Familial Mediterranean fever

Synonyms

6

Overview

Familial Mediterranean fever is an inherited condition characterized by episodes of painful inflammation of the abdominal lining (peritonitis), lining surrounding the lungs (pleurisy), and joints (arthralgia and occasionally arthritis). These episodes are often accompanied by fever and sometimes a characteristic ankle rash. Occasionally inflammation may occur in other parts of the body, such as the heart; the membrane surrounding the brain and spinal cord; and in males, the testicles. In about half of affected individuals, attacks are preceded by mild signs and symptoms known as a prodrome. Prodromal symptoms include mildly uncomfortable sensations in the area that will later become inflamed, or more general feelings of discomfort. The first episode usually occurs in childhood or the teenage years, but in some cases, the initial attack occurs much later in life. Typically, episodes last 12 to 72 hours and can vary in severity. The length of time between attacks is also variable and can range from days to years. Between attacks, people often do not have any symptoms. Without treatment, FMF can lead to kidney failure due to a buildup of certain protein deposits (amyloidosis) in the body's organs and tissues may occur, especially in the kidneys, which can lead to kidney failure.

Familial Mediterranean fever is an inherited disorder that usually occurs in people of Mediterranean origin — including Sephardic Jews, Arabs, Greeks, Italians, Armenians and Turks. But it may affect any ethnic group.

Symptoms

Familial Mediterranean fever (FMF) is characterized by relatively short, usually 1- to 3-day, episodes of fever accompanied by abdominal pain, chest pain, joint pain, pelvic pain, muscle aches, and/or a skin rash. The muscle pain is often confused with fibromyalgia and the joint pain is sometimes confused with gout. The pain symptoms are usually the result of inflammation in the lining of the abdomen, lungs, joints, heart, pelvis, and/or in the membrane that surrounds the brain and spinal cord. Headaches and amyloidosis may also occur. The majority of people with FMF experience their first episode by age 20. The frequency of such attacks is highly variable and the interval between attacks ranges from days to years. The frequency and symptoms experienced during an attack may also change over time.  Symptoms may include:

  • 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% 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% of patients, and makes it difficult to breathe or lie flat, but pericarditis is rare
  • Scrotal attacks due to inflammation of the tunica vaginalis occurs in up to 5% and may be mistaken for acute scrotum (i.e. testicular torsion)
  • Erysipeloid (a skin reaction on the legs, rare in isolation)
  • Fever without any of the other symptoms listed above (25%)
  • Achy, swollen joints
  • Constipation followed by diarrhea
  • A red rash on your legs, especially below your your knees
  • Muscle aches
  • Paroxysmal attacks
  • Chest dyspnea
  • Shoulder dyspnea
  • Joint pain
  • Monoarthralgia of big joints
  • Hives
  • Erysipelas-like skin redness
  • Inflammation of testes
  • Tender abdomen
  • Abdominal spasm
  • Abdominal guarding
  • Abdominal distention
  • Enlarged spleen
  • Chest wall tenderness
  • Localized joint redness
  • Transient peritonitis
  • Hyperemia of peritoneum
  • Increased number of neutrophils in blood
  • Anemia
  • Painful lower leg skin lesions
  • Red lower leg skin lesions
  • Swollen lower leg skin lesions

Causes

Mutations in the MEFV gene cause familial Mediterranean fever. The MEFV gene provides instructions for making a protein called pyrin (also known as marenostrin), which is found in white blood cells. This protein is involved in the immune system, helping to regulate the process of inflammation. Inflammation occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight microbial invaders and facilitate tissue repair. When this process is complete, the body stops the inflammatory response to prevent damage to its own cells and tissues.

FMF is almost always inherited in an autosomal recessive manner. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier. 

In rare cases, this condition appears to be inherited in an autosomal dominant manner.vThis means that to be affected, a person only needs a change (mutation) in one copy of the responsible gene in each cell. In some cases, an affected person inherits the mutation from an affected parent. Other cases may result from new (de novo) mutations in the gene. These cases occur in people with no history of the disorder in their family. A person with FMF inherited in an autosomal dominant manner has a 50% chance with each pregnancy of passing along the altered gene to his or her child.

In some cases, FMF may appear to be autosomal dominant when it is actually autosomal recessive. This phenomenon is called pseudodominance. This may happen in families if one parent is an unaffected, unknown carrier (with 1 mutation) and the other parent is affected (with 2 mutations). It may appear that an affected child inherited FMF from only the affected parent, when in fact he/she inherited one mutation from each parent.

Diagnosis

Tests and procedures used to diagnose familial Mediterranean fever include:

  • Physical exam
  • Review of your family medical history
  • Blood tests
  • Genetic testing

In making a diagnosis of FMF, take all of these factors into account:

  • Whether the person has the clinical symptoms common for the disease and whether the symptoms are recurrent.
  • How he or she responds to colchicine treatment.
  • Usually a positive family history in people of Middle Eastern ancestry.
  • The results of genetic testing.

Also helpful in establishing a correct diagnosis of FMF is the person's ancestry. Testing for the following can also be helpful:

  • Elevated white blood cell count, which is an indication of an immune response.
  • Elevated erythrocyte sedimentation rate (ESR), which is an indication of an inflammatory response.
  • Elevated plasma fibrinogen, which helps stop bleeding. An elevated amount would indicate that something might be wrong with this mechanism.
  • Elevated serum haptoglobin, which would indicate that red blood cells are being destroyed, a common occurrence in rheumatic diseases, such as FMF.
  • Elevated C-reactive protein, which is a special type of protein, produced by the liver, that is only present during episodes of acute inflammation.
  • Elevated albumin in the urine, which is demonstrated by urinalysis. The presence of the protein albumin in the urine can be a symptom of kidney disease, along with microscopic hematuria (very small - microscopic - amounts of blood or blood cells in the urine), during attacks.

Prognosis

People with FMF who are compliant with daily colchicine can probably expect to have a normal lifespan if colchicine is started before proteinuria develops. Even with amyloidosis, the use of colchicine, dialysis, and kidney transplantation should extend a patient's life beyond age 50 years.

Treatment

Currently, there is no known cure for FMF. Physicians can only treat the symptoms of the disease. 
A common therapy for FMF is daily use of the drug colchicine, a medicine that reduces inflammation. Many people require colchicine for life. This therapy has been successful in preventing attacks of fever in 75 percent of those who take the drug regularly. Over 90 percent of people with FMF demonstrate a marked improvement. Even if colchicine does not prevent the fever attacks, it does prevent the amyloidosis. However, compliance in taking colchicine every day is very important. If a person stops taking the drug, an attack can occur within a few days. Complications of colchicine use can also occur and include muscle weakness (myopathy) and a toxic epidermal necrolysis-like reaction.

Since the gene that causes FMF codes for the protein pyrin, researchers hope that by studying how this protein works they will ultimately develop improved treatments for FMF, and possibly for other conditions involving excess inflammation.

Approved therapies:

  • Colchicine (Colrys)  FDA-approved indication: Treatment of Familial Mediterranean Fever. 
  • Canakinumab (Ilaris) FDA-approved indication: Treatment for Familial Mediterranean Fever (FMF) in adult and pediatric patients; for Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) in adult and pediatric patients; and for Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) in adult and pediatric patients.