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ErMiao San (EMS) is composed of the Cortex Phellodendri chinensis and Atractylodes lancea, and it has the function of eliminating heat and excreting dampness in terms of traditional Chinese medicine to damp heat syndrome. Previous reports indicate that EMS possesses anti-inflammatory activity; however, its action on angiogenesis of rheumatoid arthritis (RA) has not been clarified. The present study aims to determine the antiangiogenic activity of EMS in collagen-induced arthritis (CIA) mice and in various angiogenesis models. Our data showed that EMS (5 g/kg) markedly reduced the immature blood vessels in synovial membrane tissues of inflamed joints from CIA mice. It also inhibited vascular endothelial growth factor (VEGF)-induced microvessel sprout formation ex vivo. Meanwhile, EMS suppressed VEGF-induced migration, invasion, adhesion, and tube formation of human umbilical vein endothelial cells (HUVECs). Moreover, EMS significantly reduced the expression of angiogenic activators including interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) in synovium of CIA mice. More interestingly, EMS blocked the autophosphorylation of VEGF-induced JAK1, STAT1, and STAT6 in CIA mice and VEGF-induced HUVECs. These findings suggest for the first time that EMS possesses the antiangiogenic effect in RA in vivo, ex vivo, and in vitro by interrupting the targeting of JAK/STAT activation.

Millions of people still live in cave dwellings in China and around the world. Due to high risk of earthquakes combined with material deterioration, cave dwellings exhibit poor seismic perf...

We describe a previously unreported association of ankylosing spondylitis with synovial chondromatosis, and briefly review previously reported cases and treatment of synovial chondromatosis in patients with other immune-mediated inflammatory arthritides. A 20-year-old man with ankylosing spondylitis whose axial disease was in remission with nonsteroidal anti-inflammatory drugs and oral disease-modifying anti-rheumatic drugs developed recurrent right knee pain and swelling. Magnetic resonance imaging of his right knee revealed calcified loose bodies, suggestive of synovial chondromatosis. While waiting for the surgical intervention and other invasive therapy previously reported in patients with synovial chondromatosis, a trial of etanercept eliminated the pain and swelling of the knee; however, the loose bodies have persisted during the 2-year follow-up. Thus, synovial chondromatosis should be considered in the differential diagnoses of a refractory monoarticular pain and swelling in patients with otherwise controlled inflammatory arthritis. Our report advocates a trial of anti-tumor necrosis factor drugs, which might delay the need for invasive therapy in patients with synovial chondromatosis.

Background: An increasing number of studies have applied ultrasound (US) to evaluate enthesitis in spondyloarthritis. However, there is no clear agreement on which sites should be evaluated for enthesitis. Furthermore, there are different opinions on whether US can monitor disease activity. The objectives of this study were to evaluate the common involvement of entheses and correlations between disease activity and US scores in ankylosing spondylitis (AS).Methods: A cross-sectional, monocentric, and controlled study was performed. US was used to scan 34 entheses per person and the Madrid sonography enthesitis index (MASEI) score was used. US scores were used to evaluate the elemental lesions of hypoechogenicity, thickness, erosion, calcification, bursitis, and Doppler signal. Disease activity was assessed by Disease Activity Score–C reactive protein (ASDAS-CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).Results: 104 patients with AS and 50 control subjects were included. A total of 5236 entheses were assessed. Compared with the control subjects, only three entheses – the Achilles tendon (AT), sternoclavicular joint (SCJ), and costochondral joint (CCJ) – showed significant differences in the AS group (p < 0.05). Patients with high disease activity (ASDAS-CRP ≥ 2.1) had higher scores than patients with low activity (ASDAS-CRP < 2.1) in erosion (p = 0.02). Patients who were categorized in very high disease activity (ASDAS-CRP ≥ 3.5) had a higher score in erosion (p = 0.02). The erosion score was moderately associated with ASDAS-CRP and BASDAI (r = 0.44, r = 0.21).Conclusions: The commonly involved entheses were the AT, SCJ, and CCJ in AS. Erosion occurred more often in patients with disease activity or high activity. Erosion would be more useful for monitoring disease activity in AS.

