What is Familial Mediterranean Fever?
Familial Mediterranean fever (FMF), also known by many other names, like ‘periodic peritonitis,’ ‘familial paroxysmal polyserositis,’ ‘periodic disease,’ and more, is a genetic disorder in which the body’s inflammatory response goes into overdrive. This results in repeated episodes of fever and inflammation in various body cavities such as the abdomen, lungs, and joints, causing severe pain. Often, the first bout of this disorder happens in childhood, typically before the age of 20. These episodes come on quickly, within 2 to 4 hours, and can last from 6 hours up to 4 days, sometimes even accompanied by a rash or headache.
The disorder mostly affects people of Mediterranean and Middle Eastern descent, which is why it’s named ‘Familial Mediterranean fever.’ Although formal descriptions of this disorder and similar ones were only recorded in the latter half of the last century, references to symptoms resembling these ‘periodic fevers’ have been found in historical texts.
While these discomforting episodes tend to disappear on their own, it doesn’t mean FMF is a small matter. If it’s not treated appropriately and prevention methods aren’t put in place, it can result in a severe condition known as secondary amyloidosis, particularly impacting the kidneys. This could ultimately lead to kidney failure.
This article aims to describe the causes, the widespread nature, the symptoms, and ways to manage FMF. It also emphasizes the importance of good teamwork among healthcare professionals. Their ability to diagnose and treat this disorder promptly can greatly improve the affected individual’s life experience.
What Causes Familial Mediterranean Fever?
FMF, or Familial Mediterranean Fever, is a disease that is typically passed down through families (autosomal recessive), meaning you need to inherit a gene from both your parents to get the disease. The gene that causes FMF is known as the MEFV gene, which resides on a certain part of chromosome 16. This gene is responsible for making a protein called pyrin.
About 300 different alterations, or mutations, of the MEFV gene have been discovered, all of which could potentially lead to FMF. These mutations often occur in certain areas of the gene, labeled as exons 2, 3, 5, and 10. The most common mutations, called V726A, M680I, E148Q, M694V, and M694I, account for 70 to 80 percent of all FMF cases. Interestingly, about 10 percent of patients who are clinically diagnosed with FMF do not have any detectable alterations in their MEFV gene. In some regions, one in three people could carry this gene.
While it’s mostly inherited in an autosomal recessive manner, there have been some instances where FMF appears to be inherited in an autosomal dominant manner, meaning it’s passed down from just one affected parent. The most common mutation in such cases has been M694V. Two specific mutations, M694V and M680I, have been linked to more severe symptoms and increased risk of complications.
Risk Factors and Frequency for Familial Mediterranean Fever
FMF, or Familial Mediterranean Fever, is a health condition often seen in people from the Mediterranean or Middle Eastern regions. This includes people from various ethnic groups such as Jews, Armenians, Arabs, Kurds, Greeks, Turks, Iranians, and Italians. Notably, the disease isn’t limited to these groups and can be found in the general population worldwide.
- One in five healthy individuals in Armenia are carriers of FMF.
- The carrier rate is higher in Jews of North African or Iraqi origin compared to Ashkenazi Jews.
- In Turkey, FMF is found in roughly one out of every thousand children.
- The first episode of FMF typically happens in early childhood.
- Approximately 90% of first instances of FMF occur by the end of adolescence.
- In rare cases, this condition can also appear for the first time in adulthood.
- According to studies, males and females are equally affected by FMF. This was confirmed by a Turkish survey which found a nearly equal male-to-female ratio of 1.2/1.
- In the United States, FMF is often seen among Ashkenazi Jews and immigrants from Mediterranean and Middle Eastern regions.
Signs and Symptoms of Familial Mediterranean Fever
FMF, or Familial Mediterranean fever, is a condition that presents itself through repeated episodes of fever and inflammation of the body’s tissues, causing severe pain in the chest, abdomen, or joints. People usually experience their first attack before they are 20 years old. These symptoms develop quickly, over 2 to 4 hours, and can last from 12 to 72 hours. After an attack, patients generally feel normal. Every attack can vary in severity and there’s no set pattern for when they occur; it could range from one week to several years apart. There are some patients who experience signs like irritability, nervousness, anxiety, nausea, or muscle pain before an attack. There are also certain triggers that can lead to an attack, such as stress, cold exposure, heavy exercise, recent infection, recent surgery, and menstruation. As individuals get older, they usually experience less frequent and less severe attacks.
- Fever: The most common symptom in FMF attacks, and in children, it may be the only symptom. The fever can range from mild to high (38 to 40 degrees C or 100.4 to 104 degrees F).
- Abdominal pain: Often the main type of pain in FMF, which starts localized then becomes more generalized. There might be symptoms like abdominal distension, tenderness, and decreased bowel sounds due to inflammation.
- Chest pain: Caused by inflammation of the pleural (tissue surrounding the lungs), leading to unilateral pain that worsens with deep breaths or coughing. Sometimes pericarditis (inflammation of the sac around the heart) may also occur.
