We report an exploratory subgroup analysis of a Chinese phase 3 study to investigate the effect of baseline inflammation measured by magnetic resonance imaging (MRI) on ixekizumab efficacy in radiographic axial spondyloarthritis (r-axSpA). Adults with r-axSpA were randomized (1:1) to receive ixekizumab 80 mg every 4 weeks (IXEQ4W) or placebo for 16 weeks. Endpoints analyzed by baseline Spondyloarthritis Research Consortium of Canada (SPARCC) MRI spine or sacroiliac joint (SIJ) inflammation score (< 2 or ≥ 2; elevated inflammation defined as score ≥ 2) were: Assessment of SpondyloArthritis International Society 40 (ASAS40); Bath Ankylosing Spondylitis Disease Activity Index 50 (BASDAI50); Ankylosing Spondylitis Disease Activity Score (ASDAS) < 2.1; ASDAS clinically important improvement (CII; change from baseline ≥ 1.1); Patient Global Assessment of Disease Activity (PtGA); spinal pain; nocturnal spinal pain; stiffness/inflammation; function; fatigue; Short Form-36 Physical Component Score (SF-36 PCS); European Quality of Life 5 Dimensions 5 Levels visual analog scale (EQ-5D-5L VAS). Overall, 145 patients were included. At Week 16, ASAS40 response rates were numerically improved with IXEQ4W versus placebo in the SPARCC MRI spine score < 2 subgroup (40.9

OBJECTIVES:Current PsA therapies, from conventional agents (e.g. MTX) to targeted biologics (e.g. TNF and IL-17 inhibitors), demonstrate distinct therapeutic profiles. Vunakizumab (SHR-1314) is a novel humanized mAb targeting IL-17A. The phase 2 trial evaluated the efficacy and safety of vunakizumab in patients with active PsA. METHODS:Patients aged 18-75 years with a confirmed diagnosis of active PsA were randomized (1:1:1) to receive either s.c. vunakizumab 120 mg (n = 38), vunakizumab 240 mg (n = 37) or placebo (n = 37) at weeks 0, 2, 4 and 8. At week 12, patients on placebo were switched to vunakizumab (1:1 re-randomized to 120 mg or 240 mg through week 20), while vunakizumab groups continued treatment. The primary endpoint was ACR 20% improvement (ACR20) response rate at week 12. RESULTS:At week 12, ACR20 response rates were higher in the vunakizumab 120 mg (47.4%) or 240 mg (59.5%) groups vs placebo group (21.6%; P = 0.02 and P = 0.001, respectively). In addition, improvements were sustained through 24 weeks and were noted in patients who switched from placebo after week 12. Treatment-emergent adverse events (TEAEs) incidence exhibited analogous frequencies between vunakizumab [73.7% (120 mg), 64.9% (240 mg)] and placebo (70.3%) during the 12-week core treatment period, and no severe TEAEs occurred. CONCLUSIONS:Vunakizumab demonstrated superior efficacy to placebo and was well tolerated with an acceptable safety profile in patients with active PsA. The findings support proceeding to a phase 3 study. TRIAL REGISTRATION:ClinicalTrials.gov, www. clinicaltrials.gov, NCT05055934.

Interleukin-18 (IL-18) is a member of the IL-1 cytokine family with significant homology to IL-1β. New emerging evidence indicates that IL-18 acts as a pivotal molecular bridge connecting innate and adaptive immunity, functioning through tightly regulated mechanisms involving inflammasome-dependent and -independent proteolytic processing. The activity of IL-18 is primarily maintained by IL-18 binding protein (IL-18BP), which neutralizes IL-18 under physiological conditions. However, dysregulations in the IL-18/IL-18BP axis result in excessive IL-18 bioactivity, driving tissue inflammation and damage closely associated with autoimmune pathogenesis. Herein, we review recent advances in IL-18 biology and its expanding roles in the development of various autoimmune diseases. The molecular mechanisms by which IL-18 mediates organ-specific pathology are discussed to highlight its diverse effector functions across different autoimmune conditions. In addition, we evaluate emerging therapeutic approaches targeting the IL-18 pathway, with a focus on their potential and challenges in translational clinical research.

