Review article: treatment algorithms to maximize remission and minimize corticosteroid dependence in patients with inflammatory bowel disease

Authors


Dr R. Panaccione, Department of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, Canada T2N 4N1.
E-mail: rpanacci@ucalgary.ca

Summary

Background  Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the intestine, which frequently require surgery for complications or failure of medical therapy.

Aim  To seek evidence and provide direction for clinicians on optimal strategies to enable steroid free remission in inflammatory bowel disease.

Methods  Scientific literature was reviewed using MEDLINE with a specific focus on medical therapies for inducing and maintaining remission of CD and UC. The results were discussed at a roundtable meeting to reach a consensus on key issues.

Results  Several therapies have demonstrated efficacy for the treatment of active, moderate-to-severe CD and UC. These include agents, which induce remission [corticosteroids, infliximab and adalimumab (CD only)] or maintain remission and spare corticosteroids [azathioprine, mercaptopurine, methotrexate (CD only), infliximab and adalimumab (CD only)]. Wide variability exists in the use of these agents.

Conclusion  Treatment strategy algorithms are developed for use of these therapies that maximize remission and minimize corticosteroid dependence in patients with moderate-to-severe CD and UC.

Introduction

Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic relapsing and remitting disorders of the gastrointestinal (GI) tract. During relapses or flares of disease, pharmacological or surgical intervention is often needed to re-establish remission. Ideally, strategies would be employed to maintain patients in long-term remission, while minimizing steroid dependence and therapy-related toxicity.

Many patients with UC or CD may not receive effective therapy and their disease remains moderately active, leading to uncontrolled inflammation and potentially the development of complications because of either the underlying disease or steroid dependency. Although indications and goals of treatment exist, optimal treatment outcomes are not often well defined and the duration of treatment is not addressed. The authors define treatment success in the treatment of CD or UC as a return to the patient’s normal bowel function for that individual prior to disease flare. As a consequence, patients undergo repeated cycles of corticosteroids (with or without immunosuppressive agents) without success as their disease remains active and progresses towards complications and the need for surgery. In fact, approximately 25% of patients with UC will require colectomy for uncontrolled disease.1 Setting specific time limits (i.e. time bound strategies) for evaluation of the success of therapy may lead to improved patient outcomes and reduced side effects. We propose treatment algorithms for the treatment of moderate-to-severe CD and UC with corticosteroids, immunosuppressive agents and biological agents, with the goal of maximizing remission and minimizing corticosteroid dependency.

Current treatment options

The two main focusses of inflammatory bowel disease (IBD) management are the induction and maintenance of remission. Treatment decisions are based on disease severity (mild, moderate or severe) and location within the GI tract.2–5 Standardized instruments are available to determine disease severity in clinical trials for both UC [e.g. the Truelove and Witts’ criteria6 and the MAYO score7, 8) and CD (e.g. the CD Activity Index (CDAI)];9, 10 however, symptom criteria such as vomiting, symptoms of bowel obstruction, bowel movements, presence of blood, weight loss, high fever and rebound tenderness are useful practical diagnostic criteria of severity in everyday clinical practice.2, 3 The use of endoscopy to assess mucosal disease and healing is an essential diagnostic procedure for assessing disease severity and determining drug efficacy in UC and its routine use in CD is evolving. However, the field has not evolved to a point where it is recommended that patients with CD have routine imaging or endoscopy to assess the success of therapy in treating either small- or large-intestinal disease.

The authors present the standard approach to therapy as they recognize it from referrals to their centres and their interactions with clinical gastroenterologists around the world at advisory boards, roundtables, case discussions and other educational events. The authors recognize that different strategies may be employed at different centres and have developed these recommendations on the basis of all the available clinical evidence. When level 1evidence was not available from randomized controlled trials (RCTs), the authors relied on their collective experience to develop recommendations.

Corticosteroids have been used in the treatment of active IBD for more than half a century and it is well established that these drugs are effective in inducing remission in both UC and CD.6, 11, 12 However, corticosteroids are not suitable for maintenance therapy because of lack of efficacy11–14 and because their long-term use is associated with sometimes severe and irreversible side effects.15–17 In addition, some patients become corticosteroid dependent and18, 19 others may become refractory to corticosteroids.

