The most frequent causes of death were active SLE (26.5%), thromboses (26.5%), and infections (25%) (Table 4). Most patients who died of active SLE had progressive, frequently multisystem disease. The most frequent infections were bacterial sepsis of pulmonary (8.8%), abdominal (7.4%), and urinary (5.9%) origin. Active SLE plus infection was considered to be combined causes of death in 6 patients.
Thromboses were a predominant cause of death in 18 patients and were always associated with the presence of aPL (antiphospholipid syndrome). The most common thrombotic events were cerebrovascular accidents (11.8%), coronary occlusions (7.4%), and pulmonary embolisms (5.9%).
When the causes of death during the initial 5 years of follow-up were compared with those during the ensuing 5 years, active SLE and infections (28.9% each) appeared to be the most common causes during the initial 5 years, while thromboses (26.1%) became the most common cause of death during the last 5 years.
In the present study, we describe the frequency and characteristics of the main SLE clinical manifestations and of other associated medical problems as well as the mortality rate and causes of death in a large cohort of European patients followed during a 10-year-period (1990–2000). Furthermore, we compare the early manifestations 12 with the manifestations that appeared later in the evolution of the disease.
This cohort consisted of 1,000 patients gathered by a European consortium, the Euro-Lupus Project Group. This consortium was created in 1990 as part of the network promoted by the European Working Party on SLE, a study group devoted to the development of multicenter projects with large populations of SLE patients 10. The patients of the present study were collected consecutively at 12 university centers that follow all the cases diagnosed in their referral area, including all varieties of SLE manifestations, and were assessed by a wide range of specialists and subspecialists (that is, internists, rheumatologists, dermatologists, hematologists, neurologists, etc.). Only patients with well-defined SLE, meeting the 1982 revised criteria of the ACR, 37 were included in the cohort, thus avoiding equivocal cases. Additionally, this study covers a representative European SLE population, including patients from northern, southern, central, western, and eastern Europe. The problem of potentially different medical care in the participating hospitals has been overcome by the careful selection of tertiary referral university centers having clinicians with substantial experience in the management of SLE patients and with a common background, and by a careful discussion of the definition of all outcome variables. Furthermore, in order to avoid a left censorship bias, 18 we conducted a prospective cohort study, thus ensuring that outcome data were available for all patients. Although 195 (19.5%) patients were lost to follow-up, this accounted for only 1%–3% per year (34 in the first year, 32 in the second, 31 in the third, 10 in the fourth, 8 in the fifth, 27 in the sixth, 21 in the seventh, 14 in the eighth, 11 in the ninth, and 7 in the tenth), and the appearance or absence of the different outcome variables during the period of time that these patients participated in the study was also registered. Therefore, this cohort can be considered representative of what are currently accepted to be SLE patients in Europe.
The frequencies of the main clinical manifestations related to SLE that appeared during the 10 years of the prospective study in the present European cohort are slightly lower than those reported in several large series from America 4,26 and Asia 39 published in the last decade (Table 5). In this European cohort, active nephropathy was diagnosed in 27.9% of the patients during the prospective study, while the frequencies in other studies ranges between 40.2% in an American series 4 and 74% in an Asian series 39. These lower frequencies of SLE clinical manifestations could be due to genetic or environmental differences between Europeans and Americans or Asians, but could also reflect the effect of medical care during the study because of the prospective nature of the Euro-Lupus Project. Furthermore, we found a lower frequency of most SLE manifestations during the last 5 years of this prospective study (1995–2000), compared with the cumulative clinical manifestations during the initial 5 years of the study (1990–1995) 12. For instance, the frequency of active lupus nephropathy during the last 5 years was 6.8%, while previously we had found a cumulative prevalence of 22.2% during the initial 5 years of the study 12. These lower frequencies in the last 5 years probably reflect the effect of therapy and of medical care during the study, but also may be due to less severe activity of the disease after a long time of evolution.
As for the frequency and characteristics of other medical problems that caused morbidity in SLE patients, infections, hypertension, osteoporosis, and drug-induced cytopenias were the most frequent associated conditions both in the initial 5 years 12 of the present study and in the ensuing years. It is noteworthy that their frequency was higher than that of most SLE manifestations, especially in the last 5 years of the observational period. As some of these associated medical problems are probably due to or influenced by the therapy employed in SLE, this reinforces the importance of maintaining a careful balance between benefits and side effects when selecting medication to control SLE.
Malignant tumors occurred in only 23 (2.3%) of our patients. The most frequent primary localizations were the uterus (8 patients) and the breast (4 patients), which are also the most common malignancies in women. The relationship between SLE and malignancy is uncertain, and whether malignant neoplasms occur more commonly in patients with SLE compared with the general population is unclear. There have been at least 8 clinical cohort studies, 3 hospital discharge linking studies, a meta-analysis, and several editorials and reviews produced in an attempt to clarify this question 1,2,6,7,13,19,22,24,25,27,29,30,35,36. The recent meta-analysis of the 8 clinical cohort studies 6 showed an estimated risk for all malignancies of 1.5 (95% CI = 1.3–1.8); for hematologic, 4.2 (95% CI = 2.9–5.9); and for non-Hodgkin lymphomas, 9.3 (95% CI = 5.9–14.0). For several other malignancies, the confidence intervals included the possibility of either an increased or a reduced risk among SLE patients. It is not possible to confirm from the present analysis if the occurrence of malignancy is increased in patients with SLE in this European cohort, but several retrospective and prospective large studies are currently under way to resolve this question 19.
