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ID PMID Title PublicationDate abstract
31735734 Benzoylaconitine Inhibits Production of IL-6 and IL-8 via MAPK, Akt, NF-κB Signaling in I 2020 Feb 1 Benzoylaconitine (BAC), the main hydrolysate of aconitine, is a lower toxic monoester type alkaloid considered as the pharmacodynamic constituent in Aconitum species. In this study, the effects and mechanisms of BAC on production of inflammatory cytokines interleukin (IL)-6 and IL-8 were investigated in IL-1β-stimulated human synovial SW982 cells. The SW982 cells were incubated with BAC (0, 5 and 10 µM) before stimulating with IL-1β (10 ng/mL). The results revealed that BAC suppressed gene and protein expression of IL-6 and IL-8 induced by IL-1β. BAC decreased activation of mitogen-activated protein kinase (MAPK) and phosphorylation of Akt. BAC also inhibited degradation of inhibitor of kappaB (IκB)-α, phosphorylation and nuclear transposition of p65 protein. The results demonstrate that BAC exerts an anti-inflammatory effect dependent on MAPK, Akt and nuclear factor-κB (NF-κB) pathways in human synovial cells stimulated with IL-1β, suggesting that BAC may be exploited as a potential therapeutic agent for rheumatoid arthritis (RA) treatment.
32396519 Efficacy of tofacitinib in reducing pain in patients with rheumatoid arthritis, psoriatic 2020 Feb OBJECTIVE: To describe the efficacy of tofacitinib in reducing pain in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS) in a post-hoc analysis of randomised controlled trials. METHODS: Data were collected from patients in seven tofacitinib studies: six phase III (four RA, two PsA) and one phase II study (AS), and grouped into five analysis populations based on rheumatic disease diagnosis and category of prior inadequate response (IR) to treatment: conventional synthetic disease-modifying antirheumatic drugs-IR (RA and PsA), tumour necrosis factor inhibitors-IR (RA and PsA), or non-steroidal anti-inflammatory drugs-IR (AS). Only patients who received tofacitinib 5 or 10 mg twice daily or placebo were included. Pain assessments included: Patient's Assessment of Arthritis Pain, Short-Form Health Survey 36v2 Question (Q)7 and Bodily Pain domain, Ankylosing Spondylitis Quality of Life Q9 and Q14, EuroQol Five Dimensions Pain/Discomfort dimension and Bath Ankylosing Spondylitis Disease Activity Index Q2 and Q3. Data were reported to month 6 (placebo to month 3) in the RA and PsA populations, and week 12 (tofacitinib and placebo) in the AS population. RESULTS: Overall, 3330 patients were included in this analysis. In the RA and PsA populations, pain improvements in tofacitinib-treated patients compared with placebo were observed at the earliest time point assessed and at month 3 (maintained to month 6). In the AS population, pain improvements compared with placebo were observed at week 12. CONCLUSION: Tofacitinib was associated with rapid and sustained improvements across multiple pain measures in patients with inflammatory rheumatic musculoskeletal diseases.