- Joint pain: Common in non-Ashkenazi Jews. Larger leg joints like the hip, knee, or ankle are often affected, causing severe pain in one joint. On rare occasions, multiple joints could be simultaneously impacted.
- Erysipelas-Like Lesion: Happens mostly in Jews, it occurs on the lower extremities of the body, like the leg, ankle, or feet, and resolves on its own.
- Scrotal Swelling: Which includes unilateral (one-sided) swelling of the scrotum, caused by transient inflammation of the tunica vaginalis (the outermost layer of the scrotum).
- Myalgia: This is non-specific muscle pain and can involve the upper or lower extremities. Muscle tenderness is common. Rarely, there could be prolonged febrile myalgia.
- Aseptic Meningitis and oral Ulcers: These are very rare symptoms in FMF patients.
Testing for Familial Mediterranean Fever
Familial Mediterranean Fever (FMF) is typically diagnosed based on symptoms, family history, and response to certain medications. However, medical tests can also aid in confirming the diagnosis or ruling out other possible conditions.
Patients with FMF often have a high white blood cell count and increased levels of certain acute phase reactants such as fibrinogen, erythrocyte sedimentation rate, serum amyloid A protein, and C-reactive protein. While these findings are common, they are not specific to FMF, and levels of these markers can be monitored to track the patient’s response to treatment. An electrocardiogram, which measures the heart’s electrical activity, can detect signs of pericarditis, an inflammation of the sac-like covering around the heart. Analysis of synovial fluid – which lubricates the joints – can also reveal signs of inflammation, such as an increased number of white blood cells.
An abdominal CT scan might be performed to exclude other causes of abdominal pain.
Genetic tests can provide a definitive diagnosis of FMF, particularly in cases where the presentation of symptoms is atypical. However, about 10 percent of patients who show typical symptoms of FMF do not have the mutation associated with the disease.
There are several sets of diagnostic criteria for FMF, with the Tel-Hashomer criteria set from Israel being widely used because of its high accuracy of over 95%.
This criteria set considers “typical attacks” that consist of fever, inflammation-induced pain, three or more occurrences of such attacks, and a duration of 12 to 72 hours. It provides a list of “major” and “minor” factors – referring to severity of symptoms – and supporting factors that hint at the presence of FMF. Major factors include issues involving the abdomen, joints, chest, skin, muscles, and recurrent fevers without any other identifiable cause. Minor factors are similar, with the addition of leg pain on exertion and a positive response to a drug called colchicine.
Supportive criteria includes having a family history of FMF, belonging to a high-risk ethnic group, early onset of the disease (before age 20), recovery from attacks without medical intervention, the absence of symptoms between attacks, severe attacks requiring bed rest, elevated white blood cell count or acute phase reactants, history of abdominal surgery or appendectomy without any detected pathology, periodic presence of protein or blood in urine, and having parents who are related.
Presence of at least one major or two minor criteria, or one minor with five supportive criteria, is enough to diagnose FMF.
Treatment Options for Familial Mediterranean Fever
Colchicine has been the go-to treatment for Familial Mediterranean Fever (FMF), a genetic condition that causes recurrent fevers and inflammation, since the 1970s. The main goals of using colchicine are to prevent fever attacks, lessen inflammation between attacks, and stop the progression of a severe complication called amyloidosis, where harmful proteins build up in your organs and tissues.
Colchicine works by blocking a process that causes inflammation during an FMF fever attack. This treatment is typically continued for the lifetime of the patient.
Side effects of colchicine may include diarrhea and vomiting, which are more likely with higher doses. Less common side effects include potential damage to bone marrow, liver and kidneys, muscle disease, nerve disease, and allergic reactions. The medication is generally safe to use during pregnancy and while breastfeeding.
It’s important for patients to take their medication in accordance with their doctor’s instructions, as not doing so can lead to lack of improvement in their condition. Doctors can also monitor inflammation markers in the blood to check whether the treatment is working. In some cases, if the medicine’s side effects become bothersome – usually diarrhea – the daily dose can be split into smaller doses taken throughout the day.
If a patient isn’t responding to colchicine as expected, the doctor might increase the dose. However, if even the maximum tolerated dose doesn’t reduce fever attacks or inflammation, the condition could be resistant to colchicine.
If colchicine doesn’t work or if a patient cannot tolerate it, other medications may be used. One alternative is a group of drugs called Interleukin-1 (IL-1) inhibitors, which block a different inflammation-causing process. The overall effectiveness of these drugs for FMF, especially their ability to prevent amyloidosis, is not yet completely established. For this reason, low-dose colchicine may still be recommended.
There are other medications that have been reported to be used for FMF patients in Japan, and drugs that can reduce a certain inflammation-causing protein. The effectiveness of these medications for FMF has yet to be confirmed. Finally, the use of certain antidepressants has been shown to reduce the frequency of fever attacks in FMF, suggesting that stress and depression may contribute to these attacks.
What else can Familial Mediterranean Fever be?
