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• W2019150265 abstract "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 patient-reported 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. 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 patient-reported 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. Inflammatory bowel disease (IBD) is caused by immune dysregulation of the digestive tract1Ordas I. Eckmann L. Talamini M. et al.Ulcerative colitis.Lancet. 2012; 380: 1606-1619Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar, 2Baumgart D.C. Sandborn W.J. Crohn's disease.Lancet. 2012; 380: 1590-1605Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar 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 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.3Bruining D.H. Sandborn W.J. Do not assume symptoms indicate failure of anti-tumor necrosis factor therapy in Crohn's disease.Clin Gastroenterol Hepatol. 2011; 9: 395-399Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Furthermore, it is well established that the Crohn’s Disease Activity Index (CDAI), which is heavily weighted toward symptoms, correlates poorly with endoscopy.4Cellier C. Sahmoud T. Froguel E. et al.Correlations between clinical activity, endoscopic severity, and biological parameters in colonic or ileocolonic Crohn's disease. A prospective multicentre study of 121 cases. The Groupe d'Etudes Therapeutiques des Affections Inflammatoires Digestives.Gut. 1994; 35: 231-235Crossref PubMed Google Scholar 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.5Kirshner B. Guyatt G. A methodological framework for assessing health indices.J Chronic Dis. 1985; 38: 27-36Abstract Full Text PDF PubMed Scopus (978) Google Scholar Previous reviews6Sandborn W.J. Feagan B.G. Hanauer S.B. et al.A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease.Gastroenterology. 2002; 122: 512-530Abstract Full Text Full Text PDF PubMed Google Scholar, 7D'Haens G. Sandborn W.J. Feagan B.G. et al.A review of activity indices and efficacy endponts for clinical trials of medical therapy in adults with ulcerative colitis.Gastroenterology. 2007; 132: 763-786Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar 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).8US Food and Drug Administration. US Food and Drug Administration (FDA) guidance for industry: patient-reported outcome measures use in medical product development to support labeling claims. 2009. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf.Google Scholar 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 both easily administered and readily interpretable by patients and clinicians.9US Food and Drug Administration. Gastroenterology regulatory endpoints and the advancement of therapeutics (GREAT II) workshop; October 21–22, 2013; Bethesda, MD.Google Scholar Similarly, a ClinRO for IBD trials must be a reliable measure of mucosal inflammation with well-defined operating properties.9US Food and Drug Administration. Gastroenterology regulatory endpoints and the advancement of therapeutics (GREAT II) workshop; October 21–22, 2013; Bethesda, MD.Google Scholar 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.10Todd III, K.L. Wright D. VANISH-2 Investigator GroupThe VANISH-2 study: a randomized, blinded, multicenter study to evaluate the efficacy and safety of polidocanol endovenous microfoam 0.5% and 1.0% compared with placebo for the treatment of saphenofemoral junction incompetence.Phlebology. 2014; 29: 608-618Crossref PubMed Scopus (14) Google Scholar 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.11Mesa R.A. Gotlib J. Gupta V. et al.Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial.J Clin Oncol. 2013; 31: 1285-1292Crossref PubMed Scopus (56) Google Scholar 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 54.12Keystone E. Heijde D. Mason Jr., D. et al.Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.Arthritis Rheum. 2008; 58: 3319-3329Crossref PubMed Scopus (344) Google Scholar 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,13Schroeder K.W. Tremaine W.J. Ilstrup D.M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.N Engl J Med. 1987; 317: 1625-1629Crossref PubMed Google Scholar are problematic because the concepts being evaluated are highly heterogeneous, making it difficult to assign a single measure of disease activity.9US Food and Drug Administration. Gastroenterology regulatory endpoints and the advancement of therapeutics (GREAT II) workshop; October 21–22, 2013; Bethesda, MD.Google Scholar 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) 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.14Lichtenstein G.R. Hanauer S.B. Sandborn W.J. Management of Crohn’s disease in adults.Am J Gastroenterol. 2009; 104: 465-483Crossref PubMed Scopus (438) Google Scholar 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 long-term 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. In patients with UC, important reductions in rates of colorectal cancer and colectomy have been observed over the past several decades.15Vester-Andersen M.K. Prosberg M.V. Jess T. et al.Disease course and surgery rates in inflammatory bowel disease: a population-based, 7-year follow-up study in the era of immunomodulating therapy.Am J Gastroenterol. 