Association of the polymorphisms rs179008 (TLR7), rs2004640 (IRF5), rs1800795 (IL-6) and rs2280788 (CCL5) with systemic lupus erythematosus in women of Mayan ethnicity from Yucatan.

Introduction: IFN-α is the main cytokine in SLE, and single nucleotide polymorphisms (SNP) in different genes could induce it. Aim: To determine the association of rs2004640 (IRF5), rs179008 (TLR7), rs1800795 (IL-6) and rs2280788 (CCL5) with SLE in Mexican women with Mayan ethnicity. Methods: DNA and RNA were isolated from the peripheral blood of 110 patients and 200 healthy control subjects. SNP genotyping and gene expression analysis of IRF5, TLR7, IL-6 and IFN-α were determined by real-time PCR and analyzed with SNP Stat, Stata 10.1 and Graph Pad Prism v5. Results: rs2004640, rs179008, and rs1800795 in both groups were according to Hardy-Weinberg equilibrium. Risk alleles rs179008T and rs2004640T frequencies were higher in controls (p = 0.015 and p = 0.028, respectively), whereas rs179008A frequency was higher in patients (p = 0.015). Allelic combination AGT frequency was higher in patients (p = 0.001). IL-6 rs1800795C > G and CCL5 rs2280788G > C frequencies did not show significant differences (p > 0.05), being rs2280788G (CCL5) monomorphic in controls. SLE patients showed higher TLR7, IRF5, IL6, and IFN-α mRNA levels. IRF5 expression was higher in SLE patients homozygous for rs2004640T (IRF5). Conclusion: This work showed the contribution of TLR7 and IRF5 in SLE pathogenesis in Mayan females from Yucatan.

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.

Cell - Vessel Mismatch in Glaucoma: Correlation of Ganglion Cell Layer Soma and Capillary Densities.

Purpose: The purpose of this study was to characterize the relationship between retinal ganglion cell layer (GCL) soma density and capillary density in glaucomatous eyes. Methods: Six glaucoma subjects with known hemifield defects and 6 age-matched controls were imaged with adaptive optics - optical coherence tomography (AO-OCT) at 6 locations: 3 degrees, 6 degrees, and 12 degrees temporal to the fovea above and below the midline. GCL soma density and capillary density were measured at each location. Coefficients of determination (pseudo R2) and slopes between GCL soma and capillary density were determined from mixed-effects regressions and were compared between glaucoma and control subjects, between more and less affected hemifield in subjects with glaucoma, and between subjects with early and moderate glaucoma, both in a local, bivariate model and then a global, multivariable model controlling for eccentricity and soma size. Results: The global correlation between GCL soma and capillary density was stronger in control versus subjects with glaucoma (R2 = 0.59 vs. 0.22), less versus more affected hemifields (R2 = 0.55 vs. 0.01), and subjects with early versus moderate glaucoma subjects (R2 = 0.44 vs. 0.18). When controlling for eccentricity and soma size, we noted an inverse soma-capillary density local relationship in subjects with glaucoma (-388 ± 190 cells/mm2 per 1% change in capillary density, P = 0.046) and more affected hemifields (-602 ± 257 cells/mm2 per 1% change in capillary density, P = 0.03). Conclusions: An inverted soma-capillary density local relationship in areas affected by glaucoma potentially explains weaker global correlations observed between GCL soma and capillary density, suggesting cell-vessel mismatch is associated with the disease.

Quantification of Retinal Ganglion Cell Morphology in Human Glaucomatous Eyes.

