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Assessing Severity of Disease in Patients with Ulcerative Colitis

Published:September 23, 2020DOI:https://doi.org/10.1016/j.gtc.2020.08.003

      Keywords

      Key points

      • The Truelove-Witts classification of disease severity has been the basis of severity index scoring in ulcerative colitis (UC).
      • The Ulcerative Colitis Endoscopic Index of Severity is a validated endoscopic scoring tool that may improve standardization of endoscopic disease scoring in UC.
      • Acute severe (fulminant) UC is a major source of morbidity for patients with UC. Several disease scoring systems, such as the Oxford (Travis) index and the Ho index, exist for predicting the need for colectomy. Rapid, evidence-based care remains vital to ensuring good outcomes in these patients.
      • Overall disease severity scoring and treat-to-target strategies are important concepts in disease severity. Further prospective studies supporting treat-to-target strategies will be important in helping the widespread adoption of this approach.

      Introduction

      Ulcerative colitis (UC) is a chronic disease that can present at various stages of disease activity and severity. Depending on disease activity at any moment and the overall severity of disease, treatment approaches vary considerably, from the use of topical mesalamine preparations to systemic immunosuppression. Accurately assessing these disease states as well as thoroughly understanding the role of concomitant noninflammatory causes of symptoms is vital to choosing the optimal management strategy for patients with this disease. This article reviews the history of disease severity scoring in UC and discusses the standard of care in assessing disease severity.

      Early Scales for Disease Assessment

      Early instruments for measuring disease severity relied on symptoms and basic clinical and laboratory tests assessed at a single moment. In 1955, Truelove and Witts
      • Truelove S.C.
      • Witts L.J.
      Cortisone in ulcerative colitis; final report on a therapeutic trial.
      described a severity score composed of 6 variables during their study of the effect of treatment with cortisone in patients with UC. The variables in this scoring system included number of stools per day, blood in the stools, temperature, pulse, hemoglobin, and erythrocyte sedimentation rate (ESR). Remission was defined as (1) 1 to 2 stools a day without blood, (2) no fever, (3) no tachycardia, (4) hemoglobin level normal or returning toward normal, (5) ESR normal or returning toward normal, (6) patient gaining weight. Disease activity was divided into 3 categories (mild, moderately severe, or severe) based on these criteria. Mild disease was defined as 4 or fewer bowel motions a day with no more than small amounts of macroscopic blood in stools; no fever; no tachycardia; anemia not severe; and ESR not increased more than 30 mm in 1 hour. Severe disease was defined as 6 or more motions a day with macroscopic blood in stools; fever (mean evening temperature more than 37.5°C [99.5° F], or a temperature of 37.8°C [100° F] or more on at least 2 days out of 4); tachycardia (mean pulse rate more than 90 beats/min); anemia (hemoglobin 75% or less; allowance made for recent transfusion); and ESR much increased (>30 mm in 1 hour). Moderately severe was defined as intermediate between severe and mild. Truelove and Witts
      • Truelove S.C.
      • Witts L.J.
      Cortisone in ulcerative colitis; final report on a therapeutic trial.
      also included descriptions of sigmoidoscopic assessment, indicating whether patients were (1) normal or near normal (near normal was slight hyperemia or slight granularity as the only abnormal finding); (2) improved; (3) no change or worse. These criteria helped clinicians characterize their patients with UC and served as the foundation for all severity grading for decades to come. However, the Truelove and Witts scoring system has several limitations. Chief among these limitations is the ambiguous definitions of improvement and worsening, as well as the lack of a severity score that can be tracked over time.