2014; 109: 705-714Crossref PubMed Scopus (25) Google Scholar 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.16Langholz E. Munkholm P. Davidsen M. et al.Course of ulcerative colitis: analysis of changes in disease activity over years.Gastroenterology. 1994; 107: 3-11Abstract Full Text PDF PubMed Google Scholar, 17Leijonmarck C.E. Persson P.G. Hellers G. Factors affecting colectomy rate in ulcerative colitis: an epidemiologic study.Gut. 1990; 31: 329-333Crossref PubMed Google Scholar, 18Hendriksen C. Kreiner S. Binder V. Long term prognosis in ulcerative colitis—based on results from a regional patient group from the county of Copenhagen.Gut. 1985; 26: 158-163Crossref PubMed Google Scholar, 19Hoie O. Wolters F.L. Riis L. et al.Low colectomy rates in ulcerative colitis in an unselected European cohort followed for 10 years.Gastroenterology. 2007; 132: 507-515Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 20Jess T. Riis L. Vind I. et al.Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: a population-based study from Copenhagen, Denmark.Inflamm Bowel Dis. 2007; 13: 481-489Crossref PubMed Scopus (206) Google Scholar, 21Faubion Jr., W.A. Loftus Jr., E.V. Harmsen W.S. et al.The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study.Gastroenterology. 2001; 121: 255-260Abstract Full Text Full Text PDF PubMed Google Scholar, 22Turner D. Walsh C.M. Steinhart A.H. et al.Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression.Clin Gastroenterol Hepatol. 2007; 5: 103-110Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar 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.23Peyrin-Biroulet L. Loftus Jr., E.V. Colombel J.F. et al.The natural history of adult Crohn's disease in population-based cohorts.Am J Gastroenterol. 2010; 105: 289-297Crossref PubMed Scopus (252) Google Scholar, 24Solberg I.C. Vatn M.H. Hoie O. et al.Clinical course in Crohn's disease: results of a Norwegian population-based ten-year follow-up study.Clin Gastroenterol Hepatol. 2007; 5: 1430-1438Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar 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 2003.25Domenech E. Zabana Y. Garcia-Planella E. et al.Clinical outcome of newly diagnosed Crohn's disease: a comparative, retrospective study before and after infliximab availability.Aliment Pharmacol Ther. 2010; 31: 233-239PubMed Google Scholar 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.25Domenech E. Zabana Y. Garcia-Planella E. et al.Clinical outcome of newly diagnosed Crohn's disease: a comparative, retrospective study before and after infliximab availability.Aliment Pharmacol Ther. 2010; 31: 233-239PubMed Google Scholar, 26Cannom R.R. Kaiser A.M. Ault G.T. et al.Inflammatory bowel disease in the United States from 1998 to 2005: has infliximab affected surgical rates?.Am Surg. 2009; 75: 976-980PubMed Google Scholar, 27Jones D.W. Finlayson S.R. Trends in surgery for Crohn's disease in the era of infliximab.Ann Surg. 2010; 252: 307-312Crossref PubMed Scopus (35) Google Scholar 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. As noted previously, the traditional outcome measures in UC trials consist of composite instruments that 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.28Truelove S.C. Witts L.J. Cortisone in ulcerative colitis; final report on a therapeutic trial.Br Med J. 1955; 2: 1041-1048Crossref PubMed Google Scholar These scores were not validated. Subsequently, multiple UC and CD composite clinical indices were used from 1960 to 1990.6Sandborn W.J. Feagan B.G. Hanauer S.B. et al.A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease.Gastroenterology. 2002; 122: 512-530Abstract Full Text Full Text PDF PubMed Google Scholar, 7D'Haens G. Sandborn W.J. Feagan B.G. et al.A review of activity indices and efficacy endponts for clinical trials of medical therapy in adults with ulcerative colitis.Gastroenterology. 2007; 132: 763-786Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar, 29Rutgeerts P. Geboes K. Vantrappen G. et al.Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract Full Text PDF PubMed Google Scholar 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).Table 1Indices Used for Regulatory Approval From 2005 to 2014IndicesDescriptorsUC Baron score (endoscopic items)Spontaneous bleeding, friability, moisture, distensibility, valves, vascular patternaWith >60% interobserver agreement. MBS (endoscopic items)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 MBSEndoscopic remission: MBS score of 0 MCS (endoscopic and clinical items)Stool frequency, rectal bleeding, physician’s global assessment, endoscopic severityRange: 0–12Complete response: MCS score of 0 in all subscoresPartial response: substantial but incomplete improvement in the subscores Partial MCSStool frequency and rectal bleeding