SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Objective

To determine the prevalence of anticardiolipin antibodies (aCL), anti–β2-glycoprotein I (anti-β2GPI) antibodies, and lupus anticoagulant (LAC) in a large cohort of children with systemic lupus erythematosus (SLE), and to evaluate the associations with neuropsychiatric manifestations.

Methods

A single-center retrospective cohort study with longitudinal followup of antiphospholipid antibodies (aPL) in 137 children with SLE (25 boys and 112 girls, mean age at diagnosis 13.0 years) was performed. Patients were followed up for a mean of 31 months.

Results

At the time of diagnosis, 65% of the children were aCL positive, 41% had anti-β2GPI antibodies, and 26% were LAC positive. Analysis of the association between presence of aPL and individual neuropsychiatric manifestations at diagnosis showed a statistically significant association of positive LAC with cerebrovascular disease (5 patients; P = 0.015). A persistently positive aCL was observed in 50%, anti-β2GPI antibodies in 29%, and LAC in 16% of children over time. The prevalence of anti-β2GPI antibodies, but not aCL and LAC, was found to be statistically significantly higher in children with neuropsychiatric disease compared with those without (P = 0.02). Comparison for specific neuropsychiatric manifestations showed a statistically significant association between a persistently positive LAC and chorea (2 patients; P = 0.02).

Conclusion

The prevalence of anti-β2GPI antibodies was found to be higher in the group of SLE patients with neuropsychiatric disease compared with those without. Our data suggest an association between LAC and cerebrovascular disease at the time of SLE diagnosis and chorea over the disease course, but not between aPL and other neuropsychiatric manifestations.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Neuropsychiatric involvement is one of the most common features of pediatric systemic lupus erythematosus (SLE) with a reported incidence between 25% and 75% (1–3). In the absence of secondary causes such as infection, hypertension, or metabolic abnormalities, these neuropsychiatric manifestations can be attributed to the SLE disease directly affecting the central nervous system (CNS).

The etiopathogenesis of neuropsychiatric manifestations in patients with SLE remains largely unknown and has been attributed to autoantibody-mediated neural dysfunction, vasculopathy, and/or coagulopathy. Various autoantibodies have been implicated in the pathogenesis of neuropsychiatric SLE (NPSLE), including anti–ribosomal P protein, antineuronal, antiganglioside, antiphospholipid (aPL), and antiendothelial antibodies (4–8). One of the most intriguing issues is the association of neuropsychiatric manifestations with aPL. These autoantibodies can lead to thrombosis of cerebral vessels, both arterial and venous (7, 9), and a nonthrombotic, immune-mediated neurologic impairment has been associated with aPL (10–12).

Previous studies in pediatric SLE have demonstrated a strong association of aPL and in particular lupus anticoagulant (LAC) with vascular thromboses (13, 14). The most common neuropsychiatric manifestations associated with aPL in pediatric SLE are ischemic stroke and cerebral venous sinus thrombosis, secondary to thrombosis of cerebral vessels (15). The relationship between aPL and other neuropsychiatric manifestations, in particular chorea, seizures, migraine headache, psychosis, and transverse myelopathy, has been suggested, but large, prospective pediatric SLE studies have not been performed, although one study in adult patients with SLE showed an association of aPL with headache and seizures (7). These latter manifestations are likely the result of a nonthrombotic, immune-mediated mechanism rather than thrombosis (16–20).

The present study was conducted to determine the prevalence of anticardiolipin antibodies (aCL), anti–β2-glycoprotein I antibodies (anti-β2GPI), and LAC in a large cohort of children with SLE, and to evaluate the clinical associations of aPL with neuropsychiatric manifestations. A second goal was to determine the association of aPL with disease activity, disease severity, and organ damage in children with NPSLE.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Study design.

We performed a single-center, retrospective cohort study with longitudinal followup of all patients newly diagnosed with SLE between June 1995 and August 2005 at the Hospital for Sick Children Toronto (SickKids), Pediatric Lupus Clinic. Patients were eligible for the study if the diagnosis of SLE was confirmed at the SickKids Lupus Clinic, if patients were longitudinally followed at SickKids, and if patients' aPL levels were initially determined at the time of or within the first 3 months after the SLE diagnosis. All patients fulfilled the 1982 revised American College of Rheumatology (ACR) criteria for the classification of SLE (21). Tests for the presence of aPL were performed as part of routine clinical care at the time of diagnosis and then at a minimum of 1-year intervals. The study was approved by the hospital research ethics board. All patient data were prospectively entered in the SickKids SLE database.

Study population.

