Publications

OBJECTIVE: To evaluate the effect of erenumab treatment beyond monthly migraine days in patients with high-frequency episodic migraine who did not respond to at least one previous migraine preventive treatment.

BACKGROUND: Reduction in monthly migraine days has been the efficacy standard for migraine preventive treatments; however, it does not fully capture the holistic benefit of the therapy. Erenumab, a monoclonal antibody targeting the calcitonin gene-related peptide pathway, has demonstrated reduction in monthly migraine days and improvement in function in patients with episodic and chronic migraine.

METHODS: In this phase 4, interventional, double-blind, randomized, placebo-controlled, multicenter, global study, treatment with erenumab was assessed over 4 months in adults with high-frequency episodic migraine. The study was conducted at 61 sites located across North America and Europe between September 2020 and October 2023. Patients with ≥1 qualifying oral triptan-treated migraine attack at baseline were randomized to receive erenumab 140 mg or placebo subcutaneously once monthly. The primary endpoint was change from baseline in mean monthly hours of at least moderate headache pain intensity over months 1, 2, and 3; secondary endpoints included change from baseline in mean monthly function, mean monthly duration of at least moderate pain intensity in migraine attacks, and mean monthly peak migraine pain intensity. Safety outcomes were also assessed.

RESULTS: Of 512 randomized patients, 510 received erenumab 140 mg (n = 254) or placebo (n = 256) once monthly. Demographics and baseline characteristics were balanced between the two treatment arms. Erenumab 140 mg was superior to placebo in reducing duration of moderate or severe headache pain intensity over months 1, 2, and 3 (least squares mean [95% confidence interval {CI}] difference, -7.95 [-11.45, -4.46]; p < 0.001). Compared with placebo, erenumab significantly reduced migraine functional impact as assessed by the four domains of the Migraine Functional Impact Questionnaire, with a least squares mean (95% CI) difference of -7.36 (-10.80, -3.92) for physical functioning, -7.10 (-10.34, -3.87) for usual activities, -6.82 (-10.37, -3.27) for social functioning, and - 7.05 (-10.76, -3.34) for emotional functioning (p < 0.001 for all domains). Significant reductions with erenumab compared with placebo were also observed in duration of at least moderate pain intensity in residual or break-through migraine attacks (least squares mean [95% CI] difference, -1.07 [-1.92, -0.22]; p = 0.013) and peak migraine pain intensity (-0.48 [-0.85, -0.11]; p = 0.011). Incidence of grade 3 adverse events was 1.6% with erenumab and 1.2% with placebo; no grade 4 or fatal adverse events were reported in either treatment arm.

CONCLUSION: Findings from the EMBRACE study demonstrated that treatment with erenumab in patients with high-frequency episodic migraine can provide positive therapeutic effects on ictal burden and pain, with residual migraine attacks tending to be shorter and less painful, with less overall impact.

Metabolic and alcohol-related liver disease (MetALD) is a newly defined entity within the spectrum of steatotic liver disease, characterized by the interplay of cardiometabolic risk factors and alcohol consumption. The evolving epidemiology and complex pathophysiology of MetALD present unique challenges and opportunities for clinical trial design. Inclusion criteria should require simultaneous evidence of metabolic dysfunction (at least two cardiometabolic features) and verified quantifiable alcohol exposure recorded over the preceding 3-6 months. Traditional histological end points are limited by invasiveness, sampling error and interpretative variability. Thus, imaging modalities, serum-based fibrosis biomarkers and quantitative measures of alcohol intake are gaining relevance as non-invasive, reproducible and patient-centric end points aiming to improve trial feasibility. Furthermore, incorporating alcohol biomarkers, stratifying patients by metabolic risk factor burden, and using adaptive designs of trials might enhance the precision and generalizability of MetALD clinical trials. Although uncertainties remain regarding optimal patient selection criteria, event rates and the dynamic interplay between metabolic dysfunction and alcohol intake, ongoing research efforts aim to refine diagnostic criteria, standardize methodologies and validate novel end points. These advances will ultimately accelerate drug development, improve trial efficiency and foster interventions to treat MetALD.

