Familial Mediterranean Fever

Original Editor - Khloud Shreif Top Contributors - Khloud Shreif, Kim Jackson and Kirenga Bamurange Liliane

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. It is a repeated episodes of fever, inflammation in multiple body tissues, and a strong acute phase response.

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.

Gut bacteria in FMF patients are influenced not only by genetics but also by the ongoing inflammation associated with the condition, which could potentially impact the development of amyloidosis. Researchers have observed that FMF patients co-infected with Helicobacter pylori in their stomach experienced more severe and frequent FMF attacks, but when the infection was successfully treated, it led to a decrease in both the frequency of attacks and inflammation. Additionally, another study revealed that FMF patients with an overgrowth of bacteria in their small intestine, known as Small Intestinal Bacterial Overgrowth (SIBO), suffered from more severe FMF symptoms. Remarkably, treating SIBO with antibiotics not only enhanced the effectiveness of colchicine but also eliminated the need for more expensive medications.

Clinical Presentation

FMF is marked by short, 1- to 3-day bouts of fever, often accompanied by inflammation in the body's tissues like the lining of organs or joints, and sometimes skin rashes. It usually starts early in life, with most cases appearing before age 20. These fever episodes can happen at irregular intervals, from days to years apart, and the specific symptoms can change between episodes. People with FMF are typically symptom-free between these episodes. They can be presented with:

• 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

Diagnosing FMF can be tough because it shares symptoms with other illnesses, and understanding genetic tests can be complicated because many of the 340 different MEFV gene variations don't have a clear connection to how they affect a person with MEFV. There was a functional assay developed to distinguishe FMF patients from others, utilizing IL-1β and IL-18 secretion ratios for robust results. IL-1β is particularly effective in whole blood tests, improving the diagnosis of FMF and related conditions.

The diagnosis of FMF is dependent on clinical criteria with other investigations. One of this criteria is 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

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 is the gold standard of treatment, 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.

Nutrition

The connection between diet and FMF is getting more attention in research as what we eat can affect how our immune system works. There are studies about if a special diet that's high in anti-inflammatory foods might help control FMF attacks. It's important to note that more research is needed to understand how diet affects FMF symptoms, some studies suggest salty foods may trigger inflammation, while ancient grains might reduce it due to lower levels of ATIs and FODMAPs compared to modern grains.

The first study exploring diet's impact on FMF attacks found that a low-fat diet with only 20 grams of fat seemed to reduce the number of attacks and flare-ups. However, this benefit was not consistently seen in later studies. There was a research suggests that FMF patients who prefer meals with less salt and fat may have a better response to colchicine treatment. This lower salt and fat intake might help reduce inflammation and make the disease milder. In a study, an anti-inflammatory diet and supplements (vitamin D, curcumin, flaxseed) improved FMF symptoms, cognitive tests, and reduced C-reactive protein in patients on colchicine therapy. Another study found that wheat intake worsened FMF, increasing inflammatory markers. This might be due to a wheat component called ATIs activating immune responses in the gut.

Physical Therapy Intervention

In FMF, musculoskeletal involvement is common in 70%–75% of patients, typically presenting as acute episodes of arthritis, primarily affecting larger joints in the lower extremities. However these episodes usually resolve within 1 to 3 days, but in less than 10% of cases, they can persist for up to a month or longer, potentially leading to joint damage, particularly in the hips or knees. It can also affect on cardiovascular deconditioning, often causing patients to rest due to pain and functional disabilities.

Physical Therapy Intervention can include a combination of:

• Patient education to learn how to manage their conditions, learn strategies to save energy, sleep hygiene, relief pain, relaxation methods, and exercise to improve functional abilities and psychological well-being, and how to use assistive devices in ADL if patient's condition require this.
• Electrotherapy modalities:
  • Transcutaneous electrical nerve stimulation (TENS): is effective in relieving acute and chronic pain, with reported benefits for various conditions, including chronic arthritis and was effective to reduce joint pain in patients with RA.
  • Low-level laser therapy (LLLT)
  • Interferential therapy
  • Therapeutic ultrasound (US)

• Hydrotherapy combines buoyancy and heat to aid with exercise and mobility, particularly for those with severe large-joint issues. It offers physical benefits similar to land-based exercise and may have additional psychological benefits. In addition there is balneotherapy involves the use of mineral-rich thermal water for immersion baths, including salts, sulfur, and radon-carbon dioxide baths. Its goal is to relieve pain, enhance joint mobility, and promote overall well-being.
• 
  Exercise is beneficial for enhancing mobility, improving cardiopulmonary function, and reducing complications. Moderate evidence supports therapeutic exercise in improving physical function, disease activity, and chest expansion. Lower-level evidence suggests exercise can provide pain relief, reduce stiffness, enhance spinal mobility, and boost cardiorespiratory function. Group therapy tends to yield better results than home exercise programs. Aerobic exercise programs enhance health-related fitness, improve psychological well-being, reduce pain and fatigue, and boost functional capacity, all without worsening disease activity or hastening joint damage.

Differential Diagnosis

• Crohn's disease
• Systemic Lupus Erythematosus
• Sarcoidosis
• Behçet's Disease
• Rheumatoid Arthritis