Consensus Statements on Assessments and Vaccinations Prior to Commencement of Advanced Therapies for the Treatment of Inflammatory Bowel Diseases.

BACKGROUND: Given the introduction of new advanced therapies for inflammatory bowel diseases (IBDs), expanded risk mitigation strategies are essential. AIMS: To create a comprehensive set of statements on assessment procedures and vaccinations before starting monoclonal antibodies, Janus kinase (JAK) inhibitors or sphingosine-1-phosphate (S1P) modulators for IBD. METHODS: We examined literature, guidelines and drug product information regarding vaccination and assessment recommendations for initiating advanced IBD therapies. Using a modified Delphi approach, delegates voted anonymously on the acceptability of these statements prior to and following consensus discussion. RESULTS: We developed eight statements on the domains of infectious diseases screening, vaccinations and assessments prior to commencing JAK inhibitors and S1P modulators. Six statements received agreement. Pre-advanced therapy screening for infectious diseases was established, and the vaccination protocol was revised. Malignancy, cardiovascular and thromboembolic risk assessments are necessary before initiating JAK inhibitors. Those starting S1P modulators need cardiac and ophthalmic assessments. CONCLUSIONS: These consensus statements combine vaccination and assessments on the currently available advanced therapies for IBD as a single comprehensive document that may reduce IBD complications associated with use of advanced therapies. Knowledge gaps identified during the consensus process will provide further research opportunities.

Genital rash: A manifestation of metastatic Crohn's disease.

Metastatic Crohn's disease is the rarest cutaneous manifestation of Crohn's disease, it presents as cutaneous lesions in areas that are anatomically non-contiguous with the gastrointestinal tract. It requires a high index of suspicion for diagnosis which is confirmed on histopathology. Infliximab can be an effective treatment.

A tale of two studies: is peripheral eosinophilia associated with Dientamoeba fragilis detection in adult stool samples?

The protozoan parasite Dientamoeba fragilis is a frequently isolated stool organism and postulated cause of gastrointestinal symptoms. Peripheral blood eosinophilia has been described. This is the first study amongst the Australasian adult population to assess the relationship between organism detection and eosinophilia. A case-control study took place over 7 years at a single Sydney laboratory site, evaluating patients with D. fragilis identified on stool using real-time PCR with a recent full blood count, to control groups with Giardia spp. and sequential negatives with neither organism. A nested study compared those with microscopic evidence of D. fragilis as a marker of disease burden, to molecular diagnosis alone. Sixty-four D. fragilis, 30 Giardia spp., and 94 sequential controls were enrolled. Only 60.1% of samples were preserved in sodium acetate-acetic acid formalin (SAF) fixative, indication mostly not documented. The major co-organism detected amongst all participants was Blastocystis sp., particularly in the D. fragilis cohort (37.2%). The most common pathogen amongst sequential controls was Campylobacter spp. (7.4%). Patients with D. fragilis were more likely (12.5%) to have a clinically significant eosinophilia (>0.5×109/L) compared to those with Giardia spp. (3.3%) or sequential controls (4.3%) (p=0.03). A significant difference was also noted in the overall median eosinophil count of those with D. fragilis versus all controls (0.2 vs 0.1×109/L, p=0.01); however, this was within the reference interval (where up to >0.5×109/L is accepted in healthy individuals within a typical population). No eosinophil difference was found between those with molecular versus additional microscopic detection of D. fragilis (0.1 vs 0.1×109/L). These results support an association between the identification of clinically significant peripheral blood eosinophilia and D. fragilis presence, which may impact the diagnostic approach to the patient with unexplained eosinophilia. Further prospective trials may help assess any significance further and the implication of co-carriage with other enteric organisms. The importance of clinical indication and need for appropriate fixative media in diagnostic parasitology are also highlighted.

Incidence, epidemiology, and outcomes of acute allograft rejection following liver transplantation in Australia.

