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Abstract Fibroblast-like synoviocytes (FLSs) play a central role in RA pathogenesis and are the main cellular component in the inflamed synovium of patients with rheumatoid arthritis (RA). FLSs are emerging as promising new therapeutic targets in RA. However, fibroblasts perform many essential functions that are required for sustaining tissue homeostasis. Direct targeting of general fibroblast markers on FLSs is challenging because fibroblasts in other tissues might be altered and side effects such as reduced wound healing or fibrosis can occur. To date, no FLS-specific targeted therapies have been applied in the clinical management of RA. With the help of high-throughput technologies such as scRNA-seq in recent years, several specific pathogenic FLS subsets in RA have been identified. Understanding the characteristics of these pathogenic FLS clusters and the mechanisms that drive their differentiation can provide new insights into the development of novel FLS-targeting strategies for RA. Here, we discuss the pathogenic FLS subsets in RA that have been elucidated in recent years and potential strategies for targeting pathogenic FLSs.

Abstract Background To investigate the clinical and immune characteristics of patients with primary Sjögren’s syndrome (pSS) who were negative for anti–Sjögren’s-syndrome-related antigen A antibodies (anti-SSA) and anti–Sjögren’s-syndrome-related antigen B antibodies (anti-SSB) in Chinese population. Methods A retrospective study were performed and 232 patients with pSS were analyzed. Patients positive for anti-SSA or/and anti-SSB were termed as seropositive pSS, and these negative for both anti-SSA and anti-SSB (non-antinuclear antibodies) as seronegative pSS. Clinical manifestations and laboratory findings were compared between the two groups. Results Among the 232 patients with pSS, 192 (82.8%) were seropositive pSS and 40 (17.2%) were seronegative pSS. Compared to seropositive pSS, seronegative pSS were older and with higher percentage of low disease activity (ESSDAI

Summary: Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), exhibits significant heterogeneity. Recent evidence suggests that non-immune factors contribute to end-organ damage, challenging the traditional view of LN solely arising from immune dysregulation. To investigate this, we employed autoimmune-prone Gnaq+/− mice receiving intraperitoneal pristane injections. Bone marrow transfer (BMT) distinguished the roles of immune versus non-immune cells. We observed that: (1) BMT from wild-type (WT) mice to Gnaq+/− recipients resulted in severe proteinuria and diffuse proliferative nephritis after pristane exposure; (2) GNAQ knockdown increased the expression of IFI16/Ifi202b and activated the NF-κB pathway in endothelial cells; and (3) increased IFI16 expression in human kidney biopsies correlated with proliferative LN. Taken together, these findings suggest that GNAQ acts as an inflammatory regulator in kidney endothelial cells via the IFI16/NF-κB pathway, potentially linking it to the development of LN in humans.

Abstract Microdamage and its related inflammation contribute to the development of radiographic axial spondyloarthritis (r-axSpA). Inflammation and cell death in damaged tissues are associated with cell-free DNA (cfDNA) release. Here we investigated whether circulating cfDNA could be a potential biomarker for evaluating disease activity and treatment response in r-axSpA. Circulating cfDNA was detected in the discovery and validation cohort with 79 and 60 newly diagnosed r-axSpA patients respectively and 42 healthy controls using the Quant-iT PicoGreen dsDNA reagent and kit. As a result, cfDNA levels were significantly higher in r-axSpA patients compared with healthy controls in the discovery and validation cohort. Moreover, cfDNA levels were positively correlated with CRP, ASDAS-CRP and neutrophil counts. Additionally, non-steroid anti-inflammatory drugs (NSAIDs) combined with disease-modifying anti-rheumatic drugs or tumor necrosis factor inhibitors but not NSAIDs alone could reduce cfDNA levels. Moreover, a decrease of cfDNA levels after treatment was associated with an effective therapeutic response. Intriguingly, patients with higher levels of cfDNA at diagnosis responded better to combination therapy rather than NSAIDs. However, patients with lower levels of cfDNA displayed similar responses to combination or mono-NSAID treatment. In conclusion, circulating cfDNA levels showed a significant correlation with disease activity as well as treatment efficacy in patients with r-axSpA. Moreover, cfDNA at diagnosis might predict the response to different therapy. Consequently, cfDNA may serve as a useful biomarker of inflammation in r-axSpA.

Abstract Introduction The autoimmune exocrinopathy, Sjögren’s syndrome (SjS), is associated with secretory defects in salivary glands. The cystic fibrosis transmembrane conductance regulator (CFTR) of the chloride channel is a master regulator of fluid secretion, but its role in SjS has not been investigated. Our research found a link between CFTR and SjS at the genetic and protein levels, as well as through clinical data. Methods We used single-cell RNA sequencing to identify the presence of CFTR in glandular epithelial cells of the human salivary gland (scRNA-seq) and confirmed the difference using immunofluorescence tests in labial glands and clinical data statistics from 44 non-SjS and 36 SjS patients. Results The changes of CFTR expression in salivary glands of SjS patients was assessed at both mRNA and protein levels. According to the scRNA-seq analyses, CFTR was the hallmark gene of ionocytes. We firstly identified that SjS had a lower level of CFTR expression in the labial glands than non-SjS at mRNA level. Using immunofluorescence assays, we also found that CFTR expression was decreased in SjS patients compared to non-SjS. The results of the clinical statistics revealed that CFTR expression was adversely correlated with feelings of dry mouth, lymphocyte infiltration in the labial glands, and certain autoantibodies in serum (antinuclear antibody, anti-Ro/SSA, and anti-La/SSB antibodies). Conclusion Those findings above proved an obviously downregulated expression of CFTR in salivary glands of SjS patients and its clinical significance. Dysfunction in CFTR or ionocytes may contribute to SjS pathogenesis and represents a promising therapeutic target.

