How should we treat mild and moderate-severe Crohn’s disease in 2017? A brief overview of available therapies

KEYWORDS:

• Crohn’s disease
• inflammatory bowel disease
• therapeutics
• treatment
• biologics

1. Introduction

Crohn’s disease (CD), one of two major subtypes of inflammatory bowel disease (IBD), is defined by chronic transmural inflammation that may affect any part of the gastrointestinal tract. The etiology of IBD is poorly understood, but genetic, environmental, dietary, and immunologic components all likely impact predisposition to development of Crohn’s disease. Differences in clinical courses may be related to disease location, extent, and severity of disease activity. Some patients exhibit mild disease with few complications while others experience disease progression characterized by strictures, abscesses, and fistulae requiring immune-modulating therapy and/or surgery. In 2017, there are many new and established medical therapies available for the treatment of active CD. Although many patients with Crohn’s respond to medical therapy, at the present time, we are not able to predict a priori to which medications an individual will respond. While general guidelines and recommendations exist regarding management of mild and moderate-severe CD, it is important to personalize the care of each patient taking into account the location and the characterization of the inflammatory response [1]. We offer options regarding disease management and medications, but emphasize that there is no single algorithm to follow in the medical management of Crohn’s disease.

2. Management of mild Crohn’s disease

2.1. Available therapies

The most commonly prescribed therapies for adults with mild CD include 5-ASA-based medications, sulfasalazine, and oral budesonide; in children and adolescents, exclusive enteral nutrition is recommended as initial therapy [2]. While 5-ASA-based medications or sulfasalazine are often first-line therapy for Crohn’s involving the ileum and/or colon, the data proving efficacy of these medications are not convincing and both American and European gastroenterology societies recommended against their use for induction or maintenance of remission [1,3]. A meta-analysis recently published showed no significant difference in efficacy of low or high dose mesalamine as compared to placebo [4]. In those with isolated colitis, sulfasalazine showed benefit over placebo [4]. Those with limited ileal or colonic disease may respond to mesalamine released in the ileum. Budesonide is a rapidly metabolized steroid that selectively acts in the intestine and has minimal systemic absorption [5]. It is released in the terminal ileum and is effective for distal small bowel and colonic disease. Although budesonide may be useful for patients with mild Crohn’s flares, it is not recommended for maintenance therapy [6]. Patients who are dependent on budesonide for control of symptoms and endoscopic remission should step up therapy to include immunosuppressive medications, as discussed in the following.

2.2. Considerations in choosing therapy

Disease extent and location should be considered when deciding which 5-ASA-based compound to prescribe as the different mesalamine-containing medications have varying locations of release. Another consideration is the role of medical therapy as treatment of active inflammation or maintenance of remission. There is little evidence that treatment with 5-ASA medications affects disease course or that these medications are effective in maintaining clinical remission [5]. However, they are commonly used for treatment given their favorable safety profile, and therefore may be considered first-line agents for patients who have minimal disease activity in the colon.

Recently, there is increased interest in the role of diet and Crohn’s disease. It has been previously shown that patients with IBD have distinct microbiome composition [7] and that altering their diet can result in change in the intestinal microbiome [8]. However, while trials of dietary interventions may provide symptom relief and may be beneficial, dietary intervention in the adult population is not widely utilized. We recommend that patients meet with a nutritionist to identify foods that may exacerbate their symptoms, understanding that there is limited evidence that dietary therapy is effective in adults for maintaining or achieving remission.

3. Management of moderate to severe Crohn’s disease

3.1. Available therapies

If a patient cannot attain remission, has recurrence of symptoms with discontinuation of budesonide, or develops stricturing or fistulizing disease, then a change in therapy is warranted. Thiopurines, methotrexate, and biologics, including both anti-TNF and anti-integrin medications, are immunosuppressive medications that can be prescribed to achieve and/or maintain remission. Antibiotics can also be administered to treat active inflammation, although they are not usually prescribed as long-term therapy. Ustekinumab was recently approved in the United States, and biosimilars will likely be available within the next few years. A number of additional therapies with varying mechanisms, including anti-integrin, Janus kinase inhibitors, interleukin inhibitors, and SMAD7 antisense oligonucleotide, have recently been approved or are currently being studied [9]. Choosing therapy can be a difficult decision and multiple factors might be considered, such as starting with combination or monotherapy and which biologics to initiate first. Accurate assessment of disease activity with endoscopy, serum markers, and/or fecal calprotectin is important prior to initiating new therapy. While not widely used, blood-based biomarkers may also be helpful in assessing disease activity [10].

