In this study, we have analyzed, in 6 different IMIDs including almost 10,000 patients, the association of several demographic and clinical-related variables in the CVD risk. To our knowledge, this is the first time such an analysis has been conducted in patients affected by rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, ulcerative colitis, or Crohn disease, recruited in the same time frame, with similar follow-up times, using the same inclusion/exclusion criteria, with data collected using the same protocols and questionnaires. This particular setting allowed us to compare the CVD risk among different conditions and to perform a pooled analysis to identify common risk factors.
4.1 Risk factors of CVD in IMIDs
The analysis of CVD risk factors in different IMIDs was conducted in several previous studies (S Discussion and References, http://links.lww.com/MD/B771). With regard to rheumatoid arthritis,[16–19] psoriatic arthritis,[20–22] psoriasis,[20,23] systemic lupus erythematosus,[24–26] and inflammatory bowel disease[27,28] similar findings were observed in our cohort. However, some differences have also been observed: in psoriasis and psoriatic arthritis, the severity of the skin disease was previously associated with CVD,[21,23] but no significant association was observed in our cohorts. Different definitions of severity were used, which may explain the different findings. In addition, in our psoriasis cohort, no association between younger age at disease onset and CVD was observed.
In systemic lupus erythematosus, we described for the first time 2 new independent associations of CVD with vitiligo (which in turn has been associated with a lower prevalence of abdominal obesity and dyslipidemia) and with a family history of autoimmune thyroiditis (which in turn has been associated with a higher risk of stroke). In addition, comparing with a Spanish systemic lupus erythematosus registry, we observed a lower prevalence of CVD and a lack of influence of traditional cardiovascular risk factors. However, surrogate markers of disease severity were independent risk factors in both studies. The fact that our patients came from systemic lupus erythematosus specialized units with a tighter management of both disease and CVD risk factors might explain these differences.
Finally, regarding inflammatory bowel disease, shorter disease duration was previously described as a risk factor for CVD in Crohn disease patients. However, in our cohort, this influence was not observed.
4.2 Comparison of CVD risk among IMIDs
Several studies have compared the risk of CVD among different IMIDs, although none of them included the 6 we analyzed. Zöller et al studied the risk of ischemic and hemorrhagic stroke in 32 different IMIDs (including psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn disease, and systemic lupus erythematosus) using data from the entire Swedish population. An overall higher risk was observed for these 5 conditions compared with the general population, and although no direct comparisons were performed, systemic lupus erythematosus exhibited a higher standardized incidence rate, followed by rheumatoid arthritis and Crohn disease or psoriasis. Ulcerative colitis patients had the lowest risk for both ischemic and hemorrhagic stroke. In our study, although our dependent variable included all cardiovascular events, similar results were observed.
Regarding psoriasis and psoriatic arthritis, the latter was associated with a higher cardiovascular risk, regardless of whether the psoriatic arthritis patients were selected among those with psoriasis or the psoriatic arthritis and psoriasis patients were selected separately in population-based studies. When considering only our psoriasis cohort, similar results were observed: the presence of arthritis was independently associated with a higher risk of CVD. However, when we compared the psoriasis and the psoriatic arthritis cohorts, we observed the opposite result: a lower risk of CVD, albeit not significant, among the psoriatic arthritis cohort. To address this discrepancy, we compared the subjects from the psoriasis cohort with psoriatic arthritis, without psoriatic arthritis, and the patients from the psoriatic arthritis cohort (S8 and S9 Tables, http://links.lww.com/MD/B771). In general, patients from the psoriasis cohort had a higher prevalence of traditional cardiovascular risk factors and higher skin disease severity, which could explain their higher prevalence of CVD. Taking into account that the patients from the psoriasis cohort were recruited from tertiary care outpatient clinics, it is likely that we selected patients with a more severe disease.
Few studies compared the risk of CVD between rheumatoid arthritis and psoriatic arthritis, observing a lower, although not significant, cardiovascular risk among the latter, regardless of whether the patients from both conditions were enrolled from different or similar settings. In our study, psoriatic arthritis patients had a significantly lower cardiovascular risk before and after adjusting for demographic and traditional risk factors. This observation may be related to the characteristics of the psoriatic arthritis cohort. A recent population-based study performed by Ogdie et al showed that rheumatoid arthritis and psoriasis had similar standardized CVD hazard ratios, which were higher than that of psoriatic arthritis (although no direct comparison was performed).