Decidualization, denoting the transformation of endometrial stromal cells into specialized decidual cells, is a prerequisite for normal embryo implantation and a successful pregnancy in human. Here, we demonstrated that knockout of Gαq lead to an aberrantly enhanced inflammatory state during decidualization. Furthermore, we showed that deficiency of Gαq resulted in over-activation of nuclear factor (NF)-κB signaling, due to the decreased expression of NFκBIA, which encode the IκB protein and is the negative regulator for NF-κB. Mechanistically, Gαq deficiency decreased the Protein kinase D (PKD, also called PKCμ) phosphorylation levels, leading to attenuated HDAC5 phosphorylation and thus its nuclear export. Aberrantly high level of nuclear HDAC5 retarded histone acetylation to inhibit the induced NFκBIA transcription during decidualization. Consistently, pharmacological activation of the PKD/PKCμ or inhibition of the HDAC5 restored the inflammatory state and proper decidual response. Finally, we disclosed that over-active inflammatory state in Gαq-deficient decidua deferred the blastocyst hatching and adhesion in vitro, and the decidual expression of Gαq was significantly lower in women with recurrent pregnancy loss compared with normal pregnancy. In brief, we showed here that Gαq as a key regulator of the inflammatory cytokine’s expression and decidual homeostasis in response to differentiation cues, which is required for successful implantation and early pregnancy.

Abstract Objectives To investigate longitudinal relationship between serum uric acid (SUA) and disease activity among Chinese males with axial spondyloarthritis (axSpA). Methods Two-year data from the NASA study cohort of male patients with axial spondyloarthritis were analyzed. Patients global assessment of disease activity (PtGA), BASDAI, ASDAS-CRP, BASFI, and SF-36 were used as the outcomes. The autoregressive Generalized Estimation Equation (GEE) model was used to investigate the longitudinal relationship between SUA and the above outcomes. Age and gender and symptom duration were tested as effect modifiers or confounders. Results In total, 102 male axSpA patients were included, 33.3% of who were hyperuricemia at baseline. Over time,serum uric acid levels associated with the global assessment of patient global assessment of disease activity (PtGA)[P=0.041, β=-2.059,95%CI(-4.032, -0.086)], SF-36: Vitality (VT) [P=0.01, β=1.751, 95%CI (0.415,3.087)], SF-36: Social Functioning (SF)[P=0.002, β= 2.968,95%CI (1.067,4.869)]). And these relationgships were independent of age, symptom duration, baseline uric acid levels, and medication use. Conclusions In summary, SUA levels is longitudinally related to PtGA and mental health assessment. Age, gender and symptom duration do not have an impact on the relationships.

Objectives The pathological diagnostic criteria for primary Sjögren’s syndrome (SjS) have certain limitations. We first explored the key pathogenic pathways of SjS through a bioinformatics approach, and then evaluated the diagnostic value of the important biomarker in SjS.Methods Transcriptome data from non-SjS controls and patients with SjS were analysed using integrated bioinformatics methods. In a case–control study, phosphorylated signal transducer and activator of transcription proteins 1 (p-STAT1), a key biomarker for the activation of interferon (IFN) pathway, was selected to evaluate its diagnostic value by immunohistochemical analyses in salivary gland (SG) tissues.Results The IFN-related pathways were aberrantly activated in patients with SjS. Positive staining of p-STAT1 was detected in the SjS group, but not in non-SjS control group. There was a significant difference in the integrated optical density values of p-STAT1 expressions between the controls and the SjS groups, as well as between the controls and the SjS lymphatic foci-negative groups (p

Abstract Fibroblast‐like synoviocytes (FLS) are the main cell component in the inflamed joints of patients with rheumatoid arthritis (RA). FLS intimately interact with infiltrating T cells. Fibroblasts have potent inhibitory effects on T cells, leading to the resolution of inflammation and immune tolerance. However, this “regulatory” phenotype is defect in RA, and FLS in RA instead act as “proinflammatory” phenotype mediating inflammation perpetuation. Signals that orchestrate fibroblast heterogeneity remain unclear. Here, it is demonstrated that different cytokines can induce distinct phenotypes of FLS. Interferon‐gamma (IFN‐γ) is pivotal in inducing the regulatory phenotype of FLS (which is termed FLSreg) characterized by high expressions of several inhibitory molecules. Rapamycin enhances the effect of IFN‐γ on FLS. Based on the characteristics of FLSreg, a novel biomimetic therapeutic strategy for RA is designed by coating cell membrane derived from FLSreg induced by IFN‐γ and rapamycin on nanoparticles, which is called FIRN. FIRN show good efficacy, stability, and inflammatory joint targeting ability in an RA mouse model. The findings clarify how fibroblast phenotypes are modulated in the inflammatory microenvironment and provide insights into novel therapeutic designs for autoimmune diseases based on regulatory fibroblasts.

Environmental factors are believed to influence the evolution of primary Sjögren’s syndrome (pSS). The aims of this study were to investigate the association of pSS with a high-fat diet (HFD) and to relate HFD-induced gut dysbiosis to pSS exacerbation. Male Wild Type (WT) and IL-14α transgenic mice (IL-14α TG) were fed a standard diet (SD) and HFD for 11 months. We found an increase in the autoantibody level, more severe dry eye, severe dry mouth symptoms, and an earlier presence of systemic features in the IL-14α TG mice treated with HFD. These data suggest that HFD can promote the process of pSS in the IL-14α TG mice. In addition, an HFD leads to a decrease in the richness of gut microbiota of IL-14α TG mice treated with HFD. The abundance of Deferribacterota was significantly enriched in the IL-14α TG mice treated with HFD compared with other groups. Through the mental test between gut microbiota and clinical parameters, we found that HFD-induced dysbiosis gut microbiota were associated with pSS clinical parameters. In conclusion, HFD results in the aggravation of pSS progression, likely due to the increase of potentially pathogenic microorganisms.

BackgroundRecent studies have proven the existence of distinct monocyte subsets, which play a significant role in the development of some rheumatic diseases such as systemic lupus erythematosus (SLE). This study was performed to define the changes of monocyte subsets in patients with Sjögren’s Syndrome (SjS).MethodsSingle cell RNA-sequencing (scRNA-seq) data of monocytes from SjS patients and controls were analyzed. The transcriptomic changes in monocyte subsets between SjS and controls were identified and potential key functional pathways involved in SjS development were also explored.ResultsA total of 11 monocyte subsets were identified in the scRNA-seq analyses of monocytes. A new monocyte subset characterized by higher expression of VNN2 (GPI-80) and S100A12 (Monocyte cluster 3) was identified, and it was increased in SjS patients. Compared with controls, almost all monocyte subsets from SjS patients had increased expression of TNFSF10 (TRAIL). Moreover, interferon (IFN)-related and neutrophil activation-associated pathways were main up-regulated pathways in the monocytes of SjS patients.ConclusionThis study uncovered the abnormal changes in monocyte subsets and their transcriptomic changes in SjS patients, and identified TNFSF10 high/+ monocytes as a potential key player in SjS pathogenesis and a promising target for SjS treatment.

