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Mortality from systemic erythematosus lupus in Brazil: evaluation of causes according to the government health database Work developed at the Centro Universitário do Estado do Pará (CESUPA), Serviço de Reumatologia, Belém, PA, Brazil.

Abstract

Objective:

To characterize the causes of mortality in patients with systemic lupus erythematosus (SLE) in Brazil between 2002 and 2011.

Methods:

An exploratory ecological study of a time series using data from the Mortality Information System of DATASUS, the Department of the Unified Health System (Brazil's National Health System).

Results:

Brazil's SLE mortality rate was 4.76 deaths/105 inhabitants. The mortality rate was higher in the Midwest, North and Southeast regions than in the country as a whole. There were 6.3% fewer and 4.2% more deaths than expected in the Northeast and Southeast regions, respectively. The mean age at death was 40.7 ± 18 years, and 45.61% of deaths occurred between the ages of 20 and 39. Incidence was highest in women (90.7%) and whites (49.2%). Disorders of the musculoskeletal system and connective tissue were mentioned as an underlying cause of death in 77.5% of cases, and diseases of the circulatory system and infectious and parasitic diseases were also noted in fewer cases. SLE was mentioned as an underlying cause of death in 77% of cases, with no difference between the Brazilian regions (p = 0.2058). The main SLE-related causes of death were, sequentially, diseases of the respiratory and circulatory systems and infectious and parasitic diseases.

Conclusions:

This study identified a need for greater control of risk factors for cardiovascular diseases and a better understanding of the pathogenesis of atherosclerosis in SLE. Infectious causes are still frequent, and management should be improved, especially in the early stages of the disease.

Keywords:
Systemic erythematosus lupus; Mortality; Brazil

Resumo

Objetivo:

Caracterizar as causas de mortalidade em pacientes com lúpus eritematoso sistêmico (LES) no Brasil entre 2002 e 2011.

Métodos:

Estudo ecológico exploratório de uma série cronológica com dados do Sistema de Informações sobre Mortalidade do Departamento de Informática do Sistema Único de Saúde (Datasus).

Resultados:

A taxa de mortalidade por LES no Brasil foi de 4,76 mortes/105 habitantes. A taxa de mortalidade foi maior nas regiões Centro-Oeste, Norte e Sudeste do que no país como um todo. Houve 6,3% menos e 4,2% mais mortes do que o esperado nas regiões Nordeste e Sudeste, respectivamente. A média de idade ao óbito foi de 40,7 ± 18 anos e 45,61% dos óbitos ocorreram entre 20 e 39 anos. A incidência foi maior nas mulheres (90,7%) e nos brancos (49,2%). Os distúrbios do sistema musculoesquelético e do tecido conjuntivo foram mencionados como a causa subjacente de morte em 77,5% dos casos; também foram observadas doenças do sistema circulatório e infecciosas e parasitárias, embora em menor frequência. O LES foi mencionado como a causa subjacente de óbito em 77% dos casos, sem diferença entre as regiões brasileiras (p = 0,2058). As principais causas de morte associadas ao LES foram, em ordem, doenças dos sistemas respiratório e circulatório e doenças infecciosas e parasitárias.

Conclusões:

Este estudo identificou a necessidade de maior controle dos fatores de risco para doenças cardiovasculares e uma melhor compreensão da patogênese da aterosclerose no LES. As causas infecciosas ainda são frequentes e o manejo deve ser melhorado, especialmente nos estágios iniciais da doença.

Palavras-chave:
Lúpus eritematoso sistêmico; Mortalidade; Brasil

Introduction

Systemic lupus erythematosus (SLE), a chronic autoimmune disease whose etiology is not fully known, is diagnosed based on clinical and laboratory criteria and probably results from the interaction of genetic, hormonal, environmental and infectious factors that lead to the loss of immunological tolerance with the production of autoantibodies.11 Assis MR, Baaklini CE. Lúpus eritematoso sistêmico. Rev Bras Med. 2009;66:274-85.

According to the literature, mortality in SLE follows a bimodal pattern: in the early stages, death is mainly caused by infection, followed by severe renal or central nervous system (CNS) activity, while in the more advanced stages of the disease, there is an increase in mortality from cardiovascular diseases associated with atherosclerosis, partially related to corticotherapy and chronic inflammation.11 Assis MR, Baaklini CE. Lúpus eritematoso sistêmico. Rev Bras Med. 2009;66:274-85.,22 Voss A, Laustrup H, Hjelmborg J, Junker P. Survival in systemic erythematosus lupus, 1995-2010. A prospective study in a Danish community. Lupus. 2013;22:1185-91.