Purpose: To characterize retinal ganglion cell morphological changes in patients with primary open-angle glaucoma associated with hemifield defect (HD) using adaptive optics-optical coherence tomography (AO-OCT). Methods: Six patients with early to moderate primary open-angle glaucoma with an average age of 58 years associated with HD and six age-matched healthy controls with an average age of 61 years were included. All participants underwent in vivo retinal ganglion cell (RGC) imaging at six primary locations across the macula with AO-OCT. Ganglion cell layer (GCL) somas were manually counted, and morphological parameters of GCL soma density, size, and symmetry were calculated. RGC cellular characteristics were correlated with functional visual field measurements. Results: GCL soma density was 12,799 ± 7747 cells/mm2, 9370 ± 5572 cells/mm2, and 2134 ± 1494 cells/mm2 at 3°, 6°, and 12°, respectively, in glaucoma patients compared with 25,058 ± 4649 cells/mm2, 15,551 ± 2301 cells/mm2, and 3891 ± 1105 cells/mm2 (P < 0.05 for all locations) at the corresponding retinal locations in healthy participants. Mean soma diameter was significantly larger in glaucoma patients (14.20 ± 2.30 µm) compared with the health controls (12.32 ± 1.94 µm, P < 0.05 for all locations); symmetry was 0.36 ± 0.32 and 0.86 ± 0.13 in glaucoma and control cohorts, respectively. Conclusions: Glaucoma patients had lower GCL soma density and symmetry, greater soma size, and increased variation of GCL soma reflectance compared with age-matched control subjects. The morphological changes corresponded with HD, and the cellular level structural loss correlated with visual function loss in glaucoma. AO-based morphological parameters could be potential sensitive biomarkers for glaucoma.

Asociación entre sobrepeso/obesidad y estado clínico en artritis reumatoide / Association between overweight/obesity and clinical activity in rheumatoid arthritis

INTRODUCCIÓN: La asociación entre la presencia de sobrepeso/obesidad y el estado clínico de la artritis reumatoide (AR) es un tema aún no resuelto. OBJETIVO: Evaluar la asociación entre el tipo de composición corporal y el estado clínico en pacientes con AR. MÉTODOS: Estudio prospectivo, comparativo y transversal que incluyó a 123 pacientes (98,4% mujeres, 86,3% FR+, 9,3±8,7 años de duración) con AR (criterios ACR/EULAR 2010) en quienes se determinó actividad inflamatoria (DAS 28), estado funcional (HAQ-Di) y tipo de tratamiento; además, el tipo de composición corporal evaluada por IMC, circunferencias de cintura, cadera y brazo medio, índice cintura/cadera, plicometría y bioimpedancia eléctrica. RESULTADOS: Las prevalencias de sobrepeso y obesidad (IMC-OMS) fueron del 30,9% y del 45,5%. Cuando se reclasificaron mediante los puntos de corte de Stavropoulos-Kalinoglou, las prevalencias aumentaron a 31,7 y 58,5%, respectivamente. Con este criterio, los pacientes con sobrepeso/obesidad tuvieron más articulaciones inflamadas que los pacientes con composición corporal subnormal/normal (3,8±3,3 vs. 1,9±2,5; p = 0,02). El conteo de articulaciones inflamadas mostró correlación positiva significativa con 6 de 11 métodos antropométricos: IMC, circunferencia de brazo y cadera, pliegue tricipital y porcentaje de grasa corporal (determinado por bioimpedancia eléctrica y plicometría). CONCLUSIONES: El sobrepeso y la obesidad se asociaron a mayor actividad inflamatoria caracterizada por mayor cantidad de articulaciones inflamadas. Encontramos correlación positiva significativa entre el número de articulaciones inflamadas y la mayoría de los indicadores de masa grasa corporal estudiados. La evaluación y optimización de la composición corporal podría llegar a ser una parte importante para el abordaje clínico de pacientes con AR

INTRODUCTION: The effect of overweight/obesity on clinical status in rheumatoid arthritis (RA) is still a controversial topic. AIM: To assess the association between body composition and clinical status in RA patients. METHODS: A prospective, comparative, cross-sectional study was performed on 123 (98.4% women, 86.3% FR+, 9.3±8.7 duration years) RA patients diagnosed according to ACR/EULAR 2010 criteria who were assessed for inflammatory activity (DAS 28), functional status (HAQ-Di), and type of treatment. Body composition was evaluated by BMI, waist, hip, and middle arm girths, waist/hip ratio, skin fold measurements, and bioelectrical impedance analysis. RESULTS: The prevalence of overweight and obesity (BMI-WHO cut-off points) was 30.9% and 45.5% respectively. Using Stavropoulos-Kalinoglou cut-off points, each corresponding prevalence increased to 31.7% and 58.5%, respectively. Pooled patients in the overweight/obesity classification (Stavropoulos-Kalinoglou classification) exhibited a significantly higher number of swollen joints as compared to subnormal/normal body composition subjects (3.8±3.3 vs. 1.9±2.5; p=.02). Swollen joint count showed significant positive correlation with 6 out of 11 body composition parameters: BMI; arm and hip girths, triceps skin fold, body fat average determined by bioelectrical impedance analysis, and skin fold measurements. CONCLUSIONS: Prevalence of obesity in RA varies according to BMI cut-off points. Overweight and obesity were associated with higher inflammatory activity characterized by a higher count of tender and swollen joints. A positive correlation was found between swollen joint amount and the majority of the body fat mass indicators assessed. Body composition assessment/improvement should be an important part of the routine care of RA patients