      Overview of Commonly Used Scoring Tools

      Since the Truelove and Witts
      • Truelove S.C.
      • Witts L.J.
      Cortisone in ulcerative colitis; final report on a therapeutic trial.
      study in 1955, several severity scores have been developed using several variables, including clinical symptoms, laboratory studies, and endoscopic assessment. Before delving into the plethora of scores that have been developed to describe disease severity, it is important to understand that no formally validated definitions of mild, moderate, or severe UC exist. Also, the terms disease activity and severity have often been used interchangeably in the literature, but these terms represent different, albeit overlapping, concepts.
      Disease activity refers to a cross-sectional, moment-in-time assessment of inflammation, whereas disease severity may include more longitudinal and historical factors. In UC, longitudinal factors that are relevant include prior biologic failure, history of maximum disease extent, and health care use metrics such as hospitalization and disability scoring tools. Practicing clinicians should note that each of the tools discussed allows a systematic approach to assess how to best to treat the patient in the moment as well as in the long term to avoid acute and chronic disease complications.
      Peyrin-Biroulet and colleagues
      • Peyrin-Biroulet L.
      • Panés J.
      • Sandborn W.J.
      • et al.
      Defining Disease Severity in Inflammatory Bowel Diseases: Current and Future Directions.
      described 3 main domains relevant to the evaluation of disease severity in inflammatory bowel disease (IBD): (1) impact of disease on the patient (clinical symptoms, patient-reported outcomes [PROs], quality of life, and disability); (2) inflammatory burden (extent, location, and severity of bowel involvement at a given time); (3) disease course, including structural damage.
      Traditionally, severity assessment has incorporated overlapping elements of these 3 domains with a focus on real-time clinical symptoms, PROs (which are often the clinical symptoms that comprise the scoring tools), and inflammatory burden. A detailed review of activity indices and efficacy end points in 2007
      • D’Haens G.
      • Sandborn W.J.
      • Feagan B.G.
      • et al.
      A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis.
      listed the following scores: the Baron (endoscopic) score in 1964,
      • Baron J.H.
      • Connell A.M.
      • Lennard-Jones J.E.
      Variation between observers in describing mucosal appearances in proctocolitis.
      the Powell-Tuck Index/Powell-Tuck sigmoidoscopic assessment in 1978,
      • Powell-Tuck J.
      • Bown R.L.
      • Lennard-Jones J.E.
      A comparison of oral prednisolone given as single or multiple daily doses for active proctocolitis.
      the Mayo Score (also called the Mayo Clinic Score and the Disease Activity Index)/Mayo Score Flexible Proctosigmoidoscopy Assessment in 1987,
      • Schroeder K.W.
      • Tremaine W.J.
      • Ilstrup D.M.
      Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis.
      the Sutherland Index (also called the Disease Activity Index or UC Disease Activity Index)/the Sutherland Mucosal Appearance Assessment in 1987,
      • Sutherland L.R.
      • Martin F.
      5-Aminosalicylic acid enemas in treatment of distal ulcerative colitis and proctitis in Canada.
      Clinical Activity Index (Rachmilewitz Index)/Endoscopic Index in 1988,
      • Rachmilewitz D.
      Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial.
      the Activity Index (Seo Index) in 1992,
      • Seo M.
      • Okada M.
      • Yao T.
      • et al.
      An index of disease activity in patients with ulcerative colitis.
      Lichtiger Index (Modified Trulove and Witts Severity Index) in 1990,
      • Lichtiger S.
      • Present D.H.
      Preliminary report: cyclosporin in treatment of severe active ulcerative colitis.
      the Physician Global Assessment/Sigmoidoscopic Index in 1993,
      • Hanauer S.
      • Schwartz J.
      • Robinson M.
      • et al.
      Mesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial.
      the Investigators Global Evaluation/Sigmoidoscopic Inflammation Grade Score in 1998,
      • Hanauer S.B.
      • Robinson M.
      • Pruitt R.
      • et al.
      Budesonide enema for the treatment of active, distal ulcerative colitis and proctitis: a dose-ranging study. U.S. Budesonide enema study group.
      Simple Clinical Colitis Activity Index in 1998,
      • Walmsley R.S.
      • Ayres R.C.S.
      • Pounder R.E.
      • et al.
      A simple clinical colitis activity index.
      Improvement Based on Individual Symptom Scores in 2002,
      • Levine D.S.
      • Riff D.S.
      • Pruitt R.
      • et al.
      A randomized, double blind, dose-response comparison of balsalazide (6.75 g), balsalazide (2.25 g), and mesalamine (2.4 g) in the treatment of active, mild-to-moderate ulcerative colitis1.
      Ulcerative Colitis Clinical Score/Modified Baron Score in 2005,
      • Feagan B.G.
      • Greenberg G.R.
      • Wild G.
      • et al.
      Treatment of Ulcerative Colitis with a Humanized Antibody to the α 4 β 7 Integrin.
      and patient-defined remission in 2005.
      • Higgins P.D.R.
      • Schwartz M.
      • Mapili J.
      • et al.
      Patient defined dichotomous end points for remission and clinical improvement in ulcerative colitis.
      Of these, one of the most popular and commonly used scores in clinical practice has been the Mayo Score (Table 1). The endoscopic scoring tools listed earlier, including the Mayo Score, involve several variables that have been reported to have significant interobserver variability (namely mucosal friability). In 2012, in an effort to develop an endoscopic scoring tool with lower interobserver variability, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) was developed.
      • Travis S.P.L.
      • Schnell D.
      • Krzeski P.
      • et al.
      Developing an instrument to assess the endoscopic severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS).
      The study showed that just 3 descriptors (vascular pattern, bleeding, and erosions and ulcers) were sufficient to create a model accounting for 90% of the overall assessment of endoscopic severity associated with UC (Table 2).
      Table 1Scoring system for assessment of ulcerative colitis activity
      From Schroeder KW, Tremaine WJ, Ilstrup DM. Coated Oral 5-Aminosalicylic Acid Therapy for Mildly to Moderately Active Ulcerative Colitis. N Engl J Med. 1987;317(26):1625-1629. https://doi.org/10.1056/NEJM198712243172603.
      Stool frequency0 = Normal number of stools for this patient
      1 = 1–2 stools more than normal
      2 = 3–4 stools more than normal
      3 = 5 or more stools more than normal
      Rectal bleeding
      This score represented the most severe bleeding of the day.
      0 = No blood seen
      1 = Streaks of blood with stool less than half of the time
      2 = Obvious blood with stool most of the time
      3 = Blood alone passed
      Findings of flexible sigmoidoscopy0 = Normal or inactive disease
      1 = Mild disease (erythema, decreased vascular pattern, mild friability)
      2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions)
      3 = Severe disease (spontaneous bleeding, ulceration)
      Physician's global assessment
      The physician’s global assessment acknowledged other criteria including the patient’s daily abdominal discomfort, general sense of well-being, performance status, and physical findings.
      0 = Normal
      1 = Mild disease
      2 = Moderate disease
      3 = Severe disease
      a This score represented the most severe bleeding of the day.
      b The physician’s global assessment acknowledged other criteria including the patient’s daily abdominal discomfort, general sense of well-being, performance status, and physical findings.
      Table 2Ulcerative colitis endoscopic index of severity descriptors and definitions
      From Travis SPL, Schnell D, Krzeski P, et al. Developing an instrument to assess the endoscopic severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Gut. 2012;61(4):535-542. https://doi.org/10.1136/gutjnl-2011-300486.
      Descriptor (Score Most Severe Lesions)Likert Scale Anchor PointsDefinition
      Vascular patternNormal (1)Normal vascular pattern with arborization of capillaries clearly defined, or with blurring or patchy loss of capillary margins
      Patchy obliteration (2)Patchy obliteration of vascular pattern
      Obliterated (3)Complete obliteration of vascular pattern
      BleedingNone (1)No visible blood
      Mucosal (2)Some spots or streaks of coagulated blood on the surface of the mucosa ahead of the scope, which can be washed away
      Luminal mild (3)Some free liquid blood in the lumen
      Luminal moderate or severe (4)Frank blood in the lumen ahead of endoscope or visible oozing from mucosa after washing intraluminal blood, or visible oozing from a hemorrhagic mucosa
      Erosions and ulcersNone (1)Normal mucosa, no visible erosions or ulcers
      Erosions (2)Tiny (≤5 mm) defects in the mucosa, of a white or yellow color with a flat edge
      Superficial ulcer (3)Larger (>5 mm) defects in the mucosa, which are discrete fibrin-covered ulcers in comparison with erosions, but remain superficial
      Deep ulcer (4)Deeper excavated defects in the mucosa, with a slightly raised edge
      Additional files indicating the levels of the UCEIS are available online only.

