Familial Mediterranean Fever

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Introduction

Familial Mediterranean Fever (FMF) is a common genetic, hereditary, autoinflammatory disease that mainly affects people from the Eastern Mediterranean, like Turks, Jews, Arabs, and Armenians. It occurs in about 1 out of every 500 to 1,000 people in these areas. But FMF is no longer limited to these boundaries, It's spreading to other parts of the world, like Europe, North America, and Japan. This is happening because lots of people from FMF-prone areas have moved to these new places in the last 20 years.

Mechanism of Injury / Pathological Process

MEFV gene as a set of instructions found on chromosome 16, these instructions are most important in certain types of white blood cells, like granulocytes and monocytes, which help to deal with inflammation. The MEFV gene creates a protein called pyrin, that is in different types of immune cells like neutrophils, eosinophils, monocytes, and dendritic cells and is important for the immune system. This protein has an important role in inflammation. It can affect how cells die, activate certain proteins, and release substances that make inflammation happen.

In Familial Mediterranean Fever (FMF) there was a mutation in the MEFV gene found on chromosome 16. When there's a problem with pyrin because of changes with this gene, it can cause inflammation in the body. Pyrin usually works with another protein called ASC, and together, they create something called an inflammasome. This inflammasome starts a process that leads to the release of certain proteins called IL-1beta and IL-18. These proteins cause more inflammation in the body, and the immune system goes into overdrive. Sometimes, this inflammation process can also lead to a type of cell death called pyroptosis, where cells swell up and burst. This makes the inflammation even worse. It's like a chain reaction, with the body's immune system getting more and more active. It was hypothesised that there might be other genetic or environmental reasons that can also cause FMF and not all patients with FMF caused by MEFV gene mutation.

Clinical Presentation

• Sudden, short, and irregular episodes of fever and pain that resolve spontaneously within 24–72 h.
• Abdominal pain
• Arthritis.
• Symptoms of inflammation of the serous membranes that may sometimes need hospitalization or unnecessary surgery.

FMF complications

• Ankylosing spondylitis
• Amyloidosis
• Hip involvement and may progress to need hip joint replacement
• Behcet’s syndrome
• Henoch-Schonlein purpura (inflammation of the small blood vessels in the skin, intestines, and kidneys.)
• Early atherosclerosis.

Diagnostic Procedures

The diagnosis of FMF is dependent on Tel-Hashomer clinical criteria, in which patient with 2 major clinical symptoms or two minor symptoms can be diagnosed with FMF according to the new simplified version from Livneh as the following.

• Typical attacks must meet these criteria: they happen repeatedly (at least three times),associated with a fever ( rectal temperature of 38°C or higher), and they don't last long (from 12 hours to 3 days).

• Incomplete attacks, which must occur repeatedly, are characterized by variations from typical attacks in one or two aspects:

1. Body temperature remains below 38°C.
2. The attack lasts for a duration that is shorter or longer than a typical attack but falls within a range of no less than six hours and no more than seven days.
3. No signs of peritonitis (abdominal inflammation) are evident during these episodes.
4. Attacks are limited to a specific area in the abdomen.
5. Arthritis affects joints other than the hip, knee, or ankle.

Major criteria	Minor criteria
Typical attacks	Incomplete attacks involving either or both of the following sites
1- Generalized peritonitis	1- Chest
2- Unilateral pleuritis or pericarditis	2- Joint
3- Monoarthritis (hip, knee, ankle)	3- Exertional leg pain
4- Fever alone	4- favorable response to colchicine
5- Incomplete abdominal attack

Mediterranean fever genetic testing.

Outcome Measures

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Management / Interventions

Medical Management

There isn't a definite treatment is working for this disease as the diagnoses FMF can be tricky because it looks like other illnesses. So, the treatment focuses on managing sudden episodes and stopping them from coming back.

• Colchicine can decrease the severity and duration of the symptoms, prevent sudden attacks and problems like amyloidosis.
• Methylprednisolone can be used in acute phase.
• Other treatments like; alpha interferon, IL-1 cytokine antagonist, IL1 alpha, IL-1 beta blocker, anti TNF, and dapsone.

Differential Diagnosis

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Resources

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