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Interleukin-10 (IL-10) is an essential regulator of intestinal immune homeostasis. Neutralising autoantibodies against IL-10 (anti-IL-10) have been identified in children and also adult patients with IBD. Positivity for anti-IL-10 autoantibodies was associated with carriage of HLA-DRB1*01:03 allele. To determine the prevalence of anti-IL-10 in paediatric IBD and assess the associated clinical phenotype. We conducted a cross-sectional multicentre study across paediatric IBD cohorts from four countries. Anti-IL-10 antibodies were investigated in serum and plasma from paediatric patients with IBD (mean age of IBD onset 11.2±3.8 years). IL-10-neutralisation capacity was confirmed by functional IL-10 reporter assay, competitive ELISA and cytokine release assay. Clinical data were analysed to evaluate disease phenotype and treatment outcomes, with comparison with matched controls. HLA-DRB1*01:03 analysis was performed. Anti-IL-10 positivity was identified in 26/1045 paediatric patients with IBD (2.5%) (Crohn's disease n=6, UC n=19, IBD unclassified n=1; IBD diagnosis age of 13±3 years). Anti-IL-10 autoantibodies were of the IgG class and amplified pro-inflammatory cytokine responses in vitro. Anti-IL-10-positive patients exhibited more severe disease compared with matched controls, including an increased prevalence of difficult-to-treat disease (23% vs 6%, p=0.03), higher rate of acute severe UC (26% vs 6%; p=0.038) and higher rates of colectomy (27% vs 6%, p=0.01). Eighty percent (16/20) of anti-IL-10-positive patients with available HLA data carried the HLA-DRB1*01:03 allele, compared with 1.5% in the anti-IL-10-negative group. Anti-IL-10 autoantibodies are present in a subgroup of paediatric patients with IBD and are associated with difficult-to-treat disease.

The global burden of inflammatory bowel diseases (IBD) continues to rise, placing increasing demands on primary care and specialty practices alike. Beyond disease control, patients with IBD face heightened risks related to chronic inflammation and long-term immunosuppressive therapy, including infection, cancer, bone loss, nutritional deficiencies, and mental health disorders. Proactive, structured health care maintenance encompassing vaccination, cancer screening, bone and cardiometabolic health, nutrition, and psychosocial well-being is essential to optimize long-term outcomes. Effective delivery of this care depends on close collaboration and clearly defined shared responsibilities between gastroenterologists and primary care physicians. This review outlines evidence-based strategies for health care maintenance in the outpatient management of adults with IBD.

The gut microbiome is a dynamic ecosystem in which microorganisms constantly adjust their transcriptional programmes. Here we developed metastrand, a framework that integrates strand-aware metatranscriptomics and metagenomics to quantify mRNAs and antisense RNAs (asRNAs) in complex microbial communities at gene-level resolution. In inflammatory bowel disease (IBD), microbial asRNA programmes converged across patients during active disease, correlated with faecal metabolites and calprotectin levels and remained stable during persistent inflammation, highlighting their potential as biomarkers of inflammatory activity in the gut. These programmes involved antisense-to-sense transcriptional shifts at insertion sequence elements with functionally diverse passenger genes and preceded their detection at new genomic locations, linking asRNA dynamics to structural genome rearrangements and redistribution of adaptive functions under selective pressure. Similar dynamics were observed in a mouse model of colitis, oxidative stress in vitro and in patients with pathogen-confirmed gastroenteritis, establishing asRNAs as an important dimension of microbial adaptation in health and disease.

Toll-like receptors (TLRs) are considered general sensors of bacterial encounters. Here, we examined whether other pattern recognition receptors are commonly activated during bacterial infection. TLR-independent interferon (IFN) responses were induced in macrophages in response to diverse bacterial encounters. Of the cytoplasmic receptor families examined, the cyclic dinucleotide (CDN) sensor STING was required for IFN responses to evolutionarily diverse bacteria. Various bacterial CDNs were present in murine tissues; these activated stimulator of interferon genes (STING) after bacteriolysis in phagolysosomes in a manner requiring two CDN transporters. Importantly, bacterial CDNs were increased in colonic biopsies from patients with inflammatory bowel disease. Systemic delivery of dead, CDN-laden bacteria promoted anti-tumor immunity in mice. Detection of diverse CDNs, including pyrimidine-based CDNs, was an evolutionarily conserved feature of STING, with distinct binding modes for purine- and pyrimidine-based CDNs. Thus, a phagocytosis-CDN-STING connection places cytoplasmic sensing as a common outcome of host-bacteria interactions that set the immune tone of a tissue, with implications for host defense.

