Anti-malarial drug artesunate can suppress inflammation and prevent cartilage and bone destruction in collagen-induced arthritis model in rats—suggesting it may be a potent drug for rheumatoid arthritis (RA) therapy. We aimed to investigate its effect on the invasive property of fibroblast-like synoviocytes (FLS) from patients with RA. Synovial tissues were obtained by closed needle biopsy from active RA patients, and FLS were isolated and cultured in vitro. RA-FLS were treated with artesunate at various concentrations, while methotrexate or hydroxychloroquine was employed as comparator drugs. Cell viability, proliferation, cell cycle, apoptosis, migration, invasion, and pseudopodium formation of RA-FLS were assessed by CCK-8 assays, EdU staining, Annexin V-FITC/PI staining, transwell assays, or F-actin staining, respectively. Further, relative changes of expressed proteases were analyzed by Proteome profiler human protease array and verified by quantitative real-time PCR (qPCR), Western blot, and ELISA. The expression of signaling molecules of MAPK, NF-κB, AP-1, and PI3K/Akt pathways were measured by qPCR and Western blot. PDK-1 knockdown by specific inhibitor AR-12 or siRNA transfection was used to verify the pharmacological mechanism of artesunate on RA-FLS. Artesunate significantly inhibited the migration and invasion of RA-FLS in a dose-dependent manner with or without TNF-α stimulation. The effect was mediated through artesunate inhibition of MMP-2 and MMP-9 production, and pre-treatment with exogenous MMP-9 reversed the inhibitory effect of artesunate on RA-FLS invasion. Artesunate had a stronger inhibitory effect on migration and invasion of RA-FLS as well as greater anti-inflammatory effect than those of hydroxychloroquine. Similar inhibitory effect was detected between artesunate and methotrexate, and synergy was observed when combined. Mechanistically, artesunate significantly inhibited PDK-1 expression as well as Akt and RSK2 phosphorylation—in a similar manner to PDK-1-specific inhibitor AR-12 or PDK-1 knockdown by siRNA transfection. This inhibition results in suppression of RA-FLS migration and invasion as well as decreased MMP-2 and MMP-9 expression. Our study demonstrates artesunate is capable of inhibiting migration and invasion of RA-FLS through suppression of PDK1-induced activation of Akt and RSK2 phosphorylation—suggesting that artesunate may be a potential disease-modifying anti-rheumatic drug for RA.

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. 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. 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. The presence of HBV in RA synovium may be involved in the pathogenesis of local lesions and exacerbate disease progression in RA.

Background: Muscle mass loss is common in long-standing rheumatoid arthritis (RA). The aim was to explore the prevalence and effects of RA disease characteristics in patients with early RA.Methods: This cross-sectional study was carried out based on a Chinese RA cohort and control subjects. The body composition (BC) was assessed using bioelectric impedance analysis. Myopenia was defined by an appendicular skeletal muscle mass index of ≤ 7.0 kg/m² in men and ≤ 5.7 kg/m² in women. Physical dysfunction was defined as a health assessment questionnaire disability index > 1. Propensity score matching was performed to balance age and gender differences among patients with early RA (disease duration ≤ 12 months) and established RA, and controls (with 1:3:3 matching).Results: In total, 2017 controls and 1,008 patients with RA were recruited for this study. Among the patients with RA, there were 190 (18.8%) patients with early RA, with a median disease duration of 7 (4, 11) months. The matched patients with early RA (n = 160) showed a higher prevalence of myopenia than the matched controls (41.3 vs. 15.8%, P < 0.0167), but no difference was found in the matched patients with established RA (41.3 vs. 50.4%, P > 0.0167). Compared with the patients with established RA, the patients with early RA exhibited higher disease activity scores [disease activity score in 28 joints with four variables including C-reactive protein (DAS28-CRP): median 4.76 vs. 3.93, P < 0.001] and a higher prevalence of physical dysfunction (26.3 vs. 19.4%, P = 0.035). In the patients with early RA, patients with myopenia showed a higher prevalence of physical dysfunction than those without myopenia (41.3 vs. 15.5%, P < 0.001), among which walking and common daily activities were the most involved subdimensions. Multivariate logistic regression analysis showed that DAS28-CRP was positively associated with myopenia [adjusted odds ratio (AOR) 1.558, 95% CI (1.138–2.132)], and myopenia [AOR 2.983, 95% CI (1.192–7.465)] was independently associated with physical dysfunction in the patients with early RA.Conclusion: Our data indicate the importance of early detection of muscle involvement in the early stage of RA and imply the significance of early aggressive control of disease activity for the prevention of myopenia and physical dysfunction in patients with early RA. Our study provides a new perspective on RA management.

