Association of class II HLA alleles with susceptibility to develop immune-mediated diseases in Paraguayan patients.

Genetic and nongenetic factors are involved in the pathogenesis of immune-mediated inflammatory diseases (IMIDs). The best-known genetic factor for susceptibility to IMIDs is the human leukocyte antigen (HLA). The aim of the present study was to evaluate the association of HLA class II genes with the risk of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (SSc) in the Paraguayan population. We included 254 patients with IMIDs (101 SLE, 103 RA, and 50 SSc) and 50 healthy controls. The haplotypes of five genes corresponding to HLA class II genes and their relationship to the IMIDs studied were determined. Note that 84.6% were women, with a mean age of 43.4 ± 14 years. Among the associated HLA alleles, we found the previously identified risk factors in other populations like HLA-DRB1*03:01 and HLA-DRB1*14:02 for RA, as well as new ones not previously identified, such as DPA1*02:01 for SLE and, DB1*02:01 for RA and SSc. In the genetic association analysis, already known associations have been replicated, and unpublished associations have been identified in Paraguayan patients with IMIDs. This is the first genetic association study in Paraguayan patients with IMIDs.

Association between vitamin D deficiency and disease activity in Paraguayan patients with systemic lupus erythematosus / Asociación entre la deficiencia de vitamina D y la actividad de la enfermedad en pacientes paraguayos con lupus eritematoso sistémico

ABSTRACT Objective: To identify the association between vitamin D (VD) concentrations and the activity of systemic lupus erythematosus (SLE) and determine a supplementation dose that allows patients to maintain adequate levels of VD. Methods: Longitudinal, observational study. Serum levels of 25-hydroxy-VD were measured in 100 Paraguayan SLE patients from the Hospital de Clínicas between 2016 and 2018. To analyze the response to different doses of VD supplementation, 50 patients received 1000IU/day and the other 50 patients received 2000IU. SLE disease activity measured by SELENA-SLEDAIwas scored before and after supplementation. Results: The mean age was 27.5 ±9.8 years, 88.9% of patients presented mild disease activ ity and 11.1% presented moderate to severe activity. The mean VD concentration was 30.8 ± 11.8 ng/mL. A total of 34% of patients presented VD insufficiency and 13% VD defi ciency. There was an inverse relationship between VD concentrations and SLE disease activity (p = 0.03). Increasing levels of serum VD are associated with supplementation of 2000 IU/day (p = 0.0224). Conclusion: SLE activity was associated with low levels of VD. In our cohort, SLE patients required a supplementation dose equal to or greater than 2000 IU/day to increase their serum VD.

R E S U M E N Objetivo: Identificar la asociación entre las concentraciones de vitamina D (VD) y la actividad del lupus eritematoso sistémico (LES), además de encontrar una dosis de suplementación que les permita a los pacientes mantener niveles adecuados de VD. Métodos: Estudio observacional longitudinal. Se midieron los niveles séricos de 25-hidroxi-VD en 100 pacientes paraguayos con LES, del Hospital de Clínicas, entre los años 2016 y 2018. Para analizar la respuesta a diferentes dosis de suplementación con VD, 50 pacientes recibieron 1.000 UI/día y los otros 50 pacientes recibieron 2.000 UI/día. La actividad de la enfermedad del LES medida por SELENA-SLEDAI se puntuó antes y después de la suplementación. Resultados: La media de edad fue de 27,5 ± 9,8 años, el 88,9% de los pacientes presentó actividad leve de la enfermedad y el 11,1% presentó actividad moderada a severa. La concentración media de VD fue de 30,8 ± 11,8 ng/ml. El 34% de los pacientes presentó insuficiencia de VD y el 13%, deficiencia de VD. Hubo una relación inversa entre las concentraciones de VD y la actividad de la enfermedad del LES (p = 0,03). Los niveles crecientes de VD en suero se asocian con una suplementación de 2.000 UI/día (p = 0,0224). Conclusión: La actividad del LES se asoció con niveles bajos de VD. En nuestra cohorte, los pacientes con LES requirieron una dosis de suplementación igual o superior a 2.000 UI/día para aumentar su VD sérica.

