Objective Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterised by progressive pulmonary fibrosis. This study aimed to investigate the role of programmed death-1 (PD-1)-expressing T cells in SSc-ILD pathogenesis and evaluate the therapeutic potential and mechanism of mesenchymal stromal cells (MSCs) in mitigating fibrosis.Methods PD-1 expression in T cells from 30 patients with SSc (including SSc-ILD and SSc-non-ILD (nILD) subgroups) and 15 healthy controls (HCs) was analysed via flow cytometry. A bleomycin (BLM)-induced SSc-ILD mouse model was established to evaluate the effects of MSCs in the treatment of lung collagen deposition and inflammation in SSc-ILD. MSCs were administered intravenously to BLM-treated mice, with programmed death-ligand 1 (PD-L1) knockdown (using small interfering RNA targeting PD-L1, siPD-L1) used to explore the mechanism of MSCs on PD-1/PD-L1 pathway. The effects of MSCs on CD4+PD-1+ T cell proliferation and apoptosis were evaluated by in vitro co-culture experiment.Results PD-1 expression was significantly elevated in CD3+ and CD4+ T cells of patients with SSc-ILD compared with HCs and SSc-nILD subgroups. In BLM-induced mice, CD4+PD-1+ T cells in the lung tissues increased progressively, which was correlated with the severity of lung fibrosis. CD4+PD-1+ T cells directly stimulated fibroblasts to upregulate the expression of collagen and transforming growth factor β1. Treatment with MSCs reduced pulmonary inflammation, fibrosis and PD-1+ T cell frequencies in lung tissues of BLM-induced mice. This therapeutic effect was PD-L1-dependent, as it was mediated by the MSC-induced suppression.Conclusion CD4+PD-1+ T cells drive fibrosis in SSc-ILD, and MSCs ameliorate disease by suppressing PD-1+ T cells through PD-L1-mediated mechanisms. These findings highlight PD-1 as a therapeutic target and support the clinical investigation of MSC-based interventions for SSc-ILD.

Importance A notable proportion of patients with ankylosing spondylitis (ie, radiographic axial spondyloarthritis [r-axSpA]) experience either inadequate responses or intolerance to available therapies, highlighting the need for additional treatment options that offer sustained disease control. Objective To evaluate the efficacy and safety of vunakizumab, a novel anti–interleukin (IL) 17A monoclonal antibody, in r-axSpA. Design, Setting, and Participants This randomized, double-blind, placebo-controlled, phase 2 to 3 clinical trial was conducted in 38 hospitals in China. A total of 548 adult patients (aged ≥18 years) with active r-axSpA were enrolled between June 9, 2021, and March 30, 2023. Data were analyzed from November 3, 2023, to January 14, 2024. Interventions In phase 2, patients were randomized 2:2:1 to receive a subcutaneous dose of vunakizumab, 120 mg, vunakizumab, 240 mg, or placebo; vunakizumab, 120 mg was determined to be the recommended dose after interim analysis. In phase 3, patients were randomized 2:1 to receive vunakizumab, 120 mg or placebo at weeks 0, 2, 4, 8, and 12; from week 16, all patients received vunakizumab, 120 mg every 4 weeks through week 32. Main Outcomes and Measures The primary end point was the proportion of patients with improvement of 20% or greater in Assessment of Spondyloarthritis International Society response criteria (ASAS20) at week 16. Secondary end points were ASAS20 at week 32, improvement of 40% or greater in ASAS response criteria (ASAS40) at weeks 16 and 32, improvement of 20% or greater in 5 of 6 ASAS domains (ASAS5/6) at weeks 16 and 32, and changes from baseline at weeks 16 and 32 in Bath Ankylosing Spondylitis Disease Activity Index score, Bath Ankylosing Spondylitis Functional Index score, Bath Ankylosing Spondylitis Metrology Index score, 36-Item Short Form Survey score, and Ankylosing Spondylitis Quality of Life Questionnaire score. Results During the entire study, 548 patients were randomized (mean [SD] age, 33.0 [8.9] years; 440 [80.3%] male), including 294 receiving vunakizumab, 120 mg and 146 receiving placebo. At week 16, the ASAS20 response rate was significantly higher with vunakizumab, 120 mg vs placebo (193 [65.6%] vs 62 [42.5%], respectively; difference, 23.2% [95% CI, 11.8%-34.0%]; P < .001); the ASAS40 response rate also favored vunakizumab, 120 mg vs placebo (136 [46.3%] vs 35 [24.0%], respectively; difference, 22.3% [95% CI, 13.3%-31.3%]; P < .001). Responses with vunakizumab were sustained through 32 weeks. During the placebo-controlled period, incidence of adverse events (246 [83.7%] vs 119 [81.5%]) were comparable in the vunakizumab, 120 mg and placebo groups. Conclusions and Relevance In this randomized clinical trial of patients with r-axSpA, vunakizumab, 120 mg significantly improved signs and symptoms of r-axSpA at week 16 compared with placebo, with sustained efficacy through 32 weeks, and demonstrated a tolerable safety profile. These findings support vunakizumab, 120 mg as a new treatment option for active r-axSpA. Trial Registration ClinicalTrials.gov Identifier: NCT04840485

