Description of the condition
Familial Mediterranean fever (FMF) is an autosomal recessive, hereditary auto-inflammatory disease (Online Mendelian Inheritance in Man (OMIM) ID: 249100). The primary characteristic of FMF is recurrent fever and serositis, which results in pain in the abdomen, chest, joints and muscles etc. This condition mainly affects ethnic groups living in the Mediterranean region, such as Jews, Armenians, Turks and Arabs, with a high prevalence of 1 in 200 to 1 in 1000 people affected (Shohat 2011; Soriano 2012). Regarding the rest of world, in Italy, Spain, Greece and Japan FMF is also not considered to be a rare disease (Konstantopoulos 2003; La Regina 2003; Migita 2012). Most patients with FMF (approximately 90 per cent) are diagnosed before the age of 20 years (Koné-Paut 2011).
Familial Mediterranean fever occurs as a result of mutations in the MEditerranean FeVer (MEFV gene). This is the only gene currently known to be associated with FMF and is located on chromosome 16 (Centola 2000). The MEFV gene is comprised of 10 exons encoding for a protein called pyrin (by the International FMF Consortium) (The International FMF Consortium 1997) or marenostrin (by the French FMF Consortium) (French FMF Consortium 1997). Pyrin consists of 781 amino acids, expressed in neutrophils, eosinophils, monocytes, dendritic cells and fibroblasts, and plays a key role in the regulation of inflammation and apoptosis (Chae 2009; Mansfield 2001). Pyrin contains a pyrin domain (PYD), two B-boxes, a coiled-coil domain (BBCC) and a SPRY domain (Papin 2007). The role of pyrin in the regulation of inflammation is still ambiguous. The PYD, shared with more than 20 other proteins (such as the NALP proteins), belongs to the death domain (DD) superfamily, which includes the PYD, death domain (DD), death effector domains (DED), and caspase recruitment domains (CARD). The DD superfamily is the interaction mediator which leads to apoptosis, inflammation and the innate immunity signalling pathway (Park 2012). Through homotypic PYRIN-PYRIN interaction, pyrin can interact with the adaptor protein, apoptosis-associated Speck-like protein with a CARD (ASC). This ASC (with an N-terminal PYD and a C-terminal CARD) is known as the inflammasome, which oligomerizes and mediates the proteolytic activation of caspase-1, inducing secretion of the potent pro inflammatory cytokine interleukin 1β (IL-1β) (Chae 2008). The interleukin-1 (IL-1) family, a group of 11 cytokines, plays a central role in the regulation of immune and inflammatory responses. In addition to PYD, the Pyrin SPRY domain interacts with NALP, caspase-1 and pro-interleukin-1b (proIL-1b) (Papin 2007). That means, an ineffective pyrin does not inhibit inflammation normally, resulting in inflammatory episodes. Pyrin can also interact with tubulin and colocalizes with microtubules (Mansfield 2001), suggesting a rationale for colchicine treatment.
There are mainly two phenotypes in FMF. Type 1 is commonly associated with recurrent short episodes of inflammation and serositis, including fever, peritonitis, synovitis, pleuritis and rarely pericarditis and meningitis (Shohat 2011). These symptoms and severity vary from one patient to another. The typical clinical manifestations of FMF type 1 usually last from 12 to 72 hours and include the following typical attacks (Shohat 2011; Soriano 2012):
recurrent fever, characterized by a temperature ranging from 38 ℃ to 40 ℃;
abdominal attacks, featuring abdominal pain (usually the entire abdomen is involved);
arthritic attacks, frequently featuring as monoarthritis localized in the large joints of the leg (hip, knee, ankle);
chest attacks, including pleuritis and pericarditis;
pre-attack symptoms, occurring 12 to 24 hours before any FMF attacks, usually including discomfort, abnormal taste sensation, dizziness, increased appetite, irritability and so on (Lidar 2006).
