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Predicting outcomes in acute severe ulcerative colitis Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 02/11/15 For personal use only.
Expert Rev. Gastroenterol. Hepatol. Early online, 1–11 (2014)
Nicholas T Ventham*1, Rahul Kalla2, Nicholas A Kennedy2, Jack Satsangi2 and Ian D Arnott2 1 Centre for Genomics and Molecular medicine, Western General Hospital, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK 2 Gastrointestinal Unit, Western General Hospital, Ann Ferguson Building, Crewe Road South, Edinburgh. EH4 2XU, UK *Author for correspondence: [email protected]
Response to corticosteroid treatment in acute severe ulcerative colitis (ASUC) has changed very little in the past 50 years. Predicting those at risk at an early stage helps stratify patients into those who may require second line therapy or early surgical treatment. Traditionally, risk scores have used a combination of clinical, radiological and biochemical parameters; established indices include the ‘Travis’ and ‘Ho’ scores. Recently, inflammatory bowel disease genetic risk alleles have been built into models to predict outcome in ASUC. Given the multifactorial nature of inflammatory bowel disease pathogenesis, in the future, composite scores integrating clinical, biochemical, serological, genetic and other ‘-omic’ data will be increasingly investigated. Although these new genetic prediction models are promising, they have yet to supplant traditional scores, which remain the best practice. In this modern era of rescue therapies in ASUC, robust scoring systems to predict failure of ciclosporine and infliximab must be devised. KEYWORDS: acute severe colitis . colectomy . mortality . outcomes . ulcerative colitis
Acute severe ulcerative colitis (ASUC) is an important medical problem that affects approximately 25% of patients with ulcerative colitis [1]. Mortality following ASUC fell in the 1950s after the introduction of systemic corticosteroid treatment [2]. However, the proportion of patients failing steroid treatment and requiring colectomy (~29%) has largely remained unchanged [3]. ASUC was defined by Truelove and Witt in 1955 as six or more bloody stools per day, with accompanying fever (temperature >37.8 C), tachycardia (heart rate >90/min) and deranged blood markers (hemoglobin 30 mm/h) [4]. This definition is endorsed by all of the major inflammatory bowel disease (IBD) organizations [5–7]. Infectious causes of colitis should be excluded, as concomitant Clostridium difficile infection leads to an increased risk of colectomy and mortality [8]. The extent of additional risk of colectomy conferred by superadded cytomegalovirus infection in ASUC patients is debated in the literature [9–11]. The major benefit of predicting outcomes in clinical practice is the allowance of earlier transition onto second line medical ‘rescue’ therapy or to definitive surgical management. A recent emphasis has been on deciding on informahealthcare.com
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the need for colectomy within 7 days of admission, as delays in surgery have been associated with an increase in mortality and postoperative complications [12–14]. In ASUC patients who avoid colectomy during their index admission, longer term data suggests colectomy rates of 40% after a second admission with ASUC [1]. Those who fail to completely settle following steroid treatment have a 50% chance of requiring a colectomy within 1 year of discharge, which goes up to 70% at 5 years [15]. Mortality
The mortality in all patients with UC is similar to that of the general population (standardised mortality ratio 1.19) [16]. However, patients requiring hospitalization for UC have a significantly increased risk of 3-year mortality [17–19]. Advancing age and the presence of comorbidity were found to be significantly associated with increased mortality in patients hospitalized with UC [19]. The UK IBD audit suggests that the hospital mortality for those with severe UC may be decreasing (mortality 2008 = 1.2%; 2010 = 0.7%) [20]. The audit data also confirms the higher mortality in older patients (>60 years; p < 0.001) and in those with co-morbidities [20]. Significantly, mortality was higher in those who failed first line medical
2014 Informa UK Ltd
ISSN 1747-4124
1
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Ventham, Kalla, Kennedy, Satsangi & Arnott
therapy [20], demonstrating the importance of clinical and other scoring systems used to predict response to steroid treatment.
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Clinical scores
In 1975, Lennard-Jones recognized that factors used in the Truelove and Witts definition on admission also were strongly predictive of need for surgery in 189 patients with ASUC, particularly fever (>38 C), tachycardia and high stool frequency (>8/day) during the first day of admission [21]. In addition, hypoalbuminemia and radiological evidence of colonic dilatation and ‘mucosal islands’ were predictive of colectomy [21]. Recently, an increasing number of Truelove and Witts criteria at admission (over and above stool frequency) has been associated with an increase in colectomy rate (one additional criterion = 8.5%, two criteria = 31% and three or more criteria = 48%) [1]. The Travis score is perhaps the best-known scoring system and is derived from patients admitted with severe colitis in Oxford (UK). Published in 1996, at day 3 of corticosteroid treatment, patients with greater than eight stools per day or three to eight stools per day and elevated C-reactive protein (CRP) (>45 mg/l) had an 85% chance of requiring colectomy [22]. After 7 days of therapy, patients with ongoing symptoms (>3 stools/day or visible blood) had a 40% chance of colectomy in the following year [22]. Importantly, parameters used in the Travis score have been validated in independent cohorts [23]. A second prominent clinical scoring score was derived by Ho et al. in Edinburgh in 2004 [24]. Stool frequency, colonic dilatation on day 3 and hypoalbuminemia on day 1 were defined as independent predictors of failure of corticosteroid therapy (i.e., colectomy) using multiple logistic regression analysis [24]. A score was derived from these factors that can be used to predict failure of first line medical treatment [24]. Data from 984 patients collected during the third round of the UK IBD audit demonstrated equivalence in Ho and Travis scores in predicting those at high risk of requiring rescue therapy or colectomy [25]. The Ho score was additionally able to identify those who had an intermediate response to second line medical therapy [25]. Although the Travis and Ho scores can be derived as early as day 3 of corticosteroid treatment, a novel score to predict those requiring colectomy on admission is being developed [26]. Outside of the UK, the Lindgren and Seo scores are also extensively used and have been included as end points in important trials including the randomized placebocontrolled trial of infliximab as rescue therapy for ASUC [23,27,28]. Several other clinical prediction models have been described and are summarized in TABLE 1. The use of clinical and other scoring systems in the context of clinical trial end points has been reviewed elsewhere [29]. Symptoms preceding admission with ASUC are associated with poor outcome during index admission. Carbonnel, in addition to high Truelove and Witts score, demonstrated that antecedent symptoms lasting greater than 6 weeks were a highrisk feature for colectomy [30]. Others have demonstrated that doi: 10.1586/17474124.2015.992880
steroid treatment in the year before admission with ASUC was predictive of a slow response to intravenous steroids [31]. A systematic review collating much of the literature to date found that the most frequently reproduced factors that predicted failure of medical therapy include disease extent, stool frequency, temperature, heart rate, CRP, albumin and radiological features [3]. It is noteworthy that the included trials used varying study parameters and outcomes, including colectomy and failure of medical treatment as defined by composite endpoints, and as such it was not possible to perform a quantitative meta-analysis. In pediatric practice, the pediatric Ulcerative Colitis Activity index (PUCAI) is the most popular clinical tool used to predict outcome [32,33]. In a prospective cohort, the PUCAI performed best in predicting failure of first line medical therapy (defined as colectomy or need for second-line drugs), followed closely by the Travis score in a comparison which also included the Seo and Lindgren scores and various biomarkers including fecal calprotectin [34]. A further evaluation confirmed the PUCAI score to outperform various stool biomarkers including calprotectin in predicting outcome (colectomy or need for ciclosporine/infliximab) following a course of intravenous steroids in severe pediatric UC [35]. Other biochemical markers
CRP and albumin are the most validated biochemical markers used to predict outcome in ASUC. CRP is included in several of the scoring systems including the Travis and Lindgren scores [22,23]. Although CRP did not improve the predictive power of the PUCAI score [32], a prospective multicenter study demonstrated that day 3 CRP was additionally predictive of intravenous steroid failure (colectomy or need for ciclosporine/ infliximab) in pediatric ASUC Odds Ratio (OR): 1.3; CI: 1.1–1.6 [34]. Albumin synthesis is decreased as a result of systemic inflammation, and hypoalbuminemia has been used in various risk prediction tools including the Ho score [21,24]. Calprotectin, a neutrophil cytosolic protein, has been used extensively as a fecal biomarker of intestinal inflammation. Fecal calprotectin has been studied in the context of ASUC, with levels being significantly higher in patients requiring colectomy, and a trend toward higher levels in non-responders to corticosteroids (p = 0.08) and infliximab (p = 0.06) compared with responders [36]. A more recent analysis of biomarkers in 444 patients with ASUC from the same center failed to replicate the predictive ability of calprotectin (p = 0.52), although confirmed a strong association of elevated admission CRP and low albumin (p < 0.001 for both) [26]. Recently, serum calprotectin has been investigated as a biomarker in ASUC [37]. Radiological
Predictors of need for colectomy on plain radiograph were identified by Lennard-Jones in 1975 [21]. Original predictors included ‘mucosal islands’ and colonic dilatation greater than 5.5 cm [21]. Mucosal islands are small circular opacities, representing residual mucosa isolated by surrounding ulceration [5]. Expert Rev. Gastroenterol. Hepatol.
