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

VEXAS syndrome and the risk of infections: what do we know and how can they be prevented?

Article title: Mapping the infectious burden in VEXAS syndrome:a systematic review and rationale for prevention

First author: Valentine Ribier

Journal: Lancet Rheumatology

Link to the article: https://doi.org/10.1016/S2665-9913(25)00225-5

Author of the abstract: Rim BOURGUIBA

Introduction:

VEXAS syndrome is an autoinflammatory disease associated with somatic mutations in the X‑linked UBA1 gene. Patients present with systemic inflammatory manifestations and an increased susceptibility to infections. In the French cohort, more than 50% of mortality was attributed to infections. Several factors have been identified as contributors to infection risk in these patients: long‑term corticosteroid therapy, combination and prolonged use of immunosuppressive treatments such as JAK inhibitors, and a likely functional immune deficiency of myeloid cells related to the disease itself. Multiple publications have reported opportunistic and invasive infections in VEXAS even in the absence of immunosuppressive or immunomodulatory therapy. Few recommendations existed regarding infection prophylaxis in VEXAS. The objectives of this review were: 1) to characterize the spectrum of infections in VEXAS, 2) to identify a high‑risk subgroup for infections, and 3) to propose a preventive strategy to reduce infection‑related complications.

Methods:

This systematic review followed PRISMA guidelines. The literature search included publications from October 2020 to October 31, 2024 without language restrictions on PubMed. The authors included case reports and case series. Eligibility criteria were the presence of infection, its frequency, and its nature among patients with VEXAS syndrome. Infection was confirmed when a pathogen was identified. A severe infection was defined as one requiring hospitalization with intravenous antibiotic therapy or resulting in death.

Results:

The authors identified 506 potentially eligible studies; after exclusions, 57 studies were retained, encompassing 813 patients.

Infection frequency was high: 37–60% of patients experienced at least one infection, with 12–15% dying from infections in large cohorts. Severe infections accounted for up to 60% of cases. The most frequent infection sites were respiratory (28–59%), skin and soft tissue (10–49%), and bloodstream (bacteremia 8–13%), with genitourinary and gastrointestinal infections less common. Main pathogens included bacteria (Gram‑negative bacilli and Gram‑positive cocci), and opportunistic infections such as Legionella, atypical mycobacteria, Pneumocystis jirovecii, VZV, CMV, HSV, Aspergillus, and Nocardia. (Figure 1)

Factors associated with infections included exposure to immunosuppressive treatments: azacitidine was associated with 44–62% infections, including deaths; IL‑6 inhibitors with 29–47%; and JAK inhibitors with 18–37%. IL‑1 inhibitors were associated with a lower rate (3%). Chronic corticosteroid therapy was associated with mycobacterial infections or pneumocystosis.

The authors proposed the following prevention strategy:

• Targeted anti‑infective prophylaxis, for example co‑trimoxazole to prevent Pneumocystis jirovecii pneumonia and valaciclovir to prevent VZV reactivation.

• Systematic vaccinations, including influenza, pneumococcus, VZV, and SARS‑CoV‑2, despite a potential for reduced vaccine responses.

• Comprehensive infectious disease screening before initiating immunosuppression, including serologies (HIV, HBV, HCV, TB) and chest CT.

Conclusion:

VEXAS syndrome is associated with a major predisposition to infections, resulting from both an intrinsic immune deficit linked to UBA1 mutation and the effects of immunosuppressive treatments. Infections are a leading cause of morbidity and mortality, particularly affecting the respiratory tract and skin. Prevention should be a central pillar of care, based on vaccination, targeted anti‑infective prophylaxis, and risk assessment prior to any immunosuppression. These data support an integrated, multidisciplinary, and proactive approach to improve survival and quality of life for people living with VEXAS.

Figure 1: Distribution of infection sites and pathogens across studies

Le syndrome VEXAS et le risque d’infections.pdf

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VEXAS syndrome: what can we learn from France's experience with azacitidine?

Article title: Efficacy and safety of azacitidine for VEXAS syndrome: a large-scale retrospective study from FRENVEX

First author: Vincent Jachiet

Journal: Blood

Link to the article: https://pubmed.ncbi.nlm.nih.gov/40373272/

Author of the abstract: Philippe Mertz

Three key points to remember:

1. Azacitidine is an effective treatment option for VEXAS syndrome even without associated myelodysplasia, with simultaneous effects on inflammation, cytopenias, and the UBA1 clone.

2. The response is often delayed and requires prolonged exposure (≥6 cycles) before evaluation. Adverse effects, particularly infectious ones, occur mainly in the first 3 cycles of treatment. Discontinuation of AZA leads to relapse in the majority of cases, suggesting a suspensive rather than curative effect.

3. Molecular monitoring (UBA1 VAF) allows for objective assessment of clonal response and could become a biomarker for monitoring this disease.

   
   

VEXAS syndrome is an acquired monogenic autoinflammatory disease associated with somatic mutations in the UBA1 gene. Patients present with a wide spectrum of severe inflammatory manifestations and cytopenias, which may be associated with myelodysplastic syndrome (MDS). Treatment is mainly based on corticosteroids, with frequent corticosteroid dependence despite associated sparing therapy with targeted therapies (anti-IL-6, anti-JAK, etc.) that have inconsistent efficacy. Azacitidine (AZA), a hypomethylating agent used in MDS, has shown potential in VEXAS, but published data remain limited.

This is a retrospective multicenter study conducted in France by the FRENVEX group, including 88 patients with genetically confirmed VEXAS who received at least one cycle of AZA between 2009 and 2024.

In this study, inflammatory response was defined as both clinical and biological improvement in systemic manifestations, including reduction in inflammatory symptoms and sustained decrease in biological markers such as CRP. The hematologic response followed the 2018 International Working Group criteria for MDS and corresponded to a significant improvement in cytopenias, including an increase in hemoglobin, platelets, or neutrophils, or a reduction in transfusion requirements. Finally, the molecular response was established on the basis of at least a 25% reduction in the mutational burden (VAF) of the UBA1 variant, assessed by targeted sequencing during treatment. Treatment side effects were described according to the Common Terminology Criteria for Adverse Events (version 5.0).

Inflammatory, hematological, and molecular responses were evaluated, as well as tolerance, regardless of the presence of associated MDS (present in 80%).

The main results of this study show:

• A partial or complete inflammatory response observed in 61% of patients (41% at 6 months, 54% at 12 months). The median response time was sometimes delayed (>6 cycles).

• A hematological response with improvement in hemoglobin in 65% and platelet count in 77%, with clinical benefit in terms of cytopenias and transfusion requirements.

• A molecular response with at least a 25% reduction in UBA1 mutation burden was observed in 65% of patients, correlating with the clinical response.

• Severe adverse events (grade III and IV) occurred in 60% of patients, mainly infections (34%) and cytopenias (36%), occurring predominantly in the first 3 cycles.

• 75% of patients relapse after stopping AZA (median duration of treatment-free period of 3.1 years), but resumption of treatment is effective in 80% of cases.

This study supports the use of AZA as first-line treatment in patients with VEXAS syndrome and severe cytopenias, or as second-line treatment in cases of failure of anti-inflammatory biotherapies, even in the absence of associated MDS. Treatment-related adverse effects, particularly infections, appear to occur mainly during the first 3 cycles of treatment. Prospective studies are needed to confirm its positioning and optimize the therapeutic strategy.