Network pharmacology-based strategy to investigate the mechanisms of artemisinin in treating primary Sjögren's syndrome.

OBJECTIVE: The study aimed to explore the mechanism of artemisinin in treating primary Sjögren's syndrome (pSS) based on network pharmacology and experimental validation. METHODS: Relevant targets of the artemisinin and pSS-related targets were integrated by public databases online. An artemisinin-pSS network was constructed by Cytoscape. The genes of artemisinin regulating pSS were imported into STRING database to construct a protein-protein interaction (PPI) network in order to predict the key targets. The enrichment analyses were performed to predict the crucial mechanism and pathway of artemisinin against pSS. The active component of artemisinin underwent molecular docking with the key proteins. Artemisinin was administered intragastrically to SS-like NOD/Ltj mice to validate the efficacy and critical mechanisms. RESULTS: Network Pharmacology analysis revealed that artemisinin corresponded to 412 targets, and pSS related to 1495 genes. There were 40 intersection genes between artemisinin and pSS. KEGG indicated that therapeutic effects of artemisinin on pSS involves IL-17 signaling pathway, HIF-1 signaling pathway, apoptosis signaling pathway, Th17 cell differentiation, PI3K-Akt signaling pathway, and MAPK signaling pathway. Molecular docking results further showed that the artemisinin molecule had higher binding energy by combining with the key nodes in IL-17 signaling pathway. In vivo experiments suggested artemisinin can restored salivary gland secretory function and improve the level of glandular damage of NOD/Ltj mice. It contributed to the increase of regulatory T cells (Tregs) and the downregulated secretion of IL-17 in NOD/Ltj model. CONCLUSION: The treatment of pSS with artemisinin is closely related to modulating the balance of Tregs and Th17 cells via T cell differentiation.

Disease Duration Affects the Clinical Phenotype of Primary Sjögren Syndrome: A Medical Records Review Study of 952 Cases.

OBJECTIVES: To investigate the impact of disease duration on clinical phenotypes in Chinese patients with primary Sjögren syndrome (pSS) and examine the correlation between clinical phenotypes and onset age, age at diagnosis, and disease duration. METHODS: Data from 952 patients diagnosed with pSS in China between January 2013 and March 2022 were analyzed based on medical records. Patients were categorized into 3 groups based on disease duration: short (<5 years), moderate (≥5 and <10 years), and long (≥10 years) group. Clinical characteristics were compared among the 3 groups, and pSS patients with a long disease duration were compared with the other patients after matching age at diagnosis and age at onset. RESULTS: Among the patients, 20.4% had a disease duration over 10 years. After matching for age at onset and age at diagnosis, pSS patients with a long disease duration exhibited a significantly higher prevalence of dry mouth ( p <0.001), dry eyes ( p <0.001), fatigue ( p <0.001), arthralgia ( p <0.001), and dental caries ( p <0.001) and higher rates of anti-Sjögren syndrome A ( p < 0.05), anti-Ro52 ( p < 0.05), and anti-SSB ( p < 0.05) positivity than their control groups, with prevalence increasing with disease duration ( ptrend < 0.001). However, no differences were noted in the prevalence of interstitial lung disease and leukopenia between different disease duration groups after matching for age at onset, although differences were shown when matching for age at diagnosis. CONCLUSION: Longer disease duration in pSS patients correlates with increased prevalence of sicca symptoms, fatigue, and arthralgia and higher positivity of autoantibodies associated with pSS. However, the prevalence of interstitial lung disease and leukopenia did not correlate with disease duration after matching for age at onset.

Sex Difference in Primary Sjögren Syndrome: A Medical Records Review Study.

OBJECTIVES: The aim of this study was to study clinical and biological differences between men and women with primary Sjögren syndrome (pSS) in China and perform a literature review to confirm if the clinical phenotypes are affected by sex in patients with pSS. METHODS: Data from 961 patients with pSS treated at a tertiary hospital in China between January 2013 and March 2022 were analyzed based on medical records. Clinical characteristics, including disease manifestations and serological parameters of the disease, were compared between men and women with pSS using the Mann-Whitney U test and χ 2 test. RESULTS: This study included 140 (14.6%) men and 821 (85.4%) women with pSS. Women with pSS demonstrated a higher prevalence of dry mouth, dry eyes, arthralgia, and dental caries ( p < 0.05); higher erythrocyte sedimentation rate and immunoglobulin M levels ( p < 0.05); higher prevalence of leukopenia, neutropenia, anemia, low complement 3, and low complement 4 ( p < 0.05); and higher titers of antinuclear antibody, anti-Sjögren syndrome A, anti-Ro52, and rheumatoid factor positivity ( p < 0.05) than men, whereas men with pSS had a higher prevalence of parotid enlargement and interstitial lung disease ( p < 0.05). CONCLUSIONS: Women with pSS are associated with more dryness, cytopenia, hypocomplementemia, and autoantibody positivity. Although men with pSS probably have lighter sicca symptoms and lower immunoactivity and serologic responses, regular monitoring of interstitial lung disease in men is vital.

