Anti-inflammatory effects of aucubin in cellular and animal models of rheumatoid arthritis / 中国天然药物

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. It is known that aucubin (AU) exerts anti-inflammatory activity, but its effects and mechanisms in RA are unclear. This study investigated the anti-inflammatory effects and mechanisms of AU in vivo and in vitro. Human fibroblast-like synoviocyte cells from patients with RA (HFLS-RA), RAW264.7 cells, and MC3T3-E1 cells were used to evaluate the effects of AU on migration, invasion, apoptosis, osteoclast differentiation and production. Immunofluorescence was used to observe nuclear translocation of nuclear factor (NF)-κB, the double luciferase reporter gene method was used to observe NF-κB-p65 activity in AU-treated MC3T3-E1 cells. RT-qPCR was used to measure expression of bone metabolism and inflammation-related genes, and western blot was used to measure bone metabolism and NF-κB protein expression levels. Collagen-induced arthritis (CIA) rat model was used for pharmacodynamics study. Arthritis indexes were measured in the ankle and knee, histological staining and Micro-computed tomography were performed on the ankle joints. Also, inflammatory factor gene expression and the levels of NF-κB-related proteins were detected as in vitro. AU effectively inhibited HFLS-RA cell migration and invasion, promoted apoptosis, and inhibited RAW264.7 cell differentiation into osteoclasts, as well as inhibited NF-κB-p65 activity in MC3T3-E1 cells. Notably, AU significantly reduced the gene expression levels of three cell-related inflammatory factors and bone metabolism factors, effectively inhibited the expression of p-Iκκα β, p-IκBα, and p-p65 proteins. In vivo, AU relieved joint inflammation, reduced related inflammatory factors, and inhibited NF-κB signaling. It could be used to treat RA-related synovial inflammation and bone destruction through the NF-κB pathway.

Integrating 16S sequencing and metabolomics study on anti-rheumatic mechanisms against collagen-induced arthritis of Wantong Jingu Tablet / 中国天然药物

Wantong Jingu Tablet (WJT), a mixture of traditional Chinese medicine, was reported to relieve the symptoms of rheumatoid arthritis (RA), but its pharmacological mechanism was not completely understood. The aim of this study was to investigate the therapeutic mechanisms of WJT for RA in vivo. The effects of WJT on joint pathology, as well as the levels of Bax, Bcl-2, caspase-3, cleaved-caspase-3, ERK1/2, pERK1/2, TNF-α, IL-1β, and IL-6 were measured using collagen-induced arthritis (CIA) rats. The intestinal flora composition and the metabolites alteration were analyzed by 16S rDNA sequencing and metabolomics method, respectively. We found that WJT ameliorated the severity of the CIA rats which might be mediated by inducing apoptosis, inactivating the MEK/ERK signals and reducing the production of pro-inflammatory cytokines. WJT, in part, relieved the gut microbiota dysbiosis, especially bacterial phylum Bacteroidetes, Tenericutes and Deferribacteres, as well as bacterial genus Vibrio, Macrococcus and Vagococcus. 3'-N-debenzoyl-2'-deoxytaxol, tubulysin B, and magnoline were significantly associated with the specific genera. We identified serotonin, glutathione disulfide, N-acetylneuraminic acid, naphthalene and thromboxane B2 as targeted molecules via metabolomics. Our findings contributed to the understanding of RA pathogenesis, and WJT played essential roles in gut microbiota health and metabolite modulation in the CIA rats.

Data Mining Study on Prescription Patterns of Different Dosage Forms of Chinese Herbal Medicines for Treating and Improving Immune-Inflammatory Indices in Patients with Rheumatoid Arthritis / 中国结合医学杂志

OBJECTIVE@#To explore the prescription patterns of different dosage forms of Chinese herbal medicines (CHMs) for the treatment of rheumatoid arthritis (RA) and their effects on immune-inflammatory indices.@*METHODS@#Clinical data were collected from patients with RA in 4 hospitals (3 Class A comprehensive hospitals and 1 Class B comprehensive hospital) in Anhui Province, China, from August 2012 to June 2018 via the electronic medical record gathering system. Following extraction of prescription information, each prescribed herb was quantified and standardized according to the knowledge base to establish a database of RA treatment formulae. The medical records were divided into the granules group and decoction pieces group. Core herbs and their combination patterns were obtained from the two groups of cases using Liquorice software. Changes in immune-inflammatory and hepatic and renal function indices were compared between the two groups using SPSS 23.0 software. The Aprior module of SPSS Clementine 11.1 software was applied to analyse the correlation between CHMs and improvement in indices. Finally, the ORACLE 10 g tool was used to evaluate the random walk model of the immune-inflammatory indices between the two groups.@*RESULTS@#(1) We retrospectively analysed 35,898 prescriptions for 6,829 patients with RA who received CHM treatment. There were 3,816 patients in the granules group and 3,013 in the decoction pieces group. (2) The core herbs were Pi (Spleen)-strengthening and dampness-resolving drugs, blood-activating and stasis-resolving drugs, wind/dampness-dispelling drugs and heat-clearing and detoxifying drugs. (3) Both dosage forms could improve immune-inflammatory indices in RA patients, with similar efficacy and no influence on hepatic or renal function. (4) Herba Siegesbeckiae and Oldenlandia had a stronger association with immune-inflammatory indices in the two groups. (5) The immune-inflammatory indices showed obvious improvement after treatment with granules and decoction pieces of CHMs, and there were long range correlations between the comprehensive evaluation indices and interventions.@*CONCLUSIONS@#The principal CHM treatment methods for RA in four hospitals in Anhui Province are strengthening Pi and resolving dampness, activating blood and resolving stasis, dispelling wind/dampness and clearing heat. Granules and decoction pieces of CHMs have similar efficacy in improving immune-inflammatory indices in RA patients and could be used as treatment options for RA.