According to the Ministry of Health, the death certificate is the standard document for collecting information on mortality and is the source of vital and epidemiological statistics in Brazil.33 Ministry of Health. Health Surveillance Secretariat. Department of Analysis of the Health Status. Instructions Manual for Filling in Death Certificates. Brasília/DF; 2011. The causes of death to be registered on the international death certificate are all those diseases, morbid conditions or injuries that either resulted in or contributed to death and the circumstances of the accident or violence that produced any such injuries. Underlying Cause of Death is defined as the disease or injury that initiated the train of morbid events leading directly to death.33 Ministry of Health. Health Surveillance Secretariat. Department of Analysis of the Health Status. Instructions Manual for Filling in Death Certificates. Brasília/DF; 2011.

The Conditions and Causes of Death section of the death certificate is in accordance with the international death certificate model adopted by the World Health Organization (WHO), which is extremely important given that it contains the underlying cause and injuries leading to death. It is divided into two parts. Part I is for reporting the direct cause of death (immediate cause - line A) and the morbid conditions that led to the cause registered in line A (antecedent or sequential causes - lines B and C, and the underlying cause - line D). Part II is for reporting contributing causes that were not part of the chain defined in Part I, including any diseases or injuries that contributed to death but were not directly related to the pathological state leading to death.33 Ministry of Health. Health Surveillance Secretariat. Department of Analysis of the Health Status. Instructions Manual for Filling in Death Certificates. Brasília/DF; 2011.

In Brazil, with its size and the different levels of socioeconomic development in its various regions, as well as the different levels of organization and problem-solving capabilities of health assistance networks, the causes of mortality may vary according to region and may reflect differences in care and access to health services between regions. This study therefore aims to determine the causes of mortality in SLE patients in Brazil, according to region, from 2002 to 2011.

Patients and methods

An exploratory ecological study of a time series of 8761 deaths in which SLE was recorded as the underlying or a sequential cause of death was conducted. The data were collected from the File Transfer Protocol of the Mortality Information System (SIM) of the IT Department of the Unified Health System (DATASUS),44 DATASUS. Mortality Information System. Available from: ftp://ftp.datasus.gov.br/dissemin/publicos/SIM/CID10/DORES [accessed 13.04.13].
ftp://ftp.datasus.gov.br/dissemin/public...
which is why it was not necessary to submit this study to the Human Research Ethics Committee for approval. The database was prepared using TabWin®.

The selected variables were the region where the patient lives (North, Northeast, Midwest, South and Southeast), gender (male or female), race (mixed race, white, black, east Asian and indigenous), age and underlying and sequential causes of death recorded in the years of the historical series.

This study considered as the underlying cause of death all the causes of death registered as such in accordance with the Tenth Revision of the International Classification of Diseases (ICD-10) and available in DATASUS.

SLE is a disease described in Chapter XIII of ICD-10, called "Diseases of the Musculoskeletal System and Connective Tissue" (M00 to M99).55 World Health Organization. Brazilian Center of Classification of Diseases. International Statistical Classification of Diseasesand Related Health Problems. 10th revision – ICD-10, vol. 1;1997. p. 605–52.

The data collected included information from the death certificates of patients aged 15 and over and whose Part I (lines, a, b, c and d) or II of the Conditions and Causes of Death section included disease M32 - SLE and its sub-categories (M32.0 - Drug-induced systemic lupus erythematosus M32.1 - Systemic lupus erythematosus with organ or system involvement; M32.8 - Other forms of systemic lupus erythematosus; and M32.9 - Systemic lupus erythematosus, unspecified).55 World Health Organization. Brazilian Center of Classification of Diseases. International Statistical Classification of Diseasesand Related Health Problems. 10th revision – ICD-10, vol. 1;1997. p. 605–52. Death certificates that did not mention age were excluded.

