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.

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, especially 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: 15 studies of patients established ≥3 months on IV infliximab were identified, 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), and perianal CD p=0.55 & p=0.11 at 9-12 months, and p=0.50 at 6 months respectively). Neither prior IV dose (≤10mg/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 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 10mg/kg 6-weekly. This data should provide patients and clinicians alike with confidence in SC infliximab use in IBD.

Prevalence and sociodemographic determinants of dyspepsia in the general population of Rwanda.

INTRODUCTION: Dyspepsia accounts for a significant burden of worldwide disease, but there is a relative paucity of data from the sub-Saharan African setting. We undertook to describe the burden, risk factors and severity of dyspepsia across Rwanda. METHODS: We performed a population-based clustered cross-sectional survey between November 2015 and January 2016, nationwide in Rwanda, using the Short Form Leeds Dyspepsia Questionnaire to describe the presence and severity of dyspepsia, and the Short Form Nepean Dyspepsia Index to describe the concomitant quality of life effects. Univariate and multivariate logistic regression models were constructed to correlate measured sociodemographic factors with dyspepsia. RESULTS: The prevalence of clinically significant dyspepsia in the general Rwandan population was 14.2% (283/2000). The univariate factors that significantly predicted severity were gender, profession, socioeconomic status, and non-steroidal anti-inflammatory drug, aspirin and alcohol use, with gender, current smoking, aspirin use both in the past and currently, and alcohol use in the past remaining significant on multivariate modelling. Dyspeptics had a significantly lower gastrointestinal-related quality of life, though the sociodemographic factors measured did not modify the observed quality of life. CONCLUSION: Dyspepsia is prevalent in the Rwandan setting and is associated with a significant burden on quality of life. More work is required to determine the pathological entities involved, and the optimal approach to mitigating this burden.

Systematic review: the etiology of esophageal squamous cell carcinoma in low-income settings.

INTRODUCTION: Esophageal carcinoma causes over 380 000 deaths per year, ranking sixth worldwide in mortality amongst all malignancies. Globally, the squamous cell subtype is most common and accounts for 80% of esophageal cancers. Nonetheless, esophageal squamous cell carcinoma is much more poorly understood than esophageal adenocarcinoma, including what is driving such high prevalences, why it often presents in young patients, and shows such marked geographical delineations Areas covered: The current literature was searched for articles focusing on aetiopathogenesis of squamous cell esophageal carcinoma via a systematic review, particularly in low-resource settings. This was supplemented by papers of interest known to the authors. Expert commentary: Current putative mechanisms include polycyclic aromatic hydrocarbons, nitrosamines, acetaldehyde, cyclo-oxygenase-2 pathways, androgen and their receptor levels, as well as smoking & alcohol, micronutrient deficiencies and diet, mycotoxins, thermal damage, oral hygiene and microbiotal factors, inhaled smoke, viral infections such as HPV, and chronic irritative states. Etiology is likely multifactorial and varies geographically. Though smoking and alcohol play a predominant role in high-income settings, there is strong evidence that mycotoxins, diet and temperature effects may play an under-recognized role in low and middle-income settings.

Five-year single-centre experience of carcinoma of the oesophagus from Blantyre, Malawi.

BACKGROUND: Oesophageal squamous cell carcinoma (OSCC) is increasing worldwide and has an exceptionally high prevalence in certain distinct geographical locations such as the African oesophageal SCC corridor. Despite this, there is a paucity of evidence to characterise the disease particularly in the Malawian context. METHOD: We retrospectively audited our endoscopy database over 5 years, including for patient demographics, endoscopy findings, therapeutic intervention and recommendations for treatment. RESULTS: 1586 patients with oesophageal cancer were identified from a total of 5882 endoscopy records from 2013 to 2017. Our cohort showed a larger proportion of oesophageal cancers found higher in the oesophagus compared with other African studies and a female preponderance in this upper-oesophagus disease subset though a male preponderance overall. 39% of patients with oesophageal cancer underwent bougie dilatation and 11% underwent palliative stent placement, which likely reflects local availability of resources. CONCLUSION: This study validates the observation that OSCC predominates in sub-Saharan Africa in Malawi over other forms of oesophageal carcinoma, though our cohort appears to have subtly distinct demographics and disease-specific data. This highlights the need to prioritise preventative and therapeutic strategies for OSCC in this and similar settings.