Abstract
Objective:
Although systemic lupus erythematosus (SLE) is the most common autoimmune disease associated with antiphospholipid antibodies (aPL), limited data exist on the impact of SLE on the clinical phenotype of aPL-positive patients. The primary objective was to compare the clinical, laboratory, and treatment characteristics of aPL-positive patients with or without SLE.
Methods:
A secure web-based data capture system stores patient demographics, and aPL-related clinical and laboratory characteristics. Inclusion criteria include aPL positivity according to the Updated Sapporo Classification Criteria. Patients fulfilling the SLE Classification Criteria and those with no other autoimmune diseases were included in the analysis.
Results:
672 aPL-positive patients were recruited from 24 international centers; 426 were without other autoimmune diseases and 197 with SLE. The aPL with SLE group had higher rates of thrombocytopenia, hemolytic anemia, low complements, and IgA anti-β2 glycoprotein-I antibodies (aβ₂GPI), whereas the aPL only group had higher rates of cognitive dysfunction and IgG aβ₂GPI. The frequency of arterial and venous thromboses (including recurrent) as well as the pregnancy morbidity were similar between the groups. The prevalence of cardiovascular disease risk factors at the registry entry did not differ between the two groups, except current smoking, which was more frequent in aPL with SLE group.
Conclusions:
Although the frequencies of thrombosis and pregnancy morbidity are similar between aPL-positive patients with or without SLE, the diagnosis of SLE in persistently aPL-positive patients is associated with an increased frequency of thrombocytopenia, hemolytic anemia, low complements, and IgA aβ₂GPI positivity.
Keywords: Antiphospholipid Syndrome, Systemic Lupus Erythematosus, APS ACTION, Cardiovascular Disease - Hydroxychloroquine
Introduction:
Antiphospholipid syndrome (APS) is characterized by thromboses and/or pregnancy morbidity associated with persistently positive antiphospholipid antibodies (aPL) (lupus anticoagulant [LA] test, anticardiolipin antibodies [aCL], and/or anti-β2 glycoprotein-I antibodies [aβ2GPI]) (1). Thrombocytopenia, autoimmune hemolytic anemia, livedo, aPL-associated nephropathy, cardiac valve disease, cognitive dysfunction, and skin ulcers can also occur in aPL-positive patients (1, 2), characterized as non-criteria APS manifestations.
Antiphospholipid syndrome can occur in individuals without an underlying systemic autoimmune disease (primary APS) or in the context of other systemic autoimmune diseases, with systemic lupus erythematosus (SLE) being the most common (30–50%) (3). Variable clinical features ranging from mild joint and skin involvement to life-threatening renal, hematologic, and/or central nervous system manifestations can occur in SLE. (4). Thirty-to-forty percent of SLE patients are positive for aPL (5); the prevalence of a “clinically significant” aPL profile (positive LA test based on the guidelines of International Society of Thrombosis and Haemostasis [ISTH] (6), aCL IgG/IgM greater than or equal to 40 GPL/MPL, and/or aβ2GPI IgG/IgM greater than or equal to 40 GPL/MPL, tested twice at least 12 weeks apart) is approximately 30% (7). Although aPL-positivity has an impact on the clinical presentation and prognosis of SLE patients (5), there are limited number of studies analyzing the impact of SLE on the clinical phenotype and prognosis of aPL-positive patients (8).
Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) is an international network created to design and conduct large-scale, multicenter studies and clinical trials in persistently aPL-positive patients (9). The APS ACTION clinical database and repository (“registry”) was created to study the natural course of persistently aPL-positive patients with or without autoimmune disorders over at least 10 years; the registry allows us to perform cross-sectional and prospective analyses.
In this international multicenter study, our primary objective was to compare the clinical, laboratory, and treatment characteristic of aPL-positive patients with and without SLE. Secondly, we analyzed: a) the frequencies of traditional CVD risk factors in aPL-positive patients with and without SLE; and b) the pattern of hydroxychloroquine (HCQ) use, an immunoregulatory agent with anti-thrombotic effects, among aPL-positive patients with no other autoimmune diseases. We hypothesized that aPL-positive patients with SLE have increased rates of aPL-related clinical manifestations, traditional cardiovascular disease (CVD) risk factors, lupus-related antibodies, and immunosuppressive use (including HCQ), compared to those without SLE.
