French update on hyperinflammatory actinopathies by Mertz et al (2023)

First author: P. Mertz

Review: La Revue de médecine interne

Link to the article: https://doi.org/10.1016/j.revmed.2023.06.005

Fig1: Principaux intervenants dans la régulation de la dynamique du cytosquelette d’actine.

Abstract:

Autoinflammatory diseases (AIDs) are diseases resulting from an inappropriate activation of innate immunity in the absence of any infection. The field of monogenic AIDs is constantly expanding, with the discovery of new pathologies and pathophysiological mechanisms thanks to pangenomic sequencing. Actinopathies with autoinflammatory manifestations are a new emerging group of AIDs, linked to defects in the regulation of the actin cytoskeleton dynamics. These diseases most often begin in the neonatal period and combine to varying degrees a more or less severe primary immune deficiency, cytopenias (especially thrombocytopenia), auto-inflammatory manifestations (especially cutaneous and digestive), atopic and auto-immune manifestations. The diagnosis is to be evoked essentially in front of a cutaneous-digestive auto-inflammation picture of early onset, associated with a primary immune deficiency and thrombocytopenia or a tendency to bleed. Some of these diseases have specificities, including a risk of macrophagic activation syndrome or a tendency to atopy or lymphoproliferation. We propose here a review of the literature on these new diseases, with a proposal for a practical approach according to the main associated biological abnormalities and some clinical particularities. However, the diagnosis remains genetic, and several differential diagnoses must be considered. The pathophysiology of these diseases is not yet fully elucidated, and studies are needed to better clarify the inherent mechanisms that can guide the choice of therapies. In most cases, the severity of the picture indicates allogeneic marrow transplantation.

© 2023 Published by Elsevier Masson SAS on behalf of Société Nationale Française de Médecine Interne (SNFMI).

2023 Mertz Revue Actinopathies RevMedInt.pdf

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French protocol for the diagnosis and management of familialMediterranean fever

S. Georgin-Laviallea,h,∗, L. Saveya,h, L. Cuissetc, G. Boursiere,h, J.-J. Boffab,h,M. Delplanquea,h, R. Bourguibaa,h, J.-B. Monfortd,h, I. Touitoue,h, G. Grateaua,h,I. Kone-Pautf,h, V. Hentgeng,h, Collaborators1

Link to article: https://doi.org/10.1016/j.revmed.2023.10.441

Summary:

Familial Mediterranean fever is the most common monogenic auto-inflammatory disease in the world. It mainly affects people from the Mediterranean region. The mutated gene is MEFV, which codes for pyrin. Transmission is autosomal recessive. Patients present with recurrent attacks of fever since childhood, associated with abdominal and/or thoracic pain lasting an average of 2 to 3 days, and associated with a biological inflammatory syndrome. Other symptoms include arthralgia or arthritis of large joints such as the knees and ankles, myalgia of the lower limbs and pseudo-eryzipelas of the ankles. Its most severe complication is inflammatory amyloidosis, or AA amyloidosis, which can lead to kidney failure. Treatment is based on colchicine, which helps prevent relapses and the onset of renal amyloidosis. This paper proposes national recommendations for the diagnosis, management and follow-up of familial Mediterranean fever in France, where we estimate that there are between 5,000 and 10,000 patients with the disease at all ages. The diagnosis is suspected on the basis of clinical and anamnestic elements, and confirmed by genetic analysis. These recommendations also propose a "treat-to-target" approach to the treatment of the disease, particularly in cases of suspected resistance to colchicine, a very rare situation which must remain a priority.

© 2023 Publié par Elsevier Masson SAS au nom de Société Nationale Française de Médecine Interne (SNFMI).

French recommandation for the diagnostic and care of FMF Rev Med int.pdf

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Reproductive disorders in homozygotes and heterozygotes familial Mediterranean fever patients and controls

First author : SOTSKIY P

Revue: Clin Exp Rheum

Reference: Clin Exp Rheumatol. 2024 Sep 19. doi: 10.55563/clinexprheumatol/9yc77f. Online ahead of print.PMID: 39360377

Lien vers pubmed: https://pubmed.ncbi.nlm.nih.gov/39360377/

Introduction:

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. Previous studies have shown a clear correlation between patients' genotype and the clinical severity of FMF. However, no specific study has explored a direct correlation between the patient’s genotype and the reproductive system.

This study aimed to compare reproductive disorders in homozygous and heterozygous female FMF patients with healthy controls.

FMF can be accompanied by abnormalities in women’s reproductive function through the following mechanisms:

Acute peritonitis, which can lead to peritoneal adhesions and obstruction of the fallopian tubes, resulting in mechanical infertility.

Peritonitis during an acute FMF attack in a pregnant woman can cause uterine contractions, leading to miscarriage or preterm labor.

Inflammatory amyloidosis may theoretically thicken the ova, resulting in difficulty for sperm penetration.

Patients and Methods:

The study included 249 women with reproductive disorders at a gynecology center of the National Center for Medical Genetics and Primary Health Care in Yerevan, Armenia. FMF diagnosis was confirmed using the Tel-Hashomer criteria along with genetic analysis of the 12 most common MEFV mutations: E148Q, P369S, F479L, M680I (G/C), M680I (G/A), I692del, M694V, M694I, K695R, V726A, A744S, R761H. A severity score was calculated for each FMF patient.

The women were divided into three groups:

Group 1: 40 FMF women with two identical MEFV mutations (homozygous).

Group 2: 47 FMF women with a single MEFV variant (heterozygous).

Group 3: A control group of women with reproductive problems but no other systemic disease, particularly FMF.

All patients were recruited, gave informed consent, and were examined in the same gynecology clinic for reproductive issues. Reproductive problems assessed included menstrual dysfunctions, primary and secondary infertility, endometrial hyperplasia, spontaneous miscarriages, ectopic pregnancies, and preterm deliveries.

Results:

As expected, homozygous patients had more severe FMF, with the M694V/M694V genotype found in 75% of these patients, followed by M680I/M680I and V726A/V726A. The most common genotypes in heterozygous patients were M694V/-, M680I/-, V726A/-, and E148Q/-.

Primary infertility was significantly higher in homozygous patients (79.4%) compared to heterozygous patients (38.5%). The primary cause of infertility in FMF patients was tubal-peritoneal. Adhesions in the pelvic, peritubal, and periovarian regions were more common in FMF patients than in controls. Sterility was 1.54 times more frequent in homozygous patients than in heterozygous and control groups.

Causes of infertility in the control group included endometriosis, uterine fibroids, and adenomyosis.

Homozygous FMF patients had a higher rate of spontaneous miscarriages and lower pregnancy rates compared to heterozygous patients.

Live birth rates were higher in heterozygous patients.

Non-adherence or inadequate treatment with colchicine was associated with higher infertility rates, with 38.2% of homozygous and 84.6% of heterozygous patients receiving insufficient treatment.

Delayed use of colchicine due to late diagnosis of FMF or irregular use also contributed to infertility problems.

In conclusion, the severity of FMF, genotype, and adherence to colchicine treatment impact pregnancy outcomes and reproductive health.

In practice, this study highlights the need to improve patient education on strict adherence to colchicine treatment.