Prevalence and factors associated with Lupus Nephritis in Venezuelan patients.
Isabel F. AponteMDCentro Nacional de Enfermedades Reumáticas, Hospital Universitario de Caracas[email protected]ORCID:0000-0002-5558-8820
María V. García-FrancisMDCentro Nacional de Enfermedades Reumáticas, Hospital Universitario de Caracas, Venezuela[email protected]ORCID:0000-0002-8964-3189
Javier A. García-BecerraMDCentro Nacional de Enfermedades Reumáticas, Hospital Universitario de Caracas, Venezuela[email protected]ORCID:0000-0001-6183-6870
Yurilis J Fuentes-SilvaMDCentro Nacional de Enfermedades Reumáticas, Hospital Universitario de Caracas, Venezuela[email protected]ORCID:0000-0002-5915-769X
Daniela B. Tovar-BastidasMDCentro Nacional de Enfermedades Reumáticas, Hospital Universitario de Caaracas[email protected]ORCID:0000-0002-2544-6741
Jessica C. Nieto - BarriosMDCentro Nacional de Enfermedades Reumáticas, Hospital Universitario de Caaracas[email protected]ORCID:0000-0002-3028-2550
Soham Al SnihMD, PhDDivision of Rehabilitation Sciences/School of Health Professions, Division of Geriatrics and Palliative Medicine, Sealy Center on Aging, The University of Texas Medical Branch, Galveston, TX, US[email protected]ORCID:0000-0002-0681-4641
Martin A. RodriguezMDSealy Center on Aging, The University of Texas Medical Branch, Galveston TX, US[email protected]ORCID:0000-0001-6949-9012
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Prevalence and factors associated with Lupus Nephritis in Venezuelan patients.
Introducción / Objetivo. Hay escasos datos sobre la nefritis lúpica en países individuales de América Latina. Hemos evaluado prevalencia y factores asociados a la nefritis lúpica en pacientes venezolanos con lupus eritematoso sistémico.
Métodos. Estudio transversal de 406 pacientes con LES (criterios del American College of Rheumatology 1982). Nefritis lúpica definida como proteinuria persistente ≥ 0,5 g, sedimento urinario activo más hipocomplementemia o anticuerpos anti-dsDNA. Análisis de regresión logística para estimar la razón de probabilidades (OR) de factores asociados con nefritis lúpica.
Resultados. Treinta y tres por ciento de pacientes fueron clasificados como nefritis lúpica. El análisis de regresión logística mostró que por cada aumento de un año en la edad, el OR de nefritis lúpica es 0,97 (IC del 95%, 0,95 a 0,98), y por cada aumento de un año en la duración de la enfermedad el OR es 0,96 (95% % IC, 0,94 -0,99). El consumo de alcohol, la actividad de la enfermedad y el daño orgánico se asociaron con nefritis lúpica.
Conclusión. La nefritis lúpica se asoció con menor edad y menor duración de la enfermedad. A pesar de ser una población racial / étnica de alto riesgo y en una región geográfica de alta prevalencia, los pacientes venezolanos mostraron una menor proporción de nefritis lúpica y más cercana a la de los pacientes de ascendencia europea, lo que sugiere que la expresión de la enfermedad renal puede variar dentro de países latinoamericanos individuales que comparten una raza / etnia y geografía comunes
Introduction / Objective. There are scarce data on lupus nephritis from single Latin American countries. We have assessed the prevalence and factors associated with lupus nephritis in a sample of Venezuelan patients with systemic lupus erythematosus (SLE).
Methods. A cross-sectional study of 406 SLE patients from a tertiary center in Caracas classified using the 1982 American College of Rheumatology criteria. Measures included sociodemographics, smoking, alcohol consumption, clinical features, treatment, and immunologic tests. Lupus nephritis was defined as persistent proteinuria (≥ 0.5 g per day), an active urinary sediment plus an immunological feature, either hypocomplementemia or anti-dsDNA antibodies. Logistic regression analysis was used to estimate the odds ratio (OR) of the factors associated with lupus nephritis.
