Inflammatory Bowel Diseases:
Clinical Review Articles
Mucosal Healing in Crohn's Disease: A Systematic Review
De Cruz, Peter MD*,†; Kamm, Michael A. MD, PhD*,†,‡; Prideaux, Lani MD*,†; Allen, Patrick B. MD*; Moore, Greg MD, PhD§
*Department of Gastroenterology, St Vincent's Hospital, Melbourne, Australia
†University of Melbourne, Melbourne, Australia
‡Imperial College, London, UK
§Monash Medical Centre, Melbourne, Australia.
Reprints: Professor Michael A. Kamm, St Vincent's Hospital, Victoria Parade, Fitzroy, Melbourne 3065, Australia (e-mail: email@example.com).
Received March 13, 2012
Accepted March 13, 2012
Abstract: The traditional goals of Crohn's disease therapy, to induce and maintain clinical remission, have not clearly changed its natural history. In contrast, emerging evidence suggests that achieving and maintaining mucosal healing may alter the natural history of Crohn's disease, as it has been associated with more sustained clinical remission and reduced rates of hospitalization and surgical resection. Induction and maintenance of mucosal healing should therefore be a goal toward which therapy is now directed. Unresolved issues pertain to the benefit of achieving mucosal healing at different stages of the disease, the relationship between mucosal healing and transmural inflammation, the intensity of treatment needed to achieve mucosal healing when it has not been obtained using standard therapy, and the means by which mucosal healing is defined using current endoscopic disease activity indices. The main clinical challenge relates to defining the means of achieving high rates of mucosal healing in clinical practice.
Induction and maintenance of clinical remission have been the traditional goals of management in inflammatory bowel disease (IBD).1 However, short-term amelioration of symptoms has not been shown to alter the natural course of the disease.2,3 In particular, rates of surgical intervention have remained relatively static over the last decade despite the use of immunosuppressive agents.3 This may in part be due to the poor correlation between traditional clinical disease activity indices used to guide therapy and endoscopic activity in Crohn's disease (CD). More recently, biological agents have demonstrated efficacy in inducing and maintaining healing of the gut mucosa, with improved clinical outcomes including sustained steroid-free clinical remission, decreased need for surgical intervention, reduction in hospital admissions, improvement in quality of life, and increased work productivity.4–8 Due to these associations, mucosal healing is believed to reflect diminished disease activity and deep-tissue healing with consequent modification of the disease natural history. Mucosal healing has therefore emerged as an important therapeutic endpoint in clinical trials in addition to traditional clinical activity indices.9 Mucosal healing provides an objective measurement of drug therapy and overcomes the placebo effect associated with traditional clinical indices.10 Although now a major focus in clinical trials, mucosal healing is yet to be fully integrated into clinical practice strategies. The purpose of this review, which focuses on CD, is to: 1) explore the definition of mucosal healing; 2) review the relationship between clinical and endoscopic disease activity; 3) outline the impact of mucosal healing on short and long-term outcomes and the natural history of CD; 4) evaluate the efficacy of current therapeutics in inducing and maintaining mucosal healing; 5) review the practical issues and limitations of implementing mucosal healing strategies in clinical practice; 6) review the role of noninvasive markers of mucosal healing; and 7) propose an approach towards integrating mucosal healing as a therapeutic endpoint in clinical practice.
A systematic electronic search of the English literature for the period January 1970 to August 2011 was conducted using Medline (EBSCO host) and the Cochrane Library. The search strategy employed a combination of Medical Subject (MeSH) headings and key words as follows: “inflammatory bowel disease,” “Crohn's disease,” “mucosal healing,” “endoscopic improvement,” “mucosal improvement,” “endoscopic response,” “endoscopic remission,” “stable remission,” “deep remission,” “steroid-free clinical remission,” “clinical remission,” “clinical end-point,” “disease outcome,” “Crohn's Disease Activity Index,” “CDAI,” “Simple Endoscopic Score,” “SES-CD,” “Crohn's disease endoscopic index of severity,” “CDEIS,” “Rutgeerts score,” “capsule endoscopy,” “treatment,” “immunosuppressive drugs,” “corticosteroids,” “budesonide,” “5-aminosalicylate,” “antibiotics,” “azathioprine,” “6-mercaptopurine,” “methotrexate,” “biologies,” “infliximab,” “adalimumab,” “certolizumab,” “natalizumab,” “enteral feeding,” “surgery,” “endoscopy,” “fecal calprotectin,” “fecal lactoferrin,” “computerised tomography,” “magnetic resonance enterography,” “ultrasonography,” “C-reactive protein.” Boolean operators (“not,” “and,” “or”) were also used in succession to narrow or widen the search. Four authors (P.D.C., L.P., P.A., and G.M.) screened the abstracts and identified potentially relevant articles. Additional studies were identified via a manual review of the reference list of identified studies and review articles.
DEFINITION OF MUCOSAL HEALING
There is currently no validated definition of mucosal healing in patients with IBD.9 Ileocolonoscopy is the traditional gold standard by which mucosal healing has been assessed in CD.11 Mucosal damage in CD is characterized by erythema, edema, nodularity, strictures, aphthoid ulcers, and ulcers that vary in size and depth.12 In clinical trials mucosal healing has variously been described as “partial” or “complete,” as “endoscopic improvement” or “mucosal improvement,” as “endoscopic response” or “endoscopic remission,” and has also been described anatomically by segment as well as histologically. Terms such as “stable” remission and “deep” remission have also recently developed and encompass mucosal healing as a composite end-point along with steroid-free clinical remission13,14 and/or laboratory improvement.15
Defining mucosal healing as either complete resolution of erythema or ulceration may be too simplistic and restrictive, as it does not allow for partial resolution of mucosal disease. Moreover, complete mucosal healing becomes a difficult endpoint to achieve in the clinical trial setting particularly among patients with CD for whom a partial therapeutic response may be deemed a “nonresponse” if complete mucosal healing is not achieved. It remains to be determined to what extent partial improvement in endoscopic disease activity in response to treatment is sufficient to improve clinical outcome. In clinical practice mucosal healing is often described as the absence of deep ulcers, complete absence of ulcers or erosions, complete normalization of the mucosa at endoscopy, or no inflammation.16 For practical purposes the definition of mucosal healing should qualify the extent of healing as either “partial” or “complete” as determined by recognized or validated endoscopic disease activity indices.
RELATIONSHIP BETWEEN CLINICAL ANDENDOSCOPIC DISEASE ACTIVITY
Several studies have demonstrated a poor correlation between clinical symptoms, as assessed by the Crohn's Disease Activity Index (CDAI) and endoscopic findings.16–18 In particular, clinical symptoms appear to be poor predictors of the severity of inflammation found at endoscopy.18 The lack of correlation between conventional clinical indices and endoscopic activity may reflect the weakness of the CDAI as a tool for assessing clinical activity19,20 but may also reflect the dynamic nature of the inflammatory process in IBD. As a consequence of the disparity between clinical and endoscopic activity some studies have utilized corticosteroid-free clinical remission as an endpoint, which has been shown to correlate with mucosal healing.21
A key aspect to determining whether mucosal healing should be used as a therapeutic endpoint is whether or not endoscopic activity is able to predict future clinical recurrence. In a study by Allez et al22 the presence of deep ulceration at colonoscopy in patients with CD was a risk factor for penetrating complications and colectomy. Among patients with severe endoscopic lesions the probability of colectomy was 31%, 42%, and 62% at 1, 3, and 8 years, respectively, in contrast to the absence of severe endoscopic lesions associated with colectomy rates of 6%, 8%, and 18% (P < 0.0001).
