NORD gratefully acknowledges Isabelle Touitou, MD, PhD, Laboratoire des maladies rares et auto-inflammatoires, Hopital Arnaud de Villeneuve, Montpellier, France, for assistance in the preparation of this report.
Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease characterized by recurrent episodes (attacks) of fever and acute inflammation of the membranes lining the abdomen, joints, and lungs. In some cases, affected individuals may develop skin rashes (erysipelas like erythema) affecting the lower legs. Less often, inflammation of the membrane lining the heart or covering the brain and spinal cord may occur. Some individuals may develop a serious condition known as amyloidosis, in which certain proteins called amyloid accumulates in various tissues of the body. In FMF, amyloid accumulates in the kidneys (renal amyloidosis) where it can impair kidney function potentially result in life-threatening complications such as kidney failure. The specific symptoms and severity of FMF are highly variable. Some individuals develop amyloidosis, but none of the other symptoms associated with FMF. These cases are sometimes referred to as FMF type 2. FMF is caused by mutations of the pyrin (MEFV) gene and is inherited as an autosomal recessive trait.Introduction
FMF is classified as an autoinflammatory syndrome. Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system. They are not the same as autoimmune syndromes, in which the adaptive immune system malfunctions and mistakenly attacks healthy tissue. FMF is the most common autoinflammatory syndrome. It is also classified as a hereditary periodic fever syndrome.
The symptoms and severity of FMF can vary greatly from one person to another, even among members of the same family. The classic form of FMF is characterized by short, recurrent episodes (attacks) of inflammation. These episodes often occur without warning and can last anywhere from 1 to 4 days. The duration and severity of episodes (both in different people and even the same person) are not consistent. In between episodes, affected individuals are usually symptom-free and feel normal. The amount of time between episodes will vary and can range from a week to a few months. In many cases, the initial episode occurs in infancy or early childhood. Most affected individuals experience their initial episode before the age of 20.
Approximately 50 percent of individuals with FMF experience a sensation of poor health or unpleasantness that precedes the onset of an episode of FMF. This is referred to as a prodrome or prodromal phase. Attacks can be triggered by fatigue, stress or physical effort.
Recurrent fevers during early childhood are often the initial symptom of FMF. Temperatures can rise rapidly often spiking to 100-104 degrees Fahrenheit (or up to >40 degrees Celsius). Episodes of fever can occur alone or in association with any or all of the symptoms discussed below. During mild episodes, fevers may occur without additional symptoms. In some individuals, recurrent fevers during childhood can be the only symptom associated with FMF.
Along with chronic episodes of fever, serositis is another common symptom of FMF. Serositis refers to inflammation of various serous tissues of the body. Serous tissues include the membranes that line the abdomen, lungs, and heart.
Approximately 90 percent of individuals with FMF experience abdominal symptoms that can range from mild bloating to inflammation of the lining of the abdomen (peritonitis). Abdominal symptoms can coincide with the onset of fever. Abdominal pain or tenderness is common and the abdominal muscles are often noticeably rigid and tight, sometimes described as “board-like.” The abdomen is often swollen (distended). Some individuals may develop constipation during an abdominal episode, sometimes followed by diarrhea after an episode ends. Affected individuals are often misdiagnosed as having acute abdomen (peritonitis) and may undergo unnecessary surgery.
Approximately 75 percent of affected individuals experience joint pain (arthralgia) and inflammation (arthritis) due to inflammation of the membrane (synovium) lining the joints. Pain, which can be accompanied by swelling, can be severe. During an episode, the range of motion of affected joints can be limited. Episodes of arthritis can begin suddenly and usually subside within 7 days. Joint function usually returns to normal after an episode ends. However, in some cases, these joint issues can continue for several weeks or months. In some cases, episodes are triggered by minor trauma or sustained exertion such as prolonged walking. Most episodes involve one of the large joints of the leg (i.e., knee, ankle or hip). In rare cases, recurrent arthritis of one joint can be the only symptom of FMF.
Some affected individuals may also experience chest pain due to inflammation of the thin membrane (pleura) that lines the lungs (pleuritis). Episodes usually appear suddenly and resolve quickly within 48 hours. Affected individuals can experience painful breathing and diminished breathing sounds on the affected side of the lungs. Shortness of breath and rapid, shallow breathing may also occur.
