The amino acid variants in HLA II molecules explain the major association with adult-onset Still's disease in the Han Chinese population.

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease with systemic involvement, and its pathophysiology remains unclear. Genome-wide association studies (GWAS) in the Chinese population have revealed an association between AOSD and the major histocompatibility complex (MHC) locus; however, causal variants in the MHC remain undetermined. In the present study, we identified independent amino-acid polymorphisms in human leukocyte antigen (HLA) molecules that are associated with Han Chinese patients with AOSD by fine-mapping the MHC locus. Through conditional analyses, we identified position 34 in HLA-DQα1 (p = 1.44 × 10-14) and Asn in HLA-DRß1 position 37 (p = 5.12 × 10-11) as the major determinants for AOSD. Moreover, we identified the associations for three main HLA class II alleles: HLA-DQB1*06:02 (OR = 2.70, p = 3.02 × 10-14), HLA-DRB1*15:01 (OR = 2.44, p = 3.66 × 10-13), and HLA-DQA1*01:02 (OR = 1.97, p = 1.09 × 10-9). This study reveals the relationship between functional variations in the class II HLA region and AOSD, implicating the MHC locus in the pathogenesis of AOSD.

Clinical performance of automated chemiluminescent methods for anticardiolipin and anti-ß2-glycoprotein I antibodies detection in a large cohort of Chinese patients with antiphospholipid syndrome.

INTRODUCTION: To assess the clinical performance and correlations of automated chemiluminescence assay (CIA) and enzyme-linked immunosorbent assay (ELISA) for detecting antiphospholipid (aPL) antibodies in the diagnosis of antiphospholipid syndrome (APS). METHODS: The study recruited 505 subjects, including 192 with APS, 193 with connective tissue diseases other than APS, and 120 healthy donors. We measured anticardiolipin (aCL) and anti-ß2-glycoprotein I (anti-ß2GPI) antibodies IgG, IgM, and IgA in all the samples using both CIA and ELISA. RESULTS: Total agreement between the two methods ranged from 83.50% for anti-ß2GPI IgG antibodies to 92.76% for anti-ß2GPI IgM antibodies in all the groups. Anti-ß2GPI and aCL IgG assays showed the highest Spearman's rho coefficients (anti-ß2GPI IgG = 0.742, aCL IgG = 0.715). Anti-ß2GPI IgG CIA showed the highest sensitivity for diagnosis of APS at 80.21%, which was significantly higher than the sensitivity of anti-ß2GPI IgG ELISA (52.08%). For diagnosis of APS, anti-ß2GPI IgG CIA had the best discrimination power with the area under the curves (AUC) of 0.922, followed by aCL IgG CIA (AUC of 0.905). While the CIA AUC was slightly higher in all cases, the difference was not statistically significant. CONCLUSION: CIA measurements had a good agreement and correlation with comparative ELISA assays. The CIA anti-ß2GPI IgG however was significantly more sensitive for APS diagnosis. The two assay methodologies showed comparable predictive powers and support the value of the CIA method for improved diagnosis and management of patients with APS.

Clinical features and current treatments of adult-onset Still's disease: a multicentre survey of 517 patients in China.

OBJECTIVES: As a rare systemic autoinflammatory disease, adult-onset Still's disease (AOSD) has heterogeneous clinical manifestations, response to treatment and outcome. This study tried to assess the clinical characteristics, laboratory tests, and treatments of Chinese AOSD patients, and make a retrospective analysis. METHODS: We collected from 7 hospitals in China a total of 517 Chinese patients with AOSD who satisfied the Yamaguchi criteria. We retrospectively evaluated their clinical features, laboratory tests, treatments and compared them with published data from different studies. All the data in this study were from medical records and further statistic analyses. RESULTS: We evaluated a total of 517 AOSD patients, 72% female, average age of onset was 37.7; spiking fever, rash and arthralgia occurred in 472 (91.3%), 413 (79.9%), 378 (73.1%) cases, respectively. There were 439/513 (85.6%) cases with leukocytosis and 456/476 (95.8%) cases with raised serum ferritin. The highest frequently used medications and regimens for remission were glucocorticoids (498/517, 96.3%), methotrexate (273/517, 52.8%) and hydroxychloroquine (174/517, 33.7%). 84.4%. 357/423 of AOSD cases were able to achieve initial remission with different regimens, mostly including glucocorticoids, methotrexate or hydroxychloroquine. 47.2% of them (244/517) received 30

Hydroxychloroquine Improves Obesity-Associated Insulin Resistance and Hepatic Steatosis by Regulating Lipid Metabolism.