The thiopurine immunosuppressive agents such as azathioprine (AZA) and mercaptopurine (MP) are effective for the maintenance of steroid-induced remission in CD.20, 21 Their use in UC is not as well established by published randomized clinical trials.22–27 Generally, the purine anti-metabolites are reserved for use in patients who are steroid resistant or demonstrate steroid dependency,28, 29 with the full therapeutic effect reached approximately 12–16 weeks after initiation.30 Methotrexate has been demonstrated in two well-designed placebo controlled trials to be effective in inducing and maintaining remission in CD.31, 32 Its use in patients with UC has not been established.33

In severe UC, IV ciclosporin at a dose of 4 mg/kg has been established as an option for salvage therapy for those who want to avoid surgery.34 The incidence of side effects is substantial and includes a mortality rate of approximately 3%.35 Newer data suggest that 2 mg/kg is an effective dose, but requires patients to be bridged to AZA or MP over a period of 3–4 months to ensure long-term success. However, even with this strategy, the colectomy rate over time is high.35–37

Surgical intervention is common in both UC19 and CD18, 19 and can be associated with both emotional and physical complications. A recent meta-analysis found that colectomy with ileal pouch anal anastomosis increased the risk of infertility by approximately threefold in women with UC compared with those treated medically.38 Episodes of pouchitis can occur in 45%39 of patients and seepage/incontinence occurs in over 30% of patients.40 With regard to CD, more often, 50% of patients who require an initial surgery undergo additional surgeries.41

Current conventional treatment approach in IBD

Step-up therapy in CD

The traditional treatment paradigm in CD is based on a step-up approach in which therapies with the least toxicity are utilized early and subsequent therapies are added because of lack of response or toxicity. Unfortunately, under this treatment paradigm, agents with low efficacy are used for prolonged periods of time, while uncontrolled inflammation continues, resulting in tissue damage. It is evident that individual clinicians will leave patients on therapy for a varied duration of time before deciding to switch or escalate therapy possibly because of their reluctance to step up to a therapy that is perceived as more ‘toxic’. A clearly defined treatment algorithm, for the treatment of patients with IBD that incorporates the duration of time to continue a patient on a therapy to which they are not responding before moving to another agent, may standardize treatment.

The conventional pyramid treatment strategy for the induction of remission in CD is shown in Figure 1. Current guidelines from the American College of Gastroenterology recommend a ‘step-up’ approach, with patients initially receiving oral aminosalicylates (mesalazine or sulphasalazine) or antibiotics (e.g. ciprofloxacin or metronidazole).2 If there is no response or if symptoms worsen, patients are advanced to receive oral corticosteroids (prednisolone or budesonide). Immunosuppressive agents [azathioprine (AZA), mercaptopurine (MP), methotrexate (MTX)] are then added as adjunctive therapy in steroid-resistant patients and to allow steroid tapering in steroid-dependent patients.2 AZA and MP are used to maintain remission after corticosteroid induction therapy.2 Infliximab and adalimumab tend to be used in refractory CD (including fistulizing disease)42–49 as an alternative to corticosteroids in steroid-resistant patients46, 49 or in patients not responding to immunosuppressive agents.2 In the European Union (EU), infliximab is indicated for induction and maintenance therapy for severe active CD or as a second line therapy after failing steroids. It is anticipated that adalimumab will be used in a similar manner as infliximab in the moderate-to-severe patient with nonfistulizing luminal CD.47–49

Figure 1.

 Conventional treatment approach for Crohn’s disease.59, 60

Step-up therapy in UC

A similar step-up approach is currently recommended in the treatment of UC by the American College of Gastroenterology3 As opposed to CD, an abundance of evidence exists that supports the use of aminosalicylates in mild-to-moderate UC for both induction and maintenance of remission, which establishes these drugs more firmly as a therapy in UC, compared to CD.50–52 Mesalazine (mesalamine) has been shown to be no more effective than placebo in patients treated for CD.53 However, in UC, the addition of topical mesalazine is a useful adjunct in both limited and more extensive disease.54 Corticosteroids are added in patients not responding to aminosalicylates or in patients with moderate-to-severe disease.55 AZA and MP tend to be used in steroid refractory patients or as steroid-sparing agents in steroid-dependent patients, despite randomized, controlled, double-blind trials that demonstrate inconsistent results.22, 24–26 There are several situations in which surgery is recommended including those with bona fide medically refractory disease, those with fulminant colitis, or those suffering from life-threatening complications such as bleeding, perforation or toxic megacolon.

