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Sheila M. Wilhelm, PharmD, FCCP, BCPS
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Report: Pharmacotherapy for Moderate to Severe Inflammatory Bowel Disease: Evolving Strategies
Bryan L. Love, PharmD, BCPS
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Report: Pharmacotherapy for Moderate to Severe Inflammatory Bowel Disease: Evolving Strategies

Bryan L. Love, PharmD, BCPS
Abstract
Moderate to severe disease causes substantial morbidity in inflammatory bowel disease (IBD). The approach to pharmacotherapy for patients with moderate to severe ulcerative colitis and Crohn’s disease is undergoing a fundamental transformation to change the course of disease in these patients. Disease severity is being redefined to consider the impact on the patient, its inflammatory burden, and the disease course. Prevention of disease progres-sion and complications are replacing symptomatic remission as the goal of therapy. To achieve these goals, the treatment approach is evolving from a stepwise to a treat-to-target approach, with patients stratified to treatment according to their risk of disease progression or complications. The primary drug classes for induction and maintenance of remission in moderate to severe IBD are corticoste-roids, thiopurines, tumor necrosis factor antago-nists, and vedolizumab. Use of these drug classes is changing as IBD management evolves. This article reviews the efficacy, adverse effects, drug interac-tions, and special issues for each class. The role for each class is formulated based on results of key clinical trials and meta-analyses, as well as clinical practice guideline recommendations.
Am J Manag Care. 2016;22:S39-S50


Introduction

     Ulcerative colitis (UC) and Crohn’s disease (CD) are life-long inflammatory bowel diseases (IBDs) with a progressive course characterized by exacerbations and remissions.1,2 The guiding principle of pharmacotherapy is to induce and maintain remission,1,2 and selection of pharmacotherapy is based primarily on the severity of disease, and the patient’s response to previous therapy.3

Defining Moderate to Severe Disease

     Composite instruments, such as the Mayo score in UC and the Crohn’s Disease Activity Index (CDAI), were designed to assess disease activity;4 however, they are often used, sometimes with modifications, to define moderate to severe IBD. For example, the Canadian Association of Gastroenterology (CAG) defines moderate to severe UC as a Mayo score of 6 to 12.5 The American College of Gastroenterology (ACG) includes a CDAI score of 220 to 450 in the definition of moderate to severe CD (Table 11,2,6-8).1 In clinical practice, patients who require treatment with oral corticosteroids are considered to have moderate CD.3 Because they do not assess the patient’s risk of disease progression, using composite disease activity scores to define disease severity is imperfect; therefore, experts advocate for a more comprehensive definition that measures the impact on the patient (ie, symptoms, quality of life, and disability), inflammatory burden (ie, mucosal lesions and extent of disease), and disease course (ie, flares, extraintestinal manifestations, and intestinal resection).4 The Mayo score and CDAI have been used to define disease severity in clinical trials, including premarketing clinical trials of biologics for IBD.4 In the future, the US Food and Drug Administration (FDA) is expected to require patientreported outcomes and objective measurements of disease as end points in clinical trials evaluating drugs for IBD.9

     
Redefining moderate to severe disease has the potential to more accurately identify patients who may benefit from more aggressive treatment. As shown in Table 1,1,2,6-8 clinical care pathways recently developed by the American Gastroenterological Association (AGA) stratify patients for treatment based on risk factors for a poor prognosis.6,7 In UC, patients are stratified according to their risk for colectomy.6 Risk factors for colectomy include extensive disease, deep ulcers, age less than 40 years, high erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), corticosteroid dependence, history of hospitalization, C. difficile infection, and cytomegalovirus infection. Patients with limited and mild endoscopic disease have a low risk of colectomy.10  In CD, patients are stratified according to risk for rapid progres-sion to bowel damage and disability.7

Goals of Therapy

     The primary goal of therapy in IBD is to achieve and maintain corticosteroid-free symptomatic remission.1,2 In patients with moderate to severe CD, achieving remission has been linked to fewer hospitalizations and surgeries, greater employment, and improved quality of life.11 With greater appreciation for the progressive nature of IBD and the availability of more effective therapy, clinicians are setting more ambitious goals for pharma-cotherapy of IBD that have the potential to change the course of the disease.11 Potential goals include mucosal healing, prevention of complications, surgery, and dis-ability, maintenance of normal gastrointestinal (GI) function, and restoration of normal quality of life.1,2,12 Instead of defining remission as symptomatic improve-ment alone, some experts propose the goal should be deep remission, which is defined as sustained clinical remission with complete mucosal healing and normal-ization of serological inflammatory markers (eg, CRP, ESR).13,14 The International Organization for the Study of Inflammatory Bowel Diseases recently proposed goals for treat-to-target strategies in IBD.8 For UC, the goal is resolution of rectal bleeding and normalization of bowel habits, and a Mayo endoscopic subscore of 0 (optimal) or 1 (minimal). For CD, the goal is resolution of abdominal pain and normalization of bowel habits with absence of ulcers during endoscopic evaluation.8