32328979 A 5-year Retrospective Analysis of Drug Survival, Safety, and Effectiveness of the Inflixi 2020 Jun BACKGROUND: The infliximab biosimilar CT-P13 has widely received regulatory approval in all indications of reference infliximab, including rheumatoid arthritis (RA) and ankylosing spondylitis (AS). OBJECTIVE: This retrospective analysis investigated drug survival and long-term safety and effectiveness of CT-P13 in patients with RA or AS in the Republic of Korea. METHODS: This non-interventional, retrospective, multicenter analysis collected medical record data for adult patients with RA or AS who received CT-P13 treatment at five Korean referral hospitals (2012-2017). Drug survival and long-term safety were primary outcomes. The secondary outcome was long-term effectiveness, assessed by disease activity measures. RESULTS: Overall, 491 patients were treated with CT-P13 (154 patients with RA [135 infliximab-naïve; 19 switched from reference infliximab]; 337 patients with AS [219 infliximab-naïve; 118 switched from reference infliximab]). Drug survival was similar in naïve and switched patients. Treatment-emergent adverse events (TEAEs) occurred in 31.8% and 29.4% of patients with RA and AS, respectively; incidence was similar in naïve and switched groups. Upper respiratory tract infection, influenza-like illness, and urticaria were the most common TEAEs. Overall, nine (1.8%) patients experienced serious adverse events (SAEs) deemed potentially drug-related; SAEs led to permanent CT-P13 discontinuation in five (1.0%) patients, including three with tuberculosis. Disease activity decreased over time. CONCLUSION: Up to 5 years of CT-P13 treatment was safe and effective in patients with RA and AS, based on drug survival, incidence of TEAEs, and disease activity. Drug survival and safety were similar in naïve patients and switched groups, supporting switching from reference infliximab to CT-P13.
31300458 2018 update of the EULAR recommendations for the role of the nurse in the management of ch 2020 Jan To update the European League Against Rheumatism (EULAR) recommendations for the role of the nurse in the management of chronic inflammatory arthritis (CIA) using the most up to date evidence. The EULAR standardised operating procedures were followed. A task force of rheumatologists, health professionals and patients, representing 17 European countries updated the recommendations, based on a systematic literature review and expert consensus. Higher level of evidence and new insights into nursing care for patients with CIA were added to the recommendation. Level of agreement was obtained by email voting. The search identified 2609 records, of which 51 (41 papers, 10 abstracts), mostly on rheumatoid arthritis, were included. Based on consensus, the task force formulated three overarching principles and eight recommendations. One recommendation remained unchanged, six were reworded, two were merged and one was reformulated as an overarching principle. Two additional overarching principles were formulated. The overarching principles emphasise the nurse's role as part of a healthcare team, describe the importance of providing evidence-based care and endorse shared decision-making in the nursing consultation with the patient. The recommendations cover the contribution of rheumatology nursing in needs-based patient education, satisfaction with care, timely access to care, disease management, efficiency of care, psychosocial support and the promotion of self-management. The level of agreement among task force members was high (mean 9.7, range 9.6-10.0). The updated recommendations encompass three overarching principles and eight evidence-based and expert opinion-based recommendations for the role of the nurse in the management of CIA.
31933408 Hematological malignancies in connective tissue diseases. 2020 Mar Chronic inflammation has profound tumor-promoting effects. Inflammatory cells are the key players in immunosurveillance against tumors, and immunosuppression is known to increase the risk of tumors. Autoimmune diseases, which manifest as loss of self-tolerance and chronic immune dysregulation, provide a perfect environment for tumor development. Aside from managing the direct inflammatory consequences of autoimmune pathogenesis, cancer risk profiles should be considered as a part of a patient's treatment. In this review, we describe the various associations of malignancies with autoimmune diseases, specifically systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and Sjögren's syndrome, as well as discuss the mechanisms contributing to the pathogenesis of both disorders.
32005415 A novel series of cysteine-dependent, allosteric inverse agonists of the nuclear receptor 2020 Mar 15 Inhibition of the nuclear receptor Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) is a promising strategy for the treatment of autoimmune diseases. In this paper, we describe a series of allosteric, cysteine-dependent, inverse agonists of RORγt. Site-directed mutagenesis and molecular dynamics simulations are supportive of a mechanism of action through specific binding to Cys476 on alpha helix 11 of the ligand binding domain (LBD). Representative compounds in the series selectively inhibit RORγt, potently suppress interleukin-17A (IL-17A) production by human CD4(+) T cells, and inhibit T helper 17 (Th17) differentiation from human naïve CD4(+) T cells. The advanced compound 13 is orally bioavailable and active at a dose of 3 mg/kg in a murine collagen-induced model of rheumatoid arthritis. Collectively, these data are supportive of the development of compound 13 in autoimmune diseases.
