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

Dysimmune Actinopathies: Better Understanding These Rare Diseases in the Middle East and North Africa

Article title: Clinical and molecular findings in actin-related inborn errors of immunity: the middle East and North Africa registry

First author: Zahra Chavoshzadeh

Journal: Front Genet.

Link to the article: https://pubmed.ncbi.nlm.nih.gov/40860338/

Author of the abstract: Philippe Mertz

Actinopathies are an emerging group of primary immunodeficiencies linked to abnormalities in the genes that regulate the actin cytoskeleton. These proteins control essential immune functions such as cell migration, tissue infiltration, and immunological synapse formation. Clinically, they are associated with severe and recurrent infections, allergic manifestations, cytopenias (particularly thrombocytopenia and/or abnormal mean platelet volume), autoimmunity, and sometimes malignancies.

The MENA (Middle East and North Africa) region has a high prevalence of these diseases, due in particular to a high frequency of consanguineous marriages. The aim of this retrospective multicenter study was to describe the clinical, immunological, and genetic characteristics and therapeutic approaches used in patients with actinopathy.

The authors proposed a classification of actinopathies into three main groups, according to the mechanisms affected (see Figure 1A extracted from the article). For the record, actin polymerization is essential for the formation of cell protrusions and depends mainly on two pathways associated with the RHO GTPases RAC2 and CDC42:

The group of RAC2 pathway regulators (in blue), which activates the ARP2/3 complex and induces lamellipodia formation;

The group of CDC42 pathway regulators (in red), which activates the WAVE complex and generates filopodia;

A third group mainly includes abnormalities in actin transcription factors or their regulators (in green), such as CEBPE, WDR1, or MKL1.

• 

A total of 503 patients from 17 countries were included. The median age at symptom onset was 4 months, and the median time to diagnosis was 19 months. Overall mortality was 23%, mainly due to infectious complications and cancers.

The most common initial presentations were allergic manifestations (33.7%), infections (32%), and hemorrhages (16.8%). Throughout life, infections predominated (90%), especially respiratory (72%) and skin (48%) infections. Eczema was the most common allergic manifestation (67.9%). Cytopenias (42.7%), lymphoproliferative disorders (19.1%), and lymphomas (5.9%) completed the spectrum.

Among the 391 patients who received a genetic diagnosis, the genes most commonly involved were DOCK8 (53.8%), WAS (n=24.6%), and CARMIL2 (4.3%). It should be noted that no patients with CDC42 mutations were included in the CDC42 pathway regulator group.

Hematopoietic stem cell transplantation (HSCT) was performed in 24% of patients, significantly improving survival in WAS, DOCK8, and DOCK2 deficiencies. Immunoglobulin replacement (89.4%) and antibiotic prophylaxis (93%) were almost systematic.

The authors then looked at the differences in presentation between the different groups. The main differences are shown in the figure opposite.

VPM : volume plaquettaire moyen

Key messages

1. Actinopathies are most often revealed in early childhood through severe infections (respiratory +++) and allergies (eczema, atopic dermatitis), with an overall mortality rate of around 25%. Platelet counts may be normal in the vast majority of patients (48–94% depending on the group).

   
   

2. Variants affecting the CDC42 pathway are associated with earlier onset, a more severe phenotype, and higher mortality than those affecting the RAC2 pathway, which have a later onset, often marked by lymphoproliferation.

   
   

3. Hematopoietic stem cell transplantation (HSCT) is a key therapeutic option, particularly beneficial for DOCK8, WAS, and DOCK2 deficiencies, highlighting the importance of early diagnosis and rapid referral to a center of expertise.

Clinical and molecular findings in actin-related inborn errors of immunity: the middle Eas.

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