BackgroundDry eye is often the first presenting manifestation of primary Sjögren’s syndrome (pSS). Because of the high prevalence of dry eye disease in normal population, ophthalmologists urgently need a non-invasive and reliable screening test to diagnose dry eye associated SS patients, other than ocular symptoms and signs. Currently, there is no single test available. The correlation of serum IL-14α with pSS has been found in pSS mouse model.PurposeTo evaluate whether IL-14α can serve as a biomarker to stratify dry eye in primary Sjögren’s syndrome and its correlation to BAFF in a cohort of patients with non-SS dry eye (NSDE), pSS with dry eye disease, rheumatoid arthritis (RA), and healthy controls (HC).MethodsRetrospective study based on serum levels of IL-14α (defined by Western Blot) and BAFF (measured by ELISA) were evaluated among pSS with dry eye disease, NSDE, RA, and HC groups. Serum levels of SS related autoantibodies (Ro, La, SP1, PSP, and CA6) were also measured by ELISA.ResultsOne hundred and eighty patients were included for the current study, patients were separated into four groups as defined by pSS (n=65), NSDE (n=20), RA (n=50) and HC (n=45). The level of serum IL-14α in pSS was significantly higher compared to NSDE, RA, and HC (p=0.0011, p=0.0052 and p

Tumor necrosis factor-α (TNF-α) inhibitors are the main types of biological conventional synthetic disease-modifying antirheumatic drugs and have efficacy in treating ankylosing spondylitis (AS) which is not sensitive for nonsteroidal anti-inflammatory drug. However, the impact of TNF-α inhibitors on immune cells in patients with AS is still clearly undefined, and the impact of immune cells on treatment response is also largely elusive. This study is aimed at evaluating the longitudinal changes of circulating immune cells after anti-TNF-α therapy and their associations with treatment response in AS patients. Thirty-five AS patients receiving the treatment of anti-TNF-α therapy were included into this prospective observational study. The frequencies of immune cells including Th1, Th2, Th17, regulatory T cell (Treg), T follicular helper cell (Tfh), and regulatory B cell (Breg) in the peripheral blood were measured by flow cytometry at baseline and 4 time points after therapy. The difference in the circulating immune cells between responders and nonresponders was compared. This study suggested that anti-TNF-α therapy could significantly reduce circulating proinflammatory immune cells such as Th17 and Tfh, but significantly increased the percentages of circulating Treg and Breg. Moreover, circulating Breg may be a promising predictor of response to anti-TNF-α therapy in AS patients.

Background: Increased platelet count has been reported in ankylosing spondylitis (AS) patients, but its clinical significance is still largely elusive. The objective of this study was to evaluate the clinical role of platelet count in AS patients, especially its impact on treatment outcomes.Methods: A case-control study containing 35 AS patients receiving anti-tumor necrosis factor-α (anti-TNF-α) therapy and 45 healthy controls was performed, and AS patients were followed at least 6 months after anti-TNF-α therapy. A systematic review and meta-analysis of studies containing relevant data on outcomes of interest was also performed.Results: AS patients had significantly higher platelet count than controls (p = 0.0001), and the significantly increased platelet count in AS patients was confirmed in a meta-analysis of 14 studies involving 1,223 AS patients and 913 controls (mean difference = 39.61, 95% CI 27.89–51.34, p < 0.001). Besides, platelet count was significantly correlated with ESR (p < 0.001) and was moderately correlated with ASDAS-CRP score (p = 0.002). Moreover, anti-TNF-α therapy could reduce platelet count in AS patients at the first month and the effect was maintained through the treatment duration. In the prospective follow-up study of those 35 AS patients, those responders to anti-TNF-α therapy had significantly lower platelet count than nonresponders (p = 0.015). Logistic regression analysis suggested that lower platelet count was associated with higher possibility of achieving good response to anti-TNF-α therapy in AS patients (odds ratio = 2.26; 95% CI = 1.06–4.82; p = 0.035).Conclusion: This study suggested that platelet count was associated with inflammation severity and treatment outcomes in AS patients, and elevated platelet count was a promising biomarker of poorer response to anti-TNF-α therapy. The findings above need to be validated in more future studies.

BackgroundExposure to Epstein-Barr virus (EBV) infection has been hypothesized to be an important risk factor for multiple rheumatic diseases, but the serological evidence so far for its role in Sjögren’s syndrome (SjS) is not clearly established yet. This study aimed to assess the seroepidemiological associations of antibodies to EBV with SjS.MethodsA seroepidemiological study containing 119 patients with SjS and 65 healthy controls was first performed, in which the associations of SjS with four commonly studied EBV antibodies including IgM-anti-viral capsid antigen (anti-VCA) antibody, IgG-anti-VCA antibody, IgG-anti-early antigen (anti-EA) antibody, and IgG-anti-EBV nuclear antigen 1 (anti-EBNA1) antibody were evaluated. A systematic review and meta-analysis of eligible seroepidemiological studies was also carried out, and data syntheses were performed using random-effect meta-analysis.ResultsIn the case-control study, the patients with SjS had both a significantly higher prevalence of IgG-anti-EA antibody positivity (31.9% vs. 3.1%, P < 0.001) and high titers of IgG-anti-EA antibody (P < 0.001) than healthy controls. The titer of IgG-anti-VCA antibody was significantly increased in the patients with SjS compared with healthy controls (P < 0.001). IgG-anti-EA antibody seropositive patients with SjS had lower levels of both C3 (P = 0.002) and C4 (P = 0.02), and the titer of IgG-anti-EA antibody was inversely related to the levels of both C3 (r = -0.31, P < 0.001) and C4 (r = -0.20, P = 0.03). A total of 14 eligible studies on the serological associations between EBV infection and SjS were finally included into the meta-analysis, which suggested obvious associations of SjS with IgM-anti-VCA antibody [Odds ratio (OR) = 5.77, 95%CI 1.73–19.25, P = 0.004] and IgG-anti-EA antibody (OR = 9.97, 95%CI 4.58-21.67, P < 0.00001).ConclusionsThe findings from this study provide strong serological evidence for the association between EBV infection and SjS. SjS has obvious associations with IgM-anti-VCA antibody and IgG-anti-EA antibody. IgG-anti-EA antibody is linked to low levels of C3 and C4 in the patients with SjS, the significance of which needs to be addressed in further studies.

