Familial Mediterranean fever (periodic disease): history or a real problem

The review is devoted to the most common monogenic autoinflammatory disease – familial Mediterranean fever (FML) caused by MEFV gene mutation that occurs mainly in the representatives of certain ethnic groups and manifests itself as recurrent 6–72-hour attacks of pyretic fever accompanied by the phenomena of aseptic peritonitis, pleurisy, arthritis, and inflammatory rash. The disease can lead to a life-threatening complication, such as amyloidosis. FML is noted to be comorbid with a number of other inflammatory diseases: systemic vasculitis, chronic joint inflammatory diseases, and inflammatory bowel diseases. Emphasis is laid on the therapy aspects set out in the 2016 EULAR guidelines. The mainstay of treatment for FML is colchicine that prevents recurrences of the disease, minimizes the risk of amyloidosis, and should be prescribed immediately, once diagnosed. The paper deals with the definition of colchicine resistance that is observed in 5–10% of patients. Biological agents, among which interleukin-1 are most preferred, are now used to treat this category of patients. The high efficacy of these agents in patients with FML has been confirmed in randomized controlled studies.

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Il-1antagonist Treatment in Recurrent Aseptic Meningitis Related to Familial Mediterranean Fever

10.21203/rs.3.rs-71444/v1 ◽

2020 ◽

Author(s):

Ruth Livny ◽

Yuval Bitterman ◽

Riva Brik ◽

Yonatan Butbul Aviel

Keyword(s):

Nervous System ◽

Familial Mediterranean Fever ◽

Aseptic Meningitis ◽

Inflammatory Diseases ◽

Case Reports ◽

Interleukin 1 ◽

Colchicine Treatment ◽

Cns Involvement ◽

Mediterranean Fever ◽

Recurrent Aseptic Meningitis

Abstract Background Familial Mediterranean fever (FMF) is an autosomal recessive, auto-inflammatory disease, presenting with recurrent bouts of fever and polyserositis. FMF has been associated with central nervous system (CNS) manifestations such as Headache and Myalgia. The occurrence of other forms of nervous system involvement is rare, including seizures, sinus vein thrombosis, pseudotumor cerebri and more. There are only few case reports of aseptic meningitis due to FMF. Case presentation We present the case of a 14 year-old girl diagnosed with FMF, who experienced recurrent episodes of severe headache and aseptic meningitis while on maximal dose of colchicine therapy. She had a dramatic response to anakinra with symptoms resolving completely within a few days without recurrence. Subsequently, we identified seven cases in the literature describing recurrent aseptic meningitis in patients with underlying FMF; all showed response to colchicine treatment, without treatment failure. Conclusion Our case suggests a role for Interleukin 1 (IL-1) antagonists for cases of CNS involvement secondary to FMF in patients who fail to respond to colchicine, and might imply that anakinra could be effective in other auto-inflammatory diseases with CNS involvement.

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AB0987 The relationship between anti-interleukin-1 therapies and mefv gene mutations in familial mediterranean fever patients: a single center experience

10.1136/annrheumdis-2017-eular.6487 ◽

2017 ◽

Author(s):

ME Derin ◽

S Gültekin ◽

M Şahin ◽

A Şahin

Keyword(s):

Familial Mediterranean Fever ◽

Interleukin 1 ◽

Mefv Gene ◽

Gene Mutations ◽

Single Center ◽

Single Center Experience ◽

Mediterranean Fever ◽

The Relationship

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POS1368 ANTI-IL-1 THERAPIES IN COLCHICINE-RESISTANT OR İNTOLERANT PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER: SINGLE CENTER EXPERIENCE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3257 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 966.1-966

Author(s):

