Ankle-brachial index and arterial vascular events in systemic lupus erythematosus patients: a 5-year prospective cohort.

OBJECTIVES: To determine the potential predictive value in patients with systemic lupus erythematous of the ankle-brachial index (ABI) for the occurrence of arterial vascular events. METHODS: 216 lupus patients from a prospective clinical cohort were evaluated using the ABI at the start of the study and then followed up for 5 years. Abnormal ABI was defined as an index ≤0.9 or >1.4. Several potential vascular risk factors were also evaluated. Arterial vascular events (AVE): coronary events, cerebrovascular events, peripheral arterial disease and death related to vascular disease. Survival analysis was performed using a competitive risk regression approach, considering non-vascular death as a competitive event. RESULTS: 18 arterial events and 14 deaths were identified. In the competitive risk regression analysis, independent predictors of higher risk were identified: family history of early AVE [subdistribution hazard ratio (SHR) 5.44, 95% confidence interval (CI) 1.69-17.50, p=0.004)], cumulative prednisone (grams) (SHR 1.01, 95% CI 1.01-1.03, p=0.007) and a personal history of arterial thrombosis (SHR 5.44, 95% CI 1.45-14.59, p=0.004). Female gender was a protective factor (SHR 0.22, 95% CI 0.07-0.77, p=0.017). A statistical trend was detected with abnormal ABI (SHR 2.65, 95% CI 0.86-8.14, p=0.089). CONCLUSIONS: Male gender, exposure to high cumulative doses of prednisone, family history of early arterial vascular disease and occurrence of previous arterial thrombosis are independent risk predictors of arterial vascular events in patients with systemic lupus erythematosus. Abnormal ABI may be related to high risk for arterial vascular events.

Predictors of peripheral arterial disease in SLE change with patient's age.

OBJECTIVE: To analyse the differential influence of risk factors of peripheral artery disease (PAD) according to age in patients with SLE. METHODS: 216 patients from the Lupus-Cruces cohort were divided in three age groups: ≤34 years, 35-49 years and ≥50 years. A low ankle-brachial index defined PAD. Significant variables were identified by univariant and multivariant analysis in each age group. RESULTS: Different factors were identified in different age groups: antiphospholipid antibodies/antiphospholipid syndrome and glucocorticoids in patients ≤34 years; in patients 35-49 years old, hypertension was the only statistically significant predictor, although a trend was observed for fibrinogen levels; a trend was observed for hypercholesterolaemia in those ≥50 years. CONCLUSIONS: Age may modulate the influence of risk factors for PAD in patients with SLE.

Description and Validation of Histological Patterns and Proposal of a Dynamic Model of Inflammatory Infiltration in Giant-cell Arteritis.

The extent of inflammatory infiltrates in arteries from patients with giant-cell arteritis (GCA) have been described using different terms and definitions. Studies investigating the relationship between GCA histological features and clinical manifestations have produced controversial results. The aims of this study were to characterize and validate histological patterns in temporal artery biopsies (TABs) from GCA patients, to explore additional histological features, including the coexistence of different patterns, and also to investigate the relationship of the inflammatory patterns with clinical and laboratory features.We performed histological examination of TAB from patients with GCA consecutively diagnosed between 1992 and 2012. Patterns of inflammation were defined according to the extent and distribution of inflammatory infiltrates within the artery. Clinical and laboratory variables were recorded. Two external investigators underwent a focused, one-day training session and then independently scored 77 cases. Quadratic-weighted kappa was calculated.TAB from 285 patients (200 female/85 male) were evaluated. Four histological inflammatory patterns were distinguished: 1 - adventitial (n = 16); 2 - adventitial invasive: adventitial involvement with some extension to the muscular layer (n = 21); 3 - concentric bilayer: adventitial and intimal involvement with media layer preservation (n = 52); and 4 - panarteritic (n = 196). Skip lesions were observed in 10% and coexistence of various patterns in 43%. Raw agreement of each external scorer with the gold-standard was 82% and 77% (55% and 46% agreement expected from chance); kappa = 0.82 (95% confidence interval [CI] 0.70-0.95) and 0.79 (95% CI 0.68-0.91). Although abnormalities on temporal artery palpation and the presence of jaw claudication and scalp tenderness tended to occur more frequently in patients with arteries depicting more extensive inflammation, no statistically significant correlations were found between histological patterns and clinical features or laboratory findings.In conclusion, we have described and validated 4 histological patterns. The presence of different coexisting patterns likely reflects sequential steps in the progression of inflammation and injury. No clear relationship was found between these patterns and clinical or laboratory findings. However, several cranial manifestations tended to occur more often in patients with temporal arteries exhibiting panarteritic inflammation. This validated score system may be useful to standardize stratification of histological severity for immunopathology biomarker studies or correlation with imaging.

