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Rationale Accumulation and activation of mast cells and eosinophils have been implicated in the pathogenesis of several chronic inflammatory gastrointestinal (GI) diseases, including eosinophilic gastrointestinal diseases (EGIDs) and inflammatory bowel disease (IBD). Despite the strong association of mast cell and eosinophil numbers and activation with the pathogenesis of IBD, no further characterization of these cells has been performed. Current treatment options for IBD include aminosalicylates, antibiotics, immunomodulators, biologic agents and small molecules. These therapies are only moderately effective. A significant proportion of patients fail to respond, do not fully respond, or lose response over time. Therefore, there is significant need for more selective and effective therapy options. Siglec-8 is an inhibitory receptor selectively expressed on human eosinophils and mast cells and represents a novel target for the treatment of IBD with the anti-Siglec-8 mAb, antolimab (AK002). We aimed to quantify and evaluate the activation state of mast cells and eosinophils in colonic tissue from IBD or non-diseased patients. In addition, we quantified the production of TNFa from human colon tissue mast cells and evaluated the inhibitory activity of antolimab (AK002) on these cells. Methods Single-cell suspensions were prepared by enzymatic digestion of fresh colonic biopsies from patients clinically diagnosed with IBD (n=29) or non-diseased control tissues (n=16). Multi-color flow cytometry was performed to identify major immune cell populations and evaluate the activation state of mast cells and eosinophils. Mast cells were FACS-sorted from human colon tissue to evaluate cytokine production and inhibitory activity of antolimab. Results The percentage of mast cells and the expression of the mast cell degranulation marker CD107a were significantly increased in ulcerative colitis (UC) patient biopsy tissue compared to Crohn’s disease (CD) and non-diseased colonic tissue (Figure 1A and B). Furthermore, FACS-sorted mast cells from human colon tissue produced significant quantities of TNFa that was reduced after ex vivo antolimab treatment. Colonic tissue eosinophils were also elevated in a subset of UC and CD patient biopsies, and all UC and CD tissue eosinophils displayed increased expression of the activation marker CD11b compared to control colonic tissue. Conclusions Mast cells and eosinophils may play a significant role in driving the pathogenesis of ulcerative colitis through the production of inflammatory mediators. The high expression of Siglec-8 and the inhibitory activity against mast cells suggests that antibodies that target this receptor, such as antolimab (AK002) represent a potential novel approach for the treatment of IBD.

Introduction There is significant variation in processes and outcomes of care for patients with inflammatory bowel disease (IBD), suggesting opportunities to improve quality of care. Recent efforts to define quality measures for IBD have identified emergency room (ER) visits, hospitalizations, corticosteroid use, and opioid use as indicators of care quality. We hypothesized that IBD care could be improved through a structured quality improvement (QI) program. Methods We utilized the Breakthrough Series Collaborative approach developed by the Institute for Healthcare Improvement to improve care for adults with IBD. We identified primary and secondary drivers of urgent care need for patients including those at high risk for ER use, and a multi-stakeholder panel developed 19 practice change ideas that could influence those drivers. Between January 2018 and May 2019, clinical sites participating in a QI collaborative across the United States tested and implemented various change ideas, shared ongoing results during coached monthly webinars, and participated in 3 in-person meetings to learn QI methods and share best practices. Patient-reported outcomes (PROs) were collected at clinical visits, including recent ER use and hospitalizations, use of steroids and narcotics, and measures of care utilization. Providers rated whether patients were at high risk for urgent care needs. Site performance on key measures were monitored using statistical control charts, with assessment for common cause (due to chance) variation and special cause (non-random) variation. Results We collected data prospectively from 20,382 discrete visits at twenty-six participating clinical practices (14 academic/university, 12 private/community). Disease type included Crohn’s disease (58%), ulcerative colitis (39%), and other (3%); 54% were female. During the 15-month project period, improvement with special cause variation was noted across multiple measures. Collaborative-wide decreases were seen in ER utilization (18% to 14%, relative reduction of 22%; Figure), hospitalization (14% to 11%, relative reduction of 21%), steroid use (14% to 10%, relative reduction of 29%), and narcotic utilization (8% to 4%, relative reduction of 50%). Successful change ideas tested by sites included proactive maintenance of a “high risk” patient list, reserved outpatient visits for urgent needs, “morning-after” contact with patients who went to the ER, patient education about how and when to get help, and proactively scheduling earlier follow-up for high risk patients. Conclusions Outcomes of IBD care were improved using a structured QI program that facilitates small changes in practice structure, sharing of best practices across sites, and ongoing feedback. Spread of successful change ideas may facilitate broad improvement in IBD care and significant cost savings when applied to a large population. Changes in Key Measures Over Time Statistical Process Control Chart Showing Monthly Proportion of Patients Reporting Recent ER Utilization

This letter to the editor discusses a literature review to assess the evidence on the efficacy of oral contraceptives when combined with antibiotic therapy. It formulates a rational guideline for patients with inflammatory bowel disease receiving concomitant oral contraceptives and antibiotic therapy.