Unsupervised clustering of undifferentiated systemic autoinflammatory diseases (USAID)

First author: Jeanne Chauffier

Journal: European Journal of Internal Medicine

Article link: https://doi.org/10.1016/j.ejim.2026.107224

Summary author: Jeanne Chauffier

Background:   

Undifferentiated systemic autoinflammatory diseases (USAID) comprise a heterogeneous group of disorders characterized by recurrent systemic inflammation without an identifiable monogenic cause.  

Objective:  

To describe the phenotypic and therapeutic features of adult USAID and identify phenotypic clusters. 

Methods: 

We conducted a retrospective single-center study at the French Reference Center for Autoinflammatory Diseases between 2010 and 2025. USAID was defined as recurrent systemic attacks with ≥3 documented C-reactive protein (CRP) elevations and no pathogenic variant identified. Therapeutic response was classified as complete (CR) or partial (PR). Hierarchical cluster analysis included clinical and biological variables. 

Results:  

Among 150 patients (65.3% women; median age at onset 14 [0–64] years), recurrent attacks occurred in 87.3%. The most frequent manifestations were cutaneous (87.3%), fever (84%), asthenia (80%), musculoskeletal (79.3%), and abdominal involvement (63.3%). Colchicine was prescribed in 56.7% (CR 8.2%, PR 44.7%). Biologic therapies included anti-TNFα (n = 32; CR 21.9%, PR 31.3%), anti-IL-1 (n = 24; CR 25%, PR 16.7%), anti-IL-6 (n = 22; CR 31.8%, PR 31.8%), and JAK inhibitors (n = 16; CR 18.8%, PR 37.5%). 

Four clusters were identified:  

Cluster 1 (15.3%): fever, aphthous ulcers, pharyngitis, abdominal pain and lymphadenopathy.  

Cluster 2 (27.3%): brief attacks, frequent urticaria and abdominal pain.  

Cluster 3 (18.7%): prolonged attacks, prominent arthralgia, arthritis, and myalgia.  

Cluster 4 (38%): predominantly men, higher age at the onset, frequent neutrophilic dermatoses.  

Treatment responses did not differ significantly between clusters.  

Conclusion:  

Adult USAID patients can be subdivided into four clusters. Phenotypic stratification may help structure diagnostic reasoning and guide future therapeutic research. 

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VEXAS syndrome

Journal: Nature Reviews Disease Primers

First author: David B. Beck

Country of study: international article — United States, France, Japan and Italy

CEREMAIA Tenon author: Sophie Georgin-Lavialle

Reference: Beck DB, Georgin-Lavialle S, Kirino Y, Patel BA, Ferrari S. VEXAS syndrome. Nature Reviews Disease Primers. 2026;12:19.

DOI: https://doi.org/10.1038/s41572-026-00695-w

PubMed link: https://pubmed.ncbi.nlm.nih.gov/?term=10.1038%2Fs41572-026-00695-w

5 key points:

• VEXAS syndrome is a rare adult-onset inflammatory disease, discovered in 2020, caused by an acquired mutation in the UBA1 gene in blood cells.

• It mainly affects men over the age of 50, but it can also occur in women, especially in the context of X chromosome abnormalities.

• Common signs include corticosteroid-dependent inflammation, skin lesions, cartilage and lung involvement, blood abnormalities and sometimes myelodysplastic features.

• Diagnosis is based on the combination of symptoms, laboratory abnormalities — especially macrocytic anaemia and inflammation — and confirmation by genetic testing for a UBA1 mutation.

• Treatments aim to control inflammation and/or the abnormal blood cell clone, but management remains complex and must be tailored to each patient.

Introduction:

VEXAS syndrome is a recently identified autoinflammatory disease. Its name stands for vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic. It is caused by an acquired mutation in the UBA1 gene in certain blood stem cells. This mutation disrupts immune cell function and leads to significant chronic inflammation.

Methods:

This article is a general review, called a Primer, that brings together recent knowledge about VEXAS syndrome, including its frequency, biological mechanisms, clinical signs, diagnosis, complications, treatments and impact on quality of life.

Results:

VEXAS mainly affects men over the age of 50. Symptoms may include fever, fatigue, weight loss, skin involvement, cartilage inflammation — for example of the ears — lung involvement, joint pain, blood abnormalities and an increased risk of blood clots. Many patients have anaemia with enlarged red blood cells, sometimes low platelet counts, and bone marrow abnormalities. Diagnosis is confirmed by genetic testing for a UBA1 mutation.

Discussion:

The disease is often difficult to recognize because it can resemble other inflammatory, dermatological, rheumatological or haematological diseases. Corticosteroids often improve symptoms rapidly, but long-term corticosteroid dependence is common. Other treatments may be used, including JAK inhibitors, therapies targeting specific cytokines, azacitidine or, in selected cases, stem cell transplantation.

Conclusion:

VEXAS has changed the understanding of some adult inflammatory diseases by showing the link between inflammation, acquired genetics and blood disorders. Earlier diagnosis and prospective studies are needed to improve patient care and quality of life.

PubMed link: https://pubmed.ncbi.nlm.nih.gov/?term=10.1038%2Fs41572-026-00695-w