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关键词： Psoriasis   biologic treatment   anti-IL23   guselkumab   risankizumab   tildrakizumab   efficacy  

摘要： IntroductionPsoriasis is a chronic, systemic inflammatory disease with significant physical and psychosocial burden. Advances in understanding the pathogenesis of psoriasis, particularly the role of interleukin (IL)23/Th17 axis, have led to the development of selective drugs targeting these cytokines. Among these, IL23 inhibitors (guselkumab, risankizumab, and tildrakizumab), represent the most recent class of biologic drugs approved for the management of moderate-to-severe plaque psoriasis. Since their approval, real-life data on the use of anti-IL23 have confirmed their high efficacy, durability, and favorable safety *** coveredThis narrative review summarizes real-world data on the effectiveness, also in difficult-to-treat areas, safety, and drug survival of IL23 inhibitors in *** opinionReal-world evidence consistently confirms the strong efficacy, favorable safety profile, and long-term treatment durability of IL23 inhibitors across various patient subgroups, including those with comorbidities, prior biologic failures, and the involvement of difficult-to-treat areas. IL23 inhibitors have become key components of the therapeutic arsenal in psoriasis, and their performance in real-world settings continues to support their widespread adoption in clinical practice.

关键词： Antimetabolites   immunosuppression   TNF inhibitor   uveitis  

摘要： Purpose: To compare the corticosteroid sparing efficacy of frequently used antimetabolites to tumor necrosis factor (TNF) inhibitors in the management of noninfectious ocular inflammation. Methods: Retrospective analysis of patients with noninfectious uveitis on conventional antimetabolite (methotrexate, mycophenolate mofetil, azathioprine,or leflunomide, "CONV") or a TNF inhibitor (adalimumab or infliximab, "TNFi") with active inflammation or more than 7.5 mg daily prednisone. Eyes were assessed in three groups: CONV only, TNFi only and combination of both (COMB). Cox regression models compared treatment success, adjusted for age, race, smoking, anatomic location of uveitis, duration of uveitis and visual acuity. Corticosteroid sparing success was defined as: inactive or slightly active uveitis on <=7.5 mg daily oral prednisone and <=2 drops of prednisolone acetate 1%. Results: There were 1475 eligible patients in the analysis. By 6 and 12 months, respectively, the Cox model-predicted, percentage success was 27.6% and 44.9% for the CONV group;34.2% and 53.9% in the TNFi group and 39.9% and 61.1% for the COMB group. COMB was more likely than CONV to achieve success (adjusted HR 1.58 (95% confidence interval (CI), 1.28, 1.95, p < 0.0001). Factors associated with lower success were age under 18 years, smoking, visual acuity worse than 20/50 at cohort entry, over 4-year duration of uveitis and daily baseline prednisone 7.5 mg or higher (all p < 0.05). Conclusion: Our results suggest COMB is more effective than CONV at achieving disease quiescence and corticosteroid sparing success among patients with active noninfectious uveitis. More research is needed to determine if TNFi alone is superior to CONV for uveitic corticosteroid-sparing.

关键词： psoriasis   super responders   IL-18   IL-13   biomarkers   precision medicine   biologic therapy   secukinumab  

摘要： Identifying immunologic predictors of clinical responses remains an unmet need in the era of biologic therapy for psoriasis. Super responders (SRs), defined as patients achieving complete skin clearance within weeks of treatment initiation, represent an emerging clinical endotype;however, their immunological profiles remain insufficiently characterized. We conducted a prospective observational study to characterize serum cytokine profiles associated with SR status in biologic-na & iuml;ve patients with moderate-to-severe plaque psoriasis treated with secukinumab, an IL-17A inhibitor. Twenty-eight patients were enrolled and stratified at week 12 into SR (PASI = 0;n = 9) and non-super responder (NSR;PASI > 0;n = 19) groups. Serum concentrations of 19 cytokines were analyzed at baseline and after 12 weeks of treatment. SRs displayed a distinct immunological signature characterized by significantly higher IL-13 and lower IL-18 baseline levels compared to NSRs (p = 0.002 and p = 0.007, respectively), alongside reduced baseline monocyte counts. L1-regularized logistic regression confirmed IL-13 and IL-18 as strong independent predictors of SR status (AUC = 0.91). Moreover, the IL-18/IL-13 ratio emerged as a highly discriminative biomarker (p = 0.00001, AUC = 0.86). Notably, SRs exhibited a more pronounced decline in IL-18 and IL-23 during treatment. Our findings provide novel insights into the immunopathogenesis of super response and suggest that an immunological milieu favoring Th2 polarization may promote superior outcomes with IL-17A blockade. Incorporating IL-13, IL-18, and their ratio into clinical algorithms may facilitate precision-guided biologic therapy in psoriasis.