The role of host microbes in the pathogenesis of several diseases has been established, and altered microbiomes have been related to diseases. However, the variability of the urinary microbiome in individuals with gout has not been evaluated to date. Therefore, we conducted the present prospective study to characterize the urinary microbiome and its potential relation to gout. Urine samples from 30 patients with gout and 30 healthy controls were analyzed by Illumina MiSeq sequencing of the 16S rRNA hypervariable regions, and the microbiomes were compared according to alpha-diversity indices, complexity (beta diversity) with principal component analysis, and composition with linear discriminant analysis effect size. The most significantly different taxa at the phylum and genus levels were identified, and their potential as biomarkers for discriminating gout patients was assessed based on receiver operating characteristic (ROC) curve analysis. Compared with the healthy controls, there was a dramatic decrease in microbial richness and diversity in the urine of gout patients. The phylum Firmicutes and its derivatives (Lactobacillus_iners, Family_XI, and Finegoldia), the phylum Actinobacteria and its derivatives (unidentified_Actinobacteria, Corynebacteriales, Corynebacteriale, Corynebacterium_1, and Corynebacterium_tuberculostearicum), and the genera Prevotella and Corynebacterium_1 were significantly enriched in the urine of gout patients. ROC analysis indicated that the top five altered microbial genera could be reliable markers for distinguishing gout patients from healthy individuals. These findings demonstrate that there are specific alterations in the microbial diversity of gout patients. Thus, further studies on the causal relationship between gout and the urinary microbiome will offer new prospects for diagnosing, preventing, and treating gout.

Objective: Clinical characteristics of immune thrombocytopenia (ITP) associated with primary Sjögren's syndrome (pSS) have not been clearly defined. This study aimed to evaluate the prevalence and clinical characteristics of secondary ITP in patients with pSS.Methods: 291 pSS patients in our hospital were retrospectively analyzed. Clinical manifestations and laboratory findings were compared between pSS patients with and without ITP.Results: The prevalence of secondary ITP in pSS patients was 12.03%. Compared to pSS patients without ITP, pSS patients with ITP were younger and had higher disease activity. The prevalence of interstitial lung diseases (ILD) was significantly lower in pSS patients with ITP (30.43 vs. 54.95%; P = 0.029), and it was the same with arthritis (17.14 vs. 3.9.11%; P = 0.014) and dry eye (33.33 vs. 54.17%, P = 0.027) compared with those without ITP. Serum creatinine level was lower in pSS patients with ITP (P = 0.009), while positivity of anti-histone autoantibodies was higher in pSS patients with ITP (P = 0.025).Conclusion: This study is an initial report describing clinical features of ITP in pSS. The lower incidence of ILD and arthritis among pSS patients with ITP indicated potential active roles of platelets in the pathogenesis of fibrosis or inflammatory arthritis, which may open the way for further experimental and clinical work.

Rheumatic diseases are extremely heterogeneous diseases with substantial risks of morbidity and mortality, and there is a pressing need in developing more safe and cost-effective treatment strategies. Peptide-based vaccination is a highly desirable strategy in treating noninfection diseases, such as cancer and autoimmune diseases, and has gained increasing attentions. This review is aimed at providing a brief overview of the recent advances in peptide-based vaccination therapy for rheumatic diseases. Tremendous efforts have been made to develop effective peptide-based vaccinations against rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), while studies in other rheumatic diseases are still limited. Peptide-based active vaccination against pathogenic cytokines such as TNF-α and interferon-α (IFN-α) is shown to be promising in treating RA or SLE. Moreover, peptide-based tolerogenic vaccinations also have encouraging results in treating RA or SLE. However, most studies available now have been mainly based on animal models, while evidence from clinical studies is still lacking. The translation of these advances from experimental studies into clinical therapy remains impeded by some obstacles such as species difference in immunity, disease heterogeneity, and lack of safe delivery carriers or adjuvants. Nevertheless, advances in high-throughput technology, bioinformatics, and nanotechnology may help overcome these impediments and facilitate the successful development of peptide-based vaccination therapy for rheumatic diseases.

Abstract Background Recent studies have shown a crucial role of Gαq in immune regulation, but how Gαq modulates regulatory B-cell (Breg) function is still unclear. We address this here. Methods CD19+IL-10+ Bregs of wild-type (WT) and Gnaq −/− mice were analyzed by flow cytometry after stimulation by lipopolysaccharide. The WT and Gnaq −/− Bregs were isolated and cocultured with WT CD4+CD25− T cells in the presence of T-activator, and the proliferation of T cells and differentiation of regulatory T cells (Tregs) were analyzed by flow cytometry. We used inhibitors of PI3 kinase (PI3K), extracellular regulated protein kinases 1/2 (Erk1/2), and p38 mitogen-activated protein kinase (p38 MAPK) to detect the pathways involved in the regulation of Gαq on Breg differentiation, which were confirmed by western blot analysis. Furthermore, the expression level of Gαq was assessed by quantitative real-time PCR in peripheral blood mononuclear cells (PBMCs) from healthy controls and rheumatoid arthritis patients. The frequency of CD19+CD24hiCD38hi B cells in PBMCs was detected by flow cytometry, and the association of the Gαq mRNA expression level and the frequency of CD19+CD24hiCD38hi B cells was analyzed by Spearman test. Results The differentiation of CD19+IL-10+ Bregs was inhibited in the Gnaq −/− mice. In addition, Gαq depletion showed an impaired suppressive function of Bregs on T-cell proliferation, which might be due to the decreased Treg expansion. Mechanically, our data demonstrated that the PI3K, Erk1/2, and p38 MAPK signaling pathways were required for regulation of Gαq on Bregs, and blockage of these signaling pathways impaired Breg differentiation. Consistent with our previous studies, we also found a decreased frequency of CD19+CD24hiCD38hi Bregs in rheumatoid arthritis patients. As expected, a significantly positive correlation was investigated between CD19+CD24hiCD38hi Bregs with Gαq mRNA expression. Conclusions Our results indicate that Gαq plays a critical role in the differentiation and immunosuppression of Bregs, and it may provide a new therapeutic target for autoimmune diseases.

