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

Author

Carbonell, Cristina, Marcos, Miguel, Guillén-Del-Castillo, Alfredo, Rubio-Rivas, Manuel, Argibay, Ana, Marín-Ballvé, Adela, Rodríguez-Pintó, Ignasi, Baldà-Masmiquel, Maria, Callejas-Moraga, Eduardo, Colunga, Dolores, Sáez-Comet, Luis, González-Echávarri, Cristina, Ortego-Centeno, Norberto, Marí-Alfonso, Begoña, Vargas-Hitos, José-Antonio, Todolí-Parra, José-Antonio, Trapiella, Luis, Herranz-Marín, María-Teresa, Freire, Mayka, Castro-Salomó, Antoni, Perales-Fraile, Isabel, Madroñero-Vuelta, Ana-Belén, Sánchez-García, María-Esther, Ruiz-Muñoz, Manuel, González-García, Andrés, Sánchez-Redondo, Jorge, de-la-Red-Bellvis, Gloria, Fernández-Luque, Alejandra, Muela-Molinero, Alberto, Lledó, Gema-María, Tolosa-Vilella, Carles, Fonollosa-Pla, Vicent, Chamorro, Antonio-Javier, Simeón-Aznar, Carmen-Pilar, RESCLE Investigators, Autoimmune Diseases Study Group (GEAS), Universidad de Sevilla. Departamento de Medicina, Institut Català de la Salut, [Carbonell C, Marcos M] Department of Internal Medicine, Hospital Universitario de Salamanca, Universidad de Salamanca-IBSAL, Salamanca, Spain. [Guillén-Del-Castillo A, Fonollosa-Pla V, Simeón-Aznar CP] Unitat de Malalties Autoimmunes, Servei de Medicina Interna, Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Rubio-Rivas M] Unit of Autoimmune Diseases, Department of Internal Medicine, Hospital Universitario de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain. [Argibay A] Unit of Systemic Autoimmune Diseases and Thrombosis, Department of Internal Medicine, Complejo Hospitalario Universitario de Vigo. Vigo, Pontevedra, Spain. [Marín-Ballvé A] Unit of Autoimmune Diseases, Department of Internal Medicine, Hospital Clínico Universitario Lozano Blesa, IIS Aragón. Zaragoza, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Scleroderma, Systemic, Incidence, Immunology, Primary biliary cholangitis, Esclerosi sistemàtica progressiva - Complicacions, aminoácidos, péptidos y proteínas::proteínas::proteínas sanguíneas::inmunoproteínas::inmunoglobulinas::anticuerpos::autoanticuerpos [COMPUESTOS QUÍMICOS Y DROGAS], Autoanticossos, Càncer - Complicacions, enfermedades de la piel y tejido conjuntivo::enfermedades del tejido conjuntivo::esclerodermia sistémica [ENFERMEDADES], Neoplasms [DISEASES], neoplasias [ENFERMEDADES], Scleroderma, Localized, Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Autoantibodies [CHEMICALS AND DRUGS], Risk Factors, Neoplasms, Skin and Connective Tissue Diseases::Connective Tissue Diseases::Scleroderma, Systemic [DISEASES], Immunology and Allergy, Anticentromere antibody, Systemic sclerosis, Humans, Registries, Càncer, Cancer, Autoantibodies
Abstract

Anticentromere antibody; Cancer; Systemic sclerosis Anticuerpo anticentrómero; Cáncer; Esclerosis sistémica Anticòs anticentròmer; Càncer; Esclerosi sistèmica 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