The chronic, recurring nature of Inflammatory bowel disease (IBD) and the complications associated with conventional drugs have driven the search for next-generation therapies capable of overcoming the limitations of current treatment regimens. As functional proxies of their parent bacteria, probiotic extracellular vesicles (PEVs) have become the focus of attention in recent years because of their great potential in the treatment of IBD. This review summarizes the overview of PEVs and recent advances of PEVs on the therapeutical effect and potential mechanisms in IBD. In addition, the review discusses the possible applications and challenges of PEVs in IBD. Key scientific concepts of review: PEVs facilitate a complex molecular crosstalk that preserves intestinal homeostasis in IBD by concurrently modulating immunological response, reinforcing intestinal barrier, and stabilizing the gut microbiota. Although PEVs offer powerful innovations for the treatment of IBD, they still face challenges such as high-quality and scaled-up production, purification, safety, target specificity, and bioavailability. Consequently, future investigations will focus on establishing standard procedures of isolation, purification, and quality control while engineering PEVs for enhanced target-specific delivery in IBD treatment.

Primary sclerosing cholangitis-associated UC (PSC-UC) carries excess colorectal neoplasia despite often mild-appearing endoscopy, implicating persistent microscopic inflammation and microbiota-bile acid (BA) dysfunction. To test whether PSC-UC neoplasia is driven by transferable microbiota-mediated inflammation linked to secondary BA loss. Surveillance colonoscopies (2012-2022) from PSC-UC (n=251) and UC-only (n=8839) were compared for segmental endoscopic/histological activity and dysplasia. We generated multidrug resistance protein 2 (MDR2)-/- × interleukin (IL)-10-/- double-knockout (DKO) mice and used germ-free (GF) derivation, faecal microbiota transplantation (FMT), antibiotic conditioning and cohousing with shotgun metagenomics and liquid chromatography-tandem mass spectrometry BA profiling. PSC-UC showed greater inflammatory activity and a right-shifted dysplasia burden versus UC-only. Under specific-pathogen-free conditions, DKO mice developed early right-predominant colitis and multifocal dysplasia progressing with age. DKO communities were depleted of 7α-dehydroxylation capacity with near absence of deoxycholic and lithocholic acids and no enrichment of canonical bacterial genotoxins. GF DKO mice were protected, whereas live DKO donor FMT reinstated severe colitis and dysplasia; sterile-filtered stool supernatant was inactive. IL-10-/- donor FMT or cohousing attenuated colitis and increased recipient secondary BA, whereas wild-type/MDR2-/- donor transfers were non-colitogenic. In GF DKO mice, direct deoxycholic acid repletion caused hepatotoxicity. PSC-UC neoplasia associates with transmissible microbiota-dependent inflammation and secondary BA deficiency. Controlled restoration of BA-transforming microbial functions, rather than indiscriminate secondary BA replacement, is a rational translational direction.

Emerging evidence now points to innate tissue immunity as a critical orchestrator of both local tissue adaptation and long-range hematopoietic reprogramming, including the amplification of emergency granulopoiesis through bone marrow progenitor remodeling. These findings position the intestine as an instructive niche capable of imprinting long-lived changes both locally and systemically. This review synthesizes current findings at the intersection of gut and bone marrow biology, examining how intestinal inflammation shapes granulopoietic output and how bone marrow-derived effectors, in turn, reinforce maladaptive tissue responses that underlie chronic intestinal manifestations, including colitis-associated cancer and extraintestinal inflammatory complications frequently seen in IBD. We delineate the physiological framework governing these regulatory nodes and highlight the translational implications for next-generation therapeutic intervention.

