10 Systemic lupus erythematosus Sean O’Neill a , Ricard Cervera b, * a Department of Rheumatology, Liverpool Hospital, Sydney, Australia b Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Catalonia, Spain Keywords: systemic lupus erythematosus epidemiology environment infections genetic 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 manifes- tations. Epidemiological studies have identified marked differ- ences in the prevalence and course of SLE between genders, and across different ages, races and geographic locations. Methodo- logical differences between studies may account for some of the disparity seen. Additionally, some insights into possible environ- mental 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 limita- tions, 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. Ó 2010 Elsevier Ltd. All rights reserved. SLE (Systemic lupus erythematosus) is a multisystem auto-immune disease with diverse mani- festations. There has been considerable progress in understanding the pathogenesis of SLE, and abnormalities in every facet of the immune system have been described [1]. Despite this progress, the causes of SLE remain incompletely understood. The prevailing theory on the development of SLE is of * Corresponding author. Servei de Malalties Autoimmunes, Hospital Clínic, Villarroel, 170 08036-Barcelona, Catalonia, Spain. Tel.: þ34 93 227 5774; fax: þ34 93 227 1707. E-mail address: [email protected](R. Cervera). Contents lists available at ScienceDirect Best Practice & Research Clinical Rheumatology journal homepage: www.elsevierhealth.com/berh 1521-6942/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2010.10.006 Best Practice & Research Clinical Rheumatology 24 (2010) 841–855
Transcript
Best Practice & Research Clinical Rheumatology 24 (2010) 841–855
Contents lists available at ScienceDirect
Best Practice & Research ClinicalRheumatology
journal homepage: www.elsevierheal th.com/berh
10
Systemic lupus erythematosus
Sean O’Neill a, Ricard Cervera b,*
aDepartment of Rheumatology, Liverpool Hospital, Sydney, AustraliabDepartment of Autoimmune Diseases, Hospital Clínic, Barcelona, Catalonia, Spain
1521-6942/$ – see front matter � 2010 Elsevier Ltdoi:10.1016/j.berh.2010.10.006
a b s t r a c t
Systemic lupus erythematosus (SLE) is one of the most diverseautoimmune diseases as it may affect any organ in the body anddisplay a broad spectrum of clinical and immunological manifes-tations. Epidemiological studies have identified marked differ-ences in the prevalence and course of SLE between genders, andacross different ages, races and geographic locations. Methodo-logical differences between studies may account for some of thedisparity seen. Additionally, some insights into possible environ-mental risk factors for SLE have also been provided. As thiscondition is relatively uncommon, multifactorial, and largelyinfluenced by genetic predisposition, it is inherently difficult toconfirm or exclude infectious or environmental contributors to itsetiology. Movement of people between communities and definingspecific exposures can also be problematic. Despite these limita-tions, ongoing observation of SLE cohorts in multiple countries andsettings, along with large international cooperative efforts inrecent years, have helped clarify the risks of SLE in various groupsand have defined marked differences in the worldwide occurrenceof the disease.
� 2010 Elsevier Ltd. All rights reserved.
SLE (Systemic lupus erythematosus) is a multisystem auto-immune disease with diverse mani-festations. There has been considerable progress in understanding the pathogenesis of SLE, andabnormalities in every facet of the immune system have been described [1]. Despite this progress, thecauses of SLE remain incompletely understood. The prevailing theory on the development of SLE is of
S. O’Neill, R. Cervera / Best Practice & Research Clinical Rheumatology 24 (2010) 841–855842
a multifactorial aetiology involving genetic susceptibility, age and hormonal factors and environmentaltriggers.
Epidemiological studies have identified marked differences in the prevalence and course of SLEbetween genders, and across different ages, races and geographic locations. These studies haveimplicated numerous environmental factors in the aetiology of SLE. Methodological differencesbetween studies may account for some of the disparity seen. This review summarises the currentepidemiological data on the distribution and course of SLE, and considers some of the limitations ofthis data.
Descriptive epidemiology
SLE is one of the most diverse auto-immune diseases as it may affect any organ in the body anddisplay a broad spectrum of clinical and immunological manifestations. Although it has been consid-ered a rare disease, it now appears to be relatively common in certain groups of the population. This ismost likely due to the development of immunological tests that have allowed the diagnosis of manyatypical or benign cases, that otherwise may not have been identified. Several descriptive epidemio-logical studies on SLE have been conducted worldwide. However, the most extensive available datacome 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 thatwere particularly designed to be highly specific for research projects to enable consistency betweenstudies [2]. These have been updated in 1997 to include antiphospholipid antibodies in the criteria(Table 1) [3]. This classification is based on 11 criteria. For the purposes of identifying patients in clinicalstudies, a person can be classified as having SLE if any 4 or more of the 11 criteria are present, serially orsimultaneously, during any interval of observation.
Conversely, there are no diagnostic criteria for SLE, and the ACR classification criteria are oftenmisused for the diagnosis; but this practice can result in missed cases and undertreatment [4]. Forexample, a patient may present with malaise, fevers, arthritis, Raynaud’s phenomenon, lymphade-nopathy, oral ulcers and positive ANAs (antinuclear antibodies). This patient clearly may have SLE butdoes not fulfil the four criteria needed for classification by the ACR criteria. However, investigation andtreatment 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) [5–31]. In addition, the inci-dence of SLE also depends on changes in the diagnostic criteria of the disease. In the EU, the annualincidence ranges between 2.2 cases per 100 000 persons per year in Asturias, Spain [28], and 5.8 casesper 100 000 persons per year in Iceland [11]. In the US, the annual incidence of SLE has been estimatedin several studies, with incidence rates ranging from 2.2 cases per 100 000 persons per year in the ruralarea of Rochester [8] to 7.6 in the city of San Francisco [6] (Table 2). It is important to stress that, due tothe relatively rare nature of SLE, precise incidence estimates are difficult to produce, and althoughpoint estimates frommany of these studies differ, the CIs (confidence intervals) around these estimatesmay overlap.
Prevalence
Studies on the prevalence of the disease in the general population also show variation [4–30]. Thisvariability may be due to differences in the methodology of case ascertainment and socioeconomiccauses, such as educational level and availability of medical care; and diagnostic issues (changingdefinitions of SLE over time, increased availability of tests and/or increased awareness of SLE asa disease entity) may also influence prevalence estimates. Moreover, as SLE prevalence varies by sex
*Incidence rates per 100000 persons per year, including males and females.
Table 1Modified 1997 classification criteria for systemic lupus erythematosus (SLE).
