P085 DOSE ESCALATION (Q4) OF USTEKINUMAB SHOULD BE CONSIDERED FOR CROHN’S DISEASE PATIENTS WHO FAIL STANDARD DOSING

Abstract Background Ustekinumab, a monoclonal antibody of interleukin-12 and interleukin-23, was approved for the treatment of moderate to severe Crohn’s disease (CD) in 2016. Ustekinumab is approved in CD for a weight-based IV induction dose followed by every 8 weeks of subcutaneous dosing. Response rates by 6 weeks range from 34% (anti-TNF failures) to 56% in bio-naïve patients. The remainder includes patients who partially-respond (PR) or do not respond (NR). Response by week 16 is 55% (anti-TNF failures) and 73% in bio-naïve patients suggestive of a ‘delayed response’ in some. Experience with anti-TNF drugs demonstrates that a subset of patients respond to dose escalation, which prompts the notion of a potential delayed response phenomenon with Ustekinumab. Aim Determine the efficacy of dose escalation from standard Q8 dosing to Q4 dosing of Ustekinumab in CD patients, who had PR or NR to standard Q8 dosing. Methods A Retrospective observation study of 143 adult patients with CD, on Ustekinumab standard Q8 dosing over a 2 year and 9-month period was conducted. Data was extracted pertaining to demographics, disease, and treatment-related variables (biomarkers, steroid use, interval surgery, ER visits). Patients were further subcategorized as responders, partial responders(PR), and non-responders(NR), based on changes in fecal calprotectin, albumin, CRP, and Physician Global Assessment Disease Severity (1=mild, 2=moderate, 3=severe). Q8 non-responders (NR) and partial responders (PR) were dose-escalated to Q4, and outcome variables were collected. Biomarkers, steroid utilization, interval surgery, and ER visits, and PGA were compared in Q8 partial responder(PR) and non-responders (NR) from the date of starting Ustekinmuab on Q8 dosing to the date of escalation to Q4 dosing, versus the date of escalation Q4 dosing to the end of patient follow up. Results 30% (n=8) of patients were Q8NR, and 70% (n=19) were Q8PR). In the PR group, biomarkers decreased by up to 21% when these patients were switched to Q4 dosing. 100% of patients saw clinical improvement or remained at mild disease on Q4 dosing. In the NR group, biomarkers decreased by up to 91%. 100% of patients saw clinical improvement or remained at mild disease while on Q4 dosing. In both groups, 50% of patients taking steroids on Q8 dosing were no longer taking steroids or were at a reduced dose at the end of Q4 dosing follow-up. 40% of patients on immunomodulators on Q8 dosing were no longer taking immunomodulators at the end of Q4 dosing follow-up. Conclusions

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A228 EVOLUTION OF MRE FINDINGS IN PAEDIATRIC PATIENTS WITH SMALL BOWEL CROHN’S DISEASE ON MAINTENANCE METHOTREXATE

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwz047.227 ◽

2020 ◽

Vol 3 (Supplement_1) ◽

pp. 103-104

Author(s):

A Kellar ◽

N Carmen ◽

M Greer ◽

T Walters ◽

A Griffiths ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Clinical Remission ◽

Global Assessment ◽

Activity Index ◽

Severe Disease ◽

Clinical Findings ◽

Mild Disease ◽

Surgical History

Abstract Background Observational data in children and RCT data in adults indicate that methotrexate (MTX) is associated with induction and maintenance of clinical remission in luminal Crohn’s disease, but efficacy in achieving intestinal healing has not been examined. Aims To examine the evolution of MRE signs of inflammation in children treated with MTX. Methods In this retrospective cohort study, we reviewed paediatric CD patients on maintenance MTX monotherapy for >4 months who underwent serial MREs between July 2010 and October 2015. MREs were reviewed by a radiologist blind to clinical data. Overall inflammatory activity on each MRE was scored as minimal, mild, moderate or severe, informed by the presence of bowel wall thickness, wall enhancement, T2 hyperintensity, comb sign, mesenteric edema, penetrating disease, stricturing, diffusion restriction and motility. The radiologist’s global assessment of change from MRE 1 to MRE 2 was scored as improved, unchanged or worsened. Clinical findings, disease activity (assessed by weighted paediatric CD activity index [wPCDAI]) and surgical history were also extracted from medical records by a clinician blind to MRE results. Results Thirty-five patients were included (median age at diagnosis 12 [IQR 11–14] years; 77% male; 60% inflammatory (B1), 17% stricturing (B2), 23% penetrating (B3) disease). Between baseline and follow-up MRE, wPCDAI (median 15 [IQR 7–43] decreased to 8 [IQR 0–18]; p=0.006) and CRP (median 9 [IQR 2–36] decreased to 5 [IQR 5–9]; p=0.013) and 74% (N=26) were in clinical remission (wPCDAI < 12.5) at MRE 2. MRE features that significantly improved from MRE 1 to 2 were comb sign from 63% (N=37) to 38% (N=14) (p=0.02) and penetrating disease from 14% (N=8) to 0 (p=0.03). After a median of 17 months (IQR 13–23), 51% (N=18) of patients improved, 29% (N=10) worsened and 20% (N=7) had no change based on the radiologist’s global assessment. Of the 21 patients with moderate/severe disease at MRE 1, 33% (N=7) had minimal/mild disease by MRE 2. 66% (N=14/21) continued to have moderate/severe disease at MRE 2. Additionally, a further 14% (N=2/14) of those with minimal/mild disease at baseline MRE progressed to moderate/severe disease at MRE 2. Complete details of change between MRE 1 and MRE 2 are displayed in Figure 1. Conclusions Despite signs of clinical improvement, many paediatric CD patients on maintenance MTX therapy for >4 months have unchanged or worsened MRE findings. This underscores the need for follow-up imaging in these cases. Funding Agencies None

