Confirmation of CCR6 as a risk factor for anti-topoisomerase I antibodies in systemic sclerosis.

OBJECTIVES: The current knowledge of the influence of systemic sclerosis (SSc) risk loci in the clinical sub-phenotypes is still limited. The main limitation lies in the low frequency of some sub-phenotypes which could be solved by replication studies in independent cohorts and meta-analysis between studies. In this regard, CCR6 gene variants have been recently associated with anti-topoisomerase I positive (ATA+) production in SSc patients in a candidate gene study. This gene has been proposed to have a critical role in IL-17-driven autoimmunity in human diseases. METHODS: In order to confirm the association between CCR6 and ATA+ SSc patients, we performed an independent replication study in populations of European ancestry. We studied two CCR6 genetic variants (rs968334 and rs3093024) in a total of 901 ATA+ SSc cases, 3,258 ATA- SSc cases and 7,865 healthy controls and compared allelic frequencies for those SNPs in ATA+ SSc with healthy controls and also with ATA- SSc patients. RESULTS: The comparison performed between ATA+ SSc patients and healthy controls showed significant association with SNP rs968334 (p=4.88x10(-2), OR=1.11). When we compared ATA+ SSc cases with ATA- SSc, both SNPs, rs3093024 and rs968334, showed significant associations (p=2.89x10(-2), OR=1.13; p=1.69x10(-2), OR=1.15). Finally, in order to increase even more sample size and statistical power, we meta-analysed our study with the previous reported and found a significant association between SNP rs3093024 and ATA+ SSc patients (p=1.00x10(-4), OR=1.16) comparing with healthy controls. CONCLUSIONS: Our work confirms the association of CCR6 gene and ATA+ SSc patients.

Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are related chronic autoimmune diseases of complex aetiology in which the interferon (IFN) pathway plays a key role. Recent studies have reported an association between IRF7 and SLE which confers a risk to autoantibody production. A study was undertaken to investigate whether the IRF7 genomic region is also involved in susceptibility to SSc and the main clinical features. METHODS: Two case-control sets of Caucasian origin from the USA and Spain, comprising a total of 2316 cases of SSc and 2347 healthy controls, were included in the study. Five single nucleotide polymorphisms (SNPs) in the PHRF1-IRF7-CDHR5 locus were genotyped using TaqMan allelic discrimination technology. A meta-analysis was performed to test the overall effect of these genetic variants on SSc. RESULTS: Four out of five analysed SNPs were significantly associated with the presence of anticentromere autoantibodies (ACA) in the patients with SSc in the combined analysis (rs1131665: p(FDR)=6.14 × 10(-4), OR=0.78; rs4963128: p(FDR)=6.14 × 10(-4), OR=0.79; rs702966: p(FDR)=3.83 × 10(-3), OR=0.82; and rs2246614: p(FDR)=3.83 × 10(-3), OR=0.83). Significant p values were also obtained when the disease was tested globally; however, the statistical significance was lost when the ACA-positive patients were excluded from the study, suggesting that these associations rely on ACA positivity. Conditional logistic regression and allelic combination analyses suggested that the functional IRF7 SNP rs1131665 is the most likely causal variant. CONCLUSIONS: The results show that variation in the IRF7 genomic region is associated with the presence of ACA in patients with SSc, supporting other evidence that this locus represents a common risk factor for autoantibody production in autoimmune diseases.

A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort.

OBJECTIVES: The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features. METHODS: A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers. RESULTS: A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively). CONCLUSIONS: The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.

Confirmation of association of the macrophage migration inhibitory factor gene with systemic sclerosis in a large European population.