Acute allograft rejection is a well-known complication of liver transplantation (LT). The incidence, epidemiology, and outcomes of acute rejection have not been well described in Australia. We retrospectively studied consecutive adults who underwent deceased donor LT at a single center between 2010 and 2020. Donor and recipient data at the time of LT and recipient outcomes were collected from a prospective LT database. Liver biopsy reports were reviewed, and only a graft's first instance of biopsy-proven acute rejection was analyzed. During the study period, 796 liver transplants were performed in 770 patients. Biopsy-proven rejection occurred in 34.9% of transplants. There were no significant changes in the incidence of rejection over time (linear trend p =0.11). The median time to the first episode of rejection was 71 days after LT: 2.2% hyperacute, 50.4% early (≤90 d), and 47.5% late rejection (>90 d). Independent risk factors for rejection were younger recipient age at transplant (aHR 0.98 per year increase, 95% CI: 0.97-1.00, p =0.01), and ABO-incompatible grafts (aHR 2.55 vs. ABO-compatible, 95% CI: 1.27-5.09, p <0.01) while simultaneous multiorgan transplants were protective (aHR 0.21 vs. LT only, 95% CI: 0.08-0.58, p <0.01). Development of acute rejection (both early and late) was independently associated with significantly reduced graft (aHR 3.13, 95% CI: 2.21-4.42, p <0.001) and patient survival (aHR 3.42, 95% CI: 2.35-4.98, p <0.001). In this 11-year Australian study, acute LT rejection occurred in 35%, with independent risk factors of younger recipient age and ABO-incompatible transplant, while having a simultaneous multiorgan transplant was protective. Acute rejection was independently associated with reduced graft and patient survival after adjustment for other factors.

Intravenous Versus Subcutaneous Infliximab in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Subcutaneous [SC] infliximab may provide multiple benefits over intravenous [IV] formulations. However, studies for efficacy and safety in inflammatory bowel disease [IBD] have been constrained by small sizes that limit the interpretation of outcomes, particularly for subgroups potentially at high risk of disease relapse. METHODS: We conducted a systematic review and random-effects meta-analysis up to January 2023, to evaluate the change in clinical remission after transitioning from IV to SC infliximab in patients with IBD in clinical remission. The primary outcome was measured using the relative risk for meta-analysis. RESULTS: We identified 15 studies of patients established ≥ 3 months on IV infliximab, consisting of 1371 patients and 840 patient-years of follow-up. There was no loss of clinical remission in the IBD cohort overall, Crohn's disease [CD], or perianal CD [p = 0.55 and p = 0.11 at 9-12 months, and p = 0.50 at 6 months, respectively]. Neither prior IV dose [≤ 10 mg/kg 6-weekly] [p = 0.48] nor IBD disease subtype was associated with an increased clinical relapse rate at 6 months (p = 0.48 and p = 0.45 [UC vs CD], respectively). CONCLUSION: Changing patients established on IV infliximab to an SC formulation is associated with a high ongoing clinical remission and a low adverse event rate. Furthermore, there are no signals for adverse outcomes among different IBD disease subtypes, nor in those on escalated IV infliximab dosing schedules up to 10 mg/kg 6-weekly. These data should provide patients and clinicians alike with confidence in SC infliximab use in IBD.

Paraneoplastic gastrointestinal dysmotility due to non-Hodgkin diffuse large B cell lymphoma: a case report.

Paraneoplastic gastrointestinal dysmotility is a rare entity which occurs in association with malignancy. We present the second case associated with lymphoma, characterised by generalised gastrointestinal dysmotility with constipation, malnutrition, weight loss, and capsule endoscope retention. This case highlights the importance of maintaining a high index of suspicion for malignancy in patients with unexplained gastrointestinal dysmotility.

Biological Agents in the Treatment of Crohn's Disease: A Propensity Score-Matched Analysis From the Prospective Persistence Australian National IBD Cohort (PANIC3) Study.