More recently, Baert et al23 undertook a prospective follow-up of a previously published cohort of 49 treatment-naive patients with CD. Steroid-free remission at 3 and 4 years was observed in 70.8% of patients who had achieved complete mucosal healing at year 2, defined by the Simple Endoscopic Score (SES-CD) of 0, compared with 27.3% of patients who had endoscopic activity at year 2 with a SES-CD of 1–9 (0.036). However, the CDAI at year 2 was not predictive of mucosal healing at 4-year follow-up.
In the postoperative setting mucosal disease recurrence can be observed endoscopically before symptoms develop.24,25 The severity of endoscopic lesions arising during the postoperative period predicts the development of recurrent clinical disease and the need for surgery.26 In the postoperative setting clinical symptoms alone have a poor correlation with the presence of postoperative recurrence. A study of 110 postoperative patients found that the CDAI could discriminate between those with and without endoscopic recurrence in only 65% of cases, suggesting that CDAI alone was inadequate for the detection of postoperative recurrence of CD.27 These findings were supported by a recent small randomized controlled study by Regueiro et al28 that found a poor correlation between postoperative endoscopic recurrence and clinical symptoms, CDAI, and C-reactive protein (CRP). Similarly, Walters et al29 demonstrated that the CDAI cutoff of 150 had a sensitivity of 70% and specificity of 81% for predicting the presence of recurrent endoscopic disease, leading the authors to conclude that a combination of symptom assessment plus endoscopic evidence of recurrence should remain the gold standard definition for assessing outcome in postoperative CD trials.
ENDOSCOPIC DISEASE ACTIVITY INDICES
Adequate assessment of mucosal healing and mucosal damage requires the use of reproducible and validated scoring systems. Since colonic and ileal segments can be affected to a variable degree endoscopic severity scores need to incorporate weighing factors for the extent of bowel involvement and the severity of lesions. Endoscopic scoring systems allow assessment of the impact of therapeutic intervention on endoscopic activity, as well as the predictive value of endoscopic changes on disease outcome. Moreover, endoscopic systems help minimize inter-observer variability.
There are currently three endoscopic scoring systems for CD, the Crohn's Disease Endoscopic Index of Severity (CDEIS),16 the Simple Endoscopic Score for Crohn's Disease (SES-CD),30 and the Rutgeerts endoscopic grading scale.26
The CDEIS,16 considered by some to be the gold standard endoscopic scoring index, was initially devised on the basis of specific lesions considered to be important indicators of severe disease by a group of IBD experts. An index was then calculated, based on the percentage of involvement of different ileocolonic segments, for use in clinical trials.16 The CDEIS demonstrated a good correlation with lesion severity with minimal interobserver variability, and was therefore considered to be a reproducible index. However, the CDEIS is complex to use and requires training and experience for estimating the extent of ulcerated or diseased mucosal surfaces and experience in distinguishing deep from superficial ulceration. While some studies have demonstrated a good correlation between the CDEIS and the CDAI,21 others have indicated poor correlations between clinical symptoms, assessed by the CDAI, and endoscopic findings assessed by the CDEIS.16,17,18,31 More recently, two cutoffs defining endoscopic remission (CDEIS <6) and complete mucosal healing (CDEIS <4) have been proposed.32,33 The complexity of using the CDEIS limits its usefulness in clinical practice, with use largely restricted to the clinical trial setting.
In an effort to address the complexities associated with the CDEIS, Daperno et al30,34 devised the Simple Endoscopic Score for Crohn's Disease (SES-CD). The SES-CD includes four variables: ulcer size, the extent of ulcerated surface, extent of affected surface, and stenosis, from 0 to 3 in five segments of the bowel. An advantage of the SES-CD is the emphasis on ulcers as the mucosal lesions most likely to change with therapy. The SES-CD correlates well with the CDEIS.30 However, as with the CDEIS, there is at present no agreement regarding cutoff values for defining endoscopic response to treatment, endoscopic remission, or mucosal healing.9
The Rutgeerts score is the only postoperative endoscopic grading system that has been used to describe the severity of endoscopic recurrence of lesions at the ileocolic anastomosis and preanastomotic ileum after resection. Hence, it has become the gold standard for assessment of mucosal healing in the postoperative setting.9 The Rutgeerts score was devised following the observation that endoscopic recurrence, particularly at the anastomosis, precedes clinical recurrence.24–26 Scoring is based on the presence of aphthous ulcers, presence and extent of ileitis, and the presence of nodularity and/or narrowing. Grading ranges from i0 to i4 accordingly.26 Although the reproducibility of the Rutgeerts scale has not been prospectively validated, the severity of endoscopic lesions at 1 year postoperatively has been demonstrated to be predictive of clinical recurrence24,26 Postoperative recurrence was initially defined as a Rutgeerts score ≥il but most clinical trials have used i2 as the cutoff to define endoscopic recurrence and i3 for defining “significant” or “severe” endoscopic recurrence. Rutgeerts score i2 is associated with an intermediate risk of clinical recurrence, but the definition of grade 2 is more subjective than those of the other grades. Due to the uncertain significance of i2 lesions some clinical trials have not regarded these lesions as representative of disease recurrence.35 Postoperative recurrence can occur after any type of resectional surgery. While the Rutgeerts endoscopic scoring index focuses on postoperative recurrence at the anastomosis for ileal and ileocolonic resection it does not incorporate a scoring system for the other bowel segments.36 In a recent study the preexisting Rutgeerts endoscopic score was modified to incorporate a scoring system of colonic lesions after surgery36; however, this modified Rutgeerts endoscopic grading score has not yet been validated.
The impact of detecting small bowel lesions in CD with capsule endoscopy on the clinical outcome remains uncertain.37,38 Capsule endoscopy can detect mucosal lesions within the small bowel beyond the reach of standard ileocolonoscopy. Few studies have examined the role of capsule endoscopy as a technique to assess mucosal healing. In a study by Efthymiou et al39 clinical response did not seem to correlate with mucosal healing as detected by capsule endoscopy. Disease activity indices specific for capsule endoscopy have been proposed and may provide a more objective method for assessing and monitoring mucosal healing; however, their usefulness in clinical trials and clinical practice remain to be determined.40,41
WHY IS MUCOSAL HEALING IMPORTANT?
Altering the Natural History of CD
CD is characterized by a relapsing and remitting disease course. Medical therapy is required by the majority of patients to maintain remission with intermittent induction therapy to manage flares. Approximately 90% of patients present with inflammatory nonstricturing, nonpenetrating disease. In the long term inflammation results in stricturing and penetrating disease.42 Up to 80% of patients require surgery at some point in their life.43 Surgery is not curative. Most often disease recurs at, and proximal to, the anastomosis. Up to 70% of patients require reoperation. Predictors for rapid progression to surgery include: smoking; isolated small bowel disease; nausea, vomiting, or abdominal pain on presentation; and neutrophil count and steroid use within the first 6 months of diagnosis.44 Predictors for a “disabling” disease course include: age below 40 years, the presence of perianal disease, and the initial requirement for steroids.45
Strategies aimed at altering the natural history of CD early in the disease course are likely to translate into improved clinical outcomes before stricturing and penetrating disease complications develop. A similar approach has been adopted successfully in the rheumatoid arthritis setting with the early use of methotrexate combined with corticosteroids or anti-tumor necrosis factor (TNF) therapy, resulting in altered natural history of disease associated with decreased development of deforming and disabling arthropathy.46–48 Although symptoms have traditionally been used to guide therapeutic approaches this has been insufficient to alter the natural history of CD.2,3 Directly targeting tissue damage with treatments that induce and maintain mucosal healing early in disease may reduce complications and may alter or halt the progression of disease. While symptoms may reflect underlying mucosal or transmural damage symptoms are nonspecific and can reflect intercurrent infection, irritable bowel syndrome, or adhesive bowel obstruction. Endoscopic assessment provides objective evidence of mucosal healing or damage as a consequence of which endoscopic outcomes are being increasingly used as efficacy endpoints in clinical trials.
