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Objective: Recent evidence from genetic, cell biology, and animal model studies has suggested a pivotal role of autophagy in mediating systemic lupus erythematosus (SLE). However, the genetic basis has not yet been thoroughly examined. Therefore, the aim of the present study was to identify additional susceptibility variants in autophagy‐related genes along with their functional significance. Methods: First, we performed a gene family–based genetic association analysis in SLE patients with the use of ImmunoChip arrays, and then we selected the most strongly associated polymorphisms for replication in additional cohorts. To identify regulatory clues, we analyzed publicly available blood expression quantitative trait locus data and Encyclopedia of DNA Elements data on transcription factor binding sites and cell type‐specific differential expression. Functional effects were tested by luciferase reporter assays, electrophoretic mobility shift assays, and differential gene expression assays. Results: In 14,474 samples, we observed that the rare Chinese variant rs933717T was associated with susceptibility to SLE (0.11% in cases versus 0.87% in controls; P = 2.36 × 10–10, odds ratio 0.13). The rs933717 risk allele C correlated with increased MAP1LC3B expression; increased MAP1LC3B messenger RNA was observed in SLE patients and in lupus‐prone mice. In reporter gene constructs, the risk allele increased luciferase activity up to 2.7‐3.8‐fold in both HEK 293T and Jurkat cell lines, and the binding of HEK 293T and Jurkat cell nuclear extracts to the risk allele was also increased. Conclusion: We observed a likely genetic association between light chain 3B, a widely used marker for autophagy, and susceptibility to SLE. [ABSTRACT FROM AUTHOR]

Background: Ankylosing spondylitis (AS) is a common chronic progressive rheumatic disease. The aim of this study was to explore factors influencing abnormal bone mineral density (BMD) in young and middle-aged patients with AS., Methods: From July 2014 to August 2018, hospitalized patients with AS and health examinees in the health examination center of our clinics, ranging in age from 20 to 50 years, were monitored. The BMD of the lumbar spine and femoral neck of AS patients and those of a healthy control group were measured using dual-energy X-ray absorption. The BMDs of AS patients were compared with respect to age, course of disease, iritis, smoking habits, sex, height, weight, body mass index (BMI), medication use, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), platelet volume, platelet count, uric acid (UA), alkaline phosphatase (AKP), and calcium ion levels. Single-nucleotide polymorphisms (SNPs) related to BMD were screened using genome-wide association analysis., Results: There was no statistical difference in the proportion of abnormal bone masses between the different body parts. The BMD of all bones in AS patients was lower than that in healthy controls (P < 0.05). Additionally, BMD was correlated with serum calcium and CRP in AS patients (P < 0.05), but not with age, platelet volume, platelet count, ESR, UA, AKP, height, weight, and BMI. The incidence of abnormal bone mass in AS patients was correlated with sex (P < 0.05), but not with medication use, iritis, or smoking. BMD of the lumbar spine in AS patients did not correlate linearly with the course of the disease, but BMD of the femoral neck correlated linearly with the course of the disease (P < 0.05). BMD was correlated with multiple SNPs in patients with AS. Lumbar BMD was correlated with rs7025373 and rs7848078. Femoral head BMD was correlated with 3:102157365, 3:102157417, rs1252202, rs1681355, rs3891857, rs7842614, and rs9870734, suggesting that genetic factors play a role in BMD in patients with AS., Conclusions: The proportion of abnormal bone mass in AS patients was higher than that in healthy individuals of the same age. The factors related to BMD in patients with AS are gender, CRP, and blood calcium. The BMD of the femoral neck of AS patients decreases with the course of the disease, but BMD of the lumbar spine is not related to the course of the disease. BMD in AS patients is associated with multiple SNPs., (Copyright © 2021 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

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., (© 2021 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background and Objectives: IgA nephropathy is the most common form of primary GN worldwide. The evidence of geographic and ethnic differences, as well as familial aggregation of the disease, supports a strong genetic contribution to IgA nephropathy. Evidence for genetic factors in IgA nephropathy comes also from genome-wide association patient-control studies. However, few studies have systematically evaluated the contribution of coding variation in IgA nephropathy., Design, Setting, Participants, & Measurements: We performed a two-stage exome chip-based association study in 13,242 samples, including 3363 patients with IgA nephropathy and 9879 healthy controls of Han Chinese ancestry. Common variant functional annotation, gene-based low-frequency variants analysis, differential mRNA expression, and gene network integration were also explored., Results: We identified three non-HLA gene regions ( FBXL21 , CCR6 , and STAT3 ) and one HLA gene region ( GABBR1 ) with suggestive significance ( P meta <5×10 -5 ) in single-variant associations. These novel non-HLA variants were annotated as expression-associated single-nucleotide polymorphisms and were located in enhancer regions enriched in histone marks H3K4me1 in primary B cells. Gene-based low-frequency variants analysis suggests CFB as another potential susceptibility gene. Further combined expression and network integration suggested that the five novel susceptibility genes, TGFBI , CCR6 , STAT3 , GABBR1 , and CFB , were involved in IgA nephropathy., Conclusions: Five novel gene regions with suggestive significance for IgA nephropathy were identified and shed new light for further mechanism investigation., (Copyright © 2021 by the American Society of Nephrology.)