Methods:
APS ACTION Registry and Data Collection:
An international web-based application, the REDCap (Research Electronic Data Capture) (10), captures data on patient demographics, aPL-related clinical and laboratory characteristics, and medications. Data are collected once a year and at the time of a new aPL-related thrombosis or pregnancy morbidity. The inclusion criteria are: a) age between 18 and 60 years; and b) persistent (at least 12 weeks apart) aPL-positivity within 12 months prior to screening; positivity is defined as aCL IgG/M/A (≥ 40 GPL/MPL/APL, medium-to-high titer, and/or greater than the 99th percentile), and/or aβ2GPI IgG/M/A (≥ 40 GPL/MPL/APL, medium-to-high titer, and/or greater than the 99th percentile), and/or positive LA test based on ISTH guidelines (6). Patients are followed every 12 ± 3 months with clinical data and blood collection; they also receive advice on CVD and thrombosis prevention at each visit.
Study Cohort:
Although APS ACTION registry captures data from patients with a variety of autoimmune diseases, for the purpose of this analysis, patients with autoimmune diseases other than SLE were excluded. Thus, two mutually exclusive groups were included: a) aPL-positive patients with no other systemic autoimmune diseases (“aPL-only”); and b) aPL-positive patients who also met the American College of Rheumatology (ACR) SLE Classification Criteria (“aPL with SLE’’) (11).
Covariates:
We evaluated demographic characteristics at time of cohort entry, including mean age, race (White, Latin American Mestizos, Asian, Black, American Indian or Alaskan, Native American, “Other”), ethnicity (Non-Latin American or Latin American [for United States, Canada, Europe], Afro-descendent, Mestizo, or Caucasian [for South America], Aboriginal or Non-Aboriginal [for Australia], or “Other”). Clinical data retrieved were history of arterial and venous thrombosis, biopsy proven microthrombosis (pulmonary, skin, kidney, and “other”), pregnancy morbidity based on the Updated Sapporo Classification Criteria, catastrophic APS based on the preliminary classification criteria (12), livedo reticularis/racemosa, persistent thrombocytopenia defined as platelets<100,000 tested twice at least 12 weeks apart, autoimmune hemolytic anemia, echocardiography proven cardiac valve disease, biopsy proven aPL-nephropathy, skin ulcers, and neuro-psychiatric test proven cognitive dysfunction. Laboratory data retrieved at baseline were aPL-related (LA, aCL IgG/IgM/IgA, and aβ2GPI IgG/IgM/IgA) and lupus-related [antinuclear antibody [ANA], anti-double-strand-DNA antibody [dsDNA], anti-smith antibody [anti-Sm], and complement component 3 [C3] and 4 [C4]). Cardiovascular risk factors assessed at the time of registry entry were hypertension, diabetes, and hyperlipidemia requiring treatment, current and past smoking, estrogen use, obesity, family history of CVD, and sedentary lifestyle. Medications (low-dose aspirin, warfarin, direct oral anticoagulants, corticosteroids, HCQ, intravenous immunoglobulin, rituximab, azathioprine, cyclophosphamide, cyclosporine, methotrexate, and mycophenolate mofetil) were included in the analysis as “ever” or “never” used.
Statistical Analysis:
Data from APS ACTION registry were locked in February 2017. We compared the prevalence of covariates (historical or baseline) in “aPL-only” and “aPL with SLE” patients using chi-square test for categorical variables. One-way ANOVA test was used to test the differences in means between multiple independent groups, and a Student’s t test was used for two group comparisons. The statistical software used was SPSS 24.0 (IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp). We calculated two-sided p-values to determine the significance of all findings, with a significance level set at p<0.05.
Results:
As of February 2017, 672 aPL-positive patients were recruited from 24 centers; 43 (6%) patients were excluded due to underlying autoimmune diseases other than SLE and 6 (1%) due to missing data. Of the remaining 623 patients, 426 were without other autoimmune diseases (“aPL only”) and 197 with SLE (“aPL with SLE”). Fifty-nine patients of the “aPL only” group had SLE-like disease (3 of 11 ACR SLE Classification Criteria met) (11).
Table 1 demonstrates the clinical, laboratory, and treatment characteristics collected at registry entry. The mean age (± SD) at entry was 44.2 ± 12.8 years with the majority of patients being categorized as white (74%). Three hundred and thirty-eight of 426 (79%) of “aPL only” group, and 137/426 (70%) of “aPL with SLE” group were classified as APS based on the Updated Sapporo Classification Criteria (1). Overall 422 of 623 (68%) patients had history of thrombotic APS and 57 (9%) had obstetric APS only. The mean disease duration (± SD) (time from the first available positive aPL test result to the enrollment date) was similar; 5.6 ± 4.9 years in the “aPL only” group and 6.3 ± 5.1 years in the “aPL with SLE “group (p = 0.1).
