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.

Current landscape of monogenic autoinflammatory actinopathies: A literature review

First author : P. Mertz

Review: Autoimmunity Reviews

Link to article: https://doi.org/10.1016/j.autrev.2024.103715

Autoinflammatory diseases (AID) are conditions leading to a hyperactivation of innate immunity without any underlying infection, and may be poly- (e.g. Still's disease) or monogenic. The number of monogenic AID is continuously expanding, with the discovery of novel pathologies and pathophysiological mechanisms, facilitated in part by easier access to pangenomic sequencing. Actinopathies with autoinflammatory manifestations represent a newly emerging subgroup of AID, associated with defects in the regulation of actin cytoskeleton dynamics. These diseases typically manifest in the neonatal period and variably combine a primary immunodeficiency of varying severity, cytopenia (particularly thrombocytopenia), autoinflammatory manifestations primarily affecting the skin and digestive system, as well as atopic and autoimmune features.

Diagnosis should be considered primarily when encountering an early-onset autoinflammatory skin and digestive disorder, along with a primary immunodeficiency and either thrombocytopenia or a bleeding tendency. Some of these diseases exhibit specific features, such as a risk of macrophage activation syndrome (MAS) or a predisposition to atopy or lymphoproliferation. The complete pathophysiology of these diseases is not yet fully understood, and further studies are required to elucidate the underlying mechanisms, which could guide therapeutic choices. In most cases, the severity of the conditions necessitates allogeneic marrow transplantation as a treatment option.

In this review, we discuss these novel diseases, providing a practical approach based on the main associated biological abnormalities and specific clinical characteristics, with a special focus on the newly described actinopathies DOCK11 and ARPC5 deficiency. Nonetheless, genetic testing remains essential for definitive diagnosis, and various differential diagnoses must be considered.

Current landscape of monogenic autoinflammatory actinopathies.pdf

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Iron Deficiency in Familial Mediterranean Fever: A Studyon 211 Adult Patients From the JIR Cohort

First author: Ilenia Di Cola et al

Review: American Journal of Hematology

Link to article: https://doi.org/10.1002/ajh.27549

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide, associated with mutations in the MEFV gene. Patients experience recurrent and self-limited episodes of fever, abdominal pain, and chest pain. There is no specific association between anemia and FMF, except that patients with chronic inflammation may have inflammatory microcytic anemia.

However, chronic anemia can lead to fatigue, and fatigue is known to be a trigger for FMF. Therefore, patients with fatigue due to anemia may experience more frequent flare-ups of the disease and a reduced quality of life. Iron deficiency can cause fatigue even in the absence of anemia. Fatigue is also commonly reported in FMF. Therefore, it may be beneficial to check for iron deficiency without anemia as one of the causes of fatigue in FMF, especially since fatigue can be considered a trigger for their flare-ups.

Our study explores the prevalence of iron deficiency in 211 adult patients with Familial Mediterranean Fever (FMF). The main goal was to determine the association between iron deficiency (defined by ferritin < 27 ng/mL) and various clinical, biological, and therapeutic parameters.

In total, 31.8% of FMF patients had ferritin < 27 ng/mL, mostly young women. Iron deficiency, even without anemia, potentially contributes to fatigue, a frequent trigger of inflammatory flare-ups. Possible causes include excessive menstrual losses not compensated by a diet rich in iron, low consumption of animal proteins, or digestive bleeding exacerbated by the use of NSAIDs.

Patients with low ferritin had lower hemoglobin (Hb) levels and BMI, and required higher doses of colchicine (2 mg/day on average). The impact of colchicine on intestinal iron absorption remains to be studied.

This work highlights the importance of monitoring ferritin levels in Familial Mediterranean Fever (FMF) due to the simplicity and global accessibility of this test, including in emerging countries. In the case of significant iron deficiency, supplementation is recommended to alleviate symptoms such as fatigue and anemia, which can trigger FMF flare-ups and maintain a vicious cycle of fatigue in patients.

Iron deficiency in FMF.pdf

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