Y-ECCO Literature Review: Samantha Campbell

Methods

This was a prospective, open-label cohort study, based in Belgium. It included consecutive patients with CD in whom ustekinumab therapy was initiated between September 2016 and January 2018. The ustekinumab dosing regimen was fixed with an IV loading dose of approximately 6 mg/kg at week 0 and SC maintenance doses of 90 mg every 8 weeks. Exclusion criteria included an ostomy, no active disease on endoscopy or radiology at baseline, perianal involvement without luminal disease and a diagnosis of unclassified Inflammatory Bowel Disease. Patients with follow-up in a different hospital were also excluded. Faecal calprotectin, C-reactive protein (CRP) and ustekinumab serum levels were measured at baseline and at weeks 4, 8, 16 and 24. Biological remission was defined as a CRP ≤5 mg/L and biological response as either a ≥50% decrease in CRP or a CRP ≤5 mg/L if elevated at baseline.

Clinical remission was measured at weeks 4, 8, 16 and 24 by weighted patient-reported outcomes (PRO2). PRO2 requires patients to score abdominal pain and liquid stool frequency daily, and to multiply an average by 5 or 2, respectively. Clinical remission was defined by an average liquid stool frequency of ≤2.8 and an average abdominal pain score of ≤1.21.

The Simple Endoscopic Score for Crohn’s Disease (SES-CD) was used to evaluate endoscopic outcomes. Endoscopy was performed at week 24 for all patients by the same three experienced endoscopists. Endoscopic response was acknowledged by a ≥50% decrease in SES-CD from baseline and endoscopic remission (primary endpoint) was defined as an SES-CD ≤2. .

Key Findings

The study cohort included 86 individuals who met the inclusion criteria. A total of 118 were screened. A large majority of patients had previous exposure to biologic therapy, with 95.3% having been exposed to an anti-TNF and 67.4% to vedolizumab. Forty-four patients (51.2%) had previous exposure to three biologic therapies and the median disease duration at the time of initiating ustekinumab was 14.7 years.

Endoscopic remission was achieved in only 7.1% and endoscopic response in 20.5% of patients. Despite this, SES-CD scores decreased significantly from baseline to week 24, with median values of 11.5 and 9 respectively (p=0.0009).

There was a significant reduction in faecal calprotectin from baseline to week 4 (median 1242.3 and 529, respectively, p=0.0008), and a continuing reduction was observed to week 8 (median 372.2, p=0.52×10-5). However, faecal calprotectin then increased to week 24 (median 749, p=0.03 compared to baseline). Patients had a significantly higher chance of discontinuing therapy if a 50% decrease in faecal calprotectin was not achieved by week 8 (p=0.006). Prospective endoscopic responders and non-responders had an initial decrease in faecal calprotectin, with an increase in faecal calprotectin for non-responders after week 8.

At each timepoint, serum ustekinumab levels were significantly inversely proportional to faecal calprotectin levels. Median serum ustekinumab levels were 7.2 μg/mL (IQR 3.4–10.5), 2.6 μg/mL (IQR 1.1–4.2) and 2.1 μg/mL (IQR 0.8–3.2) at weeks 8, 16 and 24 respectively. When ustekinumab serum concentrations were stratified by quartiles, significantly fewer patients in the lowest quartiles at weeks 4 and 8 experienced a 50% decrease in faecal calprotectin by week 8 (p=0.008 and p<0.001 respectively). At week 8, for a 50% decrease in faecal calprotectin, a ustekinumab serum concentration ≥4.2 μg/mL was required (p=0.004, NPV 87%). At every timepoint, analysis using the median (IQR) highlighted that endoscopic responders had higher ustekinumab levels. For the possibility of endoscopic remission after 6 months, ustekinumab levels of 2.3 μg/mL at week 16 (NPV 87.9%) and 1.9 μg/mL at week 24 (NPV 85.2%) were required. Maintenance serum ustekinumab levels were negatively influenced by prior exposure to anti-TNF agents and amount of previous anti-TNF agents used.

Conclusion

This is the first prospective, real-life cohort study of patients with CD receiving an IV induction of ustekinumab, followed by SC maintenance doses. This study highlights the significance of the switch between IV induction therapy and SC maintenance therapy, and the faecal calprotectin trends. After IV induction, the majority of patients had a significant and clinically relevant decrease in faecal calprotectin by week 8, followed by a significant rise in faecal calprotectin and unsatisfactory endoscopic outcomes after 6 months.

With infliximab and vedolizumab, dose intensification is implemented if under-exposure is detected. However, therapeutic drug monitoring for ustekinumab is not currently integrated into routine clinical practice. The literature postulates a dose-response relationship, but results vary. A post-hoc analysis of the UNITI trials recommended steady-state serum ustekinumab trough concentration targets for clinical remission during maintenance of 0.8 to 1.4 μg/mL [3]. One study suggested a maintenance trough concentration of more than 4.5 µg/ml at 26 weeks to achieve biological and endoscopic response [2]. For endoscopic response, at week 24, this study postulates a level of ≥1.9 μg/mL. Presumably for endoscopic remission, levels are higher. However, only half of the patients achieved a level of more than 2.1 μg/mL, suggesting a potential under-exposure in many patients.

The unsatisfactory endoscopic remission and response rates in this study (7.1% and 20.5%, respectively) were not too dissimilar to the UNITI post-hoc analysis (10.9% and 17.4%, respectively). [4]. The majority of patients had previous exposure to biologic therapy, which previous literature suggests makes ustekinumab less efficacious.

In conclusion, this study highlights the possible need to intensify the dosing regimen. There is potential to increase the maintenance frequency from 8 to 4 weekly, give an IV re-induction and/or increase the actual dose of ustekinumab. We have relatively little understanding of whether these changes may cause new, unwanted side effects and further prospective studies are warranted.

References

1. Feagan BG, Sandborn WJ, Gasink C, et al.; UNITI–IM-UNITI StudyGroup. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375:1946–60.
2. Battat R, Kopylov U, Bessissow T, et al. Association between ustekinumab trough concentrations and clinical, biomarker, and endoscopic outcomes in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2017;15:1427–34.e2.
3. 3. Adedokun OJ, Xu Z, Gasink C, et al. Pharmacokinetics and exposure response relationships of ustekinumab in patients with Crohn’s disease. Gastroenterology. 2018;154:1660-71.
4. 4. Rutgeerts P, Gasink C, Chan D, et al. Efficacy of ustekinumab for inducing endoscopic healing in patients with Crohn’s disease. Gastroenterology. 2018;155:1045–58.

Samantha Campbell is a Gastroenterology trainee based in North London, Royal Free London NHS Foundation Trust. She is currently on maternity leave (due to return in September 2019), but is still actively involved in gaining further experience in the research field. She is looking forward to returning to work and expanding on her IBD experience and research.