Comparison of clinical characteristics between patients with axial spondyloarthritis with and without acute anterior uveitis: a multicentre study of the Chinese Spondyloarthritis Registry.

OBJECTIVES: This study explores the clinical characteristics associated with the occurrence of acute anterior uveitis (AAU) in patients with axial spondyloarthritis (axSpA) within a large, multicentre database. METHODS: This observational, cross-sectional study of patients with axSpA used data from the Chinese Spondyloarthritis Registry between August 1, 2018, and March 31, 2020. The demographic and clinical features of patients with and without AAU were compared. Univariate and multivariate analyses were performed to determine the association between variables and uveitis. RESULTS: A total of 4304 patients were included in this study. The prevalence of AAU in patients with axSpA was 10.59%. Multivariate logistic regression analysis revealed a positive correlation between AAU and age at diagnosis (odds ratio [OR], 1.026; p<0.001), disease duration (OR, 2.117; p<0.001), current or past Achilles tendinitis (OR, 1.692; p<0.001), current or past dactylitis (OR, 1.687; p=0.002), current or past psoriasis (OR, 3.932; p<0.001), presence of human leukocyte antigen-B27 (HLA-B27) (OR, 2.787; p<0.001), and a good response to non-steroidal anti-inflammatory drugs (NSAIDs) (OR, 1.343; p=0.027). CONCLUSIONS: AAU was the most common extra-articular manifestation in the Chinese Spondyloarthritis Registry. In Chinese patients with axSpA, older age at diagnosis, longer disease duration, presence of HLA-B27, current or past Achilles tendinitis, current or past dactylitis, current or past psoriasis, and a good response to NSAIDs were positively associated with AAU.

The development and initial validation of IgG4-related disease damage index: a consensus report from Chinese IgG4-RD Consortium.

OBJECTIVE: To develop and conduct an initial validation of the Damage Index for IgG4-related disease (IgG4-RD DI). METHODS: A draft of index items for assessing organ damages in patients with IgG4-RD was generated by experts from the Chinese IgG4-RD Consortium (CIC). The preliminary DI was refined using the Delphi method, and a final version was generated by consensus. 40 IgG4-RD cases representing four types of clinical scenarios were then selected, each with two time points of assessment for at least 3 years of follow-up. 48 rheumatologists from 35 hospitals nationwide were invited to evaluate organ damage using the CIC IgG4-RD DI. The intraclass correlation coefficient (ICC) and the Kendall-W coefficient of concordance (KW) were used to assess the inter-rater reliability. The criterion validity of IgG4-RD DI was tested by calculating the sensitivity and specificity of raters. RESULTS: IgG4-RD DI is a cumulative index consisting of 14 domains of organ systems, including a total of 39 items. The IgG4-RD DI was capable of distinguishing stable and increased damage across the active disease subgroup and stable disease subgroup. In terms of scores at baseline and later observations by all raters, overall consistency in scores at baseline and later observations by all raters was satisfactory. ICC at the two time points was 0.69 and 0.70, and the KW was 0.74 and 0.73, respectively. In subgroup analysis, ICC and KW in all subgroups were over 0.55 and 0.61, respectively. The analysis of criterion validity showed a good performance with a sensitivity of 0.86 (95% CI 0.82 to 0.88), a specificity of 0.79 (95% CI 0.76 to 0.82) and an area under the curve of 0.88 (95% CI 0.85 to 0.91). CONCLUSION: The IgG4-RD DI is a useful approach to analyse disease outcomes, and it has good operability and credibility. It is anticipated that the DI will become a useful tool for therapeutic trials and studies of prognosis in patients with IgG4-RD.

Withdrawal of immunosuppressants and low-dose steroids in patients with stable IgG4-RD (WInS IgG4-RD): an investigator-initiated, multicentre, open-label, randomised controlled trial.

