Histologic assessments in ulcerative colitis: the evidence behind a new endpoint in clinical trials

ABSTRACT

Introduction

Treatment goals for ulcerative colitis (UC) are evolving from the achievement of clinical remission to more rigorous goals defined by endoscopic and histologic healing. Achievement of deeper remission targets aims to reduce the risk of colectomy, hospitalizations, and colorectal cancer.

Areas covered

This review covers histologic assessments, histologic remission as a clinical trial endpoint, and the association between histologic disease activity and clinical outcomes. Future directions are also discussed, including the use of advanced imaging and artificial intelligence technologies, as well as potential future treatment targets beyond histologic remission.

Expert opinion

Histologic assessments are used for their sensitivity in measuring mucosal inflammatory changes in UC. Due to correlation with disease activity, histologic assessments may support clinical decision-making regarding treatment decisions as such assessments can be associated with rates of clinical relapse, hospitalization, colectomy, and neoplasia. While histologic remission is limited by varying definitions and multiple histologic indices, work is ongoing to create a consensus on the use of histologic assessments in clinical trials. As research advances, aspirational targets beyond histologic remission, such as molecular healing and disease clearance, are being explored.

Plain Language Summary

Ulcerative colitis (UC) is the most common inflammatory bowel disease and often results in bloody diarrhea, frequent bowel movements, and bowel urgency. Patients with UC are at greater risk for hospitalization, surgery, and colorectal cancer. To reduce these risks, the goals of UC treatment are changing from mainly addressing symptoms to reducing inflammation at a deeper histologic, or microscopic, level. The inflammation in UC causes distinct microscopic changes in the colon, which can be assessed after collecting biopsies or tissue samples. This review provides an overview of histologic remission (when no signs of inflammation are seen in tissue samples viewed under a microscope) as a treatment goal in UC.

Histologic remission has been shown to be associated with lower rates of relapse, hospitalization, surgical removal of the colon, and colorectal cancer. However, using histologic remission as a treatment target can be difficult due to varying definitions and the many different scoring assessments available to healthcare providers. Updated guidance from regulatory agencies and academic organizations has helped align definitions of histologic remission and how to assess histologic healing in clinical trials.

The introduction of targeted advanced therapies has allowed for deeper healing with the potential for histologic resolution. This enables clinicians and researchers to aim for treatment targets that are harder to achieve but have a greater impact for patients in the course of their disease. New technologies such as artificial intelligence, high-resolution endoscopy, and digital pathology have also led to targets beyond histologic healing, aiming to restore the function of the colon’s mucosal barrier and disease clearance.

KEYWORDS:

• Ulcerative colitis
• histologic remission
• histologic healing
• mucosal healing
• endoscopic remission
• clinical trial endpoints
• inflammatory bowel diseases

Article highlights

• The rise of immunotherapies has influenced the increasing recognition of histology for its sensitivity in detecting “deeper” mucosal healing and established disease clearance and molecular healing as aspirational treatment targets.

• Assessment of histologic remission may improve the accuracy and precision of treatment decisions and serve as predictor of improved clinical outcomes, including decreased rates of hospitalization, clinical relapse, colectomy, and neoplasia.

• Significant barriers to the adoption of histology remain including inconsistent histologic target definitions, lack of standardized endoscopic and histologic recommendations, variability in biopsy interpretation, and high patient burden due to invasive biopsy collection.

Declaration of interest

RK Pai has received consulting fees from: AbbVie, Alimentiv, Allergan, Eli Lilly and Company, Genentech, and PathAI. G D’Haens has been a consultant for AbbVie, Agomab, AstraZeneca, AM Pharma, AMT, Arena Pharmaceuticals, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Exo Biologics, Galapagos, Index Pharmaceuticals, Kaleido, Roche, Gilead, GlaxoSmithKline, Gossamerbio, Pfizer, Immunic, Johnson & Johnson, Origo, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, and Protagonist; and has received speaker’s bureau fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, Pfizer, BMS, and Takeda. T Kobayashi has received grants and/or contracts from: AbbVie, Activaid, Alfresa Pharma Corporation, Bristol-Myers Squibb, EA Pharma, Eli Lilly Japan K.K., Gilead Sciences, Google Asia Pacific, Janssen Japan K.K., JIMRO, JMDC, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Otsuka Holdings, Pfizer Japan, Takeda, and Zeria Pharmaceutical; has received lecture payment or honoraria from: AbbVie, Activaid, Alfresa Pharma, Galapagos, Janssen Japan K.K., JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Nippon Kayaku, Pfizer Japan, Takeda, ThermoFisher Diagnostics, Zeria Pharmaceutical; has received payment for expert testimony from: AbbVie, Activaid, Alfresa Pharma, EA Pharma, Janssen Japan K.K., KISSEI Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe, Mochida Pharmaceutical, Nippon Kayaku, Pfizer Japan, and Takeda; and has participated on data safety monitoring boards or advisory boards for: Bristol-Myers Squibb, EA Pharma, Eli Lilly and Company, and Janssen. BE Sands has received fees for consulting and speaking from Abivax, Bristol Myers Squibb, Janssen, Lilly, Pfizer, and Takeda; for consulting from AbbVie; Adiso Therapeutics; Alimentiv; Amgen; Arena Pharmaceuticals; Artizan Biosciences; Artugen Therapeutics; AstraZeneca; Bacainn Therapeutics; Boehringer-Ingelheim; Boston Pharmaceuticals; Calibr; Celltrion Healthcare; ClostraBio; Cytoki Pharma; Connect Biopharma; Entera; Evommune; Fresenius Kabi; Galapagos; Genentech; Gilead Sciences; GlaxoSmithKline; Gossamer Bio; Imhotex; Immunic; Index Pharmaceuticals; Inotrem; Innovation Therapeutics; Ironwood Pharmaceuticals; Kaleido; Kallyope; MiroBio; Morphic Therapeutics; MRM Health; OSE Immunotherapeutics; Progenity; Prometheus Biosciences; Protagonist Therapeutics; Q32 Bio; Redhill Biopharma; Sun Pharma; Surrozen; Synlogic; Target RWE; Teva; Theravance Biopharma; TLL Pharmaceutical; USWM Enterprises; VielaBio: VTA Labs; and personal fees and stock options for consulting from Ventyx Biosciences.

