Y-ECCO Literature Review: Joseph Sleiman
Ustekinumab improves health-related quality of life in patients with moderate-to-severe Crohn's disease: Results up to week 104 of the STARDUST trial
Panes J, Vermeire S, D’Haens GR, et al., STARDUST Study Group
United European Gastroenterol J 2023 May 4. doi: 10.1002/ueg2.12384. Online ahead of print.
The concept of treat to target (T2T) in Crohn’s Disease (CD) involves optimising therapy until a predetermined clinically relevant endpoint is met. In recent years, this endpoint has most commonly been a short-term biomarker response or endoscopic healing, but this has typically been juxtaposed with long-term patient reported outcomes (PROs) such as health-related quality of life (HRQoL) . The international STRIDE-2 guidelines emphasise the need for monitoring at frequent intervals to ensure that treatment targets agreed at the commencement of any therapy are actually being achieved. One of the big unknowns of such strategies, requiring frequent monitoring, has been their cost-efficiency. However, concerns about cost have been balanced by arguments that adequate monitoring may allow earlier and more appropriate initiation of advanced therapies, which may then result in better longer-term outcomes .
STARDUST (NCT03107793) was a phase 3b, open-label, randomised controlled trial that compared ustekinumab (UST) T2T with standard-of-care (SoC) treatment strategies in adult patients with moderate to severe CD. The primary results from this trial have previously been reported, and it is notable that endoscopic and biomarker endpoints were not statistically different between the two treatment strategies . However, it is also worth noting that while more patients in the T2T arm received q4w (4-weekly) dosing of UST (18.4% vs 0%), more patients in SoC received q8w (8-weekly) dosing (61.5% vs 38.8%). The original STARDUST trial included 440 patients, of whom 336 completed the first year of treatment and 323 (T2T, n=147; SoC, n=176) were subsequently enrolled to the long-term extension (LTE) period until week 104 (2-year mark). In this study, Panes et al. report on the HRQoL outcomes from patients in the LTE study from the STARDUST trial.
Methods and key findings
A total of 258 patients (T2T, n=121; SoC, n=141) completed the LTE period in STARDUST. A notable strength of the data is that information on algorithm-driven escalation/de-escalation was available for all patients regardless of treatment arm (T2T or SoC) during this period. The authors investigated whether T2T or SoC strategies differed in terms of HRQoL at week 16 and week 48. They also evaluated the effect of UST long-term treatment on HRQoL over the 2-year follow-up period . The five questionnaires used to assess this outcome were the disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ), the EuroQoL five-dimension five-level [EQ-5D-5L; visual analogue scale (VAS) and index], Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Hospital Anxiety and Depression Scale-Anxiety and -Depression (HADS-A and HADS-D, respectively) and Work Productivity and Activity Impairment (WPAI) questionnaires. Time lost from work was also evaluated. Although statistical methods were employed for week 16 and week 48 to compare T2T with SoC strategies, no statistical testing was employed in the LTE period.
The STARDUST population had a mean age of 35 years, with a near 1:1 ratio of males to females, a mean CD duration of 6.8 years, and an almost equal distribution across ileal (29%), ileocolonic (34%) and colonic (37%) disease. More than 30% of patients were on systemic or topical corticosteroids, and 30% were on other immunomodulators. Forty percent of patients were biologic naïve. All HRQoL questionnaires showed improvements in both the T2T and the SoC treatment arm at week 16 that were maintained until week 48. No statistically significant differences were observed between the arms with respect to the improvements, though EQ-5D-5L VAS and FACIT-F showed a marginal benefit for SoC compared with T2T at week 16.
At week 104, the overall LTE population showed a continued increase in IBDQ response (76.6% at week 16; 86.9% at week 104) as well as clinical remission (60.4% and 73.5%). Similar trends were noted in the other general HRQoL measurements. At week 104, 65.2% of all mRAS patients (T2T, 60.9%; SoC, 68.7%) were in employment versus 62.6% (T2T, 61.6%; SoC, 63.4%) at baseline.
The effects of CD on QoL are well reported, with impacts on mental health and increases in sick-leave days, hospitalisation rates and medical costs , This study is unique, given that it prospectively demonstrates a positive impact of UST on standardised PROs such as HRQoL measurement and WPAI, regardless of treatment strategy (T2T or SoC).
