Distinct characteristics of the gut virome in patients with osteoarthritis and gouty arthritis.

BACKGROUND/PURPOSE(S): The gut microbiota and its metabolites play crucial roles in pathogenesis of arthritis, highlighting gut microbiota as a promising avenue for modulating autoimmunity. However, the characterization of the gut virome in arthritis patients, including osteoarthritis (OA) and gouty arthritis (GA), requires further investigation. METHODS: We employed virus-like particle (VLP)-based metagenomic sequencing to analyze gut viral community in 20 OA patients, 26 GA patients, and 31 healthy controls, encompassing a total of 77 fecal samples. RESULTS: Our analysis generated 6819 vOTUs, with a considerable proportion of viral genomes differing from existing catalogs. The gut virome in OA and GA patients differed significantly from healthy controls, showing variations in diversity and viral family abundances. We identified 157 OA-associated and 94 GA-associated vOTUs, achieving high accuracy in patient-control discrimination with random forest models. OA-associated viruses were predicted to infect pro-inflammatory bacteria or bacteria associated with immunoglobulin A production, while GA-associated viruses were linked to Bacteroidaceae or Lachnospiraceae phages. Furthermore, several viral functional orthologs displayed significant differences in frequency between OA-enriched and GA-enriched vOTUs, suggesting potential functional roles of these viruses. Additionally, we trained classification models based on gut viral signatures to effectively discriminate OA or GA patients from healthy controls, yielding AUC values up to 0.97, indicating the clinical utility of the gut virome in diagnosing OA or GA. CONCLUSION: Our study highlights distinctive alterations in viral diversity and taxonomy within gut virome of OA and GA patients, offering insights into arthritis etiology and potential treatment and prevention strategies.

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.

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.

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.

LncRNA HOTTIP from synovial fibroblast-derived exosomes: A novel molecular target for rheumatoid arthritis through the miR-1908-5p/STAT3 axis.

Rheumatoid arthritis (RA) is a chronic inflammation mediated by autoimmune responses. HOTTIP, a long noncoding RNA (lncRNA), participates in cell proliferation and invasion. However, the correlation between HOTTIP and RA remains unclear. Therefore, this study aimed to clarify how HOTTIP works in RA and to investigate its role in the development of RA. Flow cytometry was used to analyze cell cycle progression. Binding between HOTTIP, signal transducer and activator of transcription 3 (STAT3) and miR-1908-5p was demonstrated by dual-luciferase assays. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression of T cell differentiation-related proteins. We found that HOTTIP was upregulated in rheumatoid arthritis synovial fibroblasts (RASFs). HOTTIP directly bound to miR-1908-5p and negatively modulated miR-1908-5p expression while positively regulating STAT3. The effects of HOTTIP overexpression on regulating the balance of the Th17/Treg cell ratio were partly reversed by miR-1908-5p overexpression. In addition, in vivo experiments demonstrated that overexpression of HOTTIP aggravated inflammation in RA mice, which was demonstrated by hematoxylin and eosin (HE) staining and the increased expression levels of CD4+ interleukin (IL)-17+, forkhead Box P3 (FOXP3) and retinoid-related orphan receptor gamma-t (RORγt). In summary, our study suggests that HOTTIP plays a damaging role in RA by promoting inflammation, which may be related to the regulation of miR-1908-5p expression and the STAT3 signaling pathway. These results suggest that the regulation of HOTTIP may be a promising therapeutic strategy for RA.

miR-205-5p in exosomes divided from chondrogenic mesenchymal stem cells alleviated rheumatoid arthritis via regulating MDM2 in fibroblast-like synoviocytes.

OBJECTIVE: To explore the role and mechanism of chondrogenic bone marrow mesenchymal stem cells (BMSCs)-derived exosomes on Rheumatoid arthritis (RA). METHODS: The chondrogenesis of BMSCs was induced by chondrogenic medium. Exosomes from BMSCs and chondrogenic BMSCs were isolated and characterized by transmission electron microscope (TEM), laser particle size analyzer and western blot. ELISA was used to analyze the expression levels of pro-inflammatory cytokines and matrix metalloproteinases (MMPs). Western bolt was performed to assess MAPK and NF-κB pathways expression. The inflammation score and the pathological damage of RA mice were evaluated. Luciferase reporter assay and RIP were carried out to examine the relationship between microRNA-205-5p (miR-205-5p) and mouse double minute 2 (MDM2). RESULTS: Chondrogenic BMSCs-derived exosomes suppressed pro-inflammatory cytokines, MMPs and MAPK and NF-κB pathways in RA-FLSs. miR-205-5p had a high expression in chondrogenic BMSCs-derived exosomes. Functionally, exosomal miR-205-5p also played the anti-inflammation effects. Besides, MDM2 was a direct target of miR-205-5p. Additionally, chondrogenic BMSCs-secreted exosomal miR-205-5p suppressed the inflammation score, joint destruction, and inflammatory response in collagen-induced arthritis (CIA) mice through MDM2. CONCLUSION: Chondrogenic BMSCs-derived exosomal miR-205-5p suppressed inflammatory response, MAPK and NF-κB pathways through MDM2 in RA, indicating exosomal miR-205-5p might be a potential target for RA treatment.