OBJECTIVES: The aim of this study was to confirm the implication of macrophage migration inhibitory factor (MIF) gene in SSc susceptibility or clinical phenotypes in a large European population. METHODS: A total of 3800 SSc patients and 4282 healthy controls of white Caucasian ancestry from eight different European countries were included in the study. The MIF -173 single nucleotide polymorphism (SNP) was selected as genetic marker and genotyped using Taqman 5' allelic discrimination assay. RESULTS: The MIF -173 SNP showed association with SSc [P = 0.04, odds ratio (OR) = 1.10, 95% CI 1.00, 1.19]. Analysis of the MIF -173 polymorphism according to SSc clinical phenotype revealed that the frequency of the -173*C allele was significantly higher in the dcSSc group compared with controls (P = 5.30E-03, OR = 1.21, 95% CI 1.07, 1.38). Conversely, the frequency of the MIF -173*C allele was significantly underrepresented in the lcSSc group compared with dcSSc patients, supporting previous findings [(P = 0.04, OR = 0.86, 95% CI 0.75, 0.99); meta-analysis including previous results (P = 0.005, OR = 0.83, 95% CI 0.73, 0.94)]. CONCLUSION: Our results confirm the role of MIF -173 promoter polymorphism in SSc, and provide evidence of a strong association with the dcSSc subgroup of patients. Hence, the MIF -173 variant is confirmed as a promising clinical phenotype genetic marker.

High impact of antiphospholipid syndrome on irreversible organ damage and survival of patients with systemic lupus erythematosus.

BACKGROUND: Thrombosis is a frequent cause of morbidity and death in patients with systemic lupus erythematosus (SLE). Whether antiphospholipid syndrome (APS) is the cause of increased irreversible organ damage and mortality in lupus patients is not well established. METHODS: Prospective inception cohort of 202 patients with SLE (American College of Rheumatology criteria). Antiphospholipid syndrome was defined according to the Sapporo criteria. Irreversible damage was measured using the Systemic Lupus International Collaborating Clinics-American College of Rheumatology damage index (SDI) at 6 months and 1, 3, 5, 10, 15, 20, and 25 years after the diagnosis of SLE. All deaths were documented. RESULTS: A total of 88% of patients were women. Twenty-eight patients met criteria for definite APS. Mean (SD) follow-up was 9.7 (6.0) years. Nine patients could not be contacted for follow-up. All patients with APS experienced thrombosis, most of them in the arterial bed. Damage was more severe in patients with APS than in those without APS (median SDI score, 2 vs 0 at 5 years; P<.001; 4 vs 1 at 15 years; P<.001). Cumulative survival at 15 years was lower in patients with APS than in those without APS (65% vs 90%, P =.03). Older age at diagnosis, lupus nephritis, and APS were independent predictors of mortality. CONCLUSIONS: Antiphospholipid syndrome with thrombotic manifestations is a major predictor of irreversible organ damage and death in patients with SLE.

Early- versus late-onset systemic sclerosis: differences in clinical presentation and outcome in 1037 patients.

Peak age at onset of systemic sclerosis (SSc) is between 20 and 50 years, although SSc is also described in both young and elderly patients. We conducted the present study to determine if age at disease onset modulates the clinical characteristics and outcome of SSc patients. The Spanish Scleroderma Study Group recruited 1037 patients with a mean follow-up of 5.2 ± 6.8 years. Based on the mean ± 1 standard deviation (SD) of age at disease onset (45 ± 15 yr) of the whole series, patients were classified into 3 groups: age ≤ 30 years (early onset), age between 31 and 59 years (standard onset), and age ≥ 60 years (late onset). We compared initial and cumulative manifestations, immunologic features, and death rates. The early-onset group included 195 patients; standard-onset group, 651; and late-onset, 191 patients. The early-onset group had a higher prevalence of esophageal involvement (72% in early-onset compared with 67% in standard-onset and 56% in late-onset; p = 0.004), and myositis (11%, 7.2%, and 2.9%, respectively; p = 0.009), but a lower prevalence of centromere antibodies (33%, 46%, and 47%, respectively; p = 0.007). In contrast, late-onset SSc was characterized by a lower prevalence of digital ulcers (54%, 41%, and 34%, respectively; p < 0.001) but higher rates of heart conduction system abnormalities (9%, 13%, and 21%, respectively; p = 0.004). Pulmonary hypertension was found in 25% of elderly patients and in 12% of the youngest patients (p = 0.010). After correction for the population effects of age and sex, standardized mortality ratio was shown to be higher in younger patients. The results of the present study confirm that age at disease onset is associated with differences in clinical presentation and outcome in SSc patients.

