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A Multiethnic, Multicenter Cohort of Patients With Systemic Lupus Erythematosus (SLE) as a Model for the Study of Ethnic Disparities in SLE

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  A Multiethnic, Multicenter Cohort of Patients WithSystemic Lupus Erythematosus (SLE) as aModel for the Study of Ethnic Disparities in SLE MO´ NICA FERNA´ NDEZ, 1 GRACIELA S. ALARCO´ N, 1 JAIME CALVO-ALE´N, 1 ROSA ANDRADE, 1 GERALD McGWIN, JR., 1 LUIS M. VILA´ , 2 AND  JOHN D. REVEILLE, 3 FOR THE  LUMINA STUDY GROUP Objective.  To examine health disparities as a function of ethnicity using data from LUpus in MInorities, NAture versusnurture (LUMINA), a longitudinal study of patients with systemic lupus erythematosus (SLE); to build an explanatorymodel of how ethnic disparities occur in this setting; and to suggest appropriate interventions.  Methods.  LUMINA patients (meeting American College of Rheumatology criteria for SLE) ages  > 16 years of AfricanAmerican, Hispanic (from Texas), Hispanic (from Puerto Rico), or Caucasian ethnicity were studied. In addition toexamining the basic features of the cohort, we examined, by univariable and multivariable analyses, the factorsassociated with disease activity, damage accrual, lupus nephritis, and mortality. An empiric model based on the datapresented (and the literature reviewed) was derived to explain the disparities observed.  Results.  There were substantial differences in the socioeconomic/demographic, clinical, and genetic features amongpatients from the different ethnic groups, with Texan Hispanic and African American patients exhibiting overall a lowersocioeconomic status, different genetic associations, more serious disease at a younger age, and worse intermediate andfinal outcomes than the Caucasian and Puerto Rican Hispanic patients. A model of disease outcome as a function of thedisparities observed was created. Conclusion.  Ethnic disparities occur in SLE. Environmental, socioeconomic/demographic, psychosocial, genetic, andclinical factors play an important role as determinants of the ethnic differences observed. Measures aimed at eliminatingthese disparities are suggested while further research is conducted to elucidate the basis of these disparities and theirchanges at the societal level and to eliminate the gap between the rich and the poor.KEY WORDS.  Systemic lupus erythematosus; Ethnicity; Disparities; LUMINA. INTRODUCTION Health disparities, as defined by the National Institute of Health (NIH) Working Group on Health Disparities, denotedifferences in the incidence, prevalence, mortality, and burden of disease and other health conditions that existamong distinct population groups in the US (by virtue of their age, race/ethnicity, sex, sexual orientation, or othercharacteristics) (1). Health disparities within differentethnic groups have been observed in musculoskeletal dis-orders (2–6), but whether these disparities relate to geneticor environmental factors or a combination of both has yetto be defined. Systemic lupus erythematosus (SLE), a dis-ease that preferentially and more seriously affects women,ethnic minorities, and young persons, can serve to studythe basis of these health disparities. Utilizing data fromLUMINA (LUpus in MInorities, NAture versus nurture), alongitudinal study of outcome in patients with SLE, we Supported by the NIH (grants R01-AR42503 from the Na-tional Institute of Arthritis and Musculoskeletal and SkinDiseases, M01-RR02558 from the General clinical ResearchCenters to the University of Texas Health Science Center atHouston, and M01-RR00032 to the University of Alabama atBirmingham), an RCMI Clinical Research InfrastructureInitiative (award 1-P20-RR-11126 to the University of Puerto Rico), the Mary Kirkland Scholar Award Program,and Fellowships from Rheuminations, Inc. (University of Alabama at Birmingham). 