Seguimiento de la actividad clínica y del daño orgánico acumulado en una cohorte de pacientes con lupus eritematoso sistémico de la península de Yucatán, México (1995-2016) / Follow-up of clinical activity and accumulated organic damage in a cohort of patients with Systemic Lupus Erythematosus from the Yucatán peninsula, México (1995-2016)

Introducción: El lupus eritematoso sistémico (LES) es una enfermedad autoinmune con severidad variable, frecuente en individuos hispanos y afroamericanos. Objetivo: Conocer la actividad clínica y el daño acumulado, así como la prevalencia e incidencia, en una cohorte dinámica de pacientes con LES de la península de Yucatán (1995 a 2016). Pacientes y métodos: Se analizaron 200 pacientes con LES, beneficiarios del servicio médico del Hospital Regional ISSSTE de Mérida, Yucatán, durante 22 años. Se evaluó la actividad de la enfermedad y el daño acumulado mediante la escala MEX-SLEDAI y SLICC-ACR-DI, respectivamente, y su correlación con variables clínicas y demográficas. Resultados: Se analizaron 185 pacientes mujeres y 15 hombres. Los índices promedio de actividad y daño acumulado durante el seguimiento fueron de 4,63 y 1,10, respectivamente. El índice de actividad se observó significativamente menor en las mujeres respecto de los hombres (4,36 vs. 7,43), y el daño acumulado no presentó diferencia por sexo. Las manifestaciones asociadas con mayor actividad fueron las mucocutáneas y articulares, y los órganos con mayor daño acumulado el musculoesquelético, el neurológico y el gonadal. Se encontró relación de los índices con el tiempo de evolución, las remisiones/reactivaciones y la actividad persistente. La mortalidad se relacionó con actividad persistente por complicaciones vasculares sistémicas e insuficiencia renal y hepática. La incidencia y prevalencia anual del LES calculada fue de 2,86% y 48,43% en la península de Yucatán. Conclusiones: Los pacientes presentaron actividad persistente, con reactivaciones leves a moderadas y daño acumulado más agresivo en hombres. La actividad clínica disminuye e incrementa el daño acumulado a mayor tiempo de evolución, con menor afección renal y mayor sobrevida, lo que sugiere un curso más benigno en la población de la península de Yucatán.(AU)

IntroductionSystemic lupus erythematosus (SLE) is an autoimmune with variable severity, common in Hispanic and African-American individuals.Objective: To know the clinical activity and the accumulated damage, as well as the prevalence and incidence, in a dynamic cohort of patients with SLE from the Yucatan Peninsula (1995-2016). Patients and methods: A cohort of 200 patients with SLE, medical service beneficiaries of the ISSSTE Regional Hospital of Mérida, Yucatán, was analyzed for 22 years. Disease activity and accumulated damage were evaluated using the MEX-SLEDAI scale and the SLICC-ACR-DI, respectively, and its correlation with clinical and demographic variables. Results: 185 female and 15 male patients were analyzed. Average accumulated damage and activity indices during follow-up were 4.63 and 1.10, respectively. The activity index was significantly lower in females compared to males (4.36 vs 7.43), and the accumulated damage did not present a difference by sex. The manifestations associated with greater activity were the mucocutaneous and articular ones, and the organs with the greatest accumulated damage were the musculoskeletal, neurological and gonadal. A relationship between the indices was found with the evolution time, remissions / reactivations, and persistent activity. Mortality was related to persistent activity due to systemic vascular complications and kidney and liver failure. The annual incidence and prevalence of SLE calculated was 2.86% and 48.43% in Yucatán Peninsula. Conclusions: The patients presented persistent activity, with mild to moderate reactivations, and accumulated damage more aggressive in men. The clinical activity decreases and increases the accumulated damage at a longer evolution time, with less kidney disease and greater survival, which suggests a more benign course in the population of the Yucatan Peninsula.(AU)

Follow-up of clinical activity and accumulated organic damage in a cohort of patients with systemic lupus erythematosus from the Yucatán Peninsula, Mexico (1995-2016).

