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Objectives: This study aims to clarify the relationship between the changes of pancreatic size after glucocorticoid (GC) therapy and relapse in IgG4-related autoimmune pancreatitis (AIP)., Methods: We prospectively enrolled 205 newly diagnosed IgG4-related AIP patients. 145 patients were followed up for more than 3 years. These patients were divided into three groups according to the changes of pancreatic size after treatment of 6 months: pancreatic swelling, normal size, and pancreatic atrophy. Baseline clinical and laboratory parameters were compared among three groups. Kaplan-Meier survival analysis was performed in the 134 patients based on GC therapy. Besides, Cox regression analysis and logistic regression analysis were performed to identify risk factors associated with relapse and the potential variables affecting changes of pancreatic size after treatment., Results: Age at diagnosis, white blood cell count, and serum IgG1 level at baseline were significantly different among the three groups. After treatment of 6 months, the pancreas of most patients (n = 81, 55.9%) could return to normal size, while persistent pancreatic swelling was found in 24.1% patients (n = 35), and atrophy was observed in 20.0% of the patients (n = 29). Kaplan-Meier survival analysis presented patients with pancreatic swelling after 6 months of GC therapy were more likely to relapse in the follow-up of 3 years. Persistent pancreatic swelling after treatment and salivary gland involvement at baseline were independent risk variables associated with relapse in IgG4-related AIP patients, while GC-based therapy was a protective factor of relapse. Logistic regression analysis revealed that older age at diagnosis was associated with pancreatic atrophy and higher baseline serum IgG1 level was associated with pancreatic swelling after treatment of 6 months., Conclusions: Patients with persistent pancreatic swelling after GC-based therapy of 6 months were more likely to relapse in the follow-up of 3 years. Older age at diagnosis and higher baseline serum IgG1 level were potential variables associated with pancreatic atrophy or swelling after treatment of 6 months. Key Points • Patients with persistent pancreatic swelling after glucocorticoid-based therapy were more likely to relapse in IgG4-related autoimmune pancreatitis. • Older age at diagnosis was associated with pancreatic atrophy after glucocorticoid-based therapy. • Higher baseline serum IgG1 level was associated pancreatic swelling after glucocorticoid-based therapy., (© 2022. International League of Associations for Rheumatology (ILAR).)

Background: Cancer incidence and mortality have received critical attention during the long-term management of morbidities in patients with autoimmune diseases (AIDs). This study aimed to investigate and compare the risk of cancer associated with five major AIDs in a large-scale Chinese cohort., Methods: A total of 8,120 AID patients consecutively admitted to a national tertiary referral center in China were included and followed-up for 38,726.55 patient-years, including those with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome (SS), systemic scleroderma (SSc), and idiopathic inflammatory myositis (IIM). Demographic data, cancer incidence, predilecting sites and cancer onset time were recorded and compared among the five AIDs., Results: Four hundred and thirty (5.3%) patients developed cancer. Their median age was 57.5 years and AID duration was 79.8 months. The estimated total standardized incidence ratio (SIR) of cancer in AIDs patients was 3.37, with the highest SIR observed in IIM (4.31), followed by RA (3.99), SSc (3.77), SS (2.88) and SLE (2.58). The increased SIR of cancers in AID patients showed a female predominance (female vs. male: 3.59 vs. 2.77) and younger patient involvement (age <50 vs. ≥50 years: 4.88 vs. 3.04). Patients with SLE had increased SIRs for developing hematologic malignancies and solid tumors located in the urinary bladder, corpus uteri and cervix uteri. Patients with SS had a significantly high SIR for developing non-Hodgkin's lymphoma. Within 3 years of IIM diagnosis, 74.6% of the patients developed cancer and they had a high risk of ovarian cancer. RA was associated with a wide distribution of scancers, including non-Hodgkin's lymphoma, gynecologic, urinary tract, thyroid gland and lung cancers. SSc patients had increased SIRs for developing cervical uterine, lung, and breast cancers., Conclusion: Patients with five major AIDs in China had an increased risk of developing cancer, with a predominance in women and younger patients, although cancer incidence, predilection sites and cancer onset time may vary greatly in each AID entity., (© 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Objectivse: To explore the clinical characteristics and treatment efficacy of IgG4-related disease (IgG4-RD) patients with different levels of serum IgG4., Methods: A total of 299 patients newly diagnosed with IgG4-RD were enrolled in this study. Patients were classified into four groups according to baseline serum IgG4 levels: Group A: normal concentration; Group B: > normal but <2× the upper reference limit (URL); Group C: between 2× and 5× the URL; Group D: >5× the URL. All patients were followed up for 12 months. The patients' clinical characteristics, laboratory parameters, plasmablasts/plasma cells and treatment efficacy were analysed., Results: IgG4-RD patients with higher serum IgG4 levels had higher percentages of dacryoadenitis, sialadenitis, and autoimmune pancreatitis and a higher prevalence of allergy history, whereas patients with retroperitoneum and mediastinum lesions usually had lower serum IgG4 levels. In addition, the serum IgG4 re-elevation rate in Group D (19.4%) was higher than those in Group B (4.9%) and Group C (7.7%) (p=0.003 and p=0.020, respectively). Patients suffered fewer clinical relapses with a serum IgG4 reduction ≥50% of baseline serum IgG4 in Group B and ≥40% of baseline serum IgG4 in Group D (p=0.019 and p=0.043, respectively). In addition, the rate of clinical relapse in patients who received combination therapy with glucocorticoids and mycophenolate mofetil was 18.75% in Group D, which was higher than the rates in Groups B and C (0) (p=0.027)., Conclusions: IgG4-RD patients with different levels of serum IgG4 exhibit different clinical characteristics and treatment responses.

