Pediatrics

Familial Mediterranean Fever (FMF)

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Familial Mediterranean Fever? What are the typical findings for this disease?

Familial Mediterranean fever (FMF) is the most common inherited periodic fever syndrome and predominantly affects people of Mediterranean origin. FMF is characterized by lifelong recurrent episodes of fever and illness due to seemingly unprovoked systemic inflammation in the absence of autoimmunity or infection.

The diagnosis is suspected based on constellation of symptoms including fever pattern, associated symptoms, acute phase response, family history and ethnicity.

The most common symptoms are recurrent attacks of fever >38°C and abdominal pain for 1-3 days every 3-8 weeks. Patients are asymptomatic and in generally good health between attacks. The age of onset of symptoms is most often in early childhood and <20 yr in 80% patients.

The next most common symptoms are abdominal pain due to peritonitis (in 90%), fever and acute abdomen with rebound, guarding, reduced peristalsis that may lead to bowel obstruction or unnecessary abdominal surgery. FMF may present initially as functional abdominal pain in children.

Other symptoms include chest pain secondary to pleuritis (in 45%), fever, tachypnea, usually unilaterally decreased breath sounds, and pleural friction rub. A mono- or oligo- articular arthritis involving hip, knee or ankle is seen in 75%. Joint aspiration reveals cloudy synovial fluid with primarily neutrophils, increased protein, normal glucose.

During inflammatory attacks, laboratory studies demonstrate leukocytosis with left shift, elevated ESR, CRP and serum amyloid A (SAA) level. This acute phase response resolves in majority of patients when fever-free, but increased SAA may persist and increase risk of 2° amyloidosis in the future.

Less common symptoms in FMF include pericarditis, unilateral orchitis (in 5%), severe myalgias, headache and recurrent aseptic meningitis. An erysipelas-like erythema and tender, erythematous and warm areas of swelling 10-15 cm in diameter on distal lower extremities is a distinctive symptom of FMF. Cutaneous vasculitis such as Henoch-Schonlein purpura and polyarteritis nodosa may occur in FMF and may precede other more typical disease manifestations. Some patients have 2° amyloidosis as their first clinical manifestation of FMF.

Diagnostic criteria for FMF in adults:

  • Definitive diagnosis if 2 major or 1 major and 2 minor criteria

  • Probable diagnosis if 1 major and 1 minor criteria

  1. Major criteria

    • Recurrent febrile episodes of peritonitis, synovitis or pleuritis

    • Amyloid-associated protein (AA)-type amyloidosis with no other predisposing disease

    • Favorable response to continuous colchicine treatment

  2. Minor criteria

    • Recurrent febrile episodes

    • Erysipelas-like erythema

    • FMF in a first-degree relative

Diagnostic criteria for FMF in children:

  • Requires ≥2 of 5 criteria:

    • Fever

    • Abdominal pain

    • Chest pain

    • Arthritis

    • Family history of FMF

FMF is due to mutations in MEFV gene encoding pyrin, a protein critical to initiation of the innate immune response. Genotyping is used to confirm diagnosis, but is also helpful for treatment decisions and assessment of long term prognosis. The diagnosis of FMF may be confirmed in symptomatic persons without identifiable MEFV mutations if a 6-month trial of daily colchicine remits attacks that recur after discontinuation of colchicine. The diagnosis should not be excluded based solely on genetic testing forMEFV mutations if the observed clinical features are characteristic.

What other diseases/conditions share some of these symptoms?

There are many diseases that share symptoms with FMF and include: cyclic neutropenia, HIV/AIDS, tuberculosis, CMV, brucellosis, rat-bite fever, relapsing fever or other chronic viral, bacterial or parasitic infections, Takayasu's arteritis, Henoch-Schnolein purpura, polyarteritis nodosa or other systemic autoinflammatory diseases, HLA B27-associated juvenile spondyloarthropathy, leukemia, lymphoma, acute intermittent porphyria, surgical emergencies including appendicitis, intussusception, testicular torsion, pelvic inflammatory disease, endometriosis and ovarian cyst, relapsing pancreatitis, infectious pleuritis or pericarditis, pneumonia and septic arthritis.

