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 overproduction of serum amyloid A protein due to:

• 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 syndrome) 
• Hereditary periodic fever syndromes and other autoinflammatory syndromes (e.g.,familial Mediterranean fever (FMF); Muckle-Wells syndrome,PFAPA syndrome,TRAPS)
• Malignancies (renal cellcarcinoma, Hodgkin’s disease, CLL)

For more information on etiopathogenesis, see “Systemic Amyloidosis.”

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 for stabilizing or even reversing amyloid deposits is to control the underlying disease, which leads 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 individual cases, anti-IL-1 antibodies such as anakinra or canakinumab—which have already proven effective as first-line therapies for various autoinflammatory syndromes— also proven effective in patients with refractory FMF who could not achieve clinical remission 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 whose clinical presentation suggests an overlap between familial Mediterranean fever (FMF) and vasculitis (particularly in cases of concomitant polyarteritis nodosaor Henoch-Schönlein purpura).

Finally, immunomodulatory drugs have also proven 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 diseases. These include, among others, chlorambucil, cyclophosphamide, tacrolimus, and anti-TNF-alpha or anti-IL-6 antibodies such as infliximab, etanercept, or tocilizumab.

Treatment targeting amyloid deposits: In this context, tocilizumab, a humanized monoclonal anti-IL-6 antibody, has proven to be highly effective in reducing 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 effects of the aforementioned immunomodulators or of abatacept and rituximab. Tocilizumab has been successfully tested not only in RA and chronic juvenile arthritis but also in Behçet’s disease.

Dimethyl sulfoxide is a derivative of intracellular low-density lipoprotein that disrupts hydrogen bonding. It has been tested in patients with gastrointestinal and renal amyloidosis and can lower acute-phase reactant levels, improve gastrointestinal symptoms, and simultaneously reduce local amyloid deposits. 

Eprodisate is a low-molecular-weight molecule similar to heparan sulfate. By competitively binding to GAG binding sites, it inhibits the polymerization of amyloid fibrils and prevents the stabilization of amyloid deposits. Phase II studies showed stabilization of kidney function in 42% of cases, although the drug did not alter serum SAA levels and had no significant effect on proteinuria or overall survival.

Heparins and statins also have positive effects on the outcome of AA amyloidosis. The former can slow progression by breaking the stabilizing bonds between GAG and SAA in the deposits in a manner similar to that of eprodisate. The latter appear to exert their effect 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 can lead to recurrent syncope. In these cases, fludrocortisone or midodrine may prove useful. In addition, diarrhea or protein-losing enteropathy can be improved through the use of antibiotics to reduce bacterial overgrowth, prednisone pulses, or a combination of prednisolone and octreotide.

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