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Item does not contain fulltext OBJECTIVE: Real-world studies are needed to identify factors associated with response to biologic therapies in patients with axial spondyloarthritis (SpA). The objective was to assess sex differences in response to tumor necrosis factor inhibitors (TNFi) and to explore possible risk factors associated with TNFi efficacy. METHODS: A total of 969 patients with axial SpA (315 females, 654 males) enrolled in the BIOBADASER registry (2000-2019) who initiated a TNFi (first, second, or further lines) were studied. Statistical and artificial intelligence (AI)-based data analyses were used to explore the association of sex differences and other factors to TNFi response, using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), to calculate the BASDAI50, with an improvement of at least 50% of the BASDAI score, and using the Ankylosing Spondylitis Disease Activity Score, calculated using the C-reactive protein level (ASDAS-CRP). RESULTS: Females had a lower probability of reaching a BASDAI50 response with a first line TNFi treatment at the second year of follow-up (P = 0.018) and a lesser reduction of the ASDAS-CRP at this time point. The logistic regression model showed lower BASDAI50 responses to TNFi in females (P = 0.05). Other factors, such as older age (P = 0.004), were associated with unfavorable responses. The AI data analyses reinforced the idea that age at the beginning of the treatment was the main factor associated with an unfavorable response. The combination of age with other clinical characteristics (female sex or cardiovascular risk factors and events) potentially contributed to an unfavorable response to TNFi. CONCLUSION: In this national multicenter registry, female sex was associated with less response to a first-line TNFi by the second year of follow-up. A higher age at the start of the TNFi was the main factor associated with an unfavorable response to TNFi. 01 januari 2023

To assess the golimumab retention rate during up to 8 years of follow up, and any associated factors.Retrospective analysis of the BIOBADASER (Spanish registry of biological drugs) database, assessing all adults who had ever started golimumab6 months before the analysis for an approved indication (rheumatoid arthritis [RA], axial spondyloarthritis [SpA] or psoriatic arthritis [PsA]).Among 885 patients (RA 267, axial SpA 370, PsA 248) receiving 944 cycles of golimumab, the retention rate of golimumab was 71.1% (95% confidence interval: 68.0-73.9) at year 1% and 37.7% (95% CI: 33.3-42.1) at year 7 and at year 8. Retention was higher when golimumab was used as the first biological drug (81.7% at year 1, 49.9% at year 7, p 0.001). In Cox regression analysis, factors associated with golimumab retention included use as first-line therapy (hazard ratio [HR] for discontinuation 1.52 for second- and 1.79 for third/later-line vs. first-line), use in axial SpA or PsA rather than RA (HR for axial SpA vs. RA 0.59, for PsA vs. Rheumatoid arthritis 0.67), and treatment with concomitant methotrexate (HR 0.67). Factors associated with golimumab discontinuation were corticosteroid use (HR 1.46) and disease activity above median (HR 1.29) at golimumab initiation.Based on this retrospective analysis of the BIOBADASER registry, nearly two-fifths (37.7%) of adult rheumatology patients initiating golimumab will remain on treatment for 8 years, with a higher probability of retention in axial SpA or PsA indications and when golimumab is used as first biologic.