informahealthcare.com
Fulminant colitis index, Lindgren score
Activity Index (AI), Seo Score
Modified Truelove and Witts’ Severity Index
Edinburgh, UK
Malmo¨, Sweden
Fukuoka, Japan
New York, USA
Ho et al., (2004)
Lindgren et al., (1998)
Seo et al., (1992)
Lichtiger et al., (1990)
0–4 points respectively
Daily assessment
Number of daily stools (0–2, 3–4, 5–6.7–9, 10)
0/1 point 0–3 points 0/1 point 0–3 points 0–5 points
Nocturnal stools (present/absent) Percentage of blood in stools (0%, 220 = severe
150–220 = moderate
AI score >200 = 83% [85]
Number of bowel movements/day + 0.14 x CRP (mg/dl)
6 to £ 9/day =2 points, >9/day = 4 points) Radiological evidence of colonic dilatation (= 4 points)
>8
40%
Day 7
Moderate stool frequency (>3/day), bloody stools
Day 3
85%
Day 3
Positive predictive value of colectomy
High stool frequency (>8/day) or moderate stool frequency (3–8/day) and CRP (>45 mg/l)
Score used
80%
Day of assessment
Day 1
Temperature (>38 C) and high stool frequency (>8/day)
Recorded parameters
AUROC: Area under receiver operator characteristic curve; CRP: C-Reactive protein; ESR: Erythrocyte sedimentation rate; NPV: Negative predictive value; PPV: Positive predictive value.
Ho Score
Oxford, UK
Travis et al., (1996)
Travis Index
Alternative name
St Marks, London, UK
Origin
Lennard Jones, et al. (1975)
Adult
Study (year)
[86]
[27]
[23]
[24]
[22]
[21]
Ref.
Table 1. A summary of clinical composite scoring systems for predicting colectomy (or IV steroid failure) in acute severe ulcerative colitis following intravenous corticosteroid treatment.
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Predicting outcomes in ASUC
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doi: 10.1586/17474124.2015.992880
AUROC: Area under receiver operator characteristic curve; CRP: C-Reactive protein; ESR: Erythrocyte sedimentation rate; NPV: Negative predictive value; PPV: Positive predictive value.
International
Pediatric
65–85 = severe
35–64 = moderate
10–34 = mild
Day 3 and Day 5 Abdominal pain, rectal bleeding, stool consistency, number of stools in 24 h, nocturnal stools, activity level Pediatric ulcerative colitis activity index (PUCAI)
0/1 point Need for antidiarrheal drugs (yes/no)
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Turner et al., (2007)
0–3 points Abdominal tenderness (none, mild/localized, moderate, severe)
Alternative name
Recorded parameters
Day of assessment
Score used
45 PPV = 43%. NPV = 43% [34] Day 5 Score >70 PPV=100%, NPV = 79% [34]
[32]
Ref.
Ventham, Kalla, Kennedy, Satsangi & Arnott
Origin Study (year)
Table 1. A summary of clinical composite scoring systems for predicting colectomy (or IV steroid failure) in acute severe ulcerative colitis following intravenous corticosteroid treatment (cont.).
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Special Report
Small bowel dilatation on plain abdominal radiographs is also associated with colectomy (OR: 3.55; 95% CI: 2.27–5.87) [38]. MRI has been used to assess the extent of colonic inflammation using the degree of enhancement, edema and extra-luminal manifestations (e.g., lymphadenopathy) [39]. Another study used MRI performed within 2 days of ASUC admission to derive a total colonic inflammatory score (consisting of haustral loss, wall thickness, edema, small and large bowel dilatation) [40]. The total colonic inflammatory score predicted a prolonged treatment course (>7 days) with a positive predictive score of 87%, outperforming CRP and stool frequency; however, the number of patients requiring colectomy in this study was low (n = 3) [40]. Expedient access to MRI may limit the feasibility of such scores in many centers. Computed tomography (CT) retains a pivotal role in investigating the acute abdomen; however, published data suggests it is of limited benefit in determining requirement for colectomy [41]. Plain radiography with air enema to assess colonic ulceration [42] and white cell scintigraphy have also been used to predict severity [43], though are rarely used in everyday practice. Endoscopic scores
In ASUC, an unprepared flexible sigmoidoscopy with minimal air insufflation performed by an experienced endoscopist is safe and can aid diagnosis and prognostication. The Baron score is a widely used measurement in clinical trials [44]. However, when worldwide experts viewed video recordings of sigmoidoscopies, poor inter-observer correlation was noted, especially when judging mucosal friability [45]. Carbonnel described the appearance of severe endoscopic lesions associated with colectomy (deep extensive ulceration, well-like ulcerations, large mucosal abrasion, mucosal detachment) [30,46]. Extensive deep ulceration occurred in 96% of those requiring colectomy compared with 26% who did not [30,46]. Recently, Travis et al. devised the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) to assess the full spectrum of UC severity, including ASUC [45]. Using regression models, three descriptors were selected to derive the score: bleeding, ulceration and vascular pattern [45]. The UCEIS score is simple to use and performed well when tested by an independent set of investigators [47]. In a retrospective cohort, a UCEIS score of ‡7 of 8 on admission was associated with requirement of second-line medical therapy (infliximab or ciclosporine) [48]. Histopathological features associated with ASUC have also been described. Tanaka et al. described several high risk features including deep ulceration, frequent crypt abscesses, segmental mononuclear cell infiltration, paucity of eosinophils and extensive disease [49]. These criteria were validated in an independent, multicenter cohort and found to have the sensitivity of 86% and specificity of 95.2% in predicting the need for colectomy in ASUC [50]. The delay in obtaining histology results following initial sigmoidoscopic assessment limits the ability to base clinical decisions on histological scoring in ‘real time’. Another critical reason for obtaining histology during an Expert Rev. Gastroenterol. Hepatol.
