OBJECTIVES: To analyze the molecular mechanism of Xixian Pills for treatment of rheumatoid arthritis (RA). METHODS: Forty-eight rats were randomized into 6 groups (n=8), including a normal control group, a collagen-induced arthritis (CIA) model group, 3 Xixian Pills treatment (200, 400 and 800 mg/kg) groups, and a Tripterygium glycosides tablet (TGT) treatment group. In the latter 4 groups, the rats were treated with daily gavage of Xixian Pills or TGT 2 weeks after CIA modeling for 3 consecutive weeks. The differentially expressed proteins in high-dose Xixian Pills group and the model group compared with the normal control group were screened based on the tandem mass spectrometry tag (TMT) technology, and the core targets and signaling pathways were analyzed. The immune cell infiltration and gene expression data were analyzed using ggplot2 and tidyverse packages, and the correlation coefficients between the core targets and the immune cells were calculated. RESULTS: The CIA rats showed significantly increased serum levels of TNF-α and IL-6 and lowered serum IL-10 level. Treatments with high- and medium-dose Xixian Pills and TGT all significantly reduced serum TNF‑α and IL-6 and increased IL-10 levels in CIA rats. Proteomic analysis identified 160 differential proteins between the model group and high-dose Xixian Pills group, and the core targets included CCL5, STAT1, GZMB and IL7R. The areas under the ROC curve of CCL5 and STAT1 were both greater than 0.9. Immunohistochemical and immunofluorescence staining revealed increased levels of CCL5 and STAT1 in the ankle joints of CIA rats, which were significantly decreased after treatment with Xixian Pills. CONCLUSIONS Treatment with Xixian Pills offers protection of the joints in CIA rats possibly by inhibiting joint inflammation via regulating protein expressions of CCL5 and STAT1.
Animals ; Drugs, Chinese Herbal/pharmacology* ; Rats ; Arthritis, Rheumatoid/metabolism* ; Proteomics ; Tripterygium/chemistry* ; Arthritis, Experimental/metabolism* ; Tumor Necrosis Factor-alpha/blood* ; Interleukin-10/blood* ; Interleukin-6/blood* ; Male ; Rats, Sprague-Dawley ; Signal Transduction

INTRODUCTION: Rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) are used in the diagnosis and prognostication of rheumatoid arthritis (RA). We wanted to determine the specific contributions of RF and ACPA to the biological nature of RA and whether they act synergistically. METHODS: We identified 731 patients from our prospective multi-ethnic RA cohort and categorised them into four groups: ACPA-positive, RF-positive, doubly positive and doubly negative. We compared the demographics, Disease Activity Score-28, Health Assessment Questionnaire score, quality of life using Short Form 36 and the use of prednisolone and disease-modifying antirheumatic drugs (DMARDs) of these patient groups. RESULTS: Four hundred and ninety-one patients (67.2%) were ACPA+RF+, 54 (7.4%) were ACPA+RF-, 82 (11.2%) were ACPA-RF+ and 104 (14.2%) were ACPA-RF-. Mean disease duration before the study entry was not different in the four groups. Patients with older age of onset were less likely to be positive for RF and ACPA. Fewer ACPA+RF+ patients were in remission compared to those in the other groups ( P < 0.05). Erythrocyte sedimentation rate (ESR) was higher at study entry in the ACPA+RF+ group (40.4 mm/h vs. 30.6-30.9 mm/h, P < 0.05). Prednisolone and number of DMARDs used were higher in the ACPA+RF+ group compared to the doubly negative group. There were no differences in the functional status and quality of life. CONCLUSIONS RA patients who were positive for both ACPA and RF had lower remission rate, higher baseline ESR and required more corticosteroid and DMARD treatment compared to those who were singly positive or doubly negative. Being doubly positive confers a worse outcome to RA patients.