Table 1:
Clinical and Laboratory Characteristics (historically and/or at registry entry) of Persistently Antiphospholipid Antibody (aPL)-positive Patients (overall and stratified by systemic lupus erythematosus [SLE])
| Variables n(%) unless listed differently |
All aPL-positive Patients (n=623) | “aPL Only” Patients (n=426) | “aPL with SLE” Patients (n=197) | p |
|---|---|---|---|---|
| Demographics | ||||
| Age at Registry Entry (mean ± SD) | 44.2 ± 12.8 | 44.58 ± 12.9 | 43.24 ± 12.5 | 0.22 |
| Female | 459 (74%) | 307 (72%) | 152 (77%) | 0.18 |
| Race1 | ||||
| White | 397 (71%) | 274 (71%) | 123 (71%) | |
| Latin American Mestizos | 81 (15%) | 66 (17%) | 15 (9%) | |
| Asian | 48 (9%) | 28 (7%) | 20 (12%) | |
| Black | 21(4%) | 10 (3%) | 11 (6%) | |
| American Indian or Alaskan | 1 (0.2%) | 0 | 1 (0.6%) | |
| Native American | 0 | 0 | 0 | |
| Reported as “Other” | 12 (2%) | 9 (2%) | 3 (2%) | |
| Ethnicity2 | ||||
| United States, Canada, Europe | 261 (51%) | 183 (50%) | 78 (55%) | |
| Non-Latin American | 242 (48%) | 168 (46%) | 74 (48%) | |
| Latin American | 19 (4%) | 15 (4%) | 4 (3%) | |
| South America | 124 (24%) | 96 (26%) | 28 (20%) | |
| Afro-descendent | 16 (3%) | 8 (2%) | 8 (6%) | |
| Mestizo | 67 (13%) | 54 (15%) | 13 (9%) | |
| Caucasian | 41 (8%) | 34 (9%) | 7 (5%) | |
| Australia | 3 (0.6%) | 2 (0.5%) | 1 (0.7%) | |
| Aboriginal | 0 | 0 | 0 | |
| Not Aboriginal | 3 (0.6%) | 2 (0.5%) | 1 (0.7%) | |
| Other | 121 (24%) | 85 (23%) | 36 (24%) | |
| Clinical Manifestations | ||||
| Arterial Thrombosis (AT) | 193 (31%) | 139 (33%) | 54 (27%) | 0.26 |
| Venous Thrombosis (VT) | 272 (44%) | 185 (43%) | 87 (44%) | 0.13 |
| Microthrombosis (MT) | 37 (6%) | 27 (6%) | 10 (5%) | 0.23 |
| Any Vascular Event (AT/VT/MT) | 422 (68%) | 297 (70%) | 125 (64%) | 0.12 |
| Recurrent Vascular Event | 198/422 (47%) | 163/297 (55%) | 61/125 (49%) | 0.25 |
| Pregnancy History (ever) | 318 (51%) | 221(52%) | 97 (49%) | 0.06 |
| Pregnancy Morbidity | 210 (34%) | 154 (36%) | 56 (28%) | 0.1 |
| • ≥1 Fetal Death ≥ 10th Week of Gestation | 110 (18%) | 76 (18%) | 34 (17%) | 0.15 |
| • ≥1 Premature Birth < 34th Week of Gestation | 54 (9%) | 43 (10%) | 11 (6%) | 0.09 |
| • ≥3 Consecutive Unexplained Spontaneous Abortions < 10th Week of Gestation | 23 (4%) | 19 (5%) | 4 (2%) | 0.1 |
| Catastrophic APS | 6 (1%) | 4 (1%) | 2 (1%) | 0.24 |
| Livedo Reticularis/Racemosa | 80 (13%) | 52 (12%) | 28 (14%) | 0.48 |
| Persistent Thrombocytopenia | 124 (20%) | 69 (16%) | 55 (28%) | 0.001 |
| Autoimmune Hemolytic Anemia | 32 (5%) | 9 (2%) | 23 (12%) | <0.001 |
| Echocardiography Proven Cardiac Valve Disease | 50/518 (10%) | 30/349 (9%) | 20/169 (12%) | 0.31 |
| Biopsy Proven aPL-associated Nephropathy | 19/577 (3%) | 11/397 (3%) | 8/180 (4%) | 0.30 |
| Skin Ulcers | 32 (5%) | 21 (5%) | 11 (6%) | 0.12 |
| Cognitive Dysfunction | 19/148 (13%) | 14/90 (16%) | 5/58 (9%) | <0.001 |
| Complement Levels | ||||
| Low Complement C3 | 93/240 (39%) | 29/126 (23%) | 64/114 (56%) | <0.001 |
| Low Complement C4 | 92/240 (38%) | 30/126 (24%) | 62/114 (54%) | <0.001 |
| Antiphospholipid Antibodies | ||||
| Lupus Anticoagulant (LA) | 417 (67%) | 288 (68%) | 129 (66%) | 0.6 |
| Anticardiolipin Antibodies (aCL) | ||||
| IgG (cut-off 20 GPL)* | 357 (57%) | 245 (58%) | 112 (57%) | 0.87 |
| IgG (cut-off 40 GPL)** | 280 (45%) | 202 (47%) | 78 (40%) | 0.07 |