Label-free adaptive optics imaging of human retinal macrophage distribution and dynamics.

Microglia are resident central nervous system macrophages and the first responders to neural injury. Until recently, microglia have been studied only in animal models with exogenous or transgenic labeling. While these studies provided a wealth of information on the delicate balance between neuroprotection and neurotoxicity within which these cells operate, extrapolation to human immune function has remained an open question. Here we examine key characteristics of retinal macrophage cells in live human eyes, both healthy and diseased, with the unique capabilities of our adaptive optics-optical coherence tomography approach and owing to their propitious location above the inner limiting membrane (ILM), allowing direct visualization of cells. Our findings indicate that human ILM macrophage cells may be distributed distinctly, age differently, and have different dynamic characteristics than microglia in other animals. For example, we observed a macular pattern that was sparse centrally and peaked peripherally in healthy human eyes. Moreover, human ILM macrophage density decreased with age (∼2% of cells per year). Our results in glaucomatous eyes also indicate that ILM macrophage cells appear to play an early and regionally specific role of nerve fiber layer phagocytosis in areas of active disease. While we investigate ILM macrophage cells distinct from the larger sample of overall retinal microglia, the ability to visualize macrophage cells without fluorescent labeling in the live human eye represents an important advance for both ophthalmology and neuroscience, which may lead to novel disease biomarkers and new avenues of exploration in disease progression.

Association between Overweight/Obesity and Clinical Activity in Rheumatoid Arthritis. / Asociación entre sobrepeso/obesidad y estado clínico en artritis reumatoide.

INTRODUCTION: The effect of overweight/obesity on clinical status in rheumatoid arthritis (RA) is still a controversial topic. AIM: To assess the association between body composition and clinical status in RA patients. METHODS: A prospective, comparative, cross-sectional study was performed on 123 (98.4% women, 86.3% FR+, 9.3±8.7 duration years) RA patients diagnosed according to ACR/EULAR 2010 criteria who were assessed for inflammatory activity (DAS 28), functional status (HAQ-Di), and type of treatment. Body composition was evaluated by BMI, waist, hip, and middle arm girths, waist/hip ratio, skin fold measurements, and bioelectrical impedance analysis. RESULTS: The prevalence of overweight and obesity (BMI-WHO cut-off points) was 30.9% and 45.5% respectively. Using Stavropoulos-Kalinoglou cut-off points, each corresponding prevalence increased to 31.7% and 58.5%, respectively. Pooled patients in the overweight/obesity classification (Stavropoulos-Kalinoglou classification) exhibited a significantly higher number of swollen joints as compared to subnormal/normal body composition subjects (3.8±3.3 vs. 1.9±2.5; p=.02). Swollen joint count showed significant positive correlation with 6 out of 11 body composition parameters: BMI; arm and hip girths, triceps skin fold, body fat average determined by bioelectrical impedance analysis, and skin fold measurements. CONCLUSIONS: Prevalence of obesity in RA varies according to BMI cut-off points. Overweight and obesity were associated with higher inflammatory activity characterized by a higher count of tender and swollen joints. A positive correlation was found between swollen joint amount and the majority of the body fat mass indicators assessed. Body composition assessment/improvement should be an important part of the routine care of RA patients.

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.

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.

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 / 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.