Abstract Background Gout is considered one of the most painful acute conditions caused by deposition of monosodium urate (MSU) crystals within joints. Recent studies have shown that interleukin (IL)-1β is a key inflammatory mediator in acute gouty arthritis (GA), and its level is regulated by microRNAs (miRNAs). However, the molecular mechanisms of the regulation remain unclear. Methods A miRNA microarray was used to analyze the miRNA expression profiles in peripheral white blood cells (WBCs) of patients with GA. THP-1 cells were transfected with miRNA mimics, stimulated by MSU crystals, and then subjected to quantitative real-time polymerase chain reaction or Western blot analysis. Levels of IL-1β, IL-8, and tumor necrosis factor (TNF)-α in culture supernatants of THP-1 cells were measured by enzyme-linked immunosorbent assay. A luciferase reporter assay was conducted to confirm the interaction of miRNA and IL-1β 3′-untranslated regions (UTRs). Results Combining bioinformatics and miRNA expression profiles, we found five miRNAs (hsa-miR-30c-1-3p, hsa-miR-488-3p, hsa-miR-550a-3p, hsa-miR-663a, and hsa-miR-920) that possibly target IL-1β. Then, we demonstrated that miR-488 and miR-920 were significantly decreased in the WBCs of patients with GA and that MSU crystals could inhibit expression of miR-488 and miR-920. Upregulation of miR-488 and miR-920 could suppress MSU-induced IL-1β protein expression in THP-1 cells, but no significant difference in IL-1β messenger RNA levels was observed. Moreover, we found that miR-488 and miR-920 could directly target the 3′-UTR of IL-1β. Overexpression of miR-488 and miR-920 could significantly inhibit the gene and protein expression of IL-8 and TNF-α in MSU-induced THP-1 cells. Conclusions This study demonstrates the roles of miR-488 and miR-920 in regulating the production of proinflammatory cytokines in the pathogenesis of GA. These findings suggest that miR-488 and miR-920 could serve as potential therapeutic targets in the treatment of GA.

Interstitial lung disease (ILD) is a life-threating complication, commonly associated with polymyositis (PM), and dermatomyositis (DM). A subset of acute ILD associated with PM/DM patients are refractory to conventional treatment, and leads to a high rate of mortality. The efficacy of therapeutic plasma-exchange (TPE) as a PM/DM treatment to improve muscle involvement is controversial due to a lack of evidence. However, in recent reports, TPE has been effective in improving lung involvement. To evaluate the efficacy of this therapy, we retrospectively studied TPE treatment outcomes for in 18 acute PM/DM-ILD patients who were resistant to conventional therapies. Five patients were diagnosed with DM (27.8%), 11 with CADM (61.1%), and two with PM (11.1%). Among 18 patients, 11 (61.1%) achieved satisfactory improvement after four or more rounds of TPE, whereas seven died due to respiratory failure. We also analyzed risk factors to predict unresponsiveness to TPE in these patients. Notably, the prevalence of subcutaneous/mediastinal emphysema was significantly higher in the non-responsive group (6/7, 85.7%) than in the responsive group (2/11, 18.2%; P = 0.013); moreover, patients with this complication were mainly in the CADM subgroup (6/8, 75%). Subcutaneous/mediastinal emphysema and increased serum ferritin levels were shown to be poor prognostic factors, predictive of unresponsiveness to TPE, in PM/DM patients. No autoantibodies were found to be associated with TPE outcome, although we only investigated anti-Jo-1 and anti-Ro antibodies; the clinical significance of other myositis-specific autoantibodies, especially anti-melanoma differentiation-associated gene 5 (MDA5) antibody, is not known. Our results indicate that TPE might be an alternative treatment for acute PM/DM-ILD patients resistant to conventional therapies, except for those with subcutaneous/mediastinal emphysema and high serum ferritin levels.

Interleukin-33 (IL-33), a member of the IL-1 superfamily, has been shown to play a critical role in many diseases through regulating the immune cell responses, including myeloid-derived suppressor cells (MDSCs). Our previous study demonstrated that IL-33 might play a protective role in kidney injury in gout patients by regulating the lipid metabolism. However, the role of IL-33in the development of MSU-induced inflammation remains elusive. In this study, an increased IL-33 expression was observed in gout patients, which was positively correlated with inflammatory marker CRP. To explore the effects and mechanisms of the increased IL-33 expression in the gout patients, the anti-ST2 antibody and exogenous recombinant IL-33 were used in MSU-induced peritonitis animal model that mimics human gout. Compared with control group, mice with exogenous recombinant IL-33 significantly ameliorated the inflammatory cells infiltration, while blockage of IL-33 signaling by anti-ST2 had no effect on the development of MSU-induced peritonitis. Furthermore, the crucial inflammatory cytokine IL-1β was markedly decreased in IL-33-treated mice. Besides that, a large number of anti-inflammatory MDSCs with CD11b+Gr1intF4/80+ phenotype was observed in the IL-33-treated mice, and adoptive transfer of IL-33-induced MDSCs (CD11b+Gr1intF4/80+) markedly inhibited the IL-1β production in MSU-induced peritonitis. In conclusion, our data provide clear evidences that the increased expression of IL-33 in the gout patients might be due to a cause of self-negative regulation, which inhibits the development of MSU-induced inflammation through expanding MDSCs. Thus, IL-33 might serve as a promising therapeutic target for gout.

Spondyloarthritis (SpA) is an inflammatory rheumatic disease with diverse clinical presentation. The diagnosis of SpA remains a big challenge in daily clinical practice because of the limitation in specific biomarkers of SpA, more biomarkers are still needed for SpA diagnosis and disease activity monitoring. In the past, SpA was considered predominantly as auto-inflammatory disease vs. autoimmune disease. However, in recent years several researches demonstrated a broad autoantibody response in SpA patients. Study also indicated that mice lack of ZAP70 in T cell develop SpA featured inflammation. These studies indicated the autoimmune features of SpA and gave rise to the potential use of autoantibody in SpA management. In this article, we reviewed recent reports of autoantibodies associated with SpA patients, revealing the autoimmune features of SpA, suggesting the hypothesis that SpA was also an autoimmune disease, studies about the autoimmune features might provide more insights in the pathogenesis of SpA. In addition, as there are two opposite conclusions in the role of anti-CD74 autoantibody in the diagnosis of SpA, we also gave our own data on the diagnostic value of anti-CD74 in Chinese SpA patients. Though our data indicated that anti-CD74 might not be a good biomarker for SpA diagnosis in Asian people, CD74 was still a good molecule target in the research of SpA pathogenesis.