Objetivos Describir la metodología del Registro de pacientes con miopatía inflamatoria idiopática (MII) de España (Myo-Spain), así como sus fortalezas y limitaciones. El objetivo principal del proyecto es analizar la evolución y el manejo clínico de una cohorte de pacientes con MII. Material y método Estudio observacional, longitudinal, ambispectivo y multicéntrico de una cohorte de pacientes con MII atendidos en servicios de reumatología de España. Se incluirán todos los pacientes con diagnóstico de MII en seguimiento habitual por los centros participantes, sin tener en cuenta la edad de inicio del proceso. Los casos incidentes serán todos los pacientes que al inicio del estudio en cada centro estén diagnosticados desde hace menos de 12 meses y casos prevalentes desde hace más de 12 meses. Se construirá un registro en el que se incluirán los datos de la visita basal, del año y dos años. Se recogerán variables sociodemográficas, clínicas, analíticas, complicaciones, comorbilidad, asociación con otras enfermedades reumáticas, ingresos hospitalarios, mortalidad y tratamientos. Además, se determinarán índices, escalas y cuestionarios de actividad, afectación muscular, daño, discapacidad y calidad de vida. El periodo de reclutamiento será de 23 meses. El propósito es conseguir una cohorte de 400 pacientes con MII. Conclusiones El estudio Myo-Spain constituye la oportunidad para desarrollar una cohorte de pacientes incidentes y prevalentes con MII en España. Myo-Spain permitirá evaluar en detalle, las características clínicas de la enfermedad en diferentes momentos. Se espera que la información exhaustiva recogida en las visitas suponga una amplia fuente de datos para futuros análisis. Objectives: To describe the methods of the Spanish Registry of patients with idiopathic inflammatory myopathy (IIM) (Myo-Spain), as well as its strengths and limitations. The main objective of the project is to analyse the evolution and clinical management of a cohort of patients with IIM. Methods: Observational, longitudinal, ambispective and multicentre study of a cohort of patients with IIM seen in rheumatology units in Spain. All patients with a diagnosis of IMM will be included in the regular follow-up of the participating centres, regardless of age on initiation of the process. Incident cases will be all patients who at the beginning of the study have been diagnosed for less than 12 months and prevalent cases for more than 12 months. The registry will include data from the visit at baseline, one year and two years. Socio-demographic, clinical, analytical variables, complications, comorbidities, association with other rheumatic diseases, hospital admissions, mortality and treatments will be collected. In addition, indices, scales and questionnaires of activity, muscle involvement, damage, disability, and quality of life will be determined. The recruitment period will be 23 months. The purpose is to obtain a cohort of 400 patients with IMM. Conclusions: Myo-Spain registry provides the opportunity to develop a cohort of incident and prevalent patients with IMM in Spain. Myo-Spain will be able to assess in detail the clinical characteristics of the disease at different times. The comprehensive information collected during the visits is expected to provide a broad source of data for future analysis. Sin financiación No data JCR 2021 0.311 SJR (2021) Q3, 44/61 Rheumatology No data IDR 2021 UEM

ObjectivesTo evaluate effectiveness and safety of certolizumab pegol (CZP) in uveitis due to immune-mediated inflammatory diseases (IMID).MethodsMulticentre study of CZP-treated patients with IMID uveitis refractory to conventional immunosuppressant. Effectiveness was assessed through the following ocular parameters: best-corrected visual acuity, anterior chamber cells, vitritis, macular thickness and retinal vasculitis. These variables were compared between the baseline, and first week, first, third, sixth months, first and second year.ResultsWe studied 80 (33 men/47 women) patients (111 affected eyes) with a mean age of 41.6±11.7 years. The IMID included were: spondyloarthritis (n=43), Behçet’s disease (n=10), psoriatic arthritis (n=8), Crohn’s disease (n=4), sarcoidosis (n=2), juvenile idiopathic arthritis (n=1), reactive arthritis (n=1), rheumatoid arthritis (n=1), relapsing polychondritis (n=1),ConclusionsCZP seems to be effective and safe in uveitis related to different IMID, even in patients refractory to previous biological drugs.

Rheumatic diseases are extensively managed with biological disease-modifying antirheumatic drugs (bDMARDs), but a notable proportion of patients withdraw in the long term because of lack of effectiveness, adverse events, or the patient's decision. The present real-world analysis showed the effectiveness, retention, and safety data collected in the Spanish BIOBADASER registry for patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA, including ankylosing spondylitis (AS) and non-radiographic axSpA) treated with secukinumab, a human antibody against interleukin-17A (IL-17A), for more than 12 months. Six hundred and thirty-nine patients were analysed (350, 262, and 27 PsA, AS, and nr-axSpA patients, respectively). The results showed an improvement in the disease activity after 1 year of treatment, in terms of decreases of the mean Disease Activity Score 28 using C-reactive protein (DAS28-CRP), the mean Disease Activity Psoriatic Arthritis (DAPSA) score, swollen joint counts (SJC), and tender joint counts (TJC) in PsA patients and decreases in the mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the mean Ankylosing Spondylitis Disease Activity Score (ASDAS) in axSpA patients. This improvement was maintained or increased after 2 and 3 years of treatment, indicating that secukinumab is effective in both naïve and non-responder patients. Retention rates were higher when secukinumab was used as the first-line biological treatment, although they were also adequate in the second and third lines of treatment. Collected safety data were consistent with previous reports.

