Dose intensification strategy influences infliximab pharmacokinetics but not clinical response after the same number of doses.

BACKGROUND: The optimal infliximab dose intensification strategy to address secondary loss of response (LOR) remains unclear. This study aimed to compare clinical and pharmacokinetic outcomes following (i) upfront infliximab re-induction with (ii) ongoing 6-weekly dose interval shortening (DIS), after the same number of doses. METHODS: A prospective parallel cohort study of inflammatory bowel disease patients who required infliximab dose intensification for secondary LOR using (i) re-induction (i.e., repeat 5 mg/kg 0, 2, 6-week dosing) followed by 8-weekly maintenance or (ii) 6-weekly 5 mg/kg DIS was undertaken. Week 32 clinical response was the primary outcome, with secondary evaluation of infliximab pharmacokinetics and predictors of response. RESULTS: Of 104 patients, 54 underwent re-induction, and 50 underwent 6-weekly DIS; 43 per cohort had clinically active disease, with comparable baseline infliximab levels (2.03 vs 2.02 ug/mL, P = 0.83). Clinical response was similar across re-induction and DIS cohorts at weeks 12 (69.8 vs 65.1%) and 32 (53.5 vs 62.8%, each P > 0.50); however, both strategies demonstrated distinct pharmacokinetic profiles at weeks 6 (18.45 vs 5.36 ug/mL, P < 0.01), 12 (8.94 vs 5.96 ug/mL, P = 0.02) and 30 (3.89 vs 6.35 ug/mL, P = .0.02). In multivariable analyses, objectively verified active disease at baseline (OR 12.92, 95% CI [1.84-90.84], P = 0.01), subtherapeutic week 6 infliximab levels (OR 0.12, 95% CI [0.01, 0.99], P = 0.049) and week 12 clinical response (OR 5.44, 95% CI [1.20-19.97], P = 0.04) were associated with week 32 response, as were week 2 infliximab levels (OR 1.34, 95% CI [1.02-1.47], P = 0.04) following re-induction. Following re-induction, week 2 infliximab levels <15.6 ug/mL (AUROC 0.76, 95% CI [0.54-0.99], P < 0.05) predicted nonresponse at week 32. CONCLUSION: Dose intensification strategy impacted immediate and sustained infliximab levels but not clinical response. Upfront intensification was associated with short-term pharmacokinetic advantages, including predictors of response, that diminished with time. Hence, when applying upfront dose intensification, clinicians should consider continuing intensified dosing to sustain early pharmacokinetic advantages based on predictors of (non)response.

Higher Mucosal Healing with Tumor Necrosis Factor Inhibitors in Combination with Thiopurines Compared to Methotrexate in Crohn's Disease.

BACKGROUND: The differential impact of anti-tumor necrosis factor (anti-TNF) therapy with methotrexate versus thiopurine co-therapy on endoscopic remission remains uncertain. AIMS: To compare rates of endoscopic remission based on methotrexate or thiopurine co-therapy used with anti-TNF therapy in Crohn's disease. METHODS: A retrospective observational study at two tertiary centers between 2010 and 2016 compared endoscopic remission rates and persistence on anti-TNF therapy in combination with methotrexate versus thiopurines for at least 3 months. RESULTS: Of 412 patients on anti-TNF therapy, 278 (67%) received immunomodulator co-therapy for ≥ 3 months and 269 (65%) had complete data for analysis. Methotrexate was used in 77 (29%) and thiopurines in 192 (71%) patients plus either infliximab (156, 58%) or adalimumab (113, 42%), with median follow-up of 2.8 years. The methotrexate group had greater prior immunomodulator intolerance (62% vs 20%, p < 0.01). Endoscopic remission rates were higher in those treated with thiopurine compared to methotrexate co-therapy at 12 m (58% vs 17%, p < 0.01) and at last review (59% vs 40%, p = 0.03). Endoscopic remission rates were higher with thiopurines than methotrexate when combined with adalimumab (49% vs 6%, p < 0.01) but not with infliximab (65% vs 54%, p = 0.09). In multivariate analysis, thiopurine co-therapy, elevated baseline CRP, and therapeutic anti-TNF drug levels were each associated with longer persistence of co-therapy (each p < 0.05). There were no significant differences in adverse events, malignancy or infection rates. CONCLUSION: In this cohort, anti-TNF and thiopurine co-therapy resulted in higher rates of mucosal healing than methotrexate, the difference is most pronounced with adalimumab and conversely with low-dose methotrexate.

