FMF begins in childhood (90% of patients experience the first attack before the age of 20 years ), with sudden periodic febrile attacks and serositis which, in order of frequency, include peritonitis, arthritis, pleuritis, erysipelatous rash which usually resolve spontaneously over 6–96 h (Fig. 1a,b).
Figure 1. An example of the temporal profile of fever in a symptomatic patient with FMF is shown, before diagnosis was established and colchicine therapy could be initiated. (a) The febrile attacks in a year are reported as peaks according to days and months. The cut-off value of 37 °C is shown as dotted horizontal line. In the period separating each attack, the temperature has been conventionally set at 36·5 °C. A total of 14 attacks have occurred in a year in this patient. The black arrow indicates the febrile attack depicted in (b). (b) Behaviour of a single febrile attack in a patient with FMF, with respect to time (hours). The relation with the inflammatory status and symptoms is illustrated (black horizontal arrow).
Download figure to PowerPoint
The frequency of attacks can be variable, and no clear trigger event has been identified. Temperature may reach 38–40 °C and can anticipate other symptoms, although some patients may present with fever alone . Other patients may experience a prodromic syndrome heralding attacks, consisting of discomfort, physical, emotional, neuropsychological complaints .
The dominant manifestation of the disease is peritonitis with more than 90% of patients affected . During attacks, most of the patients may exhibit an initially localized pain which rapidly acquires the clinical picture of an acute abdomen, more than simple abdominal pain. Especially when FMF diagnosis has not been established, the occurrence of rebound tenderness, guarding, adynamic ileus, rigidity and fever may put patients with FMF at risk of unnecessary abdominal surgery, because peritoneal manifestations may mimic a number of other conditions including cholecystitis, appendicitis, renal colicky pain. Remarkably, patients are totally asymptomatic in between attacks, a period which can last from 1 week to several months. Visceral adhesions may develop, due to recurrent peritoneal inflammation. A consequence might be later onset of small bowel obstruction and, in the case of pelvic adhesions, reduced fertility in females.
Pleural manifestations (chest pain with transient pleural effusions due to unilateral pleuritis or a pain which referred because of subdiaphragmatic peritonitis) may occur in one-third of patients with FMF [1, 4]. Pericarditis occurs in < 1% of patients .
Synovial symptoms occur by arthritis, due to the involvement of joints, especially knees, ankles, hip, elbow and wrists, usually mono- or oligo-articular. Permanent damage of joints is unusual, and arthritis may be the only FMF manifestation. While Ashkenazi Jews and Armenians suffer less from synovitis, North Africans may present with more severe synovitis . Arthritis usually is not associated with joint destruction, although it can last for several weeks or months. Thus, deformity and functional limitations are rare. Migratory polyarthritis are rare and might mimic acute rheumatic fever.
It is frequent to encounter dermatologic manifestations in up to 50% of patients with FMF, particularly erysipelas-like rashes on the lower extremities. Lesions are generally unilateral, occur below the knee, ranging from 15 to 50 cm2, and are often associated with swelling and tenderness . Although the clinical picture can resemble the infectious cellulitis, no treatment with antibiotics is advised and recovery is spontaneous.
Physical examination in patients with FMF is unremarkable during the intercritical attacks, but show brief febrile episodes occurring with peritonitis and painful arthritis, without major joint swelling. In the typical form, paroxysms (usually without premonitory symptoms) last 2–4 days with greater intensity in the first 12 h. Constipation is typically occurring during the attacks and can be followed by late diarrhoea.
Fibromyalgia with tender muscles has been reported in FMF. Other clinical manifestations associated with FMF may include episodes of pericarditis, pelvic inflammatory disease, inflammation of the tunica vaginalis with painful scrotal swelling mimicking testicular torsion and orchitis , Henoch-Schönlein purpura, Behçet disease and polyarteritis nodosa  and protracted abdominal febrile myalgia .
No common biomarker or imaging study is specific for FMF. Inflammatory mediators include erythrocyte sedimentation rate, serum C-reactive protein level, SAA, beta-2-microglobulin, fibrinogen and white blood cells. Synovial fluid leucocyte count can be elevated during febrile attacks (up to 1 000 000/μL) and consists mainly of neutrophils [3, 67]. When renal amyloidosis has developed, proteinuria may be present in between attacks.
Deposition of SAA (anticipated by increased levels of SAA protein especially during acute attacks) is responsible for renal involvement, the most important complication of FMF . Proteinuria (> 0·5 g of protein per 24 h) observed in between attacks should suggest amyloidosis in patients with FMF . The risk of amyloidosis AA is higher in Sephardic Jews (30%) than in Ashkenazi Jews  and can be as high as 60% in Turks with FMF . The evolution towards the nephrotic syndrome and death from renal failure is higher in untreated patients. End-stage renal disease might require 2–13 years after appearance of proteinuria , and the use of colchicine has dramatically decreased the incidence of amyloidosis in FMF. Thus, amyloidosis will remain a problem for patients with FMF when the diagnosis is delayed, adherence to therapy is poor, or the drug is not available, and clinicians should put much attention to this important clinical problem . Amyloidosis, however, might also affect the gastrointestinal tract (malabsorption) and the vascular system (hypertension in about 35% of patients with amyloidosis, risk of renal vein thrombosis). Other sites at risk of AA amyloidosis can be the heart, thyroid and testes. A genetic background for amyloidosis in FMF might be important, because in the presence of M694V mutation, the phenotypic manifestations of amyloidosis and arthritis are more frequent [35, 72]. By contrast, if amyloidosis is absent, ‘protective’ beta and gamma alleles of type 1 SAA protein are more often detected . Although the ultimate diagnosis of amyloidosis is established by bone marrow or rectal biopsy , clinical criteria (persistent proteinuria in patients with FMF) are sufficient ‘per se’ and suggest amyloidosis.