Objectives To assess efficacy and safety of biologic therapy (BT) in neurobehçet’s disease (NBD) refractory to glucocorticoids and at least one conventional immunosuppressive drug. Methods Open-label, national, multicentre study. NBD diagnosis was based on the International Consensus Recommendation criteria. Outcome variables were efficacy and safety. Main efficacy outcome was clinical remission. Other outcome variables analysed were glucocorticoid-sparing effect and improvement in laboratory parameters. Results We studied 41 patients [21 women; age 40.6 (10.8) years]. Neurological damage was parenchymal (n = 33, 80.5%) and non-parenchymal (n = 17, 41.5%). First BTs used were infliximab (n = 19), adalimumab (n = 14), golimumab (n = 3), tocilizumab (n = 3) and etanercept (n = 2). After 6 months of BT, neurological remission was complete (n = 23, 56.1%), partial (n = 15, 37.6%) and no response (n = 3, 7.3%). In addition, median (IQR) dose of oral prednisone decreased from 60 (30–60) mg/day at the initial visit to 5 (3.8–10) mg/day after 6 months (P Conclusions BT appears to be effective and relatively safe in refractory NBD.

Objectives To describe the methods of the Spanish Registry of patients with idiopathic inflammatory myopathy (IIM) (Myo-Spain), as well as its strengths and limitations. The main objective of the project is to analyse the evolution and clinical management of a cohort of patients with IIM. Methods Observational, longitudinal, ambispective and multicentre study of a cohort of patients with IIM seen in rheumatology units in Spain. All patients with a diagnosis of IMM will be included in the regular follow-up of the participating centres, regardless of age on initiation of the process. Incident cases will be all patients who at the beginning of the study have been diagnosed for less than 12 months and prevalent cases for more than 12 months. The registry will include data from the visit at baseline, one year and two years. Socio-demographic, clinical, analytical variables, complications, comorbidities, association with other rheumatic diseases, hospital admissions, mortality and treatments will be collected. In addition, indices, scales and questionnaires of activity, muscle involvement, damage, disability, and quality of life will be determined. The recruitment period will be 23 months. The purpose is to obtain a cohort of 400 patients with IMM. Conclusions Myo-Spain registry provides the opportunity to develop a cohort of incident and prevalent patients with IMM in Spain. Myo-Spain will be able to assess in detail the clinical characteristics of the disease at different times. The comprehensive information collected during the visits is expected to provide a broad source of data for future analysis.