Aim of the work To describe the clinical features and prognostic factors in patients with rheumatic diseases (RDs) admitted to the intensive care unit (ICU). Patients and methods Clinical data of 33 RD patients admitted to the ICU of Shenzhen Baoan Hospital were retrospectively analyzed regarding the causes for admission, medications received, duration of stay and the management required. Disease severity of the patients was assessed using the acute physiology and chronic health evaluation (APACHE-II) score. Results The diagnoses of the patients included 16 (48.5%) systemic lupus erythematosus (SLE), 7 (21.2%) systemic vasculitis, 4 (12.1%) rheumatoid arthritis; 3 (9.1%) polymyositis/dermatomyositis; 2 (6.1%) Sjogren’s syndrome and 1 (3%) with systemic sclerosis. The mean APACHE-II score was mean 16.1 ± 7.3. The main cause for ICU admission was infection in 12 (36.4%) patients, primary disease worsening in 8 (24.2%), infection associated with disease activity in 9 (27.3%) and 4 (12.1%) cases were hospitalized for other disease processes (including 1 case of subarachnoid hemorrhage, 1 case of acute myocardial infarction and 2 with hypovolemic shock). 31 (93.9%) had more than one organ involved. Mortality was 51.5% (17 cases); including 9 (27.3%) deaths from infection, 5 (15.2%) from primary diseases, and 3 (9.1%) from other causes. Primary disease worsening and APACHE-II score were significantly increased in the mortality cases (33.3% and 20 ± 7.1) compared to survivors (13.3% and 10 ± 1.2) (p = 0.017 and 0.0001 respectively). Conclusion SLE was the most frequent cause of ICU admission; infections are the leading causes prompting admission. RDs patients often had multi-organ involvement with a high mortality rate.

Introduction: Proline-rich tyrosine kinase 2 (PYK2) provides important signals during the activation of lymphocytes, which is essential in autoimmune diseases. Systemic lupus erythematosus (SLE) is a representative autoimmune disease, and lupus nephritis (LN) is one of its most severe complications. Although glucocorticoid-binding immuno-suppression is the first-line therapy for patients with LN, the common and severe side effects of such treatment call for new strategies to improve long-term prognosis and life quality for these patients. Curcumin has been used to treat autoimmune disease with good curative effect, but little is known about the effect of curcumin on LN patients. Our aim was to investigate the mechanism of curcumin for management of LN, specifically regarding the PYK2 pathways. Material and methods: Freshly isolated peripheral blood mononuclear cells (PBMCs) from 20 LN patients and 20 healthy individuals were cultured and stimulated with either PMA, PMA+TyrA9 (PYK2 specific inhibitor), or PMA+Curcumin, and with PBS as control. After 48 hours of incubation, cells were harvested and the expression of PYK2, p-PYK2, CD40L, CTLA-4, and PBMCs proliferation were measured. Then the expression and activation of PYK2 was evaluated using Western blot, the expression of costimulatory molecules CD40L and CTLA-4 protein was evaluated using flow cytometry, and PBMC proliferation was assessed using a [3H]-thymidine incorporation assay. Results: Curcumin inhibited the expression and activation of PYK2 in PBMCs in patients with LN in vitro. The inhibition rate of curcumin was negatively correlated with the level of serum complement, but positively correlated with 24-h proteinuria. Curcumin also suppressed the expression of costimulatory molecules CD40L and CTLA-4, as well as PBMC proliferation. Interestingly, these effects were not reproduced on PBMC cultures of healthy subjects. Conclusions: The inhibition of PYK2 signalling protein may be one of the mechanisms underlying the action of curcumin in LN treatment.