Eficacia de rituximab comparado con ciclofosfamida en pacientes con manifestaciones graves de lupus eritematoso generalizado. Estudio aleatorizado y multicéntrico / Efficacy of rituximab versus cyclophosphamide in lupus patients with severe manifestations. A randomized and multicenter study

No existen a la fecha estudios controlados que evalúen la eficacia de rituximab (RTX) comparando con un tratamiento estándar, como ciclofosfamida, en pacientes con lupus eritematoso generalizado (LEG). Objetivo. Comparar la eficacia de RTX con ciclofosfamida en pacientes con manifestaciones graves de LEG. Material y método. Estudio clínico aleatorizado, multicéntrico, controlado y abierto en adultos con LEG activo. Se administró RTX o bolos de ciclofosfamida, con mismo esquema de esteroides. Se evaluó MEX-SLEDAI, dosis de esteroide y eventos adversos, durante 12 meses. Se empleó estadística descriptiva y comparativa. Resultados. Fueron 19 pacientes, 17 mujeres, con edad de: 35,7 años ±12,1, y tiempo de evolución de 5,6 años (0,35–30,8). No hubo diferencias en género, edad, tiempo de evolución, tratamientos previos o actividad de la enfermedad al inicio entre los grupos. Se observó descenso en el MEX-SLEDAI de 12 a 3 en el grupo 1, y de 9 a 2 en el grupo 2 (p=0,80). El grupo que recibió RTX tuvo mejoría más rápida. La dosis acumulada de esteroide fue similar. En ambos grupos se observó reducción en niveles de anti-DNAds e incremento de C3. Los eventos adversos fueron semejantes. Conclusión. Este ensayo clínico comparativo muestra que RTX puede ser tan eficaz como ciclofosfamida, para el control de manifestaciones graves del LEG, con respuesta más rápida. Los eventos adversos inmediatos y mediatos no fueron diferentes. RTX puede considerarse una opción terapéutica adecuada en este tipo de pacientes (AU)

There are no controlled studies that compare the efficacy of RTX with standard treatment, such as cyclophosphamide, in patients with systemic lupus erythematosus (SLE). Objective. The objective of this study was to compare the efficacy of rituximab to that of cyclophosphamide in patients with severe manifestations of SLE. Materials and method. This is a multicenter, randomized open and controlled trial in adults with a diagnosis of active SLE. Patients were randomized into two groups; group 1: treated with RTX and group 2: cyclophosphamide pulses with the same steroid scheme. We registered MEX-SLEDAI, steroid requirements and adverse events for 12 months. Descriptive and comparative statistic analysis was performed. Results. 19 patients were included, 17 females, mean age 35.7±12.1 years and duration of disease 5.6 years (range 0.35 to 30.8 years). There were no differences at baseline regarding gender, age, duration of disease, previous treatments or disease activity between both groups. MEX-SLEDAI was reduced from 12 to 3 in group 1 and from 9 to 2 in group 2 (p=0.80). Nevertheless, patients treated with RTX had a faster improvement. There was no difference in the cumulative steroid dose. Both groups had significant reduction in antinuclear antibody levels and similar increase in C3 levels. Adverse events were similar in both groups. Conclusion. This comparative clinical study in patients with SLE shows that rituximab can be as useful as cyclophosphamide for severe manifestations, maybe showing a faster response. Adverse events were no different. Rituximab should be considered as an adequate alternative for this group of patients (AU)

[Efficacy of rituximab versus cyclophosphamide in lupus patients with severe manifestations. A randomized and multicenter study]. / Eficacia de rituximab comparado con ciclofosfamida en pacientes con manifestaciones graves de lupus eritematoso generalizado. Estudio aleatorizado y multicéntrico.

