Abstract
Systemic lupus erythematosus (SLE) is one of the most diverse autoimmune diseases as it may affect any organ in the body and display a broad spectrum of clinical and immunological manifestations. Epidemiological studies have identified marked differences in the prevalence and course of SLE between genders, and across different ages, races and geographic locations. Methodological differences between studies may account for some of the disparity seen. Additionally, some insights into possible environmental risk factors for SLE have also been provided. As this condition is relatively uncommon, multifactorial, and largely influenced by genetic predisposition, it is inherently difficult to confirm or exclude infectious or environmental contributors to its etiology. Movement of people between communities and defining specific exposures can also be problematic. Despite these limitations, ongoing observation of SLE cohorts in multiple countries and settings, along with large international cooperative efforts in recent years, have helped clarify the risks of SLE in various groups and have defined marked differences in the worldwide occurrence of the disease.
SLE (Systemic lupus erythematosus) is a multisystem auto-immune disease with diverse manifestations. There has been considerable progress in understanding the pathogenesis of SLE, and abnormalities in every facet of the immune system have been described . Despite this progress, the causes of SLE remain incompletely understood. The prevailing theory on the development of SLE is of a multifactorial aetiology involving genetic susceptibility, age and hormonal factors and environmental triggers.
Epidemiological studies have identified marked differences in the prevalence and course of SLE between genders, and across different ages, races and geographic locations. These studies have implicated numerous environmental factors in the aetiology of SLE. Methodological differences between studies may account for some of the disparity seen. This review summarises the current epidemiological data on the distribution and course of SLE, and considers some of the limitations of this data.
Descriptive epidemiology
SLE is one of the most diverse auto-immune diseases as it may affect any organ in the body and display a broad spectrum of clinical and immunological manifestations. Although it has been considered a rare disease, it now appears to be relatively common in certain groups of the population. This is most likely due to the development of immunological tests that have allowed the diagnosis of many atypical or benign cases, that otherwise may not have been identified. Several descriptive epidemiological studies on SLE have been conducted worldwide. However, the most extensive available data come from the EU (European Union) and the US (United States of America).
Case definitions
The ACR (American College of Rheumatology) proposed, in 1982, a set of classification criteria that were particularly designed to be highly specific for research projects to enable consistency between studies . These have been updated in 1997 to include antiphospholipid antibodies in the criteria ( Table 1 ) . This classification is based on 11 criteria. For the purposes of identifying patients in clinical studies, a person can be classified as having SLE if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation.
| Classification criteria | |
|---|---|
| 1. Malar rash | Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds |
| 2. Discoid rash | Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions |
| 3. Photosensitivity | Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation |
| 4. Oral ulcer | Oral or nasopharyngeal ulceration, usually painless, observed by a physician |
| 5. Arthritis | Non-erosive arthritis involving two or more peripheral joints, characterised by tenderness, swelling or effusion |
| 6. Serositis | |
| Pleuritis | Convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion |
| Pericarditis | Documented by ECG or rub or evidence of pericardial effusion |
| 7. Renal disorder | |
| Persistent proteinuria | Proteinuria > 0.5 g/day or greater than +++ if quantification not performed |
| Cellular casts | May be red cell, haemoglobin, granular, tubular or mixed |
| 8. Neurological disorder | See ACR definitions of 19 separate syndromes |
| 9. Haematological disorder | |
| Haemolytic anaemia | With reticulocytosis |
| Leucopenia | <4000/mm 3 total on two or more occasions |
| Lymphopenia | <1500/mm 3 total on two or more occasions |
| Thrombocytopenia | <100 000/mm 3 in the absence of offending drugs |
| 10. Immunological disorder | |
| Anti-DNA | Antibody to native DNA in abnormal titre |
| Anti-Sm | Presence of antibody to Sm nuclear antigen |
| Positive finding of antiphospholipid antibodies | Abnormal serum level of IgG or IgM anticardiolipin antibodies A positive test result for lupus anticoagulant using a standard method A false positive serological test for syphilis, known to be positive for at least 6 months and confirmed by Treponema pallidum immobilisation or fluorescent treponema antibody absorption test |
| 11. Antinuclear antibody | Abnormal titre of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time, and in the absence of drugs known to be associated with “drug-induced lupus” syndrome |
Conversely, there are no diagnostic criteria for SLE, and the ACR classification criteria are often misused for the diagnosis; but this practice can result in missed cases and undertreatment . For example, a patient may present with malaise, fevers, arthritis, Raynaud’s phenomenon, lymphadenopathy, oral ulcers and positive ANAs (antinuclear antibodies). This patient clearly may have SLE but does not fulfil the four criteria needed for classification by the ACR criteria. However, investigation and treatment should not be delayed until these criteria are fulfiled.
