Recommendations for the treatment of Crohn's disease with tumor necrosis factor antagonists: An expert consensus report
Article first published online: 29 OCT 2011
Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 18, Issue 1, pages 152–160, January 2012
How to Cite
Feagan, B. G., Lémann, M., Befrits, R., Connell, W., D'Haens, G., Ghosh, S., Michetti, P., Ochsenkühn, T., Panaccione, R., Schreiber, S., Silverberg, M., Sorrentino, D., van der Woude, C. J., Vermeire, S. and Rutgeerts, P. (2012), Recommendations for the treatment of Crohn's disease with tumor necrosis factor antagonists: An expert consensus report. Inflamm Bowel Dis, 18: 152–160. doi: 10.1002/ibd.21870
- Issue published online: 11 DEC 2011
- Article first published online: 29 OCT 2011
- Manuscript Accepted: 1 AUG 2011
- Manuscript Received: 25 JUL 2011
- Crohn's disease;
- treatment consensus;
- mucosal healing;
- bowel preservation;
- TNF antagonists;
Symptom relief is the traditional treatment goal in Crohn's disease (CD). New goals including mucosal healing and bowel preservation are now achievable with tumor necrosis factor (TNF) antagonists. Infliximab and adalimumab are approved as second-line treatments for severe, active CD. Certolizumab pegol is approved only in the U.S. and Switzerland as second-line treatment for moderate-to-severe, active CD. Data from trials of infliximab suggest that high-risk patients and patients with active inflammation (CRP elevation and/or ileocolonic ulcers) may benefit from earlier use of this drug.
A Delphi survey was used to obtain consensus on issues surrounding bowel preservation and use of TNF antagonists. At the time of this survey, infliximab was the only TNF antagonist approved for the treatment of CD in Europe, Canada, and Australia. An expert panel of 12 gastroenterologists with substantial clinical experience using infliximab in clinical practice and trials in these areas participated.
The experts agreed that bowel preservation and mucosal healing are relevant and achievable goals, and form a rationale for using TNF antagonists in CD patients. Control of inflammation and induction of mucosal healing were considered essential for bowel preservation. Consensus areas: 1) mucosal healing is predictive of improved long-term disease course and increases the likelihood of steroid-free remission; 2) infliximab induces sustained mucosal healing, promotes bowel preservation, and reduces hospitalizations and surgeries; 3) benefits of infliximab in relation to mucosal healing, bowel preservation, and clinical remission increase when therapy is initiated earlier.
Treatment with TNF antagonists helps preserve the bowel in CD patients. (Inflamm Bowel Dis 2011;)
Crohn's disease (CD) is a chronic, relapsing, and progressive condition. Initially, most patients have inflammatory CD.1 With time, uncontrolled mucosal inflammation leads to bowel damage and subsequent stricturing or penetrating complications1 that are difficult to reverse using antiinflammatory therapy. Ultimately, hospitalization and/or surgery may be required to treat these complications. Surgery, however, does not prevent disease progression,2 places the patient at risk of operative complications, and in many instances leads to impaired bowel function. Therefore, early control of inflammation is essential to prevent mucosal damage and ensure bowel preservation and normal bowel function.