Relationship between serum lipopolysaccharide binding protein levels, disease activity, and clinical characteristics in Paraguayan patients with systemic lupus erythematosus.

INTRODUCTION: Systemic exposure to bacterial components like lipopolysaccharide (LPS) is among the non-genetic factors that could be involved in the onset or progression of systemic lupus erythematosus (SLE). Lipopolysaccharide-binding protein (LBP) participates in the recognition of LPS and in the inflammatory response. Here, we investigated LBP in SLE patients and its relationship with disease activity and SLE phenotypes. METHODS: Eighty-one adult patients with SLE from IMID-PY biobank (Paraguay) were included in the study. The clinical and laboratory variables were used to determine SLE activity. LBP levels were determined by ELISA in SLE patients and age- and sex-matched population-based controls. RESULTS: Patients with SLE have lower levels of circulating LBP compared to healthy controls (p = 0.0007). No significant correlation was found between serum LBP levels and disease activity. A significant difference was observed in LBP levels with regard to the presence of arthritis (p = 0.026). No other relation was found with clinical parameters. CONCLUSIONS: We found low levels of LBP in SLE patients compared to the control group. No correlation was detected between LBP levels and disease activity. It would be interesting for future studies to evaluate the impact of low levels of LBP on lupus immunopathogenesis.

A longitudinal multiethnic study of biomarkers in systemic lupus erythematosus: Launching the GLADEL 2.0 Study Group.

Introduction: After more than 20 years of sustained work, the Latin American Group for the Study of Lupus (GLADEL) has made a significant number of contributions to the field of lupus, not only in the differential role that race/ethnicity plays in its course and outcome but also in several other studies including the beneficial effects of using antimalarials in lupus patients and the development of consensus guidelines for the treatment of lupus in our region. Methods: A new generation of "Lupus Investigators" in more than 40 centers throughout Latin America has been constituted in order to continue the legacy of the investigators of the original cohort and to launch a novel study of serum and urinary biomarkers in patients with systemic lupus erythematosus. Results: So far, we have recruited 807 patients and 631 controls from 42 Latin-American centers including 339 patients with SLE without renal involvement, 202 patients with SLE with prevalent but inactive renal disease, 176 patients with prevalent and active renal disease and 90 patients with incident lupus nephritis. Conclusions: The different methodological aspects of the GLADEL 2.0 cohort are discussed in this manuscript, including the challenges and difficulties of conducting such an ambitious project.

Transverse Myelitis in Systemic Lupus Erythematosus: Clinical Features and Prognostic Factors in a Large Cohort of Latin American Patients.

BACKGROUND: Acute transverse myelitis (ATM) is an infrequent but severe complication of systemic lupus erythematosus (SLE). The purpose of study was to describe clinical features and prognostic factors of patients with SLE-related ATM. METHODS: In this medical records review study, data were collected from 60 patients from 16 centers seen between 1996 and 2017 who met diagnostic criteria for SLE and myelitis as defined by the American College of Rheumatology/Systemic International Collaborating Clinics and the Working Group of the Transverse Myelitis Consortium, respectively. Objective neurological impairment was measured with American Spinal Injury Association Impairment Scale (AIS) and European Database for Multiple Sclerosis Grade Scale (EGS). RESULTS: Among patients included, 95% (n = 57) were female, and the average age was 31.6 ± 9.6 years. Myelitis developed after diagnosis of SLE in 60% (n = 36). Symmetrical paraparesis with hypoesthesia, flaccidity, sphincter dysfunction, AIS = A/B, and EGS ≥ 8 was the most common presentation. Intravenous methylprednisolone was used in 95% (n = 57), and 78.3% (n = 47) received intravenous cyclophosphamide. Sensory/motor recovery at 6 months was observed in 75% (42 of 56), but only in 16.1% (9 of 56) was complete. Hypoglycorrhachia and EGS ≥ 7 in the nadir were associated with an unfavorable neurological outcome at 6 months (p < 0.05). A relapse rate during follow-up was observed in 30.4% (17 of 56). Hypoglycorrhachia and hypocomplementemia seem to be protective factors for relapse. Intravenous cyclophosphamide was associated with time delay to relapse. CONCLUSIONS: Systemic lupus erythematosus-related ATM may occur at any time of SLE course, leading to significant disability despite treatment. Relapses are infrequent and intravenous cyclophosphamide seems to delay it. Hypoglycorrhachia, hypocomplementemia, and EGS at nadir are the most important prognostic factors.

