Enhanced efficacy of brucine dissolving-microneedles as a targeted delivery system in rheumatoid arthritis treatment: a comprehensive pharmacokinetic-pharmacodynamic analysis.

Our previous studies have shown the therapeutic efficacy of brucine dissolving-microneedles (Bru-DMNs) in treating rheumatoid arthritis (RA). Bru delivered via the DMNs can bypass some of the issues related to oral and systemic delivery, including extensive enzymatic activity, liver metabolism and in the case of systemic delivery via hypodermic needles, pain resulting from injections and needle stick injury. However, the underlying mechanism of Bru-DMNs against RA has not been investigated in depth at the pharmacokinetic-pharmacodynamic (PK-PD) level. In this study, a microdialysis-based method combined with ultra-performance liquid chromatography-tandem mass spectrometry was developed for the simultaneous and continuous sampling and quantitative analysis of blood and joint cavities in fully awake RA rats. The acquired data were analyzed by the PK-PD analysis method. Bru delivered via microneedles showed enhanced distribution and prolonged retention in the joint cavity compared to its administration in blood. The correlation between the effect of Bru and its concentration at the action site was indirect. In this study, we explored the mechanism of Bru-DMNs against RA and established a visualization method to express the PK-PD relationship of Bru-DMNs against RA. This study provides insights into the mechanism of action of drugs with potential side effects administered transdermally for RA treatment.

Hydroxychloroquine-induced hyperpigmentation of the skin and bull's-eye maculopathy in rheumatic patients: a case report and literature review.

Hydroxychloroquine (HCQ) is used as a traditional disease-modifying antirheumatic drugs (DMARDs), for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, it can cause serious adverse reactions, including hyperpigmentation of the skin and bull's-eye macular lesions. Here, we present a case of HCQ-induced hyperpigmentation of the skin and bull's-eye macular lesions in a patient who received HCQ for RA. A 65-year-old female patient developed blurred vision and hyperpigmentation of multiple areas of skin over the body for one month after 3 years of HCQ treatment for RA. Based on clinical presentation, ophthalmological examination and dermatopathological biopsy, a diagnosis of drug-induced cutaneous hyperpigmentation and bullous maculopathy of the right eye was made. After discontinuation of HCQ and treatment with iguratimod tablets, the hyperpigmentation of the patient 's skin was gradually reduced, and the symptoms of blurred vision were not significantly improved. We also reviewed the available literature on HCQ-induced cutaneous hyperpigmentation and bull's-eye macular lesions and described the clinical features of HCQ-induced cutaneous hyperpigmentation and bull's-eye macular lesions. In conclusion, clinicians should be aware of early cutaneous symptoms and HCQ-associated ophthalmotoxicity in patients with rheumatic diseases on HCQ sulphate and should actively monitor patients, have them undergo regular ophthalmological examinations and give appropriate treatment to prevent exacerbation of symptoms.

Periplogenin inhibits pyroptosis of fibroblastic synoviocytes in rheumatoid arthritis through the NLRP3/Caspase-1/GSDMD signaling pathway.

Although the pathogenesis of rheumatoid arthritis (RA) remains unclear, an increasing number of studies have confirmed that pyroptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) is an important factor affecting the progression of RA. Periplogenin (PPN) is a natural cardiac glycoside; reportedly, it exerts anti-inflammatory and analgesic effects in diseases by inhibiting cell growth and migration. This study aimed to determine the effect of PPN on the growth, migration, and invasion of RA-FLS and the potential mechanism of pyroptosis regulation. We discovered that PPN could inhibit the migration and invasion abilities of RA-FLS and block their growth cycle, down-regulate the secretion and activation of NLRP3, Caspase-1, GSDMD, IL-1ß, and IL-18, and reduce the number of pyroptosis. In summary, PPN inhibited pyroptosis, reduced the release of inflammatory factors, and improved RA-FLS inflammation by regulating the NLRP3/Caspase-1/GSDMD signaling pathway.

Associations of the circulating levels of cytokines with risk of systemic sclerosis: a bidirectional Mendelian randomized study.