Humans ; Arthritis, Rheumatoid/diagnosis* ; Male ; Female ; Middle Aged ; Rheumatoid Factor/blood* ; Anti-Citrullinated Protein Antibodies/blood* ; Adult ; Quality of Life ; Prospective Studies ; Antirheumatic Agents/therapeutic use* ; Aged ; Peptides, Cyclic/immunology* ; Prednisolone/therapeutic use* ; Surveys and Questionnaires ; Severity of Illness Index ; Prognosis

This paper aims to explore the activity of Codonopsis canescens extract against rheumatoid arthritis(RA) based on the Toll-like receptors(TLRs)/mitogen-activated protein kinases(MAPKs)/nuclear factor kappa B(NF-κB) signaling pathways and its mechanism. The ultra-performance liquid chromatography-quadrupole time-of-flight/mass spectrometry(UPLC-Q-TOF-MS) was used to identify the components of C. canescens extract. Forty-eight male SD rats were randomly divided into six groups, namely the normal group, the model group, the methotrexate(MTX) tablet group, and the low, medium, and high-dose C. canescens extract(ZDS-L, ZDS-M, and ZDS-H) groups, with 8 rats in each group. The model of collagen-induced arthritis in rats was induced by injection of bovine type Ⅱ collagen emulsion. MTX(2.5 mg·kg~(-1)), ZDS-L, ZDS-M, and ZDS-H(0.3 g·kg~(-1), 0.6 g·kg~(-1), and 1.2 g·kg~(-1)) were administrated by gavage. Rats in the normal group and the model group received distilled water. MTX was given once every three days for 28 days, and the rest medicines were given once daily for 28 days. Body weight, degree of foot swelling, arthritis index, immune organ index, synovial histopathological changes, and serum levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and interleukin-6(IL-6) were observed. Protein expressions of TLR2, TLR4, NF-κB p65, p38 MAPK, and p-p38 MAPK in rats were determined by Western blot. Thirty-four main components were identified by UPLC-Q-TOF-MS, including 15 flavonoids, 7 phenylpropanoids, 4 terpenoids, 4 organic acids, 2 esters, and 2 polyalkynes. As compared with the normal group, the body weight of the model group was significantly decreased(P<0.01), and foot swelling(P<0.05, P<0.01), arthritis index(P<0.01), and the immune organ index(P<0.01) were significantly increased. The synovial histopathological injury was obviously observed in the model group. The serum levels of inflammatory factors TNF-α, IL-1β, and IL-6 were significantly increased(P<0.01), and the protein expression levels of TLR2, TLR4, NF-κB p65, p-p38 MAPK/p38 MAPK in the synovial tissue were significantly increased(P<0.01) in the model group. As compared with the model group, the body weights of the ZDS dose groups were increased(P<0.01), and the degree of foot swelling(P<0.01) and the arthritis index were decreased(P<0.05, P<0.01). The immune organ index was decreased(P<0.01) in the ZDS dose groups, and the synovial tissue hyperplasia and inflammatory cell infiltration were alleviated. The serum levels of TNF-α, IL-1β, and IL-6 were significantly decreased(P<0.05, P<0.01), and the protein expression levels of TLR2, TLR4, NF-κB p65, p-p38 MAPK/p38 MAPK were decreased(P<0.05, P<0.01) in the ZDS dose groups. C. canescens extract containing apigenin, tricin, chlorogenic acid, aesculin, ferulic acid, caffeic acid, and oleanolic acid has a good anti-RA effect, and the mechanism may be related to the inhibition of TLRs/MAPKs/NF-κB signaling pathways.
