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Primary systemic amyloidoses: Possible new directions in prophylaxis and therapy
Medical Hypotheses (1996) 46, 505-506 © Pearson Professional Ltd 1996
Primary Systemic Amyloidoses: Possible New Directions in Prophylaxis and Therapy R. J. OKEN PO Box 412, Hopatcong, New Jersey 07843, USA
The primary systemic amyloidoses comprise a rare group of painful and disabling disorders characterized by uncontrollable deposition of amyloid in vital organs such as the heart, lungs, liver and kidney. The deposits ultimately cause functional impairment and are inevitably fatal after a period of about 1-4 years. Amyloidoses are characterized as primary or secondary, depending upon whether they arise de novo, or are secondary to an identifiable disease such as leprosy, tuberculosis, inflammatory bowel disease, rheumatoid arthritis, or one of several other chronic disorders. There is no satisfactory treatment for the primary amyloidoses, although limited response has been obtained with colchicine or the combination of melphalan and prednisone (1). Regardless of cause, amyloid deposits have in common a donor protein which can form a I]-pleated structure, proteoglycans and glycosaminoglycans, the pentraxin amyloid P, and numerous other components. They are organized into insoluble fibrils which are resistant to proteolysis. The senile plaques of Alzheimer's disease (AD) are typical amyloid deposits, although the disease is confined to the brain and is therefore not a systemic amyloidosis. Reactive microglia (macrophages) are embedded in the plaques. They are richly decorated with proteins of the classical complement pathway (2). Since amyloid P, which is a component of senile plaques (3), as well as all amyloid deposits (4), can
activate the complement cascade (5), it is probable that other forms of amyloid are similarly decorated, but this does not appear to have been investigated. The insolubility of amyloid fibrils, coupled with complement activation, the assembly of macrophages and production of copious quantities of reactive oxygen species provide the nidus for a chronic inflammatory reaction which could lead to the autodestruction of tissue. One possible way of combating this problem would be to administer anti-inflammatory agents. A recent clinical study of the non-steroidal antiinflammatory drug (NSAID) indomethacin in AD suggests that this representative of the cyclooxygenase inhibitor class of anti-inflammatory agents can arrest or retard the progression of AD (6) and might also retard systemic amyloidosis. The antileprosy agent dapsone might have similar effects. It reduces or prevents the amyloidosis of leprosy. A study of the prevalence of dementia amongst leprosy patients continuously treated with dapsone, compared with those that had been taken off dapsone for at least five years, showed a clear reduction in the prevalence of dementia in the dapsone-treated group (7). Namba and colleagues (8) showed that leprosy patients had a greatly reduced prevalence of senile plaques compared with age-matched controls, suggesting that the prevention of amyloidosis extended to the brain amyloid which develops in aging and, to a greater extent, in AD. Dapsone is also effective in
Date received 23 October 1995 Date accepted 27 November 1995
505
506 a number of autoimmune disorders, suggesting that it too has anti-inflammatory action, although the mechanism is not understood (7). The primary systemic amyloidoses are fatal, while NSAIDs and dapsone are relatively safe drugs whose side-effects are well known. I therefore feel justified in proposing that these agents be tried either instead of, or in combination with, steroids or other agents. It is difficult to organize formal clinical trials with disorders as rare as the primary systemic amyloidoses, and progress is more likely to be made by physicians exploring new therapeutic routes with individual cases. References 1. Gertz M A, Kule R A. Secondary systemic amyloidosis: response and survival in 64 patients. Medicine 1991; 70: 246-256.
MEDICALHYPOTHESES 2. McGeer P L, AKiyama H, Itagaki S, McGeer E G. Immune system response in Alzheimer's disease. Can J Neurol Sci 1989; 16: 516-527. 3. Akiyama H, Yamada T, Kawamata T, McGeer P L. Association of amyloid P component with complement proteins in neurologically diseased tissue. Brain Res 1991; 548: 349-352, 4. Pepys M B. Amyloid P component and the diagnosis of amyloidosis. J Int Med 1992; 232: 519-521. 5. Hicks P S, Saunero-Nazia L, Duclos T W, Mold C J. Serum amyloid P component binds to histones and activates the classical complement pathway. J Immunol 1992; 149: 3689-3694. 6. Rogers J, Kirby L C, Hempelman S R et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology 1993; 43: 1609-1611. 7. McGeer P L, Harada N, Kimura H, McGeer E G, Schulzer M. Prevalence of dementia amongst elderly Japanese with leprosy: apparent effect of chronic drug therapy. Dementia 1992; 3: 146-149. 8. Namba Y, Kawatsu K, Izumi S, Ueki A, Ikeda K. Neurofibrillary tangles and senile plaques in brain of elderly leprosy patients. Lancet 1992; 340: 978.
