Search

Multi-ancestry genome-wide association analyses identify 124 risk loci for rheumatoid arthritis, of which 34 are novel. A polygenic risk score based on multi-ancestry data showed comparable performance between populations of European and East Asian ancestries.Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 x 10(-8)), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.

Regulatory T (T

To analyze the history of biologics usage in patients with ankylosing spondylitis (AS) in China and to evaluate the impact of drug reduction and withdrawal on disease activity.Drug administration intervals and disease activity indexes in patients with AS who regularly used etanercept (ETN) biosimilars for more than 1 year and those who withdrew the drugs during the same period in a single center were analyzed retrospectively.A total of 108 patients with AS who used ETN biosimilars for more than a year were recruited in this study for analysis. (1) Overall, 98.1% patients with AS increased the intervals between drug administrations, averaging from 4.57 ± 0.15 days during 0-3 months to 8.53 ± 0.43 days during 3-6 months, and to 10.49 ± 0.39 days during 6-12 months. Compared with the baseline parameters, after 3-month and 12-month treatments disease activities were improved significantly, including Patient Global Assessment (PTGA), overall back pain, nocturnal pain, fatigue, Ankylosing Spondylitis Disease Activity Score-C-Reactive Protein (ASDAS-CRP), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Bath Ankylosing Spondylitis Functional Index (BASFI). (2) Only 59.3% used ETN biosimilars with full dose (3.5 days' interval) in the first 3 months. At baseline, disease activities of these patients were higher than those with reduced dose (5.9 days' interval). However, at 12 months of drug administration there was no significant difference in the overall length of drug administration intervals and disease activities between the two groups. (3) Twenty patients with low disease activity (LDA) discontinued therapy spontaneously; after 3 months, 55% of them experienced disease recurrence (∆ASDAS ≥ 0.9).Spontaneous dose reduction was a common phenomenon among patients with AS in China, which becomes more notable with increasing relief of symptoms. Most patients could maintain an LDA state after dose reduction. Compared with dose reduction, ETN biosimilar withdrawal was more likely to induce disease recurrence. Therefore, disease activity-guided individualized stepwise tapering may become one of the feasible therapeutic strategies for AS in the future.

Background Ectopic ossification is an important cause of disability in patients with ankylosing spondylitis (AS). Whether fibroblasts can transdifferentiate into osteoblasts and contribute to ossification remains unknown. This study aims to investigate the role of stem cell transcription factors (POU5F1, SOX2, KLF4, MYC, etc.) of fibroblasts in ectopic ossification in patients with AS. Methods Primary fibroblasts were isolated from the ligaments of patients with AS or osteoarthritis (OA). In an in vitro study, primary fibroblasts were cultured in osteogenic differentiation medium (ODM) to induce ossification. The level of mineralization was assessed by mineralization assay. The mRNA and protein levels of stem cell transcription factors were measured by real-time quantitative PCR (q-PCR) and western blotting. MYC was knocked down by infecting primary fibroblasts with lentivirus. The interactions between stem cell transcription factors and osteogenic genes were analysed by chromatin immunoprecipitation (ChIP). Recombinant human cytokines were added to the osteogenic model in vitro to evaluate their role in ossification. Results We found that MYC was elevated significantly in the process of inducing primary fibroblasts to differentiate into osteoblasts. In addition, the level of MYC was remarkably higher in AS ligaments than in OA ligaments. When MYC was knocked down, the expression of the osteogenic genes alkaline phosphatase (ALP) and bone morphogenic protein 2 (BMP2) was decreased, and the level of mineralization was reduced significantly. In addition, the ALP and BMP2 were confirmed to be the direct target genes of MYC. Furthermore, interferon-γ (IFN-γ), which showed high expression in AS ligaments, was found to promote the expression of MYC in fibroblasts in the process of ossification in vitro. Conclusions This study demonstrates the role of MYC in ectopic ossification. MYC may act as the critical bridge that links inflammation with ossification in AS, thus providing new insights into the molecular mechanisms of ectopic ossification in AS.

