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OBJECTIVES: To explore the correlation of serum IgG4 (sIgG4) with clinical manifestations or therapeutic response in rheumatoid arthritis (RA). METHODS: Consecutive 136 RA patients were recruited and followed up at regular interval. SIgG4 was detected by immunonephelometry. Serial synovial tissue sections from 46 RA patients were stained immunohistochemically for IgG4. RESULTS: Forty-six percent of 136 RA patients had elevated sIgG4. Patients with elevated sIgG4 had higher sIgG4/sIgG ratio, C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, and anticyclic citrullinated peptide antibodies than those with normal sIgG4 (all P < 0.05). Among 45 patients who received methotrexate and leflunomide therapy, 50% (9/18) of patients with elevated sIgG4 and 85% (23/27) of patients with normal sIgG4 reached therapeutic target (disease activity score of 28 joints < 3.2) at 6-month visit (χ(2) = 6.508, P = 0.011). IgG4-positive plasma cell count correlated positively with sIgG4, total synovitis score, and CD3-, CD20-, and CD38-positive cell counts (all P < 0.05). CONCLUSIONS: Our results showed that elevated sIgG4 in RA is common and disproportional to total IgG and RA with elevated sIgG4 may be a specific clinical phenotype with higher disease activity, higher level of autoantibodies, and poor response to methotrexate and leflunomide therapy.
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Artritis Reumatoide/sangre , Inmunoglobulina G/sangre , ADP-Ribosil Ciclasa 1/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD20/metabolismo , Autoanticuerpos/sangre , Biopsia , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Complejo CD3/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Péptidos Cíclicos/sangre , Fenotipo , Factor Reumatoide/sangre , Líquido Sinovial/metabolismo , Sinovitis/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: To explore the correlation between matrix metalloproteinase- (MMP-) 3 and histological synovitis in rheumatoid arthritis (RA). METHODS: Serum MMP-3 of 62 patients with active RA was detected by ELISA. Serial synovial tissue sections from all RA patients, 13 osteoarthritis, and 10 orthopedic arthropathies patients were stained with hematoxylin and eosin and immunohistochemically for MMP-3, CD3, CD20, CD38, CD68, and CD15. RESULTS: The percentage of lining MMP3+ cells was significantly higher in RA patients especially with high grade synovitis and it was significantly correlated with Krenn's synovitis score (r = 0.574, P < 0.001) and sublining inflammatory cells. Multivariate stepwise linear regression analysis revealed that the association of the percentage of lining MMP3+ cells with activation of synovial stroma, sublining CD68+ macrophages, and CD15+ neutrophils was stronger than other histological indicators. The percentage of lining MMP3+ cells was significantly correlated with serum MMP-3 in RA (r = 0.656, P < 0.001). Serum MMP-3 was higher in RA patients with high grade synovitis than that of low grade synovitis and significantly correlated with synovitis score and activation of synovial stroma subscore (all P < 0.05). CONCLUSION: Serum MMP-3 may be an alternative noninvasive biomarker of histological synovitis and RA diagnosis.
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Artritis Reumatoide/diagnóstico , Artritis Reumatoide/enzimología , Biomarcadores/sangre , Metaloproteinasa 3 de la Matriz/sangre , Sinovitis/diagnóstico , Sinovitis/enzimología , Artritis Reumatoide/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sinovitis/sangreRESUMEN
BACKGROUND: To investigate the risk of hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients with HBV carrier state during treatment of disease-modifying antirheumatic drugs (DMARDs) and the use of antiviral prophylaxis in real-world clinical practice. METHODS: Consecutive RA patients with HBV carrier state were included. Clinical data including liver evaluation, HBV infection evaluation and the use of antiviral prophylaxis were recorded. RESULTS: Fifty-three RA patients with HBV carrier state were screened and 36 patients were qualified for analysis. Thirty-six percentage of patients developed HBV reactivation and 17% developed HBV hepatitis together with reactivation, one of which developed decompensate cirrhosis. Only 50% of patients accepted lamivudine although all patients were recommended antiviral prophylaxis with entecavir or tenofovir and only 31% continued during DMARDs therapy. Seventy-one percentage of patients who discontinued antiviral prophylaxis developed HBV reactivation 3 ~ 21 months after discontinuation. Logistic regression analyses showed discontinuation of antiviral prophylaxis (OR: 66, p = 0.027), leflunomide (OR: 64, p = 0.011) and past history of hepatitis (OR: 56, p = 0.013) were risk factors of HBV reactivation. Past history of hepatitis (OR: 10, p = 0.021) was also risk factor of HBV hepatitis together with reactivation. CONCLUSION: Our results suggest poor patient acceptance and discontinuation of antiviral prophylaxis should not be ignored for Chinese RA patients with HBV carrier state in real-world clinical practice. Discontinuation of antiviral prophylaxis, past history of hepatitis and LEF might increase risk of HBV reactivation for RA patients with HBV carrier state during DMARDs therapy.
