Themistocles Dassopoulos M.D.

Raffals, L. E., Saha, S., Bewtra, M., Norris, C., Dobes, A., Heller, C., O’Charoen, S., Fehlmann, T., Sweeney, S., Weaver, A., Bishu, S., Cross, R., Dassopoulos, T., Fischer, M., Yarur, A., Hudesman, D., Parakkal, D., Duerr, R., Caldera, F., Korzenik, J., Pekow, J., Wells, K., Bohm, M., Perera, L., Kaur, M., Ciorba, M., Snapper, S., Scoville, E. A., Dalal, S., Wong, U. and Lewis, J. D. (2022). “The Development and Initial Findings of A Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease (SPARC IBD).” Inflamm Bowel Dis 28(2): 192-199.

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BACKGROUND: Clinical and molecular subcategories of inflammatory bowel disease (IBD) are needed to discover mechanisms of disease and predictors of response and disease relapse. We aimed to develop a study of a prospective adult research cohort with IBD (SPARC IBD) including longitudinal clinical and patient-reported data and biosamples. METHODS: We established a cohort of adults with IBD from a geographically diverse sample of patients across the United States with standardized data and biosample collection methods and sample processing techniques. At enrollment and at time of lower endoscopy, patient-reported outcomes (PRO), clinical data, and endoscopy scoring indices are captured. Patient-reported outcomes are collected quarterly. The quality of clinical data entry after the first year of the study was assessed. RESULTS: Through January 2020, 3029 patients were enrolled in SPARC, of whom 66.1% have Crohn’s disease (CD), 32.2% have ulcerative colitis (UC), and 1.7% have IBD-unclassified. Among patients enrolled, 990 underwent colonoscopy. Remission rates were 63.9% in the CD group and 80.6% in the UC group. In the quality study of the cohort, there was 96% agreement on year of diagnosis and 97% agreement on IBD subtype. There was 91% overall agreement describing UC extent as left-sided vs extensive or pancolitis. The overall agreement for CD behavior was 83%. CONCLUSION: The SPARC IBD is an ongoing large prospective cohort with longitudinal standardized collection of clinical data, biosamples, and PROs representing a unique resource aimed to drive discovery of clinical and molecular markers that will meet the needs of precision medicine in IBD.

Jackson, D. N., M. Panopoulos, W. L. Neumann, K. Turner, B. L. Cantarel, L. Thompson-Snipes, T. Dassopoulos, L. A. Feagins, R. F. Souza, J. C. Mills, R. S. Blumberg, K. Venuprasad, W. E. Thompson and A. L. Theiss (2020). “Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis.” Gut Feb 28. [Epub ahead of print].

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OBJECTIVE: Although perturbations in mitochondrial function and structure have been described in the intestinal epithelium of Crohn’s disease and ulcerative colitis patients, the role of epithelial mitochondrial stress in the pathophysiology of inflammatory bowel diseases (IBD) is not well elucidated. Prohibitin 1 (PHB1), a major component protein of the inner mitochondrial membrane crucial for optimal respiratory chain assembly and function, is decreased during IBD. DESIGN: Male and female mice with inducible intestinal epithelial cell deletion of Phb1 (Phb1(i) (DeltaIEC) ) or Paneth cell-specific deletion of Phb1 (Phb1(DeltaPC) ) and Phb1(fl/fl) control mice were housed up to 20 weeks to characterise the impact of PHB1 deletion on intestinal homeostasis. To suppress mitochondrial reactive oxygen species, a mitochondrial-targeted antioxidant, Mito-Tempo, was administered. To examine epithelial cell-intrinsic responses, intestinal enteroids were generated from crypts of Phb1(i) (DeltaIEC) or Phb1(DeltaPC) mice. RESULTS: Phb1(i) (DeltaIEC) mice exhibited spontaneous ileal inflammation that was preceded by mitochondrial dysfunction in all IECs and early abnormalities in Paneth cells. Mito-Tempo ameliorated mitochondrial dysfunction, Paneth cell abnormalities and ileitis in Phb1(i) (DeltaIEC) ileum. Deletion of Phb1 specifically in Paneth cells (Phb1(DeltaPC) ) was sufficient to cause ileitis. Intestinal enteroids generated from crypts of Phb1(i) (DeltaIEC) or Phb1(DeltaPC) mice exhibited decreased viability and Paneth cell defects that were improved by Mito-Tempo. CONCLUSION: Our results identify Paneth cells as highly susceptible to mitochondrial dysfunction and central to the pathogenesis of ileitis, with translational implications for the subset of Crohn’s disease patients exhibiting Paneth cell defects.