There is emerging evidence that mucosal healing improves both short-term and long-term outcomes. In the short term, mucosal healing has been associated with reductions in CDAI and reduced steroid use. In the medium term, mucosal healing has been shown to associated with durable remission, a reduced complication rate, and a reduced need for surgery and hospitalization. Although mucosal healing is associated with improved outcomes, evidence regarding treatment escalation to induce mucosal healing and achieving improved outcomes is currently lacking.
LONG-TERM OUTCOME IN RELATION TO MUCOSAL HEALING
The long-term impact of mucosal healing on clinical outcome is one of the most important considerations in clinical practice if mucosal healing is to be used as a therapeutic target.
In the ACCENT 1 (A Crohn's disease Clinical study Evaluating infliximab in a New long-term Treatment regimen) trial mucosal healing was associated with a longer duration of clinical remission and a longer time to clinical relapse. At week 54, patients with complete mucosal healing remained in clinical remission for longer (median time to relapse 19–20 weeks) than patients without complete mucosal healing (4 weeks).49
In a further substudy of the ACCENT 1 trial the impact of mucosal healing at week 10 on outcomes at 1 year were explored by Rutgeerts et al.21 Complete mucosal healing rates were significantly higher at both weeks 10 and 52 among those receiving scheduled maintenance therapy compared with episodic therapy. Despite clinical remission being maintained in more than one-third of all patients with mucosal healing at week 10 and two-thirds of all patients with mucosal healing at week 54, the relationship between clinical remission and complete mucosal healing was not statistically significant.
In the “step-up top-down study,” comparing early induction therapy with infliximab and azathioprine versus gradual step-up induction therapy in patients who were treatment-naive with a short disease duration, a significantly greater proportion of the “top-down” group achieved mucosal healing at 2 years (73% vs. 30%, respectively). The value of the endoscopic assessment undertaken after 2 years of treatment in the “step-up top-down study” on clinical outcome in the subsequent 2 years was examined by Baert et al.23 Mucosal healing, defined as a SES-CD score of zero, was associated with steroid-free remission during the subsequent 2 years in 17 of 24 patients (71%) compared with 6 of 22 patients (27%) who had ongoing endoscopic disease activity (P = 0.036).
A large cohort study by Schnitzler et al52 evaluated the impact of mucosal healing on the long-term outcomes of patients undergoing treatment with infliximab for CD. Of the 214 patients followed up over a median of 5 years clinical remission was maintained in 65% (83/128) of those with mucosal healing compared with 40% (34/86) of patients who did not achieve mucosal healing (P = 0.0004).
A post-hoc analysis of the EXTend the Safety and Efficacy of Adalimumab Through ENDoscopic Healing (EXTEND) study presented in abstract form by Rutgeerts et al50 examined the impact of mucosal healing with adalimumab at week 12 on outcomes a year later. Mucosal healing status at week 12 was predictive of 1-year outcomes, including CDAI score and clinical remission, with statistical significance for patients with CD who received adalimumab 40 mg fortnightly. In particular, mucosal healing at week 12 was associated with a significant reduction in CDAI at week 52 by 46 points (P < 0.05). In contrast, increased SES-CD scores were associated with increased CDAI scores and decreased odds of clinical remission at 1 year.
A trial comparing azathioprine with budesonide in maintenance of remission among patients with steroid-dependent ileocolitis and proximal colitis8 demonstrated that after 1 year of treatment mucosal healing was achieved more often in the former than the latter group. At 18 months a greater proportion of those treated with azathioprine remained in clinical remission compared with those treated with budesonide (76% versus 36%, P = 0.03). When considered together these data suggest that mucosal healing is associated with maintenance of clinical remission.
Deep and extensive ulceration found at colonoscopy among patients with CD has been found to predict a more aggressive clinical course with increased rates of penetrating complications and surgery.22 Emerging clinical trial and cohort data have demonstrated that when mucosal healing is achieved there is subsequently less clinical relapse, a decreased need for hospitalization, and less need for surgery. Hence, mucosal healing may reduce the risk of complicated disease.
Decreased Need for Hospitalization
In the long-term follow-up study of infliximab by Schnitzler et al52 after a median follow-up of 69 months patients who achieved partial or complete mucosal healing with infliximab required fewer hospitalizations during follow-up (42% [54/128]) compared with patients who did not (59% [51/86], P = 0.001]).
Similar findings were observed in the endoscopic substudy of the ACCENT 1 trial where none of the nine patients who achieved mucosal healing at both week 10 and week 54 required hospitalization. Those who achieved mucosal healing at either 10 or 54 weeks (19% n = 3/16) required fewer hospitalizations than those who did not achieve mucosal healing at either week (28% n = 14/50).21
Reduced Need for Surgery
In a Norwegian population-based cohort study by Froslie et al7 a greater proportion of patients with CD who achieved mucosal healing at 1 year were able to avoid resection at the 5-year follow-up compared with those without mucosal healing (11% vs. 20% P = 0.10). Although not statistically significant at 10 years, the risk of surgery was reduced by 60% among those who achieved mucosal healing at 1 year compared to those who did not achieve mucosal healing (hazard ratio 0.42; 95% confidence interval [CI], 0.20-0.89).51 Similarly, in the long-term infliximab follow-up study Schnitzler et al52 found that patients who achieved complete or partial mucosal healing were also found to require major abdominal surgery significantly less often (14% [12/85]) than patients without mucosal healing (38% [33/86], P < 0.0001).
Possible Reduction in Dysplasia/Cancer
Although prospective studies are currently lacking, in the setting of ulcerative colitis mucosal healing may reduce the risk of colorectal cancer. This has not been examined in CD. Among patients with UC the severity of endoscopically visible “damage” and the presence of ongoing histologic inflammation are established risk factors for the development of colorectal cancer. Rutter et al53 found in a case-controlled study of 68 patients with UC that the degree of histologic inflammation positively correlated with an increased risk of neoplasia. A similar positive association between neoplastic complications with among patients with UC and degree of microscopic inflammation has also been found in other studies.54,55 Further studies among CD patients are required before a reduced cancer risk in CD can be ascribed to mucosal healing.
IS MUCOSAL HEALING ACHIEVABLE WITH CURRENT TREATMENT? INDUCTION OF MUCOSAL HEALING
Corticosteroids may induce mucosal healing acutely in a minority of patients with CD. In a study by the GETAID group treatment with high dose prednisolone (1 mg/kg) for up to 7 weeks resulted in clinical remission in 92% of patients and endoscopic remission in 29% (38/131) according to CDEIS criteria (the presence of no lesions, healed lesions, or minor lesions).18 Thirteen percent (17/131) achieved complete mucosal healing (defined as the appearance of no lesions or scars) and endoscopic lesions worsened in 9% of patients despite symptomatic improvement.