Incidence
The incidence of SLE varies according to the characteristics of the population studied (i.e., age, gender, race, ethnic and national origin and the period of time studied) . In addition, the incidence of SLE also depends on changes in the diagnostic criteria of the disease. In the EU, the annual incidence ranges between 2.2 cases per 100 000 persons per year in Asturias, Spain , and 5.8 cases per 100 000 persons per year in Iceland . In the US, the annual incidence of SLE has been estimated in several studies, with incidence rates ranging from 2.2 cases per 100 000 persons per year in the rural area of Rochester to 7.6 in the city of San Francisco ( Table 2 ). It is important to stress that, due to the relatively rare nature of SLE, precise incidence estimates are difficult to produce, and although point estimates from many of these studies differ, the CIs (confidence intervals) around these estimates may overlap.
| Location (Reference) | Date | Incidence* |
|---|---|---|
| Nueva York | 1965 | 2.0 |
| San Francisco | 1973 | 7.6 |
| Baltimore | 1977 | 4.6 |
| Rochester | 1979 | 2.2 |
| Sweden | 1982 | 4.5 |
| Nottingham | 1990 | 4.0 |
| Iceland | 1990 | 5.8 |
| Pensilvania | 1990 | 2.8 |
| Birmingham | 1991 | 3.8 |
| Rochester | 1992 | 5.8 |
| Wisconsin | 2001 | 5.1 |
| Asturias | 2002 | 2.2 |
| France | 2004 | 5.0 |
| Northern Portugal | 2007 | 2.3 |
Prevalence
Studies on the prevalence of the disease in the general population also show variation . This variability may be due to differences in the methodology of case ascertainment and socioeconomic causes, such as educational level and availability of medical care; and diagnostic issues (changing definitions of SLE over time, increased availability of tests and/or increased awareness of SLE as a disease entity) may also influence prevalence estimates. Moreover, as SLE prevalence varies by sex and age groups, the age and sex distribution of a given population can lead to variation in the overall prevalence of SLE; however, geographic differences cannot be excluded, and may result from differences in genetic or environmental factors ( Table 3 ).
| Location (Reference) | Date | Prevalence* |
|---|---|---|
| Nueva York | 1965 | 14.6 |
| San Francisco | 1973 | 50.8 |
| Finland | 1978 | 28.0 |
| Rochester | 1980 | 40.0 |
| England-Wales | 1982 | 12.5** |
| Sweden | 1982 | 36.3 |
| Hawaii | 1989 | 41.8 |
| Leicester | 1989 | 26.1 |
| Nottingham | 1990 | 24.6 |
| Birmingham | 1991 | 27.7 |
| Northern Ireland | 1993 | 25.4 |
| Wisconsin | 2001 | 78.5 |
| Asturias | 2002 | 34.1 |
| Queensland | 2003 | 45.3 |
| Francia | 2004 | 40.0 |
| Northern Portugal | 2007 | 18.8 |
The study of Hochberg , in 1982, of England and Wales, reported a prevalence of 12.5 cases per 100 000 women of all ages, and a prevalence of 17.7 cases per 100 000 in women of 15–64 years. More recent studies by Hopkinson indicate a prevalence of 24.6 cases per 100 000 persons in Nottingham, and those of Johnson et al. , a prevalence of 27.7 cases per 100 000 persons. A greater prevalence of the disease was found in Sweden , at 36.3 cases per 100 000 persons; but, methodological differences may explain this. The overall prevalence in the US has been reported to range between 14.6 cases per 100 000 persons in New York, and 78.5 in Wisconsin . Again, as SLE is relatively uncommon, precise incidence estimates are difficult to generate, and though point estimates from many of these studies differ, the CIs around these estimates may overlap.
Morbidity
The natural history of SLE is characterised by episodes of relapses or flares, interchanging with remissions, and the outcome is highly variable ranging from permanent remission to death. However, both morbidity and mortality have improved over the years for a number of reasons, including the more conservative use of corticosteroids and of modified immunosuppressive regimens. In addition, there is much more information on factors such as organ involvement and accelerated atherosclerosis that may predict morbidity and mortality.