Results. Thirty-three percent of patients were classified as having lupus nephritis. Logistic regression analysis showed that, for each one-year increase in age, the OR of having lupus nephritis was 0.97 (95% Confidence Interval [CI], 0.95-0.98) and, for each one-year increase in disease duration, the OR of having lupus nephritis was 0.96 (95% CI, 0.94-0.99). Current alcohol drinking, ever presence of anti-dsDNA antibodies, concurrent lupus disease activity, and accrued organ damage were significantly associated with lupus nephritis.
Conclusion. Lupus nephritis was associated with lower age and shorter disease duration. Despite being a high-risk race/ethnic population and in a geographical region of high prevalence, Venezuelan patients showed a lower proportion of lupus nephritis closer to that of patients of European descent, suggesting that renal disease expression may not be uniform and may vary even within individual Latin American countries which share a common race/ethnicity and geography.
Introdução / Objetivo. Existem poucos dados sobre nefrite lúpica em alguns países da América Latina. Avaliamos a prevalência e os fatores associados à nefrite lúpica em uma amostra de pacientes venezuelanos com lúpus eritematoso sistêmico.
Métodos. Estudo transversal de 406 pacientes com LES de um centro terciário em Caracas (critérios do American College of Rheumatology de 1982). As medidas incluíram sociodemográficas, tabagismo, álcool, características clínicas, tratamento e testes imunológicos. Nefrite lúpica definida como proteinúria persistente ≥ 0,5 g por dia, sedimento urinário ativo mais hipocomplementemia ou anticorpos anti-dsDNA. Análise de regressão logística usada para estimar o odds ratio (OR) dos fatores associados à nefrite lúpica.
Resultados. Trinta e três por cento dos pacientes foram classificados como nefrite lúpica. A análise de regressão logística mostrou que para cada aumento de um ano na idade, o OR de nefrite lúpica é 0,97 (IC 95%, 0,95 -0,98) e para cada aumento de um ano na duração da doença, o OR de nefrite lúpica é de 0,96 (95 % CI, 0,94 -0,99). O consumo de álcool, a atividade da doença e os danos acumulados foram associados à nefrite lúpica.
Conclusão. A nefrite lúpica foi associada a menor idade e menor duração da doença. Apesar de ser uma população de raça / etnia de alto risco e em uma região geográfica de alta prevalência, os pacientes venezuelanos apresentaram uma proporção menor de nefrite lúpica mais próxima da de pacientes de ascendência europeia, sugerindo que a expressão da doença renal pode variar dentro países latino-americanos individuais.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affecting predominantly young women all over the world (1). It is characterized by loss of tolerance to autoantigens that leads to a chronic inflammatory response, driven by the intertwined participation of the innate and adaptive branches of the immune system, potentially affecting multiple organs and systems (2). The prevalence and severity of the disease varies as a function of race, ethnicity, socioeconomic status (SES), and geographical region (1). People of African descent have the highest incidence and prevalence (1, 3, 4). The Latin America mestizo population is an admixture of European, African American, and Amerindian cultural and genetic makeup, in proportions that vary among regions and even within specific countries (5). Patients from Latin America show a prevalence of renal lupus intermediate between those of African American and Caucasian populations (1). In Venezuela, the prevalence of SLE has been estimated at 70/100000 (1,6). Patients of African American and Hispanic heritage are known to be affected more seriously for reasons related to, but not exclusively determined, by SES factors (7,8). The Grupo Latinoamericano de Estudio del Lupus (GLADEL) study, a multinational cohort of 1,214 patients with SLE in 9 Latin American countries (9), found that Mestizo and African American patients had more severe disease, including higher frequency of renal lupus, compared to Latin American whites (10). Similar results were previously reported in the LUpus in MInorities: NAture versus nurture (LUMINA) study, a multi-ethnic study including Hispanic patients residing in the US (11).
