What is Familial Mediterranean Fever. How is FMF diagnosed. What are the common symptoms of FMF. Can FMF be treated effectively. Who is at risk for developing Familial Mediterranean Fever. What complications may arise from untreated FMF. How does FMF impact daily life and long-term health.

Understanding Familial Mediterranean Fever: A Rare Genetic Condition

Familial Mediterranean Fever (FMF) is a rare genetic disorder characterized by recurrent episodes of fever and inflammation. This condition primarily affects individuals with ancestral roots in Mediterranean and Middle Eastern regions, including Arabs, Armenians, Sephardic or North African Jews, Turks, Greeks, and Italians. As an autoinflammatory syndrome, FMF is related to a defect in the innate immune system, leading to periodic bouts of inflammation and fever.

The onset of FMF typically occurs before the age of 20, with three-quarters of affected individuals experiencing their first episodes before turning 10. This condition affects all genders equally and is considered the most common autoinflammatory syndrome.

The Genetic Basis of Familial Mediterranean Fever

At the heart of FMF lies a mutation in the MEFV gene, which is responsible for producing a protein called pyrin. This protein plays a crucial role in regulating the immune system’s response. When a person has an MEFV gene mutation, their body fails to produce sufficient pyrin, leading to an overproduction of an inflammatory cytokine called interleukin-1B. This imbalance results in recurring bouts of inflammation and fevers.

While there are over 300 known MEFV mutations, only a select few are responsible for causing FMF. In most cases, children inherit faulty copies of the MEFV gene from both parents. However, some individuals may develop FMF-like symptoms even if they inherit only one copy of the mutated gene.

How is FMF inherited?

• Autosomal recessive inheritance: Both parents carry one copy of the mutated gene
• Carrier parents have a 25% chance of having a child with FMF
• Some cases may occur with only one inherited mutated gene copy

Recognizing the Symptoms of Familial Mediterranean Fever

FMF is characterized by recurrent fever attacks that can last up to three days, with temperatures potentially reaching 104 degrees Fahrenheit. These episodes are often accompanied by various symptoms that can significantly impact a person’s quality of life.

Common symptoms of FMF include:

• Joint pain and swelling, particularly in the knees and ankles
• Red skin rash on the calves, ankles, or feet
• Severe abdominal pain
• Chest pain
• Muscle aches
• Alternating constipation and diarrhea

It’s important to note that FMF flares may be triggered by various factors, including infections, stress, strenuous exercise, physical trauma, or even menstruation. Between flares, individuals with FMF often feel normal and may experience symptom-free periods lasting years.

Diagnosing Familial Mediterranean Fever: A Comprehensive Approach

Diagnosing FMF can be challenging due to its rarity and the similarity of its symptoms to other conditions. Healthcare professionals employ a combination of methods to accurately identify this genetic disorder.

The diagnostic process typically involves:

1. Physical examination
2. Detailed family history
3. Blood tests to check for inflammation markers
4. Urinalysis to detect kidney-related issues
5. Genetic testing for MEFV mutations

Early and accurate diagnosis is crucial to prevent misdiagnosis and unnecessary treatments. For instance, children with severe abdominal pains due to FMF may be mistakenly diagnosed with appendicitis, potentially leading to unnecessary surgery.

Treatment Options for Familial Mediterranean Fever

While there is no cure for FMF, effective treatments are available to manage symptoms and prevent complications. The primary goal of treatment is to control inflammation and reduce the frequency and severity of flares.

What are the main treatment approaches for FMF?

• Colchicine: This is the mainstay of FMF treatment, often prescribed as a daily medication to prevent attacks and reduce inflammation.
• Biologics: For patients who don’t respond well to colchicine, biologics targeting specific inflammatory pathways may be prescribed.
• Pain management: Over-the-counter or prescription pain relievers may be used to alleviate symptoms during flares.
• Lifestyle modifications: Stress reduction techniques, regular exercise, and a balanced diet can help manage symptoms.

