Medicine (St Vincent's) - Research Publications
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ItemEpidemiology and outcomes of primary sclerosing cholangitis: an Australian multicentre retrospective cohort study(SPRINGER, 2022-10)BACKGROUND AND AIMS: Little is known regarding the epidemiology and outcomes of patients with primary sclerosing cholangitis (PSC) in Australia. We, therefore, evaluated the epidemiology and clinical outcomes of PSC in a large cohort of Australian patients and compared these to the general population. METHODS: We conducted a multicentre, retrospective cohort study of PSC patients at nine tertiary liver centers across three Australian states, including two liver transplant centers. RESULTS: A total of 413 PSC patients with 3,285 person-years of follow-up were included. Three hundred and seventy-one (90%) patients had large duct PSC and 294 (71%) had associated inflammatory bowel disease. A total of 168 (41%) patients developed cirrhosis (including 34 at the time of PSC diagnosis) after a median of 15.8 (95% CI 12.4, NA) years. The composite endpoint of death or liver transplantation occurred in 49 (12%) and 78 (19%) patients, respectively, with a median transplant-free survival of 13.4 (95% CI 12.2-15) years. Compared to the general population, PSC accounted for a 240-fold increased risk of development of cholangiocarcinoma (CCA) and CCA-related death. CCA risk was increased with older age of PSC diagnosis, presence of dominant stricture and colectomy. Compared to same-aged counterparts in the general population, PSC patients who were diagnosed at an older age or with longer disease duration had reduced relative survival. CONCLUSION: In this large retrospective cohort study of PSC patients in Australia, increased age and time from diagnosis was associated with increased mortality and morbidity particularly from CCA and development of cirrhosis, necessitating need for liver transplant.
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ItemLenvatinib for the treatment of hepatocellular carcinoma-a real-world multicenter Australian cohort study(SPRINGER, 2022-10)INTRODUCTION: Hepatocellular carcinoma (HCC) is a serious complication of chronic liver disease. Lenvatinib is an oral multikinase inhibitor registered to treat advanced HCC. This study evaluates the real-world experience with lenvatinib in Australia. METHODS: We conducted a retrospective cohort study of patients treated with lenvatinib for advanced HCC between July 2018 and November 2020 at 11 Australian tertiary care hospitals. Baseline demographic data, tumor characteristics, lenvatinib dosing, adverse events (AEs) and clinical outcomes were collected. Overall survival (OS) was the primary outcome. Progression free survival (PFS) and AEs were secondary outcomes. RESULTS: A total of 155 patients were included and were predominantly male (90.7%) with a median age of 65 years (interquartile range [IQR]: 59-75). The main causes of chronic liver disease were hepatitis C infection (40.0%) and alcohol-related liver disease (34.2). Median OS and PFS were 7.7 (95% confidence interval [CI]: 5.8-14.0) and 5.3 months (95% CI: 2.8-9.2) respectively. Multivariate predictors of mortality were the need for dose reduction due to AEs (Hazard ratio [HR] 0.41, p < 0.01), new or worsening hypertension (HR 0.42, p < 0.01), diarrhoea (HR 0.47, p = 0.04) and more advanced BCLC stage (HR 2.50, p = 0.04). Multivariable predictors of disease progression were higher Child-Pugh score (HR 1.25, p = 0.04), the need for a dose reduction (HR 0.45, p < 0.01) and age (HR 0.96, p < 0.001). AEs occurred in 83.9% of patients with most being mild (71.6%). CONCLUSIONS: Lenvatinib remains safe and effective in real-world use. Treatment emergent diarrhoea and hypertension, and the need for dose reduction appear to predict better OS.
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ItemMaternal thiopurine metabolism during pregnancy in inflammatory bowel disease and clearance of thiopurine metabolites and outcomes in exposed neonates(WILEY, 2021-04)BACKGROUND: Azathioprine and mercaptopurine are considered safe during pregnancy. However, the pharmacokinetic effects of pregnancy on thiopurine metabolism are undefined. AIMS: To characterise thiopurine metabolism in pregnancy and measure infant metabolite levels and outcomes. METHODS: Women with IBD who were taking a thiopurine and pregnant or trying to conceive were recruited. Maternal thiopurine metabolites were measured pre-conception, in each trimester, at delivery and post-partum. Infant metabolite levels, full blood examination and liver function testing were performed at birth, and repeated until levels undetectable and haematological and biochemical abnormalities resolved. RESULTS: Forty patients were included with measurements on at least two occasions, and two with only mother-baby levels at delivery. The median maternal 6-TGN level dropped in the second trimester compared with post-partum (179.0 vs 323.5 pmol/8 × 108 RBCs, P < 0.001) and the median 6-MMP level increased in the second trimester compared with post-partum (1103.0 vs 329.5 pmol/8 × 108 RBCs, P < 0.01). At delivery, the median 6-TGN level was lower in infants (n = 20) than mothers (78.5 vs 217 pmol/8 × 108 RBCs) (P < 0.001). Metabolites were not detected at 6 weeks in any infants. Anaemia was not seen, but thrombocytosis and abnormal liver biochemistry were detected in 80% of infants from 6 weeks, which gradually improved. CONCLUSIONS: 6-TGN levels decrease and 6-MMP levels increase in the second trimester of pregnancy. Infants are exposed to thiopurine metabolites at low levels with clearance by 6 weeks and no anaemia. The cause of infant thrombocytosis and abnormal liver biochemistry in the absence of metabolites is unclear.