There are several other conditions that can cause symptoms similar to those of Familial Mediterranean Fever (FMF), which can lead to misdiagnosis. By taking an in-depth medical and family history of the patient and conducting a physical examination, doctors can rule out other conditions.
One such condition is acute abdomen, where the abdominal pain experienced in FMF might lead doctors to investigate other potential causes like appendicitis or a perforated organ. Juvenile idiopathic arthritis is another condition that can be considered due to the presence of fever and arthritis, especially in children.
Systemic diseases like Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) might also cause similar symptoms, like positive antinuclear antibodies in SLE or joint pain affecting both sides of the body (symmetrical polyarthritis) in RA.
Other familial periodic fever syndromes might cause confusion when diagnosing FMF, due to their overlapping symptoms. Some of these are:
- Periodic Fever with Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) which causes mouth ulcers, throat inflammation, and swelling in the lymph glands.
- Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS) is known to cause symptoms like rashes, muscle pain, and swelling around the eyes.
- Hyper Immunoglobulin D Syndrome (HIDS) presents with high levels of Immunoglobulin D and symptoms like fever, swollen cervical lymph nodes, vomiting, diarrhoea, abdominal pain and sometimes conjunctivitis.
FMF can also be confused with Muckle-Wells syndrome and Familial Cold Urticaria (FCU) due to the common symptom of skin rash (urticaria).
Lastly, the skin lesions that can occur in FMF might be mistaken for Cellulitis, which is a skin infection. A detailed patient history and their lack of response to antibiotics can help to distinguish between the two conditions.
What to expect with Familial Mediterranean Fever
The outcome for patients with FMF (Familial Mediterranean Fever) generally depends on how often they experience flare-ups and whether they develop any additional health issues. Typically, these flare-ups lessen in frequency and severity with age as well as with proper treatment.
However, it’s worth noting that certain genetic types, like 694V, are linked with a higher risk of developing complications such as kidney disease (renal amyloidosis) and more frequent flare-ups. These factors can lead to worse health outcomes compared to other genetic variants of FMF.
Possible Complications When Diagnosed with Familial Mediterranean Fever
Secondary AA (amyloid A) amyloidosis is a serious issue that can come up when dealing with FMF. It can affect different parts of the body including the digestive tract, spleen, liver, testicles, heart, or lungs, but it’s most often seen in the kidneys. There are certain genetic factors that can increase the risk of amyloidosis; for instance, people with the M694V mutation are more likely to develop it, whereas those with the E148Q mutation won’t typically experience it.
Taking the drug colchicine can help prevent amyloidosis, so patients who don’t take this medication, or who start it too late in their disease, have a higher risk of developing this condition. However, if a patient continues to have protein in their urine (proteinuria) despite taking colchicine, this might be due to another reason besides amyloidosis.
There are varying symptoms of FMF: some patients may have no obvious signs and only discover they have the disease due to the presence of protein in their urine. Others may develop nephrotic syndrome (a severe kidney disorder) or end-stage kidney disease as their first sign of FMF. Certain factors, such as being male or originating from the eastern Mediterranean, can increase the risk of developing amyloidosis.
Another complication that FMF patients can experience is glomerulonephritis, which is an inflammation of the tiny filters in your kidneys (glomeruli). Other rare complications include Henoch-Schönlein purpura (a disorder that causes inflammation and bleeding in the small blood vessels in your skin, joints, intestines, and kidneys) and polyarteritis nodosa (a rare disease that causes swelling and damage to small- and medium-sized blood vessels in the body).
Several other complications related to FMF include testicular amyloidosis, which can lead to male infertility, and inflammation in the pelvis and peritoneum, which can lead to the creation of firm bands of scar tissue (adhesions) and eventually blockage of the small intestine, as well as infertility in females.
Primary Complications and Risks of FMF include:
- AA Amyloidosis affecting different bodies
- High risk with M694V mutation
- Increased risk without colchicine treatment
- Risk of developing nephrotic syndrome or end-stage kidney disease
- Increased risk for males or individuals of eastern Mediterranean descent
Rare Complications and Risks:
- Glomerulonephritis
- Henoch Schönlein purpura
- Polyarteritis nodosa
- Testicular amyloidosis leading to male infertility
- Pelvic and peritoneal inflammation leading to female infertility and small intestine blockage
Preventing Familial Mediterranean Fever
FMF, or Familial Mediterranean Fever, is a disease that a person is born with because it’s caused by certain genes. It’s important for patients to keep a record or ‘diary’ of how often the attacks occur and what symptoms they experience, so their doctor or nurse can review this information. One medication that’s helpful in managing this condition is called colchicine. This drug can lessen the harshness of the attacks and prevents a dangerous condition called amyloidosis.
Amyloidosis is a serious health issue that can lead to life-threatening problems. That’s why taking the colchicine medication consistently is very important. If you’re having any problems sticking to the medication due to side effects, it’s crucial to let your doctor or nurse know. They’ll be able to help manage these side effects, making it easier to stick to the treatment plan.