32888428 Genome-wide Study Identifies Association between HLA-B(∗)55:01 and Self-Reported Penicil 2020 Oct 1 Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center's BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe's research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B(∗)55:01 allele (OR 1.41 95% CI 1.33-1.49, p value 2.04 × 10(-31)) and confirmed by independent replication in 23andMe's research cohort (OR 1.30 95% CI 1.25-1.34, p value 1.00 × 10(-47)). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B(∗)55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.
32036583 Mental health conditions and the risk of chronic opioid therapy among patients with rheuma 2020 Jun OBJECTIVE: Patients with rheumatoid arthritis (RA) often receive opioid analgesics for pain management. We examined the association between mental health conditions and the risk of chronic opioid therapy. METHODS: A retrospective cohort of veterans with RA initiating opioid use was assembled using Veterans Health Administration databases (2001-2012). Mental health conditions included anxiety (N = 1108, 12.9%), depression (N = 1912, 22.2%), bipolar disease (N = 131, 1.5%), and post-traumatic stress disorder (N = 768, 8.9%) and were identified by ICD coded diagnoses and use of specific medications. Cohort members were followed from opioid initiation through chronic opioid therapy, defined as the continuous availability of opioids for at least 90 days. Multivariable Cox proportional hazard regression models assessed the association between mental health conditions and chronic opioid therapy accounting for relevant covariates. Subgroup analyses examined whether the strength of the observed association varied by the duration of the initial opioid prescription. RESULTS: We identified 14,767 patients with RA with 22,452 episodes of opioid use initiation. Mental health conditions were identified in 8607 (38.3%) patients. Compared with patients without mental health conditions, patients with mental health conditions have a higher risk of developing chronic opioid therapy (469.3 vs 378.1 per 1000 person-years, adjusted hazard ratio [aHR] 1.18, 95% CI 1.09, 1.29). The increased risk was highest for those with a history of opioid use disorder (aHR 1.94, 95% CI 1.09, 3.46) and also elevated for those with other substance use disorders (aHR 1.35, 95% CI 1.05, 1.73). Duration of the initial opioid prescription was independently associated with chronic opioid therapy, regardless of the estimated opioid daily dose. CONCLUSIONS: History of mental health conditions and duration of the initial opioid prescription were associated with an increased risk of chronic opioid therapy among patients with RA.Key Points• Approximately a third of patients with RA are exposed to opioid analgesics.• Patients with RA and history of mental health disease, especially substance use disorders, who initiate opioid use have an increased risk of chronic opioid therapy.• This study provides insight in an underrepresented population of mainly male patients with RA.
31565784 A Picture is Worth a Thousand Words: The Role of Survey Training Materials in Stated-Prefe 2020 Apr BACKGROUND: Online survey-based methods are increasingly used to elicit preferences for healthcare. This digitization creates an opportunity for interactive survey elements, potentially improving respondents' understanding and/or engagement. OBJECTIVE: Our objective was to understand whether, and how, training materials in a survey influenced stated preferences. METHODS: An online discrete-choice experiment (DCE) was designed to elicit public preferences for a new targeted approach to prescribing biologics ("biologic calculator") for rheumatoid arthritis (RA) compared with conventional prescribing. The DCE presented three alternatives, two biologic calculators and a conventional approach (opt out), described by five attributes: delay to treatment, positive predictive value, negative predictive value, infection risk, and cost saving to the national health service. Respondents were randomized to receive training materials as plain text or an animated storyline. Training materials contained information about RA and approaches to treatment and described the biologic calculator. Background questions included sociodemographics and self-reported measures of task difficulty and attribute non-attendance. DCE data were analyzed using conditional and heteroskedastic conditional logit (HCL) models. RESULTS: In total, 300 respondents completed the DCE, receiving either plain text (n = 158) or the animated storyline (n = 142). The HCL showed the estimated coefficients for all attributes aligned with a priori expectations and were statistically significant. The scale term was statistically significant, indicating that respondents who received plain-text materials had more random choices. Further tests suggested preference homogeneity after accounting for differences in scale. CONCLUSIONS: Using animated training materials did not change the preferences of respondents, but they appeared to improve choice consistency, potentially allowing researchers to include more complex designs with increased numbers of attributes, levels, alternatives or choice sets.