M. E. Derin ◽

B. Karakaş ◽

B. Karataş ◽

N. Çabuk Çelik ◽

İ. Yalçin ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Interleukin 1 ◽

Mefv Gene ◽

Gene Mutations ◽

Recurrent Fever ◽

Long Term Effects ◽

Single Center Experience ◽

Eular Recommendations ◽

Mediterranean Fever

Background:Familial Mediterranean Fever (FMF) is a hereditary auto-inflammatory disease characterized by recurrent fever and serosal inflammation (1). The goal of FMF treatment is to prevent the attacks and to minimize subclinical inflammation between attacks The main treatment of FMF is colchicine however anti-interleukin-1 treatments are recommended in colchicine resistant and/or intolerant FMF patients (2).Objectives:The aim of this study is to evaluate the efficacy of anti-interleukin-1 (anti-IL-1) agents in 81 FMF patients with resistant/intolareted to colchicine or complicated with amyloidosis.Methods:Between January 2014 and December 2020, eighty-one patients who were diagnosed as FMF according to the criteria of Tel-Hashomer that following-up at Cumhuriyet University Medical Faculty Rheumatology-Internal Medicine Department were included in to the study.Results:45 (55.6%) male and 36 (44.4%) female were included in the study. The median age of the patients was 25 years (min:17-max: 60) and the median age at diagnosis was 15 years (min 3-max 46). 44 patients (54.3%) used Anakinra (100 mg/day), and 27 (45.7%) canakinumab (150mg/8month) were used. 49 cases were resistant to colchicine,16 were intolerant to colchicine, 16 (20%) cases were comlicated with amyloidosis. 10 patients had renal transplantation. MEFV gene mutations are shown in Table 1. Median duration of anti-IL-1 agent use was 24 month (min:4-max 52). 9 patients were resistant to anakinra, 18 patients had side effects which anakinra related. After a median follow up 12 months overall clinical response was %95 (frequency of attacks <1/6months). median proteinuria decreased from 3500 mg /day to median 1500 mg /day (p: 0.04) (Table 2). IL-6 treatment was started in 4 patients because of ineffective canakinumab. Five pregnant patients were followed up with anakinra during pregnancy and there were no problems.Conclusion:Anti-interleukin-1 agents are effectively and safely in the treatment of FMF patients. There are still unanswered questions in FMF treatment such as other factors affecting the frequency of attacks, colchicine resistance is not defined precisely and the importance of some mutations. The effect of anti IL-1 agents on FMF patients with amyloidosis is not clearly. According to our experience, these treatments are effective in patients with glomerular filtration rate> 60 ml/min. For answers to these and similar questions, Large and long follow-up studies are needed for long-term effects.References:[1]Özen S, Batu ED, Demir S., Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommendations for Management. Front Immunol. 2017 Mar 23;8:253. doi: 10.3389/fimmu.2017.00253. eCollection 2017.[2]Seza Özen ve ark. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. 2016 Apr;75(4):644-51.Disclosure of Interests:None declared

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FAMILIAL MEDITERRANEAN FEVER: ASSESSING THE OVERALL CLINICAL IMPACT AND FORMULATING TREATMENT PLANS

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2019.027 ◽

2019 ◽

Vol 11 (1) ◽

pp. e2019027 ◽

Cited By ~ 8

Author(s):

Donato Rigante ◽

Raffaele Manna

Keyword(s):

Familial Mediterranean Fever ◽

Therapeutic Option ◽

Interleukin 1 ◽

Mefv Gene ◽

Clinical Signs ◽

Gene Mutations ◽

Recessive Trait ◽

Aa Amyloidosis ◽

Mefv Mutations ◽

Mediterranean Fever

Recurrent self-limited attacks of fever and short-lived inflammation in the serosal membranes, joints and skin are the leading features of familial Mediterranean fever (FMF), the most common autoinflammatory disorder in the world, transmitted as autosomal recessive trait caused by MEFV gene mutations. Their consequence is an abnormal function of pyrin, a natural repressor of inflammation, apoptosis and release of cytokines. FMF-related mutant pyrins are hypophosphorylated following RhoA GTPases’ impaired activity and show a propensity to relapsing uncontrolled systemic inflammation with inappropriate response to inflammatory stimuli and leukocyte spread to serosal membranes, joints or skin. Typical FMF phenotype 1 consists of brief episodes of inflammation and serositis, synovitis, and/or erysipelas-like eruption, whereas phenotype 2 is defined by reactive amyloid-associated (AA) amyloidosis, which is the most ominous complication of FMF, in otherwise asymptomatic individuals. Furthermore, FMF phenotype 3 is referred to the presence of two MEFV mutations with neither clinical signs of FMF, nor AA amyloidosis. The influence of epigenetic and/or environmental factors can contribute to the variable penetrance and phenotypic heterogeneity of FMF. Colchicine, a tricyclic alkaloid with anti-microtubule and anti-inflammatory properties, is the bedrock of FMF management: daily administration of colchicine prevents the recurrence of FMF attacks and the development of secondary AA amyloidosis. Many recent studies have also shown that anti-interleukin-1 treatment is actually the best therapeutic option for FMF patients nonresponsive or intolerant to colchicine. This review aims to catch readers’ attention on the clinical diversity of phenotypes, differential diagnosis, and management of patients with FMF.

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E148Q of the MEFV Gene Causes Amyloidosis in Familial Mediterranean Fever Patients

PEDIATRICS ◽

10.1542/peds.108.1.215 ◽

2001 ◽

Vol 108 (1) ◽

pp. 215-215 ◽

Cited By ~ 4

Author(s):

N. Akar ◽

E. Akar ◽

F. Yalcinkaya; ◽

G. J. Halpern ◽

A. Mimouni ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Mefv Gene ◽

Mediterranean Fever

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AB0980 CASE-REVIEW ON FAMILIAL MEDITERRANEAN FEVER IN A SPECIALIZED CENTRE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1355 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1784.1-1784

Author(s):

R. Dos Santos Sobrín ◽

M. Martí Masanet ◽

B. Lopez-Montesinos ◽

L. Lacruz Pérez ◽

I. Calvo

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Familial Mediterranean Fever ◽

