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Rheumatology Advance Access originally published online on March 1, 2006
Rheumatology 2006 45(9):1116-1120; doi:10.1093/rheumatology/kel050
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The persistence of anticardiolipin antibodies is associated with an increased risk of the presence of lupus anticoagulant and anti-ß2-glycoprotein I antibodies

C. Neville1, J. Rauch3, J. Kassis5, S. Solymoss2, L. Joseph1,4, P. Belisle1, R. Subang3, E. R. Chang6 and P. R. Fortin6,7,

1Division of Clinical Epidemiology, 2Department of Hematology, Montreal General Hospital, McGill University Health Centre, 3Division of Rheumatology, Montreal General Hospital, Research Institute of the McGill University Health Centre, 4Department of Epidemiology and Biostatistics, McGill University, 5Laboratoire de Coagulation, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, Quebec, 6Division of Outcomes and Population Health, University Health Network Research Institute and 7Division of Rheumatology, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Correspondence to: P. R. Fortin, Arthritis Centre of Excellence, Toronto Western Hospital, Room MP 10-304, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8. E-mail: pfortin{at}uhnresearch.ca


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. We studied antiphospholipid antibodies (aPL) in blood samples from a cohort of individuals followed for thrombosis to determine whether the persistent presence of anticardiolipin antibodies (aCL) is associated with a greater likelihood of having lupus anticoagulant and/or anti-ß2-glycoprotein I antibodies (LA/aß2GPI).

Methods. Blood samples from 353 individuals who had been tested for aCL on at least two occasions were tested for aß2GPI and LA. Two groups were defined: aCL-persistent, who tested aCL-positive on at least two occasions, and aCL non-persistent, who tested aCL-positive on fewer than two occasions. Multivariate logistic regressions were performed using LA/aß2GPI, LA and aß2GPI as outcome variables and the percentage of aCL-positive tests as the predictor variable, adjusted for age, gender, family history of cardiovascular disease (CVD), systemic lupus erythematosus (SLE), smoking and number of venous (VT) and arterial thromboses (AT).

Results. Sixty-eight (19%) individuals were aCL persistent and 285 (81%) were aCL non-persistent. LA/aß2GPI was found in 36 (53%) of the aCL persistent group and 38 (13%) of the aCL non-persistent group. The two groups were similar for age, gender and smoking. Family history of CVD, SLE, VT and AT were more frequent in the aCL persistent group. Multivariate analyses revealed that odds ratios for LA/aß2GPI, LA and aß2GPI were 1.34 [95% confidence interval (CI)=1.22–1.47], 1.36 (95% CI=1.24–1.50) and 1.47 (95% CI=1.31–1.65) respectively for each 10% increase in aCL-positive tests vs 0% positive tests.

Conclusion. Persistence of aCL positivity is associated with an increased risk of LA/aß2GPI.

KEY WORDS: Antiphospholipid antibodies, Anticardiolipin antibodies, Lupus anticoagulant, Anti-ß2-glycoprotein I antibodies.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
The presence of antiphospholipid antibodies (aPL) has been shown to be associated with arterial (AT) and venous thrombosis (VT) [1]. However, thrombosis does not occur in all aPL-positive individuals, and predicting which patients may develop thrombotic events remains one of the major clinical dilemmas in this area. Hence, it would be of tremendous clinical value to determine serological markers or tests that can identify patients at high risk of thrombosis.

Persistence of anticardiolipin antibody (aCL) positivity has been shown to be of diagnostic importance in identifying systemic lupus erythematosus (SLE) patients at higher risk of thrombosis [2, 3]. aCL persistence has also been associated with a higher incidence of lupus anticoagulant (LA) [3]. Multiple different aPL [e.g. LA, anti-ß2-glycoprotein I antibodies (aß2GPI) and antiprothrombin] are often present in an individual with aCL, but the diagnostic utility of aPL other than aCL and LA remains questionable [4–6]. Other retrospective studies have shown that individuals with more than one aPL are at greater risk of thrombosis than those with a single aPL [7–12]. The mechanism responsible for the development of these multiple aPL remains unknown, but epitope spreading is one potential mechanism that can explain the presence of multiple and related autoantibodies in a given individual [13]. In fact, in patients with SLE, aPL (specifically, aCL) have been shown to precede the development of other autoantibodies and to precede the development of disease by 7 or 8 yr [13]. We propose that autoantibodies in patients with antiphospholipid syndrome also develop and emerge in an ordered pattern, and that clinical symptoms may occur only after multiple autoantibodies have been present for several to many years.

