Familial Mediterranean Fever (FMF) By: Yasser A. Abdelghani بسم الله الرحمن الرحيم Familial Mediterranean Fever (FMF) (New Look) 2011 Faculty of Medicine Minia University By: Yasser A. Abdelghani

FMF is more common in individuals of Mediterranean background : Turkish, Israeli, Arab descent, Armenian      

( Familial Mediterranean Fever ) The FMF gene ( MEFV gene )  ( Familial Mediterranean Fever ) MEFV is located on the short arm of chromosome 16 MEFV encodes a 781 amino acid protein Sites At least 23 mutations have been identified in this gene .

Inheritance of FMF Autosomal recessive inheritance (both parents must carry a recessive gene)

FMF pathogenesis The cause is MEFV gene mutations lack of pyrin, a neutrophil protein, expressed mostly in the in serosal cells lining the peritoneal and pleural spaces or in synovial cells. It prevents neutrophils accumulation when enough have reached an area (Hosp. Pract. 33: 131, April 15, 1998.)  Lacking pyrin, neutrophils mob body cavities in a periodic manner.

CLINICAL MANIFESTATIONS 90 % before the age of 20 . The initial attack occurs before the age of 10 in 65 % ,

Prodrome (pre-attack symptoms)  A prodrome is experienced by about 50% of persons with FMF. The prodrome manifests unpleasant sensation at the site of the forthcoming spell, emotional, and neuropsychological complaints

CLINICAL MANIFESTATIONS The typical manifestations of the disease are recurrent attacks of severe pain and fever, lasting one to three days, and then resolving spontaneously. In between attacks, patients feel entirely well.

Vigorous exercise is regarded as an attack trigger by a few patients   Vigorous exercise is regarded as an attack trigger by a few patients Attacks tend to abate during the second half of pregnancy           

Skin rash on the ankles. (looks like a strep infection) The rash appears as a red, warm, swollen area about 4–6 in (10–15 cm) in diameter.

CLINICAL MANIFESTATIONS (Peritonitis ) 91% Pain and tenderness may initially be focal, and then progress to become more generalized

(Peritonitis ) The pain may mimic appendicitis, cholecystitis or renal colic and the patients have frequently underwent surgery before diagnosis of FMF

Recurrent attacks of peritonitis may lead to adhesions, with the potential for causing small bowel obstruction

CLINICAL MANIFESTATIONS (Pleuritis )  Painful FMF attacks may also be localized to the chest. They may reflect either direct inflammation of the pleura or referred pain from subdiaphragmatic inflammation . Transient pleural effusion .  

CLINICAL MANIFESTATIONS (Synovitis)  Arthritis is another common manifestation of FMF . Its incidence correlates with the patient's ethnicity. The arthritis is most often monoarticular or oligoarticular Joint effusions are common during attacks of synovitis.    

CLINICAL MANIFESTATIONS Other acute manifestations   Pericarditis (rare) has been described in several patients with FMF ( 0.7 %) Self-limited orchitis and recurrent aseptic meningitis also can occur

Hepatic involvement: Acute hepatitis and recurrent hyperbilirubinemia have been reported in the course of FMF which are responsive to colchicine

Hepatic involvement: Japanese patient with FMF, in whom acute elevations of transaminase occurred. The histological findings from the liver biopsy specimens demonstrated a nonspecific hepatitis, with liver cell necrosis and interlobular inflammatory cell invasion, without the presence of interface hepatitis or bile duct injury. This case underscores the possibility that MEFV mutations contribute to hepatic inflammation, as seen in this case, by way of an alteration of the pyrin function. ttt: Colchicine

CLINICAL MANIFESTATIONS A few patients with FMF have reported prolonged bouts of febrile myalgia that may last as long as one month, and sometimes involve the abdominal muscles An enhanced incidence of some vasculitides, such as polyarteritis nodosa and Henoch-Schonlein purpura, has been described

DIAGNOSIS Labs: elevated WBC, ESR, CRP Imaging studies: pleural effusion and synovial effusion Non specific Genetic diagnosis possible

Genetic Diagnosis   Is the only method to be certain of the diagnosis.