Mechanism of Tibetan medicine Pterocephalus hookeri extract in treatment of rheumatoid arthritis based on serum metabonomics / 中国中药杂志

Ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF/MS) was used to investigate the effect of Pterocephalus hookeri on serum metabolism of adjuvant arthritis(AA) model rats induced by complete Freund's adjuvant. After the AA model was properly induced, the serum of rats was collected 30 days after treatment. UPLC-Q-TOF-MS chromatograms were collected and analyzed by principal component analysis(PCA) and orthogonal partial least squares discriminant analysis(OPLS-DA). The results revealed that compared with the control group, the model group showed increased content of 12 biomarkers in the serum(P<0.05) and reduced content of the other nine biomarkers(P<0.05). P. hookeri extract could recover the above-mentioned 19 biomarkers to a certain range. Pathway enrichment showed that these markers mainly involved eight metabolic pathways, including valine, leucine, and isoleucine degradation, arachidonic acid metabolism, arginine and proline metabolism, glycerol phospholipid metabolism, primary bile acid biosynthesis, bile acid biosynthesis, tryptophan metabolism, and unsaturated fatty acid biosynthesis. The findings of this study demonstrate that P. hookeri extract can regulate metabolic disorders and promote the regression of metabolic phenotype to the normal level to exert the therapeutic effect on AA rats. This study is expected to provide a certain scientific basis for the biological research on the treatment of rheumatoid arthritis by P. hookeri.

Risk of tuberculosis in patients with rheumatoid arthritis treated with biological and targeted drugs: meta-analysis of randomized clinical trials / 中华医学杂志(英文版)

BACKGROUND@#Concerns exist regarding the potential development of tuberculosis in patients with rheumatoid arthritis (RA) treated with biological and targeted drugs. We assessed systematically whether biological therapy increased the risk of tuberculosis in patients with RA by meta-analysis of randomized controlled trials (RCTs).@*METHODS@#A systematic literature search was conducted in PubMed, Embase, the Cochrane Library, and China Biology Medicine disc for RCTs evaluating biological therapy in patients with RA from inception through August 2021. Traditional meta-analysis and network meta-analysis were performed to compare the risk of tuberculosis for each biologics class in patients with RA. Peto odds ratio (Peto OR) and its 95% confidence interval (CI) were calculated as the primary effect measure.@*RESULTS@#In total, 39 studies with 20,354 patients were included in this meta-analysis, and 82 patients developed tuberculosis. The risk of tuberculosis was increased in patients treated with biologics compared with non-biologics (Peto OR: 3.86, 95% CI: 2.36-6.32, P < 0.001). Also, tumor necrosis factor-α (TNF-α) inhibitors had a higher probability of developing tuberculosis than placebo (Peto OR: 3.98, 95% CI: 2.30-6.88, P < 0.001). However, network meta-analysis demonstrated that there was no significant difference in the risk of tuberculosis for each biologics class in patients with RA. Noticeably, tuberculosis was significantly more common in patients treated with a high dose compared with patients receiving a low dose of tofacitinib (Peto OR: 7.39, 95% CI: 2.00-27.31, P = 0.003).@*CONCLUSION@#This meta-analysis demonstrates the evidence of an elevated risk of tuberculosis in patients with RA treated with TNF-α inhibitors, and a dose-dependent elevated risk of tuberculosis in patients treated with tofacitinib.

Perfil clínico e epidemiológico e comorbidades dos pacientes com artrite reumatoide atendidos no centro de especialidades médicas do centro universitário do Pará / Clinical and epidemiological and comorbidities of patients with rheumatoid arthritis assisted at the medical specialties center of Centro Universitário do Pará