Of the 175 newly diagnosed patients seen at the Pediatric Lupus Clinic at SickKids during the study period, 137 met the entry criteria (Table 1). Thirty-eight patients were excluded from the study because their initial aPL levels were not determined within the first 3 months after the SLE diagnosis. Neuropsychiatric manifestations were classified according to the 1999 ACR case definitions for neuropsychiatric lupus syndromes (22). Only patients with a definite diagnosis based on neurologic or psychiatric evaluations were classified as having NPSLE. At each study visit, a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score was prospectively calculated for each patient (23, 24). The degree of irreversible organ damage was prospectively measured at every clinic visit using the Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI) (25, 26). Standardized clinical assessment and laboratory data were prospectively collected in the SickKids SLE clinic database (Oracle; Redwood Shores, CA). Patients were classified as persistently positive for an aPL subtype if they were positive on 2 or more occasions at least 12 weeks apart according to the international classification criteria for definite antiphospholipid syndrome (27).

Table 1. Demographic and clinical characteristics of the study cohort and total SickKids systemic lupus erythematosus cohort*
 NP cohort at presentationNP cohort at any timeStudy cohortTotal SickKids cohort
  • *

    Values are the number (percentage) or number/total number (percentage) unless otherwise indicated. NP = neuropsychiatric disease; aPL = antiphospholipid antibodies; aCL = anticardiolipin antibodies; anti-β2GPI = anti–β2-glycoprotein I antibodies; LAC = lupus anticoagulant; NSAIDs = nonsteroidal antiinflammatory drugs.

Patients23 (17)35 (26)137175
Age, mean (range) years9.4 (8.9–17.3)13.7 (8.4–17.3)13.0 (3.1–17.7)13.1 (3.1–17.7)
Female:male19:428:7112:25145:30
No. of NP manifestations42666672
NP manifestation    
 Headache13 (10)22 (16)22 (16)24 (14)
 Psychosis8 (6)13 (10)13 (10)14 (8)
 Cognitive dysfunction7 (5)12 (9)12 (9)14 (8)
 Cerebrovascular disease6 (4)7 (5)7 (5)7 (4)
 Seizures3 (2)4 (3)4 (3)4 (2)
 Mood disorder2 (1)4 (3)4 (3)5 (3)
 Chorea2 (1)2 (1)2 (1)2 (1)
 Transverse myelitis1 (1)2 (1)2 (1)2 (1)
aPL persistently positive    
 aCL9/23 (39)17/35 (49)69/137 (50)86/174 (49)
 Anti-β2GPI6/17 (35)13/27 (48)30/104 (29) 
 LAC4/22 (18)7/34 (21)20/125 (16)23/161 (14)
Followup, mean (range) months19 (1–111)35 (1–111)31 (1–118)51 (1–122)
Medication    
 Corticosteroids23 (100)35 (100)133 (97)164 (94)
 Hydroxychloroquine17 (74)27 (77)122 (89)153 (87)
 Azathioprine18 (78)29 (83)78 (57)96 (55)
 NSAIDs8 (35)4 (40)48 (35)60 (34)
 Mycophenolate mofetil4 (17)10 (29)28 (20)33 (19)
 Cyclophosphamide11 (48)16 (46)24 (18)28 (16)
 Methotrexate1 (4)1 (3)22 (16)28 (16)
 Intravenous gammaglobulins2 (9)4 (11)7 (5)8 (5)

Detection of aCL antibodies.

Screening for aCL was performed with a commercially available enzyme-linked immunosorbent assay (ELISA), which detects IgG isotype (Varelisa Cardiolipin IgG Antibodies; Phadia GmbH, Freiburg, Germany). The manufacturer's instructions for the kit were followed, without modifications. The assay is based on the principle of ELISA with cardiolipin-coated polystyrol plates and β2GPI as a cofactor for aCL antibodies added within the sample buffer. The measuring range was 1–100 kilounits/liter. The assay had reference intervals of <10 kilounits/liter for negative aCL, 10–15 kilounits/liter for equivocal aCL, and >15 kilounits/liter for positive aCL, based upon previous cutoff determination.

Detection of lupus anticoagulant.

LAC was detected by coagulation assays including prothrombin time and an activated partial thromboplastin time. Additional assays that were performed depended on the year that the samples were obtained, and included a kaolin clotting time, dilute Russell's viper venom test, tissue thromboplastin inhibitor, and platelet neutralization product. A minimum of 3 assays were performed in patients and LAC positivity was determined following the guidelines of the International Society on Thrombosis and Haemostasis (28).

Detection of anti-β2GPI antibodies.

