Arterial Thrombosis in Systemic Lupus Erythematosus
http://www.100md.com
《新英格兰医药杂志》
To the Editor: ?hlenschl?ger et al. (July 15 issue)1 reported that they did not find a significant association between arterial thrombosis and the presence of antiphospholipid antibodies. However, no mention was made of whether arterial thrombosis was associated with the presence of the antiphospholipid-antibody syndrome, which is frequently present in patients with systemic lupus erythematosus (SLE) and is closely related to the occurrence of venous and arterial thrombosis. The data provided by the authors are insufficient to indicate how many patients had the antiphospholipid-antibody syndrome2 and how they were distributed among the three genotypes (O/O, A/O, and A/A). Moreover, the authors did not elucidate whether antiphospholipid antibodies were found only on one occasion or were confirmed a second time2; the finding of antiphospholipid antibodies on one occasion is not unusual in normal subjects and in patients with SLE without a predisposition to thrombotic events. This circumstance could explain, for example, the lack of association between arterial thrombosis and antiphospholipid antibodies. We think that the clarification of these issues could help readers in better understanding the results of this study.
José Mario Sabio, M.D.
Juan Jiménez-Alonso, Ph.D.
Virgen de las Nieves University Hospital
18012 Granada, Spain
masabio@terra.es
References
?hlenschl?ger T, Garred P, Madsen HO, Jacobsen S. Mannose-binding lectin variant alleles and the risk of arterial thrombosis in systemic lupus erythematosus. N Engl J Med 2004;351:260-267.
Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999;42:1309-1311.
To the Editor: ?hlenschl?ger and colleagues recently concluded that mannose-binding lectin may protect against atherosclerosis in SLE, on the basis of the increased incidence of arterial thrombosis associated with the presence of variant alleles for mannose-binding lectin. I have several concerns about this conclusion.
First, the authors need to consider the potential confounding effect of hyperhomocysteinemia. Hyperhomocysteinemia and dyslipidemia — both unmeasured in the study — are indeed among the strongest risk factors for atherosclerosis in SLE.1,2 Second, the study provides inadequate direct evidence of atherosclerosis. This is particularly relevant in SLE: coronary-artery vasculitis can easily be mistaken for coronary artery disease that develops from atherosclerotic plaques.3 Third, the mannose-binding lectin protein levels — on which the conclusion is based — are not provided in this study. Functional mannose-binding lectin levels can be influenced by various factors, including anti–mannose-binding lectin autoantibody.4 In fact, a previous study suggested that the level of mannose-binding lectin is not associated with the risk of atherosclerosis.5
Tawee Tanvetyanon, M.D.
Loyola University Chicago Stritch School of Medicine
Maywood, IL 60153
tan73@hotmail.com
References
Asanuma Y, Oeser A, Shintani AK, et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003;349:2407-2415.
Petri M, Roubenoff R, Dallal GE, Nadeau MR, Selhub J, Rosenberg IH. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996;348:1120-1124.
Wurzel J, Goldman BI. Premature coronary disease in systemic lupus. N Engl J Med 2004;350:1571-1575.
Seelen MA, Trouw LA, van der Hoorn JW, et al. Autoantibodies against mannose-binding lectin in systemic lupus erythematosus. Clin Exp Immunol 2003;134:335-343.
Albert MA, Rifai N, Ridker PM. Plasma levels of cystatin-C and mannose binding protein are not associated with risk of developing systemic atherosclerosis. Vasc Med 2001;6:145-149.
The authors reply: We agree with Drs. Sabio and Jiménez-Alonso that the antiphospholipid-antibody syndrome is a frequent complication in SLE, and we too would expect an association between the presence of the antiphospholipid-antibody syndrome and arterial thrombosis, given that this association is part of the definition of the syndrome. In our study, mannose-binding lectin genotypes were not associated with the presence of antiphospholipid antibodies. The power of our study with regard to antiphospholipid antibodies does not allow us to discard a reconfirmed finding of IgG antiphospholipid antibodies as a risk factor for arterial thrombosis in SLE (hazard ratio, 2.1); it just was not as strong a risk factor as homozygosity for structural mannose-binding lectin variant alleles (hazard ratio, 7.0), which was the focus of the study.
