Description of the condition
Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease that results in diffuse mucosal inflammation in the colon. The pathogenesis of UC remains unclear, but appears to involve alterations in cellular and humoral immunity in genetically predisposed individuals in concert with a complex interplay of environmental factors and the colonic microbiome.
The clinical course of UC is generally characterized by periods of asymptomatic remission interspersed by periods of abdominal cramping, urgency, and bloody diarrhea caused by colonic inflammation. The inflammation arises just above the anorectal junction and, while it can be limited to the the rectum (i.e. proctitis), it often extends proximally to the splenic flexure (i.e. left sided colitis) or can involve the more proximal colon (i.e. pancolitis). Mucosal abnormalities that can be seen endoscopically begin as mild changes such as erythema and a diminished vascular pattern and, as inflammation continues, can develop into marked erythema, an absent vascular pattern, friability, and mucosal erosions. Severe UC is characterized by mucosal friability, spontaneous bleeding and significant ulceration. While UC can often be managed with medical therapies, severe, life-threatening attacks may require a colectomy (Caprilli 2007).
Ulcerative colitis activity is typically assessed using clinical, biochemical, and endoscopic measures. The traditional approach to the medical management of UC is to use medications both to induce remission and to then maintain disease quiescence. Induction therapies typically include corticosteroids (e.g prednisone, prednisolone, methylprednisolone, and budesonide) and aminosalicylates (e.g. mesalazine or sulfasalazine), which can be used both topically and systemically. Severe attacks of UC can also be treated with biologic agents (e.g. infliximab). Immunosuppressants (e.g. azathioprine, 6-mercaptopurine) can be used as maintenance therapy to augment aminosalicylate therapy. Unlike Crohn’s disease, UC is limited to the colon so a colectomy may be performed in cases that fail to respond to standard medical therapy.
Historically the goal of treating UC was to induce clinical remission. However, the idea of treating to resolve the underlying inflammation is appealing because of mounting evidence that mucosal healing (MH) may alter future disease course (Froslie 2007; Armuzzi 2012; Ananthakrishnan 2012; Colombel 2012). In the ACT-1 and ACT-2 trials endoscopic improvement at week 8 was associated with sustained symptomatic and corticosteroid-free remission, sustained mucosal healing, and reduced need for colectomy through 54 weeks (Colombel 2012). In one Norwegian cohort study MH was also shown to decrease the risk of future colectomy (Froslie 2007). Further evidence for treating underlying inflammation comes from studies that demonstrate the degree of colonic inflammation is an important risk factor for colorectal neoplasia (Rutter 2004a; Rutter 2004b; Gupta 2007).The current review will assess the efficacy and safety of medical therapies for maintenance of MH in UC.
Description of the intervention
A variety of medical agents have been studied as potential therapies for maintenance of remission in UC. Traditional, maintenance therapies include oral or topical 5-aminosalicylic acid medications or immunosuppressant medications such as methotrexate (oral, intramuscular, or subcutaneous) or oral thiopurines including azathioprine and 6-mercaptopurine. In recent years biologic medications including infliximab, adalimumab, and vedolizumab have been developed. These medications are administered either intravenously or subcutaneously on a regular dosing schedule.
A number of endoscopic activity indices have been developed to assess disease activity. These include the Baron score (Baron 1964), the modified Baron score (Feagan 2005), the St Mark's index (Powell-Tuck 1982), the Rachmilewitz endoscopic index (Rachmilewitz 1989), the Mayo score (Schroeder 1987), the Lémann endoscopic index (Lemann 1995), the Sutherland index (Sutherland 1987), the ulcerative colitis endoscopic index of severity (UCEIS) (Travis 2012), and Truelove and Witt’s sigmoidoscopic assessment (Truelove 1955). Since each tool uses a slightly different definition for scoring mucosal abnormalities, there is no standard definition of MH. Generally, it is accepted that MH refers to the complete endoscopic healing of mucosal abnormalities that were observed at baseline assessment.
How the intervention might work
Anti-inflammatory and immunosuppressive medications are generally used to maintain remission in UC with the goal of suppressing gastrointestinal tract inflammation sufficiently to allow the mucosa to heal. The specific mechanism of action of 5-aminosalicylic acid medications is unknown. Current evidence points to an anti-inflammatory effect through alteration of local inflammatory mediators and inhibition of T-cell proliferation (MacDermott 2000). Corticosteroids decrease inflammation through a number of mechanisms, including inhibition of pro-inflammatory cytokines and arachidonic acid metabolites, and by effects on vascular permeability an the migration of circulating leukocytes (Rubin 1999). Systemic corticosteroids are avoided as maintenance therapy because of a significant adverse effect profile.
The thiopurine medications, azathioprine and 6-mercaptopurine, are purine analogues that exert an immunosuppressive effect by disrupting DNA synthesis and inducing apoptosis (Sahasranaman 2008). Methotrexate is a folate antagonist that also exerts an immunosuppressive effect. Although the exact mechanism of action is unknown, it likely involves decreased production of leukotrienes and the induction of adenosine (Cronstein 1993).
Infliximab and adalimumab are tumor necrosis factor-alpha (TNF-α) antagonists that bind to soluble and cell-bound TNF and induce apoptosis of activated lymphocytes (Van den Brande 2003). Vedolizumab is a monoclonal antibody against the alpha-4-beta-7 integrin that is relatively specific for leukocytes in the gastrointestinal tract and is thought to prevent the migration of leukocytes into inflamed tissue (Gerner 2013).
Why it is important to do this review
Ulcerative colitis is a chronic disease characterized by flares of increased disease activity interposed between periods of disease quiescence. Over the past century the use of effective medical therapies has dramatically reduced the mortality associated with UC (Caprilli 2007). While most patients present with mild disease, approximately 15% of patients with UC will develop an attack severe colitis and 30% of these patients will fail medical therapy and require a colectomy (Caprilli 2007). At 10 years post-diagnosis the overall colectomy rate for patients with UC is 24% (Langholz 1994). While a colectomy may be considered to be curative, it does not necessarily restore pre-morbid quality of life.
There is mounting evidence that MH correlates with improved long-term outcomes in UC (Froslie 2007; Baert 2010; Armuzzi 2012; Colombel 2012). This review will assess all randomized controlled trial data for interventions that have evaluated MH in UC. Evaluating the ability of UC therapies to maintain MH may be clinically relevant for the management of UC as the ability to alter the natural history of the disease, achieve sustained remission, and improve patient outcomes are the ultimate goals of therapy.