Elevated serum B-cell activator factor levels predict rapid progressive interstitial lung disease in anti-melanoma differentiation associated protein 5 antibody positive dermatomyositis.

BACKGROUND: Rapid progressive interstitial lung disease (RP-ILD) is the leading cause of anti-melanoma differentiation associated protein 5 antibody positive dermatomyositis (anti-MDA5+DM) related death. Elevated serum B-cell activating factor (BAFF) levels have been implicated in connective tissue diseases associated ILD. Here, we evaluate whether BAFF could be a prognostic biomarker for predicting RP-ILD in anti-MDA5+DM patients. METHODS: Serums were collected from 39 patients with anti-MDA5+DM (20 with RP-ILD and 19 with non-RP-ILD), 20 antisynthase syndrome (ASS) patients and 20 healthy controls (HC). BAFF concentration was measured by an enzyme-linked immunosorbent assay. RESULTS: Serum BAFF level was higher in anti-MDA5+DM patients than those in ASS patients and HC (3882.32 ± 1880.09 vs. 2540.89 ± 1403.04 and 2486.28 ± 767.97 pg/mL, p = 0.0056 and 0.0038, respectively). Within anti-MDA5+DM groups, RP-ILD patients exhibited higher BAFF concentration than non-RP-ILD group (4549.78 ± 1839.97 vs. 3297.28 ± 1794.69 pg/mL, p = 0.04). The BAFF concentration was positively correlated with levels of C-reactive protein (CRP), dehydrogenase (LDH) and cytokeratin (CK) in anti-MDA5+DM patients (r = 0.350, p = 0.035; r = 0.393, p = 0.016; r = 0.518, p = 0.001; respectively). The best cut-off value of BAFF concentration was 2971.5 pg/mL by ROC curve (AUC area = 0.690, p = 0.045) and BAFF > 2971.5 pg/mL was an independent risk factor for RP-ILD using multivariate analysis (OR = 9.389, 95% CI = 1.609-54.769; p = 0.013). CONCLUSIONS: Serum BAFF could be a useful prognostic biomarker for early detecting RP-ILD risk in anti-MDA5+DM patients.

Value of radiomics-based automatic grading of muscle edema in polymyositis/dermatomyositis based on MRI fat-suppressed T2-weighted images.

BACKGROUND: The precise and objective assessment of thigh muscle edema is pivotal in diagnosing and monitoring the treatment of dermatomyositis (DM) and polymyositis (PM). PURPOSE: Radiomic features are extracted from fat-suppressed (FS) T2-weighted (T2W) magnetic resonance imaging (MRI) of thigh muscles to enable automatic grading of muscle edema in cases of polymyositis and dermatomyositis. MATERIAL AND METHODS: A total of 241 MR images were analyzed and classified into five levels using the Stramare criteria. The correlation between muscle edema grading and T2-mapping values was assessed using Spearman's correlation. The dataset was divided into a 7:3 ratio of training (168 samples) and testing (73 samples). Thigh muscle boundaries in FS T2W images were manually delineated with 3D-Slicer. Radiomics features were extracted using Python 3.7, applying Z-score normalization, Pearson correlation analysis, and recursive feature elimination for reduction. A Naive Bayes classifier was trained, and diagnostic performance was evaluated using receiver operating characteristic (ROC) curves and comparing sensitivity and specificity with senior doctors. RESULTS: A total of 1198 radiomics parameters were extracted and reduced to 18 features for Naive Bayes modeling. In the testing set, the model achieved an area under the ROC curve of 0.97, sensitivity of 0.85, specificity of 0.98, and accuracy of 0.91. The Naive Bayes classifier demonstrated grading performance comparable to senior doctors. A significant correlation (r = 0.82, P <0.05) was observed between Stramare edema grading and T2-mapping values. CONCLUSION: The Naive Bayes model, utilizing radiomics features extracted from thigh FS T2W images, accurately assesses the severity of muscle edema in cases of PM/DM.