Lupus nephritis (LN) is one of the most common and serious manifestation in patients with SLE. The prevalence of nephritis in SLE varies greatly by race and ethnicity (12). Latin America is an area covering an extensive geographical region with a population sharing several phenotypic, ethnic, and cultural characteristics. However, ethnic/race mixing has not occurred to the same degree throughout the region, leading to variable genetic substructures potentially affecting disease expression in individual Latin American countries (13). For instance, Argentinians bear 80%, 18%, and 2% European, Amerindian, and African stock, respectively (14). Mestizo populations from Peru show a distinctive Native American ancestry signature (15), Puerto Rico and Colombia have higher levels of European as compared to Native American ancestry genes than mestizo populations from Mexico and Peru (16). The majority of the Venezuelan mestizo population now lives predominantly in urban areas and, according to analysis using autosomal, Y-chromosome, and mtDNA markers, shows a predominance of an European genetic component (40-65%), followed by Amerindian (20-35%) and African (10-20%) (17). This heterogeneous genetic substructure, as well as the influence of local environmental factors related to sociocultural differences throughout the extensive Latin American region, may influence the risk for disease and disease clinical expression between countries. For example, Native American ancestry affects the prevalence of respiratory variables in admixed Mexican individuals (16). The objective of this study was to establish the prevalence and identify factors associated with LN in a sample of Venezuelan patients with SLE. We hypothesized that, given their genetic substructure and environmental background, Venezuelan lupus patients may show distinctive clinical characteristics, including target-organ disease expression, as compared to those reported in other Latin American patient populations.
Material and Methods
This was an observational, cross-sectional study of 406 consecutive patients seen at the Division of Rheumatology, Hospital Universitario de Caracas, Venezuela, during the period 2013 to 2017.
Patient population and clinical assessment
Patients who were ≥ 18 years old were classified as having SLE if 4 or more criteria of the 1982 American College of Rheumatology (ACR) definition were present (18). All patients were interviewed and examined at the time of recruitment, following a detailed protocol to collect information on sociodemographic, clinical, and laboratory features at the time of enrollment. The study was approved by the Bioethics Committee of the Hospital Universitario de Caracas (protocol # 24/2013) and all subjects provided written informed consent to participate.
Age, gender, years of formal education, and marital status data were collected. SES was established using the modified Graffar scale (19) comprising five categories from 1 to 5 in decreasing order of SES level. These were collapsed into three variables, leaving a Graffar SES scale ranging from 1 to 3, where level 3 corresponds to the poverty level.
Disease duration, age at onset, clinical and laboratory data, family lupus history, comorbidities (hypertension, dyslipidemia, and diabetes mellitus), body mass index (BMI: weight in kilograms divided by height in squared meters), and treatment modality were collected. Disease activity at the time of the interview was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (20); a cut-off value of ≥ 6 was used to define active disease. Damage accrual was assessed at the time of the interview using the Systemic Lupus International Collaborating Clinics American College of Rheumatology (SLICC) Damage Index (DI) (21) as a binary (No =0, YES= >0) or continuous variable.
Classification into the neurolupus subset was done if the patient presented at least one of the corresponding components of the ACR criteria for neuropsychiatric manifestations, divided into central and peripheral components (22). Classification into the mucocutaneous (skin manifestations and oral ulcers) and hematologic subsets was done if patients fulfilled at least one of the corresponding components of the 1982 ACR criteria for SLE at the time of recruitment.
Lab tests corresponded to the period within the three months before inclusion in the study. Estimated glomerular filtration rate (eGFR) was calculated in ml per minute per 1.73 m2. Antinuclear antibodies (ANA) were tested by indirect immunofluorescence in Hep-2 cells; anti-dsDNA antibodies were tested by the Crithidia lucillae immunofluorescent test (CLIFT); lupus anticoagulant was measured by the dilute Russell Viper Venom Time and activated partial thromboplastin time (APPT); all other autoantibodies were detected by commercially available enzyme-linked immunosorbent assays. The positivity of an immunological test was established by the patient having at least two positive test results at least six months apart during the course of the disease. Low C3 and low C4 were defined as a value of < 60 mg/dL and < 15 mg/dL, respectively.
