Early clinical manifestations, disease activity and damage of systemic lupus erythematosus among two distinct US Hispanic subpopulations
L. M. Vilá,
G. S. Alarcón1,
G. McGwin, Jr2,
A. W. Friedman3,
B. A. Baethge4,
H. M. Bastian1,
B. J. Fessler1 and
J. D. Reveille3 for the LUMINA Study Group
Department of Internal Medicine, Division of Rheumatology, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico, 1Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, 2Department of Surgery, Section of Trauma, Burns, and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama, 3Department of Medicine, Division of Rheumatology and Clinical Immunogenetics, University of TexasHouston Health Science Center, Houston, Texas and 4Department of Medicine, Division of Rheumatology, University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
Correspondence to: L. M. Vilá, Division of Rheumatology, University of Puerto Rico, Medical Sciences Campus, PO Box 365067, San Juan, PR 009365067, USA. E-mail: lvila{at}rcm.upr.edu
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Abstract
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Objectives. To compare the baseline clinical manifestations, immunological features, disease activity and damage accrual in systemic lupus erythematosus (SLE) patients from two US Hispanic subgroups.
Methods. A total of 105 Hispanic SLE patients from Texas (a population of Mexican or Central American ancestry) and 81 from the island of Puerto Rico (all Puerto Ricans) participating in a longitudinal study of outcome were examined. The socio-economic/demographic, clinical and immunological variables were obtained at the time of enrolment (T0). Disease activity was determined with the Systemic Lupus Activity Measure (SLAM), and disease damage with the Systemic Lupus International Collaborating Clinics (SLICC) Damage Index (SDI). Disease activity was also determined at the time of diagnosis (TD).
Results. At T0 Hispanics from Texas were younger than those from Puerto Rico (33.1 ± 12.0 vs 37.5 ± 11.6 yr, P = 0.0125). Both groups were similar with regard to gender distribution (92.4 vs 95.1% females) and disease duration (1.4 ± 1.4 vs 1.7 ± 1.3 yr). Hispanics from Texas were more likely to have serositis (60.0 vs 8.6%, P < 0.0001), renal involvement (41.0 vs 13.6%, P < 0.0001), psychosis (5.7 vs 0.0%, P = 0.0365) and thrombocytopenia (21.0 vs 3.7%, P = 0.0006). On the other hand, Hispanics from Puerto Rico were more likely to have photosensitivity (81.5 vs 41.0%, P < 0.0001), malar rash (65.4 vs 45.7%, P = 0.0074) and discoid rash (13.6 vs 2.9%, P = 0.0060). At baseline, the presence of anti-dsDNA antibodies was higher in Hispanics from Texas (69.5% vs 46.9%, P = 0.0018) while anti-Ro antibodies were more frequent in Hispanics from Puerto Rico (24.7 vs 11.4%, P = 0.0175). Mean SLAM scores at TD (12.9 ± 6.4 vs 9.1 ± 4.6, P < 0.0001) and T0 (10.9 ± 6.3 vs 6.6 ± 3.8, P < 0.0001) were significantly higher in Hispanics from Texas. Similarly, mean SDI scores at T0 were higher in Hispanics from Texas (0.67 ± 1.08 vs 0.26 ± 0.54, P = 0.0026). By stepwise Poisson regression, SDI scores were associated with older age, disease activity and ethnicity (Hispanics from Texas).
Conclusions. Early in SLE, marked differences are observed between Hispanics from Texas and Puerto Rico. Higher disease activity, more major organ involvement, higher frequency of anti-dsDNA antibodies and more damage accrual occur in Hispanic lupus patients from Texas than in those from Puerto Rico.
KEY WORDS: Systemic lupus erythematosus, Hispanics, Ethnicity, Damage, Activity.
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Introduction
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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a wide spectrum of clinical and immunological abnormalities [1]. Genetic, environmental and sociodemographic factors play important roles in the pathogenesis and expression of this disease [24]. This multiplicity of aetiological factors could explain the variability of disease manifestations observed, not only between individuals, but also between ethnic groups [57]. The understanding of the distinctive manifestations, course and outcome of SLE among different ethnic groups could lead to a better understanding of the factors which contribute to these differences as well as to the delivery of better medical care to these populations.