Anti-β2GPI antibodies were subsequently tested in stored frozen sera from 122 patients, and serial serum samples were available in 104 patients. Anti-β2GPI antibodies were determined by an in-house ELISA method at the Department of Rheumatology, University Medical Center Ljubljana, Slovenia, as previously described (29). In brief, microtiter plates (Costar High Binding EIA/RIA plates; Costar, Bethesda, MD) were coated with 50 μl/well of β2GPI dissolved at 10 μg/ml in phosphate buffered saline (PBS) for 2 hours at room temperature. After one washing with 200 μl of PBS containing 0.05% Tween 20 (PBS–Tween), 50 μl/well of standards and serum samples diluted 1:100 in PBS–Tween were applied in duplicate and incubated for 30 minutes at room temperature. After 4 washes, 50 μl/well of alkaline phosphatase–conjugated goat anti-human IgG, IgM, or IgA (ACSC, Westbury, NY) diluted in PBS was added. After 30 minutes of incubation at room temperature and 4 washes, 100 μl/well of substrate was added. Optical density (OD) at 405 nm was measured first after 10 minutes and then every 3 minutes by a Rainbow Spectra Thermo microtiter plate reader (Tecan, Grödig/Salzburg, Austria) versus a reagent blank until an optimal fitting to the predicted OD of standards was obtained. The control group comprised 61 apparently healthy children at their regular routine preventive visits in the community-based health centers. The clinical parameters of the control group and the statistical test procedures used to determine the cutoff values have been reported elsewhere (29).

Statistical analysis.

Statistical tests were performed using subroutines from the statistical analysis package MegaStat version 9.0 (McGraw-Hill, Columbus, OH) for Microsoft Office and SAS software (SAS Institute, Cary, NC). Associations between categorical variables were tested using chi-square test or Fisher's exact test when required, and were summarized by odds ratios (ORs) and 95% confidence intervals (95% CIs). For continuous variables, the comparisons were carried out using Student's t-test assuming equal or unequal variances and linear regression analysis. All variables were checked for normality and all skewed data were log transformed before statistical analysis. Differences were considered statistically significant at P values less than 0.05. Survival curves were built using the Kaplan-Meier method and were compared using the log rank test. For all patients, the date of diagnosis was used as the starting point for the analyses.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

At SLE presentation.

Of 137 patients, 23 (17%) had neuropsychiatric involvement at the time of initial presentation of SLE, with headache, seen in 13 patients, being the most common neuropsychiatric manifestation, followed by psychosis, cognitive dysfunction, and cerebrovascular disease. Of these 23 patients, 13 (57%) had more than 1 manifestation (Table 1).

Of 137 patients, 91 (66%) had at least 1 detectable aPL, with aCL being the most common (65%), followed by anti-β2GPI antibodies in 41% and LAC in 26% of patients. Of the 94 children who were tested for more than 1 aPL subtype, 38 (40%) had ≥2 aPL. There was a positive correlation between aCL titer at presentation and SLEDAI scores (R2 = 0.17, P < 0.001), but there was no correlation between anti-β2GPI antibody titer and SLEDAI scores.

We next examined the association of aPL and neuropsychiatric disease and found there was no statistically significant difference in the percentage of patients with any aPL or with the different aPL subtypes between patients with and without neuropsychiatric involvement (Table 2). The only statistically significant association between the presence of individual aPL and individual neuropsychiatric manifestations was the association between positive LAC and presence of cerebrovascular disease (P = 0.015; tested in 5 of 6 patients, and 4 of 5 with cerebrovascular disease were LAC positive as compared with 18 of 79 LAC-positive patients without cerebrovascular disease), although there was a trend toward an association with chorea (2 of 2 patients with chorea at presentation were positive for LAC versus 20 of 82 without chorea; P = 0.067; aCL and anti-β2GPI tested in only 1 patient who was aCL positive). The ORs with corresponding 95% CIs for the association between the presence of LAC and neuropsychiatric manifestations at SLE presentation are shown in Table 3.

Table 2. Frequency of positive aPL at presentation of SLE and prevalence of persistently positive aPL anytime during the study period in patients with and without NP manifestations*
 At presentation of SLEPAnytimeP
Patients with NP manifestationsPatients without NP manifestationsPatients with NP manifestationsPatients without NP manifestations
  • *

    Values are the number/total number (percentage) unless otherwise indicated. SLE = systemic lupus erythematosus; see Table 1 for additional definitions.

  • Patients whose sera contained more than 1 subtype of aPL/total number tested.

  • Total number of patients whose sera contained at least 1 aPL subtype/total number tested.

aCL16/21 (76)67/107 (63)0.1717/35 (49)52/102 (51)0.81
Anti-β2GPI8/16 (50)19/50 (38)0.2913/27 (48)19/77 (25)0.02
LAC6/19 (32)16/65 (25)0.827/34 (21)13/91 (14)0.87
≥2 aPL9/21 (43)29/73 (40)0.712/34 (35)27/98 (28)0.39
Total18/23 (78)73/114 (64)0.1419/35 (54)55/102 (54)0.97
Table 3. Association of presence of lupus anticoagulant with neuropsychiatric manifestations at systemic lupus erythematosus presentation and anytime during the study period*
 At presentation OR (95% CI)Anytime OR (95% CI)
  • *

    OR = odds ratio; 95% CI = 95% confidence interval.

