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Clinical characteristics during diagnosis of a prospective cohort of patients with systemic lupus erythematosus treated in Spanish Departments of Internal Medicine: The RELES study
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Rev Clin Esp. 2016;xxx(xx):xxx---xxx
Revista Clínica Española www.elsevier.es/rce
ORIGINAL ARTICLE
Clinical characteristics during diagnosis of a prospective cohort of patients with systemic lupus erythematosus treated in Spanish Departments of Internal Medicine: The RELES study夽 J. Canora a,∗ , M. García b , F. Mitjavila c , G. Espinosa d , S. Suárez e , R. González-León f , na g , R. Boldova h , A. Castro i , G. Ruiz-Irastorza b , On behalf of the researchers B. Sope˜ from the RELES-Group of Systemic Autoimmune Diseases (GEAS)♦ a
Servicio de Medicina Interna, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain Unidad de Investigación de Enfermedades Autoinmunes, Servicio de Medicina Interna, BioCruces Health Research Institute, Hospital Universitario Cruces, Universidad del País Vasco/Euskal Herriko Unibertsitatea, Barakaldo, Vizcaya, Spain c Unidad de Enfermedades Autoinmunes, Servicio de Medicina Interna, Hospital Universitario de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain d Servicio de Enfermedades Autoinmunes, Hospital Clínic, Barcelona, Spain e Servicio de Medicina Interna, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain f Servicio de Medicina Interna, Hospital Universitario Virgen del Rocío, Sevilla, Spain g Servicio de Medicina Interna, Complejo Hospitalario Universitario de Vigo, Pontevedra, Vigo, Spain h Servicio de Medicina Interna, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain i Servicio de Medicina Interna, Hospital Universitario Sant Joan de Reus, Reus, Tarragona, Spain b
Received 7 April 2016; accepted 25 September 2016
KEYWORDS Systemic lupus erythematosus; Inception cohort; Hydroxychloroquine; Lupus nephritis; Anti-DNA;
Abstract Introduction: Patient registries are useful tools for assessing rare diseases. Our objective is to present the Spanish registry of patients with systemic lupus erythematosus (Registro espa˜ nol de pacientes con lupus eritematoso sistémico, RELES). Patients and methods: RELES was started in 2008 as an observational, prospective, multicentre cohort registry that included patients from the time they were diagnosed. The registry’s objective is to analyse the incidence and noninflammatory complications of systemic lupus erythematosus (SLE). The departments of internal medicine of 38 Spanish hospitals participate in this registry.
夽
Please cite this article as: Canora J, García M, Mitjavila F, Espinosa G, Suárez S, González-León R, et al. Características clínicas al noles: diagnóstico de una cohorte prospectiva de pacientes con lupus eritematoso sistémico atendidos en servicios de Medicina Interna espa˜ estudio RELES. Rev Clin Esp. 2016. http://dx.doi.org/10.1016/j.rce.2016.09.006 ∗ Corresponding author. E-mail address: [email protected] (J. Canora). ♦ The complete list of RELES-GEASS researchers is given in Appendix 1. 2254-8874/© 2016 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
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J. Canora et al.
Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)
PALABRAS CLAVE Lupus eritematoso sistémico; Cohorte de inicio; Hidroxicloroquina; Nefritis lúpica; Anti-DNA; Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)
Results: A total of 298 patients with a mean age of 40.8 ± 15.7 years were included, 88.9% of whom were women and 85.6% of whom were white. In the first visit, there was a predominance of joint manifestations (74.5%). One hundred and seventy-seven patients (59.4%) were positive for anti-native DNA. In these patients, there was a higher rate of lupus nephritis (26.7% vs. 14%, p = .009; relative risk [RR], 1.33), haemolytic anaemia (13.6% vs. 4.1%, p = .07; RR, 1.46) and lymphopenia (55.4% vs. 43.8%, p = .05; RR, 1.21). The median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) score was 9.64 points (interquartile range, 4---13). The patients treated with antimalarial drugs before the diagnosis of SLE had a median SLEDAI score in the first visit of 5, compared with 8 for those who were not treated with these drugs (p = .02). Conclusions: RELES constitutes the first Spanish patient cohort with SLE recorded from the time of the diagnosis. The presence of anti-DNA has been related to severe manifestations such as nephritis and haemolytic anaemia. Treatment with antimalarial drugs before the diagnosis was associated with less active disease at the initial presentation. © 2016 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
Características clínicas al diagnóstico de una cohorte prospectiva de pacientes con lupus eritematoso sistémico atendidos en servicios de Medicina Interna espa˜ noles: estudio RELES Resumen Introducción: Los registros de pacientes son herramientas útiles para evaluar enfermedades poco frecuentes. Nuestro objetivo es presentar el «Registro espa˜ nol de pacientes con lupus eritematoso sistémico» (RELES). Pacientes y métodos: RELES se inició en 2008, como un registro multicéntrico de cohortes, observacional, prospectivo, incluyendo a pacientes desde el momento del diagnóstico, cuyo objetivo es analizar la incidencia y complicaciones no inflamatorias del lupus eritematoso sistémico (LES). Participan los servicios de Medicina Interna de 38 hospitales espa˜ noles. Resultados: Se incluyó a 298 pacientes con una edad media de 40,8 ± 15,7 a˜ nos, de los que el 88,9% eran mujeres y el 85,6% de raza caucásica. En la primera visita, predominaron las manifestaciones articulares (74,5%). Ciento setenta y siete pacientes (59,4%) mostraban positividad para anti-DNA nativo, siendo superior en estos la frecuencia de nefritis lúpica (26,7% vs. 14%, p = 0,009; riesgo relativo [RR] 1,33), de anemia hemolítica (13,6% vs. 4,1%, p = 0,07; RR 1,46) y linfopenia (55,4% vs. 43,8%, p = 0,05; RR 1,21). La mediana del Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) fue de 9,64 puntos (rango intercuartílico 4-13). Los tratados con antipalúdicos antes del diagnóstico de LES tenían una mediana de SLEDAI en la primera visita de 5, frente a 8 en los que no los tomaban (p = 0,02). Conclusiones: RELES constituye la primera cohorte de pacientes con LES recogidos desde el momento del diagnóstico en Espa˜ na. La presencia de anti-DNA se ha relacionado con manifestaciones graves como nefritis y anemia hemolítica. El tratamiento con antipalúdicos antes del diagnóstico se asoció con una enfermedad menos activa al comienzo. © 2016 Elsevier Espa˜ na, S.L.U. y Sociedad Espa˜ nola de Medicina Interna (SEMI). Todos los derechos reservados.
Background Systemic lupus erythematosus (SLE) is a systemic autoimmune disease (SAD) that mainly affects young women and results in increased morbidity and mortality.1 The prevalence of SLE in Spain over the last 40 years has varied from 34.1 to 91 cases per 100,000 inhabitants,2 which could be related to an improvement in the prognosis, which is estimated at up to 80% survival at 15 years.3
Although SLE is one of the most prevalent SADs, large cohorts are not easy to obtain from a single hospital center. Additionally, most published series are retrospective and include patients recorded over long periods. Patient registries and multicenter cohorts are particularly useful tools for assessing relatively uncommon diseases. The Systemic Autoimmune Disease Group (GEAS) of the Spanish Society of Internal Medicine (SEMI) therefore decided in 2008 to launch a longitudinal, national and
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Clinical characteristics during diagnosis of RELES cohort multicenter study that exclusively included patients with a recent diagnosis of SLE, treated in the offices of departments of internal medicine. The study was called the Spanish Registry of Patients with SLE (Registro Espa˜ nol de pacientes con LES, RELES). The aim of this article is to present the design and longterm objectives of the study and analyze the initial clinical characteristics, the most common presentation forms, the degree of activity and the treatments administered during the first month after diagnosis to the patients included in RELES.
Patients and methods RELES is a multicenter, observational, prospective cohort study of patients recorded since the start of the diagnosis and was launched in 2008. The registry’s main objective was to create an observational prospective cohort of patients with SLE, with special attention to the role of noninflammatory complications in the morbidity and mortality associated with the disease. This article presents the patients recorded from January 2009 to July 2015. The departments of internal medicine of 38 Spanish hospitals participated in this registry. The Clinical Research Ethics Committee of the coordinating center (University Hospital Cruses, Barakaldo, Spain) authorized the protocol, which was subsequently endorsed by the local organizations of the participating centers. The study was performed in accordance with the Declaration of Helsinki. All study researchers expressed their commitment to confidentiality in writing. The patients signed a consent form upon entering the registry.
Data management and confidentiality All patient data were entered into online case report forms and sent to the coordinating center by Internet through a secure domain. The confidential electronic data are password protected, and all hardcopies are stored in a secured location. The quality of the data is monitored and documented through complete audits at periodic intervals. The information received is stored according to the provisions of Organic Law for the Protection of Personal Data 15/1999 of December 13. The database content may not be used for purposes other than those of the study itself. Data confidentiality is ensured by assigning a unique study number to each patient when they are included in the study and by suppressing or coding any other information that could identify the individuals or the hospital center.