Distinct clinical phenotypes of primary Sjögren's syndrome differ by onset age: a retrospective study of 742 cases and review of the literature.

OBJECTIVES: To study the clinical characteristics of primary Sjögren's syndrome (pSS) with different onset age, and perform a review of the literature to confirm if the clinical phenotypes are affected by onset age in patients with pSS. METHODS: Data of 742 patients with pSS were retrospectively analysed. Patients were divided into three groups according to onset age: young-onset pSS (YopSS, <35 years), adult-onset pSS (AopSS, ≥35 and ≤65 years), and elderly-onset pSS (EopSS, >65 years). Clinical characteristics were compared among three groups and further multiple comparisons were conducted by Bonferroni adjustment. The Chi-squared test for linear-by-linear association was used to explore variation tendency. RESULTS: This study included 105 (14.2%), 533 (71.8%), and 104 (14.0%) cases of YopSS, AopSS, and EopSS, respectively. YopSS demonstrated lower prevalence of dry mouth, abnormal Schirmer I tests, and interstitial lung disease (ILD), but higher proportions of low C3 and C4 levels, and ANA, anti-SSA, anti-SSB, and rheumatoid factor (RF) positivity than AopSS and EopSS. The proportions of dry mouth (p=0.004), abnormal Schirmer I tests (p=0.002), and ILD (p<0.001) tended to increase with the increase of onset age, while the prevalence of leukopenia (p=0.011), low C3 (p=0.001), low C4 (p=0.001), and ANA (p<0.001), anti-SSA (p<0.001), anti-SSB (p<0.001) and RF (p<0.001) positivity tended to decrease with an increase in onset age. CONCLUSIONS: YopSS demonstrated less dryness and ILD, but more immunologic disorders. ILD prevalence were directly proportional to onset age of pSS; however, leukopenia, hypocomplementaemia, and autoantibody positivity showed opposite trends.

Factors associated with secondary immune thrombocytopenia in patients with primary Sjögren's syndrome: a retrospective study of 639 cases.

OBJECTIVES: To investigate the clinical characteristics and relevant factors of secondary immune thrombocytopenia (ITP) in patients with primary Sjögren's syndrome (pSS). METHODS: Patients with pSS being treated between 2013 and 2020 in China-Japan Friendship Hospital were retrospectively analysed. Clinical characteristics were compared between pSS patients with and without secondary ITP. Logistic regression analysis was performed to identify factors associated with secondary ITP in patients with pSS. RESULTS: 639 patients with pSS were included in this study, among which 566 (88.6%) were women. The prevalence of secondary ITP in patients with pSS were 12.4%. Among pSS patients with secondary ITP, 55.7% had mucocutaneous bleeding and 8.9% experienced visceral bleeding. Lymphopenia (OR=3.154, 95% CI 1.185-8.395, p=0.021), anaemia (OR=2.416, 95% CI 1.250-4.668, p=0.009), low C4 (OR=2.904, 95% CI 1.563-5.394, p=0.001), and positive anti-RNP (OR=2.777, 95% CI 1.070-7.202, p=0.036) were significantly related to secondary ITP, while interstitial lung disease (ILD, OR=0.429, 95% CI 0.203-0.907, p=0.027), ANA ≥1:320 (OR=0.469, 95% CI 0.221-0.996, p=0.049) and positive anti-SSB (OR=0.288, 95% CI 0.126-0.685, p=0.003) were negatively associated with secondary ITP in patients with pSS. CONCLUSIONS: Over 10% of patients with pSS had secondary ITP, among whom visceral bleeding was comparatively rare. Lymphopenia and anaemia were positively related to secondary ITP, while ILD was negatively associated with secondary ITP. Low C4 and positive anti-RNP seem to be two potential risk factors for secondary ITP in patients with pSS, while ANA ≥1:320 and positive anti-SSB may be two potential protective factors.

[Effect of Bushen Qiangdu Recipe on Histomorphology and Wnt Pathway of DBA/1 Mice].