| IgM (cut-off 20 MPL)* | 223 (36%) | 154 (36%) | 69 (35%) | 0.79 |
| IgM (cut-off 40 MPL)** | 139 (22%) | 96 (23%) | 43 (22%) | 0.84 |
| IgA (cut-off 20 APL)* | 41/149 (28%) | 24/89 (27%) | 17/60 (28%) | 0.85 |
| IgA (cut-off 40 APL)** | 26/149 (17%) | 15/89 (17%) | 11/60 (18%) | 0.81 |
| Anti-β₂GPI Antibodies (aβ₂GPI) | ||||
| IgG (cut-off 20 GPL)* | 265 (43%) | 194 (46%) | 71 (36%) | 0.03 |
| IgG (cut-off 40 GPL)** | 208 (33%) | 157 (37%) | 51 (26%) | 0.01 |
| IgM (cut-off 20 GPL)* | 173 (28%) | 124 (29%) | 49 (25%) | 0.27 |
| IgM (cut-off 40 GPL)** | 114 (18%) | 81 (19%) | 33 (17%) | 0.5 |
| IgA (cut-off 20 GPL)* | 58/160 (36%) | 30/104 (29%) | 28/56 (50%) | 0.02 |
| IgA (cut-off 40 GPL)** | 37/160 (23%) | 19/104 (18%) | 18/56 (32%) | 0.04 |
| Double aPL-Positivity (LA + aCL, LA + aβ₂GPI, or aCL + aβ₂GPI) | 187 (30%) | 121 (28%) | 66 (34%) | 0.1 |
| Triple aPL Positivity (LA + aCL + aβ₂GPI) | 209 (34%) | 158 (37%) | 51 (26%) | 0.1 |
| Medications*** | ||||
| Low-dose Aspirin | 273 (44%) | 183 (43%) | 90 (44%) | 0.52 |
| Warfarin | 344 (55%) | 245 (58%) | 99 (50%) | 0.09 |
| Direct Oral Anticoagulants | 15 (2%) | 10 (2%) | 5 (3%) | 0.89 |
| Corticosteroids | 111 (18%) | 39 (9%) | 72 (37%) | <0.001 |
| Hydroxychloroquine | 276 (44%) | 133 (31%) | 143 (72%) | <0.001 |
| Immunosuppressive Agents | ||||
| Intravenous Immunoglobulin | 2 (0.3%) | 1 (0.2%) | 1 (1%) | 0.58 |
| Rituximab | 7 (1%) | 3 (1%) | 4 (2%) | 0.14 |
| Azathioprine | 46 (7%) | 11 (3%) | 35 (18%) | <0.001 |
| Cyclophosphamide | 8 (1%) | 2 (1%) | 6 (3%) | 0.008 |
| Cyclosporine | 4 (1%) | 2 (1%) | 2 (1%) | 0.43 |
| Methotrexate | 17 (3%) | 4 (1%) | 13 (7%) | <0.001 |
| Mycophenolate Mofetil | 45 (7%) | 11 (3%) | 34 (17%) | <0.001 |
more than low titer
more than moderate titer
at the time of registry entry.
Races were allowed to be collected in a total of 560 patients (387 in “aPL only” group and 173 in “aPL with SLE” group).
Ethnicities were allowed to be collected in a total of 509 patients (366 in “aPL only” group, 143 in “aPL with SLE” group).
Antiphospholipid antibody-positive patients with SLE had higher rates of persistent thrombocytopenia, autoimmune hemolytic anemia, low complement component 3 (C3) and 4 (C4), and IgA aβ₂GPI positivity, whereas the “aPL only” group had significantly higher rates of cognitive dysfunction and IgG aβ₂GPI positivity. Corticosteroids, HCQ, azathioprine, cyclophosphamide, methotrexate, and mycophenolate mofetil were more frequently used in the “aPL with SLE” group.
The prevalence of traditional CVD risk factors at the time of the registry entry did not differ between two groups, except current smoking, which was more frequent in SLE patients (9% vs 15%, p = 0.03) (Table 2). In the “aPL only” group, 262 (62%) patients were never treated with HCQ, 133 (31%) were current users (200–400mg daily), and 31 (7%) were past users; 74% (99/133) of current users and 84% (26/31) of past users were classified as APS. Patients with lupus-related clinical manifestations, low complement C4, and lupus-related autoantibodies were more likely to be treated with HCQ (Table 3). After excluding patients with SLE-like disease (3 of 11 ACR SLE Classification Criteria met) (n: 59), when we analyzed 367 patients in the “aPL only” group, we found a higher frequency of HCQ treatment in patients with low complement C4 and lupus-related autoantibodies.
