Background Tofacitinib is an oral JAK inhibitor that has been investigated for the treatment of ankylosing spondylitis (AS). Objectives To investigate for the first time the effects of tofacitinib in adult patients (pts) with active AS. Methods This was a 16-week (wk), Phase 2, multicentre, randomised, double-blind, placebo (PBO)-controlled, dose-ranging study (NCT01786668) to investigate efficacy, safety and dose-response of tofacitinib in pts with AS. Pts fulfilling the modified New York criteria (central read) were randomised 1:1:1:1 to PBO or tofacitinib 2, 5 or 10 mg BID for 12 wks plus 4 wks follow-up. Primary efficacy endpoint was ASAS20 response rate at Wk 12 using a 3-parameter Bayesian Emax model by assuming a monotonic response. Secondary endpoints included ASAS40 response rate, AS disease activity score using C-reactive protein (ASDAS), Bath AS disease activity index 50% (BASDAI50) response rate, Bath AS functional index, Bath AS metrology index (linear method), Spondyloarthritis Research Consortium of Canada (SPARCC) score of sacroiliac (SI) joints and spine. Safety endpoints included adverse events (AEs) and laboratory outcomes. Results 208 pts were randomised and 207 treated; 196 pts completed the study. 51 pts (PBO group) and 52 (each tofacitinib group) were included in analyses. Baseline demographics and disease characteristics were balanced between groups and typical of AS populations (87.4% HLA-B27 positive; 81.2% white; 69.1% male; mean age 42 years; mean disease duration 6.3 years; mean BASDAI 6.7). The table summarises safety and efficacy results. The ASAS20 Emax model showed tofacitinib 10 mg BID had a high response rate and its confidence bounds met a pre-specified efficacy decision rule. ASAS20 response rates by NRI were significantly greater with tofacitinib 5 mg BID vs PBO, compared with 2 or 10 mg BID. All tofacitinib groups had ASAS40, ASDAS and BASDAI50 improvements of similar magnitude vs PBO. Tofacitinib 2 mg BID did not differ vs PBO in remaining clinical efficacy measures or SPARCC scores. Tofacitinib 5 and 10 mg BID had greater clinical efficacy vs PBO, with minimal differences between doses, and significantly improved SPARCC SI joint and spine scores vs PBO. No tofacitinib-related safety issues unique to the AS population or new safety concerns were identified. Two treatment-related herpes zoster cases were reported (1 each with tofacitinib 2 and 10 mg BID). No cases of tuberculosis, malignancy, gastrointestinal perforation or death were reported. Dose-dependent changes in laboratory outcomes commonly reported in other tofacitinib studies were observed and returned to approximately baseline values by Wk 16. Conclusions Tofacitinib 5 and 10 mg BID demonstrated greater clinical and imaging efficacy vs PBO in reducing the signs and symptoms of AS in adults with active AS. Safety was similar to that reported for tofacitinib studies in other indications. Acknowledgement Previously presented (van der Heijde D et al. Arthritis Rheumatol 2015; 67(S10): Abstr 5L) and reproduced with permission from Arthritis Rheumatol. This study was funded by Pfizer Inc. Editorial support was provided by S Johnson of CMC and funded by Pfizer Inc. Disclosure of Interest D. van der Heijde Consultant for: AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli Lilly, Galapagos, GlaxoSmithKline, Janssen Biologics, Merck, Novartis, Novo Nordisk, Otsuka, Pfizer Inc, Roche, Sanofi-Aventis, UCB, Vertex, A. Deodhar Grant/research support from: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer Inc, and UCB, Consultant for: AbbVie, Amgen, Boehringer Ingelheim, Janssen, Novartis, Pfizer Inc, and UCB, J. Wei Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Eisai, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, TSH Taiwan, and UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Eisai, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, TSH Taiwan, and UCB, E. Drescher Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Pfizer Inc, Novartis, UCB, Amgen, Lilly, and Sanofi-Aventis, D. Fleishaker Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Hendrikx Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Li Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