In the present study, we were interested in exploring whether the persistent presence of aCL is associated with an increased risk of the development of other aPL. In particular, we focused on whether persistent aCL positivity is associated with an increased risk of the presence of LA and anti-ß2GPI antibodies, and evidence for a temporal relationship in the development of these different aPL. Such an association might provide better diagnostic criteria for identifying patients at risk of thrombosis, and a better understanding of the development and pathogenesis of aPL.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
The Montreal Antiphospholipid Antibody Study (MAPS) is a cohort of 416 persons followed prospectively for the development of new thrombotic events. Participants were recruited from two Montreal university hospitals. Written consent was obtained from all participants according to the Declaration of Helsinki. The study design was reviewed and approved by the Research Ethics Boards of McGill University Health Centre and Hôpital Maisonneuve-Rosemont.

Clinical data collected at baseline included demographic parameters (age, gender, education); history of VT or AT; family history of cerebrovascular accident, transient ischaemic attack, myocardial infarction or angina in first-degree relatives; smoking; diabetes mellitus; and SLE. Laboratory tests included: aCL immunoglobulin (Ig) G and IgM, aß2GPI IgG and IgM, and LA at entry into the study (baseline) and annually. Plasma and serum were aliquoted and stored frozen at –70°C. aCL IgG/IgM were tested using the Louisville assay (Louisville APL Diagnostics, Louisville, KY, USA). aß2GPI IgG/IgM were measured by enzyme-linked immunosorbent assay (ELISA) in our research laboratory [14]. LA was detected using a dilute activated partial thromboplastin time assay (Automated APTT; Organon Teknika, Scarborough, ON, Canada) in which the plasma tested was diluted 1:1 with normal plasma. Confirmation of LA activity was performed by neutralization with hexagonal phase phosphatidylethanolamine [15]. This cohort has been described in more detail elsewhere [8].

We report results of aPL testing in 353 participants who had had at least two aCL blood tests performed over a 4-yr period. The median follow-up time was 4.0 yr (interquartile range = 1.5–4.5). Blood tests were performed at baseline and annually over a 4-yr period, giving a total of five possible aCL tests. However, not all individuals had a complete set of tests: 212 had five tests, 31 had four tests, 87 had three tests, and 23 had two tests. Tests were considered to be aCL-positive if >15 U/ml for aCL (IgG or IgM), aß2GPI-positive if ≥0.7 OD405 units for aß2GPI (IgG or IgM), and LA-positive if ≥6.0 s above the control plasma for LA, and >8.0 s above the control for confirmation of LA. Persistence of aCL was defined as having two or more positive aCL IgG/IgM tests. Two groups of individuals were defined: aCL persistent, who tested aCL positive on at least two occasions, and aCL non-persistent, who tested aCL positive on fewer than two occasions.

All data were double-entered into Medlog (Medlog Systems, Incline Village, NV, USA) and discordant entries were verified. Analyses were performed using SAS [16]. We evaluated the presence of LA and/or aß2GPI (hitherto referred to as LA/aß2GPI) in aCL persistent and aCL non-persistent groups. We performed univariate logistic regressions, using LA/aß2GPI, LA and aß2GPI positivity as the outcome variables and the percentage of positive aCL tests within individuals over the 4-yr period as the predictor variable. Multivariate logistic regressions were performed using LA/aß2GPI, LA and aß2GPI as the outcome variables and the percentage of aCL-positive tests as the predictor variable, adjusted for age, gender, family history of cardiovascular disease in first-degree relatives, SLE, smoking, and number of VT and AT prior to entry into the cohort. In order to adjust for the variability in follow-up times between individuals, both unweighted and weighted analyses were performed, where the weights were proportional to follow-up times.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
Sixty-eight individuals (19.3%) had tested positive on at least two occasions for aCL IgG/IgM and 285 individuals had tested positive on fewer than two occasions. Baseline characteristics of the aCL persistent and aCL non-persistent groups are shown in Table 1. Although aCL persistent individuals were similar to aCL non-persistent individuals for age, gender and smoking, the aCL persistent group reported more family history of cardiovascular disease (66 vs 51%), SLE (38 vs 20%), previous VT (25 vs 7%) and previous AT (16 vs 9%).