In a study by Olaison et al56 of eight patients with preanastomotic ileal recurrence after surgery treatment with a tapering course of corticosteroids for up to 9 weeks resulted in significant symptomatic improvement without corresponding improvement in the severity of endoscopic lesions.
A recent Norwegian inception cohort study found that use of corticosteroids to control CD decreased the likelihood of mucosal healing at 1 year.7 It is unclear whether this was due to a greater disease burden or a direct effect of steroid therapy in the steroid-treated group. The ability of steroids to downregulate the inflammatory response without healing the bowel mucosa has led some authors to speculate that glucocorticoids may have a deleterious effect on tissue restitution in segments of bowel with deep ulcers.1
A recent meta-analysis by Ford et al57 concluded that aminosalicylates are of uncertain benefit in inducing clinical remission and preventing relapse of quiescent CD. There is no evidence that aminosalicylates induce mucosal healing in CD.
In a recent meta-analysis by Khan et al58 antibiotics were found to be superior to placebo in inducing remission in luminal and perianal CD. However, very few studies have examined the impact of antibiotics on mucosal healing in luminal CD and the results have been mixed. There was no evidence of mucosal healing seen in the large Australian placebo controlled trial evaluating antimycobacterial therapy (ethambutol, clofazimine, dapsone, and rifampicin) for the treatment of CD.59 In contrast a retrospective study evaluating a separate combination of antimycobacterial drugs (rifabutin, clofazimine, and clarithromycin) found that mucosal healing was achieved in 56.4% (22/39) of treated patients who received the regimen for a period of between 6 months and 9 years.60 Further studies are required to establish whether antibiotics can induce mucosal healing in CD and to determine which antibiotic regimen is most effective.
Thiopurines have been associated with both clinical improvement and mucosal healing. In a study by Sandborn et al61 examining the effect of an intravenous loading doses of azathioprine, six patients with inflammatory CD with both clinically and endoscopically active disease were included at study entry. After 16 weeks of treatment, of the four who achieved clinical remission all had endoscopic improvement and three had complete endoscopic healing.
In the postoperative setting D'Haens et al62 showed that among patients with severe postoperative recurrence of steroid-refractory ileal disease, treatment with azathioprine for at least 6 months resulted in healing of severe lesions. Of the patients who achieved clinical remission 6 of 15 (40%) achieved complete mucosal healing of their ileum. Subtotal mucosal healing was achieved in 5 (33%) and partial healing was achieved in 3 (20%).
In a separate study of patients with active ileocolitis, outside of the postoperative setting, D'Haens et al5 examined the endoscopic outcome in patients who had achieved clinical remission following full dose azathioprine therapy for a mean of 24 ± 14 months. Of the 20 patients with colonic disease there was complete mucosal healing in 14/20 (70%), near-complete healing in 2/20 (10%), and partial healing in 3/20 (15%). Among the 13 patients with ileal disease complete healing was observed in 7/13 (54%), near-complete in 2/13 (15%), and partial healing in 1/13 (8%). Histologic examination revealed disappearance of the inflammatory infiltrate, but with some architectural disturbance remaining.
A retrospective study of 53 patients found that azathioprine induced complete clinical remission in 23% and was effective in a further 42% of patients.63 Compared with pretreatment, the ulcer score improved significantly after azathioprine treatment.
Methotrexate has been shown to induce and maintain clinical remission in CD64; however, there have been relatively limited data regarding mucosal healing.
In a nonrandomized open label trial of methotrexate by Kozarek et al,4 of 5 of 14 (36%) patients with CD had colonoscopic healing and 4 had normal histology at 12 weeks.
A retrospective cohort study by Manosa et al65 evaluated mucosal healing in eight patients who developed steroid-free remission on methotrexate. Following a median duration of methotrexate treatment of 15 months (range 6–60), total mucosal healing was found in three and partial healing in two patients. Mucosal lesions worsened in two patients and no change was seen in the remaining patient, despite achieving steroid-free clinical remission. The three patients with complete healing had isolated colonic involvement.
The long-term effect of methotrexate on mucosal healing has been published in abstract form.66 Among 17 patients who responded to induction and maintenance methotrexate for a period of 52 weeks, complete healing was seen in 10/17 (59%) (four ileocolitis, three ileitis, three colitis), 2/17 (12%) had near complete healing, 2/17 (12%) had partial healing, and 3/17 (18%) had no healing.
The ability of methotrexate to induce mucosal healing compared to azathioprine and infliximab was recently evaluated by Laharie et al.33 Among patients with previously documented endoscopic mucosal ulceration who had achieved clinical remission off steroids in the previous 3 months with a single immunomodulator (methotrexate, azathioprine, or infliximab), mucosal healing was achieved in 2 of 18 (11%) with methotrexate, 9 of 18 (50%) with azathioprine (P = 0.011 vs. methotrexate), and 9 of 15 (60%) with infliximab (P = 0.008 vs. methotrexate).
The most profound impact on mucosal healing in CD has been seen with biological drugs. Van Dullemen et al67 showed dramatic endoscopic improvement in the first published trial of infliximab. Several studies have subsequently demonstrated mucosal healing with infliximab.6,21,67–73
An endoscopic substudy of the trial by Targan et al74 demonstrated that mucosal healing accompanied clinical improvement with infliximab infusions of 5, 10, or 20 mg/kg.6 There was a good correlation between improvement in CDAI and CDEIS as early as 4 weeks after the first infusion. Endoscopic improvement with disappearance of ulcers was evenly distributed in all colonic segments with resolution of ulcers ranging from 74% in the ileum to 96% in the rectum. Mucosal healing was also accompanied by disappearance of inflammatory infiltrate on histology among those receiving infliximab.
The ACCENT 1 trial, which compared the outcome in patients with active CD treated with infliximab 5 or 10 mg/kg, or placebo, for 1 year, included an endoscopic sub-study of 99 patients.21,73,75 At week 10 mucosal healing was observed in 29% of patients (13/45) who had received induction therapy with three infusions of infliximab 5 mg/kg (administered at weeks 0, 2, and 6) compared with 3% of patients (1/29, P = 0.006) who received only one infusion at baseline. At week 54, 44% (16/36) of patients treated with scheduled maintenance 8-weekly infliximab achieved complete mucosal healing compared with 18% (4/22, P = 0.041) who received infliximab episodically.
A recent retrospective study of 71 patients with active luminal CD treated with infliximab, in whom endoscopy was performed at 3 and 12 months, demonstrated mucosal healing (defined as no inflammatory activity or only mild inflammation without ulceration) in 45% at 3 months and 53% at 12 months.76 Mucosal healing at 3 months predicted the persistence of mucosal healing at 12 months (P < 0.001).
In the SONIC trial, which compared infliximab monotherapy, azathioprine monotherapy, and combined infliximab and azathioprine therapy for active luminal CD, at week 26 mucosal healing (absence of mucosal ulcers) was achieved in 30% (28/93), 19%, and 44% of patients, respectively (P < 0.001).77
The ability of certolizumab pegol to induce mucosal healing was evaluated in an open-label study known as the MUSIC (endoscopic MUcoSal Improvement in patients with active CD treated with Certolizumab Pegol) trial where the primary endpoint was endoscopic healing at 10 weeks.32 Patients were treated with subcutaneous certolizumab pegol at weeks 0, 2, and 4 followed by a further injection at week 8 as induction therapy. Maintenance therapy was continued at 400 mg 4-weekly thereafter as part of an ongoing 54-week study. At 10 weeks endoscopic remission (defined as CDEIS <6) was seen in 42% and endoscopic response in 62% of patients, but mucosal healing (defined as absence of ulcers) was seen in 5% of patients.
