Search

Since the coronavirus disease 2019 (COVID‐19) outbreak, the nosocomial infection rate worldwide has been reported high. It is urgent to figure out an affordable way to monitor and alarm nosocomial infection. Carbon dioxide (CO2) concentration can reflect the ventilation performance and crowdedness, so CO2 sensors were placed in Beijing Tsinghua Changgung Hospital's fever clinic and emergency department where the nosocomial infection risk was high. Patients’ medical records were extracted to figure out their timelines and whereabouts. Based on these, site‐specific CO2 concentration thresholds were calculated by the dilution equation and sites’ risk ratios were determined to evaluate ventilation performance. CO2 concentration successfully revealed that the expiratory tracer was poorly diluted in the mechanically ventilated inner spaces, compared to naturally ventilated outer spaces, among all of the monitoring sites that COVID‐19 patients visited. Sufficient ventilation, personal protection, and disinfection measures led to no nosocomial infection in this hospital. The actual outdoor airflow rate per person (Q c) during the COVID‐19 patients’ presence was estimated for reference using equilibrium analysis. During the stay of single COVID‐19 patient wearing a mask, the minimum Q c value was 15–18 L/(s·person). When the patient was given throat swab sampling, the minimum Q c value was 21 L/(s·person). The Q c value reached 36–42 L/(s·person) thanks to window‐inducted natural ventilation, when two COVID‐19 patients wearing masks shared the same space with other patients or healthcare workers. The CO2 concentration monitoring system proved to be effective in assessing nosocomial infection risk by reflecting real‐time dilution of patients’ exhalation.

A multidisciplinary guideline development group was established to formulate this evidence-based diagnosis and treatment guidelines for rheumatoid arthritis (RA) in China. The grading of recommendations, assessment, development, and evaluation (GRADE) system was used to rate the quality of the evidence and the strength of recommendations, which were derived from research articles and guided by the analysis of the benefits and harms as well as patients’ values and preferences. A total of 10 recommendations for the diagnosis and treatment of RA were developed. This new guideline covered the classification criteria, disease activity assessment and monitoring, and the role of disease modifying antirheumatic drugs (DMARDs), biologics, small molecule synthetic targeting drugs, and glucocorticoids in the treat-to-target approach of RA. This guideline is intended to serve as a tool for clinicians and patients to implement decision-making strategies and improve the practices of RA management in China.

The axial SpAs (axSpAs) are clearly clinically a heterogeneous set of diseases with markedly varying extra-articular features. These diseases are all highly heritable and have overlapping but differing genetic origins. Shared features include association with HLA class I alleles and genes of the IL-23 pathway, among other things. Significant differences do exist however, both in the genetic loci involved and at specific loci in the individual genetic variants associated with each disease. These similarities and differences are of great interest in regards to disease pathogenesis and treatment development, although individually they are too small in effect to be of prognostic or diagnostic value. Polygenic risk scores, which capture a high proportion of the genetic variation between disorders, have been shown to have clinically useful discriminatory capacity in axSpA. This suggests they have the potential to enable improved disease classification, incorporating basic pathogenic features such as genomics, and ultimately benefitting clinical care. The aim of this article is to review the genetic characteristics of the spectrum of axSpAs and to discuss how this influences our understanding of the disease pathogenesis and the clinical implications of this understanding.

The early stage of the COVID-19 epidemic happened to be the flu season Since some symptoms of influenza and COVID-19 are similar, symptomatic patients flocked to fever clinics and emergency departments Meanwhile, asymptomatic COVID-19 patients attending other departments in general hospitals made things worse Lack of knowledge of the pathogen, absence of awareness and short of personal protective equipment all posed threat to healthcare workers as well as other patients As SARS-CoV-2 can be spread via droplets, direct contacts and potentially aerosols, the indoor air environment of hospitals, especially fever clinics, must have strict measures to prevent hospital-acquired infection Thirty-two sensors were deployed in the Tsinghua University Affiliated Beijing Tsinghua Changgung Hospital (mentioned as Changgung Hospital hereinafter) from January 30, 2020, in order to monitor high-resolution real-time indoor environmental parameters at its fever clinic, isolation wards and other departments One sensor monitors and records CO2 concentration, PM2 5 mass concentration, relative humidity, temperature and illuminance every 5 minutes Six sensors were located at the fever clinic, where all patients with fever and/or other COVID-19 related symptoms firstly attended after arriving at the hospital The clinic has two parts, one for diagnosis and the other for quarantine Three sensors were placed in doctor's office, nursing station and waiting area in the diagnosis part, respectively Natural ventilation was chosen to dilute the environment, as the flowrate of outdoor airflow was abundant in Beijing's winter Atmospheric CO2 concentration surrounding Changgung Hospital was stable, and the rise of indoor CO2 concentration was caused by human exhalation During this pandemic, CO2 concentration can be regarded as an indicator of room ventilation condition and hospital congestion, if all the people in hospital were regarded as potential infector of SARS-CoV-2 According to the usage pattern of the fever clinic, the maximum number of patients in each functional area was set as 4 for doctor's office, 4 for nursing station and 11 for waiting area According to the ventilation regulation of infectious disease hospital, the air change rate at fever clinics should be at least 6 h(-1) In addition, the outdoor CO2 concentration was assumed to be 400 ppm Based on these conditions, the upper limits of indoor CO2 concentration were 902, 864 and 867 ppm for doctor's office, nursing station and waiting area at the Changgung Hospital's fever clinic, respectively Indoor CO2 concentration exceeding these thresholds stands for poor ventilation or overcrowds Fortunately, this didn't happen during the monitoring period and indoor CO2 concentration didn't exceed 609-711 ppm In another word, natural ventilation was sufficient and effective in this specific case at the Changgung Hospital's fever clinic Moreover, together with environment disinfection and personal protective measures, good ventilation condition led to no COVID-19 hospitalacquired infection To conclude, this article introduced a real-time environmental monitoring campaign at the Changgung Hospital's fever clinic Similar methodology can help assess ventilation conditions and risk of hospital-acquired infection at the fever clinic during and after COVID-19 pandemic Once indoor CO2 concentration exceeds the set thresholds, areas with high infection risk can be identified rapidly and timely, so that prevention measures can be taken in time

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.

ObjectivesDiverse evidence including clinical, genetic and microbiome studies support a major role of the gut microbiome in the common immune-mediated arthropathy, ankylosing spondylitis (AS). We set out to (1) further define the key microbial characteristics driving disease, and (2) examine the effects of tumour necrosis factor-inhibitor (TNFi) therapy upon the microbiome.MethodsThe stools from a case–control cohort of 250 Han-Chinese subjects underwent shotgun metagenomic sequencing. All subjects were genotyped using the Illumina CoreExome SNP microarray.ResultsPrevious reports of gut dysbiosis in AS were reconfirmed and several notable bacterial species and functional categories were differentially abundant. TNFi therapy was correlated with a restoration the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. Enrichment of bacterial peptides homologous to HLA-B27-presented epitopes was observed in the stools of patients with AS, suggesting that either HLA-B27 fails to clear these or that they are involved in driving HLA-B27-associated immune reactions. TNFi therapy largely restored the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. TNFi therapy of patients with AS was also associated with a reduction of potentially arthritogenic bacterial peptides, relative to untreated patients.ConclusionThese findings emphasise the key role that the gut microbiome plays in driving the pathogenesis of AS and highlight potential therapeutic and/or preventative targets.