Table 2:
Prevalence of Cardiovascular Disease (CVD) and Thrombosis Risk Factors (upon registry entry) Among Persistently Antiphospholipid Antibody (aPL)-positive Patients, Stratified by Systemic Lupus Erythematosus (SLE)
| Variables n (%) | aPL only (n=426) | aPL with SLE (n=197) | p |
|---|---|---|---|
| Hypertension | 118 (28%) | 66 (34%) | 0.14 |
| Diabetes | 22 (5%) | 8 (4%) | 0.55 |
| Hyperlipidemia | 103 (24%) | 36 (18%) | 0.1 |
| Smoking ever | 116 (27%) | 49 (25%) | 0.65 |
| Current Smoking | 40 (9%) | 30 (15%) | 0.03 |
| Estrogen Use | 3 (1%) | 3 (2%) | 0.54 |
| Obesity | 107 (25%) | 59 (30%) | 0.37 |
| Family History of CVD | 67 (16%) | 21 (11%) | 0.18 |
| Sedentary Lifestyle | 197 (46%) | 94 (48%) | 0.73 |
Table 3:
Analysis of 426 Antiphospholipid Antibody (aPL)-positive Patients Without Other Systemic Autoimmune Diseases, Stratified by Hydroxychloroquine (HCQ) Use
| Variables, n (%) | HCQ Users (n:164) | HCQ Non-users (n:262) | p |
|---|---|---|---|
| Clinical Profile | |||
| Thrombotic APS | 89 (54%) | 148 (57%) | 0.65 |
| • Arterial Thrombosis | 52 (32%) | 87 (33%) | 0.84 |
| • Venous Thrombosis | 75 (46%) | 110 (42%) | 0.3 |
| • Mictothrombosis | 11 (7%) | 16 (6%) | 0.74 |
| Obstetric APS | 16 (10%) | 28 (11%) | 0.76 |
| Thrombotic and Obstetric APS | 21 (13%) | 37 (14%) | 0.70 |
| 3 out of 11 ACR SLE criteria | 42 (26%) | 17 (7%) | <0.001 |
| Laboratory Profile | |||
| Persistent Triple aPL-positive | 60 (37%) | 98 (37%) | 0.87 |
| Persistent Double aPL-positive | 54 (33%) | 67 (26%) | 0.1 |
| Persistent Single aPL-positive | 50 (30%) | 97 (27%) | 0.16 |
| ANA Positive* | 102 (62%) | 86 (33%) | <0.001 |
| Anti-dsDNA Positive* | 30 (18%) | 10 (4%) | <0.001 |
| Anti-Sm Positive* | 5 (3%) | 0 (0%) | 0.008 |
| Low Complement C3** | 17/66 (26%) | 12/60 (20%) | 0.44 |
| Low Complement C4** | 20/66 (30%) | 10/60 (17%) | 0.02 |
Patients were considered positive for ANA, anti-dsDNA, or anti-Sm antibodies if they were ever tested positive for these antibodies.
“Low complement C3/C4” was determined based on: a) the levels below normal; and b) the most recent C3/4 tests before the registry entry.
Discussion:
Based on the analysis of a large scale international registry of persistently aPL-positive patients, our study demonstrates that the frequencies of thrombosis (including recurrent) and pregnancy morbidity are similar between aPL-positive patients with or without SLE. However, concomitant SLE diagnosis in persistently aPL-positive patients is associated with an increased frequency of thrombocytopenia, hemolytic anemia, low complement levels, and IgA aβ₂GPI positivity compared to aPL-positive patients without other autoimmune diseases. Additionally, aPL-positive patients with SLE had significantly higher frequency of current smoking, while aPL-positive patients without other autoimmune disease had an increased prevalence of cognitive dysfunction. Although HCQ use was more common in “aPL with SLE” group, 40% of “aPL only group” also received HCQ, especially those with lupus-related clinical and serologic manifestations.
