Familial Mediterranean fever
Familial Mediterranean fever (FMF) is the most frequent periodic syndrome characterized by recurrent attacks of polyserositis. Fever, abdominal pain, chest pain, and arthritis/arthralgia are the leading symptoms. It is an autosomal recessive disorder, which primarily affects Jewish, Armenian, Turkish, and Arab populations. The FMF gene (MEFV) has recently been cloned to chromosome 16p, which encodes pyrin. Genotype-phenotype correlation is not well established. Amyloidosis is the most severe complication of FMF. The SAA1-α/α genotype was associated with an increased risk of amyloidosis. Colchicine treatment not only decreases the frequency and severity of attacks, but also prevents amyloidosis. Certain vasculitides, namely Henoch-Schonlein purpura and polyarteritis nodosa, are more frequent among FMF patients.
KeywordsFamilial Mediterranean feverAmyloidosisMEFV geneColchicine treatment
Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent self-limited episodes of fever and serosal inflammation accompanied by a marked acute-phase response . It was described as a separate nosological entity by Siegal in 1945 , and is the most common inherited periodic syndrome. Although FMF primarily affects populations living around the Mediterranean basin (Jewish, Armenian, North African, Arab, and Turkish populations), it is also a worldwide disease due to widespread inter-continental travel in the twentieth century [2, 3, 4, 5, 6, 7, 8, 9, 10]. The prevalence reaches a high of 1 in 200 individuals; 1 in 256 to 1 in 500 in non-Ashkenazi Jews and 1 in 1,073 in the Turkish population [11, 12]. The carrier frequency among North African Jews is 1 in 5 to 1 in 10 and 1 in 5 among Ashkenazi Jews . Among Armenians it is expected to be as high as 1 in 3 . In a recent study we reported the carrier rate in Turkey also to be 1 in 5 .
The FMF gene (MEFV) has recently been cloned by two consortia and 30 point mutations causing the disease have been identified [15, 16]. MEFV maps to chromosome 16p, and encodes a 781-amino acid protein, called pyrin or marenostrin that is expressed mainly in neutrophils and myeloid bone marrow precursors . This protein was suggested to act inside the nucleus and probably functions as a transcriptional regulator of inflammation in granulocytes [17, 18]. It is proposed that pyrin acts as a repressor of a proinflammatory molecule or a transcriptional up-regulator of an anti-inflammatory protein. Defective pyrin probably results in inflammatory events, increased leukocyte migration to serosal sites, and inappropriate and prolonged response to inflammatory stimuli [19, 20, 21]. Mansfield et al.  recently demonstrated co-localization of pyrin with microtubules and actin; they proposed that pyrin regulates the inflammatory response at the level of leukocyte cytoskeletal organization .
Tel Hashomer criteria for familial Mediterranean fever (FMF), from reference 
Recurrent febrile episodes with serositis
Recurrent febrile episodes
Amyloidosis of AA type without predisposing disease
Favorable response to colchicine treatment
FMF in a first-degree relative
Definitive diagnosis: 2 major or 1 major and 2 minor
Probable diagnosis: 1 major and 1 minor
The febrile episodes are accompanied by high fever of 38.5°–40.0°C. The attacks last for 1–3 days and resolve without any treatment. The cardinal signs and symptoms of FMF are fever (96%), peritonitis (91%), pleurisy (57%), arthritis/arthralgia (45%), erysipelas-like erythema (13%), and amyloidosis (2%) . Other signs and symptoms of the disease are headache, aseptic meningitis, pericarditis, splenomegaly, acute scrotum, febrile myalgia, scattered purpura, and proteinuria. In the series reported by the Turkish FMF Study Group, the clinical features of 2,838 patients were as follows: fever (92.5%), peritonitis (93.7%), pleurisy (31.2%), arthritis (47.4%), amyloidosis (12.9%), and non-amyloid glomerular diseases (0.8%) .
Genotype-phenotype relationship is not well established. Dewalle et al.  showed that the M694 V homozygous genotype was associated with a more severe form of the disease, i.e., earlier age at onset, higher prevalence of pleurisy, higher frequency of arthritis, and a higher frequency of amyloidosis, in patients who did not have regular colchicine therapy [23, 37, 38]. It was later shown that not all the patients with amyloidosis carried the M694 V mutation [30, 39, 40]. The rate of amyloidosis varied between 10% and 15% among various genotypes in Turkish FMF patients, but the differences were insignificant [33, 41]. The distribution of four common MEFV mutations (M694 V 38%, M680I 8%, V726A 4%, and E148Q 4%) was not significantly different in phenotype II patients compared with phenotype I patients (M694 V 51.5%, M680I 9%, V726A 2.88%, and E148Q 3.55%) [14, 42].
