Familial Mediterranean Fever

Etiology

FMF is an autosomal recessive disease. The gene responsible for FMF is the MEFV gene, which is located on the short arm of chromosome 16 (16 p13.3). MEFV gene encodes the 781 amino acid protein pyrin. Around 300 different mutations of the MEFV gene have been identified, which could lead to FMF. Mutations commonly occur in exons 2, 3, 5, and 10. Out of these mutations, V726A, M680I, E148Q, M694V, AND M694I mutations are responsible for around 70 to 80 percent of cases.[2] About 10 percent of patients who are diagnosed clinically with FMF have no mutations in the MEFV gene. The carrier rate of the MEFV gene could be as high as 1:3 in some regions.[3]

Although predominantly an autosomal recessive disease, some reports of the possible autosomal dominant pattern of transmission have also been described. M694V deletion mutation has been the most common mutation found during the analysis of families showing a dominant pattern of transmission of FMF. M694V and M680I mutations are associated with the most severe phenotypic expression of FMF with more risk of complications.[4]

Epidemiology

FMF is commonly seen in people of Mediterranean and Middle Eastern descent, including Jews, Armenians, Arabs, Kurds, Greeks, Turks, Iranians, and Italians. The carrier rate of FMF is around 1 in 5 healthy individuals in Armenia.[5] For Jews, a higher carrier rate is found in the Jews of North African or Iraqi origin compared to those of Ashkenazi origin.[6] In Turkey, one of the field surveys showed the prevalence of FMF to be around 1 in 1000 children.[7]

The first attack usually occurs in early childhood. The majority (around 90%) of initial attacks occur by the end of the teenage years.[8] In rare cases, FMF can develop later in life for the first time as well. According to most of the studies, there appears to be no significant difference in the incidence of FMF in males or females. A nationwide survey in Turkey showed the ratio of the incidence of FMF was almost equal – male to female ratio of 1.2/1.[9]

In the United States, FMF is usually observed in Ashkenazi Jews and in those individuals who emigrate from the above mentioned geographical locations.

Pathophysiology

Pyrin, 781 amino acid protein, is believed to be involved in the pathophysiology of FMF. Pyrin is mainly found in the cytoskeleton of the circulation cells, including the white blood cells. White blood cells are responsible for mounting an immune response to pathogens. The exact structure and function of pyrin protein and its role in creating an inflammatory response in FMF are still not completely understood. One central hypothesis is that the pyrin binds to an apoptosis-associated speck-like protein (ASC) and caspase-1. This inhibits activation of IL-1beta (interleukin) and hence, the inflammatory pathways. Mutation of MEFV genes disrupts pyrin protein and its function, which leads to activation of IL-1beta and then the entire inflammatory pathway.[10]

History and Physical

FMF manifests as recurrent attacks of fever and serositis, leading to severe chest, abdominal, or joint pain. The first attack usually occurs by the age of 20 years. The symptoms develop over 2 to 4 hours and last for about 12 to 72 hours. Patients feel normal between attacks. The severity of attacks may vary each time, and the time between two attacks could be anywhere from one week to even several years. Many patients also complain of prodromal symptoms before the attack, such as irritability, nervousness, anxiety, nausea, or myalgia. Sometimes patients can correlate particular triggers with the appearance of attacks like severe stress, cold exposure, heavy exercise, recent infection, recent surgery, and menstruation. With time, as patients age, the frequency decreases, and the severity of attacks becomes less intense.[11]

Fever

Fever is the most common and sometimes the only symptom (especially during childhood) to occur during FMF attacks. The temperature may vary from mild to 38 to 40 degrees C (100.4 to 104 degrees F). If the patient is on treatment, the fever may be absent during attacks.

Abdominal pain

An abdominal pain attack is the most common type of attack in FMF. Abdominal pain could be localized initially and then become generalized. On physical examination, abdominal distension, guarding, rebound tenderness, and decreased bowel sounds are appreciated due to inflammation of the peritoneum. The episode spontaneously resolves in 2 to 3 days.

Chest pain

The involvement of pleura leads to the development of chest pain, which is mostly unilateral and worse with deep inspiration or coughing. Sometimes pericarditis is also present manifesting as retrosternal chest pain along with pleuritic pain. Pleuritis is more common in patients from Armenia, Japan, and Italy. On physical examination, pleural and pericardial friction rubs can be auscultated. Although pleural effusion can also develop, it is mostly a mild effusion and seldom is large enough to appreciate decreased breath sounds on examination.[12]

Joint pain

Arthralgia is common in non-Ashkenazi Jews. Large joints of lower extremities are mostly affected, including hip, knee, or ankle joints. The patient often presents with severe pain in one joint. Very rarely, multiple joints are affected simultaneously. On physical examination, a limited range of motion of the affected joint is observed. Swelling and redness are less common. Complete resolution of attack is common, but rarely chronic arthritis might develop.[12]

Other symptoms

Erysipelas-like lesion

The erysipelas-like lesion is observed on lower extremities (leg, ankle, or foot) and resolves spontaneously. On exam, it feels like a slightly raised erythema that is tender to touch. This is more common in Jews but less common in Arabs.