Objectives: Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease that affects various organs of the body. The aim of this study is to elucidate the clinical characteristics of IgG4-RD with central nervous system (CNS) involvement., Methods: Among 589 patients with IgG4-RD in a prospective single-centre cohort study in Peking Union Medical College Hospital, 15 patients had CNS involvement. The clinical data including demographic features, symptoms, involved organs, laboratory findings, radiological results, pathology, treatment and outcome were analysed., Results: Seventeen patients, including nine men and six women, had IgG4-related neuropathy, with an average age of 49.8±12.3 years. IgG4 related hypophysitis was the most common manifestation, accounting for 40% (6/15) of cases, followed by hypertrophic cranial pachymeningitis (n=4), hypertrophic spinal pachymeningitis (n=2), intracranial mass (n=2), cavernous sinus and orbital disease (n=1). Most patients had multi-organ involvement, with the most common extra-CNS manifestations were Mikulicz disease (MD) and lymphadenitis in 5 (33.3%) cases. Serum IgG4 levels were elevated in 12/15(80%) patients and the median value was 438.5 (104, 2250)mg/dL. Fourteen cases underwent biopsy, of which tissue was taken directly from CNS lesions in 4 cases. All patients received treatment with glucocorticoids (GCs) combined with immunosuppressants, including cyclophosphamide, tacrolimus, mycophenolate mofetil, and tripterygium glycosides. Complete remission was achieved in 3/15 (20.0%) patients, and 11/15 cases (73.3%) achieved partial remission., Conclusions: IgG4-related CNS involvement is a rare and distinct entity of IgG4-RD. Treatment with corticosteroids combined with immunosuppressive agents yielded favourable responses.