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune with variable severity, common in Hispanic and African-American individuals. OBJECTIVE: To know the clinical activity and the accumulated damage, as well as the prevalence and incidence, in a dynamic cohort of patients with SLE from the Yucatan Peninsula (1995-2016). PATIENTS AND METHODS: A cohort of 200 patients with SLE, medical service beneficiaries of the ISSSTE Regional Hospital of Mérida, Yucatán, was analysed for 22 years. Disease activity and accumulated damage were evaluated using the MEX-SLEDAI scale and the SLICC-ACR-DI, respectively, and its correlation with clinical and demographic variables. RESULTS: 185 female and 15 male patients were analysed. Average accumulated damage and activity indices during follow-up were 4.63 and 1.10, respectively. The activity index was significantly lower in females compared to males (4.36 vs 7.43), and the accumulated damage did not present a difference by sex. The manifestations associated with greater activity were the mucocutaneous and articular ones, and the organs with the greatest accumulated damage were the musculoskeletal, neurological and gonadal. A relationship between the indices was found with the evolution time, remissions/reactivations, and persistent activity. Mortality was related to persistent activity due to systemic vascular complications and kidney and liver failure. The annual incidence and prevalence of SLE calculated was 2.86% and 48.43% in Yucatán Peninsula. CONCLUSIONS: The patients presented persistent activity, with mild to moderate reactivations, and accumulated damage more aggressive in men. The clinical activity decreases and increases the accumulated damage at a longer evolution time, with less kidney disease and greater survival, which suggests a more benign course in the population of the Yucatan Peninsula.

Copy Number Variation and Frequency of rs179008 in TLR7 Gene Associated with Systemic Lupus Erythematosus in Two Mexican Populations.

Systemic Lupus Erythematosus (SLE) is an autoimmune disease in which genetic factors play a role in the susceptibility to develop it. Genes related to the synthesis of interferons such as TLR7 and genetics factors such as single nucleotide polymorphisms (SNPs) or copies number variation (CNV) in the gene have been involved with the development of the disease. The genetic differences between the populations contribute to the complexity of LES. Mexico has a mestizo population with a genetic load of at least three origins: Amerindian, Caucasian, and African. The mestizo of Yucatán is the only group whose contribution Amerindian is mainly Mayan, geographically distant from other Mexican Amerindians. We analyzed the CNV and the frequency of SNP rs179008 of the TLR7 as genetic risk factors in developing the disease in patients from Yucatán and Central Mexico. Results show that 14% of the cases of the Yucatecan population showed significantly >2 CNV and a higher risk of developing the disease (OR: 34.364), concerning 4% of those coming from Central Mexico (OR: 10.855). T allele and the A/T and T/T risk genotypes of rs179008 were more frequent in patients of Central Mexico than in those of Yucatán (50% vs. 30%, 93% vs. 30%, 4% vs. 1%), and association with susceptibility to develop SLE was observed (OR: 1.5 vs. 0.58, 9.54 vs. 0.66, 12 vs. 0.14). Data support the genetic differences between and within Mexican mestizo populations and the role of the TLR7 in the pathogenesis of SLE.

ITGAM is a risk factor to systemic lupus erythematosus and possibly a protection factor to rheumatoid arthritis in patients from Mexico.

INTRODUCTION: ITGAM has consistently been associated with susceptibility to systemic lupus erythematosus (SLE) in many ethnically diverse populations. However, in populations with higher Amerindian ancestry (like Yucatan) or highly admixed population (like Mexican), ITGAM has seldom been evaluated (except few studies where patients with childhood-onset SLE were included). In addition, ITGAM has seldom been evaluated in patients with rheumatoid arthritis (RA). Here, we evaluated whether four single nucleotide polymorphisms (SNPs), located within ITGAM, were associated with SLE and RA susceptibility in patients from Mexico. METHODS: Our study consisted of 1,462 individuals, which included 363 patients with SLE (292 from Central Mexico and 71 from Yucatan), and 621 healthy controls (504 from Central Mexico and 117 from Yucatan). Our study also included 478 patients with RA from Central Mexico. TaqMan assays were used to obtain the genotypes of the four SNPs: rs34572943 (G/A), rs1143679 (G/A), rs9888739 (C/T), and rs1143683 (C/T). We also verified the genotypes by Sanger sequencing. Fisher's exact test and permutation test were employed to evaluate the distribution of genotype, allele, and haplotype between patients and controls. RESULTS: Our data show that all four ITGAM SNPs are significantly associated with susceptibility to SLE using both genotypic and allelic association tests (corrected for multiple testing, but not for population stratification). A second study carried out in patients from Yucatan, a southeastern part of Mexico (with a high Amerindian ancestry), also replicated SLE association with all four SNPs, including the functional SNP, rs1143679 (OR = 24.6 and p = 9.3X10-6). On the other hand, none of the four SNPs are significant in RA after multiple testing. Interestingly, the GACC haplotype, which carries the ITGAM rs1143679 (A) minor allele, showed an association with protection against RA (OR = 0.14 and p = 3.0x10-4). CONCLUSION: Our data displayed that ITGAM is a risk factor to SLE in individuals of Mexican population. Concurrently, a risk haplotype in ITGAM confers protection against RA.