Background Primary Sjogren’s syndrome (pSS) is a systemic autoimmune disease involving multiple organ systems. The Janus kinase/signal transduction and activator of transcription (JAK/STAT) signaling pathway is a key pathway involving the pathogenesis of pSS. Baricitinib, a selective JAK1 and JAK2 inhibitor, has been approved for treatment of active rheumatoid arthritis and reported in treatment of some other autoimmune diseases including systemic lupus erythematosus. We have found that baricitinib might be effective and safe in pSS in a pilot study. However, there is no published clinical evidence of baricitinib in pSS. Hence, we conducted this randomized study to further explore the efficacy and safety of baricitinib in pSS. Methods This is a multi-center, prospective, open-label, randomized study to compare the efficacy of baricitinib + hydroxychloroquine (HCQ) with HCQ alone in pSS patients. We plan to involve 87 active pSS patients with European League Against Rheumatism pSS disease activity index (ESSDAI) ≥ 5 from eight different tertiary centers in China. Patients will be randomized (2:1) to receive baricitinib 4 mg per day + HCQ 400 mg per day or HCQ 400 mg per day alone. We will switch HCQ to baricitinib + HCQ if the patient in the latter group has no ESSDAI response at week 12. The final evaluation will be at week 24. The primary endpoint is the percentage of ESSDAI response, or minimal clinically important improvement (MCII), which was defined as an improvement of ESSDAI at least three points at week 12. The secondary endpoints include EULAR pSS patient-reported index (ESSPRI) response, change of Physician’s Global Assessment (PGA) score, serological activity parameters, salivary gland function test, and focus score on labial salivary gland biopsy. Discussion This is the first randomized controlled study to evaluate the clinical efficacy and safety of baricitinib in pSS. We hope that the result of this study can provide more reliable evidence of the efficacy and safety of baricitinib in pSS. Trial registration ClinicalTrials.gov NCT05016297. Registered on 19 Aug 2021.

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.

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.

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.

As the methodology of genetic detection has developed rapidly in recent years, through techniques such as genome-wide association studies (GWAS) and the secondary generation of sequencing, we are able to view the genomic landscape more clearly. It is well known that genes have a vital role in the pathogenesis of immune-mediated diseases (IMDs), which could provide important insight into new clinical therapeutic targets. Here, we review the genomic landscape of IMDs and analyse overlapping loci between diseases. There may be a need for more epigenetics studies to aid in the understanding of the transition from genotype to phenotype.

Background Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement. There remains limited understanding of disease aetiology, with median survival of ALS of three years and no effective treatment. Identifying genes that contribute to ALS susceptibility is an important step towards understanding aetiology. The vast majority of published human genetic studies, including for ALS, have used samples of European ancestry. The importance of trans-ethnic studies in human genetic studies is widely recognised, yet a dearth of studies of non-European ancestries remains. Here, we report analyses of novel whole-exome sequencing (WES) data from Chinese ALS and control individuals. Methods WES data were generated for 610 ALS cases and 460 controls drawn from Chinese populations. We assessed evidence for an excess of rare damaging mutations at the gene level and the gene set level, considering only singleton variants filtered to have allele frequency less than 5 × 10–5 in reference databases. To meta-analyse our results with a published study of European ancestry, we used a Cochran–Mantel–Haenszel test to compare gene-level variant counts in cases vs controls. Results No gene passed the genome-wide significance threshold with ALS in Chinese samples alone. Combining rare variant counts in Chinese with those from the largest WES study of European ancestry resulted in three genes surpassing genome-wide significance: TBK1 (p = 8.3 × 10–12), SOD1 (p = 8.9 × 10–9) and NEK1 (p = 1.1 × 10–9). In the Chinese data alone, SOD1 and NEK1 were nominally significantly associated with ALS (p = 0.04 and p = 7 × 10–3, respectively) and the case/control frequencies of rare coding variants in these genes were similar in Chinese and Europeans (SOD1: 1.5%/0.2% vs 0.9%/0.1%, NEK1 1.8%/0.4% vs 1.9%/0.8%). This was also true for TBK1 (1.2%/0.2% vs 1.4%/0.4%), but the association with ALS in Chinese was not significant (p = 0.14). Conclusions While SOD1 is already recognised as an ALS-associated gene in Chinese, we provide novel evidence for association of NEK1 with ALS in Chinese, reporting variants in these genes not previously found in Europeans. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0487-0) contains supplementary material, which is available to authorized users.

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 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.