The populations of the states and regions as disclosed by DATASUS, which are based on census and intercensus data published by the Brazilian Institute of Geography and Statistics (IBGE),66 DATASUS. Demographic data. Available from: http://www.datasus.gov.br [accessed 13.04.13].
http://www.datasus.gov.br...
were used to calculate the incidence rate, while the average population in the two middle years of the studied period (2006 and 2007) was used to calculate the average incidence in the period.

Statistical analysis was carried out using descriptive and inferential statistical methods. The number of expected deaths for each region was calculated by assuming the average Brazilian population in the historical series as the standard population under absolute risk in each region. Quantitative variables had an average standard deviation of ±1.96, were submitted to the D'Agostino normality test and were compared using the Z test. Qualitative variables were analyzed in terms of absolute and relative frequencies, and their distribution was evaluated using the Chi-square test. A significance level of α < 5% was established beforehand to reject the null hypothesis. Statistical processing was performed using BioEstat® version 5.3 and GrafTable® version 2.0.

Results

This study identified 8761 reports of deaths of SLE patients in Brazil, giving a specific mortality rate of 4.76 deaths/105 inhabitants. The Midwest, North and Southeast regions had rates of 6.44, 5.4 and 5.23 deaths/105 inhabitants, respectively, which were above the Brazilian average. The lowest rate of mortality from SLE was found in the Northeast region (3.69/105 inhabitants), and the present study identified a statistically significant difference (p < 0.0001) of 6.3% fewer deaths than expected in this region, while the Southeast region had 4.2% more deaths than expected (p < 0.0001) (Table 1).

Table 1
Distribution of observed and expected deaths of patients with systemic lupus erythematosus by region between 2002 and 2011.

Table 2 shows a significant predominance (p < 0.0001) of women (90.7%), whites (49.2%) and those aged between 20 and 39 years (45.61%).

Table 2
Distribution by gender, race and age at death of patients with systemic lupus erythematosus in Brazil between 2002 and 2011.

Between 2002 and 2011, the national mean age at death was 40.7 ± 18 years, with significant differences from this mean (p < 0.0001) in the North (34.1 ± 13.7 years) and South (44.7 ± 17 years) regions. In the Northeast, Southeast and Midwest regions, the means age at death were 37.1 ± 15.1 years, 42.9 ± 20 years and 38.8 ± 15.3 years, respectively.

In SLE patients, the ICD-10 group "Disorders of the Musculoskeletal System and Connective Tissue" (6794) accounted for 77.5% of underlying causes of death, with a statistically significant difference (p < 0.0001) in relation to the other recorded underlying causes of death in these patients. SLE (M32), as one of the diseases that is part of this ICD-10 group, represented approximately 100% (6745) of all records of underlying cause of death in this group. SLE alone accounted for 77% of records of underlying cause of death (6745/8761) among the total number of deaths of patients with this disease. There was not a statistically significant difference (p = 0.2058) between the percentage of deaths classified as M32 among the Brazilian regions (Table 3).

Table 3
Distribution of causes of death of patients with systemic lupus erythematosus (SLE) by Brazilian region between 2002 and 2011.

Other underlying causes of death recorded for SLE patients included circulatory system (6.0%), infectious and parasitic (2.8%), respiratory system (2.2%), digestive system (2.1%) and genitourinary system (1.9%) diseases (Table 3).

Table 3 shows that the predominance of records was not uniform across the regions except for those related to the circulatory system and infectious and parasitic diseases. Although the Southeast region had the lowest percentage of cases of SLE with SLE as the underlying cause of death (74.3% = 3030/4076), it accounted for 46.5% (4076/8761) of total deaths of SLE patients in the country, as well as the highest proportion of most conditions recorded as the underlying cause of death.

The distribution of sequential causes of death related to SLE (Table 4) showed highly significant differences (p < 0.0001) for respiratory system (26.4%), circulatory system (20.7%), infectious and parasitic (18.9%) and genitourinary system (14.7%) diseases.

Table 4
Distribution of the sequential causes recorded in death certificates of patients with systemic lupus erythematosus as the underlying cause of death in Brazil between 2002 and 2011.

The comparison of sequential causes between regions (Table 5) showed a predominance of diseases of the respiratory system (32.8%) and the circulatory system (34.7%) in the Southeast, with statistically significant differences in relation to the other regions (p < 0.0017 and p < 0.0022, respectively). For infectious and parasitic diseases, the Northeast accounted for the highest number of records (29.4%), and this difference was statistically significant (p < 0.0277). In regard to diseases of the genitourinary system, there were no differences between the regions (p = 0.9340), although the highest proportion of cases occurred in the North (22.6%).