Animals ; Cattle ; Male ; Rats ; Arthritis, Experimental/drug therapy* ; Arthritis, Rheumatoid/drug therapy* ; Body Weight ; Codonopsis/chemistry* ; Interleukin-6/blood* ; NF-kappa B/genetics* ; p38 Mitogen-Activated Protein Kinases/metabolism* ; Plant Extracts/therapeutic use* ; Rats, Sprague-Dawley ; Signal Transduction ; Toll-Like Receptor 2/metabolism* ; Toll-Like Receptor 4/metabolism* ; Tumor Necrosis Factor-alpha/pharmacology*

OBJECTIVE: To explore the characteristics and clinical phenotypes of rheumatoid arthritis (RA) and provide the basis for further understanding, interventions and outcomes of this disease. METHODS: RA patients attended at Peking University People's Hospital from 2018 to 2021 were enrolled in the study. Data collection included demographic data, the sites and numbers of joints involved, extra-articular manifestations (EAM), comorbidities and laboratory variables. Statistical and bioinformatical analysis was performed to establish clinical subtypes by clustering analysis based on the type of joint involved, EAM involvement and other autoimmune diseases overlapped. The characteristics of each subtype were analyzed. RESULTS: A total of 411 patients with RA were enrolled. The mean age was (48.84±15.17) years, and 346 (84.2%) were females. The patients were classified into 4 subtypes: small joint subtype (74, 18.0%), total joint subtype (154, 37.5%), systemic subtype (100, 24.3%), and overlapping subtype (83, 20.2%). The small joint subtype had no medium or large joint involvement, and 35.1% had systemic involvement. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels and platelet count (PLT) were lower than those in other subtypes, and the rates of positive rheumatoid factors (RF-IgA and RF-IgG) were significantly higher in the small joint subtype. The total joint subtype had both large and small joint involvement but no systemic involvement. The rate of morning stiffness and positive antinuclear antibodies (ANA) in this subtype were lower than those in other subtypes. In the systemic subtype, interstitial lung disease and secondary Sjögren syndrome were the most common systemic involvements, with prominent levels of disease activity score 28-joint count (DAS28-ESR and DAS28-CRP). The overlapping subtype was commonly combined with Hashimoto's thyroiditis or primary Sjögren syndrome. Female in the overlapping subtype was more common than in other subtypes. This subtype was characterized by hyperglobulinemia, hypocomplementemia and high rate of positive ANA, especially spotting type. CONCLUSION Based on the clinical features, RA patients could be classified into 4 subtypes: small joint subtype, total joint subtype, systemic subtype, and overlapping subtype. Each subtype had its own clinical characteristics. They help for further understanding and a more individualized treatment strategy of RA.
Female ; Male ; Humans ; Cross-Sectional Studies ; Sjogren's Syndrome ; Rheumatoid Factor ; Arthritis, Rheumatoid ; Blood Sedimentation ; Phenotype

Abdomen ; Acupuncture Points ; Acupuncture Therapy ; Arthritis, Rheumatoid/therapy* ; Blood Sedimentation ; Humans ; Rheumatoid Factor ; Treatment Outcome

OBJECTIVE: To explore the clinical characteristics and biological treatment of juvenile Idiopathic arthritis (JIA) after adulthood. METHODS: Selected 358 patients with previous medical history diagnosed by JIA who were hospitalized in the Department of Rheumatology and Immunology, West China Hospital of Sichuan University from January 1, 2009 to January 1, 2019. Perform retrospective analysis of basic information, clinical symptoms, diagnostic indicators, treatment plans, outpatient follow-up (inpatients require outpatient follow-up treatment) and diagnosis and treatment process of 90 eligible cases included, and observe different ages and different courses of disease. The clinical characteristics of young and middle-aged idiopathic arthritis in adults and the outpatient situation of using biological agents for 6 months. RESULTS: According to age, they were divided into ≤26 years old group (42 cases) and >26 years old group (48 cases). Under examination [rheumatoid factor (RF), anti-nuclear antibody (ANA), anti-neutrophil antibody (ANCA), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin 6 (IL-6), hemoglobin (HGB), white blood cell count (WBC), human leukocyte antigen-B27 (HLA-B27), complement 3 (C3), etc.], concurrent in terms of symptoms, treatment and prognosis, the ≤26-year-old group was generally lighter than the >26-year-old group; that was, the older the age, the heavier the onset of inflammation and other