The burden of obesity and associated cardiometabolic diseases has been considered as an important risk factor for lupus patients. Therefore, whether obesity is involved in the over-activation of autoimmune response has attracted more and more attention. Hydroxychloroquine is a synthetic antimalarial drug and has been the clinical treatment of rheumatic diseases irreplaceable first-line drugs. Hydroxychloroquine has been suggested to have beneficial effects on lipids and insulin sensitivity, which may contribute in lowering high cardiovascular risk in SLE patients. However, its mechanism on insulin sensitivity and lipid disorders is far from being completely understood. In the present study, the therapeutic effects of hydroxychloroquine were evaluated under pathological conditions in vivo. Obesity was induced in C57BL/6 mice fed with high-fed diet, or in mice fed with high-fat diet and hydroxychloroquine. In addition, healthy mice that received normal chow diet were also monitored. The present results revealed that hydroxychloroquine reduced weight, hepatic steatosis, glucose, and insulin resistance. Furthermore, hydroxychloroquine downregulated the expression of peroxisome proliferator-activated receptor gamma in the liver. According to these present results, genes about lipid metabolism went down in high-fat mice liver. Hydroxychloroquine shows potential in ameliorating obesity-induced pathology, which acts though PPARγ to facilitate the healthy function of hepatic tissues. This evidence shows that hydroxychloroquine plays a role in improving obesity-induced lipotoxicity and insulin resistance though the peroxisome proliferator-activated receptor gamma pathway.

Causes of death in hospitalized patients with systemic lupus erythematosus: a 10-year multicenter nationwide Chinese cohort.

To estimate the mortality and describe the causes of death in a large multicenter cohort of hospitalized patients with SLE in China. This was a retrospective study of a nationwide SLE cohort (10 centers, 29,510 hospitalized patients) from 2005 to 2014 in China. Standardized mortality ratios (SMRs) were calculated for all death and were stratified by sex and age. Chi-square test was used to determine whether the major causes of death vary in age, sex, duration of SLE, disease activity, or medications. Comparison between dead patients and survival controls was used to identify the risk factors for mortality. Logistic regression analysis was used to evaluate the risk factors for mortality. A total of 360 patients died during the study period, accounting for 1.22%. The overall SMR was 2.13 (95% CI 1.96, 2.30), with a particularly high SMR seen in subgroups characterized by younger age. Infection (65.8%) was the most common cause of death, followed by lupus nephritis (48.6%), hematological abnormality (18.1%), neuropsychiatric lupus/NPSLE (15.8%), and interstitial pneumonia (13.1%). Cardiovascular disease and malignancy contributed little to the causes of death. Infection, in particular severe pulmonary infection, emerged as the foremost risk factor for mortality, followed by lupus encephalopathy. However, lupus nephritis and hematological abnormalities occurred more frequently in survival patients. SLE patients at a younger age of diagnosis have a poorer prognosis. Infection dominated the causes of death in recent China. Ethnicity and medications might account for the differences in causes of death compared with western populations.

Antiphosphatidylserine/prothrombin antibodies (aPS/PT) as potential diagnostic markers and risk predictors of venous thrombosis and obstetric complications in antiphospholipid syndrome.