1 Mo´nica Ferna´ndez, MD, ScD, Graciela S. Alarco´n, MD,MPH, Jaime Calvo-Ale´n, MD, Rosa Andrade, MD, GeraldMcGwin, Jr., MS, PhD; The University of Alabama at Bir-mingham;  2 Luis M. Vila´, MD: University of Puerto RicoMedical Sciences Campus, San Juan;  3 John D. Reveille, MD:University of Texas Health Science Center at Houston.Address correspondence to Graciela S. Alarco´n, MD,MPH, 830 Faculty Office Tower, 510 20th Street South, Bir-mingham, AL 35294-3408. E-mail: graciela.alarcon@ccc.uab.edu.Submitted for publication April 28, 2006; accepted inrevised form August 23, 2006. Arthritis & Rheumatism (Arthritis Care & Research)Vol. 57, No. 4, May 15, 2007, pp 576–584DOI 10.1002/art.22672© 2007, American College of Rheumatology SPECIAL ARTICLE: DISPARITIES IN RHEUMATIC DISEASES 576   built an explanatory model of how ethnic disparities occurand suggested points at which interventions can be devel-oped; such interventions may result in effectively mini-mizing and even eliminating these disparities. To betterunderstand this model, we will first briefly describe somesalient features of this cohort. PATIENTS AND METHODS LUMINA is a multiethnic (Hispanic [Mexican or PuertoRican ancestry], African American, or Caucasian ethnic-ity), multicenter (the University of Alabama at Birming-ham, the University of Texas Health Science Center atHouston, and the University of Puerto Rico Medical Sci-ences Campus) cohort of patients with SLE (meeting theAmerican College of Rheumatology [ACR] criteria [7,8]),ages   16 years, with   5 years of disease duration (9,10).LUMINA recruitment started in 1994 except in PuertoRico, where recruitment started in 2001. The institutionalreview boards of all centers approved the study; writteninformed consent was obtained from each patient accord-ing to the declaration of Helsinki.Visits are conducted at entry into the cohort (T0), every6 months for the first year, and yearly thereafter. Time of diagnosis (TD) is the time at which patients meet 4 ACRSLE classification criteria (7). Disease duration is the in-terval between TD and T0. The cohort includes prevalentcases (  6 months since TD) and incident cases (  6months since TD) in a 2:1 proportion (9). The LUMINAdatabase is comprehensive and includes socioeconomic/demographic, clinical, immunologic, genetic, psychologi-cal, and behavioral variables. Disease activity and damageaccrual are assessed using the revised Systemic LupusActivity Measure (SLAM-R) (11) and the Systemic LupusInternational Collaborating Clinics/American College of Rheumatology Damage Index (SDI) (12), respectively. RESULTS Characteristics of the cohort.  As of January 2006, theLUMINA cohort consisted of 617 patients: 117 (19%) wereHispanics from Texas (primarily of Mexican ancestry), 103(17%) were Hispanics from Puerto Rico, 221 (36%) wereAfrican American, and 176 (28%) were Caucasian. Themajority of the patients were women (90%). As shown inTable 1, Hispanics from Puerto Rico and Caucasians wereolder at T0 and had an overall better socioeconomic status(education, income, housing, marital status, and healthinsurance) than the Hispanics from Texas and the AfricanAmericans. These socioeconomic/demographic data werecomparable with those reported in previous publications(9,10,13). Salient clinical features.  Selected clinical features aresummarized in Table 2. As published previously (14,15)and confirmed in the present study, African Americansand Texan Hispanics tend to have more serious diseasecompared with Caucasians and Puerto Rican Hispanics.For example, African Americans and Texan Hispanics ex-hibit acute disease onset and renal involvement more fre-quently. They also exhibit shorter disease duration and ashorter time to the accrual of 4 ACR criteria.Medication use is depicted in Table 2. Differences inmedication use were noted, with Puerto Rican Hispanicsand Caucasians using hydroxychloroquine more fre-quently than Texan Hispanics and African Americans(84%, 83%, 61%, and 62%, respectively;  P     0.001); thereverse occurred with glucocorticoids and cyclophospha-mide. Genetic features.  