AA (Inflammatory) Amyloidosis Treatment & Management

Updated: Aug 11, 2020
  • Author: Richa Dhawan, MD, CCD; Chief Editor: Herbert S Diamond, MD  more...
  • Print
Treatment

Approach Considerations

The lack of currently available agents that directly target amyloid deposits mandates the use of agents that strongly suppress the inflammation caused by the primary disease. At present, the major therapeutic strategy in amyloid A (AA) amyloidosis is treatment of the primary inflammatory disease in order to reduce the circulating levels of the amyloid precursor protein, serum amyloid A (SAA). Intensive treatment that lowers SAA levels to less than 10 mg/L may halt disease progression and induce a slow progressive recovery of renal function. Biologic agents, including tumor necrosis factor (TNF) inhibitors and interleukin-1 (IL-1) and IL-6 antagonists, are the main therapeutic options used for this purpose.,

The major consequence of renal amyloidosis is complete renal failure. Inpatient care may be necessary for intercurrent infections or deterioration in renal function, requiring acute dialysis or the initiation of chronic dialysis. 

Next:

Medical Care

Accounts exist of the disappearance of the amyloid deposits associated with tuberculosis or chronically infected burns with appropriate treatment of the infection. Similarly, case reports exist of the disappearance of amyloid deposition associated with chronic inflammatory bowel disease after resection of the affected section of bowel.

Colchicine

Colchicine is a plant-derived (colchicum autumnale) alkaloid that has been used for thousands of years to treat nonspecific arthritis. The use of colchicine (0.6 mg tid) by patients with familial Mediterranean fever (FMF) has been shown to reduce or eliminate the febrile episodes and to prevent the appearance of renal amyloidosis. [32] When started early and used at sufficient doses with good compliance, development of AA amyloidosis can be prevented, but established AA renal amyloidosis is much less responsive to colchicine treatment. In addition, beneficial effect in the other causes of AA amyloidosis has not been demonstrated. [33]

Alkylating agents

Data from a randomized prospective series of patients with juvenile chronic arthritis who were treated with chlorambucil or cyclophosphamide show that the occurrence of amyloidosis is markedly reduced. [34] The tradeoff for the aggressive use of alkylating agents is an increased incidence of leukemia.

Biologic agents

Biologic agents targeting proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, and IL-6 have been tried in patients with AA amyloidosis. Treatment with tumor necrosis factor–α (TNF-α) inhibitors and interleukin-1 (IL-1) inhibitors has proved effective in controlling the progression of renal amyloid in patients with inflammatory arthritides and hereditary periodic fevers. The rationale for using TNF inhibitors in secondary amyloidosis comes from the fact that these medications lower levels of serum IL-6, which is an important mediator of the acute phase inflammatory response. Lowering of IL-6 levels results in reduced synthesis of acute-phase proteins, suppression of systemic inflammation, and lower SAA levels, leading to reduction of amyloid deposits. [35]

Anakinra, a recombinant form of IL-1 receptor antagonist, has shown favorable effects on dermatologic and rheumatic manifestations in patients with Muckle–Wells syndrome and familial cold autoinflammatory syndrome. This treatment also resulted in the resolution of AA amyloidosis in these patients. [36]

IL-6 is one of the pro-inflammatory cytokines playing a critical role in the induction of SAA genes, thus inhibition of IL-6 results in dramatic suppression of SAA. Tocilizumab (TCZ), a humanized monoclonal anti IL-6 receptor antibody, was effective in the treatment of amyloidosis secondary to various rheumatic diseases. It binds to soluble and membrane-bound IL-6 receptors and down regulates the synthesis of IL-6 with significant decrease in SAA levels. [37]  

A retrospective study that indirectly compared tocilizumab to anti-TNFs, with a median treatment duration of 2 years suggested a more favorable outcome with tocilizumab. Although IL-6 blockage seems to have the advantage of significantly reducing circulating SAA levels, its long-term impact on renal function is not known. Moreover, switching between these agents is frequently necessary in inflammatory conditions due to adverse events and primary or secondary inefficacy. [38]

Investigational therapies

New approaches to the treatment of AA amyloidosis that are currently undergoing clinical trials.

A low–molecular-weight sulfonated molecule has been developed that interferes with fibril formation and deposition of amyloid by inhibiting interaction of SAA with glycosaminoglycans. In experimentally induced murine AA amyloidosis, this drug (NC-503) has been shown to reduce the amount of amyloid deposits.

