The Epidemiology of UK Autoimmune Liver Disease Varies With Geographic Latitude.

BACKGROUND & AIMS: The epidemiology of autoimmune liver disease (AILD) is challenging to study because of the diseases' rarity and because of cohort selection bias. Increased incidence farther from the Equator has been reported for multiple sclerosis, another autoimmune disease. We assessed the incidence of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) in relation to latitude. METHODS: We performed a retrospective cohort study using anonymized UK primary care records from January 1, 2002, to May 10, 2016. All adults without a baseline diagnosis of AILD were included and followed up until the first occurrence of an AILD diagnosis, death, or they left the database. Latitude was measured as registered general practice rounded down to whole degrees. RESULTS: The cohort included 8,590,421 records with 53.3 × 107 years of follow-up evaluation from 694 practices. There were 1314 incident cases of PBC, 396 of PSC, and 1034 of AIH. Crude incidences were as follows: PBC, 2.47 (95% CI, 2.34-2.60); PSC, 0.74 (95% CI, 0.67-0.82); and AIH, 1.94 (95% CI, 1.83-2.06) per 100,000 per year. PBC incidence correlated with female sex, smoking, and deprivation; PSC incidence correlated with male sex and non-smoking; AIH incidence correlated with female sex and deprivation. A more northerly latitude was associated strongly with incidence of PBC: 2.16 (95% CI, 1.79-2.60) to 4.86 (95% CI, 3.93-6.00) from 50°N to 57°N (P = .002) and incidence of AIH: 2.00 (95% CI, 1.65-2.43) to 3.28 (95% CI, 2.53-4.24) (P = .003), but not incidence of PSC: 0.82 (95% CI, 0.60-1.11) to 1.02 (95% CI, 0.64-1.61) (P = .473). Incidence after adjustment for age, sex, smoking, and deprivation status showed similar positive correlations for PBC and AIH with latitude, but not PSC. Incident AIH cases were younger at more northerly latitude. CONCLUSIONS: We describe an association in the United Kingdom between more northerly latitude and the incidence of PBC and AIH that requires both confirmation and explanation.

Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study.

BACKGROUND: Despite concerns that patients with liver transplants might be at increased risk of adverse outcomes from COVID-19 because of coexisting comorbidities and use of immunosuppressants, the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on this patient group remains unclear. We aimed to assess the clinical outcomes in these patients. METHODS: In this multicentre cohort study, we collected data on patients with laboratory-confirmed SARS-CoV-2 infection, who were older than 18 years, who had previously received a liver transplant, and for whom data had been submitted by clinicians to one of two international registries (COVID-Hep and SECURE-Cirrhosis) at the end of the patient's disease course. Patients without a known hospitalisation status or mortality outcome were excluded. For comparison, data from a contemporaneous cohort of consecutive patients with SARS-CoV-2 infection who had not received a liver transplant were collected from the electronic patient records of the Oxford University Hospitals National Health Service Foundation Trust. We compared the cohorts with regard to several outcomes (including death, hospitalisation, intensive care unit [ICU] admission, requirement for intensive care, and need for invasive ventilation). A propensity score-matched analysis was done to test for an association between liver transplant and death. FINDINGS: Between March 25 and June 26, 2020, data were collected for 151 adult liver transplant recipients from 18 countries (median age 60 years [IQR 47-66], 102 [68%] men, 49 [32%] women) and 627 patients who had not undergone liver transplantation (median age 73 years [44-84], 329 [52%] men, 298 [48%] women). The groups did not differ with regard to the proportion of patients hospitalised (124 [82%] patients in the liver transplant cohort vs 474 [76%] in the comparison cohort, p=0·106), or who required intensive care (47 [31%] vs 185 [30%], p=0·837). However, ICU admission (43 [28%] vs 52 [8%], p<0·0001) and invasive ventilation (30 [20%] vs 32 [5%], p<0·0001) were more frequent in the liver transplant cohort. 28 (19%) patients in the liver transplant cohort died, compared with 167 (27%) in the comparison cohort (p=0·046). In the propensity score-matched analysis (adjusting for age, sex, creatinine concentration, obesity, hypertension, diabetes, and ethnicity), liver transplantation did not significantly increase the risk of death in patients with SARS-CoV-2 infection (absolute risk difference 1·4% [95% CI -7·7 to 10·4]). Multivariable logistic regression analysis showed that age (odds ratio 1·06 [95% CI 1·01 to 1·11] per 1 year increase), serum creatinine concentration (1·57 [1·05 to 2·36] per 1 mg/dL increase), and non-liver cancer (18·30 [1·96 to 170·75]) were associated with death among liver transplant recipients. INTERPRETATION: Liver transplantation was not independently associated with death, whereas increased age and presence of comorbidities were. Factors other than transplantation should be preferentially considered in relation to physical distancing and provision of medical care for patients with liver transplants during the COVID-19 pandemic. FUNDING: European Association for the Study of the Liver, US National Institutes of Health, UK National Institute for Health Research.