Systemic autoinflammatory syndromes that share some of these symptoms of FMF

Systemic autoinflammatory syndromes that mimic FMF include: Systemic onset juvenile idiopathic arthritis and adult Still's disease, Periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome, TNF receptor associated periodic fever syndrome (TRAPS), Hyper-immunoglobulinemia D with periodic fever (HIDS), Muckle-Wells syndrome (MWS), Behcet's disease, Crohn's disease, Macrophage activation syndrome, Hereditary or acquired angioedema, Gout, and Autoimmune bone diseases such as CRMO (chronic recurrent multifocal osteomyelitis and SAPHO (synovitis, acne, pustulosis, hyperostosis, osteiitis).

What caused this disease to develop at this time?

Triggers may include emotional stress, menses and vigorous exercise.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

To screen initially for FMF, the following laboratory studies are helpful: a CBC with differential during fever episodes and when symptom-free, an ESR and CRP during fever episodes and when symptom-free, a complete metabolic panel, uric acid, LD, ferritin, fibrinogen, quantitative immunoglobulins (IgG, IgA, IgM, urinalysis, blood and urine cultures, a PPD, and a 24 hr urine collection for protein and creatinine clearance.

Additional laboratory studies that may be helpful in evaluation and management

Additional tests can be performed as clinically indicated and often include: C3, C4, haptoglobin, pleural, peritoneal, synovial fluids for culture, cell count, protein, and glucose, skin biopsy for histology, renal or rectal biopsy for histology and staining for amyloid deposition. Genotyping for FMF and other inherited periodic fever syndromes may confirm diagnosis.

Would imaging studies be helpful? If so, which ones?

Imaging studies helpful in confirming FMF or a related disease include: a chest x-ray for infection, inflammatory lung disease or serositis (pleuritis, pericarditis), an abdominal x-ray, ultrasound or computed tomography (CT) to evaluate abdominal pain, rule out peritonitis or a surgical emergency, an echocardiogram to rule out pericarditis, and a joint magnetic resonance imaging (MRI) with and without contrast can evaluate for arthritis.

Confirming the diagnosis

Pertinent history that can assist in suspecting FMF include: the duration of symptoms and age of onset, the peak fever temperature, the pattern of fever (hectic, quotidian, recurrent, relapsing/periodic, continuous, intermittent, remittent), the duration of fever during individual attacks of inflammation, any concurrent infectious symptoms, antecedent or prodromal symptoms prior to the onset of fever, associated symptoms (rash, arthritis, diarrhea, etc), the pattern of appearance and duration of associated symptoms, the predictability of symptoms and the illness course, the duration of fever-free intervals, the patient's overall health and persistence of symptoms when afebrile, a family history of similar febrile illnesses and response to treatment, middle eastern parental ethnicity, and individuals with abnormal numbers and types of infections and their response to treatment.

Suspect the diagnosis of FMF if a patient of middle eastern ethnicity presents with recurrent fevers in a typical pattern of 1-3 days every 3-8 weeks in association with:

  • Recurrent peritonitis or abdominal pain

  • Recurrent arthritis

  • Recurrent pleuritis or chest pain A family history of FMFResolution of fever and associated symptoms when treated with colchicine, but recur when colchicine is discontinued.

If you are able to confirm that the patient has Familial Mediterranean Fever, what treatment should be initiated?

  • Are there some therapies that should be instituted immediately?

    1. Colchicine 1 mg p.o. daily regardless of age or weight (>90% patients respond).

    2. Intravenous fluids for gastrointestinal manifestations.

    3. If serositis present, consider prednisone 0.5-2 mg/kg/day or methylprednisolone 10-30 mg/kg (max 1 gm) IV daily times 1-3 doses; taper and discontinue with symptomatic improvement.

    4. Avoid unnecessary surgery.

  • What about longer term treatment?

    1. Colchicine 1 mg daily if symptoms are severe or patient is known to carry a M694V mutation.

    2. Dose may be increased until remission achieved (usually no more than 1.8 mg/day is needed).

    3. Smaller dose (0.3-0.6 mg) sometimes prescribed for children < 5 yr.

      • May be sufficient to prevent attacks, but may or may not prevent renal amyloidosis.

