Obtención de imágenes anatómicas de articulaciones correlacionadas con imágenes de resonancia magnética para el aprendizaje auto-dirigido de la anatomía topográfica del miembro inferior

Se trata de la continuación del PIMCD2015/166 titulado "Obtención de imágenes anatómicas de huesos y articulaciones correlacionadas con RX y RM para el aprendizaje auto-dirigido de la anatomía topográfica del miembro inferior". El volumnen de trabajo a realizar en el plazo establecido no nos ha permitido completar el apartado correspondiente a las articulaciones. En el presente proyecto, nos hemos planteado el desarrollo de un sistema interactivo para mejorar el proceso de enseñanza-aprendizaje en la docencia de la artrología del miembro inferior, que pueda ser utilizado por los alumnos de Grado de Ciencias de la Salud. Su acceso será a través del campus virtual facilitando al alumno una herramienta dinámica de libre disposición durante el periodo en el que se imparte la asignatura de Anatomía, pudiendo disponer de las imágenes durante un tiempo superior al programado en el plan docente, lo que facilitará el estudio de una materia cuyo aprendizaje se basa sobre todo en la memoria visual. En una primera fase, se disecarán las articulaciones de la cadera, rodilla, tobillo y del resto del pie, para lo que se utilizarán piezas fijadas en formaldehído al 10% procedentes del depósito del Departamento de Anatomía y Embriología Humanas. Una vez disecadas las articulaciones, se fotografiarán y, posteriormente, se identificarán y rotularán los elementos anatómicos. En una segunda fase, las imágenes de las articulaciones se correlacionarán con imágenes de Resonancia Magnética (RM) obtenidas a partir de pacientes; se seleccionarán las imágenes de RM más representativas en el estudio de las articulaciones del miembro inferior; se identificarán y rotularán los elementos anatómicos visualizados en las imágenes de RM seleccionadas. En una tercera fase, se va a desarrollar una aplicación informática que permita interactuar con las imágenes anatómicas y radiológicas. La aplicación se basa fundamentalmente en dos plantillas, una para la visualización y estudio de las imágenes anatómicas y de RM, con los distintos elementos anatómicos identificados y otra para comprobar los conocimientos adquirido

Evidence of association of the NLRP1 gene with giant cell arteritis

Recent studies have focused attention on the involvement of NLRP1 to confer susceptibility for extended autoimmune/inflammatory disorders, being considered a common risk factor in autoimmunity. NLRP1 provides a scaffold for the assembly of the inflammasome that activates caspases 1 and 5, required for processing and activation of the proinflammatory cytokines interleukin 1β (IL-1β), IL-18 and IL-33 and promoting inflammation

Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis

Objective: To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA). Methods: Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays. Results: The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (PFDR=1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (PMH=2.00E-06, OR=1.51, CI 95% 1.28 to 1.79). Conclusions: Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA

Standardized incidence ratios and risk factors for cancer in patients with systemic sclerosis: Data from the Spanish Scleroderma Registry (RESCLE)

Aim: Patients with systemic sclerosis (SSc) are at increased risk of cancer, a growing cause of non-SSc-related death among these patients. We analyzed the increased cancer risk among Spanish patients with SSc using standardized incidence ratios (SIRs) and identified independent cancer risk factors in this population. Material and methods: Spanish Scleroderma Registry data were analyzed to determine the demographic characteristics of patients with SSc, and logistic regression was used to identify cancer risk factors. SIRs with 95% confidence intervals (CIs) relative to the general Spanish population were calculated. Results: Of 1930 patients with SSc, 206 had cancer, most commonly breast, lung, hematological, and colorectal cancers. Patients with SSc had increased risks of overall cancer (SIR 1.48, 95% CI 1.36-1.60; P < 0.001), and of lung (SIR 2.22, 95% CI 1.77-2.73; P < 0.001), breast (SIR 1.31, 95% CI 1.10-1.54; P = 0.003), and hematological (SIR 2.03, 95% CI 1.52-2.62; P < 0.001) cancers. Cancer was associated with older age at SSc onset (odds ratio [OR] 1.22, 95% CI 1.01-1.03; P < 0.001), the presence of primary biliary cholangitis (OR 2.35, 95% CI 1.18-4.68; P = 0.015) and forced vital capacity <70% (OR 1.8, 95% CI 1.24-2.70; P = 0.002). The presence of anticentromere antibodies lowered the risk of cancer (OR 0.66, 95% CI 0.45-0.97; P = 0.036). Conclusions: Spanish patients with SSc had an increased cancer risk compared with the general population. Some characteristics, including specific autoantibodies, may be related to this increased risk