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Antivirales/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Portador Sano/tratamiento farmacológico , Virus de la Hepatitis B/fisiología , Hepatitis B/tratamiento farmacológico , Profilaxis Posexposición/tendencias , Activación Viral/fisiología , Adulto , Artritis Reumatoide/epidemiología , Portador Sano/epidemiología , Femenino , Hepatitis B/epidemiología , Virus de la Hepatitis B/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Profilaxis Posexposición/métodos , Prevalencia , Activación Viral/efectos de los fármacosRESUMEN
Objective: To characterize BMI in Chinese patients with RA vs US patients and examine its association with joint damage in Chinese patients. Methods: Each of the 1318 patients from a real-world Chinese RA population was first stratified by gender and then individually age-matched with one American RA patient from the US National Health and Nutritional Examination Survey 1999-2018. Data on BMI, bilateral hand radiographs and risk factors at enrolment were collected but radiographs were unavailable for the American patients. Logistic regression was used to evaluate the association of BMI with radiographic joint damage (RJD) in Chinese patients. Results: Chinese patients had a significantly lower BMI [(weighted) median 21.8 vs 29.8 kg/m2; P < 0.001] and a higher prevalence of being underweight (15.2% vs 1.1%; P < 0.05) than their American counterparts. Underweight Chinese patients (BMI <18.5) had higher modified total Sharp scores (median 17 vs 10) and joint space narrowing (JSN) subscores (median 6 vs 2) (both P < 0.05) than normal-weight patients (BMI ≥18.5-<24). After controlling for confounding, continuous BMI was cross-sectionally negatively associated with RJD [adjusted prevalence odds ratio (OR) 0.90 (95% CI 0.85, 0.96)] and JSN [adjusted prevalence OR 0.92 (95% CI 0.87, 0.96)]; being underweight vs normal weight was associated with RJD [adjusted prevalence OR 2.14 (95% CI 1.37, 3.35)] and JSN [adjusted prevalence OR 1.77 (95% CI 1.10, 2.84)]. Conclusion: Low BMI and being underweight were cross-sectionally associated with joint damage in Chinese RA patients, especially JSN, suggesting the clinical importance of identifying underweight patients and focusing on weight gain to prevent joint damage.
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OBJECTIVE: To explore the association of geriatric nutrition risk index (GNRI), a traditional albumin-body weight calculation, with myopenia in patients with rheumatoid arthritis (RA) and compare its ability to identify myopenia with protein indicators. METHODS: This cross-sectional study was carried out based on a Chinese RA cohort. Clinical data and protein indicators (including albumin, globulin, albumin to globulin ratio, prealbumin, hemoglobin) were collected. GNRI was estimated by serum albumin and body weight. Myopenia was indicated as muscle mass loss measured by bioelectric impedance analysis. RESULTS: There were 789 RA patients included with mean age 52.6 ± 12.6 years and 77.6% female. There were 41.3%, 18.0%, 27.5%, 13.2% patients with no (GNRI > 98), low (GNRI 92 to ≤ 98), moderate (GNRI 82 to < 92), and major nutrition-related risk (GNRI < 82). There were 406 (51.5%) RA patients with myopenia, RA patients with major nutrition-related risk had the highest prevalence of myopenia (87.5% vs. 73.3% vs. 50.0% vs. 26.1%). Multivariate logistic analysis showed that compared with no risk, RA patients with low (OR = 3.23, 95% CI: 1.86-5.61), moderate (OR = 9.56, 95% CI: 5.70-16.01), and major nutrition-related risk (OR = 28.91, 95% CI: 13.54-61.71) were associated with higher prevalence of myopenia. Receiver operating characteristic curves showed that GNRI (AUC = 0.79) performed a better identifiable ability toward myopenia than serum albumin (AUC = 0.66) or others indicators (AUC range 0.59 to 0.65), respectively. CONCLUSION: GNRI, an objective and convenient albumin-weight index, may be preferable for identifying myopenia in RA patients. Key Points ⢠We firstly elucidated the association of GNRI with muscle mass loss among RA patients, and compared its ability to identify muscle mass loss with serum albumin or other protein indicators. ⢠Major nutrition-related risk identified by GNRI showed the highest risk of muscle mass loss, GNRI demonstrated a greater ability to identify myopenia in RA patients. which indicated GNRI was an objective and convenient albumin-weight index to identify myopenia in RA patients.