Classification criteria
1. Malar rash Fixed erythema, flat or raised, over the malar eminences, tending tospare the nasolabial folds
2. Discoid rash Erythematous raised patches with adherent keratotic scaling andfollicular plugging; atrophic scarring may occur in older lesions
3. Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patienthistory 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. SerositisPleuritis Convincing history of pleuritic pain or rub heard by a physician or
evidence of pleural effusionPericarditis Documented by ECG or rub or evidence of pericardial effusion
7. Renal disorderPersistent proteinuria Proteinuria > 0.5 g/day or greater than þþþ if quantification
not performedCellular casts May be red cell, haemoglobin, granular, tubular or mixed
8. Neurological disorder See ACR definitions of 19 separate syndromes9. Haematological disorderHaemolytic anaemia With reticulocytosisLeucopenia <4000/mm3 total on two or more occasionsLymphopenia <1500/mm3 total on two or more occasionsThrombocytopenia <100000/mm3 in the absence of offending drugs
10. Immunological disorderAnti-DNA Antibody to native DNA in abnormal titreAnti-Sm Presence of antibody to Sm nuclear antigenPositive finding ofantiphospholipid antibodies
Abnormal serum level of IgG or IgM anticardiolipin antibodiesA positive test result for lupus anticoagulant using a standard methodA false positive serological test for syphilis, known to bepositive for at least 6 months and confirmed by Treponemapallidum immobilisation or fluorescent treponemaantibody absorption test
11. Antinuclear antibody Abnormal titre of antinuclear antibody by immunofluorescence or an equivalentassay at any point in time, and in the absence of drugs known to beassociated with “drug-induced lupus” syndrome
S. O’Neill, R. Cervera / Best Practice & Research Clinical Rheumatology 24 (2010) 841–855 843
S. O’Neill, R. Cervera / Best Practice & Research Clinical Rheumatology 24 (2010) 841–855844
and age groups, the age and sex distribution of a given population can lead to variation in the overallprevalence of SLE; however, geographic differences cannot be excluded, and may result from differ-ences in genetic or environmental factors (Table 3).
The study of Hochberg [17], in 1982, of England and Wales, reported a prevalence of 12.5 cases per100 000 women of all ages, and a prevalence of 17.7 cases per 100 000 in women of 15–64 years. Morerecent studies by Hopkinson [10] indicate a prevalence of 24.6 cases per 100 000 persons in Not-tingham, and those of Johnson et al. [13], a prevalence of 27.7 cases per 100 000 persons. A greaterprevalence of the disease was found in Sweden [9], at 36.3 cases per 100 000 persons; but, method-ological differences may explain this. The overall prevalence in the US has been reported to rangebetween 14.6 cases per 100 000 persons in New York, and 78.5 in Wisconsin [5,8,18]. Again, as SLE isrelatively uncommon, precise incidence estimates are difficult to generate, and though point estimatesfrom 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 withremissions, 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 themore conservative use of corticosteroids and of modified immunosuppressive regimens. In addition,there is much more information on factors such as organ involvement and accelerated atherosclerosisthat may predict morbidity and mortality.
The Euro-Lupus cohort has been instrumental in clarifying some of these factors. This cohort wascomposed by 1000 patients with SLE, whowere gathered in 1991 and prospectively followed during 10years bya consortium that includedmore than 40 investigators from seven European countries [32–34].The frequencies of the main manifestations of SLE during the 10 years of the prospective Euro-Lupuscohort (Table 4) are slightly lower than those reported in several large series from America [35,36] andAsia [37] in thepast decade (Table5). In this European cohort, activenephropathywasdiagnosed in27.9%of patients, and ranges between 40.2% in an American series [35] and 74% in an Asian series [37]. Theselower frequencies of clinical manifestations of SLE not only could be due to genetic or environmentaldifferences betweenEuropeans andAmericans or Asians, but could also reflect the effect ofmedical careduring the study. Furthermore, therewas a lower frequency ofmost SLEmanifestations during the last 5years of this prospective study (1995–2000) compared with the cumulative clinical manifestationsduring the initial 5 years (1990–1995) [34]. For instance, the frequency of active lupus nephropathy
*Number of patients who continued in the study in 1995.a All p values are a comparison between the frequencies in the 1990–1995 and the 1995–2000 periods.
S. O’Neill, R. Cervera / Best Practice & Research Clinical Rheumatology 24 (2010) 841–855 845
during the last 5 years was 6.8% compared with a cumulative prevalence of 22.2% during the initial 5years of the study. These lower frequencies in the last 5 years probably reflect the effect of treatment andof medical care during the study, and may also reflect natural remissions, which may occur withadvancing age and menopause.
Another important aspect of SLE morbidity is organ damage. This describes irreversible eventsresulting from lupus disease activity and its treatment. The SLICC/ACR (Systemic Lupus InternationalCollaborating Clinics/American College of Rheumatology) Damage Index is validated and widely usedto describe damage [38]. The link between damage and an increased risk of morbidity and mortality isnow 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 prolongeddisease remission is quite a rare achievement.
Another important outcome measure is the risk of cancer associated with SLE. This has beena controversial area, but a recent very large study of 9547 patients from 23 centres confirmed anincreased risk of cancer, especially non-Hodgkin’s lymphoma, in patients with SLE [39]. An update ofthis study did not show a strong association between treatment with immunosuppressive agents andoverall risk of cancer, although older studies have documented the well-known risk of bladder cancerwith long-term cyclophosphamide use [40].
Table 5Comparison of the main clinical manifestations related to SLE in several large series reported during the last decade.
Petri et al. [43] Alarcón et al. [35] Wang et al. [36] Euro-Lupus cohort
No. of patients 574 555 539 1000Geographical area America America Asia EuropeMalar 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)
NR, not reported.
Table 6Causes of death in the Euro-Lupus cohort during the 10-year prospective study (1990–2000).
Causes of death 1990–1000 (total ¼ 68) 1990–1995 (total ¼ 45) 1995–2000 (total ¼ 23)
a In 6 patients the cause of death was attributed to infection plus other factors (active SLE in 5 and thrombosis in 1).b In 2 patients the cause of death was attributed to gastric bleeding plus other factors (active SLE in 1 and infection in 1).c In 1 patient the cause of death was attributed to infections plus active SLE.
S. O’Neill, R. Cervera / Best Practice & Research Clinical Rheumatology 24 (2010) 841–855846
Mortality
Over the past 40 years, there has been significant improvement in the survival of patients with SLE[16,23,41–62]. Earlier studies in 1955 reported a survival rate of less than 50% at 5 years; however, morerecent studies indicated that over 93% of patients with SLE survive for 5 years, and over 85% survive for10 years. In the Euro-Lupus cohort, the authors have found a 95% survival rate after 5 years from thetime of entry into the study [33], and a 93% survival rate after 10 years [34], slightly higher than thatfound in the earlier American series [43–45]. This is probably due to a lower prevalence of nephropathyin this series, a more recent observation period (1990–2000) and a more homogenous health-caresystem in Europe. It may also imply a better management of SLE patients in the present time (earlierdiagnosis, more appropriately used anti-SLE therapies and advances in medical therapy in general).Despite these promising results, when comparedwith the general population, some studies have foundthat the overall mortality is increased four- to fivefold in SLE patients [34].
The improved rate of survival of patients with SLE has been associated with an alteration in thepatterns of mortality (change in the main causes of death). The Euro-Lupus study indicates thatcomplications of therapy and thrombotic manifestations are increasingly the cause of death in thesepatients (Table 6). For instance, antiphospholipid antibody-related thrombotic events were responsiblefor 26.7% of the deaths in the Euro-Lupus cohort; yet, determination of a cause of death for SLE patientscan be difficult in many cases. The complex nature of this disease maymimic, or be mimicked by, otherconditions. In addition, many patients present with multisystem SLE involvement in their last days oflife (renal, cardiac, pulmonary and haematological involvement), as well as with other combinedcomplications, such as infections.
