Crohn’s disease (CD) is a chronic inflammatory disorder of the large and small intestines characterized by periods of clinical remission alternating with periods of relapse defined by recurrent clinical symptoms. However, even during periods of clinical remission, laboratory or endoscopic evidence of persistent inflammation can be seen, as evidenced by the elevation of serum and fecal inflammatory biomarkers and/or abnormal endoscopic and radiographic imaging. Persistent inflammation is believed to lead to progressive bowel damage over time, which manifests as the development of disease complications such as strictures, fistulae, and abscesses. These disease complications frequently lead to a need for surgical resection, which in turn leads to disability. Thus, CD can be characterized as a chronic, progressive, destructive, and ultimately disabling disease. Parallels can be drawn to other chronic inflammatory diseases in which treatment targets have evolved beyond treating symptoms and signs.
In rheumatoid arthritis (RA), patients who are in clinical remission can have evidence of persistent synovial inflammation that leads to progressive, destructive joint damage and disability. RA treatment paradigms have evolved beyond partial symptom control alone toward the induction and maintenance of sustained biological remission, also known as a “treat-to-target” strategy, with the goal of improving long-term disease outcomes (reduced structural damage and disability).1 In CD, there is currently no accepted well-defined treatment goal that includes the treatment of both clinical symptoms and biological inflammation.
It is important that this treatment concept begins to evolve for CD. By raising the standards for treatment outcomes, patients may potentially benefit by experiencing a more robust level of remission, which might ultimately impact the important outcomes, such as the need for surgical treatment and the development of disability. Similarly, this concept may be useful when designing the next generation of clinical trials that could determine if treating beyond symptoms to an objective target can change the natural history of the disease.
The purpose of this article is to look at elements that may be included in a new definition of remission in CD and propose a simple working definition that may serve as a starting point for future workshops or consensus conferences in this area.
THE RATIONALE FOR DEVELOPING A MORE COMPREHENSIVE TREATMENT GOAL AS AN ALTERNATIVE TO CLINICAL REMISSION IN CD
Natural history studies in both referral centers and population-based cohorts have demonstrated that, over time, patients with CD progress from luminal inflammatory disease to the development of complications, such as stricture, fistula, and abscess, and ultimately require surgical intervention to treat these complications.2–6 For example, in a referral center study of more than 2000 patients, 60% of the patient population developed a penetrating or stricturing complication.2 Five years after the diagnosis, only half of the patients were free of complications; by 20 years after the diagnosis, this had decreased to just over one tenth of patients. Similarly, in a population-based study, more than 80% of patients had uncomplicated inflammatory disease at diagnosis.4 After 90 days, 1 year, 5 years, and 20 years, the cumulative risk of developing either stricturing or penetrating disease was 19%, 22%, 34%, and 51%, respectively. In addition, a recent disease activity predicts the disease course in subsequent years.7,8 In one representative study, patients with no disease activity in the first year after diagnosis had a 77% chance of maintaining remission in the second year, whereas patients experiencing disease activity in the first year had only a 16% chance of a full year of remission in the next year.8 Even in the present era of biological therapies, the need for surgical treatment remains high.9 Studies have demonstrated that there is a poor correlation among clinical, endoscopic, and biological activity in CD.10 Taken together, these studies demonstrate that CD is a chronic, progressive, destructive disease. Furthermore, they suggest that there may be a disconnection between relapsing and remitting disease symptoms and persistent underlying biological inflammation (Fig. 1).11
These natural history studies reflect the outcomes of current treatment paradigms that are based on induction of symptomatic response and remission followed by maintenance of symptomatic remission. As the majority of patients experience disease progression and accumulation of bowel damage over time with this treatment paradigm, simply monitoring symptoms evidently is not enough. Thus, it may be prudent to develop an alternative treatment paradigm in which patients are treated to achieve a composite endpoint comprising both clinical and biological remission (resolution of inflammation). The goal of treating to this endpoint would be to alter the natural history of CD by preventing or delaying disease progression. Randomized clinical trials will be needed to prove that treating beyond symptoms is (1) feasible, (2) practical, (3) efficacious, (4) safe, and (5) cost-effective in comparison with the standard goal of clinical remission (Crohn’s Disease Activity Index [CDAI] <150 off steroids). Many such clinical trials are currently underway as the interest in this area grows.