Dimerization of human SAP molecules in vivo with a palindromic compound (CPHPC) triggers very rapid clearance of the complexed protein by the liver, depleting SAP from the circulation within a few hours of drug administration.

The plasma glycoprotein serum amyloid P component (SAP) is a universal constituent of all types of amyloid plaques, and potentiates the amyloidogenic process. A study by Bodin and colleagues tested a two-step therapeutic strategy for amyloidosis that targeted SAP by first pharmacologically depleting circulating levels of SAP with the bivalent crosslinker CPHPC, and then subsequently administering anti-human-SAP antibodies. In mice transgenic for human SAP, an experimental model of systemic AA amyloidosis, this treatment regimen produced almost complete regression of hepatic and splenic amyloid deposits 4 weeks after anti-SAP treatment. [39] In a phase I trial in 15 patients, this treatment safely triggered clearance of amyloid deposits from the liver and some other tissues. [40]

Interactions between heparan-sulfate and dermatan-sulfate glycosaminoglycan (GAG)-containing proteoglycans and the misfolded amyloid precursor protein are also considered important for amyloidogenesis and the stabilization of amyloid. This insight has been used in a clinical trial to destabilize amyloid deposits with eprodisate, a negatively charged, sulfonated GAG analog, which binds to GAG-binding sites of the amyloid fibrils. [41]  However, in the phase III trial, eprodisate did not meet the primary endpoint in slowing renal function decline. [42]

A study demonstrated the efficacy of pegylated INF-alpha once a week in FMF in the induction of a durable disease remission and the almost complete reversal of secondary renal AA amyloidosis. [43]

Previous
Next:

Surgical Care

Castleman disease, a rare group of lymphoproliferative disorders in which IL-6 is often the pathologic driver, can be complicated by AA amyloidosis. Surgical resection is effective for cases that involve a single region of enlarged lymph nodes (unicentric Castleman disease). In certain cases where surgery is not feasible or curative, the anti–IL-6 agent siltuximab may be effective. [13]

Although kidney transplantation is widely used for treating renal amyloidosis secondary to familial Mediterranean fever (FMF), some data suggest that patients who have amyloidosis do not have as favorable a prognosis as patients transplanted for other forms of renal failure. [44] Nonetheless, there have been reports of improving results and transplantation is a reasonable option. [45]

Recurrence of amyloidosis in the allograft, gastrointestinal intolerance, and fatal infections remain as major complications during the post-transplant period. Severe sepsis is the cause of 60% to 100% of all deaths with a functioning graft in kidney recipients with AA amyloidosis. [46]

In a multicentric retrospective survey to assess the graft and patient survival in 59 renal transplant recipients with AA amyloidosis, the recurrence rate of AA amyloidosis nephropathy was estimated at 14%. There was significant decrease in the 5-year and 10-year survival of patients in the AA amyloidosis group compared with the control group. [47]  

 

Previous
Next:

Consultations

Diminishing renal function demands management by an experienced nephrologist, with particular emphasis placed on the need for dialysis and the availability of transplantation. Nephrologic and surgical management of the chronic renal failure requires a coordinated team approach for an optimal outcome. Cardiac complications at the time of transplantation seem to be more common in patients with amyloidosis than in those with other forms of renal failure.

Because AA amyloidosis is usually a complication of a primary chronic infectious or inflammatory disease, consultations with specialists in infectious diseases concerning antibiotics, surgical resection, and other diagnostic and therapeutic modalities are appropriate. Consult a rheumatologist with regard to newer modes of anti-inflammatory treatment before assuming that the patient will inevitably follow a downhill course.

Previous
Next:

Diet

No specific dietary recommendations for patients with amyloid disease exist. Patients with chronic kidney disease should be managed by a nutritionist who has experience with such patients, maintaining appropriate levels of sodium and protein intake.

Occasionally, patients have significant gastrointestinal symptoms. In these cases, attention should be paid to maintaining caloric intake with minimal gastrointestinal distress.

Previous
Next:

Prevention

The use of colchicine prophylaxis in FMF has been previously mentioned, as has the need for aggressive anti-inflammatory treatment for the predisposing inflammatory disorders (see Treatment). The recent introduction of anti-inflammatory biological agents for the treatment of rheumatologic disorders may decrease the current rate of appearance of tissue AA deposition.

Previous
Next:

Long-Term Monitoring

Monitor renal function to assess progress and the ultimate need for dialysis or transplantation.

Previous