Objetivos: Descrever as características clínico e epidemiológicas e a prevalência das comorbidades que acometem os pacientes com artrite reumatóide (AR) atendidos no ambulatório de reumatologia do Centro de Especialidades Médicas do Cesupa (CEMEC). Métodos: Estudo descritivo, observacional e retrospectivo realizado por meio da coleta de dados de prontuários médicos, no período de janeiro a novembro de 2020, de pacientes com artrite reumatoide, atendidos no Centro de Especialidades Médicas do Cesupa no período de 2012 a 2020. Resultados: Foram analisados 122 prontuários. A maioria dos pacientes foi do sexo feminino (88,52%). A raça predominante foi a não branca (90,88%) e a idade média dos participantes foi 54,09 anos (DP± 11,33). A maioria dos pacientes apresentavam fatores reumatoides positivo (56,55%). O tempo médio de doença foi de 9,7 anos (±8,57). As principais comorbidades não infecciosas encontradas foram: hipertensão arterial (40,16%), osteoporose (23,77%), dislipidemia (19,67%), diabetes (12,29%), obesidade (8,19%), depressão (4,09%), neoplasias (2,45%) e osteopenia (1,63%). Os medicamentos utilizados foram metotrexato (59,83%), prednisona (55,73%), leflunomida (36,06%), tocilizumabe (7,37%), anti-TNF (7,37%), anti-inflamatórios não hormonais (6,55%), tofacitinibe (2,45%), abatacepte (2,45%) e rituximabe (0%). Conclusão: As principais comorbidades que atingiram estes pacientes foram a hipertensão, osteoporose e dislipidemia. Assim, verifica-se a necessidade do controle de fatores de risco modificáveis dessas comorbidades assim como prezar pelo uso de doses baixas e pelo menor tempo possível, a fim de, apenas enquanto as drogas modificadoras de doença reumática (DMARDs) não estão fazendo efeito, reduzir a prevalência dessas comorbidades nestes pacientes.

Objectives: To describe the clinical and epidemiological characteristics and the prevalence of the main non ­ infectious comorbidities that affect patients with rheumatoid arthritis treated at the rheumatology outpatient clinic of the Centro de Especialidades Médicas do Cesupa (CEMEC). Methods: This is a descriptive, observational and retrospective study carried out by collecting data from medical records, from January to November 2020, of patients with rheumatoid arthritis, treated a Centro de Especialidades Médicas from 2012 to 2020. Results: In total, 122 medical records were analyzed, most of which corresponded to female patients (88.52%). The predominant race was non-white (90.88%) and the mean age of the participants was 54.09 years, with a standard deviation of 11.33 years. Regarding the rheumatoid factor, most of the sample is positive (56.55%). The mean disease duration was 9.7 years, with a standard deviation of 8.57 years. The main non-infectious comorbidities found were: arterial hypertension (40.16%), osteoporosis (23.77%), dyslipidemia (19.67%), diabetes (12.29%), obesity (8.19%) depression (4,09%), neoplasms (2.45%) and osteopenia (1.63%). The drugs used were methotrexate (59.83%), prednisone (55.73%), leflunomide (36.06%), tocilizumab (7.37%), anti-TNF (7.37%), non-steroidal anti-inflammatories. hormonal agents (6.55%), tofacitinib (2.45%), abatacept (2.45%) and rituximab (0%). Conclusion: The main comorbidities that affected these patients were hypertension, osteoporosis and dyslipidemia; and the most used drugs were prednisone, methotrexate and leflunomide, which are also related to the emergence of these pathologies. Thus, there is a need to encourage the practice of physical activity, as well as to value the use of low doses of corticosteroids, only while disease-modifying anti-rheumatic drugs (DMARDs) are ineffective, in order to reduce the prevalence of these Comorbidities in these patient

Pacientes con compromiso orbitario y renal: Diagnósticos diferenciales poco frecuentes / Patients with orbitary and kidney commitment: Rare differential diagnoses

Se comunica una serie de tres casos clínicos que consultaron al servicio de Reumatología por compromiso orbitario y renal. Uno de ellos presentó pseudotumor orbitario con proteinuria en rango nefrótico; se realizó biopsia y se encontró infiltrado linfoplasmocitario denso y fibrosis estoriforme con inmunohistoquímica: 15 células IgG4+ por campo de alto poder y relación IgG/IgG4 ≤40%, concluyendo diagnóstico de enfermedad relacionada por IgG4. El segundo y tercer caso presentaron compromiso ocular con "ojos de mapache" y lesiones amarillentas en párpados, ambos con proteinuria >500 mg/24 h, con biopsia de piel rojo Congo positiva y birrefringencia verde manzana con luz polarizada. Se discuten distintos diagnósticos diferenciales poco frecuentes a tener en cuenta en estos pacientes.

A series of three cases that consulted the rheumatology service due to orbital and renal involvement is reported. One of them presented orbital pseudotumor with proteinuria in the nephrotic range, a biopsy was performed, finding dense lymphoplasmacytic infiltrate and storiform fibrosis with immunohistochemistry: 15 IgG4 positive cells per HPF and IgG/IgG4 ratio ≤40%, concluding diagnosis of IgG4 related disease. The second and third cases presented ocular involvement with raccoon eyes and yellowish lesions on the eyelids, both with proteinuria greater than 500 mg/24 h, with apple-green birefringence of amyloid on congo red staining. Different rare differential diagnoses to take into account in these patients are discussed.

Which Factors are Predictive for Presence of Insulin Resistance in Patients with Rheumatoid Arthritis?