The VEGFA -1154G/A polymorphism is associated with reduced risk of rheumatoid arthritis but not with systemic lupus erythematosus in Mexican women.

BACKGROUND: Levels of circulating vascular endothelial growth factor (VEGF) (a potent endothelial-cell-specific angiogenic factor) have been correlated with disease activity in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In addition, several single nucleotide polymorphisms (SNPs), including the VEGFA -2578C/A, have been associated with RA in some populations. By contrast, the role of different VEGFA SNPs in the susceptibility to SLE has received little attention. Thus, the present study aimed to determine whether the VEGFA -2578C/A, -1154G/A and -634G/C polymorphisms confer risk or were associated with reduced risk of RA or SLE in a Mexican population. METHODS: The present study included 903 women from Mexico: 405 were patients with RA, 282 had SLE and 216 were healthy individuals. The genotypes were obtained with TaqMan probes. RESULTS: The data obtained in the present study suggest that the VEGFA -2578C/A and -634G/C polymorphisms are not risk factors for RA or SLE; however, VEGFA -1154G/A was associated with reduced risk in women with RA (odds ratio = 0.6, pc  = 0.0051) but not with SLE (odds ratio = 0.7, pc  = 0.13). CONCLUSIONS: The present study is the first to document an association between VEGFA -1154G/A and reduced risk in women with RA but not with SLE.

Functional polymorphisms in pre-miR146a and pre-miR499 are associated with systemic lupus erythematosus but not with rheumatoid arthritis or Graves' disease in Mexican patients.

Recently, different microRNA (miRNA) gene polymorphisms have been evaluated in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Graves' disease (GD). In the present study, we examined three single-nucleotide polymorphisms (SNPs) located in the pre-miR-146a (rs2910164G/C), pre-miR-196a-2 (rs11614913C/T), and pre-miR-499 (rs3746444A/G) genes. Our study population included 900 Mexican patients with RA, SLE, or GD, as well as 486 healthy control individuals with no family history of inflammatory or autoimmune diseases. Genotyping was performed using TaqMan probes and a 5' exonuclease assay. None of the investigated SNPs were associated with RA or GD susceptibility under any genetic model (co-dominant, recessive, or dominant). Genotype and allele frequencies of the miR-196a-2 rs11614913C/T polymorphism were similar between SLE cases and controls. In contrast, the miR-146a rs2910164G/C and miR-499 rs3746444A/G polymorphisms were associated with SLE susceptibility. These SNPs were not associated with lupus nephritis (LN). Our results suggest that polymorphisms in miR-146a, miR-196a-2, and miR-499 are not associated with RA or GD susceptibility. This is the first report documenting that the miR-146a rs2910164G/C and miR-499 rs3746444 polymorphisms are associated with SLE susceptibility but not with LN.

Serological and molecular analysis of parvovirus B19 infection in Mayan women with systemic lupus erythematosus in Mexico.

BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that mainly affects women, characterized by the production of autoantibodies. Its causal agent is unknown, but the combination of environmental, hormonal and genetic factors may favor the development of the disease. Parvovirus B19 has been associated with the development of SLE, since it induces the production of anti-single stranded DNA antibodies. It is unknown whether PV-B19 infection is an environmental factor that trigger or reactivate SLE in the Mexican Mayan population. AIM: A preliminary serological and molecular study of PV-B19 infection in Mayan women with established SLE was done. METHODS: IgG and IgM anti PV-B19 were evaluated in 66 SLE patients and 66 control subjects, all women of Mayan origin. Viral DNA and viral load were analyzed by qPCR. RESULTS: Insignificant levels of IgM were observed in 14.3% (4/28) of the patients and 11.4% (4/35) of control subjects. IgG was detected in 82.1% (23/28) of the patients and 82.9% (29/35) of control subjects, but were significantly higher in patients. Viral DNA was found in 86.0% (57/66) of the patients and 81.0% (54/66) of control subjects. Viral load, quantified in 28/66 patients and 31/66 controls which were positive for IgM and IgG, was significantly higher in controls. CONCLUSION: The high prevalence of PV-B19 in Yucatan, and the presence of IgM, IgG, and viral load in Mayan women with established SLE suggest that PV-B19 infection could be an environmental factor to trigger or reactivate SLE.