      Role of Biomarkers

      Several biomarkers have been studied with a focus on the degree of correlation with endoscopic disease in UC. The most commonly used biomarkers include ESR, C-reactive protein (CRP), fecal calprotectin (FC), and fecal lactoferrin (FL). Although ESR and CRP can be helpful in differentiating inflammatory from noninfectious causes of diarrhea, these are both nonspecific markers that can be increased in various other disease states.
      • Menees S.B.
      • Powell C.
      • Kurlander J.
      • et al.
      A meta-analysis of the utility of C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin, and fecal lactoferrin to exclude inflammatory bowel disease in adults with IBS.
      ESR especially is nonspecific and does not change as rapidly as CRP does, further limiting its utility.
      • Menees S.B.
      • Powell C.
      • Kurlander J.
      • et al.
      A meta-analysis of the utility of C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin, and fecal lactoferrin to exclude inflammatory bowel disease in adults with IBS.
      ,
      • FAGAN E.A.
      • DYCK R.F.
      • MATON P.N.
      • et al.
      Serum levels of C-reactive protein in Crohn’s disease and ulcerative colitis.
      Importantly, historical studies have shown that up to 50% of patients with active disease may not have increased levels of CRP.
      • Beattie R.M.
      • Walker-Smith J.A.
      • Murch S.H.
      Indications for investigation of chronic gastrointestinal symptoms.
      ,
      • Shine B.
      • Berghouse L.
      • Jones J.E.L.
      • et al.
      C-Reactive protein as an aid in the differentiation of functional and inflammatory bowel disorders.
      Cutoffs of less than 5 to 6 mg/L have been proposed for CRP, with the main limitation of this test being its decreased sensitivity and negative predictive value; that is, a large proportion of patients with mild disease may have normal CRP levels.
      • Nancey S.
      • Boschetti G.
      • Moussata D.
      • et al.
      Neopterin is a novel reliable fecal marker as accurate as calprotectin for predicting endoscopic disease activity in patients with inflammatory bowel diseases.
      ,
      • Schoepfer A.M.
      • Beglinger C.
      • Straumann A.
      • et al.
      Fecal calprotectin more accurately reflects endoscopic activity of ulcerative colitis than the lichtiger index, C-reactive protein, platelets, hemoglobin, and blood leukocytes.
      CRP does have an important role in predicting the need for colectomy. Patients with severe acute UC with persistently increased levels greater than 45 mg/L in patients having 3 to 8 bowel movements a day despite greater than 3 days of treatment with high-dose intravenous corticosteroids (IVCS) are at increased risk for colectomy.
      • Travis S.P.
      • Farrant J.M.
      • Ricketts C.
      • et al.
      Predicting outcome in severe ulcerative colitis.
      FC and FL are more specific for intestinal inflammation, and, in general, correlate more closely with colonic disease.
      • Sipponen T.
      • Kärkkäinen P.
      • Savilahti E.
      • et al.
      Correlation of faecal calprotectin and lactoferrin with an endoscopic score for Crohn’s disease and histological findings.
      ,
      • Lewis J.D.
      The utility of biomarkers in the diagnosis and therapy of inflammatory bowel disease.
      Levels between 50 and 250 μg/g have been shown to have sensitivities varying from 71% to 93% when different endoscopic disease threshold are used, with lower negative predictive values when less severe disease cutoffs are used.
      • Nancey S.
      • Boschetti G.
      • Moussata D.
      • et al.
      Neopterin is a novel reliable fecal marker as accurate as calprotectin for predicting endoscopic disease activity in patients with inflammatory bowel diseases.
      ,
      • D’Haens G.
      • Ferrante M.
      • Vermeire S.
      • et al.
      Fecal calprotectin is a surrogate marker for endoscopic lesions in inflammatory bowel disease.
      ,
      • Schoepfer A.M.
      • Beglinger C.
      • Straumann A.
      • et al.
      Ulcerative colitis: Correlation of the Rachmilewitz Endoscopic Activity Index with fecal calprotectin, clinical activity, C-reactive protein, and blood leukocytes.
      FL levels of 7.25 to 10 μg/g have similar operating characteristics.
      • Røseth A.G.
      • Aadland E.
      • Jahnsen J.
      • et al.
      Assessment of disease activity in ulcerative colitis by faecal calprotectin, a novel granulocyte marker protein.
      • Røseth A.G.
      • Aadland E.
      • Grzyb K.
      Normalization of faecal calprotectin: a predictor of mucosal healing in patients with inflammatory bowel disease.
      • D’Incà R.
      • Dal Pont E.
      • Di Leo V.
      • et al.
      Calprotectin and lactoferrin in the assessment of intestinal inflammation and organic disease.
      • Hanai H.
      • Takeuchi K.
      • Iida T.
      • et al.
      Relationship Between Fecal Calprotectin, Intestinal Inflammation, and Peripheral Blood Neutrophils in Patients with Active Ulcerative Colitis.
      Our practice is to check inflammatory markers with ESR and CRP in addition to regular maintenance laboratory tests at baseline and biannually with patients on mesalamine and more frequently with patients on biologics. It is important to correlate these values with clinical symptoms and endoscopic findings to individualize interpretation of these results. Because of inconsistent patient billing patterns, we do not routinely check FC but use this test when endoscopy is not feasible (eg, patient not able to travel; cost concerns; or increased risk of the procedure, such as during the severe acute respiratory syndrome-coronavirus-2 epidemic).

      Newer Concepts in Disease Severity: Quality of Life, Histologic Assessment, Imaging