BACKGROUND: The aim of the study was to determine the prevalence and clinical associations of antiphosphatidylserine/prothrombin antibodies (aPS/PT) with thrombosis and pregnancy loss in Chinese patients with antiphospholipid syndrome (APS) and seronegative APS (SNAPS). METHODS: One hundred and eighty six Chinese patients with APS (67 primary, 119 secondary), 48 with SNAPS, 176 disease controls (79 systemic lupus erythematosus [SLE], 29 Sjogren's syndrome [SS], 30 ankylosing spondylitis [AS], 38 rheumatoid arthritis [RA]) and 90 healthy donors were examined. IgG and IgM aPS/PT, IgG/IgM/IgA anticardiolipin (aCL) and IgG/IgM/IgA anti-ß2-glycoprotein I (anti-ß2GPI) antibodies were tested by ELISA. RESULTS: One hundred and sixty (86.0%) of APS patients were positive for at least one aPS/PT isotype. One hundred and thirty five (72.6%) were positive for IgG aPS/PT, 124/186 (66.7%) positive for IgM aPS/PT and 99 (53.2%) positive for both. Approximately half of the SNAPS patients were positive for IgG and/or IgM aPS/PT. Highly significant associations between IgG aPS/PT and venous thrombotic events (odds ratio [OR]=6.72) and IgG/IgM aPS/PT and pregnancy loss (OR=9.44) were found. Levels of IgM aPS/PT were significantly different in APS patients with thrombotic manifestations and those with fetal loss (p=0.014). The association between IgG/IgM aPS/PT and lupus anticoagulant (LAC) was highly significant (p<0.001). When both were positive, the OR for APS was 101.6. Notably, 91.95% (80/87) of LAC-positive specimens were positive for IgG and/or IgM aPS/PT, suggesting aPS/PT is an effective option when LAC testing is not available. CONCLUSIONS: Anti-PS/PT antibody assays demonstrated high diagnostic performance for Chinese patients with APS, detected some APS patients negative for criteria markers and may serve as potential risk predictors for venous thrombosis and obstetric complications.

IgMk paraprotein from gammopathy patient can bind to cardiolipin and interfere with coagulation assay: a case report.

BACKGROUND: The monoclonal gammopathies are a group of plasma-cell proliferative disorders characterized by the secretion of monoclonal immunoglobulin (M protein or paraprotein). Some rare cases have revealed the specific affinity of paraprotein as autoantibody. Here we report a patient with monoclonal gammopathy of undetermined significance (MGUS) accompanied by a remarkable increase of anticardiolipin antibody (aCL) and an extensively decreased coagulation factor activity, however, without any clinical signs of antiphospholipid syndrome (APS) and bleeding. RESULTS: Our further investigation indicated that IgMκ paraprotein of this patient possessed an antibody activity against phospholipids so as to bind to cardiolipin and interfere with coagulation assay in vitro. CONCLUSIONS: This case might be indicative that an abnormality of coagulation tests, disturbed by IgMκ paraprotein, does not predict a risk of bleeding in this patient.

Clinical characteristics and laboratory findings of 252 Chinese patients with anti-phospholipid syndrome: comparison with Euro-Phospholipid cohort.

This study aims to characterize the Chinese Han patients with anti-phospholipid syndrome (APS) and compare the data with those of the Euro-Phospholipid cohort. We conducted a single center study consisting of 252 patients with definite APS from 2000 to 2015. We analyzed the clinical and laboratory characteristics of our cohort and compared the data with those of the Euro-Phospholipid cohort. Our cohort consisted of 216 females and 36 males, with a mean age at entry into this study of 41 years (range 11-74 years). Of these patients, 69 (27.4%) patients had primary APS, and 183 (72.6%) had secondary APS (SAPS), including 163 (64.7%) patients had systemic lupus erythematosus (SLE). Thrombotic events occurred in 190 (75.4%) patients, and the most common ones were deep vein thrombosis (40.1%) and stroke (23.8%), which were similar to the reports of the Euro-Phospholipid cohort. In contrast, our cohort had less pulmonary embolism (6.7%). Among 93 females with 299 pregnancy episodes, the rates of early (<10 weeks) and late fetal loss (≥10 weeks) were, respectively, 37.8% and 24.4%. The latter was significantly higher than that of the Euro-Phospholipid cohort. Moreover, 7 APS nephropathy patients (characterized histopathologically by thrombotic microangiopathy) and 8 catastrophic APS patients were found in our cohort. Anti-cardiolipin antibodies (aCL) were detected in 169 (67.1%) patients, lupus anti-coagulant (LA) was detected in 83 (32.9%), and anti-ß2 glycoprotein I antibodies (anti-ß2GPI) in 148 (58.7%) patients. These results show that some clinical manifestations of APS may vary among different racial groups.