Rapidly progressive interstitial lung disease risk prediction in anti-MDA5 positive dermatomyositis: the CROSS model.

Background: The prognosis of anti-melanoma differentiation-associated gene 5 positive dermatomyositis (anti-MDA5+DM) is poor and heterogeneous. Rapidly progressive interstitial lung disease (RP-ILD) is these patients' leading cause of death. We sought to develop prediction models for RP-ILD risk in anti-MDA5+DM patients. Methods: Patients with anti-MDA5+DM were enrolled in two cohorts: 170 patients from the southern region of Jiangsu province (discovery cohort) and 85 patients from the northern region of Jiangsu province (validation cohort). Cox proportional hazards models were used to identify risk factors of RP-ILD. RP-ILD risk prediction models were developed and validated by testing every independent prognostic risk factor derived from the Cox model. Results: There are no significant differences in baseline clinical parameters and prognosis between discovery and validation cohorts. Among all 255 anti-MDA5+DM patients, with a median follow-up of 12 months, the incidence of RP-ILD was 36.86%. Using the discovery cohort, four variables were included in the final risk prediction model for RP-ILD: C-reactive protein (CRP) levels, anti-Ro52 antibody positivity, short disease duration, and male sex. A point scoring system was used to classify anti-MDA5+DM patients into moderate, high, and very high risk of RP-ILD. After one-year follow-up, the incidence of RP-ILD in the very high risk group was 71.3% and 85.71%, significantly higher than those in the high-risk group (35.19%, 41.69%) and moderate-risk group (9.54%, 6.67%) in both cohorts. Conclusions: The CROSS model is an easy-to-use prediction classification system for RP-ILD risk in anti-MDA5+DM patients. It has great application prospect in disease management.

Proteomic profiling identifies SPP1 associated with rapidly progressive interstitial lung disease in anti-MDA5-positive dermatomyositis.

BACKGROUND: Anti-melanoma differentiation-associated gene five antibody positive (MDA5+) dermatomyositis (DM) is significantly associated with rapidly progressive interstitial lung disease (RP-ILD). Early detection of RP-ILD remains a major challenge. This study aims to identify and validate prognostic factors for RP-ILD in MDA5+ DM patients. METHODS: Plasma samples from 20 MDA5+ DM patients and 10 healthy controls (HC) were collected for proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The proteins of interest were validated in independent samples (20 HC, 20 MDA5+ DM with RP-ILD, and 20 non-RP-ILD patients) with enzyme-linked immunosorbent assay (ELISA). RESULTS: A total of 413 differentially expressed proteins (DEPs) were detected between the MDA5+ DM patients and HC. When comparing DEPs between RP-ILD and non-RP-ILD patients, 79 proteins were changed in RP-ILD patients, implicating acute inflammatory response, coagulation, and complement cascades. Six candidate biomarkers were confirmed with ELISA. Secreted phosphoprotein 1 (SPP1), serum amyloid A1 (SAA1), and Kininogen 1 (KNG1) concentrations were significantly elevated in RP-ILD patients than those in non-RP-ILD patients and HC. In the different clinical subgroups, SPP1 was particularly elevated in the high-risk RP-ILD subgroup of MDA5+ DM. CONCLUSION: This study provides novel insights into the pathogenesis of RP-ILD development in MDA5+ DM and suggests the plasma protein SPP1 could serve as a potential blood biomarker for RP-ILD early warning.

Coexistence of Anti-Ro52 Antibodies in Anti-MDA5 Antibody-Positive Dermatomyositis Is Highly Associated With Rapidly Progressive Interstitial Lung Disease and Mortality Risk.

