The disorder has been given various names, including familial paroxysmal polyserositis, periodic
peritonitis, recurrent polyserositis, benign paroxysmal peritonitis, periodic disease or periodic fever, Reimann periodic disease or Reimann syndrome, Siegal-Cattan-Mamou disease, and Wolff periodic disease.[9][10][11] Note that "periodic fever" can also refer to any of the
periodic fever syndromes.
Signs and symptoms
Attacks
There are seven types of attacks. Ninety percent of all patients have their first attack before they are eighteen years old. All develop over two to four hours and last anywhere from six hours to five days. Most attacks involve
fever.[12]
Abdominal attacks, featuring
abdominal pain, affect the whole abdomen with all signs of
peritonitis (inflammation of abdominal lining), and acute abdominal pain like
appendicitis. They occur in 95 percent of all patients and may lead to unnecessary
laparotomy. Incomplete attacks, with local tenderness and normal blood tests, have been reported.
Joint attacks mainly occur in large joints, especially in the legs. Usually, only one joint is affected. Seventy-five percent of all FMF patients experience joint attacks.
Chest attacks include
pleuritis (inflammation of the
pleura) and
pericarditis (inflammation of the
pericardium). Pleuritis occurs in 40 percent of patients and makes it difficult to breathe or lie flat, but pericarditis is rare.
Erysipeloid rashes (a skin reaction on the legs that can mimic
cellulitis, rare in isolation)Erysipeloid rashes in Familial Mediterranean Fever
Diagnostic criteria
Various diagnostic criteria have been set, but the Tel-Hashomer clinical criteria are widely recognized. It has more than 95 percent and 97 percent
sensitivity and
specificity, respectively.[13]
For the criteria, typical attacks consist of all the following: recurrent (three or more episodes), febrile (
rectal temperature of at least 38 °C), painful
inflammation, and a short duration of 12 to 72 hours.
Incomplete attacks (must be recurrent) are differing from typical attacks in at least one feature as follows:
temperature less than 38 °C, attack duration longer or shorter than specified (but no less than six hours and no more than seven days), localized
abdominal attacks, no signs of
peritonitis during the attacks, and
arthritis in a location other than the
hip,
knee or
ankle.
The MEFV gene is located on the short arm of
chromosome 16 (16p13). Many different mutations of the MEFV gene can cause the disorder. Having one mutation is unlikely to cause the condition. Having two mutations (either a copy from both parents, or two different mutations with one from each parent) is the threshold for a genetic diagnosis of FMF. However, most individuals who comply with the genetic diagnosis of FMF remain asymptomatic or undiagnosed. Whether this is due to modifier genes or environmental factors remains to be established.[4]
Pathophysiology
Virtually all cases are due to a mutation in the Mediterranean Fever (MEFV) gene on the
chromosome 16, which codes for a protein called pyrin or marenostrin. Various mutations of this gene lead to FMF, although some mutations cause a more severe picture than others. Mutations occur mainly in
exons 2, 3, 5 and 10.[12]
The function of pyrin is not fully known, but in short, it is a protein that binds to the adaptor
ASC and the proform of the enzyme
caspase-1 to generate multiprotein complexes called
inflammasomes in response to certain infections. In healthy individuals, pyrin-mediated inflammasome assembly (which leads to the caspase 1) dependent processing and secretion of the
pro-inflammatory cytokines (such as
interleukin-18 (IL-18) and
IL-1β) is a response to
enterotoxins from certain bacteria.[15] The
gain-of-function mutations in the MEFV gene cause pyrin more active in the body, which results in an increase in inflammasome formation. [16]
In its basal state,
pyrin is kept inactive by a chaperone protein (belonging to the family of
14.3.3 proteins) linked to pyrin through
phosphorylatedserine residues.[17][18] The dephosphorylation of pyrin is an essential prerequisite for the activation of the pyrin inflammasome. Inactivation of
RhoAGTPases (by
bacterial toxins, for example) leads to the inactivation of
PKN1 /
PKN2 kinases and dephosphorylation of pyrin.[19] In healthy subjects, the dephosphorylation step alone does not cause activation of the pyrin inflammasome. In contrast, in FMF patients, the dephosphorylation of
serines is sufficient to trigger the activation of the pyrin inflammasome.[20] This suggests that there is a two-level regulation and that the second regulatory mechanism (independent of (de)phosphorylation) is deficient in FMF patients. This deficient mechanism is probably located at the level of the B30.2 domain (
