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 In the genetic association analysis, already known associations have been replicated, and unpublished associations have been identified in Paraguayan patients with IMIDs.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.

The benefit-risk balance for biological agents in juvenile idiopathic arthritis: a meta-analysis of randomized clinical trials.

OBJECTIVE: To assess the net benefit of biological agents (BA) used in JIA. METHODS: We systematically searched databases up to March 2019 for randomized controlled trials (RCT) performed in JIA disease. Separate random-effects meta-analyses were conducted for efficacy (ACR paediatric score 30%, ACRpedi30) and serious adverse events for safety. In order to standardize the baseline risk, we performed a meta-analysis of baseline risk in the control group (for both efficacy and safety meta-analysis). The net benefit was determined as the risk difference of efficacy subtracted by the risk difference of safety. RESULTS: We included 19 trials: 11 parallel RCTs (754 patients) and 8 withdrawal RCTs (704 patients). The net benefit ranged from 2.4% (adalimumab) to 17.6% (etanercept), and from 2.4% (etanercept) to 36.7%, (abatacept) in parallel and withdrawal trials assessing non-systemic JIA, respectively. In the systemic JIA category, the net benefit ranged from 22.8% (rilonacept) to 70.3% (canakinumab), and from 32.3% (canakinumab) to 58.2% (tocilizumab) in parallel and withdrawal trials, respectively. CONCLUSION: The results suggest that a greater number of patients experienced therapeutic success without serious adverse events in the systemic onset JIA category compared with the BAs for non-systemic JIA categories. Baseline risk, design of trial and JIA categories impact the measure of net benefit of BAs in JIA patients.

Safety and Survival Associated with Biologic Therapies: First Report of the Biobadaguay on the Paraguayan-Uruguayan Registry of Adverse Events with Biologic Therapies. / Seguridad y supervivencia de las terapias biológicas: primer informe del registro paraguayo-uruguayo de acontecimientos adversos con terapias biológicas Biobadaguay.

OBJECTIVE: Analyze adverse events (AE) and survival associated with biologic therapies (BT) in the Biobadaguay, the Paraguayan Uruguayan registry of adverse events. METHODS: Prospective, observational study of undetermined duration. Patients on BT at initiation and controls were included. Clinical, biological and treatment variables were registered. RESULTS: A total of 826 registers were entered (650 BT and 176 controls); 70.9% were women and rheumatoid arthritis (RA) was the most frequent diagnosis (63.2%). The BT most often used was adalimumab and the main cause of discontinuation was loss of efficacy (42.1%). The incidence of AE of patients on BT was 143.9 (128.8-160.8) per 1000 patients/year. In the comparative study of AE related to diagnosis, juvenile idiopathic arthrosis (JIA) was associated with a higher overall number of AE (RTI = 2.3; 95%CI: 1.6-3.4; P = 4.27 ×10-6), whereas RA was associated with a higher number of serious AE (RTI = 2.2; 95% CI: 1.2-4.1; P =1.17 ×10-2). On the other hand, treatment with tocilizumab was associated with a higher rate of AE (RTI = 2.69; 95% CI: 1.9-3.82; P = 3.13 ×10-8). In JIA, treatment with corticosteroids and number of previous BT was associated with a decrease in BT survival. CONCLUSION: In this first report of the Biobadaguay registry, the main cause of BT discontinuation was loss of efficacy. In terms of the diagnosis involved, RA and JIA were associated with a higher risk of AE. In this registry, variables related to a shorter survival of BT were identified.

