Familial Mediterranean Fever (FMF) and psoriatic arthritis: a higher risk than expected

Article title: Increased risk of psoriatic arthritis in patients with familial Mediterranean fever: a population-based cohort study.

First author: Amir Haddad

Journal: Rheumatology (Oxford)

Link to the article: https://doi.org/10.1093/rheumatology/keaf607

Author of the abstract: Dr Rim Bourguiba

Summary

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is associated with mutations in the MEFV gene and characterized by excessive activation of the interleukin-1 (IL-1)β pathway. Psoriatic arthritis (PsA) is a chronic inflammatory disease belonging to the spectrum of spondyloarthritis, whose pathophysiology notably involves the IL-23/IL-17 pathways and Th17 lymphocytes. Data concerning the association between FMF and PsA have remained limited until now.

This retrospective population-based cohort study was conducted using the database of the main Israeli health insurance organization (Clalit Health Services), covering approximately 4.9 million individuals, between 2010 and 2023. The authors identified 9,736 adults with FMF treated with colchicine, with no history of PsA, matched by age and sex to 97,360 non-FMF controls. Participants were followed until the occurrence of PsA, death, or the end of the study period.

The incidence of PsA was significantly higher in FMF patients than in controls (3.26 vs 0.9 per 1,000 person-years). After adjustment for demographic factors and comorbidities, FMF was associated with a more than three-fold increased risk of developing PsA (HR 3.52; 95% CI 2.48–5.0). Other factors independently associated with PsA in FMF patients were age, smoking, and high socioeconomic status. The presence of psoriasis was, as expected, the major predictive factor.

The clinical characteristics and therapeutic strategies of PsA were overall similar in patients with or without FMF, with the exception of more frequent use of targeted synthetic DMARDs in FMF-PsA patients.

These results suggest an increased susceptibility to PsA in FMF patients, possibly related to common immunopathological mechanisms involving IL-1β and Th17 activation. They highlight the need for increased clinical vigilance regarding inflammatory joint manifestations in FMF patients.

In practice, this work encourages active screening for symptoms suggestive of psoriatic arthritis (persistent joint pain, enthesitis, dactylitis) in patients with FMF, particularly in cases of psoriasis or associated risk factors.

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.

Anakinra treatment in colchicine-resistant or colchicine-intolerant Familial Mediterranean Fever: real-world experience

Summary by Dr Catherine Grandpeix-Guyodo

First author: Tuğba Ocak

Journal: Medicina

Reference: Medicina (Kaunas). 2025 Apr 25; 61: 792

Link to PubMed: https://pubmed.ncbi.nlm.nih.gov/40428750/

Introduction:

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is associated with MEFV gene mutations and is characterized by recurrent inflammatory attacks, particularly with abdominal pain. The most severe complication is AA amyloidosis. The recommended treatment is colchicine to prevent attacks and complications. In some patients, colchicine at the maximum tolerated dose is insufficient to prevent attacks, while others do not tolerate colchicine. Anti–interleukin‑1 agents are effective in cases of colchicine resistance or intolerance. This Turkish team investigated treatment with anakinra in colchicine‑resistant/intolerant FMF patients, focusing on their clinical characteristics, treatment duration, treatment response, possible extension of injection intervals, and long‑term outcomes.

Patients and methods:

This single‑center retrospective study included 68 FMF patients with colchicine resistance or intolerance who required initiation of anakinra at a dose of 100 mg/day. Colchicine resistance was defined as at least one attack per month despite the maximum tolerated daily dose of colchicine. Colchicine intolerance was defined as the inability to increase the colchicine dose because of digestive side effects.

Results:

Among these 68 patients, the median age was 40.2 years and 57.3% were women. Of the 60 patients who had undergone genetic testing, 32 patients (53%) had two pathogenic MEFV mutations, 26 (43%) were heterozygous for pathogenic mutations, and 2 had no identified mutation.

Fifteen patients had AA amyloidosis. All patients were treated with colchicine before starting anakinra, at a median dose of 2 mg/day, and 63 patients continued colchicine in parallel. Median follow‑up was 34 months.

Treatment was effective in the majority of patients, with significant reductions in the Pras score, ESR, CRP, SAA, and proteinuria when present.

In 21 patients, remission was achieved under treatment, allowing an increase in the interval between anakinra injections to every 2 days, then every 3 days. Eight of these patients were able to discontinue anakinra completely while continuing colchicine alone. Only 2 patients relapsed within the month following complete treatment withdrawal.

The main adverse events were injection‑site reactions.

Seventeen additional treatment discontinuations were reported, mostly due to insufficient response (7 patients) or adverse events (7 patients).

Four patients received anakinra during pregnancy without adverse effects in either the mother or the baby.

Six kidney‑transplant recipients were treated with anakinra, one of whom died from COVID‑19 pneumonia.

Discussion:

This study shows that treatment with anakinra in patients who are resistant or intolerant to colchicine leads to rapid and sustained improvement in clinical signs and inflammatory markers, with good tolerability. Injection intervals could be extended to every 2 or even 3 days while maintaining clinical and biological response. Proteinuria decreased in some patients, suggesting a potential benefit in those with AA amyloidosis. Treatment was also well tolerated, with no adverse effects reported in the 4 pregnant women.

In practice:

In this study of 68 Turkish adults with FMF, anakinra was rapidly effective and well tolerated in the long term in patients who were resistant or intolerant to colchicine.