Manuel Rubio-Rivas

Mortality and survival in systemic sclerosis: Systematic review and meta-analysis

OBJECTIVE To determine the mortality, survival, and causes of death in patients with systemic sclerosis (SSc) through a meta-analysis of the observational studies published up to 2013. METHODS We performed a systematic review and meta-analysis of the observational studies in patients with SSc and mortality data from entire cohorts published in MEDLINE and SCOPUS up to July 2013. RESULTS A total of 17 studies were included in the mortality meta-analysis from 1964 to 2005 (mid-cohort years), with data from 9239 patients. The overall SMR was 2.72 (95% CI: 1.93-3.83). A total of 43 studies have been included in the survival meta-analysis, reporting data from 13,529 patients. Cumulative survival from onset (first Raynauds symptom) has been estimated at 87.6% at 5 years and 74.2% at 10 years, from onset (non-Raynauds first symptom) 84.1% at 5 years and 75.5% at 10 years, and from diagnosis 74.9% at 5 years and 62.5% at 10 years. Pulmonary involvement represented the main cause of death. CONCLUSIONS SSc presents a larger mortality than general population (SMR = 2.72). Cumulative survival from diagnosis has been estimated at 74.9% at 5 years and 62.5% at 10 years. Pulmonary involvement represented the main cause of death.

Predictors of long-term survival in nonagenarians: the NonaSantfeliu study

BACKGROUND few studies have prospectively evaluated long-term predictors of mortality in nonagenarians. OBJECTIVE to determine predictors of death in a nonagenarian cohort after 5 years of follow-up. DESIGN a prospective community-based study. SETTING a community-based study. SUBJECTS one hundred and eighty-six nonagenarians both living in the community and institutionalised. METHODS functional status was determined by the Lawton-Brody and Barthel Indexes (BI) and cognition by the Spanish version of the mental state examination (MEC). The Charlson Index was used to measure comorbidity. Nutritional status was evaluated by the short version of the Mini-Nutritional Assessment questionnaire. RESULTS mortality after 5 years was 75.53%. Patients who did not survive were significantly older, with lower cognitive and functional performance, with diminished visual acuity, higher comorbidity, high risk of malnutrition, higher number of drugs taken and a higher percentage of patients with the diagnosis of dyslipidaemia, heart failure or previous stroke. Cox regression analysis, identified the Charlson Index (hazard ratio 1.23, 95% CI 1.09-1.37) and MEC (hazard ratio 0.98, 95% CI 0.97-0.99) as independent predictors of mortality after 5 years. CONCLUSIONS better cognitive status and lesser comorbidity at baseline are the best predictors to identify which nonagenarians survived after a 5-year follow-up period.

Digital ulcers and cutaneous subsets of systemic sclerosis: Clinical, immunological, nailfold capillaroscopy, and survival differences in the Spanish RESCLE Registry

OBJECTIVE Digital ulcers (DU) are the most common vascular complication of systemic sclerosis (SSc). We compared the characteristics between patients with prior or current DU with those never affected and evaluated whether a history of DU may be a predictor of vascular, organ involvement, and/or death in patients with SSc. METHODS Data from SSc patients with or without prior or current DU were collected by 19 referral centers in an ongoing registry of Spanish SSc patients, named Registro de ESCLErodermia (RESCLE). Demographics, organ involvement, autoimmunity features, nailfold capillary pattern, survival time, and causes of death were analyzed to identify DU related characteristics and survival of the entire series and according to the following cutaneous subsets-diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc sine scleroderma (ssSSc). RESULTS Out of 1326, 552 patients enrolled in the RESCLE registry had prior or current DU, 88% were women, the mean age was 50 ± 16 years, and the mean disease duration from first SSc symptom was 7.6 ± 9.6 years. Many significant differences were observed in the univariate analysis between patients with and without prior/current DU. Multivariate analysis identified that history of prior/current DU in patients with SSc was independently associated to younger age at SSc diagnosis, diffuse cutaneous SSc, peripheral vascular manifestations such Raynauds phenomenon, telangiectasia, and acro-osteolysis but no other vascular features such as pulmonary arterial hypertension or scleroderma renal crisis. DU was also associated to calcinosis cutis, interstitial lung disease, as well as worse survival. Multivariate analysis performed in the cutaneous subsets showed that prior/current DU were independently associated: (1) in dcSSc, to younger age at SSc diagnosis, presence of telangiectasia and calcinosis and rarely a non-SSc pattern on nailfold capillaroscopy; (2) in lcSSc, to younger age at SSc diagnosis, presence of Raynauds phenomenon as well as calcinosis cutis, interstitial lung disease, and higher incidence of death from all causes; and (3) in ssSSc, to younger age at first SSc symptom and greater incidence of death from all causes. CONCLUSIONS Digital ulcers develop in patients with SSc younger at diagnosis, mainly in patients with dcSSc and lcSSc, and they are associated to other peripheral vascular manifestations such as Raynauds phenomenon, telangiectasia, and acro-osteolysis but also to calcinosis, and interstitial lung disease. History of DU in SSc leads to worse survival, also noticeable for lcSSc and ssSSc subsets but not for dcSSc patients.

