CLINICAL AND SYSTEMATIC REVIEWS
nature publishing group
1
Treatment of IBD: Where We Are and Where We Are Going Charles N. Bernstein, MD1
In assessing the best evidence for optimizing management of inflammatory bowel disease (IBD), the focus is typically on anti-inflammatory agents and therapies that modulate the immune system. The intestinal immune response remains the key focus of developing therapies as well. In the past decade, the concept of dysbiosis of the gut microbiome has emerged as a potential pathogenetic focus in IBD, and with this a burgeoning interest in manipulating the microbiome as a means of controlling the disease has emerged. In this review, anti-inflammatory, immune-modulating, and microbiome-modulating therapies will be covered in terms of what is known today, as well as treatments that may be part of the therapeutic armamentarium in the near future. Concurrent with the evolution of our understanding of the basic biology of IBD, there is an increasing appreciation for the disconnect between patients’ symptoms and inflammatory disease. As clinical trials have simultaneously addressed both symptom scores and mucosal healing, investigators and clinicians have gained a greater appreciation for the fact that many symptoms may not be driven by active inflammation, and hence focusing only on immunomodulatory therapies would not serve patients’ needs fully. Furthermore, there is an emerging recognition of the importance of stress and psychological health in symptom experience and treatment needs. In this review, approaches to managing patients’ symptoms as well as other adjunctive approaches to improving well-being will also be discussed. Finally, throughout this review, important research questions regarding different aspects of treatment will be proposed. Am J Gastroenterol advance online publication, 9 December 2014; doi:10.1038/ajg.2014.357
OPTIMIZING CURRENT ANTI-INFLAMMATORY AND IMMUNOMODULATORY TREATMENT 5-Aminosalicylates
5-Aminosalicylates (5-ASA) remain a mainstay of treating active ulcerative colitis (UC). Both oral and rectal therapies are effective in inducing and maintaining remission in UC (1–4). The combination of oral and rectal therapy is better than oral or rectal therapy alone (4). Studies of several 5-ASA products have consistently shown that once daily is the optimal dosing because it is comparably effective as split dosing and could enhance adherence. Although increasing dosing from 2–2.4 to 4–4.8 g/day can be attempted when disease activity persists, there is marginal evidence for a significant dose–response effect beyond 2.4 g/day (1). Nevertheless, subgroup analysis of the ASCEND trials using Asacol suggests that individuals with moderate disease may benefit from the higher dose of 4.8 g/day (5). Furthermore, the option of dose maximization of 5-ASA is something that is easy, safe, can mitigate the need to step-up immunomodulatory therapy, and is also something that patients can pursue independently. There is no evidence of any difference in efficacy or safety between
different oral 5-ASA formulations for induction or maintenance of remission (6). Although one trial showed a benefit for ethylcellulose-coated mesalamine (Pentasa) 4 g per day in small-bowel Crohn’s disease (CD) (7), there is consensus that there is little role for 5-ASA in CD. Although 5-ASA may be used in colonic CD, it has never been studied, and there is reason to question the rationale for using a mostly superficially active anti-inflammatory agent in a transmural disease. Nonetheless, it can be considered in colonic CD in the absence of deep ulceration and penetrating or fibrostenosing complications, the type of colitis that could be UC, except that it is labeled as CD based on colonic distribution or the presence of diffuse granulomas histologically. Corticosteroids
Corticosteroids are effective in both luminal CD and UC for inducing remission (8). They work quickly and are among the least expensive agents that can be prescribed. Their popularity among some patients because of their ease of use (easy access, low cost, pill formulation) is countered by their adverse effects that lead other patients to refuse repeat courses. Budesonide,
1
Section of Gastroenterology, University of Manitoba IBD Clinical and Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada. Correspondence: Charles N. Bernstein, MD, Section of Gastroenterology, University of Manitoba IBD Clinical and Research Centre, University of Manitoba, Winnipeg, R3E3P4 Manitoba, Canada. E-mail: [email protected] Received 26 August 2014; accepted 14 October 2014
© 2014 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
REVIEW
CME
REVIEW
2
Bernstein
formulated to be active in the distal ileum and right colon, is effective in CD involving those areas. It is “prednisone lite”; it is not quite as effective and certainly not as toxic as prednisone. Over time, response is lost, and hence it is a short-term solution for mild-to-moderate ileal and right colonic CD. Oral budesonide MMX is budesonide formulated with Multi-Matrix System to facilitate delayed pancolonic release of budesonide. In a randomized controlled trial, it was shown to be more effective than placebo at inducing combined clinical and endoscopic remission by 8 weeks in mild-to-moderate UC (17.4% vs. 4.5%, P
