Review Article

Translating STRIDE-II Into Clinical Reality–Opportunities and Challenges

Axel Dignass; Stefan Rath; Thomas Kleindienst; Andreas Stallmach

Aliment Pharmacol Ther. 2023;58(5):492-502.

Abstract and Introduction

Abstract

Background: With the introduction of novel therapies for inflammatory bowel diseases (IBD), 'treat-to-target' strategies are increasingly discussed to improve short- and long-term outcomes in patients with IBD.

Aim: To discuss opportunities and challenges of a treat-to-target approach in light of the current 'Selecting Therapeutic Targets in Inflammatory Bowel Disease' (STRIDE-II) consensus

Methods: The 2021 update of STRIDE-II encompasses 13 evidence- and consensus-based recommendations for treat-to-target strategies in adults and children with IBD. We highlight the potential implications and limitations of these recommendations for clinical practice.

Results: STRIDE-II provides valuable guidance for personalised IBD management. It reflects scientific progress as well as increased evidence of improved outcomes when more ambitious treatment goals such as mucosal healing are achieved.

Conclusions: Prospective studies, objective criteria for risk stratification, and better predictors of therapeutic response are needed to potentially render 'treating to target' more effective in the future.

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Table 1. Definition of endpoints, therapeutic targets, goals and their implications in clinical practice and research.
Endpoint¹⁰	Target¹¹	Goal⁵
• Clinical definition of success at predefined time point • May have impact on disease course • Used for comparison in clinical trials and regulatory approval	• Short-term ambition must be achievable • Will impact outcome if met • Modifiable with therapeutic optimisation	• Long-term ambition of treatment • Defined by an individual patient and physician