Table 5
Main sequential causes of death from systemic lupus erythematosus by Brazilian region between 2002 and 2011.

An evaluation of the distribution of the main sequential causes by age (Table 6) showed a decline in the proportion of diseases of the respiratory system in patients over 80 years of age, while patients between 20 and 39 years old (p < 0.0001) accounted for the largest share of the main groups of sequential causes. More than 60% of these groups of causes were identified in patients between 20 and 59 years of age.

Table 6
Main sequential causes of death from systemic lupus erythematosus by age in Brazil between 2002 and 2011.

Discussion

The mortality rate of SLE patients in Brazil is 4.76 deaths/100,000 inhabitants, and there is a predominance of women and whites in this group of patients. Differences between the regions are evident, with the South and Southeast states having lower mortality and the North region having higher mortality. It is worth noting the difference found in relation to a population study conducted in Norway, where mortality was a mere one death per 100,000 inhabitants.77 Lerang K, Gilboe IM, Steinar Thelle D, Gran JT. Mortality and years of potential life loss in systemic erythematosus lupus: a population-based cohort study. Lupus. 2014;23:1546-52.

The North region had the lowest mean age at death (34.1 ± 13.7 years) of all Brazilian regions, similar to that recorded in Saudi Arabia (33 ± 18 years).88 Heller T, Ahmed M, Siddiqqi A, Wallrauch C, Bahlas S. Systemic erythematosus lupus in Saudi Arabia: morbidity and mortality in a multiethnic population. Lupus. 2007;16:908-14. On the other hand, the mean age at death in the South region was 44.7 years, in line with the 44 ± 15 years observed in a study comprising 1000 patients in seven European countries over ten years.99 Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period. Medicine (Baltimore). 2003;82:299-308.

In 2010, a study1010 Souza DC, Santo AH, Sato EI. Trends in systemic erythematosus lupus mortality rates in the state of Sao Paulo, Brazil from 1985 to 2004. Clin Exp Rheumatol. 2010;28:519-24. was published analyzing mortality in SLE patients in São Paulo state, in Brazil's Southeast region, between 1985 and 2004. According to this study, the mean age at death in this period was 35.1 ± 15.0 years, allowing us to infer that there has been an improvement in the survival of SLE patients in recent years given that the mean age at death was higher than this figure in Brazil as a whole and in the South, Southeast and Midwest regions. On the other hand, it underlines the discrepancy between Brazilian regions, given that the mean age at death from SLE in the North and Northeast regions has been lower than that in São Paulo state for more than ten years.

The number of deaths in the Northeast and Southeast regions was respectively lower and higher than expected. According to the United Nations Development Programme (UNDP),1111 United Nations Development Programme (PNUD). MHDI Ranking of Federation Units 2010. Available from: http://www.pnud.org.br/atlas/ranking/Ranking-IDHM-UF-2010.aspx [accessed 10.02.13].
http://www.pnud.org.br/atlas/ranking/Ran...
the states with municipalities having the lowest Municipal Human Development Indices (MHDI) in the country are located the North and Northeast regions. As a result, it is necessary to be cautious when comparing mortality in the different Brazilian regions due to deficiencies in the service network currently available to the population in the North and Northeast regions. According to information provided by the IBGE,1212 Ministry of Planning, Budget, and Management. Brazilian Institute of Geography and Statistics. Socio-demographic and Health Indicators in Brazil; 2009. the North and Northeast regions have problems related to the reporting of deaths in general, with high under-reporting rates. Under-reporting is extremely high in the Northeast (more than 26%) compared with the national average (12%) and especially with the Center-South (under 10%). This difference can explain why the number of deaths was lower than expected in the Northeast and higher than expected in the Southeast.

An analysis carried out in Morocco1313 Mezalek ZT, Bono W. Challenges for lupus management in emerging countries. Presse Med. 2014;43:209-20. reported that the epidemiology of SLE in developing countries is still unknown and is probably underestimated, making it difficult to compare data with other international studies. Most Brazilian studies are restricted to the Southeast region.1414 Souza DC, Santo AH, Sato EI. Mortality profile related to systemic erythematosus lupus: a multiple cause-of-death analysis. J Rheumatol. 2012;39:496-503.