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Artritis Reumatoide , Globulinas , Humanos , Femenino , Anciano , Adulto , Persona de Mediana Edad , Masculino , Evaluación Nutricional , Estudios Transversales , Estado Nutricional , Artritis Reumatoide/complicaciones , Atrofia Muscular , Albúmina Sérica , Peso Corporal , Músculos , Factores de RiesgoRESUMEN
Background: The nomenclature from non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) is considered to identify more cardiovascular disease (CVD) risks in the general population. Patients with rheumatoid arthritis (RA) carry an excess risk for CVD. However, the prevalence of MAFLD and its relationship with CVD risks in RA have not been reported. Methods: This cross-sectional study retrospectively analyzed clinical data from a Chinese RA cohort. MAFLD was diagnosed according to the criteria proposed by an international expert panel from 22 countries in 2020. CVD risk in patients with RA was estimated by the Prediction for Atherosclerotic Cardiovascular Disease Risk in China with a 1.5 multiplication factor. Results: Among 513 included patients with RA, 78.4% were women and the mean ± SD age was 51.8 ± 12.6 years. The prevalence of MAFLD was 21.4%. There were 10.9% patients with RA concomitated with CVD events and 32.4% with a high-estimated 10-year CVD risk. Besides a higher liver fibrosis score and a higher ratio of advanced fibrosis, RA patients with MAFLD had a higher rate of CVD events (17.3 vs. 9.2%) and a higher proportion of high estimated 10-year CVD risk (55.5 vs. 26.1%) than those without. Multivariate logistic regression analysis showed that MAFLD was associated with an increase in CVD events [adjusted odds ratio (AOR) = 2.190, 95% CI 1.135-4.227] and high estimated 10-year CVD risk (AOR = 2.483, 95% CI 1.412-4.365, all p < 0.05). Conclusion: Metabolic dysfunction-associated fatty liver disease was associated with increased CVD risk in patients with RA, which implies the importance of early detection and management of MAFLD in patients with RA.
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Synovium fibroblast-like synoviocytes (FLSs) are important participants in the pathogenesis of synovitis and joint destruction in rheumatoid arthritis (RA). Pyroptosis is a pro-inflammatory and cell lytic programmed cell death mechanism mediated by gasdermin (GSDM) family proteins. In this study, we demonstrated the increased expression of GSDME and increased levels of GSDME-mediated pyroptosis in RA synovial tissues. In vitro, stimulation with TNF-α plus hypoxia mimicking the inflammatory and hypoxic environment in RA synovium induced GSDME-mediated pyroptosis in RA-FLSs in combination with the promotion of migration and invasion abilities and the release of inflammatory cytokines (IL-6, IL-8). Moreover, knockdown of GSDME significantly inhibited the proliferation rate, migration/invasion effects and cytokines released through the reduction of GSDME-mediated pyroptosis. The immunohistochemistry results showed that RA patients with high GSDME N-terminal (GSDME-NT) expression, which is the active form of GSDME, showed higher IL-6 expression in both lining and sublining layer of synovium than that in patients with low GSDME-NT expression, osteoarthritis and non-inflammatory orthopedic arthropathies. Our findings revealed a novel mechanism regulating cell proliferation, migration, invasion and inflammatory cytokines release during the process of GSDME mediated pyroptosis in RA.