Objective To observe the effect of Bushen Qiangdu Recipe (BQR) on the entheses ossification histomorphology of articular ligament of DBA/1 mice with spontaneous ankylosing spondylitis (AS) , and to study its mechanism for prevention and treatment of AS. Methods Thirty 12-week old male DBA/1 mice were randomly divided into the model group, the positive drug group, low, medium, high dose BQR groups, 6 in each group. Another 6 C57BLE mice of the same age were recruited as a blank control group. BQR containing 11. 25, 22. 50, 45.00 g/kg crude drugs was respectively adminis- tered to mice in low, medium, high dose BQR groups by gastrogavage, 0. 2 mL for each mouse, once per day. Celecoxib Capsule (0. 2 mL/0. 8 mg for each mouse, once per day) was administered to mice in the positive drug group by gastrogavage. Equal volume of normal saline was administered to mice in the model group and the blank control group by gastrogavage. All mice were fed and intragastically adminis- tered for 12 successive weeks. Body weight, diet, stools, and hair were routinely observed. Signs of ar- thritis were evaluated once per two weeks. Mice were sacrifice, and then general observation of achilles tendon was performed. The achilles tendon tissue was HE stained. Protein expressions of alkaline phos- phatase (ALP) , bone gamma-carboxyglutamic-acid-containing proteins (BGP) , Dickkopfl (DKK1) , and Wnt5a in the achilles tendon were detected using immunohistochemical method. Results Compared with the blank control group, the scoring of arthritis obviously increased in the model group (P <0. 05). But the scoring of arthritis was obviously lower in the 3 BQR groups and the positive drug group than in the model group (P <0. 05). Histopathological results of achilles tendon tissue showed that no infiltration of inflammatory cells or fibroblasts occurred in the normal group. Their histomorphological structures were normal. Cartilage formation and bone formation at various degrees occurred in the model group. Filtration of fibroblast-like cells occurred in inflammatory cells and attachment points. Scattered lymphocyte infiltra- tion was often seen in the achilles tendon tissue of each medicated group. Cartilage formation and bone formation were rarely seen. Compared with the blank control group, the scoring of arthritis increased in the model group (P <0. 05). Compared with the model group, the scoring of arthritis was decreased in the 3 BQR groups and the positive drug group (P <0. 05). Compared with the blank control group, protein expression of DKK1 decreased and protein expression of Wnt5a increased in the model group (P <0. 05). Compared with the model group, protein expression of DKK1 increased and protein expression of Wnt5a decreased in middle and high dose BQR groups (P <0. 05). Conclusion BQR could delay the occur- rence and development of arthritis and ossification in DBA/1 mice of spontaneous AS model possibly by inhibiting classical Wnt pathway.

[Efficacy and Safety Evaluation of Bushen Shuji Granule in Treating Ankylosing Spondylitis Patients: a Clinical Study].

OBJECTIVE: To evaluate the short-term efficacy and safety of Bushen Shuji Granule (BSG) in treating ankylosing spondylitis (AS) patients. METHODS: A prospective randomized controlled clinical trial was carried out in 62 active stage AS patients with Shen deficiency Du-channel cold syndrome (SDDCS), who were randomly assigned to the BSG group (treated with BSG) and the control group (treated with Celecoxib Capsule). Twelve weeks consisted of one therapeutic course. Therapeutic effects were evaluated by ASAS20 and ASAS40 (set by Assessments in Ankylosing Spondylitis working group) , BASDA150, Chinese medical (CM) syndrome efficacy evaluation standards. BASDAI, the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath AS Metrology Index (BASMI), scores for spine pain, scores for pain at night, patient global assessment (PGA) , erythrocyte sedimentation rate (ESR) , and C reactive protein (CRP) were observed before and after treatment. RESULTS: After three-month treatment by BSG, ASAS20 standard rate was 63. 33% (19/30 cases) in the BSG group and 66.67% (20/30 cases) in the control group with no significant difference between the two groups (χ2 = 0.073, P > 0.05). The efficacy for CM syndromes was 70.00% (21/30 cases) in the BSG group, higher than that in the control group [40.00% (12/30 cases), χ2 = 5.455, P < 0.05]. Scores for CM syndromes, BASDAI, night pain index, spinal pain index, PGA, CRP were improved in the BSG group (P < 0.05, P < 0.01). The incidence of adverse events in the BSG group was lower than that of the control group. CONCLUSION: BSG based on Shen supplementing, Du-channel strengthening, blood activating, and channels dredging method had good short-term clinical efficacy and safety in treating AS.

[Manifestations of rheumatoid arthritis patients of cold syndrome and heat syndrome using wrist ultrasound].