Prevalencia de valores inadecuados de vitamina D y factores de riesgo asociados en jóvenes universitarios de Asunción / Prevalence of inadequate vitamin D values and associated risk factors in university students of the city of Asunción

La vitamina D es una hormona cumple una función en la regulación de numerosos genes que participan en la proliferación y maduración celular. El objetivo de este trabajo fue determinar la prevalencia de valores inadecuados de esta vitamina en jóvenes sanos de Asunción e identificar los posibles factores de riesgo asociados. Estudio observacional descriptivo basado en datos clínico-epidemiológicos y en la determinación de la 25-hidroxivitamina D (25-OH vitamina D) por el método de quimioluminiscencia (CMIA). Se consideró valor adecuado ≥30 ng/dl, inadecuado por debajo de este rango y deficiente ≤20 ng/dl. El análisis estadístico se realizó con el programa R-proyect. Para establecer factores de riesgo para tener deficiencia de vitamina D se utilizó regresión logística bi y multivariante. Se incluyeron 817 jóvenes universitarios de edad promedio 21 años. La concentración de vitamina D tuvo una media de 25 ± 8 ng/dl, oscilando entre 64,3 y 2,4 ng/dl. El 75,5% de los participantes tenían valores inadecuados de vitamina D. La deficiencia de vitamina D fue significativamente (p = 0,006) más frecuente en mujeres, personas con sobrepeso (p = 0,03), con falta de exposición al sol (p = 0,001) y con sedentarismo (p = 0,0001). Este estudio confirma la elevada prevalencia de valores inadecuados de vitamina D en nuestro país y permite definir un perfil de muy alto riesgo para las jóvenes sedentarias y con sobrepeso, lo que justifica una atención especial de parte de los médicos y las instituciones responsables de la salud pública en nuestro país(AU)

Vitamin D is a hormone that plays a role in the regulation of numerous genes involved in cell proliferation and maturation. The objective of this work was to determine the prevalence of inadequate values of this vitamin in healthy young people of the city of Asunción and to identify the possible risk factors associated with it. Descriptive observational study based on clinical-epidemiological data and in the determination of 25-hydroxyvitamin D (25-OH vitamin D) by the chemiluminescence method (CMIA). It was considered appropriate values ≥30 ng/dl, inappropriate below this range and deficient <20 ng/dl. Statistical analyzes were carried out with the R-project program. To establish the association, bivariate and multivariate logistic regression was used. We included 817 university students with an average age of 21 years. The average value of the vitamin D concentration was 25 ± 8 ng/dl, ranging from 64.3 to 2.4 ng/dl. Inadequate vitamin D values were found in 75.5% of the participants. Vitamin D deficiency was significantly (p <0.006) more frequent in women, overweight people (p <0.03), lack of sun exposure (p = 0.001) and sedentary lifestyle (p = 0.0001). This study confirms the high prevalence of inadequate vitamin D values in our country and allows us to define a very high risk profile for sedentary and overweight young women, which justifies special attention from physicians and institutions responsible for public health in our country(AU)

Características clínico-epidemiológicas de los pacientes de la cohorte Lupus Paraguay (2013-2014) / Characteristics clinical-epidemiological of the patients of the Lupus Paraguay cohort (2013-2014)

