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Background: 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) (
| 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.
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.