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Objectives: This study aims to investigate if addition of fibroblast-stromal cell markers to a classification of synovial pathotypes improves their predictive value on clinical outcomes in rheumatoid arthritis (RA). Methods: Active RA patients with a knee needle synovial biopsy at baseline and finished 1-year follow-up were recruited from a real-world prospective cohort. Positive staining for CD20, CD38, CD3, CD68, CD31, and CD90 were scored semiquantitatively (0-4). The primary outcome was radiographic progression defined as a minimum increase of 0.5 units of the modified total Sharp score from baseline to 1 year. Results: Among 150 recruited RA patients, 123 (82%) had qualified synovial tissue. Higher scores of CD20+ B cells, sublining CD68+ macrophages, CD31+ endothelial cells, and CD90+ fibroblasts were associated with less decrease in disease activity and greater increase in radiographic progression. A new fibroblast-based classification of synovial pathotypes giving more priority to myeloid and stromal cells classified samples as myeloid-stromal (57.7%, 71/123), lymphoid (31.7%, 39/123), and paucicellular pathotypes (10.6%, 13/123). RA patients with myeloid-stromal pathotype showed the highest rate of radiographic progression (43.7% vs. 23.1% vs. 7.7%, p = 0.011), together with the lowest rate of Boolean remission at 3, 6, and 12 months. Baseline synovial myeloid-stromal pathotype independently predicted radiographic progression at 1 year (adjusted OR: 3.199, 95% confidence interval (95% CI): 1.278, 8.010). Similar results were obtained in a subgroup analysis of treatment-naive RA. Conclusions: This novel fibroblast-based myeloid-stromal pathotype could predict radiographic progression at 1 year in active RA patients which may contribute to the shift of therapeutic decision in RA.
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Antígenos CD/análisis , Artritis Reumatoide/inmunología , Fibroblastos/inmunología , Inmunohistoquímica , Articulación de la Rodilla/inmunología , Células del Estroma/inmunología , Membrana Sinovial/inmunología , Adulto , Antirreumáticos/uso terapéutico , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Biomarcadores/análisis , Biopsia con Aguja , Progresión de la Enfermedad , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Humanos , Articulación de la Rodilla/diagnóstico por imagen , Articulación de la Rodilla/efectos de los fármacos , Articulación de la Rodilla/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Inducción de Remisión , Células del Estroma/efectos de los fármacos , Células del Estroma/patología , Membrana Sinovial/diagnóstico por imagen , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/patología , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Chronic inflammation in rheumatoid arthritis (RA) can induce reduced muscle mass (myopenia) and ectopic fat deposition probably showing normal body mass index (BMI). We aimed to investigate their body composition (BC) characteristics and clinical significance. METHODS: BMI and BC were collected in consecutive RA patients and control subjects. Myopenia was defined by appendicular skeletal muscle mass index (ASMI) ⩽7.0 kg/m2 in men and ⩽5.7 kg/m2 in women. Overfat was defined by body fat percentage (BF%) as ⩾25% for men and ⩾35% for women. RESULTS: There were 620 RA patients (57.6% with normal BMI) and 2537 control subjects (62.5% with normal BMI) recruited. After 1:1 age and sex matching with control subjects, RA patients with normal BMI (n = 240) showed significantly higher prevalence of myopenia (43.3% versus 22.1%) and overfat (19.2% versus 7.1%) as well as myopenia overlapping overfat (17.1% versus 3.3%). In all RA patients with normal BMI (n = 357), there were 18.2% patients with myopenia overlapping overfat who had the worst radiographic scores and highest rates of previous glucocorticoid treatment and hypertension. Compared with those without, normal BMI RA patients with previous glucocorticoid treatment (24.4% versus 10.3%) or hypertension (27.8% versus 13.6%) had a higher rate of myopenia overlapping overfat. Previous glucocorticoid treatment [odds ratio (OR) = 2.844, 95% confidence interval (CI) 1.441-5.614] and hypertension (OR = 2.452, 95% CI 1.283-4.685) were potential associated factors of myopenia overlapping overfat in RA patients with normal BMI. CONCLUSION: Myopenia overlapping overfat is an important extra-articular manifestation which should not be ignored in RA patients with normal BMI, especially with glucocorticoid treatment and hypertension.