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

In rheumatoid arthritis (RA), there is a marked elevation of both polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and age-associated B cells (ABCs) within affected joints, which are closely associated with the progression of disease. However, the interactions between these cell types remain poorly understood. This study seeks to elucidate the regulatory influence of PMN-MDSCs on ABCs and to uncover the underlying mechanisms, thereby providing novel insights into the pathogenesis of RA and identifying potential therapeutic targets. We observed increased frequencies of both PMN-MDSCs and ABCs in the joints and spleens of collagen-induced arthritis (CIA) mouse model, with a strong positive correlation specifically in joint tissues. RNA sequencing of CD11c+ B cells derived from CIA mice revealed distinct pro-inflammatory and chemotactic profiles. In vitro, PMN-MDSCs enhanced T-bet expression in CD11c+ B cells and drove ABCs differentiation, independent of direct cell contact. B-cell activating factor (BAFF) was found to support ABCs proliferation and differentiation. Mechanistically, BAFF derived from PMN-MDSCs activated the SYK-ERK1/2 signaling pathway via the BAFF receptor (BAFFr), leading to upregulation of T-bet expression in CD11c+ B cells. SYK inhibitor ameliorated arthritis symptoms and reduced ABCs populations across tissues. And patients with RA exhibited increased PMN-MDSCs and ABCs in both blood and synovial fluid (SF), with a significant correlation between the two cell types. Furthermore, PMN-MDSCs derived from RA patients facilitated the differentiation of ABCs in vitro. These findings highlight the role of PMN-MDSCs in driving RA inflammation by promoting the proliferation and differentiation of ABCs through the BAFF-mediated SYK-ERK1/2 signaling pathway.

[This corrects the article DOI: 10.3389/fimmu.2026.1767359.].

Sjögren’s Disease (SJD) is an autoimmune disorder involving lymphocytic infiltration of exocrine glands, notably salivary and lacrimal glands, causing dysfunction. Ferroptosis, an iron-dependent cell death pathway, contributes to glandular injury. Ferritinophagy, regulated by the TFRC/FTH1/NCOA4 axis, releases iron and promotes ferroptosis. Effective therapeutic strategies targeting this axis are limited. To investigate if artesunate (ART), an artemisinin derivative with anti-inflammatory/antioxidant properties, inhibits ferroptosis by modulating the TFRC/FTH1/NCOA4 axis and alleviates salivary gland dysfunction in SJD. Non-Obese Diabetic (NOD) mice (SJD model) were orally treated with ART. IFN-γ induced ferroptosis in human salivary gland (A253) cells. Analyses included scRNA-seq, bulk RNA-seq, molecular docking, Western blotting, immunofluorescence, flow cytometry, and functional assays. ART significantly improved salivary gland histopathology and function in NOD mice, reducing inflammatory infiltration and increasing saliva flow. ART also lowered serum IgG and hepatic/renal dysfunction markers. Cellularly, ART suppressed IFN-γ-induced lipid peroxidation, mitochondrial damage, and rescued viability and aquaporin 5 (AQP5) expression. Mechanistically, ART modulated the TFRC/FTH1/NCOA4 axis: downregulating TFRC (iron uptake), upregulating FTH1 (iron storage), and reducing NCOA4 and LC3-II/I (suppressing ferritinophagy), ultimately downregulating heme iron levels. Docking indicated that ART binds the FTH1–NCOA4 interface, potentially hindering ferritin degradation. ART also upregulates GPX4 and xCT, synergistically inhibiting ferroptosis. ART mitigates SJD-associated salivary gland dysfunction by dually targeting the ferritinophagy axis (TFRC/FTH1/NCOA4 modulation) and augmenting antioxidant defense, supporting novel therapeutics targeting ferroptosis for SJD.