Objective: Systemic sclerosis(SSc) remains unclear, studies suggest that inflammation may be linked to its pathogenesis. Hence, we conducted a bidirectional Mendelian randomization (MR) analysis to evaluate the association between cytokine and growth factor cycling levels and the risk of SSc onset. Methods: In our study, the instrumental variables(IVs) for circulating cytokines were sourced from the genome-wide association study (GWAS) dataset of 8293 Finnish individuals. The SSc data comprised 302 cases and 213145 controls, and was included in the GWAS dataset. We employed four methods for the MR analysis: MR Egger, Inverse variance weighted (IVW), Weighted medium, and Weighted Mode, with IVW being the primary analytical method. Sensitivity analyses were performed using heterogeneity testing, horizontal pleiotropy testing, and the Leave One Out (LOO) method. We also conducted a reverse MR analysis to determine any reverse causal relationship between SSc and circulating cytokines. Results: After Bonferroni correction, MR analysis revealed that the Interleukin-5 (IL-5) cycle level was associated with a reduced risk of SSc [odds ratio (OR)=0.48,95% confidence interval (CI): 0.27-0.84, P=0.01]. It also indicated that the Stem cell growth factor beta (SCGF-ß) cycling level might elevate the risk of SSc (OR = 1.36, 95% CI: 1.01-1.83, P = 0.04). However, the reverse MR analysis did not establish a causal relationship between SSc and circulating cytokine levels. Additionally, sensitivity analysis outcomes affirm the reliability of our results. Conclusion: Our MR study suggests potential causal relationships between IL-5, SCGF-ß, and the risk of SSc. Further research is essential to determine how IL-5 and SCGF-ß influence the development of SSc.

Association between patient adherence and treat-to-target in gout: A cross-sectional study.

The implementation of a treat-to-target (T2T) approach has been widely recommended for achieving optimal outcomes in gout treatment, as substantiated by a wealth of compelling evidence. However, a paucity of knowledge exists regarding the barriers hindering effective T2T management in China. This study seeks to investigate the factors contributing to treatment failure within the context of the T2T strategy. A cross-sectional, multi-center investigation was conducted, involving the completion of electronic questionnaires by outpatients undergoing urate-lowering treatment for a duration exceeding 6 months. These questionnaires encompassed demographic information, disease-related conditions, comorbid conditions, and management. The study analyzed factors associated with serum uric acid levels exceeding 360 µmol/L, poor disease control, and poor medication adherence. A total of 425 valid questionnaires were collected, representing 90.8% of the patients. The T2T implementation rate was 26.82% (n = 114). Factors linked to serum uric acid levels surpassing 360 µmol/L included moderate medication adherence (odds ratio (OR) = 2.35; 95% confidence interval (CI) 1.17-4.77; P = .016), poor medication adherence (OR = 4.63; 95% CI 2.28-9.51; P < .001), and management by general practitioners (OR = 0.60; 95% CI 0.37-0.97; P = .036). The rate of well-controlled patients was 14.35% (n = 61). Predictors of not well controlled encompassed the presence of tophi (OR = 2.48; 95% CI 1.17-5.61; P = .023), general medication adherence (OR = 2.78; 95% CI 1.28-6.05; P = .009), poor medication adherence (OR = 6.23; 95% CI 2.68-14.77; P < .001), and poor patient's perception of gout (OR = 4.07; 95% CI 1.41-13.91; P = .015). A poor medication adherence rate of 55.29% (n = 235) was observed, with lower rates of poor medication adherence associated with the use of febuxostat (OR = 0.35; 95% CI 0.14-0.83; P = .02), uric acid levels exceeding 360 µmol/L (OR = 3.05; 95% CI 1.84-5.12; P = .00), moderate patient education (OR = 2.28; 95% CI 1.29-4.15; P = .01), moderate diet control (OR = 1.98; 95% CI 1.17-3.41; P = .01), and poor diet control (OR = 3.73; 95% CI 1.26-12.83; P = .02). The rate of T2T implementation in China is notably low among patients undergoing urate-lowering treatment of gout beyond 6 months. Importantly, medication adherence demonstrates a significant association with T2T outcomes.

The causal impact of saturated fatty acids on rheumatoid arthritis: a bidirectional Mendelian randomisation study.

