Inflammatory Disease Research Articles

Discovery of CHF-6523, an Inhaled Selective PI3Kδ Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease.

The design of inhaled selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors for the treatment of inflammatory lung diseases was pursued. Knowledge-based design of a novel isocoumarin scaffold that was able to adopt a propeller-shape topology ensured the desired PI3Kδ selectivity. Achievement of low nanomolar cellular potencies through hinge binder group optimization, reduction of intrinsic permeability through head group optimization to extend lung retention, and screening of crystalline forms suitable for administration as dry powders culminated in the identification of compound 18. This novel inhaled selective PI3Kδ inhibitor displayed durable anti-inflammatory activity in a disease-relevant rat model of Th-2-driven acute lung inflammation and safe in vitro and in vivo preclinical profiles. Therefore, compound 18 showed the appropriate discovery profile and was progressed to clinical trials in healthy volunteers and chronic obstructive pulmonary disease (COPD) patients as CHF-6523.

IMPACT OF INFLAMMATORY RHEUMATIC DISEASES ON THE COURSE AND OUTCOME OF COVID-19

. Literature data on the risk of SARS-CoV-2 coronavirus infection in people with inflammatory rheumatic diseases (RD) are contradictory. According to most studies, the risk of infection and development of severe forms of COVID-19 is higher in patients with RD compared to the general population, but largely depends on the type and activity of RD. Patients with severe RD most often required mechanical ventilation and died more often. This is due to immune dysfunction caused by both the disease itself and antirheumatic therapy using immunomodulatory drugs. The state of immunosuppression, additional comorbid chronic diseases and incomplete vaccination are factors in the need for hospitalization, intensive care, the risk of severe COVID-19 outcomes and reinfection with coronavirus in patients with RD. They retained their significance during the spread of the SARS-CoV-2 Omicron variant. Although there is no complete consensus in the literature regarding the association between the presence of rheumatic diseases and the severity of COVID-19, in general, rheumatic diseases are not considered to be a factor that increases the severity and mortality of COVID-19. Vaccination against SARS-CoV-2 stimulates the antibody response and reduces the incidence and severity of COVID-19. However, people with rheumatic diseases have reduced or absent antibody production in response to even full vaccination and higher rates of breakthrough infection after vaccination. Further research on specific rheumatic diseases and the use of antirheumatic drugs in the context of COVID-19 is needed to reduce the severity of COVID-19 in this population.

Efficacy and safety of 5-aminolevulinic acid photodynamic therapy in refractory genital lichen sclerosus

BackgroundGenital lichen sclerosus (GLS) is a chronic inflammatory skin disease affecting the genital and anal areas. Treatment of refractory remains a challenge in clinical practice. ObjectiveThis study aimed to evaluate the efficacy and safety of 5-aminolevulinic acid photodynamic therapy (5-ALA PDT) for refractory GLS. MethodsThirty-five patients with histopathologically confirmed GLS (including 32 females and 3 males) were treated with 5-ALA PDT. Lesion pretreatment was performed to enhance photosensitizer penetration, and fluorescence diagnosis was used for precise point-to-point treatment. Efficacy and safety were systematically evaluated by assessing treatment outcomes, symptom improvement, side effects and maintenance of efficacy over a 6-month follow-up period. ResultsAfter treatment, most patients experienced significant relief of pruritus, improved skin elasticity and color, and reduced lesion area. After 6 treatment sessions, 11 patients (31.43%) achieved complete resolution of pruritus, with 3 patients (8.57%) achieving complete remission after 3 sessions. Cattaneo scores decreased significantly after treatment and during follow-up (P<0.05). Adverse reactions were mainly mild pain, which could be relieved by ice compression or oral analgesics. Conclusions5-ALA PDT shows significant efficacy and good safety for refractory GLS, improving the clinical symptoms and signs of patients, and warrants wider clinical application.

Acupuncture for atopic dermatitis: a systematic review and meta-analysis

ObjectivesAtopic dermatitis is a chronic, relapsing, inflammatory skin disease that impacts patients’ quality of life and imposes substantial economic burdens on their families. Acupuncture holds promise as a viable treatment...

