Abstract: The optimal first-line treatment of patients (pts) with early rheumatoid arthritis (RA) is yet to be established. Objectives: The primary aim was to assess and compare the proportion of pts who achieved remission with active conventional therapy (ACT) and with three different biologic therapies after 24 wks. Secondary aims were to assess and compare other efficacy measures. Methods: The investigator-initiated NORD-STAR trial ( NCT01491815 ) was conducted in the Nordic countries and Netherlands. In this multicenter, randomized, open-label, blinded-assessor study pts with treatment-naïve, early RA with DAS28 〉 3.2, and positive RF or ACPA, or CRP 〉 10mg/L were randomized 1:1:1:1. Methotrexate (25 mg/week after one month) was combined with: 1) (ACT): oral prednisolone (tapered quickly); or : sulphasalazine, hydroxychloroquine and mandatory intra-articular (IA) glucocorticoid (GC) injections in swollen joints 〈 wk 20; 2) certolizumab 200 mg EOW SC (CZP); 3) abatacept 125 mg/wk SC (ABA); tocilizumab 162 mg/wk SC (TCZ). IA GC was allowed in all arms 〈 wk 20. Primary outcome was clinical disease activity index remission (CDAI≤2.8) at wk 24. Secondary outcomes included CDAI remission over time and other remission criteria. Dichotomous outcomes were analyzed by adjusted logistic regression with non-responder imputation (NRI). Non-inferiority analyses had a pre-specified margin of 15%. Results: 812 pts were randomized. Age was 54.3±14.7 yrs (mean±SD), 31.2% were male, DAS28 5.0±1.1, 74.9% were RF and 81.9% ACPA positive. Fig 1 shows the adjusted CDAI remission rates over time with 95% CI. Table shows crude remission and response rates and absolute differences in adjusted remission and response rates (superiority analysis). Differences in remission and response rates with CZP and TCZ, but not with ABA, remained within the pre-defined non-inferiority margin versus ACT, Fig 2. Figure 1. CDAI remission over time (adj. estimates with 95% CI) Figure 2. Non-inferiority analysis of protocol population. Estimated differences in CDAI remission rates between Arm 1 (active conventional therapy) and Arms 2, 3, and 4 (biologic arms) as reference with 95% confidence intervals, adjusted for gender, ACPA status, country, age, body-mass index and baseline DAS28-CRP. ABA, abatacept; CZP, certolizumab-pegol; MTX, methotrexate; TCZ, tocilizumab. Conclusion: High remission rates were found across all four treatment arms at 24 wks. Higher CDAI remission rate was observed for ABA versus ACT (+9%) and for CZP (+4%), but not for TCZ (-1%). With the predefined 15% margin, ACT was non-inferior to CZP and TCZ, but not to ABA. This underscores the efficacy of active conventional therapy based on MTX combined with glucocorticoids and may guide future treatment strategies for early RA. Table. Primary and key secondary outcomes at 24 weeks (ITT) Active conventional therapy (ACT) Certolizumab +MTX Abatacept +MTX Tocilizumab +MTX No of pts (ITT) 200 203 204 188 § Crude remission and response rates CDAI remission 42.0% 47.8% 52.5% 41.0% ACR/EULAR Boolean remission 34.0% 38.4% 37.3% 31.4% DAS28 remission 63.5% 68.5% 69.6% 63.3% SDAI remission 41.5% 49.8% 51.5% 42.6% EULAR good response 71.5% 76.9% 79.9% 71.3% Difference (95% CI) in rates with Arm 1 as reference (adjusted) CDAI remission Ref 4% (-5 to 13% ) 9% (0.1 to 19% ) -1% (-10 to 9% ) ACR/EULAR Boolean remission Ref 4% (-6 to 13%) 5% (-5 to 14%) -4% (-13 to 6%) DAS28 remission Ref 3% (-6 to 11%) 5% (-4 to 13%) -1% (-10 to 8%) SDAI remission Ref 6% (-3 to 18%) 9% (-0.3 to 18%) 1% (-8 to 11%) EULAR good response Ref 4% (-4 to 14%) 8% (-2 to 18%) 0.4% (-10 to 11%) § 17 patients allocated to Tocilizumab did not receive it due to its unavailability and were excluded from ITT. Acknowledgments: Manufacturers provided CZP and ABA. Disclosure of Interests: Merete L. Hetland