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This study assessed the efficacy and safety of tofacitinib in Chinese patients with RA enrolled in Phase 3 and long-term extension (LTE) studies., Methods: ORAL Sync was a 1-year, randomized, placebo-controlled, Phase 3 trial. Patients received tofacitinib 5 or 10 mg twice daily (BID) or placebo advanced to tofacitinib 5 or 10 mg BID at 3 or 6 months. All patients remained on ≥1 background conventional synthetic disease-modifying antirheumatic drug. ORAL Sequel is an open-label LTE study (data-cut: March 2015; data collection and analyses were ongoing, and study database was not locked at the time of analysis; study was closed in 2017). Efficacy outcomes: American College of Rheumatology (ACR) 20/50/70 response rates and Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-4 [ESR]). Patient- and physician-reported outcomes: Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Physician Global Assessment of Arthritis, and pain (visual analog scale). Safety was assessed throughout., Results: ORAL Sync included 218 patients; 192 were subsequently enrolled into ORAL Sequel. In ORAL Sync, more patients achieved ACR20 (tofacitinib 5 mg BID, 67.4%; 10 mg BID, 70.6%; placebo, 34.1%) and DAS28-4 (ESR) <2.6 (tofacitinib 5 mg BID, 7.1%; 10 mg BID, 13.1%; placebo, 2.3%) with tofacitinib versus placebo at Month 6. Mean changes from baseline in HAQ-DI were greater with tofacitinib versus placebo at Month 6. In ORAL Sequel, efficacy was consistent to Month 48. Incidence rates for adverse events of special interest in tofacitinib-treated patients were similar to the global population., Conclusions: Tofacitinib significantly reduced signs/symptoms and improved physical function and quality of life in Chinese patients with moderate-to-severely active RA up to Month 48. The safety profile was consistent with the global population., Clinical Trial Identifier: NCT00856544 and NCT00413699., Competing Interests: An Y, Bao CD, Chen ZW, Gu JR, Li ZG, Liu Y, Xu HJ, and Zhao DB have nothing to disclose. Kremer J has served as a consultant for, and has received research support from, AbbVie, Amgen, BMS, Genentech, Pfizer Inc, and UCB; he has also received payment for lectures, including service on speakers’ bureaus, from AbbVie. Hwang LJ was an employee and shareholder of Pfizer Inc at the time of analysis. Wang L and Wu QZ are employees and shareholders of Pfizer Inc.

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.

Many malarial antigens are poor immunogens in human. Chemical conjugation is one of the ways to enhance the immunogenicity of those poor immunogens. Its value has been demonstrated in malaria vaccine research. This article introduces the chemical linkers and the carrier proteins, which are often used for protein conjugation, and summarizes the research progress in malarial conjugate vaccine development.

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.

Hemozoin (malaria pigment) is a byproduct of malaria parasites due to hemoglobin digestion, which can stimulate host's innate inflammatory responses. However, data from different studies are controversial about how hemozoin is recognized by the host's pattern recognition receptors. This article reviews the recent progress in the area.

Toll-like receptors (TLRs) belong to the category of pattern recognition receptor. The binding of TLRs with their respective ligands activates innate immune system, thereby initiates adaptive immune responses. As such, some TLR ligands or agonists have been used as an adjuvant component in a variety of vaccine formulations. AMA1 and MSP1 from Plasmodium falciparum are two main antigens of malaria blood-stage vaccine, but they are poor immunogens in humans. To enhance the immunogenicities of these two vaccine candidates, the TLR agonists have been used in their formulations for the clinical trials. Recent progress in the field is reviewed in this article.

Objective: To determine the sensitivity and specificity of anti-cyclic citrullinated peptide antibodies (anti-CCP antibodies) in the diagnosis of rheumatoid arthritis., Method: A total of 1018 healthy donors, 212 patients with rheumatoid arthritis, 435 patients with other connective tissue disease were recruited to this study. Anti-CCP antibodies and IgM-rheumatoid factor (RF) were determined by ELISA according to manufacturer instructions, with a cut-off of 20U., Result: The frequency of positive anti-CCP antibodies in patients with rheumatoid arthritis is 48.1% (n = 102), higher than healthy donors (2.6%, n = 26) and patients with other connective tissue diseases (3.7%, n = 16). The specificity of anti-CCP antibodies is 97.4%. The titer of anti-CCP antibodies in patients with rheumatoid arthritis (429.7 U) is much higher than that in healthy donors (29.3 U) and patients with other connective tissue diseases (36.5 U). The frequency of positive IgM-RF in patients with rheumatoid arthritis is 94.3% whilst only 21.5% in healthy donors. The false positivity rate of IgM-RF is higher than anti-CCP antibody., Conclusion: Anti-CCP antibodies is a highly specific autoantibody in the diagnosis of rheumatoid arthritis.

