Vasculitis reumatoidea: una manifestación poco habitual. Presentación de tres casos clínicos y revisión de la literatura

La vasculitis reumatoidea es una complicación sistémica y poco frecuente de la Artritis Reumatoidea. Si bien su incidencia ha descendido en los últimos años con el advenimiento de las nuevas terapias inmunosupresoras y biológicas, continua teniendo una alta morbimortalidad. Predomina en el sexo masculino, en pacientes seropositivos y con un largo período de la enfermedad establecida. Requiere de alta presunción diagnostica, siendo el compromiso cutáneo y nervioso periférico el más frecuente. La biopsia de nervio o piel es requerida habitualmente para su diagnóstico. El tratamiento se basa en corticoides e inmunosupresores. Presentamos tres casos clínicos y realizamos una revisión de la literatura.

Rheumatoid vasculitis is a rare systemic complication of rheumatoid arthritis. Although its incidence has decreased in recent years with the advent of new immunosuppressive and biological therapies, it continues to have a high morbidity and mortality. It predominates in males, in seropositive patients and with a long period of established disease. It requires high diagnostic presumption, with skin and peripheral nervous involvement being the most affected. Nerve or skin biopsy is usually required for diagnosis. Treatment is based on corticosteroids and immunosuppressants. We present three clinical cases and carry out a review of the literature.

A vasculite reumatóide é uma complicação sistêmica rara da artrite reumatóide. Embora sua incidência tenha diminuído nos últimos anos com o advento de novas terapias imunossupressoras e biológicas, continua apresentando elevada morbidade e mortalidade. Predomina no sexo masculino, em pacientes soropositivos e com longo período de doença estabelecida. Exige alta presunção diagnóstica, sendo o envolvimento cutâneo e nervoso periférico os mais afetados. A biópsia de nervo ou pele geralmente é necessária para o diagnóstico. O tratamento é baseado em corticosteroides e imunossupressores. Apresentamos três casos clínicos e realizamos uma revisão da literatura.

Manifestaciones extraarticulares en pacientes con artritis reumatoide

Introducción : La artritis reumatoide (AR) es una enfermedad inflamatoria crónica, autoinmune, caracterizada por poliartritis crónica, aditiva, simétrica, que puede cursar con manifestaciones extraarticulares (MExA) asociadas a una mayor morbimortalidad. Objetivo: de describir las MExA más frecuentes en AR. Métodos: se realizó un estudio descriptivo, transversal y retrospectivo de revisión de historias clínicas de pacientes diagnosticados con AR, durante el periodo diciembre 2011-enero 2022. Resultados: Participaron 150 pacientes con AR, con una edad promedio de 53,7±12,5 años, el sexo predominante fue el femenino con 84,6%, el tiempo de evolución de la AR fue de 7,2±8,9 años; en cuanto a las características serológicas, 91,1% tenía Factor reumatoideo positivo y 76,9% tenía anticuerpos contra péptidos cíclicos citrulinados positivo. Tanto al ingreso, como en la última consulta los pacientes presentaron alguna manifestación extraarticular (MExA), 61,3% y 70%, respectivamente, siendo las más frecuentes la anemia de los trastornos crónicos (al ingreso 44,6% y en última consulta 50,6%), seguida de nódulos reumatoideos (al ingreso con 8% y en la última consulta 9,3%). Conclusiones: Las MExA se presentaron en 70% de los pacientes, siendo las más frecuentes la anemia y los nódulos reumatoideos. Estos datos muestras los cambios que han tenido la frecuencia de estas MExA en esta enfermedad a través del tiempo.

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory, autoimmune disease, characterized by chronic, additive, symmetrical polyarthritis, which can present with extra-articular manifestations (ExAM), associated with greater morbidity and mortality. Objective: to describe the most frequent ExAM in RA. Methods: a descriptive, cross-sectional and retrospective study was carried out to review the medical records of patients diagnosed with RA, during the period December 2011-January 2022. Results: 150 patients with RA participated, with an average age of 53.7±12.5 years, the predominant sex was female with 84.6%, the evolution time of RA was 7.2±8.9. years; Regarding serological characteristics, 91.1% had positive Rheumatoid Factor and 76.9% had positive antibodies against cyclic citrullinated peptides. Both upon admission and at the last consultation, patients presented some extra-articular manifestation (ExAM), 61.3% and 70%, respectively, with the most frequent being chronic anemia (at admission 44.6% and at last consultation 50.6%), followed by rheumatoid nodules (at admission with 8% and at the last consultation 9.3%). Conclusions: ExAM occurred in 70% of patients, the most frequent being anemia and rheumatoid nodules. These data show the changes in the frequency of ExAM in the disease over time.

Subluxación atlantoaxial en artritis reumatoidea. Resolución por odontoidectomía endonasal endoscópica y fusión e instrumentación por abordaje posterior. Reporte de caso

La subluxación atlantoaxial es la lesión más frecuente en la columna cervical causada por la artritis reumatoidea. Se manifiesta por rigidez de nuca, dolor cervical y déficit neurológico. El diagnóstico se realiza con tomografía computarizada e imágenes de resonancia magnética. El intervalo atlanto dental anterior mayor a 5mm indica inestabilidad atlantoaxial, el intervalo atlanto dental posterior menor a 14mm advierte riesgo neurológico. Las indicaciones más frecuentes de cirugía son: dolor cervical severo, inestabilidad y síntomas de mielopatía. Cuando existe compresión medular es necesaria la descompresión cervical alta sea por vía posterior o por vía anterior (odontoidectomía endonasal versus transoral). La línea rinopalatina nos indicará la factibilidad de una odontoidectomía endonasal endoscópica (OEE). El objetivo de la presentación del presente caso es compartir nuestra experiencia con la primera odontoidectomía endonasal endoscópica realizada en nuestro país y fomentar la utilización de la técnica. La cirugía fue realizada en un paciente con cuadriparesia espástica por subluxación atlantoaxial por artritis reumatoidea y que presentó excelente evolución pos operatoria, con recuperación casi completa. La OEE es una técnica operatoria mínimamente invasiva, ideal para pacientes con múltiples comorbilidades y que ofrece de buenos a excelentes resultados.

