Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/15/15 For personal use only.
Review
Current and emerging maintenance therapies for ulcerative colitis Expert Rev. Gastroenterol. Hepatol. 8(4), 359–368 (2014)
Anthony O’Connor and Alan C Moss* Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA *Author for correspondence: Tel.: +1 617 667 3197 Fax: +1 617 667 1171 [email protected]
Ulcerative colitis (UC) is a chronic idiopathic intestinal disease that requires life-long maintenance therapy to maintain clinical remission. This article reviews the current literature on maintenance treatments in UC. It examines the natural history of the condition and the proposed benefits of treatment. These include improving quality of life parameters, decreasing corticosteroid intake, the prevention of relapse, the prevention of colorectal cancer and the avoidance of colectomy. The immunosuppressive era appears to be reducing the need for elective colectomy in UC. The article explores the classes of drug currently used for maintenance of UC, reviews the literature around adherence issues, and summarizes emerging agents in this space. KEYWORDS: 5-ASA • adalimumab • golimumab • infliximab • maintenance • remission • thiopurines • ulcerative colitis
Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colonic mucosa, which starts in the rectum and generally extends proximally in a continuous manner through part of, or the entire colon. It is a relapsing, remitting condition with periods of quiescence interspersed with active disease. Prognosis is difficult to predict. Colectomy is required in between 10 and 30% of patients. Upon presentation, lesions are limited to the rectum (proctitis) in 30–35% of patients, to the splenic flexure (left-sided colitis) in 30–45% and to the cecum (pancolitis) in 20–25%. During the course of the disease, after 20 years, the rate of pancolitis may increase, reaching 50% of cases [1]. It is estimated to affect 1.4 million people in the USA and has a significant impact on patient quality of life, with 66% describing interference with work and 73% with leisure activities [2]. Due to the chronicity of UC and the lack of a medical cure, most patients require life-long therapy to maintain remission from active disease. Definition of remission in UC
A universal, validated definition of ‘remission’ is lacking for UC; there are different criteria for clinical remission, endoscopic remission and histological remission used in the scientific literature. When comparing studies of maintenance informahealthcare.com
10.1586/17474124.2014.896193
therapy for patients with UC, this can make the literature difficult to interpret. A review article proposed three models of remission used in most trials: clinical, complete and registration remission [3]. Clinical remission signifies cessation of rectal bleeding and normal stool frequency. In the context of clinical trials, complete remission generally implies safety and efficacy; normal stool frequency and no rectal bleeding as well as a normal or quiescent appearance of the mucosa at sigmoidoscopy. Registration remission is a term used in trials to gain drug licence, currently used by regulatory authorities and requires cessation of rectal bleeding and a sigmoidoscopy score of 0 or 1 of the Mayo Clinic score. It should be noted that eight different criteria for clinical remission have been used to support US FDA approval in the USA, highlighting the fact that no single definition has been universally used. In UC, it has become apparent that patients on stable maintenance therapy who are considered to be in clinical remission may still have endoscopic and/or histological disease activity. In one study of 103 patients with UC in clinical remission, histological features of inflammation were found in 54%, with 37% having at least moderate inflammation based on histology scores [4]. In a prospective observational study at the same center, where 45% of
2014 Informa UK Ltd
ISSN 1747-4124
359
Review
O’Connor & Moss
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/15/15 For personal use only.
Table 1. Rates of relapse in 5-aminosalicylic acid maintenance studies. Study (year)
Drug
Dose (g/day)
Relapse on Rx (%)
Relapse on Placebo (%)
Duration (months)
Dissanayake and Truelove (1973)
Sulfasalazine
2
12.1
54.8
6
[6]
Hanauer et al. (1996)
Asacol
1.6
34.5
60.3
6
[7]
Miner et al. (1995)
Pentasa
4
36
62
12
[8]
Lichtenstein et al. (2010)
Apriso
1.5
21.1
41.7
6
[9]
D’Haens et al. (2012)
Lialda
2.4
16.3
Comparative trial
6
[10]
Green et al. (1998)
Balsalazide
3
42
Comparative trial
12
[11]
patients in clinical remission were found to have endoscopic disease activity, variables independently associated with endoscopic inflammation were remission for 6 months
[33]
Adler and Korelitz (1990)
6-mercaptopurine
Variable
37
n/a
Mean 1.8 years
[34]
George et al. (1996)
6-mercaptopurine
Variable
35
n/a
>6 months
[35]
Ferna´ndez-Ban˜ares et al. (1996)
Azathioprine
Variable
10
n/a
Mean 16 months
[36]
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/15/15 For personal use only.