[Correlation Research between Pharmacological Method State and Natural Attribute of Chinese Herbs].

Pharmacological method state is a method to explain the principle of Chinese herb according to its external phenomenon such as shape, color, texture, features, and so on. The natural attribute of Chinese herb include shape, color, texture, smell, harvesting time, medicinal parts, chemical components, and so on. Though both of them have different key points, the natural attribute of Chinese herb can also be used to explain its medicinal mechanism. Therefore, the correlation research between pharmacological method state and the natural attribute of Chinese herb has some significance.

T-614 alters the production of matrix metalloproteinases (MMP-1 andMMP-3) and inhibits the migratory expansion of rheumatoid synovial fibroblasts, in vitro.

Matrix metalloproteinases (MMPs) have a pivotal role in the destruction of cartilage in rheumatoid arthritis (RA) joint, which is mainly produced by fibroblast-like synoviocytes (FLS). T-614 is effective for patients with active RA, however the mechanism has not been clarified. We first focus on the MMPs level in RA patients after T-614 treatment, in vivo. Eighty-six RA patients were assigned into 3 treatment groups randomly: T-614 group 1 (T-614 for the first 4 weeks with an oral dosage of 25mg once daily, and 50mg/day for the subsequent 20 weeks with an oral dosage of 25mg twice daily), T-614 group 2 (T-614 with an oral dosage of 25mg twice daily), or the MTX group (MTX 10 mg/week orally for the first 4 weeks and 15 mg/week for the subsequent 20 weeks). Serum samples were obtained at 0 and 24 weeks. Levels of MMP-1 and MMP-3 were decreased significantly after 24 week treatment of T-614 group 2 or MTX group. In vitro, RA FLS were pretreated with different doses of T-614 and then stimulated with TNF-α, IL-1ß or IL-17A, respectively. Protein and mRNA levels of MMP-1 and MMP-3 were further determined. MMP-1 production was significantly inhibited at 50 µg/ml T-614 and MMP-3 production was significantly inhibited at 5 µg/ml or more T-614. The mRNA expression profile was in accordance with the protein production. Inhibition of invasiveness was also seen after T-614 treatment. These results suggest that T-614 inhibits the invasiveness through decreasing the MMP-1 and MMP-3 production.

Effects of Radix aconiti lateralis preparata and Rhizoma zingiberis on energy metabolism and expression of the genes related to metabolism in rats.

