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REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Robert F. Schwabe and John W. Wiley, Section Editors Converging Goals of Treatment of Inflammatory Bowel Disease From Clinical Trials and Practice Barrett G. Levesque,1 William J. Sandborn,1 Joannie Ruel,2 Brian G. Feagan,3 Bruce E. Sands,2 and Jean-Frederic Colombel2 1 Division of Gastroenterology, University of California San Diego, La Jolla, California; 2Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York; and 3Robarts Clinical Trials, Robarts Research Institute, Department of Medicine, Western University, London, Ontario, Canada It is important to have clear goals for treating inflammatory bowel disease in clinical practice and in research. Conventional end points for trials in ulcerative colitis and Crohn’s disease have been based on composite indices, such as the Mayo Clinic Score and the Crohn’s Disease Activity Index; these indices incorporate symptoms, signs, and findings from laboratory tests and sometimes endoscopic assessments. Although definitions of clinical response and remission have been based on these indices for regulatory purposes, they are difficult to apply to practice because they are complex and not intuitive to clinicians. This has caused a disconnect between clinical trials and practice. Recently, the use of composite indices in trials has been reevaluated in Food and Drug Administration–sponsored Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics workshops due to concerns about the validity of the indices. Alternative measures of outcome and definitions of response are being developed. Patient-reported outcomes are psychometric instruments created and defined by patients to quantify symptoms. A combination of end points, comprising patientreported outcomes and objective evaluation of inflammation by endoscopy, offers a clinically meaningful and scientifically valid alternative to existing composite indices. Unlike composite indices, response definitions based on endoscopy and patient-reported outcomes can be readily applied in practice. This convergence of outcome assessment in clinical trials and practice could expedite implementation of “treat-to-target” algorithms, in which therapy is progressively intensified until a specific treatment goal is reached. This approach could improve patient care by reducing rates of disease-related complications, surgery, and hospitalization. treatment focuses more on the consequences of inflammation rather than the inflammatory process itself. This situation is not ideal, because there is a substantial overlap between the symptoms of IBD and other conditions, such as irritable bowel syndrome, bile salt diarrhea, steatorrhea, bacterial overgrowth, and scarring, that are unlikely to respond to anti-inflammatory therapy.3 Furthermore, it is well established that the Crohn’s Disease Activity Index (CDAI), which is heavily weighted toward symptoms, correlates poorly with endoscopy.4 Although there is a better correlation between symptoms and endoscopy in ulcerative colitis (UC), in many circumstances assessment of symptoms alone lacks sufficient precision for decision making. Based on these observations, we contend that an evolution in the measurement of IBD disease activity is needed that emphasizes development and use of disease activity indices that incorporate validated independent measures of both symptoms and inflammation into a coprimary end point.5 Previous reviews6,7 have characterized the clinical, endoscopic, and composite indexes historically used in IBD clinical trials. Existing instruments are predominantly symptom based, are in most instances empirically derived, and do not adequately assess either symptoms from the patient’s perspective or the underlying inflammatory process. At present, there are no patient-reported outcome (PRO) or clinician-reported outcome (ClinRO) instruments that have been created according to the guidance of the US Food and Drug Administration (FDA).8 Valid PROs, based on items generated from qualitative patient interviews, must be both reliable and responsive to clinically meaningful changes in health status. Clinically useful PROs should be Keywords: GREAT; CDAI; Outcome Measure; IBD Therapy. I nflammatory bowel disease (IBD) is caused by immune dysregulation of the digestive tract1,2 that results in chronic inflammation. Consequently, symptoms of abdominal pain, diarrhea, and bleeding occur that result in impaired quality of life. Although medical therapy is focused on controlling inflammation, disease activity is assessed in clinical trials by composite indices that predominantly measure signs and symptoms. In clinical practice, assessment of symptoms predominates. Thus, our traditional approach to Abbreviations used in this paper: CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; CDEIS, Crohn’s Disease Endoscopic Index of Severity; CI, confidence interval; ClinRO, clinician-reported outcome; FDA, Food and Drug Administration; GETAID, Groupe D’Etudes Therapeutiques Des Affections Inflammatoires due Tube Digestif; HBI, Harvey–Bradshaw Index; IBD, inflammatory bowel disease; ICC, intraclass correlation coefficient; MBS, modified Baron score; MCS, Mayo Clinic Score; MRE, magnetic resonance enterography; PRO, patient-reported outcome; SESCD, Simple Endoscopic Score in Crohn’s Disease; UC, ulcerative colitis; UCEIS, Ulcerative Colitis Endoscopic Index of Severity. © 2015 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2014.08.003 REVIEWS AND PERSPECTIVES Gastroenterology 2015;148:37–51 38 Levesque et al REVIEWS AND PERSPECTIVES both easily administered and readily interpretable by patients and clinicians.9 Similarly, a ClinRO for IBD trials must be a reliable measure of mucosal inflammation with welldefined operating properties.9 Examples of PROs that meet FDA standards for other conditions include the VVSymQ score (BTG International Ltd, London, England, UK), which was the primary end point in trials that led to the approval of Varithena (polidocanol injectable foam; Provensis Ltd) for treatment of varicose veins.10 VVSymQ is a PRO based on daily patient assessment of the symptoms of varicose veins determined to be most important to patients: heaviness, achiness, swelling, throbbing, and itching. Similarly, the modified Myelofibrosis Symptom Assessment Form PRO, in addition to spleen volume, led to the approval of Jakafi (Incyte Corporation, Wilmington, DE) (ruxolitinib) for myelofibrosis.11 The modified Myelofibrosis Symptom Assessment Form is a cumulative daily diary that scores the core symptoms of myelofibrosis (abdominal