LN was established if the patient fulfilled the revised ACR criteria for LN, consisting of persistent proteinuria ≥ 0.5 g per day plus an active urinary sediment, and an additional third immunological feature, either hypocomplementemia or the presence of anti-dsDNA antibodies (23). Exclusion criteria for classification in the renal lupus subset included renal lithiasis (N = 25), hydronephrosis (N = 2), polycystic renal disease (N = 2), and history of renal cancer (N = 1), leaving a total of 376 patients. An additional 23 patients had insufficient urinary laboratory data for classification, leaving a final total of 353 patients for analysis in the renal lupus subset.
Descriptive statistics included means or medians with standard deviations and interquartile ranges, respectively. T-test and chi-square tests were used to test the differences between sociodemographic and clinical features by the presence of renal disease. Logistic regression analysis was performed to test the association with LN of sociodemographic characteristics, current smokers, current drinkers, comorbidities, laboratory, and clinical features. Statistical significance was set at p < 0.05. Analyses were conducted using the Stata15 package (StataCorp. LLC, Stata Statistical Software: Release 15. College Station, TX).
Sample population, sociodemographic features, and health lifestyle
The sample included a total of 406 patients. The mean age was 41.0 ± 12.2 years, female sex was 95%, Hispanic ethnicity was 98%, mean years of education was 11.9 ± 4.0; most patients were single (48%), and 29% were classified in the poverty Graffar SES level 3 (Table 1).
Mean disease duration was 10.0 ± 8.2 years; age at disease onset was 30.9 ± 11.3 years. The most common cumulated 1982 ACR criteria at the time of inclusion were arthritis (89%), malar rash (60%), photosensitivity (57%), renal disease (43%), oral ulcers (42%), and hematologic disorder (40%). Mucocutaneous, hematological, and neurolupus lupus were seen in 87%, 40%, and 14% of patients, respectively. The mean SLEDAI score was 5.2 ± 5.6, and the proportion of clinically active patients at inclusion into the study (SLEDAI ≥ 6) was 41%; the mean SLICC DI was 0.8 ± 1.4 and 43% of patients scored a SLICC DI > 0. At the time of the study, 94% of patients were taking oral prednisone; anti-malarials, mycophenolate mofetil, and azathioprine were being taken by 77%, 23%, and 21% of patients, respectively (Table 1).
ANA was positive in 97% of cases, followed by anti-DNA (51%), anti-Sm (35%), anti-Ro (35%), anti-RNP (23%), and anti-La (17%) antibodies. Anti-phospholipid antibodies were observed in 23% of cases. Mean serum C3 and C4 levels were 75.8 ± 42.7 mg/dL and 20.6 ± 12.1 mg/dL, respectively.
Of the 353 patients with complete data for renal disease analysis, 117 (33%) were classified as having LN at study entry. The mean creatinine clearance was 106.1 ± 51.8 ml/min, the mean eGFR was 101.6 ± 38.4 ml/min/1.73 m2 of body surface area, and the median 24-hour urinary protein excretion was 0.18 g (Interquartile range 75-25, 0.08-0.42). A renal biopsy performed in 65 patients showed the highest frequency in class II (27.6%), followed by class IV (21.5%), class I (20.0%), class V (16.9%), and class III (13.85%). In the total patient population, 24 patients (5.9%) had persistent 24-hour proteinuria > 3.5 g and 8 (1.9%) had end-stage renal disease.
Compared to those without renal lupus, patients with renal lupus were significantly more likely to be younger [38.4 vs 42.6 years (mean ± Standard Deviation, p-value = 0.001)], to be current alcohol drinkers (33%), to have shorter disease duration, to ever have anti-DNA antibodies, to have concurrent disease activity, to have accrued organ damage, and to have ever received intravenous pulses of cyclophosphamide or methyl prednisolone (Table 2).
Logistic regression analysis showed a 2.8% and 3.0% decrease in LN for each one-year increase in age and for each one-year increase in disease duration, respectively (Table 3). Current alcohol drinking (OR=1.64, 95% CI=1.00-2.68), ever having anti-dsDNA (OR=30, 95% CI=14.7-61.3), SLEDAI ≥ 6 (OR=4.95, 95% CI=3.06-8.03), and SLICC DI > 0 (OR=2.32, 95% CI=1.46-3.69) were factors independently associated with renal lupus.