OBJECTIVE: To study the influence of Radix aconiti lateralis preparata and Rhizoma zingiberis, two species of Chinese medicinal herbs with hot property, on energy metabolism and gene expression spectrum, and to analyze the possible mechanism of their effects. METHODS: Forty-eight specific pathogen free Wistar rats were randomly divided into a Radix aconiti lateralis preparata group, a Rhizoma zingiberis group, and a control group. They were intragastrically treated with concentrated decoction of Radix aconiti lateralis preparata, Rhizoma zingiberis and normal saline respectively for 20 days. Toe temperature (TT), energy intake (EI), digestible energy (DE), and metabolizable energy (ME) were measured. The content of adenosine triphosphate (ATP) and energy charge (EC) in hepatic tissue were measured with high performance liquid chromatography (HPLC). The activity of ATPase and succinate dehydrogenase (SDH) in the liver were detected with chemical colorimetry. The gene expression in the liver was detected with Illumina's rat Ref-12 gene array. The differential expression genes were selected, annotated and classified based on Gene Ontology (GO). Real-time quantitative reverse-transcriptase PCR (Q-RT-PCR) was used to test the accuracy of results. RESULTS: Compared with the control group, the TT on the 10(th) day after the beginning of administration and ATP in the Radix aconiti lateralis preparata and Rhizoma zingiberis groups increased significantly (P<0.05). EI/body mass (BM), DE/BM, ME/BM, the hepatic EC and the activity of Na(+)-K(+)-ATPase, Ca(2+)-Mg(2+)-ATPase and SDH of liver increased significantly only in the Radix aconiti lateralis preparata group (P<0.05). There were 592 differential expression genes in the Radix aconiti lateralis preparata group and 1 159 in the Rhizoma zingiberis group compared with the control group. Among the differential expression genes, genes related to metabolic processes were the most significant based on GO analysis. There were 337 strips of gene differential expression in common in both Radix aconiti lateralis preparata and Rhizoma zingiberis groups compared with the control group. CONCLUSIONS: Herbs with hot property such as Radix aconiti lateralis preparata and Rhizoma zingiberis could improve the energy metabolism in rats, through influencing the metabolic process of sugar, lipid, and amino acid. It could also promote the production, storage, and utilization of energy by regulating the gene expression related to metabolism, which may be the main molecular mechanism of warming yang and dispelling cold for the treatment of the cold syndrome according to Chinese medicine theory.

Multicenter, randomized, double-blind, controlled trial of treatment of active rheumatoid arthritis with T-614 compared with methotrexate.

OBJECTIVE: To assess the efficacy and safety of T-614 versus methotrexate (MTX) in patients with active rheumatoid arthritis (RA). METHODS: In this multicenter, double-blind trial, 489 patients randomly received either T-614 25 mg/day for the first 4 weeks and 50 mg/day for the subsequent 20 weeks (group 1, n = 163), T-614 50 mg/day for 24 weeks (group 2, n = 163), or MTX 10 mg/week for the first 4 weeks and 15 mg/week for the subsequent 20 weeks (n = 163). Clinical and laboratory parameters were analyzed at baseline and at 4, 10, 17, and 24 weeks. RESULTS: After 24 weeks of treatment, the American College of Rheumatology 20% improvement criteria response rate for patients in T-614 group 2 (63.8%) was not statistically significantly different from that for patients receiving MTX treatment (62.0%), and was superior to that for patients in T-614 group 1 (50.9%). The result of the noninferiority analysis indicated that the efficacy of T-614 (50 mg/day) was not lower than that of MTX by <10%. Rheumatoid factor and IgA, IgG, and IgM demonstrated a statistically significant decrease in all groups. Frequently reported adverse events included hematologic disorder, skin reactions, gastrointestinal symptoms, and transient liver enzyme elevations in the T-614 therapy groups. Side effects in the T-614 groups were generally fewer and milder than in the MTX group, except for skin reactions. There were no prominent cardiovascular adverse events and gastrointestinal ulcers found in the T-614 groups. CONCLUSION: Results indicate that T-614 therapy 50 mg/day is effective and well tolerated, and represents a new option for the treatment of patients with active RA.

T-614, a novel immunomodulator, attenuates joint inflammation and articular damage in collagen-induced arthritis.