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ItemMagnetic resonance enterography for predicting the clinical course of Crohn's disease strictures(WILEY, 2020-06)BACKGROUND AND AIMS: Strictures are the most common Crohn's disease complication, but their natural history is unknown. This study aimed to characterize inflammation, predict prognosis, and understand the impact of drug therapy using magnetic resonance enterography (MRE). METHODS: Patients with a stricture diagnosed on MRE over a 5-year period were reviewed for MRE disease extent and inflammation, clinical course, C-reactive protein, response to anti-TNF therapy, endoscopic dilatation, hospitalization, and surgery. RESULTS: 136 patients had 235 strictures (77, one and 59, ≥ 2 strictures). TREATMENT: 46% of patients underwent surgery after a median 6 months; median follow-up for those not requiring surgery was 41 months. Predictors of surgery: Hospitalization because of obstruction predicted subsequent surgery (OR 2.50; 95% CI 1.06-5.90) while anti-TNF therapy commenced at stricture diagnosis was associated with a reduced risk (OR 0.23; 95% CI 0.05-0.99). MRE characteristics associated with surgery were proximal bowel dilatation ≥ 30-mm diameter (OR 2.98; 95% CI 1.36-6.55), stricture bowel wall thickness ≥ 10-mm (OR 2.42; 95% CI 1.11-5.27), and stricture length > 5-cm (OR 2.56; 95% CI 1.21-5.43). 81% of patients with these three adverse MRE features required surgery versus 17% if none were present (P < 0.001). Accuracy for these three MRE variables predicting surgery was high (AUC 0.76). CONCLUSION: Magnetic resonance enterography findings in Crohn's disease strictures are highly predictive of the disease course and the need for future surgery. MRE may also identify who would benefit from treatment intensification. Anti-TNF therapy is associated with reduced risk of surgery and appears to alter the natural history of this complication.
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ItemInfliximab, adalimumab and vedolizumab concentrations across pregnancy and vedolizumab concentrations in infants following intrauterine exposure(WILEY, 2020-11)Background The impact of pregnancy on levels of biologic agents in patients with IBD is undefined and time to elimination in vedolizumab‐exposed infants is unknown. Aims To determine the effect of pregnancy on infliximab, adalimumab and vedolizumab levels and to study infant vedolizumab clearance Methods In a prospective observational study, maternal drug levels were measured pre‐conception, in each trimester, at delivery and postpartum. The association between drug levels and gestation in weeks was assessed using generalised estimating equation modelling. Infant vedolizumab levels were performed at birth (cord blood), 6 weeks and 3 months or until undetectable. Results We included 50 IBD patients (23 on infliximab, 15 on adalimumab and 12 on vedolizumab) with at least two intrapartum observations, plus 5 patients on vedolizumab with only mother and baby samples at delivery. Modelling showed no change in adalimumab levels, an increase in infliximab levels of 0.16 (95% CI 0.08‐0.24) µg/L/week (P < 0.001) and a decrease of 0.18 (95% CI: −0.33 to −0.02) µg/L/week (P = 0.03) for vedolizumab. In 17 mother‐baby pairs, median infant vedolizumab levels at birth were lower than maternal levels (P < 0.05) with an infant:maternal ratio of 0.7 (IQR 0.5‐0.9). Vedolizumab was undetectable between 15 and 16 weeks of age in all 12 infants completing follow‐up testing. Conclusions During pregnancy, adalimumab levels remain stable, while infliximab levels increase and vedolizumab levels decrease. However, the increments were small suggesting that intrapartum therapeutic drug monitoring and dose adjustment are not indicated. Unlike infliximab and adalimumab, infant vedolizumab levels are lower in cord blood than in mothers and appear to clear rapidly.