exon 10) where most of the pathogenic
mutations associated with FMF are located. It is probably the interaction of this domain with the
cytoskeleton (
microtubules) that is failing, as suggested by the efficacy of
colchicine.[21]
It is not conclusively known what exactly sets off the attacks or why overproduction of IL-1 would lead to particular symptoms in particular organs, such as joints or the
peritoneal cavity.[12] However, steroid hormone
catabolites (
pregnanolone and
etiocholanolone) have been shown to activate the pyrin inflammasome in vitro by interacting with the B30.2 domain (coded by exon 10).[22]
Diagnosis
The diagnosis is clinically made on the basis of the history of typical attacks, especially in patients from the ethnic groups in which FMF is more highly prevalent. An
acute phase response is present during attacks, with high
C-reactive protein levels, an elevated
white blood cell count and other markers of
inflammation. In patients with a long history of attacks, monitoring the
kidney function is of importance in predicting
chronic kidney failure.[12]
A genetic test is also available to detect mutations in the MEFV gene. Sequencing of exons 2, 3, 5, and 10 of this gene detects an estimated 97% of all known mutations.[12]
A specific and highly sensitive test for FMF is the "
metaraminol provocative test (MPT)", whereby a single 10 mg infusion of metaraminol is administered to the patient. A positive diagnosis is made if the patient presents with a typical, albeit milder, FMF attack within 48 hours. As MPT is more specific than sensitive, it does not identify all cases of FMF, although a positive MPT can be very useful.[23][24]
Treatment
Attacks are self-limiting, and require
analgesia and
NSAIDs (such as
diclofenac).[12]Colchicine, a drug otherwise mainly used in
gout, decreases attack frequency in FMF patients. The exact way in which colchicine suppresses attacks is unclear. While this agent is not without side effects (such as
abdominal pain and
muscle pains), it may markedly improve quality of life in patients. The dosage is typically 1–2 mg a day. Development of amyloidosis is delayed with colchicine treatment.
Interferon is being studied as a therapeutic modality.[12] Some advise discontinuation of colchicine before and during pregnancy, but the data are inconsistent, and others feel it is safe to take colchicine during pregnancy.[25]
Approximately 5–10% of FMF cases are resistant to colchicine therapy alone. In these cases, adding
anakinra to the daily colchicine regimen has been successful.[26]Canakinumab, an anti-interleukin-1-beta
monoclonal antibody, has likewise been shown to be effective in controlling and preventing flare-ups in patients with colchicine-resistant FMF and in two additional autoinflammatory recurrent fever syndromes: mevolonate kinase deficiency (hyper-
immunoglobulin D syndrome, or
HIDS) and tumor necrosis factor receptor-associated periodic syndrome (
TRAPS).[27]
Epidemiology
FMF affects groups of people originating from around the
Levant or Eastern Mediterranean (hence its name); it is thus most prominent among those from or with ancestry from the regions including
Arabs,
Armenians,
Jews (particularly
Sephardi,
Mizrahi, and to a lesser degree
Ashkenazi Jews), and
Turks.[3][12][28][29]
History
A
New York City allergist, Sheppard Siegal, first described the attacks of
peritonitis in 1945; he termed this "benign paroxysmal peritonitis", as the disease course was essentially benign.[30]Dr Hobart Reimann, working in the
American University in Beirut, described a more complete picture which he termed "periodic disease".[31][32] French physicians Henry Mamou and Roger Cattan described the complete disease with renal complications in 1952.[33][34]
^
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^Barakat MH, El-Khawad AO, Gumaa KA, El-Sobki NI, Fenech FF (March 1984). "Metaraminol provocative test: a specific diagnostic test for familial Mediterranean fever". Lancet. 1 (8378): 656–7.
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^Huppertz HI, Michels H (May 1988). "[The metaraminol provocation test in the diagnosis of familial Mediterranean fever]". Monatsschrift Kinderheilkunde. 136 (5): 243–5.
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^Reimann HA (January 1948). "Periodic disease; a probable syndrome including periodic fever, benign paroxysmal peritonitis, cyclic neutropenia and intermittent arthralgia". Journal of the American Medical Association. 136 (4): 239–44.
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