The Euro-Lupus cohort has been instrumental in clarifying some of these factors. This cohort was composed by 1000 patients with SLE, who were gathered in 1991 and prospectively followed during 10 years by a consortium that included more than 40 investigators from seven European countries . The frequencies of the main manifestations of SLE during the 10 years of the prospective Euro-Lupus cohort ( Table 4 ) are slightly lower than those reported in several large series from America and Asia in the past decade ( Table 5 ). In this European cohort, active nephropathy was diagnosed in 27.9% of patients, and ranges between 40.2% in an American series and 74% in an Asian series . These lower frequencies of clinical manifestations of SLE not only 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. Furthermore, there was 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 (1990–1995) . For instance, the frequency of active lupus nephropathy during the last 5 years was 6.8% compared with a cumulative prevalence of 22.2% during the initial 5 years of the study. These lower frequencies in the last 5 years probably reflect the effect of treatment and of medical care during the study, and may also reflect natural remissions, which may occur with advancing age and menopause.
| SLE manifestations | 1990–2000 ( n = 1000) | 1990–1995 ( n = 1000) | 1995–2000 ( n = 840)* | p value a |
|---|---|---|---|---|
| No (%) | No (%) | No (%) | ||
| Malar rash | 311 (31.1) | 264 (26.4) | 144 (17.1) | <0.001 |
| Discoid lesions | 78 (7.8) | 54 (5.4) | 50 (5.9) | |
| Subacute cutaneous lesions | 67 (6.7) | 46 (4.6) | 21 (2.5) | 0.023 |
| Photosensitivity | 229 (22.9) | 187 (18.7) | 112 (13.3) | 0.002 |
| Oral ulcers | 125 (12.5) | 89 (8.9) | 61 (7.3) | |
| Arthritis | 481 (48.1) | 413 (41.3) | 240 (28.6) | <0.001 |
| Serositis | 160 (16.0) | 129 (12.9) | 52 (6.2) | <0.001 |
| Nephropathy | 279 (27.9) | 222 (22.2) | 57 (6.8) | <0.001 |
| Neurological involvement | 194 (19.4) | 136 (13.6) | 97 (11.5) | |
| Thrombocytopenia | 134 (13.4) | 95 (9.5) | 76 (9.0) | |
| Haemolytic anaemia | 48 (4.8) | 33 (3.3) | 24 (2.9) | |
| Fever | 166 (16.6) | 139 (13.9) | 62 (7.4) | <0.001 |
| Raynaud’s phenomenon | 163 (16.3) | 132 (13.2) | 74 (8.9) | 0.003 |
| Livedo reticularis | 70 (7.0) | 55 (5.5) | 30 (3.6) | |
| Thrombosis | 92 (9.2) | 72 (7.2) | 41 (4.9) | 0.049 |
| Myositis | 43 (4.3) | 40 (4.0) | 11 (1.3) | <0.001 |
a All p values are a comparison between the frequencies in the 1990–1995 and the 1995–2000 periods.
| Petri et al. | Alarcón et al. | Wang et al. | Euro-Lupus cohort | |
|---|---|---|---|---|
| No. of patients | 574 | 555 | 539 | 1000 |
| Geographical area | America | America | Asia | Europe |
| Malar rash | 331 (57.7) | 322 (58) | 410 (76.1) | 311 (31.1) |
| Discoid lesions | 162 (28.2) | 107 (19.3) | 30 (5.6) | 78 (7.8) |
| Photosensitivity | 335 (58.4) | 334 (60.2) | 222 (41.2) | 229 (22.9) |
| Oral ulcers | 219 (38.2) | 293 (52.8) | 185 (34.3) | 125 (12.5) |
| Arthritis | NR | 489 (88.1) | 272 (50.5) | 481 (48.1) |
| Nephropathy | 319 (55.6) | 223 (40.2) | 399 (74) | 279 (27.9) |
| Neurological involvement | NR | 67 (12.1) | 123 (22.8) | 194 (19.4) |
| Thrombocytopenia | NR | NR | 161 (29.9) | 134 (13.4) |
| Haemolytic anaemia | NR | NR | 102 (18.9) | 48 (4.8) |
Another important aspect of SLE morbidity is organ damage. This describes irreversible events resulting from lupus disease activity and its treatment. The SLICC/ACR (Systemic Lupus International Collaborating Clinics/American College of Rheumatology) Damage Index is validated and widely used to describe damage . The link between damage and an increased risk of morbidity and mortality is now clear. It therefore behoves clinicians to try, as far as possible, to achieve disease remission, although studies highlight the inadequacies of current treatments in achieving this aim; and prolonged disease remission is quite a rare achievement.