Aging is a complex, irreversible physiological process characterized by gradual deterioration of tissue structure and function, accompanied by impaired regenerative capacity, dysregulated immune homeostasis, and increased susceptibility to chronic age-related diseases (e.g., neurodegenerative disorders, metabolic syndromes, age-related skin lesions, and inflammatory bowel disease). In recent years, plant-derived extracellular vesicles (PDEVs), the lipid bilayer membrane vesicles released by plant cells, have emerged as innovative candidates for anti-aging therapy because of their inherent biocompatibility, safety, and sustainable sourcing advantages. These nanoscale particles contain proteins, lipids, and nucleic acids. Emerging evidence from in vitro and rodent in vivo models has indicated that PDEVs can effectively delay age-related phenotypes and alleviate pathological changes through multiple mechanisms, such as scavenging reactive oxygen species to mitigate oxidative damage, regulating the immune microenvironment to suppress chronic inflammation, modulating gut microbiota composition to restore intestinal homeostasis, and promoting tissue regeneration (a core application in regenerative medicine) by activating stem cell function and repairing damaged tissues. Additionally, PDEVs offer unique potential as natural or engineered cargo-carriers for drug loading and delivery. This review outlines the biogenesis, composition, isolation, characterization, and storage strategies for PDEVs. Furthermore, we systematically summarize advances in the biological functions of PDEVs and their therapeutic applications in various age-related diseases. Finally, we discuss current challenges and future prospects for PDEVs in clinical translation. We hope this work provides valuable insights for advanced research and potential applications of PDEVs in the management of aging and age-related diseases.

Inflammatory bowel disease (IBD) is a global health challenge characterized by excessive reactive oxygen species (ROS) accumulation, immune dysregulation, and impaired intestinal barrier integrity. Although montmorillonite (MMT) is clinically used for gastrointestinal protection, its limited anti-inflammatory and ROS-scavenging activities restrict its therapeutic potential in intestinal inflammatory disorders. This study aimed to develop a multifunctional clay-supported nanozyme platform and evaluate its therapeutic effects in dextran sulfate sodium (DSS)-induced acute colitis model through the rational construction and screening of MMT-supported metal oxide nanocomposite (MMT@MxOy) library. A library of MMT@MxOy was constructed by integrating different metal oxide nanozymes onto MMT. The nanocomposites were screened and optimized by electron-transfer behavior, multienzyme-mimetic activities, and ROS-scavenging performance. Therapeutic efficacy was evaluated in DSS‑induced acute colitis model. Therapeutic mechanisms were investigated using transcriptomic profiling, gut microbiota analysis, biochemical assays, and molecular validation. MMT@MnO2 was identified as the leading nanocomposite owing to favorable electron-transfer characteristics and enhanced loading-normalized multienzyme-mimetic and ROS scavenging activities. Optimizing Mn precursor feeding ratio produced the lead MMT@MnO2 formulation, which exhibited favorable biocompatibility. In vivo, MMT@MnO22 alleviated body weight loss, reduced disease activity, preserved colon length, attenuated histopathological injury, and promoted mucus barrier recovery. Improvements in disease-related indices approached the orally administered 5-aminosalicylic acid, although route differences preclude direct pharmacological comparison. Mechanistically, MMT@MnO2 attenuated oxidative stress and inflammatory responses, promoted macrophage phenotype remodeling toward less inflammatory and more reparative state, restored epithelial tight junction, and partially recovery of gut microbial homeostasis. Transcriptomic analysis and downstream molecular validation supported the involvement of NF-κB-related inflammatory suppression, phagosome-associated immune remodeling, and Rap1/ERK-related epithelial repair. This work established a rational design framework for clay-based nanotherapeutics and identified MMT@MnO2 as a promising multitarget platform for alleviating DSS-induced acute colitis, offering a basis for future translational development of local nanotherapeutic strategies for intestinal inflammatory diseases.

The prevailing notion is that effector T cell activation mediates anti-PD-1 efficacy in cancer. Here, we conducted a mechanistic study parallel to our phase 2 trial of perioperative anti-PD-1 therapy in patients with resectable recurrent hepatocellular carcinoma (HCC) (NCT04615143) to study its mechanism of action. Late-recurrence patients present two distinct subtypes characterized by T cell or B cell dominant responses in the tumor microenvironment by dynamic single-cell multi-omics analysis. Clonal antibody repertoire analysis and spatially paired scRNA-seq/BCR-seq reveal somatic hypermutation promoting antibody binding against hepatitis B virus core antigen (HBcAg) within tumor tertiary lymphoid structures (TLSs) in these type B-late recurrence patients. Mechanistically, HBcAg is exported into the extracellular space, triggering local B cell and antibody responses and complement activation. In mice, these high-affinity HBcAg-reactive antibodies lead to complement-mediated antitumor activity with enhanced anti-PD-1 efficacy. Thus, we uncover enhanced anti-virus B cell immunity within the TLS as a mechanism to anti-PD-1 in HCC.