Shortcomings of step-up therapy

Substantial evidence exists suggesting that the conventional step-up approach to the treatment of UC and CD may not represent optimum therapy. Although mild UC and CD can be treated effectively with aminosalicylates, a significant proportion of patients (43% in CD and 34% in UC) will require corticosteroids to control symptoms.19 Sulfasalazine has been shown to treat CD modestly when the disease is confined to the colon. Additionally, budesonide has shown a similar efficacy to conventional steroids with reduced adverse events.56 In patients requiring steroid therapy, the immediate outcomes are favourable, but the long-term outcomes at 1 year are disappointing. This leaves over half of patients with both CD and UC requiring additional therapy at the end of 1 year. In a study evaluating patients with CD diagnosed between 1979 and 1987 and receiving a first treatment course of steroids, 44% of patients exhibited a prolonged steroid response and 36% of patients developed steroid dependence.18 Specifically, of patients who improved, but did not reach complete remission with steroid treatment, 43% relapsed or could not be withdrawn without recurrence within 1 year of steroid treatment.18 A population-based study has shown that a year after the initial course of corticosteroid treatment, a prolonged steroid response is seen in only 32% and 49% of patients with CD and UC, respectively.19 Furthermore, steroid dependence develops in 28% of CD patients and 22% of UC patients, with surgery being required in 38% and 29% of patients, respectively.19 In paediatric patients, the results are somewhat better but still suboptimal. A similar population-based study in paediatric patients with UC or CD reported that a prolonged steroid response was observed in 58% of paediatric patients with CD and in 43% of paediatric patients with UC at 1 year. For steroid dependence, development rates from this study were 31% and 14% for CD and UC, respectively.57

Corticosteroid therapy may control symptoms in the short term in CD, but it does not reliably result in prevention of relapse or mucosal healing. Mucosal healing is a key indicator of control of inflammation and a signal that the bowel is normalizing. This limitation was best demonstrated by the GETAID (Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives) trial.58 This study examined the effect of glucocorticoids on mucosal healing of the colon and demonstrated that the correlation between clinical disease activity and disease severity (endoscopic lesions) is poor. In this study, over 90% of patients had a clinical response, yet endoscopic improvement was seen in only 29% of patients.58 This indicates that an outcome of symptom improvement alone may not be sufficient to change the course of the disease.

Immunosuppressive agents are prescribed in steroid-resistant and steroid-dependent patients; however, they have a relatively slow onset of action and tend to be not used early enough in the treatment of UC and CD. Over the past 25 years, immunosuppressive therapy has been gradually initiated earlier and earlier in the treatment of CD.59 Despite this, a decrease in the rate of intestinal resection and complications over this same period has not been observed.59 This does not undermine the ability of these drugs to induce and maintain remission, but further questions whether immunosuppressive therapy is still not being initiated early enough in patients with moderate-to-severe disease.

Current opinion on management

Emerging trend: top-down therapy

Recently, a new approach has been explored in the treatment of CD based on the premise that currently available biological therapy can heal mucosa and perhaps alter the natural history of disease. Therefore, the question arises as to whether patients with moderate CD should be treated earlier with immunosuppressants or biological therapy such as infliximab for induction therapy and immunosuppressants introduced. The goal of this highly effective approach is to induce a rapid remission in a steroid-free environment and also promote mucosal healing. This approach could also modify the natural history of the disease by leading to sustained remission with fewer complications and a reduced need for surgical interventions.

The first attempt at looking at a ‘top-down’ approach was a study conducted in children using immunomodulators such as the purine analogues, AZA and MP. In a study involving paediatric patients with newly diagnosed (with in 8 weeks) CD in whom the disease activity was severe enough to require systemic glucocorticoids, 50 mg daily of MP was introduced.60 The introduction of the immunomodulators resulted in less need for glucocorticoids over the subsequent 18 months as well as improved maintenance of clinical remission. In that particular study, glucocorticoids were not avoided because patients were in the midst of an acute flare, requiring rapid onset of therapeutic action and improvement in symptoms. For reasons of the relatively slow onset of action of the purine analogue, and the need to bring the disease under control quickly, glucocorticoids were required.

Preliminary data from a recent study explored this top-down approach and compared it with the standard step-up approach (Figure 1).61, 62 The open-label ‘Step-Up/Top-Down’ (SUTD) study compared the efficacy of standard step-up treatment (i.e. a progression from aminosalicylates, to steroids, to immunosuppressants, then infliximab with a more aggressive ‘top-down’ approach, which initiated treatment with infliximab plus immunosuppressive agents for inducing and maintaining remission.62 Patients with newly diagnosed (<4 years), active (CDAI >200) CD, not previously treated with steroids or immunosuppressive agents were randomized to receive either step-up (budesonide 9 mg/day or prednisone 40 mg/day) or top-down (three infliximab infusions plus AZA 2–2.5 mg/day) treatment.62 Patients who relapsed in the top-down group received infliximab upon flare and they received methylprednisolone, if no response was obtained. Patients who did not respond or flared in the step-up group were recycled through methylprednisolone, then started on immunosuppressants, and finally started on infliximab, if steroids and immunosuppressants failed.