INTRODUCTION: Comparative effectiveness research provides data on the relative benefits and risks between treatments. In Crohn's disease (CD), however, there are few head-to-head studies comparing advanced therapies and none with long-term follow-up. Real-world effectiveness, defined by treatment persistence, obtained from prospective population-based patient cohorts, may help determine the best sequencing and positioning of biological agents. METHODS: We analyzed the prospectively collected population-based Australian national Pharmaceutical Benefits Scheme dispensing data registry (2005-2019) for CD. There is no mandated biological agent prescribing order, and all citizens and permanent residents are eligible for treatment irrespective of insurance status. Propensity score matching was performed to reduce selection bias. RESULTS: There were 2,029 lines of therapy in 1,446 patients (median age 43 years, interquartile range 34-58, 44% male patients) over the 15-year period with 5,618 patient-years of follow-up. Per line of therapy, 915/2,029 (45.1%) patients used adalimumab, 722/2,029 (35.6%) used infliximab, 155/2,029 (7.6%) used vedolizumab, and 237/2,029 (11.7%) used ustekinumab. When used in biological agent-naive patients, there was no difference in persistence between any agent ( P > 0.05). Used after first line in biological agent-experienced CD, ustekinumab had significantly better persistence than non-ustekinumab biological agents ( P = 0.0018), vs anti-tumor necrosis factor (TNF) alpha therapy ( P = 0.006) or vedolizumab ( P < 0.001). Ustekinumab persistence was unaffected by prior biological agent exposure ( P = 0.51). After anti-TNF use, ustekinumab had superior persistence to an alternative anti-TNF agent ( P = 0.033) and to vedolizumab ( P = 0.026). Using a propensity score-matched analysis adjusted for age, immunomodulator use, and bio-exposed status, ustekinumab had superior persistence to anti-TNF ( P = 0.01). Multivariate predictors of worse persistence were the use of a non-ustekinumab biological agent (adjusted hazard ratio 2.10, P < 0.001), and bio-experienced status (adjusted hazard ratio 1.23, P < 0.001). DISCUSSION: This large national prospective database with nonhierarchical prescribing of biological agents did not identify superior persistence of any agent in bio-naive CD. However, for patients with bio-experienced CD, persistence was greater with ustekinumab.

Epidemiology, characteristics, and outcomes of patients with acute-on-chronic liver failure in Australia.

BACKGROUND AND AIM: Acute-on-chronic liver failure (ACLF) is distinct from acute decompensation (AD) of cirrhosis in its clinical presentation, pathophysiology, and prognosis. There are limited published Australian ACLF data. METHODS: We performed a single-center retrospective cohort study of all adults with cirrhosis admitted with a decompensating event to a liver transplantation (LT) centre between 2015 and 2020. ACLF was defined using the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) definition while those who did not meet the definition were classified as AD. The primary outcome of interest was 90-day LT-free survival. RESULTS: A total of 615 patients had 1039 admissions for a decompensating event. On their index admission, 34% (209/615) of patients were classified as ACLF. Median admission model for end-stage liver disease (MELD) and MELD-Na scores were higher in ACLF patients compared with AD (21 vs 17 and 25 vs 20 respectively, both P < 0.001). Both the presence and severity of ACLF (grade ≥ 2) significantly predicted worse LT-free survival compared with patients with AD. The EASL-CLIF ACLF score (CLIF-C ACLF), MELD and MELD-Na scores performed similarly in predicting 90-day mortality. Patients with index ACLF had a higher risk of 28-day mortality (28.1% vs 5.1%, P < 0.001) and shorter times to readmission compared with those with AD. CONCLUSION: ACLF complicates over a third of hospital admissions for cirrhosis with decompensating events and is associated with a high short-term mortality. The presence and grade of ACLF predicts 90-day mortality and should be identified as those at greatest risk of poor outcome without intervention such as LT.