Some individuals with FMF may develop a potentially serious complication known as amyloidosis. Amyloidosis is characterized by the accumulation of a fatty-like substance called amyloid in various parts of the body. In FMF, amyloid accumulates in the kidneys (renal amyloidosis), impairing kidney function. Renal amyloidosis can eventually progress to cause kidney failure. The prevalence of amyloidosis varies based upon ethnicity, gender and the specific mutation of the MEFV gene. Certain ethnic populations including individuals of Turkish or Sephardic Jewish descent have a relatively high incidence of amyloidosis when compared to individuals from other ethnic groups. Individuals with FMF type 2 develop amyloidosis, but none of the other symptoms associated with FMF.
Some individuals with FMF have painful, swollen and bright red (erythematous) skin lesions on the lower legs. These lesions resemble a skin infection called erysipelas. They may be warm or hot to the touch and most often occur between the ankle and the knee.
Less often, additional symptoms can affect individuals with FMF including inflammation of the sac-like membrane (pericardium) lining the heart (pericarditis). Pericarditis may be associated with pain behind the breastbone (sternum) that is worse upon swallowing. Inflammation of the membranes (meninges) lining the brain and spinal cord (meningitis) may also occur and may cause headaches. Headaches may also occur independent of meningitis.
Another occasional symptom associated with FMF is muscle pain (myalgia), which is often severe and can be widespread (diffuse) and disabling. Along with fever, myalgia can occur with abdominal and joint pain and diarrhea. Myalgic episodes can last for a short time or longer, even up to six to eight weeks (protracted febrile myalgia).
Untreated individuals with FMF have a risk of infertility. Individuals with severe FMF characterized by multiple frequent episodes and/or amyloidosis are particularly at risk if untreated. In males, inflammation of the testes (orchitis) may also occur. Orchitis is characterized by pain, redness and swelling.
Enlargement of the spleen can also occur (splenomegaly) and is quite frequent in children.
According to the medical literature, some individuals with FMF have an increased risk of developing additional inflammatory disorders, especially those characterized by inflammation of the blood vessels (vasculitides), including Bechet’s disease, polyarteritis nodosa, and Henoch-Schonlein purpura. Affected individuals may also have at greater risk of developing ulcerative colitis, Crohn’s disease and rheumatoid arthritis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
FMF is caused by mutations of the MEFV gene. The disease is inherited as an autosomal recessive trait. Hereditary diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
Although FMF is an autosomal recessive disorder, some individuals who inherited only one abnormal gene (heterozygotes) will develop symptoms of inflammatory disease very similar to FMF. These individuals are also a greater risk than the general population of developing other inflammatory diseases such as Bechet’s disease and Crohn’s disease. The severity of the disease in these individuals is often similar to individuals who inherited two disease genes (homozygotes) or individuals with two different mutations (compound heterozygotes), and these individuals usually require treatment (see Standard Therapies below). The reason that some individuals with one mutated gene develop symptoms is not fully understood. More research is necessary to determine why this occurs and whether there is a specific disease pattern associated with these cases.
Investigators have determined that the MEFV gene is located on the short arm (p) of chromosome 16 (16p13.3). More than 300 different mutations of the MEFV gene have been identified, although only four are clearly pathogenic. They are recorded on a dedicated website http://fmf.igh.cnrs.fr/ISSAID/infevers The MEFV gene contains instructions for creating (encoding) a protein known as pyrin. Mutations of the MEFV gene lead to deficient levels of functional pyrin. The exact role of pyrin in the body is not known. Researchers believe that pyrin is critical for the proper function of the innate immune system by regulating or inhibiting the body’s inflammatory response. Recent research suggests that a mutation of the MEFV gene results in excessive release of interleukin-1B. Interleukin-1B is a pro-inflammatory cytokine (a specialized protein secreted from certain immune system cells that either stimulates or inhibits the function of other immune system cells). Drugs that inhibit the activity of interleukin-1B may have a role in treating FMF (see Investigational Therapies section below).
Although episodes of FMF can occur spontaneously for no identifiable reason, certain triggers have been identified in some cases. These triggers include infection, trauma, vigorous exercise, and stress. In women, onset of their period (menses) can trigger an episode.