Faecal calprotectin delivers on convenience, cost reduction and clinical decision-making in inflammatory bowel disease: a real-world cohort study.

BACKGROUND: Faecal calprotectin (FC) is an accurate biomarker of disease activity in inflammatory bowel disease (IBD), yet the cost/resource implications of incorporating FC into 'real-world' practice remain uncertain. AIM: To evaluate the utility of FC in clinical decision-making and on healthcare costs in IBD. METHODS: Retrospective data, including colonoscopy/other investigations, medication, admission and surgical data, were collected from hospital records and compared between two groups: pre-FC historical cohort (2005-2009) where colonoscopy was used to assess IBD activity versus the cohort where FC was used first instead (2010-2014). Post-test costs were also compared. RESULTS: A total of 357 FC tests (246 patients, 2010-2014) and 450 colonoscopies (268 patients, 2005-2009) were performed. On subsequent review, both FC and colonoscopy (in their respective cohorts) were associated with changes in management in 50.7 versus 56.2% (P = 0.14), respectively, with similar proportions of subsequent IBD-related investigations within 6 months (21.8 vs 21.9%, P = 1.0). Prior to FC availability (2005-2009), a colonoscopy for disease reassessment cost AU$606 578 (cost per patient-year $1887.34) versus AU$282 048 (cost per patient-year $968.60) when FC ± colonoscopy was used (2010-2014). Within the FC cohort, 73.6% did not proceed to colonoscopy within 6 months post-FC, and 60.6% had not undergone colonoscopy post-FC by the end of follow up (median 1.8 years (0.1, 4.6) post-FC). Those with FC ≥ 250 were scoped earlier than those with FC < 100 µg/mL (median 0.49 vs 1.0 years, P = 0.03). CONCLUSION: Introduction of FC into routine IBD care aided changes in clinical management in a similar proportion, yet at potentially half the total cost, compared to a historical colonoscopy-only cohort at the same centre.

Predicting response after infliximab salvage in acute severe ulcerative colitis.

BACKGROUND AND AIM: Acute severe ulcerative colitis (ASUC) is a medical emergency requiring prompt therapeutic intervention. Although infliximab has been used as salvage therapy for over 15 years, clinical predictors of treatment success are lacking. We performed a retrospective analysis to identify factors that predict colectomy and may guide dose intensification. METHODS: Fifty-four hospitalized patients received infliximab for ASUC at seven Australian centers (April 2014-May 2015). Follow-up was over 12 months. The data were primarily analyzed for predictors of colectomy. Accelerated (AI) versus standard (SI) infliximab induction strategies were also compared. RESULTS: Of 54 patients identified, the overall colectomy rate was 15.38% (8/52) at 3 months and 26.92% (14/52) at 12 months. Two patients were lost to follow-up. There was a numerically higher colectomy rate in those treated with AI compared with SI (P = 0.3); however, those treated with AI had more severe biochemical disease. A C-reactive protein (CRP)/albumin ratio cut-off of 0.37 post-commencement of infliximab and before discharge was a significant predictor of colectomy with an area under receiver operating curve of 0.73. Pretreatment CRP and albumin levels were not predictive of colectomy. A Mayo Endoscopic Score of 2 had a 94% PPV for avoidance of colectomy following infliximab salvage. CONCLUSIONS: The baseline Mayo Endoscopic Score and the CRP/albumin ratio following infliximab salvage are significant predictors of treatment response for ASUC and identify patients at high risk of colectomy. Whether this risk can be mitigated using infliximab dose intensification requires prospective evaluation before the CRP/albumin ratio can be integrated into ASUC management algorithms.

Prospective Evaluation of Serum Free Thiols in Inflammatory Bowel Disease: A Candidate to Replace C-Reactive Protein for Disease Activity Assessment?