OBJECTIVES: IgG4-related disease (IgG4-RD) is an immune-mediated, fibroinflammatory disease. Induction treatment with glucocorticoid (GC) is usually effective, but its tendency of relapse makes the strategy for maintenance treatment a challenge. The WInS IgG4-RD (withdraw immunosuppressants (IMs) and steroid in stable IgG4-RD) trial tested whether discontinuation of GC and IM was feasible in stable IgG4-RD. METHODS: The WInS IgG4-RD trial was a multicentre, open-label, randomised controlled trial. Patients with IgG4-RD receiving GC+IM as maintenance treatment with clinically quiescent disease for at least 12 months were randomised (1:1:1) into three groups: group 1: withdraw GC+IM; group 2: withdraw GC but maintain IM; group 3: maintain GC+IM. The primary outcome was the relapse rate of disease within 18 months. The secondary outcomes included the changes of IgG4-RD Responder Index (RI), Physician's Global Assessment (PGA), serum IgG4 and IgG, as well as adverse events. RESULTS: One hundred and forty-six patients were randomised, with 48 patients in group 1, 49 patients in group 2 and group 3, respectively. Within the 18-month follow-up period, disease relapse occurred in 25 out of 48 (52.1%) patients in group 1 vs 7 out of 49 (14.2%) in group 2 and 6 out of 49 (12.2%) in group 3 (p<0.001). The changes in RI and PGA were significantly higher in group 1 than in group 2 (p<0.001) or group 3 (p<0.001). CONCLUSIONS: The maintenance of IMs, with or without low-dose GC, was found to be superior to withdraw GC+IM in preventing relapse for long-time stable IgG4-RD. TRIAL REGISTRATION NUMBER: NCT04124861.

Expansion and surface makers of age-associated B cells in IgG4-related disease.

OBJECTIVES: To assess the expression of age-associated B cells (ABCs), and characterise the surface markers of ABCs in patients with IgG4-related disease (IgG4-RD). METHODS: Fifty-one newly diagnosed patients with IgG4-RD, 18 IgG4-RD patients with disease remission, 34 patients with other autoimmune diseases, and 61 age- and sex-matched healthy controls (HCs) were included. Circulating ABCs, as well as surface markers were detected by flow cytometry, and tissue infiltration of ABCs were assessed by immunofluorescence (IF). The expression of ABCs in the affected organs of LatY136F knock-in (LAT) mouse models (IgG4-RD mouse model) were explored by flow cytometry and IF. RESULTS: The percentages and absolute numbers of ABCs (gated as CD21-T-bet+CD11c+) in CD19+ B cells raised remarkably in untreated IgG4-RD patients than HC, and reduced significantly after treatment. The percentage of CD27+ABCs, DN2 B cells and activated naive B cells was higher in patients with IgG4-RD than in HCs and patients with multiple autoimmune diseases, whereas the percentage was comparable with that in patients with systemic lupus erythematosus. Phenotypical analysis revealed upregulated levels of CD86, TACI, CD38, and downregulated level of CXCR3 in peripheral CD19+CD21-CD11c+ B cells of IgG4-RD patients compared with that of HC. In IgG4-RD patients, CD19+CD21- CD11c+ cells expressed higher levels of CD80, CXCR3, TACI, CD95, and BAFF-R, while lower levels of CD86, CD27, CD38, and CXCR5 compared with CD19+ CD21- CD11c- B cells. ABCs (CD11c+T-bet+ gated in B220+ cells) were increased significantly in lungs of LAT mice than that of wild type (WT) mice. CONCLUSIONS: ABCs were expanded both in the peripheral blood and affected tissues of patients with IgG4-RD as well as in the lungs of LAT mice, indicating the potential roles of ABCs in IgG4-RD pathogenesis.