BackgroundProgressive multiple sclerosis (PMS) is a disabling demyelinating disease characterized by irreversible neurodegeneration. Unlike relapsing-remitting MS, for which many disease-modifying therapies exist, treatment options for PMS are extremely limited. Only two agents (ocrelizumab and siponimod) have modest efficacy, and no effective therapies exist for non-active disease. Mesenchymal stem cell (MSC) transplantation has emerged as a promising strategy due to its immunomodulatory and neurotrophic properties. However, clinical trials have yielded inconsistent results, and prior meta-analyses were limited by mixed MS subtypes and non-randomized studies, leaving uncertainty about MSC’s clinical utility in PMS.ObjectiveTo rigorously evaluate the efficacy and safety of MSC transplantation in PMS patients through a systematic review and meta-analysis of exclusively randomized controlled trials (RCTs), and to provide evidence-based recommendations.MethodsTwo researchers searched PubMed, Embase, Web of Science, Cochrane Library, and Chinese databases from inception to March 2026. RCTs comparing MSC transplantation with placebo in adult PMS patients were included. Primary outcome: change in Expanded Disability Status Scale (EDSS) score. Secondary outcomes: treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Meta-analysis used RevMan 5.4 with random/fixed-effects models. Certainty of evidence was assessed by GRADE. Protocol registered on PROSPERO (CRD420261301154).ResultsThree RCTs (143 patients; 75 MSC, 68 control) were included. MSC therapy did not significantly improve EDSS scores (pooled MD = -0.08, 95% CI -0.38 to 0.22, P = 0.61; I² = 66%). MSC did not increase TEAEs (RR = 1.08, 95% CI 0.86 to 1.35, P = 0.52) or SAEs (RR = 0.79, 95% CI 0.26 to 2.36, P = 0.67). GRADE: moderate certainty for TEAEs, very low for EDSS change and SAEs.ConclusionMSC transplantation appears safe in PMS patients, with no increased adverse event risk. However, current evidence does not support significant benefit on EDSS scores in unselected patients. Given the very low to moderate certainty, further high-quality RCTs are warranted.This systematic review and meta-analysis was conducted in strict accordance with the Cochrane Handbook for Systematic Reviews of Interventions (version 6.5) and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines[24, 25]. The study protocol was prospectively registered on the International Prospective Register of Systematic Reviews (PROSPERO, registration number: CRD420261301154) prior to literature screening and data extraction.

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.

Lupus nephritis (LN) is a common renal complication of systemic lupus erythematosus, and its severity is closely correlated with disease prognosis. Conventional therapy for LN faces challenges including multiple side-effects caused by systemic administration and low drug delivery efficiency due to lack of organ targeting. Herein, we designed a renal-targeted delivery platform based on C-C Motif Chemokine Receptor 2 (CCR2)-C-C Motif Chemokine ligand 2 chemotaxis, constructed by engineering CCR2-overexpressing mesenchymal stromal cell-derived EVs loaded with mycophenolic acid (MPA)-encapsulated MSNs (MPA@CMSNs). In LN models, MPA@CMSNs enabled efficient delivery of MPA into renal region and significantly alleviated kidney inflammation. Mechanistically, MPA@CMSNs effectively inhibited the proliferation and differentiation of proinflammatory immune cells, while concurrently suppressing the Dectin3/NF-κB signaling pathway in macrophages to remodel and optimize the renal immune microenvironment. Collectively, our findings present an efficient renal-targeted strategy with profound therapeutic efficacy against LN, offering a promising approach for targeted disease treatment.