Vacunación contra el SARS-CoV-2 en pacientes paraguayos con artritis reumatoide

Introducción: La vacunación en poblaciones expuestas a mayor riesgo de enfermedad grave y muerte consecuentes a la infección por SARS-CoV-2, ha generado un gran impacto en la salud pública mundial. Indudablemente, el beneficio ha sido evidenciado mayormente en personas con comorbilidades crónicas, donde la artritis reumatoide (AR) juega un rol importante. Objetivo: Analizar la vacunación contra Sars-CoV-2 en pacientes paraguayos con AR, durante la pandemia COVID-19. Métodos: Se realizó un estudio multicéntrico, en el que se analizó transversalmente a una cohorte de pacientes con AR, durante el periodo de octubre a diciembre del año 2022. Para el estudio se registraron variables clínico-epidemiológicas y relacionadas con la vacunación (i.e. acceso a la vacunación, tipo, número de dosis). Se realizó un análisis descriptivo de las variables con el software R-4.3.2. Resultados: Se incluyeron 568 pacientes, 84,1% eran mujeres, con un promedio de edad de 55,5±13,9 años. El 88,7% (504) pacientes, recibieron al menos una dosis de vacuna contra SARS-CoV-2. 85% (483) recibieron dos dosis, mientras que el 60,9% (344) pacientes recibieron el primer refuerzo, y 21,2% el segundo refuerzo. Conclusiones: En esta serie de pacientes paraguayos con AR el porcentaje de vacunación contra SARS-CoV-2 fue más elevado que el registrado en la población general del país. Esto podría estar relacionado con la prioridad de esta población para acceder a las vacunas y a la insistencia de sus médicos en completar el esquema de vacunación.

Introduction: Vaccination in populations exposed to increased risk of severe disease and death consequent to SARS-CoV-2 infection has generated a major impact on global Public Health. Certainly, the benefit has been evidenced mostly in people with chronic comorbidities, where rheumatoid arthritis (RA) plays an important role. Objective: To analyze vaccination against Sars-CoV-2 in paraguayan patients with rheumatoid arthritis (RA) during the COVID19 pandemic. Methods: A multicenter study was carried out, in which a cohort of patients with RA was analyzed cross-sectionally, during the period from October to December 2022. For the study, clinical-epidemiological and vaccination-related variables were recorded (i.e. access to vaccination, type, number of doses). A descriptive analysis of the variables was carried out with the R-4.3.2 software. Results: 568 patients were included, 84.1% were female, with an average age of 55.5±13.9 years. 88.7% (504) patients received at least one dose of SARS-CoV-2 vaccine, 85% (483) received two doses, while 60.9% (344) patients received the first booster, and 21.2% the second booster. Conclusions: In this series of Paraguayan patients with RA the percentage of vaccination against SARS-CoV-2 was higher than that registered in the general population of the country. This could be related to the priority of this population to access vaccines and the insistence of their physicians to complete the vaccination schedule.

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.

Variation at FCGR2A and functionally related genes is associated with the response to anti-TNF therapy in rheumatoid arthritis.

OBJECTIVE: Anti-TNF therapies have been highly efficacious in the management of rheumatoid arthritis (RA), but 25-30% of patients do not show a significant clinical response. There is increasing evidence that genetic variation at the Fc receptor FCGR2A is associated with the response to anti-TNF therapy. We aimed to validate this genetic association in a patient cohort from the Spanish population, and also to identify new genes functionally related to FCGR2A that are also associated with anti-TNF response. METHODS: A total of 348 RA patients treated with an anti-TNF therapy were included and genotyped for FCGR2A polymorphism rs1081274. Response to therapy was determined at 12 weeks, and was tested for association globally and independently for each anti-TNF drug (infliximab, etanercept and adalimumab). Using gene expression profiles from macrophages obtained from synovial fluid of RA patients, we searched for genes highly correlated with FCGR2A expression. Tag SNPs were selected from each candidate gene and tested for association with the response to therapy. RESULTS: We found a significant association between FCGR2A and the response to adalimumab (P=0.022). Analyzing the subset of anti-CCP positive RA patients (78%), we also found a significant association between FCGR2A and the response to infliximab (P=0.035). DHX32 and RGS12 were the most consistently correlated genes with FCGR2A expression in RA synovial fluid macrophages (P<0.001). We found a significant association between the genetic variation at DHX32 (rs12356233, corrected P=0.019) and a nominally significant association between RGS12 and the response to adalimumab (rs4690093, uncorrected P=0.040). In the anti-CCP positive group of patients, we also found a nominally significant association between RGS12 and the response to infliximab (rs2857859, uncorrected P=0.042). CONCLUSIONS: In the present study we have validated the FCGR2A association in an independent population, and we have identified new genes associated with the response to anti-TNF therapy in RA.