The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure.

Acetaminophen (APAP) is the main cause of acute liver failure in the West. Specific efficacious therapies for acute liver failure (ALF) are limited and time-dependent. The mechanisms that drive irreversible acute liver failure remain poorly characterized. Here we report that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage after toxic liver injury. Our data demonstrate that blocking platelet CLEC-2 signalling enhances liver recovery from acute toxic liver injuries (APAP and carbon tetrachloride) by increasing tumour necrosis factor-α (TNF-α) production which then enhances reparative hepatic neutrophil recruitment. We provide data from humans and mice demonstrating that platelet CLEC-2 influences the hepatic sterile inflammatory response and that this can be manipulated for therapeutic benefit in acute liver injury. Since CLEC-2 mediated platelet activation is independent of major haemostatic pathways, blocking this pathway represents a coagulopathy-sparing, specific and novel therapy in acute liver failure.

No Gains in Long-term Survival After Liver Transplantation Over the Past Three Decades.

OBJECTIVE: The aim of this study was to assess improvements in long-term survival after liver transplant by analyzing outcomes in transplant recipients who survived beyond 1 year. SUMMARY OF BACKGROUND DATA: Gains in short-term survival following liver transplantation have been gratifying. One-year survival in 1986 was 66% improved to over 92% in 2015. However, little is known about why long-term has not seen similar success. METHODS: We analyzed 111,568 recipients from 1987 to 2016 using the Kaplan-Meier method for time-to-event analysis and multivariable Cox regression. RESULTS: There were no significant gains in unadjusted long-term outcomes among 1-year survivors over the past 30 years. Only the time periods of 1987 to 1990 [hazard ratio (HR) 1.35, confidence interval CI) 1.28-1.42] and 1991 to 1995 (HR 1.17, CI 1.13-1.21) had a minor increase in risk compared with the period 2011 to 2016. Cause of death analysis suggests malignancy after transplantation is a growing problem and preventing recurrent hepatitis C with direct-acting antivirals (DDAs) may only have a limited impact. Furthermore, rejection leading to graft failure and death had a rare occurrence (1.7% of long-term deaths) especially when compared with the sequelae of long-term immunosuppression: malignancy (16.4%), nonrejection graft failure (9.8%), and infection (10.5%) (P < 0.001). CONCLUSION: In stark contrast to short-term survival, there have been no appreciable improvements in long-term survival following liver transplantation among 1-year survivors. Long-term sequelae of immunosuppression, including malignancy and infection, are the most common causes of death. This study highlights the need for better long-term immunosuppression management.

Work in Progress: Drugs in Development.

Primary biliary cholangitis is an archetypal autoimmune disease that causes cholestasis, fibrosis, and liver failure. Ursodeoxycholic acid and obeticholic acid are approved for its treatment. Not all patients respond, some are intolerant, many have ongoing symptoms, and new therapies are required. Herein we describe drugs in development and potential future biological targets. We consider compounds acting on the farnesoid X receptor/fibroblast growth factor 19 pathway, fibrates and other agonists of the peroxisome proliferator-activated receptor family, transmembrane-G-protein-receptor-5 agonists, and several immunological agents. We also consider the roles of bile acid reuptake inhibitors, nalfurafine, and fibrates in pruritus management.