Patients' Perception of the Impact of Moderate to Severe Atopic Dermatitis on Their Sexual Well-Being: Comparison of Pre- and Posttreatment with Advanced Therapies.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease that significantly affects patients' quality of life (QoL). Limited data exists on the effects AD poses on sexual well-being. Objective: To evaluate the impact of moderate-to-severe atopic dermatitis (MtS-AD) on sexual well-being and assess the efficacy of advanced therapies, specifically abrocitinib and dupilumab, in improving sexual health. Methods: In this retrospective study, medical records and responses to an 8-item questionnaire assessing sexual well-being in patients with MtS-AD were reviewed at baseline and after 52 weeks of treatment with abrocitinib or dupilumab. Results: In total, 44 patients were included (mean age: 30.8, 43.2% female). Before treatment, 88.6% reported AD affected their sexual well-being, including feeling unattractive (79.5%), avoiding sexual activity (68.2%), feeling ashamed or embarrassed (68.2%), and experiencing rejection (56.8%). After 52 weeks of treatment with abrocitinib or dupilumab, these negative perceptions and behaviors significantly reduced. Conclusions: MtS-AD negatively impacts patients' sexual well-being; however, advanced therapies like abrocitinib and dupilumab can significantly improve the sexual lives of affected patients, highlighting the broader benefits of these treatments on QoL.

Ultrarare Cause of Childhood Chorea: Celiac Disease.

Chorea, a movement disorder that commonly affects children, may be caused by various diseases with metabolic, structural, pharmacologic, or autoimmune origins. Celiac disease is an autoimmune enteropathy that may rarely cause neurologic symptoms in children, primarily ataxia and peripheral neuropathy, even in the absence of gastrointestinal symptoms. A 9-year-old male patient diagnosed with Sydenham chorea was admitted to our clinic because of valproic acid resistance. He had involuntary, brief, random, and irregular movements in his arms over the past 2 weeks. A low-dose, high-potency dopamine-2 receptor-blocking agent was added to the patient's treatment regimen. After 2 weeks, he had maculopapular rashes on their hands and arms, as well as arthritis in his left hand. Oral prednisone was prescribed, and the patient's arthritis and rashes were completely resolved. Although movement disorder symptoms persisted in the distal left upper extremity, the chorea in the right upper extremity was recovered. Extensive investigations were conducted to rule out possible metabolic, autoimmune, inflammatory, infectious, and paraneoplastic diseases, all of which yielded normal results. Brain magnetic resonance imaging (MRI) results were normal, and genetic analysis results for chorea were negative. The patient's tissue glutaminase IgG levels exceeded 200 U/mL (normal range: 0-10 U/mL) and IgA levels at 24 U/mL (normal range: 0--10 U/mL), leading to a diagnosis of celiac disease. His duodenal biopsies showed changes consistent with gluten-sensitive enteropathy. After the diagnosis of celiac disease, the patient began a gluten-free diet and remained free of chorea at the 6-month follow-up. Chorea is a rare neurologic celiac disease manifestation that can be reversible. The celiac disease should be considered in the diagnostic workup of chorea for all ages, particularly in the treatment-resistant population, even in the absence of gastrointestinal symptoms. This report presents the first known case of chorea caused by celiac disease in a pediatric patient.

Thymic Stromal Lymphopoietin (TSLP): Evidence in Respiratory Epithelial-driven Diseases Including Chronic Rhinosinusitis with Nasal Polyps.