PARALLELS WITH OTHER CHRONIC, PROGRESSIVE, DESTRUCTIVE, INFLAMMATORY DISEASES
The concept of “treat to target” has recently evolved for patients with RA. This treatment strategy consists of tailored treatment for individual patients to achieve a prespecified level of low disease activity or remission within a certain period. Several studies have shown that this approach leads to improved outcomes compared with conventional care. In the CAMERA (Computer Assisted Management in Early Rheumatoid Arthritis) trial of methotrexate treatment, patients were randomized to either intensive management or conventional care.12 In the intensive management group, methotrexate dosage was tailored for the individual patient based on predefined response criteria using a computerized decision program. During the 2-year trial, 50% of patients in the intensive management group experienced at least 1 remission period versus 37% in the conventional treatment group. In the TICORA (Tight Control of Rheumatoid Arthritis) study, which allocated outpatients with RA to either intensive management (aiming for sustained, tight control of disease activity) or conventional care, patients in the intensive management group experienced improved control of disease activity, reduced radiographic disease progression, improved physical function, and better quality of life.13 Similar benefits have been reported in other studies, and a systematic review concluded that there is compelling evidence for the benefits of a treat-to-target approach.1
In contrast with previously held views that symptom improvement was the best outcome that could be achieved for patients, rheumatologists now accept that remission is an achievable goal. An international task force recently recommended that remission should be the ultimate therapeutic goal in RA to prevent the progression of joint damage and reverse physical disability (Table 1).14 The task force concluded that ideally, the definition of remission should not allow for any residual clinical disease activity. However, they recognized that this might be unachievable in some patients with long-standing disease (presumably as a result of symptoms arising from previous joint damage, in the absence of ongoing biological evidence of inflammation); in these patients, low levels of clinical symptoms may be a more realistic goal. Once the desired therapeutic target is achieved, it should be sustained continuously. New criteria to define clinical remission have been endorsed by the American College of Rheumatology and the European League Against Rheumatism. The new criteria define remission as no more than 1 swollen joint and 1 tender joint, a C-reactive protein (CRP) level of ≤1 mg/dL, and a patient global assessment score of ≤1.15
The 4-year BeST (Behandel Strategieen) study of patients with early RA used a treat-to-target strategy using 4 alternative treatment regimens—sequential monotherapy, step-up combination therapy, up-front combination therapy with prednisone, and initial combination therapy with infliximab.16 Treatment was adjusted based on 3 monthly disease activity score assessments. After 4 years, 43% of patients had achieved remission and 13% had achieved drug-free remission; functional ability and remission were maintained in all 4 groups with the continuation of target-driven treatment. In the OPTIMA (Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab Combination Therapy in Patients with Early Rheumatoid Arthritis) study, 20% of patients treated with adalimumab plus methotrexate achieved remission versus 10% of patients treated with methotrexate alone during the initial study period of 26 weeks.17 The second study period (up to 78 weeks) is ongoing and will evaluate the maintenance of remission and prevention of radiographic progression.
Taken together, these data suggest that the use of treat-to-target management strategies to achieve sustained remission (or sustained low level of clinical symptoms in patients with long-standing disease) leads to an improved natural history of RA, reducing the frequency of disease progression and disability.
The concept of differences between early disease and late disease and what is achievable by treating early versus late can be seen in multiple sclerosis (MS). MS is an inflammatory disorder in which focal lymphocytic infiltration leads to myelin and axon damage. In the early stages, the condition is characterized by episodic neurological dysfunction (clinically isolated syndrome); however, recovery from each episode is incomplete and symptoms accumulate, leading to secondary progressive disease. The secondary progressive phase of the disease relates to postinflammatory neurodegeneration and early immunosuppression before this stage may stabilize the cascade of events that culminates in disability.18 Given this premise, it is unsurprising that immunosuppressive therapy has had disappointing results in patients with secondary progressive disease. In contrast, immunosuppressive therapy is effective in patients who have relapsing-remitting disease.