    4. There is controversy regarding risk versus benefit of chronic colchicine use if MEFV mutations identified by genotyping are considered:

      • Standard treatment is chronic daily colchicine regardless of MEFV mutation.

      • Alternatively, management depends on genotyping since amyloidosis is associated with particular MEFV mutations:

        1. Patients homozygous for M694V mutation or compound heterozygous for M694V and another disease-causing mutation (V726A-E148Q) should start chronic daily colchicine as soon as diagnosis is confirmed.

        2. Patients homozygous for V726A-E148Q or compound heterozygous for V726A-E148Q and another non-M694V disease-causing mutation should receive colchicine at onset of attacks and not chronic colchicine unless attacks severe and/or develop amyloidosis.

        3. Patients without M694V or V726A-E148Q mutations and mild clinical symptoms may not need colchicine unless attacks severe or has amyloidosis.

      • Treatment with colchicine should not be excluded in individuals with typical clinical symptoms who lack an identifiable MEFV mutation.

  • What about alternative treatments if fails standard therapy (colchicine)?

    1. IL-1 blockade:

      • Anakinra 1-2 mg/kg (max 100 mg) SQ daily OR

      • Canakinumab 150 mg SQ q.8 wk if > 4 yr and > 40 kg or 2-3 mg/kg (max 150 mg) SQ q.8 wk if < 40 kg

    2. Thalidomide 100-300 mg p.o. daily if IL-1 blockade does not remit symptoms.

What are the adverse effects associated with each treatment option?

See Table I.

Table I.

Adverse effects of treatment options
NSAIDS Gastritis, gastric ulcer, gastroesophageal reflux, rash, edema, liver/renal toxicity uncommon in children
Corticosteroids Infection, weight gain, muscle atrophy, adrenocortical insufficiency, osteopenia, growth delay, avascular necrosis, emotional lability, rash, edema, hypertension, diabetes
Colchicine Nausea, vomiting, diarrhea, abdominal pain, anorexia, peripheral neuropathy, muscle weakness, rhabdomyolysis, renal/liver toxicity, rash, birth defects
Anakinra Infection, severe injection site reaction/pain, future malignancy
Canakinumab Infection, injection site reaction, diarrhea, nausea, vertigo, weight gain, myalgias, headache, future malignancy
Thalidomide Infection, peripheral neuropathy, somnolence, teratogenicity, rash,dizziness, mood changes

What are the possible outcomes of Familial Mediterranean Fever?

What about prognosis?

  • Major cause of mortality is renal amyloidosis.

  • Normal lifespan without amyloidosis.

  • Before colchicine, 2° amyloidosis occurred in 60-75% patients > 40 yr of age.

  • M694V mutation is associated with a severe phenotype and strongly affects prognosis:

    • Early age of disease onset

    • High frequency of arthritis and rash

    • Increased amyloidosis.

  • Daily colchicine prevents amyloid-related nephropathy in most patients:

    • On colchicine, 95% improve, 70% remit, 10-15% develop 2° amyloidosis.

Table II gives the risks and benefits of available treatment options.

Table II.

Risks/benefits of available treatment options
Drug Indication Risks Benefits
NSAIDS Arthritis; pain, fever Adverse reactions Reduce fever, pain, arthritis
Corticosteroids Fever, arthritis, serositis, vasculitis, lymphadenopathy, organ inflammation/damage Adverse reactions Relieve fever, rash; improve adenopathy, arthritis; lessen organ involvement, serositis
Colchicine Treatment of FMF; fever, aphthous stomatitis, 2°amyloidosis Adverse reactions Prevents attacks in >70% & decreases attacks in 95% (no effect in other PFS); lowers SAA; decreases/prevents 2°amyloidosis; reduces fever, oral aphthae
Anakinra Fever, rash, arthritis, elevated acute phase reactants; some FMF unresponsive to colchicine Adverse reactions; triggers flare of inflammation; no longlasting disease control off treatment Remits fever, rash, arthritis & laboratory abnomalities in some FMF; lowers SAA; may reduce 2° amyloidosis
Canakinumab Colchicine-resistant FMF; fever, rash, arthritis, elevated acute phase reactants Adverse reactions May normalize SAA; may reduce 2° amyloidosis
Thalidomide Colchicine-resistant FMF; arthritis, aphthous stomatitis Adverse reactions Reduces ESR, CRP; improves arthritis

What causes this disease and how frequent is it?