LDLR and PCSK9 Are Associated with the Presence of Antiphospholipid Antibodies and the Development of Thrombosis in aPLA Carriers.

INTRODUCTION: The identification of the genetic risk factors that could discriminate non- thrombotic from thrombotic antiphospholipid antibodies (aPLA) carriers will improve prognosis of these patients. Several human studies have shown the presence of aPLAs associated with atherosclerotic plaque, which is a known risk factor for thrombosis. Hence, in order to determine the implication of atherosclerosis in the risk of developing thrombosis in aPLA positive patients, we performed a genetic association study with 3 candidate genes, APOH, LDLR and PCSK9. MATERIAL & METHODS: For genetic association study we analyzed 190 aPLA carriers -100 with non-thrombotic events and 90 with thrombotic events- and 557 healthy controls. Analyses were performed by χ2 test and were corrected by false discovery rate. To evaluate the functional implication of the newly established susceptibility loci, we performed expression analyses in 86 aPLA carrier individuals (43 with thrombotic manifestations and 43 without it) and in 45 healthy controls. RESULTS: Our results revealed significant associations after correction in SNPs located in LDLR gene with aPLA carriers and thrombotic aPLA carriers, when compared with healthy controls. The most significant association in LDLR gene was found between SNP rs129083082 and aPLA carriers in recessive model (adjusted P-value = 2.55 x 10-3; OR = 2.18; 95%CI = 1.49-3.21). Furthermore, our work detected significant allelic association after correction between thrombotic aPLA carriers and healthy controls in SNP rs562556 located in PCSK9 gene (adjusted P-value = 1.03 x 10-2; OR = 1.60; 95%CI = 1.24-2.06). Expression level study showed significantly decreased expression level of LDLR gene in aPLA carriers (P-value <0.0001; 95%CI 0.16-2.10; SE 0.38-1.27) in comparison to the control group. DISCUSSION: Our work has identified LDLR gene as a new susceptibility gene associated with the development of thrombosis in aPLA carriers, describing for the first time the deregulation of LDLR expression in individuals with aPLAs. Besides, thrombotic aPLA carriers also showed significant association with PCSK9 gene, a regulator of LDLR plasma levels. These results highlight the importance of atherosclerotic processes in the development of thrombosis in patients with aPLA.

Prevalence and significance of persistently positive antiphospholipid antibodies in women with preeclampsia.

OBJECTIVE: To determine the prevalence of antiphospholipid antibodies (aPL) and their association with obstetric outcomes in women with preeclampsia. METHODS: The study included 150 patients. Clinical variables, risk factors, and severity criteria for preeclampsia and aPL were analyzed. RESULTS: We found aPL in 4% of patients without risk factors for preeclampsia and in no women with risk factors (p = 0.03). Fifty percent of aPL-positive patients had a fetus with intrauterine growth restriction versus 13.9% (p = 0.04). No relation between aPL and severe preeclampsia was found. CONCLUSION: The prevalence of aPL among women with preeclampsia is low. aPL can predispose women without risk factors to preeclampsia.

Peripheral arterial disease in systemic lupus erythematosus: prevalence and risk factors.

OBJECTIVE: To analyze the prevalence of peripheral arterial disease (PAD) and cardiovascular (CV) risk factors in a cohort of patients with systemic lupus erythematosus (SLE) and to identify variables potentially related to PAD. METHODS: The study included 216 patients with SLE from the Lupus-Cruces prospective observational cohort. The ankle brachial index (ABI) was determined in each patient, with values < 0.9 considered diagnostic of PAD. Demographic and clinical variables, presence of traditional risk factors and CV events, cardiovascular risk calculated by Systematic Coronary Risk Evaluation (SCORE), and treatments received by each patient were analyzed. RESULTS: Ninety-two percent of patients were women. The mean age (SD) was 49 years (15), with a mean followup (SD) of 12 years (9). The prevalence of low ABI was 21%. CV risk factors were frequent: smoking, 30% of patients; high blood pressure, 32.7%; diabetes mellitus, 3.2%; hypercholesterolemia, 34.1%; and metabolic syndrome, 9.7%. The following variables were associated with low ABI in the univariate analysis: age (p < 0.001), hypertension (p = 0.002), diabetes (p = 0.018), hypercholesterolemia (p = 0.018), CV events (p < 0.001), SCORE (p = 0.004), cumulative dose of cyclophosphamide (p = 0.03), and fibrinogen levels (p = 0.002). In the multivariate analysis, the only independent variable in the final model was age (OR 1.04, 95% CI 1.02-1.07, p < 0.001), with a tendency for the presence of any vascular risk factor (diabetes, hypertension, hypercholesterolemia, or current smoking; OR 2.3, 95% CI 0.99-5.1, p = 0.053). CONCLUSION: The prevalence of low ABI in patients with SLE is higher than expected. While the association with CV risk factors and vascular disease in other territories was strong, we could not identify SLE-specific variables independently associated with PAD.