Summary Background China approved adalimumab for the treatment of ankylosing spondylitis in 2013. However, the cost of the standard dose regimen exceeds ¥15 000 (around US$2250) per month, which is well beyond affordability for most Chinese patients. No biosimilars of adalimumab are available in China; IBI303 is a monoclonal antibody against TNFα that is currently in development. This study aimed to assess the clinical equivalence of IBI303 to adalimumab in patients with ankylosing spondylitis. Methods This phase 3, multicenter, double-blind, parallel, randomised controlled equivalence trial was done in 20 centers across China. Patients were randomly assigned in a 1:1 ratio to receive either 40 mg of IBI303 or 40 mg of adalimumab as a subcutaneous injection every 2 weeks until week 22. Patients were eligible for inclusion if they were between 18 and 65 years old, fulfilled the 1984 Modified New York Criteria for ankylosing spondylitis, were non-responders, inadequate responders, or intolerant to treatment with NSAIDs for 4 or more weeks, and had active ankylosing spondylitis defined by two or more indicators of disease severity. The investigators, site staff, patients, sponsors, and the contract research organisation were masked to treatment allocation. The primary outcome was the proportion of patients who met the Assessment of SpondyloArthritis international Society (ASAS) Response Criteria for a 20% improvement (ASAS20) at week 24 after treatment. Equivalence was established if the 95% CI of the difference in responses between groups was between −15% and 15%. Efficacy analyses were done in the full analysis population and in the per-protocol population. Safety analyses were done in all randomly assigned patients who received at least one drug dose. This trial is registered with ClinicalTrials.gov , number NCT02893254 . Findings Between Sept 22, 2016, and May 11, 2018, 438 patients were randomly allocated either to the biosimilar IBI303 group (n=220) or the adalimumab group (n=218). In the full analysis population, 165 (75%) of 220 patients in the IBI303 group (95% CI 68·7–80·6) and 158 (72%) of 218 patients in the adalimumab group (66·0–78·3) reached the primary outcome of ASAS20 at week 24. The difference between the two groups was 2·3% with a 95% CI of −5·9 to 10·6, which fell within the pre-specified equivalence boundaries at week 24 (–15 to 15). In the per-protocol population, 163 (80%) of 203 patients in the IBI303 group reached ASAS20 at week 24 (95% CI 74·1–85·5), compared with 150 (80%) of 188 patients in the adalimumab group (73·3–85·3%). The difference between the groups was 0·6% with a 95% CI of −7·4 to 8·6%, which also fell within the pre-specified equivalence boundaries at week 24. Safety and tolerability profiles were similar between the two groups; 174 (79%) of 220 patients in the IBI303 group and 178 (82%) of 218 patients in the adalimumab group had treatment-emergent adverse events. Interpretation This trial showed therapeutic equivalence of IBI303 and adalimumab in the treatment of ankylosing spondylitis. The efficacy, safety, and immunogenicity of both drugs are highly similar. IBI303 could be an alternative treatment option for patients with ankylosing spondylitis in China. Funding Innovent Biologics, National Major Scientific and Technological Special Project for “Significant New Drugs Development”.

Although many drugs and therapeutic strategies have been developed for rheumatoid arthritis (RA) treatment, numerous patients with RA fail to respond to currently available agents. In this review, we provide an overview of the complexity of this autoimmune disease by showing the rapidly increasing number of genes associated with RA.We then systematically review various factors that have a predictive value (predictors) for the response to different drugs in RA treatment, especially recent advances. These predictors include but are certainly not limited to genetic variations, clinical factors, and demographic factors. However, no clinical application is currently available. This review also describes the challenges in treating patients with RA and the need for personalized medicine. At the end of this review, we discuss possible strategies to enhance the prediction of drug responsiveness in patients with RA.

ObjectiveWe sought to test the hypothesis that Polygenic Risk Scores (PRSs) have strong capacity to discriminate cases of ankylosing spondylitis (AS) from healthy controls and individuals in the community with chronic back pain.MethodsPRSs were developed and validated in individuals of European and East Asian ethnicity, using data from genome-wide association studies in 15 585 AS cases and 20 452 controls. The discriminatory values of PRSs in these populations were compared with other widely used diagnostic tests, including C-reactive protein (CRP), HLA-B27 and sacroiliac MRI.ResultsIn people of European descent, PRS had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.924. This was significantly better than for HLA-B27 testing alone (AUC=0.869), MRI (AUC=0.885) or C-reactive protein (AUC=0.700). PRS developed and validated in individuals of East Asian descent performed similarly (AUC=0.948). Assuming a prior probability of AS of 10% such as in patients with chronic back pain under 45 years of age, compared with HLA-B27 testing alone, PRS provides higher positive values for 35% of patients and negative predictive values for 67.5% of patients. For PRS, in people of European descent, the maximum positive predictive value was 78.2% and negative predictive value was 100%, whereas for HLA-B27, these values were 51.9% and 97.9%, respectively.ConclusionsPRS have higher discriminatory capacity for AS than CRP, sacroiliac MRI or HLA-B27 status alone. For optimal performance, PRS should be developed for use in the specific ethnic groups to which they are to be applied.

Objectives: Anti-tumor necrosis factor (TNF) agents have been regarded as the most effective treatment for ankylosing spondylitis (AS) so far. However, economic factors limited the prescription of original biologicals in China. Yisaipu® is a biosimilar for etanercept as pre fill syringes (PFS), which has entered China’s national medical insurance catalog for more than 10 yr and was widely used because it greatly reduced the economic burden of AS patients. Yisaipu® is provided subcutaneous injection in hospital setting only. We collected clinical data of AS patients before, during and after COVID-19 epidemic, in an attempt to investigate the advantages and disadvantages of original biologicals and Yisaipu® during regular follow up and COVID-19 epidemic.Methods: AS patients who received original biologicals or Yisaipu® in our department for more than 1 yr were included in our study. General data, demographic characteristics, disease activity, quality of life and medical compliance were collected from regular visits. The patients were followed up through telephone interviews from April 20th to 27th, 2020 about the overall impact of the COVID-19 epidemic.Results: There was no significant difference in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score-CRP (ASDAS-CRP) between the two groups. Health Assessment Questionnaire for Spondyloarthropathies (HAQ-s) showed that Yisaipu® group was superior to original biological group in terms of eating, gripping and driving. In addition, the medical cost of Yisaipu® was lower than that of original biologicals. The overall impact of the COVID-19 epidemic on patients of original biological group was comparatively smaller than that on Yisaipu® group.Conclusions: Yisaipu® provided AS patients with an economical selection during regular follow-up, while original biologicals had certain advantages in the COVID-19 epidemic setting, including a longer time interval between two drug administrations and the self-injection dose form of medication.

Xiao Zhang,1 Huji Xu,2 Zhiyi Zhang,3 Yang Li,4 Lynne Pauer,5 Shanmei Liao,6 Fengchun Zhang7 1Department of Rheumatology, Guangdong General Hospital, Guangdong, People’s Republic of China; 2Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Affiliated to Second Military Medical University, Shanghai, People’s Republic of China; 3School of Clinical Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China; 4Department of Rheumatology and Immunology, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China; 5Global Research and Development, Pfizer, Groton, CT, USA; 6Pfizer China Statistics Department, Global Innovative Pharma Business, Shanghai, People’s Republic of China; 7Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Beijing, People’s Republic of ChinaCorrespondence: Fengchun ZhangPeking Union Medical College Hospital, No. 9, Dongdan Santiao, Dongcheng District, Beijing, People’s Republic of ChinaTel/Fax +8610-69155416Email zhangfccra@aliyun.comPurpose: Fibromyalgia (FM) may go underdiagnosed and untreated in China in part due to a lack of awareness and understanding of the condition, and limited available treatments.Patients and Methods: This randomized, double-blind, Phase III local registration trial compared the efficacy and safety of pregabalin (flexibly dosed 300– 450 mg/day) versus placebo for the management of pain in Chinese adults diagnosed with FM according to American College of Rheumatology 1990 criteria, across 22 centers within China. Patients reported pain score of ≥ 40 mm on 100-mm scale (from 0 “no pain” to 100 “worst possible pain”). The primary efficacy endpoint was change from baseline to Week 14 in mean pain score (MPS). Secondary endpoints included measures of sleep and sleep interference. Safety and tolerability were monitored throughout.Results: Median pregabalin dose was 335 mg/day. A significant reduction from baseline to Week 14 in weekly MPS was seen for patients treated with pregabalin (n=170) versus placebo (n=164) (least-squares mean difference [95% confidence interval]: – 0.73 [– 1.10 to – 0.36]; P=0.0001). Significantly greater proportions of patients experienced ≥ 30% and ≥ 50% reductions in MPS at Week 14 with pregabalin versus placebo. Pregabalin-treated subjects demonstrated improvements in measures of sleep and sleep interference. Pregabalin was generally well tolerated. The most common adverse events were dizziness and somnolence; no serious adverse events (SAEs) occurred in pregabalin-treated subjects. Nine placebo-treated subjects experienced SAEs.Conclusion: Pregabalin (300– 450 mg/day) is a safe and effective treatment for reducing pain and improving sleep in native Chinese subjects with FM.ClinicalTrials.gov Identifier: NCT01387607.Keywords: China, chronic pain, FM, Lyrica, pain management, sleep

Background Pain in AS is currently considered an inflammatory pain (IP). However, it was found that some patients still had the sensation of pain even without inflammation. Our study was to investigate whether ankylosing spondylitis (AS) pain has a neuropathic pain (NeP) component. Methods The study consisted of three parts. The first included 182 AS patients to assess neuropathic pain in AS patients. The second included63 patients to evaluate pain improvement after etanercept therapy. The third included 20 AS patients and 10 healthy controls (HCs) to detect serum neurotransmitters. Results We found out that 55 paitents (30.21%) had possible NeP, and 14 (7.70%) had definite NeP. There were significant differences between the groups with respect to nocturnal pain (NP), peripheral pain (PP), total back pain (TBP), BASDAI, ASDAS-CRP, HAD-A, HAD-D and BASDAI-fatigue but not CRP concentrations. Principal component analysis (PCA) of AS pain revealed that the weight of NeP was greater than PP in the first principal component (0.703 vs 0.639). Structural equation modelling (SEM) revealed that NeP altered disease activity (β = 0.62, P P P vs 9.98 ± 6.40, P = 0.067). Serum norepinephrine concentrations in patients with positive PDQ were greater than those in patients with negative PDQ and HC. Conclusions We conclude that NeP contributes to pain in AS patients.