The prevalence of amyloidosis among the FMF population is considered to be independent of the frequency, duration, and intensity of flares. This view is largely based on the observation of phenotype-II patients in whom amyloid nephropathy presents before the first attack of fever and inflammation. Even before the use of colchicine, however, amyloidosis was far from a universal long-term consequence of the disease. Studies have implicated ethnicity, heredity, and environment as factors affecting the risk of developing amyloidosis. The frequency is higher in non-Ashkenazi Jews (80%) and Anatolian Turks (60%) [1, 43]. Recent studies however documented amyloidosis in only 7%–13% of Turkish patients with FMF . Higher frequencies from earlier reports came from nephrology centers. Amyloidosis is less common among Iraqis, Ashkenazi Jews, and Arabs . The possibility of an environmental influence on amyloid pathophysiology is supported by the observation that Armenians living in Armenia have a much higher reported incidence of amyloidosis than Armenian Americans, even before the introduction of colchicine prophylaxis [46, 47]. The analysis of 425 FMF patients without and 180 with amyloidosis (123 phenotype I, and 57 phenotype II) showed that the consanguinity rate was the same among FMF patients with and without amyloidosis groups. Patients with a family history of amyloidosis had a sixfold increased risk of developing amyloidosis compared with patients without a family history of amyloidosis .
SAA1 and SAA2 are serum precursors of amyloid A1 (AA1) and amyloid A2 (AA2) proteins, the principal components of the secondary amyloid plaques. Acute-phase isotypes of human SAA are encoded at three different loci, SAA1, SAA2, and SAA3. Although a prolonged high plasma level of SAA may lead to the deposition of its products, AA proteins, in tissues, a high concentration of SAA is not sufficient for the development of amyloidosis. Recent studies have focused on the polymorphism of SAA as a genetic background for amyloidogenesis .
Recently Cazeneuve et al.  studied SAA1 polymorphisms in 137 Armenian FMF patients living in Armenia. They showed that the SAA1α/α genotype was associated with a sevenfold increased risk for renal amyloidosis. Similar results were obtained from the analysis of Turkish FMF patients; of the 23 patients with SAA1α/α genotype, 7 patients (30.4%) developed renal amyloidosis, whereas only 1 of 51 patients (2.0%) with non-α/α genotype developed amyloidosis .
In a recent study by Tunca et al. , C-reactive protein (CRP) and SAA levels were higher in patients with FMF and their healthy first-degree relatives (parents, children, and siblings) compared with those in controls . Although FMF is a periodic disease, i.e., patients are symptom free between the attacks, there might be an ongoing subclinical inflammation. We evaluated SAA, erythrocyte sedimentation rate (ESR), CRP, ferritin, and fibrinogen levels in 183 children with FMF as a means of detecting subclinical inflammation . Median SAA level was 74 (6–1,500) mg/l (normal <10 mg/l), it was normal in <5% of patients. Other acute-phase proteins (ESR, CRP, ferritin, fibrinogen) were within normal ranges in 49%–93% of patients. Homozygous and compound heterozygous patients had higher SAA levels than heterozygous patients [129 mg/l (8–1,500) vs. 29 mg/l (6–216), P<0.005]. We concluded that SAA was the best marker to detect subclinical inflammation, and MEFV genotype had a significant effect on SAA. On the other hand, our study showed that neither SAA1 nor SAA2 polymorphisms had a significant effect on SAA level . Whether greater macrophage uptake or increased fibrilogenesis of α/α isoform plays a role in the pathogenesis of amyloidosis in FMF merits further studies.
IgM nephropathy, IgA nephropathy, focal and diffuse proliferative glomerulonephritis, mesangiocapillary glomerulonephritis, and rapidly progressive glomerulonephritis have also been reported in patients with FMF [54, 55, 56]. It is not known whether the presence of non-amyloid glomerular diseases with FMF is coincidental or causal.
Certain vasculitides are more frequent among FMF patients. Approximately 2.6%–5.0% of children with FMF have been reported to have Henoch-Schonlein purpura (HSP) [1, 57]. Polyarteritis nodosa (PAN) occurs in 0.8%–1.0% of FMF patients [1, 57, 58, 59, 60, 61, 62]. Protracted febrile myalgia is another vasculitis associated with FMF . It was described in a group of FMF patients who had profound myalgia, fever, arthritis, and purpura lasting more than 1 month.
