Causes and Predictors of Death in South Africans With Systemic Lupus Erythematosus

8/13/2019 Causes and Predictors of Death in South Africans With Systemic Lupus Erythematosus

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Causes and predictors of death in South Africans withsystemic lupus erythematosus

S. Wadee1, M. Tikly1 and M. Hopley2

Objectives. Little is known about the long-term outcome and mortality patterns in systemic lupus erythematosus (SLE) in sub-Saharan

Africa. We undertook a retrospective study of SLE in mainly black, unemployed patients, seen at a tertiary institution in Soweto, South Africa,

to determine the causes and predictors of death.

Methods. Demographic, clinical and laboratory data and outcome were extracted from the case records of patients attending the Lupus Clinic

at Chris Hani Baragwanath Hospital.

Results. Of the 270 case records with a diagnosis of SLE, 226 met the American College of Rheumatology classification criteria for SLE.

The female to male ratio was 18 : 1. The mean (S.D.) age at presentation was 34 (12.5) yrs. Arthritis, nephritis and neuropsychiatric disease

had a cumulative frequency of 70.4, 43.8 and 15.9% of patients, respectively. During the course of a mean follow-up period of 54.9 months,

193 (85.3%) and 89 (39.3%) patients were treated with oral corticosteroids and immunosuppressive agents, respectively. There were

55 (24.5%) known deaths and 64 (28.6%) patients were lost to follow-up. The estimated 5 yr survival rates were between 57 and 72%,

depending on whether the group of patients lost to follow-up was classified in the analysis as either alive or dead. Infection (32.7%) was the

commonest cause of death followed by renal failure (16.4%). Univariate analysis revealed that nephritis, neuropsychiatric disease and

hypocomplementaemia were associated with an increased mortality, but multivariate analysis showed nephritis as the only significantpredictor of mortality.

Conclusion. Our findings suggest that SLE in indigent South Africans not only carries a poorer prognosis but also the main cause of death,

infection and renal failure differ from those reported recently in industrialized Western countries. Nephritis is common in our patients and is the

only independent predictor of poor outcome.

KEY WORDS: Lupus, Mortality, Africa, Blacks.

Introduction

Systemic lupus erythematosus (SLE) is a chronic multisystemautoimmune disorder that has a predilection for young women.Advances in the early serological detection of antinuclearantibodies coupled with discovery of a variety of immunosup-

pressive agents, including corticosteroids, have had a majorpositive impact on the outcome of the disease over the last50 years [1]. In addition, progress in several other areas of clinicalmedicine, including diagnostic imaging, intensive care services,dialysis and transplantation and antimicrobial agents, havecontributed to the reduction and mortality associated with SLE[2, 3]. Since the mid-1990s, several centres from the industrializedworld have reported 5-yr survival rates in excess of 90% [47],compared with an appalling 40% in 1956 [8]. Notwithstandingthese achievements, standardized mortality rates for SLE exceedthe general population 2.4-fold in the industrialized world [9].

The outlook for SLE patients in the developing world is lessoptimistic. Studies from India, Tunisia, Senegal, Thailand andCuracao have found that, even in the 1990s and early 21st century,5-yr survival rates are well below 90% [6, 1014]. Moreover, there

are regional differences in the patterns and causes of death in SLE.In industrialized countries, causes of death are to some extent afunction of disease duration. Early mortality, defined as a deathoccurring within 5 yrs of disease onset, is mainly related to diseaseactivity or infections. Late mortality, occurring beyond 5 yrsdisease duration, is frequently due to malignancy or cardiovas-cular disease [6, 15]. In contrast, studies from the developingworld indicate that infections and active disease, particularly renal

disease, are the major causes of death and that the early mortalityis higher than that in the industrialized world [10, 13].

One of the enigmas of SLE in sub-Saharan Africa is that whileSLE is extremely rare in tropical Africa, it is, paradoxically, morecommon and carries a worse prognosis in Africans and people ofAfrican extraction living outside of the tropics [16]. This has led to

the tropical gradient hypothesis [17] which postulates that certaintropical infections, especially malaria, alter the immune responseand protect against auto-immune disease [18].

In the absence of any recent large studies on outcome andcauses of death in SLE in sub-Saharan Africa, we undertook aretrospective study to investigate causes, patterns and predictorsof mortality in a mainly urbanized unemployed cohort of SLEpatients attending a tertiary care facility in South Africa.The study was approved by the Human Ethics Committee ofthe Faculty of Health Sciences, University of the Witwatersrand.

