Complications
Amyloid nephropathy was the cause of death in FMF before the colchicine era. In the absence of appropriate treatment, amyloidosis remains the main complication of FMF. Amyloidosis generally occurs in patients with early and severe inflammatory attacks (FMF phenotype I).[116] Indeed, amyloid A amyloidosis is tightly linked to the duration and intensity of the inflammatory state as reflected by the level of serum amyloid A (SAA). However, amyloidosis may even occur in patients with no recognised clinical inflammatory attacks (FMF phenotype II).[10] Phenotype II is rare, and it probably results - at least in part - from the existence of blood inflammation between the attacks: serum SAA was found to be elevated between clinical attacks, which suggests the presence of infra-clinical inflammation. The prevalence of amyloidosis varies according to ethnic groups. This suggests that genetic and/or environmental factors participate in the occurrence of amyloidosis during FMF.
Several correlation studies have shown the preferential association between amyloidosis and M694V mutation in the homozygous state.[48][52][66] A homozygous E148Q genotype may also be associated with amyloidosis.[29]
Modifier genes, among which genes encoding SAA, influence the occurrence of amyloidosis. Two genes (SAA1 and SAA2) encode this protein, and several polymorphic variants have been described. In FMF patients, the homozygous SAA1.1 genotype is associated with an increased risk of amyloidosis, when compared with other genotypes at the SAA1.1 locus.
Male sex is another factor contributing to the risk of occurrence of amyloidosis.[17] Although steroid hormones are known to modulate circulating levels of acute-phase proteins, the inflammatory status of FMF patients, according to sex, has not been studied.
Other genetics factors that could explain the whole spectrum of FMF-associated amyloidosis remain to be deciphered. Environmental factors probably also play a role. The patient's country has been established as a risk factor for amyloidosis, but the nature of the link is still undetermined.[59]
SAA protein is a highly sensitive but non-specific marker for amyloid associated with FMF and rises during attacks. Tissue biopsy, especially kidney biopsy, is considered the definitive test for the diagnosis. Before the development of renal failure, cases with amyloidosis are still responsive to colchicine, and emerging treatments seem promising as well. In later stages, some patients will require kidney transplant.
Occurs in 5% of patients, usually after repeated attacks. Typically in one of the large joints of the lower extremities and oligo- or polyarthritis in other joints. Although complete recovery is the rule, chronic and repeated disabling joint damage might develop, leading even to joint replacement. Case reports suggest the benefit of biological agents (e.g., TNF-alpha antagonists).[72][103]
Occurs in 10% of patients with chronic arthritis. It is HLA B27 negative. One or two of the sacroiliac joints are affected with recurrent enthesitis, inflammatory neck and back pain, and minimal spinal radiographical changes.[117]
Reduced fertility has been reported both in men and women. In males, testicular amyloidosis is the proposed mechanism. The likelihood of developing infertility is reduced with colchicine treatment. There have been no negative outcomes from colchicine treatment on fertility, pregnancy, babies born to mothers with FMF, or babies breastfeeding from mothers with FMF.[108][118][119][120]
Reduced fertility has been reported in both men and women. In women, repeated bouts of peritonitis and intra-abdominal adhesion are major factors. The likelihood of developing infertility is reduced with colchicine treatment. There have been no negative outcomes from colchicine treatment on fertility, pregnancy, babies born to mothers with FMF, or babies breastfeeding from mothers with FMF.[108][119][121]
Delayed growth may occur in children with FMF. However, likelihood is low, especially with colchicine treatment. Children on colchicine for FMF had normal growth and development charts contrary to those who were not diagnosed and treated.
High in undiagnosed patients. Usually occurs in undiagnosed patients due to the severity of their peritonitis.
This is a multigenetic disease with environmental factors. Some Behcet's disease patients with FMF gene mutations will never develop FMF but might develop amyloidosis. Some will develop FMF after the diagnosis of Behcet's disease.[124][125][126][127]
Behcet's disease could also be complicated with amyloidosis, meaning patients homozygous for a Mediterranean fever mutation might benefit from colchicine prophylaxis to prevent amyloidosis.
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