CD treatment goals should be reassessed to include complete mucosal healing and improvements in long-term outcomes (e.g., reductions in hospitalizations and surgeries).3 Effective treatment should result not only in clinical remission but also mucosal healing. Until recently, mucosal healing has not been a primary treatment goal in CD because most treatments are not disease-modifying and are unable to heal the mucosa. Although corticosteroids can induce clinical remission, they do not usually improve the severity of ileal lesions or heal the bowel.4 Immunosuppressive agents are disease-modifying and can induce complete mucosal healing in CD.5 However, they are slow to act and only modestly effective. In a recent clinical trial conducted in patients with active CD, only 16.5% of patients treated for 26 weeks with high-dose azathioprine (AZA) had mucosal healing.6 Consistent with this finding, immunosuppressive agents do not seem to significantly decrease the need for surgery or the risk of developing a stricturing or penetrating complication.7
Realization that sustained complete mucosal healing is an achievable goal in CD followed the introduction of biologic therapy (specifically, infliximab).8, 9 Published data (i.e., full-length articles in peer-reviewed journals) from trials of adalimumab and of certolizumab that endoscopically assess mucosal healing are likely to contribute additional support. (For example, EXTEND data for adalimumab presented at DDW 200910 and ECCO 201011 are promising. The Endoscopic Mucosal Improvement in Patients with Active Crohn's Disease Treated with Certolizumab Pegol [MUSIC] trial only recently concluded, so results for certolizumab are not yet known.) Furthermore, a correlation between endoscopic healing and clinical improvement was demonstrated following treatment with infliximab.8
Currently, both infliximab and adalimumab are approved in the European Union as second-line treatments for severe, active CD (in the case of infliximab, with or without fistulae) in patients not responding to or intolerant of conventional therapy.12, 13 Certolizumab pegol is approved only in the U.S. and Switzerland as a second-line treatment for moderate-to-severe, active CD in patients not responding to or intolerant of conventional therapy.14 Based on these constraints, these tumor necrosis factor (TNF) antagonists tend to be used late in the course of CD. However, growing evidence shows that earlier use in high-risk patients and patients with signs of active inflammation (C-reactive protein [CRP] elevation and/or ileocolonic ulcers) improves clinical outcomes. In patients with active CD, both the “Step-Up Top-Down” (SUTD) trial and the SONIC trial showed that infliximab-based treatment is more effective than AZA monotherapy for inducing clinical remission and mucosal healing.6, 15 These findings suggest that earlier use of infliximab may allow sustained mucosal healing and bowel preservation. (A post-hoc analysis of EXTEND presented at CDDW 201116 appears to support earlier use of TNF antagonists, but again, no definitive statements can be made until the data are published in a peer-reviewed journal. A post-hoc analysis of data from the certolizumab pegol PRECiSE 2 trial also suggested better outcomes with earlier treatment in some patients.17)
Given these observations, we used a modified Delphi process to survey current opinion among inflammatory bowel disease experts regarding the value of bowel healing as a therapeutic goal, and the use of TNF antagonists to achieve it.
MATERIALS AND METHODS
At the time of this survey, infliximab was the only biologic approved for the treatment of CD in Europe, Canada, and Australia. Therefore, the Delphi necessarily focused on infliximab.
A steering committee consisting of three gastroenterologists (B.F., M.L., and P.R.), with extensive experience in treating patients with moderate-to-severe CD, generated an initial topic-specific survey (Table 1). Once the survey was developed it was independently assessed by nonphysician medical editors. Modifications were then made to minimize ambiguities and to ensure that the questions were comprehensible.
|• Possess extensive experience using biologic therapies to treat patients with moderate-to-severe CD|
|• Involved in numerous clinical trials evaluating biologic therapies in CD|
|• Develop survey outline topics|
|• Contribute to the survey design/methodology|
|• Review survey data before sending to the expert panel|
|• Present data to the expert panel at an on-site meeting|
|• Possess substantial experience using biologic therapies to treat patients with CD|
|• Involved in some clinical trials evaluating biologic therapies in CD|
|• Participate in 2 rounds (round 1 and 2) of an anonymous questionnaire|
|• Attend a group discussion meeting (round 3) of survey results to establish consensus, where possible|
|• Develop additional/revised questions at the meeting and respond to the revised questions (round 4)|
An expert panel of 12 gastroenterologists from Canada, Europe, and Australia participated in the survey under the guidance of the steering committee. Members of the expert panel were selected based on expertise in using biologic therapy in the treatment of CD in both clinical practice and clinical studies.
The Delphi method provides a means of “structuring a group communication process so that it is effective in allowing a group of individuals to deal with a complex problem.”18 In practice, this technique is a way of establishing unbiased answers to complex questions through collaborative discussion by a group of experts in a particular field.
Although there are several types of Delphi method, all rely upon repeatedly circulating a questionnaire to a group of experts and anonymously collecting responses. Between each round of the questionnaire the results are analyzed and disclosed, so that during the subsequent round members of the expert panel can reassess/modify their answers based on the group responses.18 Opinions converge until consensus is reached. The Delphi method is a cooperative investigation that involves sharing of positions and ideas among experts to resolve complicated issues after deliberation. It provides a forum for exploring all approaches to a problem/argument, and for identifying and clarifying the advantages and disadvantages of a particular opinion.18, 19 To further help reach consensus, the Delphi methodology has been modified. The resulting “collaborative Delphi” method used in this study comprises multiple rounds of an anonymous survey plus meetings to facilitate development of a consensus opinion.
