Familial Mediterranean

Fever

By :Rasha Al-DabbaghIntern doctor at Al-Remal PHCC

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Objectives• Introduction• Background & Pathophysiology• Clinical Manifestations• Complications “Amyloidosis”• Investigations• Differential Diagnosis• Diagnosis• Treatment• Prognosis

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Introduction

• FMF is the prototype of a group of inherited “autoinflammatory” diseases –hereditary recurrent fever syndromes- that are characterized by recurrent episodes of fever with serosal, synovial, or cutaneous inflammation and, in some individuals, the eventual development of systemic AA amyloidosis.

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Background & Pathophysiology

• ♂:♀ 2:1• Frequency depends on ethnicity. It

affects people originating from around the Mediterranean Sea.

• Sephardi Jews (and, to a much lesser extent, Ashkenazi Jews), Cypriots, Turks, Armenians, Italians & Arabs.

• Occasional cases are found in absence of known Mediterranean ancestry.

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• FMF is recessively inherited, but +ve FHx can only be elicited in 50% of cases.

• Carrier frequencies reach as high as 1:3 among affected populations, suggesting that not all mutations have equal penetrance.

• Most patients have only a single demonstrable MEFV/16p13.3 mutation on DNA sequencing.

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• The FMF gene encodes a 781-amino acid, 95 kDa protein denoted pyrin (or marenostrin) that is expressed in granulocytes, eosinophils, monocytes, dendritic cells, synovial & peritoneal fibroblasts.

• Through a number of mechanisms, pyrin regulates caspase-1 [ IL-1 -converting enzyme] & thereby IL-1 secretion.

• Ineffective pyrin doesn't inhibit inflammation normally & lead to excessive IL-1 production.

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Clinical Manifestations• Acute attacks:• Age of onset: Febrile episodes may begin in early

infancy; 90% of pts have 1st attack by age 20. • Duration: generally 1-4 days. Arthritic attacks

tend to last longer. • Frequency: sometimes occur with great

regularity, but more often the frequency varies over time, ranging from once every few days to several years.

• E&R factors: often unpredictable. Some patients relate them to physical exertion, emotional stress, or menses; pregnancy may be associated with remission.

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• There are 7 types of attacks.1. Fever:

– Nearly always present. – Severe hyperpyrexia & febrile

seizures may be seen in infants.– In 25% it is the only manifestation

especially in young children.

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2. Abdominal attacks: 90%– Acute abdominal pain & signs of

peritonitis -resembling appendicitis or choleycystitis.

– May lead to unnecessary laparotomy & appendectomy.

– Severity is variable.– In many cases, patients develop

constipation during attack & diarrhea after attack resolves.

– CT scan may show small amount of fluid in abdominal cavity. A sterile, neutrophil-rich peritoneal exudate is present. Adhesions & ascites are rare.

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3. Chest attacks: – Pleuritis (25-80%), Pericarditis (rare).– Usually manifest as unilateral, sharp, stabbing

chest pain that makes it difficult to breathe or lie flat. Friction rub is rare.

– Radiographs may show atelectasis or effusion. – Thoracentesis demonstrates a neutrophil-rich

exudate. – After repeated attacks, pleural thickening may

develop.– Symptomatic pericardial disease is rare. Some

patients have small pericardial effusions as an incidental echocardiographic finding.

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4. Joint attacks: 25-75%– Acute Arthritis:

• Usually monoarticular, affecting knee, ankle, or hip.

• Large sterile neutrophil-rich effusions are frequent, w/o corresponding erythema or warmth.

• Joints are normal b/w attacks, permanent damage is unusual & radiographic changes are rare.

– Chronic Arthritis: • Before colchicine prophylaxis, chronic arthritis of

knee or hip were seen in 5% in those with arthritis.

• 10% develop seronegative spondyloarthropathy “chronic sacroiliitis”.

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5. Cutaneous manifestation: 50%– The most characteristic is erysipelas-

like erythema, a raised erythematous rash most common on dorsum of foot, ankle, or lower leg.

– Biopsy demonstrates perivascular infiltrates of granulocytes & monocytes.

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6. Myalgia:– Exercise-induced (nonfebrile) myalgia is

common. – A small % develop a protracted febrile

myalgia lasting several weeks.

7. Scrotal attacks: 5%– Unilateral acute scrotal inflammation (of

tunica vaginalis) may occur in prepubertal boys & mimic acute scrotum.

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• Aseptic meningitis has been reported, but causal connection is controversial.

• Vasculitis, including HSP, PAN & Behçet disease may be seen at increased frequency in FMF.

