When the next step in UC seems like a step too far…

It’s time to step in

Watch Glen's journey

Ulcerative colitis (UC) is a chronic, lifelong condition with challenges at each step of the patient journey.
At BMS, we're committed to understanding the gaps in UC to help patients take a step forward.1,2

The burden of UC can hold patients back at a time when they should be moving forward

  • The incidence of UC has been rising, with the current rate in the US reaching approximately 214 per 100,000 patients per year3
  • UC is a chronic disease that often begins in early adulthood1,4
  • UC can present at any age, but onset typically occurs between the ages of 15 and 30 years2,4
  • Patients typically present with symptoms like bloody diarrhea, abdominal pain, fecal urgency, and tenesmus5
  • Prognostic factors that are indicative of a more aggressive disease course have been identified, including6:
      • Diagnosis at a young age6
      • Extensive disease6
      • Severe endoscopic activity6
      • Extra-intestinal manifestations6
      • Early need for corticosteroids6
      • Elevated inflammatory markers6
  • Patients with UC experience challenges in their physical, mental, and emotional well-being—often at a time when family planning and career development are important milestones4,7,8
  • Patients with UC experience anxiety around a number of issues, including disease trajectory, hospitalization, and not having immediate access to a toilet9,10
    • Anxiety around toilet access can impact employment opportunities and work productivity, and limit social and recreational engagement9,10

In a 2007 online survey of 451 patients with UC designed to collect information on attitudes and perceptions about living with their disease7,11

84%

said that frequent trips to the bathroom have become an expected part of life

73%

said not feeling well from UC has become an expected part of life

61%

said living with the condition is a daily struggle

82%

felt like the condition makes life more stressful

70%

reported feeling embarrassed by their condition

45%

said that their disease causes relationship difficulties with their spouse or partner

60%

feel like UC has ruined important moments

84%

said they worry about the long-term health effects of having UC

Achieving clinical control can help close the gap on
symptomatic burden for patients with UC9

Management goals have evolved to include both clinical and endoscopic measures

  • Underlying inflammation can persist even when clinical symptoms have subsided, so the management of UC has evolved to include both clinical and endoscopic remission, followed by the use of a steroid-free maintenance strategy4,6,12
    • Clinical remission includes patient-reported outcomes like resolution of rectal bleeding and normalization of bowel habits4,12
    • Endoscopic remission includes measures such as a Mayo subscore of 0 or 1 and restoration of intact mucosa without friability4,12
    • Therapeutic decisions should be categorized into those for induction and maintenance, with a goal of obtaining and maintaining a steroid-free remission4,6

Dietary changes may help with symptom relief and maintenance of remission

  • Avoiding processed foods, emulsifiers, and artificial ingredients and focusing on a nutrient-rich diet should be encouraged13
  • However, dietary changes should be approached with great care, as many proposed diets involve elimination protocols and may exacerbate nutritional deficiencies13
    • Collaboration with a registered dietitian is recommended, as dietary restrictions can contribute to both macronutrient and micronutrient deficiencies13
    • Continued assessment of nutritional status and regular laboratory monitoring for micronutrient deficiencies is recommended13
  • While dietary changes may be beneficial, each individual patient's commitment level, access to specialty foods, food preparation constraints, and access to a dietitian should be considered13

Additional targets and biomarkers are emerging

  • Additional tools, such as histological assessments and biomarkers, should be explored and may be useful in identifying underlying inflammation in UC4,6
    • Histology as a marker may be important, given that microscopic inflammation is predictive of, or associated with, steroid use, clinical relapse, dysplasia, and colorectal cancer4
    • Less invasive monitoring of inflammation is needed, and several fecal markers are emerging as potential solutions4

Despite best efforts, patients and clinicians may have different perceptions of disease management14,15

In the multinational 2019 IBD GAPPS survey, designed to gain insight into the experience and perceptions of patients with CD or UC and physicians who treat IBD, UC patients (N=1030) and clinicians (N=654) differed in*:

*Note: GAPPS survey was conducted by Adelphi Real World and supported by Bristol-Myers Squibb Company.
78% of the patients with UC had self-reported moderate-to-severe disease, which was defined as having been hospitalized due to UC; having received a TNF inhibitor, anti-integrin, JAK inhibitor, anti-IL-12/23, and/or immunomodulator for their UC; or having received corticosteroids for >2 months of the last 12 months.
When asked "How long do you expect your current treatment for your CD/UC to control your disease?"

IL=interleukin; JAK=Janus kinase; TNF=tumor necrosis factor.