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BACKGROUND: Numerous cross-sectional studies have reported the associations between rheumatoid arthritis (RA) and reduced skeletal muscle. We firstly explored the dynamic change of skeletal muscle and its effect on RA clinical outcomes in a real-world prospective cohort. METHODS: Consecutive RA patients were treated according to the treat-to-target strategy and completed at least 1-year follow up. Clinical data and muscle index (assessed by bioelectric impedance analysis) were collected at baseline and visits at 3, 6, 9 and 12 months. Myopenia was defined by appendicular skeletal muscle mass index ⩽7.0 kg/m2 in men and ⩽5.7 kg/m2 in women. A 1-year radiographic progression as primary outcome was defined by a change in the total Sharp/van der Heijde modified score ⩾0.5 units. RESULTS: Among 348 recruited patients, 315 RA patients (mean age 47.9 years, 84.4% female) completed 1-year follow up. There were 143 (45.4%) RA patients showing myopenia at baseline. Compared with those without baseline myopenia, RA patients with baseline myopenia had higher rate of 1-year radiographic progression (43.4% versus 21.5%, all p < 0.05). Baseline myopenia was an independent risk factor for 1-year radiographic progression with adjusted odds ratio (AOR) of 2.5-fold, especially among RA patients in remission at baseline both defined by Disease Activity Score in 28 joints (DAS28) including C-reactive protein (DAS28-CRP) or erythrocyte sedimentation rate (DAS28-ESR) with AOR of 18.5~42.9-fold. Further analysis of six subtypes of dynamic skeletal muscle change showed that newly acquired myopenia at endpoint was associated with radiographic progression (AOR of 5.4-fold). CONCLUSIONS: Reduced skeletal muscle is an independent predicting factor for 1-year aggravated joint destruction, especially in remission RA. The importance of dynamic monitoring of skeletal muscle and muscle improvement therapy are worth exploration.
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OBJECTIVE: Activation of osteoclastogenesis at the bone site in rheumatoid arthritis (RA) is well established. The mechanisms by which circulating osteoclast precursors contribute are still unclear. Peroxisome proliferator-activated receptor γ coactivator 1ß (PGC-1ß) is implicated in transcriptional regulation of osteoclastogenesis in mouse models. This study was undertaken to investigate the contribution of PGC-1ß to circulating osteoclast precursors and its link to bone destruction in RA. METHODS: PGC-1ß expression in RA peripheral blood CD14+ monocytes was increased and showed correlation with joint destruction shown on radiographs. Cells from RA patients or healthy controls were transfected with a lentivirus vector for PGC-1ß gene silencing or overexpression and cultured with macrophage colony-stimulating factor and RANKL. Bone resorption activity, bone-degrading enzymes, and signaling molecules were measured in these mature osteoclasts. RESULTS: Increased nuclear accumulation of PGC-1ß was observed in RA peripheral blood CD14+ monocytes, and these cells had stronger osteoclastogenesis than in healthy controls. PGC-1ß protein expression was positively correlated with radiographic joint destruction (r = 0.396-0.413; all P < 0.05). PGC-1ß knockdown suppressed (51-82% reduction) the expression of cathepsin K, tartrate-resistant acid phosphatase (TRAP), and matrix metalloproteinase 9 (MMP-9), as well as osteoclast differentiation and bone resorption activity. Conversely, PGC-1ß overexpression increased these markers (by 1.5-1.8-fold) and osteoclastogenesis. VIVIT, an inhibitor of NFATc1 activation, inhibited the effect of overexpressed PGC-1ß by reducing cathepsin K, TRAP, and MMP-9 expression. Chromatin immunoprecipitation assay and dual-luciferase reporter gene assay showed PGC-1ß bound to NFATc1 promoter, leading to transcriptional activation. CONCLUSION: Activation of the PGC-1ß/NFATc1 pathway in circulating osteoclast precursors was associated with bone destruction in RA. This may represent a new treatment target.