Knowledge and attitudes towards the use of histological assessments in ulcerative colitis by gastroenterologists vs pathologists.

BACKGROUND: Histological remission is increasingly accepted as a treatment endpoint in the management of ulcerative colitis (UC). However, the knowledge of histology guidelines and the attitudes towards their use in clinical practice by gastroenterologists and pathologists is unknown. AIM: To evaluate the knowledge of histology guidelines and attitudes towards the use of histology in UC by gastroenterologists and pathologists. METHODS: A prospective, cross-sectional nationwide survey of gastroenterologists and pathologists who analyse UC specimens was conducted. The survey consisted of 34 questions to assess gastroenterologists' and pathologists' knowledge (score out of 19) and attitudes towards histological assessment in UC. Survey questions were formulated using the European Crohn's and Colitis position paper on histopathology and the British Society of Gastroenterology biopsy reporting guidelines. It included knowledge of histological assessment of disease activity and dysplasia, knowledge of histological scoring systems for ulcerative colitis, uptake of histology scoring systems in routine practice, attitudes towards the role of histological activity, and the use of histological activity in clinical scenarios. RESULTS: Of 89 responders (77 gastroenterologists, 12 pathologists), there was almost universal acceptance that histological assessment should form part of UC evaluation [95% gastroenterologists, 92% pathologists]. However, gastroenterologists reported that 92% of their pathologists do not use a histological scoring system. Utilisation of a formal histological scoring system was preferred by 77% of gastroenterologists and 58% of pathologists. Both groups lacked awareness of the Geboes Score, Nancy Index and Robarts Histopathological Index scoring systems with 91%, 87%, and 92% of gastroenterologists respectively; and 83%, 83%, and 92% pathologists respectively, being uncertain of scoring systems' remission definitions. Histology knowledge score was not significantly different between gastroenterologists and pathologists [9/19 (IQR: 8-11) vs 8/19 (IQR: 7-10), P = 0.54]. Higher knowledge scores were predicted by hospital attending gastroenterologists (P = 0.004), participation in inflammatory bowel disease (IBD) multidisciplinary teams (P = 0.009), and self-declared IBD sub-specialist (P = 0.03). CONCLUSION: Histological remission is a recognised target for both gastroenterologists and pathologists. Despite this, knowledge of histological scoring systems and their utilisation is poor.

Surgical considerations in cystic fibrosis: what every general surgeon needs to know.

Cystic fibrosis (CF) is a complex multiorgan disease, which often affects the gastrointestinal tract. With improved CF specific therapies and multidisciplinary management, patients with CF are now living longer with a median life expectancy of around 50 years. This increased life expectancy has resulted in corresponding increase in presentations of the CF patient with comorbid surgical conditions that were never important considerations. Investigations and management of these conditions, such as distal intestinal obstruction syndrome and colorectal cancer warrant good clinical understanding of the unique challenges that CF patients present including chronic immunosuppression, impaired respiratory function and their multi-organ dysfunction. The purpose of this review is to provide general surgeons with a contemporary update on the CF related surgical issues as they are likely to become increasingly involved in the care of these complex patients and form an integral part of the multidisciplinary team.

MELD-GRAIL and MELD-GRAIL-Na Are Not Superior to MELD or MELD-Na in Predicting Liver Transplant Waiting List Mortality at a Single-center Level.