Objective: The causal relationship between saturated fatty acids (SFAs) and rheumatoid arthritis (RA) remains poorly understood. This study aimed to determine whether SFAs are causally related to RA using Mendelian randomisation (MR) analyses. Methods: Genome-wide association study (GWAS) summary data for RA (ukb-d-M13_RHEUMA) and SFAs (met-d-SFA) were obtained from the Integrative Epidemiology Unit OpenGWAS database. A bidirectional MR analysis was performed using a suite of algorithms, namely the MR-Egger, weighted median, simple mode, weighted mode, and inverse-variance weighted (IVW) algorithms, all integrated using the "MR" function. The robustness of the MR findings was further evaluated through sensitivity analyses, including heterogeneity, horizontal pleiotropy, and leave-one-out tests. Results: The IVW algorithm in the forward MR analysis indicated a causal link between SFAs and RA (p = 0.025), identifying SFAs as a risk factor for RA (odds ratio = 1.001). Sensitivity analyses indicated no significant heterogeneity, horizontal pleiotropy, or severe bias, reinforcing the credibility of the forward MR results. However, the reverse MR analysis revealed that RA does not causally affect SFA levels (p = 0.195), and this finding was supported by corresponding sensitivity analyses. Conclusion: The findings of this study substantiate the positive causal effect of SFAs on the incidence of RA through bidirectional MR analysis, thereby offering a consequential direction for future research on the diagnosis and treatment of RA.

Efficacy of adalimumab combined with Tripterygium wilfordii Hook F in the treatment of patient with rheumatoid arthritis: A multicenter, open-label, randomized-controlled trial.

OBJECTIVES: To evaluate the efficacy and safety of adalimumab (ADA) combined with Tripterygium wilfordii Hook F (TwHF) in the treatment of methotrexate (MTX)-inadequate response patients with rheumatoid arthritis (RA). METHODS: In this multicenter, open-label, randomized controlled clinical trial, 64 RA patients with inadequate response to MTX were 1:1 randomly assigned into treatment or control groups. The treatment group was treated with ADA in combination with TwHF, and the control group was treated with ADA in combination with MTX for 24 weeks. The primary endpoint was the percentage of patients having low disease activity (2.6 ≤ DAS28-ESR < 3.2) and remission rates (DAS28-ESR < 2.6) at week 24. RESULTS: In total, 53 of the 64 patients (82.8%) completed this 24-week clinical trial. By intent-to-treat (ITT) analysis, a comparable outcome was observed between the two groups. The percentage of patients achieving low disease activity in the treatment group and control group were 43.8% and 46.9% (95% CI, 21.28 to 27.48, p = .802). Percentage of patients achieving low disease activity rates were respectively 28.1% and 31.3% in the treatment group and control group (95% CI, 19.18 to 25.58, p = .784). In per-protocol (PP) analysis, the results were consistent with the ITT model. The incidence of adverse events was comparable between the two groups. CONCLUSIONS: There were no significant differences in efficacy and safety between ADA combined with TwHF versus ADA combined with MTX in the treatment of RA. TwHF might be an alternative treatment for RA patients who are intolerant to MTX.

Stigmasterol Depresses the Proliferation and Facilitates the Apoptosis of Fibroblast-Like Synoviocytes via the PI3K/AKT Signaling Pathway in Collagen-Induced Arthritis Rats.

Rheumatoid arthritis (RA) is a chronic disease characterized by persistent synovitis and angiogenesis. Its clinical manifestations are synovial hyperplasia and progressive destruction of bone and cartilage, eventually leading to joint deformation and even disability. The healing effect of monomer stigmasterol, the main active ingredient of the Jinwujiangu recipe the Chinese Herbal Compound, on RA has been confirmed in several studies. Fibroblast-like synoviocytes (FLS) are related to the occurrence and development of RA. This study aims to investigate the effects of stigmasterol on FLS cell proliferation and apoptosis, as well as its impact on FLS cell cycle proteins and key genes in the Phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) pathway, providing insights into the development of stigmasterol as an alternative therapeutic drug for RA. We administered 20 g/kg stigmasterol to rats continuously for 5 d to obtain stigmasterol-containing serum, and established rat models of osteoarthritis induced by ossein to obtain FLS. To explore the effects of stigmasterol on the viability, migration, proliferation and apoptosis of collagen-induced arthritis (CIA)-FLS cells, we selected 0% (control), 5% (low concentration), 10% (medium concentration) and 20% (high concentration) drug-containing serum to intervene cells and conducted Cell Counting Kit-8 (CCK-8), Transwell, 5-ethynyl-2' -deoxyuridine (EdU) staining and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) experiments, respectively. The results showed that compared with the control group, low, medium, and high serum significantly inhibited the activity, migration, and proliferation of FLS cells, and promoted their apoptosis, and high serum had the best effect. In addition, we investigated the mechanism of stigmasterol inhibiting FLS proliferation and promoting its apoptosis by qPCR, Western blot, and immunofluorescence assays. The results showed that stigmasterol significantly inhibited the expression of Cyclin D1, cyclin-dependent kinase 4 (CDK4), and Retinoblastoma (Rb), and decreased the expression of key genes kinase insert domain-containing receptor (KDR), PI3K, AKT, phosphorylated PI3K (p-PI3K) and phosphorylated AKT (p-AKT) in the KDR-mediated PI3K/AKT signaling pathway, thus inhibiting the proliferation of FLS and promoting the apoptosis of FLS. It was suggested that stigmasterol may be a potential alternative drug for RA treatment.