S. O’Neill, R. Cervera / Best Practice & Research Clinical Rheumatology 24 (2010) 841–855 847
Prognosis studies and investigation of variables affecting mortality in SLE have identified a widerange of significant factors [34,60]. In the Euro-Lupus study, only nephropathy was found to haveprognostic significance for a lower survival probability; however, 92% of patients with nephropathy atthe beginning of the study survived after a 5-year follow-up period. Other studies performed in the US[60] observed that black patients (who have more renal disease), and those with worse socioeconomicconditions, have a more aggressive course and greater mortality.
Geographical variation
Geographical difference in occurrence or outcome
The incidence and prevalence of SLE has consistently been found to be higher in patients withAfrican ancestry. For example, a study in Birmingham, UK, found a higher age-adjusted incidence andprevalence in Afro-Caribbean subjects than in white people [13]. Age-adjusted incidence rates were25.8 and 4.3 per 100 000 persons per year in Afro-Caribbean subjects and white subjects, respectively,and prevalence rates were 112 and 21 per 100 000 persons. In this study, the age distribution ofincident cases differed significantly, with a younger median age of 34.5 years in Afro-Caribbeanwomencompared with 41 years in white women. There was also an excess prevalence of SLE among Asiansfrom the Indian subcontinent compared with white subjects. In Birmingham [13], the age-adjustedincidence and prevalence rates of SLE in Asians were 20.7 and 46.7 per 100 000 persons comparedwith4.3 and 20.7 per 100 000 persons in white subjects.
What are the reasons?
SLE is more common in women with African ancestry but is thought to be uncommon in WestAfrica, suggesting that environmental factors – possibly infections – may contribute to the develop-ment of SLE inwomenwhose ancestors migrated fromWest Africa. However, when this was examinedin women who had recently migrated from West Africa, the prevalence of SLE was similar to that inAfro-Caribbean women but much lower in European women [63]. These data suggest that SLE is notuncommon in West Africa and that there is a genetic basis for the higher risk of the disease in thesewomen.
Risk factors
What are the relevant risk factors for the occurrence of the condition?
In addition to the racial and geographic differences in the occurrence of SLE discussed above, thereare a number of epidemiological factors that appear important determinants of SLE risk. However,none of the factors below is a prerequisite for developing SLE, highlighting the multifactorial nature ofthe condition.
Age and genderSLE can present at any age. The mean age of onset in the Euro-Lupus cohort was 29 years and the
mean age at which ACR classification criteria were met was 31 years [62]. A similar mean age of onsethas been observed in multiple studies from North America, Europe and Latin America, with somecohorts observing a later age of onset in Caucasian patients [11,64–66]. Caucasian patients also appearto have a milder disease course (discussed below).
SLE is substantially more common in women than men when presenting in the childbearing years[32]. The ratio of females to males varies among cohorts but is generally estimated as 9:1 [67]. Thestrong female predominance is less pronounced in childhood-onset- and late-onset disease [62]. Thissuggests a role for oestrogens in the development of SLE although other explanations such as occu-pational exposures have been proposed.
Female predominance could also suggest a role for the X chromosome in the development of SLE.Further evidence for this theory comes from a recent study that observed that Klinefelter’s syndrome in
S. O’Neill, R. Cervera / Best Practice & Research Clinical Rheumatology 24 (2010) 841–855848
males with SLEwas 14 times more common than inmales without SLE [68]. However, the vast majorityof male lupus patients do not have Klinefelter’s syndrome, and the majority of patients with Kline-felter’s syndrome do not develop SLE; hence, the presence of two X chromosomes is neither essentialnor sufficient to cause SLE.
GeneticsThe concordance rate for SLE among monozygotic and dizygotic twins is 24% and 2%, respectively
[69]. This supports a strong but incomplete role for genes in the development of SLE. Familial aggre-gation of SLE further supports a role for genetic susceptibility [70]. Recent genome-wide associationstudies have identified a number of associations with SLE including STAT4 (signal transduction andactivator of transcription 4), IRF5 (interferon regulatory factor) and ITGAM (integrin alpha M) [71,72].More than 20 susceptibility loci have been identified to date, and these generally confer a modestincreased risk of SLE. These susceptibility loci give some insight into the pathogenesis of SLE, and havebeen well covered in several recent reviews [73–75].
InfectionSeveral infectious agents have been implicated in the development of SLE, and the observation of
flares in SLE activity following infection supports a possible association. Case reports and animalstudies have suggested possible roles for various infectious triggers of SLE [76,77]. The strongestevidence for a relationship between infection and SLE is the case of EBV (Epstein-Barr virus) [78].Studies in USmilitary recruits have identified the presence of antibodies to EBV nuclear antigen-1 priorto the onset of SLE [79]. The antibodies cross-react with Sm antigens and with the first peptide of 60kDa Ro. In animalmodels, immunisationwith an EBV nuclear antigen-1 epitope leads to antibodies thatbind multiple Ro epitopes and subsequent lupus-like auto-immunity [79].
There is also evidence for the hypothesis that exposure to infection in early childhood could lead tothe development of SLE in later life. In one study, a higher OR (odds ratio) for the presence of ANAwasseen in those with a history of diarrhoeal illnesses, rubella or mumps in childhood than in those withno early exposures to these infections [80]. However, it is difficult to determine whether the infectionsthemselves are a cause of subsequent autoimmunity, or merely a marker of other possible contributorssuch as immune abnormalities or socioeconomic factors.
SmokingThe role of cigarette smoking in the development of SLE remains controversial. A 2004 meta-analysis
of seven case-control studies and two cohort studies found that current smoking was associated with anOR of 1.5, 95% CI: 1.09–2.08 for the development of SLE [81]. Most of this association was attributable tothe very high OR seen in one outlier study and, indeed, no association was seen in six of the studies.
A number of other approaches have been used to study the relationship between smoking and SLE.A case-control study found an OR of 4.0 for the detection of anti-dsDNA (anti-double-stranded DNA)antibodies in patients with SLE who currently smoke, compared with those who had never smoked[82]. Cutaneous lupus has been associated with smoking in several studies [83,84]. A recent study ofparticipants in the Nurses’ Health Study identified 236 incident cases of adult SLE and found noassociation between maternal smoking (or paternal smoking) and adult onset SLE [85]. The studyrelied on self-reported data to ascertain early smoking exposure and did not examine the occurrence ofjuvenile SLE. Further study is needed to determinewhether smoking exposure at different ages has anyassociation with the development of SLE.
Environmental exposuresA number of occupational and environmental exposures have been implicated in the pathogenesis
of SLE, and these exposures might explain a higher-than-expected occurrence of SLE in certaincommunities. Establishing whether a true ‘cluster’ exists in a community and whether it is due toa specific pollutant is inherently challenging, as theremay be a small absolute number of definite cases,and it may be difficult to identify and quantify specific exposures. Furthermore, the multifactorialnature of SLEmeans that not all persons exposedwill necessarily develop SLE, and that SLE can developin those without the exposure in question.
S. O’Neill, R. Cervera / Best Practice & Research Clinical Rheumatology 24 (2010) 841–855 849
A study in a small community in Georgia observed a dramatically increased incidence and preva-lence of SLE compared with that seen in other USA-based studies [86]. The estimates were based on thefinding of three cases of SLE in current residents, and one case in a former resident, and the authorssuggested that there were at least 12 further unconfirmed cases that were not included in the esti-mates. A subsequent investigation by the ASTDR (Agency for Toxic Substances and Disease Registry)concluded that the available data did not constitute a risk to human health, and acknowledged that thesmall sample size of the study made interpretation difficult [87].
