Early management of acute severe UC in the biologics era: development and international validation of a prognostic clinical index to predict steroid response.

OBJECTIVES: We aimed to determine whether changes in acute severe colitis (ASC) management have translated to improved outcomes and to develop a simple model predicting steroid non-response on admission. DESIGN: Outcomes of 131 adult ASC admissions (117 patients) in Oxford, UK between 2015 and 2019 were compared with data from 1992 to 1993. All patients received standard treatment with intravenous corticosteroids and endoscopic disease activity scoring (Ulcerative Colitis Endoscopic Index of Severity (UCEIS)). Steroid non-response was defined as receiving medical rescue therapy or surgery. A predictive model developed in the Oxford cohort was validated in Australia and India (Gold Coast University Hospital 2015-2020, n=110; All India Institute of Medical Sciences, New Delhi 2018-2020, n=62). RESULTS: In the 2015-2019 Oxford cohort, 15% required colectomy during admission vs 29% in 1992-1993 (p=0.033), while 71 (54%) patients received medical rescue therapy (27% ciclosporin, 27% anti-tumour necrosis factor, compared with 27% ciclosporin in 1992-1993 (p=0.0015). Admission C reactive protein (CRP) (false discovery rate, p=0.00066), albumin (0.0066) and UCEIS scores (0.015) predicted steroid non-response. A four-point model was developed involving CRP of ≥100 mg/L (one point), albumin of ≤25 g/L (one point), and UCEIS score of ≥4 (1 point) or ≥7 (2 points). Patients scoring 0, 1, 2, 3 and 4 in the validation cohorts had steroid response rates of 100, 75.0%, 54.9%, 18.2% and 0%, respectively. Scoring of ≥3 was 84% (95% CI 0.70 to 0.98) predictive of steroid failure (OR 11.9, 95% CI 10.8 to 13.0). Colectomy rates in the validation cohorts were were 8%-11%. CONCLUSIONS: Emergency colectomy rates for ASC have halved in 25 years to 8%-15% worldwide. Patients who will not respond to corticosteroids are readily identified on admission and may be prioritised for early intensification of therapy.

Therapeutic drug monitoring in inflammatory bowel disease reduces unnecessary use of infliximab with substantial associated cost-savings.

BACKGROUND: Therapeutic drug monitoring (TDM) of infliximab (IFX) levels in inflammatory bowel disease (IBD) patients can help to guide dose adjustments or changes to therapy for selected patients in remission or with secondary loss of response (LOR). AIMS: To determine how IFX TDM is utilised in a real-life clinical setting and to quantify the potential for TDM to reduce the unnecessary use of IFX. METHODS: Data from all public IBD IFX level testing performed across Australia were prospectively collected from June 2016 to July 2017 to assess physician-reported for testing indications (induction, in remission or LOR) and associated results. The hypothetical influence of IFX TDM was based on an optimal therapeutic range of 6-10 mg/L for mucosal healing. RESULTS: Secondary LOR (reactive TDM) was the most common indication for TDM. These patients have consistently lower median IFX levels: 3.02 mg/L (IQR 1.14-6.67 mg/L) versus 5.22 mg/L (IQR 2.70-8.12 mg/L), P = 0.0001 compared with patients in remission (proactive TDM). TDM helped to identify unnecessary use of IFX in 30.6% of the TDM tests performed in luminal Crohn disease and ulcerative colitis patients, with an associated drug cost saving of $531.38 per IFX TDM test episode. Unnecessary IFX use was identified in 38.9% (96/247) of reactive IFX TDM tests performed and in 19.3% (35/181) of proactive testing. CONCLUSION: Use of both reactive and proactive IFX TDM is cost-effective for IBD management as it informs the clinician where unnecessary use of IFX can be stopped.

Hepatitis C treatment for difficult to access populations: can telementoring (as distinct from telemedicine) help?

BACKGROUND: Although hepatitis C virus (HCV) infection is curable, treatment of difficult to access populations (DTAP) presents unique challenges. Project ECHO (PE) (Extension for Community Healthcare Outcomes) is a telementoring programme adopted to support clinicians treating DTAP. AIMS: To determine if the PE model supports primary care clinicians treating HCV and to compare cohort of PE patients with those in a tertiary liver clinic (TLC). METHODS: Weekly PE group video conferences were conducted. Clinical information, laboratory indices, psychosocial elements and treatment outcomes, including sustained virological response (SVR) data were recorded in the first 100 consecutive cases and retrospectively compared to 100 consecutive patients seen at a TLC from July 2016 to April 2017. RESULTS: Some patient characteristics were similar between PE and TLC: gender (72% vs 75% male; P = 0.23), median age (45 vs 50; P = 0.344) and the proportion of treatment naïve patients (95.0% vs 90.9%). Treatment for HCV was commenced in 78% of the PE patients and 81% of the TLC patients; 67/68 of the TLC patients and 60/61 PE patients with virological follow up who completed treatment and attended follow up have confirmed SVR. PE patients are more likely to have ongoing substance use (44% vs 17% P < 0.001), be active intravenous drug users (32% vs 17%; P < 0.001) and polysubstance abusers (26% vs 7%; P < 0.001) and were more likely to be taking opioid substitution therapy (74% vs 20%; P < 0.001). Indigenous patients were three times more greatly represented in PE (15% vs 5%; P = 0.018). CONCLUSION: PE is an effective model to support primary healthcare providers treating HCV in DTAP with similar rates of treatment uptake and SVR compared to patients in TLC.