The frequency distribution of  HLA–DR  and  HLA–DQ   alleles was reexamined, and re-sults were consistent with previously published data(9,16). In short, when compared with local controls,  HLA– DRB1*0301  was found to be increased only in Caucasianpatients, whereas  HLA–DRB1*1503  was found to be in-creased only in African American patients.  HLA–DRB1*08 was found to be increased in Hispanic patients from Texas, but not Hispanic patients from Puerto Rico;  HLA– DQB1*0201  was found to be more frequent in Caucasiansand  HLA–DQB1*0602  more frequent in African Ameri-cans. These data confirm the genetic difference between Table 1. Selected baseline socioeconomic/demographic features of LUMINA (LUpus in MInorities, NAture versusnurture) patients*VariableHispanicAfrican American(n  221)Caucasian(n  176)  P  Texan(n  117)Puerto Rican(n  103) Female sex 93 95 89 85 0.032Age, mean  SD years 32.8  12.0 36.7  11.2 34.8  11.2 41.0  13.3   0.001Education, mean  SD years 10.5  3.2 14.7  2.9 12.8  2.2 13.7  2.8   0.001Married/living together 54 59 33 73   0.001Health insurance 50 99 81 87   0.001Poverty† 42 30 45 15   0.001Home ownership 53 78 50 71   0.001Exercise 40 29 46 43 0.041Smoking 12 6 14 20 0.010Drinking 9 3 9 16 0.004 * Values are the percentage unless otherwise indicated.† As defined by the US federal government guidelines (57). Disparities in SLE   577  the 2 Hispanic subgroups, and between the Hispanic sub-groups and patients from the other 2 ethnic groups.The frequency distribution of the Fc gamma receptor(FCGR) alleles was examined. Caucasian patients tendedto exhibit the homozygous high-affinity  FCGR3A  genepolymorphism ( FCGR3A*GG  ) more frequently comparedwith all other ethnic groups (16.1% versus 4.8% for TexanHispanics, 5.8% for Puerto Rican Hispanics, and 8.4% forAfrican Americans;  P     0.001); however, no differenceswere found in the distribution of   FCR2A  between thedifferent ethnic groups. The  FCGR3B  gene NA2 homozy-gous polymorphism was found to be less frequent amongTexan Hispanics than the other ethnic groups (15.7% ver-sus 38.7% for African Americans, 38.7% for Caucasians,and 25.5% for Puerto Rican Hispanics;  P   0.001).We also examined admixture using ancestral informa-tive markers (AIMs), or genes that are differentially ex-pressed among founding populations (African, European/Caucasian, and Amerindian for the US) (17), and we foundsubstantial heterogeneity within ethnic groups. For exam-ple, Texan Hispanics exhibit a much larger proportion of Amerindian ancestry (48%), followed by Puerto Rican His-panics (20%) who also have a large African ancestry(45%); this is not the case for Texan Hispanics (18%).Caucasians and African Americans exhibit   20% of an-cestral genes from the other founding population; there-fore, categorizing patients by ethnic group, even whenrequiring all 4 grandparents to be of the same group, is animperfect manner to account for the role genetic factorsmay exert in the expression of the disease in patients fromdifferent ethnic groups. Admixture should, therefore, beconsidered an adjustment variable in all analyses. Disease activity.  