Community concern lad to an investigation by the Center for Disease Control into a potential SLEcluster in Nogales, Arizona [88]. The investigation determined that there was a high prevalence of SLEthere. SLE cases and controls were examined and were found to have similarly elevated levels ofchlorinated pesticides and organophosphates when compared with the reference mean for the USpopulation [88]. There was no association between exposure and disease status. Whilst this outcomehas been interpreted as reassuring, it remains consistent with the hypothesis that environmentalexposures could trigger disease in a small number of genetically susceptible individuals. However, aspointed out by Wallace and Quismorio [89], the population of Nogales is largely Hispanic/NativeAmerican, and the reported prevalence is consistent with that seen in other studies of Hispanic/NativeAmerican populations. Overall, there is no convincing evidence to support an SLE cluster, but theseexamples highlight the challenges in confirming or excluding such concerns.
A different approach has been used to investigate the possibility of an increased incidence of SLE inGulf War veterans. The investigation into the possible increase in SLE compared hospitalisation for SLEin deployed veterans, to hospitalisation for SLE in non-deployed veterans from the same time period.No increase in hospitalisation for SLE was seen in the deployed veterans [90].
In 1979, more than 2000 Taiwanese people consumed rice oil that was contaminated with poly-chlorinated biphenyls and polychlorinated dibenzofurans [91]. Long-term follow-up has revealeda markedly increased risk of mortality due to SLE. One proposed mechanism for the association is theknown ability of these chemicals to disrupt oestrogen homeostasis.
TCE (Trichloroethylene) is a known environmental contaminant that has been proposed as a triggerfor SLE. It has a number of uses as an industrial solvent, and may be found in domestic cleaners,adhesives and typewriter-correction fluid. Exposure to TCE leads to the generation of ANAs in mice[92,93], and human exposure has been linked with a number of auto-immune syndromes includinglupus-like symptoms and scleroderma [94,95]. Overall, there is no convincing epidemiologicalevidence for TCE-induced SLE in humans, although further study is warranted [94].
Silica exposure has been linked to the development of SLE and other auto-immune syndromesincluding lung fibrosis (silicosis), scleroderma, vasculitis and rheumatoid arthritis [96]. There isa convincing body of experimental work that provides biological plausibility for the associations [97].Significant silica exposure can occur in a number of rural and urban occupations including mining,farming, construction, pottery and china manufacturing.
A comprehensive study of silica exposure in 265 SLE patients and 355 controls was performed inCarolina [98]. Medium- and high-level silica exposure was seen in 19% of the SLE patients and 8% ofcontrols. An association between SLE and silica exposure was seen with an OR of 4.6 (95% CI 1.4–15.4)for high exposure. This supports a role for silica exposure in the development of a minority of SLE cases.
Exposure to various pesticides has been proposed as a risk factor for SLE. Pesticide exposure wasassociated with SLE in a small number of cases in the Carolina Lupus Study [99]. However, no asso-ciation has been observed in several other studies [97]. Further study is indicated.
Other exposuresAlcohol intake was demonstrated to have an inverse association with risk of SLE in some but not all
studies [100–103]. This inverse association remains controversial. A recent Internet-based case-controlstudy compared alcohol consumption in 114 people with SLE and 228 matched controls [104]. In thisstudy, no protective effect of alcohol was seen before diagnosis with SLE. Those with established SLEdid have a lower alcohol intake, suggesting that symptoms of SLE lead to reduced alcohol intake ratherthan a protective benefit of alcohol consumption on the development of SLE.
Lipstick use has long been proposed as a possible explanation for the female predominance seen inSLE [105]. A recent Internet-based study suggested an increased risk of SLE in those using lipstick three
S. O’Neill, R. Cervera / Best Practice & Research Clinical Rheumatology 24 (2010) 841–855850
or more times each week (OR 1.71, 95% CI 1.04–2.82) [106]. It is possible that the association seen wasdue to other unmeasured lifestyle factors, but the result does suggest the need for further study.
The absorption of aromatic amines in hair dye has been proposed as a risk factor for SLE. A numberof case-control studies from the US and Europe have found very little evidence to support such anassociation [100,107,108], with one study suggesting a modest association [109]. The Nurses’ HealthStudy found no relationship between hair-dye use (including age of first use, frequency and duration)and the subsequent development of SLE [110].
What are the relevant risk factors for the outcome of the condition?
There is a broad spectrum of severity and outcome in SLE. Various factors that associate witha better or worse outcome have been assessed in different cohorts. In the Euro-Lupus cohort, thepresence of nephropathy was the clearest indicator of a poor prognosis, and the presence of high-titreanti-dsDNA predicted nephropathy [62]. Renal damage was also an important predictor of mortality inthe LUMINA (Lupus in minority populations, nature versus nurture) cohort [111], and the presence ofrenal involvement has been confirmed as a poor prognostic factor in a number of other studies[42,45,47,51,59].
Male gender was not a marker of outcome in the Euro-Lupus cohort but has been observed in othercohorts to predict a poorer prognosis [43,112]. The SLICC investigators presented mortality findings asstandardisedmortality ratios (SMR – ratio of deaths observed to deaths expected), in a cohort of almost10 000 patients with SLE. This study did not observe a higher SMR in males with SLE compared withfemales with SLE [113]. Males in the general population have a higher expected death rate thanfemales, and the use of SMR helps to incorporate this into the SLE estimates. This suggests that maleSLE is not inherently worse than female SLE, but that males have a higher absolute risk of mortality.However, there are numerous reports of differences between male and female SLE, and these haverecently been reviewed [114].
The SLICC study also observed an increased SMR for young patients with SLE (due, in part, to a verylow expected death rate in the general young population), whereas increasing age is a strong predictorof absolute risk of mortality in most studied cohorts of SLE.
A number of studies [60,113,115] observed greater mortality in blacks/African-Americans with SLEthan inwhites with SLE. In other cohorts, race itself was not associatedwithmortality, and other factorssuch as socioeconomic status, compliance and health insurance status have been proposed ascontributors tomortality [43,116]. The LUMINA study observed worse disease in Hispanics and African-Americans with SLE compared with Caucasians, and found that socioeconomic factors could notexplain all of the difference [117]. SLE has also been observed to be more severe in Asian patients thanin Caucasians [118].
There is considerable evidence that socioeconomic status and access to health care have an impacton the course of SLE [43,116,117,119].
What are the time trends?
The incidence of SLE is increasing [11,14]. As discussed above, mortality in SLE is improving. Thelikely reasons for this include increased recognition of mild SLE, improvements in the management ofrenal disease, infection and malignancy and an increased awareness of steroid side effects whencompared with reports from the 1960s. There are numerous methodological difficulties in identifyingwhich of these factors have made the greatest contribution to the improvement in SLE mortality.Indeed, the ACR classification criteria were only published in 1982, making comparison with priorstudies problematic.