It’s essential for individuals with FMF to work closely with their healthcare providers to develop a personalized treatment plan that addresses their specific symptoms and needs.

Potential Complications of Untreated Familial Mediterranean Fever

If left untreated, FMF can lead to several serious complications that can significantly impact a person’s health and quality of life. Understanding these potential risks underscores the importance of early diagnosis and proper management of the condition.

Possible complications of untreated FMF include:

• Amyloidosis: A buildup of protein in the urine that can cause severe kidney damage
• Infertility: Particularly in individuals with severe flares or amyloidosis
• Myositis: Inflammation of the muscles
• Pericarditis: Inflammation of the tissue surrounding the heart
• Meningitis: Inflammation of the membranes covering the brain and spinal cord
• Enlarged spleen

Additionally, people with FMF have an increased risk of developing other inflammatory conditions such as vasculitis, ulcerative colitis, Crohn’s disease, and rheumatoid arthritis. Regular medical follow-ups and adherence to treatment plans are crucial in preventing these complications and managing overall health.

Living with Familial Mediterranean Fever: Strategies for Long-Term Management

While FMF is a chronic condition, many individuals can lead fulfilling lives with proper management and support. Developing strategies to cope with the unpredictable nature of flares and maintaining overall health is essential for those affected by FMF.

Tips for managing life with FMF:

• Adhere to prescribed medication regimens
• Keep a symptom diary to identify potential triggers
• Maintain open communication with healthcare providers
• Join support groups or connect with others who have FMF
• Practice stress-reduction techniques like meditation or yoga
• Maintain a healthy lifestyle with regular exercise and a balanced diet
• Educate family members and close friends about the condition

By adopting these strategies and working closely with healthcare professionals, individuals with FMF can effectively manage their symptoms and reduce the impact of the condition on their daily lives.

Advances in Familial Mediterranean Fever Research: Hope for the Future

The field of FMF research is continually evolving, with scientists and medical professionals working tirelessly to improve our understanding of the condition and develop more effective treatments. Recent advancements have opened up new possibilities for managing FMF and improving the quality of life for those affected.

Current areas of FMF research include:

• Targeted gene therapies to address MEFV mutations
• Development of new biologic medications with fewer side effects
• Improved diagnostic tools for earlier and more accurate detection
• Investigation of potential environmental factors influencing FMF expression
• Studies on the long-term effects of current treatments

These ongoing research efforts provide hope for improved treatments and potentially even a cure for FMF in the future. Patients and their families are encouraged to stay informed about the latest developments and discuss new treatment options with their healthcare providers.

Supporting Children with Familial Mediterranean Fever: A Guide for Parents and Caregivers

Caring for a child with FMF can be challenging, but with the right approach and support, parents and caregivers can help their children lead healthy, active lives. Understanding the condition and its impact on daily life is crucial for providing effective care and emotional support.

Key considerations for supporting children with FMF:

• Educate yourself about FMF and its management
• Work closely with healthcare providers to develop a comprehensive care plan
• Help your child maintain medication adherence
• Create a supportive home environment that accommodates flare-ups
• Encourage open communication about symptoms and concerns
• Advocate for your child’s needs at school and in other settings
• Promote a healthy lifestyle with proper nutrition and appropriate physical activity
• Connect with support groups or other families dealing with FMF

By providing a strong support system and fostering a positive attitude, parents and caregivers can help children with FMF develop resilience and effectively manage their condition as they grow.

Familial Mediterranean Fever in Different Populations: Genetic and Cultural Considerations

While FMF is most commonly associated with Mediterranean and Middle Eastern populations, it can affect individuals from various ethnic backgrounds. Understanding the genetic and cultural aspects of FMF across different populations is crucial for accurate diagnosis and culturally sensitive care.