Headache1.8 (0.5–6.6)2.7 (0.9–8.0)
Psychosis1.1 (0.2–6.4)1.1 (0.2–5.2)
Cognitive dysfunction0.7 (0.1–6.5)1.2 (0.2–5.9)
Cerebrovascular disease13.6 (1.4–129)2.5 (0.5–13.8)
Seizures1.4 (0.1–16.6)2.5 (0.5–13.8)
Mood disorder1.4 (0.1–16.6)6.4 (0.9–48.3)
Chorea
Transverse myelitis06.1 (0.4–101)

Followup.

During the followup period, new neuropsychiatric involvement occurred in an additional 12 patients for a total of 35 (26%) patients with neuropsychiatric involvement out of 137 (Table 1). The most common new event in these 12 patients was headache, followed by psychosis and cognitive dysfunction; however, unlike what was seen at presentation, cerebrovascular disease was uncommon. Nineteen (54%) of 35 patients had more than 1 manifestation. There was no statistically significant difference in the frequency of individual manifestations at presentation and at followup.

Of the 91 patients who were initially aPL positive, only 65 (71%) remained persistently positive at followup and an additional 9 patients became positive and remained persistently positive, resulting in a total of 74 (54%) patients with persistent aPL positivity out of 137. Among patients who were initially positive and had serial determinations of the aPL subtypes, 61 (73%) of 83 were persistently positive for aCL, 12 (52%) of 23 for anti-β2GPI, and 15 (68%) of 22 for LAC. Overall, a persistently positive aCL was observed in 69 (50%) of 137 patients, anti-β2GPI in 30 (29%) of 104 patients, and LAC in 20 (16%) of 125 patients. Of the 132 children who had serial determinations of more than 1 aPL subtype, 39 (30%) had ≥2 persistently positive aPL. Mean values for aCL and anti-β2GPI antibodies were compared between presentation and at the last followup, and the mean values of both aCL (P < 0.001) and IgG anti-β2GPI (P = 0.01) were significantly lower at the last followup examination. Similar to what was seen at presentation, titers of aCL during followup were positively correlated with SLEDAI scores (R2 = 0.12, P < 0.001), but there was no correlation between titers of anti-β2GPI antibodies and SLEDAI scores.

Similar to our findings at presentation, we did not find a statistically significant difference in the prevalence of aCL and LAC between patients with and without neuropsychiatric involvement; however, the prevalence of anti-β2GPI antibodies was found to be statistically significantly higher in patients with neuropsychiatric disease as compared with those without neuropsychiatric disease (P = 0.02) (Table 2). Comparison of specific neuropsychiatric manifestations and aPL subtypes showed a statistically significant association between a persistently positive LAC and chorea (P = 0.02); however, there were only 2 patients with chorea (both LAC positive as compared with 18 LAC positive of the 135 patients without chorea; 1 of 2 positive for aCL, 1 of 1 positive for anti-β2GPI antibodies) (Figure 1). Two patients with transverse myelitis were both persistently positive for aCL and anti-β2GPI antibodies (1 of 2 positive for LAC), but there was insufficient power to detect an association. Table 3 shows the ORs with corresponding 95% CIs for the association between the presence of LAC and neuropsychiatric manifestations during the followup period.

thumbnail image

Figure 1. Prevalence of persistently positive anticardiolipin antibodies (aCL), anti–β2-glycoprotein I antibodies (anti-β2GPI), and lupus anticoagulant (LAC) in children with neuropsychiatric manifestations (NP) of systemic lupus erythematosus (SLE). Open bars = aCL; hatched bars = anti-β2GPI; solid bars = LAC.

Download figure to PowerPoint

Disease severity in patients with neuropsychiatric disease was assessed by adjusted mean SLEDAI (AMS), SLEDAI at the last followup, and mean annual steroid doses (30). The mean annual steroid dose for each patient was calculated by determining the total prednisone (or equivalent) dose, then dividing by the time period (in years). There was no statistically significant difference between patients with and without aPL in the mean ± SD AMS (5.8 ± 6.4 versus 5.8 ± 9.0; P = 0.94), mean SLEDAI at the last followup (4.9 ± 7.2 versus 4.6 ± 8.6; P = 0.9), or mean annual steroid dose (8.2 ± 4.4 gm versus 13.6 ± 13.7 gm; P = 0.13). Analysis for individual aPL subtypes showed no difference in disease severity scores between patients with or without aCL, anti-β2GPI, or LAC (data not shown).