Vascular events remain a major contributor to mortality in SLE [62,113]. This problem was firstrecognised more than 30 years ago [58], and, since that time, there have been a number of attempts toquantify the risk [120,121]. A number of epidemiological studies examining traditional cardiac riskfactors in SLE have shown that, although important, traditional risk factors do not account for all of theincreased risk of CVD (cardiovascular disease) in SLE [122–126]. Awareness of the increased burden ofCVD in SLE has helped to direct investigation into other novel risk factors for CVD in SLE [125–128].
S. O’Neill, R. Cervera / Best Practice & Research Clinical Rheumatology 24 (2010) 841–855 851
Despite this progress, there is evidence that CVD-related mortality has not improved in recent years. Inthe SLICC cohort, the SMR for CVD in SLE did not improve from 1970 to 2001. A similar finding was seenin a mortality study from Sweden [129]. Whilst it is possible that increased recognition of CVD in SLEled to recognition and classification of CVD deaths in the 1990s that, in the 1970s, might have beenmistakenly classified as being due to SLE alone, these studies suggest that SLE-related CVD requiresfurther study.
Difficulties in obtaining this information: what are the weaknesses of the data reported above?
There are a number of challenges in identifying true differences in the occurrence and course of SLE,rather than differences in epidemiological methods [130]. As discussed above, changes in the classi-fication criteria for SLE in 1982 [2] and 1997[3] make it difficult to compare recent data with data fromthe 1970s and earlier.
Case ascertainment is also an issue in comparing studies of SLE. Differing studies have used hospitalrecords, tertiary referral cohorts or community cohorts as the population studied. This could lead tomarked differences in apparent disease manifestations and prognosis. As an example, in the SLICCmortality study, tertiary referral centres were primarily used [113]. However, the participating cohortswith the lowest SMR (Sweden, Scotland and Iceland) used population-based cohorts. Theremay also bedemographic differences (e.g., race) or health-system differences that contributed to the lowermortality in these groups, but it is not possible to determine this when comparing a population cohortwith a tertiary referral centre cohort.
Whilst population-based studies are likely than a tertiary hospital cohort to capture more patientswith SLE, they are also more likely to rely on self-reported diagnosis or retrospective application of ACRcriteria to define cases.
Epidemiological studies have provided some insights into possible environmental risk factors forSLE. As SLE is relatively uncommon, multifactorial and largely influenced by genetic predisposition, it isinherently difficult to confirm or exclude infectious or environmental contributors to its aetiology.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, alongwith large international cooperative efforts in recent years, has helped clarify the risks of SLE in variousgroups and have defined marked differences in the worldwide occurrence of the disease. Further studyis needed to quantify these differences more accurately.
References
[1] Rahman A, Isenberg DA. Systemic lupus erythematosus. New England Journal of Medicine 2008;358(9):929–39.[2] Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus.
Arthritis & Rheumatism 1982;25(11):1271–7.*[3] Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus
erythematosus. Arthritis & Rheumatism 1997;40(9):1725.[4] Font J, Cervera R. 1982 revised criteria for classification of systemic lupus erythematosus–ten years later. Lupus 1993;
2(5):339–41. discussion 43.[5] Siegel M, Lee SL. The epidemiology of systemic lupus erythematosus. Seminars in Arthritis & Rheumatism 1973;3(1):
1–54.[6] Fessel WJ. Systemic lupus erythematosus in the community. Incidence, prevalence, outcome, and first symptoms; the
high prevalence in black women. Archives of Internal Medicine 1974;134(6):1027–35.[7] Hochberg MC, Perlmutter DL, Medsger TA, et al. Prevalence of self-reported physician-diagnosed systemic lupus
erythematosus in the USA. Lupus 1995;4(6):454–6.[8] Michet CJ, McKenna CH, Elveback LR, et al. Epidemiology of systemic lupus erythematosus and other connective
tissues disease in Rochester, Minnesota, 1950 though 1979. Mayo Clin Proc 1985;60:105–13.[9] Nived O, Sturfelt G, Wollheim F. Systemic lupus erythematosus in an adult population in southern Sweden: incidence,
prevalence and validity of ARA revised classification criteria. British Journal of Rheumatology 1985;24(2):147–54.[10] Hopkinson ND, Doherty M, Powell RJ. Clinical features and race-specific incidence/prevalence rates of systemic lupus
erythematosus in a geographically complete cohort of patients. Annals of the Rheumatic Diseases 1994;53(10):675–80.
[11] Gudmundsson S, Steinsson K. Systemic lupus erythematosus in Iceland 1975 through 1984. A nationwide epidemi-ological study in an unselected population. Journal of Rheumatology 1990;17(9):1162–7.
[12] McCarty DJ, Manzi S, Medsger Jr TA, et al. Incidence of systemic lupus erythematosus. Race and gender differences.Arthritis & Rheumatism 1995;38(9):1260–70.
S. O’Neill, R. Cervera / Best Practice & Research Clinical Rheumatology 24 (2010) 841–855852
[13] Johnson AE, Gordon C, Palmer RG, et al. The prevalence and incidence of systemic lupus erythematosus in Birming-ham, England. Relationship to ethnicity and country of birth. Arthritis & Rheumatism 1995;38(4):551–8.
[14] Uramoto KM, Michet Jr CJ, Thumboo J, et al. Trends in the incidence and mortality of systemic lupus erythematosus,1950–1992. Arthritis & Rheumatism 1999;42(1):46–50.
[15] Helve T. Prevalence and mortality rates of systemic lupus erythematosus and causes of death in SLE patients inFinland. Scandinavian Journal of Rheumatology 1985;14(1):43–6.
[16] Meddings J, Grennan DM. The prevalence of systemic lupus erythematosus (SLE) in Dunedin. New Zealand MedicalJournal 1980;91(656):205–6.
[17] Hochberg MC. Prevalence of systemic lupus erythematosus in England and Wales, 1981-2. Annals of the RheumaticDiseases 1987;46(9):664–6.
[18] Maskarinec G, Katz AR. Prevalence of systemic lupus erythematosus in Hawaii: is there a difference between ethnicgroups? Hawaii Medical Journal 1995;54(2):406–9.
[19] Samanta A, Roy S, Feehally J, et al. The prevalence of diagnosed systemic lupus erythematosus in whites and IndianAsian immigrants in Leicester city, UK. British Journal of Rheumatology 1992;31(10):679–82.
[20] Gourley IS, Patterson CC, Bell AL. The prevalence of systemic lupus erythematosus in Northern Ireland. Lupus 1997;6(4):399–403.
[21] Fukase M. The epidemiology of systemic lupus erythematosus in Japan. In: Fukase M, editor. Systemic lupus eryth-ematosus. Baltimore: University Park Press; 1980. p. 3–10.
[22] Vlachoyiannopoulos PG, Karassa FB, Karakostas KX, et al. Systemic lupus erythematosus in Greece. Clinical features,evolution and outcome: a descriptive analysis of 292 patients. Lupus 1993;2(5):303–12.
[23] Ginzler EM, Diamond HS, Weiner M, et al. A multicenter study of outcome in systemic lupus erythematosus. I. Entryvariables as predictors of prognosis. Arthritis & Rheumatism 1982;25(6):601–11.