In this study the collaborative Delphi consisted of two rounds of an anonymous questionnaire (rounds 1 and 2) and a follow-up meeting (round 3). Although panel members surrendered their anonymity at the meeting, all individual responses remained confidential to preserve objectivity. At the meeting, consensus was reached on most statements. For issues that warranted further discussion the steering committee and expert panel devised and refined questions for inclusion in the final round (round 4).
This Delphi survey focused on five topics: bowel preservation, patient-related aspects of bowel preservation, mucosal healing, using infliximab to treat CD, and optimal timing of infliximab use in CD.
Questions were designed to determine subjects of importance, relevance, agreement, and likelihood of action using a Likert scale (1–9,) where a score of 1, 2, 3, or 4 indicated degrees of disagreement with the statement or question; 6, 7, 8, or 9 indicated increasing degrees of agreement; and a score of 5 represented a neutral opinion. The expert panel completed the Internet-based questionnaire during rounds 1 and 2. An identification code assigned to each expert panel member ensured that individual responses remained anonymous when reviewed during the meeting.
The responses from round 1 of the survey were gathered and analyzed as a set. Median scores were calculated to determine the main central tendency of the set of responses. The median score was used to ensure that any considerable shifts from the central tendency or extreme opinions were disregarded. These median scores were disclosed to the expert panel before they completed round 2 of the survey questionnaire. After completion of round 2, the variability of the results was calculated using the interquartile range (IQR) prior to the round 3 meeting. The IQR measures the range between the 25th and 75th percentile, which defines the middle 50% of responses. The IQR is not affected by outlying responses and therefore provides a stable estimate of the range around the central tendency of responses.
The steering committee presented round 2 results to the expert panel at the meeting (round 3). This was followed by an open discussion moderated by the steering committee that focused on the key issues surrounding mucosal healing/bowel preservation and the use of infliximab therapy, to establish their importance to the management of patients with CD. Questions were discarded if it was highly improbable that consensus could be reached or if they were considered irrelevant.
The median Likert scale was adjusted so that the level of agreement with a question could be more interpretable. Scores of 1–3 were redefined as “highly irrelevant,” “strongly disagree,” or “highly unlikely”; 4–6 as “somewhat relevant or irrelevant,” “somewhat agree or disagree,” or “somewhat likely or unlikely”; and 7–9 as “highly relevant,” “strongly agree,” or “highly likely.” A score of 5 represented neutrality. Positive consensus was defined as the median ≥7 plus the lower quartile ≥7 (negative consensus, median ≤3 and upper quartile ≤3). Scores can be illustrated with “boxplots” (Fig. 1).
Bowel Preservation in CD
For the first topic of the survey the expert panel was asked questions addressing issues surrounding bowel preservation in CD. Consensus was reached that bowel preservation is clinically defined as the presence of normal structural imaging (median 8 [IQR 7–8.5]) and complete bowel healing (median 8 [IQR 7.5–8]). The panel strongly agreed that the preservation of normal bowel function, safeguarding the bowel by avoiding surgical resection, and maintaining gut continuity are important aspects of bowel preservation (median 8 [IQR 8–8.75]). There was consensus that achieving bowel preservation helps avoid CD-related complications including stenosis (median 8 [IQR 7–8]), fistulae (median 7 [IQR 7.5–8.5]), stricture (median 7.5 [IQR 7.5–8]); bile acid/salt diarrhea (median 7 [IQR 7–8.5]); surgeries (median 8 [IQR 7–8]), physiological short gut (median 8 [IQR 7.25–9]), true short gut (median 8 [IQR 7.75–9]), and nutrient malabsorption (median 7.5 [IQR 7–8]). The expert panel reached consensus on the factors that increase the likelihood of achieving bowel preservation, including the type (median 8 [IQR 7–9]) and timing (median 8 [IQR 7–8]) of therapy (Table 2). The panel strongly agreed that control of inflammation (median 8 [IQR 7.75–9]) and mucosal healing (median 8 [IQR 7–9]) are essential in the preservation of bowel function, and that endoscopy is an important tool for evaluating bowel preservation (median 8 [IQR 8–9]).