FMF prevalence and characteristics in different populations:

• Highest prevalence among Sephardic Jews, Armenians, Turks, and Arabs
• Increasing recognition in other populations, including Western Europeans and East Asians
• Varying genetic mutations and symptom presentations across ethnic groups
• Cultural factors influencing diagnosis, treatment acceptance, and management

Healthcare providers should be aware of these population-specific considerations to ensure accurate diagnosis and appropriate treatment for individuals from diverse backgrounds. Additionally, genetic counseling may be beneficial for families with a history of FMF, particularly in high-risk populations.

The Role of Diet and Nutrition in Managing Familial Mediterranean Fever

While there is no specific diet proven to cure or prevent FMF, proper nutrition can play a significant role in managing symptoms and supporting overall health. Some individuals with FMF report that certain dietary choices can influence the frequency and severity of their flares.

Dietary considerations for individuals with FMF:

• Anti-inflammatory foods: Incorporate foods rich in omega-3 fatty acids, antioxidants, and fiber
• Hydration: Maintain adequate fluid intake to support kidney function
• Trigger avoidance: Identify and avoid foods that may trigger flares (varies by individual)
• Balanced nutrition: Ensure a well-rounded diet to support immune function and overall health
• Consultation with a dietitian: Seek professional guidance for personalized nutrition advice

While dietary modifications alone are not a substitute for medical treatment, they can complement prescribed therapies and contribute to better symptom management. It’s important for individuals with FMF to discuss any significant dietary changes with their healthcare providers to ensure they align with their overall treatment plan.

Navigating Pregnancy and Family Planning with Familial Mediterranean Fever

For individuals with FMF who are considering starting a family, careful planning and medical guidance are essential. While FMF can pose challenges during pregnancy, many women with the condition have successful pregnancies and healthy children.

Key considerations for pregnancy and family planning with FMF:

• Pre-conception counseling: Discuss risks and management strategies with healthcare providers
• Medication adjustments: Review and potentially modify FMF treatments for pregnancy safety
• Genetic counseling: Understand the risks of passing FMF to offspring
• Close monitoring: Regular check-ups throughout pregnancy to manage symptoms and prevent complications
• Postpartum care: Develop a plan for managing FMF symptoms after childbirth
• Breastfeeding considerations: Discuss the safety of FMF medications during lactation

With proper medical care and careful management, many individuals with FMF can successfully navigate pregnancy and parenthood. It’s crucial to work closely with a team of healthcare providers, including rheumatologists and obstetricians experienced in managing high-risk pregnancies.

The Psychological Impact of Familial Mediterranean Fever: Addressing Mental Health Needs

Living with a chronic condition like FMF can have significant psychological effects on individuals and their families. The unpredictable nature of flares, potential limitations on daily activities, and concerns about long-term health can contribute to stress, anxiety, and depression.

Addressing the mental health aspects of FMF:

• Recognition of psychological challenges associated with chronic illness
• Access to mental health support services, including counseling and therapy
• Development of coping strategies for managing stress and uncertainty
• Participation in support groups or peer counseling programs
• Education on the mind-body connection and its role in managing FMF
• Integration of mental health care into overall FMF treatment plans

By addressing the psychological aspects of FMF alongside physical symptoms, healthcare providers can offer more comprehensive care that supports both mental and physical well-being. Individuals with FMF and their families should feel empowered to discuss mental health concerns with their healthcare team and seek appropriate support when needed.

Rare Familial Mediterranean Fever

Written by Susan Bernstein

• What Is Familial Mediterranean Fever (FMF)?
• Causes
• Symptoms
• Getting a Diagnosis
• Questions for Your Doctor
• Treatment
• Taking Care of Your Child
• What to Expect
• Getting Support
• More

Familial Mediterranean fever (FMF) is a rare genetic disease that runs in families. Most often, it affects people whose ancestors came from countries around the Mediterranean Sea and the Middle East. This includes ethnic groups like Arabs, Armenians, Sephardic or North African Jews, Turks, Greeks, and Italians.

