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

When first published, this article inadvertently listed the RESCLE investigators individually within the author list. The names should instead have been listed within the Acknowledgements section only. The corrected author list and the updated Acknowledgements section are presented in this Correction.

Hepatobiliary involvement in systemic sclerosis and the cutaneous subsets: Characteristics and survival of patients from the Spanish RESCLE Registry.

OBJECTIVE: To assess the prevalence and causes of hepatobiliary involvement (HBI) in systemic sclerosis (SSc), to investigate the clinical characteristics and prognosis of SSc patients with HBI (SSc-HBI) and without HBI (SSc-non-HBI), and to compare both groups according to the cutaneous SSc subsets. METHODS: In all, 1572 SSc patients were collected in the RESCLE registry up to January 2015, and all hepatobiliary disturbances were recorded. We investigated the HBI-related characteristics and survival from the entire SSc cohort and according to the following cutaneous subsets: diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc sine scleroderma (ssSSc). RESULTS: Out of 1572, 118 (7.5%) patients had HBI. Primary biliary cholangitis (PBC) was largely the main cause (n = 67, 4.3%), followed by autoimmune hepatitis (n = 19, 1.2%), and anti-mitochondrial negative PBC (n = 6, 0.4%). Other causes of HBI were as follows: secondary liver diseases (n = 11, 0.7%), SSc-related HBI (n = 7, 0.4%), nodular regenerative hyperplasia (n = 3, 0.2%), liver cirrhosis (n = 3, 0.2%), and HBI of unknown origin (n = 2, 0.1%). In multivariate analysis, HBI was independently associated to lesser risk of dcSSc (5.1% vs. 24.4%), and higher frequency of calcinosis (26% vs. 18%), left ventricular diastolic dysfunction (46% vs. 27%), sicca syndrome (51% vs. 29%), and anti-centromere antibodies (ACA, 73% vs. 44%). According to the cutaneous subsets, HBI was associated (1) in lcSSc, to longer time from SSc onset to diagnosis (10.8 ± 12.5 vs. 7.2 ± 9.3 years), sicca syndrome (54% vs. 33%), and ACA (80% vs. 56%); (2) in ssSSc, to sicca syndrome (44% vs. 19%), and (3) in dcSSc, no associations were found. HBI was the cause of death in 2.3% patients but the cumulative survival according to the presence or absence of HBI showed no differences. CONCLUSIONS: HBI prevalence in SSc is 7.5% and dcSSc is the least involved subset. PBC is the main cause of HBI. Patients with SSc-HBI exhibited specific clinical and immunologic profile. Survival is similar for SSc patients with HBI.

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.

Clinical and epidemiological differences between men and women with systemic sclerosis: a study in a Spanish systemic sclerosis cohort and literature review.

OBJECTIVES: The low overall prevalence of systemic sclerosis (SSc) and the low proportion of male patients have resulted in a scarcity of studies assessing sex differences in Ssc patients, and contradictory results have often been show among those studies that have been performed. METHODS: A prospective study was conducted with the Spanish RESCLE register to analyse the influence of gender on survival of SSc patients. RESULTS: In total, 1506 SSc patients (1341 women, 165 men) were recruited from 21 centres. Older age at onset (OR 1.02), shorter time from onset to diagnosis (OR 0.96), smoking (OR 2.57), interstitial lung disease (ILD) (OR 1.58), less predisposition to sicca syndrome and to antinuclear antibody positivity (OR 0.29 and 0.43, respectively), and higher compliance with the ACR 1980 criteria (OR 1.79) were independently associated with the male sex. During follow-up, 30.4% of men versus 14.6% of women died (p<0.001). Survival at 10 years from the onset of symptoms was 75.3% for men and 92.9% for women (p<0.001), and the difference remained after selecting only SSc-related deaths (85.6% vs. 96.1%, p<0.001). The mortality predictive factors were diffuse SSc (OR 2.26), ILD (OR 1.82), digital ulcers (OR 1.38), tendon friction rubs (OR 1.74), male sex (OR 1.53), increased age at onset (OR 1.13) and isolated PH (considering only deaths from diagnosis), both in the overall (OR 3.63) and female cohorts (OR 3.97). The same risk factors were observed in the male cohort, except for isolated PH and ILD. CONCLUSIONS: The present study confirms the existence of epidemiological, clinical, laboratory and prognostic gender differences in systemic sclerosis patients.

Influence of antibody profile in clinical features and prognosis in a cohort of Spanish patients with systemic sclerosis.