[24] Symmons DP. Frequency of lupus in people of African origin. Lupus 1995;4(3):176–8.*[25] D’Cruz DP, Khamashta MA, Hughes GRV. Systemic lupus erythematosus. Lancet 2007;369(9561):587–96.[26] Jonsson H, Nived O, Sturfelt G, et al. Estimating the incidence of systemic lupus erythematosus in a defined population
using multiple sources of retrieval. British Journal of Rheumatology 1990;29(3):185–8.[27] Naleway AL, Davis ME, Greenlee RT, et al. Epidemiology of systemic lupus erythematosus in rural Wisconsin. Lupus
2005;14(10):862–6.[28] Lopez P, Mozo L, Gutierrez C, et al. Epidemiology of systemic lupus erythematosus in a northern Spanish population:
gender and age influence on immunological features. Lupus 2003;12(11):860–5.[29] Piette JC, Papo T, Amoura Z, et-al. Lupus erythematosus systemique. In: Traité de Medicine. 4th ed. Paris; 2004.[30] Bossingham D. Systemic lupus erythematosus in the far north of Queensland. Lupus 2003;12(4):327–31 [Erratum
appears in Lupus. 2003;12(6):494].[31] Vasconcelos C. Epidemiologia clínica do lupus eritematoso sistémico; 2007. Oporto.*[32] Cervera R, Khamashta MA, Font J, et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease
expression in a cohort of 1,000 patients. The European Working Party on Systemic Lupus Erythematosus. Medicine1993;72(2):113–24.
*[33] Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 5-yearperiod. A multicenter prospective study of 1,000 patients. European Working Party on Systemic Lupus Erythematosus.Medicine 1999;78(3):167–75.
*[34] Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-yearperiod: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine 2003;82(5):299–308.
[35] Petri M. The effect of race on the presentation and course of SLE in the United States. Arthritis Rheum 1997;40:S162.[36] Alarcon GS, McGwin Jr G, Petri M, et al. Baseline characteristics of a multiethnic lupus cohort: PROFILE. Lupus 2002;
11(2):95–101 [Erratum appears in Lupus 2002;11(6):402].[37] Wang F, Wang CL, Tan CT, et al. Systemic lupus erythematosus in Malaysia: a study of 539 patients and comparison of
prevalence and disease expression in different racial and gender groups. Lupus 1997;6(3):248–53.[38] Gladman DD, Urowitz MB, Goldsmith CH, et al. The reliability of the Systemic Lupus International Collaborating
Clinics/American College of Rheumatology Damage Index in patients with systemic lupus erythematosus. Arthritis &Rheumatism 1997;40(5):809–13.
[39] Bernatsky S, Boivin JF, Joseph L, et al. An international cohort study of cancer in systemic lupus erythematosus.Arthritis & Rheumatism 2005;52(5):1481–90.
*[40] Bernatsky S, Joseph L, Boivin JF, et al. The relationship between cancer and medication exposures in systemic lupuserythematosus: a case-cohort study. Annals of the Rheumatic Diseases 2008;67(1):74–9.
[41] Gladman DD. Prognosis and treatment of systemic lupus erythematosus. Current Opinion in Rheumatology 1996;8(5):430–7.
[42] Swaak AJ, Nossent JC, Bronsveld W, et al. Systemic lupus erythematosus. I. Outcome and survival: Dutch experiencewith 110 patients studied prospectively. Annals of the Rheumatic Diseases 1989;48(6):447–54.
[43] Ward MM, Pyun E, Studenski S. Long-term survival in systemic lupus erythematosus. Patient characteristics associatedwith poorer outcomes. Arthritis & Rheumatism 1995;38(2):274–83.
[44] Ward MM, Pyun E, Studenski S. Causes of death in systemic lupus erythematosus. Long-term followup of an inceptioncohort. Arthritis & Rheumatism 1995;38(10):1492–9.
[45] Abu-Shakra M, Urowitz MB, Gladman DD, et al. Mortality studies in systemic lupus erythematosus. Results froma single center. II. Predictor variables for mortality. Journal of Rheumatology 1995;22(7):1265–70.
[46] Drenkard C, Villa AR, Alarcon-Segovia D, et al. Influence of the antiphospholipid syndrome in the survival of patientswith systemic lupus erythematosus. Journal of Rheumatology 1994;21(6):1067–72.
[47] Wallace DJ, Podell T, Weiner J, et al. Systemic lupus erythematosus–survival patterns. Experience with 609 patients.Journal of American Medical Association 1981;245(9):934–8.
[48] Studenski S, Allen NB, Caldwell DS, et al. Survival in systemic lupus erythematosus. A multivariate analysis ofdemographic factors. Arthritis & Rheumatism 1987;30(12):1326–32.
S. O’Neill, R. Cervera / Best Practice & Research Clinical Rheumatology 24 (2010) 841–855 853
[49] Karlson EW, Daltroy LH, Lew RA, et al. The relationship of socioeconomic status, race, and modifiable risk factors tooutcomes in patients with systemic lupus erythematosus. Arthritis & Rheumatism 1997;40(1):47–56.
[50] Merrell M, Shulman LE. Determination of prognosis in chronic disease, illustrated by systemic lupus erythematosus. JChron Dis 1955;1:12–32.
[51] Pistiner M, Wallace DJ, Nessim S, et al. Lupus erythematosus in the 1980s: a survey of 570 patients. Seminars inArthritis & Rheumatism 1991;21(1):55–64.
[52] Anstey NM, Bastian I, Dunckley H, et al. Systemic lupus erythematosus in Australian aborigines: high prevalence,morbidity and mortality. Australian & New Zealand Journal of Medicine 1993;23(6):646–51.
[53] Gripenberg M, Helve T. Outcome of systemic lupus erythematosus. A study of 66 patients over 7 years with specialreference to the predictive value of anti-DNA antibody determinations. Scandinavian Journal of Rheumatology 1991;20(2):104–9.
[54] Seleznick MJ, Fries JF. Variables associated with decreased survival in systemic lupus erythematosus. Seminars inArthritis & Rheumatism 1991;21(2):73–80.
[55] Abu-Shakra M, Urowitz MB, Gladman DD, et al. Mortality studies in systemic lupus erythematosus. Results froma single center. I. Causes of death. Journal of Rheumatology 1995;22(7):1259–64.
[56] Kellum RE, Haserick JR. Systemic lupus erythematosus. A statistical evaluation of mortality based on a consecutiveseries of 299 patients. Archives of Internal Medicine 1964;113:200–7.
[57] Estes D, Christian CL. The natural history of systemic lupus erythematosus by prospective analysis. Medicine 1971;50(2):85–95.
*[58] Urowitz M, Bookman A, Koehler B, et al. The bimodal mortality pattern of systemic lupus erythematosus. TheAmerican Journal of Medicine 1976;60:221–5.
[59] Rubin LA, Urowitz MB, Gladman DD. Mortality in systemic lupus erythematosus: the bimodal pattern revisited.Quarterly Journal of Medicine 1985;55(216):87–98.
[60] Reveille JD, Bartolucci A, Alarcon GS. Prognosis in systemic lupus erythematosus. Negative impact of increasing age atonset, black race, and thrombocytopenia, as well as causes of death. Arthritis & Rheumatism 1990;33(1):37–48.
[61] Fries JF, Weyl S, Holman HR. Estimating prognosis in systemic lupus erythematosus. American Journal of Medicine1974;57(4):561–5.