ObjectiveTo assess the efficacy/safety of tofacitinib in adult patients with active ankylosing spondylitis (AS).MethodsThis phase III, randomised, double-blind, placebo-controlled study enrolled patients aged ≥18 years diagnosed with active AS, meeting the modified New York criteria, with centrally read radiographs, and an inadequate response or intolerance to ≥2 non-steroidal anti-inflammatory drugs. Patients were randomised 1:1 to receive tofacitinib 5 mg two times per day or placebo for 16 weeks. After week 16, all patients received open-label tofacitinib until week 48. The primary and key secondary endpoints were Assessment of SpondyloArthritis international Society ≥20% improvement (ASAS20) and ≥40% improvement (ASAS40) responses, respectively, at week 16. Safety was assessed throughout.Results269 patients were randomised and treated: tofacitinib, n=133; placebo, n=136. At week 16, the ASAS20 response rate was significantly (pConclusionsIn adults with active AS, tofacitinib demonstrated significantly greater efficacy versus placebo. No new potential safety risks were identified.Trial registration numberNCT03502616

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that represents a prodigious challenge of diagnosis and treatment. In 2019, under the leadership of the Chinese Rheumatology Association, a multidisciplinary guideline development group was established to develop an evidence-based diagnosis and treatment guideline for patients with SLE in PR China. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to evaluate the quality of evidence and the strength of recommendations. The guideline was reported following the Reporting Items for Practice Guidelines in Healthcare (RIGHT) checklist. In this guideline, we provided recommendations for SLE classification criteria, disease activity monitoring and assessment, medication administration and considerations for SLE patients with organs and systems involved, and management of special populations such as SLE patients in the setting of pregnancy. This guideline serves as an evidence-based tool for Chinese clinicians to diagnose and treat patients with SLE.

Background: Benign Childhood Epilepsy with Centro-temporal Spikes (BECTS) is the most common form of idiopathic epilepsy in children, accounting for up to 23% of pediatric epilepsy. The pathogenesis of BECTS is unknown, but it is thought that genetic factors play a role in susceptibility to the disease. Methods: To investigate the role of common genetic variants in BECTS pathogenesis, a 2-stage genome-wide association study (GWAS) was performed in 1,800 Chinese Han BECTS patients, and 7,090 healthy controls. Genetic findings were used in a Mendelian Randomization study in the UK Biobank dataset to investigate the potential role of smoking in BECTS. Findings: Definitive evidence of a role for common-variant heritability was demonstrated, with heritability of BECTS of >10% observed even with conservative disease prevalence assumptions. Although no individual locus achieved genome-wide significance, twelve loci achieved suggestive evidence of association (5 × 10-8

Efficiently learning representations of clinical concepts (i. e., symptoms, lab test, etc.) from unstructured clinical notes of electronic health record (EHR) data remain significant challenges, since each patient may have multiple visits at different times and each visit may contain different sequential concepts. Therefore, learning distributed representations from temporal patterns of clinical notes is an essential step for downstream applications on EHR data. However, existing methods for EHR representation learning can not adequately capture either contextual information per-visit or temporal information at multiple visits. In this study, we developed a new vector embedding method called EHR2Vec that can learn semantically-meaningful representations of clinical concepts. EHR2Vec incorporated the self-attention structure and showed its utility in accurately identifying relevant clinical concept entities considering time sequence information from multiple visits. Using EHR data from systemic lupus erythematosus (SLE) patients as a case study, we showed EHR2Vec outperforms in identifying interpretable representations compared to other well-known methods including Word2Vec and Med2Vec, according to clinical experts' evaluations.

Background The association of HLA-B*27 with AS is amongst the strongest of any known association of a common variant with any human disease. Nonetheless, there is strong evidence indicating that other HLA-B alleles are involved in the disease. European ethnicity studies have demonstrated risk associations with HLA-B*40 and multiple other HLA-B, HLA-A, and HLA class II alleles, and demonstrated that in that ethnic group, the amino acid sequence at position 97 in HLA-B is the key determinant of HLA associations with AS. A recent study in Korean AS cases and controls additionally identified association at HLA-C*15:02. In the current study, we examined the MHC associations of AS in an expanded East Asian cohort. Methods A total of 1637 Chinese, Taiwanese, and Korean AS cases meeting the modified New York Criteria for AS, and 1589 ethnically matched controls, were genotyped with the Illumina Immunochip, including a dense coverage of the MHC region. HLA genotypes and amino acid composition were imputed using the SNP2HLA programme using the Han-MHC reference panel based on the data of Han Chinese subjects (n = 9689), and association tested using logistic regression controlling for population stratification effects. Results A strong association was seen with HLA-B*27 (odds ratio (OR) = 205.3, P = 5.76 × 10−244). Controlling for this association, the strongest risk association is seen with HLA-C*15 at genome-wide significant level (OR = 7.62, P = 9.30 × 10−19), and confirmed association is also seen with HLA-B*40 at suggestive level (OR = 1.65, P = 2.54 × 10−4). At amino acid level, the strongest association seen in uncontrolled analysis was with histidine at position 114 in HLA-B (P = 7.24 × 10−241), but conditional analyses suggest that the primary amino acid associations are with lysine at position 70 and asparagine at position 97. Restriction of the ERAP1 association with HLA-B27-positive AS, previously reported in European subjects, was confirmed in East Asians. Conclusions This study confirms in East Asians that the HLA associations of AS are multiple, including previously reported associations at HLA-B*27, HLA-B*40, and HLA-C*15, as well as novel association with HLA-DQB1*04. The HLA-B associations are driven by the amino acids at positions 70 and 97, in the B pocket of HLA-B.

Background: The COVID-19 pandemic is not only a traumatic event, but a collective stressor unfolding over time, causing alarming implications for the mental health. This study aims to shed light on the mental health status of patients with rheumatic disease (RD) during the massive outbreak of COVID-19 in China, especially the prevalence and severity of post-traumatic stress disorder (PTSD) compared with the levels in healthy people. Methods: A questionnaire survey was conducted in a cross-sectional study of 486 RD patients and 486 healthy control subjects. We collected participants’ demographic and clinical characteristics and surveyed the prevalence and severity of PTSD and sleep quality in the samples using the PTSD Checklist for DSM-5 (PCL-5) and 4 items from the Pittsburgh Sleep Quality Index (PSQI). Findings: Compared with healthy control subjects (n=486), RD patients (n=486) had a higher prevalence of PTSD (12·1% vs. 4·1%; p

Objectives: Studies have proven that improving patients' acceptance of chronic pain could be an effective therapy for alleviating pain and other symptoms. Our objectives were to investigate the correlation between chronic pain acceptance and clinical variables in ankylosing spondylitis (AS), and the prediction role of chronic pain acceptance for biologics treatment. Methods: First, 167 AS patients were recruited to complete a series of questionnaires, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Chronic Pain Acceptance Questionnaire (CPAQ), Hospital Anxiety and Depression Scale (HADS), and Tampa Scale for Kinesiophobia (TSK). Bivariate correlation analysis was utilized to investigate the correlation between pain acceptance and clinical variables. Based on the level of chronic pain acceptance and serum C-reactive protein (CRP), patients were separated into four subgroups. Then, another 68 patients initiating anti-tumor necrosis factor (TNF) treatment were recruited to complete the questionnaires at baseline (T0) and 3 months after treatment (T3). The changes in clinical variables and treatment response were compared between multiple subgroups. Results: Chronic pain acceptance had strong correlations with anxiety, depression and fear of movement, and moderate correlations with BASFI and pain intensity. Both activity engagement (AE) and pain willingness (PW) had significant correlations with pain intensity, BASFI and psychological status. In addition, AE had a significant correlation with disease duration, while PW had a significant correlation with ASDAS-CRP. Subgroup analysis showed that patients with low chronic pain acceptance and high levels of serum CRP had the highest BASDAI. Among patients initiating anti-TNF treatment, those with high pain acceptance and high levels of serum CRP achieved the most obvious reduction in BASDAI after 3 months treatment. Conclusion: Pain acceptance is a new tool to assess pain in AS which may also reflect physical and psychological status. Clinicians should identify high-risk patients with low chronic pain acceptance and high levels of serum CRP, and give psychological and pharmacological intervention promptly. Moreover, the combination of baseline chronic pain acceptance and serum CRP level could be used to predict the treatment response in AS patients initiating biologics treatment.