Thymic stromal lymphopoietin (TSLP) is increasingly recognized for its pivotal role in the pathogenesis of various epithelial-driven chronic inflammatory diseases. This review navigates the existing evidence on TSLP, with a particular focus on asthma, before delving into the current understanding of its role in chronic rhinosinusitis with nasal polyps (CRSwNP). We explore the role of TSLP in the pathogenesis of asthma and CRSwNP, two conditions often interconnected and collectively referred to as"Global Airway Disease". Additionally, this review assesses the therapeutic potential of TSLP inhibition as a treatment option for both CRSwNP and asthma. A systematic literature search was conducted; selected publications were used to describe the biology of TSLP, including its expression and diverse effects on inflammation. The role of TSLP in asthma is well established and supported by the efficacy of tezepelumab, the first anti-TSLP monoclonal antibody approved for both type 2 (T2)-high and T2-low severe asthma. TSLP may be a key contributor to CRSwNP pathogenesis as evidenced by genetic and mechanistic studies in which TSLP has been shown to regulate T2 inflammation and influence non-T2 responses. Preliminary data from the NAVIGATOR trial indicate that tezepelumab may reduce CRSwNP symptoms in patients with comorbid asthma. While further research is required to clarify the extent of TSLP contribution in CRSwNP, this review highlights the potential of anti-TSLP therapies as a novel approach for managing severe, uncontrolled CRSwNP. If these preliminary findings are confirmed, targeting TSLP could become a promising strategy to treat CRSwNP with or without comorbid asthma.

Human trafficking screening in Saskatoon Emergency Departments: What can be learned from high-risk patient presentations?

ObjectiveStudies have shown that Emergency Department physicians have little to no training in recognizing and supporting victims of human trafficking despite being uniquely situated to identify and intervene on behalf of these patients. We assessed if screening for human trafficking was being completed by emergency physicians in three Saskatoon emergency departments.MethodsWe performed a retrospective chart review of patients presenting to three Saskatoon emergency departments deemed to potentially be at risk of human trafficking, based on discharge diagnosis. Of the 223 included charts, data extracted included sex, age, ethnicity, chief complaint, diagnosis, disposition, HT Screening (Y/N), specific quotes relating to HT, time of visit, intimate partner violence (Y/N), and travel history. Both quantitative and qualitative thematic analyses were conducted on this data.ResultsNone of the charts (0%) included in this study had any documentation around screening for human trafficking. Furthermore, 21.1% of the high-risk patient charts included in this study -- which included many patients with a discharge diagnosis of sexually transmitted disease or pelvic inflammatory disease -- did not contain a documented sexual history. Thematic analysis revealed that the patients included in this study frequently had challenges with sexual health, substance use, and houselessness.ConclusionThis study found that Emergency physicians in Saskatoon were not routinely screening for human trafficking. Implementation of further training is needed to help these physicians recognize and subsequently support potential victims of human trafficking.

A genome-wide association meta-analysis links hidradenitis suppurativa to common and rare sequence variants causing disruption of the Notch and Wnt/β-catenin signaling pathways.

The contributions of genetic and environmental risk factors to hidradenitis suppurativa (HS) are both poorly understood. To identify sequence variants that associate with HS and determine the contribution of environmental risk factors and inflammatory diseases to HS pathogenesis. A genome-wide association meta-analysis of 4,814 HS cases (Denmark: 1,977; Iceland: 1,266; Finland: 800; UK: 569 and US: 202) and 1.2 million controls, searching for sequence variants associated with HS. We found 8 independent sequence variants associating with HS, 6 common and 2 rare (frequency <1%). Four associations point to candidate causal genes, NCSTN, PSENEN, WNT10A and TMED10, that all map to the Notch and Wnt/β-catenin signaling pathways, involved in epidermal keratinization. Limited racial diversity may prevent identification of sequence variants of particular importance in non-Caucasian populations. These findings demonstrate that genes and pathways involved in epidermal keratinization are the genetic backbone of HS pathology.