At both 6 and 12 months, significantly more patients in the top-down group were in remission (75% and 77%, respectively) than in the step-up group (48% and 64%, respectively). Furthermore, no patients receiving top-down therapy were taking corticosteroids, compared with 33% of patients receiving step-up therapy.62 In an endoscopic substudy, the effect of step-up and top-down therapies on mucosal healing demonstrated that mean ulcer scores were decreased by 90% with top-down therapy compared with 35% with step-up therapy after 2 years of treatment.63 The interpretation of these data is interesting. Although symptom response was similar between the two groups at 24 months, there was a marked difference in the rates of mucosal healing. Early initiation of infliximab therapy was associated with higher rates of mucosal healing, possibly leading to an improvement in long-term outcomes.

There are several methodological issues related to the trial that may require the results to be reproduced independently or with another biological agent. The first major criticism is that the study did not represent a true RCT. Although patients were randomly assigned to one of the two treatment strategies, neither the patients nor their treating physicians were blinded to the treatment group assignment. This would allow for potential bias. Additionally, many clinicians may introduce an immunomodulator with the need for a second course of glucocorticoids instead of waiting for a third course. In addition, the use of episodic or on demand infliximab is not currently advocated. Lastly, if there was to be widespread use of the top-down approach, there is no suggested strategy for withdrawing patients from therapy as is the case in rheumatoid arthritis. Despite these reservations, this study provides the first real evidence that early, aggressive treatment of CD, through the use of biological therapy, will enhance treatment response, reduce the need for glucocorticoids and, perhaps, change the natural history of CD.

The concept of early use of biologics improving outcomes is also highlighted in the paediatric REACH study (a randomized, multicentre, open-label study to evaluate the safety and efficacy of anti-TNF-alpha chimeric monoclonal antibody in paediatric Subjects with moderate-to-severe CD). One hundred and twelve paediatric patients (6–17 years of age) with uncontrolled moderate-to-severe CD, despite taking an immunosuppressant (e.g. AZA, MP or methotrexate) were evaluated.64 Patients received infliximab 5 mg/kg at the start of the study (week 0), followed by doses 2 and 6 weeks later. Patients showing symptom improvement or ‘response’ were randomized to one of two groups (infliximab every 8 weeks or every 12 weeks for approximately 1 year). Eighty-eight per cent of patients showed improvement in symptoms at 10 weeks. At the end of 1 year (week 54), 60% of patients receiving infliximab every 8 weeks showed symptom improvement and 56% were determined to be in remission compared to only 24% in the 12-week group. In addition, 75% of patients who received infliximab every 8 weeks were steroid-free at 54 weeks.64 Although this trial lacks a placebo comparison arm, the results are thought provoking and suggest that the introduction of biological therapy early in the disease process may be a preferred strategy given the higher rates of response and remission in this younger cohort, which arguably has ‘earlier’ disease. Additionally, data from studies in adult CD treated with certolizumab or adalimumab provide support to the early use of biologics. Subanalysis of the certolizumab PRECISE 2 study and adalimumab CHARM study demonstrated at week 26, high rates of remission achieved with these agents, especially in those with disease duration of <2 years.65, 66

There is also positive evidence of the early use of nonbiologic therapy in children with CD.60 Although further investigation is needed to determine the role of either of the biologics, MP or AZA at disease onset, early aggressive therapy seems to be associated with better outcomes.60, 64

Shortcomings of top-down therapy

Despite the highly effective approach of treating patients with moderate CD with biological therapy, there are some important considerations when interpreting the existing data for top-down therapy. On the basis of evidence from Markowitz et al.60 in paediatric patients, one must consider that the regimen used in the Step-Up/Top–Down trial, which combined both infliximab and AZA, might be even more aggressive than would routinely be used. Additionally, infliximab is typically given as routine, scheduled therapy. In the SUTD study, only three infusions of infliximab were given to patients in the top-down group and infliximab was given to patients in the step-up group, if they failed immunosuppressants.61, 62 In addition, concerns have been raised about exposing a percentage of patients to therapy they may never require along with the long-term safety concerns, if this strategy is employed broadly. However, the open-label experience with anti-TNF agents in over 2 million patients encompassing 3.5 million years of patient follow-up suggests that the safety profile is well established.67

New treatment paradigms for UC and CD

The top-down strategy assumes that all patients with IBD have a similar disease-course and therefore all patients are treated similarly. Most clinicians are reluctant to adopt this type of strategy that includes early use of anti-TNF agents without more evidence or only in particular patients, who have refractory or complicated disease early or have a high burden of disease. Therefore, it may be timely to look at other ways the treatment paradigm can be altered to improve treatment outcomes and minimize disease- and therapy-related side effects. Perhaps, the key is to recognize in a structured time frame when particular therapies are effective or ineffective and when to advance therapy. This concept has led the authors to suggest a treatment algorithm, on the basis of best available evidence and expert opinion, in which specific time limits for evaluation of the success of therapy are set. The recommendations highlight the need to evaluate patients regularly and at structured time intervals to determine whether a particular therapy has been effective and should be continued or whether a therapy should be abandoned and new therapies implemented or added to meet the defined treatment goals in IBD (Table 1). To date, studies that identify patients, who may continue to benefit from an initial top-down strategy and are later withdrawn from therapy, are lacking.