Multiple sclerosis (MS) is a chronic immune-mediated inflammatory demyelinating disease of the central nervous system (CNS), characterized by multifocal lesions, axonal damage, and progressive neurological dysfunction, imposing a heavy burden on patients and healthcare systems. While T lymphocytes have long been regarded as central to MS pathogenesis, accumulating evidence underscores the pivotal role of B lymphocytes and dysregulated cytokine networks (e.g., Th17/IL-17 and NF-κB pathways) in driving disease initiation and progression. Despite advances in symptomatic management and disease-modifying therapies (DMTs), clinical interventions for MS remain constrained by severe side effects, drug dependency, and suboptimal long-term efficacy, highlighting an urgent unmet need for novel therapeutic strategies. Natural compounds (e.g., alkaloids, flavonoids, terpenoids, and polyphenols) have emerged as promising candidates owing to their inherent biocompatibility, favorable safety profiles, and multi-targeted regulatory effects on neuroinflammation. This review critically synthesizes and evaluates current evidence on the therapeutic potential of natural compounds in MS, with a focus on cross-compound class integration of core common pathways (e.g., NF-κB inhibition and Th17/Treg balance modulation) rather than isolated mechanism descriptions. We explicitly compare the strength of evidence across different natural compounds, clarifying which findings are well-substantiated versus preliminary. Notably, we emphasize the inherent limitations of experimental autoimmune encephalomyelitis (EAE) models in recapitulating human MS pathophysiology (e.g., interspecies immune divergence and disease heterogeneity) and integrate or at least reference relevant clinical/epidemiological evidence to enhance translational relevance. Finally, we outline key future perspectives, including the integration of natural products with existing DMTs, challenges in clinical trial design, and prospects of combination therapies, aiming to provide a directional framework for advancing natural compounds from preclinical exploration to actionable clinical therapeutic targets in MS and enhancing the translational impact of this field.

HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase Family Member 6 (HERC6) is an IFN-stimulated gene (ISG) encoding an E3 ubiquitin ligase that plays significant roles in antiviral innate immunity. However, current research on HERC6 has primarily focused on the liver and immune cells. Its expression, regulation, and function in the kidney, particularly in podocytes remain largely unexplored. The aim of this study is to investigate the pathogenic role and mechanism of the E3 ubiquitin ligase HERC6 in podocyte injury of lupus nephritis (LN). Key genes were identified through bioinformatic screening of LN patient datasets. HERC6 expression was validated in renal tissues from LN patients and two lupus murine models, and the correlation between its urinary HERC6 levels and the clinical parameters of patients was analyzed. In vivo, the therapeutic efficacy of renal HERC6 knockdown was evaluated in MRL/lpr mice using AAV9-mediated delivery of HERC6-specific shRNA.In vitro, podocytes were stimulated with IFN-α to investigate gene induction. Following HERC6 knockdown, cellular phenotypes, inflammatory cytokine secretion, apoptosis, cell cycle, and mitotic spindle morphology were analyzed using qPCR, western blot, flow cytometry, ELISA, and immunofluorescence. Bioinformatic analysis identified HERC6 as a key differentially expressed gene in LN. Its significant upregulation was validated in renal tissues especially in glomerulus from LN patients and two murine lupus models. Moreover, clinical specimen analysis verified significantly elevated urinary HERC6 levels in LN patients, which correlated tightly with disease activity indicators, including proteinuria and hypocomplementemia. Renal-targeted HERC6 knockdown significantly attenuated lupus nephritis progression in MRL/lpr mice, alleviated both LN progression and podocyte injury. Mechanistically, type I interferon (IFN-α) directly induced HERC6 expression in podocytes. Functional experiments demonstrated that HERC6 knockdown markedly alleviated IFN-α-induced podocyte injury, characterized by restoring expression of podocyte markers, reducing secretion of inflammatory cytokines and decreasing apoptosis. Further investigation revealed that HERC6 deficiency reversed IFN-α-induced mitotic spindle abnormalities and G2/M phase arrest. This study unveiled a novel pathway wherein HERC6 induced podocyte injury through disruption of mitotic homeostasis, revealed its potential as a therapeutic target in LN.