discomfort, pain under the left ribs, night sweats, itching, bone/muscle pain, and early satiety). Clinical trials in rheumatoid arthritis offer an example of coprimary end points in trials for regulatory approval. Cimzia (UCB, Inc, Brussels, Belgium) (certolizumab pegol) was approved in 2009 for trials in rheumatoid arthritis that included the coprimary end point of ACR20 (a composite index of swollen joint count, tender joint count, physician’s assessment of disease activity, and patient’s assessment of physical function and levels of acute phase reactant) and the mean change from baseline in the modified total Sharp score of joint radiographs at week 54.12 The major secondary end point was a PRO: the Disability Index of the Health Assessment Questionnaire. It is important to recognize that simple composite measures that assess both PRO and ClinRO elements, such as a physician’s global assessment,13 are problematic because the concepts being evaluated are highly heterogeneous, making it difficult to assign a single measure of disease activity.9 As a response to this situation, an evolution in thinking has emerged contending that the degree of inflammation should be measured by clinicians using objective instruments such as endoscopy (and potentially in the future histology and cross-sectional imaging) and that the patients’ experience should be assessed by a validated PRO. Definitions of response and remission used for study end points should require improvement in both of these domains as a coprimary end point. This concept is attractive because it reflects clinical practice, in which in a typical patient encounter, physicians ask patients such questions as “How many stools are you having?”, “How frequently do you experience abdominal pain?”, and “Are you seeing blood in your bowel movements?”. Subsequently, clinicians objectively assess disease activity with endoscopy or potentially other measures of inflammation. In essence, this construct specifies that clinicians integrate both the patient experience and objectively measured disease activity before formulating a treatment plan or determining whether treatment goals have been met. Given these considerations, it is notable that most existing practice guidelines are exclusively symptom based. For example, the 2009 American College of Gastroenterology guidelines for management of Crohn’s disease (CD) Gastroenterology Vol. 148, No. 1 defined remission as patients with an absence of symptoms; mild to moderate disease as ambulatory patients without systemic toxicity, dehydration, tenderness, <10% weight loss, obstruction, or abdominal mass; and fulminant disease as patients with severe symptoms including fever, those with complications such as bowel obstruction, and those failing to respond to therapy.14 Ultimately, such definitions have limited value in clinical practice because they are imprecise and not based on objective and practicable criteria. Alternatively, definitions of response and remission based on the composite disease activity indices that up until now have been routinely used for regulatory approval have not become accepted for use in patient care due to their complexity and apparent lack of face validity. Commensurate with our understanding of the limitations of our traditional outcome measures and disease definitions has been the developing concept that therapy in IBD should be based on specific, well-defined treatment targets that include both resolution of inflammation and symptoms. Treatment strategy trials in which the efficacy and safety of multilevel therapeutic algorithms are evaluated for their ability to achieve specific goals of therapy (“treat to target”) have recently been initiated in IBD. The intent of these studies is to identify therapeutic strategies that will reduce the longterm burden of IBD. This review outlines the literature that describes the evolution currently taking place in assessment of treatment goals in clinical trials and clinical practice. What Has Treating to Clinical Response and Remission Accomplished? In patients with UC, important reductions in rates of colorectal cancer and colectomy have been observed over the past several decades.15 However, much of this improvement appears to come from the widespread use of mesalamine for induction and maintenance therapy in patients with mild to moderate UC and/or the widespread practice of surveillance colonoscopy, with little evidence that the prognosis for patients with moderate to severe UC who require corticosteroid therapy has improved.16–22 In CD, approximately 50% of patients develop disease-related complications such as a stricture, fistula, or abscess that frequently require surgery within 10 years of diagnosis.23,24 For example, the cumulative probability of surgery was not different between 2 Spanish cohorts of patients with newly diagnosed CD that were accrued from 1994 to 1997 and from 2000 to 2003.25 Similarly, 2 nationwide inpatient cohorts of patients with CD in the United Sates from 1993 to 2004 and from 1998 to 2005 did not show a decrease in the overall rate of surgery.25–27 One potential explanation for these observations is that the use of clinical symptoms as a treatment target fails to ensure that the underlying inflammation is adequately controlled, without which complications ensue. Where Have We Been? Prior End Points in Clinical Trials in IBD As noted previously, the traditional outcome measures in UC trials consist of composite instruments that January 2015 Emerging Treatment Goals in IBD Trials and Practice 39 Indices UC Baron score (endoscopic items) MBS (endoscopic items) MCS (endoscopic and clinical items) Partial MCS UCEIS CD CDAI HBI CDEIS SES-CD a Descriptors Spontaneous bleeding, friability, moisture, distensibility, valves, vascular patterna Normal mucosa (0), granular with an abnormal vascular pattern (1), friable (2), microulcerations with spontaneous bleeding (3), gross ulceration (4) Endoscopic response: improvement by 2 grades in the MBS Endoscopic remission: MBS score of 0 Stool frequency, rectal bleeding, physician’s global assessment, endoscopic severity Range: 0–12 Complete response: MCS score of 0 in all subscores Partial response: substantial but incomplete improvement in the subscores Stool frequency and rectal bleeding Vascular pattern (1–3), bleeding (1–4), erosions and ulcers (1–4) Severity of abdominal pain, general well-being, frequency of liquid stool, extraintestinal manifestations, need for antidiarrheal drugs, presence of an abdominal mass, body weight, hematocrit Range: 0–600 Clinical response: reduction from baseline of 70 to 100 points