The most severe complication of FMF is AA amyloidosis leading to renal failure. Type 2 FMF is characterized by amyloidosis as the first clinical manifestation of the disease, in otherwise asymptomatic individuals (Livneh 2006). However, the existence of this phenotype is still controversial. Melikoğlu failed to prove the existence of type 2 FMF in their prospective designed study, even in siblings with significant proteinuria (Melikoğlu 2000). Furthermore, the common MEFV mutations are not significantly different between patients who present with the typical phenotype and those have clinical type 2 disease (Balci 2002).
Description of the intervention
Colchicine is an anti-inflammatory drug and the most widely-chosen treatment option for preventing inflammatory attacks and the deposition of amyloid (Shohat 2011). It is an alkaloid which can be extracted from two plants of the lily family: Colchicum autumnale and Gloriosa superba and has been used for centuries in acute gout arthritis, but its anti-inflammatory efficacy has been demonstrated in other diseases as well. Colchicine was reported as an effective drug for preventing FMF attacks in the early 1970s (Goldfinger 1972). To prevent FMF attacks, it is mainly given orally, usually 1 mg to 2 mg per day in adults and 0.5 mg to 1 mg per day according to age and weight in children (Shohat 2011). After oral administration, colchicine is absorbed in the jejunum and ileum with a zero-order rate process, with a half-life of about four hours. Colchicine is mainly metabolised by the cytochrome P450 system in the liver and predominantly eliminated by biliary excretion with enterohepatic circulation (Cerquaglia 2005; Terkeltaub 2009).
For those FMF patients who are colchicine-resistant or colchicine-intolerant, a number of other drugs for treating FMF have been studied in clinical trials such as: anakinra (100 mg per day or every other day as a subcutaneous injection) (Ozen 2011); rilonacept (2.2 mg/kg (maximum, 160 mg) as a weekly, subcutaneous injection) (Hashkes 2012); etanercept (25 mg twice a week as a subcutaneous injection) (Bilgen 2011); infliximab (4 mg/kg to 5 mg/kg at zero, two and six weeks and then every eight weeks by infusion) (Özçakar 2012); thalidomide (100 mg per day, orally) (Seyahi 2006); and interferon-alpha (IFN-α) (3 million international units (IU) per attack by subcutaneous injection) (Tweezer-Zaks 2008).
How the intervention might work
preventing activation of neutrophils by binding β-tubulin to make β-tubulin-colchicine complexes, then inhibiting the assembly of microtubules and mitotic spindle formation;
inhibiting the synthesis of tumor necrosis factor alpha (TNF-α) and down-regulating the surface expression of TNF-α receptor;
inhibiting leukotriene B4 synthesis;
blocking cyclooxygenase-2 (COX-2) activity;
inhibiting tyrosine phosphorylation and superoxide anion production;
inhibiting arachidonate release and 5-lipoxygenase;
suppressing delayed hypersensitivity reactions, histamine, insulin and parathormone release.
Anakinra and rilonacept are IL-1 inhibitors. Anakinra competitively inhibits the binding of IL-1α and IL-1β to the IL-1 receptor (Alpay 2012). Rilonacept, known as IL-1 Trap (Economides 2003), is a soluble decoy receptor fusion protein that binds IL-1α and IL-1β, and as a result prevents IL-1 activation of cell surface receptors (Terkeltaub 2013).
Etanercept, infliximab and thalidomide are tumor necrosis factor (TNF) antagonists (Sampaio 1991; Seyahi 2006). The role of TNF antagonists in FMF has not been clarified exactly. However, the level of serum TNF-α increases during FMF attacks (Baykal 2003) and decreases with regular colchicine treatment (Kiraz 1998).
Finally, IFN-α is a natural species-specific immunomodulatory glycoprotein produced mainly by T and B lymphocytes. It increases macrophage and natural killer cell phagocytic activity as well as augmenting lymphocyte-specific cytotoxicity (Tweezer-Zaks 2008).
Why it is important to do this review
While there has been an evidence-based peer review of the use of colchicine for the treatment of FMF (WHO 2013), this important topic has not yet been systematically evaluated. Therefore, we are performing a Cochrane Systematic Review of available clinical evidence to evaluate the efficacy and safety of interventions for reducing inflammation in FMF.