Published
2022

2. Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

Author

Guillén-Del-Castillo, Alfredo, Meseguer, Manuel López, Fonollosa-Pla, Vicent, Sáez Giménez, Berta, Colunga-Argüelles, Dolores, Revilla-López, Eva, Rubio-Rivas, Manuel, Ropero, Maria José Cristo, Argibay, Ana, Barberá, Joan Albert, Pla Salas, Xavier, Martínez Meñaca, Amaya, Madroñero Vuelta, Ana Belén, Lara Padrón, Antonio, Sáez Comet, Luis, Domingo Morera, Juan Antonio, González-Echávarri, Cristina, Mombiela, Teresa, Ortego-Centeno, Norberto, Marín González, Manuela, Tolosa-Vilella, Carles, Blanco, Isabel, Escribano Subías, Pilar, Simeón-Aznar, Carmen Pilar, Aurtenetxe Pérez, Águeda, Barrios Garrido-Lestache, Elvira, Bedate Díaz, Pedro, Cifrián, José Manuel, Cristo Ropero, Maria Jose, Dos Subirá, Laura, Elías Hernández, Teresa, García Hernández, Francisco José, Carbonell, Juan Gil, Segovia, Ariadna González, Valverde, Tamara Hermida, Baldomero, Idaira Fámara Hernández, Hernández-González, Ignacio, Huertas, Julia Herrero, Palomares, Luis Jara, Arjona, Josefa Jiménez, Padrón, Antonio Lara, Lázaro-Salvador, María, López-Ramón, Marta, López-Reyes, Raquel, González, Manuela Marín, Meñaca, Amaya Martínez, Etxaniz, Francisco Javier Mazo, Velasco, Virginia Naranjo, Candelera, Remedios Otero, González, Isabel Otero, Lozano, Beatriz Rodríguez, Nieto, María Jesús Rodríguez, Soriano, Joaquín Rueda, Giménez, Berta Sáez, Safont, Belén, Llinas, Ernest Sala, Sebastián, Laura, Cubero, Javier Segovia, Domenech, María Teresa Subirana, Masmiquel, Maria Baldà, Moraga, Eduardo Callejas, Chamorro, Antonio-J., Freire, Mayka, Guillén-del-Castillo, Alfredo, Marín, Maria Teresa Herranz, Vuelta, Ana Belén Madroñero, Ballvé, Adela Marín, Fernández, Melany Pestaña, Salas, Xavier Pla, Pintó, Ignasi Rodríguez, Comet, Luis Sáez, Cervelló, Gonzalo Salvador, Parra, José Antonio Todolí, Trapiella, Luis, Hitos, José Antonio Vargas, Marín, Adela (REHAP Consortium), Institut Català de la Salut, [Guillén-Del-Castillo A, Fonollosa-Pla V, Simeón-Aznar CP] Unitat de Malalties Autoimmunes, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Meseguer ML, Revilla-López E] Servei de Pneumologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Sáez Giménez B] Servei de Pneumologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Departament de Fisiologia, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Colunga-Argüelles D] Department of Internal Medicine, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Respiratory Tract Diseases::Lung Diseases::Lung Diseases, Interstitial [DISEASES], enfermedades respiratorias::enfermedades pulmonares::hipertensión pulmonar [ENFERMEDADES], Hypertension, Pulmonary, Impacte, enfermedades de la piel y tejido conjuntivo::enfermedades del tejido conjuntivo::esclerodermia sistémica [ENFERMEDADES], Pulmonary hypertension, Respiratory Tract Diseases::Lung Diseases::Hypertension, Pulmonary [DISEASES], Anàlisi de supervivència (Biometria), Pulmonary diseases, polycyclic compounds, Survival analysis (Biometry), Humans, Familial Primary Pulmonary Hypertension, skin and connective tissue diseases, Hipertensió pulmonar, Pulmonary Arterial Hypertension, Respiratory tract diseases, Hipotensió arterial, Multidisciplinary, Scleroderma, Systemic, integumentary system, respiratory system, respiratory tract diseases, Malalties dels pulmons, Pulmons - Malalties, Esclerosi sistemàtica progressiva - Tractament, Impact, Scleroderma (Disease), enfermedades respiratorias::enfermedades pulmonares::enfermedades pulmonares intersticiales [ENFERMEDADES], Skin and Connective Tissue Diseases::Connective Tissue Diseases::Scleroderma, Systemic [DISEASES], Càncer de pulmó, Systemic sclerosis, Lung cancer, Esclerodèrmia, Lung Diseases, Interstitial
Abstract

