VEXAS syndrome through a rheumatologist's lens: insights from a Spanish national cohort

Summarized by: le Pr Sophie Georgin-Lavialle

Reference: Garcia-Escudero P, VEXAS syndrome through a rheumatologist’s lens: insights from a Spanish national cohort, Rheumatology, 2025, 00, 1-9

PubMed link: https://pubmed.ncbi.nlm.nih.gov/39937690/

Summary:

VEXAS syndrome is a rare, acquired autoinflammatory disease first described in 2020, associated with somatic mutations in the UBA1 gene. This article presents a Spanish multicenter case series of 39 Caucasian male patients followed in rheumatology, with a mean age at diagnosis of 73 years and an average age at symptom onset of 67. Prior diagnoses included seronegative polyarthritis (n=9), relapsing polychondritis (n=6), Sweet syndrome (n=4), polymyalgia rheumatica (n=4), systemic lupus erythematosus (n=3), and medium-vessel vasculitis (n=3). The most frequent clinical features, in decreasing order, were skin lesions (87%)—mainly neutrophilic dermatosis—polyarthritis (82%), fever (79%), chondritis (51.3%), ophthalmologic involvement (48.7%) mainly periorbital edema, pulmonary involvement (38%), deep vein thrombosis (30.8%), and renal involvement (20%).

From a hematological perspective, 92% of patients had macrocytic anemia, and 46% had myelodysplastic syndrome. A monoclonal gammopathy was present in 25.6% of cases. Cytoplasmic vacuoles were found in 82% of patients.

The three main UBA1 mutations identified were M41T (36%), M41V (15.7%), and M41L (47%). A genotype-phenotype correlation was observed: M41V was associated with renal involvement, and M41T with deep vein thrombosis and thrombocytopenia. A novel mutation (c.209T>A; p.L70H) in exon 4 was also reported.

Most patients presented with macrocytic anemia (92%), sometimes associated with myelodysplasia (46%) or monoclonal gammopathy (26%). Bone marrow examination showed vacuoles in 72% of cases.

All patients received corticosteroids, with significant improvement after diagnosis, likely due to increased doses. IL-6 inhibitors (75%) and JAK inhibitors (77%)—especially ruxolitinib (90%)—showed good efficacy. TNF inhibitors were ineffective.

Eight patients (20.5%) died during follow-up, with 5 deaths directly attributed to VEXAS syndrome.

This study highlights the crucial role of rheumatologists in identifying VEXAS syndrome, particularly in men over 50 with atypical inflammatory presentations, macrocytic anemia, and corticosteroid dependence. The described genotype-phenotype correlations may be validated in larger cohorts and could help refine diagnostic strategies and guide treatment choices.

Efficacy and safety of targeted therapies in VEXAS syndrome: retrospective study from the FRENVEX

First author: Hadjadj et al.

Link to article: DOI: 10.1136/ard-2024-225640

Summary:

Study Objective:

To assess the efficacy and safety of targeted therapies in VEXAS syndrome, an adult-onset autoinflammatory disease associated with somatic mutations in the UBA1 gene.

Methodology:

A multicenter retrospective study including 110 patients who received at least one targeted therapy. Complete response (CR) and partial response (PR) were defined based on specific clinical and biological criteria.

Results:

A total of 110 patients received 194 targeted therapies: 78 (40%) JAK inhibitors (JAKi), 51 (26%) IL-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) TNFα blockers, and 12 (6%) other targeted therapies.

At 3 months, the overall response rate (CR and PR) was 24% with JAKi, 32% with IL-6 inhibitors, 9% with IL-1 inhibitors, and 0% with TNFα blockers or other targeted therapies.

At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors.

Treatment-free survival was significantly longer with JAKi compared to other targeted therapies.

Among patients who discontinued treatment, reasons included primary failure, secondary failure, serious adverse events, or death, with varying rates depending on the therapy.

Conclusions:

JAK and IL-6 inhibitors show clinical benefits, while other therapies demonstrate lower efficacy. These findings require confirmation in prospective trials.

C-reactive protein is more suitable than Serum Amyloid A to monitor crises and attack-free periods in Systemic Auto-Inflammatory Diseases

Abstract

Background: With their broad presentations and no global biomarker to discriminate crises and attack-free periods, Systemic Auto-Inflammatory Diseases (SAID) are difficult to manage. This study assessed Serum Amyloid A (SAA), C-reactive protein (CRP) and serum calprotectin as potential biomarkers to monitor patients with SAID.

Method: SAA (already studied in Familial Mediterranean Fever (FMF)), CRP and serum calprotectin were measured on SAID adult patients from Juvenile Inflammatory Rheumatism (JIR) cohort during their follow-up visits between 2020 and 2022. Crises and attack-free periods were clinically determined.

Results: 96 measures, mainly from FMF (43 %) and Unclassified SAID (USAID) (37 %) patients were included. Using ROC curves, a threshold with sensitivity and specificity of/over 75 % was determined for SAA (9 mg/L) and CRP (9 mg/L) but not for serum calprotectin, not investigated further. With this threshold, the results were similar in FMF and USAID patients' subgroups. SAA and CRP showed a positive correlation with crises and attack-free periods in SAID patients (r = 0.4796, p < 0.001 and r = 0.5525, p < 0.001, respectively) as in FMF and USAID patients, with no significant difference between both markers in diagnosis value and ROC curves Area Under Curve (AUC) (p = 0.32). Only the CRP results were not influenced by obesity.

Conclusion: SAA and CRP can discriminate crisis and attack-free periods in our cohort of SAID patients mainly composed of FMF and USAID patients. However, only CRP can be used regardless of body mass index. It is the first report of common biomarkers for all SAID, including USAID patients, with CRP widely accessible in routine worldwide.

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