The EXTEND (Extend the Safety of and Efficacy of Adalimumab Through Endoscopic Healing) placebo-controlled trial recently evaluated the impact of adalimumab on mucosal healing in 129 patients with active ileocolonic CD.78 Patients received open-label adalimumab 160 then 80 mg induction therapy at weeks 0 and 2, and were then randomized at week 4 to blinded maintenance therapy with fortnightly adalimumab 40 mg or placebo through to week 52. The primary endpoint, absence of mucosal ulceration at week 12, was observed in 27% (17/62) of the adalimumab group compared with 13% (8/61) of placebo-treated patients (P = 0.06). After 1 year complete mucosal healing was observed in 24% of adalimumab-treated patients compared with none of those on placebo (P < 0.001). “Deep remission,” defined as clinical remission on CDAI combined with complete mucosal healing, was seen in 16% and 19% of adalimumab-treated patients at weeks 12 and 52, respectively, compared to ≈10% and 0% of patients receiving only induction treatment with adalimumab followed by placebo (P = 0.34 and P < 0.001, respectively).79 A recent post-hoc analysis of adalimumab-treated patients in the EXTEND study demonstrated improved mucosal healing rates at week 12 in those with a disease duration of <5 years compared with those with a disease duration ≥5 years (odds ratio = 15.27 and 1.21, respectively).80
Natalizumab has demonstrated efficacy in inducing and maintaining clinical remission in CD and has also been shown to induce mucosal healing.81–83 In an endoscopic substudy of the ENACT-1 trial in active CD83 of 53 with mucosal ulceration at study entry, mucosal healing at week 10 was observed in 22% of natalizumab-treated compared with 8% of placebo-treated patients.
Taken together, these studies of biologic agents indicate that the current most effective therapy for CD results in mucosal healing in 5%–44% of patients. While mucosal healing is a worthwhile treatment goal, it cannot be achieved in all patients.
Three meta-analyses and two Cochrane reviews concluded that corticosteroid therapy is more effective than enteral nutrition at inducing clinical remission among patients with CD.84–88 In contrast, a separate meta-analysis conducted in pediatric trials alone demonstrated that enteral feeds and corticosteroids were equally effective.89
Four pediatric studies have reported on mucosal healing in association with exclusive enteral nutrition.90,91 In a trial by Borelli et al90 comparing enteral nutrition with corticosteroids there was no significant different difference in clinical remission rates, but mucosal healing was achieved in a significantly higher proportion of children receiving the polymeric diet (74% [14/19] vs. 33% [6/18], P < 0.05). In a study of 26 patients by Afzal et al91 there was a significant improvement in endoscopic score following an 8-week course of exclusive enteral nutrition. A pediatric case series by Fell et al92 also demonstrated mucosal healing in association with enteral nutrition. More recently, Rubio et al93 performed a retrospective review comparing fractionated oral versus continuous enteral feeding among pediatric patients treated with exclusive nutritional therapy. Mucosal healing was found in both groups and had a clear correlation with clinical remission rates.
The impact of the opioid receptor antagonist naltrexone on induction of clinical and endoscopic remission in CD was recently evaluated in a randomized placebo-controlled trial.94 Following 12 weeks of treatment 33% of patients achieved endoscopic remission (defined by a CDEIS <6) compared with 8% in the placebo arm.
MAINTENANCE OF MUCOSAL HEALING
Maintenance of mucosal healing has been assessed after induction of endoscopic remission, achieved with either drugs or surgical resection
Corticosteroids have not been shown to maintain endoscopic or clinical remission in CD.8,95–97 A controlled trial by Mantzaris et al8 compared azathioprine with budesonide in maintenance of remission among patients with steroid-dependent ileocolitis and proximal colitis. The endoscopic findings after 12 months of treatment were compared with baseline. Complete or near-complete healing was achieved in 83% of azathioprine-treated patients compared with 24% of budesonide-treated patients (P < 0.0001).
The efficacy of budesonide in maintaining surgically induced remission has been evaluated in two controlled trials. Both studies showed no significant difference in endoscopic and clinical recurrence rates at 3 and 12 months compared with placebo.96,97
Aminosalicylates are of uncertain benefit in the maintenance of remission in luminal CD.98 In the postoperative setting a meta-analysis by Doherty et al99 found that mesalamine decreased clinical but not endoscopic recurrence and was inferior to azathioprine or mercaptopurine for all outcomes. A recent controlled trial by Reinisch et al100 comparing mesalazine and azathioprine for the prevention of clinical recurrence among patients with established moderate or severe endoscopic recurrence (Rutgeerts i2–i4) demonstrated no differences in clinical or endoscopic outcomes at 1 year. A Cochrane review indicated that the number needed to treat to prevent clinical recurrence was 12 and to prevent severe endoscopic recurrence was eight.101 The weight of evidence therefore suggests that 5-ASA is of uncertain benefit in preventing endoscopic and clinical disease recurrence, and if used at all should be restricted to those at low risk of postoperative recurrence.102–105
Outside of the postoperative setting there is no evidence that antibiotics maintain endoscopic remission. Within the postoperative setting the imidazole antibiotics (metronidazole and ornidazole) have been demonstrated in a recent meta-analysis of two randomized controlled trials to reduce the risk of endoscopic (relative risk [RR] 0.44; 95% CI 0.26–0.74, NNT = 4) and clinical recurrence (RR 0.23; 95% CI 0.09–0.57, NNT = 4) relative to placebo.106,107 However, both these drugs were associated with a higher risk of adverse events (RR 2.39, 95% CI 1.5–3.7) and patient withdrawal than placebo.108 When compared with placebo, metronidazole (20 mg/kg/day) for 3 months postoperatively reduced both severe endoscopic recurrence and clinical recurrence at 1 year.106 The reduction in clinical recurrence rates was sustained for 3 years. In the second trial, ornidazole (1 g/day) given for 1 year postoperatively significantly reduced endoscopic and clinical recurrence compared with placebo at 1 year.107 However, there was no difference in clinical recurrence after long-term follow-up at 3 years. At the dosages used side effects were experienced in about half the patients in both trials, resulting in discontinuation of the drug in 13% and 21% of patients, respectively. Fewer side effects may be experienced if lower doses of these drugs are used.109 Imidazole antibiotics prevent early endoscopic recurrence and delay clinical recurrence but their long-term use is limited by drug effects and toxicity. Long-term use of low-dose therapy has not been formally evaluated.
Azathioprine was compared with budesonide in the study referred to previously.8 The impact of azathioprine on mucosal healing has also been evaluated in a GETAID study examining the effect of azathioprine withdrawal in 43 CD patients.110,111 Eighty-three patients in clinical remission on azathioprine, with no greater than 10 mg of steroids in the previous 42 months, were randomized to receive either azathioprine (n = 40) or placebo (n = 43) for 18 months. Colonoscopy was performed at inclusion in 45 patients. At baseline (prior to azathioprine withdrawal) complete mucosal healing (CDEIS = 0) was observed in 16/45 (36%) patients and ulcerations were still present in 21/45 (47%) of the patients with residual lesions. Although a positive correlation was observed between the CDEIS scores and CDAI (P = 0.034), the presence of residual ileocolonic lesions or ulcerations at endoscopy was not predictive of relapse; the results of this study did not support the concept that mucosal healing could be used as a marker for prediction of stable remission
The efficacy of thiopurines in maintaining mucosal healing after surgical resection has been evaluated in several studies.62,112–121 Some of these have compared thiopurines with aminosalicylates.112,118,120–122 Despite the relatively small differences in efficacy found between thiopurines and aminosalicylates in these studies a recent Cochrane review found thiopurines to be more effective overall than aminosalicylates in preventing endoscopic, severe endoscopic, and clinical recurrence.101
Domenech et al123 prospectively reviewed the long-term impact of immediate thiopurine prophylaxis in the postoperative setting on endoscopic and clinical recurrence rates. During the follow-up period 23% of patients developed clinical recurrence. The cumulative probability of endoscopic recurrence was 44%, 53%, 69%, and 82%, at 1, 2, 3, and 5 years, respectively, suggesting that despite the reduction of early recurrence with azathioprine endoscopic and clinical recurrence do develop over time.