Background: Interleukin (IL)-37, also called IL1F7, is a natural inhibitor of inflammatory and immune responses. It is involved in the pathogenesis of rheumatoid arthritis (RA). This study aimed to investigate the role of IL1F7 gene polymorphism in RA susceptibility in a large cohort of patients. Methods: Five selected single-nucleotide polymorphisms in IL1F7 genes (rs2723186, rs3811046, rs4241122, rs4364030, and rs4392270) were genotyped by TaqMan Allelic Discrimination in Northern Chinese Han population. The allele and the genotype were compared between patients with RA and healthy controls. Association analyses were performed on the entire data set and on different RA subsets based on the status of the anti-cyclic citrullinated peptide antibody and the rheumatoid factor by logistic regression, adjusting for age and gender. Results: Trend associations were detected between rs2723186, rs4241122, rs4392270, and RA in Stage I (160 patients with RA; 252 healthy controls). Further validation in Stage II comprised 730 unrelated patients with RA (mean age: 54.9 ± 12.6 years; 81.6% females) and 778 unrelated healthy individuals (mean age: 53.5 ± 15.7 years; 79.5% females). No significant differences in the distributions of alleles and genotypes were observed between the case and control groups in both the entire set and the different RA subsets. Disease activity and age of RA onset were also not associated with genotype distributions. Conclusion: IL1F7 gene polymorphism does not significantly influence RA susceptibility in the Northern Chinese Han population. Key words: IL1F7 Gene; Interleukin-37; Rheumatoid Arthritis; Single-nucleotide Polymorphisms

Renal infarction is a rare clinical entity that is not easily detected by low-sensitivity ultrasound. We herein report a case of dermatomyositis with renal infarction detected during corticosteroid therapy. The patient was followed up for 18 months. A woman who was clinically diagnosed with dermatomyositis complained of severe pain in the right flank of the low back and abdomen, accompanied by nausea and vomiting during corticosteroid therapy. Based on the findings of routine blood tests, abdominal X-ray radiography, and abdominal ultrasound, the patient was diagnosed with acute gastroenteritis and treated with levofloxacin. However, her symptoms were not relieved. Abdominal contrast-enhanced computed tomography revealed renal infarction. Clinicians should be alert to the occurrence of thrombosis, especially when it manifests as vasculitis in patients with rheumatic disease who complain of severe abdominal pain, because it may suggest the presence of renal infarction.

Background: Ankylosing spondylitis (AS) is a rheumatic inflammatory disease with unknown etiology, and fatigue is one of the main systemic symptoms of AS. The aim of the current study was to explore the mechanism of AS-associated fatigue (ASF) from multiple aspects, including neuropsychological changes.Method: A total of 120 AS patients and 78 age- and sex-matched healthy individuals were recruited into the study. Fatigue was assessed by the fatigue item of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Multidimensional Assessment of Fatigue (MAF) scale. Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS). The cortical thickness and subcortical gray matter volume were assessed using a Philips Achieva 3.0 T TX MRI scanner.Result: Of the 120 AS patients, 103 (85.8%) reported varying degrees of fatigue. Among these fatigue cases, 33 (32.0%) were in the severe fatigue group (BASDAI-Fatigue ≥ 5), and 70 patients (68.0%) were considered to be in the mild fatigue group (BASDAI-Fatigue > 0 but

Background As the prototype of autoimmune disease, systemic lupus erythematosus (SLE) has complex and diverse clinical manifestations which may be harmful even life-threaten. Its pitiful that we can just passively respond to these serious complications. It will be a great advantage if the high-risk groups could be predicated and prevented with pre-treatment. The raising of risk prediction models depends on the collection of patient phenotypes, which are scattered in various forms and very cumbersome. In this study, we collected the largest database of complete medical record of inpatients of lupus in China. The clinical phenotype database was generated by using natural language processing (NLP) techniques, then lupus nephritis (LN) prediction model was built. Methods A total of 14,439 SLE patients were collected from the rheumatology and immunology departments of 13 Chinese tertiary hospitals in this study, including 13 062 females (90.46%), with an average age of 33.4 years, and the time span of EMR (Electronic Medical Records) was from October 28, 2001 to March 31, 2017. It includes basic information about patients, physical examination, inspection and diagnostic information, etc. We designed a hybrid NLP system combined NLP technical and expert knowledge at the same time, which was named as Deep Phenotyping System (DPS), to extract all the phenotypic information recorded in EMR. Based on these standard formatted entities, the machine learning and deep learning prediction methods are used to predict the LN in SLE. Results The DPS efficiently processed EMR data, and its accuracy, precision, and recall were each greater than 93%. It extracted 73 794 entities from 14,439 SLE cases, each with time attributes, and produced 18,785,000,640 entities. Thus, a LN prediction model was raised, which the likelihood of lupus patients without nephritis will develop lupus nephritis within half and one year can be predicted.) More than 35 000 phenotypes was used in this model and it was verified with independent samples. The best accuracyACC and area under the curve (AUC) can be achieved 0.88 and 0.86 respectively. Conclusions The comprehensive SLE phenotype database constructed by NLP greatly improves the research efficiency of lupus clinical phenotype. We first proposed a predictive model of lupus nephritis, which is high applicability and efficiency. The experimental results of good close and open testing fully demonstrate the authenticity and practicality of this database. The research process and method based on real world data are also applicable to predict other important complications of lupus. Funding Source(s): None

Benign Childhood Epilepsy with Centro-temporal Spikes (BECTS) is the most common form of idiopathic epilepsy in children. To explore the genetic susceptibility loci in children with BECTS, we conducted 2stage genome-wide association study (GWAS) in over 1,800 Chinese Han patients with BECTS, and 7,090 healthy controls. We combined the datasets of the two stages by meta-analysis to identify the SNPs associated to BECTS. Significant common variant heritability of BECTS was observed. Heritability in the combined phase 1 and 2 datasets was > 10% even for assumed prevalence as low as 0.00025 on the liability scale. Twelve loci achieved suggestive evidence of association (5x10-8 < P < 10-5). In addition, the intersection between the GWAS findings and gene expression in brain tissue was analyzed by Summary-data-based Mendelian Randomization (SMR). We found association of t3603436 transcripts in CHRNA5 gene with SNP rs1948, which is suggestively associated with BECTS (Peqtl = 2.10x10-12, Psmr = 7.9x10-5), suggesting that rs1948 is significantly associated with BECTS through effects on expression of CHRNA5 in brain tissue. These findings suggest involvements of KALRN and CHRNA5-A3-B4 cluster in BECTS, give new directions to biological understanding of pediatric epilepsy, and opens avenues for investigation of prognostic factors and possible prevention of epilepsy in children. Funding: The study was funded by the National Key R&D Program of China (No. 2016YFC1000707), the National Natural Science Foundation of China (No. 81771389 and No. 81471329), and China Ministry of Science and technology (973 Program of China 2014CB541800). The study was also funded by Australian Research Council grant LPl10200926, and by the Queensland Premier’s Fellowship for Science (awarded to MAB, 2013). MAB was funded by Electronic copy available at: https://ssrn.com/abstract=3384897 a National Health and Medical Research Council Senior Principal Research Fellowship (APP1024879). Declaration of Interest: The authors have no conflict of interest. Ethical Approval: Written informed consent was obtained from all the parents or guardians, and the study was approved by the relevant ethics committees of the hospitals and institutions involved.

