Background Assessment of structural damage progression, clinical efficacy and safety in patients with early-stage rheumatoid arthritis (RA) naïve to methotrexate (MTX) and with poor prognostic factors with certolizumab pegol (CZP) has not been performed so far.
Objectives To report the efficacy and safety of using CZP in combination with MTX compared to MTX alone, in early Japanese RA patients who were MTX-naïve with poor prognostic factors.
Methods Patients with early RA (<12 months from onset of persistent RA symptoms) fulfilling the 2010 ACR/EULAR Classification Criteria were enrolled in this multicenter, double-blind, randomized study (NCT01451203). Patients were included if they had poor prognostic factors: high-positive anti-CCP (>3xULN), and either positive rheumatoid factor or erosion on radiographs; were naïve to MTX, and had at least moderate disease activity (DAS28≥3.2). Patients were randomized 1:1 to either CZP+MTX or placebo (PBO)+MTX with oral MTX escalated to 16mg by Week (Wk) 8 unless safety issues and tolerability precluded further dose increase. The primary endpoint was inhibition of radiographic progression (change from baseline in modified total Sharp score [ΔmTSS]) at Wk52. Secondary endpoints were ΔmTSS at Wk24, and clinical remission rates by DAS28, ACR/EULAR (SDAI), and ACR/EULAR (Boolean) at Wks24 and 52.
Results The FAS population consisted of 316 patients with mean age 49.2±10.5yrs, symptoms duration 4.1±2.9 months, DAS28: 5.45±1.15 and mTSS: 5.55±12.43 at baseline, with the groups well-balanced. The average dose of concomitant MTX throughout the study was 11.61±2.8mg/wk. The CZP+MTX group (n=159) showed significantly greater inhibition of radiographic progression relative to the PBO+MTX group (n=157) at Wk52 (p<0.001) and at Wk24 (p=0.003) in the primary analyses of ANCOVA on the ranks. Similar results were obtained in the sensitivity analyses using ANCOVA at Wk52 (ΔmTSS=0.36 vs 1.58; p<0.001) and at Wk24 (ΔmTSS=0.26 vs 0.86; p=0.003). Clinical remission rates of the CZP+MTX group were significantly higher compared to those of the PBO+MTX group at Wk24 (DAS28: 52.8% vs 30.6% [p<0.001]; SDAI: 48.4% vs 29.3% [p<0.001]; Boolean: 36.5% vs 22.3% [p=0.007]) and at Wk52 (DAS28: 57.2% vs 36.9% [p<0.001]; SDAI: 57.9% vs 33.8% [p<0.001]; Boolean: 45.3% vs 28.0% [p=0.002]) (Figure). The combination therapy was well tolerated, with no new or unexpected safety signals observed.
Conclusions Combination of CZP with MTX was significantly more effective than PBO with MTX in inhibiting structural disease progression, as well as in achieving clinical remission in Japanese patients with early RA with poor prognostic factors.
Acknowledgements The authors acknowledge Costello Medical Consulting for editorial assistance which was funded by UCB Pharma.
Disclosure of Interest T. Atsumi Grant/research support: Kyowa Hakko Kirin, Chugai, Novartis, Mitsubishi Tanabe, Teijin, MSD, Astellas, Sanofi, Takeda, Novo Nordisk, Otsuka, Boehringer Ingelheim, AbbVie, Kissei, Pfizer, Astellas, Shionogi, Dainippon, Taisho-Toyama, Bristol-Myers Squibb, GlaxoSmithKline, Acterion, Paid instructor for: Astellas, Acterion, AbbVie, Eisai, MSD, Asahikasei, Otsuka, Daiichi-Sankyo, Mitsubishi Tanabe, Takeda, Chugai, Pfizer, Bristol-Myers Squibb, K. Yamamoto Grant/research support: UCB Pharma, Pfizer, Abbott, Santen, Mitsubishi-Tanabe, Eisai, Consultant for: UCB Pharma, Pfizer, Abbott, Bristol-Myers Squibb, Roche, Chugai, Mitsubishi-Tanabe, Eisai, T. Takeuchi Grant/research support: Abbott Japan, Astellas Pharma, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Janssen, Mitsubishi Tanabe, Pfizer Japan, Sanofi-Aventis, Santen, Takeda, Teijin Pharma, Abbvie, Asahikasei, Taisho-Toyama, Consultant for: Astra Zeneca, Eli Lilly Japan, Novartis, Mitsubishi Tanabe, Asahi Kasei Medical, Abbvie, Daiichi Sankyo, Speakers bureau: Abbott Japan, Bristol-Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi Tanabe, Pfizer Japan, Takeda, Astellas Pharma, Diaichi Sankyo, H. Yamanaka Grant/research support: AbbVie, Asahikasei Pharma, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, MSD, Nippon Kayaku, Pfizer, Santen, Taisho-Toyama, Takeda, Teijin Pharma, Speakers bureau: AbbVie, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Pfizer, Takeda, Teijin Pharma, N. Ishiguro Grant/research support: Takeda, Mitsubishi-Tanabe, Astellas, Chugai, Abbott, BMS, Eisai, Janssen, Kaken and Pfizer, Daiichi Sankyo, Speakers bureau: Daiichi Sankyo, Takeda, Hisamitsu, Otsuka, Taisho-Toyama, Kaken, Eisai, Janssen, Bristol-Myers Squibb, Abbott Japan, Chugai, Mitsubishi Tanabe, UCB Japan, Astellas Pharma, Pfizer Japan, Y. Tanaka Grant/research support: Bristol-Myers Squibb, Mitsubishi-Tanabe, Abbvie, MSD, Chugai, Astellas, Daiichi-Sankyo, Consultant for: Mitsubishi-Tanabe, Eisai, Chugai, Abbott Japan, Astellas, Daiichi-Sankyo, Abbvie, Janssen, Pfizer, Takeda, Astra-Zeneca, Eli Lilly Japan, GlaxoSmithKline, Quintiles, MSD, Asahi-Kasei, Speakers bureau: Mitsubishi-Tanabe, Eisai, Chugai, Abbott Japan, Astellas, Daiichi-Sankyo, Abbvie, Janssen, Pfizer, Takeda, Astra-Zeneca, Eli Lilly Japan, GlaxoSmithKline, Quintiles, MSD, Asahi-Kasei, K. Eguchi Consultant for: UCB Pharma, A. Watanabe Grant/research support: Daiichi-Sankyo, Kyorin, Shionogi, Taisho, Dainippon-Sumitomo, Taiho, Toyama Chemical and Meiji Seika, Speakers bureau: MSD, GlaxoSmithKline, Shionogi, Daiichi-Sankyo, Taisho-Toyama, Dainippon-Sumitomo, Mitsubishi-Tanabe, Pfizer, H. Origasa Consultant for: UCB Pharma and Astellas, T. Shoji Employee of: UCB Pharma, T. Okada Employee of: Astellas Pharma, D. van der Heijde Consultant for: AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, GlaxoSmithKline, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB Pharma, Vertex, N. Miyasaka Grant/research support: Pfizer, Takeda, Mitsubishi-Tanabe, Chugai, Abbott, Eisai and Astellas, T. Koike Speakers bureau: UCB Pharma, Pfizer, Chugai, Abbott, Mitsubishi-Tanabe, Takeda, Eisai, Santen, Astellas, Taisho-Toyama, Bristol-Myers Squibb, Teijin Pharma, Daiichi-Sankyo