OBJECTIVES:To compare efficacy and safety of various doses of tofacitinib, an oral Janus kinase inhibitor, with placebo in patients with active ankylosing spondylitis (AS, radiographic axial spondyloarthritis).METHODS:In this 16-week (12-week treatment, 4-week washout), phase II, multicentre, dose-ranging trial, adult patients with active AS were randomised (N=51, 52, 52, 52, respectively) to placebo or tofacitinib 2, 5 or 10 mg twice daily. The primary efficacy endpoint was Assessment of SpondyloArthritis International Society 20% improvement (ASAS20) response rate at week 12. Secondary endpoints included objective measures of disease activity, patient-reported outcomes and MRI of sacroiliac joints and spine. Safety was monitored.RESULTS:Emax model analysis of the primary endpoint predicted a tofacitinib 10 mg twice daily ASAS20 response rate of 67.4%, 27.3% higher than placebo. Supportive normal approximation analysis demonstrated tofacitinib 5 mg twice daily ASAS20 response rate significantly higher than placebo (80.8% vs 41.2%; p<0.001); tofacitinib 2 and 10 mg twice daily demonstrated greater response rate than placebo (51.9% and 55.8%, respectively; not significant). Secondary endpoints generally demonstrated greater improvements with tofacitinib 5 and 10 mg twice daily than placebo. Objective (including MRI) endpoints demonstrated clear dose response. Adverse events were similar across treatment groups with no unexpected safety findings. Dose-dependent laboratory outcome changes returned close to baseline by week 16.CONCLUSIONS:Tofacitinib 5 and 10 mg twice daily demonstrated greater clinical efficacy versus placebo in reducing signs, symptoms and objective endpoints of active AS in adult patients with a similar 12-week safety profile as reported in other indications.TRIAL REGISTRATION NUMBER:NCT01786668.

Background Smoking is an important environmental factor affecting the development and severity of rheumatoid arthritis (RA), likely by modulating the immune system (including protein citrullination and autoantibody production).1,2 Smoking is associated with poor response to some anti-TNF therapies for RA.3 However, the effect of smoking on RA patients (pts) treated with certolizumab pegol (CZP) is unknown. Objectives To investigate the association between past/current cigarette consumption and response to CZP in Hungarian RA pts, and to report the efficacy of CZP in a real-world setting. Methods This is a prospective, non-interventional, non-comparative, 104-week (wk) study of RA pts in Hungary, Slovakia and the Czech Republic who received CZP according to the Summary of Product Characteristics.4 Interim data are reported for the complete Hungarian pt subset observed over 104 wks; smokers and non-smokers were included. Adverse events (AEs) and serious AEs (SAEs) were assessed to Wk104 in the Safety Set (SS; pts who received ≥1 dose CZP). Observed efficacy variables were analyzed to Wk52 in the Full Analysis Set (FAS; pts who received ≥1 dose CZP with available pack-year [PY] history at baseline [BL] and DAS28 scores at BL, Wk4, 8 or 12). Primary variable was change from BL (CFB) in DAS28(ESR) at Wk12. Secondary variables included CFB in DAS28(ESR) at Wk24 and 52. Number of cigarettes smoked/day in previous month was measured at all scheduled visits. Cigarette PY history at BL was derived from a smoking habits questionnaire; 1 PY was defined as smoking 20 cigarettes/day (1 pack) over 1 year (yr). To describe the correlation, slope parameters were estimated based on simple linear regressions with CFB in DAS28(ESR) as dependent variable and PY history and current cigarette consumption as explanatory variables. Spearman9s rank correlation coefficients were also calculated. Results SS included all 197 pts enrolled. Of 144 pts in the FAS, 75 remained on CZP at Wk104. FAS BL characteristics are presented in Table A. DAS28(ESR) scores improved from BL to Wk52 (Table B). Slopes after regressing CFB in DAS28 scores on PY history and current cigarette consumption showed increases close to 0 (Table B). AEs occurred in 52 pts (26.4%), SAEs in 13 pts (6.6%). 