Clinical Guidance

(p.Met694Val). Persons who are homozygous for the pathogenic variant p.Met694Val have an earlier age of onset and higher frequencies of arthritis and arthralgia than persons who are homozygous or compound heterozygous for other pathogenic variants . Individuals with the p.Met694Val pathogenic variant, particularly homozygous individuals, are at increased risk for amyloidosis and have a decreased response to colchicine . Other pathogenic variants. Amyloidosis occurs less frequently in the presence of pathogenic variants other than p.Met694Val [, , , ]. Other possible modifiers. Intra- and interfamilial clinical differences independent of MEFV genotype suggest genetic and/or environmental modifiers. Suggested modifiers:

Source: GeneReviews — "Familial Mediterranean Fever"

Diagnostic Criteria

Suggestive Findings

Familial Mediterranean fever (FMF) should be suspected in individuals with the following:

• Recurrent febrile episodes accompanied by peritonitis, synovitis, or pleuritis

• Recurrent erysipelas-like erythema

• Repeated laparotomies for "acute abdomen" with no pathology found

• Amyloidosis of the AA type that characteristically develops after age 15 years in untreated individuals, even in those who do not have a history of recurrent inflammatory attacks

• Favorable response to continuous colchicine treatment

• A first-degree relative with FMF

• Membership in an at-risk ethnic group

Establishing the Diagnosis

The minimal (and most current) clinical criteria used to establish the diagnosis of FMF are the Tel Hashomer clinical criteria . Identification of biallelic MEFV pathogenic (or likely...

Source: GeneReviews — "Familial Mediterranean Fever"

Differential Diagnosis

Individuals of western European descent with clinical features of FMF rarely have MEFV pathogenic variants identified. Individuals from these populations likely have another condition with similar clinical features that cannot be accounted for by pathogenic variants in MEFV, and thus, another diagnosis should be considered in these individuals .

Autoinflammatory diseases

• Cryopyrin-associated periodic syndromes

Source: GeneReviews — "Familial Mediterranean Fever"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with familial Mediterranean fever (FMF), the following evaluations are recommended:

• Physical examination to assess joint problems

• Urinalysis for the presence of protein. If proteinuria is found, further evaluation is required including measurement of 24-hour urinary protein, kidney function tests, and consider a rectal biopsy for the presence of amyloid.

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

For information on treatment with colchicine see . Colchicine is not effective as treatment for an acute FMF attack. During an acute episode, the therapeutic approach should be mainly supportive, including administration of intravenous saline for hydration and use of nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol or dipyrone for pain relief . Febrile and inflammatory episodes are usually treated with NSAIDs. End-stage kidney disease caused by renal amyloidosis should be treated as for other causes of kidney failure. The long-term outcome of live related-donor kidney transplantation in individuals with FMF-related amyloidosis is similar to that in the general transplant population .

Prevention of Primary Manifestations

Colchicine

Source: GeneReviews — "Familial Mediterranean Fever"

Clinical Guidance

Cisplatin. One report suggests that cisplatin worsens symptoms of FMF . Cyclosporin A appears to adversely affect kidney transplant graft survival in individuals with FMF . It has also been reported to trigger FMF attacks, which responded well to colchicine in a previously asymptomatic individual with myelodysplastic syndrome who was heterozygous for the MEFV pathogenic variant p.Met694Ile .

Source: GeneReviews — "Familial Mediterranean Fever"

Therapies Under Investigation

The decrease of blood nitric oxide (NO) levels in individuals with FMF may trigger fever by initiating the production of IL-6. Plasma NO levels in those with FMF were significantly increased during attack-free periods following treatment with ImmunoGuard®, which has a normalizing effect both on NO and IL-6 blood levels in persons with FMF during attacks . However, further studies are needed to confirm a single report of successful treatment of FMF with ImmunoGuard® (Andrographis paniculata Nees) . The role of biologics such as other anti-tumor necrosis factor (TNF) agents (adalimumab and golimumab) in the treatment of FMF has recently been investigated .

Source: GeneReviews — "Familial Mediterranean Fever"

Surveillance Guidelines

All individuals with FMF including those not currently being treated, those being treated with colchicine, and those receiving medication other than colchicine should undergo an annual physical examination, a urine spot test for protein, and an evaluation for hematuria . additionally recommended monitoring acute-phase reactants (ESR and fibrinogen levels) at regular intervals during attack-free periods, particularly in those with the p.Met694Val pathogenic variant.

Source: GeneReviews — "Familial Mediterranean Fever"