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 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

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.

Association of intrarenal B-cell infiltrates with clinical outcome in lupus nephritis: a study of 192 cases.

BACKGROUND: Lupus nephritis (LN) remains a major cause of morbidity and end-stage renal disease. Dysfunction of B lymphocytes is thought to be important in the pathogenesis of SLE/LN. Intrarenal B cells have been found in several forms of inflammatory kidney diseases although their role in LN renal is not well defined. METHODS: Intrarenal B cells were analyzed in 192 renal biopsies from patients diagnosed with lupus nephritis. Immunohistochemical staining of serial sections was performed for each LN patient using CD20, CD3, and CD21 antibodies. RESULTS: Intrarenal B cells were more likely to be associated with class IV LN and were mainly distributed in the renal interstitium, with very few in the glomerulus. The systemic lupus erythematosus disease activity index (SLEDAI), blood urea nitrogen, and serum creatinine levels were all significantly greater in the LN-B cell groups (all P < 0.05). LN renal activity and chronicity indices correlated with B-cells infiltrates (all P < 0.0001). Renal biopsies were classified into four distinct categories according to the organizational grade of inflammatory cell infiltrates. Germinal center- (GC-) like structures were not identified in any LN biopsies. CONCLUSION: It is hypothesized that intrarenal B cells enhance immunological responses and exaggerate the local immune response to persisting autoimmune damage in the tubulointerstitium.

A plasmonic nanoparticle-embedded polydopamine substrate for fluorescence detection of extracellular vesicle biomarkers in serum and urine from patients with systemic lupus erythematosus.

There is an unmet clinical need to develop noninvasive liquid biopsy tools for systemic lupus erythematosus (SLE) diagnosis and therapeutic effect evaluation. Extracellular vesicles (EVs), which are abundant in body fluids, have emerged as a valuable resource for liquid biopsy. Herein, we describe a simple and robust EV detection platform that is based on a plasmonic nanoparticle-embedded polydopamine substrate that is modified with EV-capture molecules and detection probes. We investigated three EV biomarkers, namely, programmed cell death protein-1 (PD-1), microRNA-146a (miRNA-146a) and sialic acid (SA), in serum and urine from SLE patients and healthy controls. This platform prevents complex pretreatment while enabling highly efficient EV capture to the substrate surface, and the multiple functionalization of the detection interface with specific biomarker probes enables simultaneous detection of PD-1, miRNA-146a and SA that are carried by EVs via fluorescence (FL) imaging at the single-vesicle level. Via comparison of EV biomarker profiles, SLE patients can be distinguished from normal controls and classified into treated and untreated groups. Due to its ease of preparation, simplicity and stability, our approach shows good potential in the design of EV-based biosensors for clinical use.

Anti-annexin II antibody is associated with thrombosis and/or pregnancy morbidity in antiphospholipid syndrome and systemic lupus erythematosus with thrombosis.

This study investigated the prevalence of antibody against annexin II (A2) in patients with antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). It also explored the role of this antibody in thrombosis. Purified recombinant A2 was used in ELISA to measure the levels of IgG anti-A2 antibody in 101 APS patients, 41 SLE patients with thrombosis, 124 SLE patients without thrombosis, and 120 healthy controls. The positive rates of IgG anti-A2 antibody in APS patients and SLE patients with thrombosis were 21.8 and 26.8%, respectively. Both values are significantly higher than that in SLE patients without thrombosis (6.5%). IgG anti-A2 antibody is associated with thrombosis and/or pregnancy morbidity (P < 0.001). The data show that the levels of anti-A2 antibody are higher in APS patients and SLE patients with thrombosis. Further, the presence of this antibody is associated with thrombosis and/or pregnancy morbidity, suggesting that anti-A2 antibody may be helpful in identifying potential APS cases.

Anti-Interferon Autoantibodies in Adult-Onset Immunodeficiency Syndrome and Severe COVID-19 Infection.

Adult-onset immunodeficiency syndrome due to anti-interferon (IFN)-γ autoantibodies has attracted much attention in recent years. It usually occurs in previously healthy people and usually presents as chronic, recurrent, and hard-to-control infections that can be effectively treated with aggressive antibiotic therapy. Adult-onset immunodeficiency syndrome is also referred to as AIDS-like syndrome. Anti-type I IFN (IFN-I) autoantibodies have been reported to play a significant role in the pathogenesis of coronavirus disease 2019 (COVID-19) and preexisting anti-IFN-I autoantibodies are associated with an increased risk of severe COVID-19. This review summarizes the effects of anti-IFN autoantibodies on the susceptibility and severity of various infectious diseases, including SARS-CoV-2 infection. In addition, we discuss the role of anti-IFN autoantibodies in the pathogenesis of autoimmune diseases that are characterized by recurrent infections.