Hepatitis A to E: what's new?

Viral hepatitis contributes to significant morbidity and mortality worldwide. While acute infection may be self-limiting, unrecognised chronic infection and under-utilisation of guideline-based approaches to therapy contribute to increasing rates of cirrhosis, hepatocellular carcinoma and death. Our aim was to review the current evidence for screening, diagnosis and treatment in hepatitis A to E. Evidence for this review was sourced from international and Australian guidelines and high-quality clinical trials. MEDLINE was searched using structured key word strategy and retrieved articles were reviewed methodically to inform a brief and up-to-date synopsis of hepatitis A to E. We share some of the recent developments in viral hepatitis, specifically the new therapies for hepatitis C. Direct-acting antiviral therapies are safe, well-tolerated and effective. Subsidies allow access for all Australians with most strains of hepatitis C. We outline evidence underpinning efficacy and safety of treatment for hepatitis B, while clarifying some of the nuances in the setting of pregnancy and immunosuppression. We provide a simplified concept to facilitate understanding of the five phases of hepatitis B; practical for real-world setting. Hepatitis A to E is a broad topic, not all aspects of these viruses can be covered in this short review. We provided suggestions for evidence based guidelines, which are a suitable supplement to this article.

Sorafenib in the treatment of hepatocellular carcinoma: a multi-centre real-world study.

OBJECTIVE: Sorafenib is an oral multikinase inhibitor that improves survival in advanced hepatocellular carcinoma (HCC). In the absence of alternative therapies, sorafenib is often continued despite advancing liver disease or tumour progression. Real world studies are important to better characterise outcomes in these populations. Our aim was to review patterns of sorafenib use across eight Australian tertiary hospitals, defining variables associated with clinical outcomes. MATERIAL AND METHODS: Retrospective cohort study of medical records of 320 patients treated with sorafenib for HCC. Baseline clinical parameters, dosage, adverse effects, and survival from initiation of treatment were collected. Time to radiological progression and 3-month alpha-fetoprotein (AFP) levels were available for a subset of patients. RESULTS: Adverse effects occurred in 79% of patients, requiring dose reduction in 31% of patients. Multivariate analysis identified an increased rate of mortality with Child-Pugh C (HR 5.52, p = 0.012), ECOG performance status 2-3 (HR 2.84, p = 0.001), and extrahepatic metastases (HR 1.54, p = 0.04), and decreased rate of mortality with an AFP reduction of at least 20% at 3 months (HR 0.38, p = 0.001). An increased rate of radiological progression was associated with ECOG performance status 2-3 (HR 2.34, p = 0.041), whilst a decreased rate of radiological progression was associated with development of on-treatment diarrhoea (HR 0.55, p = 0.015). CONCLUSIONS: Survival in patients with Child-Pugh C liver function or advanced functional impairment treated with sorafenib is poor and thus routine use of this agent in these patients does not appear justified, particularly given the high rate of adverse effects. AFP concentration on therapy may help identify favourable response to treatment.

Leukocytoclastic Vasculitis-Associated Myocarditis as an Extraintestinal Manifestation of Crohn's Disease.

Cardiac extraintestinal manifestations (EIMs) of Crohn's disease (CD) are uncommon. They include pericarditis, myocarditis, and arrhythmias; however, distinguishing these from alternative causes including medication-related adverse effects is often challenging. Leukocytoclastic vasculitis is another uncommon EIM of CD that may present with systemic involvement. We present a rare case of myocarditis associated with leukocytoclastic vasculitis occurring as EIMs of CD. The myocarditis proved refractory to standard therapy and biologics targeting underlying gut inflammation. She developed an inflammatory cardiomyopathy and symptoms consistent with heart failure with preserved ejection fraction. Anakinra was tried, but despite the initial response, it should be used cautiously in patients with CD.

Inflammatory bowel disease patients have an increased risk of acute coronary syndrome: a systematic review and meta-analysis.