|Degree of permanent irreversible damage - bowel and surgically induced (median 8 [IQR 7-9])|
|• Disease duration (median 7 [IQR 7-7.25])|
|• Disease severity (median 7 [IQR 7-7])|
|• Treatment compliance (median 7 [IQR 7-8])|
|• Duration of untreated disease (median 8 [IQR 7-8])|
|• Disease location (median 8 [IQR 7-7.5])|
|• History of surgery (median 7 [IQR 7-8.5])|
Patient-Related Aspects of Bowel Restoration
The second topic of the survey examined patient-related aspects of bowel preservation. The expert panel agreed that individual patient factors do affect the course of CD and that achieving bowel preservation is likely to have a positive effect on health-related quality of life (HRQoL). It was concluded, however, that these patient factors are currently not well understood, and so consensus could not be reached.
The panel agreed that the importance of bowel preservation should be explained to patients. In clinical practice, expert panel members were highly likely to describe bowel preservation to their patients as: mucosal healing to allow the bowel to function normally (median 8 [IQR 7–8]); protection of the bowel from structural changes due to inflammation (median 8 [IQR 8–8]); enabling avoidance of surgery (median 8 [IQR 7.75–8]); leading to symptom-free living (median 7 [IQR 7–8.25]).
Mucosal Healing in CD
The third topic focused on mucosal healing in CD. Consensus was reached on the definition of mucosal healing. The expert panel agreed that mucosal healing is best defined clinically as restoration of normal mucosal appearance by endoscopy of a previously inflamed region (median 8 [IQR 7.7–8.5]) and the complete absence of ulceration, and macroscopic and histological signs of inflammation (median 8 [IQR 7–8]). Several factors were identified that influence mucosal healing (Table 3). Consensus was reached that mucosal healing is both a definable (median 8 [IQR 7.75–9]) and achievable (median 8 [IQR 7–8.25]) clinical endpoint in CD, and an important component of bowel preservation (median 8 [IQR 7.75–9.0]). The panel strongly agreed that mucosal healing is achievable with infliximab (median 8 [IQR 7–8.25]) and that this forms the rationale for initiating infliximab treatment if mucosal ulcerations are present (median 8 [IQR 7–8.25]). There was strong agreement that mucosal healing is a good predictor of long-term disease-related outcomes (median 8 [IQR 7–9]), and that achieving mucosal healing reduces the risk of hospitalization (median 8 [IQR8–8]) and surgery (median 8 [IQR 7.75–8]). Mucosal healing was also considered to increase the likelihood of disease remission (median 8 [IQR 8–8.25]) and steroid-free remission (median 8 [IQR 8–8.25]).
|• Early therapeutic intervention (median 8 [IQR 7.75-8.25])|
|• Effective therapy (median 8 [IQR 8-9])|
|• Early occurrence of complications (median 8 [IQR 7-8])|
|• Durability of therapeutic response (median 7.5 [IQR 7-8])|
|• Patient compliance (median 8 [IQR 7-8])|
|• Timing of diagnosis (median 8 [IQR 7-8])|
|• Disease severity (median 8 [IQR 7.5-8])|
|• Disease duration (median 8 [IQR 7-8])|
The panel strongly agreed that endoscopy is the best method of assessing mucosal healing (median 8 [IQR 8–9]). Although magnetic resonance imaging (MRI) (gadolinium uptake), computed tomography (CT), and histology were considered potentially useful for evaluating structural abnormalities, especially of the small bowel and the perianal region, consensus was not reached about the importance of these techniques in assessing mucosal healing. The panel was aware that MRI is being developed for assessment of luminal CD.