ABSTRACT Objective: To investigate obesity and insulin resistance and associated factors in patients with rheumatoid arthritis (RA). Methods: We included a cohort of patients with RA. In the clinical research, duration of disease, existence of clinical remission (disease activity index [DAS] 28 below 2.6) and amount of the relevant disease-modifying anti-rheumatic drugs were derived from clinical datum. Cumulative corticosteroid dose was calculated by duration of corticosteroid usage and ratio of physiologic dose. Insulin resistance was calculated with the homeostasis model of assessment of insulin resistance. Results: A total of 64 patients aged between 22 and 77 with RA were studied. Insulin resistance was detected in 34.4% (n = 22) of patients. There was a statistically significant correlation between body mass index and DAS28 scores (r = 0.469, p = 0.000). We found that the incidence of insulin resistance was lower in patients treated with methotrexate at least 1 year (p = 0.001). As long as we did not detect insulin resistance, none of the patients (n = 7) treated with tumour necrosis factor (TNF) blockers. Cumulative steroid dose, presence of obesity and DAS28 were the best predictors for insulin resistance according to multivariate linear regression analysis (R2c = 0.242, F = 6.39, p < 0.001). In this model R2c for cumulative steroid dose was 0.113 (F = 7.88 p < 0.007) and obesity was 0.147 (F = 10.67, p = 0.02). Conclusion: Obesity and long-standing corticosteroid usage were determinants of insulin resistance in patients with RA. Medications such as methotrexate, TNF blockers may help to reduce insulin resistance.

TDZD-8 suppresses rheumatoid arthritis induced by collagen type II in rats: potential role of apoptosis and inflammation / TDZD-8 suprime la artritis reumatoide inducida por colágeno tipo II en ratas: papel potencial de la apoptosis y la inflamación

SUMMARY: Rheumatoid arthritis (RA) is considered an autoimmune disease distinguished by chronic synovial membrane inflammation, degraded cartilage, as well as bone destruction, which lead to joints pain and stiffness. The pathogenesis of RA involved at least two mechanisms: Cellular proliferation and activation of glycogen synthase kinase-3β (GSK3β) enzyme. Thus, we tested the hypothesis that the GSK3binhibitor, TDZD-8, can treat the synovial tissue toward collagen type II (COII)-mediated RA linked to apoptosis induction and biomarker suppression of inflammation. Wistar rats were immunized with COII (the model group) for 21 days. Matched immunized rats were daily injected with TDZD-8 (1 mg/kg; i.p) for three additional weeks (COII+TDZD- 8).After 42 days of post-immunization, blood and tissues were collected. Histology (H&E) and immunohistochemistry (CD45; leukocyte common antigen) images showed that COII induced RA was demonstrated by profound damage to the synovial tissue and infiltration of the inflammatory cells, which were substantially ameliorated with TDZD-8. In addition, COII immunization caused the induction of rheumatoid factor (RF), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin 1 beta (IL-1β) that were substantially (p<0.05) suppressed by TDZD-8. Whereas, TDZD-8 augmented the apoptotic biomarker, Bcl-2-associated X protein (Bax), which was significantly (p<0.05) ameliorated by RA. We also showed a substantial relationship (p<0.001) between the blood levels of RF and the synovial tissue levels of TNF-α (r = 0.759), IL-1b (r = 0.969), IL-6 (r = 0.749), and Bax (r = - 0.914). These results indicate effective treatment of the injured synovial tissue by TDZD-8 against COII-induced RA in rats, which also decreases inflammatory biomarkers and augmentation of apoptosis.

RESUMEN: La artritis reumatoide (AR) es una enfermedad autoinmune que se distingue por la inflamación crónica de la membrana sinovial, el cartílago degradado y la destrucción de los huesos, lo que provoca dolor y rigidez en las articulaciones. La patogenia de la AR involucra al menos dos mecanismos: la proliferación celular y la activación de la enzima glucógeno sintasa quinasa-3b (GSK3β) Por lo tanto, probamos la hipótesis de que el inhibidor de GSK3β, TDZD-8, puede tratar el tejido sinovial hacia el colágeno tipo II (COII) - AR mediada por inducción de apoptosis y supresión de biomarcadores de inflamación. Se inmunizaron ratas Wistar con COII (el grupo modelo) durante 21 días. Se inyectaron diariamente ratas emparejadas inmunizadas con TDZD-8 (1 mg / kg; i.p) durante tres semanas adicionales (COII + TDZD-8). Después de 42 días de post-inmunización, se recolectó sangre y tejidos. Las imágenes de histología (H&E) e inmunohistoquímica (CD45; antígeno común de leucocitos) mostraron que la AR inducida por COII presentaba un daño profundo en el tejido sinovial e infiltración de las células inflamatorias, las que mejoraron con TDZD-8. Además, la inmunización con COII provocó la inducción de factor reumatoide (FR), factor de necrosis tumoral alfa (TNF-α), interleucina-6 (IL-6) e interleucina 1 beta (IL-1β) que fueron suprimidos por TDZD-8 de manera significativa (p < 0.05). Considerando que TDZD-8 aumentó el biomarcador apoptótico, la proteína X asociada a Bcl-2 (Bax), que fue mejorado (p <0,05) por RA. También se observó una relación sustancial (p <0,001) entre los niveles sanguíneos de RF y los niveles de tejido sinovial de TNF-α (r = 0,759), IL-1β (r = 0,969), IL-6 (r = 0,749), y Bax (r = -0,914). Estos resultados indicaron un tratamiento eficaz del tejido sinovial lesionado por TDZD-8 contra la AR inducida por COII en ratas, que también disminuye los biomarcadores inflamatorios y el aumento de la apoptosis.

