Real-World Methotrexate Dose on Clinical Effectiveness and Structural Damage of Certolizumab Pegol With Rheumatoid Arthritis

Abstract

Objective: Rheumatoid arthritis (RA) treatments have markedly advanced with the introduction of biological agents, e. g., tumor necrosis factor (TNF) inhibitors. TNF inhibitors are demonstrated to be quite effective in combination with methotrexate (MTX), and sufficient doses of both agents are important to control RA's disease activity. However, not all RA patients can be treated with high-dose MTX due to contraindications related to the antimetabolite action of MTX or to tolerability concerns. In daily practice, this has resulted in reduced effectiveness of TNF inhibitors. We sought to determine whether the concomitant use of dose of MTX affected the clinical effectiveness, retention rate, and side effects of certolizumab pegol (CZP) for treating RA in a real-world setting. CZP is a pegylated-conjugated Fab' fragment of a humanized anti-TNF antibody that has high affinity to TNF. Patients and Methods: We divided Japanese RA patients treated with CZP (n = 95, 25-83 years old) into groups based on those with (n = 65) and without (n = 30) concomitant MTX and those treated with a high dose (≥8 mg, n = 41) or low dose (1- <8 mg, n = 24) of MTX. We retrospectively analyzed the concomitant MTX doses' effects and side effects and the patient retention rate. Results: There were no significant differences among the CZP groups with and without MTX or the groups receiving the high vs. low MTX doses in the retention rate, the low disease activity rate, or the inhibitory effect in radiographic joint damage. Conclusion: CZP has the potential to be a useful biological agent to control RA's disease activity and the bone destruction in patients who cannot tolerate a sufficient MTX dose.

Keywords: DAS28-ESR; X ray; biological; certolizumab pegol; cytokines; rheumatoid arthritis.

Figure 1

Retention rates. Kaplan–Meier curves for all CZP treatments, low- (2– <8 mg) and high-dose MTX (≥8 mg), with MTX, and without and with MTX group regarding the time of withdrawal due to lack of effectiveness, adverse effects, or the patient's request from the start of CZP to 12 months. CZP, certolizumab pegol; MTX, methotrexate.

Figure 2

Clinical and laboratory data from baseline in certolizumab pegol (CZP) without and with methotrexate (MTX) in the clinical course. Serial changes in DAS28-ESR from baseline in (A) all CZP treatments, (B) with and without MTX, and (C) the low- and high-dose MTX. *p < 0.05 and ^†p < 0.001, baseline vs. the value at 1, 3, 6, and 12 months. DAS28-ESR, Disease Activity Score assessing 28 joints with erythrocyte sedimentation rate.

Figure 3

Disease activity in DAS28-ESR and ACR/EULAR Boolean-based criteria. By comparing the RA patients' DAS28-ESR scores at baseline and at 1, 3, 6, and 12 months, it is possible to define (A) disease activity, (B) low disease activity including remission, and (C) Boolean-based criteria in RA patients with the low- and high-dose MTX, with MTX, and without and with MTX, and all CZP treatments. The disease activity and criteria in DAS28-ESR were categorized as follows. DAS28 criteria: ■ high: 5.1 <DAS28; moderate, 3.2 ≤ DAS28 ≤ 5.1; low, 2.6 ≤ DAS28 <3.2; □ remission: DAS28 < 2.6. ACR/EULAR Boolean-based remission: TJC, SJC, PtVAS, and CRP all ≤1. CRP, C-reactive protein; EULAR, European League Against Rheumatism; PtVAS, patient's visual analog scale; RA, rheumatoid arthritis; SJC, swelling joint count; TJC, tender joint count.

Figure 4

Disease activity in EULAR response. By comparing the RA patients' DAS28-ESR scores at baseline and at 1, 3, 6, and 12 months, it is possible to define the EULAR response in RA patients in the low- and high-dose MTX, with MTX, and without and with MTX, and all CZP treatments. The EULAR responses were categorized as follows. ■ no response: DAS28 improvement ≤0.6 and DAS28 improvement >0.6 and ≤1.2 in present DAS28 >5.1. Moderate response: DAS28 improvement >0.6 and ≤1.2 in present DAS28 ≤3.2, and >3.2 and ≤5.1; DAS28 improvement >1.2 in present DAS28 >5.1, and >3.2 and ≤5.1. □ Good response: DAS28 improvement >1.2 in present DAS28 ≤3.2.

Figure 5

Joint damage in radiographic assessment. The progression of joint damage in RA patients in the low- and high-dose MTX, with MTX, and without and with MTX, and all CZP treatments according to the modified total Sharp score (mTSS) at 12 months. (A) The change in mTSS from baseline. (B) The rate of patients with progression, no change, or improvement in the mTSS (ΔmTSS ≤0.5).