First clinical symptom as a prognostic factor in systemic sclerosis: results of a retrospective nationwide cohort study.

The objective of the study is to determine the importance of the mode of onset as prognostic factor in systemic sclerosis (SSc). Data were collected from the Spanish Scleroderma Registry (RESCLE), a nationwide retrospective multicenter database created in 2006. As first symptom, we included Raynaud's phenomenon (RP), cutaneous sclerosis, arthralgia/arthritis, puffy hands, interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and digestive hypomotility. A total of 1625 patients were recruited. One thousand three hundred forty-two patients (83%) presented with RP as first symptom and 283 patients (17%) did not. Survival from first symptom in those patients with RP mode of onset was higher at any time than those with onset as non-Raynaud's phenomenon: 97 vs. 90% at 5 years, 93 vs. 82% at 10 years, 83 vs. 62% at 20 years, and 71 vs. 50% at 30 years (p < 0.001). In multivariate analysis, factors related to mortality were older age at onset, male gender, dcSSc subset, ILD, PAH, scleroderma renal crisis (SRC), heart involvement, and the mode of onset with non-Raynaud's phenomenon, especially in the form of puffy hands or pulmonary involvement. The mode of onset should be considered an independent prognostic factor in systemic sclerosis and, in particular, patients who initially present with non-Raynaud's phenomenon may be considered of poor prognosis.

No evidence of association between functional polymorphisms located within IL6R and IL6ST genes and systemic sclerosis.

Systemic sclerosis (SSc) is a complex autoimmune disease which genetic component has not been yet completely understood. IL6 encodes a cytokine with a crucial role in the development of autoimmunity and fibrosis and its actions mainly are controlled by IL-6 receptor (IL-6R). We aimed to investigate whether the functional genetic variants rs8192284 and rs2228044 previously associated with several autoimmune diseases, located within the IL-6 receptor (IL-6R) subunits IL6R and IL6ST genes, respectively, are involved in the susceptibility to SSc and/or its major clinical subphenotypes. A Spanish cohort including 1013 SSc patients and 1375 controls was genotyped using the TaqMan® allelic discrimination technology. SSc patients were subdivided according to the major clinical forms, autoantibody status and presence of fibrotic lung affection. Our data showed no influence of the selected variants in global SSc susceptibility (rs8192284: P=0.67, odds ratios (OR)=0.98; rs2228044: P=0.99, OR=1.00). Similarly, the clinical/autoantibody subphenotype analyses did not yielded significant results. Our data suggest that the analyzed polymorphisms may not play a significant role in the SSc susceptibility.

[The antiphospholipid syndrome in the 21st century]. / Síndrome antifosfolipídico en el siglo xxi.

The antiphospholipid syndrome (APS) is characterised by a great clinical variability, with diverse clinical presentations such as venous thromboembolism, preeclampsia, arterial thrombosis and renal and cerebral small vessel thrombosis. Given this wide spectrum of manifestations, it is very important to make an early diagnosis in order to start adequate medical therapy before irreversible damage ensues. Persistent positivity of lupus anticoagulant (LA), anticardiolipin antibodies (aCL) at high levels or the combined triple positivity of LA, aCL and anti-ss(2)GPI make the diagnosis of APS likely in the adequate clinical setting. The treatment of APS is based on antiaggregant and anticoagulant drugs. The optimal approach is still debated; however, indefinite anticoagulation is warranted. We recommend high intensity anticoagulation in patients with arterial and/or recurrent events, as well as a strict control of vascular risk factors. Pregnant women with APS should be best attended in combined medical-obstetric clinics. Low dose aspirin should be given to every pregnant woman with antiphospholipid antibodies, with the addition of low molecular weight heparin in those with previous thrombosis, previous fetal death or failure of monotherapy with aspirin.

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.

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.

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.

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.

Sustained response to rituximab of autoimmune hemolytic anemia associated with antiphospholipid syndrome.

Standard treatment for autoimmune hemolytic anemia (AIHA) due to warm antibodies includes combinations of glucocorticoids, immunosuppressive drugs (mainly azathioprine) and splenectomy. Patients who are refractory or intolerant to these therapies constitute an important therapeutic challenge. Rituximab, an anti-CD20 chimeric monoclonal antibody, can effectively deplete B-cells and is commonly used in B-cell non-Hodgkin lymphoma. In addition, it is being increasingly used in autoimmune disorders, such as idiopathic thrombocytopenic purpura, AIHA, systemic lupus erythematosus or vasculitis. We report a case of warm AIHA associated to primary antiphospholipid syndrome (APS). The patient was refractory to high-dose corticosteroids. Splenectomy was discarded in view of the high risk of thrombotic and/or hemorrhagic perioperative complications, due to the presence of APS. After treatment with four weekly doses of rituximab the patients had a rapid and sustained response which allowed progressive tapering of prednisone dose to 5 mg/d. In addition, IgM anticardiolipin titres decreased from > 600 MPL to < 100 MPL. Thirteen further cases of warm AIHA in adults treated with rituximab have been reviewed, showing excellent tolerance and high response rates. Rituximab may be considered prior to splenectomy in patients with refractory AIHA and high risk of complications following splenectomy.

Systemic lupus erythematosus presenting as acute symptomatic hypercalcemia.

Hypercalcemia is a common electrolyte abnormality with a wide differential diagnosis. Primary hyperparathyroidism and 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.

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 > or = 1) or severe (SDI > 2) damage at five years after diagnosis or the combined outcome 'SDI > or = 1 or death at five years'. Autoantibodies [anti-DNA, anti-Ro, anti-La, anti-Sm, anti-U1RNP, 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 > or = 1 or death at five years'. The conclusion was that aPL predict early damage in patients with SLE.

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 micromol/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.

[Giant cell arteritis: temporal arteritis, rheumatic polymyalgia]. / Arteritis de células gigantes: arteritis temporal, polimialgia reumática.

Fourteen patients have been diagnosed for Giant Cell Arteritis by temporal biopsy or clinical criteria in the last five years. Two of them started with atypical symptoms. Polymyalgia Rheumatica was the commonest symptom (71%). Two patients (14%) had an irreversible blindness in eye one. Histologic changes of arteritis were shown by temporal biopsy in 8 cases, one of which had no cranial manifestations. A raised ESR was a constant finding (100%) followed by a alpha-2 globulin increase (93%) and anaemia (57%). One patient had rare complication of this disease: an aortic arch syndrome. The whole group responded well to the treatment.