Systemic lupus erythematosus in three ethnic groups. XX. Damage as a predictor of further damage
G. S. Alarcón,
J. M. Roseman1,
G. McGwin, Jr1,2,
A. Uribe,
H. M. Bastian,
B. J. Fessler,
B. A. Baethge3,
A. W. Friedman4 and
J. D. Reveille4 for the LUMINA Study Group
Departments of Medicine (Division of Clinical Immunology and Rheumatology), 1Epidemiology and 2Surgery (Section of Trauma, Burns, and Critical Care), Schools of Medicine and Public Health, University of Alabama at Birmingham, Birmingham, AL, 3Department of Medicine (Division of Rheumatology), University of Texas Medical Branch at Galveston, Galveston, TX and 4Department of Medicine (Division of Rheumatology and Clinical Immunogenetics), University of Texas-Houston Health Science Center, Houston, TX, USA. For a complete list of current LUMINA investigators and staff, see below.
Correspondence to: G. S. Alarcón, 615 MEB, University of Alabama at Birmingham, Birmingham, AL 35294, USA. E-mail: graciela.alarcon{at}ccc.uab.edu
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Abstract
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Objective. To examine the predictors of damage in a multiethnic cohort of systemic lupus erythematosus (SLE) patients with a specific focus on damage at baseline.
Patients and methods. SLE patients from a multiethnic US (Hispanic, African-American and Caucasian) cohort (LUMINA: Lupus in Minority populations, Nature versus nurture) were included if they had
6 months of follow-up in the cohort. Damage was measured with the Systemic Lupus International Collaborating Clinics (SLICC) Damage Index (SDI). The dependent variable was the change in SDI score between study visits. Predictors were from the preceding visit. Variables known to affect damage accrual in SLE were included in the analyses.
Results. Three hundred and fifty-two patients (82 Hispanics, 153 African-Americans and 117 Caucasians) representing 1795 patient visits were included. Previous damage was found to be a significant predictor of subsequent damage accrual (P < 0.0001). Other variables predictive of subsequent damage accrual were disease activity (P < 0.0001), older age (P = 0.041) and use of corticosteroids (P = 0.0048).
Conclusions. Once damage occurs in SLE, further damage is expected to occur. This is more likely to be the case if disease activity persists. These data have clinical implications for the management of SLE patients.
KEY WORDS: Lupus, Damage, Ethnicity, Outcome, Predictors.
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Introduction
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Regardless of the period of time one chooses to examine, the outcome of patients with systemic lupus erythematosus (SLE) has improved considerably [1]. Damage occurring as a consequence of the disease or its treatments, rather than survival, has thus become a standard outcome measure in longitudinal SLE studies [27]. We have previously shown the variables associated with the occurrence of damage in a multiethnic (Hispanic, African-American and Caucasian) US cohort of patients with SLE with disease duration
5 yr [8]. These variables include older age, corticosteroid use, number of American College of Rheumatology (ACR) criteria (or weighted criteria), disease activity, acute onset type and abnormal illness-related behaviours [8, 9]. We also noted that Hispanics tended to accrue damage more rapidly than non-Hispanics [8].
Stoll et al. [10], in a predominantly Caucasian cohort of 140 lupus patients, have shown that the occurrence of damage is a risk factor for further damage, as examined 3 yr later; likewise, Gilboe et al. [11] studied 87 Caucasian lupus patients at two time points (2 yr apart) and found damage to be a risk factor for later damage. These findings, if demonstrated in different patient samples, have obvious implications for the management of the SLE patient. We therefore present such analyses in this multiethnic lupus cohort to examine the predictors of subsequent damage with a specific focus on damage at baseline.
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Patients and methods
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LUMINA (Lupus in Minority populations, Nature versus nurture) is a longitudinal study of outcome of patients from the three major ethnic groups residing in the USA (Hispanic, African-American and Caucasian). The constitution of this cohort, the variables obtained and the frequency of the study visits have been described previously [1214]. Briefly, patients with SLE according to the revised ACR criteria [15] and with disease duration
5 yr, residing in the geographical catchment areas of the participating institutions (University of Alabama at Birmingham, University of Texas-Houston Health Science Center and University of Texas Medical Branch at Galveston) and of defined ethnicity were eligible to participate. The LUMINA study has been approved by the Institutional Review Boards for the Protection of Human Subjects of the participating institutions.
Prior to the enrolment or baseline visit (T0), all available medical records were reviewed to confirm the patient's eligibility and to abstract pertinent clinical and sociodemographic data from the time of diagnosis (TD) to T0. TD was defined a priori as the time at which a patient met four ACR criteria, and disease duration at T0 was defined as the interval between TD and T0.