Irreversible disease damage was assessed by SDI scores at the last followup and time to first documented damage. The overall mean ± SD SDI score at the last followup was 0.7 ± 1.0 for the total neuropsychiatric group, and there was no statistically significant difference between patients with or without aPL (0.6 ± 0.9 versus 0.8 ± 1.2; P = 0.47). Moreover, analysis for individual aPL subtypes showed no difference in mean SDI scores between patients with or without aCL, anti-β2GPI, or LAC (data not shown). Using Kaplan-Meier survival analysis for time to first documented SDI damage, patients without persistently positive aPL tended to have a shorter interval to the first damage than patients with a persistently positive aPL (P = 0.13) (Figure 2).

thumbnail image

Figure 2. Kaplan-Meier survival curve for time to first documented damage, measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, in patients with neuropsychiatric systemic lupus erythematosus with and without persistently positive antiphospholipid antibodies (aPL). Solid line = nonpersistently positive aPL; broken line = persistently positive aPL.

Download figure to PowerPoint

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Neuropsychiatric involvement in pediatric SLE is an important cause of both morbidity and mortality (1–3, 31). Previous studies in adults and children with SLE have suggested that the presence of aPL is an important determinant of morbidity and possibly mortality in patients with neuropsychiatric disease. In this study, we determined that 50% of patients with pediatric SLE were persistently aCL positive, 29% were persistently anti-β2GPI positive, and 16% were persistently LAC positive. The frequencies of these autoantibodies were similar to the frequencies found in smaller, previously published pediatric studies (15, 32). Although 66% of patients were aPL positive at presentation, only 71% of these patients remained positive during the followup. In addition, there was a statistically significant decrease in the mean titer of both aCL and anti-β2GPI from presentation to last followup, and aCL titers, but not anti-β2GPI titers, were associated with SLEDAI scores. Taken together, the findings of higher titers at presentation (generally at a time of maximal disease activity) as compared with last followup and the association between antibody titers and SLEDAI scores suggest that titers of both of these autoantibodies may change with changes in disease activity. These findings expand on the previous reports of a concordance between aCL titers and different clinical or laboratory features of lupus activity in individual patients with pediatric SLE (32–34).

Previous studies in adults have demonstrated that neuropsychiatric disease in SLE is significantly associated with the presence of aCL and LAC (7, 9, 35), whereas a pediatric study examining this issue showed only a weak association of neuropsychiatric involvement with LAC (15). To our knowledge, there is no published study that has evaluated the prevalence of anti-β2GPI in patients with NPSLE. We found that pediatric patients with neuropsychiatric disease had a higher prevalence of anti-β2GPI antibodies compared with those without neuropsychiatric disease, but there was no difference in the prevalence of aCL and LAC between the 2 groups. The increased prevalence of anti-β2GPI antibodies in patients with neuropsychiatric involvement was observed only during followup, not at presentation. Therefore, it is not clear whether the presence of anti-β2GPI antibodies reflected a specific immune response that leads to CNS involvement or whether their presence reflected an epiphenomenon secondary to the CNS vascular endothelial damage seen in patients with NPSLE. It has been previously demonstrated that human brain microvascular endothelial cells express higher amounts of β2GPI than other endothelial cells (36) and β2GPI itself has been identified in brain cells (37). These results suggest that increased β2GPI may be either the target for CNS damage and therefore the disease association or, alternatively, the source of antigen leading to increased anti-β2GPI antibodies in patients with neuropsychiatric disease.

An association between aPL and cerebrovascular disease is well known and has been reported in several pediatric and adult SLE studies (7, 15, 38). One of the major findings of our study was the significant association between the presence of LAC and cerebrovascular disease and chorea. In our study, a positive association between LAC and cerebrovascular disease was found only at presentation, not during the followup, a finding that could be due to the small number of new cerebrovascular events during the study period or a lack of serial followup LAC results in patients with sinus vein thrombosis who received anticoagulation (testing for LAC is not reliable in patients receiving anticoagulation). Our study is the first to demonstrate a significant relationship between aPL and chorea in a large pediatric SLE cohort. This association has not been observed in large adult SLE studies, although individual case reports or case series, in particular pediatric series, have suggested this association (39–42). The pathogenic mechanism underlying chorea cannot be fully explained by the procoagulant effects of aPL, and it seems possible that chorea may be caused by the immune-mediated mechanisms of neurologic impairment associated with aPL (43) or alterations of the cerebral microcirculation due to thrombotic occlusion of capillaries. Alternatively, a local vasculitic process may affect the cerebral microcirculation in combination with noninflammatory vasculopathy. The discrepancy between pediatric and adult studies may be the result of an increased incidence of chorea in pediatric patients compared with adult patients, which may allow for the association to become more clear. Transverse myelitis is an additional nonthrombotic neurologic syndrome that has been linked to aPL in isolated case reports (44), and it is notable that both patients in our cohort who presented with transverse myelitis had positive LAC, but there was not enough power for statistical significance. However, transverse myelitis is rarely seen in either pediatric or adult patients.