OBJECTIVES: To assess the clinical manifestations and prognosis of Spanish patients with systemic sclerosis (SSc) according to their immunological profile. METHODS: From the Spanish Scleroderma Study Group or RESCLE (Registro de ESCLErodermia as Spanish nomenclature) Registry we selected those patients in which anti-centromere (ACA), anti-topoisomerase I (ATA), and anti-RNA polymerase III (ARA) antibodies had been determined, and a single positivity for each SSc specific antibody was detected. Demographic, clinical, laboratory, and survival data were compared according to the serologic status of these antibodies. RESULTS: Overall, 209 SSc patients were included. In 128 (61%) patients ACA was the only positive antibody, 46 (22%) were only positive for ATA, and 35 (17%) for ARA. Of note, the three groups were mutually exclusive. In univariate analysis, patients with ACA presented more frequently limited cutaneous SSc (lcSSc) (p<0.001), whereas diffuse cutaneous SSc (dcSSc) was the most frequent subtype in patients with ATA (54%) and ARA (62%) (both p<0.001). Positive patients for ARA showed the highest prevalence of joint involvement (p<0.001) and those from ATA group had a higher prevalence of interstitial lung disease (ILD) (p<0.001). Scleroderma renal crisis was more frequent in the ARA group (p<0.001). In multivariate analysis, ACA were associated with female gender and were protective for dcSSc and ILD. ATA were found to be protective for lcSSc and they were independently associated with interstitial reticular pattern. ARA positivity was independently associated with dcSSc. We did not find differences in mortality between the three groups. CONCLUSIONS: In Spanish SSc patients, the presence of SSc specific antibodies conferred a distinctive clinical profile.

Very early and early systemic sclerosis in the Spanish scleroderma Registry (RESCLE) cohort.

OBJECTIVES: According to the existence of subclinical organ involvement pre-scleroderma should be divided into two subsets: very early and early disease. Pre-scleroderma patients included in the Spanish Scleroderma Registry (RESCLE) Cohort were reclassified into subsets. Differences were evaluated and the risk of progression to definite systemic sclerosis was estimated. METHODS: The characteristics of very early and early SSc patients were compared. A logistic regression model was used to determine the risk factors of progression. RESULTS: 1632 patients were included, 36 (2.2%) in the very early subset and 111 (6.8%) in the early subset. There were no differences in sex, age at disease onset, duration of Raynaud's phenomenon, antinuclear antibodies or capillaroscopic findings. Three (8.3%) very early SSc patients evolved to definite SSc, 2 (5.6%) of them meeting the ACR/EULAR 2013 criteria, unlike 31 (28%) early SSc patients, 20 (24%) of them meeting the criteria (p=0.034). Digestive involvement was an independent risk factor of progression (OR 17; 95% CI, 6.1-47.2). CONCLUSIONS: The classification of early forms of scleroderma identifies patients with different prognostic risk of progression. The evolution to definite SSc is more frequent in early than in very early SSc patients. Digestive involvement is a risk factor of progression. An active assessment of organ damage in preclinical stages allows a correct classification and risk stratification, with implications for monitoring and treatment.

Changes in the pattern of death of 987 patients with systemic sclerosis from 1990 to 2009 from the nationwide Spanish Scleroderma Registry (RESCLE).

OBJECTIVES: To determine the changes in the pattern of death of patients with systemic sclerosis (SSc) throughout 20 years. METHODS: Data were collected from the Spanish Scleroderma Registry (RESCLE), retrospective multicentre database from 1990 to 2009. SSc-related and SSc-non related causes of death were assessed. RESULTS: 987 patients were recruited. Overall standardised mortality ratio (SMR) was 2.34 (2.24-2.44). SSc-related causes of death were responsible of 72% of all deaths of those patients diagnosed within 1990-99 vs. 48% within 2000-09 (p=0.006). Relative pulmonary death rate was stable over time (68.1% within 1990-99 vs. 63.9% within 2000-09, p=0.815). Relative renal death rate was decreasing over time (17% within 1990-99 vs. 5.5% within 2000-09, p=0.175). Heart distribution tripled its ratio (12.8% within 1990-99 vs. 30.6% within 2000-09, p=0.058). CONCLUSIONS: SSc-related causes of death were decreasing over time and, among them, pulmonary involvement was the leading cause of death in both decades. The ratio of renal causes decreased since 1990 at the time that the ratio of cardiac causes increased.

Applying the ACR/EULAR Systemic Sclerosis Classification Criteria to the Spanish Scleroderma Registry Cohort.

