The Impact of Autoimmune Hepatitis and Its Treatment on Health Utility

Patient reporting suggests that the physical and psychological effects of autoimmune hepatitis (AIH) can be substantial. However, health‐related quality of life (HRQOL) in patients with AIH remains incompletely characterized, and health utility remains to be explored. Treatment for AIH often includes the use of corticosteroids, which are agents that can be associated with significant adverse effects. Here we explore the impact of AIH and its treatments on patient‐reported HRQOL and health utility in a large cohort of prevalent cases from the United Kingdom Autoimmune Hepatitis (UK‐AIH) national study. Data were collected from 990 adult participants with a clinical diagnosis of AIH using validated HRQOL tools including the European Quality‐of‐Life 5‐Dimension 5‐Level (EQ‐5D‐5L) and clinical data forms. The EQ‐5D‐5L dimension scores were compared with UK population norms and with a disease control cohort with primary biliary cholangitis (PBC). Within the AIH cohort, regression analysis was used to explore associations between HRQOL and demographic and clinical variables with a particular focus on the impact of AIH therapies including corticosteroid use. HRQOL, measured by the EQ‐5D‐5L utility index, is shown to be significantly impaired in our cohort of AIH patients compared with population norms. Within the AIH cohort, corticosteroid use was found to be significantly associated with impaired HRQOL, even when controlling for biochemical disease activity status. Conclusion: Our data show evidence of HRQOL impairment in a large cohort of AIH patients compared with the general population. Furthermore, corticosteroid use is strongly associated with decreased HRQOL, independent of remission status. This highlights the need for better corticosteroid‐free therapy approaches and it emphasizes the need for future novel therapeutic trials in AIH

The inter-relationship of symptom severity and quality of life in 2055 patients with primary biliary cholangitis

BackgroundAge at presentation with primary biliary cholangitis (PBC) is associated with differ-ential response to ursodeoxycholic acid (UDCA) therapy. Younger-presentingpatients are less likely to respond to treatment and more likely to need transplantor die from the disease. PBC has a complex impact on quality of life (QoL), withsystemic symptoms often having significant impact.AimTo explain the impact of age at presentation on perceived QoL and the inter-related symptoms which impact upon it.MethodsUsing the UK-PBC cohort, symptoms were assessed using the PBC-40 and othervalidated tools. Data were available on 2055 patients.ResultsOf the 1990 patients reporting a global PBC-QoL score, 66% reported good/neutralscores and 34% reported poor scores. Each 10-year increase in age at presentationwas associated with a 14% decrease in risk of poor perceived QoL (OR = 0.86,95% CI: 0.75–0.98, P < 0.05). All sympto m domains were similarly age-associated(P < 0.01). Social dysfunction was the symptom factor with the greatest impa ct onQoL. Median (interquartile range) PBC-40 social scores for patient s with good per-ceived QoL were 18 (14–23) compared with 34 (29–39) for those with poor QoL.ConclusionThe majo rity of patients with primary biliary cholangitis do not feel their QoL isimpaired, although impairment is reported by a sizeable minority. Age at presenta-tion is associated with impact on per ceived QoL and the symptoms impairing it,with younger patients being more affected. Social dysfunction makes the greatestcontribution to QoL impairment, and it should be targeted in trials aimed atimproving life quality

Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab

Context: Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumour syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterised by MMR-deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade by pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC. Case report: A 58-year old female with known Lynch syndrome who presented with severe Cushing’s syndrome was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolaemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after twelve weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. Seven weeks later, the patient became jaundiced and died rapidly with fulminant liver failure. Conclusion: Treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supra-physiological levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage

Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients

Regulation of immune responses in primary biliary cholangitis: a transcriptomic analysis of peripheral immune cells