OBJECTIVE: Interstitial lung disease (ILD) is a common extramuscular complication contributing to significant morbidity and mortality in patients with dermatomyositis (DM) who are positive for antimelanoma differentiation-associated gene 5 antibody (anti-MDA5+). We conducted this study to investigate the association of anti-Ro52 antibodies with clinical characteristics and prognosis in patients with anti-MDA5+ DM. METHODS: We assessed a cohort of 246 patients with anti-MDA5+ DM. To calculate hazard ratios and 95% CIs for rapidly progressive ILD (RP-ILD) and death while controlling for potential confounders, variables selected by univariate Cox regression analysis were included in a multivariate Cox regression model with the stepwise forward-selection method. A 2-tailed analysis with P < 0.05 was considered to be statistically significant. RESULTS: A total of 246 patients with anti-MDA5+ DM were enrolled; 70 patients were male, and the patient group had an average age of 53.1 (12.4) years. Anti-Ro52 was present in 64.2% (158/246) patients. Patients with anti-MDA5+ DM who were positive for anti-Ro52 had a higher rate of RP-ILD (log-rank P < 0.001) and a higher mortality rate (log-rank P = 0.01). For patients with anti-MDA5+ DM who were positive for anti-Ro52, those with a short disease course and high inflammation were at increased risk of RP-ILD and death. The appearance of active rash was an independent protective factor of death. CONCLUSION: Anti-Ro52 antibodies were highly prevalent in patients with anti-MDA5+ DM, and their coexistence correlated with a higher rate of RP-ILD and mortality. Patients with a short disease course, with increased inflammation, and without rash were more likely to have a poor prognosis.

Identification of Three Different Phenotypes in Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis Patients: Implications for Prediction of Rapidly Progressive Interstitial Lung Disease.

OBJECTIVE: There is substantial heterogeneity among the phenotypes of patients with anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) dermatomyositis (DM), hindering disease assessment and management. This study aimed to identify distinct phenotype groups in patients with anti-MDA5+ DM and to determine the utility of these phenotypes in predicting patient outcomes. METHODS: A total of 265 patients with anti-MDA5+ DM were retrospectively enrolled in the study. An unsupervised hierarchical cluster analysis was performed to characterize the different phenotypes. RESULTS: Patients were stratified into 3 clusters characterized by markedly different features and outcomes. Cluster 1 (n = 108 patients) was characterized by mild risk of rapidly progressive interstitial lung disease (RPILD), with the cumulative incidence of non-RPILD being 85.2%. Cluster 2 (n = 72 patients) was characterized by moderate risk of RPILD, with the cumulative incidence of non-RPILPD being 73.6%. Patients in cluster 3 (n = 85 patients), which was characterized by a high risk of RPILD and a cumulative non-RPILD incidence of 32.9%, were more likely than patients in the other 2 subgroups to have anti-Ro 52 antibodies in conjunction with high titers of anti-MDA5 antibodies. All-cause mortality rates of 60%, 9.7%, and 3.7% were determined for clusters 3, 2, and 1, respectively (P < 0.0001). Decision tree analysis led to the development of a simple algorithm for anti-MDA5+ DM patient classification that included the following 8 variables: age >50 years, disease course of <3 months, myasthenia (proximal muscle weakness), arthritis, C-reactive protein level, creatine kinase level, anti-Ro 52 antibody titer, and anti-MDA5 antibody titer. This algorithm placed patients in the appropriate cluster with 78.5% accuracy in the development cohort and 70.0% accuracy in the external validation cohort. CONCLUSION: Cluster analysis identified 3 distinct clinical patterns and outcomes in our large cohort of anti-MDA5+ DM patients. Classification of DM patients into phenotype subgroups with prognostic values may help physicians improve the efficacy of clinical decision-making.