A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility.

INTRODUCTION: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy. METHODS: Sixty-six non-HLA SNPs showing a P value <10⁻4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. RESULTS: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10⁻6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10⁻6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10⁻7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis. CONCLUSION: Our results suggest a role of PPARG gene in the development of SSc.

Pulmonary hypertension in systemic lupus erythematosus: prevalence, predictors and diagnostic strategy.

OBJECTIVES: To investigate the prevalence and predictors of pulmonary hypertension (PH) in patients with systemic lupus erythematosus (SLE) and to validate a diagnostic strategy. METHODS: 245 patients with SLE entered a screening program. Possible PH was defined as two consecutive systolic pulmonary arterial pressure (PAP) values ≥ 40mmHg by echocardiography. The subsequent diagnostic procedure, including right heart catheterization if needed, confirmed or excluded the diagnosis of PH secondary to cardiopulmonary disease or SLE-related pulmonary arterial hypertension (PAH). Independent predictors of PH were identified by multivariant multiple linear or logistic regression models. The sensitivity (S), specificity (SP), positive (PPV) and negative predictive values (NPV) were calculated for different screening cutoff values. RESULTS: 88% patients were women. The mean (SD) age at the time of enrolment was 45 (16) years. 12 cases of PH were detected, all secondary, with a resulting prevalence of 5%. Two consecutive echocardiographic PAP measurements ≥ 40mmHg performed best as the cutoff point for screening (S 100%, SP 97%, PPV 70, NPV 100), as compared with single PAP measurements ≥ 30mmHg or ≥ 40mmHg The age at the time of enrolment was the only variable independently associated with PAP values (p=0.0001), with the SLICC damage index score showing a borderline association (p=0.08). Only the age at the time of enrolment showed an independent association with PH (OR 1.10, 95% CI 1.06-1.17). CONCLUSION: We found a low prevalence of PH. Screening echocardiograms in asymptomatic lupus patients are thus not recommended. Two consecutive PAP values ≥ 40mmHg by echocardiogram is the best screening cutoff for starting investigations in SLE patients with suspected PH.

The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis.

Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P  = 1.34×10(-8), OR  = 1.22, CI 95%  = 1.14-1.30; rs2004640: P  = 4.60×10(-7), OR  = 0.84, CI 95%  = 0.78-0.90; rs10488631: P  = 7.53×10(-20), OR  = 1.63, CI 95%  = 1.47-1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P  = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P  = 9.04×10(-22), OR  = 1.75, CI 95%  = 1.56-1.97) better explained the observed association (likelihood P-value  = 1.48×10(-4)), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific.

KCNA5 gene is not confirmed as a systemic sclerosis-related pulmonary arterial hypertension genetic susceptibility factor.

INTRODUCTION: Potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) is implicated in vascular tone regulation, and its inhibition during hypoxia produces pulmonary vasoconstriction. Recently, a protective association of the KCNA5 locus with systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) was reported. Hence, the aim of this study was to replicate these findings in an independent multicenter Caucasian SSc cohort. METHODS: The 2,343 SSc cases (179 PAH positive, confirmed by right-heart catheterization) and 2,690 matched healthy controls from five European countries were included in this study. Rs10744676 single-nucleotide polymorphism (SNP) was genotyped by using a TaqMan SNP genotyping assay. RESULTS: Individual population analyses of the selected KCNA5 genetic variant did not show significant association with SSc or any of the defined subsets (for example, limited cutaneous SSc, diffuse cutaneous SSc, anti-centromere autoantibody positive and anti-topoisomerase autoantibody positive). Furthermore, pooled analyses revealed no significant evidence of association with the disease or any of the subsets, not even the PAH-positive group. The comparison of PAH-positive patients with PAH-negative patients showed no significant differences among patients. CONCLUSIONS: Our data do not support an important role of KCNA5 as an SSc-susceptibility factor or as a PAH-development genetic marker for SSc patients.