OBJECTIVE: To explore distinctive manifestations of rheumatoid arthritis (RA) patients of cold syndrome and heat syndrome using wrist joints ultrasound. METHOD: s Totally 65 RA patients were syndrome typed as cold syndrome (29 cases, cold-damp blockage syndrome) and heat syndrome (36 cases, damp-heat obstruction syndrome). Grey-scale synovitis, power doppler (PD) signals, tenosynovitis, and bone erosion were observed using wrist ultrasound. Distinctive manifestations of cold syndrome and heat syndrome were analyzed using wrist ultrasound. RESULTS: In RA patients of cold syndrome, the positive rate of synovitis, PD, tenosynovitis, and bone erosion was 51.72%, 20.68%, 51.72%, and 37.93%, respectively, while they were 97.22%, 91.67%, 75.0%, and 63.89%, respectively in RA patients of heat syndrome. Compared with patients of cold syndrome, the positive rate of synovitis, PD, and bone erosion increased in patients of heat syndrome (P < 0.01, P < 0.01, P < 0.05). There was no statistical difference in the positive rate of tenosynovitis between the two groups (P > 0.05). Compared with the cold syndrome group, there was statistical difference in the constituent ratio of synovitis, PD, and bone erosion in the heat syndrome group (P < 0.01, P < 0.01, P < 0.05), but with no statistical difference in the constituent ratio of tenosynovitis (P > 0.05). Results of the ROC curve showed that the sensitivity was 86.1% and the specificity was 62.1% in judging heat syndrome, when the total score of synovitis in two wrists was more than 1.5; the sensitivity was 80.0% and the specificity was 93.1% in judging heat syndrome, when the total score of PD in two wrists was more than 1.5. CONCLUSIONS: Positive rates of synovitis, PD, and bone erosion were significantly higher in RA patients of heat syndrome than those of cold syndrome. Especially serious manifestations were more often seen in RA patients of heat syndrome. The total score of synovitis or PD in the two wrist joints higher than 1.5 was characteristic manifestations of heat syndrome using wrist ultrasound.

Jolkinolide B ameliorates rheumatoid arthritis by regulating the JAK2/STAT3 signaling pathway.

BACKGROUND: Jolkinolide B (JB), an ent­abietane-type diterpenoid in Euphorbia plants, has various pharmacological activities, including anticancer, anti-inflammatory, and anti-tuberculosis activities. However, no previous studies have proven whether JB can be regarded as a targeted drug for the treatment of rheumatoid arthritis (RA). PURPOSE: This study aimed to evaluate the anti-RA effects of JB and explore the potential mechanisms. METHODS: Components and targets of JB and RA were identified in different databases, and potential targets and pathways were predicted by protein-protein interaction (PPI) network analysis and pathway enrichment analysis. Then, molecular docking and surface-plasmon resonance (SPR) were used to confirm the predict. The anti-arthritic effects of JB were studied in vivo with collagen-induced arthritis (CIA) rat model and in vitro with lipopolysaccharide (LPS) and interleukin-6 (IL-6)-induced RAW264.7 macrophage. Potential mechanisms were further verified by in vivo and in vitro experiments. RESULTS: The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that Th17 cell differentiation, prolactin signaling pathway, and JAK/STAT signaling pathway might be associated with anti-RA effects of JB. Molecular docking and SPR results showed that JB bound effectively to JAK2. JB significantly decreased body weight loss, arthritis index, paw thickness, and synovial thickness in CIA rats. Histomorphological results suggested the protective effects of JB on CIA rats with ankle joint injury. Molecular biology analysis indicated that JB suppressed the mRNA expression of inflammatory factors in ankle joints for CIA rats and reduced the concentration of these factors in LPS- induced RAW264.7 macrophage. The protein expression level of the JAK2/STAT3 pathway was also significantly decreased by JB. CONCLUSION: JB had a novel inhibitory effect on inflammation and bone destruction in CIA rats, and the mechanism might be related to the JAK2/STAT3 signaling pathway.

Efficacy and safety of the modified Zhiwang decoction combined with methotrexate in early rheumatoid arthritis: study protocol for a randomised controlled trial.

INTRODUCTION: Rheumatoid arthritis (RA) is a progressive inflammatory autoimmune disease characterised by chronic systemic inflammation, which can cause swelling, stiffening and destruction of articular cartilage and bone. Early diagnosis and treatment of RA can improve outcomes and slow the progression of joint damage. Preliminary exploratory research had hinted an expected effect of modified Zhiwang decoction (MZWD) in treating early RA. However, few randomised clinical trials have evaluated the effectiveness of MZWD in early RA. Therefore, a parallel-group randomised controlled trial was designed to evaluate the efficacy and safety of MZWD combined with methotrexate (MTX) on early RA. METHODS AND ANALYSIS: This is a prospective, parallel-group, single-centre randomised controlled clinical study. A total of 150 patients will be randomly assigned to either the treatment (n=75) or control group (n=75). The treatment group will receive MZWD and MTX, and the control group will receive MTX for 12 weeks. The primary outcome of this study is Disease Activity Score-28, and the secondary outcomes are Fatigue Scale-14, Visual Analogue Scale pain scores and traditional Chinese medicine symptom scores. Safety outcomes, including adverse events and results of ECG and laboratory tests, will be monitored. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Clinical Research Ethics Committee of the China-Japan Friendship Hospital (no. 2022-KY-124) on 8 July 2022. The findings will be disseminated in peer-reviewed publications. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05508815).

