Impact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis: results from the RISING study

Tsutomu Takeuchi, Nobuyuki Miyasaka, Kazuhiko Inoue, Tohru Abe, Takao Koike, RISING study, F Hirano, K Taneichi, T Atsumi, K Ohnishi, H Takahashi, N Chiba, T Sasaki, K Chiba, T Kanno, S Ohta, T Sumida, T Yoshio, K Kurasawa, Y Handa, T Mimura, R Matsumura, N Nakagawa, N Watanabe, K Saigo, M Takei, T Suguro, T Kasama, M Hirakata, Y Kuga, A Nakajima, K Yamaji, K Yamamoto, E Saito, H Yamagata, M Tateishi, S Sawada, N Kamatani, H Yamanaka, M Nakajima, S Toma, H Endo, T Kuroda, S Honjo, I Koni, M Kawano, S Nakazaki, K Sugimoto, K Kanzaki, T Kanamono, A Suzuki, T Ohashi, Y Kusaka, H Ohashi, Y Izui, N Ogawa, T Miyamoto, N Ishiguro, Y Eto, S Yoshida, S Tamaki, T Fujii, M Tanaka, M Inaba, T Koike, Y Shimaoka, T Takeuchi, A Ogata, Y Saeki, S Osawa, K Shi, S Kumagai, T Nishiyama, H Sano, T Matsubara, Y Murakawa, M Yamamura, K Ezawa, Y Yamanishi, S Yamana, H Tanaka, K Tani, M Tokuda, H Dobashi, M Inoo, S Nakata, K Takasugi, I Furugou, Y Tanaka, K Saito, T Horiuchi, T Shuto, Y Nakashima, H Miyahara, M Kondo, K Eguchi, Y Ueki, M Tsukano, Y Fujikawa, T Matsuda, Y Shiohira, Tsutomu Takeuchi, Nobuyuki Miyasaka, Kazuhiko Inoue, Tohru Abe, Takao Koike, RISING study, F Hirano, K Taneichi, T Atsumi, K Ohnishi, H Takahashi, N Chiba, T Sasaki, K Chiba, T Kanno, S Ohta, T Sumida, T Yoshio, K Kurasawa, Y Handa, T Mimura, R Matsumura, N Nakagawa, N Watanabe, K Saigo, M Takei, T Suguro, T Kasama, M Hirakata, Y Kuga, A Nakajima, K Yamaji, K Yamamoto, E Saito, H Yamagata, M Tateishi, S Sawada, N Kamatani, H Yamanaka, M Nakajima, S Toma, H Endo, T Kuroda, S Honjo, I Koni, M Kawano, S Nakazaki, K Sugimoto, K Kanzaki, T Kanamono, A Suzuki, T Ohashi, Y Kusaka, H Ohashi, Y Izui, N Ogawa, T Miyamoto, N Ishiguro, Y Eto, S Yoshida, S Tamaki, T Fujii, M Tanaka, M Inaba, T Koike, Y Shimaoka, T Takeuchi, A Ogata, Y Saeki, S Osawa, K Shi, S Kumagai, T Nishiyama, H Sano, T Matsubara, Y Murakawa, M Yamamura, K Ezawa, Y Yamanishi, S Yamana, H Tanaka, K Tani, M Tokuda, H Dobashi, M Inoo, S Nakata, K Takasugi, I Furugou, Y Tanaka, K Saito, T Horiuchi, T Shuto, Y Nakashima, H Miyahara, M Kondo, K Eguchi, Y Ueki, M Tsukano, Y Fujikawa, T Matsuda, Y Shiohira

Abstract

This study is a prospective, randomized, double-blind study to compare the efficacy and safety of 10 mg/kg infliximab with those of 3 mg/kg infliximab treatment in methotrexate-refractory rheumatoid arthritis patients. After the patients received 3 mg/kg infliximab infusion at weeks 0, 2, and 6, they were randomly assigned to be administered 3, 6 or 10 mg/kg infliximab every 8 weeks from week 14 to 46. Mean American College of Rheumatology improvement (ACR-N) at week 54, the primary endpoint, was 51.3% and 58.3% for the 3 mg/kg and 10 mg/kg groups, respectively, with a statistically significant difference. Treatment with 10 mg/kg was found to be remarkably beneficial in patients who had not responded to three infusions with 3 mg/kg at week 10. The median changes in the modified Sharp score were 0.0 in the two groups. There were no significant differences in the incidences of adverse events between the groups. In patients who achieved better clinical response or greater inhibition of progression of joint damage, trough serum infliximab level was significantly higher than in patients who did not. The magnitudes of both efficacies were correlated with the trough serum infliximab level (ClinicalTrials.gov number: NCT00691028).

Figures

Fig. 1
Fig. 1
Randomization, reason for discontinuing treatment, and number of patients completing the study. All patients received concomitant methotrexate
Fig. 2
Fig. 2
Clinical response at week 54 in each group according to EULAR response criteria in nonresponders at week 10 to three infusions with 3 mg/kg. *p < 0.001, overall
Fig. 3
Fig. 3
Progression of joint damage in each group according to total modified Sharp score (TSS) at week 54: median (IQR) change score in TSS (a), and the rate of patients with progression, no change or improved in TSS (b). †Radiographic progression was categorized in TSS as follows: progressed (>4.1), no change (≥−4.1 and ≤4.1), and improved (<−4.1). W0*: Estimated yearly progression of TSS before infliximab therapy. W54*: Progression of TSS from baseline to week 54. **p = 0.022 versus 6 mg/kg group
Fig. 4
Fig. 4
Cumulative probability plot of the total modified Sharp score (TSS) in relation to trough serum infliximab level at week 54 in all patients (a, n = 270), and in early RA patients (b, n = 84). Patients were grouped according to four different ranges of trough serum infliximab levels as shown

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