Differences in SLE expression also appear to occur among Hispanic subpopulations [810]. For example, a comparison of the clinical manifestations and serological features of SLE Puerto Rican patients living in the island and SLE Colombian patients showed that Puerto Ricans present more frequently with cutaneous manifestations and less frequently with serositis, renal and/or neurological involvement and anti-RNP antibodies than Colombians [10]. In general, Hispanics in the American continent are a population whose ancestors can be traced to European (mostly Spaniard), African and Amerindian heritage. However, the proportion of these ancestries may vary substantially between Hispanic subpopulations [11]. This genetic variability, together with differences in sociodemographic and environmental factors, may explain the diversity in disease expression between Hispanic subgroups. To date, no studies have been performed simultaneously and systematically to assess the demographic, clinical and immunological features of SLE in patients from different Hispanic subgroups.
LUMINA (Lupus in Minority Populations: Nature versus Nurture) is a longitudinal study of SLE to determine the relative contributions of immunogenetic, clinical, sociodemographic and psychosocial factors to the course and outcome of SLE in three ethnic populations: Hispanics, African Americans and Caucasians. Initially, the participants were studied at two geographical locations: Alabama and Texas. Hispanic patients were predominantly of Mexican ancestry. Mexicans are the largest Hispanic subpopulation in the US, followed by Puerto Ricans [12]. In order to study another Hispanic subgroup, participants from Puerto Rico have been recruited to the LUMINA study, beginning in 2001. In the present study, we compare the baseline socio-economic, clinical and immunological features, disease activity and damage accrual of SLE between Hispanic patients from Texas and those from Puerto Rico.
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Patients and methods
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Patients
The eligibility and enrolment of patients, patient's evaluation and follow-ups, and data collection into LUMINA have been described in detail before [57]. Briefly, patients who meet at least four of the 11 American College of Rheumatology (ACR) classification criteria for the diagnosis of SLE [13] and who have disease duration of
5 yr at enrolment are eligible to participate. Hispanic patients of Mexican or Central American ancestry are enrolled primarily at The University of TexasHouston Health Science Center and The University of Texas Medical Branch at Galveston, and if available, at The University of Alabama at Birmingham. Hispanics from the island of Puerto Rico (all Puerto Ricans) were initially enrolled at the Universidad Central del Caribe at Bayamón, Puerto Rico, but beginning in September 2002 the enrolment and follow-up of participants have continued at The University of Puerto Rico Medical Sciences Campus in San Juan, Puerto Rico. The Institutional Review Board of each participating centre approved the LUMINA study, and written informed consent was obtained from each subject according to the declaration of Helsinki.
Of the 81 enrolled Hispanics from Puerto Rico, 38 patients were recruited from the lupus clinics at the public facilities of the Ramón Ruiz Arnau University Hospital in Bayamón, Puerto Rico and the University of Puerto Rico Medical Sciences Campus in San Juan, Puerto Rico and 43 patients were recruited from the private rheumatology practice of Dr Vilá in San Juan, Puerto Rico. Bayamón and San Juan are contiguous cities that are part of the Puerto Rico metropolitan area. The patients enrolled represent not only the clinical spectrum of SLE but also the socio-economic heterogeneity of this island's population. As previously described, Hispanic patients from Texas were recruited from those attending the affiliated practices of the University of TexasHouston Health Science Center and The University of Texas Medical Branch at Galveston, as well as from the rheumatology practices in Harlingen and Corpus Christi. Thus, the Hispanic patients recruited in Texas also encompass the clinical spectrum of the disease and the socio-economic heterogeneity of the population.
Prior to enrolment, all previously available medical records are reviewed to confirm the patient's eligibility and to gather sociodemographic and relevant clinical data from the time of diagnosis to enrolment. The time of diagnosis (TD) is defined as the time at which a patient meets four ACR criteria for SLE. Disease duration is defined as the interval between TD and time of enrolment or T0.
Variables
Structured questionnaires are completed for each patient at T0 to gather information from the following domains: socio-economic/demographic, clinical and immunological. Socio-economic/demographic variables include age, gender, ethnicity (same as that of the four grandparents), marital status, housing (ownership), income adjusted to the number of household inhabitants, education, health insurance, and unhealthy behaviours such as cigarette smoking, alcohol consumption and use of recreational drugs. Clinical manifestations are defined as per ACR criteria for the classification of patients with SLE [13]. Cumulative clinical features are recorded at T0. Immunological variables include antinuclear (ANA), anti-dsDNA, anti-Smith, anti-Ro and antiphospholipid (IgG or IgM) antibodies. Also recorded are disease activity according to the Systemic Lupus Activity Measure (SLAM) [14, 15] and disease damage according to the Systemic Lupus International Collaborating Clinics (SLICC) Damage Index (SDI) [16]. Prior to initiation of the study in Puerto Rico, the investigator at that site was trained in the application of the SLAM and SDI by a LUMINA investigator who was already familiar with them. A calibration exercise between these two investigators was completed prior to the recruitment of study patients in Puerto Rico.
