Ustekinumab dose escalation improves clinical responses in refractory Crohn's disease

Abstract

Background: Clinicians often utilize off-label dose escalation of ustekinumab (UST) in Crohn's disease (CD) patients with disease refractory to standard dosing. Previous studies report mixed results with dose escalation of UST.

Methods: A retrospective observational study of 143 adult patients with CD receiving UST over a 33-month time period was conducted. Patients receiving UST at standard dosage for a minimum of 16 weeks were included in the analysis. Primary outcomes collected were clinical response [Physician Global Assessment Score (PGA) by >1] and remission (PGA = 0). Changes in clinical parameters were calculated for dose-escalated patients beginning with the time of dose switch (~42 weeks) and compared with a group of patients who were classified as "failing" standard dosing at 42 weeks who were not dose escalated.

Results: Dose escalation improved PGA by 0.47 ± 0.19 compared with patients remaining on every 8 weeks dosing (Q8 week), who worsened by 0.23 ± 0.23 (p < 0.05). Dose escalation decreased CRP 0.33 ± 0.19 mg/L and increased serum albumin 0.23 ± 0.06 g/dL (p < 0.05). Surprisingly, disease duration and prior CD surgeries inversely correlated with the need for dose escalation.

Conclusion: Our results support UST Q4 week dose escalation for selected CD patients who fail to achieve remission on standard Q8 week dosing. Dose escalation improves clinical outcomes, prevents worsening disease severity, and positively impacts CRP and albumin levels. Together these data indicate that clinicians should attempt Q4 week UST dosing in refractory CD patients before switching to an alternative class of biologic therapy.

Keywords: Crohn’s disease; dose escalation; remission; ustekinumab.

Figure 1.

Breakdown of clinical responses in 143 ustekinumab (UST)-treated patients. Remission was achieved by 16 ± 3 weeks in 31% of patients receiving standard every 8 week (Q8 week) dosing. The remaining 86 patients remained active (Physician Global Assessment Disease Severity Score ⩾1) at 16 ± 3 weeks. Thirteen patients discontinued UST before the 16-week time point. Of these 86 patients with documented disease activity at the 16-week time point, 27 went on to Q4 week dose escalation. The remaining 59 patients were left on standard Q8 week dosing until the end of follow-up. Among the 27 patients who were dose-escalated, 42 ± 16 weeks was the mean time to dose escalation. Twelve patients lacked a follow-up visit and were excluded, leaving 15 in the dose-escalated group. In the standard-dose group, 44 “failing” patients lacked 42 weeks of follow-up and were excluded from analysis, leaving 15 in the standard-dose group.

Figure 2.

Dose escalation improves Physician Global Assessment Disease Severity Score (PGA) in patients who fail standard every 8 week (Q8 week) dosing. Crohn’s disease patients who did not achieve remission on standard dose (Q8 week) therapy by the 42 ± 16 time point and remained on standard therapy (n = 15) were compared with those who were dose-escalated to Q4 week (n = 15). The transition to Q4 week dosing improved PGA by 0.47±0.19 (dark) whereas patients who remained on Q8 week dosing exhibited a mean increase in PGA of 0.23 ± 0.23 (p < 0.02).

Figure 3.

Dose escalation improves biomarkers of disease activity in Crohn’s disease (CD) patients failing standard every 8 weeks (Q8 week) dosing. (A) Changes in CRP (ΔCRP) levels are shown for CD patients remaining on Q8 week dosing (dark) compared with those escalated to Q4 week (gray) dosing. * p < 0.01. (B) Changes in serum albumin (ΔAlbumin) for CD patients kept on Q8 week (dark) compared with Q4 week (gray) dosing. *p < 0.0001.