What Is Familial Mediterranean Fever? 

Everyone loves a summer holiday near the Mediterranean Sea, a destination known for its good weather and lovely diet. But have you ever heard of an autoimmune disease called Familial Mediterranean fever? Don’t worry - It’s a hereditary disease, meaning it passes on from family member to family member, and you can’t just catch it by going on holiday. It is a very interesting condition, however, and this article will tell you all you need to know about it. 

Introduction

Familial Mediterranean Fever (FMF) is a genetic disorder affecting people of Mediterranean origin, including Italians, Greeks, Spaniards and more. It is an autoinflammatory disease characterised by recurrent episodes of fever, often accompanied by skin rashes or serositis. The latter is defined as the inflammation of a serous membrane and leads to severe pain. In the case of FMF, this usually occurs in the lungs, abdomen and joints. The disease is hereditary and has important medical significance. The attacks will usually stop by themselves, however if they are not prevented using the correct treatment, FMF can lead to serious, sometimes life threatening complications.¹

Causes and genetics

Autosomal recessive inheritance pattern

FMF is a disease that follows an autosomal recessive inheritance pattern. This means that you can only develop the disease if you inherit two copies of the mutated gene responsible for FMF (one from each parent). If you only carry one copy of this gene, you won’t suffer from FMF yourself but may pass it on to your child if your partner also carries the gene.²

MEFV gene mutation

The gene that is to blame for FMF is the MEFV gene. This gene is responsible for the encoding of pyrin, which plays a role in signalling the body of inflammation and infections in cells. FMF is caused by a mutation of the MEFV gene, leading to excess inflammation.³ A gene mutation consists of a modification in a gene’s DNA sequence, which is what determines the structure of the protein it encodes, so in turn, causes a change in the protein itself.⁴ They can be spontaneous, and one gene can mutate in many different ways. In fact, over 300 different mutations have been linked to FMF development, some being more common than others.¹ 

Clinical presentation

• FMF is characterised by recurrent episodes of fever and serositis, which causes severe pain to the chest, abdomen or joints. In addition, the attack can sometimes be accompanied by other symptoms like skin rashes and headaches. 
• FMF patients usually experience their first attack by 20 years old, though they can sometimes occur during early childhood or later in life. 
• Common triggers include stress, intense physical activity, infection, menstruation and more.
• Patients often experience prodromal or pre-onset symptoms before an attack, such as nausea, anxiety or irritability. 
• Episodes will usually last between 12 hours to 3 days. The frequency, time and severity of attacks is highly variable, and the area of pain can also change. 
• Between episodes, patients will usually feel fine.²

Recurrent episodes of fever

The main, sometimes only symptom that appears during FMF attacks is fever. This can vary from a mild fever, around 38°C, to a more severe one (40°C). The fevers can be preceded by chills, which is the case in about a quarter of patients.⁵  

Abdominal pain and inflammation

The most common area of pain during an FMF attack is the abdominal area. This could be localised and then spread to become a more generalised pain. The pain is due to peritonitis, the inflammation of the abdominal lining.² In addition to severe abdominal pain, this can cause constipation, diarrhoea, ascites, and more. Furthermore, leaving FMF untreated can lead to more severe complications, such as amyloidosis or inflammatory bowel disease.⁶  

Joint involvement and swelling

Large, lower body joints are most commonly affected in FMF episodes. These include the knees, ankles and hips, with patients experiencing severe pain in one of these areas. Usually, no more than one joint is affected, though this can sometimes not be the case. The affected joint can appear red and swollen and usually has a limited range of motion. After the attack, the joint will usually return to normal, though chronic arthritis can sometimes develop.¹

Chest pain and pleurisy

FMF can also cause pleurisy, which involves inflammation of the thin tissue layer separating lung from chest wall.⁷ This leads to sharp chest pain that is usually unilateral (on one side) and worsens when breathing or coughing. Chest pain can also appear due to inflammation of the lining surrounding the heart, called pericarditis, and usually manifests in the space behind the sternum.¹ 

Skin manifestations

Sometimes, FMF patients develop skin lesions and rashes during an episode. For example, they can develop a condition similar to Erysipelas, which is characterised by painful, swollen and red skin lesions on the lower legs.⁵

Diagnosis

Clinical criteria for diagnosing FMF

FMF is usually diagnosed on the basis of symptom presentation, presence of family history and potential response to treatment. Several diagnostic criteria were put forward, but the Tel Hashomer criteria are the most commonly used. 