Copyright \ua9 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.Background & Aims: In patients with primary biliary cholangitis (PBC), the serum liver biochemistry measured during treatment with ursodeoxycholic acid-the UDCA response-accurately predicts long-term outcome. Molecular characterization of patients stratified by UDCA response can improve biological understanding of the high-risk disease, thereby helping to identify alternative approaches to disease-modifying therapy. In this study, we sought to characterize the immunobiology of the UDCA response using transcriptional profiling of peripheral blood mononuclear cell subsets. Methods: We performed bulk RNA-sequencing of monocytes and TH1, TH17, TREG, and B cells isolated from the peripheral blood of 15 PBC patients with adequate UDCA response (“responders”), 16 PBC patients with inadequate UDCA response (“nonresponders”), and 15 matched controls. We used the Weighted Gene Co-expression Network Analysis to identify networks of co-expressed genes (“modules”) associated with response status and the most highly connected genes (“hub genes”) within them. Finally, we performed a Multi-Omics Factor Analysis of the Weighted Gene Co-expression Network Analysis modules to identify the principal axes of biological variation (“latent factors”) across all peripheral blood mononuclear cell subsets. Results: Using the Weighted Gene Co-expression Network Analysis, we identified modules associated with response and/or disease status (q < 0.05) in each peripheral blood mononuclear cell subset. Hub genes and functional annotations suggested that monocytes are proinflammatory in nonresponders, but antiinflammatory in responders; TH1 and TH17 cells are activated in all PBC cases but better regulated in responders; and TREG cells are activated-but also kept in check-in responders. Using the Multi-Omics Factor Analysis, we found that antiinflammatory activity in monocytes, regulation of TH1 cells, and activation of TREG cells are interrelated and more prominent in responders. Conclusions: We provide evidence that adaptive immune responses are better regulated in patients with PBC with adequate UDCA response

The inter-relationship of symptom severity and quality of life in 2055 patients with primary biliary cholangitis.

BACKGROUND: Age at presentation with primary biliary cholangitis (PBC) is associated with differential response to ursodeoxycholic acid (UDCA) therapy. Younger-presenting patients are less likely to respond to treatment and more likely to need transplant or die from the disease. PBC has a complex impact on quality of life (QoL), with systemic symptoms often having significant impact. AIM: To explain the impact of age at presentation on perceived QoL and the inter-related symptoms which impact upon it. METHODS: Using the UK-PBC cohort, symptoms were assessed using the PBC-40 and other validated tools. Data were available on 2055 patients. RESULTS: Of the 1990 patients reporting a global PBC-QoL score, 66% reported good/neutral scores and 34% reported poor scores. Each 10-year increase in age at presentation was associated with a 14% decrease in risk of poor perceived QoL (OR = 0.86, 95% CI: 0.75-0.98, P < 0.05). All symptom domains were similarly age-associated (P < 0.01). Social dysfunction was the symptom factor with the greatest impact on QoL. Median (interquartile range) PBC-40 social scores for patients with good perceived QoL were 18 (14-23) compared with 34 (29-39) for those with poor QoL. CONCLUSION: The majority of patients with primary biliary cholangitis do not feel their QoL is impaired, although impairment is reported by a sizeable minority. Age at presentation is associated with impact on perceived QoL and the symptoms impairing it, with younger patients being more affected. Social dysfunction makes the greatest contribution to QoL impairment, and it should be targeted in trials aimed at improving life quality

The Dichotomous Pattern of IL-12R and IL-23R Expression Elucidates the Role of IL-12 and IL-23 in Inflammation

IL-12 and IL-23 cytokines respectively drive Th1 and Th17 type responses. Yet, little is known regarding the biology of these receptors. As the IL-12 and IL-23 receptors share a common subunit, it has been assumed that these receptors are co-expressed. Surprisingly, we find that the expression of each of these receptors is restricted to specific cell types, in both mouse and human. Indeed, although IL-12Rβ2 is expressed by NK cells and a subset of γδ T cells, the expression of IL-23R is restricted to specific T cell subsets, a small number of B cells and innate lymphoid cells. By exploiting an IL-12- and IL-23-dependent mouse model of innate inflammation, we demonstrate an intricate interplay between IL-12Rβ2 NK cells and IL-23R innate lymphoid cells with respectively dominant roles in the regulation of systemic versus local inflammatory responses. Together, these findings support an unforeseen lineage-specific dichotomy in the in vivo role of both the IL-12 and IL-23 pathways in pathological inflammatory states, which may allow more accurate dissection of the roles of these receptors in chronic inflammatory diseases in humans