Predicting outcomes in ASUC
B
100
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Proportion (%)
80 60 40 20 0 Risk A Risk B Risk C Risk D (n = 109) (n = 373) (n = 268) (n = 50) Risk score categories Non-MR-UC MR-UC
Cumulative probability of avoiding colectomy (MR-UC)
A
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1.2
1.0
0.8
0.6
0.4 Risk A Risk B Risk C Risk D
0.2
0 0
10
20
30
40
50
60
Time to surgery (months)
Figure 1. Haritunians et al. classified patients into medically refractory ulcerative colitis (MR-UC, n = 324) and non-medically refractory UC (non-MR-UC, n = 537) [58]. A genome wide association study was performed and a combination of 46 single nucleotide polymorphisms accounted for 46% of the variance of risk of colectomy. Based on genetic data, four genetic risk scores were devised (A to D, A-lowest risk, D-highest risk). The risk in each group of colectomy was 0, 17, 74 and 100%. Reprinted with permission from Wolters Kluwer Health from [58] and the Nature Publishing group.
episode of ASUC is to detect the presence of CMV superinfection. A high CMV DNA load detected in inflamed tissue (>250 copies/mg) is predictive of resistance to steroid and second-line treatment, with an area under the receiver operator characteristic curve (AUROC) of 0.85 [51].
particularly ‘pharmacogenetics’, for example, TMPT genotyping before initiation of thiopurine medication and the identification of specific HLA variants linked with thiopurine-induced pancreatitis [61,62]. Summary
Genetic predictors
Several genetic loci are associated with extensive disease and need for colectomy in UC, albeit not always in the context of ASUC. The HLA-DRB*0103 variant has been known for some time to be associated with extensive UC, and increased colectomy requirement [52–54]. The predictive nature of other HLA-DRB1 alleles have been replicated in several non-WhiteEuropean populations [55,56]. The multidrug resistance (MDR1, C3435TT allele, ABCB1) gene locus is also significantly associated with extensive disease in UC [57]. A genome-wide association study demonstrated genetic loci (including HLA, IL12B and TNFSF15) that were able to predict the need for colectomy [58]. This study generated a risk score based on 46 single nucleotide polymorphisms to account for 50% of the colectomy risk (AUROC 0.91), together with an increased risk of colectomy at 3 and 5 years (FIGURE 1) [58]. Given the large number of low penetrance genes associated with IBD susceptibility (163 in the most recent published meta-analysis [59]), together with the significant contribution of other factors including epigenetics, gut microbiota and the environment, genetic markers in isolation are unlikely to adequately predict disease course in ASUC [60]. Recent advances in other clinical aspects of IBD genetics give cause for optimism, informahealthcare.com
The ideal outcome prediction algorithm in ASUC should be quick to perform, assisting decision-making in ‘real time’, and be simple enough for clinicians to remember. Presently, scoring systems using clinical parameters with biochemical and radiological data are the only feasible measures in everyday practice. It is worthy of note that often the clinical parameters from which these scores are derived drive local clinical decision making (e.g., colonic dilatation on radiograph), and it is therefore self-fulfilling that these factors should be ‘predictive’ of poor outcomes. Moreover, these scores were often derived using data from relatively small, single-center and historic cohorts. New clinical scoring systems may be generated using large powerful multicenter datasets, such as the UK IBD audit data, and any new score should be validated in prospective cohorts. Although our current parameters reflect general systemic inflammation, in the near future, new biomolecular targets, including genomic, epigenomic, metagenomic and transcriptomic biomarkers may help to predict susceptibility to the consequences of ASUC, and assist in individualizing therapy in IBD. Expert commentary
The primary aim of scoring systems is to assist clinical teams in making decisions regarding colectomy for patients with ASUC doi: 10.1586/17474124.2015.992880
doi: 10.1586/17474124.2015.992880
Paris, France
Barcelona, Spain
Barcelona, Spain
Cacheux et al., (2008)
Aceituno et al. (2008)
Rios, et al. (2009)
Infliximab 5 mg/kg
Intravenous ciclosporine 4 mg/kg/day
Intravenous ciclosporine 4 mg/kg/day Oral ciclosporine 10 mg/ kg/day
Intravenous ciclosporine 4 mg/kg/day
Intravenous ciclosporine 2.5 mg/kg/day
Intravenous ciclosporine 3 mg/kg/day
Intervention
Older age, thrombocytosis, previous treatment with ciclosporine
Retrospective (n = 41), complete responders = 20, Partial responders = 9, colectomy = 12
High CRP (‡30 mg/l), Severe endoscopic lesions
Ho index (‡ 5)
Retrospective (n = 72), responders = 52, colectomy = 20 Split into derivation validation cohorts
Observational cohort study n = 113 Colectomy = 37
Day 1 of ciclosporine therapy
Temperature (>37.5 C), tachycardia (>90 bpm), CRP (>45 mg/l), severe endoscopic findings (deep extensive ulcers, large mucosal abrasions, welllike ulcers, mucosal detachments)
Retrospective (n = 135) Responders = 90 Colectomy = 45
Admission
Day 1 of ciclosporine therapy
Immediately prior to ciclosporine treatment
Admission
Tachycardia, hypoalbuminemia, increased immature (band) neutrophils
Retrospective (n = 36) Colectomy = 11 Responders = 25, late colectomy = 13 (within 9 months)
Day 1 and day 3 of ciclosporine administration
Day of assessment
Age on admission (>49 years), platelet count (13), day 3 - day 1 total protein (DTP > -0.4)
Recorded parameters
Retrospective (n = 52) Responders = 34, colectomy = 18
Study description
AUROC: Area under receiver operator characteristic curve; bpm: Beats per min; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; RCT: Randomized controlled trial.
Monterubbianesi et al., (2014)
Italy
LA, USA
Rowe et al., (2000)
Infliximab
Chiba, Japan
Location of study
Katsuno et al., (2012)
ciclosporine
Study (year)
–
–
66.7% (Overall AUROC for index 0.79)
Severe endoscopic lesions alone = 71% 80% at 6 months
AUROC=0.83
88.5%
Positive predictive value of colectomy
Table 2. A summary of clinical composite scoring systems for predicting requirement for colectomy in acute severe ulcerative colitis following second-line medical therapy: ciclosporine or infliximab.
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[83]
[76]
[79]
[77]
[78]
[75]
Ref.
