The challenge of controlling inflammation in UC
Indications of a poor prognosis, including relapse and colectomy, are:
- Moderate-to-severe disease at diagnosis5
- Presentation of extensive disease at diagnosis5
- Evidence of deep ulceration on endoscopy3,5
- Long-standing disease6,7
- Persistent inflammation8
- Early requirement for steroids9,10
The risk of relapse is significant in UC:
- 51% risk of relapse within 1 year of diagnosis12
- 70-80% chance of relapse after 1 year in patients with clinically active disease13
- The frequent need for steroids to manage relapses and control inflammation is associated with poor outcomes9,10
During the early stages of UC, relapses are associated with accelerating disease.14
Patients with better mucosal healing experience fewer relapses15
- Histologic healing may be a better predictor of time to relapse than macroscopic appearance11,16
- Patients with histological normalisation* compared with those with histologically active disease are almost 7X more likely to have relapse-free survival17
- Reduced histologic activity is associated with decreased risk of relapse, steroid use, colectomy, and hospitalisation17
Rapid, sustained, and early control of inflammation has the potential to improve disease course.2,14,18
* Normal mucosa without features of chronicity.
Time to intervene –
limiting the damage in UC
UC: A disease with structural and functional consequences18
- Evidence supports the existence of transmural chronic inflammation and fibrotic changes that may affect colonic motility and anorectal function in UC19
- Deep ulcerations are a risk factor for aggressive and complicated disease; these endoscopic findings are associated with poor outcomes3,5
Recognition of the damage and disability associated with inflammation in UC supports the concept of timely, effective management to have an impact on the course of disease.1
Notably, patients who need treatment with steroids are more likely to have structural damage and anorectal dysfunction.18
The risk of colorectal cancer
While early intervention with effective therapies may have contributed to an overall decline in the incidence of colorectal cancer, the risk remains elevated in some patients with UC.10
Patients with UC at higher risk of dysplasia and colorectal cancer include those with:
- Long-standing disease6,7
- Persistent histological activity (chronic mucosal inflammation assessed both macroscopically and microscopically contributes independently to cancer risk)10,20
- Extensive colitis10
Colorectal cancer risk is driven by the extent, duration, and severity of colonic inflammation.7
Better control of inflammation helps reduce colorectal cancer risk.7
Time for optimal therapy –
achievement and maintenance of steroid-free remission
Achieving steroid-free remission is key to improving patient QoL and avoiding the complications of prolonged steroid use.14 Steroid-free remission is an established therapeutic target, and clinical guidelines recommend rapid introduction of effective therapies to improve patient outcomes.21-23
Corticosteroid use is associated with numerous short- and long-term toxicities, including mood disturbances, moon face/Cushingoid appearance, cataracts, and insomnia, which can be distressing for patients.21,23,24
Steroids lack long-term efficacy for the maintenance of remission, and patients receiving oral steroid treatment are at increased risk of colectomy if they experience a moderate flare.3,21
Studies have shown that introducing highly effective treatments in appropriate patients early in the disease course is crucial in achieving deep remission and avoiding disease complications.1
Achieving deep histological remission predicts a reduced need for steroids in patients with UC
Histological “complete” remission*,†
Adapted with permission from Bryant et al.25 Histology was scored using the Trulove and Richards’ index. Histological remission is defined as “no significant inflammation” and architectural changes in the absence of erosions, crypt abcesses, and neutrophilic infiltration. Endoscopic disease activity was measured using the Baron index.25
* Complete remission refers to both histological and endoscopic remission.
† Histological remission and “complete” histological remission were virtually indistinguishable and are depicted by a single line.
Getting rapid control of disease activity can improve QoL
UC is associated with a significant impact on health-related QoL.14
Patients identify achieving rapid control of disease activity as an important part of their therapy.14 Patients with severe UC actually prioritise rapid symptom resolution over long-term control.14
Rapidly resolving inflammation can have an early impact on patient-reported outcomes, reduce steroid use, and restore patient QoL.17,26
In addition to lower QoL, patients with UC may have diminished psychological functioning and wellbeing, with poorer psychosocial outcomes during periods of active disease.27
Control of disease activity is an important determinant of QoL outcomes.27
Additional therapeutic options that provide rapid onset of clinical effect and reduce disease activity would be of value in moderate-to-severe UC.14
Steroids and immunomodulator therapies are not associated with long-term improvements in health-related QoL28
Despite this, there is evidence of prolonged corticosteroid use in patients with UC.21 Various analyses have shown:
|of patients with UC received steroids for >3 months in a 12-month period21|
|of patients with UC were treated with steroids for ≥6 months21|
|of patients with IBD demonstrated steroid dependence or excess use of steroids23,*|
|of patients with moderate-to-severe UC demonstrated steroid dependency or excess use of steroids23,*|
Evidence suggests that long-term, sustained improvements in health-related QoL may be achieved with more advanced therapies.28
Studies highlight the significance of sufficient therapy to establish remission in patients with UC to alleviate the psychosocial stress of the disease.29
Recognition of high-risk disease features in UC and concordant therapeutic strategies are key to improving patient outcomes.9
Primary non-response to advanced therapies is ~30%, and loss of response after initially responding is ~50%.30
Achieving and sustaining remission remains a challenge and is demonstrated in fewer than one-third of treated patients.21,31
There is an unmet need for additional efficacious, simply dosed, and well-tolerated therapies using novel mechanisms that can achieve early and sustained remission.14,31
* Steroid dependency and excess defined in accordance with European Crohn’s and Colitis Organisation (ECCO) and UK guidelines.23
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- Sairenji T, Collins KL, Evans DV. Prim Care. 2017;44(4):673‐692.
- Danese S, Allez M, van Bodegraven AA, et al. Dig Dis. 2019;37(4):266‐283.
- Barreiro-de Acosta M, Vallejo N, de la Iglesia D, et al. J Crohns Colitis. 2016;10(1):13-19.
- Peyrin-Biroulet L, Bressenot A, Kampman W. Clin Gastroenterol Hepatol. 2014;12(6):929-34.e2.
- Christensen B, Hanauer SB, Erlich J, et al. Clin Gastroenterol Hepatol. 2017;15(10):1557-1564.e1.
- Massinha P, Portela F, Campos S, et al. GE Port J Gastroenterol. 2018;25(2):74‐79.
- Colombel JF, Shin A, Gibson PR. Clin Gastroenterol Hepatol. 2019;17(3):380-390.e1.
- Beaugerie L, Sokol H. World J Gastroenterol. 2012;18(29):3806-3813.
- D’Haens GRAM, Lindsay JO, Panaccione R, Schreiber S. Drugs R D. 2019;19(2):227‐234.
- Feuerstein JD, Isaacs KL, Schneider Y, et al. Gastroenterology. 2020;158(5):1450‐1461.
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- Bryant RV, Burger DC, Delo J, et al. Gut. 2016;65(3):408-414.
- Armuzzi A, Tarallo M, Lucas J, et al. BMC Gastroenterol. 2020;20(1):18.
- Lix LM, Graff LA, Walker JR, et al. Inflamm Bowel Dis. 2008;14(11):1575-1584.
- Jones JL, Nguyen GC, Benchimol EI, et al. J Can Assoc Gastroenterol. 2019;2(Suppl 1):S42-S48.
- Bokemeyer B, Hardt J, Hüppe D, et al. J Crohns Colitis. 2013;7(5):355-368.
- Fernández-Clotet A, Castro-Poceiro J, Panés J. Curr Pharm Des. 2019;25(1):32-40.
- Panés J, Vermeire S. J Crohns Colitis. 2020;14(Suppl 2):S711-S712.