Table 1.   Therapeutic goals for ulcerative colitis and Crohn’s disease
Induce rapid response
Maintain remission without steroids
Achieve and maintain complete mucosal healing
Avoid complications, hospitalizations and surgery
Prevent disease-related mortality
Improve patient quality of life

Based on recent evidence from randomized controlled clinical trials and existing best practice guidelines, a treatment paradigm with structured time intervals is proposed for the induction of remission in UC and CD to help clarify the treatment decision-making process (Figures 2 and 3). These treatment paradigms focus on structured re-review of disease, allowing the physician to assess whether the patient has achieved the goals of therapy before making a choice to continue therapy or move to a new treatment. The time periods were selected based on several factors. For corticosteroid therapy, the time periods were based on definitions of steroid refractory (2–4 weeks) and steroid-dependent disease (unable to taper off steroids or repeat need for steroids within 3 months of discontinuation). With immunomodulators, the time for the purine anti-metabolites was based on the available time points from clinical trials as well as on expert opinion on how long the authors would wait before deeming that a patient had an adequate trial of purine anti-metabolite.

Figure 2.

 Treatment paradigm for remission induction in luminal Crohn’s disease. Reproduced with permission from Prof. Panaccione. ESBD, extensive small bowel disease; IFX, infliximab; ADA, adalimumab.

Figure 3.

 Treatment paradigm for remission induction in ulcerative colitis. Reproduced with permission from Prof. Panaccione. * For maintainance of ciclosporin-induced remission and for prevention of immunogenecity.

Crohn’s disease

Mild.  In mild luminal CD, oral aminosalicylates can be used in patients with left colon disease (evidence for efficacy is inconsistent) or budesonide in patients right colon/ileal disease to induce remission. Budesonide can also be used in patients with mild-to-moderate disease. If there is inadequate response [ongoing symptoms of abdominal pain, abdominal cramping or diarrhoea that continues to interfere with patient’s quality of life (QoL)] within 4–8 weeks, patients should be advanced to treatment for moderate luminal CD and receive prednisone. The rationale for this recommendation has been previously reviewed.56

Moderate.  The moderate disease algorithm for CD introduces highly effective therapy with corticosteroids for remission induction, sets a time frame for the corticosteroid use and encourages earlier use of immunosuppressive agents and infliximab or adalimumab in steroid-dependent or steroid-refractory patients. A treatment algorithm for the induction of remission in moderate CD with time intervals for decision making regarding the achievement of therapeutic goals is shown in Figure 4 and is intended for patients with moderately active disease and impaired QoL.61

Figure 4.

 Time-structured treatment algorithm for moderate Crohn’s disease. Reproduced with permission from Prof. Panaccione. * IFX is approved for severe, active CD in the US; † IFX is approved for moderate to severely active CD in the US; ‡ ADA is approved for moderate to severely active CD in the US; § ADA is approved for moderate to severe, active CD in the US.

Patients with moderate CD should initially be treated with prednisone (40 mg/day, up to 1 mg/kg) until symptoms resolve (usually within 1–4 weeks). Prednisone is then tapered (taper by 5 mg/week until down to 20 mg/day, then by 2.5–5 mg/week). If patients are not responding to high doses of prednisone (steroid refractory), these patients require an additional induction agent. In this situation, infliximab or adalimumab68–72 (see Table 2 for approved indications) should be added for induction. If a patient experiences a flare-up during taper or within 3 months of tapering off steroids (steroid dependent), a second round of steroids is acceptable; however, an immunosuppressant should be added for steroid sparing and maintenance of remission purposes (MP 1.0–1.5 mg/kg, AZA 1.5–2.5 mg/kg, MTX 25 mg weekly).

Table 2.   Approved indications for infliximab and adalimumab
DrugFirst date availableNumber of patients treatedIndications
InfliximabUS: August 1998>843 000 patients worldwideReducing signs and symptoms and inducing and maintaining clinical remission in adult and paediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy68
Reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn’s disease68
Reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in patients with moderate-to-severe active ulcerative colitis who have had an inadequate response to conventional therapy68
EU: August 1999 Treatment of severe, active Crohn’s disease, in patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies69
Treatment of fistulizing, active Crohn’s disease, in patients who have not responded despite a full and adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy)69
Treatment of moderate-to-severe active ulcerative colitis in patients who have had an inadequate response to conventional therapy including corticosteroids and MP or AZA, or who are intolerant to or have medical contraindications for such therapies69
AdalimumabUS: February 2007>180 000 patients worldwide70Reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderate-to-severe active Crohn’s disease who have had an inadequate response to conventional therapy71
Reducing signs and symptoms and reducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab71
EU: June 2007 Treatment of severe, active Crohn’s disease, in patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies72