      Quality-of-life metrics have increasingly become important to assess in patients with IBD, driven both by governmental oversight and patient advocacy groups. Specifically, the US Food and Drug Administration (FDA) has mandated a move toward using PROs as coprimary end points, which has led to increased research in this area. Of the 20 PROs in IBD analyzed in a recent systemic review, none met all of the FDA’s criteria for development, with only 2 of these indices involving patients directly in the development of these measures (1 in UC, the Simple Clinical Colitis Activity Index).
      • de Jong M.J.
      • Huibregtse R.
      • Masclee A.A.M.
      • et al.
      Patient-reported outcome measures for use in clinical trials and clinical practice in inflammatory bowel diseases: a systematic review.
      Efforts to develop validated PROs in IBD with extensive patient partnerships are underway.
      • Higgins P.D.R.
      The development of patient-reported outcome measures in inflammatory bowel disease.
      ,
      • Singh S.
      PROMises Made, PROMises to be kept: patient-reported outcome measures in inflammatory bowel diseases.
      However, the PROs that have been included in disease activity scoring for decades are not fully informative by themselves. Several studies have shown that, especially in mild to moderate UC, PROs of rectal bleeding and stool frequency have variable positive and negative predictive values, with time on therapy affecting the accuracy of these measures, emphasizing the importance of an objective assessment before consideration of any therapy change.
      • Ma C.
      • Sandborn W.J.
      • D’Haens G.R.
      • et al.
      Discordance between patient-reported outcomes and mucosal inflammation in patients with mild to moderate ulcerative colitis.
      ,
      • Colombel J.-F.
      • Keir M.E.
      • Scherl A.
      • et al.
      Discrepancies between patient-reported outcomes, and endoscopic and histological appearance in UC.
      Alternative causes of symptoms should be considered, including but not limited to concomitant irritable bowel syndrome, small intestinal bacterial overgrowth, and psychiatric disease.
      At our institution, the Short Inflammatory Bowel Disease Questionnaire (SIBDQ) and the Patient Health Questionnaire-8 (PHQ-8) are collected and used to help guide treatment decisions.
      • Irvine E.J.
      • Zhou Q.
      • Thompson A.K.
      The Short Inflammatory Bowel Disease Questionnaire: a quality of life instrument for community physicians managing inflammatory bowel disease. CCRPT Investigators. Canadian Crohn’s Relapse Prevention Trial.
      ,
      • Kroenke K.
      • Strine T.W.
      • Spitzer R.L.
      • et al.
      The PHQ-8 as a measure of current depression in the general population.
      We also use a multidisciplinary approach to manage the comorbid psychiatric illness that often develops as a result of chronic illness.
      Histologic assessment for disease activity has also become increasingly important, driven by the idea that deep remission, as defined by normal endoscopic and histologic findings, may lead to improved outcomes.
      • Korelitz B.I.
      • Sultan K.
      • Kothari M.
      • et al.
      Histological healing favors lower risk of colon carcinoma in extensive ulcerative colitis.
      ,
      • Bitton A.
      • Peppercorn M.A.
      • Antonioli D.A.
      • et al.
      Clinical, biological, and histologic parameters as predictors of relapse in ulcerative colitis.
      As early as 1966, rectal biopsies were used to assess disease activity in UC.
      • Wright R.
      • Truelove S.R.
      Serial rectal biopsy in ulcerative colitis during the course of a controlled therapeutic trial of various diets.
      What defines histologic remission, when there is also no corresponding endoscopic activity, has been a source of debate because there are several histologic scoring systems that have been developed for scoring UC disease activity, as well as several definitions of histologic activity that have been used in clinical trials evaluating efficacy of medications for the treatment of UC. However, active disease is generally defined by degeneration of the surface and crypt epithelium with associated neutrophilic infiltrate in the lamina propria and in the crypt regions, the latter termed cryptitis.
      • Goldman H.
      Interpretation of large intestinal mucosal biopsy specimens.
      There have been at least 30 histologic scoring systems developed in UC, with 11 of these systems having some form of validation.
      • Mosli M.H.
      • Parker C.E.
      • Nelson S.A.
      • et al.
      Histologic scoring indices for evaluation of disease activity in ulcerative colitis.
      The validated scores include the Truelove and Richards Index,
      • Truelove S.C.
      • Richards W.C.
      Biopsy studies in ulcerative colitis.
      Gomes Index,
      • Gomes P.
      • du Boulay C.
      • Smith C.L.
      • et al.
      Relationship between disease activity indices and colonoscopic findings in patients with colonic inflammatory bowel disease.
      Riley Score,
      • Riley S.A.
      • Mani V.
      • Goodman M.J.
      • et al.
      Microscopic activity in ulcerative colitis: what does it mean?.
      Geboes Score,
      • Geboes K.
      • Riddell R.
      • Ost A.
      • et al.
      A reproducible grading scale for histological assessment of inflammation in ulcerative colitis.