Comparison of clinical features and outcomes of proliferative, fibrotic, and mixed subtypes of IgG4-related disease: A retrospective cohort study.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized immune-mediated disorder that can affect almost any organ in the human body. IgG4-RD can be categorized into proliferative and fibrotic subtypes based on patients' clinicopathological characteristics. This study aimed to compare the clinical manifestations, laboratory findings, and treatment outcomes of IgG4-RD among different subtypes. METHODS: We prospectively enrolled 622 patients with newly diagnosed IgG4-RD at Peking Union Medical College Hospital from March 2011 to August 2021. The patients were divided into three groups according to their clinicopathological characteristics: proliferative, fibrotic, and mixed subtypes. We compared demographic features, clinical manifestations, organ involvement, laboratory tests, and treatment agents across three subtypes. We then assessed the differences in treatment outcomes among 448 patients receiving glucocorticoids alone or in combination with immunosuppressants. Moreover, risk factors of relapse were revealed by applying the univariate and multivariate Cox regression analysis. RESULTS: We classified the 622 patients into three groups consisting of 470 proliferative patients, 55 fibrotic patients, and 97 mixed patients, respectively. We found that gender distribution, age, disease duration, and frequency of allergy history were significantly different among subgroups. In terms of organ involvement, submandibular and lacrimal glands were frequently involved in the proliferative subtype, while retroperitoneum was the most commonly involved site in both fibrotic subtype and mixed subtype. The comparison of laboratory tests revealed that eosinophils ( P = 0.010), total IgE ( P = 0.006), high-sensitivity C-reactive protein ( P <0.001), erythrocyte sedimentation rate ( P <0.001), complement C4 ( P <0.001), IgG ( P = 0.001), IgG1 (P <0.001), IgG4 (P <0.001), and IgA ( P <0.001), at baseline were significantly different among three subtypes. Compared with proliferative and mixed subtypes, the fibrotic subtype showed the lowest rate of relapse (log-rank P = 0.014). CONCLUSIONS: Our study revealed the differences in demographic characteristics, clinical manifestations, organ involvement, laboratory tests, treatment agents, and outcomes across proliferative, fibrotic, and mixed subtypes in the retrospective cohort study. Given significant differences in relapse-free survival among the three subtypes, treatment regimens, and follow-up frequency should be considered separately according to different subtypes.

B cell repopulation trajectory after rituximab treatment in autoimmune diseases: a longitudinal observational study.

To investigate B-cell repopulation trajectory and the associated factors in patients with autoimmune diseases (AIDs) who underwent rituximab (RTX) treatment. This is a retrospective study in a large tertiary medical center. Kaplan-Meier analysis and Cox regression were used to investigate factors associated with B-cell repopulation. Latent class trajectory modeling (LCTM) was employed to identify distinct B-cell repopulation trajectory longitudinally. A total of 224 patients were included, with a cumulative follow-up time of 193.6 person-years. Patients with antineutrophil cytoplasm antibody-associated vasculitis (AAV), connective tissue disease, and IgG4-related disease exhibited significant differences in B-cell repopulation time (p = 0.0055 by log-rank test). Multivariate Cox regression identified that higher levels of IgA (HR 1.21, 95%CI 1.01-1.45, p = 0.040) and concurrent glucocorticoid use (HR = 0.37,95%CI 0.20-0.67, p = 0.001) were associated with B-cell repopulation. The cluster showing prolonged B-cell depletion, identified by LCTM, had lower proportions of male (27% vs. 48.5%, p = 0.033), smoke history (17.6% vs. 38.7%, p = 0.025), higher proportions of AAV (44.3% vs. 15.2%, p = 0.004), RTX dose (p = 0.042), history of cyclophosphamide use (70.4% vs. 48.5%, p = 0.003), meanwhile glucocorticoid use (94.8% vs. 72.7%, p = 0.001). The trajectory of B-cell repopulation after RTX infusion in AIDs was heterogeneous. Certain factors were associated with B-cell repopulation, and a specific cluster of patients demonstrated prolonged B-cell depletion after RTX treatment.

Corrigendum: The potential role of RNA N6-methyladenosine in primary Sjögren's syndrome.

[This corrects the article DOI: 10.3389/fmed.2022.959388.].

The external validation of the 2019 ACR/EULAR classification criteria for IgG4-related disease in a large cohort from China.

