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Abstract :
[en] Familial Mediterranean Fever (FMF) is the most prevalent monogenic hereditary autoinflammatory disease. FMF occurs mainly among Turks, Armenians, Arabs and non-Ashkenazi Jews. Signs and symptoms include reccurent fever, seritis and arthritis during 1 to 3 days. The main complication of FMF is the development of amyloidosis which may cause renal failure. In the majority of cases, life-long colchicine therapy can control the disease and prevent this complication. When colchicine is not efficient, interleukine-1 (IL-1) beta inhibitors are used and are, in general, able to control the illness.
My thesis is a case-report on a man of Armenian descent, born in 1981, who has a FMF diagnosed late at the age of 21. The disease didn’t respond to colchicine and the patient continued to develop crisis several times a month. The patient moved to Belgium and, in 2011, a nephrotic syndrome was diagnosed. The latter was caused by renal amyloidosis, itself secondary to the FMF. As of 2012, the patient was treated with anakinra (a human IL-1 receptor antagonist binding competitively to IL-1α and IL-1β) but this treatment was too expensive for the patient and was stopped. From 2014, as part of a clinical study, the patient was treated with canakinumab (an anti-IL-1β monoclonal antibody) which caused a spectacular clinical and biological response (complete stop of the attacks and decrease of the SAA blood level under 10 mg/L which is the target level for the prevention of secondary amyloidosis). Nevertheless, the renal damage progressed and finally evolved into terminal renal failure.
The likelihood of developing amyloidosis and making it progress to renal failure is directly related to the SAA blood level8 (SAA is a marker of inflammation and the precursor of AA amyloidosis). High SAA blood level was long been cosnsidered as the only risk factor for amyloidosis but our patient developed amyloidosis and renal insufficiency despite his treatment by canakinumab perfectly controlling the inflammation. This supports the emerging idea arguing that there are other amyloidosis risk factors.
One of these risk factors (and probably the most important) is the country of residence. The countries associated with an increased risk of amyloidosis are the ones associated with high infant mortality rates. Since infant mortality rate is an indicator of population health, this finding suggests that the living environnement impacts amyloidosis susceptibility (poverty, difficult access to healthcare…). If our patient had been diagnosed and treated earlier in Armenia, he could not have developed amyloidosis this early. In Armenia, one in 500 people has FMF. A better healthcare program would lead to a better prognosis for many people suffering from FMF. This sentence is actually true for plenty of people with various diseases all around the world.
The current treatment for AA amyloidosis consists of controlling the underlying inflammatory disease. Our patient exemplifies that this isn’t always possible or sufficient. Other treatments must be actively looked for. The Serum Amyloid P component (SAP) is a pentameric protein found in all types of amyloid deposits. Amyloid P component stabilizes these deposits by preventing proteolytic cleavage and by inhibiting fibrils removal. Ongoing studies show promising results on the combination of CPHPC (R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxohexanoyl] pyrrolidine-2-carboxylic acid) and anti-SAP antibodies. CPHPC liaises with two SAP pentamers, promoting their removal from the blood by the liver. Anti-SAP antibodies combined with CPHPC leads to a significant regression of the amyloid deposits. These studies could lead to new therapeutic possibilities.
In conclusion, the development of amyloidosis secondary to FMF depends on various risk factors not particulary well known. A better understanding of these ones, as well as a better healthcare program around the world, would lead to a better care of the patients. Current therapies for AA amyloidosis are not always sufficient but ongoing researches could lead to new treatment guidelines.