Although the impact of aPL on SLE is well studied (5, 7), limited data exist regarding the impact of SLE on the clinical phenotype of persistently aPL-positive patients. In a European multicenter cohort of 1,000 mainly Caucasian patients with APS, patients with concomitant SLE had higher prevalence of livedo reticularis, thrombocytopenia, arthritis, and leukopenia (13). Our multiethnic study also showed an increased frequency of thrombocytopenia and autoimmune hemolytic anemia in aPL-positive patients with SLE compared to those without, but except for cognitive dysfunction, similar frequencies of the criteria or other non-criteria aPL manifestations, namely livedo reticularis, cardiac valve disease, and aPL-associated nephropathy. Given that our SLE patients were classified based on the ACR SLE Classification Criteria (11), which incorporates thrombocytopenia and autoimmune hemolytic anemia, the increased frequency of these hematological abnormalities in aPL-positive patients with SLE was not unexpected.
Cognitive dysfunction is common in APS and SLE, frequently associated with livedo reticularis and white matter lesions on brain magnetic resonance imaging in APS patients. Tektonidou et al. found no difference in cognitive performance assessed by a three-hour battery of neurocognitive tests among patients with primary APS and those with SLE/APS (14). Kozora et al. demonstrated that 12 of 20 (60%) of the SLE and 8/20 (40%) of the aPL-positive non-SLE patients had global cognitive impairment on ACR-SLE cognitive impairment index (CII), a validated neuropsychological instrument; there were no group differences on CII or on individual measures (15). Our study included persistently aPL-positive patients with and without APS classification (1), and still found that neuro-psychiatric test-proven cognitive dysfunction was more common in aPL-positive patients without SLE. These findings further support the importance of cognitive dysfunction research and clinical assessment in aPL-positive patients without other systemic autoimmune diseases.
The Updated Sapporo APS Classification Criteria do not include IgA aCL and aβ2GPI. Although IgA isotype is common in African American SLE patients (16) and now it is included in the new Systemic Lupus Collaborating Clinics (SLICC) SLE Classification Criteria (17), the prevalence and clinical significance have been controversial (18). We found that although aPL types and isotypes as well as the double or triple aPL-positivity were generally comparable between two groups, aPL-positive patients with SLE had more frequently IgA aβ2GPI, while IgG aβ2GPI was more frequent in those without SLE. Although it remains unknown why patients develop different isotypes of aPL, our findings support previous studies (19) demonstrating a potential diagnostic and clinical significance of IgA isotype in lupus patients, compared to those without lupus.
Traditional CVD risk factors, including diabetes and smoking, increase the risk of thrombosis in aPL-positive patients (20). Systemic lupus erythematosus itself is an independent risk factor for CVD, which still remains the major cause of mortality in SLE patients (21). It is not well studied whether CVD risk factors differ among aPL positive patients with or without SLE; our study demonstrates that the prevalence of CVD risk factors was similar between aPL-positive patients with or without SLE except current smoking. In addition, although the role of smoking in the development of aPL, APS, and/or SLE is not well-established (22), smoking is associated with worse outcomes and venous thrombosis in SLE as well as the development of SLE subtypes, defined by autoantibody status (23). All these findings support the importance of similar diligence in CVD risk assessment and management measures in both aPL-positive with or without SLE.
In our analysis, corticosteroids, HCQ, azathioprine, cyclophosphamide, methotrexate, and mycophenolate mofetil were more frequently used in aPL-positive patients with SLE versus those without, at the time of cohort entry. Hydroxychloroquine use is well established in SLE; however, no strong clinical data exist to recommend HCQ for aPL-positive patients without other systemic autoimmune diseases. Given animal and in vitro studies showing that HCQ has a potential antithrombotic role in addition to its immunoregulatory and metabolic effects (24–29), HCQ has been used by some centers to prevent thrombosis in aPL-positive patients without other systemic autoimmune disease (30–32). An international effort to determine the effectiveness against thrombosis in asymptomatic aPL-positive patients was terminated early due to logistical reasons (33). Approximately 40% of aPL-positive patients without other systemic autoimmune disease reported HCQ use in our study, with higher frequency of serological features of SLE among aPL-positive patients using HCQ. Our study was not designed to determine the prophylactic role of HCQ; however, we believe that prospective follow-up of our registry patients will provide further valuable data on outcomes in HCQ-treated aPL-positive patients.
Although our study was limited in its retrospective, cross-sectional study design, we used large, multi-center international patient cohort. Our dataset is enriched with granular sociodemographic, clinical, laboratory, and medication data. However, data for CVD risk factors were collected at the time of the patient’s enrollment and not at the time of the thrombotic events, which may have resulted in inaccurate CVD prevalence estimates in different groups of aPL-positive patients.
In conclusion, our analysis of a multicenter international cohort of persistently aPL-positive patients demonstrates increased frequency of thrombocytopenia, hemolytic anemia, low complement levels, and IgA aβ₂GPI positivity, but not the risk of thrombotic, obstetric, and non-criteria APS manifestations (except cognitive dysfunction) among aPL-positive patients with concomitant SLE diagnosis compared to those without SLE. Our exploratory study provides pilot data for future risk-stratified prospective data analyses of APS ACTION registry, which will better determine the clinical impact of SLE on the presentation of aPL-positive patients.
