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Single-Cell Analysis of Crohn's Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy.

ABSTRACT: Clinical benefits of cytokine blockade in ileal Crohn's disease (iCD) are limited to a subset of patients. Here, we applied single-cell technologies to iCD lesions to address whether cellular heterogeneity contributes to treatment resistance. We found that a subset of patients expressed a unique cellular module in inflamed tissues that consisted of IgG plasma cells, inflammatory mononuclear phagocytes, activated T cells, and stromal cells, which we named the GIMATS module. Analysis of ligand-receptor interaction pairs identified a distinct network connectivity that likely drives the GIMATS module. Strikingly, the GIMATS module was also present in a subset of patients in four independent iCD cohorts (n = 441), and its presence at diagnosis correlated with failure to achieve durable corticosteroid-free remission upon anti-TNF therapy. These results emphasize the limitations of current diagnostic assays and the potential for single-cell mapping tools to identify novel biomarkers of treatment response and tailored therapeutic opportunities.

SUBMITTER: Martin JC

PROVIDER: S-EPMC7060942 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundUstekinumab and vedolizumab are both effective for treating Crohn's disease (CD). However, no head-to-head trials have been conducted thus far. We aimed to compare the effectiveness of ustekinumab and vedolizumab in CD patients either naïve or exposed to tumor necrosis factor-alpha inhibitors (TNFi).MethodsPatients treated with vedolizumab or ustekinumab for luminal CD were included from six centers in China from May 2020 to July 2023. Steroid-free remission, clinical remission, objective response, and remission at Weeks 26 and 52 were evaluated in a retrospective multicenter propensity score-weighted cohort.FindingsA total of 536 patients were included (386 ustekinumab, and 150 vedolizumab). After adjustment, ustekinumab showed higher rates of clinical remission (56.4% vs. 47.8%, P = 0.005), steroid-free remission (55.4% vs. 46.1%, P = 0.003), and objective response (67.8% vs. 42.7%, P < 0.001) than vedolizumab at Week 26. At Week 52, ustekinumab exhibited significantly higher rates of clinical remission (65.8% vs. 37.5%, P < 0.001), steroid-free remission (65.8% vs. 37.5%, P < 0.001), objective response (66.7% vs. 23.8%, P < 0.001), and objective remission (31.4% vs. 12.7%, P < 0.001). Subgroup analyses revealed that ustekinumab had higher rates of clinical remission, steroid-free remission, and objective response at Weeks 26 and 52, and objective remission at Week 52 in TNFi-exposed patients, while ustekinumab showed higher rates of objective response at Weeks 26 and 52 and clinical remission, steroid-free remission and objective remission at Week 52 in TNFi-naïve patients. Adverse event rates were similar between the groups (4.9% ustekinumab vs. 6.7% vedolizumab, P = 0.423).InterpretationUstekinumab showed superior clinical and objective outcomes compared to vedolizumab, with comparable safety outcomes. The therapeutic superiority was observed in both short-term and long-term phases in TNFi-exposed patients, and the long-term phase in TNFi-naïve patients.FundingNational Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, Key Research Projects of the Sixth Affiliated Hospital, Sun Yat-sen University, the program of Guangdong Provincial Clinical Research Center for Digestive Diseases, and National Key Clinical Discipline.

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Single-Cell Analysis of Crohn's Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy.

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