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.

Hiponatremia en pacientes ancianos ingresados en una Unidad de Agudos de Geriatría. Prevalencia y pronóstico

BACKGROUND AND OBJECTIVE In order to analyze the prevalence of hyponatremia in in-hospital elderly patients and its prognosis factor value, we performed a transversal prospective study in an Acute Geriatric Unit (AGU). PATIENTS AND METHODS Two hundred and sixty in-hospital patients were collected prospectively in an AGU. Sociodemographic and lab data were collected as well as the Barthel, Pfeiffer and Charlson tests. A questionnaire was performed in hospital. Hyponatremia was considered when the plasmatic sodium was ≤134 mmol/l. RESULTS The sample consisted of 137 women (52.7%) and 123 men (47.3%). Mean age was 83.6 years (SD 7.9). Mean plasmatic sodium values were 137.3 mmol/l (range 112-168). Emergency lab tests showed 60 patients with hyponatremia (23.7%), 35 (13.6%) in the AGU. Cardiopulmonary were the most related diseases. Mean hospital length of stay was 12.8 days (SD 12.8). In-hospital mortality was 12.9%. We observed a statistic relationship between the presence of hyponatremia and a greater mean length of stay (15.53 vs 11.99 days, P=.003). No relationship was found between hyponatremia and mortality (15 vs 12.7%, P=.588). CONCLUSION Hyponatremia in patients admitted in an AGU is a prevalent disorder related with a greater hospital length of stay, but not with mortality.

Analysis of ATP8B4 F436L Missense Variant in a Large Systemic Sclerosis Cohort

Over the last 7 years, knowledge of the systemic sclerosis (SSc) genetic component has increased considerably, due mainly to large genetic studies including genome-wide association studies (GWAS) and Immunochip analysis. However, there is still a large portion of SSc heritability that remains unexplained, as is the case with most complex traits (1). One hypothesis that has been proposed to explain the missing heritability for complex diseases involves rare and low-frequency variants. These types of genetic variations are not well covered by GWAS, which are mainly focused on common variants. However, the use of next-generation sequencing technologies, such as whole-exome sequencing, has rapidly overcome this problem. In this regard, Gao et al performed, for the first time, whole-exome sequencing in SSc and reported a novel gene, ATP8B4, as a risk factor for the disease (2). They suggested a missense rare variant (F436L [rs55687265]) as a potential causal variant for the association signal in ATP8B4. We therefore aimed to further evaluate the reported signal of association, taking advantage of our access to large cohorts of patients with SSc. The ATP8B4 rare variant rs55687265 was genotyped in 6 independent case–control cohorts of European ancestry (total 7,426 SSc patients and 13,087 healthy controls) (see Supplementary Table 1, on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.40058/abstract). All SSc patients fulfilled the American College of Rheumatology 1980 preliminary classification criteria for the disease (3) or exhibited at least 3 of 5 features of CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) (4). We first performed association analyses to test whether rs55687265 was associated with SSc susceptibility in each of the cohorts included in the present study (see Supplementary Methods, http://onlinelibrary.wiley.com/doi/10.1002/ art.40058/abstract). A trend toward association (P 5 0.071) was observed in the Spanish case–control set (odds ratio [OR] 1.58) (Table 1). However, we did not observe any suggestive or significant association signal in the remaining cohorts. We also observed opposite effects for the same allele in different populations. The meta-analysis combining all of the sample sets, which was performed using an inverse variance fixed-effects model, showed no significant association with the disease (OR 1.07, P 5 0.484) (Table 1 and Supplementary Methods). In addition, stratified analysis based on different clinical sub-phenotypes of SSc (limited and diffuse cutaneous subtypes, and the presence of the SSc-specific autoantibodies anticentromere and anti–topoisomerase I) did not show significant associations (data not shown). Thus, we did not find statistically significant differences in the frequency of the ATP8B4 rs55687265*C allele between the SSc patients and controls enrolled in the study. A meta-analysis combining the results of the present study with the results from the discovery phase of the study reported by Gao et al (2) was also performed, and again no significant P value was found (OR 1.36, Prandom 5 0.212, heterogeneity q value , 0.01, I 2 5 82.68). The impact of rare variants on the development of autoimmune diseases remains an unanswered and controversial question (5). Moreover, it has long been recognized that the identification of rare variant associations with highthroughput DNA sequencing technologies, such as wholeexome sequencing, is substantially affected by technical artifacts, which may lead to Type I error. This issue becomes especially important when the sample size of the whole-exome sequencing study is not large enough, and when there is a large difference between the case cohort size and the control cohort size (6,7). The present study highlights the importance of validation of whole-exome sequencing results with other sequencing methods, as well as replication of the newly observed associations in independent studies, in order to detect actual disease-causing mutations. In conclusion, in the present study we could not replicate the association of ATP8B4 rs55687265 with susceptibility to SSc. However, because we did not attempt to evaluate associations of other rare or common variants with SSc