FMF is an autoinflammatory syndrome. That means you have recurring episodes of inflammation and fevers related to a defect in your innate immune system. It’s the most common autoinflammatory syndrome. It’s also called hereditary periodic fever syndrome.

Nearly all people with FMF start having periodic fevers before age 20. Three-quarters of people with this condition have their first episodes before age 10. All genders can get it.

FMF is caused by a mutation in a gene called MEFV. Children who have it usually inherit copies of the faulty MEFV gene from both parents. Some can develop symptoms that are very similar to FMF even if they inherit only one copy of the faulty gene from one parent. There are more than 300 different MEFV mutations, but only a few cause FMF.

MEVF is a gene that makes a protein called pyrin. Pyrin seems to play a role in how your body’s immune system functions. If you have an MEFV gene mutation, your body doesn’t make enough pyrin. As a result, your immune system may make too much of an inflammatory cytokine called interleukin-1B. That causes recurring bouts of inflammation and fevers.

FMF often causes fever attacks that may last for up to 3 days. Fevers can spike up to 104 degrees. Along with a fever, it can cause joint pain and swelling, typically in the knee or ankle. A child’s joint may be so painful and swollen that they can’t walk.

These joint pain attacks may be misdiagnosed at first as juvenile idiopathic arthritis (JIA). Their joint may stay swollen for a week or two, then get better. Some children have long-term joint symptoms.

FMF may cause these symptoms too:

• Red skin rash on the calves, ankles, or feet
• Severe abdominal pain
• Chest pain
• Achy muscles
• Constipation followed by diarrhea

FMF flares may be triggered by an infection, stress, strenuous exercise, physical trauma, or even getting your period. Between flares, people with FMF often feel normal. They may be symptom-free for years between flares.

It’s rare, but some children with FMF can develop these serious complications:

• Myositis, or muscle inflammation
• Pericarditis, an inflammation of tissue around the outside of the heart
• Meningitis, an inflammation of tissue around the brain or spinal cord
• Inflammation of the testicles
• Enlarged spleen
• Amyloidosis, a protein buildup in the urine that may cause serious kidney damage

People with FMF have a higher risk of developing some other inflammatory diseases:

• Vasculitis, or blood vessel inflammation, such as Behçet’s disease
• Ulcerative colitis (UC)
• Crohn’s disease
• Rheumatoid arthritis (RA)

People with untreated FMF may become infertile, especially if they also have severe flares or develop amyloidosis.

Your doctor will perform these tests to diagnose FMF:

Physical exam. They’ll go over you or your child’s symptoms and rule out any other possible causes.

Family history. Because this disease is inherited, your doctor will ask if you or anyone in your family have been diagnosed with or had symptoms that suggest it.

Blood tests. Your child’s blood may show signs of high inflammation, such as high levels of some white blood cells, high erythrocyte sedimentation rate (ESR), or high C-reactive protein (CRP).

Urinalysis. High amounts of protein or small amounts of blood in the urine is a sign of kidney problems related to FMF attacks.

Genetic test. A DNA test can show if your child has one or two copies of an MEFV gene mutation. But there are hundreds of possible mutations to MEFV, so it’s possible that a genetic test could be false-negative.

Don’t delay diagnosis. Be sure to get a prompt, confirmed diagnosis of FMF. Children with severe abdominal pains may be misdiagnosed with appendicitis and have unnecessary surgery.

You’ll probably have a lot of questions for your doctor or your child’s pediatrician. Here are a few questions you might wish to ask:

• What are the possible causes for these symptoms other than FMF?
• What causes FMF?
• Why does FMF run in some families?
• What are the treatments available for my child?
• What are the possible side effects of FMF treatments that my child may experience?
• If my child has any complications of FMF like other inflammatory diseases, how will they be treated?
• Should I restrict my child’s activities, or can they continue to play sports or exercise?
• What’s the risk of FMF for my other children? Should all my children get genetic testing?
• If my partner and I wish to have more children, will they develop FMF?
• How can I lower the risk of infertility in my children diagnosed with FMF?

