Maria-Victoria Egurbide

Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus

Antimalarials have shown beneficial effects on systemic lupus erythematosus (SLE) activity. Our aim was to investigate whether antimalarials protect against thrombosis and influence survival in SLE patients. A prospective cohort including 232 patients with SLE were included in the study at the time of lupus diagnosis. End points were documented thrombosis and death due to any cause. A Cox regression-multiple-failure time survival analysis model was fitted to establish the effect of antimalarials on the development of thrombosis. Kaplan-Meier survival curves and propensity score adjusted-Cox regression analysis were performed to investigate the effect of antimalarials use on survival. Of our subjects, 204 patients (88%) were women. 230 patients (99%) were white. 150 patients (64%) had ever received antimalarials. Median time on antimalarials was 52 months (range three to 228 months). The Cox multiple-failure time survival analysis showed that taking antimalarials was protective against thrombosis (HR 0.28, 95%CI 0.08-0.90), while aPL-positivity (HR 3.16, 95%CI 1.45-6.88) and previous thrombosis (HR 3.85, 95%CI 1.50-9.91) increased the risk of thrombotic events. Twenty-three patients died, 19 of whom (83%) had never received antimalarials. No patient treated with antimalarials died of cardiovascular complications. Cumulative 15-year survival rates were 0.68 for never versus 0.95 for ever treated patients (P < 0.001). Age at diagnosis and propensity score-adjusted HR for antimalarials ever versus never users was 0.14 (95%CI 0.04-0.48). Our study shows a protective effect of antimalarials against thrombosis and an increased survival of SLE patients taking these drugs. These data support the routine use of antimalarials in all patients with SLE.

Vitamin D deficiency in systemic lupus erythematosus: prevalence, predictors and clinical consequences

OBJECTIVES We aimed to establish the prevalence, predictors and clinical consequences of vitamin D deficiency in patients with SLE. METHODS Cross-sectional study including patients fulfilling ACR criteria for the classification of SLE. Serum 25(OH)D levels at 30 and 10 ng/ml were the cut-off values for vitamin D insufficiency and vitamin D deficiency, respectively. SLE activity was measured by SLEDAI and irreversible organ damage by the SLICC-ACR index. Fatigue was quantified using a 0-10 visual analogue scale (VAS). RESULTS Ninety-two patients (90% women, 98% white) were included in the study. Sixty-nine (75%) and 14 (15%) patients presented with vitamin D insufficiency and deficiency, respectively. Female sex (P = 0.001), treatment with HCQ (P = 0.014) and treatment with calcium and vitamin D (P = 0.049) predicted higher levels of 25(OH)D. Photosensitivity [odds ratio (OR) 3.5] and photoprotection (OR 5.7) predicted vitamin D insufficiency and deficiency, respectively. Higher age (OR 0.95) and HCQ use (OR 0.29) protected against vitamin D deficiency. Patients with vitamin D deficiency had a higher degree of fatigue as quantified by a 0-10 VAS (mean 5.32 vs 4.03, P = 0.08). No relation was seen between vitamin D insufficiency or deficiency and disease duration, SLEDAI or SLICC-ACR indexes. CONCLUSIONS Vitamin D insufficiency and deficiency are common in patients with SLE and are associated with sun avoidance. HCQ prevented vitamin D deficiency. Vitamin D deficiency was related to a higher degree of fatigue. Vitamin D levels had no relation with SLE severity.

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

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).

Antimalarials may influence the risk of malignancy in systemic lupus erythematosus

Background: Recent studies suggest that antimalarials have antineoplastic properties. Objective: To investigate whether antimalarials decrease the risk of cancer in systemic lupus erythematosus (SLE). Methods: An observational prospective cohort study was carried out. 235 patients were included in the study at the time of diagnosis (American College of Rheumatology criteria). The end point was the diagnosis of cancer. Kaplan–Meier cancer-free survival curves for patients treated and not treated with antimalarials were compared. A Cox proportional hazards model was fitted, with cancer as the dependent variable. Age at diagnosis, gender, treatment with azathioprine, cyclophosphamide and methotrexate, smoking, Systemic Lupus International Collaborating Clinics (SLICC) Damage Index 6 months after diagnosis, year of diagnosis and treatment with antimalarials were entered as independent variables. Results: 209 (89%) patients were women. 233 (99%) patients were white. Mean (SD) age at diagnosis was 37 (16) years. Median (range) follow-up was 10 (1–31) years. 156 (66%) patients had ever received antimalarials. 2/156 (1.3%) ever-treated patients compared with 11/79 (13%) never-treated patients had cancer (p<0.001). Cumulative cancer-free survival in treated and not treated patients was 0.98 and 0.73, respectively (p<0.001). Adjusted hazard ratio for cancer among malaria drug users compared with non-users was 0.15 (95% CI 0.02 to 0.99). Conclusions: This study launches the hypothesis of a protective action of antimalarials against cancer in patients with SLE. This effect should be confirmed in larger multicentre studies.