Prospective, randomised data
Retrospective data
n/a: Not applicable.
endpoint) and 64.4% at 12 months. A secondary analysis in this study underlined the importance of adherence to therapy, with clinical recurrence observed in 20.6% of patients who were ‡80% adherent and 36.1% of patients with
Review
Current and emerging maintenance therapies for ulcerative colitis Expert Rev. Gastroenterol. Hepatol. 8(4), 359–368 (2014)
Anthony O’Connor and Alan C Moss* Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA *Author for correspondence: Tel.: +1 617 667 3197 Fax: +1 617 667 1171 [email protected]
Ulcerative colitis (UC) is a chronic idiopathic intestinal disease that requires life-long maintenance therapy to maintain clinical remission. This article reviews the current literature on maintenance treatments in UC. It examines the natural history of the condition and the proposed benefits of treatment. These include improving quality of life parameters, decreasing corticosteroid intake, the prevention of relapse, the prevention of colorectal cancer and the avoidance of colectomy. The immunosuppressive era appears to be reducing the need for elective colectomy in UC. The article explores the classes of drug currently used for maintenance of UC, reviews the literature around adherence issues, and summarizes emerging agents in this space. KEYWORDS: 5-ASA • adalimumab • golimumab • infliximab • maintenance • remission • thiopurines • ulcerative colitis
Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colonic mucosa, which starts in the rectum and generally extends proximally in a continuous manner through part of, or the entire colon. It is a relapsing, remitting condition with periods of quiescence interspersed with active disease. Prognosis is difficult to predict. Colectomy is required in between 10 and 30% of patients. Upon presentation, lesions are limited to the rectum (proctitis) in 30–35% of patients, to the splenic flexure (left-sided colitis) in 30–45% and to the cecum (pancolitis) in 20–25%. During the course of the disease, after 20 years, the rate of pancolitis may increase, reaching 50% of cases [1]. It is estimated to affect 1.4 million people in the USA and has a significant impact on patient quality of life, with 66% describing interference with work and 73% with leisure activities [2]. Due to the chronicity of UC and the lack of a medical cure, most patients require life-long therapy to maintain remission from active disease. Definition of remission in UC
A universal, validated definition of ‘remission’ is lacking for UC; there are different criteria for clinical remission, endoscopic remission and histological remission used in the scientific literature. When comparing studies of maintenance informahealthcare.com
10.1586/17474124.2014.896193
therapy for patients with UC, this can make the literature difficult to interpret. A review article proposed three models of remission used in most trials: clinical, complete and registration remission [3]. Clinical remission signifies cessation of rectal bleeding and normal stool frequency. In the context of clinical trials, complete remission generally implies safety and efficacy; normal stool frequency and no rectal bleeding as well as a normal or quiescent appearance of the mucosa at sigmoidoscopy. Registration remission is a term used in trials to gain drug licence, currently used by regulatory authorities and requires cessation of rectal bleeding and a sigmoidoscopy score of 0 or 1 of the Mayo Clinic score. It should be noted that eight different criteria for clinical remission have been used to support US FDA approval in the USA, highlighting the fact that no single definition has been universally used. In UC, it has become apparent that patients on stable maintenance therapy who are considered to be in clinical remission may still have endoscopic and/or histological disease activity. In one study of 103 patients with UC in clinical remission, histological features of inflammation were found in 54%, with 37% having at least moderate inflammation based on histology scores [4]. In a prospective observational study at the same center, where 45% of
2014 Informa UK Ltd
ISSN 1747-4124
359
Review
O’Connor & Moss
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/15/15 For personal use only.
Table 1. Rates of relapse in 5-aminosalicylic acid maintenance studies. Study (year)
Drug
Dose (g/day)
Relapse on Rx (%)
Relapse on Placebo (%)
Duration (months)
Dissanayake and Truelove (1973)
Sulfasalazine
2
12.1
54.8
6
[6]
Hanauer et al. (1996)
Asacol
1.6
34.5
60.3
6
[7]
Miner et al. (1995)
Pentasa
4
36
62
12
[8]
Lichtenstein et al. (2010)
Apriso
1.5
21.1
41.7
6
[9]
D’Haens et al. (2012)
Lialda
2.4
16.3
Comparative trial
6
[10]
Green et al. (1998)
Balsalazide
3
42
Comparative trial
12
[11]
patients in clinical remission were found to have endoscopic disease activity, variables independently associated with endoscopic inflammation were remission for 6 months
[33]
Adler and Korelitz (1990)
6-mercaptopurine
Variable
37
n/a
Mean 1.8 years
[34]
George et al. (1996)
6-mercaptopurine
Variable
35
n/a
>6 months
[35]
Ferna´ndez-Ban˜ares et al. (1996)
Azathioprine
Variable
10
n/a
Mean 16 months
[36]
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/15/15 For personal use only.
Prospective, randomised data
Retrospective data
n/a: Not applicable.
endpoint) and 64.4% at 12 months. A secondary analysis in this study underlined the importance of adherence to therapy, with clinical recurrence observed in 20.6% of patients who were ‡80% adherent and 36.1% of patients with