A genome-wide association study identifies risk alleles in plasminogen and P4HA2 associated with giant cell arteritis

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analysed in 2,134 cases and 9,125 unaffected controls from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, P = 1.94E-54, per-allele OR = 1.79; and rs9275592, P = 1.14E-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, P = 1.23E-10, OR = 1.28; and rs128738, P = 4.60E-09, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis

A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility

We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10−40, OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1∗04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10−43) and HLA-DQα1 47 (p = 4.02 × 10−46), 56, and 76 (both p = 1.84 × 10−45) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10−6, OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10−6, OR = 1.20), and REL (rs115674477, p = 1.10 × 10−5, OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function

Esclerosis sistémica y enfermedad hepato-biliar: Estudio bidireccional de la relación entre la esclerosis sistémica y la enfermedad hepato-biliar

La esclerosis sistémica (ES) es una enfermedad autoinmune sistémica (EAS) que puede afectar a la mayoría de órganos internos mediante la acumulación de colágeno en los tejidos y/o desarrollo de una vasculopatía obliterante, en un entorno de disfunción autoinmune. Aunque la disfunción hepato-biliar (DHB) no es un hallazgo infrecuente en la ES, su presencia no se considera característica de la enfermedad y se han publicado pocos estudios que valoren la relación bidireccional entre la ES y la DHB, en particular autoinmune órgano-específica. El primer artículo de esta Tesis doctoral es un estudio observacional multicéntrico Español de 1572 pacientes con ES y como objetivos establece la prevalencia de DHB en pacientes con ES y enumera las causas que son predominantemente autoinmunes órgano-específicas, como la colangitis biliar primaria (CBP) en 4.3% y la hepatitis autoinmune en 1.2% y CBP sin anticuerpos antimitocondria en 0.4%.. La presencia de DHB en pacientes con ES se asocia independientemente a un menor riesgo de padecer una ES cutánea difusa y a una mayor prevalencia de calcinosis cutánea, disfunción diastólica de ventrículo izquierdo, síndrome seco y positividad de los anticuerpos anticentrómero (ACA). La presencia de DHB no influyó en la supervivencia. Según los subtipos cutáneos, la DHB se asocia a: 1) en pacientes con ES cutánea limitada, a un mayor tiempo desde el inicio de la ES hasta su diagnóstico y a una mayor prevalencia de síndrome seco y presencia de ACA; 2) en pacientes con ES sine escleroderma, a una mayor prevalencia de síndrome seco, y 3) en pacientes con ES cutánea difusa, no se identificó ningún rasgo diferencial con respecto a los pacientes sin DHB. El segundo artículo es un estudio observacional que reclutó una cohorte de 62 pacientes con CBP a los que se aplicó un protocolo de estudio dirigido a determinar la prevalencia de EAS asociada a esta entidad. Los resultados muestran que la prevalencia de EAS en pacientes con CBP es del 35.4%. La ES es la entidad más frecuentemente diagnosticada (21%), en particular del subtipo cutáneo limitado (11%). Los ACA son el único parámetro inmunológico identificado con mayor frecuencia en pacientes con CBP y EAS. Los pacientes con CBP-EAS tienen más prevalencia de manifestaciones extrahepáticas como fenómeno de Raynaud, síndrome seco, telangiectasias, artritis y disnea, así como una asociación significativa a ACA y alteraciones capilaroscópicas sugestivas de ES, que pueden ser factores predictores de la asociación de ambas enfermedades. Por estos motivos, recomendamos el empleo de un protocolo de valoración clínica, inmunológica y de una capilaroscòpia periungueal.Systemic sclerosis (SSc) is a chronic autoimmune systemic disease (ASD) that may affect most internal organs caused by an accumulation of collagen in tissues and/or the development of obliterative vasculopathy in the context of autoimmune dysfunction. Although liver disturbance is not a rare finding in SSc, its presence is not considered characteristic of this disease and few studies have assessed the bidirectional relationship between SSc and hepatobiliary dysfunction (HBD), especially addressed to investigating organ-specific diseases. The first article of this doctoral thesis is a Spanish multicenter observational study including 1572 patients with SSc that establishes the prevalence of HBD in patients with SSc at 7.5% and the main causes as organ-specific autoimmune diseases, such as primary biliary cholangitis (PBC) at 4.3%, autoimmune hepatitis at 1.2% and PBC without antimitochondrial antibodies at 0.4%. The presence of HBD in patients with SSc is independently associated with a lower risk of developing diffuse cutaneous SSc and a greater prevalence of cutaneous calcinosis, diastolic dysfunction of left ventricle, Sicca syndrome and positive anticentromere antibodies. The presence of HBD did not influence survival. According to cutaneous subtypes, HBD is associated with: 1) In patients with limited cutaneous SS, a longer time-to-diagnosis since SSc onset to its diagnosis and a greater prevalence of sicca syndrome and presence of anticentromere antibodies; 2) In patients with SSc sine scleroderma, a greater prevalence of sicca syndrome, and 3) In patients with diffuse cutaneous SSc, no distinguishing feature was identified compared to patients without HBD. The second article is an observational study recruiting a cohort of 62 patients with PBC included in a study protocol to determine the prevalence of ASD associated to this entity. The results obtained show that the prevalence of ASD in patients with PBC is 35.4%. SSc is the most prevalent condition (21%), especially in the limited cutaneous subtype (11%). Anticentromere antibodies are the only immunological parameter most frequently identified in patients with PBC and ASD. Patients with PBC-ASD present extrahepatic manifestations such as Raynaud`s phenomenon, sicca syndrome, telangiectases, arthritis and dyspnea, as well as a significant association of anticentromere antibodies and capillaroscopic alterations suggestive of SSc, which may be predictive factors for the association between both diseases. Consequently, we recommend the use of a protocol for clinical and immunological assessment and periungueal capillaroscopy