Rheumatoid meningitis: report of two cases / Meningitis reumatoide. Informe de dos casos

ABSTRACT Rheumatoid meningitis (RM) is a rare complication of rheumatoid arthritis (RA). RM mimics many other conditions such as subdural empyema, unsteady gait, focal brain dysfunction, stroke, relapsing-remitting motor signs, headache, neuropsychiatric disorders, seizures, parkinsonism, and meningeal tumors. RM is considered a disease with poor prognosis. However, cases reported in the last decade show a good outcome. We report two cases with a favorable outcome. A 48-year-old man with a three-year history of RA admitted for headache, sensory disturbances, and speech difficulties. Brain magnetic resonance imaging (MRI) showed a left parietal subdural laminar lesion with restricted diffusion and a small left superior frontal acute infarction. A subdural empyema was originally suspected, and antimicrobials were prescribed. A follow-up MRI did not show progression of the subdural lesion and the patient was discharged 14 days after admission without focal deficits. A 44-year-old female patient with two years of seronegative RA was admitted for severe headache, confusion, nausea and vomiting. Brain MRI showed subtle supra and infratentorial leptomeningeal involvement and a left cerebellar acute infarct. A meningoencephalitis due to etanercept was initially thought and treated with dexamethasone. The patient was discharged but had to be admitted again and a new MRI showed a progression of the leptomeningeal involvement. She worsened and required endotracheal intubation. Cyclophosphamide was started and the patient became asymptomatic three months later. We propose that treatment should not be delayed waiting a biopsy when a diagnosis of RM is made and after a cerebrospinal fluid infection has been ruled out.

Meningitis reumatoide es una complicación rara de la artritis reumatoide. Esta enfermedad simula varias afecciones neurológicas, como empiema subdural, marcha inestable, accidente cerebrovascular, signos motores recurrentes-remitentes, cefalea, trastornos neuropsiquiátricos, convulsiones, parkinsonismo y tumores de las meninges. Es considerada de mal pronóstico, sin embargo, casos en la última década muestran lo contrario. Informamos dos casos con buen pronóstico. Un hombre de 48 años con tres años de artritis reumatoide ingresado por cefalea, trastornos sensoriales y dificultades del habla. La resonancia magnética (RM) cerebral mostró una lesión laminar subdural parietal izquierda y un pequeño infarto agudo frontal izquierdo. Inicialmente se sospechó un empiema subdural y se trató con antibióticos. Una RM de control no mostró progresión de la lesión subdural y el paciente fue dado de alta 14 días después del ingreso sin déficit focales. Una mujer de 44 años con dos años de artritis reumatoide seronegativa fue ingresada por cefalea, confusión náuseas y vómitos. La RM cerebral mostró un compromiso sutil leptomeníngeo supra e infratentorial y un infarto agudo cerebeloso izquierdo. Inicialmente se consideró una meningoencefalitis debido a etanercept y se trató con dexametasona. Fue dada de alta pero debió ingresar al hospital nuevamente y una nueva RM mostró progresión del compromiso leptomeníngeo. Ella se agravó y requirió intubación endotraqueal. Se inició ciclofosfamida y la paciente se hizo asintomática tres meses después. Proponemos que el tratamiento no debe retrasarse esperando una biopsia de meninges cuando se realiza un diagnóstico clínico de meningitis reumatoide, después de descartar infecciones meníngeas.

Expert consensus on clinical application of Wangbi Tablets in treating rheumatoid arthritis and knee osteoarthritis / 中国中药杂志

Wangbi Tablets are widely used in the treatment of rheumatoid arthritis, knee osteoarthritis and other diseases at pre-sent. Long-term clinical application and research have shown that this drug has a good effect in reducing the pain of related diseases and improving symptoms. Due to the lack of guidance in the instructions and currently no relevant norms to guide the clinical application of Wangbi Tablets, in order to further improve clinicians' understanding of the drug and fully tap the clinical advantages of the drug, the Professional Committee of Orthopedics and Traumatology Drug Research of China Association of Chinese Medicine organized experts in the fields of rheumatism, orthopedics, pharmacy and methodology in Chinese and western medicine to develop expert consensus on Chinese patent medicines in accordance with the relevant requirements of the consensus methodology. Based on full consideration of clinical research evidence and expert experience, the clinical issues were summarized in the consensus, and for those clinical problems supported by evidences, the internationally recognized recommendation evaluation and formulation method GRADE was used to evaluate the evidence and form recommendations; for those clinical issues not supported by evidences, a consensus was reached through the nominal group method to form consensus recommendations. The consensus adopted a concise and clear format to form re-commendations or reach consensus suggestions on the medication regimen, medication characteristics, intervention timing, usage and dosage, course of use and safety issues for the treatment of rheumatoid arthritis and knee osteoarthritis with Wangbi Tablets. It is suggested that its application will better improve the efficacy of Wangbi Tablets in the treatment of rheumatoid arthritis and knee osteoarthritis, at the same time provide a reference for clinicians to use Wangbi Tablets in a standardized, reasonable and safe manner.