ANTECEDENTES: Lupus eritematoso sistémico (LES) es una enfermedad sistemica autoinmune que afecta principalmente a las mujeres, caracterizada por la producción de autoanticuerpos. El agente causaal es desconocido. Pero la combinación de factores ambientales, hormonales y genéticos podría favorecer el desarrollo de la enfermedad. El parvovirus B19 se asoció con el desarrollo de LES, debido a que induce la producción de anticuerpos anti-cadena simple de DNA. Es desconocido si la infección PV-B19 es un factor ambiental que desencadena o reactiva LES en la población mexicana Maya. OBJETIVO: Se realizó un estudio serológico y molecular preliminar de la infección de PV-B19 en mujeres Mayas con LES. MÉTODOS: Se evaluó IgG and IgM anti PV-B19 en 66 pacientes con LES y 66 controles sanos, todas las mujeres fueron de origen Maya. DNAViral y la carga viral fueron analizadas por qPCR. RESULTADOS: Se determinaron niveles insignificantes de IgM en el 14.3% (4/28) de las pacientes y en el 11.4% (4/35) de los controles. IgG se detectó en el 82.1% (23/28) de los pacients y en el 82.9% (29/35) de los controles. Hubo un alta significancia en los pacientes con LES. DNA viral se encontró en el 86.0% (57/66) de los pacientes y en el 81.0% (54/66) de los controles. La carga viral se cuantifico en 28/66 pacientes y en 31/66 de los controles, la cual fueron positivos para IgM e IgG; fue significativamente mas alta en los controles. CONCLUSIÓN: La alta prevalencia de PV-B19 en Yucatan y la presencia de IgM, IgG y una carga viral en mujeres Mayas con LES sugiere que la infección con PV-B19 poria ser un factor ambiental que desencadene o reactive el LES.

Serological and molecular analysis of parvovirus B19 infection in Mayan women with systemic lupus erythematosus in Mexico / Análisis serológico y molecular de la infección por parvovirus B19 en mujeres mayas con lupus eritematoso sistémico en México

Abstract Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that mainly affects women, characterized by the production of autoantibodies. Its causal agent is unknown, but the combination of environmental, hormonal and genetic factors may favor the development of the disease. Parvovirus B19 has been associated with the development of SLE, since it induces the production of anti-single stranded DNA antibodies. It is unknown whether PV-B19 infection is an environmental factor that trigger or reactivate SLE in the Mexican Mayan population. Aim: A preliminary serological and molecular study of PV-B19 infection in Mayan women with established SLE was done. Methods: IgG and IgM anti PV-B19 were evaluated in 66 SLE patients and 66 control subjects, all women of Mayan origin. Viral DNA and viral load were analyzed by qPCR. Results: Insignificant levels of IgM were observed in 14.3% (4/28) of the patients and 11.4% (4/35) of control subjects. IgG was detected in 82.1% (23/28) of the patients and 82.9% (29/35) of control subjects, but were significantly higher in patients. Viral DNA was found in 86.0% (57/66) of the patients and 81.0% (54/66) of control subjects. Viral load, quantified in 28/66 patients and 31/66 controls which were positive for IgM and IgG, was significantly higher in controls. Conclusion: The high prevalence of PV-B19 in Yucatan, and the presence of IgM, IgG, and viral load in Mayan women with established SLE suggest that PV-B19 infection could be an environmental factor to trigger or reactivate SLE.