Special Report Ventham, Kalla, Kennedy, Satsangi & Arnott
Expert Rev. Gastroenterol. Hepatol.
informahealthcare.com
Scotland, UK
Sweden
Italy
Lees, et al. (2006)
Sjoberg et al., (2013)
Kohn et al., (2007)
France
Lahaire et al., (2012)
IV ciclosporine 2 mg/kg Infliximab 5 mg/kg
IV ciclosporine 2 mg/kg Infliximab 5 mg/kg
Infliximab 5 mg/kg
Infliximab 5 mg/kg
Infliximab 5 mg/kg
Infliximab 5 mg/kg
Intervention
Randomized controlled trial Infliximab = 57 (colectomy = 4) ciclosporine = 58 (colectomy = 3)
–
–
23%
Advanced age (>40 years), hemoglobin (9.5–12.5 g/dl, and >12.5 g/dl)
–
–
–
One rather than two or more infliximab infusions
Retrospective n = 83 Colectomy = 12
–
57.1%
–
Positive predictive value of colectomy
–
Advanced age (>50 years), prolonged period of illness (>3 weeks) Delayed rescue therapy initiation (‡ 5 days after admission)
Retrospective n = 211 Colectomy = 75
Day 3 of intravenous steroids
Day 1 of Infliximab
Day of assessment
(whole cohort) High CRP, extensive disease, no previous azathioprine exposure
Hypoalbuminemia (29 mg/l)
Recorded parameters
Retrospective n = 56 Colectomy = 22
Study description
AUROC: Area under receiver operator characteristic curve; bpm: Beats per min; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; RCT: Randomized controlled trial.
Palermo, Italy
Mocciaro et al., (2012)
Both ciclosporine and infliximab
Denmark
Location of study
Mortensen, (2011)
Infliximab (cont.)
Study (year)
Table 2. A summary of clinical composite scoring systems for predicting requirement for colectomy in acute severe ulcerative colitis following second-line medical therapy: ciclosporine or infliximab (cont.).
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[81]
[82]
[88]
[80]
[87]
[84]
Ref.
Predicting outcomes in ASUC
Special Report
doi: 10.1586/17474124.2015.992880
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Ventham, Kalla, Kennedy, Satsangi & Arnott
in a timely fashion, thus avoiding the increased complications and mortality associated with delayed surgery. We believe that simple clinical indices that do not require formulae/calculations are the most memorable and easy to use in everyday practice. As such, we feel the Travis and Ho scores are the most useful; they have also been validated in independent cohorts. The more complex scoring systems such as the Seo, Lindgren and Lichtiger scores have a more important role in the formal setting of clinical trials. In spite of our interest and optimism in new genetic and -‘ omic’-based scores, these have not supplanted clinical scores. Composite scores encompassing genetic data with clinical parameters are the likely to be the most successful in the future. Increasing research into epigenetics, metagenomics, transcriptomics and glycomics may yield further biomarkers to assist risk prediction. Next on the research agenda is to create validated indices for predicting those at risk of failing rescue therapies ciclosporine and infliximab. Reassuringly similar clinical parameters are again significantly associated with colectomy requirement as have been demonstrated with corticosteroid failure. Five-year view Other -‘ omic’ technologies
Following on from genetics, transcriptomics, or the study of gene expression, is another emerging field in biomolecular research. An elegant study from Lee et al. in Cambridge (UK) demonstrated that the gene expression profile of circulating CD8+ T-lymphocytes is able to accurately predict a relapsing disease course from a stable one in patients with newly diagnosed IBD [63]. The transcriptome has been studied in pediatric ASUC, with 41 genes being differentially expressed in those requiring second-line medical therapy or colectomy [64]. Several genes overexpressed in non-responders interacted with steroid treatment on pathway analysis (CEACAM1, MMP8) [64]. Ten of the 41 genes were predictive of non-response with a sensitivity and specificity of 80% [64]. Interestingly, there was differential expression of ABCC4, a gene in the same superfamily as the aforementioned MDR1 gene [64]. Recently, there has been fervent interest in the role of the gut microbiome in disease pathogenesis. Microbial dysbiosis, including a reduced microbiological diversity has been noted in patients with IBD [65]. A study of pediatric ASUC, albeit in small numbers of children, indicates a reduced number of phylospecies compared with control [66]. A reduction in phylospecies was also significantly lower in those who failed first-line medical treatment [66]. The other emerging exciting biomolecular disciplines such as metabolomics [67–69], proteomics, glycomics [70,71] and epigenetics [72] may also unearth promising markers, used to predict disease course in the future.
doi: 10.1586/17474124.2015.992880
Composite models
Given the multifactorial contribution to IBD pathogenesis and course, it is unlikely that any single clinical or scientific parameters will accurately predict outcome in ASUC. It is more likely that composite scores make up of a combination of clinical, genetic and other data will be most fruitful in assisting prognostication of disease course. Examples from the Crohn’s disease literature demonstrate that by combining clinical, genetic (NOD2 status) and serological data (ASCA-IgA, ASCA-IgG, anti-OmpC, antiCBir1, anti-I2, pANCA), progression to stricturing or penetrating disease behavior can be more accurately predicted compared with using any single parameter alone (AUC 0.8) [73]. Another study used clinical and genetic data to predict requirement for surgery in CD, with progression to surgery faster in those with both clinical and genetic factors (IL12B) [74]. Predicting response to second-line therapy
Almost all prediction models discussed in this review thus far have aimed to predict those who will fail intravenous steroid treatment and require colectomy. The current paradigm of ASUC management involves increasing use of rescue medical therapy: ciclosporine and infliximab. Several trials have described factors associated with colectomy following failure of rescue therapy (TABLE 2). Similar clinical factors are seen again to predict colectomy following ciclosporine rescue therapy including clinical factors (advancing age [75,76], fever [77], tachycardia [77,78]), hematological/biochemical parameters (platelet abnormalities [75,76], elevated CRP [77]) and endoscopic appearances [77]. Existing indices such as the Ho score used to predict corticosteroid failure may also predict poor response to ciclosporine [79]. Similarly, following infliximab rescue therapy, advanced age [80,81] and elevated CRP [82–84] most consistently predict outcome. Financial & competing interests disclosure
NT Ventham is funded by EU FP7 Grant (IBD BIOM contract # 305479) and has received speakers fees from MSD; R Kalla is funded by EU FP7 Grant (IBD CHARACTER contract # 2858546); NA Kennedy is funded by the Wellcome Trust (WT097943MA) and has received speakers fees from MSD, Warner Chilcott and Ferring, and expenses to attend meetings from Norgine, Abbvie, MSD, Warner Chilcott, and Shire; J Satsangi has served as a speaker, a consultant and an advisory board member for MSD, Ferring Abbvie and Shire, consultant with Takeda, speaking fees from MSD and has received research funding from Abbvie; ID Arnott has been an advisory board member for Vifor and has had travel supported by Shire. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Expert Rev. Gastroenterol. Hepatol.
Predicting outcomes in ASUC
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Key issues .
Prediction scores assist the multidisciplinary clinical team to make important decisions regarding rescue therapy and surgery in a timely fashion, thereby preventing the increase in complications and mortality seen with delayed surgery without operating on those who will respond to medical therapy.
.
Presently scoring systems encompassing clinical, biochemical and radiological parameters remain the mainstay of risk prediction in acute severe ulcerative colitis (ASUC) and outperform genetic and other recent biomarker-based scores.
.
Stool frequency, temperature, heart rate, C-reactive protein, albumin, severe endoscopic appearances and radiological features are able
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to consistently predict outcome in ASUC. .
In adults, the Travis score, Ho score, Lindgren score and Seo index are among the most commonly used and best validated scores.
.
In pediatric practice, the pediatric ulcerative colitis activity index is the best scoring system for children with ASUC.
.