Primary Systemic Amyloidoses: Possible New Directions in Prophylaxis and Therapy R. J. OKEN PO Box 412, Hopatcong, New Jersey 07843, USA
The primary systemic amyloidoses comprise a rare group of painful and disabling disorders characterized by uncontrollable deposition of amyloid in vital organs such as the heart, lungs, liver and kidney. The deposits ultimately cause functional impairment and are inevitably fatal after a period of about 1-4 years. Amyloidoses are characterized as primary or secondary, depending upon whether they arise de novo, or are secondary to an identifiable disease such as leprosy, tuberculosis, inflammatory bowel disease, rheumatoid arthritis, or one of several other chronic disorders. There is no satisfactory treatment for the primary amyloidoses, although limited response has been obtained with colchicine or the combination of melphalan and prednisone (1). Regardless of cause, amyloid deposits have in common a donor protein which can form a I]-pleated structure, proteoglycans and glycosaminoglycans, the pentraxin amyloid P, and numerous other components. They are organized into insoluble fibrils which are resistant to proteolysis. The senile plaques of Alzheimer's disease (AD) are typical amyloid deposits, although the disease is confined to the brain and is therefore not a systemic amyloidosis. Reactive microglia (macrophages) are embedded in the plaques. They are richly decorated with proteins of the classical complement pathway (2). Since amyloid P, which is a component of senile plaques (3), as well as all amyloid deposits (4), can
activate the complement cascade (5), it is probable that other forms of amyloid are similarly decorated, but this does not appear to have been investigated. The insolubility of amyloid fibrils, coupled with complement activation, the assembly of macrophages and production of copious quantities of reactive oxygen species provide the nidus for a chronic inflammatory reaction which could lead to the autodestruction of tissue. One possible way of combating this problem would be to administer anti-inflammatory agents. A recent clinical study of the non-steroidal antiinflammatory drug (NSAID) indomethacin in AD suggests that this representative of the cyclooxygenase inhibitor class of anti-inflammatory agents can arrest or retard the progression of AD (6) and might also retard systemic amyloidosis. The antileprosy agent dapsone might have similar effects. It reduces or prevents the amyloidosis of leprosy. A study of the prevalence of dementia amongst leprosy patients continuously treated with dapsone, compared with those that had been taken off dapsone for at least five years, showed a clear reduction in the prevalence of dementia in the dapsone-treated group (7). Namba and colleagues (8) showed that leprosy patients had a greatly reduced prevalence of senile plaques compared with age-matched controls, suggesting that the prevention of amyloidosis extended to the brain amyloid which develops in aging and, to a greater extent, in AD. Dapsone is also effective in
Date received 23 October 1995 Date accepted 27 November 1995
505
506 a number of autoimmune disorders, suggesting that it too has anti-inflammatory action, although the mechanism is not understood (7). The primary systemic amyloidoses are fatal, while NSAIDs and dapsone are relatively safe drugs whose side-effects are well known. I therefore feel justified in proposing that these agents be tried either instead of, or in combination with, steroids or other agents. It is difficult to organize formal clinical trials with disorders as rare as the primary systemic amyloidoses, and progress is more likely to be made by physicians exploring new therapeutic routes with individual cases. References 1. Gertz M A, Kule R A. Secondary systemic amyloidosis: response and survival in 64 patients. Medicine 1991; 70: 246-256.
MEDICALHYPOTHESES 2. McGeer P L, AKiyama H, Itagaki S, McGeer E G. Immune system response in Alzheimer's disease. Can J Neurol Sci 1989; 16: 516-527. 3. Akiyama H, Yamada T, Kawamata T, McGeer P L. Association of amyloid P component with complement proteins in neurologically diseased tissue. Brain Res 1991; 548: 349-352, 4. Pepys M B. Amyloid P component and the diagnosis of amyloidosis. J Int Med 1992; 232: 519-521. 5. Hicks P S, Saunero-Nazia L, Duclos T W, Mold C J. Serum amyloid P component binds to histones and activates the classical complement pathway. J Immunol 1992; 149: 3689-3694. 6. Rogers J, Kirby L C, Hempelman S R et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology 1993; 43: 1609-1611. 7. McGeer P L, Harada N, Kimura H, McGeer E G, Schulzer M. Prevalence of dementia amongst elderly Japanese with leprosy: apparent effect of chronic drug therapy. Dementia 1992; 3: 146-149. 8. Namba Y, Kawatsu K, Izumi S, Ueki A, Ikeda K. Neurofibrillary tangles and senile plaques in brain of elderly leprosy patients. Lancet 1992; 340: 978.