Objective: To investigate the efficacy and safety of adalimumab plus methotrexate (MTX) for the treatment of rheumatoid arthritis (RA)., Methods: This is a multi-center, randomized, double-blind, parallel-group, and placebo-controlled clinical study, included a total of 302 cases of active rheumatoid arthritis, randomized into three groups of observation: 40 mg adalimumab (121 cases), 80 mg adalimumab (121 cases), or placebo (60 cases). Upon enrollment, all subjects had been previously treated with MTX for at least 3 months, and their doses of drug had remained stable for at least 28 days. The double-blind phase lasted for 12 weeks, during which the subjects were administered with adalimumab or placebo subcutaneously every other week. Then the subjects entered into another 12 weeks of open-label study, which included subcutaneous injection of 40 mg adalimumab every other week. In both the double-blind and the open-label periods, all subjects were maintained concomitantly with MTX that had already been used before this study. The primary efficacy variables were evaluated on basis of American College of Rheumatology (ACR)20 response rate at week 12. The secondary efficacy variables included: ACR20 response rate at week 24; ACR50 and ACR70 response rates at weeks 12 and 24; and changes at weeks 12 and 24 compared with baseline observations for tender and swollen joint counts, as well as the assessment of pain with visual analog scale (VAS), the physician's and the patient's global assessment of disease activity (VAS), and the analysis on health assessment questionnaire (HAQ) and health related quality of life (HRQL) measured by Short Form-36 (SF-36); The safety variables mainly included adverse events (AE)., Result: During the double-blind period, subjects treated with 40 mg of adalimumab, 57.0% achieved ACR20 response at week 12 (P = 0.004 versus placebo), and subjects treated with 80 mg of adalimumab, 51.2% achieved ACR20 response at week 12 (P = 0.026 versus placebo), and only 35.0% of subjects treated with placebo achieved ACR20 response at week 12. On the other hand, 32.2% of subjects receiving 40 mg of adalimumab achieved ACR50 response (P = 0.009 versus placebo), and 15.7% achieved ACR70 response (P = 0.007 versus placebo) at week 12. Subjects treated with 40 mg of adalimumab got a better result versus placebo at week 12 for tender joint count, swollen joint count, and improvement in C-reactive protein; and subjects treated with 80 mg of adalimumab were also seen an amelioration versus placebo at week 12 for swollen joint count, and improvement in C-reactive protein; all of these findings were statistically significant in differences. During the open-label period all subjects received 40 mg of adalimumab, and response rates for ACR20, ACR50, and ACR70 in the two treatment groups of 40 mg and 80 mg adalimumab were maintained or improved from week 12 to week 24 (being 73.1%, 40.3% and 17.6% respectively for 40 mg group; 71.1%, 39.5% and 17.5% respectively for 80 mg group); while response in the original placebo group (being 67.8%, 44.1% and 18.6%) increased during the 12-week open-label period to match that of the original adalimumab treatment groups. While for changes in tender and swollen joint counts, VAS, HAQ, SF-36, a significant improvement was seen at week 24 when compared with baseline and week 12 values. Throughout the double-blind and open-label period, adverse events reported in >/= 5% of subjects at least possibly associated with the study drug were upper respiratory tract infection, nasopharyngitis, and injection site itching, mostly being mild to moderate in severity. There were 3 cases of tuberculosis reported during this study. And 3 cases of serious adverse event (SAE) were reported among the adalimumab subjects during the double-blind period, which were determined as unrelated or probably unrelated to the study drug. And 8 cases (2.7%) of SAE were seen among the adalimumab subjects during the open-label period, 3 of which were at least possibly unrelated with the study drug. All SAEs reported were consistent to those seen in other adalimumab trials. No other unexpected safety signals were reported., Conclusion: Adalimumab plus MTX is better than single MTX in efficacy for the treatment of RA. Being generally safe and well tolerated, adalimumab plus MTX can significantly increase the response rate, continuously reduce the arthritic signs, symptoms and the inflammatory factors in patients, and also be helpful for reducing disabilities and improving the global quality of life for the patients.

Objective: To investigate the efficacy and safety of Infliximab (IFX) plus methotrexate (MTX) combination therapy in patients with rheumatoid arthritis (RA)., Methods: Prospectively observe refractory RA patients who were treated with combination therapy of MTX and IFX. IFX was infused at the dosage of 3 mg/kg, in week 0, 2, 6, and then every 8 weeks. During treatment, clinical variables, disease activity and adverse effects were evaluated., Results: After treatment, 69.8%, 52.4%, 29.5% and 7.2% RA patients achieved ACR20, ACR50, ACR70 and ACR90 respectively. There were significant statistical differences in the changes of swollen joint counts, tender joint counts, VAS scale, patient' s global assessment, and physician's global assessment before and after therapy., Conclusion: Infliximab plus MTX achieved significant efficacy and safety in refractory RA patients.