BACKGROUND: The clinical course and outcomes of alcohol-associated hepatitis (AH) remain poorly understood. Major adverse liver outcomes (MALO) do not capture the added risk of return to drinking (RTD). We examined the natural history of AH and developed a composite endpoint using a contemporary observational cohort of AH.

METHODS: A cohort of 1127 participants: 712 AH patients, 256 heavy drinking (HD) controls without clinically evident liver disease, and 159 healthy controls, were prospectively followed for 6-months at eight United States centers as part of the Alcoholic Hepatitis Network (AlcHepNet) consortium. Outcomes included mortality and a composite endpoint (AlcHepNet composite index) that included death, liver transplantation, hepatic decompensation (new onset/worsening ascites, hepatic encephalopathy, variceal bleeding), liver-related hospital admission, MELD increase ≥5, and return to drinking (RTD).

RESULTS: Of 712 AH patients (age 45±10.7 y; 59.1% male), 558 (79.0%) had severe and 148 (21.0%) had moderate AH, 232 (32.5%) died, and 86 (12.1%) underwent liver transplantation. Mortality rates in moderate AH and severe AH were 0.7% versus 17.2% (30 d), 3.4% versus 26.5% (90 d), and 8.8% versus 30.5% (180 d), respectively (all p<0.001). Composite liver/alcohol use events were noted in 459 (64.5%) AH patients. Higher MELD score, lower mean arterial pressure, and baseline leukocytosis were associated with higher 90-day mortality in AH (all p<0.05). College education and higher alkaline phosphatase were associated with lower mortality. HD controls had low mortality (n=3; 1.2%).

DISCUSSION: This large observational study showed a high incidence of composite liver and alcohol-use events within six months, reiterating the need for early interventions.

BACKGROUND: Erenumab-induced medication overuse headache (MOH) remission in participants with chronic migraine (CM) in a prospective, Phase 4, randomized, placebo-controlled trial with an open-label treatment period (OLTP). We present 1-year results from the combined double-blind treatment period (DBTP) and OLTP for the stratified nonopioid cohort.

METHODS: Participants with CM-MOH were randomized 1:1:1 to subcutaneous 70 or 140 mg erenumab every 4 weeks (QM) or placebo for the initial 24 weeks (DBTP). Those successfully completing DBTP could continue the 28-week OLTP, maintaining the same erenumab dose received during DBTP or, if receiving placebo, randomly assigned 1:1 to erenumab 70 or 140 mg QM. OLTP endpoints were exploratory.

RESULTS: Overall, 552 participants received erenumab (70 mg, n = 274; 140 mg, n = 278); 95.3% completed OLTP. One-year MOH relapse in participants who achieved MOH remission at DBTP Month 6 was 2.7% (3/111) and 2.4% (3/124) with erenumab 70 and 140 mg, respectively; absence of MOH at study end was observed in 69.0% (189/274) and 75.5% (210/278) of participants. Sustained MOH absence over 1 year was reported in 60.5% (107/177) and 68.8% (119/173) of participants, respectively. Sustained improvements in measures of headache days, medication days, and function were observed in both groups. No new safety concerns were identified (grade ≥ 3, 35 [6.3%]; serious, 17 [3.1%]; adverse events leading to treatment discontinuation, 5 [0.9%]).

CONCLUSIONS: Erenumab was effective in inducing and sustaining MOH remission and improving function over 1 year. Treatment compliance remained high, with safety events consistent with erenumab's known safety profile.

TRIAL REGISTRATION: NCT03971071.

BACKGROUND: Alcohol use disorder (AUD) has been associated with Alzheimer's disease (AD) and dementia, yet the underlying mechanisms and specific role of ethanol in AD progression remain poorly understood. Neuroinflammation has emerged as a key contributor to both AD pathogenesis and ethanol-induced brain damage. Activation of innate immune cells and signaling pathways, in particular NLRP3 inflammasome, plays a pivotal role in both AD and ethanol-induced inflammation. Thus, we postulated that excessive ethanol consumption could contribute to AD progression via amplified neuroinflammation.

METHODS: The 12-15-month-old WT and APP/PS1 mice received water or ethanol (3.5 g/kg) binge every alternate day for a period of one month. The effects of ethanol on amyloid pathology, microglia and astrocyte activation, and NLRP3 inflammasome activation were evaluated in the mouse brains. The effect of ethanol and amyloid β on NLRP3 inflammasome signaling was further studied in primary glial cells.