New scoring systems are required to predict response to rescue therapy in ASUC, and are likely to include similar parameters that are currently used to predict colectomy following intravenous corticosteroid treatment.
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doi: 10.1586/17474124.2015.992880
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Expert Rev. Gastroenterol. Hepatol. Early online, 1–11 (2014)
Nicholas T Ventham*1, Rahul Kalla2, Nicholas A Kennedy2, Jack Satsangi2 and Ian D Arnott2 1 Centre for Genomics and Molecular medicine, Western General Hospital, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK 2 Gastrointestinal Unit, Western General Hospital, Ann Ferguson Building, Crewe Road South, Edinburgh. EH4 2XU, UK *Author for correspondence: [email protected]
Response to corticosteroid treatment in acute severe ulcerative colitis (ASUC) has changed very little in the past 50 years. Predicting those at risk at an early stage helps stratify patients into those who may require second line therapy or early surgical treatment. Traditionally, risk scores have used a combination of clinical, radiological and biochemical parameters; established indices include the ‘Travis’ and ‘Ho’ scores. Recently, inflammatory bowel disease genetic risk alleles have been built into models to predict outcome in ASUC. Given the multifactorial nature of inflammatory bowel disease pathogenesis, in the future, composite scores integrating clinical, biochemical, serological, genetic and other ‘-omic’ data will be increasingly investigated. Although these new genetic prediction models are promising, they have yet to supplant traditional scores, which remain the best practice. In this modern era of rescue therapies in ASUC, robust scoring systems to predict failure of ciclosporine and infliximab must be devised. KEYWORDS: acute severe colitis . colectomy . mortality . outcomes . ulcerative colitis
Acute severe ulcerative colitis (ASUC) is an important medical problem that affects approximately 25% of patients with ulcerative colitis [1]. Mortality following ASUC fell in the 1950s after the introduction of systemic corticosteroid treatment [2]. However, the proportion of patients failing steroid treatment and requiring colectomy (~29%) has largely remained unchanged [3]. ASUC was defined by Truelove and Witt in 1955 as six or more bloody stools per day, with accompanying fever (temperature >37.8 C), tachycardia (heart rate >90/min) and deranged blood markers (hemoglobin 30 mm/h) [4]. This definition is endorsed by all of the major inflammatory bowel disease (IBD) organizations [5–7]. Infectious causes of colitis should be excluded, as concomitant Clostridium difficile infection leads to an increased risk of colectomy and mortality [8]. The extent of additional risk of colectomy conferred by superadded cytomegalovirus infection in ASUC patients is debated in the literature [9–11]. The major benefit of predicting outcomes in clinical practice is the allowance of earlier transition onto second line medical ‘rescue’ therapy or to definitive surgical management. A recent emphasis has been on deciding on informahealthcare.com
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the need for colectomy within 7 days of admission, as delays in surgery have been associated with an increase in mortality and postoperative complications [12–14]. In ASUC patients who avoid colectomy during their index admission, longer term data suggests colectomy rates of 40% after a second admission with ASUC [1]. Those who fail to completely settle following steroid treatment have a 50% chance of requiring a colectomy within 1 year of discharge, which goes up to 70% at 5 years [15]. Mortality
The mortality in all patients with UC is similar to that of the general population (standardised mortality ratio 1.19) [16]. However, patients requiring hospitalization for UC have a significantly increased risk of 3-year mortality [17–19]. Advancing age and the presence of comorbidity were found to be significantly associated with increased mortality in patients hospitalized with UC [19]. The UK IBD audit suggests that the hospital mortality for those with severe UC may be decreasing (mortality 2008 = 1.2%; 2010 = 0.7%) [20]. The audit data also confirms the higher mortality in older patients (>60 years; p < 0.001) and in those with co-morbidities [20]. Significantly, mortality was higher in those who failed first line medical
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therapy [20], demonstrating the importance of clinical and other scoring systems used to predict response to steroid treatment.
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Clinical scores
In 1975, Lennard-Jones recognized that factors used in the Truelove and Witts definition on admission also were strongly predictive of need for surgery in 189 patients with ASUC, particularly fever (>38 C), tachycardia and high stool frequency (>8/day) during the first day of admission [21]. In addition, hypoalbuminemia and radiological evidence of colonic dilatation and ‘mucosal islands’ were predictive of colectomy [21]. Recently, an increasing number of Truelove and Witts criteria at admission (over and above stool frequency) has been associated with an increase in colectomy rate (one additional criterion = 8.5%, two criteria = 31% and three or more criteria = 48%) [1]. The Travis score is perhaps the best-known scoring system and is derived from patients admitted with severe colitis in Oxford (UK). Published in 1996, at day 3 of corticosteroid treatment, patients with greater than eight stools per day or three to eight stools per day and elevated C-reactive protein (CRP) (>45 mg/l) had an 85% chance of requiring colectomy [22]. After 7 days of therapy, patients with ongoing symptoms (>3 stools/day or visible blood) had a 40% chance of colectomy in the following year [22]. Importantly, parameters used in the Travis score have been validated in independent cohorts [23]. A second prominent clinical scoring score was derived by Ho et al. in Edinburgh in 2004 [24]. Stool frequency, colonic dilatation on day 3 and hypoalbuminemia on day 1 were defined as independent predictors of failure of corticosteroid therapy (i.e., colectomy) using multiple logistic regression analysis [24]. A score was derived from these factors that can be used to predict failure of first line medical treatment [24]. Data from 984 patients collected during the third round of the UK IBD audit demonstrated equivalence in Ho and Travis scores in predicting those at high risk of requiring rescue therapy or colectomy [25]. The Ho score was additionally able to identify those who had an intermediate response to second line medical therapy [25]. Although the Travis and Ho scores can be derived as early as day 3 of corticosteroid treatment, a novel score to predict those requiring colectomy on admission is being developed [26]. Outside of the UK, the Lindgren and Seo scores are also extensively used and have been included as end points in important trials including the randomized placebocontrolled trial of infliximab as rescue therapy for ASUC [23,27,28]. Several other clinical prediction models have been described and are summarized in TABLE 1. The use of clinical and other scoring systems in the context of clinical trial end points has been reviewed elsewhere [29]. Symptoms preceding admission with ASUC are associated with poor outcome during index admission. Carbonnel, in addition to high Truelove and Witts score, demonstrated that antecedent symptoms lasting greater than 6 weeks were a highrisk feature for colectomy [30]. Others have demonstrated that doi: 10.1586/17474124.2015.992880
steroid treatment in the year before admission with ASUC was predictive of a slow response to intravenous steroids [31]. A systematic review collating much of the literature to date found that the most frequently reproduced factors that predicted failure of medical therapy include disease extent, stool frequency, temperature, heart rate, CRP, albumin and radiological features [3]. It is noteworthy that the included trials used varying study parameters and outcomes, including colectomy and failure of medical treatment as defined by composite endpoints, and as such it was not possible to perform a quantitative meta-analysis. In pediatric practice, the pediatric Ulcerative Colitis Activity index (PUCAI) is the most popular clinical tool used to predict outcome [32,33]. In a prospective cohort, the PUCAI performed best in predicting failure of first line medical therapy (defined as colectomy or need for second-line drugs), followed closely by the Travis score in a comparison which also included the Seo and Lindgren scores and various biomarkers including fecal calprotectin [34]. A further evaluation confirmed the PUCAI score to outperform various stool biomarkers including calprotectin in predicting outcome (colectomy or need for ciclosporine/infliximab) following a course of intravenous steroids in severe pediatric UC [35]. Other biochemical markers
CRP and albumin are the most validated biochemical markers used to predict outcome in ASUC. CRP is included in several of the scoring systems including the Travis and Lindgren scores [22,23]. Although CRP did not improve the predictive power of the PUCAI score [32], a prospective multicenter study demonstrated that day 3 CRP was additionally predictive of intravenous steroid failure (colectomy or need for ciclosporine/ infliximab) in pediatric ASUC Odds Ratio (OR): 1.3; CI: 1.1–1.6 [34]. Albumin synthesis is decreased as a result of systemic inflammation, and hypoalbuminemia has been used in various risk prediction tools including the Ho score [21,24]. Calprotectin, a neutrophil cytosolic protein, has been used extensively as a fecal biomarker of intestinal inflammation. Fecal calprotectin has been studied in the context of ASUC, with levels being significantly higher in patients requiring colectomy, and a trend toward higher levels in non-responders to corticosteroids (p = 0.08) and infliximab (p = 0.06) compared with responders [36]. A more recent analysis of biomarkers in 444 patients with ASUC from the same center failed to replicate the predictive ability of calprotectin (p = 0.52), although confirmed a strong association of elevated admission CRP and low albumin (p < 0.001 for both) [26]. Recently, serum calprotectin has been investigated as a biomarker in ASUC [37]. Radiological
Predictors of need for colectomy on plain radiograph were identified by Lennard-Jones in 1975 [21]. Original predictors included ‘mucosal islands’ and colonic dilatation greater than 5.5 cm [21]. Mucosal islands are small circular opacities, representing residual mucosa isolated by surrounding ulceration [5]. Expert Rev. Gastroenterol. Hepatol.