Background: Controversy exists regarding the best predictive model of liver transplant waiting list (WL) mortality. Models for end-stage liver disease-glomerular filtration rate assessment in liver disease (MELD-GRAIL) and MELD-GRAIL-Na were recently described to provide better prognostication, particularly in females. We evaluated the performance of these scores compared to MELD and MELD-Na. Methods: Consecutive patients with cirrhosis waitlisted for liver transplant from 1998 to 2017 were examined in this single-center study. The primary outcome was 90-d WL mortality. MELD, MELD-Na, MELD-GRAIL, and MELD-GRAIL-Na at the time of WL registration were compared. Model discrimination was assessed with area under the receiver operating characteristic curves and Harrell's C-index after fitting Cox models. Model calibration was examined with Grønnesby and Borgan's modification of the Hosmer-Lemeshow formula and by comparing predicted/observed outcomes across model strata. Results: The study population comprised 1108 patients with a median age of 53.5 (interquartile range 48-59) y and male predominance (74.9%). All models had excellent areas under the receiver operating characteristic curves for the primary outcome (MELD 0.89, MELD-Na 0.91, MELD-GRAIL 0.89, MELD-GRAIL-Na 0.89; all comparisons P > 0.05). Youden index cutoffs for 90-d mortality were as follows: MELD, 19; MELD-Na, 22; MELD-GRAIL, 18; and MELD-GRAIL-Na, 17. Variables associated with 90-d mortality on multivariable Cox regression were sodium, bilirubin, creatinine, and international normalized ratio. There were no differences in model discrimination using Harrell's C-index. All models were well calibrated; however, divergence between observed and predicted mortality was noted with scores ≥25. Conclusion: There were no demonstrable differences in discrimination or calibration of GRAIL-based models compared with MELD or MELD-Na in our cohort. This suggests that GRAIL-based models may not have meaningful improvements in discriminatory ability when applied to other settings.

Ovary unusual colonic lesion.

We describe an unusual endoscopic finding, caused by a dominant ovarian follicle compressing a low-lying ascending colon just inferior to a patulous retroverted cecum. Endoscopically detected extra-colonic lesions represent a diverse group of pathologies, and it is important the endoscopist has an appreciation of the varied number of benign and malignant causes-including those of gynecological origin.

Drug-induced liver injury in Australia, 2009-2020: the increasing proportion of non-paracetamol cases linked with herbal and dietary supplements.

OBJECTIVE: To compare the characteristics and outcomes of drug-induced liver injury (DILI) caused by paracetamol and non-paracetamol medications, particularly herbal and dietary supplements. DESIGN: Retrospective electronic medical record data analysis. SETTING, PARTICIPANTS: Adults admitted with DILI to the Gastroenterology and Liver Centre at the Royal Prince Alfred Hospital, Sydney (a quaternary referral liver transplantation centre), 2009-2020. MAIN OUTCOME MEASURES: 90-day transplant-free survival; drugs implicated as causal agents in DILI. RESULTS: A total of 115 patients with paracetamol-related DILI and 69 with non-paracetamol DILI were admitted to our centre. The most frequently implicated non-paracetamol medications were antibiotics (19, 28%), herbal and dietary supplements (15, 22%), anti-tuberculosis medications (six, 9%), and anti-cancer medications (five, 7%). The number of non-paracetamol DILI admissions was similar across the study period, but the proportion linked with herbal and dietary supplements increased from 2 of 13 (15%) during 2009-11 to 9 of 19 (47%) during 2018-20 (linear trend: P = 0.011). Despite higher median baseline model for end-stage liver disease (MELD) scores, 90-day transplant-free survival for patients with paracetamol-related DILI was higher than for patients with non-paracetamol DILI (86%; 95% CI, 79-93% v 71%; 95% CI, 60-82%) and herbal and dietary supplement-related cases (59%; 95% CI, 34-85%). MELD score was an independent predictor of poorer 90-day transplant-free survival in both paracetamol-related (per point increase: adjusted hazard ratio [aHR], 1.19; 95% CI, 1.09-3.74) and non-paracetamol DILI (aHR, 1.24; 95% CI, 1.14-1.36). CONCLUSION: In our single centre study, the proportion of cases of people hospitalised with DILI linked with herbal and dietary supplements has increased since 2009. Ninety-day transplant-free survival for patients with non-paracetamol DILI, especially those with supplement-related DILI, is poorer than for those with paracetamol-related DILI.