Over the past 50 years, the survival of patients with SLE has improved significantly. Whereas an earlier study 23 in 1955 reported a survival rate of less than 50% at 5 years, more recent studies 17,21,28,32–34 indicated that over 93% of patients with SLE survive for 5 years, and 85% survive for 10 years. In our European cohort, we found a 92% survival rate after 10 years from time of entry into the study. These improved survival rates may be related to the advanced medical therapy in general (antihypertensive agents, availability of renal dialysis, transplantation, and antibiotics), along with a better understanding of the pathogenesis of the disease, earlier diagnosis, and inclusion of milder cases in recent studies, but they also may be caused by the more intensive forms of treatment, such as the use of cytotoxic drugs, immunosuppressive drugs, and high-dose prednisolone 34. The slightly higher survival in this European cohort compared with that in the American series also may be due to the predominance of white patients in the present cohort (97.1%); it is known that race influences outcome in SLE, and blacks and Hispanic Americans of mestizo or Native American origin have a poorer outcome 4.
The improved survival of patients with SLE has been associated with an alteration in the patterns of mortality 15,20,31,38. Although determining a cause of death for SLE patients can be difficult because many patients present multisystem SLE involvement in their last days of life (that is, renal, cardiac, pulmonary, and hematologic involvement) and other combined complications (such as infections and thromboses), we found a similar percentage of active SLE (26.5%), thromboses (26.5%), and infections (25%) as the main causes of death in the total 10-year observational period. However, it is important to stress that when the causes of death during the initial 5 years of follow-up were compared with those during the ensuing 5 years, active SLE and infections (28.9% each) appeared to be the most common causes during the initial 5 years, while thromboses (26.1%) became the most common cause during the last 5 years. These findings are similar to those reported in a large Canadian series 3 published in the last decade (Table 6).
In conclusion, the present study provides updated information on morbidity and mortality characteristics of SLE in the last decade of the 20th century. It is noteworthy that most of the SLE inflammatory manifestations were less common after a long-term evolution of the disease, probably reflecting the effect of therapy as well as the progressive remission of the disease in many patients. Conversely, a more prominent role of thrombotic events is becoming evident, affecting both morbidity and mortality in SLE.
The authors thank Ana Paula Vilas, Núria Calcerrada, Judith García, and Fabián Ramírez for their assistance in database processing.
APPENDIX: EUROPEAN WORKING PARTY ON SYSTEMIC LUPUS ERYTHEMATOSUS
Coordinators: Ricard Cervera, Gian Domenico Sebastiani, Josep Font, Munther A. Khamashta, and Graham R. V. Hughes. Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain: Ricard Cervera, Josep Font, Juan Carlos Mejía, Manuel Ramos-Casals, Mario García-Carrasco, Gerard Espinosa, Sònia Giménez, Gloria de la Red, Víctor Gil, and Miguel Ingelmo. Lupus Research Unit, The Rayne Institute, St. Thomas’ Hospital, London, UK: Munther A. Khamashta, Natividad Caro, Paula Alba, and Graham R. V. Hughes. Servicio de Medicina Interna, Hospital “La Paz,” Madrid, Spain: Antonio Gil, Paz Lavilla, Ignacio Bernardino, Leyre Diez-Porres, A. Robles, and Marta Mora. Divisione di Reumatologia, Ospedale San Camillo de Lellis, Rome, Italy: Gian Domenico Sebastiani. Department of Clinical Immunology and Rheumatology, Medical School of Ankara University, Ankara, Turkey: Guner Tokgöz and A. Olcay Aydintug. Department of Connective Tissue Diseases, Institute of Rheumatology, Warsaw, Poland: Hanna Chwalinska-Sadowska, Bogna Dratwianka, and Anna Jedryka-Góral. Unidad de Enfermedades Autoinmunes Sistémicas, Servicio de Medicina Interna & Servicio de Nefrología, Hospital Regional Carlos Haya, Málaga, Spain: Enrique de Ramón, María Teresa Camps, Miguel Angel Frutos, Mariela Grana, Javier Sánchez-Lora, Nuria Muñoz Roca, Julio Martínez González, and Carolina Díaz Cobos. Servicio de Medicina Interna & Sección de Reumatología, Hospital Clínico Universitario, Málaga, Spain: Antonio Fernández Nebro, Pedro González Santos, and Manuel Abarca. Istituto di Reumatologia, Università di Siena, Siena, Italy: Mauro Galeazzi. Department of Rheumatology, Haukeland Sykehus, Bergen, Norway: Merete Valen and Hans-Jacob Haga. II Cattedra di Reumatologia, Università di Cagliari, Cagliari, Italy: Alessandro Mathieu, Giuseppe Passiu, Giovanni Sanna, and Alberto Cauli. Service de Rhumatologie, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium: Frédéric Houssiau.
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