Epidemiology of Takayasu arteritis in Shanghai: A hospital-based study and systematic review.

BACKGROUND: Takayasu arteritis (TAK) is a rare large vessel vasculitis, and epidemiological data on TAK are lacking in China. Thus, we designed this study to estimate the TAK prevalence and incidence in residential Shanghai, China. METHODS: Data on diagnosed TAK cases aged over 16 years were retrieved from 22 tertiary hospitals in Shanghai through hospital electronic medical record systems between January 1, 2015 and December 31, 2017 to estimate the prevalence and incidence. A systematic literature review based on searches in PubMed, Ovid-Medline, Excerpta Medica Database (EMBASE), Web of Science, and China National Knowledge Infrastructure (CNKI) was performed to summarize TAK distribution across the world. RESULTS: In total 102 TAK patients, with 64% female, were identified. The point prevalence (2015-2017) was 7.01 (95% CI 5.65-8.37) cases per million, and the mean annual incidence was 2.33 (1.97-3.21) cases per million. The average age of TAK patients was 44 ± 16 years, with the highest prevalence (11.59 [9.23-19.50] cases per million) and incidence (3.55 [0.72 3.74] cases per million) in the 16 to 34 years population. Seventeen reports were included in the system review, showing that the epidemiology of TAK varied greatly across the world. The incidence and prevalence were both relatively higher in Asian countries, with the prevalence ranging 3.3-40 cases per million and annual incidence ranging 0.34-2.4 cases per million. CONCLUSIONS: The prevalence and incidence of TAK in Shanghai was at moderate to high levels among the previous reports. The disease burden varied globally among racial populations.

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.

Pathogenesis, disease course, and prognosis of adult-onset Still's disease: an update and review.

OBJECTIVE: Adult-onset Still's disease (AOSD) is a rare but clinically well-known polygenic systemic autoinflammatory disease. In this review, we aim to present frontiers in the pathogenesis, clinical features, diagnosis, biomarkers, disease course, prognosis, and treatment in AOSD. DATA SOURCES: We retrieved information from the PubMed database up to July 2019, using various search terms and relevant words, including AOSD and Still's disease. STUDY SELECTION: We included data from peer-reviewed journals. Both basic and clinical studies were selected. RESULTS: Pathogenesis of AOSD involves genetic background, infectious triggers, and immunopathogenesis, mainly the activation of macrophages and neutrophils followed by a cytokine storm. Diagnosis and prognosis evaluation of AOSD is still challenging; therefore, there is an urgent need to identify better biomarkers. Biologic agents, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α antagonists in the treatment of AOSD, have good prospect. CONCLUSION: This review highlights the advances in pathogenesis, potential biomarkers, disease course, and treatment in AOSD.

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.

How could we make a diagnosis of Wegener's granulomatosis?

Current classification criteria function poorly in diagnosing Wegener's granulomatosis (WG). In this study, we presented a patient with sinonasal symptoms, hematuria, and proteinuria, who had been misdiagnosed as a patient suffering from WG, but finally turned out to be a patient suffering from non-Hodgkin's T cell lymphoma. Diagnostic approach of WG was also discussed.

Lupus erythematosus and lupus valgaris: a case report and historical remarks.

Lupus erythematosus and lupus valgaris, i.e., cutaneous tuberculosis, are confusing skin lesions in the history. Here, we reported on a Chinese lupus patient manifested with multiple nodular erythematous rashes on both upper extremities, which turned out to be cutaneous mycobacterial infection.

Hemophagocytic syndrome as one of main manifestations in untreated systemic lupus erythematosus: two case reports and literature review.

Hemophagocytic syndrome (HPS) is an unusual but fatal disorder characterized by pancytopenia and activation of macrophages. We describe two cases of untreated systemic lupus erythematosus (SLE) with HPS that presented as one of the manifestations of SLE. The onset of HPS was after parturition for one patient, and after abortion for the other. Bone marrow examination revealed severe hemophagocytosis in both patients. One patient responded to pulsed methylprednisone alone, and the other responded to pulsed methylprednisone plus intravenous immunoglobulin (IVIG). We believe accurate diagnosis, intensive therapy, and sufficient supportive cares are essential in improving patients' prognosis.

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.

Could 2'5'-oligoadenylate synthetase isoforms be biomarkers to differentiate between disease flare and infection in lupus patients? A pilot study.