The efficacy of combined azathioprine with metronidazole on postoperative recurrence was recently evaluated in a controlled trial by D'Haens et al.109 All patients received metronidazole 250 mg three times daily for 3 months. Patients were randomized to receive additional azathioprine or placebo for 12 months. The endoscopic recurrence rate at 12 months was significantly lower in those receiving concurrent azathioprine (44%) compared to placebo (69%).
In a recent meta-analysis of thiopurines in the postoperative setting which included four randomized controlled trials, thiopurines were found to be more effective than control medications in preventing endoscopic recurrence (Rutgeerts score i2–i4) at 1 year, but were not effective in the prevention of very severe (i3–4) recurrence.122
Anti-TNF therapy has demonstrated efficacy in maintaining mucosal healing in CD.6,70,75,78 In the ACCENT 1 trial after 1 year of scheduled maintenance treatment with infliximab complete mucosal healing was seen in half the patients.73,75 A greater proportion of patients treated with scheduled treatment achieved complete mucosal healing at week 54 compared with those receiving episodic infliximab (50% vs. 7%, P = 0.007).21,74
The strength and speed of early induction impacts the later mucosal healing rate. Early induction with infliximab and azathioprine produced a greater rate of mucosal healing at 2 years (71%) than stepping up with steroids and azathioprine (30%, P < 0.001), despite a similar final rate of azathioprine use in both groups at 2 years.70
In the EXTEND study, maintenance treatment with adalimumab resulted in a significantly greater rate of mucosal healing than placebo maintenance at 1 year (24% vs. 0%).78
Anti-TNF therapy has been shown to maintain mucosal healing in the postoperative setting. In a recent trial by Regueiro et al,124 24 patients were randomized to receive either infliximab or placebo immediately after ileocolonic resection. Endoscopic recurrence (Rutgeerts score i2–i4) at 1 year postoperatively occurred in one of 11 (9%) of infliximab-treated patients compared to 11 of 13 (85%) placebo-treated patients (P = 0.0006).124 After 1 year patients were offered open-label infliximab and followed for a second year.125 Of the six patients originally on infliximab, four opted for open-label infliximab, with three of the four remaining in endoscopic remission. Of the six initially placebo-treated patients all received open-label infliximab and all but one demonstrated endoscopic improvement at 2 years; however, 50% (three) patients had a Rutgeerts score of i2. These 24-month data suggest that infliximab prevents clinical recurrence for at least 2 years. Infliximab did effectively heal endoscopically visible disease when started 1 year after surgery but the effect was greater when started immediately postoperatively.
Sorrentino et al154 recently explored the impact of stopping infliximab on mucosal healing after 3 years of postoperative therapy. Twelve patients treated immediately postoperatively with 5 mg/kg infliximab maintenance therapy, who did not have endoscopic or clinical recurrence after 3 years, underwent colonoscopy 4 months after stopping infliximab. Discontinuation of infliximab resulted in endoscopic recurrence in 10 of 12 patients (83%). Mucosal integrity was restored and maintained for 1 year after retreating all 10 patients with 8-weekly infliximab at a lower dose of 3 mg/kg. These data confirm the observation that endoscopic disease often recurs after infliximab is stopped. Infliximab therapy at a lower-than-standard dose of 3 mg/kg appears to be effective in reinducing mucosal healing and maintaining mucosal healing for at least 1 year.
The efficacy of a standard induction and maintenance regimen of adalimumab in maintaining mucosal healing has been evaluated in three nonrandomized studies, each of which have been presented in abstract form.126–128 In a study of 20 patients by Fernandes-Blanco et al126 at 12 months postoperatively, endoscopic recurrence (Rutgeerts score of ≤i1 or greater) was seen in two patients (10%). None of the patients had clinical recurrence. In an Australian study adalimumab was commenced in 11 high-risk, thiopurine-intolerant patients within 4 weeks of surgery. At 6 months postoperatively 10 of 11 patients (91%) maintained endoscopic remission (Rutgeerts score of ≤i1) compared to 1/11 (9%) who developed endoscopic recurrence.127 A further study by Mantzaris et al128 demonstrated that all seven patients who commenced adalimumab within 2 weeks of surgery maintained endoscopic remission (Rutgeerts ≤i1) at 6 months postoperatively. In a separate group of 13 patients with established postoperative endoscopic recurrence the same authors found that treatment of endoscopic recurrence with adalimumab resulted in endoscopic improvement in 3/4 patients (75%) with Rutgeerts i3 lesions and 5/9 (56%) of patients with Rutgeerts i2 lesions.128 These preliminary data suggest that adalimumab may also be effective in maintaining mucosal healing and preventing postoperative recurrence.
While a recent Cochrane review indicated that enteral nutrition may be effective in maintaining clinical remission129 in CD, very few studies have evaluated its effect in maintaining mucosal healing. In a recent nonrandomized study of 40 patients, Yamamoto found that at 12 months postoperatively endoscopic recurrence was observed in 6/20 (30%) in those receiving self-administered nocturnal supplemental enteral nutrition formula (Elental) compared with 14/20 (70%) who did not receive enteral nutrition (P = 0.027).130
PRACTICAL ISSUES IN INTEGRATING THE GOAL OF ACHIEVING MUCOSAL HEALING INTO CLINICAL PRACTICE
Mucosal healing may be a desirable goal, but there may be barriers to its achievement. Apart from the definition of mucosal healing being unclear, the optimal timing after surgery or initiation of drug therapy of endoscopic evaluation is yet to be determined. Premature endoscopic evaluation may lead to the false assumption that the therapeutic intervention is not effective, while delayed endoscopic evaluation may miss the opportunity to intervene prior to disease progression.
Endoscopy is invasive, associated with perforation risk, costly, and time-consuming. Its repetition is difficult to justify in patients for whom there is no opportunity available to escalate therapy based on the findings. In several countries government and funding authorities have determined that access to drugs such as anti-TNF therapy be based on clinical, not endoscopic, parameters. Although it may be reasonable to assume that a proportion of patients who have not achieved mucosal healing using less intense immunosuppression (such as with a thiopurine alone) will achieve mucosal healing if treatment if intensified, using biological or combination therapy, it has not been tested whether intensifying treatment with the goal of achieving mucosal healing in those patients who have not achieved it results in an improved outcome. Until this evidence is available access to anti-TNF therapy via government schemes is likely to be restricted to those with severe CD based on conventional clinical indices.
Escalation of therapy to achieve mucosal healing is likely to increase the risk of lymphoma and infections. This must be weighed against the benefits of preventing the complications associated with undertreatment of CD.
Despite these limitations there are several situations where mucosal healing can be integrated into clinical practice to help guide therapy.