Rheumatoid arthritis has also been compared with systemic lupus erythematosus. The latter was associated with a higher rate (compared with the general population) of first-time acute myocardial infarction than rheumatoid arthritis (although no direct comparison was performed). In our sample, although rheumatoid arthritis showed a higher CVD prevalence in the bivariate analysis, after adjusting for age and sex, systemic lupus erythematosus showed a higher risk of CVD.
Regarding inflammatory bowel disease, similar normalized rates of ischemic heart disease and higher normalized rates of stroke were described in Crohn disease compared with ulcerative colitis, although no direct comparisons were performed. In our sample, considering all CVDs, no significant differences were observed, although Crohn disease was associated with a higher standardized prevalence of CVD.
There are several limitations to our study. First, because the study is cross-sectional, the directionality of the associations could not be determined. In addition, the presence of CVD, traditional cardiovascular risk factors, and disease-related variables was based either on the previous existence of a diagnosis of such conditions or manifestations, or on the indication by the patient of their existence during the clinical interview. We did not perform any complementary tests; therefore, the prevalence may be underestimated, especially for arterial hypertension, dyslipidemia, and type 2 diabetes.
Patients were recruited from rheumatology (rheumatoid arthritis, systemic lupus erythematosus, and psoriatic arthritis), dermatology (psoriasis), and gastroenterology (ulcerative colitis and Crohn disease) tertiary care outpatient clinics. Therefore, for some IMIDs, especially psoriasis, the generalization of our results to the whole population must be undertaken with caution because it is likely that only patients with a more severe disease were included. Moreover, patients were consecutively recruited, favoring the inclusion of subjects with a more severe disease, who tend to seek care more frequently. Because patients were recruited from practices throughout the country, these cohorts may be representative of the subpopulation of patients affected with severe disease in Spain.
No replication cohorts were included in this study, and therefore the newly described risk factors (such as vitiligo or a familiar history of autoimmune thyroiditis) need to be assessed in other cohorts.
This analysis was also limited by the inclusion of living patients, that is to say, subjects who survived long enough to be included in this study. Therefore, our sample may be biased toward patients with milder CVD and IMID. Moreover, the variables identified as associated with CVD may be predictors of survival following a CVD event rather than its occurrence. These conditions are important to consider when generalizing our results.
No direct disease activity measure, either at diagnosis or encompassing the whole disease duration, was available. However, treatment with disease-modifying drugs and biological therapy was used as a surrogate marker. Unfortunately, we lacked data regarding corticosteroid use throughout the disease.
Finally, there has been a delay between the inclusion of patients in this study and the presentation of the data used in this article. It is important to consider that due to the large amount of patients and centers that participated, it is expected logistic difficulties in the collection, ensemble, and quality control of the data that defer its use and dissemination.
We reported a direct comparison of CVD and cardiovascular risk factors prevalence among 6 IMIDs. We observed that different sets of demographic and clinical-related variables contribute to the risk of CVD in the different conditions studied. Furthermore, we compared the standardized CVD prevalence among those diseases, observing that systemic lupus erythematosus exhibited the highest prevalence, followed by rheumatoid arthritis and psoriasis. Our evidence provides a compelling argument to prioritize the institution of specific prevention programs in subjects affected with systemic lupus erythematosus, rheumatoid arthritis, and psoriasis to reduce the burden of CVD associated with these conditions.