Of particular interest are a few studies that have been performed in patients with clinically isolated syndrome or early MS. A Cochrane review found 3 clinical trials investigating interferon-β in clinically isolated syndrome.19 The meta-analysis showed that early treatment is effective in preventing the conversion of the first isolated demyelinating episodes into clinically definite MS after 1 year and 2 years of follow-up. In a phase 2 trial of early, relapsing-remitting MS, alemtuzumab, a monoclonal antibody that targets CD52 on lymphocytes and monocytes, reduced the rate of sustained accumulation of disability and improved disability scores.20 The PreCISe study investigated the effect of glatiramer acetate in patients with clinically isolated syndrome and found that it is effective in delaying conversion to clinically definite MS.21
Although the data in MS are less definitive than in RA, it seems that intervention with immunosuppressive therapy either in the early phase of the disease or during the relapsing-remitting phase can reduce cumulative structural damage and progression to disability, whereas immunosuppressive therapy is less effective in patients who have advanced to the secondary progressive phase of the disease. It is currently unknown if a treat-to-target strategy used in the early phase of the disease would further improve the clinical outcomes.
THE EVOLVING CONCEPT OF REMISSION IN CROHN’S DISEASE
Remission is an evolving concept in CD. At its most fundamental level, remission should be a state with little or no risk of disease progression, likely implying the absence of biological evidence of inflammation, including the absence of histological inflammation. Measuring the absence of histological inflammation would be exceedingly difficult given the patchy nature of CD and our present technology. Most physicians would agree that clinical remission (symptom control) and endoscopic remission (also known as mucosal healing) would appear to be vital components of remission; however, given that CD is a transmural disease, the question remains whether there is also a need for radiographic transmural healing, as demonstrated by computed tomography enterography or magnetic resonance enterography (MRE). Biological remission is a term that implies control of inflammation or a more general state of disease control, which again goes beyond the symptoms to potentially encompass mucosal healing and perhaps radiographic healing, as well as improvements in serum and fecal biomarkers of active inflammation. There is an increasing interest in the utility of these biomarkers for monitoring disease activity.
For decades, gastroenterologists have considered remission to mean the absence of symptoms. However, it is now clear that inflammation may be present in the intestine without obvious signs or symptoms. Therefore, it is important to think about the true meaning of remission and what the potential candidates for measuring remission may be. Candidate targets to be included in new definitions of remission are outlined below.
Serum and Fecal Biomarkers
Elevation of both serum and fecal biomarkers can serve as markers of ongoing inflammation, and therefore, they could be potential candidates in the definition of remission. The best characterized of these biomarkers are serum CRP and fecal calprotectin. For CRP, a threshold of <5 mg/L, after ruling out infection, may be a sensitive marker correlating with the absence of inflammation and improved prognosis. Analysis of data from the STORI (infliximab diSconTinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors) study has shown that CRP concentrations of <5 mg/L can predict mucosal healing with a sensitivity of >70% but a low specificity of <40%.22 Data from clinical trials have also shown that patients with CRP concentrations <5 mg/L have higher rates of spontaneous remission and a more benign natural history than those with higher levels. A fecal calprotectin concentration of <250 μg/g may be more effective than CRP at predicting mucosal healing, particularly in the colon, because it has a sensitivity of >80%, but its specificity is still low at approximately 50%.22 Finally, the combination of these 2 potentially complementary markers may further improve the specificity, perhaps to >70%.22 More research into biomarker cutoff values may lead to revisions of these thresholds. Newer biomarkers or panels of biomarkers are under investigation and may prove to be better candidates to define remission in the future. Furthermore, biomarkers may offer information beyond just mucosal healing; in the STORI trial, patients with mucosal healing had a relapse rate of approximately 30% over 1 year, whereas it decreased by 10% to 15% with both mucosal healing and low levels of biomarkers.23
Although mucosal healing has been generally accepted as a desirable endpoint in the treatment of CD, challenges remain. There is no universally accepted definition of mucosal healing.24 Additional work is needed to develop cut points that define mucosal healing for the 2 validated endoscopic scoring systems that are currently used in clinical trials, that is, the Crohn’s Disease Endoscopic Index of Severity and the Simple Endoscopic Score for Crohn’s Disease. For example, the MUSIC (endoscopic MUcoSal Improvement in patients with active Crohn’s disease treated with certolizumab pegol) trial defined endoscopic remission as a Crohn’s Disease Endoscopic Index of Severity score of <6 points.25 Nevertheless, the ability of immunosuppressants and biologics to induce mucosal healing has been well documented and seems to be of clinical value.24,26 In several recent studies, mucosal healing has been defined as the absence of ulceration on ileocolonoscopy. However, it is still debated whether complete mucosal healing offers any substantial benefit over partial mucosal healing with a low level of residual endoscopic activity. Several clinical trials and a population-based study have demonstrated that patients who achieve mucosal healing have better outcomes than those who do not achieve mucosal healing.27–31 Partial mucosal healing may also provide benefits. In the ACCENT-1 (A Crohn’s disease Clinical study Evaluating infliximab in a New long-term Treatment regimen) trial, patients who achieved complete mucosal healing after 1 year remained in remission for a median of 20 weeks, compared with 19 weeks for patients who achieved significant but incomplete mucosal healing and only 4 weeks for patients who experienced no healing of ulcers.29 A single-center cohort study of infliximab therapy showed that mucosal healing was associated with a reduced need for major abdominal surgery compared with no healing, but there was no difference between patients who experienced full versus partial healing (14.1% of patients with complete healing required major abdominal surgery versus 14.0% of those with partial healing and 38.4% of those with no healing).30 These findings highlight that additional clinical trials are needed to determine the relative value of achieving complete versus partial mucosal healing. Nevertheless, it seems that future definitions of remission should consider including an endoscopic component.