Periodic Fever ◽

Severe Disease ◽

Strong Association ◽

Mefv Gene ◽

Systemic Juvenile Idiopathic Arthritis ◽

Case Series ◽

Case Review ◽

Mediterranean Fever

Background:Familial Mediterranean Fever (FMF) is a genetic autoinflammatory disorder caused mostly by mutations in MEFV gene. Its inheritance is autosomal recessive and is the most frequent periodic fever syndrome. First-line treatment is based in colchicine use, so biologics (anti-IL-1) are reserved for refractory cases1, 2.Objectives:To account for clinic and treatment features of patients with FMF in a specialized center as opposed to non-referent centers.Methods:This study was developed in the Pediatric Rheumatology Service in Hospital Universitario y Politécnico La Fe de Valencia. Demographic, clinic and treatment data were collected from patients diagnosed of FMF since January 2004 to September 2019.Results:106 patients met last FMF criteria3. 55% had a pathogenic mutation in genetic analysis. 52% were female. Before 10 years old, 71% of patients had the diagnosis (51% before 4 years old). Arthralgia/myalgia (73%), periodic fever (62%) and abdominal pain (54%) were the most common symptoms. Systemic Juvenile Idiopathic Arthritis (JIA, 6), other forms of JIA (9) and vasculitis (10) were the most prevalent comorbidities. When talking about treatment, 76,4% received Colchicine (60,5% with good response), 22,6% needed a classical disease modifying antirheumatic drug (mostly Methotrexate) and 22 patients got biologic treatment (73% anti-IL-1).Conclusion:When analyzing this case-review, JIA has a strong association with our patients, so it could explain severe disease activity and more articular involvement. This could be an illustration to the higher use of Methotrexate. Also, the most relevant symptom was arthralgia while fever is the most frequent in literature. Likewise, age of diagnosis has been earlier than other case-series (this would be more frequent in other autoinflammatory syndromes, as literature relates)1, 2, 4.References:[1]Ozdogan H, Ugurlu S. Familial Mediterranean Fever. Presse Med. (2019).[2]Ozen S, Demirkaya E, Erer B, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 2016;75:644-651.[3]Sag E, Demirel D, Demir S, et al. Performance of the new “Eurofever/PRINTO classification criteria” in FMF patients. Semin Arthritis Rheum. 2019;19:30369-5.[4]Rozenbaum M, Rosner I. Severe outcome of juvenile idiopathic arthritis (JIA) associated with familial Mediterranean fever (FMF). Clin Exp Rheumatol. 2004;22:S75-8.Disclosure of Interests:Raquel Dos Santos Sobrín: None declared, Miguel Martí Masanet: None declared, B Lopez-Montesinos: None declared, Lucía Lacruz Pérez: None declared, Inmaculada Calvo Grant/research support from: Bristol-Myers Squibb, Clementia, GlaxoSmithKline, Hoffman-La Roche, Merck Sharpe & Dohme, Novartis, Pfizer, Sanofi, Speakers bureau: AbbVie, GlaxoSmithKline, Hoffman-La Roche, Novartis

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Familial Mediterranean fever-associated mutation pyrin E148Q as a potential risk factor for multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458512437813 ◽

2012 ◽

Vol 18 (9) ◽

pp. 1229-1238 ◽

Cited By ~ 11

Author(s):

T Kümpfel ◽

L-A Gerdes ◽

T Wacker ◽

A Blaschek ◽

J Havla ◽

...

Keyword(s):

Multiple Sclerosis ◽

Risk Factor ◽

Familial Mediterranean Fever ◽

Mefv Gene ◽

German Population ◽

Gene Group ◽

Mefv Mutations ◽

Mediterranean Fever ◽

Group 2 ◽

Group 1

Background: Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease caused by mutations in the MEFV gene and characterized by recurrent febrile polyserositis. A possible association of FMF and multiple sclerosis (MS) has been suggested in cohorts from Turkey and Israel. Objective: The objective of this study was to investigate the prevalence of MEFV mutations in subjects with MS and in controls in Germany. Methods: One-hundred and fifty seven MS patients with at least one symptom or without symptoms suggestive of FMF from our outpatient clinic were investigated for mutations in exons 2, 3, and 10 of the MEFV gene (group 1). 260 independent MS patients (group 2) and 400 unrelated Caucasian controls (group 3) were screened selectively for the low-penetrance pyrin mutations E148Q and K695R Results: In group 1, 19 MS patients (12.1%) tested positive for a mutation in the MEFV gene, mainly the E148Q ( n=7) substitution. Fifteen of the 19 mutation-positive individuals reported at least one symptom suggestive of FMF. In three cases, we could identify additional family members with MS. In these pedigrees, the E148Q exchange co-segregated with MS ( p=0.026). Frequencies of the pyrin E148Q and K695R mutations were not statistically different between MS group 2 and controls but they occurred with a surprisingly high frequency in the German population. Conclusion: The MEFV gene appears to be another immunologically relevant gene locus which contributes to MS susceptibility. In particular, the pyrin E148Q mutation, which co-segregated with disease in three MS families, is a promising candidate risk factor for MS that should be further explored in larger studies.

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