Patients To be included in the study, the patients had to cumulatively meet at least 4 of the 1997 classification criteria of the American College of Rheumatology (ACR).4 The visit in which the 4 (or more) criteria were met was considered the moment of the diagnosis or, in other words, the first visit of the study. Both terms will be used interchangeably throughout the text. Any patient diagnosed with SLE in the study
3 period who died after recruitment could be included in the data analysis.
Description of the variables of the Spanish Registry of Patients with Systemic Lupus Erythematosus (RELES) The main objective of the RELES study was the analysis of the incidence and complications of SLE, such as infections, arterial, venous and small vessel thrombosis, symptomatic cognitive impairment, osteoporosis, avascular necrosis, diabetes, arterial hypertension, malignancies and early menopause. Other variables that were added were mortality, cumulative chronic damage quantified according to the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR)5 index and the number of hospital admissions. The demographic, clinical and laboratory characteristics were collected systematically at the time of the diagnosis and annually. The clinical variables included the ACR criteria for SLE, the clinical presentation at the first visit (active symptoms or those recorded in the case history by organ and apparatus), the autoantibody profile and various laboratory and imaging test, depending on the manifestations of the SLE. Disease activity was measured at diagnosis and regularly using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) index.6 Organ damage was assessed annually. The recorded comorbidities included smoking, diabetes, dyslipidemia (total cholesterol 240 mg/dL, low-density lipoprotein cholesterol >130 mg/dL, triglycerides >160 mg/dL or the consumption of hypolipidemic agents), hypertension (>140/90 mm Hg on at least 2 occasions or the consumption of antihypertensive drugs), peripheral arterial disease, ischemic heart disease, heart failure, thromboembolism and stroke, diagnosed by standard clinical, laboratory and imaging criteria. Given the influence of the various drugs on both the clinical course of SLE and the associated morbidity, every change in treatment was recorded. It was therefore possible to calculate the time and specific dosage of the drugs used to control SLE at a specified time. A first analysis has recently been published on the therapeutic regimens during the first year of follow-up.7
Statistical analysis The data are presented as means (standard deviation [SD]), medians (interquartile range [IQR]) or totals with percentages. The baseline characteristics among the groups were compared using the chi-squared test,2 Fisher’s exact test, Student’s t-test or the Mann---Whitney U test, as necessary. Data analysis was performed using the SPSS 22.0 statistical suite for Mac OS X (IBM Corp, Armonk, NY, USA).
Results Demographic characteristics The study included 298 patients (265 [88.9%] women), with a mean age at diagnosis of 40.8 (SD, 15.7) years. Two hundred
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J. Canora et al. Table 1 Rate of accumulated qualifying criteria of the American College of Rheumatology (ACR) at the time of diagnosis.
ANA Arthritis Native anti-DNA Lymphopenia (<1500/mm3 ) Photosensitivity Leukopenia (<3000/mm3 ) Malar rash Thrush APA Serositis Proteinuria Anti-Sm Thrombocytopenia (<100,000/mm3 ) Discoid lupus Hemolytic anemia Cellular casts Seizures Psychosis
n
%
294 188 186 154 142 107 98 97 93 72 71 61 47 33 23 22 3 3
98.7 63.1 62.4 51.7 47.7 35.9 32.9 32.6 31.2 24.2 23.8 20.5 15.8 11.1 7.7 7.4 1 1
Abbreviations: ANA, antinuclear antibodies; APA, antiphospholipid antibodies; DNA, deoxyribonucleic acid.
and fifty-five (85.6%) patients were white, 4 were black, 21 were Amerindians, 4 were Asians and 5 were of gypsy descent. The median follow-up was 60 months (IQR, 47.70).
Classification criteria All patients met at least 4 of the ACR qualifying criteria for SLE (Table 1), with a median of 5 (IQR, 4.5). Of the classification criteria that were cumulatively met at the time of the diagnosis, antinuclear antibodies (ANA) were the most common (98.7%), while the anti-DNA were observed in 62.4%. Among the clinical criteria, arthritis predominated in 188 patients (63.1%), followed by photosensitivity in 142 (47.7%) and malar rash in 98 (32.9%). Lymphopenia was detected in more than half of the patients (51.7%). In contrast, the neuropsychiatric criteria were only met by 6 patients (2%).
Clinical and immunologic profile at the first visit At the initial visit, 97.7% of the patients had positive ANA, and 59.4% were positive for anti-native DNA (Table 2). Sixtyfour patients (21.5%) were diagnosed with nephritis during the first visit. The mean indices of activity and chronicity were 7.2 (SD, 3.2) and 6.6 (SD, 9.8) in class III nephritis and 9.8 (SD, 4.1) and 3.6 (SD, 5.4) in class IV. Of the 12 patients who presented cardiovascular events, 5 (40%) were carriers of antiphospholipid antibodies (APA) and 3 (22.5%) were smokers, with a median consumption of cigarettes of 15 packs/year (IQR, 8---29). The pattern of autoantibodies is shown in Table 3. For those patients who were positive for anti-native DNA antibodies, the rate of lupus nephritis was higher (26.7% vs. 14%, p = .009; RR, 1.91) as was the rate of hemolytic
Table 2
Clinical manifestations at the first visit.
Joint pain Lymphopenia Photosensitivity Arthritis Leukopenia (<3000/mm3 ) Thrush Malar rash Nephritis Raynaud’s phenomenon Thrombocytopenia (<100,000/mm3 ) Pleurisy Alopecia Hypothyroidism Pericarditis Subacute cutaneous lupus Livedo reticularis Dyspnea Hemolytic anemia Chronic cutaneous lupus Ophthalmological impairment DVT Stroke/TIA Cutaneous vasculitis Pneumonitis PTE Hypothyroidism Valvular heart disease Pulmonary arterial hypertension Neuropathy AOBS Seizures Myositis Myelitis Intracranial hypertension Jaccoud arthropathy Psychosis AMI Chorea
n
%
222 151 135 130 98 85 79 64 54 47 41 40 38 37 33 29 29 29 25 23 22 13 11 8 7 7 6 5 4 3 3 3 2 2 1 1 1 0
74.5 50.7 45.3 43.6 32.9 28.5 26.5 21.5 18.1 15.8 13.8 13.4 12.8 12.4 11.1 9.7 9.7 9.7 8.4 7.7 7.4 4.4 3.7 2.7 2.3 2.3 2 1.7 1.3 1 1 1 0.7 0.7 0.3 0.3 0.3 0
Abbreviations: AMI, acute myocardial infarction; AOBS, acute organic brain syndrome; DVT, deep vein thrombosis; PTE, pulmonary thromboembolism; TIA, transient ischemic attack.
anemia (13.6% vs. 4.1%; p = .07; RR, 3.3) and lymphopenia (55.4% vs. 43.8%; p = .05; RR, 1.21). The other common clinical manifestations of SLE showed no statistically significant differences between the patients with and without antinative DNA. Some of the common APAs were detected in 127 patients (42.6%). Among these patients, livedo reticularis (14.2% vs. 6.4%; p = .026; RR, 2.21), transient ischemic attack (3.9% vs. 0%; p = .013) and deep vein thrombosis (14.2% vs. 2.3%; p < .001; RR, 6.17) were more frequent. Anti-U1RNP was detected in 20.1% of the patients. In these patients, Raynaud’s phenomenon was more frequent (28.3% vs. 15.6%; p = .02; RR, 1.78). Anti-RO antibodies were found in 38.6% of the patients, and anti-La antibodies were found in 16.8%. In the patients with anti-Ro and/or anti-La, there was a greater rate of Sjögren’s syndrome (26.1% vs. 14%; p = .01; RR, 1.8) and a lower rate of livedo reticularis
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Clinical characteristics during diagnosis of RELES cohort Table 3
Positivity of immunological tests in the first V.
ANA Native anti-DNA Anti-Ro Anti-La Anti-Sm Anti-U1RNP Low C3 Low C4 RF LA aCL IgG negative aCL IgG low (<40 GPL) aCL IgG medium (40---80 GPL) aCL IgG high (>80 GPL) aCL IgM negative aCL IgM low (<40 MPL) aCL IgM medium (40---80 MPL) aCL IgM high (>80 MPL) anti B2 GP 1 IgG + anti B2 GP 1 IgM +
n
%
291 177 115 50 60 60 157 140 36 72 196 17 18 23 199 20 19 11 32 38
97.7 59.4 38.6 16.8 20.1 20.1 52.7 47 12.1 24.2 65.8 5.7 6 7.7 66.8 6.7 2.4 3.7 10.7 12.8
Abbreviations: aCL, anticardiolipin antibody; LA, lupus anticoagulant; ANA, antinuclear antibodies; Anti B2 GP 1, antibody anti-beta 2 glycoprotein 1; RF, rheumatoid factor; GPL, IgG units of antiphospholipid; Ig, immunoglobulin; MPL, IgM units of antiphospholipids.