PI3K/AKT/mTOR Signaling Pathway Is Downregulated by Runzaoling (RZL) in Sjögren's Syndrome.

Infiltration and aggregation of lymphocytes in exocrine glands are the basic pathological manifestations of Sjögren's syndrome (SS), and the incidence of SS has been increasing year by year in recent years. To explore the potential signaling pathway of Runzaoling (RZL) in alleviating SS, the possible targets of RZL in SS were firstly explored through network pharmacology, and then, the regulation of PI3K/AKT/mTOR signaling in NOD mice and Th17 cells was verified. 75 8-week-old NOD mice were casually classified into 5 groups: model; hydroxychloroquine; high, medium, and low dose RZL groups, with 15 in each; and 15 BALB/c mice were employed as control group. After 10 weeks of continuous intragastric administration in mice and 24 hours of drugs intervention in Th17 cells, histopathology was observed by HE staining, and the gene transcription levels were identified by real-time quantitative PCR (RT-qPCR). The protein expressions were detected by western blotting (WB). The findings showed that high and medium dose RZL group could attenuate the submandibular gland tissue damage. The results indicated that the mRNA expressions of PI3K, AKT, mTOR, STAT3, and IL-17 in SS mice and in IL-17 stimulation of Th17 cells were dramatically increased compared with control group and decreased to varying degrees after RZL intervention. The trend of phosphorylated PI3K/AKT/mTOR and STAT3 and IL-17 protein expression in NOD mice and Th17 cells were consistent with mRNA. RZL can downregulate STAT3 and IL-17 expressions in the submandibular gland of NOD mice and in Th17 cells via regulating the PI3K/AKT/mTOR signaling pathway. Moreover, RZL could reduce the activation of CD4+ T lymphocyte differentiation to Th17 cells.

Initiation of febuxostat for acute gout flare does not prolong the current episode: a randomized clinical trial.

OBJECTIVE: Our objective was to determine whether initiation of febuxostat during an acute gout flare prolongs the current episode. METHODS: In this randomized, placebo-controlled, single-blinded, multicentre trial, patients with acute gout flares within 72 h were randomized (1:1) to the placebo and febuxostat (40 mg/day) groups. All patients were administered diclofenac (150 mg/day) for 7 days and then open-labelled on the eighth day. Febuxostat 40 mg daily and diclofenac 75 mg daily were administered from day 8 through 28 for the remission period. The dose of diclofenac was 150 mg/day before remission in both arms, and the original protocol was maintained until remission. The primary outcome was 'days to resolution'. RESULTS: We randomized 140 patients, 70 into each arm. The mean days to resolution was 5.98 days [median 7.00, interquartile range (IQR) 2.45 days] for the placebo and 6.50 days (median 7.00, IQR 3.67 days) for the febuxostat group (P = 0.578). The rate of resolution within 7 days was 84.38% for the placebo group and 76.92% for the febuxostat group (P = 0.284). There were no statistically significant differences in joint pain, swelling, tenderness and erythema scores at days 1, 3, 5 and 7. The mean serum uric acid levels were 507.54 and 362.62 µmol/l for the placebo and febuxostat group, respectively, on day 7 (P = 0.000). The rate of recurrent gout flares was 10.00% for the placebo group and 6.56% for the febuxostat group from day 8 through 28 (P = 0.492). CONCLUSION: Initiation of febuxostat administration during an acute gout flare did not prolong the duration of acute flares. TRIAL REGISTRATION: Chinese Clinical Trial Registry, http://www.chictr.org.cn/, ChiCTR1800015962.

[Effects of Jinwu Jiangu recipe on IL-17/STAT3 signals in rheumatoid arthritis synoviocytes].