Patients and methods

Chris Hani Baragwanath hospital (CHBH) is a tertiary referralcentre servicing mainly the indigent, predominantly black

population of Soweto and surrounding peri-urban and ruralareas of South Africa. Case records of patients fulfilling the 1997updated American College of Rheumatology (ACR) classificationcriteria [19] and attending the Lupus Clinic at CHBH betweenJanuary 1986 and July 2003 were reviewed. Patients who metonly 3 of the 11 classification criteria were classified as havinglupus-like disease. Demographic data, clinical and laboratoryfeatures (as defined in the ACR criteria), drug therapy andoutcome were abstracted from the case records. Antinuclearantibodies (ANA) and anti-dsDNA antibodies were tested byindirect immunoflourescence testing using HEp2 cell line andCrithidia luciliae as substrates, respectively.

Causes of death were ascertained by review of case records, bydiscussion with the attending physician and post-mortem reports,where available. Outcome was categorized as known deaths,known alive and unknown outcome for patients lost to follow-up.

1Division of Rheumatology, Department of Medicine, Chris Hani Baragwanath

Hospital and University of the Witwatersrand, Johannesburg, South Africa and2Boehringer-Ingelheim, South Africa.

Submitted 31 October 2006; revised version accepted 7 June 2007.

Correspondence to: M. Tikly, FRCP, PhD, Rheumatology Unit, Chris Hani

Baragwanath Hospital, PO Bertsham 2013, South Africa.

E-mail: [email protected]

Rheumatology 2007;46:14871491 doi:10.1093/rheumatology/kem180

Advance Access publication 5 August 2007

1487The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]


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The main clinical or pathological process resulting in death wasrecorded as the primary cause of death. Survival was calculatedfrom the date of first presentation to the Lupus Clinic oradmission to hospital with clinical features of lupus to July 2003,or until death or loss to follow-up.

Statistical methods

Univariate analysis was performed applying either the one-wayANOVA test in the case of continuous variables or chi-square test(with Yates correction) for categorical variables. KaplanMeierstatistic was applied to construct the survival curves. Multivariateanalysis was done using the Cox proportional hazard regressionmodel to test for independent predictors of death. All statisticalanalyses were performed using Statistica v6 software (StatSoft,Tulsa, USA). A P-value


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a multidrug-resistant organism was cultured. Moreover, TB wasa contributory factor in one death where the primary cause ofdeath was a dilated cardiomyopathy. Renal failure in 16.4% ofpatients was the second commonest known cause of death. HIVinfection contributed to only two infection-related deaths, fromTB and acute pneumonia. Of the seven deaths in themiscellaneous group, one was due to a myocardial infarct, threewere from dilated cardiomyopathy, two were from pulmonary

hypertension and one was pregnancy related. No deaths dueto malignancy were recorded. The causes of early death didnot differ significantly from those that caused late death(Table 3). Five deaths occurred in the lupus-like group, threedue to infection, one due to renal failure and in one case the causewas unknown.

The KaplanMeier survival curves for the SLE group demon-strated an overall 5 yr survival probability of 57% and in thebest case scenario, censored for patients lost to follow-up,the figure rose to 72% (Fig. 1). Survival was worse in patients

with nephritis at presentation, but nephritis at any stage in thecourse of the disease was also associated with a poorer survival(P0.002) (Fig. 2). The subgroup of infection-related deaths,when compared with the known alive group, were more likely tohave had CNS disease (33.3 vs 11.2%, OR 4.0, P0.03), lesslikely to be treated with azathioprine (5.9 vs 33.6%, OR0.12,P0.02.), and showed a trend towards being more likely to betreated with HD-CS (77.7 vs 56.7%, OR2.7, P0.12). No

significant associations were observed with the use of otherimmunosuppressive drugs, in particular cyclophosphamide andinfection-related deaths.

Discussion

Our findings suggest that the outcome of SLE in indigent SouthAfricans continues to be considerably poorer than in Westernindustrialized countries. The best-case scenario 5-yr survival rateof 72% is not much different from the 68 and 78% reported in twosmaller studies in 1973 and 1988, respectively [20, 21]. One of thelikely biological reasons for this poorer outcome is that the diseaseis inherently more aggressive, and therefore carries a highermortality in blacks, which has been demonstrated in African-

Americans [22, 23]. In particular, nephritis is more common inblacks and adversely affects outcome [24, 25]. In the present study,43.8% of patients had nephritis, considerably higher than the19.4% reported in Europeans [26]. More importantly, the 5-yrsurvival rate of 60% in patients with nephritis was significantlylower than the 84% 5-yr survival rate for patients withoutnephritis. Moreover, multivariate analysis showed that nephritiswas the only independent predictor of poor outcome and renalfailure was the second commonest cause of death.