[62] Cervera R, Khamashta MA, Hughes GRV. The Euro-lupus project: epidemiology of systemic lupus erythematosus inEurope. Lupus 2009;18(10):869–74.
[63] Molokhia M, Hoggart C, Patrick AL, et al. Relation of risk of systemic lupus erythematosus to west African admixture ina Caribbean population. Human Genetics 2003;112(3):310–8.
[64] Hochberg MC. The incidence of systemic lupus erythematosus in Baltimore, Maryland, 1970–1977. Arthritis &Rheumatism 1985;28(1):80–6.
[65] Petri M. Hopkins lupus cohort. Rheumatic Diseases Clinics of North America 1999;26(2):199–213. update.*[66] Pons-Estel BA, Catoggio LJ, Cardiel MH, et al. The GLADEL multinational Latin American prospective inception cohort
of 1,214 patients with systemic lupus erythematosus: ethnic and disease heterogeneity among “Hispanics”. Medicine2004;83(1):1–17.
[67] Lockshin MD. Sex differences in autoimmune disease. Lupus 2006;15(11):753–6.[68] Scofield RH, Bruner GR, Namjou B, et al. Klinefelter’s syndrome (47, XXY) in male systemic lupus erythematosus
patients: support for the notion of a gene-dose effect from the X chromosome. Arthritis & Rheumatism 2008;58(8):2511–7.
[69] Deapen D, Escalante A, Weinrib L, et al. A revised estimate of twin concordance in systemic lupus erythematosus.Arthritis & Rheumatism 1992;35(3):311–8.
[70] Alarcon-Segovia D, Alarcon-Riquelme ME, Cardiel MH, et al. Familial aggregation of systemic lupus erythematosus,rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis &Rheumatism 2005;52(4):1138–47.
[71] Kelly JA, Kelley JM, Kaufman KM, et al. Interferon regulatory factor-5 is genetically associated with systemic lupuserythematosus in African Americans. Genes & Immunity 2008;9(3):187–94.
[72] International Consortium for Systemic Lupus Erythematosus Genetics, Harley JB, Alarcon-Riquelme ME, et al.Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants inITGAM, PXK, KIAA1542 and other loci. Nature Genetics 2008;40(2):204–10.
*[73] Crow MK, Crow MK. Collaboration, genetic associations, and lupus erythematosus. New England Journal of Medicine2008;358(9):956–61.
[74] Scofield RH, Scofield RH. Genetics of systemic lupus erythematosus and Sjogren’s syndrome. Current Opinion inRheumatology 2009;21(5):448–53.
[75] Hewagama A, Richardson B, Hewagama A, et al. The genetics and epigenetics of autoimmune diseases. Journal ofAutoimmunity 2009;33(1):3–11.
[76] Doria A, Canova M, Tonon M, et al. Infections as triggers and complications of systemic lupus erythematosus. Auto-immunity Reviews 2008;8(1):24–8.
[77] Sebastiani GD, Galeazzi M. Infection–genetics relationship in systemic lupus erythematosus. Lupus 2009;18(13):1169–75.
[78] James JA, Neas BR, Moser KL, et al. Systemic lupus erythematosus in adults is associated with previous Epstein-Barrvirus exposure. Arthritis & Rheumatism 2001;44(5):1122–6.
[79] McClain MT, Heinlen LD, Dennis GJ, et al. Early events in lupus humoral autoimmunity suggest initiation throughmolecular mimicry. Nature Medicine 2005;11(1):85–9.
[80] Edwards CJ, Syddall H, Goswami R, et al. Infections in infancy and the presence of antinuclear antibodies in adult life.Lupus 2006;15(4):213–7.
[81] Costenbader KH, Kim DJ, Peerzada J, et al. Cigarette smoking and the risk of systemic lupus erythematosus: a meta-analysis. Arthritis & Rheumatism 2004;50(3):849–57.
S. O’Neill, R. Cervera / Best Practice & Research Clinical Rheumatology 24 (2010) 841–855854
[82] Freemer MM, King Jr TE, Criswell LA. Association of smoking with dsDNA autoantibody production in systemic lupuserythematosus. Annals of the Rheumatic Diseases 2006;65(5):581–4.
[83] Boeckler P, Cosnes A, Frances C, et al. Association of cigarette smoking but not alcohol consumption with cutaneouslupus erythematosus. Archives of Dermatology 2009;145(9):1012–6.
[84] Kreuter A, Gaifullina R, Tigges C, et al. Lupus erythematosus tumidus: response to antimalarial treatment in 36patients with emphasis on smoking. Archives of Dermatology 2009;145(3):244–8.
[85] Simard JF, Costenbader KH, Liang MH, et al. Exposure to maternal smoking and incident SLE in a prospective cohortstudy. Lupus 2009;18(5):431–5.
[86] Kardestuncer T, Frumkin H. Systemic lupus erythematosus in relation to environmental pollution: an investigation inan African-American community in North Georgia. Archives of Environmental Health 1997;52(2):85–90.
[87] Registry AfTSaD. Petitioned Public Health Assessment – The Newtown Community. Division of Health Assessment andConsultation, Exposure Investigations Branch. Petitions Response Section. Agency for Toxic Substances and DiseaseRegistry; 2001.
[88] Balluz L, Philen R, Ortega L, et al. Investigation of systemic lupus erythematosus in Nogales, Arizona. American Journalof Epidemiology 2001;154(11):1029–36.
[89] Wallace DJ, Quismorio Jr FP. The elusive search for geographic clusters of systemic lupus erythematosus. Criticalreview. Arthritis & Rheumatism 1995;38(11):1564–7.
[90] Smith TC, Gray GC, Knoke JD. Is systemic lupus erythematosus, amyotrophic lateral sclerosis, or fibromyalgia asso-ciated with Persian Gulf War service? An examination of Department of Defense hospitalization data. AmericanJournal of Epidemiology 2000;151(11):1053–9.
[91] Tsai P-C, Ko Y-C, Huang W, et al. Increased liver and lupus mortalities in 24-year follow-up of the Taiwanese peoplehighly exposed to polychlorinated biphenyls and dibenzofurans. Science of the Total Environment 2007;374(2-3):216–22.
[92] Griffin JM, Gilbert KM, Lamps LW, et al. CD4(þ) T-cell activation and induction of autoimmune hepatitis followingtrichloroethylene treatment in MRLþ/þ mice. Toxicological Sciences 2000;57(2):345–52.
[93] Griffin JM, Blossom SJ, Jackson SK, et al. Trichloroethylene accelerates an autoimmune response by Th1 T cell acti-vation in MRL þ/þ mice. Immunopharmacology 2000;46(2):123–37.
[94] Cooper GS, Makris SL, Nietert PJ, et al. Evidence of autoimmune-related effects of trichloroethylene exposure fromstudies in mice and humans. Environmental Health Perspectives 2009;117(5):696–702.
[95] Cooper GS, Miller FW, Germolec DR. Occupational exposures and autoimmune diseases. International Immuno-pharmacology 2002;2(2-3):303–13.
[96] Parks CG, Cooper GS. Occupational exposures and risk of systemic lupus erythematosus. Autoimmunity 2005;38(7):497–506.
[97] Parks CG, Cooper GS. Occupational exposures and risk of systemic lupus erythematosus: a review of the evidence andexposure assessment methods in population- and clinic-based studies. Lupus 2006;15(11):728–36.
