Aa-type amyloidosis E85.9

Systemic amyloidosis with deposition of amyloid A protein (AA), a fragment of serum amyloid A protein (SAA), an acute phase protein synthesized in the liver.

Idiopathic AA amyloidosis is the term used in the absence of an identifiable underlying disease.

Reactive polyformation of SAA (an acute-phase protein formed in the liver) by:

• chronic infectious diseases (osteomyelitis, tuberculosis, leprosy, syphilis, HIV, bronchiectasis).
• chronic inflammatory diseases of non-infectious origin(rheumatoid arthritis, Reiter's syndrome, ulcerative colitis, chronic glomerulonephritis, bronchiectasis, empyema, acne conglobata, epidermolysis bullosa dystrophica, Hallopeau-Siemens, )
• hereditary periodic fibrous syndromes and and other autoinflammatory syndromes (e.g., familial Mediterranean fever; Muckle-Wells syndrome, other TRAPS)
• malignancies(renal cell carcinoma, Hodgkin's disease, CLL)

For more on the etiopathogenesis, see amyloidoses, systemic.

Extracutaneous manifestation: Cardinal symptom: Progressive renal failure due to amyloid deposition in the basement membrane of the glomerula (in 90% of cases). Deposits also in the liver, spleen, gastrointestinal tract, adrenal glands and CNS.

Integument: Skin manifestations are found rather rarely overall. The occurrence of extensive hemorrhages and alopecia due to amyloid deposits in the dermis and subcutis is described.

The skin symptoms are accompanied by unspecific general symptoms caused by the primary underlying disease.

Treatment of the predisposing underlying disease: The most effective strategy to stabilize or even regress amyloid deposition is control of the underlying disease leading to a subsequent reduction in acute phase reactant levels, including circulating serum SAA levels.

High-dose colchicine (1.5-2 mg/day) is effective in controlling systemic inflammation in autoinflammatory syndromes. In addition, in isolated cases, anti-IL-1 antibodies such as anakinra or canakinumab, which have already been shown to be effective as first-line therapies in various autoinflammatory syndromes, have also been shown to be effective in patients with refractory FMF in whom clinical remission could not be achieved with high-dose colchicine, patients in whom significantly elevated serum SAA levels are still detectable despite treatment with colchicine, patients with colchicine intolerance, and patients in whom the clinical picture suggests an overlap between FMF and vasculitis (especially in the presence of concomitant polyarteritis nodosa or Henoch-Schönlein purpura).

Finally, immunomodulatory drugs have also been shown to be extremely useful in controlling the progression of amyloidosis-associated proteinuria and improving long-term survival in various inflammatory joint diseases and inflammatory bowel disease. These include chlorambucil, cyclophosphamide, tacrolimus , and anti-TNF-alpha or anti-IL-6 antibodies such as infliximab, etanercept, or tocilizumab.

Treatment targeting amyloid deposits: Here, tocilizumab, a humanized anti-IL-6 monoclonal antibody, proved highly effective in lowering circulating SAA levels and controlling the progression of amyloidosis in several autoimmune joint diseases. The effect of tocilizumab was independent of the underlying disease and of the effect of the immunomodulators mentioned above or of abatacept and rituximab. Tocilizumab has been successfully tested not only in RA or chronic juvenile arthritis, but also in Behçet's disease.

Dimethyl sulfoxide is a derivative molecule of intracellular low-density lipoprotein that disrupts hydrogen bonding. It has been tested in patients with gastrointestinal and renal amyloidosis and may lower acute-phase reactant levels and improve gastrointestinal symptoms while reducing local amyloid deposition.

Eprodisate is a low molecular weight molecule similar to heparan sulfate. By competitively binding to GAG binding sites, it inhibits polymerization of amyloid fibrils and prevents stabilization of amyloid deposits. Phase II studies showed stabilization of renal function in 42% of cases, although the drug failed to alter serum SAA levels and had no significant effect on proteinuria or overall survival.

Heparins and statins also have beneficial effects on the outcome of AA amyloidosis. The former may slow progression by breaking the stabilizing bonds between GAG and SAA in the deposits in a manner similar to eprodisate. The latter appear to exert their effects by inhibiting isoprenoid metabolism through specific blockade of farnesyltransferase. This mechanism also applies to some autoinflammatory diseases, such as hyperimmunoglobulinemia D with recurrent fever syndrome, in which amyloidosis rarely occurs despite severe recurrent inflammation.

Supportive treatment of specific symptoms: Although symptoms of dysautonomia are rare in AA amyloidosis, severe orthostatic hypotension may lead to recurrent syncope. In these cases, fludrocortisone or midodrine may prove useful. In addition, diarrhea or protein-wasting enteropathy may be ameliorated by the use of antibiotics to reduce bacterial overgrowth, prednisone pulses, or the combination of prednisolone and octreotide.

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