INTRODUCTION: T-614 is a novel oral antirheumatic agent for the treatment of rheumatoid arthritis. Whether it has immunomodulatory or disease-modifying properties and its mechanism of action are largely undetermined. METHODS: Rats with collagen-induced arthritis (CIA) were treated with T-614 (5 and 20 mg/kg) daily. Animals receiving methotrexate (1 mg/kg every 3 days) and the nonsteroidal anti-inflammatory agent nimesulide (10 mg/kg per day) were used as controls. A combination therapy group was treated with both T-614(10 mg/kg per day) and methotrexate (1 mg/kg every 3 days). Hind paw swelling was evaluated and radiographic scores calculated. Serum cytokine levels were assessed by Bio-plex analysis. Quantitative PCR was used to evaluate expression of mRNA for interferon-gamma, IL-4 and IL-17. Serum IL-17 and anti-type II collagen antibodies (total IgG, IgG1, IgG2a, IgG2b and IgM) were measured using ELISA. RESULTS: Oral T-614 inhibited paw swelling and offered significant protection against arthritis-induced cartilage and bone erosion, comparable to the effects of methotrexate. CIA rats treated with T-614 exhibited decreases in both mRNA expression of IL-17 in peripheral blood mononuclear cells and lymph node cells, and circulating IL-17 in a dose-dependent manner. T-614 also reduced serum levels of tumor necrosis factor-alpha, IL-1beta and IL-6. A synergistic effect was observed for the combination of methotrexate and T-614. In addition, T-614 (20 mg/kg per day) depressed production of anti-type II collagen antibodies and differentially affected levels of IgG2a subclasses in vivo, whereas IgM level was decreased without any change in the IgG1 level. Together, the findings presented here indicate that the novel agent T-614 has disease-modifying effects against experimental arthritis, as opposed to nimesulide. CONCLUSIONS: Our data suggested that T-614 is an effective disease-modifying agent that can prevent bone/cartilage destruction and inflammation in in CIA rats. Combination with methotrexate markedly enhances the therapeutic effect of T-614.

Safety and efficacy of T-614 in the treatment of patients with active rheumatoid arthritis: a double blind, randomized, placebo-controlled and multicenter trial.

BACKGROUND: A novel anti-rheumatic drug, T-614, has been shown to have an anti-inflammatory effect and to improve abnormal immunological findings in rheumatoid arthritis (RA). To assess the safety and efficacy of T-614 versus placebo in patients with active RA we conducted a 24-week clinical study in 280 Chinese patients. METHODS: In a multicenter, randomized, double blind, placebo controlled study, 280 patients were randomly assigned to receive placebo (n = 95) or T-614 at 50 mg (n = 93) or 25 mg (n = 92) daily. Active disease was defined by 4 of the following 5 criteria: >or= 5 tender joints, >or= 3 swollen joints, morning stiffness lasting for >or= 60 minutes, and Westergren erythrocyte sedimentation rate (ESR) >or= 28 mm/h, the assessment of pain at the rest by patient as moderate or severe. Clinical and laboratory parameters were analyzed at baseline, 2, 4, 6, 12, 18 and 24 weeks. The primary efficacy variable at week 24 was the American College of Rheumatology (ACR) response rate using the intent-to-treat population. RESULTS: The ACR response rate was significantly higher in the T-614 treatment group compared with the placebo group within 8 weeks after the initiation of treatment. After 24 weeks, the 25 mg/d and 50 mg/d dosage groups and the placebo group showed 39.13%, 61.29% and 24.21% in ACR20 and 23.91%, 31.18% and 7.37% in ACR50, respectively. A time-response in ACR response was observed, with clear superiority for the 25 mg/d and 50 mg/d dosage groups compared to placebo (P < 0.0001), and the 50 mg/d dose compared to the 25 mg/d dose (P < 0.05) when using the ACR response analyses after 24 weeks. ESR and c-reactive protein (CRP) were significantly different in the treatment groups after 24 weeks. The incidence of adverse events (AEs) was not significantly higher with T-614 than with placebo, but upper abdominal discomfort, leucopenia, elevated serum alanine aminotransferase (sALT), skin rash and/or pruritus were more common in the 50 mg and 25 mg dosage groups. CONCLUSION: T-614, a new slow-acting drug, is effective in treatment of rheumatoid arthritis and is well tolerated.

Takayasu's arteritis presenting with bilateral pulmonary granulomatosis.

Takayasu's arteritis (TA) is a vasculitis characterized by inflammation and obliteration of intermediate to large-size arteries. We report a case of Takayasu's arteritis with a presentation of bilateral pulmonary nodular infiltrates in a 21-year-old man. An open-lung biopsy showed characteristic changes of extra-vascular granulomatosis. To our knowledge, this has not been described previously in the literature.