French protocol for the diagnosis and management of familial Mediterranean fever.

Familial Mediterranean fever is the most common monogenic auto-inflammatory disease in the world. It mainly affects people originating 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 2-3days and a biological inflammatory syndrome. Other symptoms include arthralgia or arthritis in large joints such as the knees and ankles, myalgia in the lower limbs and pseudo-erysipelas in the ankles. The most serious complication is inflammatory amyloidosis, which can lead to kidney failure. Treatment is based on colchicine, which helps to prevent flares and the onset of renal amyloidosis. This paper proposes national guidelines for the diagnosis, management and follow-up of familial Mediterranean fever in France, where we estimate there are between 5000 and 10,000 patients with the disease at all stages of life. The diagnosis is suspected on the basis of clinical and anamnestic factors and confirmed by genetic analysis. These guidelines also suggest a "treat-to-target" approach to disease management, particularly in case of suspected colchicine resistance - a very rare situation that should remain a diagnosis of elimination, especially after colchicine compliance has been verified. Two special situations are also addressed in these guidelines: kidney failure and pregnancy.

French practical guidelines for the diagnosis and management of AA amyloidosis.

AA amyloidosis is secondary to the deposit of excess insoluble Serum Amyloid A (SAA) protein fibrils. AA amyloidosis complicates chronic inflammatory diseases, especially chronic inflammatory rheumatisms such as rheumatoid arthritis and spondyloarthritis; chronic infections such as tuberculosis, bronchectasia, chronic inflammatory bowel diseases such as Crohn's disease; and auto-inflammatory diseases including familial Mediterranean fever. This work consists of the French guidelines for the diagnosis workup and treatment of AA amyloidosis. We estimate in France between 500 and 700 cases in the whole French population, affecting both men and women. The most frequent organ impaired is kidney which usually manifests by oedemas of the lower extremities, proteinuria, and/or renal failure. Patients are usually tired and can display digestive features anf thyroid goiter. The diagnosis of AA amyloidosis is based on detection of amyloid deposits on a biopsy using Congo Red staining with a characteristic green birefringence in polarized light. Immunohistochemical analysis with an antibody directed against Serum Amyloid A protein is essential to confirm the diagnosis of AA amyloidosis. Peripheral inflammatory biomarkers can be measured such as C Reactive protein and SAA. We propose an algorithm to guide the etiological diagnosis of AA amyloidosis. The treatement relies on the etiologic treatment of the undelying chronic inflammatory disease to decrease and/or normalize Serum Amyloid A protein concentration in order to stabilize amyloidosis. In case of renal failure, dialysis or even a kidney transplant can be porposed. Nowadays, there is currently no specific treatment for AA amyloidosis deposits which constitutes a therapeutic challenge for the future.

Evaluation of the Ocular Surface, Conjunctival Impression Cytology and Meibomian Gland Dropout in Patients with Familial Mediterranean Fever.

PURPOSE: Familial Mediterranean fever (FMF) is an idiopathic disease with chronic inflammation. We aimed to determine the changes caused by the chronic inflammatory nature of FMF on the ocular surface, meibomian glands (MG), and conjunctiva via conjunctival impression cytology (CIC). MATERIAL-METHOD: Forty-two FMF patients with a mean age of 11.93±3.92 years and 36 control patients with a mean age of 11.83±3.38 years were included in the study. Ocular surface anomalies of the patients were evaluated using Schirmer II, TBUT and OSDI. MG function (meibum quality), morphology (meiboography), and CIC were evaluated. RESULTS: Although there was a significant difference between the groups in terms of Schirmer II and TBUT, OSDI scores did not significantly differ (P=0.022, 0.010, and 0.099 respectively), and no significant dry eye sign was observed in either group. There was significant difference between the groups in terms of the percent area of MG dropout, MG density, meiboscore (P=0.020, 0.023, and 0.031 respectively), but no significant difference was observed in relation to MG quality (P=0.650). Although conjunctival impression cytology was of a higher grade in the patients with FMF according to Nelson's classification, no significant difference was observed between the groups (P=0.109). CONCLUSION: Although there was a decrease in the number of MGs in FMF patients, no significant deterioration was observed in conjunctival cytology. In these patients, tear film stability may deteriorate in particular. Clinicians should be aware of the possibility of ocular surface disease secondary to MG dropout in patients with FMF.

[Familial Mediterranean fever in 2020]. / Fièvre méditerranéenne familiale en 2020.