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  		TABLE 1. Characteristics of the cohort

 
To determine whether the presence of LA/aß2GPI was more prevalent in individuals with persistent aCL, we evaluated the distribution of LA and aß2GPI in aCL persistent and non-persistent groups. Of the 68 persons in the aCL persistent group, 36 (53%) tested positive for LA/aß2GPI vs 38 (13%) of the aCL non-persistent group (Table 2). Thirty-two (47%) individuals in the aCL persistent group tested positive for LA vs 26 (9%) individuals in the non-persistent group and 23 (34%) cases in the persistent group tested positive for aß2GPI vs 16 (6%) cases in the non-persistent group.


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  		TABLE 2. Distribution of LA/aß2GPI in aCL persistent and non-persistent groups

 
When we looked at aPL patterns over time, we found that 28 (41%) individuals of the aCL persistent group were also persistent for LA (LA-positive at least two times), while 14 (21%) were persistent for aß2GPI (aß2GPI-positive at least two times). In contrast, only 15 (5%) in the aCL non-persistent group were LA persistent and eight (3%) were persistent for aß2GPI. Titres of aCL also differed between the aCL persistent and non-persistent groups. In the aCL persistent group, high-titre aCL was observed in 46 (68%) individuals, compared with only five (9%) of the 55 aCL-positive individuals in the non-persistent group. In addition, high-titre IgG aCL were present (n = 27, 59%) in the aCL persistent group but were completely absent in the aCL non-persistent group. The latter group had only IgM aCL. In the aCL persistent group (n = 68), there were 22 individuals who were aCL positive at baseline but did not have any other aPL at that time. Of these, nine (41%) became positive for LA/aß2GPI (six for both LA and aß2GPI, two for LA alone, and one for aß2GPI alone). In contrast, only three of the 285 aCL non-persistent group were positive for aCL with no other aPL at baseline, and these individuals did not go on to develop any other aPL over the 4-yr period studied.

We performed univariate and multivariate logistic regressions, using LA/aß2GPI, LA and aß2GPI positivity as the outcome variables and the percentage of positive aCL tests as the predictor variable. In order to adjust for the variability in follow-up times between individuals, both unweighted and weighted analyses were performed, where the weights were proportional to follow-up times. The results of unweighted and weighted analyses were similar. We report the weighted analyses. Univariate logistic regression suggested an association between the presence of LA/aß2GPI with 10% aCL-positive tests within individuals over the 4-yr period vs 0% positive tests [odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.29–1.53]. In other words, a 10% rise in the percentage of positive aCL tests over time is associated with an approximately 40% rise in the odds of the presence of LA/aß2GPI. This association remained strong in a multivariate analysis adjusting for age, gender, family history of cardiovascular disease, SLE, and number of previous VT and AT. Table 3 displays the results of the multivariate analyses using LA/aß2GPI, LA or aß2GPI as the outcome variable. For the model using LA/aß2GPI as the outcome, the presence of 10% aCL-positive tests within individuals over the 4-yr period vs 0% aCL-positive tests was associated with LA/aß2GPI (OR = 1.34, 95% CI = 1.22–1.47), smoking (OR = 2.00, 95% CI = 1.02, 3.93) and number of VT (OR = 1.76, 95% CI = 1.00–3.10). A similar association was found for 10% aCL-positive tests vs 0% aCL-positive tests with LA alone (OR 1.36, 95% CI = 1.24–1.50), but in this model the presence of LA was associated with slightly higher risks for smoking (OR = 2.75, 95% CI = 1.29–5.84) and the number of previous VT (OR = 2.20, 95% CI = 1.17–4.11). Finally, 10% aCL-positive tests vs 0% positive tests was also associated with aß2GPI alone (OR = 1.47, 95% CI = 1.31–1.65), but in this model the associations of aß2GPI with smoking and number of VT or AT were inconclusive due to wide CIs.