Integrated phytochemistry and network pharmacology analysis to reveal effective substances and mechanisms of Bushen Quhan Zhiwang decoction in the treatment of rheumatoid arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Bushen Quhan Zhiwang decoction (BQZD), a formula in traditional Chinese medicine (TCM), effectively delays bone destruction in rheumatoid arthritis (RA) patients. However, its chemical constituents, absorbed components, and metabolites remain unrevealed, and its mechanism in treating bone destruction in RA needs further investigation. AIM OF THE STUDY: Our objective is to identify the chemical constituents, absorbed components, and metabolites of BQZD and explore the potential mechanisms of BQZD in treating bone destruction in RA. MATERIALS AND METHODS: This study systematically identified the chemical constituents, absorbed components, and metabolites of BQZD using ultra-performance liquid chromatography with Q-Exactive Orbitrap mass spectrometry combined with parallel reaction monitoring. The absorbed components and metabolites were subjected to network pharmacology analysis to predict the potential mechanisms of BQZD in treating bone destruction in RA. The in vivo anti-osteoclastogenic and underlying mechanism were further verified in collagen-induced arthritis (CIA) rats. RESULTS: A total of 182 compounds were identified in BQZD, 27 of which were absorbed into plasma and organs and 42 metabolites were identified in plasma and organs. The KEGG analysis revealed that MAPK signaling pathway was highly prioritized. BQZD treatment attenuated paw swelling and the arthritis index; suppressed synovial hyperplasia, bone destruction, and osteoclast differentiation; and inhibited the levels of TNF-α, IL-1ß, and IL-6 in CIA rats. Mechanically, BQZD significantly decreased the protein expression levels of TRAF6, NFATc1, p-JNK, and p-p38, which might be related to 9 absorbed components and 1 metabolite. CONCLUSION: This study revealed the key active components and metabolites of BQZD. BQZD exhibits bone-protective effects via TRAF6/p38/JNK MAPK pathway, which may be associated with 9 absorbed components and 1 metabolite.

[Treatment of ankylosing spondylitis by modified bushen zhuanggu recipe: a clinical observation].

OBJECTIVE: To observe the clinical effect and safety of modified Bushen Zhuanggu Recipe (BZR) in treating ankylosing spondylitis (AS). METHODS: Recruited were 96 AS outpatients of Shen deficiency induced cold-dampness syndrome (SDCDS) or Shen deficiency dampness-heat syndrome (SDDHS) at clinics of China-Japan Friendship Hospital from May 2010 to May 2011. They were randomly assigned to the traditional Chinese medicine (TCM) treatment group and the Western medicine (WM) treatment group in the ratio of 1:1. Those in the TCM treatment group were syndrome typed as the SDCDS group (group A, 22 cases, treated by Bushen Zhuanggu Quhan Decoction + WM placebos) and the SDDHS group (group B, 26 cases, treated by Bushen Zhuanggu Qinghua Decoction +WM placebos). Those in the WM treatment group were syndrome typed as SDCDS group (group C, 27 cases, treated by SASP + TCM placebos) and the SDDHS group (group D, 21 cases, treated by SASP +TCM placebos). Totally 12 weeks consisted of one therapeutic course. BAS-G, BASFI, BASDAI, spine pain, pain at night, TCM symptom score, distance between occipital and wall, distance between finger and ground, thoracic activity, spine activity, Schober test, ESR, CRP were observed as the observing indices; ASAS20, ASAS50, ASAS70, BASDAI50, and criteria of TCM were explored for clinical evaluation and safety evaluation. RESULTS: In comparison with the same group before treatment,BAS-G, BASFI, BASDAI, spine pain, pain at night, TCM syndrome score,distance between finger and ground, Schober test, ESR, and CRP were improved after treatment (P < 0.01, P < 0.05). In group A and C, thoracic activity and spine activity were getting better (P < 0.01, P < 0.05). In group B distance between occipital and wall and spine activity were getting better (P < 0.01, P < 0.05). In comparison with group C, BAS-G, BASFI, BASDAI, spine pain, distance between finger and ground,thoracic activity,spine activity, Schober test, ESR, CRP were getting better in group A after treatment (P < 0.01, P < 0.05). In comparison with group D, BASFI, BASDAI, spine pain, pain at night,distance between finger and ground, distance between occipital and wall, spine activity, Schober test, and ESR were getting better in group B after treatment (P < 0.01, P < 0.05). The total effective rate, ASAS20, ASAS50, ASAS70, and BASDAI50 were higher in the TCM treatment group than in the WM treatment group (P < 0.05). CONCLUSION: Modified BZR was more effective than SASP method in relieving clinical symptoms and signs, TCM syndrome scores, and inflammatory activity indicators of AS patients.