It has been suggested that aPL antibodies are an important risk factor for disease damage in patients with both childhood-onset and adult-onset SLE (26, 45). Furthermore, several studies of adults with SLE have found that the presence of antiphospholipid antibody syndrome was an important predictor of irreversible organ damage and death (46, 47). We, however, did not find that the presence of persistently circulating aPL in children with NPSLE was associated with an increase in accumulation of irreversible organ damage or that patients with aPL accumulated damage at a faster rate than patients without aPL. This lack of association between aPL and damage was despite the association between aPL and cerebrovascular disease. The finding of a lack of association between a persistently positive aPL and damage, and in particular CNS damage secondary to thrombosis, may be influenced by the lack of recurrence of thrombosis in this cohort as a result of continual anticoagulation following an initial thrombotic event. In addition, cerebrovascular disease was a rare event after the initial presentation, occurring in only 1 patient during the followup period. It should be noted that the mean followup interval of our cohort was <3 years, therefore the long-term outcome cannot be reliably assessed. This followup time, however, is comparable with the 3.3 years in the previous pediatric study (25), but is shorter than the 7 years in the adult study (45). Of note, the mean SDI damage score was 0.7 for our NPSLE cohort, which was lower than the scores previously reported in pediatric studies (26, 31).

In our study, we did not find an association between the presence of aPL and disease severity as measured by disease activity over time or cumulative steroid dose in pediatric patients with neuropsychiatric disease. None of the previously mentioned studies examined the association of aPL with disease severity and damage in a group of patients with NPSLE. We suggest that the presence of aPL does not influence disease severity or the accumulation of damage in pediatric patients with NPSLE.

A limitation of our study was that not all aPL subtypes were serially available for all patients; another limitation was the changing over time of the assays used to measure LAC. We studied associations of neuropsychiatric manifestations only with IgG aCL, which were measured in a routine clinical laboratory. There is some evidence that IgM aCL may also be pathogenic; therefore, the association of neuropsychiatric manifestations with the presence of aCL in our study may be underestimated. Tests for the presence of anti-β2GPI antibodies were not performed as part of routine clinical care and anti-β2GPI antibodies were subsequently tested in stored frozen sera as available. Despite the large inception cohort and the prospective clinical data collection, there were still too few patients with some of the rare neuropsychiatric manifestations of pediatric SLE to enable us to confirm statistical association with aPL subtypes. Last, our study was not designed to address the impact of treatment regimens, other than corticosteroids, on long-term outcome in patients with NPSLE with positive aPL as all patients with a thrombotic event continued anticoagulation for the study period and many patients received more than 1 immunosuppressive agent.

In conclusion, we found a persistently positive aCL in 50%, anti-β2GPI in 29%, and LAC in 16% of children with SLE, and we demonstrated that there was a positive correlation of aCL titer with disease activity scores (SLEDAI and AMS). The prevalence of anti-β2GPI antibodies, but not aCL and LAC, was found to be significantly higher in the group of patients with pediatric SLE with neuropsychiatric disease as compared with those without. Our data suggest an association between positive LAC and cerebrovascular disease at the time of SLE diagnosis and between persistently positive LAC and chorea over the disease course, but not between aCL, anti-β2GPI, or LAC and other neuropsychiatric manifestations. We did not find that the presence of persistently positive aPL in children with NPSLE was associated with a more severe disease course or with increased irreversible organ damage.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Dr. Silverman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Avčin, Benseler, Silverman.

Acquisition of data. Avčin, Benseler, Tyrrell, Silverman.

Analysis and interpretation of data. Avčin, Benseler, Tyrrell, Čučnik, Silverman.

Manuscript preparation. Avčin, Silverman.