S Travis has served as a consultant for Abacus, AbbVie, Actial, ai4gi, Alcimed, Allergan, Amgen, Apexian, Aptel, Arena, Asahi, Aspen, Astellas, Atlantic, AstraZeneca, Barco, Biocare, Biogen, BLPharma, Boehringer Ingelheim, BMS, Buhlmann, Calcico, Celgene, Cellerix, Cerimon, ChemoCentryx, Chiesi, CisBio, ComCast, Coronado, Cosmo, Ducentis, Dynavax, Elan, Enterome, EQrX, Equillium, Falk, Ferring, FPRT Bio, Galapagos, Genentech/Roche, Genzyme, Gilead, Glenmark, Grunenthal, GSK, GW Pharmaceuticals, Immunocore, Immunometabolism, Indigo, Janssen, Lexicon, Lilly, Medarex, Medtrix, Merck, Merrimack, Mestag, Millenium, Neovacs, Novartis, Novo Nordisk, NPS-Nycomed, Ocera, Optima, Origin, Otsuka, Palau, Pentax, Pfizer, Pharmaventure, Phesi, Phillips, P&G, Pronota, Protagonist, Proximagen, Resolute, Robarts, Sandoz, Santarus, Satisfai, Sensyne Health, Shire, SigmoidPharma, Sorriso, Souffinez, Syndermix, Synthon, Takeda, Theravance, Tigenix, Tillotts, Topivert, Trino Therapeutics with Wellcome Trust, TxCell, UCB Pharma, Vertex, VHsquared, Vifor, Warner Chilcott, and Zeria; as a speaker for AbbVie, Amgen, Biogen, Falk; Ferring, Janssen, Pfizer, Shire, Takeda, and UCB; and received grant support from AbbVie, Buhlmann, Celgene, ECCO, Helmsley Trust, IOIBD, Janssen, Lilly, Pfizer, Takeda, UCB, UKIERI, Vifor, and Norman Collisson Foundation.

V Jairath has received grants or contracts from: AbbVie, Adare, Atlantic, Boehringer Ingelheim, Celgene/Bristol-Myers Squibb, Eli Lilly and Company, Janssen, Seres, Takeda, UCB Pharma, and VH Squared; has received consulting fees from: AbbVie, Alimentiv, Arena, Asahi, Asieris, Bristol-Myers Squibb, Celltrion, Eli Lilly and Company, Ferring, Fresenius, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Kabi, Kasei Pharma, Landos Biopharma, Merck, Mylan, Organon Pandion, Pendopharm, Pfizer, Prometheus Biosciences, Protagonist Therapeutics, Reistone Biopharma, Roche, Sandoz, Second Genome, Takeda, Teva, Ventyx Biosciences, and Vividion Therapeutics; has received payment or honoraria from: AbbVie, Ferring, Galapagos, Janssen, Pfizer, and Takeda; and has participated on data safety monitoring or advisory boards for: AbbVie, Arena, Bristol-Myers Squibb, Fresenius, Gilead Sciences, Janssen, Kabi, Mylan, Roche, and Takeda.

FR has received consulting or advisory board fees from: AbbVie, Adnovate, Agomab, Allergan, Arena, Boehringer-Ingelheim, Celgene/BMS, CDISC, Celsius, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead Sciences, Gossamer, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Jannsen, Koutif, Mestag, Metacrine, Mopac, Morphic, Organovo, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Surmodics, Surrozen, Takeda, Techlab, Theravance, Thetis, UCB Pharma, Ysios, and 89Bio.

G De Hertogh has no conflicts of interest to declare.

B Park, K McGinnis, I Redondo, and TH Gibble are employees and shareholders of Eli Lilly and Company.

NG Lipitz is an employee of Syneos Health.

F Magro has served as a speaker and received honoraria from: AbbVie, Biogen, Falk, Ferring, Hospira, Laboratórios Vitória, Merck Sharp & Dohme, and Vifor.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors would like to thank Deborah Fisher, Eli Lilly and Company, for medical review.

Additional information

Funding

This paper was not funded.