This paper aimed to investigate the effects of Jinwu Jiangu recipe total extract on the IL-17/STAT3 signals in rheumatoid arthritis synovial fibroblasts(RASF). The primary RASFs were cultured by tissue piece method in vitro， and divided into blank control group， Jinwu Jiangu recipe low dose group， Jinwu Jiangu recipe middle dose group， Jinwu Jiangu recipe high dose group， and tripterygium glycosides control group. They were then treated with corresponding serum free medium， different doses of Jinwu Jiangu recipe total extract(0.06， 0.6， 6.0 g·L⁻¹)， and tripterygium glycosides(0.03 g·L⁻¹) respectively for 24 hours. The gene expression levels of RORα， RORγt， and STAT3 mRNA were detected by polymerase chain reaction(PCR)， and the protein activity of IL-17R and pSTAT3 were measured by Western blot assay. The results showed that as compared with blank control group， the expression levels of RORα， RORγt， IL-17R and STAT3 mRNA in RASF were significantly declined(P<0.01). As compared with tripterygium glycosides control group， Jinwu Jiangu recipe total extract middle dose group and high dose group can down-regulate the expression levels of RORα， RORγt， IL-17R and STAT3 mRNA(P<0.05)， and the effect was more obvious in high dose group(P<0.01). As compared with blank control group， the protein expression levels of IL-17R and pSTAT3 in each treatment group were obviously decreased(P<0.01). As compared with tripterygium glycosides control group， Jinwu Jiangu recipe high dose group had more obvious effect in down-regulating the protein expression of pSTAT3(P<0.01). Therefore， Miao medicine Jinwu Jiangu recipe total extract can down-regulate the expressions of RORα， RORγt， and STAT3 mRNA， and inhibit the protein activity of IL-17R and pSTAT3 in RASF.

[Effect of Jinwu Jiangu Recipe on Expressions of NF-kappaB and IL-17 in Collagen Induced Arthritis Model Rats].

OBJECTIVE: To explore the effect of Jinwu Jiangu Recipe (JJR) on the expression of synovial cells' nuclear factor-kappaB (NF-kappaB) and serum interleukin 17 (IL-17) in collagen induced arthritis (CIA) rats. METHODS: Totally 60 Wistar rats were randomly divided into 6 groups, i.e., the blank control group, the model group, high, middle, and low dose JJR treatment groups, and the tripterygium control group, 10 in each group. Except rats in the blank control group, CIA model was established in rats of the rest 5 groups. Then they were treated from the 7th day of modeling. After 4 weeks of medication they were sacrificed, serum collected, and synovium of joints were isolated. The expression of serum IL-17 was detected in synovium of joints by enzyme linked immunosorbent assay (ELISA). And the expression of NF-kappaB/P65, Ikappabetaalpha and NF-KappaB/P50 were detected by Western blot. RESULTS: Compared with the blank control group, the serum IL-17 level increased in the model group (P <0. 01). Compared with the model group, the serum IL-17 level obviously decreased in high and middle dose JJR groups and the tripterygium control group (P < 0.01). Results of Western blot showed, when compared with the blank control group, protein activities of NF-kappaB/P65 and NF-kappaB/P50 were significantly enhanced in the model group (P < 0.01). Compared with the model group, protein activities of NF-kappaB/P65 and NF-kappaB/P50 significantly decreased in high and middle dose JJR groups and the tripterygium control group (P < 0.05, P < 0.01). All indices mentioned above were higher in the low dose JJR group than in the tripterygium control group (P < 0.05, P < 0.01). CONCLUSION: JJR could lower the expression of serum IL-17 in CIA model rats, and inhibit protein activities of NF-kappaB/P65 and NF-kappaB/P50.

[Chinese medical syndromes of rheumatoid arthritis: a clinical literature study].