Chronic HBV infection remains a major global health burden, with current antiviral therapies effectively suppressing viral replication but rarely achieving functional cure. Adaptive immunity is central to viral clearance but is profoundly impaired during chronic infection. Inducing and enhancing adaptive immunity through therapeutic vaccines, immune checkpoint inhibitors or T cell-based therapies represents a promising approach for HBV cure strategies. However, recent preclinical and clinical studies have demonstrated only limited efficacy, underscoring major immunological challenges. In this review, we summarise current knowledge of the correlates of viral clearance and persistence, discuss key unresolved questions and outline future research directions needed to advance immune-based HBV cure strategies.

Chronic visceral pain in IBS with diarrhoea (IBS-D) is a profound therapeutic challenge. While aberrant central processing is implicated, the key brain regions driving this visceral pain and their suitability as neuromodulatory targets remain undefined. To identify a central hub of visceral pain in IBS-D and elucidate the mechanism by which repetitive transcranial magnetic stimulation (rTMS) confers analgesic effects. Combined functional MRI with visceral sensitivity assessments was used to pinpoint hyperactive brain regions of patients with IBS-D. Mechanistic studies were conducted in a well-established IBS mouse model. A clinical trial was performed to validate the therapeutic potential of rTMS in patients with IBS-D. Clinical observations identified hyperexcitability of the medial prefrontal cortex (mPFC) as strongly correlated with visceral pain in patients with IBS-D. In IBS mice, visceral pain was driven by the hyperactivity of mPFC glutamatergic (mPFCGlu) neurons, which received nociceptive inputs from the anterior cingulate cortex via an NR2A-dependent mechanism. Low frequency (lf)-rTMS of the mPFC sustainably alleviated visceral pain in IBS mice by inhibiting mPFCGlu neurons and restoring normal synaptic plasticity. Building on these findings, a clinical trial validated that a 2-week course of mPFC-targeted lf-rTMS in patients with IBS-D effectively alleviated visceral pain and improved bowel habits, effects associated with reduced mPFC activity and sustained for at least 8 weeks. Hyperexcitability of the mPFC drives chronic visceral pain in patients with IBS-D and lf-rTMS provides analgesia by suppressing this hyperactivity, offering a novel, mechanism-based neuromodulation strategy for IBS-D treatment.

Gut dysbiosis contributes to irritable bowel syndrome (IBS) pathogenesis and fungi exert independent effects on IBS patients, independent of bacterial influence. IBS patients exhibit elevated fecal Candida levels but the specific role of Candida in IBS remains unclear. This study investigated the contributions of Candida albicans (C. albicans) and its toxin candidalysin to IBS pathophysiology and elucidated the underlying mechanisms. Fecal C. albicans in healthy controls and diarrhea-predominant IBS (IBS-D) patients were detected. Restraint stress murine models were gavaged with C. albicans, C. albicans mutant strains lacking candidalysin (ece1Δ/Δ) or PBS. RNA-seq of intestinal organoids treated with candidalysin and pyroptosis proteins were detected. Gsdmd-/- mice were generated to evaluate the relationship of candidalysin and pyroptosis. Mass spectrometry, co-immunoprecipitation, and acetylome profiling were employed to characterize GSDMD post-translational modifications. C. albicans abundance was significantly higher in IBS-D patients than controls (31% vs 13%). C. albicans exacerbated barrier disruption, visceral sensitization and inflammation in restraint stress mice by candidalysin. While these pathophysiologic abnormalities were attenuated in Gsdmd-/- mice. Mechanistically, candidalysin downregulated histone deacetylase 2 (HDAC2) in intestinal epithelial cells, which directly interacted with GSDMD. Acetylome profiling identified GSDMD-K194 as a critical acetylation site. Pharmacological HDAC2 inhibition exacerbated GSDMD-mediated pyroptosis, which was abolished by K194 mutagenesis. Candidalysin exacerbates IBS by inducing pyroptosis in intestinal epithelial cells in vivo, specifically through the inhibition of HDAC2-mediated deacetylation of GSDMD-K194. These findings identify fungal toxins and HDAC2/GSDMD-mediated pyroptosis as pathophysiological mediators in IBS and propose mycobiota-directed therapeutic strategies.