OBJECTIVE: To externally validate the performance of the 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for IgG4-related disease (IgG4-RD) within a cohort from China and to compare the criteria with the 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD. METHODS: This study included 875 IgG4-RD and 302 non-IgG4-RD cases (213 mimickers and 89 patients with other diseases). Using expert clinical judgment as the gold standard for diagnosis of IgG4-RD, the performance (sensitivity, specificity, area under the curve (AUC) of the 2019 ACR/EULAR criteria for IgG4-RD was evaluated. We also compared it with the 2020 RCD criteria. RESULTS: The 2019 ACR/EULAR classification criteria had a sensitivity of 76.6% (95% CI: 73.8% to 79.4%) and a specificity of 98.0% (96.0%-99.4%), an AUC of 0.873 (0.857-0.889) in the overall cohort. Those false negative cases under the 2019 ACR/EULAR classification criteria had significantly lower levels of serum IgG4, and fewer had pathological information, with a higher frequency in the involvement of those uncommon organs compared with the true positive cases. The cases judged as negative by the 2019 ACR/EULAR classification criteria yet judged as "definite" by the 2020 RCD criteria had more involvement of uncommon organs. CONCLUSIONS: The 2019 ACR/EULAR classification criteria for IgG4-RD show outstanding specificity and good sensitivity in real-world clinical practice. The 2020 RCD criteria are helpful for the diagnosis of IgG4-RD in clinical scenarios where IgG4-RD presents as involving an isolated organ, especially the unusual sites.

Predictive value of bone marrow megakaryocyte count for immunotherapeutic response in primary Sjögren's syndrome patients with severe immune thrombocytopenia: A single-center case-control study in China.

OBJECTIVES: To investigate potential predictors of treatment response in primary Sjögren's syndrome (pSS) patients with severe immune thrombocytopenia (ITP), with a focus on bone marrow megakaryocyte (MK) count. METHODS: This case-control study included patients with pSS and severe ITP who were admitted to Peking Union Medical College Hospital and met the 2002 AECG or 2016 American College of Rheumatology / European League Against Rheumatism criteria for SS. Patients who had overlap other connective tissue diseases and with thrombocytopenia that could be explained by other causes were excluded. Severe ITP was defined as platelet count <20 × 109 /L. Response was evaluated at 3 months after treatment. RESULTS: Sixty-eight eligible patients were included: 34 (50%) achieved complete remission (CR), 18 (26%) partial remission (PR) and 16 (24%) were non-responders (NRs). Fewer infections were found in the CR group (24%) than in the PR (50%) and NR (56%) groups (P = 0.04). The MK count (CR 32 vs PR 36 vs NR 4 per slide, P < 0.001) in the NR group was significantly lower than in the other groups. MK count >6.5 per slide predicted good treatment response, with 85.7% sensitivity, 88.1% specificity and 0.866 area under the curve. Logistic regression indicated that patients with more MKs were more likely to respond to immunotherapy (crude odds ratio [OR] 1.45, 95% CI 1.2-2.0, adjusted OR 1.68, 95% CI 1.2-2.7). CONCLUSIONS: MK count predicted response to immunosuppressive treatment in pSS patients with severe ITP. These patients are recommended to have bone marrow aspiration before treatment initiation. Clinicians should be aware of screening for infections during clinical practice.

Multiomic landscape of immune pathogenesis in Kimura's disease.

Kimura's disease is a rare chronic inflammatory disorder characterized with subcutaneous masses, lymphadenopathy, and peripheral eosinophilia. So far, the disease pathogenesis remains hardly known. Here, we perform bulk-RNA sequencing and reveal a higher expression of transmembrane 176A (TMEM176A) with over-activated extracellular-signal-regulate kinase/mitogen-activated protein kinases (Erk/MAPK) signaling pathway in eosinophils of Kimura's disease compared with healthy controls. Flow cytometry analysis shows that the composition of lymphocytes, monocytes, and dendritic cell subsets are similar between Kimura's disease and healthy controls, which is further validated by scRNA-seq. Loss of S100 calcium binding protein P (S100P) is found in the CD24+ myeloid subset of Kimura's disease. In vitro functional assays show that S100P may participate in promoting reactive oxygen species (ROS) production in myeloid cells. Taken together, we are the first to study the immune pathogenesis systematically and demonstrate that Erk/MAPK signaling pathway might be a potential therapeutic target for Kimura's disease.

Pilot study of tocilizumab monotherapy for active chronic periaortitis.