      Harpaz/Mount Sinai Index,
      • Fiel M.
      • Qin L.
      • Suriawinita A.
      • et al.
      Histologic grading of disease activity in chronic IBD: inter- and intra-observer variation among pathologists with different levels of experience.
      Modified Riley Score,
      • Feagan B.G.
      • Greenberg G.R.
      • Wild G.
      • et al.
      Treatment of Ulcerative Colitis with a Humanized Antibody to the α 4 β 7 Integrin.
      the Chicago/Rubin/Histologic inflammation Activity Scale,
      • Rubin D.
      • Huo D.
      • Hetzel J.
      • et al.
      Increased degree of histological inflammation predicts colectomy and hospitalization in patients with ulcerative colitis.
      Modified Harpaz Index,
      • Theede K.
      • Holck S.
      • Ibsen P.
      • et al.
      Level of Fecal Calprotectin Correlates With Endoscopic and Histologic Inflammation and Identifies Patients With Mucosal Healing in Ulcerative Colitis.
      the Simplified Geboes Score,
      • Jauregui-Amezaga A.
      • Geerits A.
      • Das Y.
      • et al.
      A Simplified Geboes Score for Ulcerative Colitis.
      Nancy Index,
      • Marchal-Bressenot A.
      • Salleron J.
      • Boulagnon-Rombi C.
      • et al.
      Development and validation of the Nancy histological index for UC.
      and the Robarts Histopathology Score.
      • Mosli M.H.
      • Feagan B.G.
      • Zou G.
      • et al.
      Development and validation of a histological index for UC.
      However, none of these scores has been fully validated. As an example of how histologic outcomes are being assessed in clinical trial data, the UNIFI study group, which recently reported the results of the use of ustekinumab in UC, reported on a combined histologic and endoscopic outcome that defined mucosal healing as having the following characteristics: (1) neutrophilic infiltration less than 5% of crypts; (2) no crypt destruction; and (3) no erosions, ulcerations, or granulation tissue with endoscopic improvement.
      • Sands B.E.
      • Sandborn W.J.
      • Panaccione R.
      • et al.
      Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis.
      Histologic remission has been shown to correlate with endoscopic improvement, higher rates of sustained steroid free remission, and decreased rates of clinical recurrence and hospitalizations.
      • Bryant R.V.
      • Burger D.C.
      • Delo J.
      • et al.
      Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6 years of follow-up.
      • Frieri G.
      • Galletti B.
      • Di Ruscio M.
      • et al.
      The prognostic value of histology in ulcerative colitis in clinical remission with mesalazine.
      • Narang V.
      • Kaur R.
      • Garg B.
      • et al.
      Association of endoscopic and histological remission with clinical course in patients of ulcerative colitis.
      • Ponte A.
      • Pinho R.
      • Fernandes S.
      • et al.
      Impact of histological and endoscopic remissions on clinical recurrence and recurrence-free time in ulcerative colitis.
      Several imaging modalities have been studied to assess for disease activity in UC. Bowel ultrasonography has been studied both with endoscopic ultrasonography probes and with transabdominal approaches.
      • Allocca M.
      • Fiorino G.
      • Bonovas S.
      • et al.
      Accuracy of Humanitas Ultrasound Criteria in assessing disease activity and severity in ulcerative colitis: a prospective study.
      • Parente F.
      • Molteni M.
      • Marino B.
      • et al.
      Are colonoscopy and bowel ultrasound useful for assessing response to short-term therapy and predicting disease outcome of moderate-to-severe forms of ulcerative colitis: A prospective study.
      • Antonelli E.
      • Giuliano V.
      • Casella G.
      • et al.
      Ultrasonographic assessment of colonic wall in moderate–severe ulcerative colitis: Comparison with endoscopic findings.
      • Maconi G.
      • Ardizzone S.
      • Parente F.
      • et al.
      Ultrasonography in the evaluation of extension, activity, and follow-up of ulcerative colitis.
      Although the former has been shown to be highly accurate, the utility of endoscopic ultrasonography is limited because a bowel preparation needs to be performed and the examination remains invasive. The transabdominal approach has been shown to correlate well with Mayo 2 endoscopic disease and remains an active area of research and interest. MRI has also been studied,
      • Ordás I.
      • Rimola J.
      • García-Bosch O.
      • et al.
      Diagnostic accuracy of magnetic resonance colonography for the evaluation of disease activity and severity in ulcerative colitis: a prospective study.
      ,
      • Oussalah A.
      • Laurent V.
      • Bruot O.
      • et al.
      Diffusion-weighted magnetic resonance without bowel preparation for detecting colonic inflammation in inflammatory bowel disease.
      with some protocols having the advantage of not requiring a bowel preparation coupled with fast image acquisition, and has been shown to correlate well with endoscopic findings.
      • Ordás I.
      • Rimola J.
      • García-Bosch O.
      • et al.
      Diagnostic accuracy of magnetic resonance colonography for the evaluation of disease activity and severity in ulcerative colitis: a prospective study.
      Despite these findings, uptake of these imaging modalities both for the assessment of Crohn disease (CD) and UC in the United States has been slow.