Atlantoaxial subluxation is the most common injury to the cervical spine caused by rheumatoid arthritis. It is manifested by neck stiffness, neck pain and neurological deficit. Diagnosis is made with computed tomography and magnetic resonance imaging. The anterior dental atlanto interval greater than 5mm indicates atlantoaxial instability, the posterior dental atlanto interval less than 14mm warns of neurological risk. The most frequent indications for surgery are: severe neck pain, instability and symptoms of myelopathy. When there is spinal cord compression, upper cervical decompression is necessary, either via a posterior or anterior approach (endonasal versus transoral odontoidectomy). The rhinopalatine line will indicate the feasibility of an endoscopic endonasal odontoidectomy (EEO). The objective of the presentation of this case is to share our experience with the first endoscopic endonasal odontoidectomy performed in our country and to promote the use of the technique. The surgery was performed on a patient with spastic quadriparesis due to atlantoaxial subluxation due to rheumatoid arthritis and who presented excellent postoperative evolution, with almost complete recovery. EEO is a minimally invasive surgical technique, ideal for patients with multiple comorbidities and offering good to excellent results.

Quality of life and strength, but not cytokines, are associated with DAS-28 in active and inactive rheumatoid arthritis / Qualidade de vida e força, porém não as citocinas, estão associadas ao DAS-28 em pacientes com artrite reumatoide na fase ativa e inativa

Objective: Evaluate and correlate data between relevant cytokines, disease progression, and handgrip and quality of life among RA patients at different stages of disease progression. Method: Thirty-three RA patients were recruited for analysis, using comparisons and correlations, between levels of circulating cytokines (IFN-γ, TNF-α, IL-4, IL-6, IL-10, IL-17, IL-1ß, and TNF receptors I and II), activity of the disease (evaluated using the DAS-28), handgrip (Hydraulic dynamometer), and quality of life (SF-36). Result: RA patients in different disease stages showed increases of IL-6 and IL-10 compared control group. Positive correlation between IL-6 with TNF-α, and IL-4 with IL-10 was found. Handgrip strength and quality of life were not related to cytokine levels. However, remission patients had better strength and quality of life indices compared to the active patients. In addition, handgrip of the non-dominant side, physical functions, role limitations physical health, pain, energy/fatigue and social functions have a negative correlation with the DAS28-PCR. Conclusion: High levels of IL-6 and IL-10 were observed in the chronic RA patients, but the values did not show correlation with disease activity, handgrip strength and quality of life. Disease activity show correlation with handgrip strength and quality of life. Furthermore, remission patients had better strength and quality of life indices compared to the active patients.

Objetivo: Avaliar e correlacionar dados entre citocinas relevantes, progressão da doença, preensão manual e qualidade de vida entre pacientes com AR em diferentes estágios de progressão da doença. Método: Trinta e três pacientes com AR foram recrutados para análise, por meio de comparações e correlações, entre níveis de citocinas circulantes (IFN-γ, TNF-α, IL-4, IL-6, IL-10, IL-17, IL-1ß e receptores de TNF-I e -II), atividade da doença (avaliada pelo DAS-28), preensão manual (dinamômetro hidráulico) e qualidade de vida (SF-36). Resultado: Pacientes com doença ativa e inativa apresentaram aumento de IL-6 e IL-10 comparados ao grupo controle. Foi encontrada correlação positiva entre IL-6 com TNF-α e IL-4 com IL-10. A força de preensão e a qualidade de vida não relacionaram aos níveis de citocinas. Entretanto, pacientes em remissão apresentaram melhores índices de força e qualidade de vida comparados aos pacientes com doença ativa. Além disso, preensão manual do lado não dominante, e quesitos dos SF-36, apresentam correlação negativa com o DAS28-PCR. Conclusão: Foram observados níveis elevados de IL-6 e IL-10 nos pacientes com AR crônica, mas os valores não mostraram correlação com DAS-28, força de preensão manual e SF-36. A atividade da doença apresenta correlação com força de preensão manual e qualidade de vida. Além disso, os pacientes em remissão apresentaram melhores índices de força e qualidade de vida em comparação aos pacientes ativos.

Síndrome de Kartagener y artritis reumatoide. Reporte de caso / Kartagener Syndrome and Rheumatoid Arthritis. Case Report

Presentación del caso. Se trata de una mujer de 26 años de edad, en seguimiento por la especialidad de reumatología desde los 17 años, cuando consultó con historia de un año de evolución de síndrome poliarticular de grandes y pequeñas articulaciones, aditivo, simétrico acompañado de fatiga, rigidez matutina mayor de una hora. Se reportó además factor reumatoide positivo. La radiografía de ambas manos presentó erosiones, que confirmó el diagnóstico de artritis reumatoide. Adicionalmente, la paciente tenía el antecedente de procesos sinobronquiales a repetición desde su infancia. En la evaluación médica se identificó dolor en los senos paranasales, dextrocardia y bronquiectasias, confirmados por los estudios de imágenes, que permitió concluir en el diagnóstico de síndrome de Kartagener. Intervención terapéutica. La paciente presentaba actividad clínica severa de la artritis reumatoide, se inició el tratamiento con metotrexato 10 mg vía oral un día a la semana, prednisona 5 mg al día y ácido fólico 5 mg a la semana y citas periódicas, controlando los datos de actividad y efectos adversos de los medicamentos, con pruebas hepáticas, hemograma y transaminasas. La especialidad de neumología recomendó la inclusión de la paciente en un programa de rehabilitación respiratoria, así como el uso de azitromicina 500 mg cada día por tres días en los períodos de agudización. Evolución clínica. El tratamiento logró mantener una actividad leve de la artritis reumatoide y sin exacerbación de los síntomas respiratorios

Case presentation. A 26-year-old woman, under follow-up by the rheumatology specialty since she was 17 years old, when she consulted with a history of one year of evolution of polyarticular disease of large and small joints, additive, symmetrical, accompanied by fatigue and morning stiffness for more than one hour. Positive rheumatoid factor was also reported. Additionally, the patient had a history of repeated sinobronchial processes since childhood. Medical examination revealed sinus pain in the paranasal sinuses, dextrocardia, and bronchiectasis, confirmed by imaging studies, which led to the diagnosis of Kartagener's syndrome. Treatment. The patient presented the severe clinical activity of rheumatoid arthritis. The treatment was started with methotrexate 10 mg orally one day a week, prednisone 5 mg a day, and folic acid 5 mg a week and periodic appointments, controlling the activity data and adverse effects of the drugs, with liver tests, hemogram, and transaminases. The pneumology department recommended the inclusion of the patient in a respiratory rehabilitation program as well as the use of azithromycin 500 mg every day for three days during periods of exacerbation. Outcome. The treatment was successful in maintaining a mild activity of the rheumatoid arthritis and without exacerbation of respiratory symptoms