Epidemiology:

  • Most common inherited periodic fever syndrome.

  • Predominantly affects people of Mediterranean origin.

  • Incidence: 1-3/105 in Turkey, Armenia, North Africa, Arab countries and Italy; rare elsewhere.

  • Clinical symptoms and range of MEFV mutations in Arabs distinctly different from other ethnicities and vary by country of birth.

  • Mutation frequency: 1:3 to 1:7 in North African and Iraqi Jews, Armenians and Turks.

  • Mutation frequency: 1:5 in Ashkenazi Jews.

  • Slight male predominance (13:10).

Genetics:

  • Homozygous or compound heterozygous mutations (>50) in the MEFV gene encoding pyrin, which is highly expressed in neutrophils, eosinophils, monocytes, dendritic cells and fibroblasts.

  • Four missense mutations in exon 10 of the gene (M680I, M694V, M694I and V726A) and E148Q in exon 2 account for majority of mutations.

  • All mutations decrease pyrin function.

  • 30% of symptomatic patients, including obligate carriers, have only one identifiable MEFV mutation.

  • M694V is most common mutation, confers highest disease severity and risk of amyloidosis, and predominates in North African and Iraqi Jews, Armenians and Turks.

  • In Ashkenazi Jews, most common mutations (V726A and E148Q) have reduced penetrance and confer a mild disease phenotype.

How does the MEFV gene cause FMF?

The hallmark of innate immunity is the rapid generation and release of proinflammaory cytokines, including IL-1beta, TNFalpha, and IL-6, in response to "danger signals" such as microbial products, toxins and metabolic stress. Il-1 beta is the pleiotrophic pyrogen and alarm cytokine and its activation triggers a cascade of events resulting in inflammation and production of other proinflammatory cytokines. Activation of the intracellular multi-protein complex called the "inflammasome" by danger signals in neutrophils, macrophages, dendritic and other cells is essential for release of bioactive IL-1 and initiation of inflammation.

The inflammasome is comprised of NLRP3, caspase-1 and ASC (apoptosis-associated speck-like protein). Stimulation of the inflammasome by danger signals activates caspase-1, which converts IL-1beta to its bioactive form. Mutations in one or more of the proteins comprising the inflammasome and subsequent effects on IL-1 activity have been shown to cause inherited periodic fever syndromes.

FMF is due to mutations in pyrin and is considered an extrinsic "inflammasomopathy." Pyrin plays an intrinsic role in the regulation of granulocyte and monocyte function during inflammation. Pyrin interacts with the ASC and disrupts the NLRP3-ASC interaction, consequently inhibiting NF-kappaB activation and apoptosis. Sequestration of the ASC by pyrin also prevents caspase-1activation, inhibiting activation of the inflammasome and production of bioactive IL-1beta. Loss-of-function MEFV mutations decrease binding of pyrin to the ASC, leading to inflammasome activation and increased IL-1 beta secretion. Colchicine inhibits neutrophil chemotaxis via microtubule depolymerization and reduces production of IL-1beta and other proinflammatory cytokines through NF-kappaB inhibition.

Other clinical manifestations that might help with diagnosis and management

Secondary amyloidosis is the most serious complication of FMF, which may lead to early death and significant morbidities. Renal failure due to amyloid-related nephropathy may be first clinical manifestation of FMF. Measurement of the serum SAA level may reflect active amyloid deposition and can help guide therapy.

Amyloid deposition in the kidneys is seen in > 90% of untreated patients and usually presents as proteinuria without renal insufficiency. Proteinuria is measured by a 24 hr urine collection for protein and creatinine clearance. A renal and/or rectal biopsy should be considered if >500 mg of protein in a 24 hr urine collection or an elevated BUN/creatinine is noted.

Secondary amyloidosis is then confirmed by biopsy of the kidney or rectum. Amyloidosis in the GI tract is seen in 20% patients and presents as diarrhea and malabsorption. Amyloid also can deposit in the liver, spleen, thyroid, and nervous system. Cardiac involvement from 2° amyloidosis due to chronic inflammation is rare, unlike other types of amyloidosis. The median survival time of untreated FMF patients with secondary amyloidosis is 24-53 months from time of diagnosis. Treatment with colchicine or biologic therapy can prolong survival.