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  		TABLE 3. Odds ratios for the presence of LA aß2GPI, LA or aß2GPI

 
Similar results were found when a higher and more rigorous cut-off (>40 U/ml) for aCL positivity was used in our multivariate models. ORs for LA/aß2GPI, LA and aß2GPI were 1.36 (95% CI = 1.22–1.52), 1.32 (95% CI = 1.19–1.46) and 1.56 (95% CI = 1.37–1.77), respectively, for each 10% increase in aCL-positive tests vs 0% positive tests (data not shown). Of note, Derksen et al. [17] have previously shown that the stability of aCL titres is relatively similar whether the initial aCL result is <40 or ≥40.


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
Our results show that the persistence of aCL positivity is associated with an increased risk of having LA/aß2GPI. We evaluated the distribution of LA and aß2GPI in aCL persistent and non-persistent subgroups of a cohort of individuals followed prospectively. LA/aß2GPI was found in 53% of individuals who were persistently positive for aCL, compared with only 13% in the aCL non-persistent group. This difference was also observed when LA and aß2GPI were evaluated individually in these two groups. LA positivity was observed in 47% of the aCL persistent group, compared with only 9% of individuals in the non-persistent group. Positivity for aß2GPI was lower than LA, but also differed significantly between the two groups (34 vs 6%). The results of our multivariate analysis demonstrate that the likelihood of an individual being positive for LA/aß2GPI increases with the percentage of positive aCL tests. These findings suggest that monitoring the frequency and persistence of aCL positivity provides a clinically important measure of the likelihood that an individual will become LA/aß2GPI-positive and emphasizes the importance of repeated aCL testing.

To relate our findings to a clinical context, we assessed the odds of an individual testing positive for LA/aß2GPI according to the percentage of positive aCL test results. As shown in Fig. 1, the likelihood of an individual being positive for LA/aß2GPI increases with the percentage of positive aCL tests. For example, an individual who tests positive for aCL on one (20%) of five occasions has an odds of 1.8 of having LA/aß2GPI, whereas an individual who tests positive for aCL on all five (100%) occasions has an odds of 18.8 of having LA/aß2GPI.


Figure 1
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  		FIG. 1. Schematic representation showing the ORs of LA/ß2GPI positivity for a selection of percentages of aCL-positive tests. For example, an individual who tests positive for aCL on one (20%) of five occasions has an odds of 1.8 of having LA/aß2GPI, whereas an individual who tests positive for aCL on all five (100%) occasions has an odds of 18.8 of having LA/aß2GPI. The number above each bar is the OR derived from the multiple logistic regression model shown in Table 3.

 
We also found that LA/aß2GPI was associated with smoking and with previous venous events. We expected that venous events would be associated with LA/aß2GPI, but the association with smoking was unexpected. Interestingly, Fickl et al. [18] found increased levels of circulating antibodies to both cardiolipin and oxidized low-density lipoprotein in cigarette smokers, but did not evaluate LA or aß2GPI. Cigarette smoking is proposed to cause oxidative stress, which could lead to the generation of aPL [18].

We propose that the presence of multiple autoantibodies probably precedes the development of disease in patients with aPL. In patients with SLE, aCL have been shown to appear prior to the emergence of other autoantibodies (e.g. anti-DNA) and to precede the development of clinical symptoms by 7 or 8 yr [13]. Patients with antiphospholipid syndrome also produce multiple autoantibodies, although in this case the autoantibodies are usually different types of aPL. This so-called spreading of the autoimmune response can be observed in the individuals in our cohort. Here, we show that individuals in whom aCL persisted were more likely to have other aPL (i.e. LA/aß2GPI) and that the risk of developing other aPL increased with the frequency of aCL-positive tests. Similar findings were obtained whether a lower (>15 U/ml) or more rigorous (>40 U/ml) definition of aCL positivity was used. aCL persistent individuals also had a higher titre of IgG aCL and more persistently positive LA and aß2GPI. Moreover, approximately 40% of aCL persistent individuals who were only positive for aCL at baseline developed LA/aß2GPI positivity over the 4-yr period monitored in this study. Together, these findings support a sequential emergence of multiple aPL in individuals with persistently positive aCL.