Air pollution may trigger systemic lupus erythematosus (SLE). However, few studies have investigated the associations between air pollution and complications of SLE, such as lupus nephritis (LN). In this study, multicenter longitudinal data from 13 hospitals in China, including 8552 SLE patients with 24,762 visits, were used. Based on the generalized estimating equation (GEE) model, we assessed the associations of LN occurrence with short-term exposures to different air pollutants including particulate matter with an aerodynamic diameter 2.5 μm (PM

This study aimed to assess the responsiveness of ultrasonography (US)-7 in patients with rheumatoid arthritis (RA). Eighty-two RA patients were recruited and followed up for 22 weeks. The clinical, laboratory, and X-ray assessments, along with grayscale US (GSUS) and power Doppler US (PDUS) examinations were performed at baseline, 6, 14, and 22 weeks after infliximab treatment. GSUS for synovitis and PDUS for synovitis and paratendinitis/tenosynovitis were assessed by a semi-quantitative (0 to 3) score, while GSUS for paratendinitis/tenosynovitis and bone erosion was qualitatively assessed as absent or present (0 or 1). US scores in both 7-joint (US7) and 12-joint (US12) systems were evaluated. After 6, 14, and 22 weeks of treatment with infliximab, indices such as US scores, 28-joint disease activity (DAS28) score, and tender and swelling joint count were all significantly improved compared to baseline. US7 scores were significantly correlated with that of US12. Strong correlations were identified between most US7 scores with DAS28, health assessment questionnaire (HAQ), and C-reactive protein (CRP) levels. When DAS28 was used as a reference, the US7 cutoff for disease remission was less than 35 for GS + PD and also less than 29 for GS and 1 for PD, respectively. Additionally, the positive percent agreement, negative percent agreement, and overall percent agreement for GS + PD were 77.78, 76.19, and 76.67 %, respectively, which were all higher than that of GS or PD. US7 may be a feasible tool to assess the therapeutic response in RA patients.

Kasabach–Merritt syndrome (KMS) is a rare complication of hemangioma. KMS mostly occurs in the pediatric population with typical clinical manifestations, including thrombocytopenia, consumptive coagulation, and purpura. However, the pathogenesis of KMS is still unclear and the KMS therapy is controversial. We report here a case of KMS and multiple, giant, hepatic hemangiomas in a 34-year-old female patient who was successfully treated in our hospital. Glucocorticoid along with supportive treatments was administrated immediately to reverse fatal disseminated intravascular coagulation and acute hemolysis. After the acute phase, glucocorticoid was tapered slowly and sirolimus was added to treat the hemangiomas. In conclusion, the risk factors of gestation, interventional treatment, and autoimmune disturbance might contribute to the pathogenesis of KMS. Additionally, treatment with glucocorticoid and sirolimus is effective in KMS and multiple giant hepatic hemangiomas.

This study aimed to investigate the reliability and validity of serum matrix metalloproteinase-3 (MMP-3) levels and articular ultrasound (US) scores in assessing disease activity and therapeutic response in rheumatoid arthritis (RA) patients. A total of 151 RA patients were enrolled, of whom 22 were treated with certolizumab pegol (Cimzia, CZP). The RA patients were divided into the following four subgroups according to their disease activity score in 28 joints (DAS28): stable, mild activity, moderate activity, and high activity. Forty-three healthy controls were simultaneously studied. The serum MMP-3 levels and 7-joint US (US7) scores of all subjects were determined. The patients who were treated with CZP were subsequently followed for 6 months. The serum MMP-3 levels of all the RA patients were significantly higher than those of healthy controls, and those of patients with moderate and severe RA were significantly higher than those of patients with stable RA. The US7 scores of patients with severe RA were significantly higher than those of patients in other groups. Using the DAS28 as a reference standard, the corresponding cutoff value of MMP-3 was 70.5 ng/ml. After CZP treatment, the MMP-3 levels and US7 scores were significantly decreased at week 2, and the mean changes in US7 scores at weeks 12 and 24 were significantly higher in both groups with American College of Rheumatology 50% positive response (ACR50) and ACR 70% positive response (ACR70) than in the negative groups. Serum MMP-3 and the US7 scores could both effectively reflect disease activity and therapeutic responses in patients with moderate to severe RA. CTR20140405 (RA0044), CTR20140405: A phase 3, Multicenter, Double-blind, Placebo Controlled, Parallel Group, Randomized, 24-Week Study to Evaluate the Safety and Efficacy of Certolizumab Pegol as Additional Medication to Methotrexate in Chinese Subjects With Active Rheumatoid Arthritis Who Have an Incomplete Response to Methotrexate, Registered on 13 June 2014. CTR20140412 (RA0078), CTR20140412: A phase 3, Multicenter, Open-label Extension Study to Assess the Safety and Efficacy of Certolizumab Pegol as Additional Medication to Methotrexate in Chinese Subjects With Active Rheumatoid Arthritis Who Participated in RA0044, Registered on 02 July 2014.

Background Hip involvement is a common clinical feature observed in ankylosing spondylitis (AS) patients and it often leads to substantial restriction of the body functions.1 Hip involvement in AS is mainly assessed by radiographic changes, clinical symptoms or MRI. The Harris hip score (HHS) is a valuable assessment tool to measure health status of AS patients. However, the relationship between HHS and other clinical indices is unknown. Objectives To evaluate relationship between HHS and other commonly used clinical indices. Methods In this multicentre, observational study, AS patients with hip clinical manifestation are enrolled and randomly assigned to infliximab treatment (group I, with/without DMARDs and/or NSAIDs) or conventional therapy (group II, DMARDs and/or NSAIDs). Primary endpoint: to compare functional improvement of hip joint (HHS) between two treatment groups (infliximab and conventional therapy) at week 30. Secondary endpoint: to compare disease activity and functional improvement of AS and radiologic progression of hip joint between two treatment groups at week 30 and 52. Association between baseline HHS and disease activity measures such as Bath ankylosing spondylitis (BAS)-functional index (BASFI), BAS disease activity index (BASDAI), AS disease activity score (ASDAS), CRP and ESR was analysed using Pearson correlation coefficient. BAS metrology index (BASMI) and hip imaging functions (MRI of hip, BAS radiology hip index [BASRI-h]) were analysed using independent two-sample t-test or ANOVA based on data characteristics. Results Study is ongoing; currently, only baseline information is analyzed. Baseline demographics and disease characteristics did not show any significant difference between groups. Almost all baseline disease activity measures showed significant Pearson correlation (high correlation in BASFI=0.646) with HHS, except for BASDAI (table 1). Significant association between HHS and three MRI scores (articular cartilage stripping, bone destruction under joint surface, femoral head bone marrow cavity edema) and BASRI-h was shown (table 2). Also, significant correlation was shown between BASMI and HHS (F value [degree of freedom]=4.70 [4]; p=0.0022). Conclusions The baseline results of HHS were found to be well associated with disease activity scores like BASFI, ASDAS and BASMI and four hip imaging features in AS patients with hip involvement. References Jeong H, et al. Korean J Intern Med. 2017; 32(1): 158–164. Disclosure of Interest Z. Wu: None declared, L. He: None declared, M. Yang: None declared, Y. Liu: None declared, D. He: None declared, Y. Zhang: None declared, C. Wang Employee of: Xi9an Janssen pharmaceuticals Ltd., H. Xu: None declared

To assess the clinical efficacy as well as safety profiles of Leining, a novel cytotoxic T-lymphocyte antigen-4 fusion protein, versus placebo in the treatment of Chinese active rheumatoid arthritis (RA) patients with an inadequate clinical response to methotrexate (MTX). In this 24-week, randomized, double-blind, placebo-controlled multicenter study, a total of 440 Chinese patients with active RA with an inadequate response to MTX were randomly assigned to receive Leining (10 mg/kg) or placebo. Clinical response was assessed using the American College of Rheumatology 20 % improvement criteria ACR20, ACR50, and ACR70, with ACR20 as the primary major endpoints. Disease activity scores in 28 joints with erythrocyte sedimentation rate assessment (DAS28-ESR) were used to evaluate disease activity. After 24 weeks of treatment, significantly more patients in Leining group achieved ACR20 response than those in placebo group (70.61 vs. 46.36 %; p0.001). Similarly, ACR50 and ACR70 responses of Leining group were significantly higher than those of placebo group (40.30 vs. 22.73 %; p0.001 and 16.67 vs. 7.27 %; p0.05, respectively). DAS28-ESR in Leining group was significantly reduced compared to that in placebo group, with greater clinically meaningful (1.2 unit) improvement (54.85 vs. 29.09 %, p0.05). Both the rates of remission (DAS28-ESR2.6) and low disease activity (DAS28-ESR3.2) were greater in the Leining group than those in the placebo group (12.42 vs. 2.73 %; p0.05 and 15.45 vs. 2.73 %; p0.05 respectively). The overall incidence of adverse events was similar in both Leining and placebo groups. No neutralizing antibodies were detected. Leining demonstrated clinically meaningful efficacy compared with placebo in Chinese patients with active RA despite MTX therapy. Administration of Leining in combination with MTX for 24 weeks was well tolerated.