Use and Optimal Timing of Infliximab in the Treatment of CD
The fourth and fifth topics of the survey addressed the use and optimal timing of infliximab in treating CD. The expert panel strongly agreed that several factors were highly relevant in the decision to use infliximab in patients with CD (Table 4). These included disease severity (median 8 [IQR 7.75–8.25]) and the ability to maintain symptomatic control (median 7.5 [IQR 7–9]) and achieve mucosal healing (median 8 [IQR 8–8]). Other important factors included HRQoL (median 8 [IQR 7.75–9]) and maintaining normal gut function (median 8 [IQR 7.75–8.25]). Whether a patient had failed conventional treatments previously was also an important consideration (median 8 [IQR 7–9]). The panel strongly agreed that infliximab treatment leads to mucosal healing (median 8 [IQR 8–8]) and ultimately enables bowel preservation (median 8 [IQR 7–8]), reduces the number of flares (median 8 [IQR 7–8]), and results in fewer hospitalizations and surgeries (median 8 [IQR 7.75–8]). It also strongly agreed that infliximab reduces dependence on steroids (median 8 [IQR 8.8.25]) and improves patient HRQoL (median 8 [IQR 7.75–8.25]).
|• Severity of disease (median 8 [IQR 7.75-8.25])|
|• Achieving rapid clinical improvement (median 7 [IQR 7-8.25])|
|• Maintaining symptomatic control (median 7.5 [IQR 7-9])|
|• Maximizing the likelihood of achieving bowel preservation (median 8 [IQR 7-8])|
|– Maintaining normal gut function (median 8 [IQR 7.75-8.25])|
|– Achieving mucosal healing (median 8 [IQR 8-8])|
|• Improvement in the majority of patients' QoL (median 8 [IQR 7.75-9])|
|– Improving feelings of social acceptability (median 7 [IQR 7-8.25])|
|– Reducing physical impact of the disease (median 8 [IQR 7.75-9])|
|• Patients failing previous conventional therapies (median 8 [IQR 7-9])|
Consensus was reached (Fig. 2) that earlier use of infliximab in the course of CD improves the likelihood of clinical remission (median 8 [IQR 7–8.5]), mucosal healing (median 8 [IQR 7–8.5]), bowel preservation (median 8 [IRQ 7.5–8.5]), fewer hospitalizations (median 8 [IQR 7.5–8]) and surgeries (median 8 [IQR 7–8]), reduced number of flares (median 8 [IQR 7–8]), reduced dependence on steroids (median 8 [IQR 7–8]), and improved patient HRQoL (median 8 [IQR 7–8.5]).
This Delphi survey enabled a panel of 12 experts to reach consensus in a number of areas (Table 5) relating to bowel preservation and the role of biologic agents, specifically infliximab, in patients with CD, based on situations encountered during their clinical experience.
|Topic 1. Bowel preservation in CD|
|• Bowel preservation is clinically defined as histological normality, normal structural imaging and complete bowel healing.|
|• Achieving bowel preservation helps avoid CD-related complications and leads to a reduction in surgeries.|
|• The ability to achieve bowel preservation is dependent on the type and timing of therapy.|
|• Bowel preservation is a rationale for selecting infliximab.|
|• Controlling inflammation and inducing mucosal healing are essential for preserving bowel function.|
|Topic 2. Patient-related aspects of bowel preservation|
|• Individual patient factors affect the ability to achieve bowel preservation, but they are poorly understood.|
|• Bowel preservation is likely to improve patient QoL.|
|• It is important to explain to patients the importance of bowel preservation.|
|Topic 3. Mucosal healing in CD|
|• is defined as restoration of normal mucosal appearance (by endoscopy) of a previously inflamed region, and requires complete absence of ulceration and macroscopic and histological signs of inflammation.|
|• is an achievable, definable clinical endpoint.|
|• is an important component of bowel preservation.|
|• is a rationale for initiating infliximab.|
|• is an achievable goal with infliximab.|
|• is a good predictor of long-term disease course (reduced hospitalizations and surgeries)|
|• is best assessed by endoscopy.|
|• increases the likelihood of disease remission off steroids.|
|Topic 4. Using infliximab in the treatment of CD|
|Factors influencing the use of infliximab include:|
|• Severity of disease|
|• Rapid and sustained symptomatic control|
|• Bowel preservation (mucosal healing)|
|• Improving patient's QoL|
|• Failure of previous conventional therapies|
|Topic 5. Optimal timing of infliximab use in CD|
|The likelihood of achieving the following benefits of infliximab increases when the drug is used earlier in high-risk patients and patients with signs of active inflammation (CRP elevation and/or ileocolonic ulcers):|
|• Sustained clinical remission|
|• Induction of mucosal healing|
|• Reduced number of flares|
|• Reduced dependence on steroids|
|• Promotion of bowel preservation|
|• Fewer hospitalizations and surgeries|
|• Improvement in patient QoL|
Bowel Preservation in CD