As noted in Table 3, Texan Hispanicand African American patients exhibited higher diseaseactivity than Caucasian and Puerto Rican Hispanic pa-tients as measured by the SLAM-R and the physicianglobal assessment. In contrast, African Americans andCaucasians assessed their disease as being more activecompared with both Hispanic groups, although the differ-ences were not significant. The discrepant perception of disease activity between patients and physicians may in-fluence patients’ behaviors.Recently, we examined the factors predictive of persis-tently high disease activity (18). A total of 2,066 patientvisits were examined. Younger age, African American andTexan Hispanic ethnicities, abnormal illness-related be-haviors, poor social support, lack of health insurance, andhigh levels of disease activity in the previous visit emergedas variables predictive of subsequent high disease activity.Interestingly, genetic markers (HLA, FCGR, and AIMs)were not associated with this outcome even when previ-ous disease activity was excluded from the srcinal model(because disease activity early in the disease had beenfound to be negatively associated with  HLA–DRB1*0301 ). Lupus nephritis.  As noted in Table 2, renal involve-ment at T0 (and during the disease course) occurred morefrequently in the African American patients (62%) andTexan Hispanic patients (62%) than in the Caucasian pa-tients (25%) and Puerto Rican Hispanic patients (26%). Inmultivariable analyses, after adjusting for total disease du-ration, these 2 ethnicities were of borderline statisticalsignificance whereas not being married, the number of ACR criteria, the presence of thrombocytopenia, and thepresence of anti–double-stranded DNA and anti-Smith an-tibodies were found to predict the occurrence of nephritis(data not shown). These analyses are consistent with thoseperformed prior to the inclusion of Puerto Rican Hispanicpatients in LUMINA (19), the exception being that thePuerto Rican Hispanics became the reference group in thepresent analysis. Table 2. Selected baseline clinical features of LUMINA (LUpus in MInorities, NAture versus nurture) patients*VariableHispanicAfrican American(n  221)Caucasian(n  176)  P  †Texan(n  117)Puerto Rican(n  103) Disease duration, mean  SD months‡ 16.4  16.0 19.2  15.7 16.3  16.5 17.7  15.6Number of ACR criteria, mean  SD 5.6  1.3 5.0  0.9 5.7  1.5 5.2  1.1   0.001Time to accrual of 4 ACR criteria,monthsMean  SD 17.7  39.9 26.9  36.9 29.1  63.7 42.9  61.7 0.001Median (range) 5.0 (0.0–245.0) 9.0 (0.0–181.0) 6.9 (0.0–543.1) 21 (0.0–352.0)Acute onset 27 4 17 9   0.001Renal involvement§ 62 26 62 25   0.001Glucocorticoid average dose,mean  SD mg10.6  19.2 10.4  14.1 12.9  18.5 5.9  11.7   0.001Glucocorticoid use¶ 91 84 95 86 0.005Hydroxychloroquine use¶ 61 84 62 83   0.001Azathioprine use¶ 10 19 17 13Cyclophosphamide use¶ 21 8 18 13 0.025 * Values are the percentage unless otherwise indicated. ACR   American College of Rheumatology.†  P   values  0.05 are noted.‡ From diagnosis to enrollment.§ Cumulative frequency.¶ At any time before baseline. 578  Ferna´ndez et al   To further examine the role that genetic factors mayhave in the occurrence of nephritis, we recently includedthe admixture data in the model. A total of 150 patientswith renal involvement were compared with 309 patientswho did not have renal involvement. Patients with renalinvolvement had larger proportions of African and Amer-indian ancestral genes than patients without renal involve-ment. In multivariable models, 36.8% of the variance wasaccounted for by admixture, 14.5% by socioeconomic sta-tus, and 12.2% by admixture and socioeconomic statuscombined. However, 45.9% of the variance in the modelremained unexplained (20). These data suggest that ge-netic factors are more important determinants of renalinvolvement than the socioeconomic factors. Damage.  