Ankylosing spondylitis (AS) is a chronic, immune-mediated inflammatory disorder primarily affecting the axial skeleton. It is characterized by bony fusion and syndesmophyte formation of the spine, leading to compromised mobility, reduced quality of life and increased mortality. However, the underlying immune dysregulation in AS remains poorly understood. We comprehensively profiled the peripheral immune landscape of 30 patients with active AS, all of whom were TNF-α blocker-naïve, capturing the immune profile during the active disease phase without biologic interference. Using advanced 11-color flow cytometry and FlowSOM clustering, 584 immunophenotypes were analyzed in AS and 30 age-and sex-matched healthy controls, with emphasis on both cellular composition and functional characteristics. AS patients displayed a distinctive functional “activated-exhausted” immune phenotype, dominated by CD4+CD28+CD38+PD-1+ T cells and HLA-DR+CD38+CD4−CD8− double-negative (DN) T cells. DN T cells were significantly enriched in HLA-B27-positive patients, suggesting potential as a biomarker. Network analysis revealed seven central immune subsets associated with active disease, while functional assessment demonstrated impaired CD95+CD8+ T cell apoptosis and disrupted B-cell maturation. These findings provide a detailed functional immune map of biologic-naïve active AS, offering novel mechanistic insights and identifying candidate biomarkers for precision intervention.

OBJECTIVE:To explore the clinical relevance of mitochondrial DNA (mtDNA) in systemic sclerosis (SSc) and elucidate the mechanism by which mtDNA leakage drives fibroblast activation. METHODS:Plasma mtDNA was quantified by quantitative polymerase chain reaction in 50 patients with SSc and 20 healthy controls (HCs). Primary dermal fibroblasts from five patients with diffuse cutaneous SSc and five HCs (n = 5 per group) were analyzed for mitochondrial structure, function, and RNA sequencing profiling. The opening of the mitochondrial permeability transition pore (mPTP) and oligomerization of VDAC1 were examined with Ca2+ modulators and inhibitors. Stimulator of interferon genes (STING) knockdown using small interfering RNA was performed for validation. The STING inhibitor H-151 was evaluated in vitro and in a bleomycin-induced skin fibrosis model (n = 6 mice per group). RESULTS:Plasma mtDNA levels were significantly higher in patients with SSc than in HCs, negatively correlating with forced vital capacity (r = -0.436, P < 0.01) and positively correlating with the modified Rodnan skin score (r = 0.807, P < 0.001), interleukin-6 (r = 0.667, P < 0.001), and transforming growth factor β (r = 0.678, P < 0.001). SSc fibroblasts exhibited abnormal mitochondrial morphology and dysfunction. Increased MCU and VDAC1 levels promoted mitochondrial Ca2+ overload, mPTP opening, VDAC1 oligomerization, and cytosolic mtDNA accumulation, which activated the cyclic GMP-AMP synthase (cGAS)-STING pathway and triggered profibrotic responses. Pharmacologic blockade of mPTP or VDAC1 reduced cytosolic mtDNA, whereas H-151 suppressed profibrotic markers in SSc fibroblasts and attenuated dermal thickening and collagen deposition in bleomycin-treated mice. CONCLUSION:The Ca2+-mtDNA-cGAS-STING axis drives fibroblast activation and skin fibrosis in SSc, representing a promising therapeutic target.

AIM:This Phase Ib/II study aimed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of Firsekibart in the treatment of gout flares. METHODS:Phase Ib part utilized an open-label, single-dose, dose-escalation design. Patients were enrolled and received a single subcutaneous injection of Firsekibart at a dose of 50, 100, or 195 mg. Phase II part was a multicenter, randomized, double-blind, parallel, positive-controlled study. Patients were assigned to receive either Firsekibart (100 or 195 mg) or Diprospan. RESULTS:As of June 9, 2022, a total of 120 patients (Phase Ib N = 29, Phase II N = 91) received the study drugs. In Phase Ib, Firsekibart demonstrated dose-dependent efficacy. Firsekibart 50 mg treatment provided less pain relief compared to the 100 mg and 195 mg. In Phase II, the visual analogue scale (VAS) score decreased by 5.51 ± 1.56, 4.72 ± 1.56 and 4.94 ± 2.44 cm after 72 h in Firsekibart 195 mg, 100 mg and Diprospan groups, respectively. Firsekibart 195 mg treatment showed a more effective pain relief trend. The pharmacokinetic (PK) profile of serum Firsekibart exhibits typical characteristics of monoclonal antibodies, featuring slow absorption (median Tmax approximately 5.9-6.9 days), limited distribution (distributed volume approximately 8.0-12.1 L) and slow elimination (clearance approximately 9.2-11.5 mL/h). Safety of Firsekibart was favorable and comparable across doses and relative to Diprospan. CONCLUSION:A single subcutaneous injection of Firsekibart is safe and well tolerated in the treatment of gout flares. It provides dose-dependent pain relief with favorable pharmacokinetic properties and potential for reducing the risk of gout flare recurrence. TRAIL REGISTRATION:Trial Registration: ClinicalTrials.gov NCT05328531.