The results of this survey demonstrate that bowel preservation is an important goal for physicians treating CD. The expert panel strongly agreed that bowel preservation is achievable in CD. Consensus was reached that bowel preservation is dependent on controlling inflammation and inducing mucosal healing. Uncontrolled inflammation in CD leads to mucosal damage and ulceration, which if persistent results in the development of serious complications such as fistulas, infection, perforation, and bleeding.2 The panel agreed that achieving bowel preservation helps avoid CD-related complications that lead to an increased risk of hospitalizations and surgery.2
The panel strongly agreed that the ability to achieve bowel preservation is dependent on the type and timing of therapy. An aggressive approach to treatment may induce sustained control of inflammation and complete mucosal healing. Treatment success in CD should be seen as a return to the normal bowel function present before a flare,3 with the ultimate goal being alteration of the natural disease course.
Patient-Related Aspects of Bowel Restoration
Consensus was reached that bowel preservation is likely to improve patients' QoL, and that patients should be taught the importance of achieving this treatment goal. The symptoms of CD can have a hugely negative effect on patients' QoL, severely impacting daily functioning and leading to psychosocial impairment including anxiety and depression.20 Poor levels of physical and mental well-being can make full-time employment difficult to maintain. In addition, one-third of patients with chronic or intermittent CD develop complications that require surgery within the first year following diagnosis.21 Importantly, sustained remission in patients with CD improves QoL and employability, and decreases hospitalizations and surgeries.20 The ability to achieve bowel preservation by controlling inflammation and inducing complete mucosal healing is likely to have a positive impact on QoL.
Mucosal Healing in CD
Biologic agents such as infliximab have allowed the expansion of treatment objectives in CD. Therapeutic goals must go beyond symptom relief to include mucosal healing and bowel preservation (Table 6).3 The expert panel strongly agreed that mucosal healing is a good predictor of long-term disease course and reduces the risk of hospitalizations and surgeries. Consensus was reached that patients who achieve mucosal healing are more likely to be in clinical remission off steroids and may have more durable and positive long-term outcomes.
|• Improve QoL and induce rapid response|
|• Maintain steroid-free remission|
|• Avoid complications (i.e., hospitalization and surgery)|
|• Prevent disease-related mortality|
|• Achieve and maintain complete mucosal healing|
Mucosal healing is crucial, as it significantly improves patient outcomes and affects the underlying disease course in CD. Mucosal healing has been shown to reduce rates of surgery. In a prospective, Norwegian, population-based cohort study, conducted between 1990 and 1994 (before biologic therapies were available), long-term mucosal healing was shown to reduce surgery rates.22 Patients with mucosal healing after 1 year of treatment were more likely to have reduced subsequent disease activity and a decreased need for active treatment.22 A follow-up showed that these patients had lower surgery rates at 10 years. Mucosal healing also can lead to fewer CD-related hospitalizations.9 Further, a follow-up to the SUTD study beyond year 2 showed that of several factors mucosal healing was the only one predictive of clinical remission during years 3 and 4.23
The expert panel strongly agreed that mucosal healing is an attainable goal with, and a rationale for, infliximab treatment. In ACCENT I (A CD Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen), infliximab was effective at inducing and maintaining mucosal healing. After 1 year of treatment 50% of responders receiving infliximab treatment (5 or 10 mg/kg at weeks 2, 6, and then every 8 weeks) achieved complete mucosal healing as assessed by endoscopy.9 These findings are supported by data from routine clinical practice, which showed that 76.9% (45.4% complete healing, 22.4% partial healing) of patients with primary response and receiving infliximab treatment achieved mucosal healing that was associated with the best long-term outcomes; 77.3% had sustained clinical benefit (P = 0.058).24 Significantly fewer patients achieving mucosal healing with infliximab (14.1%) needed major abdominal surgery compared to patients with no mucosal healing (38.4%; P < 0.0001).24 These patients also experienced fewer CD-related hospitalizations.9 No patients with mucosal healing after 10 weeks and 1 year of infliximab treatment required hospitalization. Even patients with mucosal healing at only one of those visits still needed fewer hospitalizations (18.8%) compared with those with no mucosal healing (28%).9
Although clinical remission may last several months after mucosal healing occurs, data from a small but influential study indicate that upon stopping infliximab mucosal damage quickly reoccurs.25, 26 Therefore, long-term treatment may be necessary to maintain both mucosal healing and clinical remission.