Table 2. Heterogeneous definitions of mucosal healing in pivotal interventional IBD studies.
CD study	Intervention	Time of endoscopy	Definition of MH	MH rate (%)
SONIC¹⁹	AZA monotherapy	Week 26	No mucosal ulcerations	17.0
	AZA + IFX dual therapy			44.0
	IFX monotherapy			30.0
ACCENT I²⁰	Infliximab Q8W	Week 54	No mucosal ulcerations in previously affected segment	44.0
ACCENT I²⁰	Infliximab episodically in case of flare	Week 54	No mucosal ulcerations in previously affected segment	18.0
EXTEND²¹	Adalimumab	Week 12	No mucosal ulcerations	27.0
	Placebo	Week 12		13.0
	Adalimumab	Week 52		24.0
	Placebo	Week 52		0.0
MUSIC²²	Certolizumab pegol	Week 10	CDEIS < 6	37.0
MUSIC²²	Certolizumab pegol	Week 54	CDEIS < 6	27.0
VERSIFY²³	Vedolizumab	Week 26	SES-CD ≤ 4	12.0
VERSIFY²³	Vedolizumab	Week 52	SES-CD ≤ 4	18.0
UNITI-1&2²⁴	Ustekinumab	Week 8	Complete absence of ulcers	9.0
UNITI-1&2²⁴	Placebo	Week 8		4.1
IM-UNITI²⁴	Ustekinumab 90 mg Q12W	Week 44		12.8
	Ustekinumab 90 mg Q8W			21.6
	Placebo			9.8
UC study	Intervention	Time of endoscopy	Definition of MH	MH rate (%)
ULTRA 1²⁵	ADA 160/80 mg^a	Week 8	Endoscopy subscore 0 or 1	46.9
	ADA 80/40 mg^b			37.7
	Placebo			41.5
ULTRA 2²⁶	ADA	Week 8	Endoscopy subscore 0 or 1	41.1
	ADA	Week 52		25.0
	Placebo	Week 8		31.7
	Placebo	Week 52		15.4
SELECTION²⁷	Filgotinib 100 mg	Week 10 (induction)	Endoscopy subscore 0 or 1 AND no or mild increase in chronic inflammatory infiltrate in lamina propria, no neutrophils in lamina propria or epithelium and no erosion, ulceration or granulation tissue (based on Geboes Scale)	14.8 (biologic naïve) 6.3 (biologic experienced)
	Filgotinib 100 mg	Week 58 (maintenance)		20.9
	Filgotinib 200 mg	Week 10 (induction)		23.3 (biologic naïve) 9.9 (biologic experienced)
	Filgotinib 200 mg	Week 58 (maintenance)		32.7
	Placebo	Week 10 (induction)		10.9 (biologic naïve) 4.2 (biologic experienced)
	Placebo	Week 58 (maintenance)		13.5 (filgotinib 100 mg during induction) 10.2 (filgotinib 200 mg during induction)
ACT 1²⁸	Infliximab 5 mg	Weeks 8, 30 and 54	Endoscopy subscore 0 or 1	62.0 (W8), 50.4 (W30), 45.5 (W54)
	Infliximab 10 mg			59.0 (W8), 49.2 (W30), 46.7 (W54)
	Placebo			33.9 (W8), 24.8 (W30), 18.2 (W54)
ACT2²⁸	Infliximab 5 mg	Weeks 8 and 30	Endoscopy subscore 0 or 1	60.3 (W8), 46.3 (W30)
	Infliximab 10 mg			61.7 (W8), 56.7 (W30)
	Placebo			30.9 (W8), 30.1 (W30)
TRUE NORTH²⁹	Ozanimod	Week 10	Mucosal endoscopy score ≤1 and Geboes score <2.0	12.6
	Placebo	Week 10		3.7
	Ozanimod	Week 52		29.6
	Placebo	Week 52		14.1
OCTAVE induction 1³⁰	Tofacitinib 10 mg BID	Week 8	Endoscopy subscore ≤ 1	31.3
OCTAVE induction 1³⁰	Placebo			15.6
OCTAVE induction 2²⁸	Tofacitinib 10 mg BID			28.4
OCTAVE induction 2²⁸	Placebo			11.6
OCTAVE maintenance³⁰	Tofacitinib 5 mg BID	Week 52	Endoscopy subscore ≤ 1	37.4
	Tofacitinib 10 mg BID			45.7
	Placebo			13.1
GEMINI 1³¹	Vedolizumab	Week 6	Endoscopy subscore 0 or 1	40.9
	Placebo	Week 6		24.8
	Vedolizumab Q4W	Week 52		56.0
	Vedolizumab Q8W			51.6
	Placebo			19.8
VARSITY³²	Vedolizumab	Week 52	Endoscopy subscore 0 or 1^c	39.7
VARSITY³²	Adalimumab	Week 52	Endoscopy subscore 0 or 1^c	27.7
U-ACHIEVE study 1³³	UPA 7.5 mg QD	Week 8	Endoscopy subscore 0 or 1^d	14.9
	UPA 15 mg QD			30.6
	UPA 30 mg QD			26.9
	UPA 45 mg QD			35.7
	Placebo			2.2
U-ACHIEVE study 2⁵⁸	UPA 45 mg QD	Week 8	Endoscopy subscore 0 or 1^d	36.3
U-ACHIEVE study 2⁵⁸	Placebo	Week 8	Endoscopy subscore 0 or 1^d	7.4
U-ACCOMPLISH⁵⁸	UPA 45 mg QD	Week 8	Endoscopy subscore 0 or 1^d	44
	Placebo	Week 8	Endoscopy subscore 0 or 1^d	8.3
	UPA 15 mg QD	Week 52	Endoscopy subscore 0 or 1^d	48.6
	UPA 30 mg QD			67.7
	Placebo			14.8

Abbreviations: ACT, active ulcerative colitis trials; ADA, adalimumab; AZA, azathioprine; BID, twice daily; CD, Crohn's disease; CDEIS, Crohn's disease endoscopic index of severity; IFX, infliximab; MH, mucosal healing; QD, once daily; Q8W, every 8 weeks; Q12W, every 12 weeks; SES-CD, Simple Endoscopic Score for Crohn Disease; UC, ulcerative colitis; UPA, upadacitinib; W, week.
^a160 mg at week 0, 80 mg at week 2 and 40 mg at weeks 4 and 6.
^b0 mg at week 0 and 40 mg at weeks 2, 4 and 6.
^cInitially listed as criteria for mucosal healing in the study protocol but later defined as 'endoscopic improvement'.
^dDefined as 'endoscopic improvement' in this study.