Further research into therapeutic goals, biomarkers, and dietary modifications
may help to fill ongoing gaps in the understanding of UC management4,6,13

Multiple therapies may be needed over the course of the UC journey

  • In a survey designed to gain insight into the experience and perceptions of patients with CD (n=1368) or UC (n=1030), one-third of patients felt that their IBD was well controlled, 61% felt that their IBD was partially controlled, and 6% reported that their disease was not controlled*14
  • Conventional therapies are effective for inducing and maintaining remission in many patients with mild disease and are available as convenient oral and topical formulations16
    • Many patients with UC will achieve and maintain remission with 5-aminosalicylates (5-ASAs), but some patients will require additional treatments16
  • Patients who experience progressively worsening symptoms and increasing disease severity despite treatment with 5-ASAs may need systemic corticosteroids, biologic therapies, or immunomodulators to induce and maintain disease remission16
  • Corticosteroids are a proven strategy for inducing remission, but are not intended for long-term maintenance of remission4
    • Treatment guidelines recommend using steroids for the shortest possible duration4
  • Biologics have helped to evolve the treatment landscape and have become a mainstay of treatment for patients with moderate-to-severe disease, but some patients may not have an optimal response17,18
    • Some patients do not respond to biologic therapy and many more will discontinue therapy within the first year19
  • Patients with a suboptimal response to therapy may be faced with invasive surgical procedures3,5,20

*The 2019 IBD GAPPS survey was an international survey designed to gain insight into the experience and perceptions of patients with CD or UC (N=1030) and clinicians (N=654).
Note: GAPPS survey was conducted by Adelphi Real World and supported by Bristol-Myers Squibb Company.

As some patients may not achieve a lasting therapeutic response with currently approved therapies, a need for additional options still exists3,17,21,22

Understanding the inflammation in UC

  • UC is a multifactorial disease caused by a dysregulated immune response to gut microbiota in genetically susceptible hosts23
  • Increased permeability of the mucosal barrier allows bacteria to enter the intestinal mucosa, activating an immune response24-26

Multiple pathways contribute to underlying inflammation in UC27

  • One pathway involves the S1P signaling molecule. Increased concentrations of S1P go from the lymph node to the blood vessels and inflamed intestinal tissue28-33
    • Lymphocytes in the circulation follow the S1P gradient leading to the inflamed tissues of the gastrointestinal tract28-33
  • Lymphocytes perpetuate inflammatory conditions in the intestinal mucosa through the release of proinflammatory cytokines, such as interleukin-1 beta, interleukin-6, and tumor necrosis factor25,26,34
    • ILs further activate immune cells25,35,36
    • TNFα stimulates additional proinflammatory cytokine production and mediates T-cell resistance against apoptosis25,36,37
  • Immune cells can then undergo cytokine-mediated activation of JAKs and TYK2, which influence gene transcription38,39
    • This gene transcription produces proteins that mediate immune responses and inflammation38,39
  • The recruitment of immune cells and inflammatory mediators to the site of inflammation exacerbates the inflammatory process40

