Can metformin relieve tibiofemoral cartilage volume loss and knee symptoms in overweight knee osteoarthritis patients? Study protocol for a randomized, double-blind, and placebo-controlled trial.

BACKGROUND: Osteoarthritis (OA) is the most common joint disease, and is most frequently seen in the knees. However, there is no effective therapy to relieve the progression of knee OA. Metformin is a safe, well-tolerated oral medication that is extensively used as first-line therapy for type 2 diabetes. Previous observational studies and basic researches suggested that metformin may have protective effects on knee OA, which needs to be verified by clinical trials. This study, therefore, aims to examine the effects of metformin versus placebo on knee cartilage volume loss and knee symptoms in overweight knee OA patients by a randomized controlled trial over 24 months. METHODS: This protocol describes a multicenter, randomized, double-blind, and placebo-controlled clinical trial aiming to recruit 262 overweight knee OA patients. Participants will be randomly allocated to the two arms of the study, receiving metformin hydrochloride sustained-release tablets or identical inert placebo for 24 months (start from 0.5 g/day for the first 2 weeks, and increase to 1 g/day for the second 2 weeks, and further increase to 2 g/day for the remaining period if tolerated). Primary outcomes will be changes in tibiofemoral cartilage volume and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score over 24 months. Secondary outcomes will be changes in visual analogue scale (VAS) knee pain, tibiofemoral cartilage defects, effusion-synovitis volume, and tibiofemoral bone marrow lesions maximum size over 24 months. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per-protocol analyses will be performed as the secondary analyses. DISCUSSION: If metformin is proved to slow knee cartilage volume loss and to relieve knee symptoms among overweight knee OA patients, it will have the potential to become a disease modifying drug for knee OA. Metformin is a convenient intervention with low cost, and its potential effects on slowing down the structural progression and relieving the symptoms of knee OA would effectively reduce the disease burden worldwide. TRIAL REGISTRATION: ClinicalTrials. gov NCT05034029 . Registered on 30 Sept 2021.

A Novel Hypothesis on Excessive Activation of Residual B Lymphocytes in Common Variable Immunodeficiency Concurrent with Aseptic, Erosive Polyarthritis.

The aim of this study was to report aseptic, erosive polyarthritis in a patient with common variable immunodeficiency (CVID), which is quite different from the vastly more common nonerosive form. Peripheral blood mononuclear cells of the patient were isolated. Flow cytometry was used to analyze the proportion and function of lymphocytes. A Parker-Pearson needle biopsy was performed on the right knee. Four of her unaffected family members were enrolled as controls. A 21-year-old woman was admitted for recurrent polyarthritis of 3-year duration. The right knee, hip, wrist, proximal interphalangeal joints, and left elbow were involved, with progressive joint destruction. She was diagnosed as having CVID based on her recurrent infections, poor response to vaccines, and marked hypogammaglobulinemia. No bacterium or mycobacterium was detected in synovium or synovial fluid. The synovium was infiltrated by lymphocytes rather than neutrophils. Polyarthritis did not resolve by adequate intravenous immunoglobulin substitution and empirical antibiotic treatment, but resolved gradually after treatment with methylprednisolone and tacrolimus, supporting the diagnosis of aseptic polyarthritis. Further analyses showed that although only 0.5% of residual B lymphocytes were existent in peripheral blood of the patient, expressions of activation marker CD69 and production of IL-1ß, IL-6, and TNF-α were high. Marked infiltration with CD19+B lymphocytes (as well as CD4+ or CD8+ T lymphocytes) was detected in the synovium. The proportion of IL21+CD4+Th cells from peripheral blood of the patient was high. CD4+ Th cells from the patient secreted nearly 3 times more IL-21 than the same cell type analyzed from unaffected family members, perhaps due to excessive compensation to assist the function of residual B lymphocytes. A novel hypothesis in CVID concurrent with aseptic, erosive polyarthritis is that excessive activation of residual B lymphocytes infiltrate into the synovium of the involved joints and lead to polyarthritis and joint destruction.