Autoimmune hepatitis (AIH) is an idiopathic autoimmune disorder characterized by chronic liver inflammation that, if untreated, can lead to liver fibrosis and cirrhosis, hepatic failure, and death. Current treatment options for this potentially life-threatening disorder include either high-dose immunosuppressants or liver transplantation (for late-stage patients). However, these options are risky and can lead to long-term complications. Therefore, there is an urgent need to develop novel treatment strategies for AIH. Therapeutic approaches based on mesenchymal stem/stromal cells (MSCs) and their derived extracellular vesicles (EVs) have emerged as a viable treatment option for AIH because of their potent immunomodulatory and anti-inflammatory properties. This review outlines the recent developments in the use of these therapies for the treatment of AIH. The use of EVs as vehicles for the delivery of therapeutic drugs or miRNAs is also discussed. In addition, we discuss the various efforts that have been made to improve the efficacy of such therapies, including their genetic modification and combination with anti-inflammatory drugs. Finally, we proposed several directions for future research aimed at developing MSCs and MSC-derived EVs for clinical applications.

Liver fibrosis is a progressive pathological process driven by liver injury, including viral hepatitis and metabolic dysfunction-associated steatohepatitis (MASH), and can progress to cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Hepatocyte-hepatic stellate cell (HSC) crosstalk plays a central role in disease progression, but its regulatory mechanisms remain incompletely understood. This study aimed to define hepatocyte-HSC crosstalk in liver fibrosis mediated by microRNA-149-5p (miR-149-5p) signaling and to explore its potential as a therapeutic target for intervention. Differentially expressed exosomal microRNAs were identified by RNA sequencing of hepatocyte-derived exosomes from fibrotic and control livers. Functional screening using collagen type I alpha 1 chain (COL1A1) reporter assays identified miR-149-5p as an anti-fibrotic candidate. Exosome-mediated intercellular communication was confirmed using co-culture systems and confirmed by tumor susceptibility 101 (TSG101) silencing. Liver fibrosis was induced by bile duct ligation (BDL) and thioacetamide (TAA) in mice. Therapeutic effects were evaluated using AAV-mediated hepatocyte-specific overexpression and miR-149-5p agomir administration. miR-149-5p was selectively enriched in hepatocyte-derived exosomes via a CCUC-based EXOmotif and directly targeted PDGFRB in HSCs, thereby inhibiting HSC activation, proliferation, and collagen deposition without affecting hepatocyte function. During fibrosis progression, PU.1 bound to the miR-149-5p promoter and suppressed its transcription, leading to reduced exosomal miR-149-5p delivery and consequent PDGFRB derepression in HSCs. Both AAV-mediated overexpression and systemic miR-149-5p agomir administration significantly attenuated BDL- and TAA-induced liver fibrosis, as evidenced by reduced collagen deposition, decreased hydroxyproline content, and downregulation of HSC activation markers. The PU.1 (hepatocyte)-miR-149-5p (exosome)-PDGFRB (HSC) axis represents a key regulatory pathway in liver fibrosis, wherein PU.1 represses miR-149-5p transcription in hepatocytes, leading to EXOmotif-dependent reduction of exosomal miR-149-5p delivery and consequent derepression of PDGFRB in HSCs, thereby promoting HSC activation and fibrosis progression. Importantly, miR-149-5p agomir administration offers a promising therapeutic strategy for liver fibrosis.

Chronic pancreatitis (CP) affects ∼3 million people worldwide, yet altering the course of the disease is challenging. We developed a patient-derived organoid (PDO) platform to investigate the molecular pathogenesis of this disease and identify therapeutic strategies. We generated 37 PDOs from patients with idiopathic, hereditary, and alcohol-related CP with a high genetic concordance. PDOs retained inflammation-associated transcriptional and proteomic features. Transcriptomic profiling revealed three molecular subtypes of CP independent of etiology. We discovered widespread dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in half of the CP PDOs, including those with wild-type CFTR. Clinically available CFTR modulators stabilized mutant or wild-type CFTR, restored CFTR function, and decreased mitogenic and inflammatory signaling. This work provides a comprehensive PDO platform for modeling CP. We demonstrate the utility of this platform for precision therapeutic investigations. Our findings reveal CFTR modulators as a broadly applicable and effective therapeutic strategy.