Design, synthesis and biological study of BTK/JAK3 dual-target inhibitors / 中国药科大学学报

@#Abstract: In the present study, the compound XL-12 from our previous work was utilized as a lead compound. Through the optimization of the terminal phenyl ring, 12 target compounds were designed and synthesized. The structures of all target compounds were confirmed by 1H NMR, 13C NMR, and H RMS. In vitro enzyme activity assay showed that most compounds demonstrated significant inhibitory activity toward Bruton’s tyrosine kinase (BTK) and Janus kinase 3 (JAK3). Among them, compound I-3 exhibited moderate cell proliferation inhibitory activity toward Daudi cells and BaF3-JAK3 cells. In the evaluation of anti-inflammatory activity in vitro, compound I-3 could effectively inhibit the production of inflammatory factors IL-6; besides, it exhibited superior anti-inflammatory activity compared to ibrutinib in xylene-induced ear swelling model in mice.

Traditional Chinese Medicine Intervention in Rheumatoid Arthritis-related Signaling Pathways： A Review / 中国实验方剂学杂志

Rheumatoid arthritis （RA）， as an autoimmune disease， is mainly characterized by persistent synovitis. It often involves multiple joints symmetrically and can lead to joint deformity， joint function loss， and even disability in severe cases. The pathogenesis of RA is complex， and the prevention and treatment are complicated. Therefore， it is difficult to cure the disease completely. Previous studies have validated important targets and mechanisms for the prevention and treatment of RA， including the nuclear factor-κB （NF-κB） signaling pathway that controls the inflammatory process， nuclear factor E2-related factor 2 （Nrf2）/heme oxygenase-1 （HO-1） signaling pathway that regulates oxidative stress， inhibits inflammation， and maintains cell homeostasis， Wnt/β-catenin signaling pathway that plays a key role in cell growth， differentiation， apoptosis， and inflammatory response， anti-inflammatory， anti-oxidation， and silent information regulator 1 （SIRT1） signaling pathway that regulates synovial cells， anti-inflammatory adenylate-activated protein kinase （AMPK） signaling pathway that regulates energy metabolism， and hypoxia-inducible factor-1α （HIF-1α）/vascular endothelial growth factor （VEGF） signaling pathway related to angiogenesis in RA. At the same time， many studies have confirmed that traditional Chinese medicine prevents and treats RA by regulating the above signaling pathways and exerting their related effects， indicating the advantages of traditional Chinese medicine such as multiple regulatory pathways， long-term effects， and less adverse reactions. In this paper， by consulting many research reports， the role of the above-mentioned signaling pathways in RA was clarified， and the latest research results of traditional Chinese medicine intervention in the above-mentioned signaling pathways in the prevention and treatment of RA in recent years were summarized in detail. This paper aims to promote the in-depth study of the pathogenesis of RA and its treatment with traditional Chinese medicine， provide a scientific basis for the rational application of traditional Chinese medicine， and offer useful enlightenment for the development of new drugs and clinical practice for the treatment of RA in the future.

Significance and successful construction of stable transfection of MH7A cells with lower TRAF2 expression using lentiviral vector / 安徽医科大学学报

Objective To construct a stable synovial cell line MH7A from rheumatoid arthritis(RA)patients using lentiviral vectors that interfere with the expression of tumor necrosis factor receptor associated factor 2(TRAF2),and to study the role of TNF-α-TRAF2 signaling in MH7A abnormal proliferation.Methods Based on the design principles of human TRAF2 gene sequence and shRNA sequence,three pairs of TRAF2 shRNA interference se-quences were designed and synthesized.The primers were annealed by PCR,and a linear vector was obtained by double enzyme digestion PLKO.1-puro.The linearized vector was connected to the annealed primers through Solu-tion I,and the connected products were introduced into receptive cells.The plates were coated,and positive colo-nies were selected for sequencing.Three different recombinant plasmids of PLKO.1-TRAF2-shRNA lentivirus were constructed,and lentivirus packaging plasmids was used to package logarithmic growth phase HEK 293T cells.Vi-rus solution was collected to infect MH7A cells.At the same time,puromycin was used to screen MH7A stable transgenic strains with low TRAF2 expression.CCK-8 method,Western blot,and qPCR were used to detect the proliferation function of MH7A induced by TNF-α and low expression of TRAF2,as well as downstream signal TRAF2,P65 protein expression and mRNA levels.Results PLKO.1-TRAF2-shRNA(1),PLKO.1-TRAF2-shR-NA(2),and PLKO.1-TRAF2-shRNA(3)lentivirus vector plasmids and control group lentivirus vector plasmids PLKO.1-puro were successfully constructed.The three TRAF2-shRNA lentivirus vector plasmids and control group lentivirus vector plasmids PLKO.1-puro were respectively introduced into the lentivirus packaging plasmid of HEK 293T to obtain virus solution.After infecting MH7A cells with the virus solution,they were treated with puromycin(2.00 μ G/mL)screening and obtaining MH7A stable transgenic plants after 2 days.Through qPCR and Western blot results,it was found that the expression of TRAF2 mRNA and protein in PLKO.1-TRAF2-shRNA(1)MH7A stably transfected cells was significantly reduced compared to the negative control group.The results of CCK-8 and Western blot showed that after knocking down TRAF2 in MH7A,the proliferation of MH7A cells with low TRAF2 expression induced by TNF-α and the phosphorylation level of P65 were significantly reduced.Conclusion A sta-ble transgenic strain of PLKO.1-TRAF2-shRNA(1)MH7A cells was successfully constructed to investigate the role of TNF-α-TRAF2 signal activation in mediating abnormal proliferation of RA synovial cells.