T helper 17 (Th17) cells are crucial for the pathogenesis of multiple sclerosis (MS) in humans and experimental autoimmune encephalomyelitis (EAE) in animals. High frequency of Th17 cells and low sensitivity to activation-induced cell death (AICD) are detected in MS patients. However, the mechanisms underlying apoptosis resistance of T cells remain unclear. Perp is an apoptosis-associated target of p53 and implicated in the development of cancers. Here, we show that loss of Perp in T cells does not affect Th1, Th17, or Treg cell differentiation, but does significantly increase the resistance of Perp−/− Th17 cells to AICD and anti-Fas in Lck-Cre × Perpfl/fl mice by inhibiting the caspase-dependent apoptotic pathway. Moreover, Lck-Cre × Perpfl/fl mice exhibited earlier onset of EAE and severe spinal cord inflammation and demyelination, accompanied by increased levels of pro-inflammatory cytokines and enlarged population of Th17 cells. Therefore, Perp deletion promoted Th17 responses and exacerbated the development and severity of EAE.

Aberrant histone acetylation and deacetylation are increasingly thought to play important roles in the pathogenesis of rheumatoid arthritis (RA). However, limited data from studies about the activity of histone deacetylases (HDACs) and histone acetyltransferase (HAT) in RA are controversial. Those conflicting results may be caused by sample size, medication, and age- and sex-matched controls. The aim of this study is to investigate the expression and activity of class I HDACs (1–3.8) and their effects on histone acetylation in peripheral blood mononuclear cells (PBMCs) from RA patients. The expression of class I HDACs in PBMCs from RA patients was decreased in both mRNA and protein levels in comparison with HCs. The nuclear HAT activities were dramatically increased. Further, we found HDAC3 activity to be the most significantly reduced in overall reduction of HDACs in the RA group. The extent of total histone H3, but not H4, acetylation in PBMCs from RA patients was increased compared to that in healthy controls (HCs) (p

Primary Sjögren’s syndrome (pSS) is a rheumatic disease characterized by the destruction of salivary and lacrimal glands, and its pathogenesis mechanism remains unclear. Gαq is the α-subunit of the heterotrimeric Gq protein. Researches demonstrated that Gαq was involved in the pathogenesis regulation of several rheumatic diseases. This study explored the role of Gαq in pSS. Gαq mRNA levels in peripheral blood mononuclear cells (PBMCs) from 39 patients and 26 healthy controls (HCs) were investigated using real-time PCR. IL-17A serum concentrations in 22 pSS patients and 23 HCs were tested by ELISA, and the clinical significance of Gαq was analyzed. The association of Gαq with interleukin-17A (IL-17A) expression was also analyzed in patients with pSS. We showed that Gαq expression in PBMCs from patients with pSS was significantly lower than that in PBMCs from HCs. Gαq expression level was closely associated with pSS disease activity. Furthermore, a negative association was also found in IL-17A and Gαq expression level. These data suggest that Gαq is involved in pSS pathogenesis regulation, possibly due to its regulation of Th17. These results provide new insights into the pSS pathogenesis mechanism involving abnormal Th17 regulation.

The Gαq-containing G protein, an important member of Gq/11 class, is ubiquitously expressed in mammalian cells. Gαq has been found to play an important role in immune regulation and development of autoimmune disease such as rheumatoid arthritis (RA). However, how Gαq participates in the pathogenesis of RA is still not fully understood. In the present study, we aimed to find out whether Gαq controls RA via regulation of Th1 differentiation. We observed that the expression of Gαq was negatively correlated with the expression of signature Th1 cytokine (IFN-γ) in RA patients, which suggests a negative role of Gαq in differentiation of Th1 cells. By using Gαq knockout (Gnaq−/−) mice, we demonstrated that loss of Gαq led to enhanced Th1 cell differentiation. Gαq negative regulated the differentiation of Th1 cell by modulating the expression of T-bet and the activity of STAT4. Furthermore, we detected the increased ratio of Th1 cells in Gnaq−/− bone marrow (BM) chimeras spontaneously developing inflammatory arthritis. In conclusion, results presented in the study demonstrate that loss of Gαq promotes the differentiation of Th1 cells and contributes to the pathogenesis of RA.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by aberrant T cell immune response. Diffuse proliferative lupus nephritis (LN-IV) is the most common, severe, and active form of lupus nephritis. In this study, we investigated the production of Th1, Th2, and Th17 cytokines in prediction of active form of LN-IV. ProcartaPlex multiplex immunoassays panels were used for detection of serum Th1, Th2, and Th17 cytokines profiling. Th1 and Th17 cytokines (IL-18, IFN-γ, IL-12p70, IL-6, and IL-17A) were considerably expressed in the serum of lupus nephritis IV patients in comparison to the healthy control. However, only IL18 and IL6 were higher in class IV versus class III lupus nephritis. Importantly, the ratios of Th1/Th2 (IL-18/IL-4) and Th17/Th2 (IL-17A/IL-4) were significantly elevated in LN-IV when compared with LN-III, LN-V, and healthy controls. Consistently, the serum cytokines IL-18, IL-17A, and IFN-γ were markedly expressed in LN-IV patient glomeruli and interstitial tissue compared to other classes of LN by IHC. ROC further suggests that IL-18 was a potential marker for LN-IV. The data from our study suggests that the early detection and quantification of these cytokines may help in prediction of active form of LN-IV.

Rheumatoid arthritis (RA) is a chronic, systematic autoimmune disease that mainly affects joints and bones. Although the precise etiology is still unknown, Th17 cell is being recognized as an important mediator in pathogenesis of RA. VSTM1-v2 is a novel cytokine which has recently been reported to promote the differentiation of Th17 cells. This study is performed to study whether VSTM1-v2 can be recognized as a biomarker of RA, and is correlated to IL-17 expression. We obtained peripheral blood mononuclear cells (PBMCs) from 40 patients with RA and 40 age- and sex-matched healthy controls by standard Ficoll-Paque Plus density centrifugation. The mRNA expression levels of VSTM1-v2 and IL-17A in PBMCs were detected by real time-PCR. Disease activity parameters of RA were measured by routine methods. Our results showed that VSTM1-v2 mRNA expression in PBMCs from RA patients was significantly increased in comparison of that in healthy individuals. The VSTM1-v2 mRNA expression level was positively correlated with IL-17A mRNA expression level, DAS28, CRP and ESR, but was not correlated to RF, Anti-CCP or ANA. VSTM1-v2 might be a biomarker of RA and a novel factor in the pathogenesis of RA.

