For endoscopic remission, our proposal is that it be defined as complete or near-complete mucosal healing on colonoscopy in both early and late disease. Currently, there is no clear and validated definition of near-complete mucosal healing, but it should certainly exclude remaining deep ulcers, and at this stage, it could be defined arbitrarily as no ulcers other than a certain number of aphthous ulcers <5 mm in diameter (Table 2). In the future, it may be that MRE and serum and fecal markers may also be incorporated into the definition of remission, but there are insufficient data to inform their inclusion at this time.
In clinical trials, clinical remission in early CD would be defined by a CDAI of <150 points (the current established gold standard), and in late CD, by a CDAI of between 150 and 220 points, which reflects mild disease (Table 2). The CDAI score threshold may be challenged in the future as more research is conducted into CDAI cutoff scores and linking them to important outcomes such as mucosal healing or sustainability of remission. In clinical practice, clinical remission in early CD would equate to the complete absence of symptoms, whereas for patients with established CD, it would be defined as inflammatory symptom improvement (Table 2). In the future, reductions in the need for hospitalization and surgical treatment may also be included. Table 3 shows some practical aspects to consider for patients to achieve remission, which extends beyond symptoms.
CAN REMISSION BEYOND SYMPTOMS BE ACHIEVED? WHAT DOES IT MEAN?
As previously mentioned, we are in the early days of evolving the definition of remission in CD beyond symptoms. One of the first attempts at this was in subanalyses from the adalimumab EXTEND program. Investigators coined the term “deep remission” that included CDAI remission and complete mucosal healing. The data from EXTEND show that remission extending beyond symptoms can be achieved with current therapies and may be associated with better outcomes that achieved CDAI-based remission alone.37–42 EXTEND was a 1-year trial comparing the efficacy of adalimumab versus placebo in inducing and maintaining mucosal healing. In this study, 19.4% of patients receiving adalimumab every other week achieved deep remission at 1 year (compared with no patients receiving placebo; P < 0.001) (Fig. 3).37 As anticipated, patients with a shorter disease duration tended to have a better chance of achieving deep remission at 1 year: 33% of patients with disease duration ≤2 years, compared with 25% for ≤5 years and 16% for >5 years (Fig. 3).38 Additional analysis identified a subgroup of patients who had a ≥34% probability of achieving early deep remission (deep remission achieved by week 12), which is double the average rate of deep remission at this time point. These patients tended to be younger with shorter disease duration, higher Inflammatory Bowel Disease Questionnaire scores, and no history of antitumor necrosis factor therapy.39
Achievement of deep remission, as defined by the EXTEND investigators, was also associated with improved outcomes. Patients who achieved early deep remission had fewer hospitalizations and CD-related surgical resections after 1 year than those who did not achieve early deep remission.40 These patients also had better quality of life and were less impaired in their workplace productivity and activity.40 Patients with early deep remission experienced fewer dose escalations,41 and early deep remission was associated with health care cost savings of approximately $9000 at 1 year.42
A treatment strategy that is aimed at completely controlling inflammation, which delays or halts progression of CD toward increasing complications and disability, is a priority. As a starting point, we propose a working definition of remission that includes endoscopic remission and symptom control, with defined patient outcomes including no disease progression. Our proposed definition for patients with early CD is clinical remission (CDAI <150 points for patients in clinical trials and absence of symptoms in clinical practice) and mucosal healing. In patients with established CD, we propose symptom improvement (CDAI 150–220 points in clinical trials and improvement of inflammatory symptoms in clinical practice) along with mucosal healing.
The concept of remission will be important as gastroenterologists strive for better outcomes for their patients. The exact definition will most certainly evolve as ongoing studies inform us of which treatment goals are associated with the most robust outcomes. Treatment algorithms will likely evolve in parallel so that a strategy is adopted similar to that in other immune-mediated diseases, such as the RA “treat-to-target” model. We are hopeful that such an approach might have the potential to result in significant improvements in patient outcomes, especially among those with early disease for whom there could be a window of opportunity to halt disease progression before it becomes irreversible. A CD treat-to-target approach might also benefit those patients with established disease and bowel damage who cannot attain clinical remission.
Clinical trials are needed to evaluate whether treatment algorithms that tailor therapy to achieve a level of remission in patients with CD can prevent disease progression and disability (Table 4). In particular, further investigation is needed to establish whether the achievement of different levels of remission alters the disease course over time and improves patient outcomes, such as disability and the need for surgical treatment. New methods of measuring and monitoring disease activity and progression are also required. We fully expect that our preliminary definition of remission will be optimized over time as new evidence becomes available.
Over the past 20 years, the treatment of RA, which shares many analogous pathologic features with CD, has moved from treating symptoms to structured treat-to-target algorithm strategies aimed at achieving a new definition of remission. We believe that the treatment of CD is also likely to move from treating symptoms to more objective parameters of disease control. We are hopeful that our preliminary definition of remission will be a first step toward meeting this goal.
Dr. Panaccione reports having received consultant and/or lecture fees from AbbVie, Amgen, AstraZeneca, Axcan Pharma (now Aptalis), Biogen Idec, Bristol-Myers Squibb, Centocor, ChemoCentryx, Eisai Medical Research Inc, Elan Pharmaceuticals, Ferring Pharmaceuticals, Genetech, GlaxoSmithKline, Janssen, Merck Sharp and Dohme Corp, Millennium Pharmaceuticals Inc (now Takeda), Ocera Therapeutics Inc, Otsuka America Pharmaceutical, Pfizer, Shire Pharmaceuticals, Prometheus Laboratories, Schering-Plough, Synta Pharmaceuticals Corp, Teva, UCB Pharma, and Warner Chilcott.
