Crohn's disease (CD) patients with higher proportions of clonal T cell expansions in the ileal mucosa are likely to smoke, have T cell-driven pathogenesis, and postoperative recurrence, a small French study found.
Compared with non-smokers, active smokers at time of surgery had a significantly higher proportion of clonal expansions, particularly of CD8 T cells (25.9% vs 17.9%, P=0.02), and this group may represent a subset of patients at risk for poor outcomes, according to Matthieu Allez, MD, PhD, of Hôpital Saint-Louis in Paris, writing in Gut.
"This subset of patients could be potentially better treated with drugs targeting T cell-driven pathways," the researchers wrote.
Smoking is an established risk factor for CD development and recurrence. Clonal T cell expansions have also been implicated in postoperative endoscopic recurrence, and smoking is associated with specific T cell changes, including reduced repertoire diversity and an increased proportion of clonal expansions. Moreover, these expanded T cell clones persist over time and may drive disease progression, the authors explained.
The investigators performed T cell receptor sequencing and microarray analysis in tissue samples from 57 patients in a prospective multicenter cohort. The mean age of patients was 37.4 years and 56% were men. Median disease duration was 7.9 years, and 35% of patients were active smokers at time of surgery, while 19% had had at least one previous resection. All patients had been operated for such complications as stricturing (61%) or penetrating (39%).
All participants underwent endoscopy within a year of surgery with a median delay to colonoscopy of 6.9 months. Twenty-nine patients (51%), including 10 smokers, received postoperative therapy, 11 with thiopurines and 18 with tumor necrosis factor (TNF) inhibition.
At tissue analysis, the researchers divided the cohort according to the percentage of high-frequency clones in the mucosa, with high or low clonality defined as above or below 26.8%, respectively.
Endoscopic recurrence was defined by a Rutgeerts inflammation score of >i0. The proportion of high-frequency clones at baseline was significantly higher in patients with recurrence at postoperative endoscopy compared with patients having no recurrence: 23.2% versus 13.8% (P=0.01; area under the curve 0.69, 95% CI 0.54-0.83). All patients with clonality above 26.8% (18/57) were found to have endoscopic recurrence, and these patients were more often smokers than those with low clonality: 61% versus 23% (P=0.005).
Active smokers at time of surgery showed an increased proportion of clonal expansions (as compared with non-smokers). The authors noted that cigarette smoke contains thousands of components with the potential to alter the intestinal microbiota, epithelium, vasculature, and immune system. "Interestingly, T cell oligoclonal expansions are found within the lungs of patients with chronic obstructive pulmonary disease, and the number of CD8 T cells found in the lungs of patients with COPD correlates with disease severity," Allez and co-authors wrote.
In addition to greater expression of CD8 T cells, high-clonality patients also showed reduced expression of inflammation-related genes. While expanded clones were found predominantly in the CD8 T cell compartment, a few were of CD4 lineage. Since most patients with major clonal expansions at surgery had endoscopic recurrence, these may represent a subgroup at risk of a poor outcome, the author said.
Ryan Ungaro, MD, of Icahn School of Medicine at Mount Sinai in New York City, who was not involved in the research, told MedPage Today that while the findings need to be replicated in larger cohorts, they shed possible light on the pathophysiological mechanisms of smoking's impact on Crohn's disease. "Is it the tobacco, the smoke, or does smoking affect the T cell's recognition of antigens?" he said.
Ungaro noted the growing interest in finding indicators and biomarkers for risk-stratifying patients before and especially after surgery. "This interesting study adds an extra clue as to why smoking is a risk factor for progression, since it suggests smoking impacts the ability of the T cell repertoire to be diverse. If the repertoire is more narrow, there appears to be a dysregulated immune response." T cell receptor testing, however, may not be broadly practical at present since it requires sophisticated laboratory techniques, he added.
Ungaro also noted that the study did not address whether anti-TNF treatment affected recurrence in high-clonality patients. "Clinically, if I see these high T cells, I ask, are there any medications in our armamentarium that might decrease the risk of recurrence in these patients?"
This study was supported by the Helmsley Charitable Trust, the Association Francois Aupetit and MSD France laboratories. Allez reported honoraria from Abbvie, MSD, Janssen, Takeda, Pfizer, Novartis, Ferring, Tillots, Celgene, and Genentech/Roche. Several co-authors disclosed ties to multiple companies including Abbvie, MSD, Janssen, Takeda, Pfizer, Novartis, Ferring, Tillots, HAC Pharma, Vifor Pharma, Sanofi-Aventis, Hospira, Boehringer Ingelheim, Danone, Biocodex, Enterome, Carenity, Astellas, Mayoly Spindler, Maat, BiomX, Biose, Nextbiotix, and Norgine. Ungaro disclosed no competing interests in relation to his comments.
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