Time-dependent changes in RPILD and mortality risk in anti-MDA5+ DM patients: a cohort study of 272 cases in China.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 positive (anti-MDA5+) DM has a close relationship with rapidly progressive interstitial lung disease (RPILD) and is associated with high mortality. However, data regarding the time-dependent risk of RPILD and deaths during disease progression are limited. We conducted this study to investigate whether the risk of RPILD and death were time-dependent or not in anti-MDA5+ DM. METHODS: We assessed a cohort of 272 patients with anti-MDA5+ DM. The clinical characteristics of patients with anti-MDA5+ were collected, and COX regression was used to analyse independent risk factors for RPILD and death. We also described changes in risk of RPILD and death over time and their potential clinical implications. RESULTS: There were 272 anti-MDA5+ DM patients enrolled in this study. According to the multivariate cox regression analysis, short disease course, high CRP level, anti-Ro52 positive and anti-MDA5 titre (++∼+++) were independent risk factors of RPILD. High creatine kinase level, high CRP level and RPILD were independent risk factors for death, and >90% RPILD and 84% mortality occurred in the first 6 months after disease onset. Notably, the first 3 months is a particularly high-risk period, with 50% of RPILD and 46% of deaths occurring. Hazards regarding RPILD and mortality diminished over time during a median follow-up of 12 months. CONCLUSION: These results suggest significant, time-dependent changes in RPILD and mortality risk in anti-MDA5+ DM patients, providing a cut-off time window to estimate disease progression and poor prognosis.

Brain-Reactive Antibodies are Potential Biomarkers for Evaluating Therapeutic Efficacy in NPSLE Patients.

Purpose: Neuropsychiatric systemic lupus erythematosus (NPSLE) is the main cause of disability and death in systemic lupus erythematosus (SLE). It can cause cognitive impairment and organic brain syndrome. Brain-reactive antibodies, such as anti-DNA/anti-N-methyl-D-aspartate receptor (NMDAR) antibodies (DNRAbs), anti-microtubule-associated protein 2 (anti-MAP2) antibodies, and anti-glial fibrillary acidic protein (anti-GFAP) antibodies are thought to participate in the progression of NPSLE and thus considered potential diagnostic biomarkers, but whether they can be used for evaluating therapeutic efficacy in NPSLE is unknown. Patients and methods: Overall, 17 NPSLE patients and 10 non-SLE controls were included in this study. All the patients were treated with glucocorticoid (GC) pulse therapy. Serum and cerebrospinal fluid (CSF) concentrations of DNRAbs and anti-MAP2 and anti-GFAP antibodies were measured using enzyme-linked immunosorbent assay. The differences between the CSF concentrations of these antibodies in NPSLE patients before and after GC pulse therapy were analyzed. Results: CSF concentrations of DNRAbs and anti-MAP2 and anti-GFAP antibodies were significantly higher in NPSLE patients compared to the non-SLE controls. Among the patients, CSF concentration of DNRAbs was significantly higher in the patients with acute confusional state (ACS) than in those with non-ACS diffuse NPSLE or focal NPSLE. Additionally, CSF concentration of DNRAbs was significantly correlated with QIgG (r=0.4884, P=0.0467) and IgG index (r=0.5319, P=0.0280) in NPSLE patients. Moreover, CSF concentrations of DNRAbs, anti-MAP2, and anti-GFAP antibodies and QIgG were significantly decreased after GC pulse therapy in NPSLE patients. Conclusion: These results indicate that CSF DNRAbs and anti-MAP2 and anti-GFAP antibodies are potential biomarkers for evaluating therapeutic efficacy in NPSLE.

Blockade of adiponectin receptor 1 signaling inhibits synovial inflammation and alleviates joint damage in collagen-induced arthritis.

