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DOI: 10.1055/s-0039-1691868
Molecular Response to Ustekinumab in Moderate-to-severe Ulcerative Colitis by Serum Protein and Biopsy Gene Expression Analysis: Results from the UNIFI Phase 3 Induction Study
Publication History
Publication Date:
16 May 2019 (online)
Background:
IL-12 and IL-23 are elevated in ulcerative colitis (UC) and genetic association suggests that they play causative roles in the disease. Ustekinumab (UST) blocks both cytokines and is an effective therapy for moderate-to-severe UC, but its molecular effects in UC patients remain unknown.
Methods:
Colonic biopsy mRNA and serum samples from ˜60% of patients (UNIFI phase 3 induction study) were analyzed, with equal representation of patients with a history of biologic therapy failure (BF) and those without (BN) (Tab. 1). Biopsy and serum samples from healthy subjects were analyzed as controls.
Results:
Colon biopsies from UC pts had a gene expression disease profile of 4095 probe sets, including genes involved in inflammatory response, tissue remodeling and wound healing, host-microbe interaction, intestinal permeability, and solute transport. BF and BN UC pts shared almost identical disease profiles. At Week 8 after UST induction therapy, the disease profile was significantly normalized in responders to UST. A smaller magnitude of normalization was observed in responders to PBO. No significant change in disease signature occurred in non-responders. At baseline, BF and BN UC pts had similar serum profiles, with significantly elevated levels of IFNγ, IL-17A, IL-22, SAA, NGAL, MMPs, and TNF versus healthy controls. Normalization of IFNγ, SAA, IL-17A, and IL-22 was first detected in responders to UST at Week 4, the earliest time point in our assessment, and continued to improve through Week 8. A trend of normalization of MMPs, IL-10, and NGAL was observed in UST responders; it was weaker or absent in UST non-responders and PBO-treated patients. TNF was elevated in UC prior to treatment and was not normalized by UST induction therapy.
Biopsy mRNA (550 UC and 18 healthy controls) |
Serum Protein (574 UC and 50 healthy controls) |
|
Time points |
Screening, Week 8, Week 16 |
Screening, Week 4, Week 8, Week 16 |
Methods |
Generalized linear model (GLM) & Gene Set Variation Analysis |
GLM |
Significance cutoffs |
|fold change| > 1.5x and p < 0.05 |
|fold change| > 1.5x and p < 0.05 |
Analytes |
Affymetrix HG U133 PM arrays |
12 serum markers: · Matrix metalloproteinases: MMP-1,3,9 · Cytokines and cytokine receptors: IFNγ, IL-17A, IL-22, IL-10, IL-2R, TNFα, TNFR1 · Acute Phase Reactant: SAA · Inflammatory marker: NGAL |
Conclusions:
Transcriptomic and protein analyses demonstrated the suppression of IL-12 (IFNγ) and Il-23 (IL-17A) pathways and normalization of the UC disease gene expression profile in response to UST.