Statistical analyses
First, descriptive analyses were performed to compare the socio-economic/demographic, clinical and immunological features and disease activity and disease damage among Hispanics from Texas and those from Puerto Rico. The relationship between T0 variables was examined by Pearson's correlations, Student's t-tests or
2-tests, as appropriate. Next, the baseline factors associated with damage accrual were examined by stepwise Poisson regression with all variables previously found to be significantly associated with damage accrual entered into the model. A significance level of 0.05 was used for the descriptive analyses as well as for the regression. Data were analysed using the SAS statistical software package (SAS Institute, Cary, NC).
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Results
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These analyses included all 105 Hispanic patients from Texas and all 81 Hispanic patients from Puerto Rico. Table 1 shows the socio-economic/demographic features in the study groups. At T0, Hispanics from Texas were younger than those from Puerto Rico (33.1 ± 12.0 vs 37.5 ± 11.6 yr, P = 0.0125). Gender distribution and disease duration were similar in both groups. The socio-economic status was lower in Hispanics from Texas. They had lower annual family income (below poverty line, 44.0 vs 28.4%, P = 0.0306) and fewer years of education (10.5 ± 3.3 vs 14.7 ± 3.1 yr, P < 0.0001) than Puerto Ricans. Also, Hispanics from Texas were less likely to to be homeowners (54.4 vs 78.8%, P = 0.0006), and to have medical insurance (49.0 vs 98.2%, P < 0.0001). No significant differences were found in cigarette smoking, alcohol consumption or use of recreational drugs.
Selected cumulative clinical manifestations at T0 are shown in Table 2. Initially, Hispanics from Texas were more likely to have serositis (60.0 vs 8.6, P < 0.0001), renal involvement (41.0 vs 13.6%, P < 0.0001), psychosis (5.7 vs 0.0%, P = 0.0365) and thrombocytopenia (21.0 vs 3.7%, P = 0.0006), while Hispanics from Puerto Rico were more likely to have photosensitivity (81.5 vs 41.0%, P < 0.0001), malar rash (65.4 vs 45.7%, P = 0.0074) and discoid rash (13.6 vs 2.9%, P = 0.0060). Except for thrombocytopenia, which was more frequent in the Hispanics from Texas, haematological manifestations were similar in both groups. No significant differences were found with regards to oral ulcers and arthritis.
Differences in the profile of autoantibodies at T0 were also found (Table 3). Hispanics from Texas were more likely to have anti-dsDNA (69.5 vs 46.9%, P = 0.0018), while Hispanics from Puerto Rico were more likely to have anti-Ro antibodies (24.7 vs 11.4%, P = 0.0175). Hispanics from Texas also had a higher tendency to present anti-Smith antibodies (26.7 vs 16.1%, P = 0.0833). The presence of ANA and antiphospholipid antibodies was similar in both groups.
We examined if the higher prevalence of anti-Ro antibodies in Hispanics from Puerto Rico could be related to secondary Sjögren's syndrome. However, that was not the case as Hispanics from Texas were more likely to have symptoms and objective signs of ocular (27.6 vs 12.4%, P = 0.0112) and oral dryness (36.2 vs 12.4%, P = 0.0002) than Hispanics from Puerto Rico. Furthermore, anti-Ro antibodies were found positive in 17 Hispanics from Texas compared with only one Hispanic from Puerto Rico who had sicca manifestations (P = 0.0184).
Striking differences of disease activity and damage were observed among Hispanics from Texas and those from Puerto Rico despite comparable disease duration at T0 for the two groups. Over half (53.5%) of Hispanics from Texas presented with acute disease onset (time interval between onset of symptoms and diagnosis of SLE
1 month) while most Hispanics from Puerto Rico had insidious disease onset. Initially, Hispanics from Texas presented with higher disease activity. SLAM scores at TD (12.9 ± 6.4 vs 9.1 ± 4.6, P < 0.0001) and T0 (10.9 ± 6.3 vs 6.6 ± 3.8, P < 0.0001) were higher in the Hispanics from Texas. Similarly, at T0 more damage had accrued in the Hispanics from Texas than in the Hispanics from Puerto Rico (SDI mean score: 0.67 ± 1.08 vs 0.26 ± 0.54, P = 0.0026). These data are depicted in Table 4.