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 ± 20.6% vs 93.6 ± 20.6%, P

Published
2022

3. A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn's disease

Author

González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, Antonio, Degenhardt, Frauke, Ortego-Centeno, Norberto, Radstake, Timothy R.D.J., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, Javier, Márquez, Ana, Assassi, Shervin, Zhou, Xiaodong, Tan, Filemon K., Arnett, Frank C., Reveille, John D., Gorlova, Olga, Chen, Wei V., Ying, Jun, Gregersen, Peter K., Lee, Annette T., Voskuyl, Alexandre E., de Vries-Bouwstra, Jeska, Magro-Checa, Cesar, Broen, Jasper, Koeleman, Bobby P.C., Simeón, Carmen P., Fonollosa, Vicente, Guillén, Alfredo, Carreira, Patricia, Castellví, Iván, González-Gay, Miguel A., Ríos, Raquel, Callejas-Rubio, Jose Luis, Vargas-Hitos, José A., García-Portales, Rosa, Camps, María Teresa, Fernández-Nebro, Antonio, González-Escribano, María F., García-Hernández, Francisco José, Castillo, Ma Jesús, Aguirre, Ma Ángeles, Gómez-Gracia, Inmaculada, Rodríguez-Rodríguez, Luis, Fernández-Gutiérrez, Benjamín, de la Peña, Paloma García, Vicente, Esther, Andreu, José Luis, Fernández de Castro, Mónica, López-Longo, Francisco Javier, Martínez, Lina, Espinosa, Gerard, Tolosa, Carlos, Pros, Anna, Rodríguez-Carballeira, Mónica, Narváez, Francisco Javier, Rubio-Rivas, Manel, Ortiz-Santamaría, Vera, Madroñero, Ana Belén, Díaz, Bernardino, Trapiella, Luis, Sousa, Adrián, Egurbide, María Victoria, Fanlo-Mateo, Patricia, Sáez-Comet, Luis, Díaz-González, Federico, Hernández, Vanesa, Beltrán, Emma, Román-Ivorra, José Andrés, Grau, Elena, Alegre-Sancho, Juan José, Blanco-García, Francisco J., Oreiro, Natividad, Freire, Mayka, Balsa, Alejandro, Ortiz, Ana M., Hunzelmann, Nicolas, Riemekasten, Gabriela, Distler, Jörg H.W., Witte, Torsten, Airó, Paolo, Beretta, Lorenzo, Santaniello, Alessandro, Bellocchi, Chiara, Lunardi, Claudio, Moroncini, Gianluca, Gabrielli, Armando, Universidad de Salamanca, Junta de Andalucía, Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad (España), Ministerio de Economía y Competitividad (España), Rheumatology, AII - Inflammatory diseases, Julià, Antonio [0000-0001-6064-3620], Franke, Andre [0000-0003-1530-5811], Mayes, Maureen D [0000-0001-5070-2535], Apollo - University of Cambridge Repository, Mayes, Maureen D. [0000-0001-5070-2535], and Universidad de Cantabria

Subjects
0301 basic medicine, Male, Settore MED/09 - Medicina Interna, 692/699/249/2510, 45/43, Gene Expression, lcsh:Medicine, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Disease, Inflammatory diseases, SLC22A5, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, medicine, Humans, Genetic Predisposition to Disease, Allele, lcsh:Science, Genetic association, 030203 arthritis & rheumatology, Genetics, Crohn's disease, Multidisciplinary, Scleroderma, Systemic, 45, biology, lcsh:R, article, medicine.disease, digestive system diseases, 3. Good health, Settore MED/16 - Reumatologia, 030104 developmental biology, Risk factors, Genetic Loci, Case-Control Studies, biology.protein, Female, lcsh:Q, 692/499, Genome-Wide Association Study
Abstract