Ankylosing spondylitis (AS) is an immune-mediated spondyloarthropathy with unmet clinical needs. We conducted a superiority, phase 3, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of XKH004, a humanized monoclonal antibody targeting interleukin-17A/F in active AS. Of 489 screened patients with inadequate response to conventional therapy, 166 were excluded based on predefined criteria. The remaining 323 eligible patients were randomized 1:1 via a centralized interactive web-response system to receive subcutaneous XKH004 160 mg every 4 weeks or placebo until week 16. All patients completed a 52-week follow-up period, comprising 44 weeks of open-label XKH004 treatment followed by an 8-week safety follow-up. Participants and investigators were blinded to treatment allocation. Efficacy analyses utilized the Cochran–Mantel–Haenszel test. The primary endpoint was Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 16; secondary endpoints included ASAS20/50, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, Ankylosing Spondylitis Quality of Life, and Ankylosing Spondylitis Disease Activity Score. At week 16, ASAS40 response was achieved by 45.4% with XKH004 (n = 161) vs 19.4% with placebo (n = 162; absolute difference, 95% confidence interval, 15.47–35.02; P < 0.001), with efficacy in the XKH004 group sustaining and further improving to 66.2% by week 52. Serious adverse events occurred in 1.2% and 2.5% of patients in the XKH004 and placebo groups, respectively. Overall, XKH004 was well tolerated and induced rapid, sustained improvements, supporting its potential as a novel therapeutic option for active AS. The trial was registered in the China Drug Experiment database (CTR20232310) and ClinicalTrials.gov (NCT07498634) and supported by the National Natural Science Foundation of China, National Key Research and Development Project, Shanghai Municipal Key Clinical Specialty, and Shanghai Science and Technology Development Funds.

To evaluate the diagnostic and clinical relevance of quantitative lung ultrasound (LUS) score in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD), and to determine its correlation with high-resolution computed tomography (HRCT) severity, pulmonary function, and laboratory parameters. The cross-sectional, single-center observational study enrolled patients with connective tissue diseases who had confirmed interstitial lung disease and underwent both HRCT and LUS within 7 days of evaluation. Lung ultrasound was performed using a 12-zone scanning protocol, and B-lines were quantified to derive a semi-quantitative LUS-B score representing subpleural interstitial involvement. ILD severity categories were defined based on HRCT Warrick scores as mild (0–7), moderate (8–15), and severe (> 15). Pulmonary function tests and laboratory parameters, including inflammatory and immune-related markers, were collected. Correlations between LUS-B score, HRCT severity, pulmonary function, and laboratory variables were analyzed, and multinomial logistic regression was used to evaluate the association between LUS-B score and ILD severity categories. Diagnostic performance was assessed using ROC analysis. 117 patients with CTD-ILD (mean age 57 ± 12 years; 74

Objective: Lupus nephritis (LN) treatment faces the challenge of balancing effective immunosuppression with systemic safety. To address this, we aimed to develop a biomimetic nanoplatform capable of simultaneously targeting multiple pathogenic pathways in LN, thereby achieving potent immunomodulation without broad toxicity. Methods: A "smart immune decoy" (RAPA@MEX-PL) was engineered by encapsulating rapamycin (RAPA) in mesenchymal stromal cell-derived exosomes (MEX) and coating the surface with a cationic polylysine (PLL) corona. The platform was designed to concurrently: (1) the polylysine corona potently scavenges cell-free DNA (cfDNA) to quench TLR9-mediated inflammation, (2) the MEX core mediates the repolarization of macrophages from an M1 to an M2 phenotype, and (3) localized RAPA release provides durable mTOR inhibition, synergistically rebalancing autoimmune responses. Renal targeting, immunomodulatory activity, and systemic safety were evaluated in lupus-prone mouse models. Results: In lupus-prone mice, RAPA@MEX-PL demonstrated precise accumulation in renal tissue, leading to a significant reduction in auto-antibody levels and resolution of glomerular inflammation. The platform concurrently addressed three key pathogenic pathways-cfDNA scavenging, macrophage repolarization and mTOR inhibition-resulting in synergistic rebalancing of autoimmune responses. Notably, it circumvented the metabolic side effects typically associated with systemic RAPA administration. Conclusions: The RAPA@MEX-PL nanoplatform represents a targeted and effective immunotherapeutic strategy for LN, capable of achieving sufficient immunosuppression without systemic toxicity. These findings emphasize its potential as a favorable candidate for the therapy for autoimmune diseases.