BACKGROUND: Serum free thiols (SFTs) reflecting oxidative stress appear to correlate with inflammatory bowel disease (IBD) activity. We aimed to evaluate the performance of SFTs concentrations vs endoscopic and histological activity, compare SFTs with established biomarkers, and identify clinical and laboratory parameters independently associated with SFT levels in IBD patients. METHODS: Patients with confirmed IBD undergoing routine ileocolonoscopy for activity assessment were prospectively recruited, with serum samples obtained concurrently for SFTs and routine bloods, plus fecal calprotectin and immunochemical tests were collected ±30 days from ileocolonoscopy. Endoscopic activity was assessed via established indices and histological activity graded as inactive/mild/moderate. Receiver-operating characteristic curve analyses were utilized to assess performance of SFTs vs endoscopic activity, and multiple regression analysis was used to identify factors associated with SFT levels. RESULTS: A total of 141 (80 Crohn's disease, 61 ulcerative colitis) patients were recruited. Median SFTs were significantly lower in moderate vs inactive/mild endoscopic activity (309 µM vs 433/471 µM, respectively; P < .01). There was no significant difference in median SFTs across inactive/mild/moderate histological activity. SFTs achieved higher sensitivity than C-reactive protein in predicting moderate, endoscopically active disease (89% vs 78%; area under the curve, 0.80 each) yet was outperformed by fecal calprotectin (100%; area under the curve, 0.93). Advancing age and increasing albumin levels were independently associated with SFT levels, and thus are possible confounders. CONCLUSIONS: This prospective study has demonstrated the potential of SFTs as a serum biomarker in IBD. It was more sensitive than C-reactive protein, yet less sensitive than fecal biomarkers for prediction of endoscopically active IBD.

Clinical trial: Combination allopurinol-thiopurine versus standard thiopurine in patients with IBD escalating to immunomodulators (the DECIDER study).

BACKGROUND: Thiopurines are established treatments for inflammatory bowel disease (IBD), yet concerns remain regarding their safety. AIM: To evaluate the use of thiopurine-allopurinol combination therapy compared to standard thiopurine therapy in IBD. METHODS: We performed a multicentre, randomised, placebo-controlled trial to compare the efficacy and safety of thiopurine-allopurinol versus thiopurine with placebo for adults commencing a thiopurine for IBD. Patients had active disease at baseline; dosing of therapy was based on a pre-specified regimen and subsequent metabolites. The primary outcome was the proportion of patients achieving a composite of symptomatic disease activity remission (Harvey Bradshaw Index <5 for Crohn's disease, Simple Clinical Colitis Activity Index <4 for ulcerative colitis) and a faecal calprotectin <150 µg/g after 26 weeks of treatment. RESULTS: The trial was terminated early due to slow recruitment. We randomised 102 participants (54 thiopurine-allopurinol, 48 thiopurine with placebo) with similar age (median 42 vs 48 years) and sex distribution (46% women per group). A higher proportion achieved the primary outcome in the thiopurine-allopurinol group (50% vs 35%, p = 0.14) and fewer participants stopped their allocated therapy due to adverse events (11% vs 29%, p = 0.02). Also, within the thiopurine-allopurinol group, thiopurine dose adjustments were less frequent (69% vs 92%, p = 0.03), a higher proportion achieved an early therapeutic 6-TGN level at week 6 (71% vs 53%, p = 0.19), and adverse events attributed to therapy were less frequent (15% vs 44%, p = 0.002). CONCLUSION: Thiopurine-allopurinol therapy is safe and mitigates thiopurine adverse effects, thus enhancing tolerability without compromising efficacy (ACTRN12613001347752).

The Utility of Faecal Calprotectin, Lactoferrin and Other Faecal Biomarkers in Discriminating Endoscopic Activity in Crohn's Disease: A Systematic Review and Meta-Analysis.

INTRODUCTION: Currently, faecal calprotectin (FC) is the predominate faecal biomarker utilised in clinical practice to monitor Crohn's disease (CD) activity. However, there are several potential faecal biomarkers described in the literature. We performed a meta-analysis to determine the accuracy of faecal biomarkers in discriminating endoscopic activity and mucosal healing in CD. METHODS: We searched the medical literature using MEDLINE, EMBASE, and PubMed from 1978 to 8 August 2022. Descriptive statistics, including sensitivity, specificity of the primary studies, their positive and negative likelihood ratios, and their diagnostic odds ratio (DOR), were calculated. The methodological quality of the included studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS) criteria. RESULTS: The search found 2382 studies, of which 33 were included for analysis after screening. FC was found to have a pooled sensitivity and specificity, DOR, and negative predictive value (NPV) in discriminating active endoscopic disease (versus inactive) of 81%, 74%, 13.93, and 0.27, respectively. Faecal lactoferrin (FL) had a pooled sensitivity and specificity, DOR, and NPV in discriminating active endoscopic disease of 75%, 80%, 13.41, and 0.34, respectively. FC demonstrated a pooled sensitivity and specificity, DOR, and NPV of 88%, 72%, 18.17, and 0.19 in predicting mucosal healing. CONCLUSION: FC remains an accurate faecal biomarker. Further evaluation of the utility of novel faecal biomarkers is needed.

