The inheritance of FMF is complicated. As research continues, we are learning more.

It was thought FMF was usually inherited in an autosomal recessive way. This means a person needs two changed copies of the gene (one from each parent) to develop the condition. Newer research shows that patients may be heterozygous (one variant), compounded heterozygous (two or more different single variants) or homozygous (have two of the same variants). People may be carriers of FMF variants and may be asymptomatic (no symptoms).

Important things to know:

• Some people with only one gene variant may still have symptoms.
• Some people with two variants may have mild symptoms or none at all.
• Sometimes a gene change happens for the first time in a person (called a de novo variant).
• Because of this, genetic testing alone cannot always confirm FMF.
• Doctors must also consider symptoms, family history, and other conditions

Genetic test results can be difficult to interpret. This is because:

• There are many different gene variants, some of which are known to cause disease, while others are uncertain or less well understood. These are called variants of unknown significance.
• Known variants that are not thought to cause disease are called benign variants.
• Some individuals will have the same gene variation as another person but one may experience more severe symptoms than the other.  This is known as variable expressivity.
• Some people with only one gene variation may still show symptoms of FMF. This is known as semidominant inheritance.
• Others may carry known diseases causing variants but have no symptoms at all. This is called incomplete penetrance.
• Not everyone with FMF has a known MEFV variation, so diagnosis is based on more than just genetic testing. This is known as a clinical diagnosis.

This is called variable expressivity.

• Others may carry known diseases causing variants but have no symptoms at all. This is called incomplete penetrance.
• Not everyone with FMF has a known MEFV variation, so diagnosis is based on more than just genetic testing. This is known as a clinical diagnosis.

As a result, genetic testing alone may not confirm a diagnosis of FMF. Doctors must also consider your symptoms, medical history, family background, and other possible conditions.

There are many other autoinflammatory diseases with similar symptoms, so a broad and careful evaluation is needed.

Symptoms often begin in childhood or before age 20, but they can start later, for example menopause may be a triggering factor.

The most common signs include:

• Fever: high or low-grade fever.
• Abdominal Pain: Often resembling appendicitis, this is the most frequent symptom, occurring in approximately 95% of patients.
• Chest Pain: Resulting from pleuritis (inflammation of the lining around the lungs) or pericarditis (inflammation of the lining around the heart).
• Joint Pain and Swelling: Particularly affecting the knees, ankles, hips, and wrists.
• Skin Rash: a painful red rash, often on the lower legs. (Erysipelas-like rash)
• Headache: Often associated with aseptic meningitis.
• Gastrointestinal Symptoms: Including nausea, vomiting, diarrhoea, or constipation.
• Muscle aches often diagnosed as Fibromyalgia
• A swollen, tender scrotum

FMF is diagnosed by looking at:

• Your symptoms
• Your family history
• Your ethnic background
• Genetic testing (if available)

Doctors often use criteria like the Tel Hashomer or Livneh criteria, which include common signs, pathology results, and response to treatment.

Pathology tests

Urine test: Protein in the urine that may indicate amyloidosis is another.

Blood tests include

• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) and Serum amyloid A (SAA) to check for high levels which is a sign of inflammation
• Full Blood counts (FBC) An elevated level of white blood cells

There is no cure for FMF, but it can be well managed.

Main Treatment: Colchicine

• Taken daily
• Helps reduce flares and prevent amyloidosis (a serious kidney complication)
• Recommended as early as possible after diagnosis (EULAR guidelines)

Most people respond well to colchicine. If colchicine does not work or causes side effects, doctors may recommend biologic therapies such as:

• anakinra
• canakinumab (not currently available in Australia/New Zealand)

These medicines block a protein called interleukin-1, which drives inflammation.

In Australia and Aotearoa New Zealand access to this type of treatment can be difficult to access. It is currently necessary for specialists to prescribe via special consideration/compassionate use.

In Australia and Aotearoa New Zealand other biologics such as TNF inhibitors (e.g., infliximab, adalimumab) have also been prescribed with effect.

NSAIDs (Non-steroidal Anti-inflammatory Drugs): These help reduce pain, inflammation, and fever. Examples include ibuprofen, naproxen and aspirin.

Flares can be very painful and may require hospital admission for pain management. It can help to have a discussion with your treating doctor to have a plan of treatment ready in the case of a flare. This may include a script for stronger pain medications to try at home first.

IMPORTANT NOTE:

Currently, not all medications commonly used to treat SAIDs are available in Australia and New Zealand, and those available may be difficult to access.

ANZFAID is committed to continuing to advocate for improved options, and timely and affordable access to treatment.

Without treatment, FMF can lead to:

• Amyloidosis – a serious condition where protein builds up in the organs, especially the kidneys
• Kidney failure

• Infertility: Due to amyloidosis affecting the ovaries or testes.

• Chronic inflammation – may cause long-term joint or organ damage