Colonic diverticulosis is the most common structural abnormality of the colon in developed countries, with an increasing global prevalence. Approximately 20-25% of affected individuals develop symptoms, collectively referred to as diverticular disease. Given its wide clinical spectrum, evolving pathophysiological insights and growing disease burden, updated guidance is essential. This International Consensus, developed by 32 experts from 14 countries through a structured Delphi process based on the PICO framework and GRADE methodology, provides evidence-based recommendations across five domains: epidemiology and pathogenesis; clinical features; diagnosis; medical therapy; and surgical management. Key statements define diverticulosis as the presence of diverticula without symptoms and diverticular disease as diverticula associated with symptoms or complications. High dietary fibre intake is protective whereas smoking, obesity and the use of non-steroidal anti-inflammatory drugs, corticosteroids, opioids or immunotherapy increase risk. Imaging is essential in suspected acute diverticulitis: ultrasound may be appropriate in experienced hands, while CT remains preferred for complicated cases. Diverticulosis itself requires no treatment. In symptomatic uncomplicated diverticular disease, dietary fibre, selected probiotics, mesalazine and rifaximin may help relieve symptoms. Routine antibiotic use is not recommended for acute uncomplicated diverticulitis, and elective surgery should be individualised, prioritising quality of life considerations over episode count. These Consensus statements aim to standardise and optimise the diagnosis, management and prevention of diverticular disease across diverse healthcare systems, while highlighting research priorities such as microbiome characterisation, genetic risk profiling and long-term outcomes of selective antimicrobial and surgical strategies.

Kupffer cells and monocyte-derived macrophages (MoMs) are difficult to study in human primary biliary cholangitis (PBC) even though they reflect a dynamic hepatic immune population. We aim to investigate the role of hepatic macrophage and its therapeutic potential in human PBC and murine autoimmune cholangitis. Phenotypic analysis of hepatic macrophages in patients with PBC and dnTGFβRII mice model was performed by single-cell RNA sequencing, flow cytometry and immunohistochemistry. Depletion of hepatic macrophages and inhibition of MoMs were performed in murine autoimmune cholangitis. Lyz2-Cre-mediated Atg5 knockout mice and co-culture experiments were applied to explore the role and mechanism of macrophage autophagy in autoimmune cholangitis. Therapeutic intervention was performed using nanoparticle-capsuled small interfering RNA against Atg5. Kupffer cells from patients with PBC and dnTGFβRII mice upregulate genes associated with inflammatory responses and exhibit increased autophagy. Further, macrophage-specific knockout of Atg5 leads to reduction of inflammation and bile duct damage. We propose that the mechanism of this modulation is secondary to decreased activation of pathogenic CD8+ T cells. Indeed, Kupffer cells maintain CD8+ T cell tolerance through expression of inducible nitric oxide synthase (iNOS) and generation of NO. Increased autophagy resulted in degradation of iNOS in Kupffer cells and abrogated their suppressive activity against CD8+ T cells. Finally, we report that targeted downregulation of Kupffer cell autophagy in vivo using cationic lipid-assisted nanoparticles encapsulating siRNA against Atg5 leads to reduction of liver inflammation and bile duct damage. Macrophage autophagy promotes autoimmune cholangitis and strongly supports this pathway as a potential therapeutic target.

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by sterile ulcerative skin lesions. Multiple comorbidities and clinical features have been associated with PG, but no standardized guidelines exist for classifying PG phenotypes. To develop an expert-established classification framework for PG phenotypes to inform treatment guidelines and future research endeavors. In this modified Delphi consensus study that included 23 board-certified dermatologists and Medical Dermatology Society members with expertise in PG, panelists completed 5 rounds of anonymous, iterative online surveys that were administered from December 2023 through July 2025. Before the beginning of the consensus exercise, a literature review was performed by nonvoting researchers to summarize existing data on PG clinical associations and comorbidities. A PubMed search from inception to September 2023 identified observational studies, narrative reviews, systematic reviews, and meta-analyses describing PG clinical associations and comorbidities that were published in English. Experts indicated their agreement with proposed PG phenotypes and disease modifiers with a consensus threshold of 70% or greater. Anonymous comments and aggregated results were presented in each subsequent round. In the final round, a framework of PG phenotypes and disease modifiers was proposed for agreement. Twenty-three board-certified dermatologists and Medical Dermatology Society members with expertise in PG completed 5 rounds of iterative surveys. Consensus was reached on the final set of PG phenotypes and disease modifiers, with 83% of experts in agreement. PG phenotypes were overall classified into 2 major groups: PG with autoinflammatory syndromes and nonsyndromic PG. Nonsyndromic PG included 4 phenotypes: inflammatory bowel disease-associated PG, PG in association with hematologic cancers and blood dyscrasias, drug-induced PG, and other (including idiopathic) PG. Disease modifiers of PG phenotype presentations included involvement of special sites (head/neck, genitals, or peristomal skin) and extracutaneous manifestations. This expert-established, descriptive framework provides a standardized classification system for distinct PG phenotypes and its modifiers. This nomenclature may inform upcoming clinical guidelines and allow for consistency in reporting epidemiological research and outcomes among patients with PG.