UCEISVascular pattern (1–3), bleeding (1–4), erosions and ulcers (1–4)CD CDAISeverity of abdominal pain, general well-being, frequency of liquid stool, extraintestinal manifestations, need for antidiarrheal drugs, presence of an abdominal mass, body weight, hematocritRange: 0–600Clinical response: reduction from baseline of 70 to 100 pointsClinical remission: <150 HBIAbdominal pain, abdominal mass, general well-being, extraintestinal manifestations, number of liquid stools for the previous dayRemission score: <5, correlates with CDAI score <150 CDEISDeep ulcerations, superficial ulcerations, percentage of involved mucosa, percentage of ulcerated mucosa in 5 segments, and global evaluation of lesion severityComplete remission: score ≤3Remission: <6Response: decrease of >5 points SES-CDPresence and size of ulcer, extent of ulcerated surface, extent of affected surface, presence and type of narrowings3 levels for each descriptor in 5 segmentsRemission: 0–2a With >60% interobserver agreement. Open table in a new tab Baron et al explored the interrater agreement of 8 endoscopic scoring descriptors in the first endoscopic index validation study30Baron J.H. Connell A.M. Lennard-Jones J.E. Variation between observers in describing mucosal appearances in proctocolitis.BMJ. 1964; 1: 89-92Crossref PubMed Google Scholar (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).31Feagan B.G. Greenberg G.R. Wild G. et al.Treatment of ulcerative colitis with a humanized antibody to the a4b7 integrin.N Engl J Med. 2005; 352: 2499-2507Crossref PubMed Scopus (440) Google Scholar 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 (MCS) is a composite instrument that includes both endoscopic and clinical items.13Schroeder K.W. Tremaine W.J. Ilstrup D.M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.N Engl J Med. 1987; 317: 1625-1629Crossref PubMed Google Scholar 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 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.13Schroeder K.W. Tremaine W.J. Ilstrup D.M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.N Engl J Med. 1987; 317: 1625-1629Crossref PubMed Google Scholar, 31Feagan B.G. Greenberg G.R. Wild G. et al.Treatment of ulcerative colitis with a humanized antibody to the a4b7 integrin.N Engl J Med. 2005; 352: 2499-2507Crossref PubMed Scopus (440) Google Scholar, 32Rutgeerts P. Sandborn W.J. Feagan B.G. et al.Infliximab for induction and maintenance therapy for ulcerative colitis.N Engl J Med. 2005; 353: 2462-2476Crossref PubMed Scopus (1765) Google Scholar, 33Sandborn W.J. Feagan B.G. Marano C. et al.Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis.Gastroenterology. 2014; 146 (quiz e14–e15): 85-95Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 34Sandborn W.J. van Assche G. Reinisch W. et al.Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.Gastroenterology. 2012; 142 (e1–3): 257-265Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar, 35Sandborn W.J. Travis S. Moro L. et al.Once-daily budesonide MMX(R) extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study.Gastroenterology. 2012; 143 (e1–2): 1218-1226Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Some trials have modified the instrument such that mild friability is scored as a 2 rather than a 1 on the Mayo endoscopic subscore36Rutgeerts P. Colombel J.F. Reinisch W. et al.Infliximab induces and maintains mucosal healing in patients with active ulcerative colitis: the ACT trial experience.Gut. 2005; 54: A58Google Scholar (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.9US Food and Drug Administration. Gastroenterology regulatory endpoints and the advancement of therapeutics (GREAT II) workshop; October 21–22, 2013; Bethesda, MD.Google Scholar 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 1.32Rutgeerts P. Sandborn W.J. Feagan B.G. et al.Infliximab for induction and maintenance therapy for ulcerative colitis.N Engl J Med. 2005; 353: 2462-2476Crossref PubMed Scopus (1765) Google Scholar 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.37Lewis J.D. Chuai S. Nessel L. et al.Use of the noninvasive components of the Mayo score to assess clinical response in ulcerative colitis.Inflamm Bowel Dis. 2008; 14: 1660-1666Crossref PubMed Scopus (108) Google Scholar 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. The CDAI has been the primary outcome measure for clinical trials since publication of the National Cooperative Crohn’s Disease Study trial in 1979.38Best W.R. Becktel J.M. Singleton J.W. et al.Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Google Scholar, 39Summers R.W. Switz D.M. Sessions Jr., J.T. et al.National Cooperative Crohn's Disease Study: results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Google Scholar 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 o" @default.
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• W2019150265 title "Converging Goals of Treatment of Inflammatory Bowel Disease From Clinical Trials and Practice" @default.
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