Aim: In order to evaluate the efficacy and safety of high versus medium doses of glucocorticoid therapy in remission induction of immunoglobulin G4-related disease (IgG4-RD), we set up a randomized controlled study., Method: Newly diagnosed IgG4-RD patients were randomly assigned to two groups: high doses of prednisone (0.8-1.0 mg/kg/day) and medium doses (0.5-0.6 mg/kg/day). Patients were assessed at weeks 0, 4, 12 and 24. The primary outcome was the remission rate at week 24. The secondary endpoints included IgG4-RD responder index (IgG4-RD RI), IgG and IgG4 levels., Results: Twenty cases in each group finished the study. At week 24, the total response rates were 95% and 80% in high and medium dose groups, respectively. There was no significant difference between the two groups. IgG4-RD RI reduced from 14.9 to 3.0 in the high dose group, while in the medium dose group it was from 13.1 to 3.2. At week 24, the average level of IgG4 reduced from 1576 to 324 mg/dL and from 1445 to 684 mg/dL in the two groups, respectively. Relapsed patients had higher baseline IgG4-RD RI. There was no severe adverse effect shown in both groups., Conclusion: The effect of remission induction was similar in high and medium glucocorticoid groups. However, patients with more organs involved and higher IgG4-RD RI score at baseline might get more benefit with high dose glucocorticoid for remission induction., (© 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Introduction: IgG4-related disease (IgG4-RD) is a multisystem-involved autoimmune disease. Abnormally activated and differentiated B cells may play important roles. Regulatory B cells (Breg) are newly defined B cell subgroups with immunosuppressive functions. In this study, we investigated the differences of B cell subsets, the expressions of co-stimulatory molecules on B cells, and the function of Breg cells in patients with IgG4-RD, primary Sjögren's syndrome (pSS) as well as in healthy controls (HC)., Methods: Newly diagnosed IgG4-RD patients (n = 48) were enrolled, 38 untreated pSS patients and 30 healthy volunteers were recruited as disease and healthy controls. To analyze B cell subsets and B cell activity, PBMCs were surface stained and detected by flow cytometry. The function of Breg cells was tested by coculturing isolated CD19 + CD24(hi)CD38(hi) Breg cells with purified CD4 + CD25- T cells. Serum cytokines were measured by ELISA and cytometric bead array. Relationship between clinical data and laboratory findings were analyzed as well., Results: Compared with pSS patients and HC, IgG4-RD patients had a lower frequency of peripheral Breg cells. Interestingly, CD19 + CD24-CD38(hi) B cell subsets were significantly higher in peripheral B cells from IgG4-RD patients than in pSS patients and HC, which correlated with serum IgG4 levels. The expression of BAFF-R and CD40 on B cells was significantly lower in IgG4-RD patients compared with those in pSS patients and HC. Unlike HC, Breg cells from pSS patients lacked suppressive functions., Conclusions: B cells in patients with IgG4-RD and pSS display a variety of abnormalities, including disturbed B cell subpopulations, abnormal expression of key signaling molecules, co-stimulatory molecules, and inflammatory cytokines. In addition, a significantly increased B cell subset, CD19 + CD24-CD38(hi) B cells, may play an important role in the pathogenesis of IgG4-RD.

Background: Extrahepatic manifestations in patients with primary biliary cholangitis (PBC) are frequently observed recently. We aimed in this study to explore the clinicopathological characteristics and prognosis of glomerulonephritis in patients with PBC. Methods: Consecutive PBC patients admitted to Peking Union Medical College Hospital from January 2002 to May 2019 were retrospectively enrolled. PBC patients with other autoimmune diseases which may have nephritis were excluded. Structured interview, systemic rheumatologic examination, and laboratory tests were conducted for each patient. Literature about patients with PBC and glomerulonephritis was reviewed and summarized. Results: Among the 330 PBC patients enrolled, glomerulonephritis were identified in 10 patients (3.0%). Eight (80.0%) were females and 2 (20.0%) were males. The mean age was 58.4 ± 9.5 years old. Membranous nephropathy (MN) was revealed in 4 patients, IgA nephropathy (IgA N) in 2 patients, minimal change disease (MCD) in 2 patients, mesangial proliferative glomerulonephritis in 1 patient, and renal amyloidosis in 1 patient. Compared to the literature reviewed, 10 cases of MN, 1 case of MCD, 1 case of IgA N, and 1 case of acute poststreptococcal glomerulonephritis (APSGN) were observed. Conclusions: Glomerulonephritis may not be a well-recognized feature of PBC and is not a rare complication and deserved to be routinely screened in clinical practice. As MN is the most common form of glomerulonephritis in PBC patients and PBC can be asymptomatic at an early stage, patients presented with MN should be screened for PBC, so to avoid cirrhosis. Key Points • Patients with primary biliary cholangitis (PBC) can be complicated with glomerulonephritis, and membranous nephropathy (MN) is the most common form. [ABSTRACT FROM AUTHOR]