Published trials of adalimumab such as CLASSIC27, 28 and CHARM29 and of certolizumab pegol such as PRECISE 1, 2, and 330, 31, 32 did not endoscopically assess mucosal healing and bowel preservation. The placebo-controlled, open-label EXTEND trial (N = 129) included endoscopic assessment and showed that adalimumab therapy induced mucosal healing and maintained it over the 1-year study.10 However, the primary endpoint—complete mucosal healing—was not achieved.
Mucosal healing should be monitored regularly. Currently, endoscopy is the gold standard for accurately assessing mucosal healing. The expert panel strongly agreed that endoscopy is an important tool for measuring mucosal healing. There also may be a role for fecal markers (e.g., calprotectin) as noninvasive measures of inflammation.32–34
Use/Optimal Timing of Infliximab in the Treatment of CD
Clinical trials have shown that infliximab induces rapid and sustained clinical remission and mucosal healing / bowel preservation. Consensus was reached by the expert panel that bowel preservation (mucosal healing/normal gut function), severity of disease, rapid and sustained symptomatic control, improved patient QoL, and failure of previous conventional therapies are highly relevant factors influencing their use of infliximab.
The panel strongly agreed that infliximab induces rapid mucosal healing, bowel preservation, clinical remission, and improves long-term outcomes (reduced hospitalizations and surgeries). They also agreed that these benefits of infliximab are much more likely when the drug is used earlier in high-risk patients and patients with active inflammation (CRP elevation and/or ileocolonic ulcers), rather than as a second-line therapy. Indeed, there is now strong evidence showing that many patients benefit from earlier use of infliximab.6, 15 A post-hoc analysis of data from the PRECiSE 2 trial of certolizumab pegol also suggested better outcomes with earlier treatment in some patients.17 We await publication of results from the Extend the Safety and Efficacy of Adalimumab Through Endoscopic Healing (EXTEND) trial, particularly a post-hoc analysis presented at CDDW 2011 that also suggested benefit to earlier use of TNF antagonists in CD.
The SUTD trial demonstrated that early initiation of infliximab + AZA combination therapy (top-down) is more effective in inducing clinical remission and mucosal healing than conventional step-up therapy in patients with newly diagnosed, active CD who had not previously received steroids, immunosuppressive agents, or biologic therapy.15 After a year of therapy, 61.5% of patients receiving infliximab + AZA were in clinical remission compared with 42.2% on conventional treatment (P = 0.0278). Furthermore, at 2 years significantly more patients receiving infliximab + AZA (73%) achieved complete mucosal healing than those treated with conventional therapy (30%, P = 0.0028).15
This is supported by the findings of the SONIC trial conducted in immunosuppressive/biologic naïve patients. At week 26, 56.8% of patients receiving infliximab + AZA combination therapy were in corticosteroid-free clinical remission, as compared with 44.4% receiving infliximab alone (P = 0.02), and 30.0% receiving AZA alone (P < 0.001 vs. combination therapy; P = 0.006 vs. infliximab).6 In addition, significantly more patients receiving infliximab monotherapy (30%; P = 0.023) or infliximab + AZA combination therapy (44%; P < 0.001) achieved mucosal healing, compared with AZA monotherapy (17%). Interestingly, patients with evidence of active inflammation (high CRP and/or endoscopic lesions) showed a particularly strong benefit from infliximab-based therapy compared with AZA monotherapy.6 These findings provide evidence for initiating infliximab therapy early in the course of CD in high-risk patients and patients with active inflammation (CRP elevation and/or ileocolonic ulcers) and suggest that a change is needed in the way CD is treated in clinical practice.