We were unable to investigate the role of socio-economicconditions and geographical place of residence (urban vs rural),but studies in the US have shown that these factors impact onoutcome [27]. Inadequacies of state health services (a legacy of theprevious apartheid system), cultural factors and the cost of travelacross large distances are all factors that are likely to contribute

to the delay in early detection of SLE and hence outcome.The problem of late presentation is particularly evident inthe lupus nephritis patients, 77 of 99 (78%) of whom hadclinically overt renal disease at first presentation. Furthermore,

TABLE3. Causes of death in patients with SLE

Cause of death

5 yrs Total (%)Infection 13 5 18 (32.7)Renal failure 6 3 9 (16.4)Active disease 4 2 6 (10.9)Other 5 2 7 (12.7)

Acute cardiovascular 1 0Cardiomyopathy 2 1Pulmonary circulatory 1 1Pregnancy related 1 0

Unknown 12 3 15 (27.3)Total (%) 40 (72.7) 15 (27.3) 55

TABLE4. Details of infective causes of death

Type of infection 5 yrs Total

Sepsis/Septicaemia unspecified 4 2 6Pneumonia unspecified 4 1 5Tuberculosis 1 2 3PCP pneumonia 1 0 1Meningitis 1 0 1Post-surgical sepsis 1 0 1Pyomyositis 1 0 1Total 13 5 18

Known deaths Still attending clinic

0 24 48 72 96 120 144 168 192

Survival Time in months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

CumulativeProportionSurviving

FIG. 1. KaplanMeier survival curves for total SLE group, censored for patients lost

to follow-up.

Chi2= 12.4, df = 3, p = 0.002

Known deaths Still attending clinic

0 24 48 72 96 120 144 168 192

Follow-up in months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

CumulativeProportionSurviving

No nephritis

Nephritis at presentation

Nephritis during follow-up

FIG. 2. KaplanMeier survival curves comparing SLE patients with and without

nephritis, censored for patients lost to follow-up.

Lupus in South Africans 1489


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the under-resourced state sector has limited facilities for renalreplacement therapy, including dialysis and transplantation.

Infections, like in other emerging countries [10, 11], were thecommonest cause of death, irrespective of disease duration. Studiesby Ansellet al. [28] and more recently by Whitelaw et al. [29] haveshown that even with specialized care in ICU, infections areassociated with a high mortality in SLE in South African statehospitals. Of note in the present study is that three of the 18

infection-related deaths (17%) were due to TB, similar to theobservations of Mody et al. [30] in hospitalized SLE patients inKwa-Zulu Natal. There is mounting evidence that patients withSLE are at increased risk for TB especially, extra-pulmonarydisease [31]. In a recent retrospective review, we found that 13.6%of all SLE and lupus-like patients at our hospital contracted TBduring the course of their follow up, of whom 26.4% had extra-pulmonary disease [32]. In a country where HIV infection isendemic, we found only two patients with HIV-related deaths, oneof whom had TB. Bearing in mind that this study covers a period inthe late 1980s and early 1990s when HIV infections were lessprevalent, it is likely that the impact of the HIV epidemic is likelyto grow.

Patients with SLE are at increased risk of infections due to both

intrinsic factors, such as functional asplenia and complementabnormalities, and drug therapy, in particular CS and immuno-suppressive agents, especially cyclophosphamide [33]. In thepresent study, the only significant risk factor for infection-relateddeaths was CNS disease and there was a trend towards anassociation with HD-CS use. The protective effect of azathio-prine observed in this study probably relates to its steroid-sparingeffect of the drug, although we did not specifically examine thecumulative doses of CS in patients who had received azathioprinevs patients who had not received the drug.

We were unable to discern a bimodal pattern of causes of death.Of particular note is that there were no late deaths attributable toatherosclerotic cardiovascular disease and cancer, which are nowthe leading causes of late deaths in SLE in industrialized countries.Some of the possible reasons for this difference include a low

prevalence of both conditions in the general black population [34],relatively short follow-up period, relatively young age andrelatively few male patients.

An obvious limitation of this study is the large number ofpatients (28.3%) lost to follow-up and our inability to establish acause of death in 27.7% of the known deaths. Both these issuesmay have an impact on the interpretation of the results. It hasbeen suggested that interpretation survival data is problematicwhen loss to follow-up rates exceed 20% [6]. We were also unableto quantify the cumulative dose of CS and other immunosup-pressive agents, which may have a bearing on the risk of infection-related deaths. Other limitations include the variation in clinicalexpertise of the clinicians and standard of care over the studyperiod and the absence of socio-economic data and global diseaseactivity scores to relate to outcome.

Notwithstanding these limitations, we believe our findingsprovide further evidence that lupus is not a rare disease inSouth Africa, that survival is not as good as in industrializedcountries, and that causes of death resemble those documented inother developing countries. There is an obvious need to improveearly detection of disease, particularly nephritis, to reducemortality.

M.T. has received consultancy fees, honoraria and/or researchsupport from Pfizer, Roche, Merck, Aspreva and BristolMyers Squibb. M.H. is employed by Boehringer-Ingelheim,South Africa.

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Rheumatology key messages

Infections and renal failure were the main causes of death inindigent South African patients with SLE.

Nephritis was the only independent predictor of death.

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Causes and Predictors of Death in South Africans With Systemic Lupus Erythematosus