Familial Mediterranean fever: a borderless disease

«When you hear hoofbeats, think horses, not zebras». This is a widely known medical aphorism meaning that when trying to diagnose a patient, doctors should first consider common diseases and not rare ones. Of course, zebras do exist, and familial Mediterranean fever (FMF), which originated more than 3000 years ago in Mesopotamia, is one of over 7,000 rare diseases [1]. In this article, we will explore the spectrum of FMF disease by highlighting the symptoms, diagnosis, and treatment of the condition.

What is Familial Mediterranean Fever?

Familial Mediterranean fever (FMF) is the oldest and the most common autoinflammatory disease. It is characterized by episodes of inflammation such as fever or rash, which can be recurrent and are known as “attacks”. It has been suggested that FMF mutations have existed for over 1800 years, long before the first deadly plague epidemic. In fact, studies have shown how FMF mutations provided humans from the Middle East with a selection advantage, probably by increasing their resistance to the plague [2].

FMF is frequently prevalent in the Eastern Mediterranean region, especially in Turkish, Arab, Armenian, and Non-Ashkenazi Jews populations. However, there are also reported patients from Europe, North America, and Japan. The disease has spread worldwide due to massive population movements, and the spread is expected to increase further [3].

Genetics

FMF is inherited in an autosomal recessive pattern. Autosomal recessive diseases occur when a person inherits two copies of a gene with a genetic change (mutation), one from each parent. FMF is caused by mutations in the MEFV gene, which encodes the pyrin enzyme. Enzymes are proteins that help speed up chemical reactions in our systems, including the immune system. The pyrin enzyme, named from the Greek word “pyr” meaning fire, is responsible for recognizing outside invaders, such as viruses and bacteria, and causing inflammation and fever as the body’s first response [4]. Mutations in the MEFV gene lead to an overactive pyrin enzyme, resulting in excessive and uncontrolled inflammatory responses even in the absence of any infection. Over the years, more than 100 disease-causing mutations have been described [5]. The most common mutations are M6941, M694V, M6801, E148Q, and V726A, which account for a large percentage of FMF cases. Other mutations are observed in non-endemic populations [6].

In addition to MEFV gene mutations, mutations in other genes, known as genetic modifiers, can influence the clinical presentation of the disease. For example, it has been described that mutations in the SAA1 gene which produces amyloid A protein, are correlated with amyloidosis in FMF patients, a condition caused by the build-up of the amyloid A protein in the body and affects the function of several human organs such as the heart, liver, and kidney [7].

Familial Mediterranean Fever Symptoms

Symptoms and severity of FMF differ widely from person to person, even among members of the same family [8]. This is influenced not only by the different mutations that can cause FMF but also by environmental factors such as diet [9].

In most cases of FMF, patients experience recurrent inflammatory attacks. The primary symptom of these attacks is fever, which occurs in 96% of inflammatory episodes [10]. Episodes last for 1 to 4 days, and they can be triggered by fatigue, stress, or physical effort, among other factors [11]. The frequency of the attacks can range from two attacks per week to one attack per year. FMF attacks typically start in early childhood with most patients experiencing onset of symptoms before the age of 20. As patients get older, the attacks tend to decrease in severity and frequency [12].

Other symptoms:

• Headache
• Abdominal pain during fever episodes
• Chest pain that lines the lungs
• Joint pain (arthralgia) and arthritis (inflammation)
• Patches of red, swollen skin (erysipelas-like erythema)
• Red rashes on legs
• Muscle aches
• Peritonitis (inflammation of the abdomen)
• Serotosis (inflammation of serous tissues of the body such as the heart)
• Pleurisy (inflammation around the lungs) and pericarditis (inflammation of the pericardium, a membrane that surrounds the heart)
• Amyloidosis [2,8,9]

Familial Mediterranean Fever Phenotypes

The term “phenotype” refers to the observable characteristics that are a result of the genes we have inherited. Depending on the mutations inherited, FMF patients can have different phenotypes. There are three main phenotypes of FMF:

1. Phenotype 1: Characterized by recurrent episodes of inflammation and serositis which includes symptoms such as fever, peritonitis, synovitis, and pleuritis [13].
2. Phenotype 2: Characterized by the high volume of amyloid A, which causes organ damage. Patients do not have phenotype 1 symptoms. The prevalence of amyloidosis varies depending on gender, ethnicity, and specific mutations in the MEFV gene [13].
3. Phenotype 3: Characterized as the ‘“silent” phenotype, the patients have two genetic changes in MEFV that cause FMF, but they remain asymptomatic [13]. Specific mutations, such as E148Q and R761H, have been identified that cause this phenotype. There is also an increased risk of phenotype 3 patients developing amyloid A amyloidosis over time, which would reclassify them as phenotype 2 [13].