      Treat to Target and Overall Severity Scoring

      In an effort to move from a reactive, disease activity–driven approach to a proactive treatment approach to improve patient outcomes, 2 major concepts have recently been promoted: (1) treat to target, and (2) overall disease severity scoring.
      In 2015, the Selective Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) guidelines were published with the goal of summarizing the current evidence behind various targets and making consensus recommendations on which targets should be prioritized in clinical practice. The investigators concluded that, in UC, disease activity should be assessed by both the resolution of clinical symptoms, including rectal bleeding and diarrhea, and with objective measures of inflammation, assessed by endoscopy with the Mayo endoscopic scoring system with a goal of a subscore of 0 to 1.
      • Peyrin-Biroulet L.
      • Sandborn W.
      • Sands B.E.
      • et al.
      Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target.
      Noting the paucity of direct evidence linking histologic remission, biomarkers, and imaging studies to improved outcomes, the committee indicated that these measures were useful as adjunctive, but not primary, targets of treatment. In addition, this committee emphasized the need to include individual patients’ goals in targets of therapy and made recommendations on the intervals for assessment in patients with active disease or ongoing symptoms. Importantly, despite making the stated goals of treatment to include an endoscopic assessment, the committee noted that there was a lack of direct evidence linking the achievement of endoscopic targets in UC to improved outcomes, with most of the evidence coming from epidemiologic studies or being inferred from clinical trial data with heterogeneous end points.
      • Colombel J.F.
      • Rutgeerts P.
      • Reinisch W.
      • et al.
      Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis.
      • Neurath M.F.
      • Travis S.P.L.
      Mucosal healing in inflammatory bowel diseases: a systematic review.
      • Inoue N.
      • Takabayashi K.
      • Takayama T.
      • et al.
      P215 Endoscopic remission (Mayo score 0 rather than score 1) predicts long-term clinical remission in ulcerative colitis.
      • Yokoyama K.
      • Kobayashi K.
      • Mukae M.
      • et al.
      Clinical study of the relation between mucosal healing and long-term outcomes in ulcerative colitis.
      Since then, mounting evidence points to the superior predictive ability of the UCEIS scoring system compared with the Mayo endoscopic subscore. In addition, several barriers to the adoption of a treat-to-target strategy continue to limit its widespread adoption.
      • Ungaro R.
      • Colombel J.-F.
      • Lissoos T.
      • et al.
      A treat-to-target update in ulcerative colitis.
      These barriers include the ongoing lack of direct evidence of improved outcomes and the increased cost of care associated with more testing. However, despite the lack of robust, direct evidence of benefit, several studies and existing clinical trial data suggest improved outcomes with endoscopic improvement, with ongoing histologic activity also predicting an increased likelihood of disease complications (discussed earlier in relation to histologic assessment). It is our practice to target endoscopic and histologic improvement without necessarily targeting histologic remission. We recently worked with our gastrointestinal pathologists to include a Robarts score for the most affected colonic segment to better quantify the degree of histologic activity, with the intent that this score may in the future further guide treatment changes. However, although we may advocate for lifestyle, dietary, and functional medicine–based changes in the management of ongoing histologic inflammation, at present we do not routinely change drug class or dosing if the patient is otherwise doing well.
      In 2018, a group of IBD specialists convened to develop an overall severity index for both CD and UC using a modified RAND panel with an adaptive choice-based conjoint (ACBD) processes.
      • Siegel C.A.
      • Whitman C.B.
      • Spiegel B.M.R.
      • et al.
      Development of an index to define overall disease severity in IBD.
      These methods helped the panelists to identify key variables of IBD disease severity, break these variables into categorical levels, rank them relative to each other, and assign relative point values to each variable.
      For UC, mucosal lesions as assessed by endoscopy, impact on daily activity, and CRP levels had the highest weight in the overall severity score (Table 3). Among several longitudinal factors included in this severity index, disease extent was dichotomized into distal colitis amenable to treatment with enemas versus extensive colitis. The Montreal classification has previously been used to classify disease extent, with 3 subtypes of UC noted: (1) ulcerative proctitis, (2) left-sided UC (distal UC), and (3) extensive UC (pancolitis) (Table 4).
      • Satsangi J.
      • Silverberg M.S.
      • Vermeire S.
      • et al.
      The Montreal classification of inflammatory bowel disease: Controversies, consensus, and implications.
      Both systems of assessing disease extent allow for the recognition that patients with extensive UC (pancolitis) have an increased risk of developing colorectal cancer and requiring colectomy.
      • Moum B.
      • Ekbom A.
      • Vatn M.H.
      • et al.
      Clinical Course during the 1st Year after Diagnosis in Ulcerative Colitis and Crohn’s Disease: Results of a Large, Prospective Population-based Study in Southeastern Norway, 1990-93.
      • Ritchie J.
      • Powell-Tuck T.
      • Lennard-Jones J.E.
      Clinical outcome of the first ten years of ulcerative colitis and proctitis.
      • Lennard-Jones J.E.
      The clinical outcome of ulcerative colitis depends on how much of the colonic mucosa is involved.
      • Farmer R.G.
      • Easley K.A.
      • Rankin G.B.
      Clinical patterns, natural history, and progression of ulcerative colitis.
      • Langholz E.
      • Munkholm P.
      • Davidsen M.
      • et al.
      Colorectal cancer risk and mortality in patients with ulcerative colitis.
      • Devroede G.J.
      • Taylor W.F.
      • Sauer W.G.
      • et al.
      Cancer risk and life expectancy of children with ulcerative colitis.
      • Mir-Madjlessi S.H.
      • Farmer R.G.
      • Easley K.A.
      • et al.
      Colorectal and extracolonic malignancy in ulcerative colitis.
      By incorporating this variable into a severity index, Siegel and colleagues allowed for this variable to be dynamically captured, as 41% to 54% of patients with proctitis will have extensive disease after 10 years.
      • Silverberg M.S.
      • Satsangi J.
      • Ahmad T.
      • et al.
      Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 montreal world congress of gastroenterology.
      Although these severity indices for UC and CD promise to allow a more comprehensive assessment of disease severity, they have yet to be prospectively validated and did not involve patients in their derivation.
      Table 3Ulcerative colitis overall disease severity index
      From Siegel CA, Whitman CB, Spiegel BMR, et al. Development of an index to define overall disease severity in IBD. Gut. 2018;67(2):244-254. https://doi.org/10.1136/gutjnl-2016-312648.
      AttributeLevelScore
      Mucosal lesionsNo active erosions or ulcers0
      Active erosions confirmed by endoscopy14
      Active ulcers confirmed by endoscopy18
      Daily activity impactDisease does not significantly affect daily activities0
      Disease significantly affects daily activities14
      CRP levelNormal CRP levels (1—3 mg/L)0
      Slightly increased CRP levels (3–5 mg/L)4
      Increased CRP levels (>5 mg/L)11
      Biologics useHas never used biologics/immunomodulators0
      Has experienced some symptom improvement with the use of biologics/immunomodulators4
      Has not experienced symptom improvement with the use of biologics/immunomodulators10
      Recent hospitalizationNo disease-related hospitalization within last 12 mo0
      Has disease-related hospitalization within last 12 mo8
      Steroid useNo steroid use within the past year0
      Has steroid use within the past year8
      AnemiaNot anemic (according to WHO criteria)0
      Anemic (according to WHO criteria)5
      Frequency of loose stoolsNo change in frequency of loose stools compared with baseline0
      Increase in frequency of loose stools by 1 per day compared with baseline4
      Increase in frequency of loose stools of at least 2 per day compared with baseline5
      Albumin levelNormal albumin level (>3.5–5.0 g/dL)0
      Low albumin level (<3.5 g/dL)5
      Disease extentDistal colitis (inflammation potentially treatable using enemas)0
      Extensive colitis (inflammation extending beyond the reach of enemas)5
      Nocturnal bowel movementsDoes not have nocturnal bowel movements0
      Has nocturnal bowel movements4
      Anorectal symptomsNone of the following: anorectal pain, bowel urgency, incontinence, discharge, tenesmus0
      At least 1 of the following: anorectal pain, bowel urgency, incontinence, discharge, Tenesmus4
      Rectal bleedingNo rectal bleeding0
      Has rectal bleeding3
      Abbreviation: WHO, World Health Organization.
      Table 4Montreal classification of extent of ulcerative colitis
      From Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: Controversies, consensus, and implications. Gut. 2006;55(6):749-753. https://doi.org/10.1136/gut.2005.082909.
      ExtentConditionAnatomy
      E1Ulcerative proctitisInvolvement limited to the rectum (that is, proximal extent of inflammation is distal to the rectosigmoid junction)
      E2Left-sided UC (distal UC)Involvement limited to a proportion of the colorectum distal to the splenic flexure
      ЕЗExtensive UC (pancolitis)Involvement extends proximal to the splenic flexure