In the stepwise Poisson regression, variables that independently and significantly associated with SDI scores at T0 included older age, disease activity and ethnicity (Hispanics from Texas). The results are shown in Table 5. Socio-economic variables (education, income and health insurance) were not retained in the model.
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TABLE 5. Variables independently associated with baseline (T0) SDI scores in Hispanic SLE patients by stepwise multivariable Poisson regression analysis
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Discussion
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This study shows marked differences of the early SLE clinical manifestations, disease activity and damage accrual between US Hispanics of Mexican and Central American ancestry and Puerto Rican patients residing in the island. Hispanics from Texas presented more often with serositis, renal involvement, psychosis and thrombocytopenia, while Hispanics from Puerto Rico had more photosensitivity, malar rash and discoid lupus. In addition, Hispanics from Texas had greater disease activity and damage than Puerto Ricans.
The results here are in agreement with previous studies from our group [57, 10, 17, 18]. Comparisons between US Hispanics of Mexican and Central American ancestry, African Americans and Caucasians with SLE showed that Hispanics have disease as severe as the African Americans, and less severe than Caucasians, regarding organ system involvement, disease activity and outcome [57, 17, 18]. On the other hand, a study performed in a cohort of 134 Puerto Rican patients with SLE, from the public and private practices of the first author while at the Universidad Central del Caribe, showed that they present with a mild form of disease, mainly manifested by cutaneous and musculoskeletal involvement, lower frequency of major organ damage and a low mortality rate [10]. As in the current study, serositis, renal and neurological involvement were found to be relatively infrequent in these Puerto Rican patients [10]. Moreover, a comparison of this cohort with other populations with similar disease duration and length of follow-up showed that Puerto Ricans had more photosensitivity and malar rash and less serositis and renal involvement than populations from the US, Curacao, Europe, Spain and Colombia [10]. This Puerto Rico cohort data, however, cannot be directly compared with the data from the current study because the first presents cumulative data for a mean disease duration of 7.4 yr whereas the data presented now are data at enrolment with a mean disease duration of 1.7 yr.
The higher SDI scores observed in Hispanics from Texas early in the disease course are probably related to the higher frequency of major organ involvement, specifically renal involvement among these patients, as well as overall higher levels of disease activity. These findings are consistent with previous studies from our group that show that Hispanics of predominantly Mexican ancestry accrue damage more rapidly than African Americans and Caucasians [18]. On the other hand, Hispanics from Puerto Rico exhibited less early damage accrual, similar to what we have observed in Caucasians [18] and in SLE patients from Spain who present with low SDI at baseline and who accumulate damage slowly over time [19].
The autoantibody profiles seen in Hispanics from Texas and from Puerto Rico are consistent with the differences observed in the clinical presentation of the disease. For example, higher frequencies of anti-dsDNA antibodies probably reflect the higher frequency of renal involvement among the Hispanics from Texas than those from Puerto Rico. Anti-dsDNA antibodies appear to cross-react with glomerular structural proteins and are found in the urine and serum (IgG1 and IgG3) of patients with lupus nephritis [2022]. On the other hand, the higher frequency of anti-Ro antibodies in the Hispanics from Puerto Rico compared with those from Texas probably relates to the higher frequency of photosensitivity in Puerto Ricans. Anti-Ro antibodies are associated with a variety of cutaneous lesions in SLE patients [2325], but specifically with photosensitivity [25].
The differences observed among Hispanic lupus patients from Texas and patients from the island of Puerto Rico appear to be mediated by several factors, including genetic, environmental and sociodemographic. Both Hispanic subgroups are populations of mixed ethnicity, mainly of Western European, African and Amerindian ancestry. However, the influences of each ethnicity vary among these ethnic groups. The Amerindian ancestry predominates in the Hispanics from Texas; that is not the case for Puerto Rico where the native population was decimated in the sixteenth century after the arrival of the Spaniards into the island [10, 26]. Some studies, however, suggest that the Amerindian contribution to the gene pool of Puerto Ricans may be much higher than expected [26]. Also, there are substantial differences among Hispanics from Texas and Puerto Rico in the specific components of the indigenous populations (e.g. Aztecs and Mayas in Mexico, among several others, and Taínos in Puerto Rico) that mixed with the Spaniards and the Africans. We are now in the process of ascertaining the African, Amerindian and Caucasian gene pool of our LUMINA patients and should, in due course, be able to determine the extent to which genetic admixture (African or Amerindian) contributes to the differences in disease expression and outcome between Hispanics from Texas and those from Puerto Rico.