OBJECTIVES:Orelabrutinib is an oral, highly selective, irreversible inhibitor of Bruton's tyrosine kinase (BTK). Preclinical mechanistic studies have demonstrated its therapeutic potential in systemic lupus erythematosus (SLE). METHODS:A multicentre, double-blind, randomised, placebo-controlled, parallel-group, phase Ib/IIa study was conducted in 11 centres in China. Patients diagnosed with SLE were randomised 1:1:1:1 to receive oral orelabrutinib at 50 mg, 80 mg, and 100 mg or placebo once daily for 12 weeks, respectively. This trial is registered with ClinicalTrials.gov, NCT04305197. RESULTS:Between July 9, 2020 and September 29, 2021, 60 patients were randomised, with 55 patients who completed 12 weeks of treatment. Adverse events (AEs) were mostly mild or moderate. In all evaluable patients, the SLE Response Index (SRI)-4 rates at week 12 were 50%, 62%, and 64% for orelabrutinib at 50 mg, 80 mg, and 100 mg, respectively, compared with 36% for placebo, indicating dose-dependent improvement. Among patients with baseline SLEDAI-2K > 8, significantly higher SRI-4 responses were noted with orelabrutinib at 50 mg (80%, p = 0·048), 80 mg (83%, p = 0·048), and 100 mg (100%, p = 0·029) compared to placebo (0%). SRI-6 responses at week 12 were 36%, 39%, and 21% for orelabrutinib at 50 mg, 80 mg, and 100 mg, respectively, compared with 7% for placebo. Reduced proteinuria, anti-dsDNA, IgG, and IgM and increased C4 were observed with orelabrutinib treatment. CONCLUSIONS:Orelabrutinib was well tolerated and potentially efficacious in patients with SLE.

OBJECTIVES: The aim of this study is to explore whether T follicular helper cells (Tfh) cells participate in the progression of systemic sclerosis related interstitial lung disease (SSc-ILD), and to observe whether mesenchymal stem cells (MSCs) therapy are able to regulate Tfh cells and the potential mechanism of treating SSc-ILD. METHODS: The expression of CXCR5+PD-1+CD4+T cells in SSc-ILD patients was verified by flow cytometry, immunohistochemistry and immunofluorescence. In vitro differentiated Tfh cells were cocultured with human lung fibroblasts. Peripheral blood mononuclear cells (PBMCs) were directly cocultured with MSCs. Naive CD4+ T cells isolated from PBMCs were cocultured with MSCs under Tfh cell-polarizing conditions. The percentage of CXCR5+PD-1+CD4+T cells, carboxyfluorescein succinimidyl ester (CFSE) fluorescence intensity and annexin V were determined by flow cytometric analysis. Bleomycin-induced SSc-ILD mice model received Bcl-6 inhibitor or MSCs treatment respectively. Then, the histopathology of lungs and pulmonary Tfh cells were examined in these mice. RESULTS: Increased frequency of Tfh cells and intracellular IL-21 were found in SSc-ILD patients and positively correlated with mRSS. CXCR5+PD-1+ Tfh cells could drive the differentiation of myofibroblasts in vitro. Tertiary lymphoid structures (TLS), where Tfh cells localized, was found in lung biopsies from pulmonary fibrosis patients and BLM induced mice model. The upregulated frequency of Tfh cells and germinal center (GC) B cells were also found in the lung and spleen of BLM mice model. After depletion of Tfh cells, the proportion of GC B cells was reduced and the manifestation of lung fibrosis was attenuated. In addition, MSCs treatment contributed to remissive pulmonary fibrosis and reduced number of pulmonary TLS, followed by decreased frequency of Tfh cells both in lung of mice model and in peripheral circulation of SSc patients. In vitro, MSCs could downregulate the proportion of Tfh cells in SSc patients through suppressing their differentiation and proliferation. CONCLUSION: Tfh cells, which could promote fibrosis both in vivo and in vitro, play pivotal role in the pathogenesis of SSc-ILD. MSCs therapy can downregulate the percentage of Tfh cells and inhibit their proliferation and differentiation, which may be the mechanism for their effective treatment for SSc-ILD.