      Assessing for Concomitant Infections

      When evaluating a patient for causes of worsening disease activity, all guidelines recommend an infectious work-up, specifically to rule out bacterial infections such as Clostridium difficile, with multistep testing now being the standard of care at many institutions.
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • et al.
      Clinical practice guidelines for clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      • Rubin D.T.
      • Ananthakrishnan A.N.
      • Siegel C.A.
      • et al.
      ACG Clinical Guideline: Ulcerative Colitis in Adults.
      • Magro F.
      • Gionchetti P.
      • Eliakim R.
      • et al.
      Third European evidence-based consensus on diagnosis and management of ulcerative colitis. part 1: definitions, diagnosis, extra-intestinal manifestations, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders.
      However, given the challenge of differentiating colonization and active C difficile infection in patients with UC, a positive polymerase chain reaction for DNA of the toxin, which may simply represent colonization, is often treated with the plan to continue treatment if the patient has an improvement in symptoms and to escalate UC therapy if there is not an improvement.
      • Khanna S.
      • Shin A.
      • Kelly C.P.
      Management of Clostridium difficile infection in inflammatory bowel disease: expert review from the clinical practice updates Committee of the AGA Institute.
      ,
      • Issa M.
      • Vijayapal A.
      • Graham M.B.
      • et al.
      Impact of Clostridium difficile on inflammatory bowel disease.
      Care should also be taken to inquire about other factors that may be contributing to disease activity, such as the use of nonsteroidal antiinflammatory drugs (NSAIDs) and recent smoking cessation. Additional nonbacterial infectious causes are important to consider because they may mimic disease activity, especially in patients on biologic therapy. In particular, there is a significantly increased risk of fungal infections in patients on anti–tumor necrosis factor alpha agents. These infectious agents are covered in detail in an earlier article in this issue and include atypical mycobacterial infections such as tuberculosis, fungal infections such as histoplasmosis, and viral infections such cytomegalovirus (CMV).
      • Lawlor G.
      • Moss A.C.
      Cytomegalovirus in inflammatory bowel disease: Pathogen or innocent bystander?.
      • Pabla B.S.
      • Scoville E.A.
      • Sarker S.
      • et al.
      Histoplasmosis as a complication of inflammatory bowel disease therapy: a case series.
      • Mukewar S.
      • Mukewar S.
      • Ravi R.
      • et al.
      Colon tuberculosis: endoscopic features and prospective endoscopic follow-up after anti-tuberculosis treatment.

      Grading

      Although overall disease severity scoring has gained interest in recent years, the original Truelove-Witts criteria remain the basis on which guidelines throughout the world grade UC. The American College of Gastroenterology (ACG) released new guidelines in 2019 that update the last practice guideline released by this organization in 2010. The update makes several changes, including reclassifying the categories of remission, mild, moderate, severe, and fulminant to remission, mild, moderate-severe, and fulminant.
      • Rubin D.T.
      • Ananthakrishnan A.N.
      • Siegel C.A.
      • et al.
      ACG Clinical Guideline: Ulcerative Colitis in Adults.
      ,
      • Kornbluth A.
      • Sachar D.B.
      Practice Parameters Committee of the American College of Gastroenterology. Ulcerative Colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee.
      The investigators also add FC, Mayo subscore, and UCEIS to these categories, in line with the UC disease severity index from Siegel and colleagues,
      • Siegel C.A.
      • Whitman C.B.
      • Spiegel B.M.R.
      • et al.
      Development of an index to define overall disease severity in IBD.
      noting the importance of endoscopic findings as well as biomarkers showing an increased inflammatory burden (Table 5). They suggest a cutoff in FC of 150 to 200 μg/g to differentiate remission from active disease based on a meta-analysis of optimal cutoffs, but acknowledge the variation in the literature regarding an optimal threshold.
      • Rokkas T.
      • Portincasa P.
      • Koutroubakis I.E.
      Fecal calprotectin in assessing inflammatory bowel disease endoscopic activity: a diagnostic accuracy meta-analysis.
      Table 5Proposed American College of Gastroenterology ulcerative colitis activity index
      From Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol. 2019;114(3):1. https://doi.org/10.14309/ajg.0000000000000152.
      RemissionMildModerate to SevereFulminant
      Stools/d (n)Formed stools<4>6>10
      Blood in StoolsNoneIntermittentFrequentContinuous
      UrgencyNoneMild, occasionalOftenContinuous
      HemoglobinNormalNormal<75% of normalTransfusion required
      ESR<30<30>30>30
      CRP (mg/L)NormalIncreasedIncreasedIncreased
      FC (μg/g)<150–200>150–200>150–200>150–200
      Endoscopy (Mayo Subscore)0–112–33
      UCEIS0–12–45–87–8
      Guidelines from the European Crohn’s and Colitis Organization (ECCO) published in 2017 add CRP and endoscopic findings to the original Truelove-Witts criteria, and reference the Montreal Classification Working Party descriptions of severity classification of remission, mild, moderate, and severe UC.
      • Satsangi J.
      • Silverberg M.S.
      • Vermeire S.
      • et al.
      The Montreal classification of inflammatory bowel disease: Controversies, consensus, and implications.
      ,
      • Magro F.
      • Gionchetti P.
      • Eliakim R.
      • et al.
      Third European evidence-based consensus on diagnosis and management of ulcerative colitis. part 1: definitions, diagnosis, extra-intestinal manifestations, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders.
      They note than any increase in CRP level greater than 30 mg/L along with bloody stools greater than or equal to 6 in a day should be considered severe disease, and note that patients in remission should have no mucosal lesions on endoscopy. In previous ECCO guidelines, they note that the use of the term fulminant UC is dated and not applicable to the modern era, because this term was initially used to describe patients who presented with a single exacerbation or initial presentation that resulted in death within 1 year.
      • Dignass A.
      • Eliakim R.
      • Magro F.
      • et al.
      Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 1: Definitions and diagnosis.
      ,
      • Rice-Oxley J.M.
      • Truelove S.
      Ulcerative colitis course and prognosis.
      Treatment has now progressed to the point where mortality is a rare complication of such presentations.