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DOP74 Effectiveness of dose escalation in Crohn’s disease patients with insufficient response to standard-dose subcutaneous ustekinumab maintenance therapy: A multicentre international cohort study

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.113 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S111-S112 ◽

Cited By ~ 1

Author(s):

U Kopylov ◽

J Hanzel ◽

C Liefferinckx ◽

D De Marco ◽

N Imperatore ◽

...

Keyword(s):

Cohort Study ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Median Duration ◽

Dose Escalation ◽

Clinical Remission ◽

Standard Dose ◽

Dose Interval ◽

Insufficient Response

Abstract Background Ustekinumab (UST) is an effective agent for induction and maintenance of response and remission in Crohn’s disease (CD). In addition to randomised controlled trials, an abundance of real-world evidence is available as well, suggesting that a substantial proportion of patients will not respond or lose response to UST therapy. To date, there is very little evidence to support the effectiveness of dose-optimisation strategy to manage primary or secondary non-response to ustekinumab. Methods This was a multicentre retrospective cohort study. The protocol was reviewed and approved by the Clinical Committee of ECCO. We included active (HBI≥5; CDAI ≥220) CD patients that received a standard-dose IV induction and at least one SC UST dose of 90 mg. Patients with ostomy were excluded. All patients received dose escalation by either shortening the interval between the doses to q4/6 weeks, intravenous reinduction or a combination of intravenous and subcutaneous escalation. The primary aim of the study was a clinical response (defined as Δ HBI≥3 or Δ CDAI ≥ 70 points) at week 16 after dose escalation. Clinical remission was defined as HBI<5 or CDAI <150. Results Of 140 patients, 83 (59.3%) were females, median age at treatment onset 36 (26–50) years, median duration of disease 9 (5–18) years from 21 centres in 13 countries (12 Europe, 1 Canada) were included. The patients were dose-escalated after a median treatment duration of 30 (20–45) weeks. Thirty-four (24,3%) were previously escalated from q12 to q8 maintenance regimen. Eighty-nine (63.5%) of the patients were escalated from q8 to q4 regimen, 20 (14.3%) – from q8 to q6, 15 (10.7%) received intravenous reinduction and 16 (11.4%) – a combination of intravenous reinduction and subcutaneous dose interval shortening. At week 16 from escalation, 83 (59.3%) responded to treatment, of them 21 (15%) were in clinical remission. Thirty-three (23.6%) of the patients were on systemic corticosteroids upon escalation; 7/33 (21.2%) achieved corticosteroid-free remission at week 16. One hundred and nine patients (77.8%) continued treatment beyond week 16. Follow-up data beyond week 16 were available for 75/150 (53.6%) of the patients (median duration of follow-up: 35 (32–54) weeks) from dose escalation. At the last follow-up, 53/75 (70.7%) continued to respond to treatment, including 42 (56%) in clinical remission; 25/75 (33%) discontinued treatment at last follow-up. Conclusion This large multicentre retrospective study demonstrates that intensification of ustekinumab maintenance dosage may be effective in up to 60% of the patients. This strategy should be considered in patients that are non-responsive to q8 ustekinumab maintenance dosing.

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Seven Weeks of High-Dose Vitamin D Treatment Reduces the Need for Infliximab Dose-Escalation and Decreases Inflammatory Markers in Crohn’s Disease during One-Year Follow-Up

Nutrients ◽

10.3390/nu13041083 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1083

Author(s):

Mia Bendix ◽

Anders Dige ◽

Søren Peter Jørgensen ◽

Jens Frederik Dahlerup ◽

Bo Martin Bibby ◽

...