symptoms, the more complications, the worse the treatment effect, and the worse the prognosis, and there were statistical differences academic significance (P < 0.05). According to the course of disease, they were divided into ≤19 years group (46 cases) and >19 years group (44 cases). In terms of examination (RF, ANA, ANCA, ESR, CRP, IL-1β, IL-6, HGB, HLA-B27, C3, etc.), complications, treatment and prognosis, the course of disease ≤19 years group was compared with the disease course> 19 years group Overall mild; that was, the longer the course of the disease, the more severe the onset of symptoms such as inflammation, the more complications, the worse the treatment effect, and the worse the prognosis, P < 0.05, the difference was statistically significant. After 6 months of outpatient treatment with biological agents, it was found that biological agents could improve some of the patients' clinical symptoms and delay the further development of the disease. Compared with the non-biological agent treatment group (48 cases), the biological agent group (42 cases) benefited, and the difference was statistically significant (P < 0.05). CONCLUSION Through retrospective analysis, this article believes that although adult JIA is diagnosed as connective tissue disease, it has special clinical characteristics with the course of the disease and age. Therefore, it should be recommended to give special attention to JIA patients after adulthood, require regular medical treatment in the adult rheumatology department, according to the corresponding connective tissue disease or JIA diagnosis, and standard treatment; at the same time, pay attention to the history of JIA. In the comparison of biological and non-biological treatment, it is proved that biological treatment can effectively improve some of the clinical symptoms of JIA patients after adulthood. Therefore, it is recommended that biological treatment be used as soon as possible if economic conditions permit to delay the development of the disease.
Adult ; Arthritis, Juvenile/drug therapy* ; Blood Sedimentation ; China ; Humans ; Infant ; Middle Aged ; Retrospective Studies ; Rheumatoid Factor

OBJECTIVE: To investigate the clinical characteristics and high risk factors of Rheumatoid arthritis (RA) complicated with tuberculosis infection. METHODS: Patients with rheumatoid arthritis diagnosed in the hospital of Sichuan Provincial People's Hospital from January 2007 to January 2017 was retrospectively collected, who were enrolled in the study group. A control group was randomly selected from the RA patients hospitalized in the same period without co-infection at a ratio of 1 :2. The general data, clinical data, laboratory test data, treatment plan, etc. of the two groups were collected in detail for single factor statistical analysis. Then multivariate Logistic regression was used to analyze the independent risk factors of RA complicated with tuberculosis infection with statistical significance in univariate analysis. RESULTS: The clinical manifestations of fever (83.3%) were most common, followed by cough (69%) and body mass loss (45.2%). In the infected group, pulmonary tuberculosis accounted for 73.3%. In the infected group the chest CT showed two or more cases, accounting for 59%. There were 9 cases (33.3%) occurring in the typical tuberculosis occurrence site. Compared with the control group, the erythrocyte sedimentation rate (ESR), C-reaction protein (CRP) levels, and the daily average dose of glucocorticoid in 1 year in the infected group were higher than those in the control group. And those differences were statistically significant(P < 0.05). There were no significant differences in gender, age, disease duration, disease activity score, white blood cell (WBC), platelet (PLT), hemoglobin (Hb), immunoglobulin G (IgG), complement (C), Anti cyclic citrullinated peptide antibody (anti-CCP), CD4⁺T cell count, and immunosuppressant use (P > 0.05). Multivariate Logistic regression analysis showed that CRP levels(OR=1.016, 95%CI:1.002-1.031) and the daily average dose of glucocorticoid in 1 year(OR=1.229, 95%CI:1.066-1.418)were the independent risk factors of RA complica-ted with tuberculosis infection. CONCLUSION RA patients with tuberculosis infection are mainly phthisis. The clinical manifestations of RA combined with tuberculosis infection are lack of specificity, and the chest imaging features of pulmonary tuberculosis are diverse, which are easy to be misdiagnosed. CRP levels and the daily average dose level of glucocorticoid in 1 year were risk factors for RA and tuberculosis infection.
