Rheumatology 2009;48:673675 Advance Access publication 9 April 2009

doi:10.1093/rheumatology/kep062

Concise Report

Damage and mortality in a group of British patients with systemic lupus erythematosus followed up for over 10 years
Sharon A. Chambers1, Elizabeth Allen2, Anisur Rahman1 and David Isenberg1
Objective. To study damage accrual and mortality in British patients with SLE under long-term follow-up for >10 years. Methods. We analysed the clinical records of 232 patients with SLE who had at least 10 years of consistent follow-up at University College London Hospital (UCLH). We noted their SLICC/ACR Damage Index (SDI) scores and category of damage at 1 year post-diagnosis of SLE and every 5 years thereafter. For patients who had died, we determined the year and cause of death. Results. Ninety per cent of patients had no damage at 1 year post-diagnosis of SLE; however by year 10, 50% had accrued some damage. Damage accrual was mostly in the neuropsychiatric, renal and musculoskeletal categories. An increase in damage score was associated with a higher risk of death overall. Forty-four patients died during the period of follow-up. Sepsis, cancer and organ failure (cardiac, renal and liver) were the main causes of death in this group of patients. Conclusions. Damage accrual is associated with an increased risk of mortality. Infections remain an important cause of death in patients with SLE.
KEY
WORDS:

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Damage, Mortality, SLICC/ACR, SLE, Survival, Sepsis, Cancer, UK, Multiethnic, Musculoskeletal.

Introduction
Survival of patients with SLE in the developed countries has improved consistently in recent years. The 5-year survival which was 50% in the 1950s is now reported to be >90% in some centres [13]. Despite improved survival rates, patients with SLE are reported to have up to a 4.6-fold higher standardized mortality rate compared with the general population [4]. Morbidity from the disease and its treatments remains high [5]. The assessment of morbidity has been greatly improved by the use of the widely accepted SLICC/ACR Damage Index (SDI) that records irreversible change attributable to lupus, concomitant diseases or treatment in 12 organs/systems [6]. Studies utilizing the SDI have demonstrated that damage predicts further damage [7] and that longer disease duration is associated with higher damage scores [8]. The importance of detecting damage early in the course of the disease was highlighted by Rahman et al. [9] who demonstrated that early damage predicted mortality in a Canadian cohort under follow-up for 10 years or until death. However, many lupus patients are surviving for well beyond a decade and there have been no long-term comparative studies in the UK assessing damage and the relationship to mortality in patients with lupus under follow-up for >10 years. There is a gap in the literature relating to damage accrual beyond 10 years. This present study conducted in January 2006 therefore focused on: (i) the type of damage accrual in patients under long-term follow-up (i.e. 1025 years) in a large multiethnic British cohort of patients with SLE; (ii) the influence of damage accrual on survival and the cause of death in these patients.
1

Methods
We reviewed the computer records of the 401 patients attending the UCLH SLE clinic between 1 January 1978 and 31 December 2004 to identify those patients who had at least 10 years of consistent follow-up since diagnosis of SLE (the date when they met at least four revised ACR criteria) [10]. For the patients thus identified, we reviewed their clinical records noting the patients age at diagnosis of SLE, duration of SLE, SLICC/ACR damage scores at 1 year post-diagnosis of SLE and every 5 years thereafter, to the time of death or loss to follow-up. The category/item of damage was also noted. Cause of death was clarified from post-mortem reports, death certificates or general practitioner records (including for patients who were lost to follow-up) where available.

Statistical analysis
Time to death and the effect of accrued damage on time to death were analysed using Cox regression. Survival time was defined as the interval from time of diagnosis until death or last contact. Patients who were lost to follow-up were censored at the time they were last seen. The analyses were performed using STATA version 9.2 (StataCorp, Texas, USA) [11]. A significance level of 5% was used in all analyses.

Results
We identified 232 patients (221 females, 12 males) who had at least 10 years of follow-up. The predominance of female patients is reflective of the entire cohort and in keeping with the female predisposition to acquire SLE. The ethnic breakdown of the patients was as follows: 168 (72%) whites, 32 (14%) blacks, 23 Indo Asians (10%) and 9 other (4%). This is reflective of the multiethnic nature of the entire cohort. The mean (S.D.) age at diagnosis of SLE in the patients was 31.2 (11.4) years.

Department of Medicine, The Centre for Rheumatology, University College London and 2The London School of Hygiene and Tropical Medicine, London, UK. Submitted 30 July 2008; revised version accepted 26 February 2009.

Correspondence to: Sharon Chambers, The Centre for Rheumatology, University College London Hospital, 250 Euston Road, 3rd Floor Central, London NW1 2PQ, UK. E-mail: shrspk@aol.com

How fast does damage accrue in these patients?

