THU0017 Genetic markers of metothrexate adverse reactions in rheumatoid arthritis patients
Authors: N. Dostanko, V. Yagur
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Adverse drug reactions (ADR) associated with metothrexate (MTX) use in rheumatoid arthritis (RA) patients frequently lead to different complications and MTX withdrawal [1] especially without folate supplementation. <h3>Objectives</h3> To reveal genetic markers associated with MTX 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 MTX was used in 30.6% (153/500) of patients. MTX withdrawal due to the adverse events occurred in 41.2% (63/153; CI<sub>95</sub> 33.7-49.1%) of them. This level of ADR frequency associated with WTX use was considered as MTX adverse reactions pretest probability (P<sub>pre</sub>). Association between MTX ADR and a number of the genetic markers (AB0, Rh<sub>0</sub>, MN, P<sub>1</sub>blood groups; haptoglobin; HLA-A, -B, -C, -DR, -DQ locuses, supertypes HLA-Bw4, HLA-Bw6, HLA-DR51-53; sensitivity to phenylthiocarbamide; dermatoglyphic characteristics) 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 MTX adverse reactions were calculated. <h3>Results</h3> Gastrointestinal ADR and hepatotoxicity were registered in 13.1% (20/153) of patients, skin and mucous ADR in 12.4%, haematological abnormalities in 10.5% and infections in 9.8% of patients. MTX adverse reactions were significantly more common in the case of following phenotypes: –P<sub>1</sub><sup>–</sup> vs P<sub>1</sub><sup>+</sup> 75.0% (9/12) and 12.5% (1/8), p<sub>2-t</sub>=0.0198; –HLA-A10<sup>+</sup> vs HLA-A10<sup>-</sup> 58.6% (17/29) and 32.1% (25/78), p<sub>2-t</sub>=0.0152; –HLA-C2<sup>–</sup> vs HLA-C2<sup>+</sup> 46.7% (28/60) and 0.0% (0/7), p<sub>2-t</sub>=0.0359 with adjustment of zero frequency by J. Haldane; –HLA-DR3<sup>+</sup> vs HLA-DR3<sup>–</sup>68.8% (11/16) and 33.3% (15/45), p<sub>2-t</sub>=0.0194; –HLA-DQ2<sup>+</sup> vs HLA-DQ2<sup>–</sup> 61.9% (13/21) and 32.5% (13/40), p<sub>2-t</sub>=0.0333. On the basis of these findings operational parameters of the revealed markers were determined as predictors of A<sub>1</sub> outcome (MTX ADR<sup>+</sup>) and A<sub>2</sub> outcome (MTX ADR<sup>-</sup>): –P<sub>1</sub>: pOR=21.0; P<sub>1</sub><sup>–</sup>: LR<sup>+</sup>=3.0, P<sub>post</sub>=61.7%; P<sub>1</sub><sup>+</sup>: LR<sup>–</sup>=0.14 P<sub>post</sub>= 8.9%; –HLA-A10: pOR=3.0; A10<sup>+</sup>: LR<sup>+</sup>=2.2, P<sub>post</sub>=60.7%; A10<sup>–</sup>: LR<sup>-</sup>=0.73, P<sub>post</sub>= 33.8%; –HLA-C2: pOR=13.1; C2<sup>–</sup>: LR<sup>+</sup>=1.2, P<sub>post</sub>=45.7%; C2<sup>+</sup>: LR<sup>–</sup>=0.09, P<sub>post</sub>= 5.9%; –HLA-DR3: pOR=4.4; DR3<sup>+</sup>: LR<sup>+</sup>=3.0, P<sub>post</sub>=75.5%; DR3<sup>–</sup>: LR<sup>–</sup>=0.67, P<sub>post</sub>= 31.9%; –HLA-DQ2: pOR=3.0; DQ2<sup>+</sup>: LR<sup>+</sup>=2.0, P<sub>post</sub>=58.4%; DQ2<sup>–</sup>: LR<sup>-</sup>=0.67, P<sub>post</sub>= 31.9%. There was no association between sensitivity to phenylthiocarbamide or dermatoglyphic characteristics and MTX adverse reactions. <h3>Conclusions</h3> Revealed phenotypes are useful as supplementary predictors of MTX adverse reactions in RA patients in the case of uncertain prognosis on the basis of clinical variables [2]. Availability of several independent predictors leads to considerable increase of the post-test probability of prediction of ADR, associated with MTX, oversteping the significant threshold levels of prediction: 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> Bologna C, et al. Long-term follow-up of 453 rheumatoid arthritis patients treated with methotrexate: an open retrospective, observational study. Br J Rheum 1997;36:535-40. Hoekstra M, et al. Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis. Ann Rheum Dis 2003;62:423-426. <h3>Disclosure of Interest</h3> None Declared