Clinical remission: <150 Abdominal pain, abdominal mass, general well-being, extraintestinal manifestations, number of liquid stools for the previous day Remission score: <5, correlates with CDAI score <150 Deep ulcerations, superficial ulcerations, percentage of involved mucosa, percentage of ulcerated mucosa in 5 segments, and global evaluation of lesion severity Complete remission: score 3 Remission: <6 Response: decrease of >5 points Presence and size of ulcer, extent of ulcerated surface, extent of affected surface, presence and type of narrowings 3 levels for each descriptor in 5 segments Remission: 0–2 With >60% interobserver agreement. incorporate symptoms, laboratory criteria, and sigmoidoscopic findings. The end points in the trial by Truelove and Witts of cortisone in patients with UC was based on symptoms, laboratory results, and a 3-point endoscopy scale that were required to be met independently.28 These scores were not validated. Subsequently, multiple UC and CD composite clinical indices were used from 1960 to 1990.6,7,29 None of these scores were completely validated. Our review will focus on indices that have been used for regulatory approval between 2005 and 2014 (Table 1). Recent Developments in Trial End Points in UC Modification of the Baron Score Baron et al explored the interrater agreement of 8 endoscopic scoring descriptors in the first endoscopic index validation study30 (Table 1). Categorical score items (friability, bleeding) had higher agreement (90% and 87%, respectively) than continuous score items (erythema, granularity) (30% and 47%, respectively). Agreement was not adjusted for chance, the score was not validated against clinical symptoms, and no definition of endoscopic remission was given. The Baron score was developed using rigid sigmoidoscopy, and friability was determined by touching the mucosa with a cotton swab inserted through the rigid instrument. Subsequently, the Baron score was used with fiber-optic scopes and then video endoscopes. In 2005, the Baron score was empirically modified by Feagan et al; the modified Baron score (MBS) has 5 grades (0–4).31 The modification removed qualitative assessment of different levels of bleeding (moderately, severely) and defined the 4 levels by categorical items (normal, granular, friable, bleeding, ulcerated). Endoscopic response is defined as an improvement of 2 grades in the MBS, and endoscopic remission is defined as an MBS score of 0. The Mayo Clinic Score The Mayo Clinic Score (MCS) is a composite instrument that includes both endoscopic and clinical items.13 The MCS (range, 0–12 points) was created empirically for a clinical trial in patients with mild to moderate UC. The items and severity levels were based on the investigators’ clinical experience. The MCS consists of 4 descriptors: stool frequency, rectal bleeding, physician’s global assessment, and assessment of endoscopic severity based on fiber-optic flexible sigmoidoscopy (Table 1). Complete response is defined as an MCS score of 0 in all subscores. Partial REVIEWS AND PERSPECTIVES Table 1.Indices Used for Regulatory Approval From 2005 to 2014 40 Levesque et al REVIEWS AND PERSPECTIVES response is defined as “substantial but incomplete improvement in the subscores.” The index has been used in multiple clinical trials of mesalamine, budesonide MMX, infliximab, adalimumab, and golimumab.13,32–35 Some trials have modified the instrument such that mild friability is scored as a 2 rather than a 1 on the Mayo endoscopic subscore36 (Figure 1). The MCS has important limitations; it is a composite score that assimilates items (symptoms and endoscopy) that are not logically combinable and are not easy to appropriately weight. These properties increase measurement variability and decrease statistical efficiency.9 As a response to these limitations, the MCS has been adapted to functionally create coprimary end points for trials by separating its subcomponents into symptom-based and endoscopic criteria of response and remission. In 2 clinical trials that compared infliximab with placebo in patients with moderate to severe UC, clinical response was defined as a reduction in the MCS of at least 3 points and a decrease of 30% from the baseline score, with a decrease of at least 1 point on the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1.32 Clinical remission was defined as a MCS of 2 and no subscore >1. Mucosal healing was defined as an endoscopic subscore of 0 or 1. Partial MCSs have been defined as 3-item (stool frequency, rectal bleeding, and physician’s global assessment) and 2-item (stool frequency and rectal bleeding) instruments.37 These instruments, which do not include endoscopy, have good correlation with the full MCS. The 2-item MCS only includes items that are reported by patients and from a practical perspective comprises a PRO. This evolution in using the MCS illustrates the desire to independently assess symptoms and inflammation defined by endoscopy. The score has not been completely validated. CDAI The CDAI has been the primary outcome measure for clinical trials since publication of the National Cooperative Crohn’s Disease Study trial in 1979.38,39 The CDAI was created by regressing 18 clinical items identified by physicians (ie, abdominal pain, pain awakening patient from sleep, appetite), physical signs (ie, average daily temperature, abdominal mass), use of medication (ie, loperamide or opiate use for diarrhea), and laboratory tests (ie, hematocrit) against the dependent variable of a 4-point global rating of disease activity generated by physicians. Eight independent predictors were identified: severity of abdominal pain, general well-being, liquid stool frequency, extraintestinal symptoms, need for antidiarrheal drugs, presence of an abdominal mass, body weight, and hematocrit. Regression coefficients (weights) for the 8 predictors were then standardized to create an overall CDAI score that ranged from 0 to 600. Benchmarks for disease activity were then as follows: CDAI <150, clinical remission; 150 to 219, mild actively disease; 220 to 450, moderately active disease; and >450, very severe disease. Clinical response was subsequently defined as a reduction from the baseline score of 70 or 100 points. Gastroenterology Vol. 148, No. 1 Figure 1. UC with friability. Complete loss of vascular pattern. The CDAI has served as the basis for acceptance into clinical practice and in many instances regulatory approval of multiple drugs, including prednisone, azathioprine, methotrexate, controlled ileal release budesonide, infliximab, adalimumab, certolizumab pegol, and natalizumab.40–46 The majority of