Incidence and risk factors of deep vein thrombosis in patients with rheumatoid arthritis / 北京大学学报(医学版)

Objective:To investigate the incidence and risk factors of deep vein thrombosis(DVT)in patients with rheumatoid arthritis(RA).Methods:The clinical data of RA patients who were hospi-talized in the Department of Rheumatology and Immunology of Aerospace Center Hospital from May 2015 to September 2021 was retrospectively analyzed,including demographic characteristics,concomitant diseases,laboratory examinations(blood routine,biochemistry,coagulation,inflammatory markers,rheumatoid factor,antiphospholipid antibodies and lupus anticoagulant,etc.)and treatment regimens.The patients were compared according to the presence or absence of DVT,and the t test,Mann-Whitney U test or Chi-square test were applied to screen for relevant factors for DVT,followed by Logistic regres-sion analysis to determine risk factors for DVT in patients with RA.Results:The incidence of DVT in the RA patients was 9.6％(31/322);the median age of RA in DVT group was significantly older than that in non-DVT group[64(54,71)years vs.50(25,75)years,P＜0.001];the level of disease activity score using 28 joints(DAS28)-erythrocyte sedimentation rate(ESR)in DVT group was higher than that in non-DVT group[5.2(4.5,6.7)vs.4.5(4.5,5.0),P＜0.001];the incidence of hypertension,chronic kidney disease,fracture or surgery history within 3 months,and varicose veins of the lower ex-tremities in DVT group was higher than that in non-DVT group(P＜0.001).The levels of hemoglobin and albumin in DVT group were significantly lower than that in non-DVT group(P=0.009,P=0.004),while the D-dimer level and rheumatoid factor positive rate in DVT group were significantly higher than that in non-DVT group(P＜0.001).The use rate of glucocorticoid in DVT group was higher than that in non-DVT group(P=0.009).Logistic regression analysis showed that the age(OR=1.093,P＜0.001),chronic kidney disease(OR=7.955,P=0.005),fracture or surgery history with-in 3 months(OR=34.658,P=0.002),DAS28-ESR(OR=1.475,P=0.009),and the use of glu-cocorticoid(OR=5.916,P=0.003)were independent risk factors for DVT in RA patients.Conclu-sion:The incidence of DVT in hospitalized RA patients was significantly increased,in addition to tradi-tional factors,such as age and chronic kidney disease,increased DAS28-ESR level and the use of glu-cocorticoid were also independent risk factors for DVT.

Advances in the SNPs of TNFAIP3 gene and autoimmune diseases / 国际儿科学杂志

The gene TNFAIP3 acts as a negative regulator of the NF-κB signaling pathway. TNFAIP3 encodes the A20 protein，which exerts a potent anti-inflammatory effect and plays a pivotal role in the regulation of inflammation and immunity. In recent years，TNFAIP3 has garnered significant attention as a susceptibility gene for numerous autoimmune diseases，including but not limited to systemic lupus erythematosus，rheumatoid arthritis，psoriasis. Additionally，high-penetrance heterozygous mutations in TNFAIP3 cause a haploinsufficiency of A20（HA20）. HA20 is a monogenic autoinflammatory disease. But some individuals of HA20 exhibit clinical features of autoimmune diseases，including varying degrees of autoantibody positivity，lupus-like phenotypes，and autoimmune thyroid disease.This article focuses on the single nucleotide polymorphism of TNFAIP3 and related autoimmune diseases，to underscore the crucial role of TNFAIP3 in the pathogenesis of autoimmune diseases，and to provide new research directions and potential drug targets for these conditions.

Expression Level of CCP/AST in Synovial Fluid and Synovial Tissue of Rheumatoid Arthritis Patients and Its Clinical Significance / 现代检验医学杂志

Objective To investigate the expression level and clinical significance of cyclic citrullinated peptide antigen-specific T cells(CCP/AST)in synovial fluid and synovial tissue of rheumatoid arthritis(RA)patients.Methods A total of 128 RA patients in Shijiazhuang Hospital of Traditional Chinese Medicine from January to December 2021 were selected as the RA group,and 50 patients who needed arthroscopy for joint pain in the hospital during the same period were selected as the control group.Among the RA group,there were 46 cases in the mild group,52 cases in the moderate group,and 30 cases in the severe group.The protein expression levels of rheumatoid factors(RF)and anticitrullinated protein antibodies(ACPA)in synovial tissues of the subjects in each group were analyzed by Western blot.The frequency of CCP/AST in the synovial fluid of the subjects was analyzed by flow cytometry.The intensity of the staining of CCP/AST in synovial tissues was observed by double immunofluorescence staining/laser confocal scanning.Pearson correlation analysis was used to assess the correlation between the CCP/AST expression of synovial fluid and synovial tissue and RF and ACPA.Logistic regression was used to analyze the risk factors for the development of rheumatoid arthritis.Results In the order of control,mild,moderate and severe groups,RF(1.01±0.01,1.53±0.03,2.01±0.08,2.66±0.12 kDa)and ACPA proteins(1.03±0.01,1.61±0.03,2.04±0.10,2.59±0.13 kDa)in synovial tissues of patients were sequentially elevated,and the differences were all statistically significant(F=14.207,12.446,all P＜0.05).The expression of CCP/AST in synovial fluid of patients in the control,mild,moderate and severe groups was increased sequentially(8.26%±1.68%,22.46%±3.28%,33.58%±4.37%,46.15%±5.44%),and the difference was statistically significant(F=25.306,P＜0.05).Meanwhile,the intensity of CCP/AST staining in synovial tissues of patients in the control,mild,moderate and severe groups was also increased sequentially(1.05±0.26,1.35±0.89,2.04±0.56,2.78±0.15 score),and the difference was statistically significant(F=70.67,P＜0.05).The expression of CCP/AST in the synovial fluid and synovial tissues of patients with RA was positively correlated with RF(r=0.861,0.934,all P＜0.05)and ACPA in synovial fluid and synovial tissue(r=0.854,0.913,all P＜0.05).Logistic regression analysis showed that hypertension(OR=3.241,95%CI:1.491～6.752),diabetes mellitus(OR=2.565,95%CI:1.126～5.813),synovial fluid(OR=4.450,95%CI:1.652～11.622),and CCP/AST expression in synovial tissues(OR=5.629,95%CI:2.474～12.390)were independent risk factors for the development of RA(P＜0.05).Conclusion CCP/AST showed high expression in synovial fluid and synovial tissue of RA patients and related to disease activity and joint destruction,which can be used to assess the clinical joint mobility and bone destruction degree in such patients.