Acute generalized exanthematous pustulosis caused by hydroxychloroquine in a patient with rheumatoid arthritis and CARD14 mutation: Case report.

RATIONALE: Acute generalized exanthematous pustulosis (AGEP) is a serious adverse skin reaction characterized by the rapid appearance of densely distributed, small, sterile pustules with erythema. However, its pathogenesis is not fully understood. Hydroxychloroquine is widely used for the treatment of autoimmune diseases. Some patients presenting with AGEP have IL36RN and CARD14 gene mutations. Our report describes a patient with rheumatoid arthritis and AGEP associated with hydroxychloroquine and a newly discovered CARD14 gene mutation. PATIENT CONCERNS: A 28-year-old woman with rheumatoid arthritis, treated with leflunomide therapy without marked relief of joint pain, developed multiple rashes with pruritis covering the body 5 days after switching to hydroxychloroquine treatment. DIAGNOSES: Based on the patient's history, symptoms, and histopathological findings, AGEP was diagnosed. INTERVENTIONS: Whole-exome sequencing and Sanger validation revealed no mutations in the IL36RN gene; however, a CARD14 gene mutation was present. The patient was treated using ketotifen fumarate tablets, dexamethasone sodium phosphate, calcium gluconate injection, methylprednisolone injection, vitamins C and B12, hydrocortisone butyrate cream, Reed acne cream, potassium chloride tablets, and pantoprazole enteric-coated capsules. OUTCOMES: The rash improved after 15 days. LESSONS SUBSECTIONS: There has been little basic research on AGEP-related genetics, and the CARD14 mutation may underlie several pustular rashes, including AGEP and generalized pustular psoriasis. Follow-up studies and further accumulation of patient data are required.

Characterizations of the multi-kingdom gut microbiota in Chinese patients with gouty arthritis.

OBJECTIVE: The gut microbial composition has been linked to metabolic and autoimmune diseases, including arthritis. However, there is a dearth of knowledge on the gut bacteriome, mycobiome, and virome in patients with gouty arthritis (GA). METHODS: We conducted a comprehensive analysis of the multi-kingdom gut microbiome of 26 GA patients and 28 healthy controls, using whole-metagenome shotgun sequencing of their stool samples. RESULTS: Profound alterations were observed in the gut bacteriome, mycobiome, and virome of GA patients. We identified 1,117 differentially abundant bacterial species, 23 fungal species, and 4,115 viral operational taxonomic units (vOTUs). GA-enriched bacteria included Escherichia coli_D GENOME144544, Bifidobacterium infantis GENOME095938, Blautia_A wexlerae GENOME096067, and Klebsiella pneumoniae GENOME147598, while control-enriched bacteria comprised Faecalibacterium prausnitzii_G GENOME147678, Agathobacter rectalis GENOME143712, and Bacteroides_A plebeius_A GENOME239725. GA-enriched fungi included opportunistic pathogens like Cryptococcus neoformans GCA_011057565, Candida parapsilosis GCA_000182765, and Malassezia spp., while control-enriched fungi featured several Hortaea werneckii subclades and Aspergillus fumigatus GCA_000002655. GA-enriched vOTUs mainly attributed to Siphoviridae, Myoviridae, Podoviridae, and Microviridae, whereas control-enriched vOTUs spanned 13 families, including Siphoviridae, Myoviridae, Podoviridae, Quimbyviridae, Phycodnaviridae, and crAss-like. A co-abundance network revealed intricate interactions among these multi-kingdom signatures, signifying their collective influence on the disease. Furthermore, these microbial signatures demonstrated the potential to effectively discriminate between patients and controls, highlighting their diagnostic utility. CONCLUSIONS: This study yields crucial insights into the characteristics of the GA microbiota that may inform future mechanistic and therapeutic investigations.