(4.2% vs. 13.5%; p = .008; RR, 0.3). Twenty percent of the patients were carriers of anti-Sm antibodies, but the presence of these antibodies was not associated with any specific clinical manifestation. Some 59.1% of the patients had a decrease in one of the complement factors (C3 or C4), which was significantly associated with hemolytic anemia (13.1% vs. 4.9%; p = .02; RR, 2.6) and thrombocytopenia (19.3% vs. 10.7%; p = .04; RR, 1.8). Hypocomplementemia was also more frequently associated with lupus nephritis (29.1% vs. 10.7%; p < .001; RR, 2.7). The median SLEDAI in the first visit was 9.64 points (IQR, 4---13). One hundred and ninety-five patients (65.4%) had an SLEDAI ≥6 points. The clinical differences according to SLEDAI are shown in Table 4.
Treatments before and after the systemic lupus erythematosus (SLE) diagnosis The treatments undergone before and 30 days after the diagnosis were recorded (Table 5). Before the diagnosis, 255 (85.6%) patients had not undergone treatment, while in the 30 days after the diagnosis, 85.2% were treated with a drug. The patients who were already taking antimalarial drugs by the first visit had a lower median SLEDAI (5 vs. 8; p = .02). However, the median SLEDAI did not differ between those who took corticosteroids and those who did not (7 vs. 8; p = .25).
5 Table 4 Clinical differences according to the SLEDAI score at diagnosis.
Mean age at diagnosis, years White Smoker Malar rash Chronic cutaneous lupus Subacute cutaneous lupus Livedo reticularis Alopecia Raynaud’s phenomenon Cutaneous vasculitis Photosensitivity Thrush Joint pain Arthritis Jaccoud arthropathy AOBS Seizures Psychosis Myelitis Neuropathy Intracranial hypertension Ophthalmological impairment Pulmonary arterial hypertension Pleurisy Pneumonitis Pericarditis Valvular heart disease Hemolytic anemia Leukopenia Lymphopenia Thrombocytopenia DVT PTE Stroke TIA Hypothyroidism Hypothyroidism Dry syndrome Nephritis ANA Native anti-DNA Anti-Ro Anti-La Anti-Sm Anti-U1 RNP Low complement RF APA Antimalarial drugs prior to diagnosis Corticosteroids prior to diagnosis
SLEDAI >6 %
SLEDAI <6 %
p
39.9
42
84.6 23.6 26.2 6.2 10.3 9.7 16.4 17.4 5.1 40 29.2 78.5 50.8 0.5 1.5 1 0.5 0 1 1 6.7
87.3 25.5 27.5 12.7 12.7 9.8 7.8 19.6 1 54.9 26.5 66.7 30.4 0 0 1 0 2 2 0 9.8
.9 .72 .81 .052 .52 .99 .4 .65 .1 .01 .61 .03 .001 .47 .55 1 1 .12 .61 .55 .34
2.1
1
.66
15.8 3.6 17.9 2.6 12.8 31.3 44.4 18.5 7.2 2.6 3.6 2.1 1.5 10.3 16.9 30.4 97.9 65.6 38.1 16.5 21.6 20.6 70.3 9.4 39 6.2
4.9 1 2 1 3.9 36.3 42.2 10.8 7.8 2 1 0 3.9 16.7 23.5 4.9 97.1 48 40.2 17.6 17.6 19.6 37.3 17.2 49 13.7
.001 .27 <.001 .67 .013 .39 .03 .09 .84 1 .27 .3 .24 .11 .17 <.001 .7 .003 .73 .8 .42 .84 <.001 .053 .09 .03
9.2
8.8
.9
.22
Abbreviations: AMI, acute myocardial infarction; ANA, antinuclear antibodies; AOBS, acute organic brain syndrome; APA, antiphospholipid antibodies; DNA, deoxyribonucleic acid; DVT, deep vein thrombosis; PTE, pulmonary thromboembolism; RF, rheumatoid factor; TIA, transient ischemic attack.
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J. Canora et al. Table 5
Treatments administered.
NSAIDs Prednisone Methylprednisolone bolus Antimalarial agents Azathioprine Intravenous cyclophosphamide Oral cyclophosphamide Methotrexate Cyclosporine Mycophenolate sodium Mycophenolate mofetil. Biological agents (belimumab/rituximab) Thalidomide ASA Acenocoumarol Calcium Vitamin D Bisphosphonates Statins Hypotensive agents Tacrolimus Heparin
Before the SLE diagnosis N (%)
In the 30 days after the SLE diagnosis N (%)
9 (3) 27 (9.1) 1 (0.3)
25 (8.4) 160 (53.7) 30 (10.1)
26 (8.7) 4 (1.3) 0
204 (68.5) 16 (5.4) 23 (7.7)
0 4 (1.3) 0 4 (1.3) 0 0
0 12 (4) 0 9 (3) 15 (5%) 7 (2.3)
0 4 (1.3) 7 (2.3) 12 (4) 10 (3.4) 4 (1.3) 1 (0.3) 9 (3) 0 0
0 40 (13.4) 14 (4.7) 82 (27.5) 81 (27.2) 11 (3.7) 19 (6.4) 47 (15.8) 0 5 (1.7)
Abbreviations: ASA, acetylsalicylic acid; NSAIDs, nonsteroidal anti-inflammatory drugs; SLE, systemic lupus erythematosus.
Discussion Medical registries can be considered organized systems for collecting and storing patient information, all of which help us better understand certain aspects of a disease.8 Administrative database registries have been employed to study issues of incidence rate, prevalence, mortality, demographics and clinical characteristics of patients with SLE.9---11 However, specific observational cohorts of patients with SLE have provided a better understanding of the disease. Examples include the Hopkins Lupus Cohort,12 the Lupus in Minorities: Nature versus Nurture cohort,13 the EuroLupus registry,14 the University of Toronto cohort15 and the multicenter international SLICC cohort.16 These cohorts have yielded important results such as the definition by Urowitz et al. in 1974 of the bimodal mortality pattern in SLE.17 RELES is the first Spanish, prospective, multicenter longitudinal cohort of patients recorded during an initial phase of the disease. The demographic characteristics and the degree of activity at diagnosis (quantified by SLEDAI) were similar to those of other cohorts.13,15,16 Compared with the Euro-Lupus series, our patients had a higher rate of photosensitivity, oral thrush, hemolytic anemia, thrombocytopenia and livedo reticularis and a lower rate of lupus nephritis, neuropsychiatric manifestations, arthritis
and serositis. Although they are not entirely comparable studies (due to the lack of data regarding the SLEDAI score in the European registry, among other reasons), the patients of RELES did present a lower degree of organ impairment. This fact could be explained, at least partially, by the tendency in recent years towards an early diagnosis of the disease, due to a greater index of clinical suspicion and to the availability of specific immunologic techniques. A more important distinguishing feature is that the Euro-Lupus cohort was not designed for patients with a recent diagnosis of SLE. Therefore, the patient characteristics when entering the study do not reflect, as in our case, the characteristics at the start of the disease. In Spain, we have the recent results of the cohort of the Systemic Lupus Erythematosus Registry of the Spanish Society of Rheumatology,18,19 a national multicenter registry that includes more than 4000 patients. Once again, the results are difficult to compare, because the data from this registry were collected retrospectively and include patients in any phase of the disease. Nevertheless, its sponsors predicted the prospective collection of variables and included patients with a recent diagnosis, which helps establish comparisons on the clinical aspects and treatment among Spanish patients with SLE treated in the departments of internal medicine and rheumatology. The presence of seronegative SLE is increasingly challenged,20 although in most observational cohorts (both the classical14 and the more recent21 ), ANA positivity does not reach 100% of the patients. In our series, 4 patients (1.3%) were ANA negative, all of whom were positive for some APA. As in other series, the presence of anti-native DNA antibodies in the RELES cohort was associated with severe manifestations such as nephritis and hemolytic anemia. Hypocomplementemia was also associated with severe manifestations, with a higher incidence of lupus nephritis at diagnosis. APAs were associated with deep vein thrombosis and transient ischemic attack but not with other arterial thrombosis such as ischemic heart disease and cerebral infarction, probably due to the low number of patients with these manifestations as a presentation of SLE. Sixty-four (21.5%) patients presented lupus nephritis, most of whom (56%) were type III or IV. At 30 days of the diagnosis, 68.5% of the patients were taking antimalarial drugs. This percentage increased up to 81% during the first year7 and remained steady among the patients with lupus nephritis and an SLEDAI >6. These data reflect the use of hydroxychloroquine as the base treatment for SLE, beyond the specific clinical manifestations, remaining steady in the patients with more severe disease. A noteworthy aspect of our results is that the patients treated with antimalarial drugs before the SLE diagnosis started with a less active disease, as reflected by a lower SLEDAI score (5 vs. 8 from those not treated with antimalarial drugs). The indication of hydroxychloroquine in these patients was made by a previous incomplete diagnosis of SLE, i.e., patients with a clinical suspicion of SLE who did not meet all the required criteria for classifying the disease as such. Our data are similar to those of James et al. who found a protective effect of hydroxychloroquine, resulting in a later initial presentation and with fewer manifestations of activity such as proteinuria and leukopenia, in patients
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Clinical characteristics during diagnosis of RELES cohort with incomplete SLE who ultimately met the qualifying criteria.22 One hundred and sixty patients (53.7%) were treated with prednisone, 60 of whom were also treated with a bolus of methylprednisolone, intravenous cyclophosphamide or biological drugs since the moment of the diagnosis, most due to lupus nephritis and hematological disorders. RELES reflects the presentation form of SLE, from a clinical and immunological point of view, in an actual and contemporary clinical practice setting. Despite the limitations resulting from the heterogeneity of the participating centers and the lack of unified laboratory tests, especially immunological tests, RELES is the first national, multicenter, prospective patient cohort during follow-up from the initial phase of SLE. This cohort will help us understand the characteristics of patients who are treated on a daily basis, the most relevant prognostic factors and the best treatments.