Keyword(s):

Vitamin D ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Dose Escalation ◽

Inflammatory Markers ◽

High Dose ◽

One Year ◽

Group D ◽

High Dose Vitamin

Background: Seven weeks of high-dose vitamin D treatment decreases intestinal IL17A and IFN-γ mRNA expression in active Crohn’s disease (CD). In this follow-up study, we investigated whether seven-week vitamin D treatment affected the infliximab response in the following 45 weeks compared to placebo. Methods: CD patients (n = 40) were initially randomised into four groups: infliximab + vitamin-D; infliximab + placebo-vitamin-D; placebo-infliximab + vitamin-D; and placebo-infliximab + placebo-vitamin-D. Infliximab (5 mg/kg) or placebo-infliximab was administered at weeks 0, 2 and 6. Vitamin D (5 mg bolus followed by 0.5 mg/day for 7 weeks) or placebo-vitamin D was handed out. After the 7-week vitamin D period, all patients received infliximab during follow-up. Results are reported for Group D+ (infliximab + vitamin-D and placebo-infliximab + vitamin-D) and Group D- (infliximab + placebo-vitamin-D and placebo-infliximab + placebo-vitamin-D). Results: Group D- patients had greater needs for infliximab dose escalation during follow-up compared to group D+ (p = 0.05). Group D+ had lower median calprotectin levels week 15 (p = 0.02) and week 23 (p = 0.04) compared to group D-. Throughout follow-up, group D+ had 2.2 times (95% CI: 1.1–4.3) (p = 0.02) lower median CRP levels compared with group D-. Conclusions: Seven weeks high-dose vitamin D treatment reduces the need for later infliximab dose-escalation and reduces inflammatory markers. EudraCT no. 2013-000971-34.

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P478 Effectiveness of ustekinumab dose escalation in Crohn’s disease patients with insufficient response to standard-dose subcutaneous maintenance therapy: an observational multicentre study

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.601 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S467-S468

Author(s):

R Olmedo-Martín ◽

M D M Martín-Rodríguez ◽

L Lorenzo-González ◽

M Lázaro-Sáez ◽

M Lopez-Vico ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Dose Escalation ◽

Clinical Remission ◽

Standard Dose ◽

Human Monoclonal Antibody ◽

Treatment Persistence ◽

Insufficient Response ◽

History Of

Abstract Background Ustekinumab is a human monoclonal antibody that targets interleukin (IL)-12 and IL-23 and it is effective for the treatment of Crohn’s disease (CD). However, a group of patients will not respond or over time will experience loss of response (LOR) to ustekinumab. Evidence supporting the effectiveness of ustekinumab dose escalation for LOR is scarce. The aim of this study was to assess the effectiveness of ustekinumab dose escalation in a cohort of patients with active CD Methods Multicentric retrospective cohort study conducted in 5 tertiary Andalusian centers. Patients with active CD who received a standard-dose intravenous (IV) induction and at least one subcutaneous (SC) ustekinumab dose were included. All enrolled patients received dose escalation by either shortening the interval between the maintenance doses to every 4 or 6 weeks, IV reinduction or a combination of strategies. The primary outcome of the study was to assess corticosteroid (CS)-free clinical remission (HBI ≤4) at week 16. Secondary outcomes were CS-free clinical response (decrease of HBI ≥ 3 points from baseline) at week 16 and on the last follow-up, CS-free clinical remission on the last follow-up and ustekinumab persistence after dose escalation Results A total of 84 patients were included (54,8% female, median duration of CD 13,5 years). A 47,5% of the patients had history of previous abdominal surgery and 55% had been treated with 2 or more biologics. Patients were dose-escalated after a median treatment duration of 37 weeks (IQR 23–54). The most frequent type of dose escalation was the 90 mg every 4 weeks regimen (58%). A 25% of the patients were on concomitant immunomodulators at escalation. At week 16 from dose escalation the proportion of patients in CS-free response was 50/84 (59%) including 18/84 (21,4%) in CS-free remission. Follow-up data beyond week 20 were available for 61/84 patients (72.6%). On the last follow-up visit, 29/61 (47,5%) patients responded to treatment without concomitant CS of which 19/61 (31%) were in CS-free clinical remission. Systemic CS were discontinued in 21/44 (47.7%) patients who were on CS at the time of dose escalation. Ustekinumab was discontinued in 14/84 (17%) of the patients due to clinical non-response (ustekinumab persistence was 81% at 14 months of follow-up). Adverse events following dose escalation were reported in 4 of the 84 patients (7.7%), none of them were serious. Conclusion Dose escalation of ustekinumab maintenance was effective in over 50% of the patients and the treatment persistence was high. This strategy should be considered in patients who are not responsive or have LOR to ustekinumab on an 8-week dose maintenance interval

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