Correlation Between Histologic Indices and Ulcerative Colitis Activity Measures Among Patients in the HICKORY (Etrolizumab) Open-Label Induction Cohort

BACKGROUND: Cross-sectional studies in ulcerative colitis (UC) have shown at best a moderate association between histologic and clinical measures of disease activity, but few longitudinal studies have evaluated this relationship. As endoscopy and histology are both independent predictors of clinical outcomes in UC, there remains a need to assess these measures in parallel to demonstrate clinical benefit. HICKORY (NCT02100696) is an ongoing Phase 3 study evaluating etrolizumab in anti-tumor necrosis factor (aTNF)–experienced patients with moderate-to-severe UC. The correlation between histologic changes and established disease activity measures at end of induction (week 14) was assessed using data from the open-label induction (OLI) cohort of HICKORY.

METHODS: Study analysis is based on data from patients in the OLI cohort who received ?1 dose of etrolizumab 105 mg subcutaneously every 4 weeks during the 14-week induction phase. Baseline and week 14 biopsies were scored by 1 of 4 central readers using the Nancy histologic index (NHI) and the Robarts histopathology index (RHI) in patients who had active baseline histology (NHI >1 and RHI >3) and complete scoring at week 14 (n = 97). Binary week 14 histologic outcomes were characterized by presence or absence of neutrophils (NHI ?1 or RHI ?3 and Geboes subgrades 2B.0/3.0). Mayo Clinic score (MCS) endoscopic subscore (ES) was used to assess endoscopy. Pairwise associations were quantified by Spearman correlation (?; for correlation between change from baseline scores) and Cohen kappa coefficients (?; for agreement among week 14 outcomes). ?NHI and ?RHI were compared to determine presence of a minimum clinically important difference (MCID) in MCS ([INCREMENT]MCS ?3 from baseline).

RESULTS: At week 14, 22% (21/97), 23% (22/97), and 8% (8/97) of patients achieved resolution of neutrophilic inflammation based on either NHI or RHI/Geboes, endoscopic improvement (ES ? 1), and endoscopic remission (ES = 0), respectively. Among patients with endoscopic improvement and endoscopic remission, neutrophilic resolution was achieved in 55% (12/22) and 75% (6/8) of patients, respectively. ?NHI and ?RHI were highly correlated (? = 0.91). There was weak to no association between ?NHI/?RHI/?ES and ?fecal calprotectin (? = –0.02 to 0.38), ?C-reactive protein (? = 0.03 to 0.07), ?albumin (? = –0.19 to –0.10), ?hemoglobin (? = –0.22 to –0.19), and ?segmented neutrophils in the blood (? = –0.06 to 0.01). Weak correlations were observed between ?NHI/?RHI and ?ES (? = 0.26–0.27), ?rectal bleeding (? = 0.24–0.28), and ?stool frequency (? = 0.40–0.42). Correlations between NHI, RHI/Geboes, and ES with symptomatic outcomes were weak (? = 0.28–0.45). Difference in the mean grouped by achievement of ?MCS ?3 suggests MCIDs in ?NHI and ?RHI of 1.2 and 8.6, respectively.

CONCLUSION(S): The analysis showed weak to moderate agreement between changes in histologic scores and changes in endoscopic scores, and weak to no agreement between changes in histologic scores and changes in laboratory results at week 14. There was a weak correlation between histologic scores and symptoms at the end of induction. MCID results suggest that both the NHI and RHI appear to effectively evaluate neutrophilic resolution, making the changes in score more clinically interpretable.