Understanding underlying inflammatory pathways furthers our knowledge of UC41

References: 1. IsHak WW, Pan D, Steiner AJ, et al. Patient-reported outcomes of quality of life, functioning, and GI/psychiatric symptom severity in patients with inflammatory bowel disease (IBD). Inflamm Bowel Dis. 2017;23(5):798-803. 2. Lynch WD, Hsu R. Ulcerative Colitis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; June 18, 2020. 3. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet. 2017;389(10080):1756-1770. 4. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG clinical guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019;114(3):384-413. 5. Feuerstein JD, Moss AC, Farraye FA. Ulcerative colitis. [published correction appears in Mayo Clinic Proc. 2019 Oct;94(10):2149]. Mayo Clin Proc. 2019;94(7):1357-1373. 6. Feuerstein JD, Isaacs KL, Schneider Y, et al. AGA clinical practice guidelines on the management of moderate to severe ulcerative colitis. Gastroenterology. 2020;158(5):1450-1461. 7. Rubin DT, Dubinsky MC, Panaccione R, et al. The impact of ulcerative colitis on patients' lives compared to other chronic diseases: a patient survey. Dig Dis Sci. 2010;55(4):1044-1052. 8. Jones JL, Nguyen GC, Benchimol EI, et al. The impact of inflammatory bowel disease in Canada 2018: quality of life. J Can Assoc Gastroenterol. 2019;2(Suppl 1):S42-S48. 9. Yarlas A, Rubin DT, Panés J, et al. Burden of ulcerative colitis on functioning and well-being: a systematic literature review of the SF-36® health survey. J Crohns Colitis. 2018;12(5):600-609. 10. Sammut J, Scerri J, Xuereb RB. The lived experience of adults with ulcerative colitis. J Clin Nurs. 2015;24(17-18):2659-2667. 11. Rubin DT, Siegel CA, Kane SV, et al. Impact of ulcerative colitis from patients' and physicians' perspectives: results from the UC: NORMAL Survey. Inflamm Bowel Dis. 2009;15(4):581-588. 12. Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110(9):1324-1338. 13. Nazarenkov N, Seeger K, Beeken L, et al. Implementing dietary modifications and assessing nutritional adequacy of diets for inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2019;15(3):133-144. 14. Rubin DT, Sninsky C, Siegmund B, et al. International Perspectives on Management of Inflammatory Bowel Disease: Opinion Differences and Similarities Between Patients and Physicians From the IBD GAPPS Survey [published online ahead of print, 2021 Jan 29]. Inflamm Bowel Dis. 2021;izab006. 15. Rubin DT, Sninsky C, Sigmund B, et al. Definition of remission in inflammatory bowel disease: assessment of patient and physician perspectives. Poster presented at: Crohn's & Colitis Congress; January 23-25, 2020; Austin, TX. 16. Ko CW, Singh S, Feuerstein JD, et al. AGA clinical practice guidelines on the management of mild-to-moderate ulcerative colitis. Gastroenterology. 2019;156(3)748-764. 17. Paramsothy S, Rosenstein AK, Mehandru S, Colombel JF. The current state of the art for biological therapies and new small molecules in inflammatory bowel disease. Mucosal Immunol. 2018;11(6):1558-1570. 18. Vermeire S, Gils A, Accossato P, Lula S, Marren A. Immunogenicity of biologics in inflammatory bowel disease. Therap Adv Gastroenterol. 2018;11:1756283X17750355. Published 2018 Jan 21. 19. Patel H, Lissoos T, Rubin DT. Indicators of suboptimal biologic therapy over time in patients with ulcerative colitis and Crohn's disease in the United States. PLoS One. 2017;12(4):e0175099. Published 2017 Apr 20. 20. Loftus EV Jr, Davis KL, Wang CC, Dastani H, Luo A. Treatment patterns, complications, and disease relapse in a real-world population of patients with moderate-to-severe ulcerative colitis initiating immunomodulator therapy. Inflamm Bowel Dis. 2014;20(8):1361-1367. 21. Burri E, Maillard MH, Schoepfer AM, et al. Treatment algorithm for mild and moderate-to-severe ulcerative colitis: an update. Digestion. 2020;101(suppl1):2-15. 22. Neurath MF. Current and emerging therapeutic targets for IBD [published correction appears in Nat Rev Gastroenterol Hepatol. 2017 Oct 11]. Nat Rev Gastroenterol Hepatol. 2017;14(5):269-278. 23. Coskun M. Intestinal epithelium in inflammatory bowel disease. Front Med (Lausanne). 2014;1:24. 24. Barbalho SM, Bechara MD, de Alvares Goulart R, et al. Reflections about inflammatory bowel disease and vitamins A and D. J Med Food. 2016;19(12):1105-1110. 25. Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014;14(5):329-342. 26. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361(21):2066-2078. 27. Tatiya-Aphiradee N, Chatuphonprasert W, Jarukamjorn K. Immune response and inflammatory pathway of ulcerative colitis. J Basic Clin Physiol Pharmacol. 2018;30(1):1-10. 28. Peyrin-Biroulet L, Christopher R, Behan D, Lassen C. Modulation of sphingosine-1-phosphate in inflammatory bowel disease. Autoimmun Rev. 2017;16(5):495-503. 29. Karuppuchamy T, Behrens EH, González-Cabrera P, et al. Sphingosine-1-phosphate receptor-1 (S1P1) is expressed by lymphocytes, dendritic cells, and endothelium and modulated during inflammatory bowel disease. Mucosal Immunol. 2017;10(1):162-171. 30. Schwab SR, Cyster JG. Finding a way out: lymphocyte egress from lymphoid organs. Nat Immunol. 2007;8(12):1295-1301. 31. Jaigirdar SA, Benson RA, Elmesmari A, et al. Sphingosine-1-phosphate promotes the persistence of activated CD4 T cells in inflamed sites. Front Immunol. 2017;8:1627. 32. Roviezzo F, Brancaleone V, De Gruttola L, et al. Sphingosine-1-phosphate modulates vascular permeability and cell recruitment in acute inflammation in vivo. J Pharmacol Exp Ther. 2011;337(3):830-837. 33. Schwab SR, Pereira JP, Matloubian M, Xu Y, Huang Y, Cyster JG. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science. 2005;309(5741):1735-1739. 34. de Souza HS, Fiocchi C. Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol. 2016;13(1):13-27. 35. Sabino J, Verstockt B, Vermeire S, Ferrante M. New biologics and small molecules in inflammatory bowel disease: an update. Therap Adv Gastroenterol. 2019;12:1756284819853208. Published 2019 May 26. 36. Ahluwalia B, Moraes L, Magnusson MK, Öhman L. Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies. Scand J Gastroenterol. 2018;53(4):379-389. 37. Sands BE, Kaplan GG. The role of TNFalpha in ulcerative colitis. J Clin Pharmacol. 2007;47(8):930-941. 38. Fernández-Clotet A, Castro-Poceiro J, Panés J. JAK inhibition: the most promising agents in the IBD pipeline?. Curr Pharm Des. 2019;25(1):32-40. 39. Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: what can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis?. Ann Rheum Dis. 2018;77(2):175-187. 40. Danese S, Furfaro F, Vetrano S. Targeting S1P in inflammatory bowel disease: new avenues for modulating intestinal leukocyte migration. J Crohns Colitis. 2018;12(suppl_2):S678-S686. 41. Coskun M, Vermeire S, Nielsen OH. Novel targeted therapies for inflammatory bowel disease. Trends Pharmacol Sci. 2017;38(2):127-142.

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