OBJECTIVE: To compare American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for systemic sclerosis (SSc) with previous American Rheumatology Association (ARA) criteria. METHODS: This was a cross-sectional multicenter study comparing sensitivity of both criteria in the cutaneous subsets in the Spanish scleroderma registry (RESCLE) cohort. RESULTS: In 1222 patients with SSc, the most prevalent items were Raynaud phenomenon (95%), skin thickening (91%), and abnormal capillaroscopy (89%). ARA criteria classified as SSc 63.5% of all patients, and 63%, 100%, 11.2%, and 0% in the limited, diffuse, sine, and pre-SSc subsets, respectively. ACR/EULAR criteria classified 87.5% of all patients and 98.5%, 100%, 41.8%, and 15.9% in the same subsets, respectively. CONCLUSION: ACR/EULAR criteria are more sensitive than ARA criteria, especially in limited, sine, and pre-SSc subsets.

Prevalencia de la infección por Trypanosoma cruzi y transmisión vertical en mujeres gestantes latinoamericanas en un área de salud de Vizcaya / Prevalence of Trypanosoma cruzi infection and vertical transmission in Latin-American pregnant women in a health area of Biscay

Objetivos Determinar la prevalencia de la infección por Trypanosoma cruzi, los factores epidemiológicos asociados y el riesgo de transmisión materno-fetal en las mujeres gestantes procedentes de zonas endémicas atendidas en el área de influencia del Hospital de Cruces (País Vasco, España).Métodos Estudio descriptivo. Diagnóstico de la infección por T. cruzi en las mujeres gestantes y en neonatos por serología y detección del parásito mediante PCR. Encuesta epidemiológica y análisis multivariante para identificación de los factores de riesgo asociados a la infección por T. cruzi. Resultados Se incluyeron en el estudio un total de 158 mujeres atendidas entre el 15 de diciembre de 2008 y el 15 de enero de 2010, con una edad media de 28,5 (±5,3) años. Diecinueve (12,0%) gestantes presentaban infección por T. cruzi, de las cuales 16 (84,2%) procedían de Bolivia, con una prevalencia en estas del 22,2%. Los factores de riesgo epidemiológicos que se asociaron de forma independiente con la infección por T. cruzi fueron el antecedente de residencia en casa de adobe (OR: 4,62; IC95%: 1,54-13,87; p=0,006) y el conocimiento del vector (OR: 9,07; IC95%: 1,91-43,11; p=0,006). Hubo un recién nacido infectado, lo que supone una tasa de transmisión congénita del 5,8%.ConclusionesLa elevada prevalencia detectada de infección por T. cruzi en mujeres gestantes latinoamericanas y el riesgo de transmisión vertical hacen recomendable la implantación de programas de cribado basados fundamentalmente en la identificación del origen geográfico y variables epidemiológicas (AU)

Objectives To estimate the prevalence of Trypanosoma cruzi infection, the epidemiological factors associated with it, and the risk of maternal-foetal transmission in pregnant women from endemic areas seen in the catchment area of Cruces Hospital (Basque Country, Spain).Methods Descriptive study. Diagnosis of T. cruzi infection in pregnant women and neonates by performing serological tests and parasitological diagnosis using PCR. Epidemiological survey and multivariate analysis to identify the risk factors associated with T. cruzi infection. Results A total of 158 women participated in the study between December 2008 and January 2010, with mean age of 28.5 (±5.3). Nineteen (12%) pregnant mothers were seropositive, of whom 16 (84.2%) came from Bolivia, with a prevalence, in this group, of 22.2%. Independent epidemiological risk factors associated with T. cruzi infection were a history of living in mud houses (OR: 4.62; 95%IC: 1.54-13.87; P=.006) and knowledge of the vector (OR: 9.07; 95%IC: 1.91-43.11; P=.006). There was one newborn infected, which assumed a congenital transmission rate of 5.8%ConclusionsOn the basis of the high prevalence of T. cruzi infection detected in Latin-American pregnant women and the risk of vertical transmission, a screening program would be recommended, which would be fundamentally based on the identification of geographic origin and epidemiological variables (AU)

[Prevalence of Trypanosoma cruzi infection and vertical transmission in Latin-American pregnant women in a health area of Biscay]. / Prevalencia de la infección por Trypanosoma cruzi y transmisión vertical en mujeres gestantes latinoamericanas en un área de salud de Vizcaya.