FMF affects males and females in equal numbers, although some studies suggest a slight male preponderance. FMF can affect individuals of any ethnic group, but the rates are much higher for certain Mediterranean populations including individuals of Armenian, Turkish, Arabic and North African Jewish descent. In these populations, the prevalence is estimated to be 1 in 200.
A diagnosis of FMF is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. These tests can aid in obtaining a diagnosis of FMF or in assessing the extent of the disorder. Prompt diagnosis in FMF is important to avoid misdiagnosis and unnecessary surgery (as many children are misdiagnosed as having appendicitis).
Clinical Testing and Work-Up
During an episode, a blood test known as an erythrocyte sedimentation rate may be performed. Sedimentation rate measures how long it takes red blood cells (erythrocytes) to settle in a test tube over a given period. Many individuals with FMF have an elevated sedimentation rate, which is an indication of inflammation. Blood tests can also reveal elevated levels white blood cell levels, which are indicative of an immune system response, elevated C-reactive protein, which is elevated during periods of inflammation, and/or elevated levels of fibrinogen (a substance that helps stop bleeding). However, these tests are only effective during an episode of FMF, and they return to normal or near normal when an episode ends.
Urinary examination may reveal excess loss of a protein called albumin, which can be indicative of kidney disease.
A diagnosis of FMF can be confirmed by molecular genetic testing, which can identify the characteristic MEFV gene mutation that causes the disorder. Molecular genetic testing is available through commercial and academic diagnostic laboratories.
There is no cure for FMF, but there are effective treatments. Specific treatments are aimed at the specific symptoms apparent in each individual. Many individuals are treated with a medication called colchicine, a complex compound that reduces inflammation. Most affected individuals who take the medication show a marked improvement in the duration and frequency of episodes. Colchicine is also effective in preventing the accumulation of amyloid in the kidneys. However, colchicine requires strict daily adherence and it does not treat an episode once an episode has begun. Therefore, increasing the dosage during an episode is not beneficial. On July 30, 2009, the U.S. Food and Drug Administration (FDA) approved the oral colchicine product Colcrys to treat FMF.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and pain medications (analgesics) can be used to treat individuals during a febrile or inflammatory episode. NSAIDs are also used to treat joint and muscle pain, which do not respond to colchicine.
Colchicine can prevent the development of renal amyloidosis, even if it is ineffective in treating FMF attacks. Early stage renal amyloidosis is reversible. Some individuals with FMF and amyloidosis eventually develop end stage renal disease (ESRD), ultimately requiring a kidney transplant. Initially, an affected individual may undergo dialysis. Dialysis is a procedure in which a machine is used to perform some of the functions of the kidney – filtering waste products from the bloodstream, helping to control blood pressure and helping to maintain proper levels of essential chemicals such as potassium. ESRD is not reversible so individuals will eventually require a kidney transplant. The rate of progressive of kidney dysfunction to ESRD can vary greatly from one individual to another. With the advent of colchicine therapy, the number of individuals with FMF requiring a kidney transplant has dropped. Most individuals with FMF who ultimately require a kidney transplant were unable to take colchicine or failed to be compliant with the required daily dosage.
Genetic counseling may be of benefit for affected individuals and their families. Any additional treatment is symptomatic and supportive.
Some individuals who have not responded to colchicine therapy have been treated with anakinra (Kineret). Anakinra is an interkeukin-1 receptor antagonist; it blocks the activity of interleukin-1. Initial reports have suggested that this drug is a safe and effective alternative for individuals who do not respond to colchicine. More research is necessary to determine the long-term safety and effectiveness of anakinra for individuals with FMF.
Two drugs that have been approved by the FDA for the treatment of autoinflammatory disorders such as cold autoinflammatory syndrome are being studied as potential therapies for individuals with FMF. The drugs are rilonacept (Arcalyst) by Regeneron Pharmaceuticals and canakinumab (Ilaris) by Novartis Pharmaceuticals. More research is necessary to determine the long-term safety and effectiveness of these medications in the treatment of individuals with FMF.
Additional drugs that have been used in individuals who are unresponsive to colchicine include thalidomide, etanercept, interferon alpha, and sulphasalazine. More research is necessary to determine the long-term safety and effectiveness of these potential treatments for FMF.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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