Bioinformatics Analysis and Validation of Differential Expression of miRNAs in Plasma Exosomes from Patients with Active Rheumatoid Arthritis / 现代检验医学杂志

Objective To screen differentially expressed microRNAs(miRNAs)in plasma exosomes of active rheumatoid arthritis(RA)patients and healthy controls and conduct bioinformatics analysis for exploring the role and potential clinical application value of miRNAs in the pathogenesis of RA.Methods From January 2023 to April 2023,39 RA patients who visited the Rheumatology and Immunology Department of the Second Affiliated Hospital of Soochow University were selected as the study subjects,while 39 healthy individuals were selected as normal controls.The expression levels of miRNAs in plasma exosomes were detected by Illumina high-throughput sequencing technology,and the differentially expressed miRNAs were obtained by log2(Fold Change)absolute value>1 and P value<0.05.Six miRNAs were selected by the order from small to large P-value for bioinformatics analysis and validated using quantitative real-time fluorescence PCR(qRT-PCR).Results Compared with healthy controls,22 aberrantly expressed miRNAs were detected in plasma exosomes of RA patients,of which 4 were up-regulated and 18 were down-regulated.Among them,miR-30b-5p,miR-144-3p,miR-20a-5p,miR-223-5p,miR-425-3p,and miR-589-5p showed changed significantly.GO and KEGG enrichment analysis indicated that differentially expressed miRNAs may be involved in disease progression through regulation of signaling pathways such as TGF-β and PI3K/AKT,which were related to biological processes such as Th17 differentiation,intercellular interactions,and protein phosphorylation.The qRT-PCR validation results showed that the expression of miR-144-3p and miR-425-3p were significantly reduced in plasma exosomes of RA patients compared to healthy controls(t=3.617,3.595,all P<0.001),while the differences of miR-30b-5p,miR-223-5p,miR-589-5p,and miR-20a-5p expression were not statistically significant(t=1.956,1.331,1.662,1.861,all P>0.05).Conclusion The expression profile of plasma exosomal miRNAs changed in RA patients,which may be involved in disease progression through TGF-β and other signaling pathways.Exosome-derived miR-144-3p and miR-425-3p may be potential serological markers for RA diagnosis.

Correlation analysis of serum Chemerin with disease activity and Th17/Treg in patients with rheumatoid arthritis / 天津医药

Objective To explore the correlation of serum Chemerin level with disease activity and the ratio of T helper 17/regulatory T cells(Th17/Treg)in patients with rheumatoid arthritis(RA).Methods A total of 180 patients with RA who were admitted to our hospital were regarded as the observation group.According to the DAS28 score,the observation group was divided into the high activity group(60 cases),the moderate activity group(60 cases)and the low activity group(60 cases).Another 180 healthy people who underwent physical examination in our hospital during the same period were regarded as the control group.Enzyme-linked immunosorbent assay(ELISA)was used to detect serum levels of Chemerin,interleukin-9(IL-9),interleukin-10(IL-10)and interleukin-17(IL-17).Flow cytometry was used to detect the Th17/Treg ratio.Spearman correlation analysis was applied to analyze the correlation between serum Chemerin level and DAS28 score.Pearson correlation analysis was used to analyze the correlation between serum Chemerin level and Th17,Treg cell percentage and Th17/Treg ratio.Results The results of this study showed that the serum level of Chemerin was higher in the observation group than that in the control group(P＜0.05).The serum Chemerin level was positively correlated with DAS28 score(P＜0.05).Serum Chemerin levels and DAS28 scores decreased in turn in the high,moderate and low activity groups(P＜0.05).The percentage of Th17 cells and the ratio of Th17/Treg were higher in the observation group than those in the control group,and the percentage of Treg cells was lower in the observation group than that in the control group(P＜0.05).The level of IL-10 was lower in the observation group than that in the control group,while levels of IL-17 and IL-9 were higher in the observation group than those in the control group(P＜0.05).The results of Pearson correlation analysis showed that serum Chemerin level was positively correlated with the percentage of Th17 cells and the ratio of Th17/Treg,and negatively correlated with the percentage of Treg cells(P＜0.05).Conclusion Serum Chemerin level is elevated in patients with RA,which is closely related to disease activity and Th17/Treg ratio.

Molecular docking analysis of the anti-inflammatory mechanism of Cibotium barometz and Epimedium for rheumatoid arthritis:animal experiment validation / 中国组织工程研究

BACKGROUND:In clinical practice,Cibotium barometz and Epimedium have shown significant efficacy in the treatment of rheumatoid arthritis,but the complex active ingredients contained in the two have an unclear mechanism of action at the molecular level for the treatment of rheumatoid arthritis. OBJECTIVE:Based on network pharmacology and molecular docking technology,to establish a collagen-induced arthritis model and to verify the potential targets and pathways of Cibotium barometz and Epimedium in the treatment of rheumatoid arthritis,providing reliable experimental evidence for the use of clinical formulas with Cibotium barometz and Epimedium as the main components. METHODS:Utilizing traditional Chinese medicine research platforms,traditional Chinese medicine encyclopedias,and databases of traditional Chinese medicine and chemical components from the Shanghai Institute of Organic,effective ingredients were retrieved and identified.3D molecular formulas were obtained from the PubChem platform and target predictions were made using PharmMapper and SwissTargetPrediction.Disease targets for rheumatoid arthritis were obtained from gene databases such as DrugBank,GeneCards,and OMIM.The intersections of targets and Cibotium barometz and Epimedium were plotted using VENNY 2.1 after calibration with the Uniport database.A protein-protein interaction network graph was constructed using the STRING platform.Gene Ontology function analysis and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed using the Metascape platform for data visualization.A four-layered network model of traditional Chinese medicine,ingredients,targets,diseases,and pathways was constructed using Cytoscape 3.9.0.The main effective ingredients were docked with core targets using AutoDock-Vina software to explore the best binding targets.A type II collagen+adjuvant-induced arthritis rat model was established,and the effects of Cibotium barometz and Epimedium on relevant pathway targets and inflammatory cell factors were observed after 21 days of intervention. RESULTS AND CONCLUSION:A total of 28 active ingredients from Cibotium barometz and Epimedium were selected,yielding 288 intersection targets for rheumatoid arthritis.The main ingredients included isobavachalcone,cibotium,and epimedium.The main targets included protein kinase 1 for serine/threonine(AKT1),tumor necrosis factor,and vascular endothelial growth factor A.Gene ontology analysis yielded 2 232 biological processes,mainly related to serine protein phosphorylation,positive regulation of serine/threonine protein kinase,and reactive oxygen metabolism.Kyoto Encyclopedia of Genes and Genomes enrichment analysis yielded 202 pathways,mainly involving the PI3K/AKT signaling pathway and epidermal growth factor receptor signaling pathway,which may exert therapeutic effects by regulating synovial cell apoptosis and proliferation and suppressing inflammatory factors.Molecular docking results showed the strongest binding activity and stable structure of Cibotium barometz and Epimedium with AKT1 and estrogen receptor transcription factor 1,which was closely related to apoptosis and proliferation and inflammatory signaling pathways such as PI3K/AKT.Cibotium barometz and Epimedium reduced the expression of interleukin-1β,interleukin-6,and tumor necrosis factor-α in the serum of collagen-induced arthritis rat models.Cibotium barometz and Epimedium reduced the expression of p-PI3K,p-AKT,and p-FOXO1 in the synovium of collagen-induced arthritis rat models.The results indicate that the combination of Cibotium barometz and Epimedium may exert therapeutic effects by inhibiting the proliferation of synovial cells and suppressing the expression of inflammatory factors via the PI3K/AKT/FOXO1 signaling pathway.This may be closely related to the occurrence of inflammation and bone destruction in rheumatoid arthritis,and provides a reference for the rational use and development of new drugs in clinical practice.