Scrotal swelling

This presents as a unilateral scrotal swelling, which is tender to palpation on the exam. This is caused by transient inflammation of tunica vaginalis and resolves within 24 hours.[12]

Myalgia

Myalgia is non-specific and could involve upper or lower extremities. Muscle tenderness is observed on physical examination. Prolonged febrile myalgia is very rare.

Aseptic meningitis and oral ulcers are very rarely reported.[13]

Evaluation

FMF is generally a clinical diagnosis. The classic presentation of symptoms supported by the presence of family history and response to colchicine help confirm a diagnosis. Laboratory and radiographic studies may help support the diagnosis or exclude other causes.

Laboratory analysis can reveal elevated white blood cell count with neutrophil predominance. Elevation of the acute phase reactants such as fibrinogen, erythrocyte sedimentation rate, serum amyloid A (SAA) protein, and C-reactive protein, although commonly found, are nonspecific. They can be monitored while the patient is on treatment to document the response to the therapy.[14] Electrocardiogram may reveal diffuse ST-segment elevation in the case of pericarditis. The synovial fluid analysis shows sterile fluid with elevated nucleated while cells. A computed tomography scan of the abdomen is commonly performed to exclude other causes of abdominal pain, including an acute abdomen.

Genetic testing can help confirm the diagnosis in cases with atypical presentation of FMF. However, around 10 percent of patients who meet diagnostic criteria based on the clinical presentation do not have any mutation.

Diagnostic criteria

Several criteria sets have been published, but the Tel-Hashomer criteria set of Israel is widely used for the diagnosis of FMF. Its sensitivity and specificity are more than 95% and 97%, respectively.[15]

For the criteria, typical attacks consist of fever (rectal - 38° C), pain due to inflammation, three or more recurrences of the attacks, and duration of 12 to 72 hours.

Major criteria (typical attack with one or more of the following)

1. Abdomen
2. Joint (hip, knee, ankle)
3. Chest - unilateral pleuritis or pericarditis
4. Scrotum
5. Skin
6. Muscle
7. Fever alone (usually recurrent attacks with fever only and no other identifiable cause)

Minor criteria (incomplete attack including one or more of the following)

1. Abdomen
2. Joints
3. Chest
4. Leg pain on exertion
5. Positive response to colchicine
6. Nephropathic amyloidosis

Supportive criteria

1. Family history of FMF
2. Vulnerable ethnic origin
3. Early age at onset (under 20)
4. Attacks with spontaneous resolution
5. No symptoms between the attacks
6. Severe attacks requiring bed rest
7. Presence of elevated white cell count or elevated acute phase reactants in the blood
8. History of laparotomy or appendectomy with no pathology
9. Episodic proteinuria or hematuria
10. Consanguinity of parents

The presence of one major or two minor criteria, or one minor with five supportive criteria can establish the diagnosis.

Treatment / Management

Colchicine

Colchicine has been the treatment of choice for FMF since the 1970s. The aim of the treatment is to prevent attacks, normalize inflammation between the attacks, and prevent the development of amyloidosis. It can also halt the progression of amyloidosis.[16]

Colchicine works by inhibiting neutrophil chemotaxis, which is necessary for the inflammatory events in FMF.

The treatment with colchicine is usually lifelong. Dosing varies according to age and severity of symptoms. Children under five years can be given 0.03-0.07mg/kg/day of colchicine.[17] The dose can be increased in 0.5 mg increments as the child grows. 1mg colchicine is ideal for children over ten years and adults. Patients with a more complicated disease such as frequent attacks or presence of amyloidosis can be given higher doses (2 to 2.5mg) as tolerated by the patients and if the liver and kidney function are normal. Patients who undergo renal transplantation due to amyloidosis related end-stage renal disease should continue receiving colchicine even after transplantation.(B3)

The most common side effects of the treatment are diarrhea and vomiting. These side effects are dose-dependent and more common at higher doses. Other uncommon side effects are myelosuppression, hepatotoxicity, nephrotoxicity, myopathy, neuropathy, and hypersensitivity reaction. Colchicine is considered safe during pregnancy and breastfeeding.

Compliance with the treatment must be addressed strongly to the patients since it is a common cause of lack of response to the therapy. Serial monitoring of acute-phase reactants in the blood can help to monitor the response and adherence to the treatment. Consideration can also be given to split the daily dose of colchicine into two or three divided doses if the patients stop taking colchicine due to its side effects - most commonly, diarrhea.