Resumen Antecedentes: Lupus eritematoso sistémico (LES) es una enfermedad sistemica autoinmune que afecta principalmente a las mujeres, caracterizada por la producción de autoanticuerpos. El agente causaal es desconocido. Pero la combinación de factores ambientales, hormonales y genéticos podría favorecer el desarrollo de la enfermedad. El parvovirus B19 se asoció con el desarrollo de LES, debido a que induce la producción de anticuerpos anti-cadena simple de DNA. Es desconocido si la infección PV-B19 es un factor ambiental que desencadena o reactiva LES en la población mexicana Maya. Objetivo: Se realizó un estudio serológico y molecular preliminar de la infección de PV-B19 en mujeres Mayas con LES. Métodos: Se evaluó IgG and IgM anti PV-B19 en 66 pacientes con LES y 66 controles sanos, todas las mujeres fueron de origen Maya. DNAViral y la carga viral fueron analizadas por qPCR. Resultados: Se determinaron niveles insignificantes de IgM en el 14.3% (4/28) de las pacientes y en el 11.4% (4/35) de los controles. IgG se detectó en el 82.1% (23/28) de los pacients y en el 82.9% (29/35) de los controles. Hubo un alta significancia en los pacientes con LES. DNA viral se encontró en el 86.0% (57/66) de los pacientes y en el 81.0% (54/66) de los controles. La carga viral se cuantifico en 28/66 pacientes y en 31/66 de los controles, la cual fueron positivos para IgM e IgG; fue significativamente mas alta en los controles. Conclusión: La alta prevalencia de PV-B19 en Yucatan y la presencia de IgM, IgG y una carga viral en mujeres Mayas con LES sugiere que la infección con PV-B19 poria ser un factor ambiental que desencadene o reactive el LES

The PTPN22 R263Q polymorphism confers protection against systemic lupus erythematosus and rheumatoid arthritis, while PTPN22 R620W confers susceptibility to Graves' disease in a Mexican population.

OBJECTIVE: The functional PTPN22 R620W polymorphism (rs2476601) is clearly associated with susceptibility to several autoimmune diseases (ADs). However, the PTPN22 R263Q polymorphism (rs33996649) has been scarcely explored in different ADs. Here we aimed to examine the associations of the PTPN22 R620W and R263Q polymorphisms with susceptibility to or protection against rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Graves' disease (GD) among Mexican patients. METHODS: We conducted a case-control study including 876 patients (405 with SLE, 388 with RA, and 83 with GD) and 336 healthy control individuals. PTPN22 genotypes were determined using the TaqMan 5' allele discrimination assay. RESULTS: PTPN22 R620W was associated with GD susceptibility (OR 4.3, p = 0.004), but was not associated with SLE (OR 1.8, p = 0.19). We previously demonstrated that this polymorphism is associated with RA susceptibility (OR 4.17, p = 0.00036). Moreover, PTPN22 R263Q was associated with protection against SLE (OR 0.09, p = 004) and RA (OR 0.28, p = 0.045), but was not associated with GD. CONCLUSIONS: Our data provide the first demonstration that PTPN22 R620W confers GD susceptibility among Latin-American patients. Moreover, this is the second report documenting the association of PTPN22 R263Q with protection against SLE and RA.

Expression of TLR-7, MyD88, NF-kB, and INF-α in B Lymphocytes of Mayan Women with Systemic Lupus Erythematosus in Mexico.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease involving multiple organs. It is currently accepted that several genetic, environmental, and hormonal factors are contributing to its development. Innate immunity may have a great influence in autoimmunity through Toll-like receptors. TLR-7 recognizing single-strand RNA has been involved in SLE. Its activation induces intracellular signal with attraction of MyD88 and NF-kBp65, leading to IFN-α synthesis which correlate with disease activity. OBJECTIVE: To assess the expression of TLR-7, MyD88, and NF-kBp65 in B lymphocytes of Mayan women with SLE. METHODS: One hundred patients with SLE and 100 healthy controls, all of them Mayan women, were included. TLR-7 was analyzed on B and T lymphocytes, and MyD88 and NF-kB only in B lymphocytes. Serum INF-α level was evaluated by ELISA. RESULTS: Significant expression (p < 0.0001) of TLR-7 in B and T lymphocytes and serum IFN-α increased (p = 0.034) was observed in patients. MyD88 and NF-kBp65 were also increased in B lymphocytes of patients. TLR-7 and NF-kBp65 expression correlated, but no correlation with INF-α and disease activity was detected. CONCLUSION: Data support the role of TLR-7 and signal proteins in the pathogenesis of SLE in the Mayan population of Yucatán.