OBJECTIVES: Adiponectin (AD) highly expressed in synovial tissue correlates closely with progressive bone erosion in rheumatoid arthritis (RA). However, it remains unknown whether AD receptor mediates the pathogenesis of RA. This study aimed to investigate the effects of adiponectin receptor 1 (AdipoR1) signaling on synovial inflammation and joint damage in collagen-induced arthritis. METHODS: AD and AdipoR1 expression in synovial tissue of RA and osteoarthritis (OA) patients were tested by PCR and western blotting. The frequency of AdipoR1 on RA synovial fibroblasts (RASFs) was examined by flow cytometry after stimulation with AD, IL-6, or TNF-α. AdipoR1 was knocked down in human RASF cell line (MH7A) and CIA mice joints using lentiviral particles carrying the AdipoR1 short hairpin RNA (shAdipoR1). Both the proliferation and apoptosis of MH7A and the secretion of inflammatory factors from MH7A were examined in vitro. The therapeutic effect of local AdipoR1 inhibition on CIA mice was assessed in vivo. RESULTS: Both the expression of AD and AdipoR1 were significantly higher in RA synovial tissue. AdipoR1 on RASFs was upregulated by AD. Silencing AdipoR1 remarkably reduced lipopolysaccharides-induced proliferation and promoted the apoptosis of MH7A. Moreover, AdipoR1 knockdown inhibited the release of inflammatory factors in vitro. In CIA mice, local AdipoR1 inhibition effectively decreased joint inflammation and alleviated bone destruction via suppressing RANKL and RANKL/OPG ratio in vivo. CONCLUSIONS: AdipoR1 signaling participates in the process of synovial inflammation and joint damage in CIA. Local blockade of AdipoR1 might be a new target for the clinical treatment of RA. Key points • Local AdipoR1 inhibition decreased joint inflammation and alleviated bone destruction in CIA.

Serum Krebs von den Lungen-6 concentrations reflect severity of anti-melanoma differentiation-associated protein 5 antibody positive dermatomyositis associated interstitial lung disease.

OBJECTIVES: Rapidly progressive interstitial lung disease (RP-ILD) is a major complication of anti-melanoma differentiation-associated protein 5 antibody positive dermatomyositis (anti-MDA5+DM) with a high mortality rate. The aim of the study is to determine whether serum Krebs von den Lungen-6 (KL-6) could be a prognostic biomarker to predict RP-ILD and prognosis in anti-MDA5+DM patients. METHODS: A total of 21 anti-MDA5+DM patients with RP-ILD and 20 anti-MDA5+DM patients without RP-ILD were retrospectively included in this study. Serum KL-6 concentration (pg/mL) was measured using the latex agglutination test. RESULTS: Serum KL-6 level was higher in RP-ILD patients than those in non-RR-ILD patients (1195.61±872.93 vs. 452.6±465.51 pg/mL, p=0.002). The best cut-off value of KL-6 serum level was 500.9 pg/mL using ROC curve (AUC area = 0.7976, p=0.0011). KL-6 >500.9 pg/mL was an independent risk factor for RP-ILD using multivariate analysis (OR=56.38, 95% CI 5.51-577.504, p=0.001). Serum KL-6 concentrations were significantly higher in dead patients than those in the survivor group (1209.34±840.55 vs. 592.41±667.76, p=0.0033), and higher KL-6 concentration was also an independent risk factor for all-cause death after adjusting confounders (OR = 21.94, 95% CI 3.3-145.73, p=0.001). Anti-MDA5+DM patients with higher KL-6 level displayed a significantly decreased one-year survival rate, as compared with lower KL-6 level (36.36% vs. 89.47%, p=0.0008). CONCLUSIONS: The serum KL-6 levels reflect severity of lung injury and serve as a clinically useful biomarker in detection and monitoring RP-ILD progression in anti-MDA5+DM patients.

Prevalence and risk factors of active tuberculosis in patients with rheumatic diseases: a multi-center, cross-sectional study in China.