Table 1 shows the number of patients on follow-up over the study period and the number and percentage of patients who had
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Sharon A. Chambers et al. were the neuropsychiatric, musculoskeletal and renal categories (Table 2).

damage (SLICC/ACR score of 51) at 1, 5 and 10 years after the diagnosis of SLE. The mean damage score at each time point is also presented. By 10 years of follow-up, just over half the patients had developed damage. No patient accrued a damage score >5 during the entire period of follow-up.

Damage and mortality

A Cox model was used to examine the effect of a patients last available damage score on death. For every 1 point increase in damage score, the patient was 1.32 times more likely to die; hazard ratio 1.32 (95% CI 1.09, 1.60) (P 0.005). The adjusted hazard ratio (adjusted for age at SLE onset) is 1.40 (1.14, 1.72) meaning that the effect of damage is not simply reflecting the effect of age at the onset of SLE. The mean (S.D.) duration of SLE for those patients who died was 16.7 (4.7) years. During the 26-year period of observation, there were 44 deaths (four of these deaths were not included in the Cox analysis, as the year of their death is either unknown or is after the end of follow-up and therefore they were censored at the last time they were seen). The causes of death in these 44 patients are presented in Table 3 and included sepsis (n 11); cancer (n 8) including haematological malignancies (n 3) as well as cancer of the bowel (n 1), breast (n 2), prostate (n 1) and lung (n 1); organ failure (n 6) including renal, liver and heart failure; myocardial infarction (n 4); cerebrovascular accidents (n 3); atherosclerosis (n 2); other causes (n 5) including suicide (n 2) and motor vehicle accidents (n 1), old age (n 2); and unknown (n 5).

What types of damage accrue in these patients?

Table 2 shows the number of patients accruing damage in each of the 12 categories over the study period. The item of damage in each category is also outlined in the table. The most common categories in which damage was accrued

TABLE 1. Number of patients with damage over the 26-year period of follow-up Number of patients on follow-up 232 232 232 143 75 6 Year post-diagnosis of SLE 1 5 10 15 20 25 Number of patients (%) with damage score 1 24 77 119 80 50 6 (10) (33) (51) (55) (65) (100) Mean damage score 0.11 0.42 0.77 1.01 1.26 2.17

TABLE 2. Number of patients with damage in each category over the 25-year period of follow-up (categories not mutually exclusive) Year 1 (232 patients) 6 1 3 1 1 0 0 0 0 1 0 0 1 0 0 0 0 0 0 1 1 0 0 0 2 1 0 0 1 4 4 0 5 0 3 1 1 5 2 0 3 0 0 0 (2.6) Year 5 (232 patients) 26 6 4 14 2 0 0 0 0 16 11 2 3 0 0 0 0 0 0 4 3 0 1 0 8 4 2 1 1 6 4 2 13 4 6 1 2 9 5 0 4 0 0 2 (11.2) Year 10 (232 patients) 34 7 5 19 2 1 3 2 1 30 15 8 6 8 3 2 1 1 1 11 5 3 2 1 11 6 3 1 1 8 5 3 28 7 15 2 4 12 6 0 6 1 1 5 (14.7) Year 15 (143 patients) 18 6 2 7 3 0 3 2 1 20 10 4 6 7 2 2 0 1 2 11 5 4 2 0 12 6 3 2 1 8 5 3 31 10 15 2 4 5 3 0 2 3 1 5 (12.5) Year 20 (75 patients) 12 2 5 3 1 1 1 1 0 10 4 2 4 3 1 1 0 0 1 7 4 1 2 0 7 4 1 1 1 9 6 3 19 6 9 2 2 5 3 1 1 1 1 8 (16.0) Year 25 (6 patients) 1 0 1 0 0 0 0 0 0 2 1 0 1 0 0 0 0 0 0 2 0 1 1 0 2 1 1 0 0 1 1 0 2 1 1 0 0 0 0 0 0 0 0 2 (16.7)

Category Neuropsychiatric Seizures Cerebrovascular accident Cognitive impairment or major psychosis Cranial/peripheral neuropathy Transverse myelitis Ocular Cataracts Retinal change Renal GFR < 50% Proteinuria > 3.5 g/24 h End-stage renal disease Pulmonary Pulmonary hypertension Pulmonary fibrosis Shrinking lung Pleural fibrosis Pulmonary infarction Cardiovascular Angina or coronary bypass Myocardial infarction Valvular disease Pericarditis Peripheral vascular Venous thrombosis Claudication Minor tissue loss Significant tissue loss Gastrointestinal Resection of bowel Upper gastrointestinal tract surgery Musculoskeletal Muscle atrophy or weakness Deforming/erosive arthritis Osteoporosis with fracture Avascular necrosis Skin Scarring alopecia Scarring of panniculum Skin ulceration Premature ovarian failure Endocrine (diabetes) Malignancy