Discussions and conclusions
We examined the prevalence of LN and associated factors in Venezuelan patients with SLE from a tertiary center in Caracas. We found that the prevalence of LN was lower than expected and greater in younger patients and those with a shorter disease duration. Alcohol drinking, ever having anti-dsDNA antibodies, disease activity, and accrued organ damage were also associated with LN.
Female sex predominated in a proportion of 9/1 as seen worldwide (1, 24), and similar to that previously reported in Hispanic patients (25). The mean age at disease onset in our patients was within the 15-to-45 years bracket, as is typical for SLE populations worldwide (1) and in Hispanic patients (8, 9). Mean years of education was comparable to findings in the Latin American GLADEL and the mestizo LUMINA subset. A lower proportion of our patients, 29% vs. 63% in the GLADEL mestizo subset (9) and 39% in the mestizo LUMINA subset (11), were classified in the SES level of poverty. Our frequency of current smokers, those with comorbid diabetes, and mean BMI were comparable to those from the SLICC multiracial and multinational series (26).
The distribution of clinical manifestations in our series was comparable to that of a large national registry of Spanish lupus patients (27) and the GLADEL and PROFILE cohorts (9, 28), except for more frequent hematological manifestations and renal disease in the latter two. Musculoskeletal symptoms are the most prevalent manifestation of SLE, affecting up to 95% of patients, followed by mucocutaneous symptoms (9, 27-31). Serositis, as well as renal and neurological manifestations, prevail in African American patients (1). Progress to end-stage renal disease occurs more frequently among African American (1, 32) and Hispanic patients (33). Interestingly, LN was seen in a lower proportion of our patients (33%) as compared to the PROFILE Hispanic subset (59%) (28) and the GLADEL (52%) cohort (9), and closer to the proportion of 34% in white patients of the Spanish SLE national registry (27), 31.9% of those in the Michigan Registry (29), and 39.5% of those in the California Lupus Surveillance Project (30). It is possible that the more stringent criteria used to define renal disease in our study, including the need for an immunological criterion of disease activity (the presence of either anti-DNA or low complement values) (23), can account for these differences. However, even when using the original, less stringent, 1982 ACR criteria for renal disease, the proportion of our patients with LN was 43%, still lower than that described in those other Hispanic cohorts.
European ancestry genes are known to protect against renal disease in lupus patients (1, 9, 28, 34-36). Thus, it is possible that the genetic substructure of our patient population, with a relatively high component of European stock (17), may partially explain these findings. The most recent immigration wave from Europe to Venezuela after World War II further contributed to this genetic component, after previous successive waves from Spain, Germany, and Corsica in the colonial and post-colonial past (17).
It is worth observing that, in the limited subsample of our patients with renal biopsy (N = 65), only 21% had type IV glomerulonephritis, the most aggressive form of lupus nephropathy; furthermore, only 6% of our total patient population sample had persistent nephrotic-range proteinuria and only 2% had reached an end-stage renal disease level at inclusion in the study. We cannot rule out a biased selection of patients for renal biopsy, from those with less firm clinical evidence of LN as opposed to those with overt renal disease, as an explanation for the lower proportion of patients with the most severe forms of LN. Compared to the LUMINA Hispanic subset and the GLADEL mestizo subset, a relatively lower proportion of our patients (29%) were classified at the SES level of poverty, another variable associated with increased risk for renal disease (37-39). However, as also seen in a multi-ethnic lupus study (36), we found no effect of SES level on predisposition to renal disease, possibly explained by the cross-sectional design of our study. In addition, data from the LUMINA study support the notion of genetic factors prevailing over SES level in susceptibility to renal disease (11).
Lower mean age and shorter disease duration were associated with increased frequency of LN, as previously reported in Hispanic patients (1, 10 39). The relationship between alcohol and risk of lupus has been a controversial subject, with one study showing a moderate protective effect (40) and another showing none (41).
Clinical disease activity and accrued organ damage correlated with the presence of LN in our study, consonant with previous reports (8, 20, 42, 43). However, a lower proportion of our patients (43%) accrued tissue damage compared to Hispanics and Afro-Americans in the LUMINA cohort (61% and 51%, respectively).