关键词： antitumor   immune therapy   interferon   NanoCa  

摘要： Immune checkpoint inhibitors have revolutionized cancer therapy;however, many patients exhibit suboptimal responses, which is due to inadequate T cell priming by the innate immune response. Metal ions play a critical role in modulating the innate immune response. However, the mechanisms by which metal ions facilitate dendritic cell maturation through the activation of interferon remain poorly understood. This research identifies a nanomaterial Calcium phosphate-containing liposome (NanoCa), characterized by an atypical crystal structure and pH-responsive profile. NanoCa promotes bone marrow-derived dendritic cell maturation and exhibits antiviral effects and anti-tumor properties in different tumor models. Also, NanoCa acts as an immunostimulant by fostering antibody production. Furthermore, when combined with programmed cell death 1 receptor (PD-1) blocking antibodies, NanoCa synergistically enhances anti-tumor efficacy in CT26 models. Mechanistically, NanoCa rapidly releases Ca2+ via the lysosome pathway post-endocytosis, subsequently triggering interferon through the Ca2+-calcineurin (CaN) - nuclear factor of activated T cells 2 (NFATc2) - protein kinase C beta (PKC beta) - interferon regulatory factor 3 (IRF3) signal pathway. Single-cell RNA sequencing (scRNA-seq) shows NanoCa increases the population of tumoral infiltrating dendritic cell (DC), C1qc+ TAM, and CD8T_eff cells and decreases the CD8T_ex and immunosuppressive SPP1+ TAM population in tumor-draining lymph nodes. Overall, NanoCa shows translational potential for anti-tumor immune therapeutics.

关键词： HLA-E   COVID-19   NK cells  

摘要： Natural killer (NK) cells play a key role in the innate immune response against viral infections. Their activity is regulated by a balance of activating and inhibitory signals, which are modulated by interactions with HLA class I molecules, including HLA-E. The HLA-B 21M/T dimorphism influences the availability of HLA-B leader peptides that stabilize HLA-E expression and modulate NK cell function via the NKG2A/CD94 receptor. To investigate the association between the HLA-B -21M/T dimorphism and the clinical severity of COVID-19, we analyzed a cohort of hospitalized patients with primary SARS-CoV-2 infection, who were genotyped for the HLA-B -21M/T dimorphism. Clinical data, lymphocyte counts, the neutrophil-to-lymphocyte ratio (NLR), and inflammatory markers were compared across genotypes. Contrary to previous studies suggesting a protective effect of the M/M genotype, we found no significant association between the HLA-B -21M/T dimorphism and COVID-19 severity, lymphocyte parameters, or inflammatory biomarkers. Our findings do not support a role for the HLA-B -21M/T dimorphism in modulating COVID-19 outcomes. These results underscore the complexity of NK cell regulation and highlight the need for integrative studies combining genetic, immunological, and functional data to better understand host factors influencing disease progression.

关键词： Biologics   adverse drug reactions   inflammatory rheumatism   longitudinal study   burden of ADRs  

摘要： BackgroundThere is a lack of knowledge on patient perspectives on adverse drug reactions (ADRs) attributed to the use of biologics. The aim of this study is to quantify the burden over time of ADRs attributed to TNF-alpha inhibitors in patients with inflammatory rheumatic diseases (IRDs) and investigate whether the burden over time differs between different types of *** design and methodsData were used from the Dutch Biologic Monitor (DBM), an observational prospective cohort study for patient-reported ADRs attributed to biologics. Patients with an IRD using a TNF-alpha inhibitor reporting an ADR, lasting for three consecutive questionnaires, were included. Questionnaires were sent every 2 months and the burden was scored on a 5-point Likert-type scale. Burden scores were analyzed using linear mixed *** from 166 unique patients reporting 274 ADRs were included. The burden score decreased every month by 0.29 points (95% CI -0.34 - -0.24) on average on a 5-point Likert-type scale. The burden score for infections and infestations decreased significantly faster than the burden score for injection site ***-reported burden of ADRs attributed to the use of a TNF-alpha inhibitor in patients with IRDs decreased significantly over time, especially for infections and infestations.