Mangiferin inhibits proliferation,migration and inflammatory factor expression of fibroblast-like synoviocytes in rheumatoid arthritis / 中国组织工程研究

BACKGROUND:Mangiferin is a biphenylpyridone compound extracted from mango leaves,bark and roots.Previous studies have shown that mangiferin can exert anti-systemic inflammatory effects through the activation of transcription factors such as NF-κB and JAK/STAT. OBJECTIVE:To investigate the effects and mechanisms of mangiferin on proliferation,migration and inflammatory factor release of rheumatoid arthritis fibroblast-like synovial cells(RA-FLS). METHODS:RA-FLS were divided into blank group,R848(TLR7/8 agonists)stimulated group,mangiferin low-,medium-,high-dose groups(2,4 and 8 μg/mL)and positive control group(Cu-CPT8,TLR8 pathway inhibitor).The cytotoxic effect of different mass concentrations of mangiferin was detected using cell counting kit-8 method and the final cellular dosing mass concentration was screened.The proliferation ability of RA-FLS was detected by cell clone formation assay,the migration ability of RA-FLS was detected by scratch assay and Transwell migration assay,and the expression of interleukin 1β,interleukin 6 and tumor necrosis factor α mRNA in RA-FLS was detected by qRT-PCR. RESULTS AND CONCLUSION:Compared with the blank group,the viability of RA-FLS was inhibited after treatment with mangiferin at 2-10 μg/mL,but there was no significant difference among groups(P>0.05),indicating that the toxic effect on RA-FLS was minimal.Compared with the R848-stimulated group,mangiferin decreased the number of cell clones,the scratch healing rate and the number of migrating cells in all dosing groups(P<0.01);and the expression of interleukin 1β,interleukin 6 and tumor necrosis factor α mRNA was also reduced in the mangostin medium-and high-dose groups(P<0.01).Compared with the R848-stimulated group,the number of cell clones,the scratch healing rate and the number of migrating cells as well as the expression levels of interleukin 6 and tumor necrosis factor α mRNA were significantly reduced in the positive control group(P<0.05,P<0.01).But there was no significant difference in the expression level of interleukin 1β.To conclude,mangiferin may exert its anti-rheumatoid arthritis effects through the TLR7/8 signaling pathway by inhibiting RA-FLS proliferation,migration,and inflammatory factor release.

CeRNA interaction network and immune manifestation of ferroptosis-related signature genes in rheumatoid arthritis / 中国组织工程研究

BACKGROUND:Ferroptosis-related genes have been found to play an important role in the pathogenesis of rheumatoid arthritis.However,there is currently a lack of immune expression of ferroptosis-related signature genes in rheumatoid arthritis and the construction of competing endogenous RNA(CeRNA)interaction networks.Machine learning,as a powerful signature gene selection algorithm based on bioinformatics,can more accurately identify ferroptosis-related signature genes that dominate the pathogenesis of rheumatoid arthritis. OBJECTIVE:To screen ferroptosis-related signature genes in rheumatoid arthritis using bioinformatics and machine learning methods,and to analyze the correlation between ferroptosis-related signature genes and immune infiltration and the construction of CeRNA network of ferroptosis-related signature genes. METHODS:Rheumatoid arthritis-related microarrays were obtained from the GEO database,and ferroptosis-related genes and their differential gene expression were extracted using R language.The differentially expressed genes were screened using machine learning methods.The LASSO regression and SVM-RFE methods were used for signature gene screening,and the genes filtered by both were re-intersected to finally obtain the signature genes in rheumatoid arthritis.Receiver operating characteristic curves were used to assess the accuracy of the screened signature genes for disease diagnosis.Immune infiltration of rheumatoid arthritis and normal synovial tissues was analyzed using the CIBERSORT algorithm,and the correlation between the signature genes and immune cells was analyzed.Finally,the CeRNA network of ferroptosis-related signature genes for rheumatoid arthritis was constructed and the disease signature genes were validated. RESULTS AND CONCLUSION:A total of 150 ferroptosis-related genes in rheumatoid arthritis were obtained,including 55 up-regulated genes and 95 down-regulated genes.GO and KEGG enrichment analyses identified 18 GO significantly correlated entries and 30 KEGG entries respectively,mainly involving metal ion homeostasis,ferric ion homeostasis and oxidative stress response.Machine learning analysis finally identified disease signature genes GABARAPL1 and SAT1.GSEA analysis found that adipocytokine signaling pathway,drug metabolism cytochrome P450,fatty acid metabolism,PPAR signaling pathway,tyrosine metabolism were mainly concentrated when GABARAPL1 was highly expressed,and chemokine signaling pathway,intestinal immune network on IGA production were mainly concentrated when SAT1 was highly expressed.Immune infiltration analysis found that nine immune cells were significantly different in rheumatoid arthritis and normal synovial tissues,in which plasma cells,T-cell CD8,and T-cell follicular helper were highly expressed and the rest were lowly expressed in the disease group.Single gene and immune cell correlation analysis found that GABARAPL1 was positively correlated with dendritic resting cells,activated NK cells,and macrophage M1,with the most significant correlation with dendritic resting cells,while SAT1 was positively correlated with T cell CD4 and γδ T cells and negatively correlated with NK resting cells.GSVA analysis found that SAT1 was upregulated in ascorbic acid and aldehyde metabolism,while downregulated in B-cell receptor signaling pathway,Toll-like receptor signaling pathway,T-cell receptor signaling pathway,and natural killer cell-mediated cytotoxicity.GABARAPL1 showed a down-regulation trend in PPAR signaling pathway,metabolism of nicotinate and nicotinamide,tryptophan metabolism,fatty acid metabolism,and steroid biosynthesis.Sixty long non-code RNAs may play a key role in the development of rheumatoid arthritis.To conclude,the occurrence of rheumatoid arthritis is significantly correlated with the abnormal expression of rheumatoid arthritis-induced ferroptosis-related signature genes,and the signature genes induce disease development via relevant signaling pathways.By analyzing rheumatoid arthritis-related long non-code RNAs-mediated ceRNA networks,potential therapeutic targets and signaling pathways can be identified to further elucidate its pathogenesis and provide a reference basis for subsequent experimental studies.

