Kevin Tom1,2, Bhaven K Mehta3, Aileen Hoffmann2, Kathleen Aren2, Mary Carns2, Jungwha Lee4,5, Viktor Martyanov3, Dillon Popovich3, Noelle Kosarek3, Tammara Wood3, Darren Brenner6, Dustin A Carlson6, Lorena Ostilla7, Emma Willcocks7, Paul Bryce7,8,9, Joshua B Wechsler7,8, Michael L Whitfield3, Monique Hinchcliff2,10. 1. Midwestern University, Chicago College of Osteopathic Medicine, 555 31 Street, Downers Grove, IL 60515. 2. Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Rheumatology, McGaw Pavilion, 240 E. Huron Street, Suite M-300. 3. Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. 4. Department of Preventive Medicine, 680 N. Lake Shore Drive, Suite 1400. 5. Institute for Public Health and Medicine, 633 N. St. Clair Street, 18th Floor. 6. Division of Gastroenterology, 676 N. St. Clair Street, Suite 1400. 7. Division of Allergy and Immunology, 240 E. Huron Street, McGaw Pavilion, Suite M-300, Chicago, IL 60611. 8. Northwestern University Feinberg School of Medicine, Department of Pediatrics, Division of Gastroenterology, Hepatology & Nutrition, 225 E. Chicago, Box 65, Chicago, IL 60611. 9. Immunology & Inflammation Therapeutic Area, Sanofi US, Cambridge, MA 02139. 10. Yale School of Medicine, Department of Medicine, Section of Rheumatology, Allergy & Immunology, 300 Cedar Street, The Anylan Center, PO BOX 208031, New Haven, CT 06473.
Abstract
INTRODUCTION: Previously, we discovered similar esophageal gene expression patterns in patients with systemic sclerosis (SSc) and eosinophilic esophagitis (EoE) where eosinophil/mast cell-targeted therapies are beneficial. Because SSc and EoE patients experience similar esophageal symptoms, we hypothesized that eosinophil/mast cell-directed therapy may potentially benefit SSc patients. Herein, we determine the association between esophageal mast cell quantities, gene expression and clinical parameters in order to identify SSc patients who may benefit from eosinophil/mast cell-directed therapy. METHODS: Esophageal biopsies from SSc patients and healthy participants were stained for tryptase, a mast cell marker, and associations with relevant clinical parameters including 24h esophageal pH testing were assessed. Intra-epithelial mast cell density was quantified by semi-automated microscopy. Microarray data were utilized for functional and gene set enrichment analyses and to identify intrinsic subset (IS) assignment, an SSc molecular classification system that includes inflammatory, proliferative, limited and normal-like subsets. RESULTS: Esophageal biopsies from 40 SSc patients (39 receiving proton pump inhibition) and eleven healthy participants were studied. Mast cell numbers in both the upper esophagus (rs = 0.638, p = 0.004) and the entire (upper + lower) esophagus (rs = 0.562, p = 0.019) significantly correlated with acid exposure time percentage. The inflammatory, fibroproliferative, and normal-like ISs originally defined in skin biopsies were identified in esophageal biopsies. Although esophageal mast cell numbers in SSc patients and healthy participants were similar, gene expression for mast cell-related pathways showed significant upregulation in the inflammatory IS of SSc patients compared to patients classified as proliferative or normal-like. DISCUSSION: Esophageal mast cell numbers are heterogeneous in SSc patients and may correlate with acid exposure. Patients with inflammatory IS profiles in the esophagus demonstrate more tryptase staining. Mast cell targeted therapy may be a useful therapeutic approach in SSc patients belonging to the inflammatory IS, but additional studies are warranted.
INTRODUCTION: Previously, we discovered similar esophageal gene expression patterns in patients with systemic sclerosis (SSc) and eosinophilic esophagitis (EoE) where eosinophil/mast cell-targeted therapies are beneficial. Because SSc and EoE patients experience similar esophageal symptoms, we hypothesized that eosinophil/mast cell-directed therapy may potentially benefit SSc patients. Herein, we determine the association between esophageal mast cell quantities, gene expression and clinical parameters in order to identify SSc patients who may benefit from eosinophil/mast cell-directed therapy. METHODS: Esophageal biopsies from SSc patients and healthy participants were stained for tryptase, a mast cell marker, and associations with relevant clinical parameters including 24h esophageal pH testing were assessed. Intra-epithelial mast cell density was quantified by semi-automated microscopy. Microarray data were utilized for functional and gene set enrichment analyses and to identify intrinsic subset (IS) assignment, an SSc molecular classification system that includes inflammatory, proliferative, limited and normal-like subsets. RESULTS: Esophageal biopsies from 40 SSc patients (39 receiving proton pump inhibition) and eleven healthy participants were studied. Mast cell numbers in both the upper esophagus (rs = 0.638, p = 0.004) and the entire (upper + lower) esophagus (rs = 0.562, p = 0.019) significantly correlated with acid exposure time percentage. The inflammatory, fibroproliferative, and normal-like ISs originally defined in skin biopsies were identified in esophageal biopsies. Although esophageal mast cell numbers in SSc patients and healthy participants were similar, gene expression for mast cell-related pathways showed significant upregulation in the inflammatory IS of SSc patients compared to patients classified as proliferative or normal-like. DISCUSSION: Esophageal mast cell numbers are heterogeneous in SSc patients and may correlate with acid exposure. Patients with inflammatory IS profiles in the esophagus demonstrate more tryptase staining. Mast cell targeted therapy may be a useful therapeutic approach in SSc patients belonging to the inflammatory IS, but additional studies are warranted.
Authors: Alfredo J Lucendo; Javier Molina-Infante; Ángel Arias; Ulrike von Arnim; Albert J Bredenoord; Christian Bussmann; Jorge Amil Dias; Mogens Bove; Jesús González-Cervera; Helen Larsson; Stephan Miehlke; Alexandra Papadopoulou; Joaquín Rodríguez-Sánchez; Alberto Ravelli; Jukka Ronkainen; Cecilio Santander; Alain M Schoepfer; Martin A Storr; Ingrid Terreehorst; Alex Straumann; Stephen E Attwood Journal: United European Gastroenterol J Date: 2017-01-23 Impact factor: 4.623
Authors: Scott M Bolton; Amir F Kagalwalla; Nicoleta C Arva; Ming-Yu Wang; Katie Amsden; Hector Melin-Aldana; Evan S Dellon; Paul J Bryce; Barry K Wershil; Joshua B Wechsler Journal: Am J Gastroenterol Date: 2020-02 Impact factor: 12.045
Authors: Jaclyn N Taroni; Viktor Martyanov; Chiang-Ching Huang; J Matthew Mahoney; Ikuo Hirano; Brandon Shetuni; Guang-Yu Yang; Darren Brenner; Barbara Jung; Tammara A Wood; Swati Bhattacharyya; Orit Almagor; Jungwha Lee; Arlene Sirajuddin; John Varga; Rowland W Chang; Michael L Whitfield; Monique Hinchcliff Journal: Arthritis Res Ther Date: 2015-07-29 Impact factor: 5.156