Conflict of interest The authors declare that they have no conflict of interest.
Acknowledgments The authors would like to thank Mar Ajubita and all members of the coordinating center of RELES, S & H Medical Science Service, for their organizational, logistic and administrative support. This study was supported by the Spanish Society of Internal Medicine (SEMI).
Appendix 1. Members of the RELES Group Akasbi M., Department of Internal Medicine, University Hospital Infanta Leonor, Madrid (Spain); Boldova R., Department of Internal Medicine, University Clinic Hospital Lozano Blesa, Zaragoza (Spain); Callejas J.L., Department of Internal Medicine, University Hospital San Cecilio, Granada (Spain); Caminal L., Department of Internal Medicine, University Central Hospital of Asturias, Oviedo, Asturias (Spain); Canora J., Department of Internal Medicine, University Hospital of Fuenlabrada, Fuenlabrada, Madrid (Spain); Castillo M.J., Department of Internal Medicine, University Hospital Virgin del Rocío, Seville (Spain); Castro A., Department of Internal Medicine, University Hospital Sant Joan de Reus, Reus, Tarragona (Spain); Erdozain J.G., Department of Internal Medicine, Hospital of Mendaro, Mendaro, Guipúzcoa (Spain); Espinosa G., Department of Autoimmune Diseases, Clinic Hospital, Barcelona (Spain); Fernández-Monrás F., Department of Internal Medicine, University Hospital Sagrat Cor, Barcelona (Spain); Fonseca E.M., Department of Internal Medicine, Hospital of Cabue˜ nes, Gijón, Asturias (Spain); Fraile G., Department of Internal Medicine, University Hospital Ramon y Cajal, Madrid (Spain); Frutos B., Department of Internal Medicine, University Hospital of Fuenlabrada, Fuenlabrada, Madrid (Spain); García M., Autoimmune Diseases Research Unit, Department of Internal Medicine, BioCruces Health Research Institute, University Hospital Cruces, Basque University/Euskal Herriko Unibertsitatea, Barakaldo, Vizcaya (Spain); García-Morales M.,
7 Department of Internal Medicine, University Hospital San Cecilio, Granada (Spain); García-Sánchez A.I., Department of Internal Medicine, university Hospital Infanta Leonor, Madrid (Spain); Gil A., Department of Internal Medicine, University Hospital La Paz, Madrid (Spain); González-Echavarri C., Autoimmune Diseases Research Unit, Department of Internal Medicine, BioCruces Health Research Institute, University Hospital Cruces, Basque University/Euskal Herriko Unibertsitatea, Barakaldo, Vizcaya (Spain); González-Leon R., Department of Internal Medicine, University Hospital Virgin del Rocío, Seville (Spain); Herranz M.T., Department of Internal Medicine, Hospital J.M. Morales Meseguer, Murcia (Spain); Hurtado R., Department of Internal Medicine, University General Hospital of Elche, Elche, Alicante (Spain); Jiménez-Alonso J.F., Department of Internal Medicine, University Hospital Virgin de las Nieves, Granada (Spain); López-Dupla J.M., Department of Internal Medicine, University Hospital Joan XXIII, Tarragona (Spain); Marín-Ballvé A., Department of Internal Medicine, University Clinic Hospital Lozano Blesa, Zaragoza (Spain); Martín-Álvarez H., Department of Internal Medicine, Hospital Foundation of Alcorcon, Alcorcon, Madrid (Spain); Micó M.L., Department of Internal Medicine, University and Polytechnic Hospital La Fe, Valencia (Spain); Mitjavila F., Autoimmune Diseases Unit, Department of Internal Medicine, University Hospital of Bellvitge, L’Hospitalet of Llobregat, Barcelona (Spain); Navarrete N., Department of Internal Medicine, University nez-Cuerda Hospital Virgin de la Nieves, Granada (Spain); Nú˜ E., Department of Internal Medicine, General Hospital Nuestra Se˜ nora del Prado, Talavera de la Reina, Toledo (Spain); Pallarés L., Department of Internal Medicine, University Hospital Son Dureta, Palma of Mallorca, Balearic Islands (Spain); Parra S., Department of Internal Medicine, University Hospital Sant Joan de Reus, Reus, Tarragona (Spain); Pérez-Conesa M., Department of Internal Medicine, University Hospital Miguel Servet, Zaragoza (Spain); Pinilla B., Department of Internal Medicine, University General Hospital Gregorio Mara˜ nón, Madrid (Spain); Rodríguez A.P., Department of Internal Medicine, University Hospital Complex of Orense, Orense (Spain); Rodríguez-Carballeira M., Department of Internal Medicine, University Hospital Mutua de Terrasa, Terrasa, Barcelona (Spain); Ruiz-Irastorza G., Autoimmune Diseases Research Unit, Department of Internal Medicine, BioCruces Health Research Institute, University Hospital Cruces, Basque University/Euskal Herriko Unibertsitatea, Barakaldo, Vizcaya (Spain); Sáez L., Department of Internal Medicine, University Hospital Miguel Servet, Zaragoza (Spain); Salvador G., Department of Internal Medicine, Hospital of Manises, Manises, Valencia (Spain); Sánchez-García E., Autoimmune Diseases Unit, Department of Internal Medicine, University Hospital Reina Sofía, Cordoba (Spain); Serralta G., Department of Internal Medicine, Hospital Infanta Sofía, San Sebastian de los Reyes, Madrid (Spain); Sope˜ na B., Department of Internal Medicine. University Hospital Complex of Vigo, Pontevedra, Vigo (Spain); Suárez S., Department of Internal Medicine, University Central Hospital of Asturias, Oviedo, Asturias (Spain); Tolosa C., Department of Internal Medicine, Corporació Sanitària Parc Taulí, Department of Pulmonology, Corporació Parc Taulí, Barcelona (Spain); Villalba M.V., Department of Internal Medicine, University General Hospital Gregorio Mara˜ nón, Madrid (Spain).
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References 1. Bernatsky S, Boivin JF, Joseph L, Manzi S, Ginzler E, Gladman DD, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum. 2006;54:2550---7. 2. Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus. 2006;15:308---18. 3. Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med. 2008;358:929---39. 4. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:1725. 5. Gladman DD, Urowitz MB, Goldsmith CH, Fortin P, Ginzler E, Gordon C, et al. The reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in patients with systemic lupus erythematosus. Arthritis Rheum. 1997;40:809---13. 6. Gladman DD, Iba˜ nez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002;29:288---91. 7. Ruiz-Irastorza G, García M, Espinosa G, Cabezas-Rodríguez I, Mitjavila F, González-León R, et al., RELES, Autoimmune Diseases Study Group GEAS. Patterns of drug therapy in newly diagnosed Spanish patients with systemic lupus erythematosus. Clin Exp Rheumatol. 2016;34:466---72. 8. Lu LJ, Wallace DJ, Navarra SV, Weisman MH. Lupus registries: evolution and challenges. Semin Arthritis Rheum. 2010;39:224---45. 9. Fries JF, McShane DJ. A.R.A.M.I.S. (The American Rheumatism Association Medical Information System): a prototypical national chronic disease data bank. West J Med. 1986;145:798---804. 10. Krishnan E, Hubert HB. Ethnicity and mortality from systemic lupus erythematosus in the US. Ann Rheum Dis. 2006;65:1500---5. 11. Nightingale AL, Farmer RD, de Vries CS. Systemic lupus erythematosus prevalence in the UK: methodological issues when using the General Practice Research Database to estimate frequency of chronic relapsing-remitting disease. Pharmacoepidemiol Drug Saf. 2007;16:144---51. 12. Petri M. Hopkins lupus cohort (1999 update). Rheum Dis Clin N Am. 2000;26:199---213. 13. Fernández M, Calvo-Alén J, Alarcón GS, Roseman JM, Bastian HM, Fessler BJ, et al. Systemic lupus erythematosus in a multiethnic U.S. cohort (LUMINA): XXI. Disease activity, damage accrual, and vascular events in pre- and postmenopausal women. Arthritis Rheum. 2005;52:1655---64.