Patients with Coexistence of Circulating Hepatitis B Surface Antigen and Its Antibody May Have a Strong Predisposition to Virus Reactivation During Immunosuppressive Therapy: A Hypothesis.

Hepatitis B virus (HBV) reactivation is a well-recognized complication in patients who undergo immunosuppressive drug therapy. Although the recommendation of antiviral prophylaxis made by the American Gastroenterological Association in 2015 focuses on the risk stratification of different immunosuppressive drugs, risk factors for HBV reactivation are also worth identifying in clinical practice. Recent studies have shown that the uncommon serological pattern of coexistent circulating HBV surface antigen (HBsAg) and its antibody (anti-HBs) was associated with double mutations (A1762T/G1764A) in the basal core promoter (BCP) region of the HBV genome, which is critical for HBV replication. Here, we depicted rheumatoid arthritis (RA) patients with coexistent HBsAg and anti-HBs in our medical center, who developed HBV reactivation during immunosuppressive drug therapy. DNA sequencing analysis of the HBV genome revealed triple mutations (A1762T, G1764A, and T1753V) in the BCP region, which could further enhance the ability of HBV replication. Hence, a novel hypothesis is advanced for the first time that patients with coexistent HBsAg and anti-HBs may have a strong predisposition to HBV reactivation due to specific BCP mutations. This hypothesis would, if correct, justify the concurrent detection of HBsAg and anti-HBs in HBV screening in patients with rheumatic diseases and quickly recognize patients with high risk of HBV reactivation. Further controlled studies are needed to confirm this hypothesis.

[Value of serum matrix metalloproteinase-3 in the assessment of active disease in patients with rheumatoid arthritis].

OBJECTIVE: To investigate the value of serum matrix metalloproteinase-3 (sMMP-3) in the assessment of active disease in patients with rheumatoid arthritis (RA). METHODS: One hundred and ninety-one RA patients were recruited from the Department of Rheumatology of Sun Yat-sen Memorial Hospital from June 2010 to June 2014. sMMP-3 level of these RA patients and 58 healthy people was tested by enzyme-linked immunosorbent assay, while clinical data was collected simultaneously. Receiver operating characteristic (ROC) curve was used for the analysis of optimal cut-off point for the evaluation of disease activity. RESULTS: There were 128 female patients and 63 male patients recruited. sMMP-3 was significantly higher in RA patients than healthy control and it was higher in patients with active disease than that in patients in remission (all P < 0.01). ROC curve analysis showed that the optimal cut-off point for diagnosing active RA was 84 µg/L with area under the curve (AUC) 0.822 in female and 168 µg/L with AUC 0.824 in male (both P < 0.01). According to the optimal cut-off points, the sensitivity of sMMP-3 + CRP combined detection was 97.2% for diagnosing active RA, which was significantly higher than that of sMMP-3 (84.7%) or C-reactive protein (CRP) (88.2%, both P < 0.05). The specificity of combined detection was 95.7%, which was significantly higher than that of sMMP-3 (68.1% , P < 0.01). And Youden's index of combined detection (0.951) was significantly higher than that of sMMP-3 (0.528) or CRP (0.754, both P < 0.05). CONCLUSION: sMMP-3 is a helpful indicator for disease activity measurement in RA patients. Combined detection of sMMP-3 and CRP can improve the accuracy of disease activity assessment.

[Liver safety of biosimilar of recombinant tumor necrosis factor-α receptor-antibody fusion protein in Spondyloarthritis patients under different status of HBV infection: a prospective observational study].