Mechanism of Xinfeng Capsules improving rheumatoid arthritis based on CD19~+B cells regulating FAK/CAPN/PI3K pathway / 中国中药杂志

To observe the effect of Xinfeng Capsules on rheumatoid arthritis (RA) B lymphocytes,inflammatory mediators,FAK/CAPN/PI3K pathway,in order to explore the mechanism of Xinfeng Capsules in improving clinical symptoms of RA.Joint and systemic symptoms of RA patients were observed,and laboratory indicators[hemoglobin (HGB),platelet count (PLT),erythrocyte sedimentation (ESR),immunoglobulin (Ig) G,Ig A,Ig M,rheumatoid factor (RF),anti-cyclic citrulline antibody (CCP-AB),C-reactive protein (CRP)]were detected.ELISA was used to detect serum interleukin (IL)-1β，IL-10,IL-33,chemokine 5 (CCL5),and vascular endothelial growth factor (VEGF).CD3~-CD19~+B cells were measured by flow cytometry.Western blot was used to detect FAK,p-FAK,CAPN,PI3K protein.The results showed that Xinfeng Capsules could significantly alleviate RA joint and systemic symptoms and improve clinical efficacy.And Xinfeng Capsules could increase HGB,decrease PLT,CCP-AB,CRP,ESR index,upregulate IL-10 expression,and down-regulate IL-1β，IL-33,CCL5,VEGF,CD3~-CD19~+B cells,FAK,p-FAK,CAPN,PI3K expressions (P<0.01).Based on the above results,Xinfeng Capsules may reduce the expression of CD3~-CD19~+,regulate the balance of inflammatory cytokines and chemokines,inhibit abnormal activation of FAK/CAPN/PI3K pathway,and improve clinical symptoms of RA.

Oral Mucosal Diffuse Large B-cell Lymphoma Caused by Long-term Oral Methotrexate:Report of One Case / 中国医学科学院学报

A case of primary oral mucosal diffuse large B-cell lymphoma(DLBCL)due to long-term use of methotrexate(MTX)for the treatment of rheumatoid arthritis(RA)was admitted to the Department of Hematology,Fujian Medical University Union Hospital.We analyzed and discussed the clinical features,diagnosis and treatment,and prognosis of specific malignant lymphoma induced by MTX in this RA patient.Our purpose is to improve the awareness and knowledge of other iatrogenic immunodeficiency-associated lymphoproliferative disorders of clinicians and pathologists.This study provides a new reference for the clinical diagnosis and treatment of MTX-associated DLBCL.

Therapeutic effect of neohesperidin on TNF-α-stimulated human rheumatoid arthritis fibroblast-like synoviocytes / 中国天然药物

During the pathogensis of rheumatoid arthritis (RA), activated RA fibroblast-like synoviocytes (RA-FLSs) combines similar proliferative features as tumor and inflammatory features as osteoarthritis, which eventually leads to joint erosion. Therefore, it is imperative to research and develop new compounds, which can effectively inhibit abnormal activation of RA-FLSs and retard RA progression. Neohesperidin (Neo) is a major active component of flavonoid compounds with anti-inflammation and anti-oxidant properties. In this study, the anti-inflammation, anti-migration, anti-invasion, anti-oxidant and apoptosis-induced effects of Neo on RA-FLSs were explored to investigate the underlying mechanism. The results suggested that Neo decreased the levels of interleukin IL-1β, IL-6, IL-8, TNF-α, MMP-3, MMP-9 and MMP-13 in FLSs. Moreover, Neo blocked the activation of the MAPK signaling pathway. Furthermore, treatment with Neo induced the apoptosis of FLSs, and inhibited the migration of FLSs. It was also found that Neo reduced the accumulation of reactive oxygen species (ROS) induced by TNF-α. Taken together, our results highlighted that Neo may act as a potential and promising therapeutic drug for the management of RA.

Animal model analysis of rheumatoid arthritis based on clinical characteristics of Chinese and Western medicine / 中国中药杂志

Rheumatoid arthritis(RA) is an autoimmune disease involving multiple joints bilaterally with symmetrical polyarthritis as the main symptom. The high disability rate of this disease seriously affects the quality of life of patients and even threatens their lives. The establishment of a good animal model is of great significance for the diagnosis and clinical prevention of RA. Based on the clinical characteristics of RA in traditional Chinese and Western medicine, the common animal models of RA were summarized, including drug-induced, gene-related, and syndrome and disease combined models. Joint swelling, pain, redness, nodules, and joint deformity are the main criteria for model evaluation, which have certain differences from the clinical diagnostic criteria of RA. From the perspective of syndrome differentiation, the animal model combining syndrome and disease only simulates the syndrome of traditional Chinese medicine and has no direct causal relationship with the formation of RA. In this paper, we analyzed the advantages and disadvantages of animal models of RA and the coincidence degree of the models with the clinical characteristics and then put forward the corresponding recommendations for the evaluation and improvement of these models, aiming to make the animal models of RA closer to the clinical symptoms and play an important role in the clinical diagnosis and treatment of RA.