J. Canora et al. 14. Cervera R, Abarca-Costalago M, Abramovicz D, Allegri F, Annunziata P, Aydintug AO, et al., European Working Party on Systemic Lupus Erythematosus. Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the Euro-Lupus Project. Autoimmun Rev. 2006;5:180---6. 15. Urowitz MB, Gladman DD. Contributions of observational cohort studies in systemic lupus erythematosus: the University of Toronto lupus clinic experience. Rheum Dis Clin N Am. 2005;31:211---21. 16. Gladman DD, Goldsmith CH, Urowitz MB, Bacon P, Fortin P, Ginzler E, et al. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR). Damage Index for Systemic Lupus Erythematosus international comparison. J Rheumatol. 2000;27:373---6. 17. Urowitz MB, Bookman AA, Koehler BE, Gordon DA, Smythe HA, Ogryzlo MA. The bimodal mortality pattern of systemic lupus erythematosus. Am J Med. 1976;60:221---5. 18. Rúa-Figueroa I, López-Longo FJ, Calvo-Alén J, GalindoIzquierdo M, Loza E, García de Yebenes MJ, et al., Grupo de trabajo en Enfermedades Autoinmunes Sistémicas de la Sociedad Espa˜ nola de Reumatología (EAS-SER); Unidad de nola de Reumatología (UIInvestigación de la Sociedad Espa˜ SER). Registro nacional de pacientes con lupus eritematoso nola de Reumatología: objetivos sistémico de la Sociedad Espa˜ y metodología. Reumatol Clin. 2014;10:17---24. 19. Rúa-Figueroa I, Richi P, López-Longo FJ, Galindo M, CalvoAlén J, Olivé-Marqués A, et al., EAS-SER (Systemic Diseases Study Group of the Spanish Society of Rheumatology). Comprehensive description of clinical characteristics of a large systemic lupus erythematosus cohort from the Spanish Rheumatology Society Lupus Registry (RELESSER) with emphasis on complete versus incomplete lupus differences. Medicine (Baltimore). 2015;94:e267. 20. Cross LS, Aslam A, Misbah SA. Antinuclear antibody-negative lupus as a distinct diagnostic entity --- does it not longer exist. Q J Med. 2004;97:303---8. 21. Ferucci ED, Johnston JM, Gaddy JR, Sumner L, Posever JO, Choromanski TL, et al. Prevalence and incidence of systemic lupus erythematosus in a population-based registry of American Indian and Alaska native people, 2007---2009. Arthritis Rheumatol. 2014;66:2494---502. 22. James JA, Kim-Howard XR, Bruner BF, Jonsson MK, McClain MT, Arbuckle MR, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus. 2007;16:401---9.
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Revista Clínica Española www.elsevier.es/rce
ORIGINAL ARTICLE
Clinical characteristics during diagnosis of a prospective cohort of patients with systemic lupus erythematosus treated in Spanish Departments of Internal Medicine: The RELES study夽 J. Canora a,∗ , M. García b , F. Mitjavila c , G. Espinosa d , S. Suárez e , R. González-León f , na g , R. Boldova h , A. Castro i , G. Ruiz-Irastorza b , On behalf of the researchers B. Sope˜ from the RELES-Group of Systemic Autoimmune Diseases (GEAS)♦ a
Servicio de Medicina Interna, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain Unidad de Investigación de Enfermedades Autoinmunes, Servicio de Medicina Interna, BioCruces Health Research Institute, Hospital Universitario Cruces, Universidad del País Vasco/Euskal Herriko Unibertsitatea, Barakaldo, Vizcaya, Spain c Unidad de Enfermedades Autoinmunes, Servicio de Medicina Interna, Hospital Universitario de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain d Servicio de Enfermedades Autoinmunes, Hospital Clínic, Barcelona, Spain e Servicio de Medicina Interna, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain f Servicio de Medicina Interna, Hospital Universitario Virgen del Rocío, Sevilla, Spain g Servicio de Medicina Interna, Complejo Hospitalario Universitario de Vigo, Pontevedra, Vigo, Spain h Servicio de Medicina Interna, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain i Servicio de Medicina Interna, Hospital Universitario Sant Joan de Reus, Reus, Tarragona, Spain b
Received 7 April 2016; accepted 25 September 2016
KEYWORDS Systemic lupus erythematosus; Inception cohort; Hydroxychloroquine; Lupus nephritis; Anti-DNA;
Abstract Introduction: Patient registries are useful tools for assessing rare diseases. Our objective is to present the Spanish registry of patients with systemic lupus erythematosus (Registro espa˜ nol de pacientes con lupus eritematoso sistémico, RELES). Patients and methods: RELES was started in 2008 as an observational, prospective, multicentre cohort registry that included patients from the time they were diagnosed. The registry’s objective is to analyse the incidence and noninflammatory complications of systemic lupus erythematosus (SLE). The departments of internal medicine of 38 Spanish hospitals participate in this registry.
夽
Please cite this article as: Canora J, García M, Mitjavila F, Espinosa G, Suárez S, González-León R, et al. Características clínicas al noles: diagnóstico de una cohorte prospectiva de pacientes con lupus eritematoso sistémico atendidos en servicios de Medicina Interna espa˜ estudio RELES. Rev Clin Esp. 2016. http://dx.doi.org/10.1016/j.rce.2016.09.006 ∗ Corresponding author. E-mail address: [email protected] (J. Canora). ♦ The complete list of RELES-GEASS researchers is given in Appendix 1. 2254-8874/© 2016 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
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Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)
PALABRAS CLAVE Lupus eritematoso sistémico; Cohorte de inicio; Hidroxicloroquina; Nefritis lúpica; Anti-DNA; Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)
Results: A total of 298 patients with a mean age of 40.8 ± 15.7 years were included, 88.9% of whom were women and 85.6% of whom were white. In the first visit, there was a predominance of joint manifestations (74.5%). One hundred and seventy-seven patients (59.4%) were positive for anti-native DNA. In these patients, there was a higher rate of lupus nephritis (26.7% vs. 14%, p = .009; relative risk [RR], 1.33), haemolytic anaemia (13.6% vs. 4.1%, p = .07; RR, 1.46) and lymphopenia (55.4% vs. 43.8%, p = .05; RR, 1.21). The median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) score was 9.64 points (interquartile range, 4---13). The patients treated with antimalarial drugs before the diagnosis of SLE had a median SLEDAI score in the first visit of 5, compared with 8 for those who were not treated with these drugs (p = .02). Conclusions: RELES constitutes the first Spanish patient cohort with SLE recorded from the time of the diagnosis. The presence of anti-DNA has been related to severe manifestations such as nephritis and haemolytic anaemia. Treatment with antimalarial drugs before the diagnosis was associated with less active disease at the initial presentation. © 2016 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
Características clínicas al diagnóstico de una cohorte prospectiva de pacientes con lupus eritematoso sistémico atendidos en servicios de Medicina Interna espa˜ noles: estudio RELES Resumen Introducción: Los registros de pacientes son herramientas útiles para evaluar enfermedades poco frecuentes. Nuestro objetivo es presentar el «Registro espa˜ nol de pacientes con lupus eritematoso sistémico» (RELES). Pacientes y métodos: RELES se inició en 2008, como un registro multicéntrico de cohortes, observacional, prospectivo, incluyendo a pacientes desde el momento del diagnóstico, cuyo objetivo es analizar la incidencia y complicaciones no inflamatorias del lupus eritematoso sistémico (LES). Participan los servicios de Medicina Interna de 38 hospitales espa˜ noles. Resultados: Se incluyó a 298 pacientes con una edad media de 40,8 ± 15,7 a˜ nos, de los que el 88,9% eran mujeres y el 85,6% de raza caucásica. En la primera visita, predominaron las manifestaciones articulares (74,5%). Ciento setenta y siete pacientes (59,4%) mostraban positividad para anti-DNA nativo, siendo superior en estos la frecuencia de nefritis lúpica (26,7% vs. 14%, p = 0,009; riesgo relativo [RR] 1,33), de anemia hemolítica (13,6% vs. 4,1%, p = 0,07; RR 1,46) y linfopenia (55,4% vs. 43,8%, p = 0,05; RR 1,21). La mediana del Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) fue de 9,64 puntos (rango intercuartílico 4-13). Los tratados con antipalúdicos antes del diagnóstico de LES tenían una mediana de SLEDAI en la primera visita de 5, frente a 8 en los que no los tomaban (p = 0,02). Conclusiones: RELES constituye la primera cohorte de pacientes con LES recogidos desde el momento del diagnóstico en Espa˜ na. La presencia de anti-DNA se ha relacionado con manifestaciones graves como nefritis y anemia hemolítica. El tratamiento con antipalúdicos antes del diagnóstico se asoció con una enfermedad menos activa al comienzo. © 2016 Elsevier Espa˜ na, S.L.U. y Sociedad Espa˜ nola de Medicina Interna (SEMI). Todos los derechos reservados.