FC08 Characterization of plasmacytoid dendritic cells-targeted CAR-T cells from patients with immune-mediated inflammatory diseases

Abstract Since the study by Mougiakakos et al., published in 2021 demonstrated the remission of a patient with systemic lupus erythematosus thanks to treatment with anti-CD19 CAR-T cells, (1) a growing number of studies have focused on autoimmune diseases (AID). Plasmacytoid dendritic cells (pDCs), which express highly the CD123 molecule, also play a major role in the pathophysiology of many types of AID. In psoriasis, pDCs secrete IFN-I intensively, leading to inflammation and recruitment of inflammatory cells to the skin, promoting Th17 polarization of LTs and phenotypic changes in keratinocytes. (2) Recently, our team has developed an anti-CD123 CAR-T targeting the pDCs in the context of AID. Our project aims to deeply characterize the phenotype and functional capacities of CD123 CAR-T using T cells from patients (psoriasis, hidradenitis suppurativa, systemic sclerosis and systemic lupus erythematosus) at different stages of the disease and treated with various biotherapies. T cells from patients or healthy donors (HD) were isolated from peripheral blood mononuclear cells and then activated and modified to express a third-generation CD123 CAR (CAR123). CAR-T proliferation, transduction efficiency and phenotype were assessed before (Day 0), after CAR insertion and at the end of in vivo culture (Day 10). The functionality of CAR-T was assessed through their cytotoxic activity and their ability to secrete cytokines in the presence of their target. The in vitro functional persistence of CAR-T is assessed using a model in which CAR-T are challenged with CD123+ cells every 3–4 days for 15 days. Transduction efficiency of the CAR123 is high in all patients (72.4% ± 18.9%, n = 28) and HD (70.4% ± 15.3%, n = 4) (P = ns). Patient-derived CAR123 effectively lysed autologous pDCs in vitro in a similar manner to HD (82.8% ± 14.2%, n = 28 for patients and 67.3% ± 10.7%, n = 4 for HD, P = ns). Importantly, CAR123 maintained their in vitro cytotoxic activity after 6 rechallenges with no difference with HD CAR123. Upon engagement with their target, CAR123 secreted Th1-type cytokines (IFN-γ and TNF-α) as HD CAR123. In the AID context, CAR-T are produced from potentially activated or autoreactive T cells from patients. Importantly, our preliminary results show the feasibility of the production and in vitro efficacy of CAR123 from patient T cells to a similar extend to CAR123 from HD. Further characterization of CAR-T phenotype and function is underway. In addition, in vivo experiments to demonstrate the value of CD123 CAR-T cells in these diseases are ongoing.

Evaluating methods for integrating single-cell data and genetics to understand inflammatory disease complexity

Evaluating methods for integrating single-cell data and genetics to understand inflammatory disease complexity

Interleukin-17 in Health and Disease: A Double-Edged Sword in Immunity

Interleukin-17 (IL-17), a key pro-inflammatory cytokine primarily produced by T-helper 17 (Th17) cells, plays a crucial role in immune regulation and host defense, particularly against extracellular pathogens such as bacteria and fungi. As part of the IL-17 family of cytokines, IL-17A and IL-17F are the most well-characterized members, essential for recruiting neutrophils and promoting the production of antimicrobial peptides. However, IL-17’s potent inflammatory effects make it a double-edged sword in immunity, contributing not only to protective immune responses but also to chronic inflammation and autoimmunity when dysregulated. IL-17 is implicated in the pathogenesis of various autoimmune and inflammatory diseases, including rheumatoid arthritis (RA), psoriasis, multiple sclerosis (MS), inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE). In these conditions, IL-17 promotes the production of other pro-inflammatory cytokines and matrix metalloproteinases, driving sustained inflammation and tissue damage. This dual role of IL-17—protective in infection but harmful in chronic inflammation—highlights its complexity in immune regulation. The therapeutic targeting of IL-17 has led to the development of biologics such as secukinumab and ixekizumab, which have shown significant efficacy in treating autoimmune diseases like psoriasis and ankylosing spondylitis. However, the use of IL-17 inhibitors presents challenges, particularly in balancing infection control with immune modulation. This review examines the biology of IL-17, its role in health and disease, and the potential therapeutic implications of modulating its activity in clinical settings. Keywords: Interleukin-17 (IL-17), Th17 cells, Autoimmunity, Chronic inflammation, Biologic

Emerging Role of NAT10 as ac4C Writer in Inflammatory Diseases: Mechanisms and Therapeutic Applications.