Network pharmacology analysis and clinical verification of Jishe Qushi capsules in rheumatoid arthritis treatment.

The study aimed to elucidate the effective chemical composition and molecular mechanism of rheumatoid arthritis (RA) treatment with Jishe Qushi capsules (JSQS) and perform clinical validation. The effective chemical components were screened by a database. We used Cytoscape software to construct the key target-RA composite target network of JSQS. Gene Ontology biofunctional analysis and Kyoto encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed for the key targets, followed by molecular docking validation of core key targets. Ninety-nine patients chosen were divided into 49 cases in the treatment group and 50 cases in the control group according to the random number table method. The control group was treated with the combination of methotrexate (MTX) plus Glucosidorum Tripterygll Totorum. The treatment group was treated with MTX plus JSQS. The treatment effects of the 2 groups were evaluated. A total of 118 key anti-RA targets were obtained for JSQS. Quercetin in Panax notoginseng, vanillic acid, scopoletin, physcion in Gardneria angustifolia, 3,5-dimethyl-4-hydroxybenzaldehyde in Zaocys dhumnades, kaempferol in Radix Paeoniae Alba, and protocatechuic aldehyde in Cibotium barometz were the main active chemical components in the composite target network. Topology analysis yields core key targets, such as TP53, INS, IL6, VEGFA, MYC, CASP3, ESR1, EGF, CCND1, PPARG, ERBB2, NFKBIA, TLR4, RELA, and CASP8, and the results of KEGG enrichment analysis showed that JSQS mainly works through pathways in cancer, phosphatidylinositol-3-kinaseRAC-serine/threonine-protein kinase signaling, and mitogen-activated protein kinase (MAPK) signaling pathway, and aryl hydrocarbon receptor nuclear translocator signaling pathway. Molecular docking results showed that the binding fraction of PPARG, VEGFA and the effective active ingredients of ridged snake dispelling capsule was >70. In the clinical trial, morning stiffness, joint pain, and VAS scores of post-treatment in the treatment group were lower than those in the control group (P < .05). Additionally, ESR, CRP, RF, anti-CCP, TNF-α, IL-6, IL-17, and Th17/Treg were lower in the treatment group than in the control group (P < .05). JSQS exert multicomponent, multipathway, and multitarget synergistic actions in RA treatment. It can significantly improve the clinical symptoms and quality of life and delay the progression of RA disease.

Gut microbiota combined with fecal metabolomics reveals the effects of FuFang Runzaoling on the microbial and metabolic profiles in NOD mouse model of Sjögren's syndrome.

OBJECTIVE: Sjögren's syndrome (SS) is an inflammatory autoimmune disease characterized by high levels of chronic lymphocyte infiltration. Differences and dysfunction in the gut microbiota and metabolites may be closely related to the pathogenesis of SS. The purpose of this study was to reveal the relationship between the gut microbiota and metabolome in NOD mice as a model of SS and the role of FuFang Runzaoling (FRZ), which is a clinically effective in treating SS. METHODS: NOD mice were gavaged with FRZ for 10 weeks. The ingested volume of drinking water, submandibular gland index, pathologic changes of the submandibular glands, and serum cytokines interleukin (IL)-6, IL-10, IL-17 A, and tumor necrosis factor-alpha (TNF-α) were determined. The roles of FRZ on gut microbiota and fecal metabolites were explored by 16 S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MC), respectively. The correlation between them was determined by Pearson correlation analysis. RESULTS: Compared with the model group, the drinking water volume of NOD mice treated with FRZ increased and the submandibular gland index decreased. FRZ effectively ameliorated lymphocyte infiltration in the small submandibular glands in mice. Serum levels of IL-6, TNF-α, and IL-17 A decreased, and IL-10 increased. The Firmicutes/Bacteroidetes ratio in the FRZ treatment group was higher. FRZ significantly downregulated the relative abundance of the family Bacteroidaceae and genus Bacteroides, and significantly upregulated the relative abundance of genus Lachnospiraceae_UCG-001. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) revealed the significant change in fecal metabolites after FRZ treatment. Based on criteria of OPLS-DA variable influence on projection > 1, P < 0.05, and fragmentation score > 50, a total of 109 metabolites in the FRZ-H group were differentially regulated (47 downregulated and 62 upregulated) compared to their expressions in the model group. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed enriched metabolic of sphingolipid metabolism, retrograde endocannabinoid signaling, GABAergic synapse, necroptosis, arginine biosynthesis, and metabolism of histidine, alanine, aspartate, and glutamate. Correlation analysis between gut microbiota and fecal metabolites suggested that the enriched bacteria were related to many key metabolites. CONCLUSIONS: Taken together, we found FRZ could reduce the inflammatory responses in NOD mice by regulating the gut microbiota, fecal metabolites, and their correlation to emerge a therapeutic effect on mice with SS. This will lay the foundation for the further studies and applications of FRZ, and the use of gut microbiotas as drug targets to treat SS.