Evidence of active tuberculosis (ATB) in patients with rheumatic diseases are research priorities but limited data from China have been reported. Research targeting patients not taking anti-TNF biologics are especially insufficient. We aimed to investigate the prevalence and risk factors of ATB in this at-risk population. We conducted a tertiary hospital-based, multi-center, cross-sectional study by using stratified multi-stage cluster sampling strategy to screen ATB in patients with rheumatic diseases. We estimated the prevalence of ATB in patients with rheumatic diseases and identified risk factors among those who were not taking anti-TNF biologic. A total of 13,550 eligible patients were enrolled, and the result showed the standardized prevalence of ATB according to the composition ratio of various types of rheumatic disease was 882/100000 (95% confidence interval (CI): 706-1057). Multivariable logistic regression analysis in patients not taking anti-TNF biologics showed that the independent risk factors of ATB were having systemic lupus erythematosus (SLE) (OR=2.722, 95% CI: 1.437-5.159, p=0.002), having Behcet's disease (BD) (OR= 5.261, 95% CI: 2.071-13.365, p<0.001), taking azathioprine(AZA) within the past two years (OR=2.095, 95% CI: 0.986-4.450, p=0.054), exposing to glucocorticoids ≥30mg/d for more than four weeks within the past two years (OR=2.031, 95% CI: 1.247-3.309, p=0.004) and having evidences of previous TB (OR= 6.185, 95% CI: 3.487-10.969, p<0.001). The prevalence of ATB was higher in patients with rheumatic diseases compared to the general population. Patients with SLE or BD, prolonged exposure to moderate to high dose of glucocorticoids and previous TB were independent risk factors for ATB.

Clinical analysis of macrophage activation syndrome in adult rheumatic disease: A multicenter retrospective study.

AIM: To evaluate the clinical and laboratory characteristics, prognostic factors, and outcome of adult rheumatic disease-associated macrophage activation syndrome (MAS). METHOD: A multicenter retrospective study was performed across 4 tertiary hospitals in China between January 1, 2017 to December 31, 2019. RESULTS: There were 61 rheumatic disease patients with MAS enrolled into this retrospective clinical study. Fever and hyperferritinemia are the most frequent clinical feature and laboratory abnormality in MAS patients. Serum ferritin > 6000 ng/mL (odds ratio [OR] = 9.46, 95% CI = 2.53-47.13, P = .005) and hemophagocytosis in bone marrow smear (OR = 11.12, 95%, CI = 3.29-50.65, P = .001) were the 2 most prominent predictive factors indicating MAS occurrence. The 90-day all-cause mortality rate of all rheumatic disease patients with MAS was 22.9% (hazards ratio [HR] = 2.15, 95% CI = 0.81-6.78, P = .05). Platelets < 100 × 109 /L (HR = 3.23, 95% CI = 2.51-4.81, P = .01) and ferritin > 6000ng/mL (HR = 6.12, 95% CI = 2.93-16.27, P = .005) were independent predictors of poor outcome in rheumatic disease-associated MAS. CONCLUSION: Macrophage activation syndrome could be a fatal complication in rheumatic disease. Patients presenting with unexplained fever, serum ferritin > 6000 ng/mL, hepatosplenomegaly and cytopenia at baseline should raise the suspicion of MAS. The presence of serum ferritin > 6000 ng/mL, hepatosplenomegaly and low number of platelets was associated with poor outcome.

High serum level of haptoglobin is associated with the response of 12 weeks methotrexate therapy in recent-onset rheumatoid arthritis patients.

BACKGROUND: We previously found, using microarray, haptoglobin (HP) expression signal was 5.1-fold increased in peripheral blood mononuclear cells (PBMCs) from methotrexate (MTX)-resistant rheumatoid arthritis (RA) patients. OBJECTIVES: To investigate whether serum levels of HP are associated with the response of 12 weeks MTX therapy in recent-onset RA patients. METHODS: Sixty-nine active RA patients with recent onset (< 24 months) were treated with MTX. Clinical variables, levels of HP messenger RNA (mRNA) in PBMCs and HP serum levels were tested at week 0 and week 12. RESULTS: After 12 weeks of MTX treatment, 34.7% of RA patients were categorized as responders according to European League Against Rheumatism (EULAR) response criteria (Week 12 Disease Activity Score of 28 joints [DAS-28] ≤ 3.2 and decrease > 1.2) and all others (65.2%) were defined as non-responders. The baseline HP mRNA in PBMCs from non-responders is significantly higher than those in responders (P < 0.05). Similar to mRNA expression, non-responders showed significantly elevated serum HP levels at baseline (369.9 ± 159.8 mg/dL) compared to those in responders (255.3 ± 143.9 mg/dL) (P = 0.01). Serum HP levels were decreased significantly from 255.3 ± 143.9 mg/dL at baseline to 186.4 ± 108.5 mg/dL at week 12 (P = 0.04) in responders, but remained at high levels in non-responders. CONCLUSIONS: High serum levels of HP at baseline are associated with inadequate response of 12 weeks MTX treatment in recent-onset RA patients. Further replication studies in larger samples are needed to validate HP as a potential predictive biomarker for response to MTX therapy in RA.