Evolving Treatment Strategies

     Accumulating evidence suggests that early combined immunosuppression (ECI) is more effective than step-care in preventing complications in patients with moderate to severe CD.15-17 Therefore, similar to the evolution of treatment for rheumatologic diseases, the treatment of IBD is undergoing a transition from step-care to a treat-to-target approach.8 Most recently, the REACT (Randomised Evaluation of an Algorithm for Crohn’s Treatment) trial compared standard step-care and algorithm-based care with ECI.17 This real-world study was conducted in com-munity GI practices and included patients with any disease severity or duration. Remission rates at 1 year, the primary outcome of the study, were similar with step-care and ECI (61.9% vs 66.0%, respectively; P = .52). However, at 2 years, ECI was associated with a lower rate of surgery (HR, 0.69;95% CI, 0.50-0.97) and serious complications (HR, 0.73; 95% CI, 0.61-0.87). The composite of hospitalization, surgery, and serious complications was significantly reduced with ECI (27.7% vs 35.1%; P = .0003) with a number needed to treat (NNT) of 14. The incidence of serious drug-related adverse effects (AEs) was 1% in both groups.17

     The focus of this article is pharmacotherapy for the management of moderate to severe UC and CD. Four primary classes of drugs are used to induce and maintain remission for this level of disease severity: corticosteroids, thiopurines, tumor necrosis factor (TNF) antagonists, and vedolizumab. Clinical practice guidelines from the ACG, AGA, and CAG provide evidence-based recom-mendations that help define the role of each agent, and when they should be used together.1,2,5,18 In special cir-cumstances, methotrexate, cyclosporine, and tacrolimus may be used as alternatives, but these immunosuppres-sants are beyond the scope of this article.

Corticosteroids

     Oral corticosteroids (eg, prednisone) are commonly used to induce remission in IBD.1,2 “Gut-specific” oral formulations deliver budesonide to the bowel, reducing systemic corticosteroid exposure. Budesonide (Uceris) delivers the drug to the colon and is FDA-approved for inducing remission in mild to moderate active UC.19 Budesonide (Entocort EC) delivers the drug to the ileum and ascending colon and is FDA-approved for mild to moderate active CD.20 These formulations are not inter-changeable.19,20 Their role in moderate to severe disease is not well-defined, and their high cost puts them out of reach for most patients.

Efficacy

     Oral corticosteroids are superior to placebo for induc-ing remission in UC (relative risk [RR] of no remission: 0.65; 95% CI, 0.45-0.93), with an NNT of 3 to achieve 1 remission.21 The efficacy of prednisone for inducing remission in CD was established in the National Cooperative Crohn's Disease study and the European Cooperative Crohn's Disease study.22,23 At doses of 0.5 to 0.75 mg/kg/day and 1 mg/kg/day, the NNT to achieve 1 remission was 3 and 2, respectively.24 Standard corticosteroids, like prednisone, are more effective than budesonide for inducing remission in CD (RR, 0.82; 95% CI, 0.68-0.98), but have a higher incidence of corticoste-roid-related AEs (RR, 1.64; 95% CI, 1.34-2.00).21 Although corticosteroids induce symptomatic remission in IBD, response rates for mucosal healing appear low.25-27

AEs

     With long-term use, corticosteroid toxicity includes osteoporosis, cataracts, adrenal suppression, impaired wound healing, immunosuppression, weight gain, and hyperglycemia.28,29 In a registry study, corticosteroids were associated with an increased risk of serious infection (HR, 1.57; 95% CI, 1.17-2.10; P = .002) and mortality (HR, 2.14; 95% CI, 1.55-2.95; P <.001) in CD.30 Strong cytochrome P450 3A4 inhibitors (eg, clarithromycin and voricon-azole) can substantially increase budesonide exposure, increasing the risk of iatrogenic Cushing syndrome.31 The World Congress of Gastroenterology encourages greater use of biologic agents to limit corticosteroid exposure.32

Role in Therapy

     The CAG recommends oral corticosteroids as first-line therapy for inducing remission in moderate to severe UC.5 The AGA also considers a short course of corticosteroids with early initiation of a thiopurine as an option for inducing remission in patients at high risk for colectomy.6

     For induction of remission in CD, the ACG recom-mends prednisone 40 to 60 mg/day until symptoms resolve and the patient begins to gain weight.1 For inducing remission in patients at moderate to high risk of disease progression, the AGA recommends a TNF inhibitor rather than a corticosteroid.7

     Because corticosteroids are ineffective and have a sub-stantial burden of toxicity with chronic use, they have no role in maintaining remission in UC or CD.1,5,7,24,33 In fact, the CAG considers maintenance of corticosteroid-free remission an important goal of therapy in UC.5

Special Issue: Corticosteroid-refractory and -dependent Disease

     Up to 40% of patients with IBD become corticosteroid-dependent.24 In CD, patients who require corticosteroids to remain well are considered corticosteroid-dependent and are not considered to be in remission.1 Patients with UC who do not respond to 14 days of oral prednisone 40 to 60 mg/day are considered corticosteroid-refractory, while those who are unable to taper corticosteroids after 3 months without disease flaring are considered cortico-steroid-dependent.5 In UC, corticosteroid dependence increases the risk of relapse and colectomy.5 The CAG and AGA recommend a TNF inhibitor, which has dem-onstrated corticosteroid-sparing activity. Vedolizumab, which reduces the risk of colectomy, is also recommended for patients with UC who are corticosteroid-dependent or -refractory.5,6,34

Thiopurines

     Thiopurines are first-line immunosuppressants in IBD, but a 2- to 6-month delay in onset of action limits their role.6,7,35 Although azathioprine and mercaptopu-rine are considered equivalent options for managing IBD, most studies have been conducted with azathioprine.36,37

Efficacy

 
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