[Treating rheumatoid arthritis patients of Shen deficiency and cold invading syndrome by bushen quhan zhiwang decoction combined methotrexate: an evaluation of clinical efficacy and safety].

OBJECTIVE: To evaluate the clinical efficacy and safety of bushen quhan zhiwang decoction (BQZD) combined methotrexate (MTX) in treating rheumatoid arthritis (RA). METHODS: A prospective, randomized controlled study was carried out. RA patients of Shen deficiency and cold invading syndrome in the treatment group (120 cases) were treated with BQZD and MTX (10 mg/week), while those in the control group (120 cases) were treated with MTX (10 mg/week) alone. The therapeutic course for all was 24 weeks. The efficacy and safety indices were evaluated at the baseline and 24 weeks after treatment, including clinical signs and symptoms, condition assessment, Health Assessment Questionnaire (HAQ), disease activity index 28 (DAS28), laboratory parameters of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), safety indicators, and Chinese medical syndrome integrals. RESULTS: The total effective rate was 80. 0% in the treatment group, better than that of the control group (66.7%), showing statistical difference (P <0.01). In the two groups significant improvement of clinical signs and symptoms, ESR, CRP, visual analogue scale (VAS) by both physicians and patients, HAQ, DAS28, and Chinese medical syndrome integrals after treatment were shown (P <0.01). Better effects were obtained in the treatment group in lessening tender joint numbers and swollen joint numbers, VAS by both physicians and patients, DAS28, and Chinese medical syndrome integrals (P < 0.05). Besides, adverse reactions occurred less in the treatment group than in the control group (P < 0.05). CONCLUSIONS: BQZD had roles in relieving symptoms, improving joint functions, signs, ESR, and CRP. It was an effective herb for RA patients of Shen deficiency and cold invading syndrome. It could enhance the efficacy and reduce adverse reactions of MTX through synergistic effects with MTX.

Total Flavonoids of Rhizoma Drynariae Treat Osteoarthritis by Inhibiting Arachidonic Acid Metabolites Through AMPK/NFκB Pathway.

Objective: Previous clinical studies have found that total flavonoids of Rhizoma Drynariae (TFRD) have a good therapeutic effect on osteoarthritis (OA), but its therapeutic mechanism needs further research. Methods: OA rat model was established by Hulth method and was intervened by TFRD. Pathological assessments were conducted to assess the protective effect of TFRD on cartilage. Serum metabolomics and network pharmacology were detected to predict the mechanism of TFRD treating OA. In further experiments, molecular biology experiment was carried out to confirm the predicted mechanisms in vivo and in vitro. Results: TFRD can effectively reduce chondrocyte apoptosis and cartilage degeneration in OA model rats. Serum metabolomics revealed that the intervention effect may be closely related to arachidonic acid metabolism pathway. Network pharmacologic prediction showed that COX-2 was the key target of TFRD in treating OA, and its mechanism might be related with NFκB, apoptosis, AMPK and arachidonic acid metabolism pathway. In vivo experiments indicated that TFRD can inhibit the abnormal expression of COX-2 mRNA in OA model rats. In the in vitro studies, the expression of COX-2 mRNA and protein increased, AMPK phosphorylation was inhibited, and NFκB signaling pathway was activated in IL-1ß-induced chondrocytes, and these changes can be reversed by TFRD. After the activation of AMPK signaling pathway or the block-down of NFκB signaling pathway, the effect of TFRD on COX-2 mRNA expression was significantly weakened. Conclusion: TFRD can inhibit COX-2-mediated arachidonic acid metabolites, and its mechanism is closely related to AMPK/NFκB pathway, which may be a key mechanism in the treatment of OA.

Eosinophilic fasciitis difficult to differentiate from scleroderma: A case report.

BACKGROUND: Eosinophilic fasciitis (EF) is a rare connective tissue disease that can cause swelling and sclerosis of the extremities, and special attention is needed to differentiate EF from systemic sclerosis. Misdiagnosis or omission markedly delays treatment of EF, and severe skin sclerosis in advanced stages can cause joint contracture and tendon retraction, worsening the patient's prognosis and quality of life. CASE SUMMARY: We report a case of EF in a young woman diagnosed by tissue biopsy, confirming the difficulty of differential diagnosis with scleroderma. CONCLUSION: Focusing on skin manifestations, completing tissue biopsy and radiography can help diagnose EF effectively. Clinicians should enhance their understanding of the differences between EF and scleroderma, and early diagnosis and standardized treatment can improve the prognosis of patients with EF.