Mendelian randomization study on the association between rheumatoid arthritis and osteoporosis and bone mineral density / 中国组织工程研究

BACKGROUND:Many clinical research observations have indicated a close association between rheumatoid arthritis and osteoporosis as well as bone mineral density(BMD).However,it remains unclear whether there is a causal genetic relationship between rheumatoid arthritis and the development of osteoporosis and alterations of BMD. OBJECTIVE:To assess the potential causal relationship between rheumatoid arthritis and osteoporosis as well as BMD using a two-sample Mendelian randomization approach,provide meaningful insights from a genetic perspective into the underlying mechanisms and offer a reference for early prevention of osteoporosis and improvement in the progression of the disease. METHODS:We conducted a study using data from publicly available genome-wide association studies databases to identify single nucleotide polymorphisms associated with rheumatoid arthritis as instrumental variables(P＜5×10-8).The main outcomes of the study included osteoporosis and BMD at five different sites,including total body BMD,lumbar spine BMD,femoral neck BMD,heel BMD,and forearm BMD.The inverse variance-weighted method was used as the primary analysis method to evaluate causal effects.Weighted median,simple median,weighted mode and MR-Egger regression were used as supplementary analyses.Causal relationships between rheumatoid arthritis and the risk of osteoporosis and BMD were assessed using odds ratios(OR)and 95%confidence intervals(CI).Heterogeneity was assessed using Cochran's Q test and horizontal pleiotropy was evaluated using MR-Egger intercept tests. RESULTS AND CONCLUSION:The inverse variance-weighted analysis demonstrated a positive association between genetically predicted rheumatoid arthritis and osteoporosis(OR=1.123,95%CI:1.077-1.171;P=4.02×10-8).Heterogeneity test(P=0.388)indicated no significant heterogeneity among the single nucleotide polymorphisms.MR-Egger intercept(P=0.571)tests did not detect horizontal pleiotropy,and sensitivity analysis showed no evidence of bias in the study results.There was no causal relationship between rheumatoid arthritis and BMD at the five different sites.The total body BMD(OR=1.000,95%CI:0.988-1.012;P=0.925),lumbar spine BMD(OR=0.999,95%CI:0.982-1.016;P=0.937),femoral neck BMD(OR=1.001,95%CI:0.986-1.016;P=0.866),heel BMD(OR=0.996,95%CI:0.989-1.004;P=0.419),and forearm BMD(OR=1.063,95%CI:0.970-1.031;P=0.996)indicated no significant association.MR-Egger intercept analysis did not detect potential horizontal pleiotropy(total body BMD:P=0.253;lumbar spine BMD:P=0.638;femoral neck BMD:P=0.553;heel BMD:P=0.444;forearm BMD:P=0.079).Rheumatoid arthritis may contribute to the development of osteoporosis through the interaction between chronic inflammation and bone formation,resorption,and absorption.Additionally,the use of glucocorticoids and the presence of autoantibodies(such as anti-citrullinated protein antibody)in patients with rheumatoid arthritis showed associations with osteoporosis.Future research should focus on monitoring systemic inflammatory markers,standardized use of glucocorticoids,and regular screening for osteoporosis risk in patients with rheumatoid arthritis.

Meta-analysis of the incidence and related factors for cervical spine instability in patients with rheumatoid arthritis / 中国组织工程研究

OBJECTIVE:At present,there are many reports on the related factors associated with the incidence of cervical spine instability in patients with rheumatoid arthritis,but there are problems such as small sample size and many confounding factors,and the research results of various studies on the same related factors are also different.This article analyzed the factors related to cervical spine instability in patients with rheumatoid arthritis by means of a systematic review. METHODS:Articles related to cervical spine instability in patients with rheumatoid arthritis were collected by searching both Chinese and English databases until March 2023.The outcome of cervical spine instability in patients with rheumatoid arthritis was used as the grouping criterion to abstract basic information,baseline patient characteristics,laboratory-related tests,medication use,and other relevant risk factors.Meta-analysis was done using Stata 14.0 software. RESULTS:(1)Sixteen relevant studies,all of moderate or above quality,were included,including seven studies with case-control studies and nine with cross-sectional studies.The overall incidence of cervical spine instability in patients with rheumatoid arthritis was 43.08%.(2)Meta-analysis showed:Related risk factors included female(OR=0.60,95%CI:0.44-0.82,P=0.002);age at disease onset(SMD=-0.52,95%CI:-0.86 to-0.18,P=0.003);duration of disease(SMD=0.58,95%CI:0.14-1.02,P=0.01);body mass index(OR=0.74,95%CI:0.63-0.88,P=0.001);rheumatoid factors positive univariate analysis subgroup(OR=1.33,95%CI:1.02 to 1.72,P=0.04),C-reactive protein(SMD=0.26,95%CI:0.16-0.35,P=0.00),erythrocyte sedimentation rate(SMD=0.15,95%CI:0.002-0.29,P=0.047),anti-cyclic-citrullinated peptide antibodies(OR=1.73,95%CI:1.19-2.51,P=0.004),28-joint Disease Activity Score(SMD=0.20,95%CI:0.04-0.37,P=0.02),destruction of peripheral joints(OR=2.48,95%CI:1.60-3.85,P=0.00),and corticosteroids(OR=1.91,95%CI:1.54-2.37,P=0.00)were strongly associated with the development of rheumatoid arthritis-cervical spine instability.Female and corticosteroid use were independently associated with the occurrence of rheumatoid arthritis-cervical spine instability. CONCLUSION:Based on clinical evidence from 16 observational studies,the overall incidence of rheumatoid arthritis-cervical spine instability was 43.08%.However,the incidence of cervical spine instability in rheumatoid arthritis patients varied greatly among different studies.Gender(female)and the use of corticosteroids were confirmed as independent correlation factors for the onset of cervical spine instability in patients with rheumatoid arthritis.The results of this study still provide some guidance for early clinical recognition,diagnosis,and prevention of rheumatoid arthritis-cervical spine instability.