Utility of panenteric capsule endoscopy for the detection of small-bowel Crohn's disease in patients with a normal magnetic resonance enterography: A prospective observational pilot study.

Background and Aim: Capsule endoscopy allows the direct visualization of the small bowel. We examined the diagnostic utility of a new modality, namely panenteric Crohn's capsule endoscopy (CE), in detecting active small-bowel Crohn's disease (CD) in those with normal magnetic resonance enterography (MRE). Methods: We prospectively recruited patients with a diagnosis of CD or suspected small-bowel CD in whom the MRE was normal. Inclusion criteria included abdominal symptoms and abnormal serum or fecal biomarkers. The primary outcome was the detection of active small-bowel CD (measured through the Lewis score [LS]). Secondary outcomes included change in Montreal classification for those with a pre-existing CD diagnosis, change in medical therapy, clinical activity, and biomarkers at baseline and 6 months, and quality-of-life measures. Results: A total of 22 patients with a diagnosis of CD or suspected new diagnosis were recruited, with CE complete to the caecum in 21 and 18/21 (86%) showing evidence of active small-bowel CD (LS > 135). Of the patients with a pre-existing diagnosis of CD, 9/11 (82%) had a change in Montreal classification. At 6 months following CE, 17/18 (94%) had clinician-directed change in therapy. This correlated with an improvement in the quality of life (P < 0.05 as per the Short Inflammatory Bowel Disease Questionnaire), a reduction in the Harvey Bradshaw index (median: 7-4, P < 0.001), and favorable CRP and albumin response. Conclusion: Crohn's CE is a useful diagnostic test for assessing active small-bowel CD when imaging is normal but clinical suspicion is high. Crohn's CE should be integrated into the diagnostic algorithm for small-bowel CD.

Challenges and Strategies to Optimising the Quality of Small Bowel Magnetic Resonance Imaging in Crohn's Disease.

Magnetic resonance enterography (MRE) is one of the most highly utilised tools in the assessment of patients with small bowel Crohn's disease (CD). As a non-invasive modality, it has both patient and procedure-related advantages over ileocolonoscopy which is the current gold standard for Crohn's disease activity assessment. MRE relies upon high-quality images to ensure accurate disease activity assessment; however, few studies have explored the impact of image quality on the accuracy of small bowel CD activity assessment. Bowel distension and motion artifacts are two key imaging parameters that impact the quality of images obtained through MRE. Multiple strategies have been employed to both minimise the effects of motion artifacts and improve bowel distension. This review discusses the definitions of bowel distension and motion artifacts within the literature with a particular focus on current strategies to improve bowel distension and limit motion artifacts in MRE.

Biomarker dynamics during infliximab salvage for acute severe ulcerative colitis: C-reactive protein (CRP)-lymphocyte ratio and CRP-albumin ratio are useful in predicting colectomy.

