Publications

BACKGROUND: Recurrent alcohol use is a major determinant of liver-related outcomes in patients recovering from alcohol-associated hepatitis (AH). However, the timing and predictors of return to drinking (RTD) are not well-studied.

METHODS: We analyzed alcohol use among patients with AH enrolled in two AlcHepNet multicenter studies: a Phase 2b randomized controlled trial and a prospective observational study. TimeLine FollowBack (TLFB) assessed drinking at each visit. RTD was defined as any alcohol use since the previous visit. The cumulative incidence of RTD was evaluated using the Fine-Gray method, with death as a competing risk. Factors associated with RTD were evaluated using univariate and multivariate Cox regression.

RESULTS: Among 518 patients alive at Day 28, RTD occurred in 7.7%, 21.7%, and 30.8% at 30, 90, and 180 days, respectively. Patients with moderate AH (mAH, MELD 11-19, n = 103) had a higher RTD incidence at 180 days than those with severe AH (sAH, MELD ≥20, n = 415) (44.3% vs. 27.5%; p = 0.01). RTD was associated with higher AUDIT scores, family history of alcohol use disorder (AUD), lower education, greater alcohol use at baseline, lower MELD scores, and less ascites (all p ≤ 0.01). In multivariable analysis, >20 drinking days in the prior month was associated with increased risk of RTD (HR: 3.46, 95% CI: 2.21-5.39), whereas college education or higher was protective (HR: 0.53, 95% CI: 0.32-0.88).

CONCLUSION: RTD occurred in 22% of AH patients within 90 days postrecovery, highlighting the need for early AUD interventions. Frequent drinking days at baseline and lower education were strongly linked to early RTD.

BACKGROUND: Increased circulating pro-inflammatory cytokine levels correlate with mortality in severe alcohol-associated hepatitis (AH), but their kinetics during disease progression or response to treatment remain unexplored.

OBJECTIVE: We longitudinally assessed circulating biomarkers in a severe AH cohort enrolled in a multicenter, double-blind clinical trial.

DESIGN: Eighty-nine patients with severe AH (MELD≥20) from 4 US sites were randomly assigned to treatment with IL-1receptor antagonist (IL-1Ra) + pentoxifylline + zinc (anakinra: 47) or methylprednisolone + placebo (steroid: 42). Plasma levels of 43 indicators of AH pathology (inflammation, bacterial translocation, liver regeneration, tissue remodeling, and cell-activation) were assessed on days 0, 7, 28, 90 and 180 after enrollment, and in 27 healthy controls.

RESULTS: Baseline characteristics and cytokine levels were similar between treatment groups but significantly different compared to healthy controls. Consistent with anakinra administration, day 7 IL-1Ra levels were significantly increased in the anakinra group accompanied by elevated levels of several other cytokines. IL-1β levels were increased in the steroid group on day 28. Strong correlations were observed between IL-1α and IL-17A as well as IL-1β and IL-13 both prior to and during treatment. Although the dysregulated biomarkers demonstrated improving trends in survivors, most did not normalize by day 180. Markers associated with 90-day mortality were distinct between the treatment groups with few exceptions (IL-13-absolute level; Sonic hedgehog and sTNFR-1-level change).

CONCLUSIONS: Circulating cytokine and immune biomarkers dynamically change in AH during treatment, disease progression and/or resolution. Our results highlight the importance of treatment-specific biomarkers in future clinical trials.

BACKGROUND: Cyclic GMP-AMP synthase (cGAS) catalyzes the production of cGAMP, which activates the STING-IRF3 signaling pathway. Previous investigations indicated a role for STING-IRF3 in early alcohol-associated liver disease (ALD). In this study, we examined the role of cGAS in liver damage and inflammation in early ALD.

METHODS: Wild-type (WT) or cGAS knockout (cGAS-KO) mice received a single dose of alcohol (5 g/kg), and in WT mice with or without a cGAS inhibitor, RU.521 (5 mg/kg) or 2'-3' cGAMP or control. Liver and serum were evaluated after 9 hours of alcohol administration.

RESULTS: Alcohol gavage in cGAS knockout (cGAS-KO) mice led to increased liver damage compared with WT mice. Inhibition of cGAS with the small molecule, RU.521, also resulted in increased serum alanine and aspartate aminotransferases. cGAS deficiency or inhibition made the liver susceptible to alcohol-induced apoptosis. Alcohol-fed cGAS-KO mice and WT mice treated with the cGAS inhibitor showed enhanced unfolded protein response in the liver. This was associated with elevated levels of the proinflammatory cytokines, macrophage migration inhibitory factor, CD68+ cells, Ly6G+ cells, and chemokines like lipocalin-2 and neutrophil elastase. Primary hepatocytes isolated from cGAS-KO mice displayed increased levels of cleaved caspase-3, XBP1s, and CHOP after alcohol administration as compared with WT control hepatocytes. Interestingly, restoration of cGAMP levels after cGAS inhibition improved liver damage and autophagic flux.