the CDAI score comes from the symptombased diary card items (pain, stool frequency, well-being). Studies have shown that the CDAI can be simplified to these patient-reported items without a large loss of instrument responsiveness.47,48 The Harvey–Bradshaw Index (HBI) was derived to simplify calculation of the CDAI. The HBI consists of 5 descriptors: general well-being, complications, abdominal mass, and abdominal pain and number of liquid stools for the previous day. Remission is defined as a score of <5.49 Recently, Vermiere et al correlated HBI and CDAI scores.50 A 3-point change in the HBI correlated with a 100-point change in the CDAI. An HBI 4 corresponded with a CDAI score 150. Relationships between the CDAI and endoscopic disease. The CDAI has several limitations as a valid index for clinical trials of CD. First, the CDAI correlates poorly with endoscopic inflammation (Spearman rank correlation coefficient, 0.15), serum biomarkers of inflammation (C-reactive protein and interleukin-6), and fecal biomarkers of inflammation (calprotectin and lactoferrin).4,51 Second, a prospective cross-sectional cohort study of patients with either CD or irritable bowel syndrome found a CDAI score >150 in the majority of patients with irritable bowel syndrome.52 Third, the CDAI is an inefficient primary outcome measure that has been associated with high placebo rates in clinical trials (natalizumab, 48.6%46; certolizumab, 27%45; and sargramostim, 51%53). An analysis of SONIC (Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease) revealed that 18% of patients who met the trial inclusion criteria of a CDAI score >220 lacked objective evidence of endoscopic disease, implying that their symptoms arose from noninflammatory sources.54 In these patients, no treatment effect of combination therapy with January 2015 Emerging Treatment Goals in IBD Trials and Practice 41 REVIEWS AND PERSPECTIVES infliximab and azathioprine was observed. Finally, the CDAI was not created according to FDA guidance for PRO development, which specifies that index items must be generated by patients. Based on these deficiencies, the FDA recently indicated that the CDAI will no longer be acceptable as a measure of disease activity in clinical trials of CD.9 Crohn’s Disease Endoscopic Index of Severity In 1989, the Groupe D’Etudes Therapeutiques Des Affections Inflammatoires due Tube Digestif (GETAID) presented their multiphase study of the development of the first validated endoscopic index for CD.55 In the development phase, 2 endoscopists simultaneously assessed colonoscopies from 75 patients and scored 9 items, the percentage of mucosa involved by disease, the percentage of ulcerated mucosa in 5 segments (ileum, right colon, transverse colon, sigmoid and left colon, and rectum), and a global evaluation of lesion severity (Supplementary Figure 1). The interobserver agreement was high. Intraclass correlation coefficients (ICCs) for the Crohn’s Disease Endoscopic Index of Severity (CDEIS) and global evaluation of lesion severity were 0.96 and 0.86, respectively (P < .001). The 2 endoscopists were in the same room while scoring took place, thus potentially compromising independence. Regression modeling and weighting of independent items that correlated with the global evaluation of lesion severity were used to create the CDEIS. Four descriptors (superficial and deep ulcerations and both ulcerated and nonulcerated stenosis) are summed with the average extents of ulcerated and affected mucosa disease in the explored segments (Figure 2). The total CDEIS score ranges from 0 to 44. Subsequently, the GETAID investigators empirically defined complete endoscopic remission as a score of <3, endoscopic remission as a score of <6, and endoscopic response as a decrease of >5 points.56 Other studies defined a CDEIS response as a decrease from baseline of 3 points,57 5 points,58 or 75%.59 Levels of disease severity (mild, moderate, severe) have been described as CDEIS scores <5, 5 to 15, and >15, respectively.60 The CDEIS has been used as an inclusion criterion58,61 and end point58,62–89 in clinical trials but has not been completely validated. Figure 2. Ulcerated surface in CD. as 0.985 (95% confidence interval [CI], 0.939–1.000) and 0.994 (95% CI, 0.976–1.000) for CDEIS and SES-CD, respectively90; however, the independence of SES-CD scoring during the trial was limited because the endoscopists were in the same endoscopy suite and were not blinded to clinical disease activity. Similar to the CDEIS, the SES-CD showed a weak correlation with the CDAI (Spearman rank correlation coefficient, 0.206). The investigators recommended the SES-CD as a simple to use and reliable endoscopic scoring instrument for CD. A separate study of repeat procedures performed in patients with active disease showed that changes in the CDEIS and SES-CD were highly correlated (r ¼ 0.828 between DCDEIS and DSES-CD; P < .001). The investigators91,92 have empirically created the following grades of disease activity: remission, 0–2; mild inflammation, 3–6; moderate inflammation, 7–16; and severe inflammation, >16. The SES-CD has recently been used for assessment of assessment of eligibility93 and outcome94–103 in clinical trials. Although it has been partially validated, its responsiveness to change remains to be defined. Simple Endoscopic Score in Crohn’s Disease Presence or Absence of Ulceration as an Endoscopic Outcome In 2004, Daperno et al developed the Simple Endoscopic Score in Crohn’s Disease (SES-CD) to improve the CDEIS, which they found to be cumbersome for use in both clinical trials and practice.90 The 4 descriptors selected from the CDEIS for use in the SES-CD were ulcer size, proportion of surface covered by ulcer, proportion of surface covered by other lesions, and stenosis. Each descriptor is graded based on 3 levels and is scored in 5 segments (ileum, right colon, transverse colon, left colon, and rectum). The total score is calculated as the sum of all the items in each segment and can range from 0 to 60 (Supplementary Figure 2). Interobserver ICCs for the SES-CD and CDEIS were 0.9815 and 0.9090, respectively. The CDEIS item “superficial ulcers” had the lowest level of agreement (0.628–0.767). In the SES-CD validation phase, the interobserver agreement was reported Although the SES-CD is easier to calculate than the CDEIS, the presence or absence of ulcerations is an even simpler measure of endoscopic disease activity. In the endoscopic substudy of ACCENT I (A Randomized, Doubleblind, Placebo-Controlled Trial of Anti-TNFa Chimeric Monoclonal Antibody [Infliximab, Remicade] in the Longterm Treatment of Patients