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Fulminant colitis index, Lindgren score
Activity Index (AI), Seo Score
Modified Truelove and Witts’ Severity Index
Edinburgh, UK
Malmo¨, Sweden
Fukuoka, Japan
New York, USA
Ho et al., (2004)
Lindgren et al., (1998)
Seo et al., (1992)
Lichtiger et al., (1990)
0–4 points respectively
Daily assessment
Number of daily stools (0–2, 3–4, 5–6.7–9, 10)
0/1 point 0–3 points 0/1 point 0–3 points 0–5 points
Nocturnal stools (present/absent) Percentage of blood in stools (0%, 220 = severe
150–220 = moderate
AI score >200 = 83% [85]
Number of bowel movements/day + 0.14 x CRP (mg/dl)
6 to £ 9/day =2 points, >9/day = 4 points) Radiological evidence of colonic dilatation (= 4 points)
>8
40%
Day 7
Moderate stool frequency (>3/day), bloody stools
Day 3
85%
Day 3
Positive predictive value of colectomy
High stool frequency (>8/day) or moderate stool frequency (3–8/day) and CRP (>45 mg/l)
Score used
80%
Day of assessment
Day 1
Temperature (>38 C) and high stool frequency (>8/day)
Recorded parameters
AUROC: Area under receiver operator characteristic curve; CRP: C-Reactive protein; ESR: Erythrocyte sedimentation rate; NPV: Negative predictive value; PPV: Positive predictive value.
Ho Score
Oxford, UK
Travis et al., (1996)
Travis Index
Alternative name
St Marks, London, UK
Origin
Lennard Jones, et al. (1975)
Adult
Study (year)
[86]
[27]
[23]
[24]
[22]
[21]
Ref.
Table 1. A summary of clinical composite scoring systems for predicting colectomy (or IV steroid failure) in acute severe ulcerative colitis following intravenous corticosteroid treatment.
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Predicting outcomes in ASUC
Special Report
doi: 10.1586/17474124.2015.992880
AUROC: Area under receiver operator characteristic curve; CRP: C-Reactive protein; ESR: Erythrocyte sedimentation rate; NPV: Negative predictive value; PPV: Positive predictive value.
International
Pediatric
65–85 = severe
35–64 = moderate
10–34 = mild
Day 3 and Day 5 Abdominal pain, rectal bleeding, stool consistency, number of stools in 24 h, nocturnal stools, activity level Pediatric ulcerative colitis activity index (PUCAI)
0/1 point Need for antidiarrheal drugs (yes/no)
doi: 10.1586/17474124.2015.992880
Turner et al., (2007)
0–3 points Abdominal tenderness (none, mild/localized, moderate, severe)
Alternative name
Recorded parameters
Day of assessment
Score used
45 PPV = 43%. NPV = 43% [34] Day 5 Score >70 PPV=100%, NPV = 79% [34]
[32]
Ref.
Ventham, Kalla, Kennedy, Satsangi & Arnott
Origin Study (year)
Table 1. A summary of clinical composite scoring systems for predicting colectomy (or IV steroid failure) in acute severe ulcerative colitis following intravenous corticosteroid treatment (cont.).
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Special Report
Small bowel dilatation on plain abdominal radiographs is also associated with colectomy (OR: 3.55; 95% CI: 2.27–5.87) [38]. MRI has been used to assess the extent of colonic inflammation using the degree of enhancement, edema and extra-luminal manifestations (e.g., lymphadenopathy) [39]. Another study used MRI performed within 2 days of ASUC admission to derive a total colonic inflammatory score (consisting of haustral loss, wall thickness, edema, small and large bowel dilatation) [40]. The total colonic inflammatory score predicted a prolonged treatment course (>7 days) with a positive predictive score of 87%, outperforming CRP and stool frequency; however, the number of patients requiring colectomy in this study was low (n = 3) [40]. Expedient access to MRI may limit the feasibility of such scores in many centers. Computed tomography (CT) retains a pivotal role in investigating the acute abdomen; however, published data suggests it is of limited benefit in determining requirement for colectomy [41]. Plain radiography with air enema to assess colonic ulceration [42] and white cell scintigraphy have also been used to predict severity [43], though are rarely used in everyday practice. Endoscopic scores
In ASUC, an unprepared flexible sigmoidoscopy with minimal air insufflation performed by an experienced endoscopist is safe and can aid diagnosis and prognostication. The Baron score is a widely used measurement in clinical trials [44]. However, when worldwide experts viewed video recordings of sigmoidoscopies, poor inter-observer correlation was noted, especially when judging mucosal friability [45]. Carbonnel described the appearance of severe endoscopic lesions associated with colectomy (deep extensive ulceration, well-like ulcerations, large mucosal abrasion, mucosal detachment) [30,46]. Extensive deep ulceration occurred in 96% of those requiring colectomy compared with 26% who did not [30,46]. Recently, Travis et al. devised the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) to assess the full spectrum of UC severity, including ASUC [45]. Using regression models, three descriptors were selected to derive the score: bleeding, ulceration and vascular pattern [45]. The UCEIS score is simple to use and performed well when tested by an independent set of investigators [47]. In a retrospective cohort, a UCEIS score of ‡7 of 8 on admission was associated with requirement of second-line medical therapy (infliximab or ciclosporine) [48]. Histopathological features associated with ASUC have also been described. Tanaka et al. described several high risk features including deep ulceration, frequent crypt abscesses, segmental mononuclear cell infiltration, paucity of eosinophils and extensive disease [49]. These criteria were validated in an independent, multicenter cohort and found to have the sensitivity of 86% and specificity of 95.2% in predicting the need for colectomy in ASUC [50]. The delay in obtaining histology results following initial sigmoidoscopic assessment limits the ability to base clinical decisions on histological scoring in ‘real time’. Another critical reason for obtaining histology during an Expert Rev. Gastroenterol. Hepatol.