(0) (0.4)

(0) (6.9)

(1.3) (12.9)

(2.1) (14.0)

(1.3) (13.3)

(0) (33.3)

(0)

(0)

(3.4)

(4.9)

(4)

(0)

(0.4)

(1.7)

(4.7)

(7.7)

(9.3)

(33.3)

(0.9)

(3.4)

(4.7)

(8.4)

(9.3)

(33.3)

(1.7) (2.2)

(2.5) (5.6)

(3.4) (12.1)

(5.6) (21.7)

(12) (25.3)

(16.7) (33.3)

(2.2)

(3.9)

(5.2)

(3.5)

(6.7)

(0)

(0) (0) (0)

(0) (0) (0.9)

(0.43) (0.4) (2.2)

(2.1) (0.7) (3.4)

(1.3) (1.3) (10.7)

(0) (0) (33.3)

Values are given as n (%). GFR: glomerular filtration rate.

Follow-up of British patients with SLE

TABLE 3. Causes of death in the patients Cause of death Sepsis Cancer Organ failure Myocardial infarction Cerebrovascular accidents Other Atherosclerosis Unknown Total (n 44) 11 8 6 4 3 5 2 5

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with higher risk of mortality [20]. After 10 years of SLE, over half of our patients had developed damage, especially neuropsychiatric, musculoskeletal or renal damage. Patients with damage are at risk of further damage and should be monitored closely for adverse effects of medication and the development of co-morbidities and complications of SLE.

Rheumatology key messages

 Damage accrual is associated with higher risk of mortality in patients with SLE.  Patients with damage are at a risk of more rapid progression to further damage.

Discussion
To the best of our knowledge, this is the first UK study which reports damage accrual and mortality in patients who have had SLE for at least 10 years. Our findings in this group of patients concur with previous observations that the damage is associated with an increased risk of death. Half of our patients had accrued damage by 10 years postdiagnosis of SLE. Other studies have reported that as many as 70% of patients had damage at 10 years post-diagnosis of SLE [12]. An earlier study in 1996 involving an inception cohort of 80 patients at UCLH who had been diagnosed with SLE for at least 10 years prior to 1994 reported that 32, 51 and 68% of patients had damage at 1, 5 and 10 years, respectively, post-diagnosis of SLE [13]. Our present figures suggest that a lower proportion of patients in our cohort have developed damage at 10 years. This may be due to the departments more aggressive approach in identifying and treating active disease and modifying risk factors for damage wherever possible. The change in protocols used for treating the disease, including the use of lower doses of cyclophosphamide, greater use of steroid sparing agents and drugs to prevent the development of osteoporosis, may have translated to slower development of damage for patients who entered our cohort since the previous study. Despite these measures, damage in musculoskeletal categories remains high. Several patients (particularly those with renal disease) had osteoporosis and steroid-related muscle atrophy. Other factors which were not examined in this study, but which could potentially contribute to the improvement in damage accrual at 10 years could include earlier identification of the disease leading to more prompt referral of patients from the community as well as changes in patient health seeking behaviour. Factors which could potentially influence outcomes include the degree of disease activity, and the socio-economic status of the patients [14, 15]. Higher disease activity scores have been shown to correlate with damage and mortality [12, 16]. However, disease activity was not assessed in this study and no attempts were made to analyse the prognostic significance for mortality of the patients clinical and immunological parameters, demographic factors or socio-economic status. This study considered deaths occurring in those patients who had at least 10 years of follow-up for SLE. Sepsis and malignancy were the leading causes of mortality in these patients. Sepsis/ infection is well recognized to be a cause of early and late deaths in lupus [4, 17]. Mortality related to malignancy has also been reported in other studies of patients with SLE [17, 18], and is more often associated with late-onset SLE [4]. There appears to be an increased incidence of lymphomas in patients with SLE [19], but a link between these cancers and immunosuppressive therapies has not been firmly established.

Acknowledgements
Funding: This research was sponsored by a grant from LUPUS UK. This work was undertaken at UCLH/UCL, which received a proportion of funding from the Department of Healths NIHR Biomedical Research Centres funding scheme. Disclosure statement: The authors have declared no conflicts of interest.

References
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Conclusion
Our long-term study concurs with the findings of a recent European study which indicates that damage accrual is associated