Limitations of our study are its cross-sectional design, which may veil the role of sociodemographic and clinical factors in conferring the risk of LN over time; the site of the study in a tertiary referral hospital, limiting its generalizability; and the low proportion of patients with histological confirmation of LN. Its strengths are the racial/ethnic homogeneity of the patient population; its single-country nature testing the specificities of cultural and genetic factor interactions within a common population; and the location of Venezuela in the Caribbean, a known high-risk area for LN as a test for the influence of ambience.
In summary, the prevalence of LN was lower than expected for an Hispanic SLE population. Independent factors associated with lupus renal disease were age, disease duration, current alcohol drinking, ever having anti-DNA antibodies, lupus disease activity, and accrued tissue damage. The lower frequency of renal disease observed in Venezuelan patients, as compared to other Hispanic lupus populations, underscores the need to examine differences in the clinical expression of SLE within individual Latin American countries.
The authors have no conflict of interest to declare.
No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.
1. Carter EE, Barr SG, Clarke AE (2016) The global burden of SLE. Prevalence, health disparities and socioeconomic impact. Nat Rev Rheumatol 12:605-620. doi:10.1038/nrrheum.2016.137.
2. Tsokos G (2020) Autoimmunity and organ damage in SLE. Nat Immunol 21:605–614. doi.org/10.1038/s41590-020-0677-6.
3. Rees F, Doherty M, Garinge MJ, Lanyon P, Zhang W (2017) The worldwide incidence and prevalence of systemic lupus erythematosus. A systematic review of epidemiological studies. Rheumatology 56:1945-1961. doi:10.1093/rheumatology/kex260
4. Borchers AT, Naguwa SM, Shoenfeld Y, Gershwin ME (2010). The geoepidemiology of systemic lupus erythematosus. Autoimmunity Rev 9:A277-A287. doi:10.1016/j.autrev.2009.12.008
5. González Burchard E, Borrell LN, Choudhry S, et al (2005) Latino populations: A unique opportunity for the study of race, genetics, and social environment in epidemiological research. Am J Public Health 95:2161–2168. doi:10.2105/AJPH.2005.068668
6. Granados Y, Cedeño L, Rosillo C, et al (2015). Prevalence of musculoskeletal disorders and rheumatic diseases in an urban community in Monagas state, Venezuela: a COPCORD study. Clin Rheumatol 34:871-877. DOI 10.1007/s10067-014-2689-9
7. Gómez-Puerta JA, Barbhaiya M, Guan H, Feldman, Alarcón GS, Costenbader KH (2015) Racial/Ethnic Variation in All-Cause Mortality among U.S. Medicaid Recipients with Systemic Lupus Erythematosus: A Hispanic and Asian Paradox. Arthritis Rheumatol. 67:752–760. doi:10.1002/art.38981.
8. Fernández M, Alarcón GS, Calvo-Alén J, et al (2007) A Multiethnic, Multicenter cohort of patients with systemic lupus erythematosus (SLE) as a model for the study of ethnic disparities in SLE. Arthritis Rheum (Arthritis Care Res) 57:576-584. DOI 10.1002/art.22672
9. Pons-Estel BA, Catoggio LJ, Cardiel MH, et al (2004). The GLADEL Multinational Latin American prospective inception cohort of 1,214 patients with systemic lupus erythematosus. Ethnic and disease heterogeneity among ‘‘Hispanics’’. Medicine 83:1–17. doi: 10.1097/01.md.0000104742.42401.e2.
10. Pons-Estel GJ, Alarcón GS, Burgos PI, et al (2013) Mestizos with systemic lupus erythematosus develop renal disease early while antimalarials retard its appearance: Data from a Latin American Cohort. Lupus 22:899-907. doi:10.1177/0961203313496339.
11. Alarcón GS, Bastian HM, Beasley TM, et al (2006) Systemic lupus erythematosus in a multi-ethnic cohort (LUMINA): contributions of admixture and socioeconomic status to renal involvement. Lupus 15:26–31. doi:10.1191/0961203306lu2260oa.
