AB0501 Genetic Markers of Glucocorticoid Adverse Drug Reactions in Rheumatoid Arthritis Patients

BackgroundAdverse drug reactions (ADRs) associated with glucocorticoid (GK) use are registered in 30-60% cases of GK therapy in rheumatoid arthritis (RA) patients when the prescribed daily doses exceed 10 mg during the period more than month. In the case of continuous GK therapy with the daily doses above 20 mg during the period more than 6 months GK dependence (GKD) develops. GK withdrawal syndrome is the main GKD criterion.ObjectivesTo reveal genetic markers of GK ADRs as GKD in RA patients.MethodsIn the observational trial of RA patients (n=522: 423 women, 99 men) detailed pharmacological anamnesis/catamnesis was collected. We investigated a number of genetic markers: erythrocytic antigens of AB0, Rh0, MN, P and Lewis blood groups, haptoglobin phenotypes, HLA antigens of A, B, C, DR, DQ locuses and Bw4-6 and DR51-53 super-types. Statistical significance was estimated by Fisher exact test (F). We selected the prognostic markers by means of Gamma correlation coefficient (RG). Likelihood ratio of positive (LR+) and negative (LR–) tests and prognostic odds ratio (pOR) of revealed markers as well as GK ADRs and GKD pre-test (Ppre) and post-test (Ppost) probabilities were calculated. Ppost was calculated by means of formula based on the Bayes theorem (Kullback information estimate).ResultsWe revealed GK ADRs in 50.9% RA patients (CI95 46.3-55.5%), in 54.6% women and in 34.9% men (F, p2-t=0,0015). GK ADRs as GKD was revealed in 45.5% RA patients (CI95 41.0-50.2%): in 48.8% women and in 31.3% men (p2-t=0.0048). Ppre=50% in women and Ppre=30% in men. Thus female sex is a predictor of GK ADRs and GKD. We revealed no association between AB0, Rh0, MN, P and Lewis blood groups and GKD (pi) for GKD presence and absence were calculated for 3 ranges: JHp1-1=0.252, JHp2-1=0.058, JHp2-2=0.204; total Ji=0.514 was above the significant level (Jxi≥0.5). Diagnostic coefficients (DC) used for the GKD prognosis in women were -4.7, -1.1 and 1.9 correspondingly, so Hp1-1 phenotype is GKD protective factor, and Hp2-2 phenotype is GKD risk factor.Some HLA antigens associated with GKD (table 1). Their informative values for the GKD prognosis were calculated (table 2).Table 1.Significant associations between HLA antigens and GKDHLA antigenRGZppcor1A190.512.90.00360.0284B120.362.90.00350.0546DR10.502.70.00620.0426DQ10.452.80.00470.01871p value after the Bonferroni correction.Table 2.Information value of HLA antigens for the GKD prognosisHLA antigenPhenotypeJxijJxiDCA19A19+0.280.672.1