Background: Serum uric acid (SUA) acts as an antioxidant and abnormally low SUA may raise the risk of developing atherosclerotic disorders. There is a U-shaped association between SUA with cardiovascular diseases (CVDs) in general population. However, the prevalence of hypouricemia and its influence on CVDs in rheumatoid arthritis (RA) remains unclear. Methods: This cross-sectional study collected clinical data from a Chinese RA cohort. Hypouricemia was defined as SUA ≤ 3.0 mg/dL, and hyperuricemia was defined as SUA ≥ 7.0 mg/dL. CVDs were defined as a history of angina pectoris, myocardial infarction, heart failure, stroke and peripheral arterial disease. Restricted cubic spline regression and logistic regression analysis were conducted to evaluate the associations between SUA levels and CVDs. Results: Among 1130 RA patients recruited, the mean age was 53.2 years and 79.0% were female. The prevalence of hypouricemia and hyperuricemia were 10.6% and 12.0%, respectively. RA patients with hyperuricemia had a higher rate of CVDs than normouricemic patients (27.9% vs. 7.1%, P < 0.05). Surprisingly, RA patients with hypouricemia also had a higher rate of CVDs (20.7% vs. 7.1%, P < 0.05) even without higher traditional cardiovascular risk factors. A U-shaped association between SUA levels and total CVDs was found (P_non-linear < 0.001). Multivariate logistic regression analysis revealed that compared with normouricemia, both hypouricemia [adjusted OR (AOR) = 4.707, 95% CI 2.570–8.620] and hyperuricemia (AOR = 3.707, 95% CI 2.174–6.321) were associated with higher risk of CVDs. Conclusions: Hypouricemia may be a potential risk factor of CVDs in RA patients

Previous studies have revealed that hepatitis B virus (HBV) infection may be associated with rheumatoid arthritis (RA), while there are no further clinical studies regarding the role of HBV infection in RA progression during disease-modifying anti-rheumatic drug (DMARD) therapy. Here, we aimed to explore the influence of HBV infection on radiographic and clinical outcomes among patients with RA in a clinical practice setting. Thirty-two consecutive patients with RA (Disease Activity Score 28-joint assessment based on C-reactive protein (DAS28-CRP) ≥2.6) with chronic HBV infection (CHB) were retrospectively recruited as the CHB group and 128 age-matched, sex-matched, and disease activity-matched contemporary patients with RA without CHB were included in the non-CHB group. Clinical data were collected at baseline and visits at month 1, 3, 6, and 12. The therapeutic target was defined as DAS28-CRP <2.6 in all patients or 24 months). The primary outcome was the percentage of patients with one-year radiographic progression (a change in modified total Sharp score ≥0.5). Compared with the non-CHB group, a significantly higher percentage of patients with one-year radiographic progression was observed in the CHB group (53% vs. 17%, p < 0.001), with smaller proportions of patients achieving therapeutic target at month 6 and month 12 (53% vs. 82% and 53% vs. 75%, both p < 0.05), remission at month 6 (DAS28-CRP <2.6, 50% vs. 72%, p = 0.039), and American College of Rheumatology (ACR)20/50 responses and good or moderate European League Against Rheumatism (EULAR) responses mainly at month 6 and 12 (all p < 0.05). Multivariate logistic regression analysis revealed that CHB status was significantly associated with one-year radiographic progression and failure to achieve therapeutic target within 6 months. HBV reactivation occurred in 34% of patients with CHB during one-year follow up, with two patients suffering hepatitis flare. HBV infection may play a deleterious role in radiographic and clinical outcomes in patients with RA, and HBV reactivation should be paid close attention during immunosuppressive therapy.

Background and Objectives: Sarcopenia is a notable comorbidity of rheumatoid arthritis (RA), affecting about one third of patients. However, the characteristic of muscle function and its association with RA disease remains unknown. Materials and Methods: This cross-sectional study collected clinical data from a real-world Chinese RA cohort. Sarcopenia was defined as both myopenia and low muscle function (LMF). Myopenia was defined as appendicular skeletal muscle mass index (ASMI) < 7.0 kg/m² in men and <5.7 kg/m² in women. LMF was defined as low muscle strength (LMS, hand grip < 28 kg in men and <18 kg in women) or low physical performance (LPP, 6 m gait speed < 1.0 m/s). Results: Among 1125 RA patients recruited in this study, 928 RA patients were eligible for analysis. The prevalence of sarcopenia, myopenia, LMF, LMS, and LPP in all RA patients was 36.5%, 46.1%, 69.0%, 57.8%, and 37.1%, respectively. According to their trends in age and disease activity, there were 111 (11.9%) patients in the young (age < 50 years) and remission (CDAI ≤ 2.8) subgroup, 199 (21.4%) patients in the young and active (CDAI > 2.8) subgroup, 198 (21.3%) patients in the old (age ≥ 50 years) and remission subgroup, and 420 (45.2%) patients in the old and active subgroup. Compared with the two remission subgroups, respectively, the young and active subgroup had significantly lower grip strength, higher prevalence of sarcopenia, LMF, and LMS, and worse activity function. After adjustment for potential confounders, multivariate multinominal logistic regression analysis showed that the young and active subgroup was positively associated with sarcopenia (OR = 3.193, 95%CI: 1.477–6.899), LMF (OR = 2.390, 95%CI: 1.207–4.731), and LMS (OR = 3.520, 95%CI: 1.743–7.110). Conclusions: Worse muscle strength, rather than reduced physical performance, is more common in patients with active RA at a young age. It underscores the critical need for early identification and intervention of muscle dysfunction to improve their quality of life.