Dr. Tanvetyanon correctly points out that our study does not provide direct evidence of atherosclerosis, which we acknowledged in our discussion, but our results should be seen in the context of other studies that show a direct association between mannose-binding lectin variant alleles and evidence of atherosclerosis. We agree that an expansion of the panel of potential risk factors would have been most interesting.
Blood mannose-binding lectin levels, which are closely associated with mannose-binding lectin genotypes, were measured in the original description of our study cohort, but the levels did not deviate from what we expected.1,2 Most studies of the association of diseases with mannose-binding lectin show the strongest effect for homozygosity for mannose-binding lectin variant alleles, whereas many studies based on plasma or serum levels of mannose-binding lectin do not reveal such associations. This pattern has been an enigma. Recently, we found that persons who are heterozygous for structural mannose-binding lectin variant alleles in which mannose-binding lectin antigen cannot be detected with the use of conventional techniques still have some mannose-binding lectin highly oligomerized in the blood.3 By contrast, persons who are homozygous for mannose-binding lectin variant alleles may have considerable amounts of mannose-binding lectin antigen, which does not properly oligomerize and is dysfunctional.3,4 Thus, only knowledge about the underlying molecular structure of mannose-binding lectin provides the information necessary for disease-association studies, information that, at the moment, is most easily obtained by means of correct mannose-binding lectin genotyping. We concur with the view that the level of functional mannose-binding lectin may partly be influenced by various factors, but this will still not change the conclusion regarding inherited dysfunctional mannose-binding lectin in disease-association studies.
S?ren Jacobsen, M.D.
Peter Garred, M.D.
Rigshospitalet
DK-2100 Copenhagen, Denmark
sj@dadlnet.dk
References
Garred P, Madsen HO, Halberg P, et al. Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus. Arthritis Rheum 1999;42:2145-2152.
Madsen HO, Satz ML, Hogh B, Svejgaard A, Garred P. Different molecular events result in low protein levels of mannose-binding lectin in populations from southeast Africa and South America. J Immunol 1998;161:3169-3175.
Garred P, Larsen F, Madsen HO, Koch C. Mannose-binding lectin deficiency -- revisited. Mol Immunol 2003;40:73-84.
Larsen F, Madsen HO, Sim RB, Koch C, Garred P. Disease-associated mutations in human mannose-binding lectin compromise oligomerization and activity of the final protein. J Biol Chem 2004;279:21302-21311.
José Mario Sabio, M.D.
Juan Jiménez-Alonso, Ph.D.
Virgen de las Nieves University Hospital
18012 Granada, Spain
masabio@terra.es
References
?hlenschl?ger T, Garred P, Madsen HO, Jacobsen S. Mannose-binding lectin variant alleles and the risk of arterial thrombosis in systemic lupus erythematosus. N Engl J Med 2004;351:260-267.
Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999;42:1309-1311.
To the Editor: ?hlenschl?ger and colleagues recently concluded that mannose-binding lectin may protect against atherosclerosis in SLE, on the basis of the increased incidence of arterial thrombosis associated with the presence of variant alleles for mannose-binding lectin. I have several concerns about this conclusion.
First, the authors need to consider the potential confounding effect of hyperhomocysteinemia. Hyperhomocysteinemia and dyslipidemia — both unmeasured in the study — are indeed among the strongest risk factors for atherosclerosis in SLE.1,2 Second, the study provides inadequate direct evidence of atherosclerosis. This is particularly relevant in SLE: coronary-artery vasculitis can easily be mistaken for coronary artery disease that develops from atherosclerotic plaques.3 Third, the mannose-binding lectin protein levels — on which the conclusion is based — are not provided in this study. Functional mannose-binding lectin levels can be influenced by various factors, including anti–mannose-binding lectin autoantibody.4 In fact, a previous study suggested that the level of mannose-binding lectin is not associated with the risk of atherosclerosis.5
Tawee Tanvetyanon, M.D.