Primary Sjögren's syndrome (pSS) is a prevalent autoimmune disorder wherein CD4+ T cells play a pivotal role in its pathogenesis. However, the underlying mechanisms driving the hyperactivity of CD4+ T cells in pSS remain poorly understood. This study aimed to investigate the potential role of immunometabolic alterations in driving the hyperactivity of CD4+ T cells in pSS. We employed Seahorse XF assay to evaluate the metabolic phenotype of CD4+ T cells, conducted flow cytometry to assess the effector function and differentiation of CD4+ T cells and measured the level of intracellular reactive oxygen species (ROS). Additionally, transcriptome sequencing, PCR, and Western blotting were utilized to examine the expression of glycolytic genes. Our investigation revealed that activated CD4+ T cells from pSS patients exhibited elevated aerobic glycolysis, rather than oxidative phosphorylation, resulting in excessive production of IFN-γ and IL-17A. Inhibition of glycolysis by 2-Deoxy-D-glucose reduced the expression of IFN-γ and IL-17A in activated CD4+ T cells and mitigated the differentiation of Th1 and Th17 cells. Furthermore, the expression of glycolytic genes, including CD3E, CD28, PIK3CA, AKT1, mTOR, MYC, LDHA, PFKL, PFKFB3, and PFKFB4, was upregulated in activated CD4+ T cells from pSS patients. Specifically, the expression and activity of LDHA were enhanced, contributing to an increased level of intracellular ROS. Targeting LDHA with FX-11 or inhibiting ROS with N-acetyl-cysteine had a similar effect on reversing the dysfunction of activated CD4+ T cells from pSS patients. Our study unveils heightened aerobic glycolysis in activated CD4+ T cells from pSS patients, and inhibition of glycolysis or its metabolite normalizes the dysfunction of activated CD4+ T cells. These findings suggest that aerobic glycolysis may be a promising therapeutic target for the treatment of pSS. [ABSTRACT FROM AUTHOR]

This prospective cohort study aims to investigate the incidence, related factors and prognosis of IgG4-related disease (IgG4-RD) with malignancies in the Chinese cohort. We prospectively analyzed the IgG4-RD patients recruited in Peking Union Medical College Hospital from January 2011 to August 2018 and identified patients diagnosed with IgG4-RD complicating malignancies. Data regarding demographics, clinical features, treatment and prognosis of IgG4-RD patients complicating malignancies were collected and compared to those of age- and sex-matched controls. Among the 587 Chinese patients with IgG4-RD, 17 malignancies were identified. Ten of them developed malignancy after the diagnosis of IgG4-RD, given a standard incidence ratio (SIR) of 2.78 (95%CI 1.33–5.12). Multivariate logistic analysis indicated that autoimmune pancreatitis (OR = 6.230, 95%CI 1.559–24.907, p = 0.010) was positively associated with malignancy, whereas eosinophilia (OR = 0.094, 95%CI 0.010–0.883, p = 0.039) was negatively related with malignancies. During a median follow-up period of 61.4 ± 26.4 months, all patients with IgG4-RD and malignancies survived. We conclude that an increased incidence of malignancy was found in Chinese IgG4-RD cohort. Autoimmune pancreatitis is a potential risk factor, whereas eosinophilia is a possible protective factor for complicating malignancies. [ABSTRACT FROM AUTHOR]