Variables
As noted previously [12], variables from the socioeconomicdemographic, clinical and immunological, immunogenetic, behavioural, psychological and cultural domains were obtained. The following variables were included in the analyses presented in this paper: age, gender, ethnicity (same as that of the four grandparents), disease onset type (acute vs insidious), ACR criteria [15], disease activity [using the Systemic Lupus Activity Measure (SLAM)] [16, 17], disease damage [using the Systemic Lupus International Collaborating Clinics (SLICC) Damage Index (SDI)] [24], medication use, hospitalization data, self-reported functioning/health-related quality of life (HRQOL) [according to the Short Form-36 (SF-36) physical and mental component summary measures (PCS and MCS respectively)] [18, 19].
Study visits
Study visits were conducted every 6 months for the first year and yearly thereafter.
Statistical analyses
Only patients with at least 6 months of follow-up and with disease duration >6 months at T0 were included in these analyses. Independent variables included age, gender, ethnicity and the following variables previously found to be important predictors of damage, as measured at the preceding study visit: disease activity (SLAM), medication intake (corticosteroid and hydroxychloroquine) and ACR criteria [8]. The dependent variable was the change in SDI score between study visits. For example, for a patient with SDI scores of 0 at T0, 0 at year 1 (T1) and 2 at year 2 (T2), the dependent variable (SDI scores) for the first (T1) and second (T2) records would have values of 0 and 2 respectively; the independent damage variable associated with these records would be drawn from T0 and T1 and would therefore be 0 in both cases. Thus, the independent variables reflect information at the visit immediately preceding the SDI score being assessed. Because patients could contribute more than one observation, generalized estimating equations (GEEs) were used in these analyses. The regressions were performed with and without the SF-36, including its eight subscales, and the PCS and MCS [19]. These variables were included in the analyses because of their possible modifying effect on damage accrual [10]. The odds ratio (OR) calculated for each variable using GEEs is assumed to hold constant across all years of the study. Therefore, after the modelling procedure had been carried out the interaction between the clinical variables and time was assessed by introducing a multiplicative term into the GEE model. Because many variables necessary for the statistical analyses contained a substantial number of missing observations, multiple imputation (n = 5) was used to create values for missing observations using the Markov chain Monte Carlo method [20]. This technique was chosen rather than several other alternatives given that the pattern of missing data tended to be predominantly arbitrary rather than monotone. Values were imputed using known values for the PCS and MCS and the eight subscales of the SF-36, and for disease activity and medication intake. The study results were very similar whether subjects with imputed data were included or excluded from the analyses. All analyses were done with SAS version 8.1 (SAS Institute, Cary, NC, USA).
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Results
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The baseline features of the LUMINA cohort have been described in detail previously [14]. As shown in Table 1, the baseline characteristics of the LUMINA patients included in these analyses (n = 352; 82 Hispanics, 153 African-Americans and 117 Caucasians) were comparable to those of the entire cohort and to those not included; the majority of the patients (91%) were women, their mean (S.D.) age was 37 (13) yr and their mean (S.D.) disease duration was 18 (16) months. Their mean (S.D.) SLAM scores at TD and at T0 were 11.7 (6.5) and 9.8 (5.5) respectively; their mean (S.D.) SDI score at T0 was 0.9 (1.2) and their mean (S.D.) T0 PCS and MCS scores were 34.3 (11.7) and 43.7 (11.3) respectively.
Disease activity (SLAM scores), damage accrual (SDI scores), self-reported health-related quality of life (SF-36 PCS and MCS) and medication use over the follow-up period are shown in Table 2. These features were stable over time with the exception of disease activity, which tended to decrease, and damage, which tended to increase. The maximum dose of corticosteroids also tended to decrease over time but the proportion of patients using them remained stable. A total of 1795 visit intervals were included in the analyses; there were 498 intervals in the Hispanics, 729 in the African-Americans and 568 in the Caucasians. Thirty-seven per cent of the intervals occurred between T0 and T1, 28% between T1 and T2, 11% between T2 and T3, 9% between T3 and T4, 7% between T4 and T5, 5% between T5 and T6, and 2% between T6 and T7. The proportion of intervals was comparable for patients in the three ethnic groups (data not shown).
Table 3 shows the data from the longitudinal analysis. As can be appreciated, previous damage was a very significant (P < 0.0001) and strong predictor of the occurrence of subsequent damage in this multiethnic cohort of lupus patients. Other variables predictive of damage accrual included older age (P = 0.041), disease activity (P < 0.0001) and the use of corticosteroids (P = 0.0048). Ethnicity, ACR criteria and use of hydroxychloroquine were not retained in the model. Likewise, time, as described in the Patients and methods section, was not retained in the model. In the regression in which the SF-36 variables were included, the variables retained were the same as in the regression shown in Table 3, although the parameter estimates and Z statistic values were slightly different. Neither the PCS nor the MCS measures of the SF-36 were retained in the model; however, when the eight subscales were included, Role Physical, but not the other seven subscales, was retained in the model (P = 0.0031) (data not shown).