Significance and Innovation:
Although systemic lupus erythematosus (SLE) is the most common autoimmune disease associated with aPL, limited data exist on the impact of SLE on the clinical phenotype of antiphospholipid antibody (aPL)-positive patients.
Based on the analysis of a large scale international registry, our study demonstrates that concomitant SLE diagnosis in persistently aPL-positive patients does not increase the frequencies of thrombosis (including recurrent) and pregnancy morbidity. However, aPL-positive patients with SLE have increased frequency of thrombocytopenia, hemolytic anemia, low complement levels, and IgA aβ₂GPI positivity compared to aPL-positive patients without other autoimmune diseases.
Additionally, aPL-positive patients with SLE had significantly higher frequency of current smoking, while aPL-positive patients without other autoimmune disease had an increased prevalence of cognitive dysfunction.
Although hydroxychloroquine (HCQ) use was more common in aPL-positive patients with SLE, 40% of aPL-positive patients with no other autoimmune diseases also received HCQ, especially those with lupus-related clinical and serologic manifestations.
Acknowledgments:
We want to thank: Joann Vega, CCRC for her research/administrative assistance including patient recruitment and data monitoring. Data management was performed using REDCAP provided by the Clinical and Translational Science Center at Weill Cornell Medicine (CTSC grant UL1 TR000457).
The study was partially supported by New York Community Trust.
Michael H. Belmont, MD is a consultant to Exagen Diagnostics, Inc.
Doruk Erkan, MD received research grants from New York Community Trust, Hospital for Special
Surgery Medical Education Academy, Lupus Clinical Trials Consortium, and NHLBI; is a clinical trial investigator for EMD Serono, GSK, and Xencor; and is a consultant for Ablynx.
Footnotes
Financial Disclosure:
Remaining authors do not have any financial disclosures.
References
- 1.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: 295–306. [DOI] [PubMed] [Google Scholar]
- 2.Erkan D, Lockshin MD. Non-criteria manifestations of antiphospholipid syndrome. Lupus 2010; 19: 424–7. [DOI] [PubMed] [Google Scholar]
- 3.Cervera R, Serrano R, Pons-Estel GJ, Ceberio-Hualde L, Shoenfeld Y, de Ramon E, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2015; 74: 1011–8. [DOI] [PubMed] [Google Scholar]
- 4.Pons-Estel GJ, Andreoli L, Scanzi F, Cervera R, Tincani A. The antiphospholipid syndrome in patients with systemic lupus erythematosus. J Autoimmun 2017; 76: 10–20. [DOI] [PubMed] [Google Scholar]
- 5.Ünlü O, Zuily S, Erkan D. The clinical significance of antiphospholipid antibodies in systemic lupus erythematosus. Eur J Rheumatol 2016; 3: 75–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2009; 7: 1737–40. [DOI] [PubMed] [Google Scholar]
- 7.Taraborelli M, Leuenberger L, Lazzaroni MG, Martinazzi N, Zhang W, Franceschini F, et al. The contribution of antiphospholipid antibodies to organ damage in systemic lupus erythematosus. Lupus 2016; 25: 1365–8. [DOI] [PubMed] [Google Scholar]
- 8.Garcia-Carrasco M, Galarza C, Gomez-Ponce M, Cervera R, Rojas-Rodriguez J, Espinosa G, et al. Antiphospholipid syndrome in Latin American patients: clinical and immunologic characteristics and comparison with European patients. Lupus 2007; 16: 366–73. [DOI] [PubMed] [Google Scholar]
- 9.Barbhaiya M, Andrade D, Erkan D. AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION): 5-Year Update. Curr Rheumatol Rep 2016; 18: 64. [DOI] [PubMed] [Google Scholar]
- 10.Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42: 377–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheumatol 1997; 40: 1725. [DOI] [PubMed] [Google Scholar]
- 12.Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, et al. Catastrophic antiphospholipid syndrome: international consensus statement on classification and treatment guidelines. Lupus 2003;12:530.4. [DOI] [PubMed] [Google Scholar]
- 13.Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheumatol 2002; 46: 1019–27. [DOI] [PubMed] [Google Scholar]
- 14.Tektonidou MG, Varsou N, Kotoulas G, Antoniou A, Moutsopoulos HM. Cognitive deficits in patients with antiphospholipid syndrome: association with clinical, laboratory, and brain magnetic resonance imaging findings. Arch Intern Med 2006; 166: 2278–84. [DOI] [PubMed] [Google Scholar]