Loyola University Chicago Stritch School of Medicine
Maywood, IL 60153
tan73@hotmail.com
References
Asanuma Y, Oeser A, Shintani AK, et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003;349:2407-2415.
Petri M, Roubenoff R, Dallal GE, Nadeau MR, Selhub J, Rosenberg IH. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996;348:1120-1124.
Wurzel J, Goldman BI. Premature coronary disease in systemic lupus. N Engl J Med 2004;350:1571-1575.
Seelen MA, Trouw LA, van der Hoorn JW, et al. Autoantibodies against mannose-binding lectin in systemic lupus erythematosus. Clin Exp Immunol 2003;134:335-343.
Albert MA, Rifai N, Ridker PM. Plasma levels of cystatin-C and mannose binding protein are not associated with risk of developing systemic atherosclerosis. Vasc Med 2001;6:145-149.
The authors reply: We agree with Drs. Sabio and Jiménez-Alonso that the antiphospholipid-antibody syndrome is a frequent complication in SLE, and we too would expect an association between the presence of the antiphospholipid-antibody syndrome and arterial thrombosis, given that this association is part of the definition of the syndrome. In our study, mannose-binding lectin genotypes were not associated with the presence of antiphospholipid antibodies. The power of our study with regard to antiphospholipid antibodies does not allow us to discard a reconfirmed finding of IgG antiphospholipid antibodies as a risk factor for arterial thrombosis in SLE (hazard ratio, 2.1); it just was not as strong a risk factor as homozygosity for structural mannose-binding lectin variant alleles (hazard ratio, 7.0), which was the focus of the study.
Dr. Tanvetyanon correctly points out that our study does not provide direct evidence of atherosclerosis, which we acknowledged in our discussion, but our results should be seen in the context of other studies that show a direct association between mannose-binding lectin variant alleles and evidence of atherosclerosis. We agree that an expansion of the panel of potential risk factors would have been most interesting.
Blood mannose-binding lectin levels, which are closely associated with mannose-binding lectin genotypes, were measured in the original description of our study cohort, but the levels did not deviate from what we expected.1,2 Most studies of the association of diseases with mannose-binding lectin show the strongest effect for homozygosity for mannose-binding lectin variant alleles, whereas many studies based on plasma or serum levels of mannose-binding lectin do not reveal such associations. This pattern has been an enigma. Recently, we found that persons who are heterozygous for structural mannose-binding lectin variant alleles in which mannose-binding lectin antigen cannot be detected with the use of conventional techniques still have some mannose-binding lectin highly oligomerized in the blood.3 By contrast, persons who are homozygous for mannose-binding lectin variant alleles may have considerable amounts of mannose-binding lectin antigen, which does not properly oligomerize and is dysfunctional.3,4 Thus, only knowledge about the underlying molecular structure of mannose-binding lectin provides the information necessary for disease-association studies, information that, at the moment, is most easily obtained by means of correct mannose-binding lectin genotyping. We concur with the view that the level of functional mannose-binding lectin may partly be influenced by various factors, but this will still not change the conclusion regarding inherited dysfunctional mannose-binding lectin in disease-association studies.
S?ren Jacobsen, M.D.
Peter Garred, M.D.
Rigshospitalet
DK-2100 Copenhagen, Denmark
sj@dadlnet.dk
References
Garred P, Madsen HO, Halberg P, et al. Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus. Arthritis Rheum 1999;42:2145-2152.
Madsen HO, Satz ML, Hogh B, Svejgaard A, Garred P. Different molecular events result in low protein levels of mannose-binding lectin in populations from southeast Africa and South America. J Immunol 1998;161:3169-3175.
Garred P, Larsen F, Madsen HO, Koch C. Mannose-binding lectin deficiency -- revisited. Mol Immunol 2003;40:73-84.
Larsen F, Madsen HO, Sim RB, Koch C, Garred P. Disease-associated mutations in human mannose-binding lectin compromise oligomerization and activity of the final protein. J Biol Chem 2004;279:21302-21311.