Eventos cardiovasculares en pacientes con lupus eritematoso sistémico y su asociación con factores de riesgo cardiovascular / Cardiovascular events in patients with systemic lupus erythematosus and their association with cardiovascular risk factors

Los pacientes con lupus eritematoso sistémico (LES) presentan un elevado riesgo cardiovascular, cuya etiología aún no se conoce con exactitud. Se ha postulado que podrían estar implicados tanto los factores de riesgo cardiovascular tradicionales como determinados factores relacionados a la propia enfermedad. En el presente estudio, se ha analizado a un grupo de pacientes con LES y se ha determinado la presencia de eventos cardiovasculares (EC), así como también a los factores de riesgo cardiovascular (FRCV) tradicionales y los relacionados a la enfermedad. Además, se ha estudiado la asociación de estos últimos con el desarrollo de un EC (i.e. infarto de miocardio agudo, hipertensión arterial, accidente cerebrovascular). En el total de 83 pacientes analizados, el EC más frecuente fue la hipertensión arterial (HTA) en un 41%. En relación a los FRCV tradicionales, el sedentarismo fue el hallado con más frecuencia, seguido por la obesidad. Al analizar cada EC y su asociación con los FRCV, se observó una asociación significativa entre la HTA y la dislipidemia (p = 0,001). En relación a los accidentes cerebrovasculares, se observó una asociación con la edad avanzada (p = 0,037) y la presencia de síndrome antifosfolípido (p = 0,001). La elevada frecuencia de EC en los pacientes con diagnóstico de LES pone de manifiesto la necesidad de una evaluación inicial detallada para estratificar tanto FRCV tradicionales como los no tradicionales de los pacientes con LES para permitir una mejor supervisión y así mejorar el pronóstico cardiovascular de estos pacientes

Patients with systemic lupus erythematosus (SLE) have a high cardiovascular risk, whose etiology is not yet known accurately. It has been postulated that both traditional cardiovascular risk factors and certain factors related to the disease itself could be involved. In this study, we analyzed a group of patients with SLE and determined the presence of cardiovascular events (CE), and cardiovascular risk factors (CVRF), both traditional ones and those inherent to the disease. Besides, the association of the risk factors with the development of a CE (i.e. acute myocardial infarction, arterial hypertension (AHT), cerebrovascular accident) was studied. In a total of 83 patients, the most frequent CE was AHT in 41% of the patients. In relation to traditional CVRF, sedentary lifestyle was the most frequent (72%) followed by obesity. When we analyzed each CE and their association with the CVRF, we found a significant association between AHT and dyslipidemia (p = 0.001). In relation to cerebrovascular accidents, we observed an association with advanced age (p = 0.037) and presence of antiphospholipid syndrome (p = 0.001). The high frequency of CE in patients with diagnosis of SLE showed the need of a detailed initial assessment to stratify both traditional and non-traditional CVRF of a patient with SLE to allow a better monitoring and thus improve cardiovascular prognosis of these patients.

Can we predict the severity of pulmonary hypertension in patients with scleroderma?

OBJECTIVES: To describe the clinical-biological characteristics of patients with scleroderma (SSc) and pulmonary artery hypertension (PAH). To establish the relationship between pulmonary functional tests (PFT), Doppler echocardiography (ECHO) and the severity of the PAH. MATERIAL AND METHODS: Retrospective study of patients with scleroderma treated at a tertiary center. All participants received a protocol study, which included a complete analysis and additional tests: Doppler Echocardiography and pulmonary functional tests (PFT) with carbon monoxide diffusing capacity (DLCO). RESULTS: Overall, 331 patients were treated, including 68 (20.5%) with PAH. The limited subtype of Scleroderma was the most prevalent. The Person's correlation coefficient was used for the following variables: FVC-sPAP, FVC/DLCO-sPAP, DLCO-sPAP and TRV-sPAP, showed a significant moderate linear association in the relationship DLCO-sPAP and TRV-sPAP. 29 deaths occurred, with 12 of them related to PAH. The median time between the PAH diagnosis and death was 1.8 years. CONCLUSIONS: The decrease in DLCO and the increase in TRV are negative predictor factor of PAH which, at the same time, means a worsening prognosis for patients with Scleroderma.