Ictus de repetición como presentación de una arteritis de células gigantes

uy controvertida por la afectación multiorgánica y la probabilidad e recidiva sobre el órgano trasplantado7,8. En casos seleccionaos, la estrategia más aceptada sería realizar primero el trasplante ardiaco (de alto riesgo) y después el tratamiento etiológico de la miloidosis (quimioterapia y/o trasplante de MO)7. La formación de equipos multidisciplinarios que permitiesen un ratamiento integral que incluya trasplante multiorgánico, junto a a aparición de tratamientos más efectivos y nuevas técnicas para l diagnóstico y monitorización del tratamiento, contribuirían sin uda a mejorar el pronóstico de esta enfermedad8.

Carta científicaIctus de repetición como presentación de una arteritis de células gigantesRepetition stroke as onset of giant cell arteritis

uy controvertida por la afectación multiorgánica y la probabilidad e recidiva sobre el órgano trasplantado7,8. En casos seleccionaos, la estrategia más aceptada sería realizar primero el trasplante ardiaco (de alto riesgo) y después el tratamiento etiológico de la miloidosis (quimioterapia y/o trasplante de MO)7. La formación de equipos multidisciplinarios que permitiesen un ratamiento integral que incluya trasplante multiorgánico, junto a a aparición de tratamientos más efectivos y nuevas técnicas para l diagnóstico y monitorización del tratamiento, contribuirían sin uda a mejorar el pronóstico de esta enfermedad8.

Multidisciplinary approach and long-term follow-up in a series of 640 consecutive patients with sarcoidosis: Cohort study of a 40-year clinical experience at a tertiary referral center in Barcelona, Spain

Abstract Cohort studies of large series of patients with sarcoidosis over a long period of time are scarce. The aim of this study is to report a 40-year clinical experience of a large series of patients at Bellvitge University Hospital, a tertiary university hospital in Barcelona, Spain. Diagnosis of sarcoidosis required histological confirmation except in certain specific situations. All patients underwent a prospective study protocol. Clinical assessment and follow-up of patients were performed by a multidisciplinary team. From 1976 to 2015, 640 patients were diagnosed with sarcoidosis, 438 of them (68.4%) were female (sex ratio F/M 2:1). The mean age at diagnosis was 43.3 ± 13.8 years (range, 14–86 years), and 613 patients (95.8%) were Caucasian. At diagnosis, 584 patients (91.2%) showed intrathoracic involvement at chest radiograph, and most of the patients had normal pulmonary function. Erythema nodosum (39.8%) and specific cutaneous lesions (20.8%) were the most frequent extrapulmonary manifestations, but there was a wide range of organ involvement. A total of 492 patients (76.8%) had positive histology. Follow-up was carried out in 587 patients (91.7%), over a mean of 112.4 ± 98.3 months (range, 6.4–475 months). Corticosteroid treatment was administered in 255 patients (43.4%), and steroid-sparing agents in 49 patients (7.7%). Outcomes were as follows: 111 patients (18.9%) showed active disease at the time of closing this study, 250 (42.6%) presented spontaneous remission, 61 (10.4%) had remission under treatment, and 165 (28.1%) evolved to chronic sarcoidosis; among them, 115 (19.6%) with mild disease and 50 (8.5%) with moderate to severe organ damage. A multivariate analysis showed that at diagnosis, age more than 40 years, the presence of pulmonary involvement on chest radiograph, splenic involvement, and the need of treatment, was associated with chronic sarcoidosis, whereas Löfgren syndrome and mediastinal lymphadenopathy on chest radiograph were indicators of good outcome. Sarcoidosis is a multisystem disease with protean clinical-radiographic manifestations. Although almost half of patients follow a spontaneous resolution or under treatment, a significant number of them may have several degrees of organ damage. This study emphasizes the value of a multidisciplinary approach and long-term follow-up by specialized teams in sarcoidosis.

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.