There is a good correlation between mucosal healing demonstrated by colonoscopy and noninvasive imaging methods, such as computed tomography enterography or MRE, which have the advantage of being able to assess transmural inflammation. These radiographic modalities have the potential to measure both disease activity and structural damage. However, there is only preliminary information regarding serial radiographic imaging in the context of clinical trials.11,32 More recently, an abundance of work has been done in the field of MRE to define an index of disease activity that could be used in clinical trials and clinical practice. Given that cross-sectional imaging can give information about ongoing inflammation beyond or deep within the mucosa, it is important that this tool is included in the definition of remission as the concept evolves.
HOW DOES EARLY AND LATE DISEASE AFFECT THE CONCEPT OF REMISSION?
One point for consideration is whether the treatment goal should be different in patients with early versus late disease because of the progressive nature of CD, as is the case in RA.14 Patients diagnosed late in the course of CD or who have already experienced a disease complication or required surgical treatment may not be capable of achieving a state of complete absence of clinical symptoms (as a result of irreversible structural damage inflicted by the CD itself or by surgical resection). Several subanalyses of clinical studies have suggested that higher remission rates may be achieved in patients with early disease, as defined by time from diagnosis. For example, the CHARM (Crohn’s trial of the fully Human antibody Adalimumab for Remission Maintenance) study of adalimumab showed the highest remission rates in patients with disease duration of <2 years.33 Similarly, the PRECiSE 2 (PEGylated antibody fragment evaluation in Crohn’s disease: Safety and Efficacy) trial of certolizumab pegol showed decreasing response or remission rates with longer disease duration.34 A similar impact of disease duration on the effect of adalimumab on mucosal healing was seen in the EXTEND (EXTend the safety and Efficacy of adalimumab through eNDoscopic healing) study.35 Thus, it seems that there may be a window of opportunity to prevent disease progression before it becomes irreversible. Patients with long-standing disease may still benefit from achieving biological remission in terms of preventing further disease progression, but they may not be able to become completely symptom free because of the presence of irreversible structural damage. Therefore, disease duration and disease state will be important considerations when deciding what is achievable in patients.
FUTURE DIRECTIONS: TOWARD A WORKING DEFINITION OF REMISSION
The concept of remission beyond symptoms may have relevance in both clinical practice and the design of future clinical trials. Therefore, we propose definitions of remission that may be used in both clinical practice and clinical trials. These definitions include both biological remission and symptom-based remission (Table 2; Fig. 2). Given that patients with late disease may have irreversible noninflammatory symptoms, we propose different definitions for patients with early CD and those with late CD.36 In clinical trials, early CD may be defined as disease duration ≤18 months without previous exposure to immunosuppressants or biologics.36 Important considerations in clinical trials will include the presence or absence of bowel damage, the presence or absence of inflammatory activity (as measured by endoscopy or imaging), symptom activity, and previous use of corticosteroids. Alternatively, in clinical practice, early CD could be simply defined as patients with no evidence of bowel damage and no previous resection, irrespective of disease duration.
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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