BACKGROUND/AIMS: The residual risk of colectomy after infliximab salvage in steroid-refractory acute severe ulcerative colitis (ASUC) is required to inform the need for subsequent maintenance biologic therapy. The aim of this study was to determine the dynamic response of common serum biomarkers to infliximab salvage and assess their utility in predicting subsequent colectomy. METHODS: A retrospective single-center cohort study was conducted on all patients who received infliximab salvage for steroid-refractory ASUC between January 1, 2010, and July 31, 2019. Biomarkers were assessed on admission and days 1 and 3 post infliximab, and included C-reactive protein (CRP)-albumin-ratio (CAR), CRP-lymphocyte-ratio (CLR), platelet-lymphocyte-ratio (PLR) and neutrophil-lymphocyte-ratio (NLR). RESULTS: Of 94 patients (median age, 35 years; 67% of male), 20% required colectomy at 12 months. Biomarkers on day 3 post-infliximab best differentiated nonresponders, who had higher CRP, lower albumin and lower lymphocyte count (each P< 0.05). Day 3 predictive performance (area under the curve) for 12-month colectomy was best for CAR (0.871) and CLR (0.874), which were similar to Lindgren (0.829; P> 0.05) but superior to Mayo (0.726), partial Mayo (0.719), PLR (0.719), Ho index (0.714), NLR (0.675), Travis score (0.657) and endoscopic Mayo (0.609) (each P< 0.05). A day 3 CAR cutoff of 0.47 mg/g had 79% sensitivity, 80% specificity, 94% negative predictive value (NPV) to predict colectomy; while a day 3 CLR cutoff of 6.0 mg/109 had 84% sensitivity, 84% specificity, 96% NPV. CONCLUSIONS: CAR and CLR measured on day 3 post infliximab salvage for steroid-refractory ASUC represent simple and routinely performed biomarkers that appear to be strong predictors of colectomy. Prospective studies are required to confirm the utility of these predictive scores.

Functional gastrointestinal disorders in inflammatory bowel disease: impact on quality of life and psychological status.

BACKGROUND AND AIM: In inflammatory bowel disease (IBD), ongoing gastrointestinal (GI) symptoms consistent with coexistent functional GI disorders (FGID) might occur. It is uncertain what effect these symptoms have on health-related quality of life (HRQoL) and psychological comorbidity. The aim of the present study was to identify interrelationships among IBD, symptoms consistent with FGID, HRQoL, and psychological comorbidity. METHODS: A total of 256 consecutive IBD patients had diagnoses and disease activity verified at case-note review. Patients completed a contemporaneous survey assessing HRQoL, anxiety/depression, and GI symptoms (classified by Rome III criteria). RESULTS: Of 162 respondents (response rate: 63%), 95 (58.6%) had Crohn's disease and 63 (38.8%) had ulcerative colitis. By Rome III criteria, 66% met criteria for at least one FGID. Those with significant (Hospital Anxiety and Depression Scale ≥ 8) anxiety and/or depression were more likely to meet criteria for coexistent FGID (78% vs 22% and 89% vs 11%, respectively; each P < 0.001). A "load effect" was noted, such that the number of symptoms consistent with FGID in each patient correlated positively with anxiety and depression and negatively with HRQoL. Symptoms of any coexistent FGID were highly prevalent, even in those with currently-inactive IBD (57%). CONCLUSIONS: Symptoms consistent with FGID are highly prevalent in IBD and correlate with greater psychological comorbidity and poorer HRQoL in a "load-dependent" fashion. Therapy directed either at symptom load or psychological comorbidity might independently improve HRQoL in IBD.

Deep learning vs conventional learning algorithms for clinical prediction in Crohn's disease: A proof-of-concept study.

BACKGROUND: Traditional methods of developing predictive models in inflammatory bowel diseases (IBD) rely on using statistical regression approaches to deriving clinical scores such as the Crohn's disease (CD) activity index. However, traditional approaches are unable to take advantage of more complex data structures such as repeated measurements. Deep learning methods have the potential ability to automatically find and learn complex, hidden relationships between predictive markers and outcomes, but their application to clinical prediction in CD and IBD has not been explored previously. AIM: To determine and compare the utility of deep learning with conventional algorithms in predicting response to anti-tumor necrosis factor (anti-TNF) therapy in CD. METHODS: This was a retrospective single-center cohort study of all CD patients who commenced anti-TNF therapy (either adalimumab or infliximab) from January 1, 2010 to December 31, 2015. Remission was defined as a C-reactive protein (CRP) < 5 mg/L at 12 mo after anti-TNF commencement. Three supervised learning algorithms were compared: (1) A conventional statistical learning algorithm using multivariable logistic regression on baseline data only; (2) A deep learning algorithm using a feed-forward artificial neural network on baseline data only; and (3) A deep learning algorithm using a recurrent neural network on repeated data. Predictive performance was assessed using area under the receiver operator characteristic curve (AUC) after 10× repeated 5-fold cross-validation. RESULTS: A total of 146 patients were included (median age 36 years, 48% male). Concomitant therapy at anti-TNF commencement included thiopurines (68%), methotrexate (18%), corticosteroids (44%) and aminosalicylates (33%). After 12 mo, 64% had CRP < 5 mg/L. The conventional learning algorithm selected the following baseline variables for the predictive model: Complex disease behavior, albumin, monocytes, lymphocytes, mean corpuscular hemoglobin concentration and gamma-glutamyl transferase, and had a cross-validated AUC of 0.659, 95% confidence interval (CI): 0.562-0.756. A feed-forward artificial neural network using only baseline data demonstrated an AUC of 0.710 (95%CI: 0.622-0.799; P = 0.25 vs conventional). A recurrent neural network using repeated biomarker measurements demonstrated significantly higher AUC compared to the conventional algorithm (0.754, 95%CI: 0.674-0.834; P = 0.036). CONCLUSION: Deep learning methods are feasible and have the potential for stronger predictive performance compared to conventional model building methods when applied to predicting remission after anti-TNF therapy in CD.