Familial Mediterranean Fever Diagnosis

The diagnosis of FMF relies on the patient’s medical history and clinical manifestations [4]. When FMF is suspected, the healthcare provider conducts blood tests during an attack to detect inflammation [8]. As the symptoms resemble or mimic those of other diseases such as Crohn’s syndrome and ulcerative colitis, diagnosis can be challenging [4]. More recently, with the advancement of medical technology, genetic testing has emerged as a valuable tool for confirming or providing FMF diagnosis. Scientists have proposed classification criteria for FMF diagnosis including association between clinical findings and genetic testing to ensure an accurate diagnosis and classification. Genetic testing allows for the earlier diagnosis of asymptomatic patients, patients with phenotype 2, or patients in non-endemic countries where healthcare providers may not suspect FMF due to its low incidence. By identifying the specific mutations in the MEFV gene causing FMF, healthcare providers can recommend the best clinical management and treatment for the patient [14].

Familial Mediterranean Fever Carrier Rate

Genetic carrier screening is also an important option for individuals who are planning to start a family. It is estimated that in endemic countries, the carrier rate is as high as 1 in 6 people [15]. By being aware of whether individuals are carriers of FMF disease, they can make informed reproductive decisions and minimize the risk of transmitting the disease to their children.

Familial Mediterranean Fever Treatment

The goal of current and prospective treatments of FMF is to improve the patients’ quality of life by reducing the severity and frequency of symptoms and preventing long-term complications [8]. During acute episodes, treatment is supportive, such as analgesics or saline, as it focuses on hydration and pain relief [16]. Other prophylactic forms of treatment aiming to prevent attacks or amyloidosis development are also available.

Colchicine

The mainstay treatment for FMF patients is colchicine. With life-long colchicine treatment, FMF patients can have a better quality of life. Colchicum, the herbal form of colchicine, was first described by Ibn Sina (Avicenna) as the “Canon of Medicine” in the early 11^th century where it was used as a relief for joint pains and gout. In 1974, colchicine was introduced as a treatment for FMF. Currently, colchicine is used as a prophylactic treatment for FMF attacks, and it also helps to prevent the build-up of amyloid in the kidneys [17]. Patients who take colchicine have shown a remarkable improvement in the duration and frequency of the attacks. However, a small percentage of patients may develop resistance or have an intolerance to colchicine, which is why it is crucial to have more FMF treatment options [9].

Interleukin-1 Inhibitors and Anti-IL-6 drugs

One new prophylactic treatment for colchicine-resistant or -intolerant patients is the use of IL-1 inhibitors or anti-IL-6 drugs. Interleukin inhibitors can block the function of interleukins, a group of proteins produced by our immune system in response to infection. By blocking the production of interleukins, inflammation attacks can be reduced. There are three IL-1 inhibitors available: Anakinra, Rilonacept, and the FDA-approved Canakinumab [18]. All of them have shown the ability to reduce the frequency of attacks and improve the quality of life of the patients [19,20,21]. Tocilizumab, an anti-IL-6 drug, inhibits amyloid production in patients with amyloidosis [22].

What are the potential complications of FMF if not treated?

If FMF patients are not diagnosed or misdiagnosed and left untreated, they may develop more severe symptoms, which may be fatal. They include

• Amyloidosis
• Kidney damage caused by amyloidosis
• Infertility
• Splenomegaly (enlargement of the spleen)
• Heart or lung inflammation [8]

A balanced diet approach

Since our diet can impact our immune system function and intestinal microbiota, certain foods may trigger inflammation in some FMF patients. Food that patients with FMF should avoid include

• Fatty and salty foods
• Cow’s milk
• Wheat [23]

On the other hand, an anti-inflammatory diet may help manage FMF inflammations. A diet containing curcumin, flaxseed, as well as vitamin D supplementation, has been reported to reduce FMF inflammations [24].

Conclusion

FMF is a genetic autoinflammatory disease that can pass on from parents to children and can occur in people of any ethnicity. As clinical manifestations of FMF vary among patients or mimic other conditions, diagnosis can be very challenging. To shorten or even avoid a never-ending diagnostic odyssey, healthcare providers should consider all the appropriate diagnostic tools to identify the condition, such as genetic testing. For the treatment of the disease, except from colchicine, which is used as a prophylactic treatment, there are ongoing clinical studies of IL-1 inhibitors anti-IL-6 drugs for FMF patients with resistance to or intolerance of colchicine. Currently, there is an international multicentre clinical study on the safety and efficacy of RPH-104, an IL-1 inhibitor, for prevention of recurrent episodes in FMF adult patients [25]. Although there has been major progress in the diagnosis and treatment of FMF, there is still much to be done to improve the patients’ quality of life.

The content of this article is for informational purposes and is not intended to replace medical advice. Please visit your healthcare provider if you have concerns about your health and well-being.

References

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