Objectives To study the impact of sex on the clinical presentation of IgG4-related disease (IgG4-RD). Methods We prospectively enrolled 403 newly diagnosed IgG4-RD patients. We compared the demographic features, clinical manifestations, organ involvement, laboratory tests and treatment outcomes between female and male patients. The organs involved were divided into superficial organs (salivary glands, lacrimal glands, orbit, sinus and skin) and internal organs (all the other organs). The patients treated with glucocorticoids with or without additional immunosuppressants were included in the assessment of treatment outcomes, and potential confounding factors were corrected by propensity score matching or multivariate Cox regression analysis. Results Female patients showed younger age at both symptom onset and diagnosis, and a longer interval between symptom onset and diagnosis. Allergy history, Mikulicz's disease and thyroiditis were more common in female patients, while autoimmune pancreatitis, sclerosing cholangitis and retroperitoneal fibrosis were more common in male patients. In accordance, female patients more frequently presented with superficial organ involvement, while male patients more frequently had internal organ involvement, and the discrepancy was more prominent in the patients with older age. Male sex was associated with higher peripheral eosinophils, CRP and IgG4 levels at baseline. In response to glucocorticoid-based therapies, male sex was associated with a higher IgG4-RD responder index during follow-up as well as a greater risk of relapse (hazard ratio 3.14, P = 0.003). Conclusion Our study revealed the sex disparities in clinical characteristics of IgG4-RD, and indicated that male sex was independently associated with worse prognosis in response to glucocorticoid-based therapies. [ABSTRACT FROM AUTHOR]

Patients with primary biliary cholangitis (PBC) can have extrahepatic manifestations. However, data about cardiac involvement of PBC is limited. We aimed in this study to analyze the clinical characteristics in patients with PBC complicated with and without cardiac involvement, and the risk factors of cardiac involvement in PBC. PBC patients admitted to Peking Union Medical College Hospital between January 2002 and February 2016 were consecutively enrolled. Structured interview, systemic rheumatologic examination, and laboratory tests were conducted for each patient, and risk factors of cardiac involvement were analyzed by comparing patients with and without cardiac involvement. In total, 580 PBC patients were enrolled, and cardiac involvement was identified in 24 patients (4%), with 11 male (46%) and a mean age of 57±8 year. Cardiomyopathy and arrhythmias were presented in 17 (70.8%) and 21 (87.5%) patients, respectively. Patients with cardiac involvement were more frequently male (46% vs. 11%, P<0.01), complicated with inflammatory myopathy (IM) (58% vs. 1%, P<0.01), and had a longer disease course (median, 72 vs 24 month, P<0.01). Furthermore, concomitant IM was the independent risk factor of cardiac involvement in PBC (OR = 77.333, 95% CI: 23.704–252.294). Cardiac involvement was a rare complication of PBC, which was more frequently observed in male or long-course patients. Importantly, concomitant IM was the strong independent risk factor of cardiac involvement in PBC. Given cardiac involvement is a serious complication, thorough evaluation of cardiac manifestation in high-risk PBC patients is highly recommended. [ABSTRACT FROM AUTHOR]

The pathogenesis of rheumatoid arthritis (RA), a systemic autoimmune disease characterized by autoreactive T-cell accumulation and pro-inflammatory cytokine overproduction, is unclear. Systematically addressing T-cell receptor (TCR) repertoires of different CD4+ T-cell subsets could help understand RA pathogenesis. Here, peripheral CD4+ T cells from treatment-naïve RA patients and healthy controls were sorted into seven subsets including naïve, effector, central memory, effector memory (EMT), Th1, Th17, and regulatory T cells. T-cell receptor β chain repertoires were then analyzed by next-generation sequencing. We identified T-cell clonal expansion in EMT and Th17 cells of RA patients, with highly similar TCR repertoires. Ex vivo experiments demonstrated the preferred differentiation from EMT to Th17 cells in RA. Notably, we showed that TCR diversity and abundance of differentiated T cells of Th17 were significantly correlated with RA disease activity. Based on these observations, we propose that abnormal differentiation from EMT to Th17 and expansion of Th17 play pivotal role in RA pathogenesis. • The abnormal uses of TRBV3-1 and TRBJ2-7 genes are detected in effector memory T (EMT) and Th17 cells in rheumatoid arthritis (RA) patients. • The T-cell receptor (TCR) repertoire diversities of EMT and Th17 cells are decreased in RA patients. • Stronger correlations between EMT and Th17 cells exist in RA patients. • Ex vivo experiments demonstrate the preferred differentiation from EMT to Th17 cells in RA. • Clonotypes of Th17 cells differentiated from EMT correlated with RA disease activity. [ABSTRACT FROM AUTHOR]