With Moderately to Severely Active Crohn’s Disease) and SONIC with infliximab, endoscopic mucosal healing was defined as the absence of ulceration among patients with ulcerations at baseline.43,54 The EXTEND (Extend the Safety and Efficacy of Adalimumab through Endoscopic Healing) trial with adalimumab was the first controlled trial in CD in which endoscopic mucosal healing, defined as the absence of ulceration at week 12, was the primary end point.59 Twenty-seven 42 Levesque et al REVIEWS AND PERSPECTIVES percent of patients in the adalimumab group had this outcome compared with 12% in the placebo group (P ¼ .056). The major limitation of using the presence/ absence of endoscopic ulcers as an outcome measure is that it is cannot measure changes from baseline that fall short of complete ulcer healing, which may define a meaningful treatment effect. Ferrante et al recently examined the change from baseline in the CDEIS and SES-CD that predicted subsequent sustained clinical benefit.104 Using receiver operating characteristic curves, endoscopic response (defined by the cutoff of a decrease from baseline in the CDEIS and SES-CD of 50%) and endoscopic mucosal healing (defined as the absence of ulceration 26 weeks after initiation of treatment) were the most robust predictors of corticosteroid-free clinical remission at week 50. Endoscopic response at week 26 predicted corticosteroid-free remission at week 50 with an area under the curve of 0.611 (95% CI, 0.538–0.683). The minimally important difference and responsiveness to change of all endoscopic scoring indices require further definition. The Future of Outcome Assessments in IBD: New PROs and ClinROs The MCS, CDAI, and other composite clinical outcome measures were not created according to FDA guidance for development of a PRO. The development of a valid PRO includes patient concept elicitation interviews, expert interviews, item generation, content validity, patient cognitive interviews, and a quantitative validation study.8 The patients themselves need to generate the items, and the process can take years to complete. Efforts are under way to develop PROs for both UC and CD. While these new PROs are under development, there is a need for interim PRO-like measures that can be used for drug development over the next few years. Fortunately, 2 interim PRO measures have evolved. For UC, a 2-item PRO developed from the rectal bleeding and stool frequency components of the MCS has been described (partial MCS). Lewis et al analyzed patientlevel data in a randomized controlled trial of rosiglitazone for UC. Cutoffs for detecting remission, defined by a patient rating of disease activity as “perfect or very good,” were 4.5 for the full MCS (sensitivity of 88% and specificity of 78%), 2.5 for the partial MCS (sensitivity of 71% and specificity of 84%), and 1.5 on a 6-point MCS (sensitivity of 65% and specificity of 81%). Using the outcomes of clinical remission and clinical response, the effect size of the partial MCS was similar to that estimated by the full MCS.37 For CD, a 2-item PRO composed of the abdominal pain and stool frequency items from the CDAI has been developed (PRO-2). Khanna et al analyzed patient-level data in randomized controlled trials of rifaximin and methotrexate.105 Cutoffs were an average daily stool frequency 1.5 points and abdominal pain score 1 point. The total PRO-2 score is calculated like the CDAI, that is, the daily scores for abdominal pain and stool frequency, averaged over 7 days, are weighted with the original CDAI multiplication factors; then, the weighted average scores for both items are summed. Using the outcomes of clinical remission and corticosteroid-free Gastroenterology Vol. 148, No. 1 remission, the effect size for a treatment of known efficacy of the PRO-2 was similar to CDAI-defined remission (13%–20%). Values corresponding to CDAI scores of 150, 220, and 450 points were 8, 14, and 34 points, respectively, and the corresponding values for change from baseline in CDAI scores of 50, 70, and 100 points were 2, 5, and 8 points, respectively, for the PRO-2. Ulcerative Colitis Endoscopic Index of Severity In contrast to the previous empiric efforts to develop endoscopic scoring systems for UC, Travis et al recently developed the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) based on a formal quantitative validation process.106 The score was derived by the analysis of 630 assessments of 60 videos by 10 IBD specialists. Weighted k scores were modest and ranged from 0.34 (contract friability) to 0.65 (erosions and ulcers). Regression modeling against an overall assessment of disease severity created the UCEIS, which accounted for 90% of the variation in the overall evaluation of disease severity. The UCEIS was initially an 11-point score composed of erosions/ulcers (score 1–4), vascular pattern (score 1–3), and bleeding (score 1–4). Weighted k scores for interobserver variation of the grades were 0.45, 0.42, and 0.37, respectively. The 48 combinations of items (4 4 3) were each correlated with an assessment of severity. The UCEIS was subsequently simplified to an 8-point instrument with the items of erosions and ulcers (score 0–3), vascular pattern (score 0–2), and bleeding (score 0–3). In a reliability study, interobserver agreement was moderate (k of 0.5).107 A high correlation was shown overall between a global assessment of endoscopic disease activity and UCEIS scores (correlation coefficient, 0.93).107 The cutoffs for remission and severe disease have not yet been defined, and this instrument has not yet been used in a clinical trial. For the future, the UCEIS has the potential to measure changes from baseline that fall short of complete endoscopic mucosal healing yet represent a potentially meaningful treatment effect. This increased sensitivity in comparison to existing instruments may be advantageous for dose finding in early drug development programs. Toward Central Reading of Endoscopic Indices in UC and CD ClinRO-reported outcome measures need clear definitions of index items to ensure reproducibility. Reproducibility is a fundamental property of a valid index for clinical trials.5 Observer variation in endoscopic assessments can lead to differences in the rates of response to treatment with placebo. In UC, central reading of endoscopic videos has recently been shown to be highly reliable and to reduce the rate of placebo response.108 A recent trial of mesalamine for mild to moderate UC measured intraobserver and interobserver agreement among scoring of 7 expert central readers of videos of flexible sigmoidoscopy for multiple endoscopic scores: the