Grant/research support from: BMS, MSD, AbbVie, Roche, Novartis, Biogen and Pfizer, Consultant of: Eli Lilly, Speakers bureau: Orion Pharma, Biogen, Pfizer, CellTrion, Merck and Samsung Bioepis, Espen A Haavardsholm Grant/research support from: AbbVie, UCB Pharma, Pfizer Inc, MSD Norway, Roche Norway, Consultant of: Pfizer, AbbVie, Janssen-Cilag, Gilead, UCB Pharma, Celgene, Lilly, Paid instructor for: UCB Pharma, Speakers bureau: Pfizer, AbbVie, UCB Pharma, Celgene, Lilly, Roche, MSD, Anna Rudin Consultant of: Astra/Zeneca, Dan Nordström Consultant of: Abbvie, Celgene, Lilly, Novartis, Pfizer, Roche and UCB., Speakers bureau: Abbvie, Celgene, Lilly, Novartis, Pfizer, Roche and UCB., Michael Nurmohamed Grant/research support from: Not related to this research, Consultant of: Not related to this research, Speakers bureau: Not related to this research, Björn Gudbjornsson Speakers bureau: Novartis and Amgen, Jon Lampa Speakers bureau: Pfizer, Janssen, Novartis, Kim Hørslev-Petersen: None declared, Till Uhlig Consultant of: Lilly, Pfizer, Speakers bureau: Grünenthal, Novartis, Gerdur Gröndal: None declared, Mikkel Ǿstergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Merck, and Novartis, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Marte Heiberg: None declared, Jos Twisk: None declared, Simon Krabbe: None declared, Kristina Lend: None declared, Inge Olsen: None declared, Joakim Lindqvist: None declared, Anna-Karin H Ekwall Consultant of: AbbVie, Pfizer, Kathrine L. Grøn Grant/research support from: BMS, Meliha C Kapetanovic: None declared, Francesca Faustini: None declared, Riitta Tuompo: None declared, Tove Lorenzen: None declared, Giovanni Cagnotto: None declared, Eva Baecklund: None declared, Oliver Hendricks Grant/research support from: Pfizer, MSD, Daisy Vedder: None declared, Tuulikki Sokka-Isler: None declared, Tomas Husmark: None declared, Maud-Kristine A Ljosa: None declared, Eli Brodin: None declared, Torkell Ellingsen: None declared, Annika Soderbergh: None declared, Milad Rizk Speakers bureau: AbbVie, Åsa Reckner: None declared, Per Larsson: None declared, Line Uhrenholt Speakers bureau: Abbvie, Eli Lilly and Novartis (not related to the submitted work), Søren Andreas Just: None declared, David Stevens: None declared, Trine Bay Laurberg Consultant of: UCB Pharma (Advisory Board), Gunnstein Bakland Consultant of: Novartis, UCB, Ronald van Vollenhoven Grant/research support from: BMS, GSK, Lilly, UCB, Pfizer, Roche, Consultant of: AbbVie, AstraZeneca, Biogen, Biotest, Celgene, Gilead, Janssen, Pfizer, Servier, UCB, Speakers bureau: AbbVie, Pfizer, UCB

Abstract: The optimal first-line treatment of patients with early rheumatoid arthritis (eRA) is not established. Objectives To compare clinical and radiographic outcomes of active conventional therapy (ACT) with each of three biological therapies with different modes of action. Methods In this investigator-initiated, randomized, open-label, blinded-assessor study ( NCT01491815 ), patients with treatment-naïve eRA with DAS28 〉 3.2 and RF+/ACPA+/CRP 〉 10mg/L, were randomized 1:1:1:1 to methotrexate combined with: 1) oral prednisolone (tapered quickly; discontinued at w36); or: sulphasalazine, hydroxychloroquine and mandatory intra-articular (IA) glucocorticoid injections in swollen joints (ACT); 2) certolizumab-pegol (CZP); 3) abatacept (ABA) or 4) tocilizumab (TCZ). IA glucocorticoid was allowed in all arms except w20-24 and w44-48. Co-primary outcomes at w48 were CDAI remission (CDAI≤2.8) and change in total van der Heijde-modified Sharp Score from baseline (ΔvdHSS w0-w48 ). A combination of Bonferroni and Dunnet’s procedure adjusted for multiple testing. The primary endpoints were estimated using logistic regression and analysis of covariance, adjusted for sex, anti-CCP status and country. Results 812 patients