Approach
Diagnosis of FMF relies on clinical assessments, with additional genetic testing. Different sets of criteria have been developed, but they are yet to be validated in all populations affected by FMF. The most widely used criteria are the 1997 Tel Hashomer criteria; however, these do not incorporate genetic testing.[61] In children, the Yalcinkaya-Ozen criteria have been shown to be more sensitive for diagnosis of FMF in children, compared with the Tel Hashomer criteria.[62][63] In 2019, genotype and clinical manifestations were combined to form a classification criteria for hereditary recurrent fevers.[5] Although these are useful for the accurate identification of diseases for studies, they are not designed for diagnostic purposes.
In the typical form of FMF, the diagnosis is often obvious. At the beginning of the disease, when clinical signs are atypical or when the familial history is lacking, genetic testing is of great value. In a clinical context of FMF, the presence of 2 mutations on different alleles (homozygosity or compound heterozygosity) confirms the diagnosis.[54] When only 1 mutation is present, the diagnosis is unconfirmed; nevertheless, diagnosis should not be ruled out if the clinical presentation is typical, because some rare or unknown mutations do exist.[36][55] The registry of hereditary auto-inflammatory disorders mutations Opens in new window
Those same 'true' heterozygotes may display a complete clinical picture of FMF. It is also likely that some heterozygous patients, as in many recessive diseases, may have attenuated clinical signs. Even though the genetic diagnosis provides no final solution for every patient, it has become an important diagnostic tool for the confirmation of FMF diagnosis and, consequently, the provision of appropriate treatment, especially in children.[60]
FMF’s major complication is systemic secondary amyloidosis. This can readily be prevented by colchicine prophylaxis, which explains the need for prompt and accurate diagnosis.
History and examination
Classically, patients are children or adolescents from Turkish, Arabic, Armenian, Sephardic Jewish, or Italian backgrounds, with 24 to 72 hours of fever, severe abdominal pain, arthralgias or monoarthritis, pleurisy, or erythematous rash on one ankle or foot. Complete resolution of attacks in 24 to 72 hours is highly suggestive of FMF. In very young children, the disease may begin with fever alone, but progresses to typical symptoms over time.[64]
Classically, fever is associated with signs of acute serosal inflammation, with only one site affected during an attack. The most severe attacks may involve more than one site. Rarely, patients may suffer from scrotitis, pericarditis, or aseptic meningitis. Attacks stop spontaneously, and their recurrences have no regular periodicity. Their frequency varies considerably from one patient to another, and from one period of life to another for the same patient. Some factors can trigger inflammatory attacks in FMF, especially stress, viral disease in infancy, or physical exertion. Prodromes of FMF attacks may include discomfort at the impending attack site or various constitutional, emotional, and physical complaints, including irritability, dizziness, increased appetite, and altered taste sensation. A prodrome is a valid sign of an imminent attack in a subgroup of FMF patients.
Patients may also present with protracted febrile myalgia: this is an uncommon but severe condition characterised by severe paralysing myalgia, high fever, abdominal pain, diarrhoea, arthritis/arthralgia, and transient vasculitic rashes mimicking Henoch-Schonlein purpura. Other than amyloidosis, chronic manifestations of the disease (e.g., encapsulating peritonitis and chronic destructive arthritis, which especially affect the hips and knees) are rare. Splenomegaly, most often without any specific consequences, may also be observed in a subgroup of patients with incompletely controlled inflammation.
Amyloid nephropathy was the cause of death in FMF before the colchicine era. FMF-associated amyloidosis is a canonical form of inflammatory or amyloid A (AA) amyloidosis, which complicates longstanding inflammatory diseases.[29][65][66] In the absence of FMF diagnosis and appropriate treatment, amyloidosis remains the main complication of FMF. Amyloidosis generally occurs in patients with early and severe inflammatory attacks. This fits with current data of the pathogenesis of AA amyloidosis, which show that the risk of developing AA amyloidosis is tightly linked to the duration and intensity of the inflammatory state as reflected by the level of serum amyloid A (SAA). In fact, SAA, as well as C-reactive protein, is increased during FMF attacks. However, amyloidosis may even occur in patients with no recognised clinical inflammatory attacks (FMF phenotype II). Phenotype II is certainly rare, and it probably results - at least in part - from the existence of blood inflammation between the attacks: SAA was found to be elevated between clinical attacks, which suggests the presence of infra-clinical inflammation. On the other hand, not all patients with FMF develop amyloidosis. It has long been established that the prevalence of amyloidosis varies according to ethnic groups. This suggests that genetic and/or environmental factors participate in the occurrence of amyloidosis during FMF.