Influence of the IL6 gene in susceptibility to systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and phenotype expression of SSc. METHODS: We performed a large metaanalysis including a total of 2749 cases and 3189 controls from 6 white populations (Germany, The Netherlands, Norway, Spain, Sweden, and United Kingdom). Three IL6 single-nucleotide polymorphisms (SNP; rs2069827, rs1800795, and rs2069840) were selected by SNP tagging and genotyped using TaqMan(®) allele discrimination technology. RESULTS: Individual SNP metaanalysis showed no evidence of association of the 3 IL6 genetic variants with the global disease. Phenotype analyses revealed a significant association between the minor allele of rs2069840 and the limited cutaneous SSc clinical form (Bonferroni p = 0.036, OR 1.14, 95% CI 1.04-1.25). A trend of association between the minor allele of the rs1800795 and the diffuse cutaneous SSc clinical form was also evident (Bonferroni p = 0.072, OR 0.86, 95% CI 0.77-0.96). In the IL6 allelic combination analyses, the GGC allelic combination rs2069827-rs1800795-rs2069840 showed an association with overall SSc (Bonferroni p = 0.016, OR 1.13, 95% CI 1.04-1.23). CONCLUSION: Our results suggest that the IL6 gene may influence the development of SSc and its progression.

Bosentan in clinical practice for treating digital and other ischemic ulcers in Spanish patients with systemic sclerosis: IBER-DU cohort study.

OBJECTIVE: To describe treatment outcomes and safety experience with bosentan in patients with systemic sclerosis (SSc) and digital ulcers (DU), in a clinical setting in Spain. METHODS: This was a multicenter, noninterventional retrospective cohort study. Data were collected retrospectively from patients with DU, with or without pulmonary arterial hypertension (PAH), who were initiating bosentan therapy in 2003 (n = 26) or 2004 (n = 41) and followed until May 2005. Data were obtained from centers prescribing bosentan. Relevant measures included number of DU, occurrence of new DU, overall DU clinical status (improved, stabilized, worsened), and bosentan-associated adverse events. RESULTS: Sixty-seven patients with SSc and DU or other ulcers were included. PAH was also present in 12 patients (18%). At the start of bosentan treatment, the median number of DU per patient was 3.0. The median change in number of DU was -3.6 and -5.0 at 12 and 24 months, respectively. Sixty-eight percent of the patients did not develop any new DU at 12 months. DU clinical status was reported at 12 months for 22 patients: 18 patients (81.8%) improved and 4 (18.2%) stabilized. The median treatment duration was 13.0 months. The main adverse event was increase of aminotransferase, observed in 5 patients (7%), leading to discontinuation of treatment in 3 patients (4.4%). CONCLUSION: Previously reported results of bosentan efficacy in DU management are reproducible in clinical practice. This efficacy is maintained in the longterm followup. Bosentan treatment was well tolerated and adverse events were comparable with those observed in previous reports.

Changes in vitamin D levels in patients with systemic lupus erythematosus: Effects on fatigue, disease activity, and damage.

OBJECTIVE: To analyze whether changes in serum 25-hydroxyvitamin D (25[OH]D) levels affect activity, irreversible organ damage, and fatigue in systemic lupus erythematosus (SLE). METHODS: We performed an observational study of 80 patients with SLE included in a previous cross-sectional study of 25(OH)D, reassessed 2 years later. Oral vitamin D(3) was recommended in those with low baseline 25(OH)D levels. The relationship between changes in 25(OH)D levels from baseline and changes in fatigue (measured by a 0-10 visual analog scale [VAS]), SLE activity (measured by the Systemic Lupus Erythematosus Disease Activity Index [SLEDAI]), and irreversible organ damage (measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]) were analyzed. RESULTS: Sixty patients took vitamin D(3). Mean 25(OH)D levels increased among all treated patients (P = 0.044), in those with baseline vitamin D levels <30 ng/ml (P < 0.001), and in those with baseline vitamin D levels <10 ng/ml (P = 0.005). Fifty-seven patients (71%) still had 25(OH)D levels <30 ng/ml and 5 (6%) had 25(OH)D levels <10 ng/ml. Inverse significant correlations between 25(OH)D levels and the VAS (P = 0.001) and between changes in 25(OH)D levels and changes in the VAS in patients with baseline 25(OH)D levels <30 ng/ml (P = 0.017) were found. No significant correlations were seen between the variation of the SLEDAI or SDI values and the variation in 25(OH)D levels (P = 0.87 and P = 0.63, respectively). CONCLUSION: Increasing 25(OH)D levels may have a beneficial effect on fatigue. Our results do not support any effects of increasing 25(OH)D levels on SLE severity, although they are limited by the insufficient 25(OH)D response to the recommended regimen of oral vitamin D(3) replacement.

