Gut microbiota alterations are associated with phenotype and genotype in Familial Mediterranean Fever

Marion Delplanque1,2,3,†, Nicolas Benech2,3,†, Nathalie Rolhion2,3, Cyriane Oeuvray2,3, Marjolène Straube2,3, Chloé Galbert2,3, Loic Brot2,3, Thomas Henry 4 , Yvan Jamilloux4 , Le´ a Savey1 , Gilles Grateau1 , Harry Sokol 2,3,5, Sophie Georgin-Lavialle1,2,3,*

Link to article: https://pubmed.ncbi.nlm.nih.gov/37402619/

Summary: 

The intestinal microbiota has attracted growing interest in recent years due to its involvement in a number of diseases. In Familial Mediterranean Fever (FMF), its role was suspected because certain digestive bacterial infections caused attacks of the disease, such as Helicobacter pylori in the stomach. With the help of Professors Georgin-Lavialle and Sokol from the "Microbiota and Immunity" Avenir Team (INSERM U938 unit), and all the patients and their relatives who agreed to take part, Dr Marion Delplanque, Assistant Clinical Head of the FMF National Reference Centre at Tenon Hospital, conducted research over a year to compare the composition of the intestinal microbiota of patients with FMF with a control group of healthy subjects. The technique used to study the genetic content of the intestine is called metagenomics; it enables the microorganisms present in the faeces to be identified.The faecal microbiota of 119 patients with FMF was compared with that of 61 healthy subjects. Of the FMF patients, 88 carried 2 pathogenic mutations in the MEFV gene and 31 carried a single mutation. Twenty-seven patients (22.7%) were resistant to colchicine, 17 had inflammatory amyloidosis, also known as AA amyloidosis (14.2%) and 10 were on anti-interleukin-1 biotherapy.

We demonstrated an imbalance in the intestinal flora (known as dysbiosis) in patients with FMF compared with healthy subjects. Bacterial diversity, measured by the number of different species present in the intestine, was reduced in patients with FMF. In addition, certain inflammation-promoting bacteria were predominant in FMF patients. In patients with severe FMF, defined by the presence of AA amyloidosis and/or colchicine resistance, inflammation-promoting bacteria were significantly more abundant than in less severe patients. Finally, the composition of the microbiota differed according to the response to colchicine: colchicine-resistant patients had a different structure and composition to colchicine-sensitive patients, and the connectivity of their bacterial network was reduced.

Overall, this is the most important study to date of stool composition in FMF. It confirms that there is an imbalance in the composition of the intestinal flora (or dysbiosis) in patients with FMF compared with healthy controls. Further work is needed to determine whether the intestinal flora could be a therapeutic target in FMF, particularly in the case of colchicine-resistant forms or severe complications such as AA amyloidosis.

Référence :

Delplanque M et al. Gut microbiota alterations are associated with phenotype and genotype in familial Mediterranean fever. Rheumatology (Oxford).  2023 Jul 4 (ahead print). PMID : 37402619

Hip involvement in familial Mediterranean fever

First author : François Rodrigues et al

Journal: European Journal of Internal Medicine, 10.1016/j.ejim.2022.11.008

Link to article: https://pubmed.ncbi.nlm.nih.gov/36435696/

Introduction: 

Familial Mediterranean Fever (FMF) is a monogenic autoinflammatory disorder that is linked to homozygous mutations of the MEFV gene. The field of FMF is expanding as many patients with FMF phenotype are heterozygous with monoallelic variants. Arthritis is a frequent manifestation of FMF, involving 50 to 75% of patients.

The hip is the third most commonly affected joint after the knee andankle. Aseptic necrosis of the femoral head caused by disruption of local blood supply has also been reported in FMF patients. Meanwhile, hip inflammation or coxitis can be caused by axial spondyloarthritis, which develops at an increased rate in FMF patients. Therefore, the literature is controversial as to whether coxitis in FMF is a distinct entity or a manifestation of an associated axial spondyloarthritis. Our objectives were to describe the clinical, functional and radiological features of hip involvement in FMF.

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Pregnancy occurring in AA amyloidosis: a series of 27 patients including 3 new French cases

First author :  Delplanque M et al 

Review: J Nephrol

Reference :  doi: 10.1007/s40620-024-02038-y 

PMID: 39266930

Link to article :  Pregnancy occurring in AA amyloidosis: a series of 27 patients including 3 new French cases - PubMed (nih.gov)

Introduction:

AA amyloidosis (AAA) is a multisystemic disease caused by the deposition of serum amyloid A (SAA) protein in tissues, which complicates chronic inflammatory conditions. It is a potentially life-threatening complication, with renal involvement being the most common manifestation. Pregnancy in women with chronic kidney disease is considered a risk factor for specific pregnancy complications and worsening of their underlying kidney disease. Data on pregnancy occurring during AA amyloidosis are limited, highlighting the importance of studying maternal and fetal outcomes. The objective of this study was to report pregnancy cases in patients with AA amyloidosis discussed within our reference center and to review the literature on the subject.

Patients and Methods:

Francophone cases were collected via the national multidisciplinary consultation on AA amyloidosis. A literature review was conducted using the MEDLINE and EMBASE databases. The analyzed data included maternal age, pregnancy complications, outcomes, and renal and inflammatory parameters.

Results:

Three new cases are described: a Turkish woman with familial Mediterranean fever (FMF) and postpartum nephrotic syndrome, a woman with cryopyrinopathy who had an uncomplicated pregnancy, and a Georgian patient with FMF, a kidney transplant recipient, whose pregnancy was complicated by infection and preterm delivery.

Results from the 3 New Cases and the Literature Review:

Among the 27 cases, including 24 from the literature and 3 new ones, 8 patients were diagnosed with AA amyloidosis during or just after pregnancy. The median age at diagnosis was 25 years [19-32]. FMF was the main cause of AA amyloidosis (19 cases), followed by cryopyrinopathies (2 cases), chronic inflammatory bowel disease (2 cases), and infections (2 cases). Renal complications were common: 33% (3/9) of patients with an eGFR < 60 mL/min/1.73 m² experienced renal deterioration during pregnancy; 66% (8/12) had increased proteinuria. Ninety-two percent (23/25) of patients had obstetric complications, including preterm birth (11/25), intrauterine growth restriction (10/25), preeclampsia (4/25), and hypertension (3/25). The median gestational age at delivery was 36.5 weeks [32.5; 38], mostly by cesarean section (17/22), and no hemorrhagic complications were reported. Two patients had undergone kidney transplantation before pregnancy. Estimated glomerular filtration rate (eGFR) was known before pregnancy in 10 patients, with a median of 55 mL/min/1.73 m² [38; 57], and 8/15 had significant proteinuria (> 0.5g/24h). Among those with known baseline eGFR before pregnancy, 33% (3/9) experienced a decline in renal function during pregnancy, but all recovered afterward. Two patients whose prior kidney function was unknown required hemodialysis. Proteinuria increased during pregnancy in 66% of patients (8/12).

Conclusion:

Pregnancy is a critical moment in the natural course of AA amyloidosis in terms of diagnosis and the risk of renal and obstetric complications. When possible, pregnancy should be planned with pre-conception counseling, multidisciplinary management, and close monitoring to minimize these risks.