Performance of the 2019 ACR/EULAR Classification Criteria for IgG4-Related Disease in a Large Chinese Cohort.

OBJECTIVE: The purpose of this research was to ascertain the effectiveness of the newly established criteria for classifying IgG4-related disease (IgG4-RD), as applied to a large Chinese cohort in real-world clinical settings. METHODS: Patient data were procured from the digital health records of 4 prominent academic hospitals. The criterion standard for identifying IgG4-RD patients was from a seasoned rheumatologist. The control group consisted of individuals with other ailments such as cancer, other forms of pancreatitis, infectious diseases, and illnesses that mimic IgG4-RD. RESULTS: A total of 605 IgG4-RD patients and 760 mimickers were available for analysis. The 2019 EULAR/ACR criteria have a sensitivity of 69.1% and a specificity of 90.9% in this large Chinese cohort. IgG4-RD had a greater proportion of males (55.89% vs 36.25%, p < 0.001), an older average age at diagnosis (54.91 ± 13.44 vs 48.91 ± 15.71, p < 0.001), more pancreatic (29.59% vs 6.12%, p < 0.001) and salivary gland (63.30% vs 27.50%, p < 0.001) involvement, and a larger number of organ involvement (3.431 ± 2.054 vs 2.062 ± 1.748, p < 0.001) compared with mimickers. CONCLUSIONS: The 2019 EULAR/ACR criteria are effective in classifying IgG4-RD in Chinese patients, demonstrating high specificity and moderate sensitivity.

Liquiritigenin Attenuated Collagen-Induced Arthritis and Cardiac Complication via Inflammation and Fibrosis Inhibition in Mice.

Rheumatoid arthritis (RA) is a common autoimmune disease with increased cardiovascular disease risk. Liquiritigenin (LG) is a triterpene with anti-inflammatory properties. Our study aimed to explore the effect of LG on RA and the cardiac complication. Collagen-induced arthritis (CIA) mice with LG treatment exhibited obvious alleviation in histopathological changes, accompanied by the decreased expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-17A in synovium and serum. LG attenuated cartilage destruction by reducing matrix metalloproteinase (MMP)-3 and MMP-13 expression in the synovium of CIA mice. The echocardiography results proved the alleviation of cardiac dysfunction in CIA mice. The electrocardiogram, biochemical, and histochemical analysis proved the cardioprotection effect of LG against RA. The decreased expression of inflammatory factors (TNF-α, IL-1ß, and IL-6) and fibrotic markers (fibronectin, Collagen I, and Collagen III) in cardiac tissues of CIA mice further corroborated the attenuation of myocardial inflammation and fibrosis by LG. Mechanistic studies showed that LG could inhibit transforming growth factor ß-1 (TGF-ß1) and phos-Smad2/3 expression in cardiac tissues of CIA mice. Our study suggested that LG could relieve RA and its cardiac complication probably by inhibiting the TGF-ß1/Smad2/3 pathway. All these suggested that LG might be a potential candidate for RA and its cardiac complication therapy.

Loss of AKAP12 aggravates rheumatoid arthritis-like symptoms and cardiac damage in collagen-induced arthritis mice.

A-kinase anchoring protein 12 (AKAP12) has been identified as an anti-inflammatory and anti-fibrotic regulator in chronic inflammation and cardiovascular disease. However, the potential of AKAP12 in autoimmune disorders, rheumatoid arthritis (RA) and associated cardiac complications remains elusive. Here, a murine model of collagen-induced arthritis (CIA) was successfully induced, followed by adenovirus-mediated AKAP12 short hairpin RNA (shRNA) treatment. AKAP12 silenced mice displayed elevated clinical arthritis scores and significant ankle joint swelling. AKAP12 loss in CIA mice increased inflammatory cell infiltration and cartilage erosion, increased the levels of anti-IIC IgG and inflammatory cytokines IL-1ß, IL-6, tumor necrosis factor (TNF)-α in serum, and upregulated the expression of cartilage-degrading enzymes MMP-1, MMP-3, MMP-13 in synovium, but reduced IL-10. The number of M1 macrophages and the expression of the markers (CCR7, IL-6, TNF-α and iNOS) was enhanced in synovial tissues, while M2 polarized macrophages and the makers (IL-10 and arginase-1) were reduced in response to AKAP12 loss. Moreover, low expression of AKAP12 was detected in the hearts of CIA mice. Loss of AKAP12 results in increased cardiac inflammation and fibrosis. This work suggests that AKAP12 loss aggravates joint inflammation likely through the promotion of M1 macrophage polarization and exacerbates inflammation-caused cardiac fibrosis.

Malignancy Risk of Immunoglobin G4-Related Disease: Evidence from a Large Cohort Multicenter Retrospective Study.