Statistical analysis. Avčin, Benseler, Tyrrell, Silverman.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  • 1
    Parikh S, Swaiman KF, Kim Y. Neurologic characteristics of childhood lupus erythematosus. Pediatr Neurol 1995; 13: 198201.
  • 2
    Quintero-Del-Rio AI, Van Miller. Neurologic symptoms in children with systemic lupus erythematosus. J Child Neurol 2000; 15: 8037.
  • 3
    Sibbitt WL Jr, Brandt JR, Johnson CR, Maldonado ME, Patel SR, Ford CC, et al. The incidence and prevalence of neuropsychiatric syndromes in pediatric onset systemic lupus erythematosus. J Rheumatol 2002; 29: 153642.
  • 4
    Press J, Palayew K, Laxer RM, Elkon K, Eddy A, Rakoff D, et al. Antiribosomal P antibodies in pediatric patients with systemic lupus erythematosus and psychosis. Arthritis Rheum 1996; 39: 6716.
  • 5
    Isshi K, Hirohata S. Differential roles of the anti–ribosomal P antibody and antineuronal antibody in the pathogenesis of central nervous system involvement in systemic lupus erythematosus. Arthritis Rheum 1998; 41: 181927.
  • 6
    Greenwood DL, Gitlits VM, Alderuccio F, Sentry JW, Toh BH. Autoantibodies in neuropsychiatric lupus. Autoimmunity 2002; 35: 7986.
  • 7
    Sanna G, Bertolaccini ML, Cuadrado MJ, Laing H, Khamashta MA, Mathieu A, et al. Neuropsychiatric manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies. J Rheumatol 2003; 30: 98592.
  • 8
    Conti F, Alessandri C, Bompane D, Bombardieri M, Spinelli FR, Rusconi AC, et al. Autoantibody profile in systemic lupus erythematosus with psychiatric manifestations: a role for anti-endothelial-cell antibodies. Arthritis Res Ther 2004; 6: R36672.
  • 9
    Toubi E, Khamashta M, Panarra A, Hughes GR. Association of antiphospholipid antibodies with central nervous system disease in systemic lupus erythematosus. Am J Med 1995; 99: 397401.
  • 10
    Ziporen L, Shoenfeld Y, Levy Y, Korczyn AD. Neurological dysfunction and hyperactive behavior associated with antiphospholipid antibodies: a mouse model. J Clin Invest 1997; 100: 6139.
  • 11
    Chapman J, Cohen-Armon M, Shoenfeld Y, Korczyn AD. Antiphospholipid antibodies permeabilize and depolarize brain synaptoneurosomes. Lupus 1999; 8: 12733.
  • 12
    Steens SC, Bosma GP, Steup-Beekman GM, le Cessie S, Huizinga TW, van Buchem MA. Association between microscopic brain damage as indicated by magnetization transfer imaging and anticardiolipin antibodies in neuropsychiatric lupus. Arthritis Res Ther 2006; 8: R38.
  • 13
    Levy DM, Massicotte MP, Harvey E, Hebert D, Silverman ED. Thromboembolism in pediatric lupus patients. Lupus 2003; 12: 7416.
  • 14
    Male C, Foulon D, Hoogendoorn H, Vegh P, Silverman E, David M, et al. Predictive value of persistent versus transient antiphospholipid antibody subtypes for the risk of thrombotic events in pediatric patients with systemic lupus erythematosus. Blood 2005; 106: 41528.
  • 15
    Harel L, Sandborg C, Lee T, von Scheven E. Neuropsychiatric manifestations in pediatric systemic lupus erythematosus and association with antiphospholipid antibodies. J Rheumatol 2006; 33: 18737.
  • 16
    Angelini L, Zibordi F, Zorzi G, Nardocci N, Caporali R, Ravelli A, et al. Neurological disorders, other than stroke, associated with antiphospholipid antibodies in childhood. Neuropediatrics 1996; 27: 14953.
  • 17
    Besbas N, Damarguc I, Ozen S, Aysun S, Saatci U. Association of antiphospholipid antibodies with systemic lupus erythematosus in a child presenting with chorea: a case report. Eur J Pediatr 1994; 153: 8913.
  • 18
    Eriksson K, Peltola J, Keranen T, Haapala AM, Koivikko M. High prevalence of antiphospholipid antibodies in children with epilepsy: a controlled study of 50 cases. Epilepsy Res 2001; 46: 12937.
  • 19
    Cimaz R, Romeo A, Scarano A, Avcin T, Viri M, Veggiotti P, et al. Prevalence of anti-cardiolipin, anti-beta2 glycoprotein I, and anti-prothrombin antibodies in young patients with epilepsy. Epilepsia 2002; 43: 529.
  • 20
    Cimaz R, Meroni PL, Shoenfeld Y. Epilepsy as part of systemic lupus erythematosus and systemic antiphospholipid syndrome. Lupus 2006; 15: 1917.
  • 21
    Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 12717.
  • 22
    ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999; 42: 599608.
  • 23
    Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH, and the Committee on Prognosis Studies in SLE. Derivation of the SLEDAI: a disease activity index for lupus patients. Arthritis Rheum 1992; 35: 63040.
  • 24
    Brunner HI, Feldman BM, Bombardier C, Silverman ED. Sensitivity of the Systemic Lupus Erythematosus Disease Activity Index, British Isles Lupus Assessment Group Index, and Systemic Lupus Activity Measure in the evaluation of clinical change in childhood-onset systemic lupus erythematosus. Arthritis Rheum 1999; 42: 135460.