Patients with recurrent acute gout flares who are unable to use nonsteroidal anti-inflammatory drugs (NSAIDs) or colchicine have limited alternatives and remain at high risk of flare recurrence. Firsekibart is a fully human monoclonal antibody targeting interleukin-1βeta (IL-1β) The objective of this study is to evaluate the longer-term efficacy and safety of firsekibart through 48 weeks in patients with acute gout unsuitable for standard anti-inflammatory therapy. This was a multicenter, randomized, double-blind, positive-controlled phase 3 study of firsekibart with compound betamethasone. Followed by a 24-week open-label extension (OLE), conducted at hospitals in China. The double-blind phase was conducted from Week 0 to Week 24, followed by an OLE through Week 48 and a 12-week safety follow-up period after the last dose. Adults with ≥ 2 acute gout flares in the past year and a contraindication, intolerance, or inadequate response to NSAIDs and/or colchicine were enrolled. Patients completing the double-blind phase entered the OLE, during which firsekibart was administered for acute gout flares as needed. Efficacy included proportion of patients experiencing ≥ 1 gout flare recurrence, number of flares per patient, and time to first recurrence through Week 48, as well as rescue medication use during the OLE. Exploratory outcomes included health-related quality of life and flare-related pain. Safety included adverse events (AEs), laboratory tests, and immunogenicity. Of 313 patients (double-blind phase), 300 entered the OLE. By week 48, gout flare recurrence occurred in 70 patients (44.9

OBJECTIVES:This phase II trial aimed to evaluate the efficacy and safety of SSGJ-613, a fully human anti-interleukin 1β monoclonal antibody, compared with compound betamethasone (CB) in Chinese patients with acute gouty arthritis. METHODS:In this multicenter, double-blind, double-dummy, active-controlled study, 90 adults with gout according to the 2015 American College of Rheumatology (ACR) criteria and who had experienced an acute gouty arthritis flare within 7 days were randomized (1:1:1) to receive a single subcutaneous injection of SSGJ-613 (200 mg or 300 mg) or intramuscular CB. The primary endpoint was the change from baseline in visual analog scale (VAS) pain scores at 72 h post-dosing. Safety was evaluated through monitoring of adverse events and laboratory parameters. RESULTS:The mean changes from baseline in VAS scores at 72 h were comparable between SSGJ-613200 mg (-45.8 mm), 300 mg (-40.4 mm), and CB (-48.2 mm) groups. However, SSGJ-613 significantly reduced the risk of new flares: 16.7% (200 mg) and 14.3% (300 mg) of patients experienced new flares versus 54.8% with CB (p = 0.0037 and p = 0.0019, respectively). The safety profile of SSGJ-613 was similar to CB, with no drug-related serious adverse events reported. CONCLUSION:A single injection of SSGJ-613 demonstrated rapid pain relief comparable to corticosteroid therapy at 72 h and provided superior protection against gout flare recurrence over 12 weeks in Chinese patients, supporting its potential as an effective treatment option for acute gouty arthritis with prolonged therapeutic benefits. CLINICAL TRIALS:NCT06169891.