Exercise alleviates neovascular age-related macular degeneration by inhibiting AIM2 inflammasome in myeloid cells.

The neovascular form of age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Vascular endothelial growth factor (VEGF) plays a crucial role in choroidal neovascularization (CNV), and anti-VEGF therapy is recommended as first-line therapy for nvAMD. However, many patients do not radically benefit from this therapy. Epidemiological data suggest that physical exercise is beneficial for many human diseases, including nvAMD. Yet, its protective mechanism and therapeutic potential remain unknown. Here, using clinical samples and mouse models, we found that exercise reduced CNV and enhanced anti-angiogenic therapy efficacy by inhibiting AIM2 inflammasome activation. Furthermore, transfusion of serum from exercised mice transferred the protective effects to sedentary mice. Proteomic data revealed that exercise promoted the release of adiponectin, an anti-inflammatory adipokine from adipose tissue into the circulation, which reduced ROS-mediated DNA damage and suppressed AIM2 inflammasome activation in myeloid cells of CNV eyes through AMPK-p47phox pathway. Simultaneous targeting AIM2 inflammasome product IL-1ß and VEGF produced a synergistic effect for treating choroidal neovascularization. Collectively, this study highlights the therapeutic potential of an exercise-AMD axis and uncovers the AIM2 inflammasome and its product IL-1ß as potential targets for treating nvAMD patients and enhancing the efficacy of anti-VEGF monotherapy.

Clinical features of acute generalized exanthematous pustulosis caused by hydroxychloroquine in rheumatology patients and exploration of CARD14 gene mutations.

Introduction: Acute generalized exanthematous pustulosis (AGEP) is a rare condition characterized by superficial pustules following drug ingestion or infection. Currently, there is no clear link between rheumatism and AGEP. It has been described that hydroxychloroquine (HCQ) is a rare cause of acute generalized epidermal necrolysis (AGEP). Presently, there are limited studies on HCQ-induced AGEP. We aimed to explore the clinical features and associated gene expression of AGEP induced after HCQ treatment exposure in rheumatology patients. Methods: We assessed patients with HCQ-induced AGEP diagnosed at the Second Affiliated Hospital of Guizhou University of Chinese Medicine between January 1, 2017, and May 1, 2022. We also reviewed similar cases reported in specific databases. Results: The study included five females (mean age, 40.2 years), and the mean time from initiation of HCQ treatment to symptom onset was 12.2 d. All patients received steroids and allergy medications after HCQ discontinuation, and the rash completely resolved within an average of 25.2 d. We performed whole exome sequencing and Sanger validation in our patient sample. CARD14 gene mutations were detected in three patients. Additionally, seven mutation sites were detected. Discussion: HCQ-induced AGEP may have a longer latency period and regression time than AGEP induced by other drugs. Our patients all experienced CARD14 gene mutations. AGEP often resolves with topical therapy and drug discontinuation, although some cases require systemic steroid therapy. In the future, patients with rheumatism should pay attention to the effectiveness of HCQ during treatment and be aware of the associated skin toxicity.

Genome-wide analysis of genetic pleiotropy and causal genes across three age-related ocular disorders.