The parasympathetic nervous system has been known to modify innate immune responses. In animal models, acetylcholine (Ach) released from the distal ends of nerves has been shown to inhibit inflammatory responses such as endotoxic shock, pancreatitis, intestinal inflammation, etc. However, its role in LPS-induced fulminant hepatitis remains to be elucidated. Here, we demonstrate that the vagus nerve acts as a suppressor in the liver after challenge with LPS plus D-gal. The vagus nerve acts through the α7 AchR expressed on the surface of Kupffer cells, inhibiting the production of the proinflammatory cytokines TNF and IL-6. A mechanism study revealed that the suppressive effect of Ach may occur through the activation of Src kinase and subsequent inhibition of the Myd88 signal pathway. Our study has suggested a suppressive role of vagus nerve in the modulation of liver inflammatory responses, which should be noticed during clinical massive hepatectomy and liver transplantation. The nicotinic anti-inflammatory pathway may also be a potential target for sepsis after liver transplantation.

Human leukocyte antigen (HLA) alleles are associated with a variety of autoimmune diseases. The composition of gut microbiome can be influenced by host immunity, which is partially regulated by HLA. In this review, first we provide evidence from animal and human studies on: if and how HLA-B27, HLA-DRB1 (shared epitope (SE)), and other HLA alleles alter the gut microbiome, then we analyzed the data for several hypotheses to explain the mechanism(s) of HLA alleles influences on gut microbiome, and finally, we discussed several potential clinical implications of HLA alleles and microbial data, such as bacterial biomarkers for diagnosis, treatment, and the screening of high-risk population.

Free to read Objective Ankylosing spondylitis (AS) is a highly heritable common inflammatory arthritis that targets the spine and sacroiliac joints of the pelvis, causing pain and stiffness and leading eventually to joint fusion. Although previous studies have shown a strong association of IL23R with AS in white Europeans, similar studies in East Asian populations have shown no association with common variants of IL23R, suggesting either that IL23R variants have no role or that rare genetic variants contribute. The present study was undertaken to screen IL23R to identify rare variants associated with AS in Han Chinese. Methods A 170-kb region containing IL23R and its flanking regions was sequenced in 50 patients with AS and 50 ethnically matched healthy control subjects from a Han Chinese population. In addition, the 30-kb region of peak association in white Europeans was sequenced in 650 patients with AS and 1,300 healthy controls. Validation genotyping was undertaken in 846 patients with AS and 1,308 healthy controls. Results We identified 1,047 variants, of which 729 were not found in the dbSNP genomic build 130. Several potentially functional rare variants in IL23R were identified, including one nonsynonomous single-nucleotide polymorphism (nsSNP), Gly149Arg (position 67421184 GA on chromosome 1). Validation genotyping showed that the Gly149Arg variant was associated with AS (odds ratio 0.61, P = 0.0054). Conclusion This is the first study to implicate rare IL23R variants in the pathogenesis of AS. The results identified a low-frequency nsSNP with predicted loss-of-function effects that was protectively associated with AS in Han Chinese, suggesting that decreased function of the interleukin-23 (IL-23) receptor protects against AS. These findings further support the notion that IL-23 signaling has an important role in the pathogenesis of AS.

Background and objectivesEfficacy of adalimumab for ankylosing spondylitis (AS) has been established for Western populations but not in the Chinese population. This study is the first to evaluate the efficacy and safety of adalimumab in Chinese patients with AS.MethodsChinese adults with active AS who had an inadequate response or were intolerant to ≥1 non-steroidal anti-inflammatory drugs were randomised to adalimumab 40 mg (N=229) or matching placebo (N=115) subcutaneously every other week (EOW) for 12 weeks, followed by a 12-week open-label adalimumab 40 mg EOW phase. The primary efficacy endpoint was the percentage of patients meeting the Assessment in Spondyloarthritis International Society (ASAS20) response criteria at week 12. The recently developed AS Disease Activity Score (ASDAS), as well as efficacy measures of spinal mobility, disease activity, physical function and quality of life were evaluated.ResultsAt week 12, adalimumab treatment resulted in a significantly greater percentage of ASAS20 responders than placebo (67.2% versus 30.4%, respectively; pConclusionsAdalimumab significantly reduced the signs and symptoms, improved physical function and quality of life of Chinese patients with active AS, and was generally safe and well tolerated in this population.

OBJECTIVES: Recent association studies by the Australo-Anglo-American Spondyloarthritis Consortium (TASC) in Caucasian European populations from Australia, North America and the UK have identified a number of genes as being associated with ankylosing spondylitis (AS). A candidate gene study in a Han Chinese population was performed based on these findings to identify associated genes in this population. METHODS: A case-control study was performed in a Han Chinese population of patients with AS (n = 775) and controls (n = 1587) from Shanghai and Nanjing. All patients met the modified New York criteria for AS. The cases and controls were genotyped for 115 single nucleotide polymorphisms (SNPs) tagging IL23R, ERAP1, STAT3, JAK2, TNFRSF1A and TRADD, as well as other confirmation SNPs from the TASC study, using the Sequenom iPlex and the ABI OpenArray platforms. Statistical analysis of genotyped SNPs was performed using the Cochran-Armitage test for trend and meta-analysis was performed using METAL. SNPs in AS-associated genes in this study were then imputed using MaCH, and association with AS tested by logistic regression. RESULTS: SNPs in TNFRSF1A (rs4149577, p = 8.2 × 10⁻⁴), STAT3 (rs2293152, p = 0.0015; rs1053005, p = 0.017) and ERAP1 (rs27038, p = 0.0091; rs27037, p = 0.0092) were significantly associated with AS in Han Chinese. Association was also observed between AS and the intergenic region 2p15 (rs10865331, p = 0.023). The lack of association between AS and IL23R in Han Chinese was confirmed (all SNPs p > 0.1). CONCLUSIONS: The study results demonstrate for the first time that genetic polymorphisms in STAT3, TNFRSF1A and 2p15 are associated with AS in Han Chinese, suggesting common pathogenic mechanisms for the disease in Chinese and Caucasian European populations. Furthermore, previous findings demonstrating that ERAP1, but not IL23R, is associated with AS in Chinese patients were confirmed.

Objective. To analyse the potential risk factors of nosocomial infections in patients with active rheumatoid arthritis (RA). Methods. A total of 2452 active RA patients at Hospitals in Shanghai between January 2009 and February 2011 were analyzed. Their demographic and clinical characteristics were compared with those without infection, and the potential risk factors were determined by logistic regression analysis. Results. Multivariate analysis indicated the gender (OR=0.70, 95% CI 0.53–0.92), duration in hospital (OR=1.03, 95%CI 1.01–1.05), number of organs involved (OR=0.82, 95%CI 0.72–0.92), number of disease-modifying antirheumatic drugs ((DMARDs) (OR=1.22, 95%CI 1.061–1.40)), corticosteroid therapy (OR=1.02, 95%CI 1.01–1.03), peripheral white blood cell counts ((WBC) (OR=1.04, 95%CI 1.00–1.08)), levels of serum albumin (OR=0.98, 95%CI 0.97–0.99), and C-reactive protein ((CRP) (OR=1.03, 95%CI 1.01–1.04)) that were significantly associated with the risk of infections. Conclusion. The female patients, longer hospital stay, more organs involved, more DMARDs, corticosteroid usage, high counts of WBC, lower serum albumin, and higher serum CRP were independent risk factors of infections in active RA patients.