关键词： Genetic variations   haplotypes   IL-23/IL-17 pathway   polymorphisms   scleritis  

摘要： PurposeTo examine the relationship between IL-23/IL-17 pathway gene polymorphisms and scleritis susceptibility in the Chinese Han *** assessed IL-23/IL-17 pathway-related SNPs in 898 scleritis cases and 1,573 controls, employing stratified analysis to evaluate subtype-specific impacts and a discovery-validation cohort strategy to ensure genetic association ***-23 R/rs10789229 TC genotype and C allele, and the IL-21/rs2221903 TT genotype and T allele were more frequent in scleritis patients (Pc = 2.07 x 10-3-2.77 x 10-6, OR = 1.497-2.327, 95% CI = 1.216-3.219), particularly anterior scleritis (Pc = 3.88 x 10-3-2.95 x 10-6, OR = 1.507-2.378, 95% CI = 1.209-3.321). The IL-23 R/rs10789229 TT genotype and T allele, and the IL-21/rs2221903 TC genotype and C allele were found less common among scleritis patients overall (Pc = 2.07 x 10-3-4.18 x 10-6, OR = 0.436-0.668, 95% CI = 0.316-0.822) and in the anterior scleritis subgroups (Pc = 3.88 x 10-3-4.43 x 10-6, OR = 0.427-0.664, 95% CI = 0.306-0.827). The analysis of haplotypes showed a noteworthy surge of IL-23 R CCCG haplotype in both scleritis patients in general (Pc = 1.91 x 10-4) and those with anterior scleritis (Pc = 1.15 x 10-4). Conversely, the frequency of the IL-17A GAA haplotype was significantly lower among scleritis patients overall (Pc = 4.17 x 10-12) and in the anterior or posterior scleritis subgroups (Pc = 7.41 x 10-11;Pc = 0.021). Only the IL-23 R/rs10789229 variant demonstrated consistent replication in the validation *** findings suggest that specific polymorphisms of IL-23/IL-17 pathway-related genes could confer risk to the development of scleritis in the Chinese Han population. Patients with varying subtypes of scleritis exhibit somewhat similar genetic profiles.

关键词： brain death   kidney donor   TNF alpha  

摘要： Kidney transplant outcomes depend on various factors, including donor type. Brain death (BD) has been associated with significant kidney injury, with long-term sequelae. Deciphering the impact of BD versus circulatory death on kidney pathophysiology may help to prevent kidney transplant injury. We developed three rat models: 6 h of BD [donor after brain death (DBD, n = 10)];donor after circulatory death (DCD, n = 10) with 20 min of warm ischemia;and 6-h BD with renal denervation before BD (DNRV, n = 6). RNA-Seq was performed on kidney tissue, followed by differential gene expression and pathway enrichment analyses. Circulating cytokines were measured by Luminex/ELISA. Our findings were validated in 10 human preimplantation biopsies matching our rat models (n = 5 DBD;n = 5 DCD). After BD, serum creatinine levels increased from 0.33 [0.31-0.38] to 0.61 [0.59-0.67] mg/dL (P < 0.0001). Compared with DCD, DBD rats exhibited significantly higher levels of IL-6 (26.67 [19.10-32.35] vs. 10.32 [9.76-13.28] ng/mL, P = 0.006) and TNF alpha (21.98 [16.48-32.60] vs. 9.64 pg/mL [7.96-11.13], P = 0.0012) and lower levels of IL-10 (1.28 [1.11-1.65] vs. 1.79 [1.46-2.18] ng/mL, P = 0.049). Differential expression analysis revealed that DBD kidneys exhibited CD11b-associated inflammation, Caspase-3-mediated apoptosis, and TNF alpha-driven injury (P = 7.34 x 10(-7);z-score = 2.475), whereas DCD kidneys activated EIF2/NRF2 stress-response pathways. Notably, denervation did not mitigate BD-induced injury. Human biopsies confirmed the positive enrichment of inflammatory pathways (P = 0.01 to 1.18 x 10(-7)) in DBD compared with DCD, with 6 out of the top 15 pathways shared across species. Our findings highlight specific mechanisms affecting differently kidneys derived from DBD versus DCD donors, with a potential role of TNF alpha in BD-associated kidney injury. Kidney denervation before BD does not prevent kidney injury.