Arthritis, Rheumatoid/complications* ; Autoantibodies ; Blood Sedimentation ; Humans ; Peptides, Cyclic ; Retrospective Studies ; Rheumatoid Factor ; Tuberculosis/epidemiology*

OBJECTIVE: To detect the levels of Dickkopf-1 (DKK-1) in the plasma of patients with rheumatoid arthritis (RA), and to analyze their correlation with peripheral blood T cell subsets and clinical indicators. METHODS: Enzyme-linked immunosorbent assay (ELISA) was used to detect plasma DKK-1 levels in 32 RA patients and 20 healthy controls, and to record the various clinical manifestations and laboratory indicators of the RA patients, and flow cytometry to detect peripheral blood T cell subsets in the RA patients (Including Treg, nTreg, aTreg, sTreg, Teff, Tfh, CD4⁺CD161⁺T, CD8⁺T, CD8⁺CD161⁺T cells). The plasma DKK-1 levels between the two groups were ompared, and its correlation with peripheral blood T cell subsets and clinical indicators analyzed. RESULTS: (1) The plasma DKK-1 concentration of the RA patients was (124.97±64.98) ng/L. The plasma DKK-1 concentration of the healthy control group was (84.95±13.74) ng/L. The plasma DKK-1 level of the RA patients was significantly higher than that of the healthy control group (P < 0.05), and the percentage of CD8⁺CD161⁺T cells in the peripheral blood of the RA patients was significantly higher than that of the healthy control group (P < 0.05). (2) The plasma DKK-1 level was positively correlated with erythrocyte sedimentation rate (r=0.406, P=0.021), DAS28 score (r=0.372, P=0.036), immunoglobulin G(r=0.362, P=0.042), immunoglobulin A(r=0.377, P=0.033); it had no correlation with age, course of disease, C-reactive protein, rheumatoid factor, anti-cyclic citrullinated peptide antibody, immunoglobulin M, complement C3, complement C4, white blood cell, neutrophil ratio. (3) The plasma DKK-1 level in the RA patients was positively correlated with the percentage of peripheral blood CD161⁺CD8⁺T cells (r=0.413, P=0.019);it had no correlation with Treg, nTreg, aTreg, sTreg, Teff, Tfh, CD4⁺CD161⁺T, CD8⁺T cells. (4) The percentage of CD161⁺CD8⁺T cells was negatively correlated with erythrocyte sedimentation rate (r=-0.415, P=0.004), C-reactive protein (r=-0.393, P=0.007), DAS28 score(r=-0.392, P=0.007), rheumatoid factor (r=-0.535, P < 0.001), anti-citrullinated protein antibody (r=-0.589, P < 0.001), immunoglobulin G(r=-0.368, P=0.012) immunoglobulin M (r=-0.311, P=0.035); it had no correlation with age, disease course, immunoglobulin A, complement C3, complement C4, white blood cell, and neutrophil ratio. CONCLUSION RA patients' plasma DKK-1 levels and the percentage of CD8⁺CD161⁺T cells in T cell subsets in peripheral blood increase, which may be related to the secretion of proinflammatory cytokines in patients; DKK-1 is involved in the regulation of bone homeostasis and can be used as a marker of bone destruction in RA.