OBJECTIVES: To estimate the prevalence of Trypanosoma cruzi infection, the epidemiological factors associated with it, and the risk of maternal-foetal transmission in pregnant women from endemic areas seen in the catchment area of Cruces Hospital (Basque Country, Spain). METHODS: Descriptive study. Diagnosis of T. cruzi infection in pregnant women and neonates by performing serological tests and parasitological diagnosis using PCR. Epidemiological survey and multivariate analysis to identify the risk factors associated with T. cruzi infection. RESULTS: A total of 158 women participated in the study between December 2008 and January 2010, with mean age of 28.5 (±5.3). Nineteen (12%) pregnant mothers were seropositive, of whom 16 (84.2%) came from Bolivia, with a prevalence, in this group, of 22.2%. Independent epidemiological risk factors associated with T. cruzi infection were a history of living in mud houses (OR: 4.62; 95%IC: 1.54-13.87; P=.006) and knowledge of the vector (OR: 9.07; 95%IC: 1.91-43.11; P=.006). There was one newborn infected, which assumed a congenital transmission rate of 5.8% CONCLUSIONS: On the basis of the high prevalence of T. cruzi infection detected in Latin-American pregnant women and the risk of vertical transmission, a screening program would be recommended, which would be fundamentally based on the identification of geographic origin and epidemiological variables.

Registry of the Spanish network for systemic sclerosis: clinical pattern according to cutaneous subsets and immunological status.

OBJECTIVE: To investigate the incidence of clinical and immunological characteristics of a large cohort of Spanish patients with scleroderma (SSc) and identifying factors associated with particular organ manifestations assessed by a nationwide cross-sectional analysis. METHODS: We classified SSc patients in 4 subsets using a modification of LeRoy and Medsger classification that included: "prescleroderma" (pre-SSc), limited cutaneous SSc (lcSSc), diffuse cutaneous SSc (dcSSc), and SSc sine scleroderma (ssSSc). Fourteen Spanish centers participated in patient recruitment. On January 2008, the database included 916 consecutive Spanish SSc patients, 801 women (87.4%) and 115 men (12.6%), all of whom fulfilled the classification criteria proposed by LeRoy and Medsger. Epidemiological, clinical, and laboratory data were collected according to a standard protocol. Mean age at diagnosis was 51.2 ± 15.1 years and mean age at disease onset was 44.9.0 ± 15.8 years. lcSSc was the most frequent subset (61.8%) followed by dcSSc (26.5%), ssSSc (7.5%), and preSSc (4%) subsets. Gender ratios were as follows: dcSSc subset, 200 women and 43 men (4.7:1); lcSSc subset, 503 women and 63 men (ratio 7.9:1), and ssSSc subset, 62 women and 7 men (ratio 8.9:1). Digital ulcers, interstitial lung disease (ILD), musculoeskeletal and esophageal involvement, and scleroderma renal crisis were more frequent in dcSSc than lcSSc and ssSSc subsets. The incidence of pulmonary arterial hypertension assessed by echocardiography was similar in all subsets but mean estimated systolic pulmonary arterial pressure was higher in ssSSc than in lcSSc subset (47.3 ± 23.9 mm Hg vs 39.6 ± 19.2 mm Hg; P < 0.03). Cardiac involvement was identified more frequently in ssSSc than in dcSSc and lcSSc subsets (49.3% vs 32.5% and 31.1%, respectively; P = 0.015 and P = 0.004 for both comparisons). Acro-osteolysis (8.2% vs 2.4%, P = 0.049), calcinosis (19.8% vs 7.2%, P < 0.05), and sicca syndrome (37.5% vs 14.5%, P < 0.0001) were more frequent in lcSSc than in ssSSc subsets. The frequency of clinical manifestations related to the presence of anticentromere antibodies or antitopoisomerase I antibodies was very similar to that identified in patients categorized to lcSSc and dcSSc, respectively. However, in multivariate studies, the ranking of the variables according to their overall explanatory effect on the model showed that the contributory effect of the antibody status was not greater than that of the clinical categorization into lcSSc and dcSSc for the majority of disease manifestations, but, in important manifestations, as ILD, absence of anticentromere antibodies was an independent predictor factor. CONCLUSIONS: The classification of SSc into dcSSc, lcSSc, and ssSSc subsets is the one that most closely reflects the natural history of the disease, as they presented clear clinical differences. The immunological profile helps to define important visceral alteration as ILD. Finally, to improve early diagnosis of SSc, patients with preSSc should be considered both to trace the true evolution of the disease and to define which patients could benefit from therapeutic measures able to prevent the appearance of visceral involvements.