Modulatory effect of 1,25-dihydroxyvitamin D 3 on IL1 ß -induced RANKL, OPG, TNF α , and IL-6 expression in human rheumatoid synoviocyte MH7A.

Receptor activator of nuclear factor κ B ligand (RANKL) plays a crucial role in the bone erosion of rheumatoid arthritis (RA) by prompting osteoclastogenesis. Considering that 1,25(OH)2D3 has been suggested as a potent inducer of RANKL expression, it should clarify whether vitamin D supplement could result in RANKL overexpression and thereby facilitate excessive osteoclastogenesis and bone resorption in RA. Here, we investigated modulatory effect of 1,25(OH)2D3 on the expression of RANKL and its decoy receptor osteoprotegerin (OPG) in an inflammatory condition of human rheumatoid synoviocyte MH7A. MH7A cells were stimulated with IL1 ß and then treated with different concentrations of 1,25(OH)2D3 for 48 h. A significantly elevated OPG/RANKL ratio and markedly decreased levels of IL-6 and TNF ß mRNA expression in cells and IL-6 protein in supernatants were observed in IL1 ß -induced MH7A in the presence of 1,25(OH)2D3 compared with those in the absence of it. Osteoclast formation was obviously decreased when RAW264.7 cells were treated with both 1,25(OH)2D3 and IL1 ß . In summary, although it has a biological function to induce RANKL expression, 1,25(OH)2D3 could upregulate OPG/RANKL ratio and mediate anti-inflammatory action in an inflammatory milieu of synoviocyte, contributing to the inhibition of inflammation-induced osteoclastogenesis in RA.

Correlation of increased blood levels of GITR and GITRL with disease severity in patients with primary Sjögren's syndrome.

Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is a type I transmembrane protein belonging to the TNFR superfamily. After activated by its ligand GITRL, GITR could influence the activity of effector and regulatory T cells, participating in the development of several autoimmune and inflammatory diseases included rheumatoid arthritis and autoimmune thyroid disease. We previously reported that serum GITRL levels are increased in systemic lupus erythematosus (SLE) patients compared with healthy controls (HC). Here, we tested serum soluble GITR (sGITR) and GITRL levels in 41 primary Sjögren's syndrome (pSS) patients and 29 HC by ELISA and correlated sGITR and GITRL levels with clinical and laboratory variables. GITR and GITRL expression in labial salivary glands was detected by immunohistochemistry. pSS patients had significantly increased serum levels of sGITR and GITRL compared with controls (GITR: 5.66 ± 3.56 ng/mL versus 0.50 ± 0.31 ng/mL; P < 0.0001; GITRL: 6.17 ± 7.10 ng/mL versus 0.36 ± 0.28 ng/mL; P < 0.0001). Serum sGITR and GITRL levels were positively correlated with IgG (GITRL: r = 0.6084, P < 0.0001; sGITR: r = 0.6820, P < 0.0001) and ESR (GITRL: r = 0.8315, P < 0.0001; sGITR: r = 0.7448, P < 0.0001). Moreover, GITR and GITRL are readily detected in the lymphocytic foci and periductal areas of the LSGs. In contrast, the LSGs of HC subjects did not express GITR or GITRL. Our findings indicate the possible involvement of GITR-GITRL pathway in the pathogenesis of pSS. Further studies may facilitate the development of targeting this molecule pathway for the treatment of pSS.