Objective We evaluated the reliability and responsiveness of available but incompletely validated UC histological disease activity indices using standardised rules for centralised assessment.
Design Disease activity was assessed in biopsies collected in a phase II placebo-controlled ozanimod trial by four blinded pathologists using the Geboes (GS) and modified Riley (MRS) scores, the Robarts Histopathology (RHI) and Nancy Histological (NHI) indices and a Visual Analogue Scale. Reliability was assessed with intraclass correlation coefficients (ICCs). Index responsiveness was evaluated by assessing longitudinal validity (Pearson correlations of changes in index scores and other disease measures), and effect size estimates (standardised effect size (SES)) using two criteria for change (treatment assignment and >2 point decrease in total Mayo Clinic score). Area under the receiver operating characteristic (AUROC) curve estimates evaluated the probability of the indices to discriminate between treatment and placebo.
Results Inter-rater reliability of the histological indices was substantial to almost perfect (ICC>0.61), and responsiveness was moderate to large (SES estimates>0.5); 0.81 (0.52, 1.10), 0.87 (0.58, 1.17), 0.57 (0.30, 0.84) and 0.81 (0.52, 1.09) when treatment assignment was the criterion for change and 1.05 (0.80, 1.31), 1.13 (0.87, 1.39), 0.88 (0.64, 1.12) and 1.06 (0.80, 1.31) for the change in Mayo score criterion for the GS, MRS, RHI and NHI, respectively. The indices had similar drisciminative ability based on AUROC estimates (range 0.608–0.649).
Conclusion All four existing histological indices were similarly reliable and responsive based on this dataset.
- ulcerative colitis
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Contributors Guarantor of the article: VJ. Development of study concept and design: VJ, LP-B, GZ, AM-B, LWS, WJS, GRD’H, BGF, RKP. Central histopathology reading: AM-B, ReKP, MAK, RKP. Acquisition, analysis and interpretation of the data: VJ, LP-B, GZ, MM, NVC, ReKP, MAV, AM-B, LWS, LMS, RK, GRD’H, WJS, BGF, RKP. Statistical analysis: GZ, LWS. Drafting of the manuscript: VP, LMS, BGF, RKP. Critical revision of the manuscript for important intellectual content: all authors.
Funding Robarts Clinical Trials, Inc., University of Western Ontario, London, Ontario, Canada (Central Reading, Database Management).
Competing interests VJ reports scientific advisory board fees from Abbvie, Sandoz, Ferring and Janssen; speaker’s fees from Takeda and Ferring; and travel support for conference attendance from Vifor Pharmaceuticals. LP-B reports consulting fees from AbbVie, Amgen, Biogaran, Biogen, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Ferring, Forward Pharma, Genentech, H.A.C. Pharma, Hospira, Index Pharmaceuticals, Janssen, Lycera, Merck, Lilly, Mitsubishi, Norgine, Pfizer, Pharmacosmos, Pilège, Samsung Bioepis, Sandoz, Takeda, Therakos, Tillots, UCB Pharma and Vifor; and lecture fees from AbbVie, Ferring, H.A.C. Pharma, Janssen, Merck, Mitsubishi, Norgine, Takeda, Therakos, Tillots and Vifor. GZ is an employee of Robarts Clinical Trials, which was the research organisation that conducted this study. NVC reports consulting fees from Janssen, Pfizer, Takeda and UCB. LWS and LMS report consulting fees from Robarts Clinical Trials, which was the research organisation that conducted this study. RK reports fees from Janssen, AbbVie, Shire, Pfizer and Takeda Canada and from Robarts Clinical Trials outside the submitted work. GRD’H reports consulting fees from Robarts Clinical Trials; personal fees from Ablynx, Amakem, Amgen, AM Pharma, Boehringer-Ingelheim, Bristol Myers Squibb, Cosmo, Celgene, Celtrion, Covidien, Engene, Galapagos, Medimetrics, Mundipharma, Mitsubishi, Novonordisk, Pfizer, Receptos, Salix, Sandoz, Setpoint, Shire, Teva, Tigenix, Topivert, Versant and Vifor; grants and personal fees from Abbvie, Ferring, Glaxo Smith Kline, Jansen Biologics, Hospira, Merck Sharp Dome, Prometheus Labs, Robarts Clinical Trials, Takeda and Tillotts; and grants from Dr Falk Pharma and Photopill, outside the submitted work. WJS reports consulting fees from University of Western Ontario (previous owner of Robarts Clinical Trials, Inc.), Abbvie, Akros Pharma, Allergan, Ambrx Inc., Amgen, Ardelyx, Arena Pharmaceuticals, Atlantic Pharmaceuticals, Avaxia, Biogen, Boehringer-Ingelheim, Bristol Meyers Squibb, Celgene, Conatus, Cosmo Technologies, Escalier Biosciences, Ferring, Ferring Research Institute, Forward Pharma, Galapagos, Genentech, Gilead Sciences, Immune Pharmaceuticals, Index Pharmaceuticals, Janssen, Kyowa Hakko Kirin Pharma, Lilly, Medimmune, Mesoblast, Miraca Life Sciences, Nivalis Therapeutics, Novartis, Nutrition Science Partners, Oppilan Pharma, Otsuka, Palatin, Paul Hastings, Pfizer, Precision IBD, Progenity, Prometheus Laboratories, Qu Biologics, Regeneron, Ritter Pharmaceuticals, Robarts Clinical Trials, Salix, Seattle Genetics, Seres Therapeutics, Shire, Sigmoid Biotechnologies, Takeda, Theradiag, Theravance, Tigenix, Tillotts Pharma, UCB Pharma, Vascular Biogenics and Vivelix; research grants from Atlantic Healthcare Limited, Amgen, Genentech, Gilead Sciences, Abbvie, Janssen, Takeda, Lilly and Celgene/Receptos; payments for lectures/speaker’s bureau from Abbvie, Janssen and Takeda; and stock/stock options in Escalier Biosciences, Oppilan Pharma, Precision IBD, Progenity and Ritter Pharmaceuticals. AO is an employee of Celgene Corporation. BGF reports grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor Inc., Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix and Wyeth Pharmaceuticals Inc.; consulting fees from Millennium Pharmaceuticals, Merck, Centocor Inc., Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, Astra Zeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging Inc., Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma Inc. and Sigmoid Pharma; and speaker’s bureau fees from UCB, AbbVie and J&J/Janssen. RKP reports fees from Genentech outside the submitted work.
Patient consent Not required.
Ethics approval Approval for this study was obtained from the Research Ethics Board at the University of Western Ontario.
Provenance and peer review Not commissioned; externally peer reviewed.
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