Abstract
Familial Mediterranean fever (FMF) is a genetic autoinflammatory disease with autosomal recessive transmission, characterized by periodic fever attacks with self-limited serositis. Secondary amyloidosis due to amyloid A renal deposition represents the most fearsome complication in up to 8.6% of patients. Amyloidosis A typically reveals a nephrotic syndrome with a rapid progression to end-stage kidney disease still. It may also involve the cardiovascular system, the gastrointestinal tract and the central nervous system. Other glomerulonephritis may equally affect FMF patients, including vasculitis such as IgA vasculitis and polyarteritis nodosa. A differential diagnosis among different primary and secondary causes of nephrotic syndrome is mandatory to determine the right therapeutic choice for the patients. Early detection of microalbuminuria is the first signal of kidney impairment in FMF, but new markers such as Neutrophil Gelatinase-Associated Lipocalin (NGAL) may radically change renal outcomes. Serum amyloid A protein (SAA) is currently considered a reliable indicator of subclinical inflammation and compliance to therapy. According to new evidence, SAA may also have an active pathogenic role in the regulation of NALP3 inflammasome activity as well as being a predictor of the clinical course of AA amyloidosis. Beyond colchicine, new monoclonal antibodies such as IL-1 inhibitors anakinra and canakinumab, and anti-IL-6 tocilizumab may represent a key in optimizing FMF treatment and prevention or control of AA amyloidosis.
Highlights
Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease, characterized by periodic rapid fever attacks associated with self-limited serositis, like pericarditis and peritonitis, with prodromal symptoms [1]
Other renal diseases develop in 22% of cases in FMF and include recurrent pyelonephritis, urinary abnormalities such as hematuria and/or proteinuria, glomerular involvement with IgA nephropathy, membranous nephropathy, mesangioproliferative or rapid progressive glomerulonephritis, and vasculitis [18,19]
The periodic evaluation of serum amyloid A (SAA) titer has a central role in the clinical management of FMF patients, because of its higher sensitivity in detecting the subclinical residual inflammation even in attack-free periods compared to C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) [31]
Summary
Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease, characterized by periodic rapid fever attacks associated with self-limited serositis, like pericarditis and peritonitis, with prodromal symptoms [1]. Allelic variant 2 was significantly more frequent in the subgroup of FMF patients MEFV(-) than in healthy controls (p = 0.001) and the carriers had a higher risk of development of amyloidosis or arthritis (p = 0.026) than other FMF patients into the same group [11] This effect may be a consequence of the dysregulation of vitamin D levels and the impairment of its immunomodulatory and anti-inflammatory actions. Vitamin D may counteract the activation of the NF-κB pathway both via VDR-mediated sequestration of NF-κB signaling products and by inhibiting NF-κB transactivation through the modulation of advanced glycation end-products and their receptor (AGE-RAGE system) [12,13] Both heterozygous and homozygous deletion polymorphisms of the angiotensinconverting enzyme (ACE) gene, located on chromosome 17q23, may be associated with a higher risk of FMF. Other renal diseases develop in 22% of cases in FMF and include recurrent pyelonephritis, urinary abnormalities such as hematuria and/or proteinuria, glomerular involvement with IgA nephropathy, membranous nephropathy, mesangioproliferative or rapid progressive glomerulonephritis, and vasculitis [18,19]
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