There’s no cure for FMF, but treatments can prevent and relieve symptoms.

Colchicine

Colchicine is a generic medicine that controls inflammation in FMF. It’s taken as a pill once or twice a day. Colchicine can prevent FMF flares, but if you or your child is already having an episode, the drug won’t treat it. Colchicine needs to be taken regularly to work. Flares can return if you miss even one dose. Children who take colchicine regularly can have a full, normal life with FMF.

Colchicine’s most common side effects are abdominal pain and diarrhea. Your doctor can reduce your child’s dose for a little while if side effects occur. Milk and other dairy products may trigger these side effects, so cut back on milk or switch to lactose-free dairy products. Colchicine may also cause nausea, vomiting, or belly cramps.

• Rarely, colchicine can cause muscle weakness, especially if taken with statins or the antibiotic drug erythromycin.
• Children on colchicine will need blood and urine tests twice a year.
• Colchicine is safe to use while pregnant or breastfeeding.

IL-1 blockers

If colchicine doesn’t work or your child can’t tolerate it, drugs that block interleukin-1, a protein linked to inflammation in FMF, may help. These drugs include anakinra (Kineret), canakinumab (Ilaris), and rilonacept (Arcalyst).

NSAIDs and analgesics. Nonsteroidal anti-inflammatory drugs (NSAIDs) and pain medications, or analgesics, may help relieve fevers or joint pain during a flare.

Your child may need emotional support or counseling when they’re diagnosed and learn that they have to take medicine every day for life. If your child’s fevers keep them out of school or social activities, it may be upsetting.

Tell your child’s school principal, teachers, and counselors that your child has been diagnosed with FMF so they can be aware of symptoms and help them keep up with schoolwork if they have to stay home for a few days.

Having FMF means you must take your medication for life to prevent flares and control inflammation. Make sure you or your child takes the medication on schedule. With treatment, you can have a normal, full life with FMF.

FMF can raise the risk of amyloidosis. Daily colchicine prevents amyloidosis, and if caught early, amyloidosis is treatable. If it gets worse, amyloidosis can require kidney dialysis or transplant. You’ll need urine tests twice a year to look for signs of high amyloid proteins.

Living with FMF or any lifelong disease can be stressful. You may be upset that you’ve passed a gene mutation to your children. Here are some tips to help you or your child cope:

• Check out online support groups for people with autoinflammatory diseases like FMF, such as rareconnect.org.
• Learn more about FMF. Ask your doctor questions about your child’s diagnosis and to suggest resources to help you and your family manage any stress you feel.
• Reach out for help when you need it. Ask family members or friends to help you with tasks when you’re caring for your child during fever episodes. Find someone you trust to talk to when you just need to vent.

Top Picks

Lower doses for greater safety

Published: November 2005

Prescriber Update 26(2): 26–27

November 2005

Medsafe Pharmacovigilance Team

The dosage advice for colchicine has been revised, coinciding
with the introduction of a 0.5mg strength tablet.  Colchicine is now
indicated as second-line therapy for acute gout.   For healthy adults
the dosing interval has been increased to six hourly, with a maximum dose
of 2.5mg in the first 24 hours and a maximum cumulative dose of 6mg over
four days.  In elderly patients, patients with renal or hepatic impairment,
and patients weighing less than 50kg other treatments should be considered
or lower doses of colchicine used.  Patients should be warned of the
symptoms of colchicine toxicity and advised to discontinue therapy immediately
if they occur.