INTRODUCTION: The aim of this work was to evaluate the prevalence of malignancies in a multicenter cohort of Chinese patients with immunoglobulin G4-related disease (IgG4-RD) and to identify the related risk factors of malignancy in IgG4-RD patients. METHODS: We retrospectively analyzed 602 IgG4-RD patients who were recruited in five medical centers from 2009 to 2020. Standardized prevalence ratios (SPRs) against the general Chinese population were calculated along with 95% confidence intervals (CIs). We identified the risk factors of malignancy in IgG4-RD and calculated the odds ratios (ORs) of different factors. We then developed and validated a prediction model for malignancy risk of IgG4-RD based on our cohort. RESULTS: We observed a significantly increased prevalence of total malignancies in this cohort compared to the general Chinese population (SPR 8.66 [95% CI 5.84, 12.31]). Logistic regression analysis indicated that eosinophil percentage (OR 1.096 [95% CI 1.019-1.179], P = 0.016), serum albumin-to-globulin ratio (AGR) (OR 0.185 [95% CI 0.061-0.567], P = 0.002) and autoimmune pancreatitis (OR 2.400 [95% CI 1.038-5.549], P = 0.041) were three potential risk factors of malignancy in IgG4-RD patients. Four predictors were included in our final prediction model: age at IgG4-RD diagnosis, eosinophil percentage, AGR and autoimmune pancreatitis. The nomogram performed well in the internal validation cohort, with a concordance index (C-index) of 0.738. CONCLUSIONS: A significantly increased prevalence of total malignancies was observed in our multicenter cohort. Eosinophil percentage and autoimmune pancreatitis are risk factors, whereas AGR is negatively associated with malignancy in IgG4-RD. A prediction model for malignancy risk of IgG4-RD was first developed and validated in our study.

Pathogenic mechanism of miR-21 in autoimmune lymphoid hyperplasia syndrome.

miR-21 plays an important role in immune responses and inflammatory diseases, but the mechanism of action of miR-21 in autoimmune lymphoid hyperplasia syndrome still remains unclear. The aim of the present study was to assess the mechanism of miR-21 in autoimmune disease, particularly, the autoimmune lymphoid hyperplasia syndrome. The pathology and immunity-related phenotypes of miR-21 transgenic mice, and the lymphocyte subsets were analyzed. The related T cell subsets and germinal center B (GCB) cells generated at the germinal center were detected with flow cytometry. The target genes of miR-21 were evaluated with the luciferase reporter gene method. The homeostatic proliferation of the lymphocytes was detected with the EdU incorporation assay. Inflammatory infiltration occurred to the lung and liver of the transgenic mice at 8 weeks. The frequency of the regulatory helper T cells decreased slightly. Significantly increased double negative T cells were observed in the spleen of the transgenic mice (P<0.05). The immunoglobulins IgG1, IgG2a, IgG2b, and IgG3 in the serum of the transgenic mice aged 8 weeks were significantly higher than those in the wild-type mice aged 8 weeks (P<0.05). The percentages of the GCB cells in the peripheral lymphoid organs such as lymph nodes, mesenteric lymph nodes, PP and spleen in the transgenic mice aged 8-52 weeks increased significantly (P<0.05). The percentage (26.32%) of the newly-formed GCB cells derived from transgenic mice was significantly higher than that (3.87%) of the GCB cells derived from the wild-type mice. miR-21 played a role of negative feedback regulation by inhibiting the NF-κB signal pathway. The highly-expressed miR-21 B cells promoted homeostatic proliferation of the T cells. miR-21 can promote homeostatic proliferation of lymphocytes by inhibiting the NF-κB signal pathway.

Insulin-like growth factor 1 regulates growth of endometrial carcinoma through PI3k signaling pathway in insulin-resistant type 2 diabetes.

Previous studies have shown that insulin-like growth factor 1 (IGF-1) may be responsible for the higher risk for developing endometrial carcinoma (EMC) in insulin-resistant type 2 diabetes mellitus (T2DM) patients. However, the underlying mechanisms are not understood. Here, we compared T2DM patients with or without EMC. We did not find difference in the serum levels of IGF-1, insulin-like growth factor 2 (IGF-2), IGF-1 binding protein 3, as well as the activation of IGF-1 receptor (IGF1R) in endometrial cells between T2DM patients with or without EMC. However, the levels of IGF2R activation and activation of PI3k, an IGF1R downstream factor, were significantly higher in endometrial cells in T2DM patients with EMC. In vitro analyses of activation of IGF1R, IGF2R, PI3k and CCND1 in EMC cells or IGF2R-overexpressing EMC cells by IGF-1 or IGF-2 suggest that increases in IGF2R in endometrial cells in T2DM may increase PI3k/CCND1-dependent cell growth through loss of competitive binding of IGF-2 to IGF1R, as a possible explanation for the higher risk for developing EMC in T2DM.