In ileal Crohn's disease, cell signature correlates with resistance to therapy

By Marilynn Larkin

NEW YORK (Reuters Health) - 3/9/2019

A cell signature present at ileal Crohn's disease (iCD) diagnosis is associated with resistance to standard anti-TNF therapy, researchers say.

Only a subset of patients with iCD benefit from treatment, note Dr. Miriam Merad of the Icahn School of Medicine at Mount Sinai in New York City and colleagues.

To investigate whether cellular heterogeneity is involved in treatment resistance, the team analyzed biopsy samples of both inflamed and uninflamed iCD lesions upon removal from 15 patients.

As reported online August 29 in Cell, single-cell RNA sequencing and mass cytometry (CyTOF) technologies identified a signature of precise cell types that correlated with resistance. The unique cellular module, which the team named GIMATS, was expressed in inflamed tissue of a subset of patients and consisted of IgG plasma cells, inflammatory mononuclear phagocytes, activated T cells, and stromal cells.

Analysis of ligand-receptor interaction pairs identified a distinct connectivity network that likely drives the GIMATS module.

"Importantly, we found that the presence of the GIMATS module in patients was independent of pathology severity, disease duration, and systemic markers of inflammation," the authors note.

The GIMATS module was also present in four independent iCD cohorts including 441 patients, and its presence at diagnosis correlated with failure to achieve corticosteroid-free durable remission upon anti-TNF therapy. For those analyses, the team selected patients who received anti-TNF antibody blockade within the first year of disease, and had clinical remission assessed between 18 and 24 months after diagnosis.

The GIMATS module score at baseline (prior to initiation of anti-TNF treatment) showed significantly distinct distributions between non-responders and responders. Expression of a high GIMATS score at baseline was enriched in patients unable to achieve durable corticosteroid-free clinical remission at least six months after anti-TNF induction (area under the curve = 0.69).

"As was observed in the discovery cohort, patients with high and low GIMATS module scores had similar markers of systemic inflammation, indicating that the GIMATS score conveys information regarding response to biologic therapy that is not provided by standard CD biomarkers," the authors note.

Dr. Merad said in an email to Reuters Health, "The take-home message is that current diagnostic assays - clinical and histological - are not informative enough and there is a great need for more granular cellular and molecular classification of disease to guide therapeutic strategies."

Dr. Randy Longman, Director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and NewYork-Presbyterian in New York City commented by email, "Crohn's disease is a heterogenous inflammatory disease and the underlying pathogenesis is still poorly understood."

Like Dr. Merad, he noted, "There is a significant clinical need for diagnostic biomarkers that can predict disease and treatment response."

"This work is significant because the authors used emerging technology to provide high-resolution, single-cell definition of Crohn's disease," he said. "They discovered new inflammatory modules which not only reveal new molecular characterization of Crohn's disease subtypes, but also the impact of these subtypes on treatment response."

"Although additional clinical studies are needed, these findings highlight the potential for these signatures to be used clinically to guide medical therapy," he concluded.

This study was funded in part by a grant from Boehringer Ingelheim to Dr. Merad. One coauthor also received a research grant from the company.


Cell 2019.

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