Predicting outcomes in ASUC
B
100
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Proportion (%)
80 60 40 20 0 Risk A Risk B Risk C Risk D (n = 109) (n = 373) (n = 268) (n = 50) Risk score categories Non-MR-UC MR-UC
Cumulative probability of avoiding colectomy (MR-UC)
A
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1.2
1.0
0.8
0.6
0.4 Risk A Risk B Risk C Risk D
0.2
0 0
10
20
30
40
50
60
Time to surgery (months)
Figure 1. Haritunians et al. classified patients into medically refractory ulcerative colitis (MR-UC, n = 324) and non-medically refractory UC (non-MR-UC, n = 537) [58]. A genome wide association study was performed and a combination of 46 single nucleotide polymorphisms accounted for 46% of the variance of risk of colectomy. Based on genetic data, four genetic risk scores were devised (A to D, A-lowest risk, D-highest risk). The risk in each group of colectomy was 0, 17, 74 and 100%. Reprinted with permission from Wolters Kluwer Health from [58] and the Nature Publishing group.
episode of ASUC is to detect the presence of CMV superinfection. A high CMV DNA load detected in inflamed tissue (>250 copies/mg) is predictive of resistance to steroid and second-line treatment, with an area under the receiver operator characteristic curve (AUROC) of 0.85 [51].
particularly ‘pharmacogenetics’, for example, TMPT genotyping before initiation of thiopurine medication and the identification of specific HLA variants linked with thiopurine-induced pancreatitis [61,62]. Summary
Genetic predictors
Several genetic loci are associated with extensive disease and need for colectomy in UC, albeit not always in the context of ASUC. The HLA-DRB*0103 variant has been known for some time to be associated with extensive UC, and increased colectomy requirement [52–54]. The predictive nature of other HLA-DRB1 alleles have been replicated in several non-WhiteEuropean populations [55,56]. The multidrug resistance (MDR1, C3435TT allele, ABCB1) gene locus is also significantly associated with extensive disease in UC [57]. A genome-wide association study demonstrated genetic loci (including HLA, IL12B and TNFSF15) that were able to predict the need for colectomy [58]. This study generated a risk score based on 46 single nucleotide polymorphisms to account for 50% of the colectomy risk (AUROC 0.91), together with an increased risk of colectomy at 3 and 5 years (FIGURE 1) [58]. Given the large number of low penetrance genes associated with IBD susceptibility (163 in the most recent published meta-analysis [59]), together with the significant contribution of other factors including epigenetics, gut microbiota and the environment, genetic markers in isolation are unlikely to adequately predict disease course in ASUC [60]. Recent advances in other clinical aspects of IBD genetics give cause for optimism, informahealthcare.com
The ideal outcome prediction algorithm in ASUC should be quick to perform, assisting decision-making in ‘real time’, and be simple enough for clinicians to remember. Presently, scoring systems using clinical parameters with biochemical and radiological data are the only feasible measures in everyday practice. It is worthy of note that often the clinical parameters from which these scores are derived drive local clinical decision making (e.g., colonic dilatation on radiograph), and it is therefore self-fulfilling that these factors should be ‘predictive’ of poor outcomes. Moreover, these scores were often derived using data from relatively small, single-center and historic cohorts. New clinical scoring systems may be generated using large powerful multicenter datasets, such as the UK IBD audit data, and any new score should be validated in prospective cohorts. Although our current parameters reflect general systemic inflammation, in the near future, new biomolecular targets, including genomic, epigenomic, metagenomic and transcriptomic biomarkers may help to predict susceptibility to the consequences of ASUC, and assist in individualizing therapy in IBD. Expert commentary
The primary aim of scoring systems is to assist clinical teams in making decisions regarding colectomy for patients with ASUC doi: 10.1586/17474124.2015.992880
doi: 10.1586/17474124.2015.992880
Paris, France
Barcelona, Spain
Barcelona, Spain
Cacheux et al., (2008)
Aceituno et al. (2008)
Rios, et al. (2009)
Infliximab 5 mg/kg
Intravenous ciclosporine 4 mg/kg/day
Intravenous ciclosporine 4 mg/kg/day Oral ciclosporine 10 mg/ kg/day
Intravenous ciclosporine 4 mg/kg/day
Intravenous ciclosporine 2.5 mg/kg/day
Intravenous ciclosporine 3 mg/kg/day
Intervention
Older age, thrombocytosis, previous treatment with ciclosporine
Retrospective (n = 41), complete responders = 20, Partial responders = 9, colectomy = 12
High CRP (‡30 mg/l), Severe endoscopic lesions
Ho index (‡ 5)
Retrospective (n = 72), responders = 52, colectomy = 20 Split into derivation validation cohorts
Observational cohort study n = 113 Colectomy = 37
Day 1 of ciclosporine therapy
Temperature (>37.5 C), tachycardia (>90 bpm), CRP (>45 mg/l), severe endoscopic findings (deep extensive ulcers, large mucosal abrasions, welllike ulcers, mucosal detachments)
Retrospective (n = 135) Responders = 90 Colectomy = 45
Admission
Day 1 of ciclosporine therapy
Immediately prior to ciclosporine treatment
Admission
Tachycardia, hypoalbuminemia, increased immature (band) neutrophils
Retrospective (n = 36) Colectomy = 11 Responders = 25, late colectomy = 13 (within 9 months)
Day 1 and day 3 of ciclosporine administration
Day of assessment
Age on admission (>49 years), platelet count (13), day 3 - day 1 total protein (DTP > -0.4)
Recorded parameters
Retrospective (n = 52) Responders = 34, colectomy = 18
Study description
AUROC: Area under receiver operator characteristic curve; bpm: Beats per min; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; RCT: Randomized controlled trial.
Monterubbianesi et al., (2014)
Italy
LA, USA
Rowe et al., (2000)
Infliximab
Chiba, Japan
Location of study
Katsuno et al., (2012)
ciclosporine
Study (year)
–
–
66.7% (Overall AUROC for index 0.79)
Severe endoscopic lesions alone = 71% 80% at 6 months
AUROC=0.83
88.5%
Positive predictive value of colectomy
Table 2. A summary of clinical composite scoring systems for predicting requirement for colectomy in acute severe ulcerative colitis following second-line medical therapy: ciclosporine or infliximab.
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[83]
[76]
[79]
[77]
[78]
[75]
Ref.
