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.

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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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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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Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome: A comprehensive review of cases across different ethnicities

First author: Yixiang Yves-Jean Zhu

Journal: European Journal of Internal Medicine

Reference: https://doi.org/10.1016/j.ejim.2025.05.023

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a rare autoinflammatory disease associated with somatic pathogenic variants in the UBA1 gene. First described in 2020, it has since been reported in many countries, but its distribution across the world remained unclear. We conducted a literature review between October 2020 and April 2025, identifying more than 670 cases across 32 countries and 4 continents. Among patients with documented origins, several ethnic groups were represented, including Caucasian, East and South Asian, Middle Eastern, and South American. These findings confirm that VEXAS syndrome diverse ethnic backgrounds and has a broad worldwide distribution. It is therefore crucial to consider VEXAS in patients with compatible symptoms, regardless of their country or ancestry, to avoid diagnostic delays.

(VEXAS) syndrome: A comprehensive review of cases across different ethnicities.pdf

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