OBJECTIVES: To investigate the effectiveness and safety of TCZ (tocilizumab) monotherapy for chronic periaortitis (CP) patients at acute active stage. METHODS: Twelve patients with definite or possible diagnosis of CP were enrolled and received intravenous infusions of TCZ (8 mg/kg) every 4 weeks for at least 3 months. Clinical features, laboratory and imaging findings were recorded at baseline and during the follow-up. The primary endpoint was the rate of partial and complete remission after 3 months TCZ monotherapy and the secondary endpoint was the frequency of treatment related adverse events. RESULTS: Three patients (27.3%) achieved partial remission and seven patients (63.6%) obtained complete remission after 3 months TCZ treatment. The total remission rate achieved 90.9%. All patients reported improvement in clinical symptoms. Inflammatory markers such as erythrocyte sedimentation rate and C reactive protein decreased to normal levels after TCZ treatment. Nine patients (81.8%) showed remarkable shrinkage of perivascular mass greater than or equal to 50% on CT. CONCLUSION: Our study showed that TCZ monotherapy contributed to remarkable clinical and laboratory improvement in CP patients and could be an alternative treatment option for CP.

The influence of intrathecal injection of methotrexate and dexamethasone on neuropsychiatric systemic lupus erythematosus (NPSLE): a retrospective cohort study of 386 patients with NPSLE.

BACKGROUND: Neuropsychiatric involvement is one of the major concerns in systemic lupus erythematosus (SLE). The therapeutic effect of intrathecal treatment of methotrexate and dexamethasone has been investigated in some exploratory studies, but its influence on the long-term prognosis of neuropsychiatric SLE (NPSLE) remains unknown. METHODS: This was a propensity score-matched retrospective study. Outcomes at discharge and time free from NPSLE relapse or death were evaluated by multivariate logistic regression, survival analysis, and Cox regression as appropriate. RESULTS: Among 386 hospitalized patients with NPSLE, the median [IQR] age was 30.0 [23.0-40.0] years, and 342 patients (88.4%) were female. Of those, 194 patients received intrathecal treatment. Patients in the intrathecal treatment group had higher Systemic Lupus Erythematosus Disease Activity Index 2000 scores (median 17 vs. 14 points, IQR 12-22 vs. 10-19 points, P <0 .001) and were more likely to receive methylprednisolone pulse therapy (71.6% vs. 49.5%, P < 0.001) than those who did not receive intrathecal therapy. Intrathecal treatment was associated with a higher probability of survival and being free from NPSLE relapse than control treatment among the 386 unmatched patients (P =0.042 by log-rank test) and within 147 propensity score-matched pairs (P =0.032 by log-rank test). In the subgroup of NPSLE patients with increased levels of protein in cerebrospinal fluid, intrathecal treatment had a positive influence on their prognosis (P < 0.001). CONCLUSIONS: Intrathecal treatment of methotrexate and dexamethasone was associated with a more favorable prognosis of NPSLE and may serve as a valuable additional therapy for NPSLE patients, especially for those with elevated levels of protein in cerebrospinal fluid.

Memory CD4+T cell profile is associated with unfavorable prognosis in IgG4-related disease: Risk stratification by machine-learning.

IgG4-related disease (IgG4-RD) is a chronic immune-mediated disease with heterogeneity. In this study, we used machine-learning approaches to characterize the immune cell profiles and to identify the heterogeneity of IgG4-RD. The XGBoost model discriminated IgG4-RD from HCs with an area under the receiver operating characteristic curve of 0.963 in the testing set. There were two clusters of IgG4-RD by k-means clustering of immunological profiles. Cluster 1 featured higher proportions of memory CD4+T cell and were at higher risk of unfavorable prognosis in the follow-up, while cluster 2 featured higher proportions of naïve CD4+T cell. In the multivariate logistic regression, cluster 2 was shown to be a protective factor (OR 0.30, 95% CI 0.10-0.91, P = 0.011). Therefore, peripheral immunophenotyping might potentially stratify patients with IgG4-RD and predict those patients with a higher risk of relapse at early time.

Mortality and prognostic factors in connective tissue disease-associated pulmonary arterial hypertension patients complicated with right heart failure.