15 Souza DC, Santo AH, Sato EI. Mortality profile related to systemic lupus erythematosus: a multiple cause-of-death analysis. J Rheumatol. 2012;39:496-503.
-1616 Telles RW, Lanna CC, Souza FL, Rodrigues LA, Reis RC, Ribeiro AL. Causes and predictors of death in Brazilian lupus patients. Rheumatol Int. 2013;33:467-73.

In one of the few Brazilian studies carried out outside the Southeast region, an analysis of 63 SLE patients monitored in Paraíba state, in Brazil's Northeast region, established a relationship between poorer quality of life, measured at the beginning of the study, and a higher likelihood of death after a second analysis six years later. Of the deaths observed in that study, two were caused by systemic infection, two by renal complications and two by SLE-related nervous system complications.1717 Freire E, Bruscato A, Ciconelli R. Quality of life in systemic erythematosus lupus patients in Northeastern Brazil: is health-related quality of life a predictor of survival for these patients?. Acta Reumatol Port. 2009;34:207-11.

A review published in 20141818 Tazi Mezalek Z, Bono W. Challenges for lupus management in emerging countries. Presse Med. 2014;43(Pt 2):e209-20. emphasized that SLE patients in emerging countries, such as Brazil, had a worse prognosis as a result of the low socioeconomic and educational level of these populations, in addition to delay in diagnosis, difficulties accessing health services and more frequent infections and disease complications.

SLE affects more women than men, with a ratio of 10:1.1919 Ippolito A, Petri M. An update on mortality in systemic erythematosus lupus. Clin Exp Rheumatol. 2008;26(Suppl 51):S72-9. However, according to studies carried out in the United Kingdom,2020 Rees F, Doherty M, Grainge MJ, Lanyon P, Davenport G, Zhang W. Mortality in systemic erythematosus lupus in the United Kingdom 1999-2012. Rheumatology (Oxford). 2016;55:854-60. Saudi Arabia88 Heller T, Ahmed M, Siddiqqi A, Wallrauch C, Bahlas S. Systemic erythematosus lupus in Saudi Arabia: morbidity and mortality in a multiethnic population. Lupus. 2007;16:908-14. and in the United States,2121 Andrade RM, Alarcón GS, Fernández M, Apte M, Vilá LM, Reveille JD. Accelerated damage accrual among men with systemic lupus erythematosus. Arthritis Rheum. 2007;56:622-30. as well as by multinational teams,2222 Bernatsky S, Boivin JF, Joseph L, Manzi S, Ginzler E, Gladman DD, et al. Mortality in systemic erythematosus lupus. Arthritis Rheum. 2006;54:2550-7. mortality from SLE is higher in men. The disagreement with the findings of the present study may have been caused by the use of death records, which did not allow for the assessment of the prevalence of the disease in the population or its lethality by gender.

The main underlying cause of death observed was SLE itself, which is consistent with the findings of a European study.99 Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period. Medicine (Baltimore). 2003;82:299-308. Diseases of the circulatory system, including all types of heart, vessel and cerebrovascular diseases, were the second most common underlying cause of death, in line with other studies.1919 Ippolito A, Petri M. An update on mortality in systemic erythematosus lupus. Clin Exp Rheumatol. 2008;26(Suppl 51):S72-9.,2323 Mok CC, Kwok CL, Ho LY, Chan PT, Yip SF. Life expectancy, standardized mortality ratios and causes of death in six rheumatic diseases in Hong Kong, China. Arthritis Rheum. 2011;63:1182-9.

24 Bartels CM, Buhr KA, Goldberg JW, Bell CL, Visekruna M, Nekkanti S, et al. Mortality and cardiovascular burden of systemic erythematosus lupus in a US population-based cohort. J Rheumatol. 2014;41:680-7.
-2525 Thomas G, Mancini J, Jourde-Chiche N, Sarlon G, Amoura Z, Harlé JR, et al. Mortality associated with systemic erythematosus lupus in France assessed by multiple-cause-of-death analysis. Arthritis Rheumatol. 2014;66:2503-11.