OBJECTIVES:Stromal-immune crosstalk shapes the pathogenic microenvironment of systemic sclerosis (SSc), but the spatial regulatory networks underlying fibrogenesis remain poorly defined. We aimed to explore tissue organisation and cell coordination in SSc skin, providing spatiotemporal insights into disease mechanisms and bridging the gap between omics discovery and precision medicine. METHODS:We performed spatial transcriptomics on skin biopsies from 10 patients with diffuse cutaneous SSc and 4 healthy controls using the 10× Visium platform. These findings were confirmed using higher-resolution Stereo-seq transcriptomics, spatial proteomics, and single-cell RNA sequencing data from patients with SSc, SSc mouse models, and wound-healing reindeer models. In vivo and in vitro studies were conducted to validate the key regulatory pathways. RESULTS:Fourteen skin biopsies were analysed, revealing significant expansion of fibrotic niches enriched with fibroblasts and macrophages in SSc, correlating with clinical severity. We revealed disease-specific cell states of fibroblasts and macrophages and evaluated their spatial dependency and cell-cell communication. Stratification based on signature genes enabled the identification of patients with SSc with progressive disease and treatment-nonresponsive phenotype. ACKR3 (a CXCL12 decoy receptor) was selectively expressed in myofibroblast progenitors, which diminished during differentiation towards mature myofibroblast, potentially serving to regulate CXCL12/CXCR4-mediated proinflammatory macrophage recruitment. Inhibition of CXCR4 attenuated skin and lung fibrosis in experimental fibrosis mouse models. CONCLUSIONS:Our spatially resolved atlas uncovered dynamic fibroblast-macrophage interplay as a hallmark of fibrotic niche expansion. These findings offer spatiotemporal insights into disease mechanisms and pave the way for advanced mechanistic and therapeutic studies, bridging the gap between omics discovery and precision medicine.

To evaluate the association of anti-IFI16 antibodies with peripheral vasculopathy and the predictive value of anti-IFI16 antibodies for the development or persistence of digital ulcers (DPDU) in SSc. A total of 42 SSc patients and 42 age- and sex-matched healthy controls were enrolled. Anti-IFI16 antibodies were examined by ELISA. Nailfold videocapillaroscopy (NVC) and power Doppler ultrasound (PDUS) were used to assess the micro- and macro-vascular involvement in SSc. All patients were followed up for 6 months to evaluate DPDU. Potential risk factors for DPDU were analyzed by a Firth’s penalized logistic regression model. Of the 42 SSc patients enrolled, 19.05

This phase 3 trial evaluated the efficacy and safety of Firsekibart, a novel, fully human anti-interleukin-1β monoclonal antibody, in patients with frequent acute gout flares unsuitable for standard therapy. Patients were randomized (1:1, stratified by baseline pain visual analog scale [VAS]) to the Firsekibart (200 mg) or compound betamethasone (CB; 7 mg) group. Co-primary endpoints included change in pain intensity in the target joint at 72 h (non-inferiority testing) and time to first new flare within 12 weeks (superiority testing). The non-inferiority margin was 10 mm. The full analysis set included 311 patients (Firsekibart: N = 156; CB: N = 155). At 72 h, the least squares mean change in pain VAS scores from baseline was -57.09 mm (95% confidence interval [CI]: -60.08 to -54.10) for Firsekibart and -53.77 mm (95% CI: -56.77 to -50.77) for CB, with treatment difference of -3.32 mm (95% CI: -7.56 to 0.91), establishing non-inferiority. The median time to first new flare was not reached within 12 weeks in the Firsekibart group compared with 45.0 days (95% CI: 28.00 to 63.00) in the CB group. Firsekibart significantly reduced the risk of new flare by 90% vs. CB (hazard ratio: 0.10; 95% CI: 0.06 to 0.17; stratified log rank p < 0.0001). Efficacy was consistent across subgroups. Treatment-emergent adverse events occurred in 71.2% of Firsekibart-treated patients and 69.9% of those receiving CB. In conclusion, Firsekibart is effective and well tolerated for acute gout flares in patients unsuitable for standard therapy, demonstrating non-inferiority in rapid pain relief and significant superiority in preventing flare compared with CB.

Acute gouty arthritis is characterized by sudden, severe attacks of pain, swelling, redness, and tenderness in joints. Managing acute gout attacks requires timely and effective control of the inflammatory reaction caused by monosodium urate (MSU) crystals. In clinical practice, intra-articular drug injection is a common treatment which partially reduces the side effects of oral administration. However, due to the low retention time and persistence of small-molecule drugs in the joints, the effects are often minimal. Therefore, a sustainable and on-demand drug delivery system is warranted. In the present study, a novel in situ sustained and pH-responsive hydrogel microsphere loaded with Gas6 (CMCS@SAG) was fabricated for acute gouty arthritis treatment, and the therapeutic effect was evaluated in vitro and in vivo. The results showed that CMCS@SAG was a spherical porous structure with a diameter of 100 μm. The loaded Gas6 was slowly released and referred to release under acidic pH conditions. In vitro, it was observed that CMCS@SAG effectively inhibited acute inflammatory response induced by macrophages, and enhanced mitochondrial function. In vivo, the joint swelling level decreased, infiltration of inflammation decreased, and multiple immunofluorescences showed significantly increased M2 polarization and anti-inflammatory effects in CMCS@SAG group. These results indicated that CMCS@SAG may be a promising avenue for alleviating acute gouty arthritis.