Additional complications seen in patients with FMF (especially untreated) included subclinical cardiac autonomic dysfunction, similar to dysautonomia described in a variety of rheumatic disorders .
Clues to diagnosis
Diagnosis of FMF is based on clinical features, response to treatment with colchicine  (see below), and genetic analysis. Patients with typical symptoms and MEFV gene mutation are defined as Type I phenotype. Those patients who have developed amyloidosis but had no typical attacks are defined as Type II phenotype . The so-called Tel Hashomer (named from the city in central Israel) criteria have been developed and are based on both major and minor criteria listed in a short or extensive form  (Table 2). The overall diagnostic performance of the criteria is good in diagnosing FMF adult patients, but the specificity might be low (55%) in children, as shown previously in the Turkish paediatric population . The explanation might be that children might poorly describe severity and location of pain and that other clinical features of attack might be different from those included in Tel Hashomer criteria. Based on such assumption, a new set of clinical criteria with high sensitivity and specificity for FMF in childhood has been proposed and will require validation in different populations and/or in geographical areas different from Turkey, where FMF prevalence is lower . Differential diagnoses of FMF are reported in Table 3  and include other autoinflammatory syndromes and surgical and systemic conditions which may resemble the FMF attacks.
Table 2. Clinical criteria for the diagnosis of FMF
|(a) Tel Hashomer criteria|
|Major criteria|| |
- Recurrent febrile episodes with serositis
- Amyloidosis of AA type without predisposing disease
- Favourable response to colchicine treatment
|Minor criteriaDiagnosis: definitive (2 major or 1 major + 2 minor criteria), probable (1 major + 1 minor criterion).|| |
- Recurrent febrile episodes
- Erysipelas-like erythema
- FMF in a first-degree relative
|(b) Detailed criteria|
|Major criteria|| |
- Peritonitis (generalized)
- Pleuritis (unilateral) or pericarditis
- Monoarthritis (hip, knee, ankle)
- Fever alone
|Minor criteria|| |
1–3. Incomplete attacks involving one or more of the following sites:
- Exertional leg pain
- Favorable response to colchicine
|Supportive criteria|| |
- Family history of FMF
- Appropriate ethnic origin
- Age of < 20 years at disease onset
4–7. Features of attacks:
- Severe, requiring bed rest
- Spontaneous remission
- Symptom-free interval
- Transient inflammatory response, with one or more test result(s) for white blood cell count, ESR, SAA, and/or fibrinogen
- Episodic proteinuria/hematuria
- Unproductive laporatomy or removal of white appendix
- Consanguinity of parents
Table 3. Commonest differential diagnoses of FMF
| Autoinflammatory syndromes ||Cyclic neutropenia||  |
|Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA)||  |
Cryopyrin-associated periodic syndromes
- Muckle–Wells syndrome
- Chronic infantile neurological cutaneous articular (CINCA)/neonatal onset multisystem inflammatory disease (NOMID)
- Familial cold autoinflammatory syndrome (FCAS)
|  |
|Hyper-IgD syndrome (HIDS)||  |
|TNF-alpha associated periodic fever syndrome (TRAPS)||  |
|Blau syndrome||  |
|Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE)||  |
|Syndromes associated with deficiency of IL-alpha receptor antagonists||  |
|Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA)||  |
|Behcet's disease||  |
| Surgical emergencies ||Pancreatitis|| |
|Peptic ulcer disease|| |
| Miscellanea ||Systemic lupus erythematosus|| |
|Lyme arthritis|| |
|HIV infection|| |
|Crystal-induced arthritis (gout, pseudogout)|| |
|Still's disease|| |
|Sclerosing cholangitis|| |
|Whipple's disease|| |
|Inflammatory bowel diseases|| |
|Hereditary angioedema|| |
|Acute intermittent porphyria|| |
Polymerase chain reaction may be able to establish diagnosis, although genetic studies might not be ready for diagnostic use [36, 37]. In the Israeli FMF population, the 3 most common MEFV mutations are M694V, V726A (alanine for valine at position 726) and E148Q (glutamine [Q] substitutes for glutamic acid [E] at position 148), and they appear to be related to clinical presentation and disease severity using the Tel Hashomer severity score . All three mutations have more amyloidogenic capability . So far, total current number of sequence variants for MEFV is 271 as obtained at the Hereditary Autoinflammatory Disorders Registry (Infevers database [78-81]; Fig. 2). The use of clinical criteria in establishing the diagnosis of FMF is still essential , because some patients might display two classical mutations, some patients display only one mutation, whereas some other might not display known mutations at all (percentage ranging from about 30% to 45%, depending on location) [77, 82, 83]. Indeed, it appears that most subjects with two mutations remain clinically silent .