Johnson, C. M., C. D. Linzay and T. Dassopoulos (2019). “Maneuvering Clinical Pathways for Ulcerative Colitis.” Curr Gastroenterol Rep 21(10): 52.

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PURPOSE OF REVIEW: Recent years have brought about several advances in the treatment of patients with ulcerative colitis (UC). Here, we discuss salient recommendations of recent treatment guidelines; review the efficacy, safety, and real-world data of vedolizumab and tofacitinib; appraise their place vis-a-vis established agents; and consider the newly proposed approaches of risk-stratified and treat-to-target therapy. RECENT FINDINGS: Once daily oral mesalamine dosing is equivalent to split dosing in mild-moderate UC. Real-world data are accumulating on the effectiveness and safety of vedolizumab for moderate to severe UC, while there are few such data on the most recently approved agent, tofacitinib. High-dose infliximab is being investigated for severe UC. New approaches are challenging the established paradigm of selecting therapy based on current disease activity. The risk-stratified approach incorporates long-term risk as well as the current burden of inflammation. The treat-to-target approach aims at improved long-term outcomes by adjusting therapy to resolve intestinal inflammation. The therapeutic options for UC are continually expanding. Risk-stratified therapy and the treat-to-target approach represent paradigm shifts in UC management. Optimal disease control requires an individualized approach that takes into consideration current inflammatory burden, long-term risk, patient preferences, and ongoing assessment of response to treatment.

Johnson, C. M. and T. Dassopoulos (2018). “Update on the Use of Thiopurines and Methotrexate in Inflammatory Bowel Disease.” Curr Gastroenterol Rep 20(11): 53.

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PURPOSE OF REVIEW: The increased use of biologic agents over the past two decades has led to a reappraisal of the role of the immunomodulators (thiopurines and methotrexate) in the treatment of inflammatory bowel disease. The purpose of this review is to summarize recent data on the use of thiopurines and methotrexate either as monotherapy or as part of combination therapy with biologic agents. RECENT FINDINGS: Recent studies have addressed the need for concomitant immunomodulatory therapy in treatment-naive patients starting anti-TNF-alpha therapy, the appropriate dose of the immunomodulator in this setting, the minimum duration of combination therapy, and the possible mechanisms by which immunomodulators enhance the effectiveness of anti-TNF-alpha agents. Little is known about the role of immunomodulators in combination with agents belonging to other classes of biologic therapies. Recent studies have shown that methotrexate is not effective in inducing or maintaining remission in ulcerative colitis. Finally, several studies have broadened our understanding of the infection and malignancy risks of the immunomodulators. Immunomodulators continue to have a place in the treatment of inflammatory bowel disease. However, with the ever-increasing list of biologic agents, properly positioning the immunomodulators within the overall therapeutic scheme is a complicated task. In order to optimize outcomes, each patient requires an individualized approach, which takes into account risks, benefits, cost, alternatives, and patient preferences.

Nguyen, V. Q., J. L. Mays, M. Lang, Y. Wu, T. Dassopoulos, M. Regueiro, A. Moss, D. D. Proctor and D. Sorrentino (2017). “Knowledge gaps in the management of postoperative crohn’s disease: A us national survey.” Dig Dis Sci: 2017 Nov [Epub ahead of print].

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BACKGROUND: Postoperative recurrence (POR) of Crohn’s disease (CD) is common. Guidelines on POR management have recently been issued, but clinical practice may vary. AIMS: To examine the current clinical practice of POR management in the USA METHODS: A web-based survey was sent to all members of the American Gastroenterological Association and the American College of Gastroenterology. The survey consisted of multiple-choice questions with clinical scenarios to assess how participants manage POR. RESULTS: A total of 189 responses were received from practices in 34 states. 44% of participants were from academic settings. The median number of CD patients seen each month was 20-30 patients per participant. The majority of participants considered smoking, prior intestinal surgery, penetrating disease, perianal fistula, early disease onset, and long extent of disease as high-risk factors for POR. To diagnose and grade endoscopic recurrence, 57% of participants used an endoscopic scoring system; 86% defined clinical recurrence using a combination of symptoms and endoscopic findings; and 79% of participants routinely performed colonoscopy after surgery. In high-risk patients, 65% offered medical prophylaxis-most often biologics and/or immunomodulators-immediately after surgery, while 34% offered medical prophylaxis regardless of the patient’s risk of POR. 64% of participants never stopped medical prophylaxis once initiated. CONCLUSIONS: Most gastroenterologists routinely perform colonoscopy to guide POR management. The majority of these providers continue medical prophylaxis indefinitely regardless of subsequent endoscopic findings. Further research is needed to determine the risks and benefits of continuing versus deescalating therapy in patients with potentially surgically induced remission.