Predictors of major infections in systemic lupus erythematosus.

INTRODUCTION: Infections commonly complicate the course of systemic lupus erythematosus (SLE). Our aim is to investigate the clinical predictors of major infections in patients with SLE. METHODS: A nested case-control study design was used within the prospective Lupus-Cruces cohort. The endpoints of the study were major infections. Cases were defined as patients with a major infection. Two controls (SLE patients without major infections), matched for time of follow-up until the event and age at diagnosis, were selected for each case. Univariate analysis and logistic regression models were used for the analysis of data. RESULTS: Two hundred and forty-nine patients (83 cases, 166 controls) were selected. Eighty-three episodes of major infections were analyzed; E. coli, S. aureus, M. tuberculosis and S. pneumoniae being the most frequent isolates. Univariate analysis identified several variables related with infection: lung and renal involvement, at or previous to the study point; leukopenia at the study point; antiphospholipid antibody-positivity and treatment with prednisone within 3 months previous to the study point, and the dose of prednisone received. Treatment with antimalarials, on the other hand, showed a strong inverse association with major infections. Logistic regression models identified treatment with antimalarials (odds ratio (OR) = 0.06, 95% confidence interval (CI) = 0.02 to 0.18), prednisone dose (OR = 1.12, 95% CI = 1.04 to 1.19) and lung involvement (OR = 4.41, 95% CI = 1.06 to 18.36) as significant and independent predictors of major infections. No significant interactions among these three variables were found. Further adjustment for potential confounders related with antimalarial treatment did not change the results. CONCLUSIONS: The risk of major infections in patients with SLE is mostly influenced by treatment. Prednisone treatment, even at moderate doses, increases the risk, whilst antimalarials have a protective effect.

Transiently positive anticardiolipin antibodies and risk of thrombosis in patients with systemic lupus erythematosus.

Fluctuations in the titers of anticardiolipin antibodies (aCL) have been reported in systemic lupus erythematosus (SLE) patients, but their relation with thrombosis is not completely understood. Prospective inception cohort of 237 patients with SLE (American College of Rheumatology criteria). Positivity for antiphospholipid antibodies (aPL) was defined according to Sapporo criteria. aCL was defined as persistently positive when more than two-thirds of the determinations were positive during follow-up. Patients were classified into four groups: A [positive lupus anticoagulant (LA)], B (negative LA and persistently positive aCL), C (negative LA and transiently positive aCL) and D (negative LA and aCL). Of these 237 patients, 211 (89%) patients were women. Median age at diagnosis and follow-up were 32 (2-78) and 10 (1-31) years, respectively; 33 (13.9%), 23 (9.7%), 42 (17.7%) and 139 (58.6%) patients were classified in groups A, B, C and D, respectively. Thirty (12.6%) and 23 (9.7%) patients suffered arterial and venous thrombotic events, respectively. Adjusted risk for arterial thrombosis was increased in groups A [odds ratio (OR) 15.69, 95% confidential interval (CI) 4.79-51.42, P < 0.001] and B (OR 7.63, 95% CI 2.00-29.08, P = 0.003), but not in group C when compared with group D. Adjusted risk of venous thrombosis was increased in group A (OR 4.24, 95% CI 1.36-13.20, P = 0.013), but not in groups B or C when compared with group D. Risk of thrombosis is not increased in SLE patients with negative LA and transiently positive aCL, even fulfilling Sapporo laboratory criteria, when compared with aPL-negative SLE patients.