Neurology -- Correspondence for Buxbaum, 66 (1_suppl

Correspondence published:

Reply from the Author: Joel Buxbaum (13 February 2006)

Treatment and prevention of amyloidoses: Can the lessons learned be applied to sporadic IBM?: Kostas Konstantopoulos, George Vaiopoulos(1) and Antonis Mailis(2) (13 February 2006)

Reply from the Author 13 February 2006

Joel Buxbaum,
Department of Molecular and Experimental Medicine, Scripps Institute
10550 N. Torrey Pines Rd La Jolla CA
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Re: Reply from the Author

jbux{at}scripps.edu Joel Buxbaum

Drs. Konstantopoulos, Vaiopoulos and Mailis raise an interesting question: Does colchicine interfere with amyloidogenesis in some manner other than suppressing the inflammatory response? It is clear that colchicine, in some circumstances (i.e., gout and FMF) is anti-inflammatory, suppressing the inflammatory response in both conditions.
It is also effective in inhibiting the AA amyloid deposition found in mice given a variety of inflammatory stimuli. There is little evidence that it works in any manner other than suppressing the inflammation, subsequently suppressing the cytokine response responsible for increased production of the amyloidogenic substrate SAA.
The effect of colchicine on AL amyloidosis suggested in a retrospective analysis using historical controls [3] has not been borne out by subsequent studies including one from the same institution. [6] and two larger studies, one with a crossover design [7] and one with a prospective randomized design. [8] All three showed, with various degrees of statistical reliability, that colchicine alone was inferior to melphalan and prednisone, nor did it add any benefit when added to melphalan and prednisone.
The mechanism of action of colchine as both an anti-inflammatory and as a prophylactic agent in inflammation appears to be related to its action in suppressing expression of cell surface molecules on neutrophils and endothelial cells, inhibiting interactions required for sustaining an inflammatory response. [9] With respect to so-called type II FMF, where amyloid deposition precedes the acute inflammatory episodes or develops in their absence, I would speculate that the individuals are undergoing subclinical inflammation even without the acute episodes and colchicine would be useful. Such seems to be the case in sickle cell disease where homozygous individuals appear to have ongoing mild inflammation with elevated IL-6 levels even in the absence of overt clinical attacks.
It is clear that not all individuals with FMF get amyloidosis, the latter occurring more frequently in the presences of particular SAA alleles, depending on the population involved. It is also possible that other genes, presently unknown, also impact on susceptibility. Those genes could also play a role in sIBM where the substrate is Abeta.
References
6. Skinner M, Anderson J, Simms R, et al. Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med. 1996;100:290-298.
7. Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis. Comparison of melphalan/prednisone versus colchicine. Am J Med. 1985;79:708-716.
8. Kyle RA, Gertz MA, Greipp PR, et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997;336:1202-1207.
9. Cronstein BN, Molad Y, Reibman J, Balakhane E, Levin RI, Weissmann G. Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J Clin Invest. 1995;96:994-1002.

Disclosure: The author reports no conflicts of interest.

Treatment and prevention of amyloidoses: Can the lessons learned be applied to sporadic IBM? 13 February 2006

Kostas Konstantopoulos,
Athens Medical School, Athens, GR-11527 Greece
Laikon University Hospital (1) Eginiteion University Hospital (2), Athens Medical School,
George Vaiopoulos(1) and Antonis Mailis(2)
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Re: Treatment and prevention of amyloidoses: Can the lessons learned be applied to sporadic IBM?

kkonstan{at}med.uoa.gr Kostas Konstantopoulos, et al.

Buxbaum's excellent paper on amyloidoses refers to amyloidosis of Familial Mediterranean fever (FMF). [1] AA amyloidosis related with FMF represents a distinct entity of the disease. Although it is associated with a certain molecular background (i.e., pyrin gene mutations) and it is usually complicating a long manifested FMF, it may also develop in an otherwise asymptomatic state. It can be the presenting symptom of FMF called phenotype II. Accordingly, FMF-amyloidosis may be a direct disease-associated condition rather than a complication of the disease inflammatory activity.
Recent advances in our understanding of the role of pyrin (both normal and mutated) in apoptosis and inflammation support this hypothesis. Colchicin, the drug for controlling the frequency and severity of FMF crises, may also undergo a modifying effect in amyloidosis. This effect may be not only indirect--by controlling FMF attacks and thus reducing SAA--but also direct by blocking amyloid fibers deposition. [1]
Reversal of FMF-amyloidosis after colchicine is now widely accepted. [2] A favorable action of colchicine in AL-amyloidosis where the structure of amyloid fibrils is different has also been reported (3). Testing for pyrin mutations in every AA amyloidosis case with no profound predisposing factor(s) is currently acceptable. In Italy and Greece, FMF is frequent but is underdiagnosed [4,5] and some AA amyloidoses may be related to a mutated pyrin background.
Molecular detection of pyrin mutations and colchicin treatment may be an effective approach towards AA amyloidosis control. The lessons can be applied to other forms of this heterogenous disease.
References
1. Buxbaum JN. Treatment and prevention of amyloidoses. Can the lessons learned be applied to sIBM? Neurology 2005; 66 (Suppl 1): 8110- 8113
2. Livneh A, Zemer D, Langevitz P, Laor A, Sohar E, Pras M. Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome. Arthritis Rheum 1994; 37:1804�1811
3. Cohen AS, Rubinow A, Anderson JJ, et al. Survival of patients with primary (AL) amyloidosis. Colchicine- treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987;82:1182-90
4. Konstantopoulos K, Kanta A, Deltas C, et al. Familial Mediterranean fever associated pyrin mutations in Greece. Ann Rheum Dis. 2003;62:479-481
5. La Regina M, Nucera G, Diaco M, et al. Familial Mediterranean fever is no longer a rare disease in Italy. Eur J Hum Genet 2003; 11: 50- 56.
Disclosure: The authors report no conflicts of interest.