Assessing adherence to infusion-based biologic therapies in patients with inflammatory bowel disease.

BACKGROUND: The intravenous biologics infliximab and vedolizumab are effective long-term therapies for inflammatory bowel disease (IBD). Though highly effective, suboptimal adherence may result in loss of response and adverse sequelae. The extent and outcomes of suboptimal adherence with intravenous biologics, including in IBD, requires further evaluation. OBJECTIVES: To ascertain adherence to infliximab and vedolizumab infusions, and determine factors associated with poorer adherence within an IBD cohort. METHODS: A retrospective single-centre cohort study of IBD patients, assessing adherence to infliximab and vedolizumab over 2 years (July 1, 2017 to June 30, 2019) was conducted. Medical and pharmacy dispensing records were used to determine date of infusion. Adherence was assessed using the continuous, multiple interval measure of medication gaps (CMG). Objectively measured disease remission was achieved if one or more of endoscopic remission, faecal calprotectin <100 µg/mL and/or CRP <5 mg/mL occurred within 3 months of end of follow-up. Bivariate analysis and multiple linear regression elucidated factors associated with poorer adherence. RESULTS: Of 193 IBD patients, 132 (68.4%) had Crohn's disease. One hundred and thirty six (70.5%) patients received infliximab and 57 (29.5%) received vedolizumab with a median 13 [IQR 11-14] doses administered per patient over 2 years. Adherence according to CMG was similar between infliximab and vedolizumab groups (median 1.5% vs 1.2%, p = 0.31). In multiple linear regression analysis male sex, shorter IBD duration and clinic non-attendances were each associated with poorer adherence (Beta 4.69, 3.90, 3.56 respectively, p < 0.05) and objective disease remission was inversely associated with poorer adherence (Beta -3.27, p < 0.05). CONCLUSION: There was a wide range of adherence to biologic infusions in this IBD cohort with poorer adherence associated with patient related factors. Conversely, objectively measured remission was strongly associated with adherence. This emphasises the need for targeted interventions to improve adherence and monitoring, and mitigate treatment delays.

Development of a Simple, Serum Biomarker-based Model Predictive of the Need for Early Biologic Therapy in Crohn's Disease.

BACKGROUND: Early or first-line treatment with biologics, as opposed to conventional immunomodulators, is not always necessary to achieve remission in Crohn's disease [CD] and may not be cost-effective. This study aimed to develop a simple model to predict the need for early biologic therapy, in order to risk-stratify CD patients and guide initial treatment selection. METHODS: A model-building study using supervised statistical learning methods was conducted using a retrospective cohort across two tertiary centres. All biologic-naïve CD patients who commenced an immunomodulator between January 1, 2004 and December 31, 2016, were included. A predictive score was derived using Cox regression modelling of immunomodulator failure, and was internally validated using bootstrap resampling. RESULTS: Of 410 patients [median age 37 years, 47% male, median disease duration 4.7 years], 229 [56%] experienced immunomodulator failure [39 required surgery, 24 experienced a new stricture, 44 experienced a new fistula/abscess, 122 required biologic escalation] with a median time to failure of 16 months. Independent predictors of treatment failure included raised C-reactive protein [CRP], low albumin, complex disease behaviour, younger age, and baseline steroids. Highest CRP and lowest albumin measured within the 3 months preceding immunomodulator initiation outperformed baseline measurements. After model selection, only highest CRP and lowest albumin remained and the resultant Crohn's Immunomodulator CRP-Albumin [CICA] index demonstrated robust optimism-corrected discriminative performance at 12, 24, and 36 months (area under the curve [AUC] 0.84, 0.83, 0.81, respectively). CONCLUSIONS: The derived CICA index based on simple, widely available markers is feasible, internally valid, and has a high utility in predicting immunomodulator failure. This requires external, prospective validation.