Systemic sclerosis (SSc) is a connective tissue disease characterized by progressive fibrosis of the skin and visceral organs, to date, skin fibrosis remains a clinical therapeutic challenge. Adipose-derived mesenchymal stem cells (AMSCs) have been considered extremely promising for the treatment of SSc, and the biological effects of MSCs are partly attributed to the secretion of exosomes (exos). Our aim was to determine whether exosomes derived from AMSCs have parental biological effects to AMSCs in the therapy of SSc skin fibrosis. In vitro cellular experiments, AMSCs and SSc skin fibroblasts were cocultured in direct contact and transwell indirect contact at a ratio of 1:5 and 1:10, respectively, then exosomes were extracted from the cell culture supernatant of AMSCs and identified, and the exosomes were cocultured with fibroblasts to investigate the effects of AMSCs and exosomes on fibroblast collagen synthesis. Repeated subcutaneous injections of bleomycin (BLM) to construct a model of SSc skin fibrosis in vivo experiments, then AMSCs and exosomes were injected subcutaneously to investigate their effects on skin fibrosis in the BLM mice. The results revealed that exosomes had similar biological functions to AMSCs, by inhibiting the TGF-β1/Smad3 axis, which alleviated collagen synthesis in skin fibroblasts from SSc patients and skin fibrosis in BLM models. In conclusion, AMSCs-derived exosomes may be “rising star candidates” for the treatment of SSc skin fibrosis.

Social isolation is common and associated with many adverse outcomes. The evidence regarding social isolation and mortality among middle-aged and older adults with arthritis was lacking. The study aimed to examine the association between social isolation and mortality in this population. This study used data from four prospective cohorts: National Health and Aging Trends Study (NHATS), English Longitudinal Study of Ageing (ELSA), China Health and Retirement Longitudinal Study (CHARLS), and Chinese Longitudinal Healthy Longevity Survey (CLHLS). Individuals with arthritis (including osteoarthritis and rheumatoid arthritis) in these cohorts were included. Social isolation was assessed using self-reported questionnaires. Cox proportional hazards regression models were conducted to evaluate these associations. At baseline, a total of 16,035 individuals with arthritis (3872 from NHATS, 3259 from ELSA, 5645 CHARLS, and 3259 from CLHLS) were included. Social isolation was associated with increased risk of mortality in meta-analysis (hazard ratio [HR] 1.42, 95% confidence interval [CI]: 1.26-1.59), and individual cohorts (NHATS: HR 1.53, 95% CI 1.19-1.97; ELSA: HR 1.31, 95% CI 1.02-1.67; CLHLS: HR 1.50, 95% CI 1.36-1.64) after being adjusted for confounder factors. Additionally, with increasing social isolation score, the risk of mortality also increased in meta-analysis (HR 1.19, 95% CI 1.15-1.24), as well as in individual cohorts (NHATS: HR 1.22, 95% CI 1.14-1.30; CLHLS: HR 1.19, 95% CI 1.13-1.26). Subgroups analysis results suggested that social isolation was independently associated with a higher likelihood of mortality in middle-aged and older adults with arthritis, regardless of gender, lifestyles, and chronic diseases.

Fibrosis is a common pathological feature of most chronic diseases progressing to the end stage, with its specific pathogenesis still unclear and lacking effective therapeutic approaches. Mitochondria are essential organelles responsible for energy production and the maintenance of cellular homeostasis. Increasing evidence indicates that mitochondrial dysfunction is closely associated with the onset and progression of fibrotic diseases. In this review, we explore the relationship between mitophagy, oxidative stress, mitochondrial dynamics, mtDNA release, and progression of fibrosis from the perspective of mitochondrial dysfunction. Furthermore, we summarized the latest research advances of mitochondrial dysfunction in lung, liver, kidney and skin fibrosis, and provided an overview of the potential therapeutic use of mesenchymal stem cell-derived exosomes in the treatment of fibrotic diseases by improving mitochondrial function, aiming to deepen the understanding of mitochondrial dysfunction in the pathogenesis of fibrotic diseases and provide new insights into targeting mitochondria in the treatment of fibrotic diseases.

Authors’ Response to Letter to Editor from Yan Shen and Xianxian Fu.