Background Genetic factors related to treatment response in rheumatoid arthritis (RA) have been described. International recommendations for the management of RA suggest initial therapy with synthetic DMARDs, with methotrexate (MTX) typically administered as first-line therapy. However, responses to MTX are variable, and more than 30%1 of patients fail to respond. Despite many studies, few genetic factors specifically associated with MTX response have been identified. Objectives To identify genetic variants associated with response to MTX in patients with early RA. Methods OPTIMA was a 78-week, multicenter, randomized, double-period, double-blind study in which patients were randomized 1:1 to combination therapy with adalimumab plus MTX or MTX alone during the initial study period (26 weeks). Enrolled patients were invited to participate in a genetic sub-study and asked to provide written, informed consent. 384 variants in genes previously shown to be associated with RA or treatment response were assayed using the Illumina BeadXpress GoldenGate Assay. Changes in the 28-joint disease activity score (DAS28) and the total Sharp score (TSS) following 26 weeks of treatment were assessed for association with allele status using genotypic tests. Results A total of 448 patients randomized to MTX were included in the genetic sub-study. Two SNPs in MTHFR (rs1801133 and rs1801131) and one SNP in ATIC (rs2372536)1, previously shown to be associated with MTX response, were not associated with a change in DAS28 or TSS following MTX treatment. However, other SNPs within genes that have been associated with RA or treatment response, such as ABCB1, TNF-alpha, PTPRC, STAT4 and HLA-DRB1, did show association with MTX treatment (Table). For some genes, such as ABCB1, multiple SNPs were identified, suggesting that haplotype analysis could identify stronger associations. SNPs within ABCB1 and PTPRC were also associated with a change in TSS. In addition, a SNP within ADORA2a associated with a change in TSS. SNPs within this gene have previously been associated with MTX toxicity, however, analysis of the impact of this gene on efficacy have been more limited. Conclusions Genetic polymorphisms in genes such as ABCB1, TNF-alpha, PTPRC, STAT4 and HLA-DRB1 were shown to associate with MTX treatment in the OPTIMA study. These results may prove useful for the development of future diagnostic tests or personalized therapeutics for MTX treatment. References Malik et al. Pharmacogenomics (2013). 14(3), 305-314. Acknowledgements AbbVie sponsored the study (NCT00420927), contributed to its design, and participated in the collection, analysis, and interpretation of the data, and in the writing, reviewing, and approval of the final version. Medical writing support was provided by Laurel M. Farmer, PhD, of AbbVie Inc. Disclosure of Interest A. Skapenko: None declared, H. Schulze-Koops Consultant for: AbbVie Inc., V. Devanarayan Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., K. Idler Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., F. Hong Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., J. Smolen Grant/research support: AbbVie Inc., Amgen, AstraZeneca, BMS, Celgene, Janssen, Glaxo, Lilly, Pfizer, MSD, Novo-Nordisk, Roche, Sandoz, and UCB, Consultant for: AbbVie Inc., Amgen, AstraZeneca, BMS, Celgene, Janssen, Glaxo, Lilly, Pfizer, MSD, Novo-Nordisk, Roche, Sandoz, and UCB, A. Kavanaugh Grant/research support: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, Consultant for: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, H. Kupper Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., J. Waring Shareholder of: AbbVie Inc., Employee of: AbbVie Inc. DOI 10.1136/annrheumdis-2014-eular.1318