Prof. Colombel reports having received consulting and/or lecture fees from AbbVie, ActoGeniX, Albireo Pharma, Amgen, AstraZeneca, Bayer AG, Biogen Idec, Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Cellerix, Centocor, ChemoCentryx, Cosmo Technologies, Danone Research, Elan Pharmaceuticals, Genetech, Giuliani SpA, Given Imaging, GlaxoSmithKline, Hutchison MediPharma, Merck Sharp and Dohme Corp, Millennium Pharmaceuticals Inc (now Takeda), Neovacs, Ocera Therapeutics Inc, Otsuka America Pharmaceutical, Pfizer, Shire Pharmaceuticals, Prometheus Laboratories, Sanofi-Aventis, Schering-Plough, Synta Pharmaceuticals Corp, Teva, Therakos, Tillotts Pharma, UCB Pharma, and Wyeth. He has stock ownership in Intestinal Biotech Development, Lille, France.
Prof. Louis reports having received consulting and/or lecture fees from AbbVie, AstraZeneca, Dr Falk Pharma, Ferring Pharmaceuticals, Millenium (now Takeda), MSD, Schering-Plough, and Shire Pharmaceuticals.
Dr. Peyrin-Biroulet reports having received consulting and/or lecture fees from AbbVie, Actelion, Bristol-Myers Squibb, Celgène, Ferring Pharmaceuticals, Janssen, Merck, Mitsubishi, Shire Pharmaceuticals, Therakos, Norgine, Pharmacosmos, Pilège, Therakos, Tillotts Pharma AG (acquired by Zeria Pharmaceutical Co, Ltd), and Vifor.
Dr. Sandborn reports having received consulting fees from AbbVie, ActoGeniX NV, AGI Therapeutics, Inc, Alba Therapeutics Corporation, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas Pharma, Athersys, Inc, Atlantic Healthcare Limited, Axcan Pharma (now Aptalis), BioBalance Corporation, Boehringer Ingelheim Inc, Bristol-Myers Squibb, Celegene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, Eisai Medical Research Inc, Elan Pharmaceuticals, EnGene Inc, Eli Lilly, Enteromedics, Exagen Diagnostics Inc, Ferring Pharmaceuticals, Flexion Therapeutics Inc, Funxional Therapeutics Limited, Genzyme Corporation, Genentech (now Roche), Gilead Sciences, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood Pharmaceuticals (previously Microbia Inc), Janssen (previously Centocor), KaloBios Pharmaceuticals Inc, Lexicon Pharmaceuticals, Lycera Corporation, Meda Pharmaceuticals (previously Alaven Pharmaceuticals), Merck Research Laboratories, MerckSerono, Millennium Pharmaceuticals (subsequently merged with Takeda), Nisshin Kyorin Pharmaceuticals Co Ltd, Novo Nordisk A/S, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics Inc, PDL Biopharma, Pfizer, Procter & Gamble, Prometheus Laboratories, ProtAb Limited, Purgenesis Technologies Inc, Receptos, Relypsa Inc, Salient Pharmaceuticals, Salix Pharmaceuticals Inc, Santarus, Schering-Plough Corporation (acquired by Merck), Shire Pharmaceuticals, Sigmoid Pharma Limited, Sirtris Pharmaceuticals Inc (a GSK company), S.L.A. Pharma (UK) Limited, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG (acquired by Zeria Pharmaceutical Co Ltd), TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics Limited, Warner Chilcott UK Limited, Wyeth (now Pfizer). He has received lecture fees from AbbVie, Bristol-Myers Squibb, and Janssen (previously Centocor). He has received research support from AbbVie, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen (previously Centocor), Millennium Pharmaceuticals (now Takeda), Novartis, Pfizer, Procter & Gamble Pharmaceuticals, Shire Pharmaceuticals, and UCB Pharma.
Topics included in this article were based on, but not limited to, broad discussions at advisory board meetings, which were sponsored and funded by AbbVie. AbbVie paid consultancy fees to R. Panaccione, J. -F. Colombel, E. Louis, and W. J. Sandborn, for their participation in these meetings and travel to and from the meetings was reimbursed. AbbVie participated in developing the content for these meetings. AbbVie did not review or approve the manuscript content and had no influence on the decision to submit for publication. No payments were made to the authors for the development of this manuscript. Mary Greenacre, PhD, and Lucy Hampson of Leading Edge Medical Education (part of the Lucid Group), Burleighfield House, Buckinghamshire, United Kingdom, provided medical writing and editorial support to the authors in the development of this manuscript and financial support for these services was provided by AbbVie.
Author Contributions: The authors maintained complete control over the direction and content of the paper. R. Panaccione, J. -F. Colombel, E. Louis, and W. J. Sandborn developed an initial concept and provided a brief for the medical writer, who prepared an outline and first draft. All authors reviewed drafts of the manuscript and further developed the concept. R. Panaccione critically revised later drafts of the manuscript for intellectual content. All authors read and approved the final version for submission. R. Panaccione is the guarantor.
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Keywords:© Crohn's & Colitis Foundation of America, Inc.
clinical trials; Crohn’s disease; disease activity measurements; mucosal healing; serologic markers/testing