2025: A Year Rich in Autoinflammation, FMF, and VEXAS

In 2025, together with the team of the CEREMAIA Reference Center (Tenon Hospital, AP-HP / Sorbonne University), within the FAI2R network and the European Reference Network ERN RITA, we carried out extensive work focused on:

Familial Mediterranean Fever (FMF) and pyrin-associated diseases,

VEXAS syndrome, a prototype of hemato-inflammatory diseases,

AA amyloidosis and other rarer autoinflammatory diseases.

🔬 FMF and pyrin

We contributed to the update of the international EULAR/PReS recommendations for FMF, which incorporate recent advances regarding colchicine resistance and the use of biologic therapies (published in Annals of the Rheumatic Diseases, 2025).

Several studies based on the adult cohort of our reference center explored the following aspects: iron deficiency, liver involvement, FMF onset after the age of 65, the optimal daily dose of colchicine, and patients’ and prescribers’ perceptions of colchicine treatment.

We also conducted biological and genetic research on variants of the MEFV gene and pyrin-associated diseases, as well as on the role of IL-18 as a monitoring biomarker and as a specific signature of diseases involving the pyrin inflammasome.

🧬 VEXAS syndrome

In collaboration with the French VEXAS group and the MINHEMON club:

international reviews and recommendations were developed to structure the diagnosis and management of VEXAS syndrome, including a consensual definition of “flares,” infectious risks, and therapeutic strategies;

studies focused on specific organ involvement (kidney, nervous system, erythroblastopenia), as well as a multicenter study on VEXAS in women and across different ethnic backgrounds.

🧩 AA amyloidosis and other rare autoinflammatory diseases

We participated in a systematic review on AA amyloidosis in inflammatory rheumatic diseases, highlighting the importance of long-term strict control of inflammation.

We authored literature reviews on autoinflammatory actinopathies, A20 haploinsufficiency, and undifferentiated autoinflammatory diseases.

We also published work on diagnostic delay and the clinical presentation of cryopyrin-associated periodic syndromes (CAPS) in adulthood.

🧠 Therapeutic patient education programs

We continued the deployment of our three therapeutic education programs dedicated to AA amyloidosis, cryopyrinopathies (CAPS), and FMF. These programs aim to help patients and their relatives better understand the disease, treatments, monitoring, and warning signs.

In 2025, we notably led a session dedicated to CAPS during the weekend organized in July by the Muckle-Wells / CINCA association, in close collaboration with patient associations.

🎥 Patient webinars and online information

We launched a series of informational webinars for patients and their relatives on FMF, as well as educational videos on rare autoinflammatory diseases (AA amyloidosis, VEXAS syndrome, etc.), freely available on the CEREMAIA Tenon YouTube channel: CEREMAIA Tenon – Patient Webinars. These formats allow us to translate research findings and recommendations into practical messages for patients’ daily lives.

• All of this work shares a common goal:

• to better characterize these rare diseases,

• to refine diagnostic and monitoring strategies,

and ultimately, to provide more personalized and safer care for patients.

We warmly thank the patients, healthcare teams, colleagues from rare disease networks, and international partners for their commitment.

For those who would like to access specific articles in more detail, please feel free to contact us via private message or by email at:

ceremaia-medecine-int.tenon@aphp.fr

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.

Diagnosis traps for patients with acquired NLRP3 mutation (CAPS)

First author: M. DELPLANQUE et al,

Journal: European Journal of Internal Medicine

Reference: https://doi.org/10.1016/j.ejim.2024.01.028

Summary:

The article highlights the diagnostic challenges of cryopyrin-associated periodic syndromes CAPS, caused by NLRP3 gene mutations. These autoinflammatory diseases include three main forms: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and Chronic Infantile Neurological Cutaneous and Articular (CINCA) syndrome.

The study presents two cases of patients with acquired somatic NLRP3 mutations, illustrating the difficulty of diagnosis due to atypical phenotypes:

• Patient 1 (P1): A 46-year-old woman with neuroinflammatory symptoms (persistent headaches, aseptic meningitis, hearing loss), initially misdiagnosed. A somatic M406I mutation was identified after 10 years of diagnostic wandering, explaining her atypical presentation. Treatment with anti-IL-1 drastically improved her condition.

• Patient 2 (P2): A male patient with severe CINCA syndrome since infancy, presenting with urticaria, arthritis, and growth delay. His genetic diagnosis was challenging, and the M406V mutation was only detected at the age of 15 using deep sequencing techniques.

The authors emphasize that somatic mutations in the NACHT domain of NLRP3 lead to constitutive activation of the inflammasome, resulting in excessive IL-1β production and severe chronic inflammation. The study underscores the importance of advanced genetic sequencing to detect these mutations, particularly in atypical cases.

Conclusion

Identifying somatic mutations in NLRP3 is crucial to avoid misdiagnosis and ensure effective treatment. Diagnostic delays can be prolonged in the absence of classic clinical signs (such as urticaria), and next-generation sequencing is essential for detecting low-percentage mosaicism.

Nouvelles mutations CAPS.

Download • 2.84MB