Knowledge mapping of biological disease-modifying anti-rheumatic drugs for axial spondyloarthritis: a bibliometric study.

Various biological disease-modifying anti-rheumatic drugs (bDMARDs) have been applied for treating axial spondyloarthritis (axSpA). However, there is a glaring absence of a bibliometric analysis on bDMARDs against axSpA. Articles related to use of bDMARDs in treating axSpA published from 2004 to 2022 were searched from the Web of Science Core Collection. VOS viewer 1.6.18 and CiteSpace 6.1.R2 were used to analyze and visualize the quantity and citations of publications, as well as to identify "research hotspots" and trends in this field. BibExcel version 1.0.0 and gCLUTO version 1.0 were used to build matrices for bi-clustering analysis. A total of 2546 articles referring to bDMARDs for treatment of axSpA were included in this bibliometric analysis. Overall, the number of publications has been increasing steadily annually. The USA (23.21%, 591 publications) ranked first with the largest output of papers, followed by Germany, and the Netherlands. Rheumazentrum Ruhrgebiet ranked first as the most frequent publisher (119 articles). Annals of the Rheumatic Diseases published the most documents (6.76%, 172 publications) in this field. The predominant hotspots have been "tuberculosis," "IL-17," and "quality of life" in the field until 2020. Since 2015, "biosimilar pharmaceuticals" has retained the popularity. Current research hotspots are "spinal radiographic progression," Janus kinase (JAK) inhibitors, and adverse events (AEs). Machine learning has become popular gradually. Globally, there has been a steady increase in the number of studies on bDMARDs use against axSpA. JAK inhibitors, spinal radiographic progression, biosimilar pharmaceuticals, and AEs are current research hotspots. Machine learning is emerging research hotspots and trends in this field.

Network Pharmacology Analysis and Experimental Validation to Investigate the Mechanism of Total Flavonoids of Rhizoma Drynariae in Treating Rheumatoid Arthritis.

Objective: The study aimed to explore the mechanism of total flavonoids of Rhizoma Drynariae (TFRD) in the treatment of rheumatoid arthritis (RA) based on network pharmacology and experimental validation. Methods: The active components of TFRD were identified from TCMSP and TCMID databases. Relevant targets of the active compounds of TFRD and RA-related targets were predicted by public databases online. A component-target (C-T) regulatory network was constructed by Cytoscape. The genes of TFRD regulating RA were imported into STRING database to construct a protein-protein interaction (PPI) network in order to predict the key targets. KEGG enrichment analysis was performed to predict the crucial mechanism of TFRD against RA. The active components of TFRD underwent molecular docking with the key proteins. Collagen-induced arthritis (CIA) model of rats and inflammatory factors-stimulated fibroblast-like synoviocytes were used in vivo and in vitro to validate the efficacy and predicted critical mechanisms of TFRD. Results: Network Pharmacology analysis revealed that TFRD had 14 active compounds, corresponding to 213 targets, and RA related to 2814 genes. There were 137 intersection genes between TFRD and RA. KEGG indicated that therapeutic effects of TFRD on RA involves T cell receptor signaling pathway, Th17 cell differentiation, IL-17 signaling pathway, TNF signaling pathway, MAPK signaling pathway and PI3K/AKT signaling pathway. In vivo experiments suggested TFRD can alleviate the inflammatory response, joint swelling and synovial abnormality of CIA rats. TFRD contributed to the decrease of Th17 cells and the down-regulated secretion of IL-17A and TNF-α of activated lymphocyte in CIA model. In vitro experiments confirmed TFRD can effectively inhibit the inflammatory response of fibroblast-like synoviocytes and suppress the abnormal activation of MAPK, PI3K/AKT and NFκB signaling pathways. Conclusion: The treatment of RA with TFRD is closely related to inhibiting Th17 differentiation and inflammatory response of synoviocytes.

Integrating Network Pharmacology and Experimental Validation to Explore the Key Mechanism of Gubitong Recipe in the Treatment of Osteoarthritis.