were randomized. Adjusted CDAI remission rates at w48 were: 59.3% (ABA), 52.3% (CZP), 51.9% (TCZ) and 39.2% (ACT). Compared to ACT, CDAI remission rates were superior for ABA (adjusted difference +20.1%; adjusted p 〈 0.001) and CZP (+13.1%; p=0.021), but not TCZ (+12.7%; p=0.030) (Table 1). Key secondary clinical outcomes were consistently better in biological groups compared to ACT. Adjusted mean ΔvdHSS w0-w48 was low (Table 1), with no significant differences between drugs. Table 1. Baseline characteristics ACT (n=200) CZP+MTX (n=203) ABA+MTX (n=204) TCZ+MTX (n=188) § Age (y) 55 (15) 55 (15) 55 (14) 52 (15) Women, % 139 (70%) 139 (69%) 140 (69%) 129 (69%) Time from diagnosis to baseline, days 13 (21) 12 (17) 16 (34) 16 (33) Anti-CCP/RF positive, % 82% / 76% 82% / 73% 83% / 78% 82% / 72% CDAI 28.7 (12.1) 27.9 (12.4) 28.6 (11.3) 26.6 (11.7) Total vdHSS (0-448) [median; IQR) 6.3 (8.2) [4; 1 - 8.5] 5.9 (7.6) [3; 1 - 8] 5.8 (9.8) [3; 1 - 6] 4.2 (6.7) [2; 0.5 - 5] Estimated adjusted outcome (ITT) 1 , Primary CDAI remission, w48 39.2% (32.5 - 45.9) 52.3% (45.5 - 59.1) 59.3% (52.6 - 66) 51.9% (44.9 - 59.0) Δ1.9% (44.9 - 0.45 (0.31 to 0.59) 0.47 (0.33 to 0.61) 0.62 (0.48 to 0.76) 0.5 (0.36 to 0.64) Estimated adjusted treatment difference (ITT) 2 , Primary CDAI remission, w48 Ref 13.1% (3.5 to 22.6 )* 20.1% (10.6 to 29.5 )* 12.7% (3 to 22.5) Δ2.7% (3 to 2 Ref 0.02 (-0.17 to 0.22) 0.17 (-0.02 to 0.37) 0.05 (-0.15 to 0.25) Key secondary ACR/EULAR Boolean remission, w48 Ref 14.7% (5.4 to 23.9) 19.4% (10.1 to 28.7) 13% (3.5 to 22.4) DAS28 remission,w48 Ref 12.9% (3.5 to 22.2) 17.4% (8.2 to 26.6) 14.4% (5 to 23.9) EULAR good response, w48 Ref 8.2% (-0.6 to 17.1) 11.3% (2.7 to 20) 2.9% (-6.3 to 12.2) vdHSS progression ≤0.5, w0-w48 Ref -3.3% (-11.1 to 4.6) 3.5% (-4.7 to 11.8) -2.2% (-10.3 to 5.9) Values are mean (SD), if not otherwise indicated. §Finnish patients randomised to TCZ+MTX, but not receiving it due to unavailability, are not included. 1 Values are estimated adjusted marginal means and estimated marginal differences against ACT with 95% CI. ITT: intention to treat population. *Superiority compared with ACT was demonstrated. No new safety signals were reported. Total numbers of serious adverse events (% patients with ≥1 event) were for ABA 21 (8.3%), CZP 28 (12.4%), TCZ 20 (9.2%) and ACT 23 (10.7%). Conclusion Compared with active conventional therapy (csDMARD + glucocorticoids), superiority regarding CDAI remission rates was demonstrated for abatacept and certolizumab-pegol, and not for tocilizumab. Radiographic progression was low and similar between treatments. Figure 1. Acknowledgements We thank the patients, investigators, nurses, joint assessors and study teams who were involved in the NORD-STAR trial; Eleonore Nilsson, chief study nurse, Lise Hejl Hyldstrup, coordinating study nurse, Niels Steen Krogh, data manager, Monica Rydén Aulin study coordinator and Eva Larsson, patient research partner. We also thank members of the NORD-STAR study group: Anders Bengtsson, Anders Gülfe, Annelies Blanken, Annette Schlemmer, Åsa Reckner Olsson, Aulikki Kononoff, Carl Turesson, Christina Dackhammar, Cidem Gentline, Elisabet Lindqvist, Ellen-Margrethe Hauge, Emma Grenholm, Erik af Klint, Erik Rødevand, Eva Baecklund, Fredrik Markros, Hamed Rezaei, Hanne Merete Lindegaard, Heikki Relas, Heikki Valleala, Ilia Qirjazo, Inger Marie Jensen Hansen, Jarno Rutanen, Jens Kristian Pedersen, Jens Rathmann, Johan Wallman, Johanna Carlestam, Jon Einarsson, Jörgen Lysholm, Kajsa Öberg, Katarina Almehed, Kathrine Lederballe Grøn, Kati Mykkänen, Lena Karlberg, Malin Hemberg, Maria K. Stilling-Vinther, Marjatta Leirisalo-Repo, Mohaned Hameed, Nancy Vivar, Oili Kaipiainen-Seppänen, Peter Olsson, Petrus Linge, Pia Lindell, Pia Neuer Jensen, René Østgård, Riitta Tuompo, Sabine Dieperink, Sara Nysom Christiansen, Sofia