El lupus eritematoso sistémico (LES) es una enfermedad autoinmune, de etiología desconocida que presenta manifestaciones clínicas de gravedad y curso impredecible. Se ha observado en varias cohortes que esta enfermedad tiene un comportamiento más agresivo en la población no caucásica debido a diferencias socioeconómicas, demográficas y genéticas. El objetivo del estudio es describir las características clínico-epidemiológicas de los pacientes con LES incluidos en la cohorte LUPUS-PY y la situación actual de las muestras custodiadas en el BIOBANCO IMID-PY. Estudio basado en la revisión de historias clínicas y en los cuestionarios clínico-epidemiológicos del día de la inclusión al registro LUPUS-PY. Se calcularon las frecuencias para las variables categóricas y las medias con su desvío estándar para las continuas. Se incluyeron de forma consecutiva, 83 pacientes con diagnóstico de LES (edad media: 34,4±10,0 años), el 86,7% era del sexo femenino, el 55% provenía de Asunción, el 49,1% tenía nivel educativo básico, el 45% percibía un ingreso mensual de un sueldo mínimo (aproximadamente 350 dólares americanos) o menos. El 46,8% no realizaba ningún tipo de actividad física. La media del tiempo trascurrido desde el inicio de los síntomas y el diagnóstico del LES fue de 9,3±13,7 años y el tiempo de evolución de la enfermedad hasta el ingreso al registro fue de 5,9±6,3. El 16% refirió antecedentes familiares de enfermedades autoinmunes. La primera manifestación de la enfermedad más descripta fue la articular (45%). Los pacientes con LES de nuestro centro tienen características tanto clínicas como epidemiológicas similares a las reportadas por otras cohortes(AU)

Manifestaciones clínicas y laboratoriales en el lupus eritematoso sistémico - LES / Clinical and laboratory manifstations in systemic Lupus erythematosus

El Lupus eritematoso sistémico (LES) es una enfermedad autoinmune compleja que se caracteriza por su capacidad de afectar a diversos órganos, lo que determina las diferentes manifestaciones clínicas objetivadas durante la evolución de la enfermedad. De forma asociada se ha descrito que estas manifestaciones presentan una variación geográfica o étnica, siendo por lo general menos grave en pacientes con ascendencia europea que en aquellos que presentan ascendencia africana, asiática o hispana. Alteraciones, tanto del sistema inmune adaptativo (células T y B) como del innato (Toll like receptorx-TLR), contribuyen al desarrollo del LES. Las células B tienen su papel en la producción de los autoanticuerpos (i.e. anticuerpos anti-ADN y anticuerpos anti-nucleosoma) y de determiandas citocinas. Las pruebas de laboratorio son de gran valor cuando se evalúa a un paciente con sospecha de enfermedad autoinmune. Los resultados pueden confirmar el diagnóstico, estimar la severidad de la enfermedad, evaluar el pronóstico y son de suma utilidad para el seguimiento de la actividad del LES.

Systemic Lupus Erythematosus (SLE) is a complex autoimmnune disease characterizedby its ability to affect different organs, which determines different clinical manifestationsobserved during the course of the disease. It has been described that thesemanifestations have geographic or ethnic varations being generally less serious in patientsof European descent than in those with African, Asian or Hispanic descents. Alterations ofboth the adaptative (T and B cells) and innate (Toll like receptorx-TLR) immnune systemscontribute to the development of SLE. B cells have a role in the production of autoantibodies(i.e. anti-DNA and anti-nucleosome antibodies) and some cytokines. Laboratorytests are invaluable when evaluating a patient with suspected autoimmune disease. Theresults can confirm the diagnosis, estimate the severity of the disease, assess prognosisand are extremely useful for monitoring the activity of SLE.

GWAS replication study confirms the association of PDE3A-SLCO1C1 with anti-TNF therapy response in rheumatoid arthritis.

AIM: The present study was undertaken to replicate the association of candidate genes for anti-TNF response in rheumatoid arthritis. Candidate genes were selected from a recent genome-wide association study on anti-TNF response performed in a population from Denmark. MATERIALS & METHODS: Genomic DNA was obtained from 315 Spanish rheumatoid arthritis patients having received an anti-TNF agent as their first biological therapy. SNPs from NR2FR2, MAP2K6, CBLN2 and PDE3A-SLCO1C1 candidate loci were genotyped. RESULTS: The PDE3A-SLCO1C1 locus rs3794271 SNP showed a highly significant association with anti-TNF treatment response (p = 1.74 × 10⁻5). Combining the statistical evidence from the Spanish and Danish rheumatoid arthritis cohorts, the associated rs3794271 SNP reached a genome-wide significance level of association (p = 3.3 × 10⁻¹°). CONCLUSION: The present findings establish the PDE3A-SLCO1C1 locus as a strong genetic marker of anti-TNF therapy response.