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Artritis Reumatoide/sangre , Resorción Ósea/sangre , Factores de Transcripción NFATC/metabolismo , Osteoclastos/metabolismo , Proteínas de Unión al ARN/metabolismo , Adulto , Femenino , Humanos , Leucocitos Mononucleares , Factor Estimulante de Colonias de Macrófagos , Masculino , Persona de Mediana Edad , Osteogénesis/fisiología , Ligando RANK , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND: Previous studies have revealed that hepatitis B virus (HBV) infection may be related to rheumatoid arthritis (RA), but there are no studies on the presence of HBV antigens or nucleic acid in synovium from patients with RA with HBV infection. In the present study, we investigated the presence of HBV in the synovium and its clinical significance in RA. METHODS: Fifty-seven consecutive patients with active RA (Disease Activity Score 28-joint assessment based on C-reactive protein ≥ 2.6) and available synovial tissue who had completed 1 year of follow-up were recruited from a prospective cohort. The patients were divided into chronic HBV infection (CHB, n = 11) and non-CHB groups according to baseline HBV infection status. Clinical data were collected at baseline and at 1-, 3-, 6-, and 12-month follow-up. Radiographic changes of hand/wrist at baseline and month 12 were assessed with the Sharp/van der Heijde-modified Sharp score (mTSS). HBV in synovium was determined by immunohistochemical staining for hepatitis B virus surface antigen and hepatitis B virus core antigen (HBcAg) and by nested PCR for the HBV S gene. RESULTS: HBcAg was found in the synovium of patients with RA with CHB (7 of 11, 64%), which was confirmed by PCR for the HBV S gene. Compared with the non-CHB group, more CD68-positive macrophages, CD20-positive B cells, and CD15-positive neutrophils infiltrated the synovium in the CHB group (all p < 0.05). There were smaller improvements from baseline in most disease activity indicators mainly at month 12, and a significantly higher percentage of CHB patients experienced 1-year radiographic progression (ΔmTSS ≥ 0.5 unit/yr, 64% vs. 26%, p = 0.024). Multivariate logistic regression analysis showed that CHB status (OR 14.230, 95% CI 2.213-95.388; p = 0.006) and the density of synovial CD68-positive macrophages (OR 1.002, 95% CI 1.001-1.003; p = 0.003) were independently associated with 1-year radiographic progression. CONCLUSIONS: The presence of HBV in RA synovium may be involved in the pathogenesis of local lesions and exacerbate disease progression in RA.
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Artritis Reumatoide/inmunología , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Membrana Sinovial/inmunología , Adulto , Artritis Reumatoide/patología , Artritis Reumatoide/virología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos B/patología , Progresión de la Enfermedad , Femenino , Antígenos de la Hepatitis B/genética , Antígenos de la Hepatitis B/inmunología , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica/virología , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/patología , Índice de Severidad de la Enfermedad , Membrana Sinovial/virologíaRESUMEN
AIM: To investigate the impact of short-course tocilizumab (TCZ) on hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients. METHODS: RA patients with moderate to high disease activity, with at least one feature of poor prognosis and inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) were recruited. Three consecutive doses of intravenous TCZ were given combined with csDMARDs. Liver function and HBV infection status were evaluated at baseline, weeks 4, 8 and 12. RESULTS: Sixty-three RA patients who were qualified for statistics were classified as chronic HBV infection (n = 7), resolved HBV infection (n = 41) and non-HBV infection (n = 15). Three patients with chronic HBV infection and without antiviral prophylaxis developed HBV reactivation after 1-3 doses of TCZ. They were asymptomatic of hepatitis B with normal aminotransferases and the HBV-DNA of three patients with HBV reactivation became undetectable after therapeutic antiviral therapy. No HBV reactivation developed in patients with resolved HBV infection. Aminotransferases elevated in 22% of all patients, but became elevated ≥ 2-fold of normal range in only two patients: one was treated with adefovir before TCZ for active hepatitis B and the other had resolved HBV infection, with aminotransferases returning to normal 4 weeks later. Thirty-two patients with resolved HBV infection had positive anti-HBs (≥ 10 IU/L) which is a protective antibody. The anti-HBs titer reduced significantly at week 4 and week 8 after the first dose of TCZ compared to baseline (P < 0.05) and even reduced to negative in six (19%). The anti-HBs did not return to positive in three patients during follow-up of 12-36 weeks. CONCLUSIONS: This prospective clinical observation preliminarily indicated three-dose TCZ combined with csDMARDs might increase the risk of HBV reactivation in RA patients with chronic HBV infection, but in this study patients remained asymptomatic and had a benign outcome after antiviral treatment. To identify the exact risk of TCZ on HBV infection and the prognosis of TCZ-related HBV reactivation, further studies with larger sample sizes and fewer confounding factors are needed.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Virus de la Hepatitis B/patogenicidad , Activación Viral , Administración Intravenosa , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antirreumáticos/administración & dosificación , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/inmunología , Biomarcadores/sangre , ADN Viral/genética , Esquema de Medicación , Femenino , Anticuerpos contra la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Humanos , Huésped Inmunocomprometido , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Carga ViralRESUMEN