2'5'-Oligoadenylate synthetase (OAS) was shown to be related to systemic lupus erythematosus (SLE) 20 years ago, and was rediscovered to be involved in type I interferon pathway in SLE by several microarray gene expression studies recently. The goal of this study was to investigate OAS isoform expressions in lupus patients, to evaluate whether they could become biomarkers to differentiate between disease flare and infection. Fifty-four SLE patients presented with fever or systemic inflammatory syndrome, or both, were enrolled. Gene expressions of OAS1, OAS2, and OASL were studied by using real time PCR in active SLE (SLEDAI >or=9, n=29) and in those complicated with infections (n=25). The latter group was composed of 19 patients with invasive bacterial infections, and six patients with viral infections. C reactive protein (CRP) and other clinical parameters were also measured. Twenty-nine healthy individuals made up a normal control group. The mRNA expressions of OAS1, OAS2, and OASL were higher in patients with lupus flares than those with infections (p<0.03), or normal controls (p<0.001). SLE complicated with infections have higher OAS1 expression level (P=0.002), lower OASL (P=0.004), and equivalent OAS2 (P=0.135), when compared with those of normal controls. OASL expression level was negatively correlated with infection in lupus by logistic regression analysis (p=0.008). Area under the receiver operating characteristic curve for the prediction of infection was 0.92 (p<0.0001) for OASL, and 0.77 (p=0.007) for CRP. Therefore, our preliminary data suggest that the pattern of OAS isoform expressions, OASL in particular, may provide useful information in differentiating disease flares from certain infections in SLE.

Clinical features, prognostic and risk factors of central nervous system infections in patients with systemic lupus erythematosus.

The purpose of this study is to describe the etiology, characteristics and outcomes of central nervous system (CNS) infections in patients with systemic lupus erythematosus (SLE), while also identifying prognostic and risk factors. Thirty-eight SLE patients with CNS infections were identified from review of all charts of patients with SLE hospitalized from January 1995 to June 2005. These patients were divided into 3 groups, i.e., Mycobacterium tuberculosis (TB), non-TB bacterial and fungal infection groups. Of the 38 SLE cases with CNS infections, TB was identified in 19 patients, Listeria monocytogenes in 3 patients, Klebsiella pneumoniae in 1 patient, Staphylococcus aureus in 1 patient, Gram's stain positive bacteria in 1 patient, Cryptococcus neoformans in 12 patients, and Aspergillus fumigatus in 1 patient. The rate of unfavorable outcome in patients with fungal infection was lower than in patients with TB (P=0.028) and non-TB bacterial CNS infections (P=0.046). SLE patients with TB or fungal CNS infections had a more insidious or atypical clinical presentation. Compared to SLE patients without CNS infections, those with CNS infections were more likely to have low serum albumin levels (P=0.048) and have been receiving higher doses of prednisolone at the onset of CNS infection (P=0.015) or higher mean doses of prednisolone within the previous year (P=0.039). In conclusion, low levels of serum albumin and higher doses of received prednisolone are important risk factors for the development of CNS infections in SLE patients.

Adult clinically amyopathic dermatomyositis with rapid progressive interstitial lung disease: a retrospective cohort study.

The aim of the study was to investigate the characteristics of adult clinically amyopathic dermatomyositis (CADM) with rapid progressive interstitial lung disease (ILD). Hospitalized patients with dermatomyositis (DM) and polymyositis (PM) between 1998 and 2005 in the Shanghai Renji Hospital were retrospectively studied. One hundred and forty-five patients were classified into CADM, classic DM or PM according to the modified Sontheimer's definition or Bohan-Peter's classification criteria. They were further stratified based on the presence or absence of clinical ILD. The Kaplan-Meier survival analysis and COX regression were performed. The predictive factors for ILD and other clinical properties of CADM-ILD were explored. The presence of clinical ILD was a significant risk factor for the poor outcome of DM/PM (OR = 4.237, CI 95%: 1.239-14.49, p = 0.021). Other risk factors are the presence of rashes and elevated urea nitrogen. Patients with DM/PM complicated by ILD had different clinical courses. Patients with CADM-ILD showed a rapidly progressive pattern with 6-month survival rate of 40.8%. The DM-ILD manifested a progressive pattern with a 5-year survival rate of 54%, while PM-ILD was chronic with 5- and 10-year survival rate of 72.4% and 60.3%, respectively. Better preserved muscle strength, elevated erythrocyte sedimentation rate, and hypoalbuminemia may herald ILD in DM/PM. Patients with CADM-ILD who later died had lower PO(2), higher lactate dehydrogenase, and prominent arthritis/arthralgia compared with those who survived. The presence of antinuclear antibody seems to be protective. Rapid progressive CADM-ILD is refractory to conventional treatment. ILD is a common complication in over 40% of our hospitalized DM/PM cohort and is also a prominent prognostic indicator. CADM is a special phenotype of DM/PM. CADM-ILD, which is usually rapidly progressive and fatal, requires further investigation.