MBS, MCS, and UCEIS. ICCs were used to quantify agreement. The strength of agreement was evaluated according to the criteria of Landis and Koch, whereby ICCs of Emerging Treatment Goals in IBD Trials and Practice <0.00, 0.00 to 0.20, 0.21 to 0.40, 0.41 to 0.60, 0.61 to 0.80, and 0.81 to 1.00 indicated poor, slight, fair, moderate, substantial, and almost perfect agreement, respectively.109 The intrarater agreement for the MBS, modified MCS, and UCEIS was 0.88 (95% CI, 0.84–0.92), 0.89 (95% CI, 0.85–0.92), and 0.89 (95% CI, 0.85–0.93), respectively, and the interrater agreement was 0.78 (95% CI, 0.71–0.85), 0.79 (95% CI, 0.72–0.85), and 0.83 (95% CI, 0.77–0.88), respectively.5 In the clinical trial, where the modified Ulcerative Colitis Disease Activity Index (analogous to the modified MCS for endoscopy scores) was interpreted by the site investigator in real time and after the fact by a blinded central reader, 31% of patients with modified MCS endoscopic scores 2 points by the site endoscopists had their scores downgraded to a score <2 points by central reading and would have been ineligible for the trial. Exclusion of the ineligible patients reduced placebo response rates at weeks 6 or 10 from 20% and 21%, respectively, to 13% and 16%, respectively. Subsequent studies have defined the responsiveness to change of these endoscopic scores in a trial of mesalamine therapy.108,110 In these studies, the UCEIS had the greatest numerical responsiveness as well as the greatest reproducibility. However, the MCS functioned well and was not substantially inferior to the UCEIS. Now that the favorable operating characteristics of these instruments in a central reading environment are clear, it may be feasible to conduct relatively small proof-of-concept and dose-finding trials in which centrally read endoscopy is the primary outcome measure and statistically efficient techniques such as measuring shifts from baseline in distributions of index scores are used for data analysis. In CD, Khanna et al recently examined the reproducibility of evaluation of independent central readers of the CDEIS and SES-CD. Four independent central readers scored 50 representative videos 3 separate times. The readers had “almost perfect” intrarater agreement (intraobserver ICC, 0.89; 95% CI, 0.86–0.93). However, interrater agreement was lower (ICC, 0.71; 95% CI, 0.61–0.79).111 A key area of disagreement between the readers was the definition of superficial versus deep ulceration, which is used as an item in the CDEIS (similar to the original GETAID development study). In comparison, central reading of the SES-CD had “substantial” to “almost perfect” intraobserver 43 and interobserver reliability (intraobserver ICC, 0.91 [95% CI, 0.87–0.94]; interobserver ICC, 0.83 [95% CI, 0.75–0.89]).112 Assessment of Histological Inflammation An important question for both clinical trials and clinical practice is whether or not to treat beyond endoscopic remission to histological remission. Truelove and Richards first reported that active histological inflammation was commonly present in patients with UC who had normalappearing mucosa at endoscopy and that such patients were at an increased risk for relapse.113 This finding has been replicated by other investigators who showed that plasmacytosis on biopsy increases the chance of relapse.114 A retrospective cohort study in patients with UC found that 21% of 385 patients with mucosal healing had persistent histological activity.115 Conversely, the decrease in plasmacytosis on biopsy after therapy has been reported.116,117 These relationships support the possibility that a future definition of complete mucosal healing could include both endoscopic and histological healing. There is a need for a valid histological index if a definition of complete mucosal healing that includes histological healing will one day be included in clinical trials. A recent systematic review identified multiple indexes that have been used to measure histological disease activity in UC.118 Commonly included index items assessed the degree of acute and chronic inflammation, the presence or absence of architectural distortion of colonic crypts, and the integrity of the colonic epithelium (Table 2 and Figure 3). Mosli et al recently evaluated the intrarater and interrater agreement of expert pathologist central reader scoring in several commonly used UC histological indices.119 The Geboes score and modified Riley score intrarater agreement was “substantial” to “almost perfect,” respectively, whereas the interrater agreement was “moderate” to “substantial,” respectively. Items that require additional definition were identified, including crypt distortion and basal plasmacytosis. In CD, potential histological indices include the global histological activity score and the Naini Cortina score.120-121 Items included in these indices evaluate architectural damage, epithelial damage, neutrophilic infiltrate, Table 2.Potential ClinROs: Histological Indices Histological indices UC Geboes score Modified Riley score CD Global histological activity score Naini Cortina score Descriptors Architectural changes, chronic inflammation infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction, erosion or ulceration Neutrophils in epithelium, lamina propria neutrophils, erosion or ulceration Epithelium damage, architectural changes, infiltration of mononuclear cells in the lamina propria, infiltration of polymorphonuclear cells in the lamina propria, polymorphonuclear cells in the epithelium, presence of erosions and/or ulcers, presence of granulomas, number of biopsies affected Architectural distortion, increased lymphocytes and plasma cells in lamina propria, neutrophilic inflammation including erosions/ulcers, granulomas REVIEWS AND PERSPECTIVES January 2015 44 Levesque et al Gastroenterology Vol. 148, No. 1 REVIEWS AND PERSPECTIVES been correlated with histopathologic inflammation in the terminal ileum (Kendall s, 0.40; 95% CI, 0.11–0.64; P ¼ .02). Future trials are needed to determine the predictive value of bowel healing as measured by MRE, low-dose radiation, computed tomographic enterography, or ultrasonography for clinically relevant outcomes such as disease progression, hospitalization, and surgery. Treat-to-Target, Therapeutic Drug Monitoring, and Treatment Strategy Trials Figure 3. Histopathology showing severe acute inflammatory infiltrate and marked neutrophils in the lamina propria. erosions/ulcers, granulomas, and the number of biopsy specimens affected. Additional studies are needed to determine the predictive value of histological healing on long-term outcomes such as disease