[98] Parks CG, Cooper GS, Nylander-French LA, et al. Occupational exposure to crystalline silica and risk of systemic lupuserythematosus: a population-based, case-control study in the southeastern United States. Arthritis & Rheumatism2002;46(7):1840–50 [Erratum appears in Arthritis Rheum. 2004 May;50(5):1694].
[99] Cooper GS, Parks CG, Treadwell EL, et al. Occupational risk factors for the development of systemic lupus eryth-ematosus. Journal of Rheumatology 2004;31(10):1928–33.
[100] Bengtsson AA, Rylander L, Hagmar L, et al. Risk factors for developing systemic lupus erythematosus: a case-controlstudy in southern Sweden. Rheumatology 2002;41(5):563–71.
[101] Hardy CJ, Palmer BP, Muir KR, et al. Smoking history, alcohol consumption, and systemic lupus erythematosus: a case-control study. Annals of the Rheumatic Diseases 1998;57(8):451–5.
[102] Ghaussy NO, Sibbitt Jr WL, Qualls CR. Cigarette smoking, alcohol consumption, and the risk of systemic lupuserythematosus: a case-control study. Journal of Rheumatology 2001;28(11):2449–53.
[103] Formica MK, Palmer JR, Rosenberg L, et al. Smoking, alcohol consumption, and risk of systemic lupus erythematosus inthe Black Women’s Health Study. Journal of Rheumatology 2003;30(6):1222–6.
[104] Wang J, Kay AB, Fletcher J, et al. Alcohol consumption is not protective for systemic lupus erythematosus. Annals of theRheumatic Diseases 2009;68(3):345–8.
[105] Burry JN. Lipstick and lupus erythematosus. New England Journal of Medicine 1969;281(11):620–1.[106] Wang J, Kay AB, Fletcher J, et al. Is lipstick associated with the development of systemic lupus erythematosus (SLE)?
Clinical Rheumatology 2008;27(9):1183–7.[107] Hardy CJ, Palmer BP, Muir KR, et al. Systemic lupus erythematosus (SLE) and hair treatment: a large community based
case-control study. Lupus 1999;8(7):541–4.[108] Petri M, Allbritton J. Hair product use in systemic lupus erythematosus. A case-control study. Arthritis & Rheumatism
1992;35(6):625–9.[109] Cooper GS, Dooley MA, Treadwell EL, et al. Smoking and use of hair treatments in relation to risk of developing
systemic lupus erythematosus. Journal of Rheumatology 2001;28(12):2653–6.[110] Sanchez-Guerrero J, Karlson EW, Colditz GA, et al. Hair dye use and the risk of developing systemic lupus eryth-
ematosus. Arthritis & Rheumatism 1996;39(4):657–62.[111] Danila MI, Pons-Estel GJ, Zhang J, et al. Renal damage is the most important predictor of mortality within the damage
index: data from LUMINA LXIV, a multiethnic US cohort. Rheumatology 2009;48(5):542–5.[112] Manger K, Manger B, Repp R, et al. Definition of risk factors for death, end stage renal disease, and thromboembolic
events in a monocentric cohort of 338 patients with systemic lupus erythematosus. Annals of the Rheumatic Diseases2002;61(12):1065–70.
[113] Bernatsky S, Boivin JF, Joseph L, et al. Mortality in systemic lupus erythematosus. Arthritis & Rheumatism 2006;54(8):2550–7.
[114] Lu LJ, Wallace DJ, Ishimori ML, et al. Review: male systemic lupus erythematosus: a review of sex disparities in thisdisease. Lupus 2010;19(2):119–29.
S. O’Neill, R. Cervera / Best Practice & Research Clinical Rheumatology 24 (2010) 841–855 855
[115] Mody GM, Parag KB, Nathoo BC, et al. High mortality with systemic lupus erythematosus in hospitalized Africanblacks. British Journal of Rheumatology 1994;33(12):1151–3.
[116] Petri M, Perez-Gutthann S, Longenecker JC, et al. Morbidity of systemic lupus erythematosus: role of race andsocioeconomic status. American Journal of Medicine 1991;91(4):345–53.
[117] Alarcon GS, Roseman J, Bartolucci AA, et al. Systemic lupus erythematosus in three ethnic groups: II. Featurespredictive of disease activity early in its course. LUMINA Study Group. Lupus in minority populations, nature versusnurture. Arthritis & Rheumatism 1998;41(7):1173–80.
[118] Samanta A, Feehally J, Roy S, et al. High prevalence of systemic disease and mortality in Asian subjects with systemiclupus erythematosus. Annals of the Rheumatic Diseases 1991;50(7):490–2.
[119] Sule S, Petri M. Socioeconomic status in systemic lupus erythematosus. Lupus 2006;15(11):720–3.[120] Manzi S, Meilahn EN, Rairie JE, et al. Age-specific incidence rates of myocardial infarction and angina in women with
systemic lupus erythematosus: comparison with the Framingham Study. American Journal of Epidemiology 1997;145(5):408–15.
[121] Roman MJ, Shanker B-A, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupuserythematosus. New England Journal of Medicine 2003;349(25):2399–406 [see comment] [erratum appears in N EnglJ Med. 2006 Oct 19;355(16):1746].
[122] Esdaile JM, Abrahamowicz M, Grodzicky T, et al. Traditional Framingham risk factors fail to fully account for accel-erated atherosclerosis in systemic lupus erythematosus. Arthritis & Rheumatism 2001;44(10):2331–7 [see comment].
[123] Bessant R, Hingorani A, Patel L, et al. Risk of coronary heart disease and stroke in a large British cohort of patients withsystemic lupus erythematosus. Rheumatology 2004;43(7):924–9.
[124] O’Neill SG, Pego-Reigosa JM, Hingorani AD, et al. Use of a strategy based on calculated risk scores in managingcardiovascular risk factors in a large British cohort of patients with systemic lupus erythematosus. Rheumatology2009;48(5):573–5.
[125] Bruce IN. ’Not only.but also’: factors that contribute to accelerated atherosclerosis and premature coronary heartdisease in systemic lupus erythematosus. Rheumatology 2005;44(12):1492–502.
*[126] Hahn BH. Systemic lupus erythematosus and accelerated atherosclerosis. New England Journal of Medicine 2003;349(25):2379–80 [see comment] [comment].
[127] O’Neill SG, Giles I, Lambrianides A, et al. Antibodies to apolipoprotein A-I, high-density lipoprotein, and C-reactiveprotein are associated with disease activity in patients with systemic lupus erythematosus. Arthritis & Rheumatism2010;62(3):845–54.
[128] McMahon M, Grossman J, FitzGerald J, et al. Proinflammatory high-density lipoprotein as a biomarker for athero-sclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis & Rheumatism 2006;54(8):2541–9 [see comment].
[129] Bjornadal L, Yin L, Granath F, et al. Cardiovascular disease a hazard despite improved prognosis in patients withsystemic lupus erythematosus: results from a Swedish population based study 1964-95. Journal of Rheumatology2004;31(4):713–9.
[130] Lim SS, Drenkard C. Epidemiology of systemic lupus erythematosus: capturing the butterfly. Current RheumatologyReports 2008;10(4):265–72.