Expression of immune-related genes in rheumatoid arthritis and a two-sample Mendelian randomization study of immune cells / 中国组织工程研究

BACKGROUND:Rheumatoid arthritis is a chronic systemic autoimmune disease.It is important to study the immunological changes involved in it for diagnosis and treatment. OBJECTIVE:To identify immune-related biomarkers associated with rheumatoid arthritis utilizing bioinformatics techniques and examine alterations in immune cell infiltration as well as the relationship between immune cells and biomarkers. METHODS:Differential expression analysis was used to identify the immune-related genes that were up-regulated in rheumatoid arthritis based on the GEO and Immport databases.Kyoto encyclopedia of genes and genomes(KEGG)and gene ontology(GO)enrichment analyses were used to investigate the possible function of these elevated genes.The immunological characteristic genes associated with rheumatoid arthritis were screened using least absolute shrinkage and selection operator(Lasso)and support vector machine recursive feature elimination(SVM-RFE).Independent datasets were used for difference validation,and the diagnostic performance was evaluated by plotting receiver operating characteristic curves for feature genes.Immune cell infiltration was used to analyze the differential profile of immune cells in rheumatoid arthritis and the correlation between the characterized genes and immune cells.In order to ascertain the causal relationship between monocytes and rheumatoid arthritis in immune cells,Mendelian randomization analysis was ultimately employed. RESULTS AND CONCLUSION:There were 39 upregulated differentially expressed genes in rheumatoid arthritis.The genes were primarily enriched in chemotaxis,cytokine activity,and immune receptor activity,according to GO enrichment analysis,while kEGG enrichment analysis revealed that the genes were considerably enriched in the tumor necrosis factor signaling pathway and peripheral leukocyte migration.Lasso and SVM-RFE identified five feature genes:CXCL13,SDC1,IGLC1,PLXNC1,and SLC29A3.Independent dataset validation of the feature genes found them to be similarly highly expressed in rheumatoid arthritis samples,with area under the curve values greater than 0.8 for all five feature genes in both datasets.Immune cell infiltration indicated that most immune cells,including natural killer cells and monocytes,exhibited increased levels of infiltration in rheumatoid arthritis samples.The correlation analysis revealed a significant positive correlation between memory B cells and immature B cells and these five feature genes.Correlation analysis showed that the five feature genes were positively correlated with memory B cells and immature B cells.The inverse variance weighting method revealed that monocytes were associated with the risk of developing rheumatoid arthritis.

Network meta-analysis on efficacy and safety of different biological agents in treatment of rheumatoid arthritis / 中国组织工程研究

OBJECTIVE:There are many kinds of biological agents for the treatment of rheumatoid arthritis in clinic,but the differences in therapeutic efficacy and safety are still unclear.The purpose of this study is to compare the differences in effectiveness and safety of different biological agents for the treatment of rheumatoid arthritis. METHODS:CNKI,VIP,WanFang,China Biomedical Literature System,PubMed,Cochrane Library,Web of Science,and Embase databases were searched to collect the randomized controlled trials on biological agents for rheumatoid arthritis that meet the requirements from inception to October 1,2022.The literature was selected by EndNote software,and the quality of the included literature was evaluated by RevMan 5.3 software.The software Stata 14.2 was used for direct meta-analysis and network meta-analysis of ACR20(American College of Rheumatology 20%response),ACR50(American College of Rheumatology 50%response),ACR70(American College of Rheumatology 70%response),erythrocyte sedimentation rate,and adverse reactions. RESULTS:Totally 39 articles were included,including 5 low-risk articles,4 high-risk articles,and the remaining 30 articles contained unknown risk bias,with a total of 13 treatment measures.The results of network meta-analysis:(1)In ACR20,infliximab combined with methotrexate(OR=5.54,95%CI:1.33-23.01,P<0.05),abatacept+methotrexate tablets(OR=3.21,95%CI:1.13-9.10,P<0.05),and tocilizumab(OR=2.95,95%CI:1.61-5.44,P<0.05)were better than methotrexate tablets.The probabilistic ranking of ACR20 was:infliximab+methotrexate tablets>abatacept+methotrexate tablets>tocilizumab>certlizumab>etanercept+methotrexate tablets.(2)In the aspect of ACR50,etanercept combined with methotrexate tablets(OR=4.04,95%CI:2.13-7.66,P<0.05),infliximab combined with methotrexate tablets(OR=4.79,95%CI:1.19-19.26,P<0.05),and tocilizumab combined with methotrexate tablets(OR=3.54,95%CI:1.36-9.22,P<0.05)had better therapeutic effects than methotrexate tablets.The probabilistic ranking of ACR50 was:etanercept+methotrexate tablets>infliximab+methotrexate tablets>tocilizumab+methotrexate tablets>tocilizumab>certlizumab+methotrexate tablets.(3)In terms of ACR70,the therapeutic effects of infliximab combined with methotrexate tablets(OR=8.00,95%CI:2.31-27.69,P<0.05),etanercept combined with methotrexate tablets(OR=4.26,95%CI:2.51-7.21,P<0.05),and tocilizumab combined with methotrexate tablets(OR=3.51,95%CI:1.82-6.80,P<0.05)were better than methotrexate tablets.The probabilistic ranking of ACR70 was infliximab+methotrexate tablets>etanercept+methotrexate tablets>tocilizumab+methotrexate tablets>certlizumab>adalimumab+methotrexate tablets.(4)In erythrocyte sedimentation rate,etanercept combined with methotrexate tablets(SMD=-9.23,95%CI:-16.55 to-1.92,P<0.05)was better than etanercept and methotrexate tablets(SMD=14.59,95%CI:7.28-21.91,P<0.05).The probabilistic ranking of erythrocyte sedimentation rate was etanercept+methotrexate tablets>infliximab+methotrexate tablets>etanercept>adalimumab+methotrexate tablets>methotrexate tablets.(5)In terms of adverse reactions,placebo(OR=0.62,95%CI:0.39-0.99,P<0.05)was better than infliximab and certlizumab(OR=0.44,95%CI:0.25-0.78,P<0.05).The probabilistic ranking of adverse reactions was placebo>infliximab>etanercept+methotrexate tablets>certlizumab>etanercept. CONCLUSION:Based on evidence from 39 randomized controlled trials,infliximab combined with methotrexate tablets(highly recommended)can be the first choice in clinic,and etanercept combined with methotrexate tablets(highly recommended)can be the second choice in terms of good effectiveness and safety.