2 deaths were reported, which were not considered related to the study drug. The safety profile of CZP observed in this study was in line with the CZP label. Conclusions CZP treatment resulted in clinical improvements in Hungarian RA pts in a real-world setting; long-term efficacy of CZP in these pts was similar to efficacy seen in the pivotal CZP studies: RAPID1 and its open-label extension.5 There was no relevant linear relationship between past or current cigarette consumption and clinical response to CZP. References Heliövaara M. J Rheumatol 1993;20:1830–1835; 2. Saag K. Ann Rheum Dis 1997;56:463–469; 3. Hyrich K. Rheumatology 2006;45:1558–1565; 4. European Medicines Agency. Cimzia SmPC 2014; 5. Keystone E. Ann Rheum Dis 2014;73:2094–2100 Acknowledgements The authors acknowledge Costello Medical Consulting for writing and editorial assistance which was funded by UCB Pharma. Disclosure of Interest Z. Szekanecz: None declared, J. Pulai: None declared, E. Drescher: None declared, T. Varga: None declared, C. Kiss: None declared, J. Gál: None declared, K. Kerekes: None declared, R. Orosz: None declared, J. Dunkel Employee of: UCB Pharma, Ά. Koncz Employee of: UCB Pharma

Background Clazakizumab (CLZ) is a humanized anti-interleukin-6 (IL-6) monoclonal antibody that potently neutralizes IL-6 signalling. Objectives This study evaluated the safety and efficacy of subcutaneous CLZ with or without MTX versus placebo (pbo) or adalimumab (ADA). Methods Patients with moderate-to-severe RA and an inadequate response to MTX were randomized equally to receive pbo + MTX; 25, 100 or 200 mg CLZ + MTX; 100 or 200 mg CLZ without MTX; and ADA 40 mg every other week + MTX for 24 weeks. The primary endpoint was ACR 20 response rate at Week 12. Key secondary endpoints at Week 24 were ACR 20, ACR 50 and ACR 70 response rates, Health Assessment Questionnaire-Disability Index (HAQ-DI) improvements and remission defined as Disease Activity Score (DAS)28 (C-reactive protein, CRP) <2.6, Clinical Disease Activity Index (CDAI) <2.8 and Simplified Disease Activity Index (SDAI) <3.3. Results A total of 418 patients were randomized and received treatment. Baseline characteristics were balanced across the arms; 82% female, mean age 50 years, mean duration of RA 5.9 years, mean DAS28 (CRP) 5.94, and 80% rheumatoid factor positive. The primary endpoint was met; ACR 20 response rates were statistically significantly higher in all CLZ arms versus pbo + MTX. All CLZ treatment groups were associated with improved ACR 20/50/70 response rates, HAQ-DI and remission versus pbo + MTX through Week 24. Rates of remission per DAS28 (CRP) <2.6, SDAI <3.3 and CDAI <2.8 were numerically higher in the CLZ + MTX arms compared with ADA + MTX. Treatment with CLZ in combination with MTX resulted in higher response rates than monotherapy. However, no clear dose response for efficacy was noted. The rates of serious adverse events ranged from 8.3 to 13.3% in CLZ arms versus 3.3% for pbo + MTX and 5.1% for ADA + MTX. Rates of serious infections were similar as reported for all CLZ arms and ADA versus none in pbo. CLZ was associated with mostly mild injection-site reactions, few of which led to discontinuation. As expected based on its mode of action, CLZ treatment was associated with increased transaminases (mainly in combination with MTX), increased lipids and haemoglobin, and decreased polymorphonuclear neutrophils and platelets. Conclusions Clazakizumab as monotherapy or in combination with MTX demonstrated efficacy in controlling the signs and symptoms of RA. At Week 24, remission rates with clazakizumab + MTX trended higher than with ADA + MTX. Its safety profile was consistent with