      Inpatient Severe Disease Considerations

      In patients admitted to the hospital with severe UC (fulminant disease), additional work-up should be undertaken to assess for toxic megacolon and CMV.
      • Rubin D.T.
      • Ananthakrishnan A.N.
      • Siegel C.A.
      • et al.
      ACG Clinical Guideline: Ulcerative Colitis in Adults.
      ,
      • Harbord M.
      • Eliakim R.
      • Bettenworth D.
      • et al.
      Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 2: Current Management.
      Severe colitis requiring hospital admission remains a major source of morbidity, with up to 25% of patients with UC requiring hospitalization for severe disease, and ultimately requiring colectomy in 40% of cases.
      • Dinesen L.C.
      • Walsh A.J.
      • Protic M.N.
      • et al.
      The pattern and outcome of acute severe colitis.
      Colonic dilatation greater than 5.5 to 6 cm on imaging in combination with systemic toxicity are consistent with the diagnosis of toxic megacolon; however, the epidemiology of toxic megacolon has shifted to mainly infectious causes in the past few decades with advances in the care of UC and increase of infectious agents such as C difficile.
      • Autenrieth D.M.
      • Baumgart D.C.
      Toxic megacolon.
      Cross-sectional imaging should be reserved for patients in whom there is a clinical concern for complication such as a bowel perforation, which may present in a more subtle fashion in patients on high-dose steroids. An endoscopic evaluation should be pursued, with an early evaluation if there is a high clinical suspicion for an infectious cause. A flexible sigmoidoscopy is sufficient given the concern for an increased rate of perforation with a full colonoscopy in severe disease, and biopsies to assess for CMV should be obtained.
      • Rubin D.T.
      • Ananthakrishnan A.N.
      • Siegel C.A.
      • et al.
      ACG Clinical Guideline: Ulcerative Colitis in Adults.
      ,
      • Harbord M.
      • Eliakim R.
      • Bettenworth D.
      • et al.
      Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 2: Current Management.
      ,
      • Makkar R.
      • Bo S.
      Colonoscopic perforation in inflammatory bowel disease.
      Rescue therapy with infliximab, cyclosporine, tacrolimus, and possibly tofacitinib can then be considered as alternatives to surgery if pursued early in the disease course (day 3 of admission). The strategies regarding rescue therapy are discussed in another article in this issue.
      There are several disease scores used to determine the risk of requiring rescue therapy or colectomy in patients with severe colitis. Recent studies have shown a potential advantage of using the UCEIS scoring system, with 1 study showing improved accuracy of the UCEIS score in predicting the need for colectomy compared with the Mayo Score, with score greater than 7 showing a sensitivity of 60.3% with a specificity of 85.5%.
      • Xie T.
      • Zhang T.
      • Ding C.
      • et al.
      Ulcerative Colitis Endoscopic Index of Severity (UCEIS) versus Mayo Endoscopic Score (MES) in guiding the need for colectomy in patients with acute severe colitis.
      Another study showed that a UCEIS score of 5 or more was associated with a 50% chance of requiring rescue therapy and 33% rate of colectomy compared with 27% and 9% for those with a score of less than or equal to 4. As mentioned previously, the commonly used Oxford (or Travis) index, developed in 1996, predicted the need for colectomy to be 85% in patients with a CRP level greater than 45 mg/L and 3 to 8 bowel movements a day after 3 days of IVCS treatment.
      • Travis S.P.
      • Farrant J.M.
      • Ricketts C.
      • et al.
      Predicting outcome in severe ulcerative colitis.
      Another score, developed in 1998 by Lindgren and colleagues
      • Lindgren S.C.
      • Flood L.M.
      • Kilander A.F.
      • et al.
      Early predictors of glucocorticosteroid treatment failure in severe and moderately severe attacks of ulcerative colitis.
      using these same variables of bowel movements and CRP on day 3 after IVCS, showed favorable test characteristics for predicting the need for colectomy. The Ho index has also been used to risk stratify patients into low, intermediate, or high risk for colectomy.
      • Ho G.T.
      • Mowat C.
      • Goddard C.J.R.
      • et al.
      Predicting the outcome of severe ulcerative colitis: development of a novel risk score to aid early selection of patients for second-line medical therapy or surgery.
      This index was derived from a cohort of patients from 1995 to 2002 and found aggregate scores of 0 to 1, 2 to 3, and greater than or equal to 4 from 3 variables (mean stool frequency, averaged over the first 3 days; colonic dilatation, defined as >5.5 cm in the transverse colon within the first 3 days of admission; and serum albumin level on admission less than 3 g/L) correlated with a risk of progression to colectomy of 11%, 45%, and 85% respectively (Table 6).
      Table 6Integer score attributes to each category derived from the coefficients of the logistic regression equation
      From Ho GT, Mowat C, Goddard CJR, et al. Predicting the outcome of severe ulcerative colitis: development of a novel risk score to aid early selection of patients for second-line medical therapy or surgery. Aliment Pharmacol Ther. 2004;19(10):1079-1087. https://doi.org/10.1111/j.1365-2036.2004.01945.
      VariablesScore
      Mean stool frequency:
       <40
       4 ≤ 61
       6 ≤ 92
       >94
      Colonic dilatation4
      Hypoalbuminemia
       <30 g/L1
      Overall risk core = [score attributable to mean stool frequency (0, 1, 2 or 4)] + [presence of colonic dilatation (0 or 4)] + [presence of hypoalbuminemia (0 or 1)]. Minimum score = 0, maximum score = 9.

      Summary

      Although there has been a tremendous advance in the therapy for UC over the last several decades, guideline-based recommendations for disease severity scoring remain largely the same. New concepts of overall disease severity in UC hold the promise of improving access to care in patients with high-risk historical attributes but relatively quiescent disease activity, although these tools require further validation. Treat-to-target strategies offer hope for improved patient outcomes, although prospective data showing improved outcomes are scant. Practicing clinicians should use a combination of patient-reported variables, obtained both through a routine history and through a validated tool such as the SIBDQ, in combination with objective markers of inflammation such as endoscopy and biochemical testing, to determine disease severity. The management of acute severe UC remains a crucial area of ongoing research and has ample room for clinical improvement. Optimal treatment depends on the accurate assessment of disease severity and response to treatment with high-dose IVCS.

      Clinical care points

      • There remain no formally validated definitions of mild, moderate, or severe UC. Instead, modern scoring systems are based on historical definitions that have been shown to be useful in distinguishing patients into categories of disease likely to respond to various treatments. A new overall severity scoring system in UC may provide a crucial link between point-in-time disease activity scoring systems and longitudinal high-risk attributes of disease.
      • There are no IBD-specific PRO measures that meet FDA guidelines. PRO measures as they currently exist do not always correlate with endoscopic findings of disease activity.
      • In assessing disease severity, several non-UC factors need to be considered, and include concomitant infection (especially C difficile), NSAID use, recent smoking cessation, and comorbid psychiatric illness.
      • Acute severe (fulminant) UC remains a major source of morbidity. Care must be taken to adequately diagnose and assess response to treatment in these patients.
      • Treat-to-target strategies offer the promise of improved patient outcome, although prospective studies showing their superiority are scant.

      Disclosure

      Dr B.S. Pabla has no relevant financial disclosures. Dr D.A. Schwartz has the following financial disclosures: Abbvie , consultant; UCB, consultant, grant support; Janssen , consultant; Takeda, consultant; Gilead, consultant; Pfizer, consultant; Genetech, consultant.

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