What complications might you expect from the disease or treatment of the disease?

Most complications of FMF are self-limited, but some do affect health and quality of life: abdominal serositis may lead to unnecessary abdominal surgery and can cause infertility in women secondary to pelvic adhesions and defective ovulation. The major cause of mortality in FMF is 2° amyloidosis leading to renal failure and early death unless renal transplantation is performed. Treatment complications may be more common than complications from the disease and may include worsening inflammation, organ toxicity, infection and the possibility of a future malignancy.

Are additional laboratory studies available; even some that are not widely available?

Serum amyloid A protein (SAA).

How can Familial Mediterranean Fever be prevented?

FMF cannot be prevented since it is a genetic disease. Genetic counseling is important if FMF is suspected. Prenatal diagnosis may be helpful for some families and requires prior identification of disease-causing mutation(s) in the parents.

What is the evidence?

The following references provide general and historical overview of FMF and related conditions:

Bodar, EJ, Drenth, JPH, van der Meer, JWM, Simon, A. "Dysregulation of innate immunity: hereditary periodic fever syndromes". Brit J Hematol. 2008. pp. 144-279.

Glaser, RL, Goldbach-Mansky, R. "The Spectrum of Monogenic Autoinflammatory Syndromes: Understanding Disease Mechanisms and Use of Targeted Therapies". Curr Allergy Asthma Rep. 2008. pp. 8-288.

Kastner, DL, Aksentijevich, A, Goldbach-Mansky, R. "Autoinflammatory Disease Reloaded: A Clinical Perspective". Cell. 2010. pp. 140-784.

van der Hilst, JCH, Simon, A, Drenth, JPH. "Hereditary periodic fever and reactive amyloidosis". Clin Exp Med. 2005. pp. 5-87.

Samuels, J, Ozen, S. "Familial Mediterranean fever and the other autoinflammatory syndrome: evaluation of the patient with recurrent fever". Curr Opin Rheumatol. 2006. pp. 18-108.

Pathogenesis of FMF:

Simon, A, van der Meer. "Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes". Am J Physiol Regul Integr Comp Physiol. vol. 292. 2006. pp. R86.

Goldbach-Mansky, Kastner, DL. "Autoinflammation: The prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses". J Allergy Clin Immunol. vol. 124. 2009. pp. 1141.

Masters, SL, Simon, A, Aksentijevich, Kastner, DL. "Horror Autoinflammaticus: The Molecular Physiology of Autoinflammatory Disease". Ann Rev Immunol. vol. 27. 2009. pp. 621.

Henderson, C, Goldbach-Mansky, R. "Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis". Curr Opin Rheumatol. vol. 22. 2010. pp. 567.

Yalçinkaya, F, Ozen, S, Ozçakar, ZB, Aktay, N, Cakar, N, Düzova, A. "A new set of criteria for the diagnosis of familial Mediterranean fever in childhood". Rheumatology. vol. 48. 2009. pp. 395.

Complications of FMF:

Bilginer, Y, Akpolat, T, Ozen, S. "Renal amyloidosis in children". Pediatr Nephrol March. 2011.

Treatement of FMF:

Goldfinger, SE. "Colchicine for familial Mediterranean fever". New Engl J Med. vol. 287. 1972. pp. 1302.

Chae, JJ, Aksentijevich, I, Kastner, DL. "Advances in the understanding of familial Mediterranean fever and possibilities for targeted therapy". Br J Haematol. vol. 146. 2009. pp. 467.

Ozen, S, Bilginer, Y, Ayaz, NA, Calguneri, M. "Anti-Interleukin 1 Treatment for Patients with Familial Mediterranean Fever Resistant to Colchicine". J Rheumatol. vol. 38. 2011. pp. 516.

Ongoing controversies regarding etiology, diagnosis, treatment

Long term risks/benefits of treatment with biologics, given uncertain future risks, particularly for malignancies, opportunistic infections, autoimmune diseases, organ toxicity.

Use of colchicine for treatment or prophylaxis in FMF patients with one identified mutation (not M694V) or mild presentation.

Role of pharmacogenomics in management of FMF.

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