Meta-analysis of efficacy and safety of sinomenine combined with methotrexate in treatment of rheumatoid arthritis / 中国中药杂志

To systemically evaluate the efficacy and safety of sinomenine combined with methotrexate(SIN+MTX) in the treatment of rheumatoid arthritis(RA). Literature databases of Wanfang, CNKI, VIP, SinoMed, PubMed, Cochrane Library and Web of Science were retrieved comprehensively for relevant clinical trials. The literature retrieval time was from database establishment to February 4, 2020. The quality of literatures was assessed by the Cochrane Evaluation Handbook 5.1.0, and qualified literature was reviewed and analyzed by using the RevMan 5.3 statistical software. Twenty randomized controlled trials met the inclusion criteria, and were enrolled in the Meta-analysis. The results showed that SIN+MTX remarkably reduced DAS28(MD=-0.85, 95%CI[-1.03,-0.67], P<0.000 01), and improved total efficiency(P<0.000 01). SIN+MTX could inhibit swollen joint count(MD=-1.19, 95%CI[-1.75,-0.63], P<0.000 1), tender joint count(MD=-1.58, 95%CI[-2.89,-0.28], P=0.02) and reduce morning stiffness time(MD=-8.44, 95%CI[-11.82,-5.07], P<0.000 01) compared with control group. The results showed that SIN+MTX was equal to control group in grip strength(SMD=0.20,95%CI[-1.11,1.51],P=0.77). SIN+MTX remarkably alleviated the erythrocyte sedimentation rate(MD=-9.87, 95%CI[-14.52,-5.22], P<0.000 1), C-reactive protein(SMD=-0.30, 95%CI[-0.51,-0.09], P=0.005), and rheumatoid factor(MD=-11.23,95%CI[-13.81,-8.65],P<0.000 01). The frequency of adverse reactions were reduced compared with that in the control group(P<0.000 01). Current clinical studies demonstrate that the efficacy and safety of SIN+MTX in the treatment of RA were superior to control group. However, due to the low quality and quantity of the included studies, high-quality randomized controlled trials are necessary to support the clinical evidences.

Chinese registry of rheumatoid arthritis: IV. Correlation and consistency of rheumatoid arthritis disease activity indices in China / 中华医学杂志(英文版)

BACKGROUND@#Disease activity indices (DAIs) including disease activity score 28 (DAS28), simplified disease activity index (SDAI), and clinical disease activity index (CDAI) have been widely used in clinical practice and research studies of rheumatoid arthritis (RA). The objective of our study was to evaluate the correlation and concordance among different DAIs in Chinese patients with RA.@*METHODS@#A cross-sectional study, including patients enrolled in the Chinese registry of rheumatoid arthritis from November 2016 to August 2018, was conducted. The correlations were evaluated using Spearman correlation coefficient and concordance with Bland-Altman plots, quadratic weighted kappa, and discordance rates in the crosstab. For other indices, the optimal cutoff points corresponding to SDAI remission were explored through receiver operating characteristic curve analysis.@*RESULTS@#A total of 30,501 patients were included, of whom 80.46% were women. Most individuals were with moderate disease activity or high disease activity. High correlations among DAS28-erythrocyte sedimentation rate (ESR) and DAS28-C-reactive protein (CRP), SDAI and CDAI were observed. Similarly, the weighted kappa value among the indices was high. In Bland-Altman plots, a positive difference between DAS28-ESR and DAS28-CRP was observed, with an absolute difference of >1.2 in 3079 (10.09%) patients. In crosstab, approximately 30% of the patients were classified into different groups. Concordance values between SDAI remission and the optimal cutoff points of DAS28-ESR, DAS28-CRP, and CDAI were 3.06, 2.37, and 3.20, respectively.@*CONCLUSIONS@#Although DAIs had high correlations and weighted kappa values, the discordance between DAIs was significant in Chinese patients with RA. The four DAIs are not interchangeable.