Although both SoC and T2T strategies with UST yielded improvements in HRQoL over a 2-year period, there were no significant differences between the strategies, which reflects the primary results reported from the STARDUST trial . This parallels other UST studies where clinical remission portrays an improvement in HRQoL [6–8]. Nevertheless, noting that the T2T strategy involves more frequent visits and monitoring tests, the reported absence of difference in this study means that patients also did not suffer negatively as a result of the T2T strategy compared with the SoC strategy. This was reflected especially in the WPAI domains, where T2T and SoC arms had statistically similar work productivity loss (p=0.42) and unemployment rates (37.3% and 27.7%) at week 48, although only 1.1% of patients in the T2T arm gained employment compared with 8.8% in the SoC arm.
There are several possible reasons for these findings, including the attrition of patients from week 16 to weeks 48 and 104, which could have led to a population enriched with treatment responders; this could explain the lack of difference in HRQoL outcomes, regardless of treatment strategy. An important aspect of UST use in real-world clinical settings is the lack of prospective data to assess clinical outcomes with UST dose intensification [9, 10]. Given this study’s findings, one may postulate that UST is already well dosed to achieve clinical remission, and thus PRO response would not change once clinical remission has been achieved with SoC strategies.
Panes and colleagues have demonstrated that, independent of treatment strategy (T2T or SoC), UST was effective in improving HRQoL and WPAI over a 2-year period. No major differences in HRQoL measurements were noted between T2T and SoC strategies, yet both showed important efficacy for clinical remission as well as PROs. This is an intriguing study which perhaps suggests the need both to revisit guidance on ubiquitous use of a T2T approach in the field and to adopt a more personalised approach to monitoring for patients receiving advanced therapies.
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- Colombel JF, D’Haens G, Lee WJ, Petersson J, Panaccione R. Outcomes and strategies to support a treat-to-target approach in inflammatory bowel disease: A systematic review. J Crohns Colitis 2020;14:254–66. doi:10.1093/ecco-jcc/jjz131.
- Danese S, Vermeire S, D'Haens G, et al. Treat to target versus standard of care for patients with Crohn's disease treated with ustekinumab (STARDUST): an open-label, multicentre, randomised phase 3b trial. Lancet Gastroenterol Hepatol 2022;7:294–306. doi: 10.1016/S2468-1253(21)00474-X.
- Panés J, Vermeire S, D'Haens GR, et al. Ustekinumab improves health‐related quality of life in patients with moderate‐to‐severe Crohn's disease: Results up to Week 104 of the STARDUST trial. United European Gastroenterol J 2023 May 4. doi.org/10.1002/ueg2.12384.
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- Loftus EV, Danese S, Panaccione R, et al. S770 Health-related quality of life with ustekinumab vs adalimumab for induction and maintenance therapy in biologic-naïve patients with moderate-to-severe Crohn’s disease: IBDQ in the SEAVUE study. Official J Am Coll Gastroenterol 2021;116:S355–7. doi.org/10.14309/01.ajg.0000776612.28121.
- Forss A, Clements M, Myrelid P, et al. Ustekinumab is associated with real-world long-term effectiveness and improved health-related quality of life in Crohn's disease. Dig Dis Sci 2022;68:65–76. doi.org/10.1007/s10620-022-07501-z.
- Sands BE, Han C, Gasink C, et al. Ustekinumab maintained clinically meaningful improvement in health-related quality of life in patients with moderate to severe Crohn's disease: results from the IM-UNITI long-term extension. Am J Gastroenterol. 2019;114: S404. doi.org/10.14309/01.ajg.0000592296.98724.38.
- Dalal RS, Njie C, Marcus J, Gupta S, Allegretti JR. Predictors of ustekinumab failure in Crohn’s disease after dose intensification. Inflamm Bowel Dis 2021;27:1294–301. doi.org/10.1093/ibd/izaa282.
- Gonczi L, Szanto K, Farkas K, et al. Clinical efficacy, drug sustainability and serum drug levels in Crohn's disease patients treated with ustekinumab – A prospective, multicenter cohort from Hungary. Dig Liver Dis 2022;54:207–13. doi.org/10.1016/j.dld.2021.07.008.
Joseph Sleiman - Short Biography
Joseph Sleiman is currently a Gastroenterology Fellow at the University of Pittsburgh Medical Center, and an incoming IBD Fellow at the Cleveland Clinic, in the USA. His research interests are in IBD, immunotherapy-induced colitis and machine learning for GI research purposes. He is currently working on a radiomics project in advanced imaging detection for stricturing Crohn’s Disease. He is the Social Media Associate Editor for Evidence-Based GI, a monthly publication by the American College of Gastroenterology. He is involved in medical #SoMe (social media) education and trainee mentorship and is part of social education platforms, including #MondayNightIBD and #GIJournal Club.