Background Systemic lupus erythematosus (SLE) is a systemic autoimmune disease (SAD) that mainly affects young women and results in increased morbidity and mortality.1 The prevalence of SLE in Spain over the last 40 years has varied from 34.1 to 91 cases per 100,000 inhabitants,2 which could be related to an improvement in the prognosis, which is estimated at up to 80% survival at 15 years.3
Although SLE is one of the most prevalent SADs, large cohorts are not easy to obtain from a single hospital center. Additionally, most published series are retrospective and include patients recorded over long periods. Patient registries and multicenter cohorts are particularly useful tools for assessing relatively uncommon diseases. The Systemic Autoimmune Disease Group (GEAS) of the Spanish Society of Internal Medicine (SEMI) therefore decided in 2008 to launch a longitudinal, national and
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Clinical characteristics during diagnosis of RELES cohort multicenter study that exclusively included patients with a recent diagnosis of SLE, treated in the offices of departments of internal medicine. The study was called the Spanish Registry of Patients with SLE (Registro Espa˜ nol de pacientes con LES, RELES). The aim of this article is to present the design and longterm objectives of the study and analyze the initial clinical characteristics, the most common presentation forms, the degree of activity and the treatments administered during the first month after diagnosis to the patients included in RELES.
Patients and methods RELES is a multicenter, observational, prospective cohort study of patients recorded since the start of the diagnosis and was launched in 2008. The registry’s main objective was to create an observational prospective cohort of patients with SLE, with special attention to the role of noninflammatory complications in the morbidity and mortality associated with the disease. This article presents the patients recorded from January 2009 to July 2015. The departments of internal medicine of 38 Spanish hospitals participated in this registry. The Clinical Research Ethics Committee of the coordinating center (University Hospital Cruses, Barakaldo, Spain) authorized the protocol, which was subsequently endorsed by the local organizations of the participating centers. The study was performed in accordance with the Declaration of Helsinki. All study researchers expressed their commitment to confidentiality in writing. The patients signed a consent form upon entering the registry.
Data management and confidentiality All patient data were entered into online case report forms and sent to the coordinating center by Internet through a secure domain. The confidential electronic data are password protected, and all hardcopies are stored in a secured location. The quality of the data is monitored and documented through complete audits at periodic intervals. The information received is stored according to the provisions of Organic Law for the Protection of Personal Data 15/1999 of December 13. The database content may not be used for purposes other than those of the study itself. Data confidentiality is ensured by assigning a unique study number to each patient when they are included in the study and by suppressing or coding any other information that could identify the individuals or the hospital center.
Patients To be included in the study, the patients had to cumulatively meet at least 4 of the 1997 classification criteria of the American College of Rheumatology (ACR).4 The visit in which the 4 (or more) criteria were met was considered the moment of the diagnosis or, in other words, the first visit of the study. Both terms will be used interchangeably throughout the text. Any patient diagnosed with SLE in the study
3 period who died after recruitment could be included in the data analysis.
Description of the variables of the Spanish Registry of Patients with Systemic Lupus Erythematosus (RELES) The main objective of the RELES study was the analysis of the incidence and complications of SLE, such as infections, arterial, venous and small vessel thrombosis, symptomatic cognitive impairment, osteoporosis, avascular necrosis, diabetes, arterial hypertension, malignancies and early menopause. Other variables that were added were mortality, cumulative chronic damage quantified according to the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR)5 index and the number of hospital admissions. The demographic, clinical and laboratory characteristics were collected systematically at the time of the diagnosis and annually. The clinical variables included the ACR criteria for SLE, the clinical presentation at the first visit (active symptoms or those recorded in the case history by organ and apparatus), the autoantibody profile and various laboratory and imaging test, depending on the manifestations of the SLE. Disease activity was measured at diagnosis and regularly using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) index.6 Organ damage was assessed annually. The recorded comorbidities included smoking, diabetes, dyslipidemia (total cholesterol 240 mg/dL, low-density lipoprotein cholesterol >130 mg/dL, triglycerides >160 mg/dL or the consumption of hypolipidemic agents), hypertension (>140/90 mm Hg on at least 2 occasions or the consumption of antihypertensive drugs), peripheral arterial disease, ischemic heart disease, heart failure, thromboembolism and stroke, diagnosed by standard clinical, laboratory and imaging criteria. Given the influence of the various drugs on both the clinical course of SLE and the associated morbidity, every change in treatment was recorded. It was therefore possible to calculate the time and specific dosage of the drugs used to control SLE at a specified time. A first analysis has recently been published on the therapeutic regimens during the first year of follow-up.7
Statistical analysis The data are presented as means (standard deviation [SD]), medians (interquartile range [IQR]) or totals with percentages. The baseline characteristics among the groups were compared using the chi-squared test,2 Fisher’s exact test, Student’s t-test or the Mann---Whitney U test, as necessary. Data analysis was performed using the SPSS 22.0 statistical suite for Mac OS X (IBM Corp, Armonk, NY, USA).
Results Demographic characteristics The study included 298 patients (265 [88.9%] women), with a mean age at diagnosis of 40.8 (SD, 15.7) years. Two hundred
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J. Canora et al. Table 1 Rate of accumulated qualifying criteria of the American College of Rheumatology (ACR) at the time of diagnosis.
ANA Arthritis Native anti-DNA Lymphopenia (<1500/mm3 ) Photosensitivity Leukopenia (<3000/mm3 ) Malar rash Thrush APA Serositis Proteinuria Anti-Sm Thrombocytopenia (<100,000/mm3 ) Discoid lupus Hemolytic anemia Cellular casts Seizures Psychosis
n
%
294 188 186 154 142 107 98 97 93 72 71 61 47 33 23 22 3 3
98.7 63.1 62.4 51.7 47.7 35.9 32.9 32.6 31.2 24.2 23.8 20.5 15.8 11.1 7.7 7.4 1 1
Abbreviations: ANA, antinuclear antibodies; APA, antiphospholipid antibodies; DNA, deoxyribonucleic acid.
and fifty-five (85.6%) patients were white, 4 were black, 21 were Amerindians, 4 were Asians and 5 were of gypsy descent. The median follow-up was 60 months (IQR, 47.70).
Classification criteria All patients met at least 4 of the ACR qualifying criteria for SLE (Table 1), with a median of 5 (IQR, 4.5). Of the classification criteria that were cumulatively met at the time of the diagnosis, antinuclear antibodies (ANA) were the most common (98.7%), while the anti-DNA were observed in 62.4%. Among the clinical criteria, arthritis predominated in 188 patients (63.1%), followed by photosensitivity in 142 (47.7%) and malar rash in 98 (32.9%). Lymphopenia was detected in more than half of the patients (51.7%). In contrast, the neuropsychiatric criteria were only met by 6 patients (2%).
Clinical and immunologic profile at the first visit At the initial visit, 97.7% of the patients had positive ANA, and 59.4% were positive for anti-native DNA (Table 2). Sixtyfour patients (21.5%) were diagnosed with nephritis during the first visit. The mean indices of activity and chronicity were 7.2 (SD, 3.2) and 6.6 (SD, 9.8) in class III nephritis and 9.8 (SD, 4.1) and 3.6 (SD, 5.4) in class IV. Of the 12 patients who presented cardiovascular events, 5 (40%) were carriers of antiphospholipid antibodies (APA) and 3 (22.5%) were smokers, with a median consumption of cigarettes of 15 packs/year (IQR, 8---29). The pattern of autoantibodies is shown in Table 3. For those patients who were positive for anti-native DNA antibodies, the rate of lupus nephritis was higher (26.7% vs. 14%, p = .009; RR, 1.91) as was the rate of hemolytic
Table 2
Clinical manifestations at the first visit.
Joint pain Lymphopenia Photosensitivity Arthritis Leukopenia (<3000/mm3 ) Thrush Malar rash Nephritis Raynaud’s phenomenon Thrombocytopenia (<100,000/mm3 ) Pleurisy Alopecia Hypothyroidism Pericarditis Subacute cutaneous lupus Livedo reticularis Dyspnea Hemolytic anemia Chronic cutaneous lupus Ophthalmological impairment DVT Stroke/TIA Cutaneous vasculitis Pneumonitis PTE Hypothyroidism Valvular heart disease Pulmonary arterial hypertension Neuropathy AOBS Seizures Myositis Myelitis Intracranial hypertension Jaccoud arthropathy Psychosis AMI Chorea
n
%
222 151 135 130 98 85 79 64 54 47 41 40 38 37 33 29 29 29 25 23 22 13 11 8 7 7 6 5 4 3 3 3 2 2 1 1 1 0
74.5 50.7 45.3 43.6 32.9 28.5 26.5 21.5 18.1 15.8 13.8 13.4 12.8 12.4 11.1 9.7 9.7 9.7 8.4 7.7 7.4 4.4 3.7 2.7 2.3 2.3 2 1.7 1.3 1 1 1 0.7 0.7 0.3 0.3 0.3 0
Abbreviations: AMI, acute myocardial infarction; AOBS, acute organic brain syndrome; DVT, deep vein thrombosis; PTE, pulmonary thromboembolism; TIA, transient ischemic attack.
anemia (13.6% vs. 4.1%; p = .07; RR, 3.3) and lymphopenia (55.4% vs. 43.8%; p = .05; RR, 1.21). The other common clinical manifestations of SLE showed no statistically significant differences between the patients with and without antinative DNA. Some of the common APAs were detected in 127 patients (42.6%). Among these patients, livedo reticularis (14.2% vs. 6.4%; p = .026; RR, 2.21), transient ischemic attack (3.9% vs. 0%; p = .013) and deep vein thrombosis (14.2% vs. 2.3%; p < .001; RR, 6.17) were more frequent. Anti-U1RNP was detected in 20.1% of the patients. In these patients, Raynaud’s phenomenon was more frequent (28.3% vs. 15.6%; p = .02; RR, 1.78). Anti-RO antibodies were found in 38.6% of the patients, and anti-La antibodies were found in 16.8%. In the patients with anti-Ro and/or anti-La, there was a greater rate of Sjögren’s syndrome (26.1% vs. 14%; p = .01; RR, 1.8) and a lower rate of livedo reticularis
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Clinical characteristics during diagnosis of RELES cohort Table 3
Positivity of immunological tests in the first V.