Exarchou, Thiab Saleh, Tomas Husmark, Tor Olofsson, Torkell Ellingsen, Trude Bruun, Vappu Rantalaiho and Ylva Borgas. Disclosure of Interests Mikkel Østergaard Speakers bureau: AbbVie, BMS, Boehringer-Ingelheim, Eli Lilly, Janssen, Merck, Pfizer, Roche, UCB, Celgene, Sanofi, Regeneron, Novartis, Orion, Hospira, Consultant of: AbbVie, BMS, Boehringer-Ingelheim, Eli Lilly, Janssen, Merck, Pfizer, Roche, UCB, Celgene, Sanofi, Regeneron, Novartis, Orion, Hospira, Grant/research support from: AbbVie, BMS, Merck, UCB, Celgene, Novartis, Ronald van Vollenhoven Speakers bureau: AbbVie, AstraZeneca, Biogen, Celgene, Galapagos, Gilead, Janssen, Pfizer, Servier, UCB, Consultant of: AbbVie, AstraZeneca, Biogen, Celgene, Galapagos, Gilead, Janssen, Pfizer, Servier, UCB, Grant/research support from: BMS, GSK, Eli Lilly, UCB, Pfizer, Roche, Anna Rudin Grant/research support from: AstraZeneca, Merete L. Hetland Speakers bureau: Merck, Biogen, Pfizer, Eli Lilly, Orion Pharma, CellTrion, Samsun Bioepsi, Janssen Biologics BV, MSD, Consultant of: Merck, Biogen, Pfizer, Eli Lilly, Orion Pharma, CellTrion, Samsun Bioepsi, Janssen Biologics BV, MSD, Grant/research support from: BMS, AbbVie, Roche, Novartis, Merck, Biogen, Pfizer, Marte Heiberg Speakers bureau: Eli Lilly, Consultant of: Eli Lilly, Dan Nordström Grant/research support from: UCB, BMS, AbbVie, Celgene, MSD, Novartis, Pfizer, Michael Nurmohamed Speakers bureau: Celltrion, Eli Lilly, Consultant of: Celltrion, Eli Lilly, Grant/research support from: BMS, AbbVie, MSD, Pfizer, Amgen, Björn Gudbjornsson Speakers bureau: Novartis, Consultant of: Novartis, Lykke Midtbøll Ørnbjerg Grant/research support from: Novartis, Pernille Bøyesen: None declared, Inge Olsen: None declared, Kristina Lend: None declared, Kim Hørslev-Petersen: None declared, Till Uhlig Speakers bureau: Grünenthal, Eli Lilly, Novartis, Pfizer, Consultant of: Grünenthal, Eli Lilly, Novartis, Pfizer, Grant/research support from: NORDFORSK, Tuulikki Sokka-Isler Speakers bureau: AbbVie, BMS, Celgene, Medac, Merck, Novartis Orion Pharma, Pfizer, Roche, Sandoz, UCB, Boehringer Ingelheim, Consultant of: AbbVie, BMS, Celgene, Medac, Merck, Novartis Orion Pharma, Pfizer, Roche, Sandoz, UCB, Boehringer Ingelheim, Gerdur Gröndal: None declared, Simon Krabbe Grant/research support from: AbbVie, MSD, Novartis, Joakim Lindqvist: None declared, Inger Gjertsson: None declared, Daniel Glinatsi Speakers bureau: AbbVie, Eli Lilly, Consultant of: AbbVie, Eli Lilly, Meliha C Kapetanovic: None declared, Anna-Birgitte Aga Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer, Consultant of: AbbVie, Eli Lilly, Novartis, Pfizer, Francesca Faustini: None declared, Pinja Parmanne Speakers bureau: Novartis, Consultant of: Novartis, Tove Lorenzen Speakers bureau: UCB, Consultant of: UCB, Giovanni Cagnotto: None declared, Johan Back: None declared, Oliver Hendricks Speakers bureau: AbbVie, Novartis, Consultant of: AbbVie, Novartis, Daisy Vedder: None declared, Tuomas Rannio: None declared, Emma Grenholm: None declared, Hanne Merete Lindegaard: None declared, Maud-Kristine A Ljosa: None declared, Eli Brodin: None declared, Annika Soderbergh: None declared, Milad Rizk: None declared, Elsa Hermansson: None declared, Line Uhrenholt Speakers bureau: AbbVie, Eli Lilly, Novartis, Consultant of: AbbVie, Eli Lilly, Novartis, Per Larsson: None declared, Søren Andreas Just: None declared, Gunnstein Bakland Speakers bureau: BMS, Consultant of: BMS, David Stevens Grant/research support from: KLINBEFORSK, Trine Bay Laurberg Speakers bureau: UCB, Consultant of: UCB, Espen A Haavardsholm Speakers bureau: Pfizer, AbbVie, Celgene, Novartis, Janssen, Gilead, Eli Lilly, UCB, Consultant of: Pfizer, AbbVie, Celgene, Novartis, Janssen, Gilead, Eli Lilly, UCB, Grant/research support from: NORDFORSK, Jon Lampa: None declared.