Esclerosis sistémica y enfermedad hepato-biliar : estudio bidireccional de la relación entre la esclerosis sistémica y la enfermedad hepato-biliar /

La esclerosis sistémica (ES) es una enfermedad autoinmune sistémica (EAS) que puede afectar a la mayoría de órganos internos mediante la acumulación de colágeno en los tejidos y/o desarrollo de una vasculopatía obliterante, en un entorno de disfunción autoinmune. Aunque la disfunción hepato-biliar (DHB) no es un hallazgo infrecuente en la ES, su presencia no se considera característica de la enfermedad y se han publicado pocos estudios que valoren la relación bidireccional entre la ES y la DHB, en particular autoinmune órgano-específica. El primer artículo de esta Tesis doctoral es un estudio observacional multicéntrico Español de 1572 pacientes con ES y como objetivos establece la prevalencia de DHB en pacientes con ES y enumera las causas que son predominantemente autoinmunes órgano-específicas, como la colangitis biliar primaria (CBP) en 4.3% y la hepatitis autoinmune en 1.2% y CBP sin anticuerpos antimitocondria en 0.4%.. La presencia de DHB en pacientes con ES se asocia independientemente a un menor riesgo de padecer una ES cutánea difusa y a una mayor prevalencia de calcinosis cutánea, disfunción diastólica de ventrículo izquierdo, síndrome seco y positividad de los anticuerpos anticentrómero (ACA). La presencia de DHB no influyó en la supervivencia. Según los subtipos cutáneos, la DHB se asocia a: 1) en pacientes con ES cutánea limitada, a un mayor tiempo desde el inicio de la ES hasta su diagnóstico y a una mayor prevalencia de síndrome seco y presencia de ACA; 2) en pacientes con ES sine escleroderma, a una mayor prevalencia de síndrome seco, y 3) en pacientes con ES cutánea difusa, no se identificó ningún rasgo diferencial con respecto a los pacientes sin DHB. El segundo artículo es un estudio observacional que reclutó una cohorte de 62 pacientes con CBP a los que se aplicó un protocolo de estudio dirigido a determinar la prevalencia de EAS asociada a esta entidad. Los resultados muestran que la prevalencia de EAS en pacientes con CBP es del 35.4%. La ES es la entidad más frecuentemente diagnosticada (21%), en particular del subtipo cutáneo limitado (11%). Los ACA son el único parámetro inmunológico identificado con mayor frecuencia en pacientes con CBP y EAS. Los pacientes con CBP-EAS tienen más prevalencia de manifestaciones extrahepáticas como fenómeno de Raynaud, síndrome seco, telangiectasias, artritis y disnea, así como una asociación significativa a ACA y alteraciones capilaroscópicas sugestivas de ES, que pueden ser factores predictores de la asociación de ambas enfermedades. Por estos motivos, recomendamos el empleo de un protocolo de valoración clínica, inmunológica y de una capilaroscòpia periungueal.Systemic sclerosis (SSc) is a chronic autoimmune systemic disease (ASD) that may affect most internal organs caused by an accumulation of collagen in tissues and/or the development of obliterative vasculopathy in the context of autoimmune dysfunction. Although liver disturbance is not a rare finding in SSc, its presence is not considered characteristic of this disease and few studies have assessed the bidirectional relationship between SSc and hepatobiliary dysfunction (HBD), especially addressed to investigating organ-specific diseases. The first article of this doctoral thesis is a Spanish multicenter observational study including 1572 patients with SSc that establishes the prevalence of HBD in patients with SSc at 7.5% and the main causes as