Concurrent OX40 and CD30 Ligand Blockade Abrogates the CD4-Driven Autoimmunity Associated with CTLA4 and PD1 Blockade while Preserving Excellent Anti-CD8 Tumor Immunity.

Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, their widespread implementation for cancer immunotherapy has been hampered by significant off-target autoimmune side effects that can be lethal. Our work has shown that absence of OX40 and CD30 costimulatory signals prevents CD4 T cell-driven autoimmunity in Foxp3-deficient mice, suggesting a novel way to block these side effects. In this study, we show that excellent antitumor CD8 T cell responses can be achieved in Foxp3KO mice deficient in OX40 and CD30 signals, particularly in the presence of concurrent PD1 blockade. Furthermore, excellent antitumor immune responses can also be achieved using combinations of Abs that block CTLA4, PD1, OX40, and CD30 ligands, without CD4 T cell-driven autoimmunity. By dissociating autoimmune side effects from anticancer immune responses, this potentially shifts this antitumor approach to patients with far less advanced disease.

OX40, OX40L and Autoimmunity: a Comprehensive Review.

The tumour necrosis factor receptor OX40 (CD134) is activated by its cognate ligand OX40L (CD134L, CD252) and functions as a T cell co-stimulatory molecule. OX40-OX40L interactions have been proposed as a potential therapeutic target for treating autoimmunity. OX40 is expressed on activated T cells, and in the mouse at rest on regulatory T cells (Treg). OX40L is found on antigen-presenting cells, activated T cells and others including lymphoid tissue inducer cells, some endothelia and mast cells. Expression of both molecules is increased after antigen presentation occurs and also in response to multiple other pro-inflammatory factors including CD28 ligation, CD40L ligation and interferon-gamma signaling. Their interactions promote T cell survival, promote an effector T cell phenotype, promote T cell memory, tend to reduce regulatory function, increase effector cytokine production and enhance cell mobility. In some circumstances, OX40 agonism may be associated with increased tolerance, although timing with respect to antigenic stimulus is important. Further, recent work has suggested that OX40L blockade may be more effective than OX40 blockade in reducing autoimmunity. This article reviews the expression of OX40 and OX40L in health, the effects of their interactions and insights from their under- or over-expression. We then review OX40 and OX40L expression in human autoimmune disease, identified associations of variations in their genes (TNFRSF4 and TNFSF4, respectively) with autoimmunity, and data from animal models of human diseases. A rationale for blocking OX40-OX40L interaction in human autoimmunity is then presented along with commentary on the one trial of OX40L blockade in human disease conducted to date. Finally, we discuss potential problems with clinical use of OX40-OX40L directed pharmacotherapy.

Surveillance for hepatocellular carcinoma in a mixed-aetiology UK cohort with cirrhosis: does α-fetoprotein still have a role?

Mortality from hepatocellular carcinoma (HCC) in people with cirrhosis is increasing whereas mortality from other causes is declining. Surveillance appears to reduce mortality but the optimal strategy is uncertain. Current guidelines differ by recommending ultrasonography alone or with α-fetoprotein (αFP). Records in three UK hospitals were analysed from 2006 to 2011. Of 111 HCC cases identified, 24 (47.1%) of those eligible were under surveillance: 21 (87.5%) were under combined ultrasonography-αFP, 2 (8.3%) ultrasonography-only and 1 (4.2%) αFP-only surveillance. αFP was elevated in 19 (86.4%), and αFP alone triggered a confirmatory study in 11 (9.9%) overall and 7 (29.1%) under surveillance. Surveillance, but not αFP, correlated with smaller tumours. Survival did not differ significantly between groups. Given that αFP use is associated with identifying smaller HCCs and that several diagnoses would have been delayed without αFP in this real-life cohort, these data support ongoing αFP use. However, further work is necessary with regard to whether αFP translates into improved clinical outcome and overall cost effects. In our area, stopping αFP use would also represent a significant change in practice.