the known pharmacology of IL-6 blockade. Clazakizumab is a promising future treatment for RA that warrants further investigation. Disclosure of Interest M. Weinblatt Grant/research support: BMS, Crescendo Bioscience, UCB, Consultant for: AbbVie, BMS, Crescendo Bioscience, Janssen, Roche, UCB, P. Mease Grant/research support: AbbVie, Amgen, Biogen Idec, BMS, Celgene, Eli Lilly, Genentech, Janssen, Novartis, Pfizer, Roche, UCB, Vertex, Consultant for: AbbVie, Alder Pharmaceuticals, Amgen, Biogen Idec, BMS, Celgene, Cypress Biosciences, Eli Lilly, Genentech, Janssen, Novartis, Pfizer, Roche, UCB, Vertex, Speakers bureau: AbbVie, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB, E. Mysler Grant/research support: BMS, Consultant for: BMS, Speakers bureau: BMS, T. Takeuchi Speakers bureau: Abbott, Astellas Pharma, BMS, Chugai Pharma, Eisai Pharma, Mitsubishi-Tanabe Pharma, Pfizer, Takeda Pharaceutical, E. Drescher: None declared, A. Berman: None declared, M. Zilberstein Employee of: BMS, J. Xing Shareholder of: BMS, Employee of: BMS, P. Emery Grant/research support: AbbVie, BMS, Merck, Pfizer, Roche, Consultant for: AbbVie, BMS, Merck, Pfizer, Roche, Takeda DOI 10.1136/annrheumdis-2014-eular.3754

Background Anti-TNF agents are recommended treatment for NSAID-resistant radiographic ankylosing spondylitis (AS). Long-term quality of life (QoL) data available in axial spondyloarthritis (axSpA), prior to radiographic detection of change (i.e., non-radiographic [nr-axSpA]) are limited. Objectives To investigate long-term effects of etanercept (ETN) treatment on QoL in patients with nr-axSpA (who had an insufficient response to NSAID treatment) after 12 weeks of randomized treatment to ETN or placebo (PBO). Methods Enrolled patients fulfilling ASAS axSpA criteria, not meeting the modified New York criteria for AS, who were symptomatic for 3 months–5 years, with BASDAI ≥4, and failed ≥2 NSAIDs, were randomized to ETN 50 mg weekly or PBO (double blind) for 12 weeks followed by open-label ETN 50 mg. QoLs were recorded over a total of 48 weeks. Patients were allowed stable NSAID therapy throughout the study. Analyses used an ANCOVA model with baseline scores, treatment, and MRI sacroiliitis positive/negative status as variables. Results Of 208 participants who entered the open-label period (safety population; ETN=102; PBO=106) baseline mean age was 31.9 years; 60.6% were male, and mean disease duration was 2.5 years. By week 12, QoL improvements favoured ETN versus PBO in disease-specific, functional, and productivity domains such as BASDAI, BASFI, BAS-G, WPAI-AS, SF-36 physical component summary, and pain measures (P<0.05).1 During the open label phase, substantial improvements from baseline at weeks 24 and 48 were observed regardless of original 12-week treatment arm (table). Improvements with ETN treatment were sustained with little distinction between the groups receiving ETN for 12, 24 and 48 weeks. Conclusions In patients with early, active nr-axSpA and an inadequate response to ≥2 NSAIDs, ETN demonstrated improvement in QoL measures for disease specific and functional domains compared to PBO during the first 12 weeks.1 Improvements in PROs were rapid and sustained after all patients were treated with etanercept (weeks 12-48) and similar between original 12-week treatment groups. References Dougados M, et al. Arthritis Rheum. 2013;65(10):S656-657. Acknowledgements The nr-axSpA trial (ClinicalTrials.gov, NCT01258738) was sponsored by Pfizer Inc. Medical writing support was provided by Stephanie Eide of Engage Scientific Solutions and was funded by Pfizer Inc. Disclosure of Interest J. Sieper: None declared, E. Drescher: None declared, J. Rosa: None declared, R. Pedersen Employee of: Pfizer Inc., R. Bonin Employee of: Pfizer Inc., B. Vlahos Employee of: Pfizer Inc., J. Bukowski Employee of: Pfizer Inc., S. Kotak Shareholder of: Pfizer Inc., Employee of: Pfizer Inc. DOI 10.1136/annrheumdis-2014-eular.2242

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.