Reactive systemic AA amyloidosis is one of the most severe complications of several chronic rheumatic disorders, particularly rheumatoid arthritis (RA), juvenile idiopathic arthritis, ankylosing spondylitis (AS), and the hereditary autoinflammatory syndromes. Organ and tissue damage results from the extracellular aggregation of proteolytic fragments of the circulating acute-phase reactant protein serum amyloid A (SAA) as insoluble amyloid fibrils. The kidneys, liver, and spleen are mostly targeted by AA amyloid deposits, and AA amyloidosis becomes clinically overt mainly when renal damage occurs, manifesting either as proteinuria, nephrotic syndrome, or derangement in renal function . Due to the risk of progression to end-stage renal disease and possible gastrointestinal and bladder bleeding, the occurrence of AA amyloidosis severely impacts the prognosis of patients with rheumatic disorders. In recent studies, amyloidosis has been reported as the cause of death in 5–17% of patients with RA. A sustained high concentration of SAA is the prerequisite for AA amyloidogenesis. However, AA amyloidosis actually develops in only a minority of patients with active, longstanding inflammatory diseases, indicating that significant disease-modifying factors might play a role in modulating either the occurrence, the rate of tissue deposition, or the induction of tissue damage in this form of amyloidosis. Here, we review genetic, biologic, and clinical factors underlying susceptibility to the development of AA amyloidosis in patients with chronic rheumatic disorders and provide a critical interpretation that also is supported by the well-characterized mouse model of the disease.
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