Background: Ustekinumab (UST) has been shown to induce & maintain clinical response & remission & to produce clinically meaningful endoscopic improvement in patients (pts) with moderate-severe Crohn's disease (CD). Effects of UST on histologic CD activity were evaluated in a substudy of the induction (UNITI-1&2) & maintenance (IM-UNITI) Phase 3 studies.
Methods: At endoscopy, 2 biopsies were collected at induction baseline (I-Wk0), Wk8 (I-Wk8), & maintenance Wk44 (M-Wk44) from 3 anatomical regions (ileum, splenic flexure, rectum). One expert GI pathologist (GDH) blindly scored all biopsies using the Global Histology Activity Score (GHAS  for each region. At I-Wk0, pts received a single IV dose (UST 130 mg, UST ∼6 mg/kg, or PBO). At maintenance Wk0 (i.e. I-Wk8), UST induction responders (R, CDAI decrease ≥100 [CR]) were re-randomized to SC PBO, UST 90mg q12w or UST 90mg q8w; UST induction non-responders (NR) received SC UST 90mg → SC UST 90mg q8w if in CR after 8wks; PBO induction NR received UST IV 130mg → SC UST 90mg q12w if in CR after 8wks; and PBO induction R received PBO. Histology data from 251 substudy pts with simple endoscopic score for CD (SES-CD) ≥3 (i.e. ulceration in any segment) at I-Wk0 were eligible for analysis. The relationship between GHAS & SES-CD was evaluated by Spearman correlation. Histologic improvements (i.e. change in GHAS from I-Wk0 at I-Wk8, M-Wk44) were assessed within each group (UST, PBO) & between groups (UST vs PBO, among pts with evaluable data at both I-Wk0 & I-Wk8, M-Wk44).
Results: Regional & overall GHAS were moderately correlated with SES-CD at all timepoints (r=0.6, p<0.001). GHAS was significantly reduced at I-Wk8 in pts treated with UST (from 10.4 to 7.1, p<0.001) but not PBO (from 9.2 to 7.8). At M-Wk44 in the randomized maintenance population, a continued reduction in GHAS from I-Wk8 was observed with UST 90mg SC q8w (from 7.39 to 6.07, p=0.07) but not UST 90mg SC q12w (from 5.29 to 8.67) or PBO (from 9.19 to 10.85). In the pooled maintenance population (randomized & non-randomized), continued histologic improvement from I-Wk8 was observed with UST 90mg q8w (7.14 to 5.19, p<0.0001), but not UST 90mg q12w (from 6.14 to 7.18) or PBO (from 8.19 to 8.85). Consistent results are observed in between-group (UST vs. PBO) analyses, numerically greater GHAS reduction was observed for UST.
Conclusions: Histologic & endoscopic disease activities were moderately correlated. Consistent with previously reported endoscopic results, statistically significant histologic improvements were observed in pts induced with UST, but not PBO. Trends for greater & continued histologic improvement were observed in pts who received UST 90mg q8w maintenance.
 D'Haens GR, Geboes K, Peeters M, et al. Gastroenterology. 1998;114(2):262–267