Background: Systemic sclerosis (SS) is an autoimmune disease of unknown etiology, characterized by the presence of fibrosis and vasculopathy in skin and multiple internal organs such as the lungs, the kidneys and the digestive tract. The course of the disease is unpredictable and could remain relatively stable or have a rapid evolution. Multiple studies have been carried out to determine the clinical characteristics and survival prognosis on SS patients. Objectives: To analyze the demographic characteristics, clinical features, treatment and prognosis in a SS disease cohort. Methods: We performed an observational and retrospective study of patients whit SS. The patients had been attended by the Rheumatology department of a tertiary care hospital. We collected demographic, clinical and analytical variables, as well as treatment and prognosis. We classified the disease employing the LeRoy and Medsger, VEDOSS criteria and 2013 aCR/EULAR criteria. Results: Of our 43 patients, 36 (83.7%) were female and only 7 (16.3%) were male. The average age was 60.4 years (SD 15.6), the average age at diagnosis was 53.3 years (SD 17.6) and the mean time of evolution of the disease was 7.9 years (SD 6.3). Of all the patients, 3 patients (6.9%) died, the mean age at death being 53.6 years (SD 23.7) and the mean time from diagnosis to death of 19 years (SD 10.1). The most frequently ocurring presentation was limited SS (with 18 patients (41.9%), followed by preescleroderma with 14 patients (32.6%), diffuse SS with 6 patients (14%) and escleroderma sine escleroderma with 2 patients (4.7%). Three patients (7%) were labeled with MCTD. SS was associated with other autoimmune diseases in 20% of patients. Five (11.6%) patients developed neoplasms throughout the course of the study. The rest of the clinical characteristics are listed in Table 1 and 2, as well as the strength of association of these with the type of SS, calculated using chi square and Fischer test. Conclusion: Worthy of noting in our cohort is the absence of scleroderma in more than 40% of our patients, probably because the new criteria have allowed us to diagnose the disease at an earlier stage and also due to the scarce frequency of puffy fingers with respect to other larger series. Digestive involvement was the most frequent visceral manifestation, followed by pulmonary manifestations, specifically interstitial lung disease (ILD). Despite the small sample size, lung disease was significantly associated with the two forms of systemic sclerosis, but not with the antibody pattern. Both the ILD and the pulmonary arterial hypertension (PAH) were more frequent in patients with SSd. Mortality in all cases was due to interstitial lung involvement. As is frequently described, SS is associated with other systemic autoimmune diseases, constituting an overlap syndrome. References [1] Canete Crespillo, J. (2008). Manual SER de las enfermedades reumaticas. Madrid: Editorial Medica Panamericana [2] Dougherty, D., Kwakkenbos, L., Carrier, M., Salazar, G., assassi, S., Baron, M., Bartlett, S., Furst, D., Gottesman, K., van den Hoogen, F., Malcarne, V., Mouthon, L., Nielson, W., Poiraudeau, S., Sauve, M., Boire, G., Bruns, a., Chung, L., Denton, C., Dunne, J., fortin, P., Frech, T., Gill, a., Gordon, J., Herrick, a., Hinchcliff, M., Hudson, M., Johnson, S., Jones, N., Kafaja, S., Larche, M., Manning, J., Pope, J., Spiera, R., Steen, V., Sutton, E., Thorne, C., Wilcox, P., Thombs, B. And Mayes, M. (2018). The Scleroderma Patient-Centered intervention Network Cohort: baseline clinical features and comparison with other large scleroderma cohorts. Rheumatology, 57(9), pp.1623-1631. [3] CLINICAL FEATURES aND PROGNOSTIC FACTORS for SYSTEMIC SCLEROSIS RELATED inTERSTITIAL LUNG DISEASE. (2018). Respirology, 23, pp.155-155. Disclosure of interests: None declared