ANA Native anti-DNA Anti-Ro Anti-La Anti-Sm Anti-U1RNP Low C3 Low C4 RF LA aCL IgG negative aCL IgG low (<40 GPL) aCL IgG medium (40---80 GPL) aCL IgG high (>80 GPL) aCL IgM negative aCL IgM low (<40 MPL) aCL IgM medium (40---80 MPL) aCL IgM high (>80 MPL) anti B2 GP 1 IgG + anti B2 GP 1 IgM +
n
%
291 177 115 50 60 60 157 140 36 72 196 17 18 23 199 20 19 11 32 38
97.7 59.4 38.6 16.8 20.1 20.1 52.7 47 12.1 24.2 65.8 5.7 6 7.7 66.8 6.7 2.4 3.7 10.7 12.8
Abbreviations: aCL, anticardiolipin antibody; LA, lupus anticoagulant; ANA, antinuclear antibodies; Anti B2 GP 1, antibody anti-beta 2 glycoprotein 1; RF, rheumatoid factor; GPL, IgG units of antiphospholipid; Ig, immunoglobulin; MPL, IgM units of antiphospholipids.
(4.2% vs. 13.5%; p = .008; RR, 0.3). Twenty percent of the patients were carriers of anti-Sm antibodies, but the presence of these antibodies was not associated with any specific clinical manifestation. Some 59.1% of the patients had a decrease in one of the complement factors (C3 or C4), which was significantly associated with hemolytic anemia (13.1% vs. 4.9%; p = .02; RR, 2.6) and thrombocytopenia (19.3% vs. 10.7%; p = .04; RR, 1.8). Hypocomplementemia was also more frequently associated with lupus nephritis (29.1% vs. 10.7%; p < .001; RR, 2.7). The median SLEDAI in the first visit was 9.64 points (IQR, 4---13). One hundred and ninety-five patients (65.4%) had an SLEDAI ≥6 points. The clinical differences according to SLEDAI are shown in Table 4.
Treatments before and after the systemic lupus erythematosus (SLE) diagnosis The treatments undergone before and 30 days after the diagnosis were recorded (Table 5). Before the diagnosis, 255 (85.6%) patients had not undergone treatment, while in the 30 days after the diagnosis, 85.2% were treated with a drug. The patients who were already taking antimalarial drugs by the first visit had a lower median SLEDAI (5 vs. 8; p = .02). However, the median SLEDAI did not differ between those who took corticosteroids and those who did not (7 vs. 8; p = .25).
5 Table 4 Clinical differences according to the SLEDAI score at diagnosis.
Mean age at diagnosis, years White Smoker Malar rash Chronic cutaneous lupus Subacute cutaneous lupus Livedo reticularis Alopecia Raynaud’s phenomenon Cutaneous vasculitis Photosensitivity Thrush Joint pain Arthritis Jaccoud arthropathy AOBS Seizures Psychosis Myelitis Neuropathy Intracranial hypertension Ophthalmological impairment Pulmonary arterial hypertension Pleurisy Pneumonitis Pericarditis Valvular heart disease Hemolytic anemia Leukopenia Lymphopenia Thrombocytopenia DVT PTE Stroke TIA Hypothyroidism Hypothyroidism Dry syndrome Nephritis ANA Native anti-DNA Anti-Ro Anti-La Anti-Sm Anti-U1 RNP Low complement RF APA Antimalarial drugs prior to diagnosis Corticosteroids prior to diagnosis
SLEDAI >6 %
SLEDAI <6 %
p
39.9
42
84.6 23.6 26.2 6.2 10.3 9.7 16.4 17.4 5.1 40 29.2 78.5 50.8 0.5 1.5 1 0.5 0 1 1 6.7
87.3 25.5 27.5 12.7 12.7 9.8 7.8 19.6 1 54.9 26.5 66.7 30.4 0 0 1 0 2 2 0 9.8
.9 .72 .81 .052 .52 .99 .4 .65 .1 .01 .61 .03 .001 .47 .55 1 1 .12 .61 .55 .34
2.1
1
.66
15.8 3.6 17.9 2.6 12.8 31.3 44.4 18.5 7.2 2.6 3.6 2.1 1.5 10.3 16.9 30.4 97.9 65.6 38.1 16.5 21.6 20.6 70.3 9.4 39 6.2
4.9 1 2 1 3.9 36.3 42.2 10.8 7.8 2 1 0 3.9 16.7 23.5 4.9 97.1 48 40.2 17.6 17.6 19.6 37.3 17.2 49 13.7
.001 .27 <.001 .67 .013 .39 .03 .09 .84 1 .27 .3 .24 .11 .17 <.001 .7 .003 .73 .8 .42 .84 <.001 .053 .09 .03
9.2
8.8
.9
.22
Abbreviations: AMI, acute myocardial infarction; ANA, antinuclear antibodies; AOBS, acute organic brain syndrome; APA, antiphospholipid antibodies; DNA, deoxyribonucleic acid; DVT, deep vein thrombosis; PTE, pulmonary thromboembolism; RF, rheumatoid factor; TIA, transient ischemic attack.
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J. Canora et al. Table 5
Treatments administered.
NSAIDs Prednisone Methylprednisolone bolus Antimalarial agents Azathioprine Intravenous cyclophosphamide Oral cyclophosphamide Methotrexate Cyclosporine Mycophenolate sodium Mycophenolate mofetil. Biological agents (belimumab/rituximab) Thalidomide ASA Acenocoumarol Calcium Vitamin D Bisphosphonates Statins Hypotensive agents Tacrolimus Heparin
Before the SLE diagnosis N (%)
In the 30 days after the SLE diagnosis N (%)
9 (3) 27 (9.1) 1 (0.3)
25 (8.4) 160 (53.7) 30 (10.1)
26 (8.7) 4 (1.3) 0
204 (68.5) 16 (5.4) 23 (7.7)
0 4 (1.3) 0 4 (1.3) 0 0
0 12 (4) 0 9 (3) 15 (5%) 7 (2.3)
0 4 (1.3) 7 (2.3) 12 (4) 10 (3.4) 4 (1.3) 1 (0.3) 9 (3) 0 0
0 40 (13.4) 14 (4.7) 82 (27.5) 81 (27.2) 11 (3.7) 19 (6.4) 47 (15.8) 0 5 (1.7)
Abbreviations: ASA, acetylsalicylic acid; NSAIDs, nonsteroidal anti-inflammatory drugs; SLE, systemic lupus erythematosus.