organ-specific autoimmune diseases, such as primary biliary cholangitis (PBC) at 4.3%, autoimmune hepatitis at 1.2% and PBC without antimitochondrial antibodies at 0.4%. The presence of HBD in patients with SSc is independently associated with a lower risk of developing diffuse cutaneous SSc and a greater prevalence of cutaneous calcinosis, diastolic dysfunction of left ventricle, Sicca syndrome and positive anticentromere antibodies. The presence of HBD did not influence survival. According to cutaneous subtypes, HBD is associated with: 1) In patients with limited cutaneous SS, a longer time-to-diagnosis since SSc onset to its diagnosis and a greater prevalence of sicca syndrome and presence of anticentromere antibodies; 2) In patients with SSc sine scleroderma, a greater prevalence of sicca syndrome, and 3) In patients with diffuse cutaneous SSc, no distinguishing feature was identified compared to patients without HBD. The second article is an observational study recruiting a cohort of 62 patients with PBC included in a study protocol to determine the prevalence of ASD associated to this entity. The results obtained show that the prevalence of ASD in patients with PBC is 35.4%. SSc is the most prevalent condition (21%), especially in the limited cutaneous subtype (11%). Anticentromere antibodies are the only immunological parameter most frequently identified in patients with PBC and ASD. Patients with PBC-ASD present extrahepatic manifestations such as Raynaud's phenomenon, sicca syndrome, telangiectases, arthritis and dyspnea, as well as a significant association of anticentromere antibodies and capillaroscopic alterations suggestive of SSc, which may be predictive factors for the association between both diseases. Consequently, we recommend the use of a protocol for clinical and immunological assessment and periungueal capillaroscopy

The challenge of comprehensive nailfold videocapillaroscopy practice: a further contribution.

Although classification systems and scores for capillaroscopy interpretation have been published, there is a lack of homogenization for the procedure, especially in the way and place the images are taken, the counting of the capillaries and the measuring of their size. Our objective is to provide a deep learning-based software to obtain objective and exhaustive data for the whole nailfold without increasing the time or effort needed to do the examination, or requiring expensive equipment. An automated software to count nailfold capillaries has been designed, through an exploratory image dataset of 2,713 images with 18,000 measurements of 3 different types. Subsequently, application rules have been created to detect the morphology of nailfold videocapillaroscopy images, through a training set of images. The software reliability has been evaluated with standard metrics used in the machine learning field for object detection tasks, comparing automatic and manual counting on the same NVC images. A mean average precision (mAP) of 0.473 is achieved for detecting and classifying capillaries and haemorrhages by their shape, and a mAP of 0.515 is achieved for detecting and classifying capillaries by their size. A precision of 83.84% and a recall of 92.44% in the identification of capillaries was estimated. Deep learning is a useful tool in nailfold videocapillaroscopy that allows to analyse objectively and homogeneously images taken with multiple devices. It should make the assessment of the capillary morphology in nailfold video capillaroscopy easier, quicker, more complete and accessible to everyone