Methotrexate (MTX) dosage does not appear to impact the efficacy of the antitumor necrosis factor (anti-TNF) agent certolizumab pegol (CZP) in patients with rheumatoid arthritis (RA) who are receiving these agents in combination with other antirheumatic drugs.1 This finding emerged from pooled data from the RAPID 1 (Rheumatoid Arthritis Prevention of Structural Damage 1) and RAPID 2 trials and was recently published in Arthritis Care & Research.
MTX is often prescribed in combination with other antirheumatic agents to boost drug efficacy and ameliorate adverse events. The ability to confidently adjust MTX dosage in individual patients without compromising efficacy or tolerability is critically important, considering that many patients on MTX monotherapy require dose escalation to achieve or maintain a desired therapeutic effect.
An international research team led by Bernard Combe, MD, PhD, director of the Research Center at Montpellier-Nimes University in Montpellier, France, sought to clarify whether the efficacy of antirheumatic drugs were dependent on MTX dosage. The team compared background MTX dosages of 10 to 15 mg/week and ≥15 mg/week. Study subjects were randomly assigned to receive CZP 200 mg, CZP 400 mg, or placebo for management of RA.
Study participants, randomized in a 2:2:1 fashion, received a 400-mg loading dose of CZP at weeks 0, 2, and 4, followed by 200 mg (n=638) or 400 mg (n=635) or placebo (n=325) every 2 weeks. The primary efficacy end point was defined as the American College of Rheumatology criteria for 20%, 50%, and 70% improvement from baseline utilizing the Disease Activity Score erythrocyte sedimentation rate (DAS28-ESR), and the modified Sharp/van der Heijde score (SHS) at 24 weeks of treatment.
Incidence of treatment-emergent adverse events (TEAEs) in relation to baseline MTX dosage also was categorized. A post hoc sensitivity analysis also assessed MTX dose categories of ≤ 10 mg/week, 10 to 15 mg/week, and >15 mg/week.
No impact of MTX on CZP efficacy
At week 24, baseline MTX dosage did not appear to have an influence on treatment responses in either CZP dose cohort. ACR20/50/70 response rates at week 24 were all greater in patients receiving CZP 200 mg or 400 mg in addition to MTX than in patients receiving placebo.
For example, in the ACR20 assessment, response rates for patients receiving MTX ≤15 mg/week were 60% for both the CPZ dosage groups and 10% for the placebo group. Rates for patients receiving MTX ≥15 mg/week were: 56% in the CPZ 200 mg group, 59% in the CPZ 400 group, and 15% in the placebo group.
Similar trends were seen for ACR 50 and ACR 70. Although differences between CPZ dosage groups were statistically insignificant, response rates trended higher for patients receiving MTX at higher dosages in the ad hoc ACR20 analysis and the ACR50 and ACR 70 analyses.
The mean change from baseline was greater for DAS28-ESR and lower for SHS at week 24 in patients receiving CZP in addition to MTX compared with those receiving placebo, regardless of CPZ dosage or baseline MTX dosage category. As expected, incidence of TEAEs was higher in patients receiving MTX ≥15 mg/week across treatment groups.
Summary and clinical applicability
The efficacy of the antirheumatic drug CZP, at doses of 200 mg/week and 400 mg/week, was unaffected by the background dosage of MTX. This finding suggests that the dosage of MTX can be modified to individual patient needs and tolerance without compromising therapeutic effect when given in combination with CZP.
1. Combe B, Furst DE, Keystone EC, et al. Certolizumab pegol efficacy across methotrexate regimens: a pre-specified analysis of two phase III trials. Arthritis Care Res. 2016;68(3):299-307.