OBJECTIVE: To investigate the influence of recombinant human tumor necrosis factor α receptor-antibody fusion protein (rhTNFR: Fc) to the Hepatitis B virus (HBV) infection status and liver function of Spondyloarthritis (SpA) patients under different HBV infection status. METHODS: Active SpA patients with normal liver function were enrolled in Sun Yat-sen Memorial hospital from February 2012 to August 2014. All were treated with rhTNFR: Fc based therapy (monotherapy or combined therapy) for at least 12 weeks. SpA disease activity, HBV infection status and liver function were evaluated at each interview (baseline, 4(th) and 12(th) week, as primary endpoint). Part of the patients were evaluated at 24(th) week with or without extended rhTNFR: Fc treatment(as secondary endpoint) based on their choice. RESULTS: Eighty-one patients who completed 12-week follow-up visit were divided into chronic HBV carrier group (n=21), past HBV exposure group (n=25) and free of HBV infection group (n=35). Alanine transaminase (ALT) elevated (no more than 3-fold of normal) in 3 patients from 3 groups respectively at 4th week. During 24-week follow-up, none in past HBV exposure group or in free of HBV infection group developed HBV reactivation or HBV infection; and 4 patients in chronic HBV carrier group developed HBV reactivation without more than 2-fold of normalelevation of ALT. Among 7 patients with negative baseline HBV-DNA and without antiviral prophylaxis, 2 patients developed HBV reactivation at 10(th) 24(th) week of rhTNFR: Fc therapy respectively and 1 patient developed reactivation at 16(th) week (12-week rhTNFR: Fc+ thalidomide therapy and following 4-week thalidomide monotherapy), whose HBV-DNA load returned to normal spontaneously or after antiviral therapy. Four chronic HBV carriers with low-load of baseline HBV-DNA did not develop reactivation. One of 9 chronic HBV carriers with high-load of baseline HBV-DNA developed reactivation due to resistance of antiviral prophylaxis. CONCLUSIONS: Short-term rhTNFR: Fc based therapy may induce mild and transient HBV reactivation, usually without hepatitis.

Elevated serum IgG4 defines specific clinical phenotype of rheumatoid arthritis.

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.

Serum matrix metalloproteinase-3 as a noninvasive biomarker of histological synovitis for diagnosis of rheumatoid arthritis.

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.

Discontinuation of antiviral prophylaxis correlates with high prevalence of hepatitis B virus (HBV) reactivation in rheumatoid arthritis patients with HBV carrier state: a real-world clinical practice.

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.

[Correlation between synovial TRAF6 expression and serum bone metabolism markers in rheumatoid arthritis].

OBJECTIVE: To evaluate the correlation between synovial tumor necrosis factor receptor-associated factor (TRAF) 6 expression and serum bone metabolism markers in rheumatoid arthritis (RA). METHODS: Serum biochemical markers of bone formation (N-terminal propeptide of type I collagen, PINP and N-terminal midfragment of osteocalcin, N-MID.OC) and bone resorption (C-terminal telopeptide of type I collagen, CTX-I) were detected by chemiluminescence in 51 RA patients and 102 age and gender-matched healthy controls from Sun Yat-sen Memorial Hospital during the period of April 2010 to December 2012. Clinical and other serological parameters of reflecting RA activity and severity were collected and correlated with bone metabolism markers. TRAF6 was stained immunohistochemically in synovium from 30 active RA patients and the intensity of TRAF6+ cells was analyzed semiquantitatively. Correlation between synovial TRAF6 expression and serum bone metabolism markers was analyzed. RESULTS: Serum CTX-I level was significantly higher in RA patients than healthy controls ((0.53 ± 0.33) × 10⁻³ vs (0.33 ± 0.16) × 10⁻³ g/L, P < 0.01). Serum PINP and N-MID. OC levels of RA patients were correlated negatively with morning stiffness (P < 0.05), Health Assessment Questionnaire (HAQ) score (P < 0.05) and pain visual analogue scales (VAS) score (P < 0.05). Serum PINP level of RA patients correlated positively with gripping power (r = 0.296, P < 0.05). TRAF6 expression was observed in lining and sublining area of RA synovium and a higher expression of TRAF6 was seen in patients with severe synovitis than those with mild synovitis. Significant correlation was found between synovial TRAF6 expression and serum PINP level (r = 0.381, P < 0.05), as well as serum N-MID.OC level (r = 0.345, P < 0.05). CONCLUSION: Increased bone resorption and altered skeletal bone metabolism are present in RA. An elevated expression of synovial TRAF6 may be correlated with increased compensatory bone formation. And TRAF6 is probably involved in the pathogenesis of bone metabolism imbalance through modulating synovial inflammation in RA.