Background: Gubitong Recipe (GBT) is a prescription based on the Traditional Chinese Medicine (TCM) theory of tonifying the kidney yang and strengthening the bone. A previous multicentral randomized clinical trial has shown that GBT can effectively relieve joint pain and improve quality of life with a high safety in treating osteoarthritis (OA). This study is aimed at elucidating the active compounds, potential targets, and mechanisms of GBT for treating OA. Method: The network pharmacology method was used to predict the key active compounds, targets, and mechanisms of GBT in treating OA. An OA rat model was established with Hulth surgery, and the pathological changes of articular cartilage were observed to evaluate the effects of GBT. Chondrocytes were stimulated with LPS to establish in vitro models, and key targets and mechanisms predicted by network pharmacology were verified via qRT-PCR, ELISA, western blot, and immunofluorescence. The Contribution Index Model and molecular docking were used to determine the key active compounds of GBT and the major nodes affecting predicted pathways. Result: A total of 500 compounds were acquired from related databases, where 87 active compounds and their 254 corresponding targets were identified. 2979 OA-related genes were collected from three databases, 150 of which were GBT-regulating OA genes. The compound-target network weight analysis and PPI results showed that IL-6 and PGE2 are key targets of GBT in treating OA. KEGG results showed that PI3K/AKT, Toll-like receptor, NFκB, TNF, and HIF-1 are the key signaling pathways. An in vivo experiment showed that GBT could effectively suppress cartilage degradation of OA rats. In vitro experiments demonstrated that GBT can inhibit the key targets of KEGG-related pathways. Molecular-docking results suggested that luteolin, licochalcone A, and ß-carotene were key targets of GBT, and the mechanisms may be associated with the NFκB signaling pathway. Blockage experiments showed that the NFκB pathway is the key pathway of GBT in treating OA. Conclusion: This study verified that GBT can effectively protect articular cartilage through multitarget and multipathway, and its inhibitory effect on the NFκB pathway is the most key mechanism in treating OA.

Network Pharmacology-Based Strategy to Investigate the Mechanisms of Cibotium barometz in Treating Osteoarthritis.

Cibotium barometz is a representative tonifying kidney drug and is widely used for osteoarthritis (OA) in traditional Chinese medicine. However, its regulatory mechanisms in treating OA remain to be sufficiently investigated. The main chemical components of Cibotium barometz were screened through the TCMID database and the corresponding targets were acquired through SwissTargetPrediction. The OA-related targets were obtained from the OMIM, Genecards, Genebank, TTD, and DisGeNET databases. The prediction of key targets and pathways of Cibotium barometz in the treatment of OA was achieved by constructing a compounds-targets network and performing KEGG enrichment analysis. The OA model rats were established by the Hulth method and used to explore the protective effect of Cibotium barometz via cartilage pathological assessment. In vitro models of OA were built by the proinflammatory factor interleukin-1ß (IL-1ß) induced SW1353 cells and used to validate the mechanisms predicted by network pharmacology. Network pharmacology results suggested that the therapeutic effects of Cibotium barometz were closely related to matrix metalloproteinase (MMP)-1, 3, 13 and inflammation-related gene COX2, which are regulated by the NFκB pathway. In vivo experiments revealed that Cibotium barometz could effectively restrain cartilage from degeneration and inhibit the mRNA expression of MMP-1, MMP-3, MMP-13, and COX2 in cartilage. In vitro experiments indicated that Cibotium barometz water extract (CBWE) could significantly inhibit the expression of MMP-1, MMP-3, MMP-13, and PGE2 in IL-1ß-induced SW1353 cells and markedly prevent the translocation of NFκB p65 from the cytoplasm to the nuclei and decrease its phosphorylation level. After small-interfering RNA (siRNA) was used to suppress the synthesis of NFκB p65 to block NFκB signaling pathway, the ability of CBWE to inhibit MMP-1, MMP-3, MMP-13, and PGE2 was greatly reduced. Cibotium barometz has a chondroprotective effect on OA by inhibiting the response to inflammation and substrate degradation, and the related mechanism is associated with the inhibition of the NFκB pathway.

Epimedii Herba: An ancient Chinese herbal medicine in the prevention and treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, progressive inflammatory and systemic autoimmune disease resulting in severe joint destruction, lifelong suffering and considerable disability. Diverse prescriptions of traditional Chinese medicine (TCM) containing Epimedii Herba (EH) achieve greatly curative effects against RA. The present review aims to systemically summarize the therapeutic effect, pharmacological mechanism, bioavailability and safety assessment of EH to provide a novel insight for subsequent studies. The search terms included were "Epimedii Herba", "yinyanghuo", "arthritis, rheumatoid" and "Rheumatoid Arthritis", and relevant literatures were collected on the database such as Google Scholar, Pubmed, Web of Science and CNKI. In this review, 15 compounds from EH for the treatment of RA were summarized from the aspects of anti-inflammatory, immunoregulatory, cartilage and bone protective, antiangiogenic and antioxidant activities. Although EH has been frequently used to treat RA in clinical practice, studies on mechanisms of these activities are still scarce. Various compounds of EH have the multifunctional traits in the treatment of RA, so EH may be a great complementary medicine option and it is necessary to pay more attention to further research and development.