Background: This analysis assessed, on a group level, whether there is a long-term advantage for early RA patients treated with adalimumab (ADA) + MTX vs those initially treated with placebo (PBO) + MTX who either responded to therapy or added ADA following inadequate response (IR). Methods: OPTIMA was a 78- week, randomized, controlled trial of ADA + MTX vs PBO + MTX in MTX-naïve early (<1 year) RA patients. Therapy was adjusted at week 26: ADA + MTX-responders (R) who achieved DAS28 (CRP) <3.2 at weeks 22 and 26 (Period 1, P1) were re-randomized to withdraw or continue ADA and PBO + MTX-R continued randomized therapy for 52 weeks (P2); IR-patients received open-label (OL) ADA + MTX during P2. This post hoc analysis evaluated the proportion of patients at week 78 with DAS28 (CRP) <3.2, HAQ-DI <0.5, and/or ΔmTSS ≤0.5 by initial treatment. To account for patients who withdrew ADA during P2, an equivalent proportion of R was imputed from ADA + MTX-R patients. Results: At week 26, significantly more patients had low disease activity, normal function, and/or no radiographic progression with ADA + MTX vs PBO + MTX (Table 1). Differences in clinical and functional outcomes disappeared following additional treatment, when PBO + MTX-IR (n = 348/460) switched to OL ADA + MTX. Addition of OL ADA slowed radiographic progression, but more patients who received ADA + MTX from baseline had no radiographic progression at week 78 than patients who received initial PBO + MTX. Conclusions: Early RA patients treated with PBO + MTX achieved comparable long-term clinical and functional outcomes on a group level as those who began ADA + MTX, but only when therapy was optimized by the addition of ADA in PBO + MTX-IR. Still, ADA + MTX therapy conferred a radiographic benefit although the difference did not appear to translate to an additional functional benefit. Disclosures: P.E., AbbVie, Merck, Pfizer, UCB, Roche, BMS—Provided Expert Advice, Undertaken Trials, AbbVie—AbbVie sponsored the study, 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. R.F., AbbVie, Pfizer, Merck, Roche, UCB, Celgene, Amgen, AstraZeneca, BMS, Janssen, Lilly, Novartis—Research Grants, Consultation Fees. S.F., AbbVie—Employee, Stocks. A.K., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, UCB—Research Grants, Consultation Fees. H.K., AbbVie—Employee, Stocks. S.R., AbbVie—Employee, Stocks. J.S., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, GlaxoSmithKline, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, UCB—Research Grants, Consultation Fees. R.V., AbbVie, BMS, GlaxoSmithKline, Human Genome Sciences, Merck, Pfizer, Roche, UCB Pharma—Consultation Fees, Research Support. Week 78 clinical, functional, and radiographic outcomes in patients who received continued ADA + MTX vs those who continued PBO + MTX or added open-label ADA following an inadequate response aIncludes patients from the ADA Continuation (n = 105) and OL ADA Carry On (n = 259) arms, as well as the proportional equivalent number of responders from the ADA Withdrawal arm (n = 102). bIncludes patients from the MTX Continuation (n = 112) and Rescue ADA (n = 348) arms. Last observation carried forward: DAS28 (CRP) and HAQ-DI; Multiple imputations: ΔmTSS. ***P < 0.001 and **iP < 0.01, respectively, for differences between initial treatments from chi-square. Week 78 clinical, functional, and radiographic outcomes in patients who received continued ADA + MTX vs those who continued PBO + MTX or added open-label ADA following an inadequate response aIncludes patients from the ADA Continuation (n = 105) and OL ADA Carry On (n = 259) arms, as well as the proportional equivalent number of responders from the ADA Withdrawal arm (n = 102). bIncludes patients from the MTX Continuation (n = 112) and Rescue ADA (n = 348) arms. Last observation carried forward: DAS28 (CRP) and HAQ-DI; Multiple imputations: ΔmTSS. ***P < 0.001 and **iP < 0.01, respectively, for differences between initial treatments from chi-square.

Background A recent genome wide association study identified the variant rs26232 in the first exon of an uncharacterized gene C5orf30 as a rheumatoid arthritis susceptibility variant1. In addition, it has been associated with severity of radiological joint damage suggesting a role in tissue breakdown2. To date there is no function assigned for C5orf30 and neither the gene or protein coded show homology to any known functional sequences. However, C5orf30 is highly conserved in chimpanzee, dog, cow, mouse, chicken, and zebrafish (orthologs). Objectives The aim of this study is to determine the biological roles of C5orf30 in rheumatoid arthritis. Methods Real time PCR and western blotting were used to examine C5orf30 transcript and protein levels in fibroblast-like synovial cells (FLS stimulated with TNF & hypoxia) and peripheral blood leukocytes isolated from RA patients and healthy individuals. Immunohistochemistry on synovial samples was used to determine expression of C5orf30 including co-localisation using antibodies to macrophages (CD68), fibroblasts (5B5), T (CD3) & B (CD19) cells. To investigate gene function siRNA was used to knockdown C5orf30 in synovial FLS in vitro. Results Expression of C5orf30 was detected at lower levels in peripheral blood leukocytes of RA patients compared to healthy controls (117 patients vs. 102 controls, p=0.00052). C5orf30 was expressed in FLS and was found to be up-regulated by hypoxia (8-fold) and down-regulated by TNF (0.5-fold). Confocal microscopy revealed C5orf30 to be strongly expressed in both the nuclear and cytoplasmic compartment of synovial lining cells including macrophages and fibroblasts, but not T & B cells. C5orf30 was undetectable in arthroscopy sections obtained from osteoarthritis or control synovium. Approximately 80% C5orf30 knockdown has been achieved by siRNA, and preliminary studies have shown C5orf30 knockdown increased FLS invasion into matrigel. Conclusions C5orf30 is expressed in synovial cells but not in circulating peripheral blood leukocytes obtained from RA patients, implying that C5orf30 is expressed in a tissue-specific manner. C5orf30 knockdown increased FLS migration into matrigel suggesting C5orf30 is negatively regulating cellular invasion. Together this points to an anti-inflammatory role for C5orf30 in RA and this may be a promising target for novel therapeutic strategies. References Stahl EA, Raychaudhuri S, Remmers EF, et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 2010;42:508-14. Wilson AG, Teare M, van der Helm-van AH, Moore D, Knevel R, Kleszcz A, Huizinga T (2011). Identification and validation of a novel marker for radiological severity in RA. Abstract N° OP0229. EULAR Disclosure of Interest None Declared