A complex interaction of several factors, including the disease's chronic inflammatory nature, contributes to SLE being a risk factor for cardiovascular events. Inflammatory and immunological mechanisms are responsible for both the formation of atherosclerotic plaques and their instability, which may cause ruptures, thromboses and vessel occlusion, leading to ischemia and tissue infarction.2626 Libby P, Okamoto Y, Rocha VZ, Folco E. Inflammation in atherosclerosis: transition from theory to practice. Circ J. 2010;74:213-20. Renal involvement, which is frequently present, contributes to the development of premature coronary artery disease. Traditional risk factors, such as high blood pressure and hyperlipidemia, are common in lupus patients due to disease activity and the use of glucocorticoids.2727 Nikpour M, Gladman DD, Urowitz MB. Premature coronary heart disease in systemic erythematosus lupus: what risk factors do we understand?. Lupus. 2013;22:1243-50. These conditions are in addition to endothelial dysfunction and antiphospholipid antibodies, also implicated in accelerated atherosclerosis in SLE.2828 Haque S, Bruce IN. Cardiovascular outcomes in systemic erythematosus lupus: big studies for big questions. J Rheumatol. 2009;36:467-9. The overall result is high premature mortality from diseases of the circulatory system, as observed in a Finnish study in which 37% of deaths of SLE patients were attributed to cardiovascular causes.2929 Elfving P, Puolakka K, Kautiainen H, Virta LJ, Pohjolainen T, Kaipiainen-Seppänen O. Mortality and causes of death among incident cases of systemic erythematosus lupus in Finland 2000-2008. Lupus. 2014;23:1430-4.

In 2012, a study that analyzed mortality in SLE patients in São Paulo state during the period between 1985 and 2007 cited circulatory system causes of death as being among the most important in that region, in addition to renal failure and infectious causes led by pneumonia and septicemia.1515 Souza DC, Santo AH, Sato EI. Mortality profile related to systemic lupus erythematosus: a multiple cause-of-death analysis. J Rheumatol. 2012;39:496-503.

The results regarding infectious and parasitic diseases as a cause of death in patients with SLE were in line with the results of a European study.99 Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period. Medicine (Baltimore). 2003;82:299-308. In a Brazilian study3030 Iriya SM, Capelozzi VL, Calich I, Martins MA, Lichtenstein A. Causes of death in patients with systemic erythematosus lupus in Sao Paulo, Brazil: a study of 113 autopsies. Arch Intern Med. 2001;161:1557. that evaluated 113 autopsies of SLE patients, infection was the cause of death in 58% of the cases. It is well established in the literature that infections, usually attributed to the use of immunosuppressive drugs, are a frequent cause of death in SLE patients.2222 Bernatsky S, Boivin JF, Joseph L, Manzi S, Ginzler E, Gladman DD, et al. Mortality in systemic erythematosus lupus. Arthritis Rheum. 2006;54:2550-7. The incidence of infections in patients with SLE varies between 50 and 150 episodes for every 100 patients/year3131 Hidalgo-Tenorio C, Jiménez-Alonso J, Luna JD, Tallada M, Martínez-Brocal A, Sabio JM. Urinary tract infections and erythematosus lupus. Ann Rheum Dis. 2004;63:431-7.; the most common sites are the respiratory, digestive and urinary tracts1919 Ippolito A, Petri M. An update on mortality in systemic erythematosus lupus. Clin Exp Rheumatol. 2008;26(Suppl 51):S72-9.; and the most frequent etiological agents are fungi, Gram-negative bacteria, and opportunistic agents, such as pneumocystis pneumonia, cytomegalovirus and members of the Herpesviridae family.3232 Ferreira M, Salgueiro AB, Estrada J, Ramos J, Ventura L, Vale MC, et al. Lúpus eritematoso sistêmico. Acta Med Port. 2008;21:199-204.