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ItemAccuracy of point-of-care intestinal ultrasound for Crohn's disease.(Wiley, 2020-08)BACKGROUND: Point-of-care ultrasound (POCUS), performed by a gastroenterologist, provides safe and convenient imaging allowing for immediate clinical decision in Crohn's disease. The minimum training required to gain competency, its accuracy and clinical utility requires evaluation. METHODS: In this pilot study, Crohn's disease activity and extent were assessed using POCUS (performed by a single gastroenterologist following the completion of 200 supervised scans), magnetic resonance enterography (MRE) and ileo-colonoscopy. The presence of complications was assessed by POCUS and MRE. Accuracy of POCUS was analysed with respect to MRE and ileo-colonoscopy. Agreement between modalities was assessed using kappa coefficient. RESULTS: Forty-two patients had a POCUS paired with MRE. Thirty-eight patients had a POCUS paired with ileo-colonoscopy. When compared to MRE, POCUS was accurate in the assessment of disease activity (sensitivity 87.5%, specificity 61.1%, ROC 0.74), extent (sensitivity 77.8%, specificity 83.3%, ROC 0.81) and complications (sensitivity 85.7%, specificity 94.3%, ROC 0.90). Agreement between POCUS and MRE was moderate (kappa estimates 0.50, P < 0.001, 0.61, P < 0.001 and 0.76, P < 0.001) for disease activity, extent and complications, respectively. When compared to ileo-colonoscopy, POCUS was accurate in the assessment of disease activity (sensitivity 72%, specificity 86%, ROC 0.79) and extent (sensitivity 85.7%, specificity 86%, ROC 0.86). For POCUS and ileo-colonoscopy, kappa estimates were 0.55, P < 0.001 for disease activity and 0.62, P < 0.001 for disease extent. CONCLUSION: POCUS performed by a gastroenterologist after completion of limited training is accurate for assessing Crohn's disease activity, extent and the presence of complications.
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ItemLong-term outcomes of perianal fistulizing Crohn's disease in the biologic era(WILEY, 2020-12-20)While the advent of biologic therapy has led to improved outcomes in perianal fistulizing Crohn's disease (pfCD), loss of response is common. Previous studies suggest that patients who achieve radiological healing (with healing of underlying tracts on magnetic resonance imaging [MRI]) have a longer duration of response. The aim of this study was to characterize MRI outcomes of pfCD at a specialist inflammatory bowel disease (IBD) unit and compare the long‐term clinical outcomes between patients achieving MRI and clinical healing.
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ItemAddressing pregnancy-related concerns in women with inflammatory bowel disease: Insights from the patient's perspective(WILEY, 2021-01)BACKGROUND AND AIM: Therapeutic options for inflammatory bowel disease (IBD) have expanded, as has the use of IBD medications in women during the reproductive period. However, no qualitative data exist that examine the pregnancy-related concerns of women with IBD in the current era of widespread immunomodulator and biologic use. Hence, we aimed to explore in detail the impact of IBD on pregnancy from the patient's perspective. METHODS: This qualitative study used semistructured interviews to explore participants' experiences regarding IBD and pregnancy until no new themes emerged. Key themes were identified using thematic analysis. RESULTS: Fifteen women with IBD were interviewed. The majority of participants reported lingering concerns regarding their IBD medications, despite advice from their gastroenterologist that the drugs were considered safe in pregnancy. Participants more often reported medication-related fears, such as potential negative effects on their child's immune system, than concerns regarding the effect of the disease itself on their pregnancy outcomes. A common theme was a perceived lack of knowledge among non-IBD clinicians regarding IBD medications during pregnancy, which augmented pre-existing anxiety. CONCLUSIONS: This study is the first of its kind to provide an in-depth assessment of female patients' perspectives of IBD in relation to conception, pregnancy, and caring for offspring. In particular, this research characterizes the unique fears and persisting anxieties regarding IBD medications in pregnancy. The study has unearthed important insights into the specific concerns and support needs of women with IBD in order to facilitate nonjudgmental counseling designed around patient concerns and beliefs.
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ItemUstekinumab levels in pregnant women with inflammatory bowel disease and infants exposed in utero(WILEY, 2022-03)BACKGROUND: Ustekinumab is increasingly used in pregnant women with inflammatory bowel disease (IBD). Existing safety data are reassuring, but the stability of ustekinumab levels in pregnancy, degree of transfer to the infant and time to infant clearance are unknown. METHODS: In this prospective observational study, ustekinumab-exposed women with IBD had trough levels measured in each trimester of pregnancy and at delivery. Infant ustekinumab levels were measured at delivery and ongoing until clearance was achieved. Trough ustekinumab level stability in individuals across pregnancy was compared by Skillings-Mack test. Spearman coefficients were used to correlate maternal and infant delivery levels, and median time to infant ustekinumab clearance was defined. RESULTS: 19 pregnant women receiving ustekinumab were included. There was no difference in ustekinumab levels across pregnancy in those with two or more representative trough levels (P = 0.83, n = 11). Infant delivery ustekinumab levels were higher than maternal levels, with a median infant:maternal ratio of 1.79 (IQR 1.26-3.1). There was a positive correlation between maternal and infant delivery ustekinumab levels (r = 0.75, P = 0.001) and an inverse correlation between the number of days from final antenatal dose and delivery infant ustekinumab level (r = -0.65, P = 0.006). Median time of infant ustekinumab clearance was 9 (range 6-19) weeks (n = 9). CONCLUSION: Ustekinumab drug levels appear stable in pregnancy, with a delivery infant:maternal ratio similar to that of anti-TNFs. Infant ustekinumab clearance was complete by 20 weeks post-partum, however, infants exposed in utero should avoid live vaccination before 12 months of age until further clearance data are obtained.