关键词： Inflammatory bowel disease   Crohn's disease   T cells   4-1BB   mucosal immunology   PD-1   anti-TNF alpha treatment  

摘要： Objective: Pro-inflammatory T-cell responses dominate in Crohn's disease (CD). This may result from a dysbalanced expression of co-stimulatory and inhibitory T-cell receptors. The present study investigated if a dysbalanced co-stimulatory and inhibitory T-cell receptor expression are present in CD and can be rebalanced by anti-TNF alpha treatment. Methods: Mucosal biopsies from 27 patients with active CD receiving anti-TNF treatment were examined for the mRNA levels of the co-stimulatory 4-1BB and inhibitory PD-1 T-cell receptor. Levels of mRNA were compared between inflamed and noninflamed tissue, and before and after treatment. Peripheral T cells from 12 healthy controls (HC) and 11 active CD patients were evaluated for their expression of 4-1BB and PD-1 by flow cytometry. Results: The 4-1BB mRNA levels in inflamed mucosa were upregulated (> 2-fold) compared with uninflamed mucosa (p < 0.05). Anti-TNF alpha treatment reduced the 4-1BB and PD-1 mRNA levels in the inflamed gut tissue (p < 0.05). In in vitro activated T cells, the percentage of both 4-1BB and PD-1 positive CD4+ and CD8+ T cells increased more than 1.5 fold compared with HC (p < 0.05). The 4-1BB/PD-1 ratio on activated peripheral T cells was significantly reduced in CD after anti-TNF therapy (p < 0.05). Conclusions: A dysbalanced mucosal proinflammatory co-stimulatory T cell receptor expression was present in active CD and modified by anti-TNF alpha treatment. However, anti-TNF alpha treatment did not normalize the expression of 4-1BB or PD-1 on peripheral T cells although a modest increased immunoregulatory capacity could be demonstrated.

关键词： Anti-IL-23   Biologics   Psoriasis   Psoriatic arthritis   Real-life   Guselkumab  

摘要： IntroductionGuselkumab is a monoclonal antibody targeting the p19 subunit of interleukin (IL)-23, approved for the treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis (PsA). While patients with psoriasis often achieve high clinical response rates (Psoriasis Area and Severity Index [PASI] 90 and PASI 100), the presence of PsA may influence long-term outcomes. We conducted a 260-week, multicenter, retrospective study to compare the effectiveness, safety, and drug survival of guselkumab in patients with and without concomitant *** total of 1765 patients were enrolled, including 352 with a concomitant diagnosis of PsA and 1413 with isolated skin involvement. All patients were treated with guselkumab following the approved dosing schedule for moderate-to-severe plaque psoriasis for at least 1 year. Treatment effectiveness was evaluated in terms of PASI 90, PASI 100, and absolute PASI <= 2 at weeks 16, 28, 52, 104, 156, 204, and 260. Guselkumab drug survival was assessed using the Kaplan-Meier method at the same time points. The safety profile was evaluated by analyzing adverse events recorded in medical charts at each follow-up *** the study period, response rates remained comparable between the two cohorts of patients, with a significant difference at 2 years of follow-up in terms of PASI 90 (80.51% versus 74.02%). Drug survival overall remained stable and similar, with 79.5% (95% confidence interval (CI) 76.9-81.9) of patients without PsA and 78.5% (95% CI 72.9-83.1) of patients with PsA still receiving guselkumab treatment after 5 *** results confirm the long-term effectiveness, persistence, and favorable safety profile of guselkumab in patients with moderate-to-severe psoriasis, regardless of the presence of concomitant PsA.