Association of serum concentrations of remnant cholesterol with incident cardiovascular disease in patients with rheumatoid arthritis: A real-world data from 2001 to 2022.

BACKGROUND: Remnant cholesterol (RC) promotes cardiovascular disease (CVD) in the general population, but its role among rheumatoid arthritis (RA) patients remains unknown. We aimed to investigate circulating RC levels associated with incident CVD among Chinese patients with RA. METHODS: A total of 1018 RA patients free of baseline CVD were included and followed up in a prospective RA CVD cohort from 2001 to 2022. Fasting serum levels of triglycerides, total cholesterol (TC), low-density (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured, while RC and Non-HDL-C levels were calculated. The primary exposure was RC levels. A LASSO Cox model was used to select covariates. The Fine-Gray competing risk model was used to estimate hazard ratios (HRs). RESULTS: RA patients had a mean age of 53.9 years, and 802 (78.8%) were females. After a median follow-up of 5.54 years, 131 patients developed CVD with an incidence rate of 21.6 per 1000 person-years. Continuous and quartile-categorized RC levels were associated with incident CVD before and after multivariate adjustment and Bonferroni correction (all P < 0.001). There were no robust associations of other lipids with incident CVD. The fully adjusted HRs for RC were 2.30 (95% CI 1.58-3.35) per 1 mmol/L increase, and 2.40 (1.36-4.25) and 2.81 (1.60-4.94) for patients in the 3rd and 4th versus the 1st quartile, respectively. CONCLUSIONS: Circulating RC levels are positively associated with incident CVD among Chinese RA patients independent of known risk factors, implying its clinically preferable use for improving the stratification of CVD risk in RA patients.

Diagnostic value of ultrasound evaluation of major salivary glands for Sjögren's syndrome based on the novel OMERACT scoring system.

OBJECTIVE: The novel Outcome Measures in Rheumatology Clinical Trials (OMERACT) scoring system was used to evaluate the diagnostic effectiveness of major salivary gland ultrasonography (SGUS) for Sjögren's syndrome (SS). MATERIALS AND METHODS: SGUS was performed on the parotid glands (PGs) and submandibular glands of 242 patients (145 patients with SS and 97 patients without SS) using the OMERACT scoring system (grade 0-3). We also evaluated the association of SGUS scores with unstimulated whole salivary flow rate (UWSF), stimulated whole salivary flow rate (SWSF), and labial salivary gland biopsy (LSGB) results. RESULTS: The SGUS scores were significantly higher for the SS group than for the non-SS group (p < 0.001). Using a cutoff value of 8 for the total score yielded the highest sensitivity (76%), specificity (90%), and area under the receiver operating characteristic curve (AUC, 0.828). The correlation between SGUS scores and salivary gland function was moderate to good. A cutoff value of 10 for the total score was more effective in predicting SWSF outcomes than UWSF outcomes (sensitivity: 73% > 58%, specificity: 98% > 87%, and AUC: 0.856 > 0.723). The association of OMERACT scores with LSGB results was fair to moderate. Among 61 anti-SSA-negative patients, 17 had positive PG scores (including ten SS and seven non-SS patients), and 44 had negative PG scores (including 37 non-SS and seven SS patients). CONCLUSION: The OMERACT scoring system had good sensitivity and excellent specificity, demonstrating excellent diagnostic potential for SS and efficacy in assessing salivary gland function. Negative SGUS results may help reduce unnecessary biopsies in anti-SSA-negative patients.