OBJECTIVE: To explore the distribution features of Chinese medical syndromes of rheumatoid arthritis (RA) by literature retrieval. METHODS: Pertinent articles on treating RA by syndrome differentiation were retrieved from China National Knowledge Infrastructure Databases (CNKI), VIP Chinese Biomedical Journal Database, Guizhou Digital Library, and Duxiu Chinese Academic Periodicals full papers database from January 2000 to December 2011. RESULTS: A total of 33 documents were recruited covering 4 233 cases. Damp-heat blocking collaterals syndrome occupied the top in the occurrence frequency (20 times, 60.61%), followed by deficiency of Gan and Shen syndrome (18 times, 54.55%), intermingled phlegm and blood-stasis syndrome (17 times, 51.52%), wind-cold-damp impediment syndrome (15 times, 45.45%), cold-damp blocking collaterals syndrome (14 times, 42.42%), wind-damp-heat impediment and deficiency of qi and blood syndrome (10 times, 30.30%), and intermingled cold and heat syndrome (9 times, 27.27%). According to the case number of patients, it was sequenced as damp-heat blocking collaterals syndrome syndrome (768 cases, 18.14%), wind-damp-heat impediment syndrome(666 cases, 15.73%), wind-cold-damp impediment syndrome(584 cases, 13.80%), cold-damp blocking collaterals syndrome syndrome (517 cases, 12.21%), intermingled cold and heat syndrome (415 cases, 9.80%), intermingled phlegm and blood-stasis syndrome (364 cases, 8.60%), deficiency of Gan and Shen syndrome (235 cases, 5.55%),asthenia of healthy energy due to lingering arthralgia syndrome (223 cases, 5.27%). The case numbers of remaining syndromes did not exceed 5%. CONCLUSION: Damp-heat blocking collaterals syndrome was the main syndrome in RA patients, followed by wind-cold-damp impediment syndrome,wind-damp-heat impediment syndrome,cold-damp blocking collaterals syndrome,intermingled phlegm and blood-stasis syndrome, and deficiency of Gan and Shen syndrome.

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.

16S rRNA Gene Sequencing of Gut Microbiota in Rheumatoid Arthritis Treated with 99Tc-MDP.

Background: Rheumatoid arthritis (RA) is a common autoimmune disease with the main symptoms being joint swelling and pain. In severe cases, joint deformity or even complete loss of function occurs. Technetium methylene diphosphonate (99Tc-MDP) is widely used for RA treatment in China, but there are no studies on the effects of 99Tc-MDP on intestinal flora. Objective: To explore the effects of 99Tc-MDP treatment on the composition and function of the intestinal flora and to provide new information on the mechanism of 99Tc-MDP in RA treatment. Methods: Stool samples from RA patients before and after 99Tc-MDP treatment were collected to form two groups (Before and After). Total genomic DNA of the samples was extracted for 16S rRNA gene sequencing. The altered composition of the intestinal flora, the key target bacteria regulated by 99Tc-MDP, and the pathways of action of 99 Tc-MDP were analyzed by bioinformatics. Results: A total of 64 fresh stool samples were collected from 32 RA patients. Compared to the Before group, the After group showed increased Bacteroidetes abundance and decreased Firmicutes abundance. At the genus level, Prevotella increased whereas Escherichia decreased. Both α and ß diversity analyses showed that 99Tc-MDP treatment did not affect gut microbial diversity in RA patients. LEfSe analyses and random forest analyses showed Bacteroidetes, Prevotella, Enterococcus, Escherichia and Ruminococcaceae were the main 99Tc-MDP regulating bacteria. Functional enrichment analysis revealed that the functional differences in gut flora of the two groups centered on Metabolism and Genetic Information Processing. Conclusion: This study revealed differences in the composition of the gut microbiota in RA patients before and after 99Tc-MDP treatment. The therapeutic effect of 99Tc MDP is mainly achieved through Bacteroidetes, Prevotella, and Enterococcus. Regulating metabolism and genetic information processing of gut flora may be the mechanism of 99Tc-MDP in treating RA.

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.

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.

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.

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.

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.

Case report: Successful treatment of anti-MDA5-positive to negative dermatomyositis-associated interstitial lung disease with the JAK inhibitor tofacitinib.

OBJECTIVE: Anti-MDA5 antibody-positive dermatomyositis (DM) is a rare clinical autoimmune disease, and anti-MDA5-positive DM with interstitial lung disease (ILD) is the most important cause of death in DM patients. We reported the efficacy of the JAK1/3 inhibitor tofacitinib as an anti-MDA5-negative treatment option for patients with anti-MDA5-positive DM-ILD. METHOD AND PROCESS: Here we report a 51-year-old female patient with cough, sputum, shortness of breath for 5 months, rash for 3 months, and muscle pain in the extremities for 1 month. After conventional immunosuppressive therapy plus hormone therapy, the remission was slow. Methylprednisolone was successfully reduced after we administered tofacitinib and tacrolimus. After 132 weeks of follow-up, anti-MDA5 antibody turned negative, clinical symptoms were relieved, and lung Imaging tests were successfully reversed. RESULTS AND CONCLUSION: There is currently no report of tofacitinib supplement therapy for anti-MDA5 positive to negative DM. With this case report, tofacitinib is an option for the treatment of anti-MDA5-positive DM-ILD, which deserves attention.

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.