Morbimortalidad cardiopulmonar en pacientes con lupus eritematoso sistémico / Cardiopulmonary morbidity and mortality in patientswith systemic lupus erythematosus

Los pacientes con diagnóstico de lupus eritematoso sistémico (LES) presentan unaelevada morbi-mortalidad asociada a las manifestaciones cardiopulmonares que sedesarrollan durante la evolución de la enfermedad. En este sentido, se han descrito dospicos de incidencia de mortalidad de esta enfermedad inmunológica. El primer pico estárelacionado a la actividad de la enfermedad y se observa durante los tres primeros añosposteriores al diagnóstico. El segundo pico está relacionado principalmente a lascomplicaciones cardiopulmonares y se presenta entre los 4 y 20 años posteriores aldiagnóstico. Si bien la mortalidad temprana ha disminuido gracias a un mayorconocimiento de la fisiopatología de la enfermedad y al uso de terapiasinmunosupresoras, la mortalidad tardía presenta un aumento progresivo de sufrecuencia a pesar del avance en el manejo terapéutico. El estudio de estascomplicaciones se ha convertido en un tema de gran interés debido a su efecto negativoen el pronóstico de los pacientes que las presentan. Algunos estudios epidemiológicossugieren que los pacientes con LES tienen un mayor riesgo cardiovascular al sercomparados con la población sana. En este sentido, se ha descrito que estos presentanun mayor riesgo de desarrollar eventos cardiovasculares (infarto agudo del miocardio,accidente cerebro vascular y enfermedad arterial periférica) en comparación con lapoblación general. De forma asociada, se ha objetivado que la presencia demanifestaciones pleuro-pulmonares (pleuritis lúpica, neumonitis, hemorragia pulmonar,embolismo pulmonar e hipertensión pulmonar) aumenta la morbimortalidad de lospacientes con LES. El conocimiento adecuado de las complicaciones cardiopulmonaresen los pacientes con diagnóstico de lupus eritematoso sistémico permitirá realizar unmanejo individualizado y por lo tanto más eficaz, permitiendo disminuir la morbilidadasociada a las citadas complicaciones...

Patients with the diagnosis of systemic lupus erythematosus (SLE) have an elevatedmorbidity and mortality from cardiopulmonary complications that develop during theevolution of the disease. Considering the incidence of the mortality in this immunologic disease, two peaks have been described. The first one is related to the immune activityitself and it is observed in the first three years the diagnosis. The second peak is relatedto the cardiopulmonary complications and it is observed after 4 to 20 years afterdiagnosis. Although, early mortality has diminished due to better knowledge of thephysiopathology of the disease and to the use of immunosuppressive drugs, latemortality has a progressive increment despite advances in the therapeutic management.There is a great interest in the study of these complications due to the negative impacton the prognosis of the SLE patients. Some epidemiologic studies suggest that patientswith SLE have a higher cardiovascular risk than the healthy population. Indeed, theyhave greater risk of developing cardiovascular events (acute myocardial infarction,cerebrovascular accidents, and peripheral artery disease) in comparison to the generalpopulation. The presence of pulmonary complications (pleuritic effusion, pneumonitis,pulmonary hemorrhage, pulmonary embolism, pulmonary hypertension) increases themortality in SLE patients. The proper knowledge of the cardiopulmonary complicationsin SLE patients will provide an individual and more effective management allowing adecrease in morbidity and mortality...