Interleukin-33 (IL-33), the most recently discovered member of the IL-1 superfamily, has been linked to several human pathologies including autoimmune diseases, sepsis, and allergy through its specific IL-1 receptor ST2. However, there is little information regarding the role of IL-33 in gout. In this study, we investigated the potential role of IL-33 in gout patients. The serum level of IL-33 was measured by ELISA, and the clinical and laboratory parameters, serum creatinine, urea, and lipid, were extracted from medical record system. The serum IL-33 expression was predominantly increased in gout patients compared to healthy controls, and the IL-33 levels were higher in patients without kidney injury. Furthermore, IL-33 showed a negative correlation with biomarkers of kidney injury, such as CRE and urea. The lipid metabolism dysfunction, tophi, and hypertension are the common reasons for kidney injury in gout. Interestingly, inverse and positive correlation of IL-33 expression was observed in LDL and HDL, respectively. However, there was no significant alteration in the gout patients with hypertension and tophi. These data suggested that IL-33 might act as a protective role in kidney injury through regulating the lipid metabolism in gout.

Heterotrimeric G proteins can be divided into Gi, Gs, Gq/11, and G12/13 subfamilies according to their α subunits. The main function of G proteins is transducing signals from G protein coupled receptors (GPCRs), a family of seven transmembrane receptors. In recent years, studies have demonstrated that GPCRs interact with Gq, a member of the Gq/11 subfamily of G proteins. This interaction facilitates the vital role of this family of proteins in immune regulation and autoimmunity, particularly for Gαq, which is considered the functional α subunit of Gq protein. Therefore, understanding the mechanisms through which Gq-coupled receptors control autoreactive lymphocytes is critical and may provide insights into the treatment of autoimmune disorders. In this review, we summarize recent advances in studies of the role of Gq-coupled receptors in autoimmunity, with a focus on their pathologic role and downstream signaling.

The G-protein-coupled estrogen receptor-1 (GPER-1), also known as GPR30, is a novel estrogen receptor mediating estrogen receptor signaling in multiple cell types. The progress of estrogen-related cancer is promoted by GPER-1 activation through mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K), and phospholipase C (PLC) signaling pathways. However, this promoting effect of GPER-1 is nonclassic estrogen receptor (ER) dependent manner. In addition, clinical evidences revealed that GPER-1 is associated with estrogen resistance in estrogen-related cancer patients. These give a hint that GPER-1 may be a novel therapeutic target for the estrogen-related cancers. However, preclinical studies also found that GPER-1 activation of its special agonist G-1 inhibits cancer cell proliferation. This review aims to summarize the characteristics and complex functions of GPER-1 in cancers.

Introduction. Systemic lupus erythematosus (SLE) is one of the systemic autoimmune diseases characterized by the polyclonal autoantibody production. The human homologue of the mouse double minute 2 (MDM2) is well known as the negative regulator of p53. MDM2 has been reported to be overexpressed in SLE animal model and to promote SLE. Since abnormally expressed proteins can induce autoimmune response, anti-MDM2 autoantibody was examined in SLE patients. Methods. Anti-MDM2 antibody in sera from 43 SLE patients and 69 healthy persons was investigated by ELISA. Positive samples were further confirmed by western blotting. The immunological feathers of anti-MDM2 positive sera were analyzed by indirect immunofluorescence assay. Anti-p53 was also investigated in SLE patients by ELISA, and the correlation of anti-MDM2 and anti-p53 was analyzed. Results. The presence of anti-MDM2 in SLE patients was 23.30%, much higher than normal healthy persons (4.30%). These anti-MDM2 positive sera present a nuclear staining pattern. The presence of anti-p53 in SLE patients was 39.50%, and the titer of anti-MDM2 was positively correlated with anti-p53 in SLE patients. Conclusions. Anti-MDM2 autoantibody was detected at high prevalence in SLE patients. The detection of anti-MDM2 in SLE patients should be clinically useful.

To study the serum Procalcitonin (PCT) level in inflammatory arthritis including gouty arthritis (GA), Rheumatoid arthritis (RA), and ankylosing spondylitis (AS) without any evidence of infection were evaluated the possible discriminative role of PCT in gouty arthritis susceptibility in southern Chinese Han Population.From Feb, 2012 to Feb, 2015, 51 patients with GA, 37 patients with RA, 41 patients with AS and 33 healthy control were enrolled in this study with no evidence of infections. The serum level of PCT (normal range < 0.05 ng/ml) was measured by electrochemiluminescence immunoassay (ECLIA). Disease activity was determined by scores of VAS (4.07 ± 1.15), DAS28 (4.97 ± 1.12), and ASDAS (2.97 ± 0.81) in GA, RA and AS groups respectively. Other laboratory parameters such as, serum creatinine (CRE), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), uric acid (UA) and white blood cells (WBC) were extracted from medical record system.Serum PCT level was predominantly higher in gouty arthritis than in RA and AS patients, especially in the GA patients with tophi. PCT was significantly positively correlated with VAS, CRP and ESR in gouty arthritis and CRP in AS. PCT also had positive correlation-ship with ESR, DAS28 and ASDAS in RA and AS patients respectively, but significant differences were not observed.These data suggested that PCT is not solely a biomarker for infection, but also an indicator in inflammatory arthritis, especially in gouty arthritis.

Bullous systemic lupus erythematosus (BSLE) is an autoantibody-mediated vesiculobullous disease in patients with SLE. Autoimmunity in BSLE is characterized by the presence of circulating anti-type VII collagen antibodies. BSLE patients often present with multiple, tense, clear fluid-filled vesicles and bullae overlying erythematous edematous plaques. Skin biopsy from BSLE patients shows subepidermal bullae with numerous neutrophils and only occasional eosinophils. Furthermore, immunofluorescence examination showed linear deposition of lgG, lgA, C3, and C1q along the basement membrane zone. BSLE patients with corticosteroids treatment constantly do not receive a marked improvement, while dapsone generally dramatically improved the skin condition. Recently, it has been reported that quite a few cases of BSLE were successfully treated with other immune suppressive drugs. Therefore, a comprehensive review of the treatment of BSLE would be beneficial to cure the disease.