- 15.Kozora E, Erkan D, Zhang L, Zimmerman L, Ramon G, et al. Coginitive dysfunction in antiphospholipid antibody (aPL)-negative systemic lupus erythematosus (SLE) versus aPL-positive non-SLE patients. Clin Exp Rheumatol 2013;32:34–40. [PubMed] [Google Scholar]
- 16.Mehrani T, Petri M. Assocaition of IgA Anti-beta2 glycoprotein-I clinical and laboratory manifestation of systemic lupus erythematosus. J Rheumatol 2011;38:64–8. [DOI] [PubMed] [Google Scholar]
- 17.Petri M, Orbai AM, Alarcon GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheumatol 2012; 64: 2677–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Kelchtermans H, Pelkmans L, de Laat B, Devreese KM. IgG/IgM antiphospholipid antibodies present in the classification criteria for the antiphospholipid syndrome: a critical review of their association with thrombosis. J Thromb Haemost 2016; 14: 1530–48. [DOI] [PubMed] [Google Scholar]
- 19.Andreoli L, Fredi M, Nalli C, Piantoni S, Reggia R, Dall’Ara F, et al. Clinical significance of IgA anti-cardiolipin and IgA anti-beta2glycoprotein I antibodies. Curr Rheumatol Rep 2013; 15: 343. [DOI] [PubMed] [Google Scholar]
- 20.Posch F, Gebhart J, Rand JH, Koder S, Quehenberger P, Pengo V, et al. Cardiovascular risk factors are major determinants of thrombotic risk in patients with the lupus anticoagulant. BMC Med 2017; 15: 54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Tektonidou MG, Wang Z, Ward MM. Brief Report: Trends in Hospitalizations Due to Acute Coronary Syndromes and Stroke in Patients With Systemic Lupus Erythematosus, 1996 to 2012. Arthritis Rheumatol 2016; 68: 2680–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Kim SK, Lee SS, Choe JY, Park SH, Lee H. Effect of alcohol consumption and smoking on disease damage in systemic lupus erythematosus: data from the Korean Lupus Network (KORNET) registry. Lupus 2017: 961203317709346. [DOI] [PubMed]
- 23.Barbhaiya MTS, Lu B, Malspeis S, Sparks JA, Karlson EW, Costenbader KH. Cigarette Smoking Increases the Risk of Anti-Double-Stranded DNA Positive SLE Among Women in the Nurses’ Health Studies [abstract]. Arthritis Rheumatol 68 (suppl 10). [Google Scholar]
- 24.Edwards MH, Pierangeli S, Liu X, Barker JH, Anderson G, Harris EN. Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice. Circulation 1997; 96: 4380–4. [DOI] [PubMed] [Google Scholar]
- 25.Rand JH, Wu XX, Quinn AS, Ashton AW, Chen PP, Hathcock JJ, et al. Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug. Blood 2010; 115: 2292–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Nuri E, Taraborelli M, Andreoli L, Tonello M, Gerosa M, Calligaro A, et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res 2017; 65: 17–24. [DOI] [PubMed] [Google Scholar]
- 27.Jung H, Bobba R, Su J, Shariati-Sarabi Z, Gladman DD, Urowitz M, et al. The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheumatol 2010; 62: 863–8. [DOI] [PubMed] [Google Scholar]
- 28.Kaiser R, Cleveland CM, Criswell LA. Risk and protective factors for thrombosis in systemic lupus erythematosus: results from a large, multi-ethnic cohort. Ann Rheum Dis 2009; 68: 238–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Ruiz-Irastorza G, Egurbide MV, Pijoan JI, Garmendia M, Villar I, Martinez-Berriotxoa A, et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus 2006; 15: 577–83. [DOI] [PubMed] [Google Scholar]
- 30.Petri M Hydroxychloroquine use in the Baltimore Lupus Cohort: effects on lipids, glucose and thrombosis. Lupus 1996; 5 Suppl 1: S16–22. [PubMed] [Google Scholar]
- 31.Tektonidou MG, Laskari K, Panagiotakos DB, Moutsopoulos HM. Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies. Arthritis Rheumatol 2009; 61: 29–36. [DOI] [PubMed] [Google Scholar]
- 32.Schmidt-Tanguy A, Voswinkel J, Henrion D, Subra JF, Loufrani L, Rohmer V, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost 2013; 11: 1927–9. [DOI] [PubMed] [Google Scholar]
- 33.Erkan D, Unlu O, Sciascia S, Belmont HM, Branch DW, Cuadrado MJ, et al. Hydroxychloroquine in the primary thrombosis prophylaxis of antiphospholipid antibody positive patients without systemic autoimmune disease. Lupus 2018;27:399–406. [DOI] [PubMed] [Google Scholar]