The pathogenesis of vasculitis in patients with FMF is unknown. The occurrence of circulating immune complexes in 50% of FMF patients, complement consumption, defective inhibition of complement activation (C5a), and uncontrolled release of tumor necrosis factor (TNF) support the view that an immune-related mechanism plays a role [64, 65, 66]. The presence of immunoglobulins, C3, and fibrinogen in skin and kidney biopsies of some patients are interesting features. Some infectious agents may play a triggering role . FMF patients are more vulnerable to acute vascular injury and cyclosporin A toxicity due to defective inhibition of complement activation, leading to widespread vasculitis of PAN . PAN tends to occur at a younger age in FMF and is likely to be complicated by perirenal hematoma. Myalgia and subcutaneous nodules are more common. FMF should be considered as an underlying disease in the evaluation of children with PAN, particularly in the aforementioned ethnic groups. FMF and Behçet syndrome have some common clinical features. The association of Behçet syndrome in FMF and FMF in Behçet syndrome is yet to be determined .
Diagnosis of FMF
In patients presenting with typical clinical features and with an appropriate ethnic origin, the diagnosis can be made without genetic confirmation. If the patients present with atypical clinical manifestations, absence of family history, and unusual ethnic origin, genetic testing can be contributive. However, there are about 30 mutations of the MEFV gene, and in most centers patients are screened for the most common mutations only; i.e., patient may still be suffering from FMF even if genetic analysis reveals no mutations or a single mutation (heterozygous). In this case, when the manifestations are convincing the patient is put on a trial of colchicine. If there is a positive response to the colchicine trial, and symptoms return after cessation of colchicine, it is assumed that there are mutations in other parts of the gene or other genes that have not been identified yet.
Daily colchicine treatment was suggested by Goldfinger, and Ozkan et al. in 1972 [69, 70]. Zemer et al.  showed that colchicine prevented FMF attacks and the development of amyloidosis. In adult patients the treatment is started with 1 mg/day, regardless of age and body weight, and the dose is increased to 1.5–2.0 mg/day until remission is achieved. In children the starting dose is 0.5–1.0 mg/day. Complete remission is achieved in 65% and partial remission is achieved in 30% of patients; 5% of patients remain unresponsive .
Colchicine may modulate cytokine production by polymorphonuclear leukocytes, and alters the expression of the e-selectin on vascular endothelium and α-selectin in neutrophils . These adhesion molecules are essential for extravasation and migration to the inflammatory site. Colchicine may inhibit leukocyte chemotaxis, collagen transport to the extracellular space, formation of intracellular fibrillar structures that are vital to mitosis and motility, and prevent the extracellular assembly of amyloid subunits into mature amyloid fibrils [73, 74, 75, 76].
Side effects of colchicine are diarrhea, pancytopenia, myopathy, and less frequently rash. In a major study on 225 completed pregnancies, there were no unusual frequencies of fetal abnormality among women taking colchicine before or during pregnancy . It remains to be determined whether FMF increases the risk of developing trisomy 21, rather than colchicine . Recommendations for the pregnant patient would be to continue colchicine, but the dose might be decreased to 0.5–1.0 mg/day, if possible, and amniocentesis is advised. Fertility problems attributed to colchicine are more frequent among male Behçet patients than FMF, which was attributed to higher rate of epididymitis.
Interferon alpha and thalidomide have been tried in patients unresponsive to colchicine [79, 80]. A patient with congenital dyserythropoietic anemia and FMF entered remission after bone marrow transplantation . Milledge et al.  suggested that bone marrow transplantation should be considered in patients who are extremely unresponsive to all therapies, including colchicine and interferon alpha.
Characteristic and distinguishing features of diseases characterized by episodic fever include the following.
Hyperimmunoglobulin D syndrome
This is an autosomal recessive disease in a population originating from central or western Europe, with a mutation in the gene (12q) encoding mevalonic acid kinase, absence of peritonitis, periodic fever before 5 years of age, cervical adenopathy, symmetrical oligo-arthritis, generalized maculopapular rash, and mevalonic aciduria .
TNF receptor-associated periodic syndrome
TNF receptor-associated periodic syndrome (TRAPS), formerly known as familial Hibernian fever, is an autosomal dominant disease in patients of Irish or Scottish ancestry, with a mutation in the gene (12p) coding encoding TNF receptor 1, longer attacks (>1 week), severe migratory myalgia, migratory erysipelas-like erythema, conjunctivitis, and periorbital edema .
Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome (PAPA)
This periodic fever occurs before 5 years of age, with aphthous stomatitis, pharyngitis, cervical adenopathy, and a dramatic response to steroids .
Chronic infantile, neurological, cutaneous, articular syndrome (CINCA)
This includes chronic urticaria, deforming polyarthritis, chronic neurological manifestations, and mental retardation .
This presents with recurrent oral-genital ulcers, uveitis, erythema nodosum, thrombotic events, central nervous system disease, longer attacks, and HLA-B5 association. Some patients may have both FMF and Behçet disease.
FMF is a frequent disease, which is not only confined to the eastern Mediterranean region, but is also scattered throughout the western world. Amyloidosis is its most important complication and it can be prevented by colchicine treatment. Some diseases, mainly vasculitides, seem to be more common in FMF.