Mucosal healing in Crohn’s disease: a goal, a challenge and a new paradigm
Dr Daniel Van Langenberg
Bond Street Gastroenterology, Victoria
How do we define mucosal healing? Should it be the ultimate goal of therapy in routine practice? Does mucosal healing matter?
Answers to these questions remain uncertain but are in evolution. The mere fact that there is such worldwide interest signifies the exciting advances in inflammatory bowel disease (IBD) in the last decade.
What is mucosal healing?
One consensus group defined mucosal healing in Crohn’s disease as the ‘restoration of normal mucosal appearance by endoscopy of a previously inflamed region and complete absence of ulceration.1 Since its introduction as an endpoint in clinical trials, mucosal healing has typically been defined as a complete absence of ulceration in the colon and terminal ileum. Whether histological and more subtle macroscopic signs of inflammation should be incorporated into the definition remains controversial. In ulcerative colitis (UC) the definition is even more heterogeneous depending on which of many proposed endoscopic criteria are used. Whichever definition is used, the term mucosal healing is a gross oversimplification of a complex process of suppressing inflammation along with improvements in intestinal barrier function, regulated by a myriad of growth factors, cytokines and other signalling factors.2
In the 1980–1990’s, Crohn’s disease was typically managed through a symptom-based approach, especially because studies, particularly on corticosteroids, found little correlation between endoscopic mucosal healing and symptom resolution (‘clinical remission’) of disease.3 This was further compounded by the development and popularity of the Crohn’s disease activity index (CDAI) used in many seminal drug trials resulting in high placebo rates and further confusion relating to disease activity assessment and outcomes.
Current therapies and mucosal healing
The arrival of the initial anti-TNF biologic agent trials heralded new interest in mucosal healing. In an early open label study (n=10) of infliximab in Crohn’s disease, 90% of patients achieved symptomatic resolution and macroscopic healing of ulcers after only four weeks of treatment.4 Subsequent, more rigorous, trials such as ACCENT I showed mucosal healing occurred in 45% of patients after 12 months of scheduled maintenance infliximab therapy.5 With adalimumab, the EXTEND trial demonstrated that 27% and 24% of patients had mucosal healing at weeks 12 and 52 respectively.6 Importantly, those that achieved mucosal healing in the initial 2–3 months of anti-TNF therapy were far more likely to maintain mucosal healing at 12 months than those who never achieved initial healing. Furthermore, while direct comparison of mucosal healing rates between these biologic agents is not possible in these trials due to different methodologies, patient selection and definitions of mucosal healing, much of the available data suggest that, as a class, anti-TNF therapies are far superior in attaining mucosal healing at 12 months than other traditional medical therapies in IBD. For instance, the GETAID group showed that prednisolone 1 mg/kg daily only induced mucosal healing in 13% at 7 weeks which, together with similar outcomes in other studies, suggests that corticosteroids have little or no effect on the induction of mucosal healing in Crohn’s disease.7 Unlike steroids, azathioprine are somewhat effective at inducing mucosal healing, though most studies are small and methodologies vary widely. There are reports of mucosal healing rates as high as 83% of patients treated with azathioprine for one year, and as low as 16% in the SONIC study after six months of azathioprine.8,9 Finally, albeit based on limited data, azathioprine appears superior to methotrexate therapy in achieving mucosal healing.10
Why does mucosal healing matter?
The above data suggest that with currently available therapies, mucosal healing may only be attainable in less than half of patients with Crohn’s disease. Nevertheless, for the proportion of those achieving (and maintaining) mucosal healing there are significant long-term benefits. In addition, the principle of aiming for a deeper remission rather than just resolving symptoms is a crucial spinoff of studies evaluating mucosal healing. For instance, we know that extensive, deep ulceration in Crohn’s disease predicts a higher risk of penetrating complications and surgery whereas those with mild or no ulceration had fewer complications, even though many of this latter group had not achieved mucosal healing per se.11 Furthermore, those with only minor mucosal inflammation (but not necessarily mucosal healing) in the post-operative setting of Crohn’s disease do not appear to carry a higher risk of relapse.12 Finally, a study by Meucci et al13 showed that, at least in UC, there was no difference in 1-year relapse rates between those achieving a Mayo endoscopy subscore of 1 versus 0. So while mucosal healing is the goal, ‘coming up short’ and achieving as deep an endoscopic remission as possible may be just, or nearly, as good for long-term outcomes.
For those achieving and maintaining mucosal healing, most would agree that the potential extra efforts, investigations (especially endoscopy) and therapeutics involved in doing so appear worthwhile. The benefits include improved quality of life, lower risk of relapse, lower rates of hospitalisation and surgery (including post-operative recurrence) and lower risk of penetrating complications such as fistulae in Crohn’s disease. In UC, mucosal healing is associated with a lower risk of colorectal cancer, but this is yet to be confirmed in Crohn’s disease (colitis).14 The long-term effect of mucosal healing was illustrated by Schnitzler et al15 – in those achieving mucosal healing early with infliximab therapy, clinical response to infliximab maintenance dosing remained in almost two-thirds of patients after a median of 5.8 years. Furthermore, in the STORI trial, the presence of mucosal healing on combined infliximab and immunomodulator therapy was the most important factor in predicting lower risk of relapse after infliximab cessation.16
Where are we now, where to in the future?