Another important outcome measure is the risk of cancer associated with SLE. This has been a controversial area, but a recent very large study of 9547 patients from 23 centres confirmed an increased risk of cancer, especially non-Hodgkin’s lymphoma, in patients with SLE . An update of this study did not show a strong association between treatment with immunosuppressive agents and overall risk of cancer, although older studies have documented the well-known risk of bladder cancer with long-term cyclophosphamide use .
Mortality
Over the past 40 years, there has been significant improvement in the survival of patients with SLE . Earlier studies in 1955 reported a survival rate of less than 50% at 5 years; however, more recent studies indicated that over 93% of patients with SLE survive for 5 years, and over 85% survive for 10 years. In the Euro-Lupus cohort, the authors have found a 95% survival rate after 5 years from the time of entry into the study , and a 93% survival rate after 10 years , slightly higher than that found in the earlier American series . This is probably due to a lower prevalence of nephropathy in this series, a more recent observation period (1990–2000) and a more homogenous health-care system in Europe. It may also imply a better management of SLE patients in the present time (earlier diagnosis, more appropriately used anti-SLE therapies and advances in medical therapy in general). Despite these promising results, when compared with the general population, some studies have found that the overall mortality is increased four- to fivefold in SLE patients .
The improved rate of survival of patients with SLE has been associated with an alteration in the patterns of mortality (change in the main causes of death). The Euro-Lupus study indicates that complications of therapy and thrombotic manifestations are increasingly the cause of death in these patients ( Table 6 ). For instance, antiphospholipid antibody-related thrombotic events were responsible for 26.7% of the deaths in the Euro-Lupus cohort; yet, determination of a cause of death for SLE patients can be difficult in many cases. The complex nature of this disease may mimic, or be mimicked by, other conditions. In addition, many patients present with multisystem SLE involvement in their last days of life (renal, cardiac, pulmonary and haematological involvement), as well as with other combined complications, such as infections.
| Causes of death | 1990–1000 (total = 68) | 1990–1995 (total = 45) | 1995–2000 (total = 23) |
|---|---|---|---|
| No (%) | No (%) | No (%) | |
| Active SLE | 18 (26.5) | 13 (28.9) | 5 (21.7) |
| Multisystem | 5 (7.4) | 4 (8.9) | 1 (4.3) |
| Renal | 6 (8.8) | 4 (8.9) | 2 (8.7) |
| Cardiopulmonary | 3 (4.4) | 3 (6.7) | 0 (0) |
| Haematological | 1 (1.5) | 1 (2.2) | 0 (0) |
| Neurological | 3 (4.4) | 1 (2.2) | 2 (8.7) |
| Infections | 17 (25) | 13 (28.9) a | 4 (17.4) c |
| Bacterial sepsis | 15 (22.1) | 11 (24.4) | 4 (17.4) |
| Pulmonary | 6 (8.8) | 4 (8.9) | 2 (8.7) |
| Abdominal | 5 (7.4) | 4 (8.9) | 1 (4.3) |
| Urinary | 4 (5.9) | 3 (6.7) | 1 (4.3) |
| Fungal | 1 (1.5) | 1 (2.2) | 0 (0) |
| Viral | 1 (1.5) | 1 (2.2) | 0 (0) |
| Thromboses | 18 (26.5) | 12 (26.7) | 6 (26.1) |
| Cerebral | 8 (11.8) | 5 (11.1) | 3 (13) |
| Pulmonary | 4 (5.9) | 3 (6.7) | 1 (4.3) |
| Coronary | 5 (7.4) | 3 (6.7) | 2 (8.7) |
| Other | 1 (1.5) | 1 (2.2) | 0 (0) |
| Malignancies | 4 (5.9) | 3 (6.7) | 1 (4.3) |
| Breast | 1 (1.5) | 1 (2.2) | 0 (0) |
| Lung | 2 (2.9) | 1 (2.2) | 0 (0) |
| Lymphoma | 1 (1.5) | 1 (2.2) | 0 (0) |
| Gastric bleeding | 2 (2.9) | 2 (4.4) b | 0 (0) |
| Obstetric | 1 (1.5) | 1 (2.2) | 0 (0) |
| Suicide | 1 (1.5) | 1 (2.2) | 0 (0) |
| Surgical | 1 (1.5) | 1 (2.2) | 0 (0) |
| Accident | 1 (1.5) | 0 (0) | 1 (4.3) |
| Unknown | 14 (20.6) | 7 (15.6) | 7 (30.4) |
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