• Episodes of PID in ♀ patients may occur.• Infertility: 1/3 of ♀ FMF patients are

infertile & 20-30% of pregnancies result in fetal loss.

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Complications “Amyloidosis”

• Before colchicine prophylaxis, systemic amyloidosis was a common complication.

• It is caused by deposition of fragment of serum amyloid A, an acute-phase reactant, in kidneys, adrenals, intestine, spleen, lung & testes.

• As a result, proteinuria, followed by nephrotic syndrome, & inevitably, death from renal failure may occur& thus renal function should be monitored.

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• Amyloidosis should be suspected in patients who have proteinuria b/w attacks; renal or rectal biopsy is used to establish diagnosis.

• Risk factors for developing amyloidosis include: – M694V homozygous genotype,– +ve family hx (independent of FMF mutational

status), – SAA 1 genotype, – ♂ gender, – noncompliance with colchicine therapy,– having grown up in the Middle East.

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Investigations

• Lab features during attacks are consistent with acute inflammation & include:– ↑ ESR,– ↑ WBC’s, – ↑ Plt (in children), – ↑ CRP, fibrinogen, haptoglobin & serum

immunoglobulins.– Transient albuminuria & hematuria may be

seen.

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Differential Diagnosis• If a patient is seen during 1st attack, DDx may

be broad, narrowed by specific organ involvement.

• After several attacks DDx may include: – Other hereditary recurrent fever syndromes; – Syndrome of periodic fever with aphthous ulcers,

pharyngitis, and cervical adenopathy (PFAPA); – Systemic-onset juvenile RA or adult Still's disease; – Porphyria; – Hereditary angioedema; – IBD; – & in women, gynecologic disorders.

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Diagnosis

• For typical cases, physicians experienced in FMF can often make diagnosis on clinical grounds alone.

• Clinical criteria.• Genetic testing can provide a useful

adjunct in ambiguous cases or for physicians not experienced in FMF.

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• Genetic testing may be of prognostic value: – M694V homozygotes have an earlier age of onset and

a higher frequency of arthritis, rash & amyloidosis. – E148Q variant is usually associated with milder

disease. • In cases where genetic testing is inconclusive,

clinical judgment is very important, and sometimes a therapeutic trial of colchicine may help to confirm diagnosis.

• Genetic testing of unaffected individuals is usually inadvisable, because of the possibility of nonpenetrance & potential impact of a +ve test on future insurability.

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Treatment• Attacks are self-limiting, require analgesia &

NSAIDs (e.g. diclofenac).• The TOC is daily oral colchicine, which ↓

attack frequency & intensity, & prevents amyloidosis in compliant patients.

• Colchicine is an alkaloid that may interfere with microtubule formation, thereby affecting mitosis and other microtubule-dependent functions.

• Colchicine & metabolites are excreted through urinary & biliary tracts.

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• The adult dose of colchicine is 1.2–1.8 mg/d ( ↑ 0.3 mg/day as needed & tolerated; max. 2.4 mg/day)

• It causes substantial reduction in symptoms in 2/3 of patients & some improvement in >90%.

• Children may require lower doses, although not proportionately to body weight.

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• Common side effects of colchicine include: bloating, abdominal cramps, muscle pain, lactose intolerance, & diarrhea.

• They can be minimized by: starting at a low dose & gradually advancing as tolerated, splitting the dose, use of simethecone for flatulence, & avoidance of dairy products.

• If taken by “either” parent at time of conception, colchicine may cause a small increase in the risk of trisomy 21 (Down syndrome).

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• Colchicine toxicity include: bone marrow suppression (3-5 days post exposure), acute renal failure, rhabdomyolysis & neuromyopathy (proximal muscle weakness & elevation of creatine kinase). Severe toxicity results in MOF, convulsions, coma & death.

• IV colchicine should not be administered to patients taking oral colchicine, because severe fatal toxicity can occur.

• Cyclosporine inhibits hepatic excretion of colchicine, sometimes leading to colchicine toxicity in patients who have undergone renal transplantation for amyloidosis.

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• There are no established alternatives for the 5-10% of patients who do not respond to colchicine or cannot tolerate therapeutic dosages, although interferon-α, IL-1 receptor antagonist & TNF inhibitors are investigational.

• Bone marrow transplantation has been suggested for refractory FMF, but the risk-benefit ratio is currently regarded as unacceptable.

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Prognosis

• Compliant patients with daily colchicine can expect to have a normal lifespan if colchicine is started before proteinuria develops.

• Even with amyloidosis, the use of colchicine, dialysis & renal transplantation should extend a patient's life beyond age 50 years.

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