OBJECTIVES: Systemic inflammation is increasingly being recognised as a possible mechanism for acute arterial thrombotic events, including acute coronary syndrome (ACS). Despite this, there is conflicting data on the risk of ACS in patients with inflammatory bowel disease (IBD). We performed a contemporary systematic review and meta-analysis to identify the risk of ACS in patients with IBD. METHODS: PubMed, MEDLINE, EMBASE, CENTRAL and Web of Science were searched up to 27 October 2022. Multivariable-adjusted or propensity matched studies with a non-IBD control cohort were included. HRs were pooled using a random-effects model. Subgroup and sensitivity analyses were conducted in order to explore sources of heterogeneity. RESULTS: Twelve retrospective cohort studies were included (225 248 IBD patients). Patients with IBD were associated with an increased risk of ACS in both adjusted (HR 1.23; 95% CI 1.08 to 1.41) and unadjusted analyses (HR 1.50; 95% CI 1.16 to 1.92). Substantial heterogeneity was observed (i2=88, p=0.002 and i2=98%, p=0.002, respectively). Subgroup analysis of age revealed a greater association of ACS in IBD patients <40 years of age (relative HR 1.50; 95 CI 1.15 to 1.96). CONCLUSION: Patients with IBD demonstrated an independently increased risk of ACS. Prospective studies are required to explore the relationship with disease activity and duration, concomitant medication use and angiographic characteristics and outcomes. PROSPERO REGISTRATION NUMBER: CRD42022367846.

Older adults with acute severe ulcerative colitis have similar steroid non-response and colectomy rates as younger adults.

BACKGROUND: There is paucity of data on outcomes of acute severe ulcerative colitis (ASUC) in older adults (≥ 60 years of age). AIM: To assess steroid non-response rates during the index admission for ASUC in older adults. Secondary outcomes were response to medical rescue therapy and colectomy rates; at index admission, 3 and 12 mo. METHODS: This retrospective multicentre cohort study included ASUC admissions who received intravenous steroids between January 2013 and July 2020 at two tertiary hospitals. Electronic medical records were reviewed to collect clinical, biochemical, and endoscopic data. A modified Poisson regression model was used for analysis. RESULTS: Of 226 ASUC episodes, 45 (19.9%) occurred in patients ≥ 60 years of age. Steroid non-response rates were comparable in older adults and patients < 60 years of age [19 (42.2%) vs 85 (47%), P = 0.618, crude risk ratio (RR) = 0.89 [95% confidence interval (CI): 0.61-1.30], adjusted RR = 0.99 (0.44-2.21). Rates of response to medical rescue therapy in older adults was comparable to the younger cohort [76.5% vs 85.7%, P = 0.46, crude RR = 0.89 (0.67-1.17)]. Index admission colectomy [13.3% vs 10.5%, P = 0.598, crude RR = 1.27 (0.53-2.99), adjusted RR = 1.43 (0.34-6.06)], colectomy at 3 mo [20% vs 16.6%, P = 0.66, crude RR = 1.18 (0.61-2.3), adjusted RR = 1.31 (0.32-0.53)] and colectomy at 12 mo [20% vs 23.2%, P = 0.682, crude RR = 0.85 (0.45-1.57), adjusted RR = 1.21 (0.29-4.97)], were similar between the two groups. CONCLUSION: In older adults with ASUC, the steroid non-response rate, response to medical rescue therapy, and colectomy rate at index admission, 3 and 12 mo is similar to patients less than 60 years of age.

Predicting Outcome in Acute Severe Colitis-Controversies in Clinical Practice in 2021.

Acute severe ulcerative colitis [ASUC] remains a common medical emergency, with 25% of patients with ulcerative colitis experiencing at least one event in their disease course. Despite advances in medical therapy, ASUC continues to be associated with considerable morbidity and mortality, with up to 30% of patients requiring colectomy during initial admission. Our aim was to review the current controversies and recent progress in risk stratification, prediction of outcome, and personalisation of care in ASUC. We re-assess the use of Truelove and Witts' criteria, serum biomarkers, and the use of composite clinical indices in current clinical practice. We explore the potential for endoscopic prediction using defined validated indices for accurate and early prognostication, and the need to define outcome. We also consider the impact of the current COVID-19 pandemic. Finally, we discuss the current research agenda, including the application of new and emerging biomarkers coupled with multi-omics and the implications in management and optimisation of outcome. Research priorities for the prediction of outcome in acute severe colitis include the following. 1. Development of an accurate admission score to guide early medical rescue therapy or colectomy. 2. Utility of point-of-care faecal calprotectin, with determination of optimal cut-off values. 3. Role of serum and faecal infliximab levels to both predict outcome and guide accelerated infliximab dosing. 4. Role of novel biomarkers, including serum calprotectin, in predicting response to corticosteroids or rescue therapy. 5. Specific predictors of response to ciclosporin and infliximab to allow rationalisation of drug use. 6. Utility of validated endoscopic scores. 7. Utility of radiological assessment beyond use of plain abdominal X-ray. 8. The use of multiomics and machine learning to predict risk of Acute Severe Colitis in patients with Ulcerative Colitis.