Response to immunosuppressive therapy should be assessed after 12–16 weeks with AZA or 12 weeks with MTX.21, 31 The selection of a time frame for MTX was based on the original RCT in which patients who responded to MTX did so by week 8; thus, evaluation at week 12 that would ensure response or lack of response would be observed.31 The patient should be in remission and off steroids, at these time points. If the patient is not in remission or has failed to enter into remission at these time points, they should be re-evaluated and started on infliximab or adalimumab for induction and maintenance. A summary of therapy in moderate CD is provided in Table 3.

Table 3.   Moderate ulcerative colitis and Crohn’s disease treatment summary
  1. UC, ulcerative colitis; CD, Crohn’s disease.

  2. * Infliximab is indicated for moderate-to-severe active CD and UC in the US and severe, active CD and moderate-to-severe active UC in the EU.

  3. † Adalimumab is indicated for moderate-to-severe active CD in the US and severe, active CD in the EU.

In moderate UC and CD, it is recommended to
 Administer 1–2 courses of steroids [provided treatment does not exceed 12–16 weeks (at most 24 weeks) for patients who are responding] and immunosuppressive therapy
 Treat with infliximab* or adalimumab† (CD only) plus immunosuppressive therapy after one course of steroids for patients who are refractory to steroids
It is unacceptable, however, to initiate a third course of steroids

Severe.  Severe disease may be defined by the burden or extent of disease, pace of deterioration, lack of response to previous therapies or active disease despite use of immunosuppressants. These patients should receive rapid induction therapy with an anti-TNF agent (i.e. infliximab 5 mg/kg at 0, 2 and 6 weeks, or adalimumab 160 mg at 0 weeks and 80 mg at 2 weeks) followed by maintenance therapy.69, 72 Some patients with severe disease would already be receiving corticosteroids, but with a worsening condition they may require admission to the hospital for intravenous steroids. Patients who do not respond within 7–10 days of IV steroids should also receive an anti-TNF agent (i.e. infliximab or adalimumab). At least two doses of infliximab (5 mg/kg) at 0 and 2 weeks or loading doses of adalimumab 160 mg/80 mg) should be administered without any response before concluding that the patient has failed induction therapy with an anti-TNF agent.69, 72 It should be noted that approximately 30–40% of adalimumab patients will have a delayed response after week 4, up until week 12 and global labels reflect that if there is no response in the first 12 weeks, the therapy should be discontinued.48

Fistulizing CD.  Patients with simple perianal fistulizing CD should start a trial of antibiotics. This trial should be over 2–4 weeks (Figure 5). For patients who are classified as failures (continued drainage, recurrent abscess formation) infliximab with or without immunomodulators should be started and maintained. Those patients with complex fistulizing CD should be adequately evaluated73 and commence and maintain infliximab treatment immediately.2 Evaluation may include MRI, endoscopic ultrasound or examination under anaesthesia with the placement of setons. Adalimumab may be considered an alternative option; however, adalimumab is not currently approved for use in fistulizing CD. In the CHARM trial, the second largest cohort with perianal fistulizing disease to date (n = 117), patients received open-label induction therapy with adalimumab 80 mg at week 0 and 40 mg at week 2.49 At week 4, patients were randomized to receive treatment with placebo, adalimumab 40 mg every other week or adalimumab 40 mg weekly through week 56. At week 26 and 56, 30% and 33% of patients in both adalimumab groups achieved complete fistula closure vs. placebo (13% and 13%, respectively; = 0.043 and 0.016, respectively). Of those patients who had complete fistula closure at week 26, all continued to have complete fistula closure at week 56.49

Figure 5.

 Treatment paradigm for remission induction in fistulizing Crohn’s disease. Reproduced with permission from Prof. Panaccione. * Adalimumab may be considered an alternative option; however, adalimumab is not currently approved for use in fistulizing CD.

Sandborn et al.74 demonstrated in a randomized, double-blind, placebo-controlled multicentre clinical trial that oral tacrolimus is effective for fistula improvement in patients with perianal CD.74 However, this was not significant for fistula healing and nephrotoxic events were seen. Beyond the Sandborn study, there is little controlled evidence for the use of tacrolimus in the treatment of fistulizing disease. Similarly, there is a paucity of evidence for the efficacy of purine anti-metabolites or MTX in the treatment of fistulizing disease with the only evidence being in small open-label cohorts.