progression, hospitalization, and surgery. Radiographic Assessment of Inflammation Another potential ClinRO to assess inflammatory disease activity in CD is magnetic resonance enterography (MRE). MRE can identify the presence of important disease complications before initiation of therapy and can measure the progression of bowel damage over time (Lemann score).122 MRE has high diagnostic accuracy for both the detection of CD-related complications (ie, stenosis, fistula, and abscesses), which are key sequelae to inflammatory disease, and for assessment of luminal disease activity and extent. Two MRE indices have been formally derived to quantitate inflammatory activity in CD: the Magnetic Resonance Index of Activity123 and the London Index.124 The Magnetic Resonance Index of Activity, which is scored in both the terminal ileum and the colon, is highly correlated (r > 0.80; P < .001) with the CDEIS.83 Similarly, the London Index has The treat-to-target strategy is based on the hypothesis that treating endoscopic mucosal inflammation not only improves symptoms but also decreases the long-term burden of disease125 (Figure 4). There is emerging evidence that treating to endoscopic healing as a target meets this standard. In a 5-year, 157-patient cohort study, patients with UC without complete mucosal healing had greater rates of hospitalization (hazard ratio, 3.6; 95% CI, 1.6–8.5) and were more likely to undergo colectomy (hazard ratio, 8.4; 95% CI, 1.3–55.2) than those with complete mucosal healing.126 In trials of infliximab for moderate to severe UC, patients with Mayo Clinic endoscopic scores of 0 or 1 had less risk of hospitalization or surgery at 1 year compared with those with higher scores. In addition, patients with an endoscopic score of 0 had less need for future treatment with corticosteroids than those with a score of 1.127 In the ACCENT I trial of infliximab for moderate to severe CD, mucosal healing at week 10 and week 54 was associated with a trend toward fewer hospitalizations and surgeries. Similarly, the absence of mucosal ulceration in CD within 1 year of diagnosis or initiating therapy has been associated with reduced corticosteroid use and decreased clinical disease activity,128 fewer major abdominal surgeries,129 and sustained corticosteroid-free remission.130 Conversely, deep colonic ulcerations in CD are associated with an increased risk of colectomy.131 Treating to target can also be described as treat-to-target anti–tumor necrosis factor trough concentrations (ie, therapeutic drug monitoring). In the optimization phase of the TAXIT (Trough Level Adapted Infliximab Treatment) trial, adjusting infliximab dosing to Figure 4. Treat-to-target strategy. goal trough concentrations between 3 and 7 mg/mL led to improved outcomes and costs.132 Utilization of a target drug concentration is possible once a robust relationship has been established between drug pharmacokinetics and the desired pharmacodynamics effect. The cost-effectiveness of treat-to-target strategies and therapeutic drug monitoring remains to be shown. A recent decision analytic model showed cost savings by testing for inflammation, trough concentration, and antibodies to infliximab in patients who lose responsiveness to infliximab.133 These savings remain to be validated in larger clinical trials134 in CD and UC of testing strategies, assessments of antibodies, trough concentrations, and response to therapy with colonoscopy or MRE. Although biomarkers such as fecal calprotectin or C-reactive protein levels may have a future role in these strategies, their lack of sensitivity and specificity135 for inflammation and responsiveness to therapy precludes a recommendation to use them as a target for clinical practice or clinical trials at the present time. Treating to target has been shown to be a feasible strategy in clinical practice. A pilot study of 60 patients with UC who underwent 2 to 5 endoscopies over a median follow-up of 76 weeks showed cumulative mucosal healing rates of 60% and cumulative histological healing rates of 50%. Any adjustment in medical therapy for persistent endoscopic activity was associated with mucosal healing (hazard ratio, 9.8; 95% CI, 3.6–34.5; P < .0001).136 Similarly, in a pilot study of 67 patients with CD who underwent 2 to 4 endoscopies over a median follow-up of 62 weeks, cumulative mucosal rates of 51%, and cumulative endoscopic improvement rates of 61% were observed. Factors associated with mucosal healing were less than 26 weeks between endoscopic procedures (hazard ratio, 2.35; 95% CI, 1.15–4.97; P ¼ .035) and adjustment of medical therapy for persistent mucosal inflammation (hazard ratio, 4.28; 95% CI, 1.9–11.5; P ¼ .0003).137 In clinical practice, disease activity is often assessed through evaluation of symptoms and severity of intestinal inflammation by endoscopy. Given the evolution of clinical trial end points for UC toward a 2-item partial MCS PRO (rectal bleeding and stool frequency) and endoscopy (MCS endoscopy score 0 or 1), it is now possible to directly apply these clinical trial end points to clinical practice, treating to a target of symptom resolution and endoscopic mucosal healing. Given the evolution of clinical trial end points for CD toward a PRO-2 (abdominal pain and stool frequency) and endoscopy, it should be possible to directly apply these clinical trial end points to clinical practice, with the intent of treating to the targets of symptom resolution and endoscopic mucosal healing. Testing treatment strategies in the future may take the shape of either traditional patient-level trials in which patients are randomized to one strategy or another or novel cluster randomization trial designs in which centers are randomized to different strategies. These trials will go beyond testing the efficacy of individual drugs to testing treatment algorithms and strategies that aim to change the natural history of CD and UC, seeking to prevent bowel damage, surgical resection, and disability. In 2000, D’Haens Emerging Treatment Goals in IBD Trials and Practice 45 et al conducted the first trial of alternative treatment algorithms in CD, which showed that the early combination of azathioprine and infliximab led to significantly more mucosal healing than a traditional “step-up” approach.132 Recently, REACT-1 (A Cluster Randomized Controlled Trial of a Treatment Algorithm for the Management of Crohn’s Disease) showed that clinical practice outcome goals can be tested for real-world effectiveness and their impact on hospitalization and surgery.138 In a cluster randomization trial, 21 centers (1084 patients) were assigned to early