Association Between Metabolic Dysfunction-Associated Fatty Liver Disease and Cardiovascular Risk in Patients With Rheumatoid Arthritis: A Cross-Sectional Study of Chinese Cohort.

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.

Prevalence and influence of hypouricemia on cardiovascular diseases in patients with rheumatoid arthritis.

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 (Pnon-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.

Sugar-Sweeten Beverage Consumption Is Associated With More Obesity and Higher Serum Uric Acid in Chinese Male Gout Patients With Early Onset.

Background: Early onset gout has received increasing interest from researchers. Previous studies have reported that serum urate (sUA) levels and prevalence of obesity are higher in early onset gout patients than in later-onset gout patients. We explored the dietary habits of early onset and later-onset gout patients and their association with clinical features. Materials and Methods: Gout patients completed a 10-item food frequency questionnaire. Early onset gout patients were defined as gout onset before the age of 40, and onset after age 40 was classified as later-onset. Associations between dietary factors, obesity, and sUA level of ≥600 µmol/L were assessed using logistic regression. Results: Among the 655 gout patients, 94.6% were males, and 59.1% presented with early onset gout. All early onset patients were males. sUA level was significantly higher in the early onset group than in the later-onset group (550.7 vs. 513.4 µmol/L). The proportion of patients with a sUA level of ≥ 600 µmol/L (40.3 vs. 26.2%) and obesity (27.6 vs. 10.7%) was higher in the early onset group than in the later-onset group (all p < 0.05). The early onset group consumed more red meat (101-200 g/day: 43.6 vs. 26.0%), sugar-sweetened beverages (>4 times/week: 27.9 vs. 7.7%), and milk and milk products (1-2 times/week: 28.5 vs. 16.6%), but less alcohol (>84 g/day: 8.5 vs. 21.5%) and tea (>4 times/week: 35.7 vs. 52.4%; all p < 0.05). Sugar-sweetened beverage intake was positively correlated with sUA level of ≥600 µmol/L (compared with 4 times/week: adjusted odds ratio = 2.2, 95% confidence interval: 1.4, 3.7) and obesity (compared with 4 times/week: adjusted odds ratio = 2.2, 95% confidence interval: 1.2, 3.7). These correlations remained significant for early onset gout patients. Conclusion: Sugar-sweetened beverage intake replaced alcohol as the main dietary risk factor for gout in early onset patients, and this change was associated with a greater prevalence of obesity and higher sUA level. Clinicians should provide specific dietary education for different generations of gout patients. The epidemic of sugar-sweetened beverage consumption should be considered for the development of public health policies for the prevention of gout.

Myokine myostatin is a novel predictor of one-year radiographic progression in patients with rheumatoid arthritis: A prospective cohort study.