Typical attacks should consist of fevers and inflammation-induced pain, last between 12 to 72 hours and must have recurred at least 3 times. Diagnosis is established in the presence of 1 major + 2 minor criteria or 1 minor + 5 supportive criteria.³

Major criteria (typical attack + one/more of the following):

• Peritonitis
• Unilateral pleurisy or pericarditis
• Joint (hip, knee, ankle)
• Fever alone

Minor Criteria (attack excludes one of the typical symptoms + one/more of the following):

• Exertional leg pain
• Favourable response to colchicines (typical FMF treatment)
• Abdomen/joint/chest pain

Supportive criteria:

• Family history
• Vulnerable ethnic origin
• Under the age of 20 years at disease onset
• Symptom-free between attacks
• Spontaneous remission from attacks
• Needing bed rest after severe attacks
• Abnormal test results for white blood cell count
• Increased acute phase reactants in blood (linked to inflammatory response) 
• History of laparotomy or appendectomy without pathology
• Episodic hematuria/proteinuria
• Parental consanguinity

Changes in white blood cell levels or reactants in the blood can be revealed through laboratory analysis. In addition, these are often monitored during treatment to assess the patient’s response to therapy. The symptoms should also be exclusive to FMF and should not be able to be explained by a different condition or medication.³

Genetic testing for MEFV mutations

On top of the clinical criteria, genetic testing is used to confirm FMF diagnosis. This is also helpful when patients do not display a typical set of symptoms. The laboratory test involves analysing the MEFV gene of the patient and assessing it for any pathogenic mutations. Several variants of the gene have been associated with FMF, and as mentioned, mutations in both MEFV alleles are usually necessary for disease development. Sometimes, FMF can still be developed even if there is only one or no pathogenic mutation, but this is less common. Additionally, some people may have two pathogenic mutations of FMF but don’t show any symptoms. These patients should be monitored closely and perhaps considered for treatment. Thus, genetic testing is mostly used as a support for diagnosis and cannot be used on its own.⁵ 

Differential diagnosis from similar conditions

Although there are many diagnostic criteria for FMF, many diseases share recurrent fever as a main feature. For example, PFAPA syndrome is a disorder commonly diagnosed in the case of recurrent fevers at a paediatric age, but this can be a misdiagnosis. Early-onset Behçets disease is another condition that is often misdiagnosed as the cause of FMF symptoms in children. The discrimination between these three disorders is difficult, but some characteristics do allow for it. Therefore, it is important to take a detailed note of all the symptoms experienced during attacks. 

Mevalonate kinase deficiency, observed in early childhood, is also similar to FMF. Its main symptoms involve gastrointestinal and muscular problems lasting up to 3 days. However, mevalonate kinase deficiency can be distinguished due to the presence of increased mevalonate levels in the patient’s urine during episodes. Tumour necrosis factor receptor-associated periodic syndrome is an autoinflammatory disorder that is similar to FMF but has one main distinguishing factor: patients will also experience fever episodes, but these will be much longer than those in FMF. 

Lastly, the abdominal pain commonly experienced during FMF episodes can be related to other conditions. These include inflammatory bowel disease, cholecystitis, pancreatitis and more.⁵

Pathophysiology

The role of pyrin protein

Pyrin is a protein created through the MEFV gene and is mainly found in the cytoskeleton of multiple cell types, including white blood cells. The cytoskeleton is a structure around cells that helps maintain their shape and internal formation. White blood cells play a particular role in the immune response against pathogens, which are organisms that cause disease.