Abstract: Considerable proportion of patients with SpA have been immunized to the subcutaneous anti-TNF drug they are using. Concomitant use of MTX protects from immunization, whereas SASP does not. Patients with SpA using subcutaneous anti-TNF drugs can benefit from monitoring of the drug trough levels. Abstract Immunization to biological drugs can lead to decreased efficacy and increased risk of adverse effects. The objective of this cross-sectional study was to assess the extent and significance of immunization to subcutaneous tumor necrosis factor (TNF) inhibitors in axial spondyloarthritis (axSpA) patients in real-life setting. A serum sample was taken 1–2 days before the next drug injection. Drug trough concentrations, anti-drug antibodies (ADAb) and TNF-blocking capacity were measured in 273 patients with axSpA using subcutaneous anti-TNF drugs. The clinical activity of SpA was assessed using the Bath AS Disease Activity Index (BASDAI) and the Maastricht AS Entheses Score (MASES). ADAb were found in 11% of the 273 patients: in 21/99 (21%) of patients who used adalimumab, in 0/83 (0%) of those who used etanercept, in 2/79 (3%) of those who used golimumab and in 6/12 (50%) of those who used certolizumab pegol. Use of methotrexate reduced the risk of formation of ADAb, whereas sulfasalazine did not. Presence of ADAb resulted in decreased drug concentration and reduced TNF-blocking capacity. However, low levels of ADAb had no effect on TNF-blocking capacity and did not correlate with disease activity. The drug trough levels were below the consensus target level in 36% of the patients. High BMI correlated with low drug trough concentration. Patients with low drug trough levels had higher disease activity. The presence of anti-drug antibodies was associated with reduced drug trough levels, and the patients with low drug trough levels had higher disease activity. The drug trough levels were below target level in significant proportion of patients and, thus, measuring the drug concentration and ADAb could help to optimize the treatment in SpA patients.

Abstract: A patient-derived composite measure of the impact of rheumatoid arthritis (RA), the rheumatoid arthritis impact of disease (RAID) score, takes into account pain, functional capacity, fatigue, physical and emotional wellbeing, quality of sleep and coping. The objectives were to finalise the RAID and examine its psychometric properties. Methods An international multicentre cross-sectional and longitudinal study of consecutive RA patients from 12 European countries was conducted to examine the psychometric properties of the different combinations of instruments that might be included within the RAID combinations scale (numeric rating scales (NRS) or various questionnaires). Construct validity was assessed cross-sectionally by Spearman correlation, reliability by intraclass correlation coefficient (ICC) in 50 stable patients, and sensitivity to change by standardised response means (SRM) in 88 patients whose treatment was intensified. Results 570 patients (79% women, mean±SD age 56±13 years, disease duration 12.5±10.3 years, disease activity score (DAS28) 4.1±1.6) participated in the validation study. NRS questions performed as well as longer combinations of questionnaires: the final RAID score is composed of seven NRS questions. The final RAID correlated strongly with patient global (R=0.76) and significantly also with other outcomes (DAS28 R=0.69, short form 36 physical −0.59 and mental −0.55, p 〈 0.0001 for all). Reliability was high (ICC 0.90; 95% CI 0.84 to 0.94) and sensitivity to change was good (SRM 0.98 (0.96 to 1.00) compared with DAS28 SRM 1.06 (1.01 to 1.11)). Conclusion The RAID score is a patient-derived composite score assessing the seven most important domains of impact of RA. This score is now validated; sensitivity to change should be further examined in larger studies.