High doses no longer appropriate

A new 0.5mg strength of colchicine tablets is now available in New Zealand,
under the brand name of Colgout^®,
with revised dosage advice.¹  While
colchicine is effective for treating acute gout it has a slow onset of action,
with limited effectiveness if treatment is delayed and a narrow therapeutic
index.²  Due to the risk of dose-related
serious adverse effects the use of high doses of colchicine to treat acute
gout is no longer appropriate, especially in elderly patients,³
patients with impaired hepatic or renal function,¹ and patients
who weigh less than 50kg. ⁴

Indications limited to second-line

Colchicine is now indicated as second-line therapy in the treatment of
acute gout.  Colchicine should not be used unless non-steroidal anti-inflammatories
are contraindicated, or have been used and found to lack analgesic efficacy
or to have unacceptable side effects in the individual patient.¹

Dosing interval increased to six hourly

The dosing interval for colchicine has been increased from 2-3 hourly
to six hourly.  The dose for otherwise healthy adults is 1mg initially,
then 0.5mg every six hours until pain relief is obtained.¹ 
From a safety perspective, it is no longer acceptable to continue dosing
until gastrointestinal adverse effects occur.

Maximum daily and cumulative doses updated

For otherwise healthy adults the maximum dose of colchicine in the first
24 hours is 2.5mg and the total dose given in an acute attack should not
exceed 6mg over four days. ¹

Consider other treatments for the elderly

The elderly may be more susceptible to cumulative toxicity with colchicine,⁵
and due to age-related renal function impairment, other treatments such
as corticosteroids should be considered.  If colchicine is used in
the elderly lower doses should be given and a maximum cumulative dose of
3mg over four days should be observed.¹

Reduce the dose in renal and hepatic impairment

Colchicine is contraindicated in severe renal impairment (creatinine
clearance <10ml/min¹) or hepatic impairment,
and concomitant renal and hepatic disease.  If colchicine is used in
patients with less severe impairment a reduction in the individual doses,
an increase in the interval between doses or a reduction in the total daily
dose may be necessary.  Specifically, the dose should be reduced by
half if the patient’s creatinine clearance is 50ml/min or less; and close
monitoring is advised. ¹

Intensive regimen should not be repeated for at least
three days

Prescribers are reminded that for all patients at least three days must
elapse between courses of acute treatment with colchicine, in order to avoid
the risk of toxicity due to colchicine accumulation.¹

Warn patients of the symptoms of colchicine toxicity

Colchicine in overdose is extremely toxic and has resulted in fatalities.⁶ 
Patients should be warned that the first signs of toxicity are nausea, vomiting
and diarrhoea.  A burning sensation of the throat, stomach or skin
may also occur.  Symptoms usually appear 2 to 12 hours post-ingestion
and often before pain relief is obtained.⁵ 
If symptoms of toxicity occur patients should immediately discontinue colchicine
therapy and see their doctor.  If toxicity is suspected, prompt hospital
admission is essential.⁴

This revised dosage advice is consistent with that issued in the New
Zealand Rheumatology Association’s 2005 Consensus Statement on the Use
of Colchicine in the Treatment of Gout. ³

Competing interests (authors): none declared.

References

1. Anspec New Zealand Ltd. Colgout tablets data sheet1
   November 2005. www.medsafe.govt.nz/profs/Datasheet/c/Colgouttab.htm
2. Gow P. Gout – An update on a deadly disease. NZ Pharmacy
   Journal 2005;25;4:21-24.
3. New Zealand Rheumatology Association. NZRA Consensus
   Statement on the Use of Colchicine in the Treatment of Gout. November
   2005.
   
   http://www.rheumatology.org.nz/colchicine.htm
4. Medsafe Editorial Team. Colchicine toxicity prompts dosage
   change. Prescriber Update 1998;(17):9-11.
   www.medsafe.govt.nz/Profs/PUarticles/colchicinetoxicity.htm
5. Antigout Drugs. In Sweetman SC (Ed) Martindale
   34th Edn. 2005: Great Britain, p.412-416.
6. Kubler P. Fatal colchicine toxicity. MJA 2000;172:498-499.