Background Factors related to increased susceptibility to rheumatoid arthritis (RA) have been described, with numerous genes and alleles having been identified that may be associated with the onset of the disease or disease progression. In-depth knowledge about RA susceptibility genes may thus prove useful for the development of future diagnostic tests or personalized therapeutics. Objectives Previously reported RA susceptibility gene frequencies from patients enrolled in the OPTIMA trial were compared to a control database to identify genetic risk factors for RA. Methods OPTIMA was a 78-week, multicenter, randomized, double-period, double-blind study designed to assess adalimumab plus methotrexate therapy. The study enrolled 1,032 early RA patients, of which 921 signed informed consents for genetic analysis. Frequency rates for 168 identified RA susceptibility alleles from 53 genes were compared to the European cohort of the 1000 Genomes Project as a reference control.1 Genotypic variants were assayed using the Illumina BeadXpress GoldenGate Assay. Deviations in the OPTIMA minor allele frequencies (MAFs) >0.05 were further investigated. Results The majority of MAFs from the OPTIMA study did not deviate >0.05 from MAFs reported in the European cohort from the 1000 Genomes Project. Five gene SNPs demonstrated a MAF deviation >0.05 compared to reference controls (Table). The BTLA gene G allele (MAF 0.15 compared to 0.04 control) displayed the highest odds ratio (OR) for RA risk (3.60 OR, 95% CI 2.49 – 5.20); the minor allele was weakly associated with DAS28 baseline score, but significantly more associated with reduced age of study participants suggesting susceptibility to early onset of disease. The PTPN22 gene minor allele was associated with increased RA risk when homozygous, supporting previous findings.2 STAT4 minor allele homozygosity was associated with higher baseline DAS28 scores; however, HLA-DRB1 and NOS3 were not associated with elevated DAS28 scores in this study. Conclusions Genes identified with increased RA risk have known roles in autoimmunity including mediation of lymphocyte signaling, proliferation, and differentiation. For five gene SNPs, MAFs in the OPTIMA study differed from a healthy control population, strengthening their potential role in RA susceptibility. References Clarke et al; Nat Methods. 2012 Apr 27;9(5):459-62. Begovich et al; Am J Hum Genet. 2004 Aug;75(2):330-7. Acknowledgements AbbVie was responsible for the study design, research, analysis, data collection, interpretation of data, and writing, reviewing, and approving of the publication. Medical writing support was provided by Douglas E. Dylla, PhD, of AbbVie Inc. Disclosure of Interest J. Waring Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., V. Devanarayan Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., K. Idler Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., F. Hong Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., J. Smolen Grant/research support from: AbbVie Inc., Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, Glaxo, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, and UCB, Consultant for: AbbVie Inc., Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, Glaxo, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, and UCB, A. Kavanaugh Grant/research support from: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, Consultant for: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, H. Kupper Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., H. Schulze-Koops Consultant for: AbbVie Inc., A. Skapenko: None Declared

Hydrocodone is oxidized to a more potent mu-opioid agonist hydromorphone by cytochrome P450 2D6 (CYP2D6). CYP2D6 poor metabolizers (PMs) cannot convert hydrocodone to hydromorphone. It is believed that PMs will not gain meaningful analgesia from hydrocodone. Responses of PMs were compared with those of competent metabolizers (non-PMs) during hydrocodone/acetaminophen extended release (HC/APAP CR) treatment following bunionectomy surgery and in osteoarthritis patients, to learn whether CYP2D6 PMs might be effectively treated with HC/APAP CR. DNA samples collected from patients recruited into two multi-center placebo-controlled clinical trials were genotyped for major CYP2D6 PM alleles and assigned PM or non-PM status. In a study of acute pain relief after bunionectomy, efficacy variables were assessed descriptively. In a chronic pain study in osteoarthritis, efficacy of HC/APAP CR treatment was evaluated prospectively for the percentage change from baseline to week 12 of pain intensity score (VAS%), using analysis of covariance with a factor for PM status and baseline pain-intensity score as a covariate. Other efficacy endpoints were assessed to support the prospective analysis. Tolerability of HC/APAP CR in PMs was assessed descriptively in both studies. Among 130 bunionectomy subjects, four of six PMs dosed with HC/APAP CR experienced meaningful analgesia. Among 614 osteoarthritis subjects, eleven of nineteen PMs dosed with HC/APAP CR experienced meaningful analgesia. No difference was observed between PMs and non-PMs for VAS% (43.5% v –46.5%, p=0.770). PMs treated with placebo (–21.0%, n=19) did not respond as well as PMs treated with HC/APAP CR. Results for other key efficacy variables were consistent with those for VAS%. Safety-related study dropout and adverse event patterns were similar in PMs and non-PMs in both studies. These results indicate that PMs and non-PMs have similar analgesic responses to HC/APAP CR. This may distinguish HC/APAP CR from tramadol and possibly other opioid-based analgesics. Funded by Abbott Laboratories.

BACKGROUND Polymorphisms within cytochrome P450 2D6 (CYP2D6) result in different metabolizer phenotypes, but some discordance suggests the possibility of additional unknown alleles or factors contributing to metabolism. A recent study showed a high frequency frameshift-causing deletion, CYP2D7 138delT, which converted the CYP2D7 pseudogene to a functional gene within the brain.1 The high frequency of the deletion and the resulting CYP2D7 expression could have important implications for brain-specific metabolism of psychoactive substances. Our goal was to determine the frequency of this deletion in a larger ethnically diverse population. METHODS The CYP2D7 138delT genotypes for 163 Caucasians, 95 East Asians, 50 South Asians, 68 Hispanic Latinos, and 68 African Americans were determined by Pyrosequencing. RESULTS The 138delT allele was observed at a frequency of 1.0% in East Asians and 0.74% in Hispanic Latinos. The deletion was not observed in the other ethnic populations. CONCLUSIONS The very low frequency of the CYP2D7 138delT polymorphism in our panel is in contrast to the high frequency (50%) reported in the Indian population.1 Our results suggest that CYP2D7 138delT is unlikely to be highly relevant for population variation of pharmacokinetics or drug response. Clinical Pharmacology & Therapeutics (2005) 79, P42–P42; doi: 10.1016/j.clpt.2005.12.149