The incidence of inflammatory diseases, including infections, autoimmune disorders, and tumors, is consistently increasing year by year, posing a significant and growing threat to human health on a global scale. Recent research has indicated that RNA acetylation modification, a specific type of post-transcriptional modification, may play a critical role in the pathogenesis of these diseases. Among the various mechanisms of RNA modification, N-acetyltransferase 10 (NAT10) has been identified as the sole cytidine acetyltransferase in eukaryotes. NAT10 is responsible for acetylating mRNA cytosine, which leads to the formation of N4-acetylcytidine (ac4C), a modification that subsequently influences mRNA stability and translation efficiency. Despite these insights, the specific roles and underlying mechanisms by which RNA acetylation contributes to the onset and progression of inflammatory diseases remain largely unclear. This review aimed to elucidate the alterations in NAT10 expression, the modifications it induces in target genes, and its overall contribution to the pathogenesis of various inflammatory conditions. It has been observed that NAT10 expression tends to increase in most inflammatory conditions, thereby affecting the expression and function of target genes through the formation of ac4C. Furthermore, inhibitors targeting NAT10 present promising therapeutic avenues for treating inflammatory diseases by selectively blocking NAT10 activity, thereby preventing the modification of target genes and suppressing immune cell activation and inflammatory responses. This potential for therapeutic intervention underscores the critical importance of further research on NAT10's role in inflammatory disease pathogenesis, as understanding these mechanisms could lead to significant advancements in treatment strategies, potentially transforming the therapeutic landscape for these conditions.

Health-related Quality of life among patients with Ankylosing Spondylitis and its correlation with disease-related variables. A Cross-Sectional Study in Erbil City

Background and objectives: Ankylosing spondylitis is a chronic, rheumatic, inflammatory disease that basically involves axial skeleton. As a result, functional limitations develop that may negatively affect quality of life. Our aim is to assess the quality-of-life in patients with ankylosing spondylitis and to determine its’ correlation with disease variables including disease activity, functional status, spinal mobility, and bodily pain. Methods: A cross-sectional study enrolled fifty patients with ankylosing spondylitis in the Rizgari teaching hospital was conducted between November 2022 to March 2023. Both short form-36 and ankylosing spondylitis quality of life instruments were used to evaluate Health related quality of life. Bath Disease Activity Index, Bath Functional Index, Bath Metrology Index, and total pain visual analogue scale used to assess disease related variables. Results: fifty patients aged (20-50) years participated, their mean age was (35.4), the majority (80%) were males. The peripheral joints were involved in 42% of these patients. The mean ankylosing spondylitis quality of life score was 8.7 ± (4.6) SD, short form-36 domains of physical role limitation, general health, vitality, and bodily pain had the lowest scores (43.5, 44.6, 45.8, 50.7) respectively. both Bath disease activity index (B = 1.047; p = 0.010) and Bath functional index (B=0.974; p=0.012) were poor predictors of Ankylosing Spondylitis Quality of Life score, while Bath Metrology Index (B = -3.444; p = 0.043) was the main predictor for physical functioning. Conclusion: The health-related Quality of life in participants was significantly impaired. High disease activity, poor functional status and limitation in spinal mobility were recognized as poor predictors of Health-related quality of life.

Histopathological diagnostics of infections in rheumatology

The histopathological differential diagnoses of inflammatory infectious and inflammatory noninfectious diseases of the musculoskeletal system, particularly infectious and noninfectious arthritis, soft tissue inflammation and osteomyelitis in rheumatology are presented with afocus on the differential diagnostic possibilities and limitations; however, adiverse spectrum of pathogenic mechanisms underly these diseases, which can present with similar inflammatory response patterns. This wide spectrum of inflammatory pathogenesis of infectious and noninfectious diseases includes diseases such as rheumatoid arthritis, gouty arthritis, osteomyelitis and pyoderma gangrenosum, which cannot clinically be manifested thus necessitating a histopathological clarification. In terms of tissue sampling the following general principle applies: the larger the tissue sample and the more diverse the sites of tissue extraction, the more conclusive are the histopathological diagnostics. This diagnostic approach to infections, especially in arheumatological context, is generally considered complementary and even supplementary to microbiological diagnostics. Furthermore, consideration of the virulence-resistance relationship, which can alter the inflammatory pattern, is of additional relevance. Consequently, definitive causal diagnostics are only achievable within the clinical, rheumatological, microbiological, laboratory medical and infectiological context.

