Pharmacological and Clinical Basis of Treatment of Familial Mediterranean Fever (FMF) with Colchicine or Analogues: An Update

Abstract

Familial Mediterranean Fever (FMF), an autosomal recessive disorder, is characterised by recurrent attacks of fever and serositis, lasting 24-72 hours. Since 1972 colchicine has become the drug of choice for prophylaxis against FMF attacks and amyloidosis FMF-associated. Colchicine, an alkaloid neutral, is absorbed in the jejunum and ileum. It metabolised by liver and only small amounts are recovered unchanged in the urine. Really plasma half-life is prolonged in patients with liver or renal failure. Colchicine is able to prevent activation of neutrophils, binding beta-tubulin and making beta-tubulin-colchicine complexes; this way inhibits assembly of microtubules and mitotic spindle formation; moreover its mode of action includes modulation of chemokines, prostanoids production, inhibition of neutrophil and endothelial cell adhesion molecules. The minimal daily dose in adults is 1.0 mg/die, but in children there is not a definite dose. Since in vitro high dosages of colchicine stop mitosis, this drug might interfere with male and female fertility and with children growth, but, according to current guidelines and because of rare side effects of the drug, FMF patients are recommended to take colchicine. Since colchicine treatment is often complicated by frequent gastrointestinal side effects, by our experience, in order to improve colchicine tolerance we recommend: lactose-free diet and treatment of intestinal bacterial overgrowth and/or Hp-infection, assessed by breath tests. Since our data showed that 10-15% of FMF patients seem are non-responders or intolerant to colchicine, today we are working in the design of colchicine analogues which may have lesser toxicities and a larger therapeutic window.

Familial Mediterranean Fever as an Emerging Clinical Model of Atherogenesis Associated with Low-Grade Inflammation

“…However, the first report on successful treatment of attacks of FMF with colchicine published in 1972 [74] and large clinical trials [75,76] distinguished colchicine as a drug of choice for prevention of attacks and amyloidosis in FMF. As a result, nowadays, regular colchicine intake at a dose of 1-2 mg/day is considered as a relatively safe and effective therapeutic option for the suppression of inflammation and prevention of inflammatory co-morbidities in FMF [77].…”

The role of adalimumab in the treatment of colchicine-resistant familial mediterranean fever: a case report

“…However, in 5 to 15% of patients treatment fails and they get labeled as non-responders. In these patients compliance should be checked and reinforced as it may be the causative agent [12,13,23,25]. Multiple genetic and pharmacological factors play a role in true non-responders and they are not well clarified yet [23,26].…”

“…Colchicine remains the mainstay of therapy in FMF patients, except for the 5-15% of patients who appear to be resistant to this therapy [12,13]. Biologic agents have shown significant impact on symptoms improvement as well as a positive effect on the quality of life.…”

A possible relationship between respiratory muscle weakness and familial mediterranean fever: a case report

“…So for the modification of the effect of the triggers on the risk of FMF attacks, physiotherapy could be an alternative approach. Treatment with 1-2 mg of colchicine a day has been shown to prevent or alleviate the attacks in the majority of patients (20,21). In the presence of colchicine, low and moderate-intensity exercise, relaxation exercises, breathing exercises for the pulmonary manifestations of FMF and relaxation could be used.…”