INTRODUCTION: Core disease activity indicators of rheumatoid arthritis (RA) have been found to be limited in predicting joint destruction progression. Matrix metalloproteinase (MMP) 3 plays an essential role in joint destruction and was found elevated in some remission patients. We aimed to monitor dynamic core disease activity indicators and serum MMP-3 for one year and evaluate their value for predicting radiographic progression. METHODS: Patients with active RA (Simplified disease activity index > 3.3) were treated according to the treat-to-target strategy. Serum MMP-3 was detected by enzyme-linked immunosorbent assay and clinical data were collected simultaneously at 0, 1st, 3rd, 6th and 12th month. X-ray assessment of hand/wrist was repeated at baseline and the 12th month and a change of total Sharp score > 0.5 units was defined as radiographic progression. RESULTS: Fifty-six patients completed one year follow-up and 29 % showed radiographic progression. Although not significantly different at baseline, serum MMP-3 and all core disease activity indicators, except for erythrocyte sedimentation rate, at the 12th month were significantly higher in the progressive group than in the non-progressive group. Among sixteen progressive patients, 69 % achieved the therapeutic target and 56 % had continuous elevated serum MMP-3, 38 % had continuous elevated serum MMP-3 and normal C-reactive protein (CRP) at the 6th month. Log-rank tests and repeated measures analysis revealed a significant difference in dynamic serum MMP-3 between progressive and non-progressive patients. Receiver operating characteristic curve and univariate logistic regression analysis showed that elevated serum MMP-3 at 0, 1st, 3rd and 6th months, compared with CRP at the 1st month, were significant predictors for one-year radiographic progression (MMP-3 odds ratio (OR):10.500 ~ 27.000, all P < 0.05; CRP: OR = 7.400, P = 0.011). CONCLUSIONS: Our data showed that continuously elevated serum MMP-3 for 3 ~ 6 months predicted one-year radiographic progression which implied that monitoring of dynamic serum MMP-3 combined with core disease activity indicators may be more helpful for predicting radiographic progression and treatment decision in RA.
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Artritis Reumatoide/diagnóstico por imagen , Biomarcadores/sangre , Metaloproteinasa 3 de la Matriz/sangre , Adulto , Área Bajo la Curva , Artritis Reumatoide/sangre , Artritis Reumatoide/enzimología , Estudios de Cohortes , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Curva ROC , Radiografía , Sensibilidad y EspecificidadRESUMEN
INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and disability. Peroxisome proliferator-activated receptor-gamma coactivator-1 beta (PGC-1ß) is a transcriptional coactivator that plays important roles in regulating multiple aspects of energy metabolism and cytokine signaling pathways. PGC-1ß overexpression leads to the attenuation of macrophage-mediated inflammation. In this study, we aimed to determine the expression of PGC-1ß in RA synovium and fibroblast-like synoviocytes (FLS), and explore the mechanisms of PGC-1ß on both the proinflammatory effects and apoptosis in RA-FLS. METHODS: Synovium was obtained from 31 patients with active RA, as well as 13 osteoarthritis (OA) and 10 orthopedic arthropathies (Orth.A) as "less inflamed" disease controls. FLS were then isolated and cultured. Synovial PGC-1ß expression was determined by immunohistochemistry staining, while FLS PGC-1ß expression was detected by immunofluorescence staining, quantitative real-time PCR (qPCR) assay and western blot. PGC-1ß was depleted by lentivirus sh-RNA, and up-regulated by pcDNA3.1- PGC-1ß. The expression of proinflammatory cytokines, matrix metalloproteinases and receptor activator of nuclear factor-kappaB ligand was analyzed by qPCR, cytometric bead array and western blot. The expression of mitogen-activated protein kinases and nuclear factor-kappaB (NF-κB) was determined by qPCR and western blot. Besides, cell apoptosis was examined using flow cytometry. The interaction between PGC-1ß and NF-κB was performed by dual-luciferase reporter gene assays. RESULTS: (A) Synovial PGC-1ß was over-expressed in RA patients compared with OA or Orth.A patients. (B) PGC-1ß expression significantly increased in RA-FLS compared with OA-FLS. (C) PGC-1ß mediated the expression of proinflammatory cytokines and apoptosis through extracellular signal-regulated kinase (ERK), p38 and NF-κB in RA-FLS. (D) PGC-1ß mediated NF-κB transcription in RA-FLS, but did not affect ERK and p38. CONCLUSION: The results indicate that PGC-1ß may play important roles in the proinflammatory effects and apoptosis of RA-FLS.