Ulcerative colitis

Mild.  Patients with mild UC should begin treatment with topical/oral aminosalicylates. Some may benefit from a combination of topical and oral 5-ASA. If patients fail to respond (experience a decrease in stool frequency, abdominal cramping, urgency and passage of blood) within 4 weeks, they should be advanced to treatment of moderate disease and should receive prednisone.

Moderate.  A treatment algorithm with structured follow-up to assess achievement of the therapeutic goal of remission induction in moderate UC is shown in Figure 6. Prednisone (40 mg/day up to 1 mg/kg) until symptoms resolve (usually within 1–4 weeks) should be considered as initial therapy for the treatment of patients with moderate UC. The use of prednisone in this regard, should follow a standardized tapering regimen with the preferred method being a decrease of 5 mg/week until a dose of 20 mg/day is achieved, after which tapering should be adjusted by 2.5–5 mg/week. However, corticosteroids should not be used for an extended duration. Patients who are steroid refractory may be identified within 2–4 weeks. Having been identified, they should be administered IV infusions of infliximab at 0, 2 and 6 weeks, followed by maintenance therapy.76 Although a common practice, there is no evidence that admitting patients for administration of intravenous corticosteroids is associated with improvement in outcomes in the steroid refractory patient.

Figure 6.

 Time-structured treatment algorithm for moderate ulcerative colitis. Reproduced with permission from Prof. Panaccione.

Aminosalicylate therapy should be continued in UC patients who have responded to prednisone for maintenance of remission. To date, no trials have demonstrated an ability to maintain steroid-induced remission with the use of mesalazine; however, as opposed to CD, this approach is successful in the opinion of the authors. Although to date, the only RCT evaluating the efficacy of MTX in UC was proved negative,33 there is an emerging body of evidence from observational studies suggesting that MTX may have some efficacy. At present, an RCT evaluating the efficacy of higher doses of MTX in UC is underway. The results of this trial may provide new evidence for a role of MTX in the treatment of UC. In patients who are on an immunosuppressive or anti-TNF therapy, they may be continued for the purposes of chemoprevention. No data exist indicating that patients on these agents have added benefit for chemoprevention. If a patient experiences a flare-up during taper, a second course of steroids should be administered. Currently, however, many patients receive three or four rounds of corticosteroids, often for periods up to or greater than a year; this is not recommended because there is no evidence that such a strategy is ultimately effective and it results in an additional 3–6 months of corticosteroid treatment for patients who are refractory or dependant. Patients who become severely active or steroid nonresponsive during the corticosteroid treatment period should receive infliximab infusions (at 0, 2 and 6 weeks) followed by infliximab maintenance therapy. Treatment should be assessed after 2–4 weeks and if there is no response, patients should be advanced to treatment for severe disease.3, 4, 75 This suggested time frame for assessment is based on a definition of steroid-refractory disease.

It is recommended that concomitant immunosuppressive therapy be administered to patients who are taking steroids for prolonged periods of time and repetitively in short intervals. The most common immunosuppressive agent used in this regard is AZA 2.5 mg/kg/day.3, 76 It is also recommended that patients be evaluated for a response after having received AZA for 12 weeks.3 Steroid taper and maintenance therapy with either AZA or aminosalicylates should be started in those patients who respond to treatment and have achieved remission. Patients who fail to respond to treatment with AZA after 12 weeks of therapy should be started on infliximab at 0, 2 and 6 weeks and maintenance therapy thereafter. The authors suggest that physicians assess if an infliximab response is adequate following two doses of therapy. An overview of the recommendations for patients with moderate UC is provided in Table 3.3, 75

Severe.  Patients presenting with severe UC should be admitted for a 3- to 7-day course of IV prednisolone. Patients failing a 3–7 day course of IV corticosteroids should be started on infliximab.77 Ciclosporin is an alternative therapeutic option following IV corticosteroid failure in severe UC.34 It is strongly recommended that the decision to use either infliximab or ciclosporin occurs within the first 7 days of therapy. Use of these agents outside of this window may be associated with undesirable outcomes. There are, however, no data to support the use of sequential therapy (i.e. trying ciclosporin then infliximab, or vice versa). If infliximab or ciclosporin fails to induce remission, surgery is the next option.