CONCLUSIONS: Our findings highlight that cGAS deficiency or cGAS inhibition predisposes the liver to increased damage, apoptosis, and unfolded protein response in early ALD. An increase in the proinflammatory cytokine MIF and chemokines involved in neutrophil recruitment might contribute to the increased liver damage. In summary, our findings indicate a protective role for cGAS activation in early ALD.

Metabolic dysfunction and alcohol-associated liver disease (MetALD) is a recently implemented nomenclature and disease terminology for patients with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol. MetALD is diagnosed in individuals who have at least one metabolic risk factor (such as obesity, type 2 diabetes mellitus, hypertension, etc) and consume 140-350 g/week of alcohol for women or 210-420 g/week for men. Conversely, alcohol-associated liver disease is diagnosed in individuals who consume >350 g/week of alcohol for women and >420 g/week for men. MetALD represents a heterogeneous spectrum of liver disease, with variations in clinical presentation and severity driven by differences in metabolic profiles, drinking patterns and individual susceptibility. Alcohol and metabolic risk factors are thought to act synergistically to accelerate steatohepatitis, fibrosis and hepatocellular carcinoma. However, the precise mechanisms underlying liver injury in MetALD still remain poorly understood. In this comprehensive review, we summarise the current definition, diagnostic criteria and clinical management of MetALD. We also discuss emerging insights into understanding its pathogenesis, examine relevant experimental models and highlight future challenges and research priorities in this evolving field.

The authors report the case of a patient diagnosed and treated with schizophrenia for nearly 20 years. A rapid change in the neurological status of the patient necessitated a diagnostic revision. The patient's additional medical history included narcolepsy and psoriasis. With a stable maintenance antipsychotic combination regime, one and a half years after the last inpatient treatment for a psychotic relapse, initially mild lower limb hyperkinesis developed. At first, this hyperkinesis was hypothesized to be antipsychotic side effects. The decrease of the antipsychotic daily dose resulted in no improvement of the motor symptoms. On the contrary, the generalization of the hyperkinesis and rapid progression of the motoric status were observed. Therefore, further neurological investigation was initiated. Finally, genetic testing confirmed Huntington's disease. The neuropsychological examination at the time of the diagnosis could not confirm major cognitive impairment, however, alterations in a number of cognitive domains were present. During the follow-up period, and by use of the combination of a low-dose partial dopamine receptor agonist and clozapine, no psychotic relapse was detected. The cognitive status exhibited a mild deterioration compared to baseline. In line with the prognosis of Huntington's disease, the motor symptoms slightly progressed despite the pharmacotherapy. We present our case in the context of a literature review. Orv Hetil. 2025; 166(52): 2064-2072.

BACKGROUND & AIMS: Aging and alcohol misuse independently alter monocyte (MO) and macrophage (MØ) function, leading to impaired antimicrobial responses. However, how alcohol misuse contributes to impaired MO/MØ function during aging remains unclear.

METHODS: We compared the transcriptomes of MOs and MØs from alcohol-modulated niches (liver, brain, and bone marrow [BM]) in young (3-month-old) and old (20-24-month-old) female C57BL/6N mice (n = 4-6 per group). Statistical significance was determined using two-way ANOVA.

RESULTS: MO/MØ transcriptomes showed unique organ-specific responses to aging and alcohol. Aging elicited a common deregulation of pathogen-responsive pathways, while alcohol misuse commonly inhibited IFN signaling in the aged populations. Our studies on intercellular communication using ligand-receptor interactions revealed that BM MOs were the least communicative and liver MØs were the most communicative. Alcohol misuse specifically increased MO/MØ communication in aging. We also identified and validated specific pathways driving inter-organ MO/MØ crosstalk in alcohol misuse during aging, including APOE-TREM2 signaling from the liver to microglia and the NRXN2 and SPP1 pathways.

CONCLUSION: Our results provide a unique insight into the heterogeneity of the MO/MØ transcriptome and define the inter-organ crosstalk between BM, liver, and brain during aging and alcohol misuse.

IMPACT AND IMPLICATIONS: Aging and alcohol misuse are linked to immune dysfunction, systemic inflammation, and altered innate immune responses. Here, we examined monocyte/macrophage responses in the liver, brain, and bone marrow of young and aged mice under alcohol exposure at the transcriptomic level. We observed that aging and alcohol predominantly elicited organ-specific changes in gene expression, with minimal overlap between the monocyte/macrophage populations across different tissues. However, aging commonly upregulated pathogen response pathways while alcohol misuse inhibited interferon signaling. We also assessed cell-cell communication by analyzing ligand-receptor expression in the different monocyte/macrophage populations and identified candidate molecules (APOE, TREM2, NRXN2, SPP1) from the top pathways guiding inter-organ signaling specifically in aging and alcohol misuse. Our findings have generated a unique repository and provide novel insights on how aging and alcohol impact tissue-specific monocytes/macrophages and their crosstalk.

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.