In rheumatoid arthritis, treatment goals no longer include symptom control but rely on assessing the underlying biological process of synovial inflammation and thus, altering the natural course of progressive joint destruction. Similarly now in IBD, if we are able to achieve both clinical (symptomatic) remission and mucosal healing, we can finally alter the natural history of bowel inflammation otherwise leading to cumulative bowel damage, surgery and other complications. Furthermore, we know that intervening sooner post-diagnosis with anti-inflammatory therapy increases the likelihood of achieving mucosal healing.17 This mandates the introduction of effective treatment in Crohn’s disease; thiopurines and the anti-TNF biologics are the keys as they have been reliably shown to induce and maintain mucosal healing. Conversely, while corticosteroids remain useful in management of symptoms of an acute flare of Crohn’s disease, they have no role in achieving mucosal healing or altering disease course and thus no long-term benefit.
The management of chronic diseases like Crohn’s disease must be patient-centred and personalised to the individual. Hence a patient should be adequately informed and involved in the discussion of treatments, risks and benefits, and targets of therapy like mucosal healing. Furthermore, patients typically dislike colonoscopy which is the current gold standard of mucosal healing assessment, but also is expensive, inconvenient and often limited in accessibility. Surrogate measures of mucosal healing which are cheaper and non-invasive, such as faecal calprotectin, are appealing options and will likely become the most practical method to serially monitor patients and inform day-to-day treatment decisions in the consulting room.
Future directions in this space include the need for simplification and standardisation of endoscopic activity indices, incorporation of newer endoscopic and other imaging technology in disease assessment and acknowledging that the mucosa is only one component of the bowel wall, thus cross-sectional imaging to evaluate ‘transmural healing’ in Crohn’s disease may be more relevant if we wish to change the course of this lifelong disease in our patients.
5ASA, 5-aminosalicylic acid; AZA, azathioprine; CD, Crohn’s disease; MTX, methotrexate, TNF, tumour necrosis factor.
Please note, the views expressed in this article are not necessarily those of the sponsor.
- Feagan BG et al. Recommendations for the treatment of Crohn's disease with tumor necrosis factor antagonists: an expert consensus report. Inflamm Bowel Dis 2012; 18: 152–160.
- Neurath MF and Travis SPL. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut 2012; 61: 1619–1635.
- Li XF et al. [Analysis of clinical characteristics of 43 surgical patients with Crohn disease using the Montreal classification]. Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery 2010;13:210–212.
- Dullemen HM et al. Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995; 109: 129–135.
- Rutgeerts P et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease. Gastrointest Endosc 2006; 63: 433–442.
- Rutgeerts P et al. Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: Data from the EXTEND trial. Gastroenterology 2012; 142: 1102–1111.
- Modigliani R et al. Clinical, biological, and endoscopic picture of attacks of Crohn's disease. Evolution on prednisolone. Groupe d'Etude Thérapeutique des Affections Inflammatoires Digestives. Gastroenterology 1990; 98(4): 811–818.
- Mantzaris GJ et al. Azathioprine is superior to budesonide in achieving and maintaining mucosal healing and histologic remission in steroid-dependent Crohn’s disease. Inflamm Bowel Dis 2009; 15: 375–382.
- Colombel JF et al. Infliximab, azathioprine or combination therapy for Crohn’s disease. N Engl J Med 2010; 362: 1383–1395.
- Laharie D et al. Mucosal healing with methotrexate in Crohn’s disease: a prospective comparative study with azathioprine and infliximab. Aliment Pharmacol Ther 2011; 33: 714–721.
- Allez M et al. Long term outcome of patients with active Crohn’s disease exhibiting extensive and deep ulcerations at colonoscopy. Am J Gastroenterol 2002; 97: 947–953.
- D’Haens G et al. Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn’s disease. Gastroenterology 1997; 112: 1475–1481.
- Meucci G et al. Prognostic significance of endoscopic remission in patients with active ulcerative colitis treated with oral and topical mesalazine: A prospective, multicenter study. Inflamm Bowel Dis 2010; 17: 1006–1010.
- Peyrin-Biroulet L et al. Results from the 2nd Scientific Workshop of the ECCO (I): Impact of mucosal healing on the course of inflammatory bowel disease. J Crohns Colitis 2011; 5: 477–483.
- Schnitzler F et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn’s disease: results from a single-centre cohort. Gut 2009; 58: 492–500.
- Louis E et al. Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology 2012;142:63–70 e5; quiz e31.
- D'Haens G et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet 2008;371:660–667.