Our Delphi survey necessarily focused on infliximab. Currently, infliximab has the longest and most extensive history of published clinical trial data and clinical experience in CD.35 This consensus study provides recommendations for achieving bowel preservation and using infliximab in patients with CD. Main areas of consensus were: 1) bowel preservation is an important, achievable treatment goal; 2) bowel preservation can improve patient QoL, and this information must be conveyed to patients; 3) mucosal healing is predictive of improved long-term disease course and increases the likelihood of steroid-free remission; 4) infliximab induces sustained mucosal healing, promotes bowel preservation, and reduces hospitalizations and surgeries; 5) the benefits of infliximab in relation to mucosal healing, bowel preservation, clinical remission, and long-term outcomes increase when the drug is initiated earlier in the course of CD. This consensus may provide useful and practical advice for improving therapeutic strategies in patients with CD. As other therapies and data become available, they should meet the new standards of mucosal healing and bowel preservation, and thereby offer disease-modification potential.
The consensus meeting was sponsored by Merck, Sharp, and Dohme Corp., Whitehouse Station, NJ. Consultancy fees were paid to meeting participants, and travel to and from the meeting was reimbursed. Merck employees did not participate in any discussions of the steering committee or expert panel. This consensus statement reflects only the opinions of the participants. The sponsor reviewed the article per ethical guidelines. The authors determined the final content. No payments were made to the authors for the writing of this article.
The Steering Committee (W.R., G.vA., and J.P.) helmed the Delphi process, developed topics for the survey, and helped with design and methodology, but did not participate in the survey. Synergy Medical Education, Conshohocken, PA, collected and analyzed the data. All authors helped to draft the article and read and approved this final version.
Jacqueline M. Mahon, MA, Synergy Medical Education, Conshohocken, PA, provided editorial assistance in preparing each draft, acted as liaison among the 15 authors when reviews of each draft were under way, and secured approval of each draft from all authors before the article progressed to the next step. Merck paid Synergy for this work.
Disclosures: R. Befrits has worked as a paid consultant for Schering-Plough. G. D'Haens has been a consultant and speaker and has developed educational presentations for MSD, and has received grants and travel reimbursement for unrelated projects from MSD. B. Feagan has received grants and research support from Abbott, Merck, Centocor, and Schering Canada; has consulted for BMS, Millenium, Genentech, GSK, Shire, Wyeth, Merck, Centocor, and Schering-Plough; and has participated on scientific advisory boards for AstraZeneca, Celgene, Novartis, Merck, Centocor, Pfizer, and UCB. S. Ghosh has been a speaker and consultant for Abbott, Merck, and Shire, and has received research grants from Abbott and Merck. M. Lémann had received research support from and served as consultant to Abbott Laboratories. Dr. Lémann is now deceased. P. Michetti has been a consultant for Abbott, Ferring, Merck-Serrano, MSD, and UCB; a board member for Abbott, AstraZeneca, MSD, Nycomed, and UCB; and a speaker for Abbott, MSD, and UCB; and has received grants from MSD and UCB. T. Ochsenkuhn has been a consultant and speaker and has developed educational presentations for Abbott and MSD; and has received travel reimbursement from Abbott. R. Panaccione has been a speaker and consultant for Abbott, Schering-Plough (SP), Centocor, and Elan; has received research grants from Abbott, SP, Centocor, Millenium, Elan, Proctor & Gamble, and BMS Canada; and has served on advisory boards for Ferring, Abbott, SP, Elan, and UCB. P. Rutgeerts has been a speaker and consultant and has received research grants from Centocor, Merck, UCB, and Abbott. D. Sorrentino has been a board member for Centocor; a consultant for Centocor, Schering-Plough, Abbott, MSD, AstraZeneca, Giuliani, and Hoffmann-LaRoche; and has developed educational presentations and been a speaker for Centocor, Schering-Plough, Abbott, MSD, and Hoffmann-LaRoche. S. Vermeire has received a grant (paid to his institution) from UCB and has been a consultant for Abbott, Centocor, MSD, and UCB. W. Connell, C.J. van der Woude, S. Schreiber, and M. Silverberg have nothing to disclose.
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