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.

A nationwide real-world study on dynamic ustekinumab dosing and concomitant medication use among Crohn’s disease patients in Finland

“…Our data on dosing patterns support the findings of other real-world registry studies of ustekinumab maintenance treatment where the majority or all the patients commenced their ustekinumab maintenance therapy with q8w dosing [6,10,12,13,22]. Interestingly, data on recapturing or improvement of ustekinumab response in CD patients with q4w dosing is emerging [11,[22][23][24][25]. In the present study, a sixth of patients received shorter dosing than q8wat the end of follow-up.…”

“…However, some recent studies report clinical outcomes derived from specific real-world cohorts consisting of only dose optimized patients [11,[23][24][25]. Where reported, 22-52% of patients needed dose intensification, which appeared successful in around half of the patients [10,11,[22][23][24][25].In the present study, one-third of patients on ustekinumab maintenance therapy required dose intensification. Among patients initiating maintenance therapy with q12w dosing, two-thirds shortened the interval.…”

“…We observed a significant reduction in corticosteroid use within first year of ustekinumab maintenance treatment irrespective of ustekinumab dose intensification. Kopylov et al [25] also report discontinuation of systemic corticosteroids in 67.6% of patients at week 16 after dose intensification to q4w.On the contrary, Haider et al [22] reported that a higher number of dose-intensified patients received steroids at the end of follow-up, although this study included low patient numbers. In our study, 21% of the patients who underwent a dose intensification were still on corticosteroid treatment at one year, probably due their more refractory CD also indicated by the higher CRP levels at baseline.…”

“…While the analysis of dosing patterns in IM-UNITI trial suggested regaining clinical response in 55% of patients following dose intensification from q12w to q8w [3,21], data on dose optimization in real-world situations remains scarce [10,22]. However, some recent studies report clinical outcomes derived from specific real-world cohorts consisting of only dose optimized patients [11,[23][24][25].…”

How to Optimize Treatment With Ustekinumab in Inflammatory Bowel Disease: Lessons Learned From Clinical Trials and Real-World Data

“…Patients already being intensified to 4-weekly dosing can also benefit from iv re-induction, with approximately half of patients (53%) achieving clinical remission and 67% response ( 99 ). Younger patients ( 98 ) with shorter disease duration ( 97 ), no prior surgery ( 97 ), perianal disease ( 96 ), higher clinical disease activity ( 96 , 98 ) and corticosteroid use ( 96 ) have shown reduced response rates to these rescue strategies. There is an ongoing study (POWER) that will compare the efficacy of q8w 90 mg sc with re-induction with 6 mg/kg iv UST in patients with loss of response to maintenance sc UST (NCT03782376).…”