BackgroundThe genome-wide association study era has made great progress in identifying susceptibility genes and genetic loci for rheumatoid arthritis (RA) in populations of White European ancestry. However, few studies have tried to dissect disease aetiopathogenesis in other ethnic populations.ObjectiveTo investigate these associations in the Han Chinese population.MethodsHaplotypes from the HapMap database Chinese population were used to select tag-single-nucleotide polymorphisms (SNPs) (r2=0.8) across 19 distinct RA genomic regions. A two phase case–control association study was performed, with 169 SNPs genotyped in phase I (n=571 cases, n=880 controls), and 64 SNPs achieving pResultsRobust association was detected for MMEL1 and CTLA4, and modest association was identified for another six loci: PADI4, STAT4, PRDM1, CDK6, TRAF1-C5 and KIF5A-PIP4K2C. All three markers genotyped in MMEL1 demonstrated association, with peak signal for rs3890745 (p=2.6×10−5 unadjusted, p=0.003 adjusted, OR=0.79). For CTLA4, significance was detected for three of five variants showing association, with peak association for marker rs12992492 (p=4.3×10−5 unadjusted, p=0.0021 adjusted, OR=0.77). Lack of association of common variants in PTPN22 with RA in Han Chinese was confirmed.ConclusionThis study identifies MMEL1 and CTLA4 as RA susceptibility genes, provides suggestive evidence of association for a further six loci in the Han Chinese population and confirms lack of PTPN22 association in Asian populations. It also confirms the value of multiethnic population studies to help dissect disease aetiopathogenesis.

The HLA-B27 subtypes have a varied racial and ethnic prevalence throughout the world. However, the association of B27-subtypes with ankylosing spondylitis (AS) in the mainland China is unknown. To determine the association of B27-subtypes with AS in the Mainland Chinese Han population, a total of unrelated 153 patients with AS were enrolled in a large case-control association study, and 1545 unrelated, healthy, ethnically matched blood donors were included as controls. The genotyping of B27 and its subtypes was performed using the polymerase chain reaction with sequence specific primers (PCR-SSP). A total of 130 (84.97%) AS patients and 61 (3.95%) healthy controls were B27 positive. Three B27-subtypes, B*2704, B*2705 and B*2710, were further identified, of which both B*2704 and B*2705 were strongly AS associated. B*2710 was only detected in one AS patient and two other healthy controls. Considering only B27-positive cases and controls, a statistically different frequency of B27-subtypes was observed, with an over-representation of B*2704 (P = 0.018). B*2704 was clearly more strongly associated than B*2705 with AS [odds ratio (OR) = 2.4, P = 0.011]. Furthermore, a combined analysis including three previous studies of B27-subtype distributions in Chinese AS cases confirmed the stronger association of B*2704 with AS than B*2705 (OR = 2.5, P = 0.00094).

The pathological features of adult-onset Still's disease remain unclear. An original case study of the histopathological changes in various organs of a patient with the disorder is presented. Interstitial inflammation was found in the heart, lung, liver, mucosa of total alimentary canal, and urinary bladder. Previous reports that involved the pathology of visceral organs are also reviewed.

Objective To test the effects of a novel monoclonal antibody (mAb) against human osteopontin (OPN) in the prevention and treatment of collagen-induced arthritis (CIA) and to elucidate the underlying mechanisms of these effects. Methods DBA/1J mice immunized with type II collagen to induce CIA were monitored to assess the effects of anti-OPN mAb on the clinical severity of the disease, and pathologic changes in the joints were examined histologically. The effects of anti-OPN mAb on survival of activated T cells from arthritic mice and from the synovial fluid of patients with rheumatoid arthritis (RA) were determined by TUNEL assay or annexin V assay. The levels of apoptosis-related proteins (Bim, Bax, and Bcl-2) and NF-κB were detected by immunoblot analysis. Results One anti-OPN mAb, 23C3, was effective in inhibiting the development of CIA and even reversing established disease in DBA/1J mice. Monoclonal antibody 23C3 reduced the levels of serum type II collagen–specific autoantibodies and proinflammatory cytokines, and suppressed T cell recall responses to type II collagen. Mechanistic studies demonstrated that OPN prevented the death of type II collagen–activated murine T cells and synovial T cells from RA patients. Monoclonal antibody 23C3 promoted apoptosis of the activated T cells, particularly CD4+ T cells, by inhibiting activation of NF-κB and by altering the balance among the proapoptotic proteins Bim and Bax and the antiapoptotic protein Bcl-2. Screening of a phage display peptide library led to identification of the epitope ATWLNPDPSQKQ as being recognized by this novel antibody. Conclusion Because of its ability to effectively promote apoptosis of activated T cells, mAb 23C3 may be a novel therapeutic agent for the treatment of RA.

Recent data are presented which indicate a critical role for interleukin (IL)‐18 in rheumatoid arthritis (RA). The T cells and macrophages invading the synovium or in the synovial fluid are the chief cellular targets of IL‐18 in RA. Neutrophils, dendritic cells and endothelial cells may also be cellular mediators of IL‐18. The direct effect of IL‐18 on fibroblast‐like synoviocytes or chondrocytes may not be essential or important. In RA, IL‐18, which is mainly produced by macrophages, activates T cells and macrophages to produce proinflammatory cytokines, chemokines, adhesion molecules and RANKL which, in turn, perpetuate chronic inflammation and induce bone and cartilage destruction.

The association of endoplasmic reticulum aminopeptidase 2 (ERAP2) with ankylosing spondylitis (AS) was recently described in the large International Genetics of AS Consortium Immunochip study. Variants in ERAP2 have also been associated with inflammatory bowel disease, psoriasis, acute anterior uveitis and birdshot chorioretinopathy. Subsequent investigation demonstrated an association of ERAP2 with AS which was present when one conditioned on one of the two independent haplotypes of ERAP1 associated with AS or when HLA-B27-negative patients were analysed separately. These two analyses provide analogous evidence for the association of ERAP2 with AS in HLA-B27-negative cases because of the genetic interaction between HLA-B27 and the AS-associated ERAP1 variants in AS cases. ERAP1 and ERAP2 are located on chromosome 5q15 in the opposite orientation. The locus is challenging to analyse because of the strong linkage disequilibrium (LD) across the locus and the epistasis between ERAP1 and HLA-B alleles associated with AS. We therefore sought to investigate the association of ERAP2 with AS in HLA-B27-positive patients. This is of clinical importance because functional studies have demonstrated that the strongly AS-protective variant rs2248374 causes a functional ERAP2 protein knockout, because its G allele causes a loss of ERAP2 protein expression. There is also a variant of ERAP2 which changes its enzyme catalytic activity and specificity (rs2549782, K392A). Because this is in almost complete LD with rs2248374 (1000 Genomes D′=1.00, r2=0.90), it is almost never translated in vivo. Further, the very strong LD between these markers means that analysis of rs2549782 for association would yield results almost identical to the results for rs2248374 presented below. Therefore, it is of relevance to determine whether the association of ERAP2 with HLA-B27-negative disease is also found in HLA-B27-positive cases, since ERAP inhibition may offer a novel therapeutic for AS...

Rationale: Systemic Scleroderma (SSc) is a rare connective tissue disease clinically characterized by cutaneous sclerosis and variable systemic involvement. No drug is currently available to effectively reverse the fibrotic process in SSc. Previous reports have suggested that the tumor necrosis factor (TNF) antagonists could be useful for the treatment of fibrotic disorders. However, TNFα has long been considered as an antifibrotic cytokine. Whether TNF antagonist is effective for SSc patients needs to be tested. Patient concerns-Diagnosis: Here we report a case with a 2-year history of SSc who was effectively treated with infliximab in our clinic. Interventions: The patient manifested skin thickening, chest tightness and arthralgia. Before admitted to our clinic, he was treated with methylprednisolone, prostacyclin, D-penicillamine and calcium antagonists but without significant improvement of his signs and symptoms. In our clinic, the patient was treated with infliximab. Outcomes: His signs and symptoms were continued improving during the course of treatment. His skin biopsy showed significant reduction in fibroplasia finally. Lessons: TNF antagonist is an effective treatment for SSc.