The authors would like to thank all the physicians and health professionals who participated in the IMID Consortium: Pilar Nos (Hospital Universitari La Fe, Valencia, and CIBERehd, Instituto de Salud Carlos III, Madrid, Spain), Lluís Puig (Hospital de la Santa Creu i Sant Pau, Barcelona, and Universitat Autònoma de Barcelona, Barcelona, Spain), Isidoro González-Álvaro (Hospital Universitario de la Princesa and IIS-IP, Madrid, Spain), José A. Pinto-Tasende (Rheumatology Department, Complejo Hospitalario Universitario A Coruña, INIBIC, A Coruña, Spain), Ricardo Blanco (Hospital Universitario Marqués de Valdecilla and Facultad de Medicina. Universidad de Cantabria, Santander, Spain), Ana Gutiérrez Casbas (Gastroenterology Department, Hospital General Universitario de Alicante, Alicante, and CIBERehd, Instituto de Salud Carlos III, Madrid, Spain), Emilia Fernández (Hospital Universitario de Salamanca, Salamanca, Spain), Raimon Sanmartí (Hospital Clínic de Barcelona and IDIBAPS, Barcelona, Spain), Jordi Gratacós (Hospital Parc Taulí, Sabadell, Spain), Víctor Martínez Taboada (Hospital Universitario Marqués de Valdecilla and Facultad de Medicina. Universidad de Cantabria, Santander, Spain), Fernando Gomollón (Hospital Clínico Universitario, Zaragoza, and CIBERehd, Instituto de Salud Carlos III, Madrid, Spain), Esteban Daudén (Hospital Universitario de la Princesa and IIS-IP, Madrid, Spain), Joan Maymó (Hospital del Mar, Barcelona, Spain), Rubén Queiró (Hospital Universitario Central de Asturias, Asturias, Spain), Francisco Javier Lopez Longo (Hospital General Universitario Gregorio Marañón, Madrid, Spain), Esther García-Planella (Hospital de la Santa Creu i Sant Pau, Barcelona, Spain), Jose Luís Sánchez Carazo (Consorcio Hospital General Universitario de Valencia, Spain), Mercedes Alperi-López (Hospital Universitario Central de Asturias, Asturias, Spain), Carlos Montilla (Hospital Universitario de Salamanca, Salamanca, Spain), José Javier Pérez-Venegas (Hospital de Jerez de la Frontera, Cádiz, Spain), Juan L Mendoza (Gastroenterology Department, Hospital Clínico San Carlos, IDISSC, Madrid, Spain), José Luís López Estebaranz (Hospital Universitario Fundación Alcorcón, Madrid, Spain), Àlex Olivé (Hospital Universitari Germans Trias i Pujol, Badalona, Spain), Juan Carlos Torre-Alonso (Hospital Monte Naranco, Oviedo, Spain), Manuel Barreiro-de Acosta (Hospital Clínico Universitario, Santiago de Compostela, Spain), David Moreno Ramírez (Hospital Virgen de la Macarena, Sevilla, Spain), Héctor Coromines (Hospital Moisès Broggi, Barcelona, Spain), Santiago Muñoz-Fernández (Hospital Universitario Infanta Sofía, Madrid, Spain), José Luis Andreu (Hospital Universitario Puerta de Hierro, Madrid, Spain), Fernando Muñoz (Complejo Hospitalario de León, León, Spain), Pablo de la Cueva (Department of Dermatology, Hospital Universitario Infanta Leonor, Madrid, Spain), Alba Erra (Hospital Sant Rafael, Barcelona, Spain), Carlos M González (Hospital General Universitario Gregorio Marañón, Madrid, Spain), María Ángeles Aguirre-Zamorano (Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Córdoba, Spain), Maribel Vera (Hospital Universitario Puerta de Hierro, Madrid, Spain), Francisco Vanaclocha (Hospital Universitario Doce de Octubre, Madrid, Spain), Daniel Roig (Hospital Moisès Broggi, Barcelona, Spain), Paloma Vela (Rheumatology Department, Hospital General Universitario de Alicante, Alicante, Spain), Cristina Saro (Hospital de Cabueñes, Gijón, Spain), Enrique Herrera (Hospital Virgen de la Victoria, Málaga, Spain), Pedro Zarco (Hospital Universitario Fundación Alcorcón, Madrid, Spain), Joan M. Nolla (Hospital Universitari de Bellvitge, Barcelona, Spain), Maria Esteve (Hospital Universitari Mútua de Terrassa, Barcelona, and CIBERehd, Instituto de Salud Carlos III, Madrid, Spain), José Luis Marenco de la Fuente (Hospital del Valme, Sevilla, Spain), M. Jesus Garcia Villanueva (Hospital Universitario Ramón y Cajal, Madrid, Spain), José María Pego-Reigosa (Hospital do Meixoeiro, Vigo, and Grupo IRIDIS, IBI (Instituto de Investigación Biomédica de Vigo, Pontevedra y Orense), Spain), Laia Codó (LifeSciences, Barcelona Supercomputing Centre, National Institute of Bioinformatics, Barcelona, Spain), Josep Lluís Gelpí (LifeSciences, Barcelona Supercomputing Centre, National Institute of Bioinformatics, Barcelona, Spain), Andrés C. García-Montero (Banco Nacional de ADN Carlos III, University of Salamanca, Salamanca, Spain), Adrià Aterrido (Rheumatology Research Group, Vall d’Hebron Hospital Research Institute, Barcelona, Spain), María López-Lasanta (Rheumatology Research Group, Vall d’Hebron Hospital Research Institute, Barcelona, Spain), Arnald Alonso (Rheumatology Research Group, Vall d’Hebron Hospital Research Institute, Barcelona, Spain), Raül Tortosa (Rheumatology Research Group, Vall d’Hebron Hospital Research Institute, Barcelona, Spain).
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cardiovascular disease; epidemiology; immune-mediated inflammatory diseases
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