Confirming Inflammatory Disease Activity in a Symptomatic Patient
In a patient established on a therapeutic agent the relapse of symptoms does not always signify mucosal damage. In order to establish true “therapeutic failure” endoscopic evaluation may be warranted to exclude complications such as stricture and infection (cytomegalovirus [CMV]) and to confirm the presence of mucosal disease activity prior to intensifying or switching the therapeutic regimen. In such cases the timing of endoscopy and interpretation of findings should be such that the drug regimen has been allowed adequate time to take effect.
Establishing Depth of Remission in a Patient Who Has Achieved Clinical Remission
In a patient who has achieved clinical remission endoscopic evaluation allows the “depth” of remission, endoscopically and/or histologically, to be assessed. If mucosal healing has not been achieved escalation maybe warranted.
Identifying Patients with Poor Prognostic Factors
Not all patients require intense treatment. A number of clinical and endoscopic predictors of an aggressive disease course have been identified.44,45 Ileal disease location and the combination of small bowel and colonic disease location are predictors of more rapid progression to surgery44 and disabling disease,45 respectively. Endoscopically identified deep and extensive ulceration is a predictor of a more aggressive disease course.22 Therefore, in addition to clinical risk factors, disease location and extent, depth of ulceration, and ongoing mucosal disease activity (representing a lack of mucosal healing) may help to identify patients more likely to progress to complications for whom a more aggressive therapeutic approach is required.77
In the postoperative setting endoscopic recurrence precedes clinical recurrence.24–26 The extent and severity of endoscopic mucosal lesions have been found to be predictive of subsequent clinical disease course.26 Endoscopic evaluation undertaken within a year postoperatively may therefore help guide therapeutic decision making131,132; however, this approach remains to be prospectively evaluated.
Knowing when to stop immunosuppressive or biologic agents has emerged as a key issue in the management of patients with IBD. The GETAID azathioprine withdrawal study found that among patients in clinical remission on azathioprine withdrawal of therapy more often led to disease relapse than maintenance of azathioprine.111 The presence of residual lesions at endoscopy was not predictive of relapse; however, only 54% were evaluated endoscopically at baseline. Therefore, the predictive value of mucosal healing prior to azathioprine withdrawal could not be deduced from the study.111,133
The STORI study investigated the effect of infliximab discontinuation in 115 patients in steroid-free clinical remission for 6 months or more on combined infliximab and azathioprine. Of the patients who achieved “stable remission” (steroid-free, mucosal healing, and normal CRP) more than 80% maintained remission after ceasing infliximab after a period of 10 months.15 Therefore, mucosal healing may be used to identify patients among whom stopping anti-TNF therapy may be considered.
NONINVASIVE METHODS OF ASSESSING MUCOSAL DISEASE
If the attainment of mucosal healing is to play a greater role in evaluating the therapeutic response in clinical practice there will be a need for noninvasive surrogate markers to quantify asymptomatic disease activity, allow serial monitoring, and help predict disease course. Noninvasive methods of assessing mucosal healing include computed tomography (CT) and magnetic resonance imaging (MRI), measurement of fecal biomarkers (calprotectin and lactoferrin), and serum biochemical markers such as erythrocyte sedimentation rate (ESR) and CRP. None of these measurements are sufficiently validated currently to guide treatment recommendations.20
Fecal Calprotectin and Fecal Lactoferrin
Fecal calprotectin and lactoferrin are biomarkers of gastrointestinal inflammation that have demonstrated a strong association in IBD with endoscopically and histologically active disease, but a poor correlation with CDAI.134–136 Fecal calprotectin and lactoferrin correlate closely with the CDEIS and SES-CD.134–136 In a study of patients in whom fecal calprotectin concentrations were measured during both active disease and remission, a normal fecal calprotectin level was shown to correlate well with mucosal healing.137,138
A few studies have evaluated the role of fecal biomarkers in monitoring response to therapy. Fecal calprotectin and lactoferrin concentrations have been found to decrease in parallel with anti-TNF therapy induced endoscopic mucosal improvement.139,140 In a study by Sipponen et al139 in patients commenced on infliximab, the median fecal calprotectin concentration fell from 1173 to 130 μg/g following 3 months of treatment. The reduction in fecal calprotectin with anti-TNF therapy correlated strongly with endoscopic mucosal healing as measured by the CDEIS. In a separate study by the same authors using a variety of conventional drugs for CD, fecal calprotectin and lactoferrin normalized among endoscopic responders but remained elevated among nonresponders irrespective of the type of drug therapy used.141 Normalization of the fecal biomarkers appeared to be a good correlate of mucosal healing as measured by SES-CD during CD therapy. Calprotectin levels have been found to decrease in response to glucocorticoid therapy in parallel with clinical activity; however, the levels seldom normalize suggesting ongoing subclinical inflammatory activity.142 Other small studies that have included CD patients have also indicated a reduction in fecal biomarker concentrations in response to drug treatment but endoscopic evaluation posttreatment to assess correlation with mucosal healing has been lacking.143,144
The value of fecal inflammatory markers in predicting future clinical activity and outcome has been evaluated in a number of studies. In CD fecal calprotectin and lactoferrin have been shown to predict the rate of relapse within 1 year with a sensitivity and specificity that range from 69%–90% and 43%–83%, respectively.145–149
In the STORI study investigating infliximab discontinuation, in those with mucosal healing and normal CRP, fecal calprotectin levels were higher in patients who relapsed than in those who had sustained remission.15 Raised calprotectin despite macroscopic mucosal healing in the ileum and colon presumably related to either active disease more proximally within the small bowel or persistent epithelial microscopic inflammation.
In predicting a flare of disease activity during the ensuing 3 months, a normal fecal calprotectin has a high negative predictive value of 100%. Predictive accuracy diminishes beyond 3 months. Stool biomarkers in CD may correlate poorly with isolated ileal disease.150
Fecal Biomarkers in the Postoperative Setting
Few studies have investigated the role of fecal biomarkers in the postoperative setting. Although a crosssectional study151 showed that fecal calprotectin and lactoferrin concentrations remained elevated at long-term follow-up, even in patients who remained in clinical remission, a more recent longitudinal and cross-sectional study by Lamb et al152 found a good correlation between fecal calprotectin, fecal lactoferrin, and clinical recurrence as measured by the Harvey–Bradshaw index. Both fecal biomarkers permitted discrimination between active and inactive disease among symptomatic patients. However, the fecal biomarkers did not correlate with endoscopic activity among the small numbers of patients who underwent colonoscopy, indicating that further assessment of the relationship between these fecal markers, mucosal inflammation, and endoscopic changes is required.
The ability of a single fecal calprotectin to predict future endoscopic recurrence among asymptomatic patients has been examined in a prospective, longitudinal study of 50 patients after ileocecal resection. Fecal calprotectin measurement and abdominal ultrasonography at 3 months were followed by colonoscopy at 1 year.153 At 3 months postoperatively ultrasound had a greater specificity than fecal calprotectin (90% compared to 75%) for the prediction of mucosal endoscopic recurrence at 1 year; however, fecal calprotectin values greater than 200 μg/L showed a higher sensitivity than ultrasound (63% compared to 26%). When a number of different cutoff values were compared the best cutoff value for calprotectin sensitivity (63%) and specificity (75%) was >200 mg/L, leading Orlando et al153 to conclude that a fecal calprotectin value >200 μg/L could be used as a tool to decide which patients should have colonoscopy after surgery to detect early mucosal recurrence.