Background: Associations between rheumatoid arthritis (RA) and reduced skeletal muscle have been studied, and we firstly reported myopenia independently predict one-year radiographic progression in RA. Myokine myostatin can negatively regulate skeletal muscle mass and promote osteoclast differentiation. However, there is no report about their relationships in RA patients. We firstly explored the relationship of serum myostatin and disease characteristics, as well as aggravated joint destruction during one-year follow-up. Methods: Consecutive RA patients were recruited from a real-world prospective cohort and completed at least one-year follow-up. Baseline serum level of myostatin was measured by enzyme-linked immunosorbent assay. Clinical data in RA patients as well as muscle index in both RA patients and healthy controls were collected. One-year radiographic progression as primary outcome was defined by a change in the total Sharp/van der Heijde modified score ≥0.5 units. Results: Totally 344 RA patients (age 47.9 ± 12.5 years, 84.0% female) and 118 healthy control subjects (age 42.8 ± 11.3 years, 74.6% female) were recruited. Compared with healthy controls, RA patients showed a higher level of serum myostatin at baseline (3.241 ± 1.679 ng/ml vs. 1.717 ± 0.872 ng/ml, P<0.001), although lower appendicular skeletal muscle mass index (ASMI, 6.0 ± 0.9 kg/m2 vs. 6.5 ± 1.0 kg/m2, P<0.001). In RA patients, those with high myostatin level showed a higher rate of radiographic progression than low myostatin group (45.3% vs. 18.6%, P<0.001). Furtherly, RA patients were stratified into four subgroups according to serum myostatin and myopenia. Compared with other three subgroups, RA patients with high myostatin overlapping myopenia had the highest rate of radiographic progression (67.2% vs. 10.3%-31.4%, P<0.001), as well as the lowest proportion of remission and the highest rate of physical dysfunction during one-year follow-up. After adjustment for confounding factors, high serum myostatin (AOR=3.451, 95%CI: 2.016-5.905) and myopenia (AOR=2.387, 95%CI: 1.416-4.022) at baseline were risk factors for one-year radiographic progression, especially for those with high myostatin overlapping myopenia (AOR=10.425, 95%CI: 3.959-27.450) as the highest-risk individuals among four subgroups. Significant synergistic interaction effect was observed between high myostatin and myopenia on one-year radiographic progression (AP=66.3%, 95%CI: 43.2%-89.3%). Conclusion: Myostatin is a novel predictor of aggravated joint destruction in RA patients which has synergistic interaction with myopenia for predicting value.

A Matrix Prediction Model for the 6-Month Mortality Risk in Patients With Anti-Melanoma Differentiation-Associated Protein-5-Positive Dermatomyositis.

Objectives: The purpose of this study was to investigate the baseline independent risk factors for predicting 6-month mortality of patients with anti-melanoma differentiation-associated gene 5 (anti-MDA5)-positive dermatomyositis (DM) and develop a matrix prediction model formed by these risk factors. Methods: The hospitalized patients with DM who completed at least 6-month follow-up were recruited as a derivation cohort. The primary exposure was defined as positive anti-MDA5 at the baseline. The primary outcome was all-cause 6-month mortality after enrollment. A matrix prediction model was developed in the derivation cohort, and another published cohort was used for external validation. Results: In derivation cohort, 82 patients with DM were enrolled (mean age of onset 50 ± 11 years and 63% women), with 40 (49%) showing positive anti-MDA5. Gottron sign/papules (OR: 5.135, 95%CI: 1.489-17.708), arthritis (OR: 5.184, 95%CI: 1.455-18.467), interstitial lung disease (OR: 7.034, 95%CI: 1.157-42.785), and higher level of C4 (OR: 1.010, 95%CI: 1.002-1.017) were the independent associators with positive anti-MDA5 in patients with DM. Patients with anti-MDA5-positive DM had significant higher 6-month all-cause mortality than those with anti-MDA5-negative (30 vs. 0%). Among the patients with anti-MDA5-positive DM, compared to the survivors, non-survivors had significantly advanced age of onset (59 ± 6 years vs. 46 ± 9 years), higher rates of fever (75 vs. 18%), positive carcinoma embryonic antigen (CEA, 75 vs. 14%), higher level of ferritin (median 2,858 ug/L vs. 619 ug/L, all p < 0.05). A stepwise multivariate Cox regression showed that ferritin ≥1,250 µg/L (HR: 10.4, 95%CI: 1.8-59.9), fever (HR: 11.2, 95%CI: 2.5-49.9), and positive CEA (HR: 5.2, 95%CI: 1.0-25.7) were the independent risk factors of 6-month mortality. A matrix prediction model was built to stratify patients with anti-MDA5-positive DM into different subgroups with various probabilities of 6-month mortality risk. In an external validation cohort, the observed 6-month all-cause mortality was 78% in high-risk group, 43% in moderate-risk group, and 25% in low-risk group, which shows good accuracy of the model. Conclusion: Baseline characteristics such as fever, ferritin ≥1,250 µg/L, and positive CEA are the independent risk factors for 6-month all-cause mortality in patients with anti-MDA5-positive DM. A novel matrix prediction model composed of these three clinical indicators is first proposed to provide a chance for the exploration of individual treatment strategies in anti-MDA5-positive DM subgroups with various probabilities of mortality risk.