The exact role of pyrin in FMF is not completely understood, but research suggests that the protein is involved in triggering the inflammatory responses observed during disease attacks. Under normal conditions, pyrin can interact with an apoptosis-associated speck-like protein (ASC) and other enzymes, eventually inhibiting and modulating inflammatory pathways. However, this function is disrupted due to mutation of the MEFV gene in FMF patients, leading to decreased inhibition of the inflammatory pathways.¹

Inflammation and cytokine production

As mentioned, the pyrin protein plays an important role in the modulation of inflammatory pathways. More precisely, dysfunction of the protein causes overproduction of cytokines, especially interleukin (IL) -1𝛽, IL-6 and IL-18.⁸ A cytokine is a small protein which plays a crucial role in the immune- and inflammation systems of the body.⁹ The activation of cytokine networks due to the mutated pyrin proteins is what causes an autoinflammatory response in FMF.

Epidemiology

FMF is most common in Mediterranean and Middle Eastern populations, such as Jews, Armenians, Greeks, Italians and Turks. Approximately 1 in 200 individuals from one of these backgrounds is believed to suffer from FMF.² However, due to migration, FMF has spread to other countries as well. Most commonly, the first attack will occur before 20 years old, but occasionally can develop later in life. Symptoms may also start very early on in childhood, during the first months of life. There is no apparent difference in FMF incidence rates between males and females.¹

Management and treatment

Colchicine as primary treatment

Colchicine is a medicine that can prevent FMF attacks, return inflammation to a normal state between episodes and prevent the development of amyloidosis, a severe complication of untreated FMF. Its basic function is that it inhibits a specific process essential to inflammation, therefore stopping the inflammatory process associated with FMF. 

Colchicine treatment is usually lifelong, with dosing depending on the patient’s age and the severity of their symptoms. Higher doses will be given to those with more frequent attacks or who are developing amyloidosis, for example, whereas children with milder symptoms will be given much lower dosages. Treatment can only be increased if kidney and liver function are normal, as the drug needs to be metabolised correctly. 

Common side effects of colchicine, especially at a higher dosage, include vomiting, nausea and diarrhoea. Sometimes, more severe adverse effects can also appear, though these are not common. Additionally, the drug is safe to use during pregnancy and breastfeeding. 

Supplementary treatments for resistant cases 

Compliance with the colchicine treatment is very important for it to work. Close monitoring of the patient and increasing dosage when needed are essential parts of the therapy. However, if the patient does not comply with the treatment, for example, due to side effects or not responding to the therapy, alternative treatments have been put forward. 

Interleukin inhibitor drugs are sometimes used as an FMF treatment, as they help modulate autoinflammatory responses. However, this drug has not shown to be effective in preventing amyloidosis, so a low dosage of colchicine is often needed. 

Other drugs include interleukin antagonists, specific tumour necrosis factor (TNF) inhibitors and more, though their efficiency has not yet been established. Lastly, some suggest the use of antidepressants to reduce stress and depression and thus prevent the development of FMF attacks.¹ 

Prognosis

Depending on how frequently attacks occur and whether or not any complications develop, the prognosis of FMF can vary. Treatment will usually ensure that episodes occur less often and are less severe, and frequency also tends to reduce with age. Between attacks, people are usually symptom-free and can live life like usual. Early diagnosis and correct treatment can allow for patients to have a good quality of life and a normal life expectancy.³ 

There are some possible complications that can develop from FMF, however. As mentioned, amyloidosis is a very serious problem that can arise from FMF if not treated correctly. Although colchicine treatment can prevent this development, patients could be resistant or non-compliant to the treatment, putting them at risk.³ In brief, amyloidosis is a disease characterised by the formation of abnormal protein clumps in tissues, leading to organ dysfunction and death.¹⁰ 

Summary

• FMF is a hereditary autoimmune disease caused by a mutation in the MEFV gene, which leads to a dysfunction of the pyrin protein and an increased inflammatory response of the cells through cytokine release. 
• The disorder presents itself in episodes, or attacks, during which patients suffer from fevers and inflammation-induced pain. Depending on where the inflammatory response occurs, this pain could be in the abdomen, chest/lungs and joints. 
• The attacks can also be accompanied by other symptoms, such as skin rashes.
• The most common treatment for FMF is colchicine, which has been proven to be highly effective and has little side effects. If the patient is non-responsive or resistant to this medicine, other alternatives have also been put forward. 
• In general, FMF is a disorder for which an effective treatment has been developed, which can promise patients a good, rich life.