Discussion Medical registries can be considered organized systems for collecting and storing patient information, all of which help us better understand certain aspects of a disease.8 Administrative database registries have been employed to study issues of incidence rate, prevalence, mortality, demographics and clinical characteristics of patients with SLE.9---11 However, specific observational cohorts of patients with SLE have provided a better understanding of the disease. Examples include the Hopkins Lupus Cohort,12 the Lupus in Minorities: Nature versus Nurture cohort,13 the EuroLupus registry,14 the University of Toronto cohort15 and the multicenter international SLICC cohort.16 These cohorts have yielded important results such as the definition by Urowitz et al. in 1974 of the bimodal mortality pattern in SLE.17 RELES is the first Spanish, prospective, multicenter longitudinal cohort of patients recorded during an initial phase of the disease. The demographic characteristics and the degree of activity at diagnosis (quantified by SLEDAI) were similar to those of other cohorts.13,15,16 Compared with the Euro-Lupus series, our patients had a higher rate of photosensitivity, oral thrush, hemolytic anemia, thrombocytopenia and livedo reticularis and a lower rate of lupus nephritis, neuropsychiatric manifestations, arthritis
and serositis. Although they are not entirely comparable studies (due to the lack of data regarding the SLEDAI score in the European registry, among other reasons), the patients of RELES did present a lower degree of organ impairment. This fact could be explained, at least partially, by the tendency in recent years towards an early diagnosis of the disease, due to a greater index of clinical suspicion and to the availability of specific immunologic techniques. A more important distinguishing feature is that the Euro-Lupus cohort was not designed for patients with a recent diagnosis of SLE. Therefore, the patient characteristics when entering the study do not reflect, as in our case, the characteristics at the start of the disease. In Spain, we have the recent results of the cohort of the Systemic Lupus Erythematosus Registry of the Spanish Society of Rheumatology,18,19 a national multicenter registry that includes more than 4000 patients. Once again, the results are difficult to compare, because the data from this registry were collected retrospectively and include patients in any phase of the disease. Nevertheless, its sponsors predicted the prospective collection of variables and included patients with a recent diagnosis, which helps establish comparisons on the clinical aspects and treatment among Spanish patients with SLE treated in the departments of internal medicine and rheumatology. The presence of seronegative SLE is increasingly challenged,20 although in most observational cohorts (both the classical14 and the more recent21 ), ANA positivity does not reach 100% of the patients. In our series, 4 patients (1.3%) were ANA negative, all of whom were positive for some APA. As in other series, the presence of anti-native DNA antibodies in the RELES cohort was associated with severe manifestations such as nephritis and hemolytic anemia. Hypocomplementemia was also associated with severe manifestations, with a higher incidence of lupus nephritis at diagnosis. APAs were associated with deep vein thrombosis and transient ischemic attack but not with other arterial thrombosis such as ischemic heart disease and cerebral infarction, probably due to the low number of patients with these manifestations as a presentation of SLE. Sixty-four (21.5%) patients presented lupus nephritis, most of whom (56%) were type III or IV. At 30 days of the diagnosis, 68.5% of the patients were taking antimalarial drugs. This percentage increased up to 81% during the first year7 and remained steady among the patients with lupus nephritis and an SLEDAI >6. These data reflect the use of hydroxychloroquine as the base treatment for SLE, beyond the specific clinical manifestations, remaining steady in the patients with more severe disease. A noteworthy aspect of our results is that the patients treated with antimalarial drugs before the SLE diagnosis started with a less active disease, as reflected by a lower SLEDAI score (5 vs. 8 from those not treated with antimalarial drugs). The indication of hydroxychloroquine in these patients was made by a previous incomplete diagnosis of SLE, i.e., patients with a clinical suspicion of SLE who did not meet all the required criteria for classifying the disease as such. Our data are similar to those of James et al. who found a protective effect of hydroxychloroquine, resulting in a later initial presentation and with fewer manifestations of activity such as proteinuria and leukopenia, in patients
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Clinical characteristics during diagnosis of RELES cohort with incomplete SLE who ultimately met the qualifying criteria.22 One hundred and sixty patients (53.7%) were treated with prednisone, 60 of whom were also treated with a bolus of methylprednisolone, intravenous cyclophosphamide or biological drugs since the moment of the diagnosis, most due to lupus nephritis and hematological disorders. RELES reflects the presentation form of SLE, from a clinical and immunological point of view, in an actual and contemporary clinical practice setting. Despite the limitations resulting from the heterogeneity of the participating centers and the lack of unified laboratory tests, especially immunological tests, RELES is the first national, multicenter, prospective patient cohort during follow-up from the initial phase of SLE. This cohort will help us understand the characteristics of patients who are treated on a daily basis, the most relevant prognostic factors and the best treatments.
Conflict of interest The authors declare that they have no conflict of interest.
Acknowledgments The authors would like to thank Mar Ajubita and all members of the coordinating center of RELES, S & H Medical Science Service, for their organizational, logistic and administrative support. This study was supported by the Spanish Society of Internal Medicine (SEMI).
Appendix 1. Members of the RELES Group Akasbi M., Department of Internal Medicine, University Hospital Infanta Leonor, Madrid (Spain); Boldova R., Department of Internal Medicine, University Clinic Hospital Lozano Blesa, Zaragoza (Spain); Callejas J.L., Department of Internal Medicine, University Hospital San Cecilio, Granada (Spain); Caminal L., Department of Internal Medicine, University Central Hospital of Asturias, Oviedo, Asturias (Spain); Canora J., Department of Internal Medicine, University Hospital of Fuenlabrada, Fuenlabrada, Madrid (Spain); Castillo M.J., Department of Internal Medicine, University Hospital Virgin del Rocío, Seville (Spain); Castro A., Department of Internal Medicine, University Hospital Sant Joan de Reus, Reus, Tarragona (Spain); Erdozain J.G., Department of Internal Medicine, Hospital of Mendaro, Mendaro, Guipúzcoa (Spain); Espinosa G., Department of Autoimmune Diseases, Clinic Hospital, Barcelona (Spain); Fernández-Monrás F., Department of Internal Medicine, University Hospital Sagrat Cor, Barcelona (Spain); Fonseca E.M., Department of Internal Medicine, Hospital of Cabue˜ nes, Gijón, Asturias (Spain); Fraile G., Department of Internal Medicine, University Hospital Ramon y Cajal, Madrid (Spain); Frutos B., Department of Internal Medicine, University Hospital of Fuenlabrada, Fuenlabrada, Madrid (Spain); García M., Autoimmune Diseases Research Unit, Department of Internal Medicine, BioCruces Health Research Institute, University Hospital Cruces, Basque University/Euskal Herriko Unibertsitatea, Barakaldo, Vizcaya (Spain); García-Morales M.,
7 Department of Internal Medicine, University Hospital San Cecilio, Granada (Spain); García-Sánchez A.I., Department of Internal Medicine, university Hospital Infanta Leonor, Madrid (Spain); Gil A., Department of Internal Medicine, University Hospital La Paz, Madrid (Spain); González-Echavarri C., Autoimmune Diseases Research Unit, Department of Internal Medicine, BioCruces Health Research Institute, University Hospital Cruces, Basque University/Euskal Herriko Unibertsitatea, Barakaldo, Vizcaya (Spain); González-Leon R., Department of Internal Medicine, University Hospital Virgin del Rocío, Seville (Spain); Herranz M.T., Department of Internal Medicine, Hospital J.M. Morales Meseguer, Murcia (Spain); Hurtado R., Department of Internal Medicine, University General Hospital of Elche, Elche, Alicante (Spain); Jiménez-Alonso J.F., Department of Internal Medicine, University Hospital Virgin de las Nieves, Granada (Spain); López-Dupla J.M., Department of Internal Medicine, University Hospital Joan XXIII, Tarragona (Spain); Marín-Ballvé A., Department of Internal Medicine, University Clinic Hospital Lozano Blesa, Zaragoza (Spain); Martín-Álvarez H., Department of Internal Medicine, Hospital Foundation of Alcorcon, Alcorcon, Madrid (Spain); Micó M.L., Department of Internal Medicine, University and Polytechnic Hospital La Fe, Valencia (Spain); Mitjavila F., Autoimmune Diseases Unit, Department of Internal Medicine, University Hospital of Bellvitge, L’Hospitalet of Llobregat, Barcelona (Spain); Navarrete N., Department of Internal Medicine, University nez-Cuerda Hospital Virgin de la Nieves, Granada (Spain); Nú˜ E., Department of Internal Medicine, General Hospital Nuestra Se˜ nora del Prado, Talavera de la Reina, Toledo (Spain); Pallarés L., Department of Internal Medicine, University Hospital Son Dureta, Palma of Mallorca, Balearic Islands (Spain); Parra S., Department of Internal Medicine, University Hospital Sant Joan de Reus, Reus, Tarragona (Spain); Pérez-Conesa M., Department of Internal Medicine, University Hospital Miguel Servet, Zaragoza (Spain); Pinilla B., Department of Internal Medicine, University General Hospital Gregorio Mara˜ nón, Madrid (Spain); Rodríguez A.P., Department of Internal Medicine, University Hospital Complex of Orense, Orense (Spain); Rodríguez-Carballeira M., Department of Internal Medicine, University Hospital Mutua de Terrasa, Terrasa, Barcelona (Spain); Ruiz-Irastorza G., Autoimmune Diseases Research Unit, Department of Internal Medicine, BioCruces Health Research Institute, University Hospital Cruces, Basque University/Euskal Herriko Unibertsitatea, Barakaldo, Vizcaya (Spain); Sáez L., Department of Internal Medicine, University Hospital Miguel Servet, Zaragoza (Spain); Salvador G., Department of Internal Medicine, Hospital of Manises, Manises, Valencia (Spain); Sánchez-García E., Autoimmune Diseases Unit, Department of Internal Medicine, University Hospital Reina Sofía, Cordoba (Spain); Serralta G., Department of Internal Medicine, Hospital Infanta Sofía, San Sebastian de los Reyes, Madrid (Spain); Sope˜ na B., Department of Internal Medicine. University Hospital Complex of Vigo, Pontevedra, Vigo (Spain); Suárez S., Department of Internal Medicine, University Central Hospital of Asturias, Oviedo, Asturias (Spain); Tolosa C., Department of Internal Medicine, Corporació Sanitària Parc Taulí, Department of Pulmonology, Corporació Parc Taulí, Barcelona (Spain); Villalba M.V., Department of Internal Medicine, University General Hospital Gregorio Mara˜ nón, Madrid (Spain).
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