SAT0083 The genetic and clinical prediction models for efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis
Authors: A. Onishi, M. Nishida, M. Takahashi, Y. Yoshida, M. Kobayashi, S. Kamitsuji, M. Kawate, K. Nishimura, K. Misaki, Y. Nobuhara, S. Hatachi, T. Nakazawa, G. Tsuji, S. Kumagai
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The efficacy and toxicity of methotrexate (MTX) depend on individual patients with rheumatoid arthritis (RA) and are difficult to predict before treatment although MTX is the anchor drug and achieving the treatment target earlier is desirable to prevent progression of structural and functional damage. Our previous studies revealed high predictive accuracy of single nucleotide polymorphisms (SNPs) to predict the efficacy and toxicity of MTX, suggesting the influence of genetic variations in enzymes associated with MTX metabolism and folate metabolic pathway<sup>1,2</sup>. However, higher accuracy and replicability is demanded for clinical application. <h3>Objectives</h3> To develop combined genetic and clinical models to predict the efficacy and hepatotoxicity of MTX. <h3>Methods</h3> Patients with RA under the treatment of MTX according to Japanese guideline for the management of RA with MTX were enrolled. To predict the efficacy and hepatotoxicity, 1971 polymorphisms of 246 enzymes/transporters potentially relevant to pharmacokinetics and pharmacodynamics of MTX were measured by the DMET microarray (Affymetrix Inc.) and direct-sequencing method and clinical variables at baseline were collected. As for efficacy, the EULAR-CRP response criteria was chosen to classify patients with RA as responders (good response) and non-responders (moderate or no response). Hepatotoxicity was defined as either serum AST or ALT levels higher than 1.5 times the upper limit of the normal range. Among SNPs and clinical variables with significant association with outcomes using univariate analyses, stepwise model selection was conducted by Akaike information criterion in logistic regression model and receiver operating characteristic (ROC) analyses were performed. Bootstrapping (n=100,000) was used to assess the robustness of the results. <h3>Results</h3> A total of 166 patients with RA was included. The median age was 61.5 years with 81.3% of women. For efficacy, genetic prediction model using 7 SNPs showed area under the curve of ROC (AUC) was 0.822 with sensitivity of 74.3% and specificity of 76.8%, while combined clinical and genetic model indicated AUC was 0.844 with sensitivity of 81.5% and specificity of 76.9%. By incorporating clinical variables into the genetic model, overall category-free net reclassification improvement (NRI) was 0.700 (p&lt;0.0001) and overall integrated discrimination improvement (IDI) was 0.089 (p=0.0005). For hepatotoxicity, genetic prediction model using 7 SNPs showed AUC was 0.783 with sensitivity of 70.0% and specificity of 80.0%, while combined clinical and genetic model indicated AUC was 0.906 with sensitivity of 85.1% and specificity of 87.8%. Overall category-free NRI was 1.122 (p&lt;0.0001) and overall IDI was 0.279 (p&lt;0.0001). <h3>Conclusions</h3> Genetic and clinical models showed higher predictive accuracy for both efficacy and hepatotoxicity of MTX. These models should be validated with a larger scale of prospective study. <h3>References</h3> [1] Kumagai S. Ann Rhem Dis. 2015;74(suppl2):263. [2] Kumagai S. Ann Rhem Dis. 2014;73(suppl2):119. <h3>Acknowledgements</h3> None. <h3>Disclosure of Interest</h3> None declared