RESULTS: In this study, we show that repeated ethanol binges aggravate the amyloid pathology and plaque burden in the hippocampus of APP/PS1 mice. Furthermore, we demonstrate the additive effect of ethanol administration on NLRP3 inflammasome activation, IL-1β release, and ASC aggregation in the brains of APP/PS1 mice and primary glia cultures. Our study also reveals a strong astrocyte activation by ethanol in the hippocampus of APP/PS1 mice as demonstrated by significantly increased GFAP and ALDH1L1 protein levels. Further in vitro analysis revealed that ethanol potentiates the effect of amyloid β to increase the NLRP3 inflammasome activation in both primary astrocytes and microglia. Lastly, we demonstrate that glia-produced ASC specks induce IL-1β in microglia and astrocytes and induce ROS in SH-SY5Y neurons, contributing to sustained neuroinflammation in AD.

CONCLUSION: Collectively, our results demonstrate that ethanol consumption exacerbates features of AD pathology associated with amplified neuroinflammation and NLRP3/ASC inflammasome activation, which may play an important role in the disease progression and severity.

Venous thromboembolism is frequent in ovarian cancer especially after surgery. Elaboration of tissue factor bearing extracellular vesicles (TF+EV) has been linked to thrombosis in cancer and hypercoagulability of surgery. Rosuvastatin can reduce the generation of EV and decrease VTE risk in non-cancer populations. The use of rosuvastatin to mitigate post-surgical thrombosis by lowering TF+EV following ovarian cancer surgery has not been investigated. In a pilot phase 2 trial in women undergoing ovarian cancer, women were randomized to enoxaparin 40 mg daily for 30 days with or without rosuvastatin 40 mg daily (administered from days 15- 60). Women who elected to forgo randomization received enoxaparin 40 mg daily for 30 days per standard of care. Total EV and TF+EV were assessed at baseline, day 30, and day 60. Bilateral lower extremity ultrasound was performed on day 30 and 60. A total of 24 women enrolled in the trial, 15 underwent randomization and 7 women were randomized to enoxaparin with rosuvastatin (17 received enoxaparin alone). There were no statistical differences observed in circulating TF+EV with the addition of rosuvastatin to enoxaparin at day 30 or day 60. Similarly, there were no differences in C-reactive protein or D-dimer between groups. There were no lower extremity deep vein thrombosis identified on screening ultrasounds, although portal vein thrombosis was diagnosed in enoxaparin-only arm. No major hemorrhages were observed. The addition of rosuvastatin to enoxaparin following ovarian cancer surgery does not appear to impact number of circulating TF+EV nor alter markers of thromboinflammation.

BACKGROUND: How parental alcohol use disorder and liver disease-related mortality influence the risk and the outcomes of alcohol-associated hepatitis (AH) in the offspring is unknown.

METHODS: We analyzed data from 2 prospective observational studies of AH cases and heavy drinking controls (HDCs). Family history of parental alcohol use disorder and liver disease mortality was assessed at the study entry. Logistic regression and Cox proportional hazard models were used to assess the influences of family history on AH development and outcome.

RESULTS: Data from 1356 participants in two prospective cohorts (926 AH cases and 430 HDC) were combined and analyzed. Parental alcohol use disorder was found in 56.9% of AH cases and 61.1% of HDC; parental death due to liver disease was reported in 7.5% of AH cases and 5.7% of HDC. Multivariable logistic regression showed that parental liver disease-related mortality was associated with more than a doubled risk of AH development in the offspring after controlling for their demographic characteristics and drinking behavior (OR=2.26, 95% CI: [1.22, 4.20]). Moreover, among the AH cases, having a parent die of liver disease significantly increased the 90-day mortality of study participants after adjusting for the effects of other risk factors (HR=2.26, 95% CI: [1.05, 4.86]).

CONCLUSIONS: The study highlights the influences of parental death due to liver disease on AH development and mortality. Identifying patients at risk of AH through family history might help facilitate discussions on reducing alcohol consumption.

