So, what are the specific therapies we have at the present time for the different forms of systemic amyloidosis? We have already alluded to the chemotherapy treatment of AL (primary) amyloidosis, its effectiveness, and that it continues to evolve with new drugs and new regimens. We will, however, leave further discussion of treatment of systemic AL amyloidosis to others and only emphasize that it is not considered the best medicine to treat other forms of amyloidosis with chemotherapeutic drugs as a result of less than rigorous pathologic diagnosis.

AA (reactive) amyloidosis appears to be much less common than it was when there was less effective therapy for the inflammatory diseases (rheumatoid arthritis, Crohn’s disease, psoriatic arthritis) or infectious diseases (osteomyelitis, tuberculosis). Even so, there continue to be occasional patients who present with renal or hepatic amyloidosis on biopsy, and clinically, there is no apparent predisposing inflammatory condition. Some of these patients may have type II familial Mediterranean fever, one of the various TRAPS syndromes, or some as yet unrecognized condition that generates chronic elevated blood levels of serum amyloid A (SAA) [2]. For the pathologist, these patients can be easily identified by immunohistochemistry using specific antibody to amyloid AA protein. These antisera are available commercially and are reliable when used on formalin-fixed and paraffin-embedded biopsy tissues.

Treatment of AA amyloidosis has been nonspecific and principally aimed at suppressing the inflammatory condition that predisposed to hepatic synthesis of SAA. With the advent of biologic agents to treat inflammatory arthritis, this form of therapy presents a viable option for AA patients. Recently, a drug (sodium eprodisate) with the clinical name, Kiacta, has been tested for inhibiting AA amyloid formation. This drug is effective in the murine model of induced AA amyloidosis [3]. The initial human trial did not meet the levels of significance required by the FDA [4]. Further clinical trials are being done.

β ₂ -Microglobulin amyloidosis is seen in patients with renal failure who have usually been on hemodialysis for a number of years. Therapy is aimed at lowering serum levels of β2-microglobulin, and, with the newer dialysis membranes, the frequency of this form of amyloidosis has dwindled. Diagnosis of this form of amyloidosis is essentially made at the clinical level with the recognition of osseous involvement, although it is important to distinguish it from the bone involvement of AL amyloidosis. Immunohistochemistry may, or may not, be definitive or very helpful.

Transthyretin (TTR) amyloidosis is the most common form of hereditary amyloidosis, and, in addition, increasing numbers of senile systemic or senile cardiac amyloidosis patients are being identified. These patients in the past have been the most common victims of inappropriate treatment with chemotherapeutic agents due to misdiagnosis as AL amyloidosis. While TTR amyloidosis is hereditary, a considerable number of patients do not have an informative family history due to lack of penetrance of the condition or delayed clinical onset until advanced age. Many of these patients have cardiomyopathy which is indistinguishable from the AL cardiac presentation. From the surgical pathology viewpoint, immunohistochemistry with anti-TTR antibodies may be helpful, but this is not 100 % reliable perhaps due to variations in fixation techniques. The only specific treatment for TTR amyloidosis developed so far has been liver transplantation [5, 6]. Plasma TTR is synthesized by the liver, and liver transplantation will eliminate the source of the amyloidogenic variant protein. Approximately 2000 liver transplantations for TTR amyloidosis have been performed since 1990 and reported to the Transplant Registry [7]. It is recognized that an additional number of treated patients may not have been reported to the Transplant Registry. Results have been good but are somewhat variable depending upon the TTR mutation. The Val30Met patients from Portugal, Sweden, and Japan, where neuropathy is the major manifestation of the disease, have shown significant benefit with 5-year survival at 80–85 %. It is now recognized that patients in a more advanced stage of the disease with a modified body mass index (BMI) less than 600 (modified BMI = BMI × serum albumin level expressed in grams per liter) have not fared as well [8]. Hepatic transplant patients who have a non-Val30Met mutation, which includes at least 45 different TTR mutations, have only a 50–55 % 5-year survival. In these patients, there is often progression of amyloid deposition by amyloid fibrils made from wild-type (normal) TTR. This is logical since we already know that senile systemic amyloidosis occurs in elderly individuals (mainly male) without the benefit of any TTR mutation.

The lack of consistent response from liver transplantation has spurred efforts to find medical treatments for TTR amyloidosis. Two drugs shown to stabilize the TTR tetramer in vitro have been studied for slowing the progression of peripheral neuropathy in patients with TTR amyloidosis. Tafamidis (Vyndaqel) has been approved in Europe for treatment of patients with stage 1 peripheral neuropathy and, while not approved in the United States, is the subject of additional studies [9]. Diflunisal (Dolobid) has shown statistically significant results for slowing the progression of peripheral neuropathy in patients with TTR amyloidosis and, while only FDA approved for treatment of arthritis, is available by prescription (off-label) [10]. Another drug available by prescription is doxycycline which has shown some evidence for preventing amyloid fibril formation in vivo. Efficacy in humans has not been proven to date. The same is true for the use of sulfites and other compounds which have been available to patients on a nonprescription basis. Potential treatments aimed at decreasing variant transthyretin synthesis by the liver include gene conversion which has only been reported in an animal model and the use of antisense oligonucleotide (ASO) or siRNA compounds which specifically target TTR mRNA [11, 12]. Both TTR-specific ASO and siRNA have been shown to be effective in suppressing hepatic synthesis of TTR in vivo and are now being evaluated for safety and potential efficacy in humans.

Apolipoprotein A-I (ApoA-I) amyloidosis, whether due to mutations that cause nephropathy or cardiomyopathy, is a form of amyloidosis that can be easily mistaken for AL amyloidosis. ApoA-I mutations associated with laryngeal amyloid may be confused with AL amyloidosis which also has a high frequency of laryngeal involvement. Fortunately, AL laryngeal amyloidosis is usually a localized phenomenon and does not warrant chemotherapy. A number of liver transplants have been done for ApoA-I amyloidosis. Most have been for patients with the Gly26Arg mutation [13]. It is not entirely clear whether this form of specific therapy is beneficial [14]. Some patients have definitely benefited, but others appear to have progression of disease. One problem is that the renal disease has often progressed to a relatively advanced stage before liver transplantation is entertained. At that point, liver and kidney transplantation or liver transplantation followed by the need for renal transplantation has often been the course of events. Some patients with mutations associated with cardiomyopathy have benefited from cardiac transplantation without liver transplantation. Not enough subjects have been studied to know whether affected organ replacement or liver transplantation is the better option. ApoA-I is synthesized by both the liver and small intestine, so liver transplantation does not entirely eliminate circulating variant ApoA-I [13].