Regulatory B cells (Bregs), a newly described subset of B cells, have been proved to play a suppressive role in immune system. Bregs can inhibit other immune cells through cytokines secretion and antigen presentation, which give them the role in the pathogenesis of autoimmune diseases and cancers. There are no clear criteria to identify Bregs; different markers were used in the different experimental conditions. Massive researches had described the functions of immune cells such as regulatory T cells (Tregs), dendritic cells (DCs), and B cells in the autoimmune disorder diseases and cancers. More and more researches focused on the roles of Bregs and the cytokines such as Interleukin-10 (IL-10) and transforming growth factor beta (TGF-β) secreted by Bregs. The aim of this review is to summarize the characteristics of Bregs and the roles of Bregs in cancer.

All randomized controlled trials (RCTs) of iguratimod for rheumatoid arthritis (RA) to assess its efficacy and safety are included in this paper. The Review Manager software was used for meta-analysis to assess risk bias of the studies included, and GRADE profiler software was used for the evidence quality of the studies included. Four RCTs involving 1407 patients with RA were included. Meta-analyses showed that, after 24-week therapy, ACR20, tender joint count, swollen joint count, rest pain, physician and patient global assessment of disease activity, HAQ score, ESR, and CRP in iguratimod group were better than those in placebo group and that the difference between those of iguratimod group and those of other DMARDs (MTX and SASP) group was not significant. GRADE evidence classification of the studies included was moderate. Iguratimod for RA had few adverse events, and its efficacy and safety were the same as those of MTX and SASP for RA. The results of this systematic review suggest that more high-quality and large-scaled RCTs were needed to determine the efficacy of iguratimod for RA and whether iguratimod is as effective as other DMARDs besides MTX and SASP.

Objective. To analyze the methylation status of miR-124a loci in synovial tissues of rheumatoid arthritis (RA) patients using methylation-specific polymerase chain reaction (MSP). Materials and Methods. DNA obtained from the frozen tissue of 7 RA samples, 6 osteoarthritis (OA) samples, and 3 healthy controls were undergoing bisulfite conversion and then analyzed for miR-124a promoter methylation using MSP assay. Results. miR-124-a1 and miR-124-a2 promoter methylation were both seen in 71.4% of RA samples compared to 16.7% of OA samples. miR-124-a3 promoter methylation was seen in 57.1% of RA samples and 0% of OA samples. All the three loci were unmethylated in 3 healthy controls. Conclusion. The methylation status of miR-124a seen in this study concurs with that reported in tumor cells, indicating epigenetic dysregulation constituents, a mechanism in the development of rheumatoid arthritis.

Our study compared the prevalence and characteristics of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD), undifferentiated connective tissue disease-associated interstitial lung disease (UCTD-ILD), or idiopathic pulmonary fibrosis (IPF) between January 2009 and December 2012 in West China Hospital, western China. Patients who met the criteria for ILD were included and were assigned to CTD-ILD, UCTD-ILD, or IPF group when they met the criteria for CTD, UCTD, or IPF, respectively. Clinical characteristics, laboratory tests, and high-resolution CT images were analyzed and compared among three groups. 203 patients were included, and all were Han nationality. CTD-ILD was identified in 31%, UCTD-ILD in 32%, and IPF in 37%. Gender and age differed among groups. Pulmonary symptoms were more common in IPF, while extrapulmonary symptoms were more common in CTD-ILD and UCTD-ILD group. Patients with CTD-ILD had more abnormal antibody tests than those of UCTD-ILD and IPF. Little significance was seen in HRCT images among three groups. A systematic evaluation of symptoms and serologic tests in patients with ILD can identify CTD-ILD, UCTD-ILD, and IPF.

Objective. To analyze serum interleukin-6 (IL-6) expression level and its clinical significance in patients with dermatomyositis. Methods. Blood samples from 23 adult patients with dermatomyositis (DM), 22 with systemic lupus erythematosus (SLE), 22 with rheumatoid arthritis (RA), 16 with Sjögren's syndrome (SS), and 20 healthy controls were collected. The IL-6 concentration was detected by chemiluminescence immunoassay. Correlations between IL-6 expression levels and clinical features or laboratory findings in patients with DM were investigated. Results. IL-6 expression level of DM patients was significantly higher than that of normal controls, significantly lower than that of RA patients, and slightly lower than that of SLE or SS patients with no significant differences. The incidence of fever was significantly higher in the IL-6 elevated group. Serum ferritin (SF) and C-reactive protein (CRP) were positively correlated with IL-6. Conclusions. IL-6 plays a less important role in DM than in RA. IL-6 monoclonal antibodies may have poor effect in patients with DM.

Background. PERP, p53 apoptosis effector related to PMP-22, is a p53-dependent apoptosis in diverse cell types and has cell type-specific roles in p53-mediated apoptosis. However, its role in PBMCs of RA patients has remained largely unclear. Objectives. The aim of this study was to detect the expression levels of PERP on PBMCs of RA patients and healthy controls and analyze the role of PERP in the pathogenesis of RA. Methods. The mRNA expression levels of PERP and IL-17 were detected by real-time PCR in PBMCs from patients with RA (n=40) and healthy controls (n=40). The correlations of PERP expression levels to IL-17 transcripts and disease activity parameters were analyzed. Results. The PERP and IL-17 expression levels in the PBMCs were significantly decreased and increased in comparison of which in healthy controls. The mRNA expression levels of PERP in PBMCs from patients with RA were negatively correlated with IL-17 and disease activity parameters DAS28, RF, CRP, and ESR rather than Anti-CCP and ANA. Conclusions. These results demonstrated that PERP might be involved in the pathogenesis and a potential therapeutic target of RA by regulating the expression of IL-17.

Interleukin-33 (IL-33), a novel member of IL-1 family, has been recently implicated in several inflammatory and autoimmune diseases. IL-33 can be produced by various types of tissues and cells and induce gene expression of Th2-associated cytokines via binding to the orphan receptor ST2. By promoting Th2 type immune response, IL-33 plays important roles in the allergy, whereas its function in autoimmune diseases attracts more attention. Recent studies reported the correlation of IL-33 with rheumatic diseases, and most of them found that the IL-33 expression levels were consistent with disease activity and development. Furthermore, evidence has indicated that IL-33-related treatment may ameliorate the pathogenic conditions and attenuate disease progression of those rheumatic diseases. Therefore, elucidation of the roles of IL-33 in rheumatic diseases would be beneficial to understand the pathogenesis and therapy of these diseases. In this paper, we will summarize the roles of IL-33 in the rheumatic diseases.