Prednisone in lupus nephritis: how much is enough?

OBJECTIVE: To assess the effectiveness and safety of a protocol using medium doses of prednisone to treat lupus nephritis. METHODS: Patients receiving the 'Cruces-protocol cohort' (CPC) were paired 1:2 with patients from the 'historic cohort' (HC). The CPC received medium doses of prednisone combined with methyl-prednisolone pulses, hydroxychloroquine and immunosuppressive drugs, usually cyclophosphamide. The HC received cyclophosphamide and high-dose prednisone. Partial and complete remission rates and glucocorticoid-related toxicity were assessed. RESULTS: 15 CPC and 30 HC patients were analysed. The mean (SD) initial dose of prednisone was 22 (8) mg/d in the CPC vs. 49 (19) mg/d in the HC (p<0.001). The 6-month mean (SD) cumulative dose of prednisone was 1.7 (0.5) g (average daily dose 9mg) vs. 4.5 (2.1) g (average daily dose 25mg), respectively (p<0.001). The median cumulative dose of cyclophosphamide at six months was 3 (0-4.5) g in the CPC vs. 5 (0-16.8) in the HC (p<0.001). 15/15 (100%) vs. 10/30 (33%) patients were treated with hydroxychloroquine (p<0.001). At six months, 12/15 (80%) patients in the CPC achieved partial or complete remission vs. 14/30 (47%) in the HC (p=0.015). At 12months, 13/15 (87%) vs. 19/30 (63%) patients, respectively, were in complete or partial remission (p=0.055). Toxicity attributable to glucocorticoids was observed in 1/15 (7%) vs. 20/30 (67%) patients, respectively (p<0.0001). CONCLUSION: A combination of medium-dose prednisone, methylprednisolone pulses, cyclophosphamide and hydroxychloroquine is at least as effective in achieving remission of lupus nephritis as regimes containing high-dose prednisone and causes less toxicity.

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.

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.

Correction of allopurinol dosing should be based on clearance of creatinine, but not plasma creatinine levels: another insight to allopurinol-related toxicity.

BACKGROUND: Dosing of allopurinol should be corrected depending on renal function, but corrections based on either plasma creatinine (Pcr) or creatinine clearance (CrCl) have been suggested to be minimal standards of care. METHODS: Data from a cohort database of 484 gouty patients were used to calculate estimated allopurinol doses using CrCl and estimation of the clearance of creatinine using the equation of Cockroft and Gault (CrCl-CG) if, as a hypothesis, a dosage of 300 mg/d would be prescribed in any patient with Pcr <2.0 mg/dL. Also, allopurinol-related toxicity previous to rheumatologic consultation, during previous allopurinol therapy, and the relationship between both and estimated allopurinol doses were reviewed. RESULTS: The cutoff point of plasma creatinine <2 showed 13% sensitivity and 100% specificity to detect CrCl <50 mL/min. Correlation and agreement between CrCl and CrCl-CG were good, as was the correlation between corrected doses using CrCl and CrCl-CG. One third of patients with Pcr 1.0-1.5 mg/dL and 90% of those with Pcr 1.5-2.0 mg/dL would receive estimated doses over 400 mg/dL/d CrCl. Also, 10% and 34% would receive estimated doses over 600 mg/dL/d CrCl, respectively. Allopurinol-related toxicity previous to consultation (11%) was associated with estimated doses over 400 mg/dL/d CrCl and severe toxicity with estimated doses over 600 mg/dL/d CrCl. When patients were given doses corrected on CrCl, few side effects were observed during follow up (6.7%), and the only severe one was associated with corrected dose over 600 mg/d. CONCLUSIONS: Dosage adjustment of allopurinol should be based on clearance of creatinine or estimation of glomerular filtration using the Cockcroft-Gault equation. Pcr is insensitive enough to detect renal function impairment so that patients may be placed at risk for overdosing side effects. Corrected doses over 600 mg/dL/d CrCl may be associated with increased risk of severe toxicity.