  • 25
    Gladman D, Ginzler E, Goldsmith C, Fortin P, Liang M, Urowitz M, et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum 1996; 39: 3639.
  • 26
    Brunner HI, Silverman ED, To T, Bombardier C, Feldman BM. Risk factors for damage in childhood-onset systemic lupus erythematosus: cumulative disease activity and medication use predict disease damage. Arthritis Rheum 2002; 46: 43644.
  • 27
    Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295306.
  • 28
    Brandt JT, Triplett DA, Alving B, Scharrer I, on behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Criteria for the diagnosis of lupus anticoagulants: an update. Thromb Haemost 1995; 74: 118590.
  • 29
    Avcin T, Ambrozic A, Kuhar M, Kveder T, Rozman B. Anticardiolipin and anti-beta(2) glycoprotein I antibodies in sera of 61 apparently healthy children at regular preventive visits. Rheumatology (Oxford) 2001; 40: 56573.
  • 30
    Ibanez D, Urowitz MB, Gladman DD. Summarizing disease features over time. I. Adjusted mean SLEDAI derivation and application to an index of disease activity in lupus. J Rheumatol 2003; 30: 197782.
  • 31
    Ravelli A, Duarte-Salazar C, Buratti S, Reiff A, Bernstein B, Maldonado-Velazquez MR, et al. Assessment of damage in juvenile-onset systemic lupus erythematosus: a multicenter cohort study. Arthritis Rheum 2003; 49: 5017.
  • 32
    Seaman DE, Londino V, Kwoh CK, Medsger TA, Manzi S. Antiphospholipid antibodies in pediatric systemic lupus erythematosus. Pediatrics 1995; 96: 10405.
  • 33
    Shergy WJ, Kredich DW, Pisetsky DS. The relationship of anticardiolipin antibodies to disease manifestations in pediatric systemic lupus erythematosus. J Rheumatol 1988; 15: 138994.
  • 34
    Ravelli A, Caporali R, Di Fuccia G, Zonta L, Montecucco C, Martini A. Anticardiolipin antibodies in pediatric systemic lupus erythematosus. Arch Pediatr Adolesc Med 1994; 148: 398402.
  • 35
    Mok CC, Lau CS, Wong RW. Neuropsychiatric manifestations and their clinical associations in southern Chinese patients with systemic lupus erythematosus. J Rheumatol 2001; 28: 76671.
  • 36
    Meroni PL, Tincani A, Sepp N, Raschi E, Testoni C, Corsini E, et al. Endothelium and the brain in CNS lupus. Lupus 2003; 12: 91928.
  • 37
    Caronti B, Pittoni V, Palladini G, Valesini G. Anti-beta 2-glycoprotein I antibodies bind to central nervous system. J Neurol Sci 1998; 156: 2119.
  • 38
    Nojima J, Kuratsune H, Suehisa E, Kitani T, Iwatani Y, Kanakura Y. Strong correlation between the prevalence of cerebral infarction and the presence of anti-cardiolipin/beta2-glycoprotein I and anti-phosphatidylserine/prothrombin antibodies: co-existence of these antibodies enhances ADP-induced platelet activation in vitro. Thromb Haemost 2004; 91: 96776.
  • 39
    Khamashta MA, Gil A, Anciones B, Lavilla P, Valencia ME, Pintado V, et al. Chorea in systemic lupus erythematosus: association with antiphospholipid antibodies. Ann Rheum Dis 1988; 47: 6813.
  • 40
    Cervera R, Asherson RA, Font J, Tikly M, Pallares L, Chamorro A, et al. Chorea in the antiphospholipid syndrome: clinical, radiologic and immunologic characteristics of 50 patients from our clinics and the recent literature. Medicine (Baltimore) 1997; 76: 20312.
  • 41
    Kiechl-Kohlendorfer U, Ellemunter H, Kiechl S. Chorea as the presenting clinical feature of primary antiphospholipid syndrome in childhood. Neuropediatrics 1999; 30: 968.
  • 42
    Watanabe T, Onda H. Hemichorea with antiphospholipid antibodies in a patient with lupus nephritis. Pediatr Nephrol 2004; 19: 4513.
  • 43
    Chapman J, Rand JH, Brey RL, Levine SR, Blatt I, Khamashta MA, et al. Non-stroke neurological syndromes associated with antiphospholipid antibodies: evaluation of clinical and experimental studies. Lupus 2003; 12: 5147.
  • 44
    D'Cruz DP, Mellor-Pita S, Joven B, Sanna G, Allanson J, Taylor J, et al. Transverse myelitis as the first manifestation of systemic lupus erythematosus or lupus-like disease: good functional outcome and relevance of antiphospholipid antibodies. J Rheumatol 2004; 31: 2805.
  • 45
    Mikdashi J, Handwerger B. Predictors of neuropsychiatric damage in systemic lupus erythematosus: data from the Maryland lupus cohort. Rheumatology (Oxford) 2004; 43: 155560.
  • 46
    Drenkard C, Villa AR, Alarcon-Segovia D, Perez-Vazquez ME. Influence of the antiphospholipid syndrome in the survival of patients with systemic lupus erythematosus. J Rheumatol 1994; 21: 106772.
  • 47
    Ruiz-Irastorza G, Egurbide MV, Ugalde J, Aguirre C. High impact of antiphospholipid syndrome on irreversible organ damage and survival of patients with systemic lupus erythematosus. Arch Intern Med 2004; 164: 7782.