OBJECTIVE: To identify predictive factors associated with mortality in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) patients who were complicated with right heart failure (RHF). METHODS: In this single-center retrospective study, baseline demographics, clinical features, laboratory results, and hemodynamic assessments were collected. Kaplan-Meier analysis was applied to analyze all-cause mortality. Univariate and forward stepwise multivariate Cox proportional regression analyses were performed to identify independent predictors of mortality. RESULTS: A total of 51 right heart catheterization-confirmed CTD-PAH patients complicated with RHF were consecutively enrolled in this study from 2012 to 2022. Forty-eight (94%) enrolled patients were female and the mean age was 36.0 ± 11.8 years. Thirty-two (61.5%) were systemic lupus erythematosus-PAH and 33%/67% showed World Health Organization functional class III/IV, respectively. Twenty-five (49%) of those patients died and Kaplan-Meier analysis showed the overall 1-, 3-, and 5-week survival rates from the time of hospitalization as 86.28%, 60.78%, and 56.86%, respectively. RHF in CTD-PAH patients mainly resulted from progression of PAH (n = 19) and infection (n = 5), which also contributed to the leading causes of death. Statistical analysis between survivors and non-survivors showed that death from RHF was associated with higher levels of urea (9.66 vs 6.34 mmol/L, P = 0.002), lactate (cLac: 2.65 vs 1.9 mmol/L, P = 0.006), total bilirubin (23.1 vs 16.9 µmol/L, P = 0.018) and direct bilirubin (10.5 vs 6.5 µmol/L, P = 0.004), but with lower levels of hematocrit (33.7 vs 39, P = 0.004), cNa+ (131 vs 136 mmol/L, P = 0.003). Univariate and forward stepwise multivariate Cox proportional regression analyses indicated that the level of cLac (hazards ratio:1.297; 95% CI: 1.076-1.564; P = 0.006) was an independent risk factor for mortality. CONCLUSION: The short-term prognosis of CTD-PAH complicated with RHF was very poor, and hyperlactic acidemia (cLac > 2.85 mmoL/L) was an independent predicting factor for mortality of CTD-PAH patients complicated with RHF.

Potential impact of autoimmune diseases family history in IgG4-related disease: a retrospective cohort study.

OBJECTIVE: Autoimmune comorbidities may be associated with IgG4-related disease (IgG4-RD), here we aimed to determine the correlation of autoimmune diseases (AID) family history and IgG4-RD in a Chinese cohort. METHODS: This retrospective cohort study identified 628 cases of IgG4-RD in Peking Union Medical College Hospital. Patients were classified into two groups, with AID family history group (AID-positive) and without AID family history group (AID-negative). We viewed the potential value of AID family history on IgG4-RD by comparing the differences between the two groups. In addition, Cox regression analysis estimated CIs and HR for IgG4-RD risk. RESULTS: 93 (14.8%) IgG4-RD patients had AID family history. Compared with AID-negative group, baseline data analysis revealed that AID-positive group patients had an earlier age of IgG4-RD onset (50.4±14.8 vs 54.2±12.6, p=0.014*), a higher percentage of antinuclear antibody (ANA) positivity (38.9% vs 22.7%, p=0.0277*) and Riedel thyroiditis (10.9% vs 2.4%, p=0.001*), were prone to comorbid with other AID (16.1% vs 6.2%, p=0.0238*). Cox analysis found that younger age (HR 0.97 (95% CI 0.94 to 0.99), p=0.0384*) and higher proportions of baseline peripheral eosinophils (HR 1.1 (95% CI 1.02 to 1.2), p=0.0199*) increased the risk of unfavourable prognosis for AID-positive IgG4-RD patients. CONCLUSIONS: 14.8% of IgG4-RD patients had AID family history, with younger age of disease onset age and higher frequency of ANA positivity in AID-positive group, indicating that IgG4-RD may share genetic background with other AID.

Comparison of the efficacy and safety of leflunomide versus mycophenolate mofetil in treating IgG4-related disease: a retrospective cohort study.