Incomplete presentations are more common in heterozygous patients, and heterozygosity may be a risk factor for various other inflammatory diseases (e.g., Crohn's disease, Behcet's disease, or multiple sclerosis).
Past surgical history may reveal appendectomy and/or other abdominal surgery due to misdiagnosed appendicitis and other falsely acute surgical abdomens. Past medical history may reveal seronegative spondyloarthropathy and/or Henoch-Schonlein purpura.
Laboratory tests
The following tests are routinely performed as part of the evaluation:
FBC
ESR, CRP, and serum fibrinogen
LFTs and LDH
Urinalysis.
Acute-phase reactants are usually elevated during flare-ups. However, these are not specific and may remain elevated after the resolution of the attacks. In atypical cases it is important to evaluate for other causes of prolonged or unexplained fever or organ involvement. SAA measurement in between attacks may be a valuable tool for the solution of some diagnostic dilemmas, because SAA remains elevated during attack-free periods in a significant proportion of patients.[67] Proteinuria might also be present during attacks, which should trigger an evaluation for the potentially fatal complication of renal amyloidosis.
Radiological testing
Chest and abdominal imaging (x-ray, CT) is not specific or diagnostic, but may be helpful in suggesting diagnosis and/or excluding differential diagnoses.
Chest x-ray is indicated in patients whose history or physical examination suggests cardiopulmonary involvement. This is usually done in the emergency department but may be done by specialists if patients are not responding after several days of classic treatment.
Echocardiography is indicated in patients whose history or physical examination suggests serositis/pericarditis.
Abdominal CT is indicated in patients with severe abdominal pain, in those who are not responding to treatment, or in those with an acute abdomen.
Joint x-ray is indicated in patients who have significant single joint involvement (severe pain, inability to ambulate, limited range of motion), or in those with joint pain who are not responding after 2 days of treatment.
Joint MRI is indicated in patients with negative x-rays, in those with atypical presentations, or in those with soft-tissue involvement that is unresponsive to treatment.
Response to colchicine
Unique among other hereditary periodic fever syndromes, clinical response to a trial of colchicine is almost always diagnostic of FMF.[68][69]
Genetic testing
Genetic testing may be helpful in confirming the diagnosis of atypical cases or in between attacks to support diagnosis, but it is more helpful in countries where FMF is not common.[26] The 4 most common mutations (M680I, M694V, V726A, and M694I) are present in more than two-thirds of cases.[11][49] Patients who are homozygotic for the M694V mutation have more severe disease at an early age; have more frequent attacks, arthritis, and erysipeloid erythema; are more likely to develop amyloidosis and nephritic syndrome; and are less likely to respond to colchicine.
Controversy exists as to the role of the amino acid substitution E148Q, where glutamine (Q) substitutes for glutamic acid (E). Initially this sequence variation was described as a disease-causing mutation with low penetrance and mild symptoms.[22][23][24] Subsequent studies suggest it may be no more than a benign polymorphism with a high frequency in the general population (up to 30% in some Asian populations).[25][26] The 2015 Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) guideline concludes that the E148Q variant is common, of unknown pathogenic significance, and as the only MEFV variant, does not support a diagnosis of FMF.[26] However, the debate still exists. Physicians should closely monitor patients with a specifically homozygous E148Q genotype due to its possible association with amyloidosis.[27][28][29]
Many laboratories now offer efficient genetic testing.[55] Some commercially available assays such as the 'FMF StripAssay' provide quicker results with high sensitivity for the most frequent mutations.
To obtain genetic tests, physicians should contact their local laboratory provider (or local research laboratories at university centres).
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