Arthritis, Rheumatoid ; Blood Sedimentation ; Humans ; Intercellular Signaling Peptides and Proteins/blood* ; Plasma ; Rheumatoid Factor ; T-Lymphocyte Subsets

BACKGROUND: Several factors, including clinical manifestations and laboratory data, have been used to evaluate the disease activity of Sjögren's syndrome (SS). We investigated saliva indicators of disease activity in primary SS patients. METHODS: We enrolled 138 Taiwanese patients with primary SS and 100 Taiwanese normal controls. Interleukin (IL)-6, IL-17A, tumor necrosis factor-alpha (TNF-α), and rheumatoid factor (RF)-IgA levels in saliva samples were measured using ELISA or fluorescent enzyme-linked immunoassay. Serum IgG, IgA, and IgM levels were measured by nephelometry. Erythrocyte sedimentation rate (ESR) was measured with an automatic ESR analyzer. The t-test and Pearson correlation test were used. RESULTS: IL-6 level was higher in primary SS patients than in normal controls (14.23±14.77 vs 9.87±7.32, P=0.012), but there were no significant differences in IL-17A, TNF-α, and RF-IgA levels. In primary SS patients, IL-6 level correlated weakly with ESR and IgG levels (r=0.252, P=0.015, and r=0.248, P=0.017, respectively), and TNF-α level correlated weakly with IgG level (r=0.231, P=0.024). CONCLUSIONS: IL-6 may play a role in SS pathogenesis. Saliva IL-6 might be an indicator of disease activity in primary SS patients.
Blood Sedimentation ; Enzyme-Linked Immunosorbent Assay ; Humans ; Immunoassay ; Immunoglobulin A ; Immunoglobulin G ; Immunoglobulin M ; Interleukin-17 ; Interleukin-6 ; Interleukins ; Nephelometry and Turbidimetry ; Rheumatoid Factor ; Saliva ; Tumor Necrosis Factor-alpha

OBJECTIVE: To evaluate the value of anti-carbamylated protein (CarP) antibody in the diagnosis of rheumatoid arthritis-associated intersitial lung diseas (RA-ILD). METHODS: Clinical and laboratory data and serum samples of patients with RA between December 2017 and June 2019 in Department of Rheumatology, General Hospital of Ningxia Medical University were collected. The patients were subclassified as RA-ILD and RA-without ILD based on computed tomography scans of the chest, Enzyme 1inked immunosorbent assay (ELISA) was used to assess anti-CarP antibody in the serum of each group. The occurrence of ILD and other laboratory indexes were analyzed. Comparison of measurement data between the 2 groups was performed by two independent sample t-test or Mann-Whitney U nonparametric test, while the count data were compared by Chi square test; Receiver operating characteristic curve (ROC) was drawn to determine the cut-off value of anti-CarP antibody to RA-ILD diagnosis and to analyze its diagnostic efficacy. RESULTS: The anti-CarP antibody level in the RA-ILD group was 21.14 (12.29, 29.75), which was significantly higher than that in the RA-without ILD group 11.6 (6.66, 19.05) (P=0.000). The difference was statistically significant (P<0.05). The positive rate of anti-CarP antibody in RA-ILD group (53%) was significantly higher than that in RA-without ILD group (16%) (P<0.05); There was no significant differences in the levels of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) between the two groups (P>0.05). The age and disease activity score (DAS28) in the RA-ILD group were significantly higher than those in the RA-withhout ILD group (P<0.05). The proportion of men and smoking in the RA-ILD group was higher than that in the RA-without ILD group, but the difference was not statistically significant. The ROC curve showed that the anti-CarP antibody had a cut off value of 20.56 U/mL, with the sensitivity of 53.50%, and specificity of 84.20%, the area under the ROC curve were 0.76. Spearman correlation analysis showed that rheumatoid factor (RF) and age were positively correlated with anti-CarP antibody (r=0.172, P=0.043; r=0.200, P=0.006). Anti-CarP antibody level was not associated with the DAS28 score, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anti-CCP antibody, swollen joint count, and tender joint count (P>0.05). CONCLUSION The anti-CarP antibody level in RA-ILD patients is higher than that in RA-without ILD, suggesting that anti-CarP antibody may have a role in the development of RA-ILD.
Arthritis, Rheumatoid ; Autoantibodies ; Blood Sedimentation ; Humans ; Lung Diseases ; Male ; Peptides, Cyclic ; Rheumatoid Factor