We thank Sofia Vargas and Gema Robledo for her excellent technical assistance and all the patients and control donors for their essential collaboration. We thank WTCCC (Welcome Trust Case Control Consortium) for the access to GWAS data of Crohn’s disease patients and healthy controls, Banco Nacional de ADN (University of Salamanca, Spain) who supplied part of the control DNA samples, and dbGap for granting access to the IBD Genetics Consortium (IBDGC) Crohn’s Disease GWAS data (phs000130.v1.p1). The IBDGC Crohn’s Disease Genome-Wide Association Study was conducted by the IBDGC Investigators and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). This manuscript was not prepared in collaboration with Investigators of the IBDGC Crohn’s Disease Genome-Wide Association Study and does not necessarily reflect the opinions or views of the IBDGC Crohn’s Disease Genome-Wide Association Study, the NIDDK Central Repositories, or the NIDDK., Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohn’s disease (CD), some of which confer susceptibility to both diseases. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of European origin. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. In addition, an enrichment in the IL-12 family and type I interferon signaling pathways was observed among the set of SSc-CD common genetic risk loci. In conclusion, through the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotropic effects on two clinically distinct immune-mediated disorders. The fact that all these pleiotropic SNPs have opposite allelic effects in SSc and CD reveals the complexity of the molecular mechanisms by which polymorphisms affect diseases., This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2015-66761-P; IPT-010000-2010-36, cofunded by the European Regional Development Fund), Consejería de Innovación, Ciencia y Tecnología, Junta de Andalucía (Spain) (P12-BIO-1395) and the Cooperative Research Thematic Network (RETICS) programme (RD16/0012/0013) (RIER) from Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Economy, Industry and Competitiveness). AM is recipient of a Miguel Servet fellowship (CP17/00008) from ISCIII (Spanish Ministry of Economy, Industry and Competitiveness). DGS was supported by the Spanish Ministry of Economy and Competitiveness through the FPI programme (SAF2015-66761-P). This work is part of the Doctoral Thesis “Bases Genéticas de la Esclerosis Sistémica: Integrando Genómica y Transcriptómica”.

Published
2020
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4. Early- versus Late-Onset Systemic Sclerosis

Author

Alba, Marco A., Velasco, César, Simeón, Carmen Pilar, Fonollosa, Vicent, Trapiella, Luis, Egurbide, María Victoria, Sáez, Luis, Castillo, María Jesús, Callejas, José Luis, Camps, María Teresa, Tolosa, Carles, Ríos, Juan José, Freire, Mayka, Vargas, José Antonio, and Espinosa, Gerard

Subjects
ANA = antinuclear antibodies, Adult, Male, RR = relative risk, IIF = indirect immunofluorescence, RP = Raynaud phenomenon, OR = odds ratio, CI = confidence interval, ssSSc = systemic sclerosis sine scleroderma, Risk Factors, ILD = interstitial lung disease, SSc = systemic sclerosis, ACR = American College of Rheumatology, RESCLE = Registro de ESCLErodermia, Humans, Original Study, RSHC = right-sided heart catheterization, Age of Onset, FVC = forced vital capacity, Scleroderma, Systemic, SMR = standardized mortality ratio, lcSSc = limited cutaneous systemic sclerosis, Middle Aged, ACA = anticentromere antibodies, PH = pulmonary hypertension, dcSSc = diffuse cutaneous systemic sclerosis, Treatment Outcome, PAP = pulmonary arterial pressure, Female, SD = standard deviation
Abstract

Peak age at onset of systemic sclerosis (SSc) is between 20 and 50 years, although SSc is also described in both young and elderly patients. We conducted the present study to determine if age at disease onset modulates the clinical characteristics and outcome of SSc patients. The Spanish Scleroderma Study Group recruited 1037 patients with a mean follow-up of 5.2 ± 6.8 years. Based on the mean ± 1 standard deviation (SD) of age at disease onset (45 ± 15 yr) of the whole series, patients were classified into 3 groups: age ≤30 years (early onset), age between 31 and 59 years (standard onset), and age ≥60 years (late onset). We compared initial and cumulative manifestations, immunologic features, and death rates. The early-onset group included 195 patients; standard-onset group, 651; and late-onset, 191 patients. The early-onset group had a higher prevalence of esophageal involvement (72% in early-onset compared with 67% in standard-onset and 56% in late-onset; p = 0.004), and myositis (11%, 7.2%, and 2.9%, respectively; p = 0.009), but a lower prevalence of centromere antibodies (33%, 46%, and 47%, respectively; p = 0.007). In contrast, late-onset SSc was characterized by a lower prevalence of digital ulcers (54%, 41%, and 34%, respectively; p < 0.001) but higher rates of heart conduction system abnormalities (9%, 13%, and 21%, respectively; p = 0.004). Pulmonary hypertension was found in 25% of elderly patients and in 12% of the youngest patients (p = 0.010). After correction for the population effects of age and sex, standardized mortality ratio was shown to be higher in younger patients. The results of the present study confirm that age at disease onset is associated with differences in clinical presentation and outcome in SSc patients.

Published
2014

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