Hydroxychloroquine (HCQ) improves the lipid profile in patients with systemic lupus erythematosus (SLE). Whether the lipid profile-improving efficacy of HCQ relates to its metabolism by cytochrome P450 (CYP450) enzymes remains unclear. In this prospective cohort study, 459 Chinese adult patients with SLE who had received stable HCQ therapy for at least 3 months were enrolled. The whole‑blood concentrations of HCQ, desethylhydroxychloroquine (DHCQ), and desethylchloroquine (DCQ) were quantified. Genotyping was performed for 10 single‑nucleotide polymorphisms (SNPs) in CYP2C8, CYP2D6, CYP3A4, and CYP3A5. The primary outcome was lipid profile improvement, defined as achieving at least one predefined lipid profile parameter (LDL‑C < 1.8 mmol/L, TG < 1.7 mmol/L, non‑HDL‑C < 3.36 mmol/L [calculated as total cholesterol minus HDL‑C], or HDL‑C > 1.0 mmol/L) after treatment. Adjusted odds ratio (OR) and 95

Psoriasis has been successfully treated by directly blocking the interleukin (IL)-23/IL-17 pathway and several inhibitors that specifically target the IL-23/IL-17 signaling axis have been approved by the Food and Drug Administration for clinical use and show excellent efficacy. However, all the approved IL-23/IL-17 axis targeting agents cannot be non-invasively delivered as topical treatment due to their biological and physicochemical properties, e.g., susceptibility to degradation, large molecular size, hydrophobicity and charge. Herein, we used novel ionic liquid biomaterials, amino acid esters and octanoic acids, as a non-invasive transdermal drug delivery system for bicyclic peptide inhibitors targeted to IL-23R and IL-17A. Using phenotypical images, psoriasis area and severity index, hematoxylin-eosin, and immunohistochemistry, we demonstrate that a biocompatible ionic liquid-based topical delivery approach of peptide inhibitors alleviates psoriasis in an imiquimod-induced psoriasis mouse model. Flow cytometry of innate lymphoid cells (ILCs) within the spleen, peripheral blood, and lesional epidermis shows that treatment with ionic liquids-peptides selectively blocks and reconfigures the spectrum of skin-resident and circulating ILCs. These results provide a framework for a topical delivery approach for peptides. Our findings highlight the potential of topical administration of peptide inhibitors of the IL-23/IL-17 pathway by biocompatible ionic liquids to treat psoriasis. The main immunopathogenic mechanism of peptide inhibitors mitigating psoriasis is reconfiguration of a spectrum of skin-resident and circulating ILCs.

Lupus nephritis (LN) is a complex autoimmune disease and mesenchymal stem cells (MSCs), given their unique immune-modulatory potential, have emerged as a promising route for treating LN. Understanding the multiscale dynamic LN–MSC interactions and selecting the optimal clinical design for MSCs is critical to enhance their therapeutic potential and achieve meaningful benefit-risk differentiation in patients. To guide MSC clinical development, we constructed the first mechanistic quantitative systems pharmacology model of LN pathophysiology that integrated multimodal preclinical–clinical data, with detailed illustration of standard-of-care immunosuppressant pharmacology and physiologically-based biodistribution and therapeutic mechanisms of MSCs. We created model-based virtual LN patients that well captured clinical interpatient heterogeneity and were validated by numerous sets of clinical efficacy readouts, including first-hand results from our investigator-initiated trial testing MSCs in LN patients. We used this computational framework and identified that a spaced two-infusion MSC dosing strategy would yield optimal clinical response in LN patients, which directly informed the phase Ⅱ design of a novel MSC therapy. Modeling analyses further identified that CXCL10 in combination with proteinuria are potential predictive biomarkers that could boost clinical renal response to MSCs. These results demonstrated the exceptional importance of our QSP framework in driving MSC clinical development for LN patients.