Conclusions

Optimizing outcomes in UC and CD requires rapid control of inflammation. Intuitively, ongoing inflammation will lead to ongoing symptoms, organ damage and disease-related complications. Conventional therapy is not always fully effective in moderate-to-severe UC or CD, and therapy is often continued for a long periods of time without structured reassessment to ensure that therapeutic goals are achieved. Consequently, many patients are under-treated and remain mildly to moderately active and without a healed mucosa. Although in theory, treating mucosal healing appears to be attractive and should logically lead to improved outcomes, this is not currently a common practice. It is likely that future investigators will reveal to what degree mucosal healing impacts patient outcomes and how current treatment strategies may need to be modified to achieve this goal.78 A strategy that includes restricting overall exposure to corticosteroids and encouraging earlier use of immunosuppressive agents and anti-TNF therapies like infliximab or adalimumab in steroid-dependent and steroid-refractory patients should be adopted in these patients to avoid complications leading to surgery and impairment of QoL. The structured treatment algorithms for moderate CD and UC defined in this paper are intended to clarify the treatment decision-making process and help better achieve the treatment goals for CD and UC.

In CD and UC, the goal of biological therapy and more importantly the appropriate timing of therapy, is to aim for remission and normalization of QoL. Importantly, the perception of improved or normalized QoL may be patient specific and patients should be managed and monitored based on the patient and physician conclusion that their therapeutic goals have been met whether that includes symptomatic response, remission or mucosal healing. Although practically it may not be possible to perform routine repeated endoscopic or radiographic assessments for mucosal healing, the achievement of mucosal healing does appear to impact outcomes and therefore it warrants consideration as a treatment goal. Future research will determine the degree to which mucosal healing not only restores normal bowel function, but also improves long-term outcomes and reduces complications such as hospitalizations and surgeries.

Acknowledgements

Declaration of personal interests: Editorial support for the development of this publication was provided by Schering-Plough Corporation. An expert round table was convened to discuss treatment strategies. The proceedings were audio taped and from this a transcript was presented to the authors. The manuscript was developed based on the transcript by the authors. Declaration of funding interests: Remo Panaccione has served as a speaker, a consultant and an advisory board member for Astra Zeneca, Procter & Gamble Pharmaceuticals, Shire, Prometheus Laboratories, Centocor, Schering-Plough, Elan Biogen, Bristol Myers Squibb, Ferring Pharmaceuticals, Glaxo-Smith Kline, UCB Pharma, Axcan Pharma and Abbott Laboratories, has participated in continuing medical education events indirectly sponsored by Astra Zeneca, Elan Biogen, Procter & Gamble Pharmaceuticals, Shire, Axcan Pharma, Centocor, Schering-Plough and Abbott Laboratories, and has received research funding from Procter & Gamble Pharmaceuticals, Elan Biogen, Centocor, Schering-Plough, Millenium, Bristol Myers Squibb and Abbott Laboratories. Paul Rutgeerts has served as a speaker for Centocor, Schering-Plough, UCB, Abbott Pharmaceuticals and PDL; a consultant for Centocor, Schering-Plough, UCB, Abbott Pharmaceuticals, Elan and GlaxoSmithKline, and has received funding from Centocor, Schering-Plough, UCB and Abbott Pharmaceuticals. William Sandborn has served as a consultant or an advisory board member for Procter & Gamble Pharmaceuticals, Shire, Prometheus Laboratories, Centocor, Schering-Plough and Abbott Laboratories, has participated in continuing medical education events indirectly sponsored by Procter & Gamble Pharmaceuticals, Shire, Prometheus Laboratories, Centocor, Schering-Plough and Abbott Laboratories, and has received research funding from Procter & Gamble Pharmaceuticals, Shire, Centocor, Schering-Plough and Abbott Laboratories. Brian Feagan has served as a speaker, a consultant and an advisory board member for Synta, Millennium, Schering Canada, Celltech, Centocor, Elan/Biogen, Serono, Janssen-Ortho, Protein Design Labs, ISIS, Teva Pharmaceuticals, Santarus, Schering-Plough, Bristol-Myers Squibb, Celgene, Combinatorx, UCB Pharma, Napo Pharma, Abbott Laboratories, Procter and Gamble Pharmaceuticals, Osiris and Astra Zeneca, and has received research funding from Schering-Plough, Otsuka, Milllennium, Tillotts, Abbott Laboratories, Protein Design Labs, Boehringer Engelheim, Novartis, Centocor, Berlex and Synta. Brian Feagan is an employee of University of Western Ontario, Department of Medicine and owns stock and shares in Santarus. Stefan Schreiber has served as a speaker, a consultant and an advisory board member for Abbott Laboratories, AstraZeneca, BMS, Centocor, Chemocentryx, Elan, Genentech, Falk, Ferring, Merckle-Recordati, Giuliani, Otsuka, Procter & Gamble Pharmaceuticals, Schering-Plough, Shire and UCB Celltech. Stefan Schreiber owns stock in CONARIS Research Institute AG. Subrata Ghosh has served as a speaker, a consultant and an advisory board member for Schering-Plough, Centocor, Abbott Laboratories and UCB, and has received research funding from Schering-Plough and Astra Zeneca.

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