12. Almaani S, Meara A, Rovin BH (2017) Update on lupus nephritis. Clin J Am Soc Nephrol 12:825-835. doi.org/10.2215/CJN.05780616
13. Healy ME, Hill D, Berwick M, Edgar H, Gross J, Hunley K (2017) Social-group identity and population substructure in admixed populations in New Mexico and Latin America. Plos One 12:e0185503. doi: 10.1371/journal.pone.0185503.
14. Seldin MF, Tian C, Shigeta R, et al (2007). Argentine population genetic structure: Large variance in Amerindian contribution. Am J Phys Anthropol 132:455-462.
15. Harris DN, Song W, Shetty AC, et al (2018) Evolutionary genomic dynamics of Peruvians before, during, and after the Inca empire. Proc Natl Acad Sci 115: E6526-E6535.
16. Moreno-Estrada A, Gravel S, Zakharia F, et al (2013) Reconstructing the population genetic history of the Caribbean. PLoS Genet 9:e1003925. doi:10.1371/journal.pgen.1003925
17. Castro de Guerra D, Figuera Pérez C, Izaguirre MH, et al (2011). Gender differences in ancestral contribution and admixture in Venezuelan populations. Human Biol 3:345-361
18. Tan EM, Cohen AS, Fries JF, et al (1982). The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271-7. doi: 10.1002/art.1780251101.
19. Méndez Castellano, H., Méndez, M. C. D (1994) Sociedad y estratificación: método Graffar-Méndez Castellano, Caracas, Venezuela, Fundacredesa.
20. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH (1992) Derivation of the SLEDAI. A disease activity index for lupus patients. Arthritis Rheum 35:630-640. doi.org/10.1002/art.1780350606
21. Gladman D, Ginzler E, Goldsmith C, et al (1996) The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum 39:363-369. doi: 10.1002/art.1780390303
22.The American College of Rheumatology Nomenclature and Case Definitions for Neuropsychiatric Lupus Syndromes (1999) Arthritis Rheum 42:599-608. doi: 10.1002/1529-0131(199904)42:4<599::AID-ANR2>3.0.CO;2-F
23. Dooley MA, Aranow C, Ginzler EM (2004) Review of ACR renal criteria in systemic lupus erythematosus. Lupus 13:857-860. doi: 10.1191/0961203304lu2023oa.
24. Lisnevakaia L, Murphy G, Isenberg D (2014) Systemic lupus erythematosus. Lancet 384:1878-1888. doi.org/10.1016/S0140-6736(14)60128-8
25. Ugarte-Gil M, Pons-Estel GJ, Molineros J, et al (2016) Disease features and outcomes among US lupus of Hispanic origin and their mestizo counterparts in Latin America. A commentary. Rheumatology 55:436-440. doi:10.1093/rheumatology/kev280
26. Legge A, Kirkland S, Rockwood K, et al (2020) Prediction of damage accrual in systemic lupus erythematosus using the Systemic Lupus International Collaborating Clinics Frailty Index. Arthritis Rheumatol 72: 658-666. DOI 10.1002/art.41144
27. Rúa-Figueroa I, López-Longo FJ, Calvo-Alén J, et al (2014) National registry of patients with systemic lupus erythematosus of the Spanish Society of Rheumatology: Objectives and Methodology. Reumatol Clin 10:17–24. doi: 10.1016/j.reuma.2013.04.013
28. Alarcón GS, McGwin G Jr, Petri M, Reveille JD, Ramsey-Goldman R, Kimberly RP (2002) PROFILE Study Group. Baseline characteristics of a multiethnic lupus cohort: PROFILE. Lupus 11: 95–101. doi.org/10.1191/0961203302lu155oa
29. Somers EC, Marder W, Cagnoli P, et al (2014) Population-based incidence and prevalence of systemic lupus erythematosus. The Michigan Lupus Epidemiology and Surveillance Program. Arthritis Rheumatol 66:369-378. doi:10.1002/art.38238.