Table 3. Summary of challenges to overcome in order to establish STRIDE-II in daily clinical practice and to further improve the concept of treating to target.
Developing a common definition of the term mucosal healing
Showing long-term benefits of mucosal healing and further analysing the risk–benefit-ratio of 'treating to target' in randomised, controlled trials (i.e. closing data gaps, especially in UC)
Establishing cost- and time-efficient monitoring strategies in day-to-day practice (e.g. intestinal ultrasound ➔ are transmural healing and/or control of intestinal inflammation as seen on sonographic imaging may be even better targets compared to mucosal healing?)
Identifying risk factors for patient stratification (e.g. individual strategies for asymptomatic, geriatric, paediatric and/or comorbid patients are needed)
Identifying predictors that allow choosing the best first-line option among currently available therapies capable of reaching ambitious treatment targets reliably
Researching new therapeutic concepts and updating the STRIDE-II recommendations accordingly, possibly with modified or entirely new targets
Improving IBD screening and identifying afflicted patients as early as possible (since early intervention in the window of opportunity is of the essence)
Making a treat-to-target approach feasible in countries with limited healthcare resources

Authors and Disclosures

Axel Dignass¹, Stefan Rath², Thomas Kleindienst² and Andreas Stallmach³

¹Department of Medicine I, Agaplesion Markus Hospital, Frankfurt/Main, Germany
²Department of Medical Immunology, AbbVie Deutschland GmbH & Co. KG, Wiesbaden, Germany
³Department of Internal Medicine IV, University Hospital Jena, Jena, Germany

Correspondence
Axel Dignass, Department of Medicine I, Agaplesion Markus Hospital, Wilhelm-Epstein-Str. 4, D-60431 Frankfurt/Main, Germany. Email: axel.dignass@agaplesion.de

Author Contributions
Axel Dignass: Conceptualization (lead); methodology (equal); writing – original draft (equal); writing – review and editing (equal). Stefan Rath: Conceptualization (equal); writing – original draft (equal); writing – review and editing (equal). Thomas Kleindienst: Conceptualization (equal); writing – original draft (equal); writing – review and editing (equal). Andreas Stallmach: Conceptualization (lead); writing – original draft (equal); writing – review and editing (equal).

Conflict of Interest Statement
AD has received fees for participation in clinical trials, review activities such as data monitoring boards, statistical analysis and endpoint committees from Abivax, AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb/Celgene, Dr Falk Foundation, Galapagos, Gilead, Janssen and Pfizer; consultancy fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Roche/Genentech, Sandoz/Hexal, Takeda, Tillotts and Vifor Pharma; payment from lectures including service on speakers bureaus from AbbVie, Biogen, CED Service GmbH, Celltrion, Falk Foundation, Ferring, Galapagos, Gilead, High5MD, Janssen, Materia Prima, MedToday, MSD, Pfizer, Streamed-Up, Takeda, Tillotts and Vifor Pharma; and payment for manuscript preparation from Falk Foundation, Takeda, Thieme and UniMed Verlag. AS reports research funding from AbbVie and Celltrion; has received lecture fees from AbbVie, Amgen, Astellas, Biogen, Celltrion, Janssen, Falk Foundation, Ferring, MSD, Recordati Pharma, Streamed-Up and Takeda; and consulting fees from AbbVie, Astellas, Amgen, Biogen, CLS Behring, Consal, Galapagos, Hexal, Janssen, MSD, Norgine, Pfizer Pharma, Takeda and Tillots Pharma. SR and TK are employees of AbbVie Deutschland GmbH & Co. KG and may own AbbVie stock.