Special Report Ventham, Kalla, Kennedy, Satsangi & Arnott
Expert Rev. Gastroenterol. Hepatol.
informahealthcare.com
Scotland, UK
Sweden
Italy
Lees, et al. (2006)
Sjoberg et al., (2013)
Kohn et al., (2007)
France
Lahaire et al., (2012)
IV ciclosporine 2 mg/kg Infliximab 5 mg/kg
IV ciclosporine 2 mg/kg Infliximab 5 mg/kg
Infliximab 5 mg/kg
Infliximab 5 mg/kg
Infliximab 5 mg/kg
Infliximab 5 mg/kg
Intervention
Randomized controlled trial Infliximab = 57 (colectomy = 4) ciclosporine = 58 (colectomy = 3)
–
–
23%
Advanced age (>40 years), hemoglobin (9.5–12.5 g/dl, and >12.5 g/dl)
–
–
–
One rather than two or more infliximab infusions
Retrospective n = 83 Colectomy = 12
–
57.1%
–
Positive predictive value of colectomy
–
Advanced age (>50 years), prolonged period of illness (>3 weeks) Delayed rescue therapy initiation (‡ 5 days after admission)
Retrospective n = 211 Colectomy = 75
Day 3 of intravenous steroids
Day 1 of Infliximab
Day of assessment
(whole cohort) High CRP, extensive disease, no previous azathioprine exposure
Hypoalbuminemia (29 mg/l)
Recorded parameters
Retrospective n = 56 Colectomy = 22
Study description
AUROC: Area under receiver operator characteristic curve; bpm: Beats per min; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; RCT: Randomized controlled trial.
Palermo, Italy
Mocciaro et al., (2012)
Both ciclosporine and infliximab
Denmark
Location of study
Mortensen, (2011)
Infliximab (cont.)
Study (year)
Table 2. A summary of clinical composite scoring systems for predicting requirement for colectomy in acute severe ulcerative colitis following second-line medical therapy: ciclosporine or infliximab (cont.).
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[81]
[82]
[88]
[80]
[87]
[84]
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Predicting outcomes in ASUC
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Ventham, Kalla, Kennedy, Satsangi & Arnott
in a timely fashion, thus avoiding the increased complications and mortality associated with delayed surgery. We believe that simple clinical indices that do not require formulae/calculations are the most memorable and easy to use in everyday practice. As such, we feel the Travis and Ho scores are the most useful; they have also been validated in independent cohorts. The more complex scoring systems such as the Seo, Lindgren and Lichtiger scores have a more important role in the formal setting of clinical trials. In spite of our interest and optimism in new genetic and -‘ omic’-based scores, these have not supplanted clinical scores. Composite scores encompassing genetic data with clinical parameters are the likely to be the most successful in the future. Increasing research into epigenetics, metagenomics, transcriptomics and glycomics may yield further biomarkers to assist risk prediction. Next on the research agenda is to create validated indices for predicting those at risk of failing rescue therapies ciclosporine and infliximab. Reassuringly similar clinical parameters are again significantly associated with colectomy requirement as have been demonstrated with corticosteroid failure. Five-year view Other -‘ omic’ technologies
Following on from genetics, transcriptomics, or the study of gene expression, is another emerging field in biomolecular research. An elegant study from Lee et al. in Cambridge (UK) demonstrated that the gene expression profile of circulating CD8+ T-lymphocytes is able to accurately predict a relapsing disease course from a stable one in patients with newly diagnosed IBD [63]. The transcriptome has been studied in pediatric ASUC, with 41 genes being differentially expressed in those requiring second-line medical therapy or colectomy [64]. Several genes overexpressed in non-responders interacted with steroid treatment on pathway analysis (CEACAM1, MMP8) [64]. Ten of the 41 genes were predictive of non-response with a sensitivity and specificity of 80% [64]. Interestingly, there was differential expression of ABCC4, a gene in the same superfamily as the aforementioned MDR1 gene [64]. Recently, there has been fervent interest in the role of the gut microbiome in disease pathogenesis. Microbial dysbiosis, including a reduced microbiological diversity has been noted in patients with IBD [65]. A study of pediatric ASUC, albeit in small numbers of children, indicates a reduced number of phylospecies compared with control [66]. A reduction in phylospecies was also significantly lower in those who failed first-line medical treatment [66]. The other emerging exciting biomolecular disciplines such as metabolomics [67–69], proteomics, glycomics [70,71] and epigenetics [72] may also unearth promising markers, used to predict disease course in the future.
doi: 10.1586/17474124.2015.992880
Composite models
Given the multifactorial contribution to IBD pathogenesis and course, it is unlikely that any single clinical or scientific parameters will accurately predict outcome in ASUC. It is more likely that composite scores make up of a combination of clinical, genetic and other data will be most fruitful in assisting prognostication of disease course. Examples from the Crohn’s disease literature demonstrate that by combining clinical, genetic (NOD2 status) and serological data (ASCA-IgA, ASCA-IgG, anti-OmpC, antiCBir1, anti-I2, pANCA), progression to stricturing or penetrating disease behavior can be more accurately predicted compared with using any single parameter alone (AUC 0.8) [73]. Another study used clinical and genetic data to predict requirement for surgery in CD, with progression to surgery faster in those with both clinical and genetic factors (IL12B) [74]. Predicting response to second-line therapy
Almost all prediction models discussed in this review thus far have aimed to predict those who will fail intravenous steroid treatment and require colectomy. The current paradigm of ASUC management involves increasing use of rescue medical therapy: ciclosporine and infliximab. Several trials have described factors associated with colectomy following failure of rescue therapy (TABLE 2). Similar clinical factors are seen again to predict colectomy following ciclosporine rescue therapy including clinical factors (advancing age [75,76], fever [77], tachycardia [77,78]), hematological/biochemical parameters (platelet abnormalities [75,76], elevated CRP [77]) and endoscopic appearances [77]. Existing indices such as the Ho score used to predict corticosteroid failure may also predict poor response to ciclosporine [79]. Similarly, following infliximab rescue therapy, advanced age [80,81] and elevated CRP [82–84] most consistently predict outcome. Financial & competing interests disclosure
NT Ventham is funded by EU FP7 Grant (IBD BIOM contract # 305479) and has received speakers fees from MSD; R Kalla is funded by EU FP7 Grant (IBD CHARACTER contract # 2858546); NA Kennedy is funded by the Wellcome Trust (WT097943MA) and has received speakers fees from MSD, Warner Chilcott and Ferring, and expenses to attend meetings from Norgine, Abbvie, MSD, Warner Chilcott, and Shire; J Satsangi has served as a speaker, a consultant and an advisory board member for MSD, Ferring Abbvie and Shire, consultant with Takeda, speaking fees from MSD and has received research funding from Abbvie; ID Arnott has been an advisory board member for Vifor and has had travel supported by Shire. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Expert Rev. Gastroenterol. Hepatol.
Predicting outcomes in ASUC
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Key issues .
Prediction scores assist the multidisciplinary clinical team to make important decisions regarding rescue therapy and surgery in a timely fashion, thereby preventing the increase in complications and mortality seen with delayed surgery without operating on those who will respond to medical therapy.
.
Presently scoring systems encompassing clinical, biochemical and radiological parameters remain the mainstay of risk prediction in acute severe ulcerative colitis (ASUC) and outperform genetic and other recent biomarker-based scores.
.
Stool frequency, temperature, heart rate, C-reactive protein, albumin, severe endoscopic appearances and radiological features are able
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to consistently predict outcome in ASUC. .
In adults, the Travis score, Ho score, Lindgren score and Seo index are among the most commonly used and best validated scores.
.
In pediatric practice, the pediatric ulcerative colitis activity index is the best scoring system for children with ASUC.
.
New scoring systems are required to predict response to rescue therapy in ASUC, and are likely to include similar parameters that are currently used to predict colectomy following intravenous corticosteroid treatment.
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