Orally administered small-molecule programmed death ligand 1 (PD-L1) inhibitors may have the potential to improve patient outcomes in the treatment of a range of cancers compared with their antibody-based counterparts. A small molecule might achieve better tumor tissue penetration, and oral administration could significantly improve convenience and access for patients. Three phase 1 open-label, non-randomized, dose escalation, and expansion studies evaluated the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of three agents in patients with advanced solid tumors: INCB086550 (NCT03762447), INCB099280 (NCT04242199), and INCB099318 (NCT04272034). Overall, 138, 182, and 104 patients received INCB086550, INCB099280, and INCB099318, respectively. Most had previously received ≥2 lines of cancer therapy for advanced or metastatic disease; 9.6%-16.5% had received prior immunotherapy. All three agents were rapidly absorbed and showed stable dose-dependent PK. With INCB086550, 88 patients (63.8%) had ≥1 treatment-related treatment-emergent adverse event (TEAE), and 19 (13.8%) had ≥1 treatment-related grade ≥3 TEAE. In total, 14 patients (10.1%) had a nervous system-associated TEAE for which an immune-mediated etiology could not be ruled out; events were predominantly peripheral sensory and motor neuropathies. With INCB099280 and INCB099318, 144 (79.1%) and 69 (66.3%) of patients had ≥1 treatment-related TEAE, and 25 (13.7%) and 12 (11.5%) had ≥1 treatment-related grade ≥3 TEAE, respectively. The most frequent immune-related adverse events were skin reactions (INCB099280 and INCB099318) and hepatitis (INCB099280). No dose-limiting toxicities (DLTs) occurred during dose escalation with INCB086550 or INCB099318; two DLTs occurred in two patients with INCB099280 (grade 2 vomiting with 600 mg once daily and grade 2 maculopapular rash with 800 mg two times per day). Overall objective response rates for INCB086550, INCB099280, and INCB099318 were 10.9% (95% CI 6.2% to 17.3%; n=15), 8.8% (95% CI 5.1% to 13.9%; n=16), and 8.7% (95% CI 4.0% to 15.8%; n=9), respectively. Target engagement and PD activity were demonstrated, including PD-L1 binding, and increases in cytokine and chemokine production, as well as T-cell activation and proliferation. Both INCB099280 and INCB099318 had an acceptable safety profile, with preliminary evidence of antitumor activity. The risk of immune-mediated neuropathy led to discontinuation of the clinical program for INCB086550.

Idiosyncratic drug-induced liver injury (DILI) resolves following discontinuation of the causative drug in about 80% of individuals. The injury may persist in 10%-15% beyond 6 months and about 10% die within 2 years from the time of DILI onset. DILI may progress to liver failure even after the withdrawal of the medication in up to 10% of people and therefore treatment with corticosteroids for its anti-inflammatory property has been used to prevent the progression of DILI. With the advent of highly effective checkpoint inhibitors for the treatment of variety of cancers, corticosteroids are used liberally in high doses with an intent to accelerate resolution of liver injury. However, there is no evidence that corticosteroids hasten the resolution of acute liver injury, nor avert death or need of liver transplantation in acute DILI. Corticosteroids can impair repair and regeneration as well as induce resistance especially when used in checkpoint inhibitor-induced liver injury (ChILI) in high doses over longer periods; in fact, treatment has been associated with a delayed resolution of ChILI and increased adverse effects. When used to treat immune-related adverse events within 2 months of initiation of checkpoint inhibitors for wide range of cancers, corticosteroids have even been associated with reduced overall survival. Corticosteroid sparing approaches are safe and effective in majority of patients with ChILI. A modest dose of prednisolone that is tapered off over 4 weeks may selectively be used in ChILI when bilirubin rises progressively after the drug withdrawal, when liver histology demonstrates marked ongoing necroinflammation and once cholestasis or cholangiopathy have been excluded.