nature publishing group
1
Treatment of IBD: Where We Are and Where We Are Going Charles N. Bernstein, MD1
In assessing the best evidence for optimizing management of inflammatory bowel disease (IBD), the focus is typically on anti-inflammatory agents and therapies that modulate the immune system. The intestinal immune response remains the key focus of developing therapies as well. In the past decade, the concept of dysbiosis of the gut microbiome has emerged as a potential pathogenetic focus in IBD, and with this a burgeoning interest in manipulating the microbiome as a means of controlling the disease has emerged. In this review, anti-inflammatory, immune-modulating, and microbiome-modulating therapies will be covered in terms of what is known today, as well as treatments that may be part of the therapeutic armamentarium in the near future. Concurrent with the evolution of our understanding of the basic biology of IBD, there is an increasing appreciation for the disconnect between patients’ symptoms and inflammatory disease. As clinical trials have simultaneously addressed both symptom scores and mucosal healing, investigators and clinicians have gained a greater appreciation for the fact that many symptoms may not be driven by active inflammation, and hence focusing only on immunomodulatory therapies would not serve patients’ needs fully. Furthermore, there is an emerging recognition of the importance of stress and psychological health in symptom experience and treatment needs. In this review, approaches to managing patients’ symptoms as well as other adjunctive approaches to improving well-being will also be discussed. Finally, throughout this review, important research questions regarding different aspects of treatment will be proposed. Am J Gastroenterol advance online publication, 9 December 2014; doi:10.1038/ajg.2014.357
OPTIMIZING CURRENT ANTI-INFLAMMATORY AND IMMUNOMODULATORY TREATMENT 5-Aminosalicylates
5-Aminosalicylates (5-ASA) remain a mainstay of treating active ulcerative colitis (UC). Both oral and rectal therapies are effective in inducing and maintaining remission in UC (1–4). The combination of oral and rectal therapy is better than oral or rectal therapy alone (4). Studies of several 5-ASA products have consistently shown that once daily is the optimal dosing because it is comparably effective as split dosing and could enhance adherence. Although increasing dosing from 2–2.4 to 4–4.8 g/day can be attempted when disease activity persists, there is marginal evidence for a significant dose–response effect beyond 2.4 g/day (1). Nevertheless, subgroup analysis of the ASCEND trials using Asacol suggests that individuals with moderate disease may benefit from the higher dose of 4.8 g/day (5). Furthermore, the option of dose maximization of 5-ASA is something that is easy, safe, can mitigate the need to step-up immunomodulatory therapy, and is also something that patients can pursue independently. There is no evidence of any difference in efficacy or safety between
different oral 5-ASA formulations for induction or maintenance of remission (6). Although one trial showed a benefit for ethylcellulose-coated mesalamine (Pentasa) 4 g per day in small-bowel Crohn’s disease (CD) (7), there is consensus that there is little role for 5-ASA in CD. Although 5-ASA may be used in colonic CD, it has never been studied, and there is reason to question the rationale for using a mostly superficially active anti-inflammatory agent in a transmural disease. Nonetheless, it can be considered in colonic CD in the absence of deep ulceration and penetrating or fibrostenosing complications, the type of colitis that could be UC, except that it is labeled as CD based on colonic distribution or the presence of diffuse granulomas histologically. Corticosteroids
Corticosteroids are effective in both luminal CD and UC for inducing remission (8). They work quickly and are among the least expensive agents that can be prescribed. Their popularity among some patients because of their ease of use (easy access, low cost, pill formulation) is countered by their adverse effects that lead other patients to refuse repeat courses. Budesonide,
1
Section of Gastroenterology, University of Manitoba IBD Clinical and Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada. Correspondence: Charles N. Bernstein, MD, Section of Gastroenterology, University of Manitoba IBD Clinical and Research Centre, University of Manitoba, Winnipeg, R3E3P4 Manitoba, Canada. E-mail: [email protected] Received 26 August 2014; accepted 14 October 2014
© 2014 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
REVIEW
CME
REVIEW
2
Bernstein
formulated to be active in the distal ileum and right colon, is effective in CD involving those areas. It is “prednisone lite”; it is not quite as effective and certainly not as toxic as prednisone. Over time, response is lost, and hence it is a short-term solution for mild-to-moderate ileal and right colonic CD. Oral budesonide MMX is budesonide formulated with Multi-Matrix System to facilitate delayed pancolonic release of budesonide. In a randomized controlled trial, it was shown to be more effective than placebo at inducing combined clinical and endoscopic remission by 8 weeks in mild-to-moderate UC (17.4% vs. 4.5%, P
