Relationship Between Combined Histologic and Endoscopic Endpoints and Efficacy of Ustekinumab Treatment in Patients With Ulcerative Colitis

Background & aims: Ustekinumab induces and maintains histologic improvement in patients with ulcerative colitis (UC). The clinical relevance of this endpoint alone, and in combination with endoscopic improvement, is unknown.

Methods: Histologic disease activity was evaluated in 2630 colonic biopsy samples from patients with UC treated in the UNIFI phase 3 UC clinical studies of ustekinumab. We evaluated associations between histologic improvement (defined as the composite of neutrophil infiltration in less than 5% of crypts and no crypt destruction, erosions, ulcerations, or granulation tissue) and clinical endpoints at the end of induction (week 8 and 16) and maintenance (week 44) periods. We assessed the validity of a combined histologic and endoscopic (Mayo endoscopy subscore, 0 or 1) improvement endpoint, which we called histo-endoscopic mucosal healing (or histo-endoscopic mucosal improvement).

Results: Histologic improvement was significantly (P < .0001) associated with clinical remission, lower mean disease activity scores, and greater improvement in disease activity at the end of induction and maintenance studies. Ustekinumab induced and maintained significantly higher rates of histologic improvement at induction week 8 and maintenance week 44 than placebo when more stringent definitions of histologic improvement were used. Histologic improvement and endoscopic improvement following induction were associated with 10% to 20% higher rates of histo-endoscopic mucosal healing, clinical remission, and corticosteroid-free remission at week 44 (all P < .05) in patients who received ustekinumab maintenance therapy. At week 44, 61% of patients (56/92) with histo-endoscopic mucosal healing after induction therapy achieved clinical remission, versus 39% of patients (9/23, P = .0983) and 34% of patients (24/71, P = .0009) with endoscopic or histologic improvement alone after induction, respectively.

Conclusion: Data from the UNIFI program of ustekinumab in patients with UC treated with ustekinumab indicated the achievement of histo-endoscopic mucosal healing after induction therapy is associated with lower disease activity at the end of maintenance therapy than either histologic or endoscopic improvement alone. ClinicalTrials.gov number: NCT02407236.