As reported earlier (n  258 patients) (21), half of the current cohort of patients had yet to accrue anydamage at T0. As shown in Table 3, the SDI score washigher at T0 in the African Americans compared with allother ethnic groups; however, at the last visit the TexanHispanics had caught up with the African Americans and both groups had accrued more damage than patients in theother 2 ethnic groups. In fact, when only patients who hadyet to accrue any damage were examined, the Texan His-panics, followed by the African Americans, were the onesaccruing any damage at a faster pace (22).We examined the variables predictive of damage accrualand compared these results with data from analyses per-formed prior to the inclusion of the Puerto Rican Hispan-ics (21). Given the distribution of the damage scores, aPoisson multivariable analysis was performed, adjustingfor total disease duration. Variables found in both sets of analyses included age, Texan Hispanic ethnicity, poverty,number of ACR criteria met, disease activity at TD, and themean dose of glucocorticoids ( P   0.001 for all). Addition-ally, African American and Caucasian ethnicities weresignificantly associated with increased risk of damage ac-crual ( P     0.001) when compared with the Puerto RicanHispanics. Mortality.  Five- and 10-year survival analyses have re-cently been performed (10-year rates are not available forthe Puerto Rican Hispanics due to their late recruitment).As shown in Figure 1, the 5-year survival rates were lowerfor Texan Hispanics (86.9%) and African Americans(89.8%) than for Caucasians (93.6%) and Puerto RicanHispanics (97.2%); these differences were significant (logrank    9.687,  P     0.021). As noted in Table 4, ethnicitywas not retained in the multivariable Cox regression ana-lysis but disease activity damage, poverty, and older agewere found to significantly predict mortality; these resultsare consistent with those of our previously published ana-lyses (23). DISCUSSION SLE is undoubtedly a disease in which health disparities,as defined by the NIH (1), are clearly present because itaffects primarily one sex (women), young persons (repro-ductive age), and less-privileged individuals (ethnic mi-norities) in the US and around the world. Any of theseareas could be elaborated further, but we have chosen toemphasize primarily health disparities in lupus in relationto ethnicity. Given that LUMINA is a multiethnic cohortwe had the opportunity to compare and contrast data frompatients of the 3 main US ethnic groups: Caucasians, Af-rican Americans, and Hispanics; in addition, we providedata for 2 Hispanic subgroups, those inhabiting the islandof Puerto Rico and those of Mexican origin (the mostfrequent country of srcin for all US Hispanics) recruitedprimarily in Texas. Inclusion of Hispanics when examin-ing health disparities is quite relevant because they con-stitute the nation’s largest (14% of the total population notincluding the 3.9 million residents of Puerto Rico) and Table 3. Disease activity and damage accrual in LUMINA (LUpus in MInorities, NAture versus nurture) patients*VariableHispanicAfrican American(n  221)Caucasian(n  176)  P  †Texan(n  117)Puerto Rican(n  103) SLAM-R score at baseline visit 11.1  6.4 6.8  4.0 11.1  6.5 7.7  4.1   0.001SLAM-R score at last visit 9.4  6.0 5.4  3.3 8.5  5.8 5.5  4.4   0.001SLAM-R score over time 7.6  4.4 7.6  3.9 8.4  5.1 8.1  4.3Physician global assessment of diseaseactivity at baseline‡2.6  2.4 1.1  1.1 3.1  2.3 2.1  1.6   0.001Patient global assessment of diseaseactivity at baseline‡3.4  3.0 3.5  2.8 3.9  3.0 3.8  2.6Discrepancy at baseline§ 0.8  2.8 2.3  2.6 0.8  3.0 1.7  2.7   0.001SDI  0 at baseline visit, % 37 23 49 40   0.001SDI  0 at last visit, % 70 35 74 58   0.001SDI at baseline 0.6  1.0 0.3  0.6 1.0  1.4 0.7  1.1   0.001SDI at last visit 2.2  2.6 0.5  0.9 2.3  2.5 1.4  1.7   0.001 * Values are the mean  SD unless otherwise indicated. SLAM-R  Systemic Lupus Activity Measure revised; SDI  Systemic Lupus InternationalCollaborating Clinics/American College of Rheumatology Damage Index.†  P   values  0.05 are noted.‡ Using a 10-cm visual analog scale.§ Between patient and physician global assessments visual analog scale. Disparities in SLE   579
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