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Discussion
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Using the LUMINA database in its entirety, we have been able to determine the extent to which previous damage predicts the occurrence of further damage in the course of SLE. The longitudinal approach allowed us to utilize all patient visits, to take into consideration disease duration (a variable expected to explain damage accrual to a certain extent) and to consider simultaneously the three ethnic groups. Indeed, and as shown in Table 3, the existence of previous damage was a very important factor explaining further damage in these patients. These data are particularly relevant if we consider that hydroxychloroquine has been shown by us and by others to have a protective effect in terms of damage in patients with SLE [2123]. The protective effect of hydroxychloroquine may be attenuated significantly once damage has already occurred. Hispanic ethnicity was not retained in the models. This suggests that it is not ethnicity per se that is responsible for the rapid progression we have observed among the Hispanic patients, but other, unidentified factor(s). Our analyses concur with the data from Stoll et al. [10] and Gilboe et al. [11] regarding the importance of previous damage. As in the study by Gilboe et al. [11], in our patients disease activity remained a very important factor explaining later damage. The fact that disease activity was not an important factor in predicting later damage in the study of Stoll et al. may have more to do with the relatively modest disease activity of their patients compared with ours, the different instruments used, or the different analytical methods employed.
Role Physical, but not the summary measures of the SF-36, was predictive of subsequent damage, whereas in the study by Stoll et al. [10], using the amended version of the SF-20 (which includes a specific question on fatigue), general health perception was associated with further damage accrual. Although the SF-20 and the SF-36 have been shown to be highly correlated [24], the SF-36 does not include a construct comparable to the SF-20's general health perception, making our data and those from Stoll et al. [10] difficult to compare. Moreover, the SF-36 has been proposed as the instrument of choice for the assessment of HRQOL in SLE [25]. A significant number of visit intervals from patients who did not have at least 6 months of follow-up (n = 99) could not be included in the analyses presented. However, given the fact that patients not included in these analyses had, by and large, similar features to those who were included, we think our data are probably valid. We also think that our analytical approach is more powerful than that used by Stoll et al. as we utilized the entire longitudinal database, examined three different ethnic groups, and used the variables that were present during the previous visits to assess their effect on the accrual of damage occurring over subsequent visit intervals. Of importance, our overall results do not merely reflect the interaction between time in the cohort and other pertinent characteristics, as this interaction variable was not retained in the different models examined.
In summary, our findings highlight the importance of identifying patients at risk of developing organ system damage early in the course of their disease. SLE patients accruing any damage should be viewed as patients potentially capable of subsequent irreversible organ system dysfunction as a result of persistent or recurrent bouts of disease activity or of the therapies used to lessen the effects of such events. Given this reality, there is a need to exercise a proper therapeutic balance in which patients are treated aggressively during periods of disease exacerbation (and to prevent flares), but not to the point of producing irreversible consequences. Perhaps as important as using a drug such as cyclophosphamide for the treatment of severe lupus manifestations will be the use of hydroxychloroquine, which may prevent the occurrence of any damage at disease onset as well as the occurrence of subsequent flares [21]. It is also hoped that upcoming new therapies will have a better efficacy/toxicity ratio than those currently in use, and will inflict less damage on our SLE patients.
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Acknowledgments
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We are grateful to our patients, without whom this study would not have been possible, and to Ella Henderson for her most expert technical assistance in the preparation of this manuscript. This work was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Disorders (grant R01-AR42503) and the General Clinical Research Center [grants M01-RR02558 (UTH-HSC), M01-RR00073 (UTMB) and M01-RR00032 (UAB)].
Conflict of interest
The authors have declared no conflicts of interest.
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Notes
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Current LUMINA investigators and staff: (University of Alabama at Birmingham) G. S. Alarcón, H. M. Bastian, B. J. Fessler, G. McGwin Jr, J. Roseman, S. Toloza, A. G. Uribe, B. S. Agee, M. L. Sanchez, E. Sowell and B. Johnson; (University of Texas-Houston Health Science Center) J. D. Reveille, A. W. Friedman, K. Ho, C. Ahn, R. Sandoval, J. Charles and L.-L. Wang; (University of Texas Medical Branch at Galveston) B. A. Baethge and S. Hunnicutt; (University of Puerto Rico Medical Sciences Campus) L. M. Vilá, W. Borges and C. Pinilla. 
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Submitted 11 February 2003;
Accepted 3 July 2003