Age-related macular degeneration (AMD), cataract, and glaucoma are leading causes of blindness worldwide. Previous genome-wide association studies (GWASs) have revealed a variety of susceptible loci associated with age-related ocular disorders, yet the genetic pleiotropy and causal genes across these diseases remain poorly understood. By leveraging large-scale genetic and observational data from ocular disease GWASs and UK Biobank (UKBB), we found significant pairwise genetic correlations and consistent epidemiological associations among these ocular disorders. Cross-disease meta-analysis uncovered seven pleiotropic loci, three of which were replicated in an additional cohort. Integration of variants in pleiotropic loci and multiple single-cell omics data identified that Müller cells and astrocytes were likely trait-related cell types underlying ocular comorbidity. In addition, we comprehensively integrated eye-specific gene expression quantitative loci (eQTLs), epigenomic profiling, and 3D genome data to prioritize causal pleiotropic genes. We found that pleiotropic genes were essential in nerve development and eye pigmentation, and targetable by aflibercept and pilocarpine for the treatment of AMD and glaucoma. These findings will not only facilitate the mechanistic research of ocular comorbidities but also benefit the therapeutic optimization of age-related ocular diseases.

Inhibitory Effect of Jinwujiangu Prescription on Peripheral Blood Osteoclasts in Patients with Rheumatoid Arthritis and the Relevant Molecular Mechanism.

Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease characterized with high recurrence, high disability, poor prognosis, and long treatment cycles. Versus western medicine, traditional Chinese medicine has the traits of definite efficacy, low toxicity, and side effects in the treatment of RA. Moreover, traditional Chinese medicine also has the advantages of multiple targets, multiple links, and multiple approaches. This study was committed to exploring the effect of Jinwujiangu prescription on peripheral blood osteoclasts in those patients with RA and relevant molecular mechanisms. We first identified 159 common targets by online pharmacology, and there were correlations among these targets; besides, the main signaling pathways involved were inclusive TNF signaling pathway, rheumatoid arthritis, IL-17 signaling pathway, NF-kappa B signaling pathway, Toll-like receptor signaling pathway, etc. Through experimental verification, we found that PBMC cells extracted from human peripheral blood could be successfully induced into osteoclasts, and Jinwujiangu prescription inhibited the generation of osteoclasts from PBMCs of RA patients. CCK-8 and flow cytometry showed that osteoclast viability was significantly decreased and osteoclast apoptosis was significantly increased in the HIF-1α interference group; low-, medium-, and high-dose Jinwujiangu prescription groups; sinapine group; and hydroxychloroquine control group. Moreover, Jinwujiangu prescription and sinapine could inhibit the production of cytokines in peripheral blood osteoclasts and inhibit autophagy in RA patients. The expression level of mTOR was significantly increased in both Jinwu middle- and high-dose groups. In conclusion, this study demonstrated that sinapine, the active target in Jinwujiangu prescription, can act as a HIF-1α inhibitor; activate the mTOR pathway; downregulate the level of autophagy rate, ATG5, beclin-1, and LC3 expression; and inhibit the occurrence of autophagy. The trial registration number of the study is KYW2021010.

Characterizations of the Gut Bacteriome, Mycobiome, and Virome in Patients with Osteoarthritis.