It is not surprising that Hispanics from Puerto Rico have more cutaneous manifestations than Hispanics from Texas. Given the geographical location of the island of Puerto Rico (18.1° north and 66.3° west in the Caribbean Sea), SLE patients are exposed to a great intensity of ultraviolet light (UV) all year long. In fact, according to the US National Weather Service, in 2001 the reported UV index for San Juan, Puerto Rico was high (79) or very high (
10) during 87% of the year, whereas in Houston, Texas it was only 39.7%. The UV index is calculated based on the latitude, day of year, total ozone in the atmosphere above, elevation and what the predicted cloud conditions will be at solar noon time [27]. UV light is well known to aggravate or even induce cutaneous lupus [28, 29]. Exposure to UVA and UVB results in pathological skin reactions in most patients with SLE, which are more severe in those patients with anti-Ro and anti-La antibodies [28]. Moreover, sunlight exposure in SLE can result not only in worsening and induction of cutaneous lesions, but also in the induction of other manifestations such as constitutional and musculoskeletal symptoms [29].
Socio-economic factors could also mediate the variations in disease activity and damage observed in the current study. There is ample evidence that lower socio-economic status is related to higher morbidity and mortality in SLE and other diseases [57, 17, 18, 3032]. Here, Hispanics from Texas exhibited lower levels of education, family income and home ownership. Most importantly, almost all Puerto Ricans had health insurance compared to only half of the Hispanics from Texas. Several studies have shown less disease activity in SLE patients with health insurance than in those without it [31, 32]. In addition, a long-term study showed that survival of SLE patients was significantly higher in patients with private medical insurance [33].
In Puerto Rico, SLE patients receive their medical care either from a private insurance based on fee for service or a public insurance based on managed care [34]. Those patients who cannot afford private health insurance are covered by the government health system. The availability of health insurance for almost all the Puerto Rican population definitely has an overall positive impact on their health status in general, and probably on the outcome of specific disorders, lupus included. However, when we entered the socio-economic variables into the regression analyses none became significant. Ethnicity remained the most significant variable.
We must emphasize, however, that all Puerto Rican patients studied here are residents of the island and not of the continental US. Puerto Ricans living in the continental US may have more serious disease manifestations, although published data are scarce and probably biased [3537]. Thus, no firm conclusions about disease characteristics among Puerto Rican patients living in the island and Puerto Ricans living in the continental US can be drawn from this study or from the available literature. For once, there is not a similarly constituted cohort of Puerto Rican patients from the continental US. The available data from New York City, for example, either purposely excluded Puerto Rican patients (based on differences in incidence and age distribution), or have been derived from hospitalized patients as well as from death certificates, with particular emphasis given to possible different mortality rates due to lupus in Puerto Ricans vs Caucasians [3537]. It is also difficult, if not impossible, to compare our study and its results with the data from López-Acuna et al. [38] that showed a slight increase in the age-adjusted mortality for Puerto Rican SLE patients living in the island when compared with US Caucasians. First, their data have been presented only in abstract form and thus are difficult to interpret. Second, their data correspond to the years 19691977 whereas our data are contemporary, with overall better socio-economic status and health-care delivery now than in the past. Third, it is unclear how the rates for Puerto Rican patients or patients of Puerto Rican heritage compare with other Hispanic subgroups in the US.
In summary, at baseline presentation, Hispanic SLE patients of Mexican and Central American ancestry appear to have more severe disease than Puerto Rican patients from the island, having major organ involvement more frequently and greater disease activity and damage accrual. This diversity appears to be a reflection of the great variability that exists between these populations with regards to their genetic, environmental and sociodemographic backgrounds. Furthermore, this study emphasizes the importance of studying Hispanics with SLE not only as a group but also within their particular individual ethnicities.
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Acknowledgments
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This study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases #R01-AR42503, General Clinical Research Center #M01-RR02558 (UTH-HSC), M01-RR00073 (UTMB) and M01-RR00032 (UAB) and from the National Center for Research Resources (NCRR/NIH) RCMI Clinical Research Infrastructure Initiative (RCRII) award #1P20 RR11126 (UPR-MSC).
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Submitted 27 June 2003;
Accepted 21 August 2003