combination therapy and 18 centers (898 patients) to conventional management. The proportion of patients in symptomatic remission (as measured by the HBI) at 12 and 24 months did not differ statistically between the 2 approaches (3.7%; 95% CI, 4.1% to 11.5%; P ¼ .354; at 24 months). However, significant and clinically important differences in the rates of complications, surgeries, and the combined outcome of hospitalizations, complications, and surgeries were observed in favor of early combination therapy over 24 months (27.7% and 35.1% in the early combination and conventional groups, respectively) (difference, 7.4%; hazard ratio adjusted for CD caseload and country, 0.74; 95% CI, 0.62–0.87; P < .001). In summary, the effectiveness of a treat-to-target strategy could be due to a patient’s disease (location, duration, patient genetics), the drug (pharmacokinetics), and/or the treatment strategy.139 Conclusions Clinical trials in IBD need to include patients with both symptoms as defined by PROs and documented inflammation as defined by ClinROs. Currently, symptomatic remission and endoscopic improvement are appropriate coprimary end points for clinical trials. The individual end points are meaningful to patients (PRO remission) and show that the therapy is affecting the underlying inflammatory process (endoscopic improvement). The combination of symptomatic remission and endoscopic improvement may also be useful in clinical practice as the target in treat-totarget disease management strategies. Additional studies are needed to show that treat-to-target strategies will change the natural history of IBD by preventing bowel damage and disability. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at http://dx.doi.org/10.1053/ j.gastro.2014.08.003. References 1. Ordas I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet 2012;380:1606–1619. 2. Baumgart DC, Sandborn WJ. Crohn’s disease. 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Reprint requests Address requests for reprints to: William J. Sandborn, MD, University of California San Diego, 9500 Gilman Drive, MC 9056, La Jolla, California 92093-9056. e-mail: [email protected]; fax: (858) 657-5022; or JeanFrédéric Colombel, MD, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1069, New York, New York 10029. e-mail: [email protected]; fax: (646) 537-8647. Conflicts of interest The authors disclose the following: B.G.L. has received consulting fees from AbbVie, Takeda, Nestle Health Sciences, Santarus, and Prometheus Laboratories and has served on a speakers bureau for Warner Chilcott and UCB Pharma. W.J.S. has received consulting fees from Abbott Laboratories, ActoGeniX, AGI Therapeutics Inc, Alba Therapeutics Corp, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas, Athersys Inc, Atlantic Healthcare Ltd, Aptalis, BioBalance Corp, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine PharmaSciences, Eagle Pharmaceuticals, EnGene Inc, Eli Lilly, EnteroMedics, Exagen Diagnostics Inc, Ferring Pharmaceuticals, Flexion Therapeutics Inc, Funxional Therapeutics Ltd, Genzyme Corp, Gilead Sciences, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood Pharmaceuticals, KaloBios Pharmaceuticals, Lexicon Pharmaceuticals, Lycera Corp, Meda Pharmaceuticals, Merck Research Laboratories, Merck Serono, Millennium Pharmaceuticals, Nisshin Kyorin Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics Inc, PDL BioPharma, Pfizer Inc, Procter & Gamble, Prometheus Laboratories, ProtAb Ltd, PurGenesis Technologies Inc, Relypsa Inc, Roche, Salient Pharmaceuticals, Salix Pharmaceuticals, Santarus, Schering-Plough Corp, Shire Pharmaceuticals, Sigmoid Pharma Ltd, Sirtris Pharmaceuticals, SLA Pharma UK Ltd, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG, TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics Ltd, Warner Chilcott UK Ltd, and Wyeth; has received research grants from Abbott Laboratories, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen, Millennium Pharmaceuticals, Novartis, Pfizer Inc, Procter & Gamble, Shire Pharmaceuticals, and UCB Pharma; has received payments for lectures/ speakers bureau from Abbott Laboratories, Bristol-Myers Squibb, and Janssen; and holds stock/stock options in EnteroMedics. J.R. has received consulting fees from AbbVie, Janssen, and Takeda. B.G.F. has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, Abbott Laboratories, Novartis Pharmaceuticals, Centocor Inc, Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGeniX, and Wyeth Pharmaceuticals; has received consulting fees from Millennium Pharmaceuticals, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, Abbott Laboratories, AstraZeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging, Salix Pharmaceuticals, Novo Nordisk, GlaxoSmithKline, ActoGeniX, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead Sciences, Pfizer Inc, Shire, Wyeth, Zealand Pharma, Zyngenia, gIcare Pharma, and Sigmoid Pharma; and has served on a speakers bureau for UCB, Abbott Laboratories, and Johnson & Johnson/Janssen. B.E.S. has received consulting fees from AbbVie, Amgen, AstraZeneca, Avaxia Biologics, Bristol-Myers Squibb, Janssen Biotech, Luitpold Pharmaceuticals, MedImmune, Pfizer Inc, PureTech Ventures, Salix, Shire, Takeda, TopiVert Pharma Ltd, and Vedanta Biosciences; has received research grants for his institution from AbbVie, Amgen, Celgene, Janssen R&D, Millennium Pharmaceuticals, Pfizer Inc, and Prometheus Laboratories; has received honoraria for lecturing in a CME program from Imedex, Strategic Consultants International, Focus Medical Communications, Curatio CME Medical Institute/Huntsworth Health NA, Creative Educational Concepts, and Scripps; has received honoraria for work as an associate editor from the American Gastroenterological Association Institute; and holds stock in Avaxia Biologics, a nonpublicly traded company. J.-F.C. has served as consultant, advisory board member, or speaker for AbbVie, AB Science, Amgen, Bristol-Myers Squibb, Celltrion, Danone, Ferring Pharmaceuticals, Emerging Treatment Goals in IBD Trials and Practice 51 Genentech, Giuliani SPA, Given Imaging, Janssen, Immune Pharmaceuticals, Merck & Co, Millennium Pharmaceuticals, Nutrition Science Partners Ltd, Pfizer Inc, Prometheus Laboratories, Protagonist, Receptos Inc, Sanofi, Schering-Plough, Second Genome, Takeda, Teva Pharmaceuticals, UCB Pharma, Vertex, and Dr August Wolff GmbH & Co and holds stock options in Intestinal Biotech Development. REVIEWS AND PERSPECTIVES January 2015 51.e1 Levesque et al Gastroenterology Vol. 148, No. 1 Supplementary Figure 1. Calculation CDEIS. Supplementary Figure 2. Calculation SES-CD. of of