Alcohol-associated liver disease (ALD) is a major global health challenge, with inflammation playing a central role in its progression. As inflammation emerges as a critical therapeutic target, ongoing research aims to unravel its underlying mechanisms. This review explores the immunological pathways of ALD, highlighting the roles of immune cells and their inflammatory mediators in disease onset and progression. We also examine the complex interactions between inflammatory cells and non-parenchymal liver cells, as well as their crosstalk with extra-hepatic organs, including the gut, adipose tissue, and nervous system. Furthermore, we summarize current clinical research on anti-inflammatory therapies and discuss promising therapeutic targets. Given the heterogeneity of ALD-associated inflammation, we emphasize the need for precision medicine to optimize treatment strategies and improve patient outcomes.

BACKGROUND & AIMS: Alcohol abuse is the most frequent precipitating factor of acute-on-chronic liver failure (ACLF). We aimed at developing an alcohol-induced ACLF model and dissecting its underlying molecular mechanisms.

METHODS: ACLF was triggered by a single alcohol binge (5 g/kg) in a bile duct ligation (BDL) liver fibrosis murine model. Liver, kidney, and brain tissues and behavior were assessed in mice. Livers from patients with sclerosing cholangitis with and without ACLF were also evaluated.

RESULTS: In advanced fibrosis induced by BDL, an alcohol binge induced features of ACLF, including significant liver damage, systemic inflammation (increased endotoxin and pro-inflammatory cytokines), and hepatocyte dysfunction compared with BDL alone. ACLF was associated with extrahepatic manifestations, including increased blood urea nitrogen and creatinine, impaired coagulation, and features of encephalopathy. We discovered significantly increased neutrophil count and neutrophil extracellular traps (NETs) in the liver, kidney, and brain in murine ACLF. Livers from ACLF mice showed increased pyroptosis (gasdermin D) and necroptosis (receptor-interacting protein kinase 3 [RIPK3]), when compared with BDL. In vitro, cell-free NETs were induced by alcohol and/or bile acids and triggered pyro-/necroptotic death in hepatocytes. NETosis, pyroptosis, and RIPK3 activation were validated in human livers with ACLF. Moreover, pharmacological inhibition of necroptosis with a RIPK3 inhibitor-ameliorated inflammation, NETs, and liver fibrosis, improving multi-organ ACLF pathophysiology.

CONCLUSIONS: Our novel ACLF model triggered by alcohol binge mimics key features of pathophysiology and multi-organ impairment in human ACLF. Our results indicate that neutrophil infiltration and NETs contribute to hepatocyte cell death via pyroptosis and necroptosis in ACLF, identifying RIPK3 as a potential therapeutic target.

UNLABELLED: Liver disease, including hepatocellular carcinoma (HCC), is a major global health concern, claiming approximately 2 million lives worldwide annually, yet curative treatments remain elusive. In this study, we aimed to investigate the role of microRNA-21-5p (miR-21) in metabolic dysfunction-associated steatotic liver disease (previously NAFLD), metabolic-associated steatohepatitis (previously NASH), and HCC within the context of a Western high-fat diet, without additional choline (HFD) and offering potential therapeutic insights. We found that reduced miR-21 levels correlated with liver disease progression in WT mice fed on HFD, while miR-21 knockout mice showed exacerbated metabolic dysfunction, including obesity, hepatomegaly, hyperglycemia, insulin resistance, steatosis, fibrosis, and HCC. Our study reveals that miR-21 plays a protective role in metabolic syndrome and in the progression of liver disease to cancer. MiR-21 directly targets Transforming growth factor beta-induced ( Tgfbi ), a gene also known to be significantly upregulated and a potential oncogene in HCC. Further, our study showed that intervention with the administration of a miR-21 mimic in WT livers effectively improves insulin sensitivity, steatosis, fibrosis, Tgfbi expression and tumor burden in HFD conditions. These findings indicate that miR-21 could serve as an effective strategy to delay or prevent liver disease in high-fat-diet environments.

SIGNIFICANCE: Our study demonstrates in vivo that miR-21 has protective functions in the broad spectrum of high-fat diet-based, progressive liver disease and cancer, and we show potential therapeutic value of a microRNA-21 mimic.