OP0045 Genetic markers of sulphasalazine adverse reactions in rheumatoid arthritis patients
Authors: N. Soroka, V. Yagur, N. Dostanko
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Adverse drug reactions (ADR) associated with sulphasalazine (SS) use and leading to its withdrawal occur in 20-30% of rheumatoid arthritis (RA) patients treated with SS and include dose-dependent (gastrointestinal and central nervous system abnormalities) and immunomediated (vasculitis, pneumonitis, hepatitis, leucopenia, agranulocytosis, haemolytic and aplastic anemia) events [1,2]. <h3>Objectives</h3> To reveal genetic markers associated with SS adverse reactions in RA patients and to estimate their prognostic value. <h3>Methods</h3> In the observational trial of RA patients (n=500: 405 women, 95 men) treated with disease modifying antirheumatic drug SS was used in 11.6% (58/500) of patients. SS withdrawal due to the adverse reactions was registered in 43.1% (25/58; CI<sub>95</sub> 31.2-55.9%) of them. This level of ADR frequency associated with SS use was considered as SS adverse reactions pretest probability (P<sub>pre</sub>). Association between SS ADR and a number of genetic markers (erythrocytic antigens of AB0 and Rh<sub>0</sub> blood groups and leucocyte antigens of A, B, C, DR, DQ locuses of major histocompatibility complex) was investigated. All markers were dichotomic (marker<sup>+</sup>, marker<sup>–</sup>). Statistical significance of the revealed association was estimated by Fisher exact test. Likelihood ratio of positive (LR<sup>+</sup>) and negative (LR<sup>–</sup>) tests and prognostic odds ratio (pOR) as well as post-test probability (P<sub>post</sub>) of SS adverse reactions were calculated. <h3>Results</h3> Gastrointestinal ADR were registered in 20.7% (12/58) of patients, mucocutaneous ADR in 8.6%, urine analysis abnormalities in 8.6%, and haematological abnormalities in 5.2% of patients. The rates of SS adverse events were significantly higher in the case of following phenotypes: –HLA-A1<sup>+</sup> vs HLA-A1<sup>–</sup>: 80.0% (8/10) and 35.5% (11/31), p<sub>2-t</sub>=0.0265; –HLA-A2<sup>–</sup> vs HLA-A2<sup>+</sup>: 64.0% (16/25) and 18.8% (3/16), p<sub>2-t</sub>=0.0092; –HLA-B8<sup>+</sup> vs HLA-B8<sup>–</sup>: 87.5% (7/8) and 36.4% (13/33), p<sub>2-t</sub>=0.0157; –HLA-B15<sup>–</sup> vs HLA-15<sup>+</sup>: 54.5% (18/33) and 12.5% (1/8), p<sub>2-t</sub>=0.0268. On the basis of these findings operational parameters of the revealed markers were determined as predictors of A<sub>1</sub> outcome (SS ADR<sup>+</sup>) and A<sub>2</sub> outcome (SS ADR<sup>-</sup>): –HLA-A1: pOR=7.3; A1<sup>+</sup>: LR<sup>+</sup>=4.6, P<sub>post</sub>=77.7%; A1<sup>–</sup>: LR<sup>–</sup>=0.64, P<sub>post</sub>= 32.6%; –HLA-A2: pOR=7.7; A2<sup>–</sup>: LR<sup>+</sup>=2.1, P<sub>post</sub>=61.4%; A2<sup>+</sup>: LR<sup>–</sup>=0.27, P<sub>post</sub>= 17.0%; –HLA-B8: pOR=12.3; B8<sup>+</sup>: LR<sup>+</sup>=8.1, P<sub>post</sub>=86.0%; B8<sup>–</sup>: LR<sup>–</sup>=0.66, P<sub>post</sub>= 33.3%; –HLA-B15: pOR=8.4; B15<sup>–</sup>: LR<sup>+</sup>=1.4, P<sub>post</sub>=51.5%; B15<sup>+</sup>: LR<sup>–</sup>=0.17, P<sub>post</sub>= 11.4%. <h3>Conclusions</h3> Revealed phenotypes are useful as supplementary predictors of SS adverse reactions in RA patients in the case of uncertain prognosis (outcome A<sub>3</sub>, P<sub>post</sub>≥95% for the approval of the hypothesis (A<sub>1</sub> outcome) or P<sub>post</sub>≤5% for the acceptance of the alternative hypothesis (A<sub>2</sub> outcome). <h3>References</h3> Box SA and Pullar T. Sulphasalazine in the treatment of rheumatoid arthritis. Br J Rheumatol 1997;36:382-386. Van Riel PLCM, Van Gestel AM, Van De Putte LBA. Long-term usage and side effect profile of sulphasalazine in rheumatoid arthritis. Br J Rheumatol. 1995;34:40-42. <h3>Disclosure of Interest</h3> None Declared