30. Dall’Era M, Cisternas MG, Snipes K, Herrinton LJ, Gordon C, Helmick CG (2017) The incidence and prevalence of systemic lupus erythematosus in San Francisco County, California. The California Lupus Surveillance Project. Arthritis Rheumatol 69:1996-2005. doi:10.1002/art.40191
31. Lim SS, Bayakly AR, Helmick CG, Gordon C, Easley K, Drenkard C (2014) The incidence and prevalence of systemic lupus erythematosus, 2002-2004. The Georgia Lupus Registry. Arthritis Rheumatol 66:357-368. doi:10.1002/art.38239.
32. Contreras G, Lenz O, Pardo V, et al (2006) Outcomes in African Americans and Hispanics with lupus nephritis. Kidney Int 69:1846–1851. doi:10.1038/sj.ki.5000243
33. Maningding E, Dall’Era M, Trupin L, Murphy LB, Yazdany J (2020) Racial and ethnics differences in prevalence and time to onset of systemic lupus erythematosus. The California Lupus Surveillance Project. Arthritis Care Res 72:622-629. doi:10.1002/acr.23887
34. Richman IB, Taylor KE, Chung SA, et al (2012) European genetic ancestry is associated with a decreased risk of lupus nephritis. Arthritis Rheum 64: 3374-3382. doi:10.1002/art.34567.
35. Seligman V, Lum RF, Olson JL, Li H, Criswell LA (2002) Demographic differences in the development of lupus nephritis. A retrospective analysis. American J Med 112:726-729. doi: 10.1016/s0002-9343(02)01118-x
36. Johnson SR, Urowitz MB, Ibañez D, Gladman DD (2006) Ethnic variation in disease patterns and health outcomes in systemic lupus erythematosus. J Rheumatol 33:1990 1995. PMID: 16924690
37. Barr RG, Seliger S, Appel GB, et al (2003) Prognosis of proliferative lupus nephritis. The role of socioeconomic status and race ethnicity. Nephrol Dial Transplant 18:2039-2046. doi: 10.1093/ndt/gfg345
38. Feldman CH, Hiraki LT, Liu J, et al (2013) Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among US adults with Medicaid coverage, 2000-2004. Arthritis Rheumatol 65:753-763. DOI 10.1002/art.37795
39. Burgos PI, McGwin G, Pons-Estel GJ, Reveille JD, Alarcón GS, Vilá LM (2011) Patients of Hispanic background develop lupus nephritis (LN) early in the course of the disease course. Data from a multiethnic US cohort. Ann Rheum Dis 70:393-394. doi:10.1136/ard.2010.131482
40. Wang J, Kay AB, Fletcher J, Formica MK, McAlindon TE (2009) Alcohol consumption is not protective for systemic lupus erythematosus. Ann Rheum Dis. 68: 345–348. doi:10.1136/ard.2007.084582.
41. Barbhaiya M, Costenbader KH (2016) Environmental exposures and the development of systemic lupus erythematosus. Curr Opin Rheumatol 28:497-505. doi:10.1097/BOR.0000000000000318
42. Galindo-Izquierdo M, Rodriguez-Alamaraz E, Pego-Reigosa JM, et al (2016) Characterization of patients with lupus nephritis included in a large cohort from the Spanish Society of Rheumatology Registry of patients with systemic lupus erythematosus (RELESSER). Medicine 95: doi: 10.1097/MD.0000000000002891
43. Calvo-Alén J, Reveille JD, Rodríguez-Valverde V, et al (2003) Clinical, immunogenetic and outcome features of Hispanic systemic lupus erythematosus patients of different ethnic ancestry. Lupus 12:377-385. doi:10.1136/ard.2007.076059
44. Bruce IN, O'Keeffe AG, Farewell V, et al (2015) Factors associated with damage accrual in patients with systemic lupus erythematosus. Results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort. Ann Rheum Dis 74:1706-1713. doi:10.1136/annrheumdis-2013-205171
45. Alarcón GS, McGwin G, Bartolucci AA, et al (2001) Systemic lupus erythematosus in three ethnic groups. IX. Differences in damage accrual. Arthritis Rheumatol 44:2797-2806