If patients are still not responding to the treatment, then the dose of colchicine should be increased. If a maximum tolerated dose of colchicine (up to 3mg in adults) does not improve the frequency and severity of the attacks despite adherence to the treatment, and if acute phase reactant levels in the blood continue to stay high in between the attacks, then colchicine resistance should be suspected.[18]

Interleukin-1 (IL-1) inhibitors

IL-1 inhibitors are the second-line drugs for the patients who have colchicine resistant FMF or who have an intolerance to colchicine. It is not entirely proven if IL-1 inhibitors help prevent the development of amyloidosis in FMF, and sometimes low dose colchicine is still continued to prevent amyloidosis.

Anakinra - It is a recombinant Il-1 antagonist.

Canakinumab – It is a human immunoglobulin G (IgG) against IL-1 beta.

Other drugs

There are some reports describing the use of prazosin, reserpine, and azelastine in FMF patients in Japan.[19](B3)

Tumor necrosis factor (TNF)-alpha inhibitors thalidomide, infliximab, and etanercept (a biologic TNF inhibitor that binds both TNF-alpha and TNF-beta) have also been described in some cases, but the real efficacy is still not established.

A study by Onat et al. demonstrated that the use of selective serotonin reuptake inhibitors can reduce the frequency of attacks in FMF, indicating that stress and depression could also be contributing to the development of attacks in these patients.[20](B2)

Differential Diagnosis

Many diseases can mimic the signs and symptoms associated with FMF. Therefore, a detailed history and physical examination of patients, including the history of attacks, history of fever, and family history, can help differentiate other diagnoses from FMF.

Acute abdomen

Peritonitis attacks in FMF can be easily mistaken with an acute abdomen. It is not uncommon for patients to undergo radiologic diagnostic studies or surgical procedures to look for the causes of the acute abdomen such as appendicitis, cholecystitis, perforated viscus, or other abdominal pathologies before the diagnosis of FMF is confirmed.

Juvenile idiopathic arthritis

Children who present with attacks of arthritis and fever can be misdiagnosed with juvenile idiopathic arthritis.

Systemic lupus erythematosus (SLE), rheumatoid arthritis (RA)

Positive antinuclear antibodies test with low complements levels are usually found in SLE. Rheumatoid factor and anti-cyclic citrullinated peptide antibodies are found in RA. Moreover, in RA, the arthritis is symmetric polyarthritis and involves the hands and feet.

Other familial periodic fever syndromes

• Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA)
  • Aphthous ulcers, pharyngitis, lymphadenopathy common
  • Abdominal pain is not common
  • Attacks typically last longer than FMF
  • Responds to steroid therapy but not to colchicine
• Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS)
  • Autosomal dominant
  • Attacks last longer than FMF
  • Rash, myalgia, and periorbital edema common
  • Responsive to treatment with steroids[21]
• Hyper immunoglobulin D syndrome (HIDS)
  • Mevalonate kinase deficiency
  • Elevated immunoglobulin D levels
  • Fever with cervical lymphadenopathy, vomiting, diarrhea, abdominal pain
  • Conjunctivitis in some cases
• Muckle-Wells syndrome and familial cold urticaria (FCU)
  • Urticaria is more common
• Cellulitis
  • Erysipelas-like lesion of FMF can be confused with cellulitis. Again, a detailed history of the patient and unresponsiveness to the antibiotics can help differentiate it from cellulitis.

Prognosis

The prognosis of FMF depends mainly on the frequency of the attacks and the development of complications. Generally, the attacks improve with the treatment and decrease in frequency with age. Certain genotypes such as 694V are associated with a higher risk of complications such as renal amyloidosis and more frequent attacks. Hence, they are associated with an adverse prognosis compared to other genotypes.[22]

Complications

Secondary AA (amyloid A) amyloidosis is a severe complication of FMF. Although it can involve the gastrointestinal tract, spleen, liver, testes, heart, or lungs, renal amyloidosis is more common. M694V mutation is usually associated with amyloidosis. On the other hand, FMF patients with mutation E148Q rarely have amyloidosis. Colchicine prevents the development of amyloidosis, so patients who have never been on colchicine or patients who present late in the disease process have higher chances of developing amyloidosis. However, patients who have persistent proteinuria despite taking colchicine should be evaluated for causes other than amyloidosis for the proteinuria. Patients can present with asymptomatic proteinuria, while sometimes nephrotic syndrome or end-stage kidney disease can be the first manifestation of FMF. Male sex and eastern Mediterranean origin are risk factors for developing amyloidosis.[23]

Glomerulonephritis has also been reported on kidney biopsies of FMF patients with suspected amyloidosis. Henoch Schönlein purpura and polyarteritis nodosa can occur but rarely in FMF.[9][24] Among other disease complications, testicular amyloidosis can lead to infertility in males, and pelvic and peritoneal inflammation can lead to the development of adhesions and, eventually, small bowel obstruction as well as infertility in females.