[Plasma homocysteine levels in systemic lupus erythematosus]. / Homocisteína plasmática en pacientes con lupus eritematoso sistémico.

BACKGROUND AND OBJECTIVE: Cardiovascular disease is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). An association between hyperhomocysteinemia and increased cardiovascular risk has been reported. On the other hand, renal failure and deficiency of vitamin B12 and/or folic acid are common causes of hyperhomocysteinemia. The aims of this study were to determine plasma total homocystein (tHcy) concentrations in SLE patients and to analyze the association of plasma tHcy with age, sex, plasma creatinine, vitamin B12, folates and total cholesterol, as well as with other clinical conditions linked to atherothrombosis in SLE patients. PATIENTS AND METHOD: Fasting plasma levels of tHcy, vitamin B12, folates, total cholesterol and creatinine were measured in 94 SLE patients (11 males, 83 females) and in a control group of 308 healthy volunteers (122 males, 186 females). A review of the medical records of SLE patients was performed. RESULTS: Plasma tHcy concentrations were higher in patients with SLE (median 10.54 (mol/L) than in controls (median 8.49 (mol/L, p < 0.001). Hyperhomocysteinemia (tHcy >=15 (mol/L) was found in 17.02% SLE patients. In a multivariate analysis, plasma creatinine (p < 0.001), total cholesterol (p = 0.038), male sex (p = 0.003) and smoking (p = 0.001) were associated with higher plasma tHcy concentrations. No associations were found between plasma tHcy and hypertension, SLE duration, prednisone therapy and antiphospholipid antibodies. CONCLUSIONS: Plasma tHcy concentrations are higher in SLE patients than in healthy controls. High concentrations of plasma creatinine and total plasma cholesterol, male sex and smoking are associated with a higher concentration of plasma tHcy in SLE. Since the clinical consequences of hyperhomocysteinemia are not well established, routine determination of plasmatic tHcy and supplemental therapy in patients with high levels of tHcy are not recommended.

Homocisteína plasmática en pacientes con lupuseritematoso sistémico / Plasma homocysteine levels in systemic lupus erythematosus

FUNDAMENTO Y OBJETIVO: Las complicaciones cardiovasculares son una causa importante de morbimortalidad en pacientes con lupus eritematoso sistémico (LES). Se ha descrito una asociación positiva entre hiperhomocisteinemia y riesgo cardiovascular. El déficit de vitamina B12 o ácido fólico y el deterioro de la función renal son causas frecuentes de hiperhomocisteinemia. El objetivo de este estudio fue determinar la concentración plasmática de homocisteína en pacientes con LES y analizar su relación con la edad, el sexo, valor de creatinina, vitamina B12 y folatos plasmáticos y ciertas condiciones clínicas asociadas con aterotrombosis en pacientes con LES. PACIENTES Y MÉTODO: Se determinaron las concentraciones plasmáticas de homocisteína, vitamina B12, folatos, colesterol total y creatinina en 94 pacientes (83 mujeres y 11 varones) diagnosticados de LES y en un grupo control de 308 voluntarios sanos (186 mujeres y 122 varones), y se revisaron los historiales clínicos de los pacientes con LES. RESULTADOS: Las concentraciones de homocisteína plasmática fueron superiores en los pacientes con LES (mediana: 10,54 (mol/l) respecto a los controles (mediana: 8,49 (mol/l; p < 0,001). La prevalencia de hiperhomocisteinemia (concentraciones iguales o superiores a 15 µmol/l) en los pacientes con LES fue del 17,02 por ciento. Mediante el análisis multivariante se encontró asociación entre homocisteína plasmática y colesterol plasmático (p = 0,038), sexo masculino (p = 0,003), creatinina plasmática (p < 0,001) y tabaquismo (p = 0,001) en los pacientes con LES. No se halló asociación entre homocisteinemia e hipertensión arterial, tiempo de evolución, tratamiento con glucocorticoides ni anticuerpos antifosfolípido. CONCLUSIONES: Las concentraciones plasmáticas de homocisteína en pacientes con LES son superiores a las de la población sana y se asocian directamente con el sexo masculino, tabaquismo y colesterol total y creatinina plasmáticos. A la espera de los resultados de los estudios intervencionistas con vitaminas en pacientes de alto riesgo, no está justificada la cuantificación sistemática de la homocisteína total ni su modificación farmacológica salvo en situaciones específicas (AU)