Retrospective studies have shown that the occurrence of thrombosis in persons with more than one aPL is greater than in individuals with a single aPL [8–11]. Prospective data on our cohort at 3 yr of follow-up also indicate that the presence of multiple aPL increases the risk of thrombosis [19]. Taken together, these findings suggest that monitoring of aCL persistence provides insight into the spectrum of autoantibodies and clinical manifestations that may develop. In summary, the persistence of aCL appears to define a clinically important subgroup of individuals with more profound autoimmunity and thrombophilic risk.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
We are grateful to Martine Le Comte for the follow-up telephone interviews and entry of data, and to Marie-Louise Alonso and Karine Nadeau for their technical assistance. This work was supported by operating grants from The Arthritis Society (97/0007, P.R.F.) and an operating grant from the CIHR (89548, P.R.F.; MT-42391, J.R.). P.R.F. is an Investigator of The Arthritis Society/Institute of Musculoskeletal Health and Arthritis and is partly supported by The Arthritis Centre of Excellence, Arthritis and Autoimmune Research Centre Foundation, University of Toronto and the Lupus Clinical Trial Consortium.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Levine JS, Branch DW, Rauch J. (2002) The antiphospholipid syndrome. N Engl J Med 346:752–63.[Free Full Text]
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  3. Ishii Y, Nagasawa K, Mayumi T, Niho Y. (1990) Clinical importance of persistence of anticardiolipin antibodies in systemic lupus erythematosus. Ann Rheum Dis 49:387–90.[Abstract/Free Full Text]
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  6. Galli M, Luciani D, Bertolini G, Barbui T. (2003) Anti-ß2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood 102:17–23.[Free Full Text]
  7. Detková D, Gil-Aguado A, Lavilla P, Cuesta MV, Fontán G, Pascual-Salcedo D. (1999) Do antibodies to ß2-glycoprotein 1 contribute to the better characterization of the antiphospholipid syndrome? Lupus 8:430–8.[Abstract/Free Full Text]
  8. Neville C, Rauch J, Kassis J, Chang ER, Joseph L, Le Comte M, Fortin PR. (2003) Thromboembolic risk in patients with high titre anticardiolipin and multiple antiphospholipid antibodies. Thromb Haemost 90:108–15.[ISI][Medline]
  9. Hudson M, Herr AL, Rauch J, et al. (2003) The presence of multiple prothrombotic risk factors is associated with a higher risk of thrombosis in individuals with anticardiolipin antibodies. J Rheumatol 30:2385–91.[ISI][Medline]
  10. von Landenberg P, Scholmerich J, von Kempis J, Lackner KJ. (2003) The combination of different antiphospholipid antibody subgroups in the sera of patients with autoimmune diseases is a strong predictor for thrombosis. A retrospective study from a single center. Immunobiology 207:65–71.[ISI][Medline]
  11. Lee EY, Lee CK, Lee TH, et al. (2003) Does the anti-beta2-glycoprotein I antibody provide additional information in patients with thrombosis? Thromb Res 111:29–32.[CrossRef][ISI][Medline]
  12. Derksen W, Erkan D, Kaplan V, Sammaritano L, Lockshin MD. (2004) Real world experience with APL: comparison between APS and asymptomatic APL-positive patients. Thrombosis Res 114:635.
  13. Arbuckle MR, McClain MT, Rubertone MV, et al. (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 349:1526–33.[Abstract/Free Full Text]
  14. Price BE, Rauch J, Shia MA, et al. (1996) Anti-phospholipid autoantibodies bind to apoptotic, but not viable, thymocytes in a beta 2-glycoprotein I-dependent manner. J Immunol 157:2201–8.[Abstract]
  15. Rauch J, Tannenbaum M, Neville C, Fortin PR. (1998) Inhibition of lupus anticoagulant activity by hexagonal phase phosphatidylethanolamine in the presence of prothrombin. Thromb Haemost 80:936–41.[ISI][Medline]
  16. SAS Institute. (2002) The SAS System for Windows [8.2] (SAS Institute, Cary, NC).
  17. Derksen W, Erkan D, Kaplan V, Sammaritano L, Pierangeli S, Lockshin M. (2004) Real world experience with antiphospholipid antibodies (APL): how stable are APL over time? Thromb Res 114:635.
  18. Fickl H, Van Antwerpen VL, Richards GA, et al. (1996) Increased levels of autoantibodies to cardiolipin and oxidised low density lipoprotein are inversely associated with plasma vitamin C status in cigarette smokers. Atherosclerosis 124:75–81.[CrossRef][ISI][Medline]
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Submitted 9 November 2005; revised version accepted 17 January 2006.
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