Familial Mediterranean fever is the most frequent autoinflammatory disease with autosomal recessive transmission. Most patients carry mutations in the MEFV gene encoding the protein marenostrin/pyrin. It is characterised by short ant recurrent attacks of fever and serositis with abdominal or thoracic pain, usually lasting less than 3 days, raised inflammatory biologic markers in an individual of Mediterranean origin. Colchicine has been shown to be effective in prevention of inflammatory attacks and development of amyloidosis which is responsible of nephrotic syndrome and chronic renal failure. Better knowledge in pathogenic mechanisms permitted identification of interleukin-1 beta (Il-1 ß) as the main cytokine target. Anti-IL-1 therapy must be considered as a second line treatment in case of persistent inflammation or colchicine intolerance.

[Periodic fever syndrome associated with mutations in the TNF type 1 receptor gene: A differential diagnosis of familial Mediterranean fever that should not be overlooked in patients of Mediterranean origin]. / Le syndrome de fièvre prolongée associée aux mutations du gène du récepteur au TNF de type 1 : un diagnostic différentiel de la fièvre méditerranéenne familiale à ne pas méconnaître chez les patients d'origine méditerranéenne.

INTRODUCTION: Tumor Necrosis Factor Type 1 Receptor Associated Periodic Syndrome (TRAPS) is a rare autosomal dominant autosomal autoinflammatory disease associated with mutations in the TNF type 1 receptor gene (TNFRSF1A). It is characterized by relatively long recurrent febrile seizures with an average duration of 7 days accompanied by arthralgia, myalgia, and usually a rash. In a patient of Mediterranean origin with recurrent fever, familial Mediterranean fever is the first diagnosis to be suspected by argument of frequency. METHODS: A retrospective observational study was conducted on patients from Mediterranean origin followed for TRAPS and included in the "Juvenile Inflammatory Rheumatism" (JIR) observational cohort in the national French autoinflammatory center. The age of onset of symptoms, age of diagnosis, number of years of wandering and treatments received were collected for each index case. RESULTS: Nine patients from 6 families of Mediterranean origin were included. A molecular diagnosis confirmed TRAPS in all patients. The median age at diagnosis was 26 years, the mean number of years of wandering was 17 years. The diagnosis of FMF was made first in all patients. AA amyloidosis revealed TRAPS in 2 patients. Colchicine was started without any efficacy in all cases. Five patients were treated with interleukin-1 inhibitory biotherapy with 100% efficacy. CONCLUSION: In a patient of Mediterranean origin presenting with recurrent febrile abdominal pain of AA amyloidosis, the first diagnosis to be suspected is FMF. Long relapses, dominant transmission, a non-Mediterranean relative, and the ineffectiveness of colchicine should evoke TRAPS.

[Familial Mediterranean fever]. / La fièvre méditerranéenne familiale.

Familial Mediterranean Fever (FMF) is the most frequent monogenic auto-inflammatory disease. FMF is an autosomal recessive disease, which affects populations from Mediterranean origin and is associated with MEFV gene mutations encoding for the protein pyrin. Pyrin activation enhances the secretion of interleukin 1 by myelo-monocytic cells. Main features of the disease are acute attacks of serositis mainly located on the abdomen, less frequently on chest and joints, accompanied by fever and biological inflammatory markers elevation. Usually attacks last 1 to 3 days and spontaneously stop. A daily oral colchicine intake of 1 to 2mg/day is able to prevent attack's occurrence, frequency, intensity and duration among most patients. Colchicine is also able to prevent the development of inflammatory amyloidosis, the most severe complication of FMF. This state of the art article will focus on the diagnosis of FMF, the treatment and an update on the pathophysiology including the recent described dominant form of MEFV-associated new auto-inflammatory diseases.

[Mesothelioma and familial Mediterranean fever: A relationship?]. / Mésothéliome et fièvre méditerranéenne familiale : quelle relation ?

INTRODUCTION: The majority of pleural and peritoneal mesotheliomas are linked to asbestos exposure but, in around 20% of cases, no history of such exposure is found. Periodic disease is associated with recurrent serositis, which could favor the development of mesothelioma. CASE REPORT: We report a case of pleural mesothelioma in a 50-year-old Lebanese woman, with no detectable exposure to asbestos but suffering from periodic disease (familial Mediterranean fever) with recurrent episodes of serositis. DISCUSSION: Many cases of peritoneal mesothelioma in patients with FMF are reported in the literature. This is the second reported case of pleural mesothelioma associated with periodic disease. Because of the low incidence of both diseases, further publications are required to support the hypothesis of a causal link. It is important, therefore, that all cases of an association of periodic disease and mesothelioma are reported.