UNLABELLED: There are no controlled studies that compare the efficacy of RTX with standard treatment, such as cyclophosphamide, in patients with systemic lupus erythematosus (SLE). OBJECTIVE: The objective of this study was to compare the efficacy of rituximab to that of cyclophosphamide in patients with severe manifestations of SLE. MATERIALS AND METHOD: This is a multicenter, randomized open and controlled trial in adults with a diagnosis of active SLE. Patients were randomized into two groups; group 1: treated with RTX and group 2: cyclophosphamide pulses with the same steroid scheme. We registered MEX-SLEDAI, steroid requirements and adverse events for 12 months. Descriptive and comparative statistic analysis was performed. RESULTS: 19 patients were included, 17 females, mean age 35.7±12.1 years and duration of disease 5.6 years (range 0.35 to 30.8 years). There were no differences at baseline regarding gender, age, duration of disease, previous treatments or disease activity between both groups. MEX-SLEDAI was reduced from 12 to 3 in group 1 and from 9 to 2 in group 2 (p=0.80). Nevertheless, patients treated with RTX had a faster improvement. There was no difference in the cumulative steroid dose. Both groups had significant reduction in antinuclear antibody levels and similar increase in C3 levels. Adverse events were similar in both groups. CONCLUSION: This comparative clinical study in patients with SLE shows that rituximab can be as useful as cyclophosphamide for severe manifestations, maybe showing a faster response. Adverse events were no different. Rituximab should be considered as an adequate alternative for this group of patients.

[Renal tumors smaller that 3 cm]. / Aproximación a los tumores renales menores de 3 cm.

OBJECTIVES: To analyze the characteristics of renal adenocarcinoma less than 3 cm in size and to determine the therapeutic approach in these tumors. METHODS: 286 cases with a histological diagnosis of renal adenocarcinoma that had undergone surgery at our hospital over the last 25 years were reviewed. RESULTS: The study showed 11 cases had renal tumors less than 3 cm in size. Six had been incidentally diagnosed. Two patients presented metastasis during the course of the disease and one patient had massive lymph node invasion (N3) at the time of diagnosis. Seven patients had a low tumor stage and grade. CONCLUSION: Renal tumors less than 3 cm in size have been considered to have a low potential for malignancy. However, the availability of more sophisticated diagnostic imaging techniques have led to earlier detection of renal masses, when the tumor is of a smaller size. Therefore determining whether the tumor is benign or malignant should be based exclusively on the histopathological findings. Treatment of this type of lesions is by surgery and performing a partial nephrectomy should be considered.

Lupus eritematoso generalizado (LEG) adulto e infantil. Evaluación mediante el índice de actividad de la enfermedad (SLEDAI) al establecer el diagnóstico y después del tratamiento / Systemic Lupus Erithematosus (SLE) in adults and infants. Evaluation the disease activity index (SLEDAI) in diagnosis and after treatment

El lupus eritematoso generalizado (LEG) se caracteriza por reactivaciones y remisiones. El índice de actividad de la enfermedad SLEDAI es un modelo válido de evaluación global de actividad de la enfermedad. Estudiamos 51 pacientes que reunieron 4 o más criterios para el diagnóstico de LEG (ACR 1982) en el Sevicio de Reumatología del Hospital Regional Mérida, Yucatán ISSSTE, de los cuales 38 iniciaron en la edad adulta (>16 años; F35 : M3) y 13 femeninos con inicio infantil (< 16 años). Se cuantificó el grado de actividad de la enfermedad en cada paciente, utilizando el cuestionario de la SLEDAI y se comparó el x ñ DE de la puntuación obtenida al establecer el diagnóstico de la enfermedad en nuestro servicio en ambos grupos, con la calificación obtenida en la evaluación final de ambos grupos respectivamente, mediante la prueba stadística T de Student. Se revisó el tratamiento que recibieron los pacientes con LEG, adultos e infantiles durante su seguimiento: prednisona, cloroquinas, azatioprina, pulsos de ciclofosfamida y pulsos de metilprednisolona. Los pacientes adultos tuvieron edad de inicio de 34.23 ñ 13.53 años y evolución de 6.13 ñ 3.92 años y los infantiles edad inicio de 12.07 ñ 1.84 años y evolución de 4.61 ñ 1.55 años. El valor de la puntuación de SLEDAI en los adultos (x ñ DE) fue mayor al inicio (18.94 ñ 9.05) que en la calificación final después del tratamiento (6.02 ñ 5.73) con una p<0.05, al igual que los infantiles que presentaron mayor puntaje al inicio (16.61 ñ 7.45) que al final (5.61 ñ 5.82) con una p<0.05. La disminución de la calificación SLEDAI en ambos grupos posteriormente al tratamiento nos indica una adecuada respuesta al tratamiento. Al mismo tiempo observamos que el cuestionario SLEDAI es reproducible en un Servicio de Reumatología de un hospital de tercer nivel de la provincia del país