A double-blind, double-dummy, randomized controlled, multicenter trial of 99Tc-methylene diphosphonate in patients with moderate to severe rheumatoid arthritis / 中华医学杂志(英文版)

BACKGROUND@#Clinical observational studies revealed that 99Tc-methylene diphosphonate (99Tc-MDP) could reduce joint pain and swollenness in rheumatoid arthritis (RA) patients. This multicenter, randomized, double-blind, double-dummy study aimed to evaluate the effects of 99Tc-MDP plus methotrexate (MTX) vs. MTX alone or 99Tc-MDP alone on disease activity and structural damage in MTX-naïve Chinese patients with moderate to severe RA.@*METHODS@#Eligible patients with moderate to severely active RA were randomized to receive 99Tc-MDP plus MTX (n = 59) vs. MTX (n = 59) alone or 99Tc-MDP (n = 59) alone for 48 weeks from six study sites across four provinces in China. The primary outcomes were the American College of Rheumatology 20% improvement (ACR20) response rates at week 24 and changes in modified total Sharp score at week 48.@*RESULTS@#At week 24, the proportion of participants achieving ACR20 was significantly higher in the MTX + 99Tc-MDP combination group (69.5%) than that in the MTX group (50.8%) or 99Tc-MDP group (47.5%) (P = 0.03 for MTX + 99Tc-MDP vs. MTX, and MTX + 99Tc-MDP vs.99Tc-MDP, respectively). The participants in the MTX + 99Tc-MDP group and the 99Tc-MDP group had significantly less important radiographic progression than the participants in the MTX group over the 48 weeks (MTX + 99Tc-MDP vs. MTX: P = 0.03, 99Tc-MDP vs. MTX: P = 0.03, respectively). There was no significant difference in terms of adverse events (AEs) among the groups. No serious AEs were observed.@*CONCLUSIONS@#This study demonstrated that the combination of 99Tc-MDP with MTX inhibited structural damage and improved disease activity in RA patients compared with MTX and 99Tc-MDP monotherapies, without increasing the rate of AEs. Additional clinical studies of 99Tc-MDP therapy in patients with RA are warranted.@*TRIAL REGISTRATION@#Chictr.org, ChiCTR-IPR-14005684; http://www.chictr.org.cn/showproj.aspx?proj=10088.

Clinical effect and mechanism of moxibustion combined with western medication for rheumatoid arthritis of liver-kidney deficiency / 中国针灸

OBJECTIVE@#To observe the clinical effect of moxibustion combined with western medication for rheumatoid arthritis (RA) of liver-kidney deficiency, and explore the mechanism of moxibustion for RA.@*METHODS@#A total of 60 patients with RA of liver-kidney deficiency were randomly divided into an observation group and a control group, 30 cases in each group. In the control group，leflunomide tablets were taken orally, once a day. On the base of the treatment as the control group, moxibustion was applied at Sanyinjiao (SP 6), Shenshu (BL 23), Zusanli (ST 36) and @*RESULTS@#After treatment, the TCM syndrome scores, HAQ scores and DAS-28 scores were decreased in the two groups (@*CONCLUSION@#Moxibustion combined with western medication can effectively relieve clinical symptoms, improve quality of life in RA patients, the curative effect is better than simple western medication. And its mechanism may be related to the regulation of serum level of Ca

Analysis of cervical instability and clinical characteristics in treatment-naive rheumatoid arthritis patients / 北京大学学报(医学版)

OBJECTIVE@#To study the proportion of cervical spine instability in treatment-naive rheumatoid arthritis (RA) patients, to investigate the associated neck symptoms, and to analyze the clinical characteristics in treatment-naive RA patients and treated RA patients.@*METHODS@#RA patients who underwent cervical spine X-ray imaging from the Department of Rheumatology and Immunology of Peking University Third Hospital and Peking University Shenzhen Hospital from August 2015 to October 2019 and had clinical records of medication administration were included. Clinical and laboratory data including cervical symptoms and X-ray imaging data of cervical spine were collected. The constituent ratio of cervical spine instability in treatment-naive RA patients was statistically analyzed. The clinical data and laboratory data were analyzed by t-test, u-test and chi square to explore the clinical characteristics of the treatment-naive RA patients with cervical instability.@*RESULTS@#Of the 408 RA patients, 105 patients were treatment-naive. Of the 105 treatment-naive patients, 82.9% (87/105) were female, with an average age of (52±14) years, the median duration of the disease was 24 months, the shortest history was 2 weeks, and the longest history was 30 years. 28.6% (30/105) of the treatment-naive RA patients showed cervical spine instability. The prevalence of cervical instability was 13.6% in the treatment-naive RA patients with disease duration less than 24 months. Among them, there were no significant differences in neck symptoms between cervical spine instability group and none cervical spine instability group. The patients with cervical spine instability had a longer duration of disease [60 (18, 180) months vs.16 (8, 51) months], a higher proportion of peripheral joint deformity (63.3%vs.21.3%), and a lower hemoglobin [(106.90±21.61) g/L vs. (115.77±14.69) g/L]. There was no significant difference in the occurrence of cervical instability in the treatment-naive RA patients compared with treated RA patients. Among the RA patients with cervical instability, there was no statistically significant difference in the composition of each type between the patients with treatment-naive RA and patients with treated RA, except for a shorter duration of disease [120.0 (72.0, 240.0) months vs. 60.0 (27.0, 167.5) months].@*CONCLUSION@#28.6% of treatment-naive RA patients showed cervical spine instability. Cervical instability was also common in RA patients with a duration less than 24 months. There was no significant correlation between cervical instability and neck symptoms. Patients with cervical spine instability had a long-term disease, a higher proportion of peripheral joint deformity and a lower hemoglobin. Controlling the condition of RA early may help to control the progression of cervical involvement in patients with RA.