Background/Purpose: In the START (Safety Trial for Rheumatoid Arthritis with Remicade Therapy) trial, patients (pts) with active rheumatoid arthritis (RA) received placebo (PBO), or infliximab (IFX) 3 mg/kg or 10 mg/kg, with a primary endpoint of safety at week 22. Pts receiving IFX 3 mg/kg had dose escalation if they met prespecified criteria for lack of response at week 22, which was assessed by combined swollen and tender joint count, S/TJC, (primary nonresponders). They also received dose escalation if they experienced a flare after week 22 (secondary nonresponders, not analyzed here) (1,2). In a post hoc analysis, we examine the effects of IFX dose escalation in the primary nonresponders, using the more relevant tool Clinical Disease Activity Index (CDAI), which includes the 28 S/TJC as well as pt and physician global assessments.

Methods: Adult START pts (N=1082) with 6 swollen and 6 tender joints, despite treatment with methotrexate (MTX), were randomized: PBO (n=363), IFX 3 mg/kg (n=360), or IFX 10 mg/kg (n=361) at weeks 0, 2, 6, and 14. At week 22, PBO pts switched to IFX 3 mg/kg for the remainder of the study, and pts randomized to IFX 3 mg/kg continued dosing every 8 weeks or received dose escalation (in increments of 1.5 mg/kg) every 8 weeks if there was lack of response (< 20% improvement from baseline in S/TJC). The study was terminated after 54 weeks (2).

Results: Among the 360 pts randomized to 3 mg/kg, 220 did not receive dose escalation during the study, 109 pts received dose escalation, and 31 discontinued or were from an excluded site. 53 of those receiving dose escalation were primary non-responders with lack of response at week 22 (2). Baseline characteristics were generally similar among these subgroups (80% female, mean 53 years old, SJC=15, TJC=22, and MTX 15 mg/week). Of the primary non-responders (n=53), IFX doses escalated to an average of 6.3 mg/kg (range 4.5 – 10 mg/kg). CDAI scoring (high, moderate, and low) improved from 89%, 9%, and 2% at week 22 to 46%, 24%, and 30% at week 46, and did not substantially improve further at week 54 (Figure 1). Among the subset of these pts who received doses ≥6 mg/kg (n=26), the average IFX dose was 7.7 mg/kg (range 6 – 10 mg/kg), and the CDAI scores (high, moderate, and low) of 92%, 8%, and 0% at week 22 improved to 58%, 27% and 15% at week 46, and also did not substantially improve further at week 54 (Figure 2).

Conclusion: In this analysis of CDAI in pts who initiated IFX 3 mg/kg and were dose escalated starting at week 22 (average dose 6.3 mg/kg), dose escalation generally improved pts’ CDAI category (Figure 1). In a subset of pts who were escalated to doses ≥ 6 mg/kg (average dose 7.65 mg/kg), no further improvements in categorical CDAI were noted (Figure 2). Although START showed no increased risk of serious infections among pts receiving approved doses of INF vs PBO, pts who were treated with 10 mg/kg loading doses and maintenance therapy had more serious infections (relative risk=3.1) (1). These findings may be of clinical significance when considering dose escalation to higher doses of IFX.

1. Westhovens et al. Arthritis Rheum. 2006;54:1075.
2. Rahman et al. Ann Rheum Dis. 2007;66:1233.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cdai-analysis-of-dose-escalation-in-a-trial-of-infliximab-for-rheumatoid-arthritis/