Prospective single-blinded single-center randomized controlled trial of Prep Kit-C and Moviprep: Does underlying inflammatory bowel disease impact tolerability and efficacy?

BACKGROUND: Colonoscopy remains the gold standard for detection of colonic disease. An optimal evaluation depends on adequate bowel cleansing. Patients with inflammatory bowel disease (IBD), require frequent endoscopic assessment for both activity and dysplasia assessment. Two commonly used bowel preparations in Australia are Prep Kit-C (Pc) and Moviprep (Mp). Little is known about tolerability, efficacy and safety of split protocols of Mp and Pc in both IBD and non-IBD patients. AIM: To primary aim was to compare the tolerability, efficacy and safety of split protocols of Mp and Pc in patients having a colonoscopy. The secondary aim was to compare the efficacy, tolerability and safety of either preparation in patients with or without IBD. METHODS: Patients were randomized to Pc or Mp bowel preparation. Patients completed a questionnaire to assess tolerability. Efficacy was assessed using the Ottawa Bowel Preparation Score. Serum electrolytes and renal function were collected one week prior to colonoscopy and on the day of colonoscopy. RESULTS: Of 338 patients met the inclusion criteria. Of 168 patients randomized to Mp and 170 to Pc. The efficacy of bowel preparation (mean Ottawa Bowel Preparation Score) was similar between Mp (5.4 ± 2.4) and Pc (5.1 ± 2.1) (P = 0.3). Mean tolerability scores were similar in Mp (11.84 ± 5.4) and Pc (10.99 ± 5.2; P = 0.17). 125 patients had IBD (73 had Crohn's Disease and 52 had Ulcerative colitis). Sixty-four IBD patients were allocated to Mp and 61 to Pc. In non-IBD patients, 104 were allocated to Mp and 109 to Pc. The mean tolerability score in the IBD group was lower than the non-IBD group (mean tolerability scores: IBD: 10.3 ± 5.1 and non-IBD: 12.0 ± 5.3; P = 0.01). IBD patients described more abdominal pain with Mp when compared with Pc; (Mp: 5.7 ± 4.4 vs Pc: 3.6 ± 2.6, P = 0.046). Serum magnesium level increased with Pc compared with Mp in all patients (mean increase in mmol/L: Mp: 0.03 ± 0.117 and Pc: 0.11 ± 0.106; P < 0.0001). CONCLUSION: In this study, the efficacy, tolerability and safety of Mp and Pc were similar in all patients. However, patients with IBD reported lower tolerability with both preparations. Specifically, IBD patients had more abdominal pain with Mp. These results should be considered when recommending bowel preparation especially to IBD patients.

Patients with non-viral liver disease have a greater tumor burden and less curative treatment options when diagnosed with hepatocellular carcinoma.

AIM: To assess the impact of underlying liver disease etiology on the presenting features and outcomes in a large cohort of patients with hepatocellular carcinoma (HCC). METHODS: A prospective database of all patients with HCC was established from 1998 to March 2012. One thousand and seventy-eight patients were categorized into three groups, based on the etiology of their liver disease: hepatitis B virus (HBV), hepatitis C virus (HCV) and non-viral liver disease (NVLD). Overall survival was determined by Kaplan Meier analysis to time of death or last follow-up. RESULTS: HCC patients with HCV (85%) were more likely to be diagnosed as part of a surveillance program, compared to HBV or NVLD (both 71%) (P < 0.001). Patients with NVLD were more likely to receive best supportive care (29%) compared to those with HBV (21%) or HCV (20%) (P < 0.02). Twelve percent of NVLD and 13% of HBV patients underwent liver transplantation compared to 21% of HCV patients (P = 0.001). Median survival from presentation was lowest in NVLD (1.7 years) when compared to HBV (2.8 years) and HCV (2.6 years) (P < 0.05). In multivariate analysis, independent predictors of survival included Child Turcotte Pugh score, size of dominant lesion, absence of vascular invasion, and management with surgical resection or liver transplantation. Patient age and the etiology of the underlying liver disease were not independent predictors of survival. CONCLUSION: Patients with NVLD and HCC were less likely to be enrolled in a HCC surveillance program and are less likely to have curative therapies such as liver resection and transplantation after diagnosis with HCC, when compared to patients with Hepatitis B and Hepatitis C.