Adverse clinical phenotype in inflammatory bowel disease: a cross sectional study identifying factors potentially amenable to change.

BACKGROUND AND AIM: A significant proportion with inflammatory bowel disease (IBD) exhibit an adverse clinical phenotype reflected in endpoints like surgery and hospitalizations. We sought to identify clinico-demographic factors associated with these adverse consequences that may be amenable to change. METHODS: Over 6 months IBD patients visiting a metropolitan center were prospectively identified and given a comprehensive survey addressing patient knowledge, mental health and satisfaction with medical care along with other clinical data. Logistic regression analyses assessed for associations between clinico-demographic variables and adverse clinical endpoints (previous surgery [ever] and/or recent inpatient admission over a 16 month observation period). RESULTS: Of 256 IBD patients, 162 responded (response rate 63%); 95 (59%) had Crohn's disease (CD), 63 (40%) ulcerative colitis (UC), four indeterminate colitis; 53% were female. Factors associated with a greater likelihood of hospitalization included moderate/severe disease activity, psychological co-morbidity, numbers of medications and outpatient visits (odds ratio [OR] 7.09 [2.83-17.76], 4.13 [1.25-13.61], 1.26 [1.03-1.54], 1.17 [1.00-1.37] respectively; all P < 0.05). Post-surgical patients were more likely to have CD, more currently active disease and longer disease duration (OR 8.55 [2.43-29.4], 3.52 [1.26, 9.87], 1.14 [1.08, 1.21] respectively; all P < 0.02), yet were less likely to have previously seen a gastroenterologist, OR 0.25 [0.08-0.76] (P = 0.01). CONCLUSIONS: 'At risk' patients (those previously operated, with ongoing disease activity, dissatisfaction and/or psychological comorbidities) may benefit from early identification and more intensive management. Specialist gastroenterology care appears to be under-utilized in operated patients yet may reduce future IBD morbidity.

Outcomes of a drug shortage requiring switching in patients with ulcerative colitis.

BACKGROUND: Drug shortages are common yet their impact on patient care and their commercial ramifications has not been adequately researched. In Australia a shortage of balsalazide (2012-2013) necessitated substitution with alternative 5-aminosalicylate (5-ASA) formulations for ulcerative colitis (UC). AIM: To assess and compare the clinical and commercial sequelae of non-medical switching from balsalazide to another 5-ASA and/or return to balsalazide once supply resumed. METHODS: A prospective cohort study of patients on balsalazide for mild-moderate UC was conducted where, strictly due to the national shortage (November 2012- January 2013), were switched to alternative 5-ASA and/or then returned to balsalazide once supply resumed. Clinical (Partial Mayo), endoscopic (Mayo score) activity, adverse effects (to alternative 5-ASA) and percentage market share (of continuous 5-ASA users) from baseline (i.e., time of switching due to shortage) through to five years were assessed. RESULTS: Of 31 patients switched due to the shortage, 12 (38.7%) resumed balsalazide immediately once supply resumed, 8 (25.8%) prompted by adverse effects to the alternative 5-ASA used. Three patients (9.7%) had documented symptomatic improvement, 15 (48.4%) were unchanged and 13 (41.9%) had symptomatic worsening vs baseline (P < 0.01), after switching to an alternative 5-ASA. At 3 and 5y post switch, overall 26/31 (83.9%) and 23/31 (74.2%) had remained continuously on any 5-ASA therapy respectively. Twelve (38.7%) and 11 (35.5%) patients remained on balsalazide continuously at three and five years respectively after drug supply returned, equating to a loss of market share (within 5-ASA class) of 45.2% and 38.7% respectively. CONCLUSION: This study of a balsalazide shortage in UC patients exemplifies the detrimental impact of a drug shortage on long term patient, disease and commercial outcomes.