Lysosomal exocytosis of HSP70 stimulates monocytic BMP6 expression in Sjögren's syndrome.

BMP6 is a central cytokine in the induction of Sjögren's syndrome-associated (SS-associated) secretory hypofunction. However, the upstream initiation leading to the production of this cytokine in SS is unknown. In this study, RNA ISH on salivary gland sections taken from patients with SS indicated monocytic lineage cells as a cellular source of BMP6. RNA-Seq data on human salivary glands suggested that TLR4 signaling was an upstream regulator of BMP6, which was confirmed by in vitro cell assays and single-cell transcriptomics of human PBMCs. Further investigation showed that HSP70 was an endogenous natural TLR4 ligand that stimulated BMP6 expression in SS. Release of HSP70 from epithelial cells could be triggered by overexpression of lysosome-associated membrane protein 3 (LAMP3), a protein also associated with SS in several transcriptome studies. In vitro studies supported the idea that HSP70 was released as a result of lysosomal exocytosis initiated by LAMP3 expression, and reverse transcription PCR on RNA from minor salivary glands of patients with SS confirmed a positive correlation between BMP6 and LAMP3 expression. BMP6 expression could be experimentally induced in mice by overexpression of LAMP3, which developed an SS-like phenotype. The newly identified LAMP3/HSP70/BMP6 axis provided an etiological model for SS gland dysfunction and autoimmunity.

Ultrasonography predicts the results of labial salivary gland biopsy in patients with suspected Sjögren's syndrome: a matrix risk model.

OBJECTIVE: Although a positive result of labial salivary gland biopsy (LSGB) is critical for the diagnosis of Sjögren's syndrome, rheumatologists prefer assessing the non-invasive objective items and hope to learn the predicted probability of positive LSGB before referring patients with suspected Sjögren's syndrome to receive biopsy. This study aimed to explore the predictive value of combined B-mode ultrasonography (US) and shear-wave elastography (SWE) examination on LSGB results. METHODS: A derivation cohort and later a validation cohort of patients with suspected Sjögren's syndrome were recruited. All participants received clinical assessments, B-mode US and SWE examination on bilateral parotid and submandibular glands before LSGB. Positive LSGB was defined by a focus score ⩾1 per 4 mm2 of glandular tissue. RESULTS: In the derivation cohort of 91 participants, either the total US scores or the total SWE values of four glands significantly distinguished patients with positive LSGB from those with negative results (area under the curve (AUC) = 0.956, 0.825, both p < 0.001). The positive predictive value (PPV) was 100% in patients with total US scores ⩾9 or with total SWE values ⩾33 kPa. The negative predictive value (NPV) was 100% in patients with total US scores <5, but 68% in patients with total SWE values <27 kPa. A matrix risk model was derived based on the combination of total US scores and total SWE values. Patients can be stratified into high, moderate, and low risk of positive LSGB. In the validation cohort of 52 participants, the PPV was 94% in the high-risk subpopulation and the NPV was 93% in the low-risk subpopulation. CONCLUSION: A novel matrix risk model based on the combined B-mode US and SWE examination can help rheumatologists to make a shared decision with suspected Sjögren's syndrome patients on whether the invasive procedure of LSGB should be performed.

Addition of Fibroblast-Stromal Cell Markers to Immune Synovium Pathotypes Better Predicts Radiographic Progression at 1 Year in Active Rheumatoid Arthritis.

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.

Reduced skeletal muscle independently predicts 1-year aggravated joint destruction in patients with rheumatoid arthritis.

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.