Objective: To evaluate the safety of tumor necrosis factor-alpha (TNF-alpha) monoclonal antibody (infliximab) therapy in patients with rheumatoid arthritis (RA) and previous exposure to hepatitis B virus (HBV) who had normal liver function.Methods: This is a retrospective study from a 26-week, prospective, multicenter trial in 234 patients with RA who received infusions of infliximab (3 mg/kg at week 0, 2, 6, 14 and 22). The medical records of these patients were reviewed, including the information on disease duration, laboratory tests and HBV markers. The data on liver function during the study was analyzed, as well as comparison between patients with previous exposure to HBV and patients without such exposure.Results: Forty-one patients with previous exposure to HBV were HBsAg(-). Forty patients had normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and only one patient with positive anti-HBc showed an elevated ALT level before administration of infliximab, and had a further increase of ALT level at week 14, but decreased thereafter. The average ALT and AST levels rose slightly during the treatment but remained in normal range and the differences were insignificant compared with baseline. There was no statistically significant difference in the incidence of liver function abnormalities during the treatment of infliximab between the patients with previous exposure to HBV and those without such exposure.Conclusion: In patients with RA and previous exposure to HBV but with a negative HBsAg and normal liver function at baseline, liver function abnormalities were not observed during infliximab treatment.

The clinical trial of allogenic mesenchymal stem cells (MSCs) transplantation for refractory SLE patients has shown significant safety and efficacy profiles. However, the optimum frequency of the MSCs transplantation (MSCT) is unknown. This study was undertaken to observe whether double transplantations of MSCs is superior to single transplantation. Fifty-eight refractory SLE patients were enrolled in this study, in which 30 were randomly given single MSCT, and the other 28 were given double MSCT. Patients were followed up for rates of survival, disease remission, and relapse, as well as transplantation-related adverse events. SLE disease activity index (SLEDAI) and serologic features were evaluated. Our results showed that no remarkable differences between single and double allogenic MSCT were found in terms of disease remission and relapse, amelioration of disease activity, and serum indexes in an SLE clinical trial with more than one year followup. This study demonstrated that single MSCs transplantation at the dose of one million MSCs per kilogram of body weight was sufficient to induce disease remission for refractory SLE patients.

OBJECTIVES--To evaluate the role of low molecular weight (LMW) IgM and CD5 B cells in rheumatoid arthritis (RA) and to explore the possibility that LMW IgM is derived selectively from this subset of B cells. METHODS--LMW IgM in sera and culture supernatants was detected by a sensitive immunoblot technique with an enhanced chemiluminescence detection system. CD5 B cells were determined by FACScan cytometry. In vitro studies were established in culture plates containing pokeweed mitogen with or without 2-mercaptoethanol (2-ME). Supernatants were obtained from CD5 positive hybridomas and CD5 negative hybridomas. Other immunological indices were measured by laser nephelometry. RESULTS--Circulating LMW IgM was detected in all rheumatoid patients with significantly higher levels being observed in sero-positive patients. LMW IgM correlated significantly with total IgM and RF. Peripheral blood mononuclear cells (PBMC) from the majority of the patients with RA secreted LMW IgM in vitro as did mononuclear cells from a synovial fluid sample. The addition of low concentrations of 2-ME to the culture medium enhanced the proportions of secreted monomeric IgM. In contrast, PBMC from healthy subjects secreted only trace quantities of LMW IgM. In RA no significant correlations were observed between CD5 B cells and LMW IgM and RF. LMW IgM could be detected in the supernatants from both CD5+ and CD5- B cell lines. Finally, CD5 B cells were not significantly elevated in RA and levels remained constant over time. CONCLUSION--LMW IgM exists in high concentrations in RA sera and synovial fluid. Serum level correlates with RF and IgM. In vitro studies have suggested that the occurrence of LMW IgM may be due to an intrinsic defect(s) in the assembly of the IgM pentameric molecule. LMW IgM is unlikely to be derived solely from CD5 B cells.

The Spondyloarthritis Research and Therapy Network (SPARTAN), founded in 2003 to promote research, education, and treatment of ankylosing spondylitis (AS) and related forms of spondyloarthritis (SpA), held its 7th Annual Research and Education Meeting in July 2009 in Houston, Texas. Current controversies in SpA discussed during the meeting included an update on the epidemiology of AS, axial SpA, and inflammatory back pain; the adequacy of the mSASS to assess radiographic involvement; the helpfulness of magnetic resonance imaging in assessing disease progression; the reliability of metrology in assessing damage; and whether biologic agents alter the course of AS. Presentations also were made on psoriasis in the SCID mouse model; the challenges and opportunities of SpA in China; a discussion of the special needs in managing SpA in Ibero-America, and the SPARK Survey in Europe and North America.

The aim of this study is to assess the efficacy of anakinra, a recombinant human interleukin 1 receptor antagonist, plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) refractory to MTX therapy. A total of 54 patients with active RA, who were taking MTX at a stable dosage, were randomized to receive daily subcutaneous injections of anakinra (80 mg) or placebo. Clinical outcomes were assessed every 4 weeks for 24 weeks by using the criteria of the American College of Rheumatology. After 24 weeks, more patients achieved clinical benefits as determined by the ACR20 improvement treated with anakinra plus MTX compared with MTX alone (64% vs. 17%, P = 0.004). In the anakinra group, an ACR50 response was observed in 38% and an ACR70 response in 17%. None of the patients treated with MTX alone achieved ACR50 or ACR 70 improvement. However, nine of 42 (21.4%) patients in the anakinra group, who showed therapeutic response initially, had secondary drug failure to anakinra therapy thereafter. A significant increase in mean DAS28 from baseline was found in the non-responders to anakinra compared with placebo (0.83 ± 1.38 vs. −1.28 ± 0.78, P < 0.001). Anakinra is effective in the treatment of patients with active RA by blocking IL-1. However, the efficacy of anakinra is soon lost in about one fifth of patients in spite of initial good response.

Objective The results of a recent genome-wide association study have shown that ERAP1 and IL23R are associated with ankylosing spondylitis (AS) in Caucasian populations from North America and the UK. Based on these findings, we undertook the current study to investigate whether single-nucleotide polymorphisms (SNPs) covering the genes ERAP1 and IL23R are associated with AS in a Han Chinese population. Methods A case-control study was performed in Han Chinese patients with AS (n = 527) and controls (n = 945) from Shanghai and Nanjing. All patients met the modified New York criteria for AS. The Sequenom iPlex platform was used to genotype cases and controls for 21 tag SNPs covering IL23R and 38 tag SNPs covering ERAP1. Statistical analysis was performed using the Cochran-Armitage test for trend. Results Multiple SNPs in ERAP1 were significantly associated with AS (for rs27980, P = 0.0048; for rs7711564, P = 0.0081). However, no association was observed between IL23R and AS (for all SNPs, P > 0.1). The nonsynonymous SNP in IL23R, rs11209026, widely thought to be the primary AS-associated SNP in IL23R in Europeans, was found not to be polymorphic in Chinese. Conclusion Our results demonstrate that genetic polymorphisms in ERAP1 are associated with AS in Han Chinese, suggesting a common pathogenic mechanism for the disease in Chinese and Caucasian populations, and that IL23R is not associated with AS in Chinese, indicating a difference in the mechanism of disease pathogenesis between Chinese and Caucasian populations. This may result from the fact that rs11209026, the nonsynonymous SNP in IL23R, is not polymorphic in Chinese patients, providing further evidence that rs11209026 is the key polymorphism associated with AS (and likely inflammatory bowel disease and psoriasis) in this gene.

OBJECTIVES: The aim of the current study was to determine the contribution of interleukin (IL)1 gene cluster polymorphisms previously implicated in susceptibility for ankylosing spondylitis (AS) to AS susceptibility in different populations worldwide. METHODS: Nine polymorphisms in the IL1 gene cluster members IL1A (rs2856836, rs17561 and rs1894399), IL1B (rs16944), IL1F10 (rs3811058) and IL1RN (rs419598, the IL1RA VNTR, rs315952 and rs315951) were genotyped in 2675 AS cases and 2592 healthy controls recruited in 12 different centres in 10 countries. Association of variants with AS was tested by Mantel-Haenszel random effects analysis. RESULTS: Strong association was observed with three single nucleotide polymorphisms (SNPs) in the IL1A gene (rs2856836, rs17561, rs1894399, p = 0.0036, 0.000019 and 0.0003, respectively). There was no evidence of significant heterogeneity of effects between centres, and no evidence of non-combinability of findings. The population attributable risk fraction of these variants in Caucasians is estimated at 4-6%. CONCLUSIONS: This study confirms that IL1A is associated with susceptibility to AS. Association of the other IL1 gene complex members could not be excluded in specific populations. Prospective meta-analysis is a useful tool in confirmation studies of genes associated with complex genetic disorders such as AS, providing sufficiently large sample sizes to produce robust findings often not achieved in smaller individual cohorts.