The role of fecal calprotectin in monitoring response to anti-TNF therapy has been examined in the postoperative setting by Sorrentino et al.154 Following reinduction of endoscopic remission with low-dose infliximab, fecal calprotectin levels were found to correlate well with endoscopic improvement as measured by the Rutgeerts score.
Noninvasive Cross-sectional Imaging
Several studies of noninvasive imaging modalities, including CT and MR enterography and colonography, and ultrasonography, have demonstrated a good correlation with endoscopically assessed mucosal healing and clinical outcome.155–159 The utilization of these techniques in the diagnosis, assessment of activity, and complications of CD have been summarized in recent reviews by Panes et al,155 Allen et al,160 and De Cruz et al.161 These noninvasive imaging modalities avoid the risks associated with endoscopy, such as perforation, bleeding, and sedation-related complications. CT and MR enable assessment of the upper gastrointestinal tract beyond the reach of standard ileocolonoscopy. CT, MRI, and ultrasound also allow transmural characterization of CD and are able to identify fistulas, abscesses, and stenosis with sensitivities and specificities greater than 80%. All three Imaging modalities allow assessment of deep-tissue damage and therefore may allow monitoring of not only mucosal healing but deep-tissue healing.
MRI has a sensitivity of 93% and specificity of 90% for the assessment of disease extent and severity of luminal CD and is less dependent on the operator and disease location than ultrasonography.155 An MRI activity index (MRAI) for CD activity that correlates well with the CDEIS has been devised by Rimola et al162,163 and recently externally validated.164 In the postoperative setting MRE (MR enterography) has a sensitivity of 100% and specificity of 89% in detecting postoperative recurrence.165 An MRE score has been devised to grade the severity of recurrence; it correlates well with the Rutgeerts score, and exhibits reasonable interobserver agreement of 78% with a kappa coefficient of 0.673.165 The MRE scoring system and ileocolonoscopy have been found to be of similar value in predicting postoperative clinical recurrence.159 MR enterography is currently limited by its lack of widespread availability.
CT has similar accuracy to MRI for assessment of disease extent and activity in luminal CD.155 In the postoperative setting it maybe be useful to detect structural change, but has not been proven to detect early mucosal disease.161 The main limitation of CT is that it exposes patients to ionizing radiation and contrast dye.
Ultrasonography has a sensitivity of 84% and specificity of 92% for the evaluation of disease activity in luminal CD.155 In the postoperative setting compared to ileocolonoscopy, bowel ultrasonography was able to detect postoperative recurrence with a sensitivity of 79% and specificity of 95%.155 Compared with ileocolonoscopy small intestine contrast ultrasonography (SICUS) has a sensitivity of 92% and diagnostic accuracy of 87.5% for postoperative recurrence.167–169 Ultrasonography avoids exposure to ionizing radiation. However, its accuracy is lower for disease proximal to the terminal ileum. Availability is limited and operator dependence is great.167,170,171
CRP is the most common laboratory marker used to measure CD activity. There is good correlation between CRP and severe clinical and endoscopic activity in the majority of patients.172,173 However, it is less sensitive as a biomarker for asymptomatic biologically significant disease activity. Although CRP correlates well with severe endoscopic activity it is relatively insensitive for mild to moderate disease activity.135 Among patients in clinical remission (CDAI <150) but with endoscopically active disease a single retrospective study found that CRP remained normal in 60% of cases.174 When collected at a single timepoint CRP has not been demonstrated to correlate well with endoscopic activity or long-term prognosis.175,176 Moreover, its ability to predict future clinical outcome and response to therapy have not been consistently demonstrated. Nonetheless, a CRP of less than 20 mg/L and an ESR of less than 15 have, in one prospective study, been found to have a negative predictive value of 97% for flare in the next 6 weeks.175
In the review by Schnitzler et al177 of 614 CD patients treated with infliximab and followed for a median of 55 months, improved outcomes were observed if CRP fell and remained less than 3 mg/L. CRP currently has some value in the detection of asymptomatic disease activity including mucosal inflammation when collected at a single timepoint; however CRP elevation is not observed in all patients and the impact of elevated CRP on long-term clinical and endoscopic activities are unknown.135,156
Very few studies have evaluated the impact of treatment on histologic activity in CD and there is currently no validated scoring system to quantify histologic disease activity in CD. Nonetheless, histologic remission has been achieved previously with azathioprine, methotrexate, and infliximab.4,6,8,62,71 The speed with which histologic improvement could be achieved was demonstrated by D'Haens et al,6 who found histological improvement with disappearance of inflammatory infiltrate after a single infusion of infliximab. The impact of infliximab on morphologic features of mucosal inflammation was evaluated by Geboes et al,71,178 who found an alteration in the presence of neutrophils in the setting of mucosal healing. Although these changes were associated with a reduction in inflammatory markers the correlation of clinical and endoscopic findings with histology was not clear.71,178
More recently, in the postoperative CD setting there was a marked reduction in histologic recurrence with infliximab (27%) versus placebo-treated (85%) patients.124 While the impact of histologic remission on future clinical disease activity is yet to be determined it may signify “deep remission” when considered as a composite endpoint together with clinical, endoscopic, and biochemical remission.
AN APPROACH TO THE INTEGRATION OF MUCOSAL HEALING INTO CLINICAL PRACTICE
Therapies for CD have traditionally been directed toward symptom resolution. While still important, this has not changed the natural history of CD. Mucosal healing is associated with several short- and long-term benefits including steroid-free clinical remission, reduced hospitalization and surgery, improved quality of life, and increased work productivity, all of which are surrogate markers that suggest that mucosal healing has the capacity to change the natural history of CD.
Mucosal healing may be difficult to achieve in some patients who do not achieve this goal using standard drug therapy, and is yet to be demonstrated. Whether treatment intensification can achieve healing, at what cost in terms of drug dose and safety, and whether it can be maintained the long term in those patients are all questions that remain to be answered.
Based on the available evidence we propose the following approach to the integration of mucosal healing in clinical practice: 1) Therapeutic strategies should take into account clinical risk factor assessment, including consideration of adverse prognostic factors. 2) Endoscopic assessment of mucosal disease should provide further direct evidence to assist with risk stratification. 3) Therapy should be targeted at achieving “stable” remission, that is, steroid-free with normalization of laboratory biomarkers 4) In the symptomatic patient endoscopic evaluation has a role in “defining treatment failure” and confirming inflammatory disease activity prior to intensifying within class or switching drug regimens. 5) In the asymptomatic patient endoscopic evaluation along with laboratory biomarkers can establish the “depth” of remission. If endoscopic and/or laboratory inflammation persist it may prompt evaluation of compliance with the drug regimen, optimization of therapy within class, or escalation of therapy depending on the patients risk profile. For such patients timing of subsequent endoscopic evaluations can be tailored according to their clinical and endoscopic risk profile. If “deep remission” has been achieved and the patient is symptom-free, with complete mucosal healing and normal laboratory markers, it may prompt consideration of de-escalation of therapy.
Noninvasive imaging, and stool and blood biomarkers, may play an adjunctive role in the assessment of tissue damage and assessment of mucosal healing in response to therapy. In particular, noninvasive imaging modalities allow characterization of the transmural complications of CD and assessment of disease beyond the reach of the standard endoscope. Stool and blood biomarkers are sensitive detectors of inflammatory activity; however, they are susceptible to false positives, are only able to predict short-term outcomes, and are therefore likely to require serial monitoring in order to optimize their utility.
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Crohn's disease; mucosal healing; endoscopy; drug therapy
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