Disease activity was identified as an independent risk factor for infections.3333 Danza A, Ruiz-Irastorza G. Infection risk in systemic erythematosus lupus patients: susceptibility factors and preventive strategies. Lupus. 2013;22:1286-94.,3434 Bosch X, Guilabert A, Pallarés L, Cerveral R, Ramos-Casals M, Bové A, et al. Infections in systemic erythematosus lupus: a prospective and controlled study of 110 patients. Lupus. 2006;15:584-9. The clinical hematological manifestations of SLE, such as lymphopenia and neutropenia, as well as the treatment itself, are also risk factors for infectious diseases.3535 Janoudi N, Bardisi ES. Haematological manifestations in systemic erythematosus lupus. Available from: http://cdn.intechopen.com/pdfs-wm/33017.pdf [accessed 13.04.13].
http://cdn.intechopen.com/pdfs-wm/33017....
Glucocorticoids exert their anti-inflammatory and immunosuppressive effects through several mechanisms, such as interference in the functioning of leukocytes, fibroblasts and endothelial cells, as well as reduction in the number of circulating monocytes and macrophages. The intensity of these effects is proportional to the dosage and the duration of the treatment, and it is not clear if there is a threshold below which these drugs are considered safe.3636 Ruiz-Irastorza G, Danza A, Khamashta M. Glucocorticoid use and abuse in SLE. Rheumatology. 2012;51:1145-53. Antimalarial drugs, on the other hand, reduce the occurrence of infections. Both chloroquine and hydroxychloroquine have antibacterial, antifungal and antiviral effects in addition to their known antiparasitic activity.3333 Danza A, Ruiz-Irastorza G. Infection risk in systemic erythematosus lupus patients: susceptibility factors and preventive strategies. Lupus. 2013;22:1286-94.

In Minas Gerais, a state in Brazil's Southeast region, a prospective observational study that analyzed 179 SLE patients during 3.3 years observed a higher frequency of deaths in this population than in the general population, especially deaths related to infections and SLE itself.1616 Telles RW, Lanna CC, Souza FL, Rodrigues LA, Reis RC, Ribeiro AL. Causes and predictors of death in Brazilian lupus patients. Rheumatol Int. 2013;33:467-73.

Due to the clinical relevance of infections in SLE, it is necessary to adopt preventive measures. Vaccination is the most important of these preventive measures and should be performed in periods when the disease is stable, avoiding the BCG and live virus vaccines.3333 Danza A, Ruiz-Irastorza G. Infection risk in systemic erythematosus lupus patients: susceptibility factors and preventive strategies. Lupus. 2013;22:1286-94. Although slightly weak immune responses have been observed, they are still effective.3333 Danza A, Ruiz-Irastorza G. Infection risk in systemic erythematosus lupus patients: susceptibility factors and preventive strategies. Lupus. 2013;22:1286-94.,3737 Assen SV, Agmon-Levin N, Elkayam O, Cervera R, Doran MF, Dougados M, et al. EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2011;70:414-22.

38 Mosca M, Tani C, Aringer M, Bombardieri S, Boumpas D, Brey R, et al. European League Against Rheumatism recommendations for monitoring patients with systemic erythematosus lupus in clinical practice and in observational studies. Ann Rheum Dis. 2010;69:1269-74.
-3939 Bühler S, Eperon G, Ribi C, Kyburz D, van Gompel F, Visser LG, et al. Vaccination recommendations for adult patients with autoimmune inflammatory rheumatic diseases. Swiss Med Wkly. 2015;145:w14159.

Deaths from infection are still higher in SLE patients than in the general population; however, in recent years, there has been a decline in total SLE mortality, and this decline has been associated with a reduction in the cases of infection and renal problems,1515 Souza DC, Santo AH, Sato EI. Mortality profile related to systemic lupus erythematosus: a multiple cause-of-death analysis. J Rheumatol. 2012;39:496-503. although the proportion of deaths with diseases of the circulatory system as a sequential cause have been increasing.2222 Bernatsky S, Boivin JF, Joseph L, Manzi S, Ginzler E, Gladman DD, et al. Mortality in systemic erythematosus lupus. Arthritis Rheum. 2006;54:2550-7.

Patients with SLE have a higher chance of developing malignancies than does the general population.1919 Ippolito A, Petri M. An update on mortality in systemic erythematosus lupus. Clin Exp Rheumatol. 2008;26(Suppl 51):S72-9. In a study involving 23 collaborating centers from seven countries,2222 Bernatsky S, Boivin JF, Joseph L, Manzi S, Ginzler E, Gladman DD, et al. Mortality in systemic erythematosus lupus. Arthritis Rheum. 2006;54:2550-7. cancer accounted for more deaths than infectious diseases and was second only to cardiovascular diseases; the most frequent types were non-Hodgkin lymphoma and lung cancer. In the present study, it was not possible to evaluate the association between SLE and malignancies due to the use of causes classified according to ICD-10 groups in the methodology.