OBJECTIVE: Combination therapy of glucocorticoids (GCs) plus leflunomide (LEF) and GCs plus mycophenolate mofetil (MMF) was reported to have good efficacy and safety in the management of IgG4-RD. However, studies comparing the efficacy and safety of these two combination therapies were unavailable. Herein, this study aimed to compare the efficacy and safety of GCs plus LEF and GCs plus MMF in treating IgG4-RD. METHODS: This study included 130 newly diagnosed IgG4-RD patients who received the therapy of GCs plus LEF (group I) and GCs plus MMF (group II). Clinical data at baseline and after treatment, treatment response, relapse rate, and adverse effects were recorded and analyzed. RESULTS: Patients in both groups responded well to the treatment in the 1st-month follow-up, and 100% of patients achieved treatment response. However, at the 6th and 12th-month follow-up, the total response rate of group II was higher than that in group I (75.6 vs. 53.7%, p = 0.038 and 85.4% vs. 61.0%, p = 0.013, respectively). In addition, the duration of disease remission in group II was longer than that in group I (9 (6-9) vs. 6 (6-6) months, p = 0.014). Moreover, more patients in group I had adverse effects compared with group II (36.6 vs. 7.3%, p < 0.01); and the most common adverse events of LEF were rash (12.2%) and elevation of liver enzymes (9.8%). CONCLUSION: The combination therapy of GCs plus low-dose MMF had better efficacy and safety in the management of IgG4-RD compared with the therapy of GCs plus LEF.

Differential CpG DNA methylation of peripheral B cells, CD4+ T cells, and salivary gland tissues in IgG4-related disease.

OBJECTIVES: Immunoglobulin-G4-related disease (IgG4-RD) is a distinct systemic autoimmune-mediated disease manifesting as chronic inflammation and tissue fibrosis. Since the role of DNA methylation in the pathogenesis of IgG4-RD is still unclear, we conduct this study to investigate epigenetic modifications in IgG4-RD. METHODS: A genome-wide DNA methylation study was conducted with B cells, CD4+ T cells, and salivary gland tissues from IgG4-RD patients and matched controls by using the Illumina HumanMethylation 850K BeadChip. We further performed pyrosequencing and immunohistochemistry assays to validate the methylation status of some targets of interest. RESULTS: We identified differentially methylated CpG sites including 44 hypomethylated and 166 hypermethylated differentially methylated probes (DMPs) in B cells and 260 hypomethylated and 112 hypermethylated DMPs in CD4+ T cells from 10 IgG4-RD patients compared with 10 healthy controls. We also identified 36945 hypomethylated and 78380 hypermethylated DMPs in salivary gland tissues of 4 IgG4-RD patients compared with 4 controls. DPM2 (cg21181453), IQCK (cg10266221), and ABCC13 (cg05699681, cg04985582) were hypermethylated and MBP (cg18455083) was hypomethylated in B cells, CD4+ T cells, and salivary gland tissues of IgG4-RD patients. We also observed the hypomethylated HLA-DQB2 in CD4+ T cells from IgG4-RD patients. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DMPs in salivary gland tissues of IgG4-RD patients revealed enrichment of pathways involved in the regulation of immune cell responses and fibrosis. CONCLUSION: This is the first DNA methylation study in peripheral B cells, CD4+ T cells, and salivary gland tissues from IgG4-RD patients. Our findings highlighted the role of epigenetic modification of DNA methylation and identified several genes and pathways possibly involved in IgG4-RD pathogenesis.

mTORC1-GLUT1-mediated glucose metabolism drives hyperactivation of B cells in primary Sjogren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease characterized by B cell hyperactivation and hypergrammaglobulinemia. Currently, the role of metabolic pathways in the B cells of pSS patients is poorly defined. Here, we showed that upon cytosine phosphate-guanine (CpG)/sCD40L/IL-4 stimulation, B cells proportionally increased glycolysis and oxygen consumption, and compared with B cells from healthy controls (HCs), B cells from pSS patients exhibited higher glycolysis capacity and maximal oxidative respiration (OXPHOS). We also found that glucose transporter 1 (GLUT1) expression in B cells from pSS patients was significantly higher than that in B cells from HCs. Treatment with 2-deoxy-d-glucose (2-DG) inhibited the activation of B cells in pSS patients. Both 2-DG and Metformin inhibited the proliferation, formation of plasma/plasmablasts and decreased the IgG and IgM levels in the supernatants of B cells from pSS patients. Furthermore, inhibition of mTORC1 by rapamycin had an effect similar to that of 2-DG, suppressing B cell activation, proliferation and antibody production. Taken together, we demonstrated that B cells from pSS patients are more metabolically active than those from HCs and suggested that the mTORC1-GLUT1 glycolysis pathways were the major drivers of B cell hyperactivation and autoantibody production in pSS patients.