3.2. Step up or top down/combo versus monotherapy?

Various opinions exist regarding whether to step up therapy or start with combination therapy. In 2010, the SONIC trial showed superiority of combination therapy in achieving steroid-free clinical remission and mucosal healing as compared to monotherapy with azathioprine or infliximab [11]. Sequential combination therapy was not shown to be superior to monotherapy in a meta-analysis of six trials [12]. Another meta-analysis showed that combination therapy after failing a thiopurine was not beneficial over monotherapy with an anti-TNF agent, though fewer infusion reactions with infliximab were noted among those on combination therapy [13]. No difference in time to surgery was seen among patients treated with monotherapy or sequentially added combination therapy [14]. The decision to start monotherapy or combination therapy should be personalized, taking into account potential adverse effects of combination therapy such as risks of infection and/or malignancy. Additional factors that may favor combination therapy include perianal disease, surgical history, more extensive disease, and patient demographics [15]. Patients with a history of antibody formation on prior biologics may benefit from combination therapy to prevent future antibody formation. If combination therapy is initiated, one should frequently review the need for each medication, and discontinue one of the medications if possible. In practice, thiopurines are often stopped first, but the decision to initially discontinue the biologic may be made on a case-by-case basis. As shown in the STORI trial, 50% of patients on combination therapy may relapse when anti-TNF medication is stopped [16].

Determining which biologic to start is guided by patient characteristics or external factors. For example, insurance may dictate a trial of one biologic before another; a patient’s lifestyle may be more conducive to self-injections rather than frequent visits for infusions; past medical history, such as a history of malignancy, may favor anti-integrin over anti-TNF; or disease characteristics may affect decision-making. Currently, the cost of vedolizumab is significantly greater than that of infliximab or adalimumab, and thus is less frequently prescribed as a first-line agent. In addition, vedolizumab is not as effective for fistulizing Crohn’s disease as anti-TNF therapy and may take longer to be effective. Currently, predicting a priori which patients will respond to specific therapies is not possible, although there are ongoing efforts to phenotype patients in order to personalize therapy algorithms. Patients who are non-responders to an anti-TNF may switch to another anti-TNF or vedolizumab. Patients who develop antibodies may benefit from the addition of a thiopurine plus a different biologic if they were previously on monotherapy with a biologic.

Additional questions that arise in treatment of moderate-severe CD include duration of therapy, step down of therapy, and disease monitoring. While the decision to decrease combination therapy to monotherapy may be more straightforward, there are not sufficient data to advise when to stop monotherapy. If a patient is in deep remission, it may be reasonable to stop therapy and monitor. Our center is also currently exploring de-escalation of biologic dosing based on drug levels. The decision to discontinue therapy should be based on (i) risks and benefits of continuing the medication versus flaring; (ii) a patient’s concerns about lifelong therapy; and (iii) a patient’s co-morbid conditions and Crohn’s history. If a patient and provider elect to stop therapy, and the patient flares, returning to the previously discontinued medication may be an option, if it had been effective and no antibodies were present. There is always the concern with biologic agents that an interruption in treatment may increase the likelihood of an adverse event when the medication is restarted.

For patients who do not respond to medical therapy, surgery is an option. Surgical resection of a diseased segment of bowel may enable medical therapy post-operatively to be more effective. In addition, complicated CD, such as perforation or obstruction, may require surgical intervention.

3.3. What is the role of steroids in moderate-severe CD?

Steroids should be used as a bridge and not maintenance of therapy. The oral prednisone dose for treatment of a flare should not exceed 40 mg daily. Tapers should be over the course of a number of weeks, and often include decrease of dose by 5 or 10 mg weekly.

3.4. Additional considerations

Regardless of therapy, monitoring disease is important. Modalities for disease monitoring include radiographic (magnetic resonance enterography), fecal calprotectin, and endoscopic evaluation. Serum inflammatory markers, such as C-reactive protein and erythrocyte sedimentation rate, may also be helpful in determining disease activity. Presence of perianal disease must be considered, as perianal disease is a predictor of poor outcomes, and treatment to achieve fistula closure should be pursued [17].

There is significant overlap among patients with IBD who also have irritable bowel syndrome (IBS). Distinguishing between symptoms caused by inflammation and IBS may be challenging, but impacts therapeutic decisions. A trial of a low FODMAP diet or nutrition consultation may be beneficial if the patient continues to be symptomatic without evidence of active disease.

4. Future directions

At the present time, reliable predictors of response to treatment are not available. Investigation to further characterize and phenotype patients may enable us to use data from microbiome analysis, genetic studies, biomarkers, and patient characteristics to determine who will respond to one medication versus another and allow for personalized therapy and better response rates. In addition, the current model is to treat to target. Will endoscopic remission continue to be the goal to which we treat? If so, will there be non-invasive modalities to assess intestinal inflammation without biopsy? These are the critical questions that will guide future decisions.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.