The main causes of mortality resulting from SLE were diseases of the respiratory and circulatory systems, infectious and parasitic diseases, and diseases of the genitourinary system. These findings are similar to the results of another study1515 Souza DC, Santo AH, Sato EI. Mortality profile related to systemic lupus erythematosus: a multiple cause-of-death analysis. J Rheumatol. 2012;39:496-503. in which the main sequential causes were related to the circulatory, respiratory, digestive and genitourinary systems and to certain infectious diseases.

According to studies carried out in the United States4040 Fernández M, Alarcó NGS, Calvo-Alén J, Andrade R, Mcgwin G, Vilá LM, et al. A multiethnic, multicenter cohort of patients with systemic erythematosus lupus (SLE) as a model for the study of ethnic disparities in SLE. Arthritis Rheum. 2007;57:576-84.,4141 Gómez-Puerta JA, Barbhaiya M, Guan H, Feldman CH, Alarcón GS, Costenbader KH. Racial/Ethnic variation in all-cause mortality among United States Medicaid recipients with systemic erythematosus lupus: a Hispanic and Asian paradox. Arthritis Rheumatol. 2015;67:752-60. and in Tunisia,4242 Khanfir MS, Houman MH, Cherif E, Hamzaoui A, Souissi S, Ghorbel IB, et al. TULUP (TUnisian LUPus): a multicentric study of systemic erythematosus lupus in Tunisia. Int J Rheum Dis. 2013;16:539-46. in emerging countries and ethnic minorities, SLE tends to be more severe and more symptomatic. Disease activity rates are higher, leading to accelerated damage accrual in target organs and higher mortality.

In lupus patients of Asian ethnicity evaluated in a U.S. study,4343 Mok CC, Mak A, Chu WP, To CH, Wong SN. Long-term survival of southern Chinese patients with systemic erythematosus lupus: a prospective study of all age groups. Medicine (Baltimore). 2005;84:218-24. the prevalence of nephritis was high, ranging between 45% and 75%, and the mortality rate was three times higher than that of white patients.

A Moroccan study raised a question about the discrepancies in severity and mortality between minority groups and white individuals. It questioned whether the aggressive symptoms in ethnic minorities can, in fact, be explained by genetic risk factors or biological differences or whether they simply reflect the socioeconomic differences between these groups and white people.1313 Mezalek ZT, Bono W. Challenges for lupus management in emerging countries. Presse Med. 2014;43:209-20.

Diseases of the circulatory system and infections were more frequently mentioned in the deaths of patients over the age of 50 years.1515 Souza DC, Santo AH, Sato EI. Mortality profile related to systemic lupus erythematosus: a multiple cause-of-death analysis. J Rheumatol. 2012;39:496-503. Respiratory system involvement can occur at some stage of the disease in more than 50% of patients, who can present pleurisy, pneumonitis, interstitial lung disease or pulmonary hypertension.4444 Karim MY, Miranda LC, Tench CM, Gordon PA, D'cruz DP, Khamashta MA, et al. Presentation and prognosis of the shrinking lung syndrome in systemic erythematosus lupus. Semin Arthritis Rheum. 2002;31:289-98.

It is thus clear that there is a need for more effective control of the risk factors for cardiovascular diseases, both traditional risk factors and those related to SLE treatment and activity; additionally, a better understanding of the pathogenesis of atherosclerosis in this disease is needed. Infectious diseases are still very frequent, underlining the fact that there has not been appropriate control of risk factors, especially in the early stages of SLE, and that health professionals need to focus more on prevention with vaccines.

Conclusion

In Brazilian SLE patients, SLE itself was cited as the main underlying cause of death, followed by diseases of the circulatory system, infectious and parasitic diseases and diseases of the respiratory, digestive and genitourinary systems, which together accounted for the approximately 23% of the cases in which lupus was not identified as the underlying cause. There are also important differences between the studied regions, and it is important to take into consideration the under-reporting and socioeconomic differences among them.

  • Work developed at the Centro Universitário do Estado do Pará (CESUPA), Serviço de Reumatologia, Belém, PA, Brazil.

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Publication Dates

  • Publication in this collection
    Nov-Dec 2017

History

  • Received
    18 Aug 2016
  • Accepted
    10 May 2017
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