Background: Behcet’s disease (BD) is a variable vessel vasculitis and typically presents with mucocutaneous involvement. However, any organ can be affected, being the neurological affectation (neurobehcet, NB) one of the most serious manifestations. Objectives: Our aim was to assess the efficacy and safety of biological therapy as treatment of NB. Methods: We set up a multicenter observational study of 29 patients with NB on treatment with biological therapy (BT). NB diagnosis was made by neuroimaging, CSF analysis and/or suggestive clinical signs of central and/or peripheral nervous system involvement, excluding infectious causes or more prevalent pathology. Results are expressed as mean±SD or as median and interquartile range (IQR) as appropriate. Results: 29 patients (15♂/14♀) with an average age of 39.6 ± 10.5 years. HLA-B51 was positive in 48.3% of the patients. Table shows the non-neurological manifestations. Regarding the neurological manifestations, 23 patients (79.3%) had parenchymal involvement (hemiparesis (n=6), brainstem involvement (n=1), encephalopathy (n = 4), optic neuropathy (n=3), dysphasia (n=1), polyneuropathy (n=6), cognitive impairment (n=4), and non-steroidal psychosis (n=1), while the remaining 6 patients (20.7%) presented aseptic meningitis as a non-parenchymal affectation (Table). Prior to BT, patients had received the following treatment: oral prednisone (n=27), methylprednisolone bolus (n=9), CsA (n=8), AZA (n=16), MTX (n=14) and mycophenolate (n=2). After a median of 31 [10-60] months since the beginning of the neurological symptoms, the following BT was initiated: infliximab (IFX)(n=17), adalimumab (ADA)(n=7), tocilizumab (TCZ) (n=2), golimumab (GOL) (n=2) and Etanercept (ETN) (n=1). A first switch to ADA was necessary in 8 patients with IFX due to primary failure. In addition, 2 of them needed a second switch to TCZ, getting a partial response. The BT was discontinued in 5 patients, 2 of them for obtaining clinical remission and the remaining 3 for inefficacy. After a median follow-up of 5.4±4.6 years, complete response was obtained in 15 patients, partial response in 11 and no response in the remaining 3. We observed an anaphylactic reaction and psoriasis induced by IFX, without other serious adverse events (Table). Conclusion: BT, especially anti-TNF, seems effective and safe for treatment in NB. Disclosure of Interests: Jose Luis Martin-Varillas: None declared, Inigo Gonzalez-Mazon: None declared, Belen Atienza-Mateo: None declared, Monica Calderon-Goercke: None declared, D. Prieto-Pena: None declared, Lara Sanchez Bilbao: None declared, Vanesa Calvo-Rio: None declared, Santos Castaneda Consultant for: Amgen, BMS, Pfizer, Lilly, MSD, Roche, Sanofi, UCB, Esther Vicente: None declared, Olga Maiz: None declared, Clara Moriano: None declared, Elvira Diez Alvarez: None declared, Jose Luis Andreu Sanchez: None declared, Concepcion Delgado Beltran: None declared, Marta Loredo Martinez: None declared, J. Narvaez Consultant for: Bristol-Myers Squibb, Angel Ramos Calvo: None declared, Francisca Sivera: None declared, Enrique Raya: None declared, Norberto Ortego: None declared, Jose Luis Callejas-Rubio: None declared, Anahy Brandy-Garcia: None declared, Alejandro Olive: None declared, Sabela Fernandez: None declared, Ricardo Gomez de la Torre: None declared, Ignacio Torre-Salaberri: None declared, Julio Sanchez: None declared, ANA URRUTICOECHEA-ARANA: None declared, Eva Salgado-Perez: None declared, Rafael Melero: None declared, Olga Martinez Gonzalez: None declared, Susana Romero-Yuste: None declared, Miguel A Gonzalez-Gay Grant/research support from: Prof. MA Gonzalez-Gay received grants/research supports from Abbvie, MSD, Jansen and Roche., Speakers bureau: Consultation fees/participation in company sponsored speaker’s bureau from Pfizer, Lilly, Sobi, Celgene, Novartis, Roche and Sanofi., Ricardo Blanco Grant/research support from: Abbvie, MSD, and Roche, Consultant for: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen, Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen

The complex chronic disease requires a model of care based found on multidisciplinary teams. The aim of this study was to analyse the development of nursing leadership in managing the complex chronic patient (CCP) and to identify how the resources for the attention and follow up of these patients are managed.A qualitative descriptive approach was followed through participant observation, in-depth interview to 7 health professionals (5 nurses, a doctor, and a social worker) and a discussion group with 9 Primary Health Care nurses from a intentional sample. Discourse analysis was undertaken following Conde approach: fixing discurse positions, creating and analyzing symbolic configuratons, analyzing and interpreting semantic configurations and drawing up the discourse.From discourse analysis two main dimensions emerged on the nursing leadership and management: a) nursing as the leader of care: the need of nursing leadership and of improvement in the coordination structures were recognized, and b) nursing as resources manager in the CCP care related to social and health risks and resources coordination.Our findings enhance the case management and the home delivery care as foundations to be effective handle of CCP, where nursing has a privileged role.

SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome is a cluster of osteo-cutaneous manifestations that can lead to serious complications such as thrombosis of the subclavian vein or superior vena cava, mainly in patients with significant inflammatory involvement of the anterior chest wall. The objective of this study was to review the cases published in the medical literature related with the presence of thrombotic complications in patients diagnosed with SAPHO syndrome and to try to determine their possible pathogenic mechanism and risk factors. We analyzed 11 published reports of isolated clinical cases or case series, a total of 144 patients, which described a total of 15 cases of venous thrombosis. The clinical characteristics of these patients, evaluated to determine whether they meet the ASAS criteria for axial and peripheral spondyloarthritis, are analyzed and the need for early diagnosis and treatment is highlighted.