MEFV molecular genetic testing is used to confirm the diagnosis

However it is not yet possible to detect all MEFV gene mutations that might cause FMF. Thus if DNA analysis is negative, clinical methods must be relied upon.

Clinical Diagnosis FMF should be suspected for any patient who: 1) Has had at least four Intermittent episodes of fever abdominal pain or chest pain or both, lasting from 1-3 days. 2) Without symptoms between attacks. 3) Does not have any other condition that would explain the symptoms. 4) Has positive family history of FMF (usually -ve). 5) Responds to colchicine.

DIAGNOSIS Other proposed tests for FMF : Metaraminol provocation test .   Measurement of the serum concentration of dopamine beta-hydroxylase (DBH): increased.

Differential diagnosis 1 -  Surgical emergencies – appendicitis, intussusception, perforated peptic ulcer, etc.   2 -  Hereditary angioedema   3 -  Acute intermittent porphyria   4 -  Relapsing pancreatitis   5 -  Systemic lupus erythematosus  

6 -  Hypertriglyceridemia 7- PFAPA Syndrome (periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome). The episodes of periodic fever in PFAPA are frequently indistinguishable from those in FMF; molecular testing of MEFV and close follow-up may be needed to make the correct diagnosis. Treatment with steroids in the early stages of an attack is effective. [Padeh 2005].

8 -  Other rare hereditary periodic fevers : tumor necrosis factor receptor-1-associated periodic syndrome (also called TRAPS), hyper-IgD syndrome

ميدان التحرير ,,,,, جمعة النصر

Therapy for FMF are two fold: Symptomatic relief from the acute attacks: NSAIDs, Colchicine, Steroids  Prevention of complications of the disease: Colchicine

The regimen for acute attacks in patients not taking daily colchicine is 0.6 mg every hour for 4 doses, then 0.6 mg every 2 hours for 2 doses and then 0.6 mg every 12 hours for 4 doses

Prevention of complications of the disease   Prevention of complications of the disease   Colchicine is effective in preventing, delaying, or reversing renal disease associated with amyloidosis. The dose is 0.6 mg PO, once daily, BID  (TID, rarely QID ) In children the optimal effective dosage of colchicine is about 0.02-0.03 mg/kg/24 hr (maximum of 2 mg/24 hr)  Patients who already have significant proteinuria should receive a dose of 1.5 to 2.0 mg/day.

Daily Colchicine Therapy for life Compliance with taking colchicine every day may be hampered by its side effects, which include diarrhea, nausea, abdominal bloating, and gas.

Intermittent colchicine therapy If attacks are rare and patients can determine when they are beginning (prodrome) , treatment with intermittent colchicine therapy at the onset of attacks may be sufficient therapy.

Unresponsiveness To Oral Colchicine IV Colchicine 1 mg IV once a week ,effective in reducing the number of attacks

Colchicine use during pregnancy and lactation: Safe

Steroids in FMF ?? Patients who experience episodes of prolonged myalgia with fever and severe pain may need treatment with prednisone Dose: 1 mg/kg for as long as 6 weeks.

Colchicien-Resistant FMF ??

Colchicien-Resistant FMF   Several approaches can be tried : 1-Interferon alpha (single dose 3 to 10 million I.U. s.c ) The drug may suppress the acute inflammation of FMF only if administered at the earliest phase. 2- alpha blocker prazosin (3 mg BID) 3- Adhering to a very low fat diet

Colchicine and fertility There is a theoretical risk that colchicine use could damage chromosomes in sperms and Ova, therefore it might reduce fertility. However, studies looking at reproduction in men and women who have used colchicine have so far not shown any increased risks.   Recently, Untreated individuals with FMF, especially those with multiple attacks and/or amyloidosis, have a higher chance of infertility. Colchicine treatment increases fertility, Ben-Chetrit & Levy 2003].

Prognosis Patients who are compliant with daily colchicine can probably expect to have a normal lifespan if colchicine is started before proteinuria develops.

The End

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