Human leukocyte antigen, isotype DR (HLA-DR) expression in the normal endometrium and in endometrial pathology

BACKGROUND: Human leukocyte antigen, isotype DR (HLA-DR) expression is associated with inflammatory and autoimmune diseases. It is also found on the surface of tumor cells. The role of HLA-DR in endometrial pathology has not been sufficiently studied. AIM: The aim of this study was to determine HLA-DR expression features in the endometrium under normal and pathological conditions. MATERIALS AND METHODS: We performed immunohistochemical examination of endometrial biopsy specimens, namely, 18 cases of endometrioid carcinomas, 139 cases of chronic endometritis, and 37 cases of endometrial polyps. The control group included 50 cases of the endometrium without pathology. Positive HLA-DR expression was detected as brown staining of varying intensity of immune cells of the cytogenic stroma, as well as the cytoplasm and membranes of endometrial epithelial cells. The average number of positively stained stromal cells in ten visual fields was counted. HLA-DR expression in the cytoplasm and on the membrane of endometrial epithelial cells was assessed semi-quantitatively as weak (low) (with staining up to 50% of the glands) or pronounced (high) (with staining more than 50% of the glands). RESULTS: HLA-DRim expression was detected on immune cells of the cytogenic stroma of the endometrium in all of the study groups. HLA-DR expression in the endometrial epithelium was characterized by two main immunophenotypes — negative and positive. Negative HLA-DR expression was found in 55.6% of endometrial cancer cases, in 25.2% of chronic endometritis cases, in 27.7% of endometrial polyp cases, and in all cases of the normal endometrium. The positive HLA-DR (high) immunophenotype was found in 21.6% of chronic endometritis cases, in 28.6% of endometrial polyp cases, and in 16.7% of endometrial cancer cases. Pronounced HLA-DR expression in the epithelium was associated with a high HLA-DR level in the cytogenic stroma and a significantly frequent detection of HLA-DR+ lymphoid follicles in endometrial cancer. The positive HLA-DR (low) immunophenotype was established in 51.8% of chronic endometritis cases and in 27.8% of endometrial polyp cases, and in 27.7% of endometrial cancer cases, and was associated with low HLA-DR levels in the stroma. CONCLUSIONS: The revealed heterogeneity of HLA-DR expression in chronic inflammation and endometrial cancer allows for distinguishing two main immunophenotypes of endometrial cancer, namely, with negative and positive HLA-DR expression. HLA-DR may be an early predictor of adverse background endometrium and endometrial cancer. The positive HLA-DR immunophenotype of endometrial cancer probably indicates a specific mechanism of carcinogenesis associated with chronic inflammation and requires further comprehensive clinical, morphological and molecular genetic research.

Advances of the exposome at individual levels and prevention in atopic dermatitis.

Atopic dermatitis (AD), or eczema, is an inflammatory skin disease related to environmental factors. As a heterogeneous disease, it presents with complex phenotypes and endotypes. A variety of intrinsic and extrinsic factors can promote the development of AD. While there has been extensive discussion on environmental exposure at the population and community levels, discourse on exposome at individual levels in AD remains insufficient. For example, allergens, microorganisms, parasites, dietary factors, and psychological factors such as stress and anxiety play important roles in AD development. Microorganisms, in particular, exhibit altered composition and diversity on the skin of AD patients, influencing skin barrier integrity and immune responses. The impact of certain microorganisms, such as fungi and viruses, on AD has garnered increasing attention because of their important role in maintaining skin homeostasis. Dietary factors, including sugar intake and histamine-rich foods, may modulate AD risk and severity, although findings are controversial. Allergens, particularly house dust mite allergens, and aeroallergens, exacerbate AD symptoms by promoting inflammation and barrier dysfunction. Since AD is often the first step in the atopic march, its primary prevention measures are crucial. Some preventive measures involving microorganisms, diet, and moisturizers remain controversial. Effective preventive strategies necessitate a clear understanding of the complex mechanisms of AD, especially host-microbe-environment interactions. This review summarizes recent advances in understanding various risk and protective factors, as well as primary prevention measures for AD.

