1–76 years), with two patient subgroups: an early‑onset group (< 5 years) including 6 patients, and a late‑onset group (> 45 years) including 6 patients. The most frequent manifestations were a urticaria‑like rash (100%), arthralgia (87%), recurrent fever (75%), arthritis (68%), and headache (56%).

- Response to treatment: All symptomatic patients received an IL‑1 inhibitor: anakinra (14 patients) or canakinumab (2 patients). A complete response with CRP normalization and clinical improvement was observed in 94% of patients. One case with partial response to anakinra was successfully controlled after switching to canakinumab.

- Genetic and functional data: Sixteen different NLRP3 variants were identified, all located in exon 4, with allele frequencies ranging from 1.3% to 34.8%. In vitro studies confirmed hyperactivation of the inflammasome, which was sensitive to the specific NLRP3 inhibitor MCC950, except for the D303H variant, which was partially resistant.

- Clonal evolution: Longitudinal follow‑up showed stable allele frequency in 54% of cases, an increase in 23% (mainly in patients older than 50 years, suggesting possible clonal hematopoiesis carrying the pathogenic NLRP3 variant, and a decrease in 23%, which may reflect “fatigue” of the mutant clone.

- Distribution of mosaicism: In 64% of patients, mosaicism involved at least myeloid and lymphoid cells, while 36% had mosaicism restricted to myeloid cells. No major clinical differences were observed between these mosaic patterns.

Practical message:

This largest‑to‑date study of mosaic CAPS shows that:

- The clinical picture and treatment response are comparable to those of germline CAPS, and functional studies reveal a similar activation profile.

- Mosaicism may remain stable or fluctuate over time, and the usefulness of monitoring allele frequency for follow‑up remains to be determined.

- Mosaicism may be restricted to myeloid cells, suggesting a later‑acquired variant, without apparent impact on clinical features.

A diagnosis of CAPS should not be ruled out in patients with a compatible phenotype solely on the basis of negative family history. Screening for NLRP3 mosaicism is essential in any adult with a suggestive CAPS presentation, as these patients also show an excellent response to IL‑1 inhibitors. Because mosaicism is more sensitively detected by high‑throughput sequencing, this technique should be preferred when CAPS is suspected, with sufficient read depth to identify low‑frequency allele mosaicism.