espanolEste estudio evaluo una terapia, la respiracion manejada a voluntad, sobre la ansiedad y el estres en una poblacion con edades comprendidas entre 55 y 65 anos. Un total de 54 sujetos fueron asignados a un grupo de tratamiento, de informacion sobre estres, y a un grupo sin intervencion. Un diseno experimental con medidas repetidas para la evaluacion pretratamiento y postratamiento mostro, despues de 3 semanas, un descenso significativo en sintomas de estres en el grupo experimental. La variabilidad en los grupos y el pequeno numero de sesiones podria explicar que no se encontraran diferencias intergrupales significativas. EnglishThis study evaluated the differential efficacy of the voluntary management breathing therapy, in decreasing anxiety and stress in a population with ages between 55 and 65 years. 54 subjects were randomly assigned to a treatment group, an information group and a no-intervention group. An experimental design with repeated measures for evaluation was used (pre-treatment and post-treatment). After 3 weeks, the experimental group presented a lower stress symptomatology. The intragroup variability and the short number of sessions could explain that significant intergrupal differences were not found.

Resumen El sindrome SAPHO (sinovitis, acne, pustulosis, hiperostosis y osteitis) comprende un conjunto de manifestaciones cutaneo-osteoarticulares. Se han descrito algunas complicaciones graves que pueden aparecer durante la evolucion de la enfermedad, como la trombosis venosa, principalmente en pacientes que desarrollan afectacion inflamatoria grave de la pared toracica anterior. El objetivo de la presente revision fue analizar los casos descritos en la literatura medica relacionados con la presencia de complicaciones tromboticas en pacientes diagnosticados de sindrome SAPHO e intentar establecer los probables factores de riesgo y su posible mecanismo patogenico. Se analizaron 11 articulos publicados de casos clinicos aislados o series de casos, con un total de 144 pacientes, que describen en total 15 casos de trombosis venosa. Se exponen las caracteristicas clinicas de estos pacientes, se evalua si cumplen los criterios de clasificacion ASAS para espondiloatritis axial y periferica, y se resalta la necesidad de realizar un diagnostico y tratamiento precoces.

Background Plasma concentrations of lipoprotein (a) (Lp(a)), a lipoprotein with atherogenic and thrombogenic properties, have a strong genetic basis, although high concentrations of Lp(a) have also been reported in the context of inflammation, as in rheumatoid arthritis (RA). Few studies evaluate the impact of biologic therapies (BT) on Lp(a) in RA, taking into account that with these new therapies a better control of inflammation is achieved. Objective The aim of the study was to evaluate the plasma concentrations of Lp(a) in Spanish RA patients on BT attending rheumatology outpatient clinics. Methods Baseline analysis of the CARdiovascular in rheuMAtology project, a 10-year prospective study, evaluating the risk of cardiovascular events in RA and other forms of inflammatory arthritis. RA patients were classified according to treatment: no biologic, anti-tumor necrosis factor, anti-interleukin-6 receptor tocilizumab (TCZ), and other biologic (rituximab or abatacept). A model of linear multivariate regression was built in which the dependent variable was Lp(a) concentration and the explanatory variable was BT. The model was adjusted for confounding factors. Results Seven hundred and seventy-five RA patients were analyzed. Plasma concentrations of total cholesterol and triglyceride were significantly higher in TCZ-treated patients. Nevertheless, no significant difference in the atherogenic index between TCZ-treated patients and patients without BT was found. After adjusting for confounding factors, patients with BT had lower concentrations of Lp(a) than those without BT; however, only TCZ-treated patients achieved statistically significant differences (?: ?0.303, 95% confidence interval: ?0.558 to ?0.047; P = .02). Conclusions RA patients treated with TCZ show lower plasma concentrations of Lp(a) compared with patients without BT. This project has been supported by an unrestricted grant from Abbvie, Spain. The design, analysis, interpretation of results, and preparation of the article have been done independently of Abbvie. Dr González-Gay's studies have been supported by grants from “Fondo de Investigaciones Sanitarias” PI06/0024, PS09/00748, and PI12/00060 and RD12/0009/0013 (RIER) from “Instituto de Salud Carlos III” (ISCIII) (Spain).

Resumen Este trabajo pretende realizar una revision de los articulos publicados en relacion con los factores asociados al desarrollo de efectos secundarios en pacientes con artritis reumatoide (AR) tratados con anti-factor de necrosis tumoral alfa (anti-TNFα). Los efectos secundarios asociados mas relevantes estudiados en este trabajo son los procesos infecciosos, los episodios cardiovasculares, el desarrollo de neoplasias y el riesgo de mortalidad.