The present findings establish the PDE3A-SLCO1C1 locus as a strong genetic marker of anti-TNF therapy response.

Anti-Tumor Necrosis Factor (anti-TNF) drugs are biologic agents commonly used to treat rheumatoid arthritis (RA). However, anti-TNFs are not effective in approximately one out of four treated patients. We conducted a Genome-Wide Association Study (GWAS) to identify the genetic variation associated with the response to anti-TNF therapy in RA. In the discovery stage, 372 RA patients treated with an anti-TNF agent (infliximab, adalimumab or etanercept) were analyzed and treatment response was defined at 12 weeks of therapy. We found a genome-wide significant association in the MED15 gene with the response to etanercept (P<1.5e-8). Using an independent cohort of 245 RA patients, we performed a replication study of the most significant GWAS associations. We replicated the association at the MED15 locus and found suggestive evidence of association in the previously associated MAFB locus. The results of this study suggest novel mechanisms associated with the response to anti-TNF therapies.

Este es un artículo publicado en acceso abierto bajo una Licencia Creative Commons

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 In the genetic association analysis, already known associations have been replicated, and unpublished associations have been identified in Paraguayan patients with IMIDs.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

Background:The mechanism of increased cardiovascular risk in RA is not well understood and is independent of traditional CV risk factors. Intima-media thickness of the common carotid wall measured by ultrasonogram is a safe and useful biomarker of early stage atherosclerosis that correlates with coronary involvement; and it correlates with severity and duration of disease. Several studies have shown a relationship between inflammation markers, endothelial dysfunction markers, and carotid involvement. (1)Objectives:To determine the presence of inflammation biomarkers and its relationship with subclinical atherosclerosis measured by carotid ultrasound, and with the clinical characteristics in patients with established Rheumatoid Arthritis (RA)Methods:Descriptive, cross sectional, prospective study, in a Paraguayan cohort of patients with RA meeting ACR/EULAR2010 criteria. This study had two phases: the first one, included a standardized questionnaire according to the variables included in the Cardiovascular Risk project (PINV15-0346), from the National Sciences and Technology Council (CONACYT), and physical examination; the second one included laboratory sample collection performed by a specialized laboratory for serum biomarkers measurement for cardiovascular risk prediction (i.e endothelin, alpha-TNF, E-selectin, homocysteine, apolipoprotein, fibrinogen, and high sensitivity-CRP levels) and carotid ultrasound evaluation by a trained specialist, to evaluate subclinical atherosclerosis. Subclinical atherosclerosis was defined as carotid intima-media thickness (CIMT) >0,9mm and/or presence of carotid plaques. All patients signed informed consent. SPSS 23rd version was used for data analysis. Quantitative variables were presented as means and qualitative as frequencies. Chi square test was performed for comparisons between dichotomous variables and t Student for continuous, and p ≤ 0.05 for statistical significance.Results:100 patients were included, 87% were women, mean disease duration 130.9±102.64 months, 77% were RF positive, and 84.4% were ACPA positive, 43.4% had bone erosions, mean ESR-DAS28 was 3,42±1,1; 30% had remission criteria. 39% had extra-articular manifestations.Elevated serum biomarkers were found: fibrinogen >400 mg/dL 88.2%, high sensitivity-CRP (hs-CRP) >5mg/dL 42.9%, endothelin >2 ng/mL 20%, alpha-TNF >15,6 pg/mL 13.1%, E-selectin >79,2 ng/mL 6%. 25.3% had CIMT >0,9 mm and mean CIMT was 0.68±0.25mm. 27.14% had carotid plaques. Patients with CIMT>1mm had higher frequency of family history of arterial hypertension (p=0.006), greater mean disease duration (p=0.0007), hip circumference (p=0.014), blood pressure (SBP p=0.038, DBP p=0.027), HAQ levels (p=0,019) and hs-CRP levels (p=0.013), also lower mean height (p=0,04); while carotid plaques were related to higher homocysteine (p=0.026) and hs-CRP levels (p=0.024).Conclusion:A considerable percentage of patients had subclinical atherosclerosis. Patients with CIMT>0,9mm had a longer disease duration, higher HAQ levels, hip circumference, as well as higher BP. High levels of hs-CRP were more frequently related to the presence of subclinical atherosclerosisReferences:[1]Aday, A. targeting residual inflammatory risk: a shifting paradigm for atherosclerotic disease. Frontiers in cardiovascular medicine. 2019. 6:16.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403155/pdf/fcvm-06-00016.pdfDisclosure of Interests:None declared