High risk of tuberculosis in systemic lupus erythematosus

The incidence and severity of tuberculosis (TB) in patients with systemic lupus erythematosus (SLE) varies greatly among different series. In addition, prospective data are scarce. The aim of this study is to analyse the frequency and severity of TB in our cohort of lupus patients. We analysed data from a prospective database of a single center cohort of 232 patients with SLE (ACR criteria). Prophylaxis with isoniazid was not regularly administered. We identified all cases of TB diagnosed during 10 years (January 1994 to December 2003). The following variables were analysed: annual incidence of TB, location of infection and response to therapy. Data from published series reporting on the incidence of TB among SLE patients were extracted. Three patients (1.3%) suffered clinically manifest TB in 1603 patient-years of follow-up, resulting in an incidence of 187 cases/100 000 patient-years (95% CI 39-547). The pooled annual incidence of TB infection in our area during this period was 30/100 000 individuals. We recorded two cases of pulmonary TB and one case of tuberculous pleurisy. All patients had good response to therapy. The annual incidence of TB among SLE patients in other series, most of them from developing countries, varied between 150/100 000 patients in Turkey and 2450/100 000 patients in India. Of note, high prevalence of extrapulmonary forms as well as elevated TB-associated mortality was reported in most series. TB was more frequent in SLE patients than expected in the general population. We did not see any cases of disseminated infection and all patients had good response to treatment. Our data compare favourably in terms of incidence, severity and outcome with those from highly endemic areas.

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. Lupus (2007) 16, 810—816.

Antiphospholipid antibodies predict early damage in patients with systemic lupus erythematosus.

The aim of this study was to determine whether the different autoantibodies predict early damage in patients with systemic lupus erythematosus (SLE). The patients comprised a prospective inception cohort of 205 patients with SLE, 154 on follow-up for at least five years after diagnosis. Eight patients who died before the fifth year of disease course were included in analyses comprising survival. Organ damage was measured using the Systemic Lupus International Collaborating Clinics - American College of Rheumatology damage index (SDI). Endpoints were the development of some (SDI ≥1) or severe (SDI > 2) damage at five years after diagnosis or the combined outcome ‘SDI ≥1 or death at five years’. Autoantibodies [anti-DNA, anti-Ro, anti-La, anti-Sm, anti-U1 RNP, any anti-ENA and antiphospholipid (aPL)] were included in univariate and multivariate analysis. ‘Age at diagnosis’ was also included as an independent variable in multivariant analyses. Sapporo criteria were used to define aPL positivity. Eighty-four patients (54.5%) had accrued damage at five years, 17 patients (11.0%) having severe damage. Patients with aPL had damage in a higher proportion (63.2% any damage, 17.6% severe damage). Only aPL were related to damage in univariate analysis (P = 0.03). In logistic regression models, aPL were the only independent predictors of damage at five years (OR 1.94, 95% CI 1.01-3.73), severe damage at five years (OR 3.34, 95% CI 1.11-10.03) and increasing damage since diagnosis (OR 2.46, 95% CI 1.24-4.87). No autoantibody was a predictor of the outcome ‘SDI ≥1 or death at five years’. The conclusion was that aPL predict early damage in patients with SLE.

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.

Homocysteine, antiphospholipid antibodies and risk of thrombosis in patients with systemic lupus erythematosus

Cardiovascular disease is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Antiphospholipid syndrome (APS) is one of the most important causes of thrombosis in SLE. In addition, an association between hyperhomocysteinemia and increased cardiovascular risk has also been reported. Our aim is to analyse the association of thrombosis with plasma total homocysteine (ptHcy), antiphospholipid antibodies (aPL) and other vascular risk factors in SLE patients. Fasting plasma levels of ptHcy, vitamin B12, folate, total cholesterol and creatinine were measured in 117 SLE patients. Clinical and immunological data were obtained from our prospective computerized database. aPL-positivity was defined according to Sapporo criteria. There was no association between aPL and ptHcy. ptHcy was higher in patients with arterial (median 13.02 versus 10.16 mmol/L, P = 0.010) but not venous thrombosis. In the subgroup analysis, this association was only seen in aPL-negative patients. In logistic regression, aPL (OR 6.60, 95% CI 1.86-23.34) and ptHcy (OR 1.10, 95% CI 1.01-1.19) were independently associated with arterial thrombosis. However, when hypertension, smoking and plasma total cholesterol were added to the model, only aPL (OR 7.38, 95% CI 2.02-26.91) and hypertension (OR 7.70, 95% CI 2.33-25.39), but not ptHcy, remained independently related to arterial events. aPL was the only variable independently related to venous thrombosis (OR 7.68, 95% CI 1.60-36.86). ptHcy concentrations are higher in SLE patients with arterial thrombosis. No interaction between homocysteine and aPL was found. Raised ptHcy may be a marker of increased vascular risk in aPL-negative SLE patients. The role of homocysteine as a marker of vascular risk may depend on the presence of traditional risk factors, although a modest intrinsic effect cannot be entirely excluded.

Systemic lupus erythematosus presenting as acute symptomatic hypercalcemia

Hypercalcemia is a common electrolyte abnormality with a wide differential diagnosis. Primary hyperparathyroidismand malignancy are the most frequent causes, accounting for more than 90% of cases. We report the case of a woman presenting with symptomatic severe hypercalcemia, who was subsequently diagnosed with systemic lupus erythematosus (SLE) due to the presence of arthritis, lymphopenia, antinuclear antibodies (ANA), anti-DNA and anti-Ro antibodies and low C3 levels. After acute treatment with intravenous fluids, steroids, diuretics and pamidronate, calcium levels corrected and have remained normal on low-dose prednisone.Five similar cases have been reported in the literature. Thus, SLE is an uncommon cause of hypercalcemia, which can also be the presenting feature of lupus.