The gut microbiota plays an essential role in the regulation of the immune system and the etiology of human autoimmune diseases. However, a holistic understanding of the gut bacteriome, mycobiome, and virome in patients with osteoarthritis (OA) remains lacking. Here, we explored the gut microbiotas of 44 OA patients and 46 healthy volunteers via deep whole-metagenome shotgun sequencing of their fecal samples. The gut bacteriome and mycobiome were analyzed using a reference-based strategy. Gut viruses were identified from the metagenomic assembled contigs, and the gut virome was profiled based on 6,567 nonredundant viral operational taxonomic units (vOTUs). We revealed that the gut microbiome (including bacteriome, mycobiome, and virome) of OA patients is fundamentally altered, characterized by a panel of 279 differentially abundant bacterial species, 10 fungal species, and 627 vOTUs. The representative OA-enriched bacteria included Anaerostipes hadrus (GENOME147149), Prevotella sp900313215 (GENOME08259), Eubacterium_E hallii (GENOME000299), and Blautia A (GENOME001004), while Bacteroides plebeius A (GENOME239725), Roseburia inulinivorans (GENOME 001770), Dialister sp900343095 (GENOME075103), Phascolarctobacterium faecium (GENOME233517), and several members of Faecalibacterium and Prevotella were depleted in OA patients. Fungi such as Debaryomyces fabryi (GenBank accession no. GCA_003708665), Candida parapsilosis (GCA_000182765), and Apophysomyces trapeziformis (GCA_000696975) were enriched in the OA gut microbiota, and Malassezia restricta (GCA_003290485), Aspergillus fumigatus (GCA_003069565), and Mucor circinelloides (GCA_010203745) were depleted. The OA-depleted viruses spanned Siphoviridae (95 vOTUs), Myoviridae (70 vOTUs), and Microviridae (5 vOTUs), while 30 Siphoviridae vOTUs were enriched in OA patients. Functional analysis of the gut bacteriome and virome also uncovered their functional signatures in relation to OA. Moreover, we demonstrated that the OA-associated gut bacterial and viral signatures are tightly interconnected, suggesting that they may impact disease together. Finally, we showed that the multikingdom signatures are effective in discriminating the OA patients from healthy controls, suggesting the potential of gut microbiota for the prediction of OA and related diseases. Our results delineated the fecal bacteriome, mycobiome, and virome landscapes of the OA microbiota and provided biomarkers that will aid in future mechanistic and clinical intervention studies. IMPORTANCE The gut microbiome of OA patients was completely altered compared to that in healthy individuals, including 279 differentially abundant bacterial species, 10 fungal species and 627 viral operational taxonomic units (vOTUs). Functional analysis of the gut bacteriome and virome also revealed their functional signatures in relation to OA. We found that OA-associated gut bacterial and viral signatures were tightly interconnected, indicating that they may affect the disease together. The OA patients can be discriminated effectively from healthy controls using the multikingdom signatures, suggesting the potential of gut microbiota for the prediction of OA and related diseases.

Multiple joint dislocations and bone disintegration in rheumatoid arthritis: A case report.

Rheumatoid arthritis (RA) is a chronic inflammatory disease, which typically affects the small joints of the hands and feet. Anti-rheumatism drugs should be promptly administered upon a diagnosis. Without standardized treatment, patients are prone to different degrees of deformities in the later stages of disease development, which negatively impact quality of life. We here report a case of a 52-year-old woman with an 18-year history of RA. After intermittent immunotherapy with anti-rheumatism drugs, the patient presented with multiple joint pain, dislocation, and disintegration of the bone. The interphalangeal joints of both hands were deformed to varying degrees and movement was significantly limited. After anti-rheumatism treatment, the patient experienced reduced joint pain. This case should enhance understanding and serve as a guide for patient management toward the prevention of joint deformities caused by RA.

The causal effect of cytokine cycling levels on osteoarthritis: a bidirectional Mendelian randomized study.

Objective: Osteoarthritis (OA) is the most prevalent joint disease globally, serving as a primary cause of pain and disability. However, the pathological processes underlying OA remain incompletely understood. Several studies have noted an association between cytokines and OA, yet the causal link between them remains ambiguous. This study aims to identify cytokines potentially causally related to OA using Mendelian randomization (MR) analysis, informing early clinical diagnosis and treatment decisions. Methods: We conducted a genome-wide association study (GWAS) on 12 OA traits involving 177,517 cases and 649,173 controls from 9 international cohorts. For discovery MR analysis, we used 103 cytokines from two European populations as instrumental variables (IVs). Concurrently, another European population OA GWAS database (36,185 cases and 135,185 controls) was used to replicate MR analysis, employing the inverse variance weighted (IVW) method as the primary analytic approach. Additional methods tested included MR Egger, Weighted median, and Weighted mode. We merged the MR findings through meta-analysis. Heterogeneity testing, level pleiotropy testing (MR Egger intercept test and MRPRESSO), and sensitivity analysis via Leave One Out (LOO) were conducted to verify result robustness. Lastly, reverse MR analysis was performed. Results: The meta-analysis merger revealed a correlation between CX3CL1 cycle levels and increased OA risk (OR=1.070, 95% CI: 1.040-1.110; P<0.010). We also observed associations between MCP4 (OR=0.930, 95% CI: 0.890-0.970; P<0.010) and CCL25 (OR=0.930, 95% CI: 0.890-0.970; P<0.010) with reduced OA risk. The sensitivity analysis results corroborate the robustness of these findings. Conclusion: Our MR analysis indicates a potential causal relationship between CX3CL1, MCP4, CCL25, and OA risk changes. Further research is warranted to explore the influence of cytokines on OA development.