Sex differences in the association of dietary inflammatory index with chronic kidney disease in US adults

Studies on the association between dietary inflammatory index (DII) and chronic kidney disease (CKD) are limited. We aimed to examine the association between DII and CKD among U.S. adults with particular attention paid to sex differences. A total of 19317participants were included in this study. The exposure variable was DII, which was calculated based on overall inflammatory effect scores. The outcome was CKD, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or urinary albumin/creatinine (uACR) ≥ 30 mg/g. The mean (SD) of age our study participants was 47.84 (18.35); and the mean (SD) of DII was 1.50 (1.91) (median 1.74). In multivariate logistic regression analysis, we observed that the OR value (95%CI) of CKD is 1.19 (1.14, 1.23), 1.12 (1.06, 1.19), and 1.16 (1.06, 1.27) in models 1, 2 and 3 for Per SD increment of DII. Compared with Participants with Q1(DII < 0.15), the adjusted ORs for participants in Q2 (0.15 ≤ DII < 1.74), Q3 (1.74 ≤ DII < 3.02) and Q4 (≥ 3.02)were 1.46 (95% CI 1.14–1.88), 1.55 (95% CI 1.20–1.99) and 1.52 (95% CI 1.17, 1.98) ( p for trend < 0.05), respectively. However, this study observed that the independent positive correlation between DII and CKD appeared in women rather than men. Higher DII levels were significantly and linearly associated with an increased prevalence of chronic kidney disease, and sex modified the association. This suggests that gender-specific dietary interventions can be developed to reduce the risk of CKD.

Th22 cells promote the transition from homeostatic to reactive microglia in diabetic encephalopathy.

Diabetic encephalopathy (DE) is one of the most serious complications of diabetes mellitus (DM), and its pathogenesis has not yet been clarified. Th22 cells are a newly discovered class of CD4+ T cells that play important roles in inflammatory, autoimmune and infectious diseases. However, it is unclear whether Th22 cells are involved in the pathogenesis of DE. We established a T2DM mouse model in vivo and cocultured Th22 cells with microglia under high glucose (HG) conditions in vitro. Cognitive dysfunction was evaluated using the Morris water maze (MWM) test; blood‒brain barrier (BBB) integrity was evaluated using the Evans blue (EB) extravasation assay; Th22 cells and IL-22 receptors were detected by immunofluorescence; and IL-1β, TNF-α, iNOS, CD86, Arg-1, and CD206 protein expression was measured by Western Blot (WB) analysis. Th22 cells passed through the BBB into the hippocampus and secreted interleukin-22 (IL-22), and the mice subsequently exhibited decreased learning and memory abilities. In the DE model, IL-22 promoted the transformation of homeostatic microglia into reactive microglia as well as the inflammatory response. Additionally, coculture of Th22 cells with BV2 microglia cultured under HG conditions increased the production of proinflammatory cytokines, and the microglia showed reactive changes. Mechanistically, IL-22Rα1 acted as a ligand, and IL-22 bound to IL-22Rα1 on microglia to drive primary microglia-induced inflammatory responses. Interestingly, interleukin-22 binding protein (IL-22BP) directly binds to IL-22Rα1 on microglia to inhibit the proinflammatory effects of IL-22. Th22 cells secrete IL-22 after passing through the BBB into the hippocampus and promote the transformation of homeostatic microglia into reactive microglia, which induces an inflammatory response, exacerbates learning and memory impairment and cognitive deficits, and contributes to and accelerates the development of DE.