Introduction: Leukocyte immunoglobulin-like receptor A3 (LILRA3) belongs to the LILR family with unique feature of a 6.7-kb deletion variation among individuals. Frequencies of the 6.7-kb deletion vary widely across populations, but so far it has not been carefully investigated among Han Chinese subpopulations. Furthermore, we previously identified the non-deleted (functional) LILRA3 as a novel genetic risk for multiple autoimmune diseases. The current study aimed to investigate (i) whether frequencies of the LILRA3 6.7-kb deletion differ within Han Chinese subpopulations and (ii) whether the functional LILRA3 is a novel genetic risk for ankylosing spondylitis (AS).Methods: The LILRA3 6.7-kb deletion was genotyped in two independent cohorts, including 1,567 subjects from Shenzhen Hospital and 2,507 subjects from People’s Hospital of Peking University. Frequencies of the 6.7-kb deletion were first investigated in combined healthy cohort according to the Chinese administrative district divisions. Association analyses were performed on whole dataset and subsets according to the geographic regions. Impact of the functional LILRA3 on AS disease activity was evaluated.Results: Frequencies of LILRA3 6.7-kb deletion were highly differentiated within Han Chinese subpopulations, being gradually decreased from Northeast (80.6%) to South (47.4%). Functional LILRA3 seemed to be a strong genetic risk in susceptibility to AS under almost all the alternative genetic models, if the study subjects were not geographically stratified. However, stratification analysis revealed that the functional LILRA3 was consistently associated with AS susceptibility mainly in Northern Han subgroup under the alternative genetic models, but not in Central and Southern Hans. Functional LILRA3 conferred an increased disease activity in AS patients (P < 0.0001 both for CRP and ESR, and P = 0.003 for BASDAI).Conclusions: The present study is the first to report that the frequencies of LILRA3 6.7-kb deletion vary among Chinese Hans across geographic regions. The functional LILRA3 is associated with AS susceptibility mainly in Northern Han, but not in Central and Southern Han subgroups. Our finding provides new evidence that LILRA3 is a common genetic risk for multiple autoimmune diseases and highlights the genetic differentiation among different ethnicities, even within the subpopulations of an ethnic group.

Objective: Smad7 is an inhibitory Smad and plays a protective role in many inflammatory diseases. However, the roles of Smad7 in rheumatoid arthritis (RA) remain unexplored, which were investigated in this study. Methods: The activation of TGF-β/Smad signaling was examined in synovial tissues of patients with RA. The functional roles and mechanisms of Smad7 in RA were determined in a mouse model of collagen-induced arthritis (CIA) in Smad7 wild-type (WT) and knockout (KO) CD-1 mice, a strain resistant to autoimmune arthritis induction. Results: TGF-β/Smad3 signaling was markedly activated in synovial tissues of patients with RA, which was associated with the loss of Smad7, and enhanced Th17 and Th1 immune response. The potential roles of Smad7 in RA were further investigated in a mouse model of CIA in Smad7 WT/KO CD-1 mice. As expected, Smad7-WT CD-1 mice did not develop CIA. Surprisingly, CD-1 mice with Smad7 deficiency developed severe arthritis including severe joint swelling, synovial hyperplasia, cartilage damage, massive infiltration of CD3+ T cells and F4/80+ macrophages, and upregulation of proinflammatory cytokines IL-1β, TNFα, and MCP-1. Further studies revealed that enhanced arthritis in Smad7 KO CD-1 mice was associated with increased Th1, Th2 and, importantly, Th17 over the Treg immune response with overactive TGF-β/Smad3 and proinflammatory IL-6 signaling in the joint tissues. Conclusions: Smad7 deficiency increases the susceptibility to autoimmune arthritis in CD-1 mice. Enhanced TGF-β/Smad3-IL-6 signaling and Th17 immune response may be a mechanism through which disrupted Smad7 causes autoimmune arthritis in CD-1 mice.

Recurrent pregnancy loss (RPL) is the most common manifestation of anti-phospholipid syndrome (APS), and activated CD4+ T cells are involved in its pathogenesis. Treatment with low-molecular weight heparin (LMWH) and aspirin combination improves pregnancy outcome, however, its mechanism of action is unclear. We investigated the effect of this therapy on Th1/Th2 cells in 89 patients with APS-RPL. The results showed that serum cytokine levels, T cell phenotypes, and transcription factors' gene expression levels representing Th1 responses were higher, whereas those representing Th2 responses were lower in patients with APS-RPL at the time of early pregnancy. This Th1-bias was reversed in patients who had live birth after receiving the combination therapy at the time of delivery. Patients with miscarriages continued to exhibit Th1-bias. In conclusion, these data support a role of Th1-bias in the pathogenesis of APS-RPL and suggest restoring T-cell phenotype as a new immunomodulatory mechanism of LMWH/aspirin combination.