Assessment of clinical benefit, cost and uptake of biosimilars versus reference biologics in immune-mediated inflammatory diseases in China.

As China is one of the countries with the highest recorded cases of Immune-Mediated Inflammatory Diseases (IMIDs), these diseases have also emerged as a serious public health concern. Biosimilars, potentially lower-cost versions of biologics, may improve access to more affordable yet comparably effective treatments. Encouragingly, China launched its abbreviated biosimilar pathway in 2015, and since then, a large number of biosimilars have been approved. However, systematic studies on the therapeutic efficacy and economic impact of IMIDs biosimilars are lacking in China. This study aims to assess the clinical benefits (including efficacy/effectiveness, safety, and immunogenicity), cost and uptake of adalimumab biosimilars, tocilizumab biosimilars, and infliximab biosimilars compared with their reference biologics in patients with IMIDs in China. IMIDs biosimilars and their reference drugs approved in China between 2015 and 2024 were identified. Head-to-head randomized clinical trials (RCTs) and real-world cohort studies on adalimumab, tocilizumab and infliximab and their biosimilars for the treatment of IMIDs were assessed. PubMed, Embase, Cochrane Library, Clinicaltrials.gov, and Listed Drug Database of China National Medical Products Administration were searched for clinical trials and cohort studies on biosimilars for IMIDs from their inception to November 1, 2024. We evaluated the monthly treatment costs and quarterly uptakes of these biosimilars and their reference biologics in China. Besides, we simulated the impact of biosimilar substitution in different scenarios. Meta-analyses were performed using a random-effects model to evaluate the efficacy, safety, and immunogenicity of treatments, including pooled risk ratios (RR) for ACR20 for rheumatoid arthritis, ASAS20 for ankylosing spondylitis, and PASI for plaque psoriasis, treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), anti-drug antibodies (ADAs), and neutralizing antibodies (Nabs), with 95% credible intervals (CrIs). A total of 12 RCTs involving 5,717 patients with IMIDs were analyzed, including 12 approved biosimilars of adalimumab, infliximab, and tocilizumab. The primary endpoints of adalimumab (7 RCTs with 3,174 patients; RR, 1.02; 95% CrI, 0.99-1.06, p = 0.33), infliximab (3 RCTs with 1,291 patients; RR, 1.02; 95% CrI, 0.94-1.11, p = 0.98), tocilizumab (2 RCTs with 1,252 patients; RR, 1.01, 95% CrI, 0.94-1.08) met equivalence with reference biologics. Additionally, there was no significant difference between biosimilars and their reference biologics in the secondary endpoints. Overall, biosimilars demonstrated comparable safety (TEAEs: RR, 0.99; 95% CrI, 0.95-1.02, p = 0.44) (SAEs: RR, 0.80; 95% CrI, 0.42-1.54, p = 0.50) and immunogenicity (ADA: RR, 1.00; 95% CrI, 0.95-1.04, p = 0.85) (Nabs: RR, 0.93; 95% CrI, 0.82-1.05, p = 0.25) profiles to reference biologics. These findings were consistent with the cohort studies. In 2024, IMIDs biosimilars are available at 63 to 82% of the price per unit of the reference drugs, with uptake rates of 16.5 to 72.1% in China. Patients with IMIDs using these biosimilars could save between $874 and $2,184 per month in treatment costs, equivalent to 1.8 to 7.0 times the per capita monthly disposable income in China in 2024. Simulation showed that with 100% biosimilar substitution, savings would increase to $22.98 M, $33.83 M, and $3.82 M for adalimumab, infliximab, and tocilizumab, respectively. This would enable treatment for an additional 6,700, 9,863, and 4,373 patients, respectively. Our study revealed that IMID biosimilars in China provide clinical benefits comparable to their reference biologics evidenced by high-quality RCTs and cohort studies with offer significant cost savings in China. Encouraging China's national volume-based procurement and multi-stakeholder collaboration may help accelerate the substitution of IMIDs biosimilars.