31836304 Expression and activity of AIM2-inflammasome in rheumatoid arthritis patients. 2020 Mar INTRODUCTION: AIM2 inflammasome activation leads to the release of IL-β, which plays an important role in rheumatoid arthritis pathogenesis. In this work, we evaluated AIM2 expression and activity in RA patients and healthy controls. METHODS: AIM2 and RANKL expression were evaluated by flow cytometry. Inflammasome activity was determined in monocyte cultures stimulated with synthetic DNA by measuring IL-1β levels in supernatants using an ELISA assay. The caspase-1 expression in monocytes was measured by western blot, the POP3 expression was analysed by qPCR, and serum levels of IFN-γ were evaluated using ELISA assay. RESULTS: We observed a diminution of CD14+AIM2+ cells in RA patients, associated with disease activity and evolution. Likewise, the levels of IL-1β were increased in monocyte cultures un-stimulated and stimulated with LPS from RA patients with DAS28 ≥ 4. The Caspase-1 activity and RANKL + monocytes in RA patients were slightly increased. Finally, augmented POP3 expression and diminished IFN-γ serum levels were detected in RA patients. CONCLUSION: Our results showed that the monocytes from RA patients were prone to release IL-1β in the absence of the AIM2 inflammasome signal. The down-regulation of AIM2 to a systemic level in RA patients might be a consequence of augmented POP3 expression and might imply the survival of pro-inflammatory cells contributing to the inflammation process.
32940208 Peripheral blood circular RNA hsa_circ_0082688-hsa_circ_0008675 can be used as a candidate 2020 Sep OBJECTIVES: This research aimed to investigate the level of peripheral blood circular RNAs (circRNAs) from systemic lupus erythematosus (SLE) patients with renal involvement (SLE+RI) to identify novel biomarkers for SLE+RI screening. METHODS: circRNAs expression in peripheral blood from 3 SLE+RI patients, 3 SLE patients without renal involvement (SLE-RI) and 3 healthy controls (HC) were performed by microarray. All upregulated expressed circRNAs coming from "circBase" between the three groups were determined by real time-quantitative polymerase chain reaction (qRT-PCR) in SLE+RI, SLE-RI, HC, neprhritis without SLE (NWS) and rheumatoid arthritis (RA) patients. The diagnostic value of these circRNAs for SLE+RI was evaluated by receiver operating characteristic (ROC) curve. A 15-day follow-up was evaluated in 7 newly diagnosed SLE+RI patients to investigate the level change of these circRNAs after treatment. RESULTS: We confirmed that the level of hsa_circ_0082688, hsa_circ_0082689 and hsa_circ_0008675 were significantly elevated in SLE+RI patients with respect to the SLE-RI, RA, NWS patients and the HC. The level of hsa_circ_0082688, hsa_circ_0082689 and hsa_circ_0008675 were associated with C4, anti-dsDNA, anti-nucleosome. The level of hsa_circ_0008675 was associated with C3, and the level of hsa_circ_0082688 and hsa_circ_0008675 were associated with treatment. ROC curve analysis suggested that hsa_circ_0082688-hsa_circ_0008675 had significant value in the diagnosis of new-onset SLE+RI patients than the controls (new-onset SLE-RI patients, RA patients, NWS patients and HC) with an area under the curve of 0.925, sensitivity of 79.17% and specificity of 96.64%. CONCLUSIONS: This study suggests that peripheral blood hsa_circ_0082688-hsa_circ_0008675 level in SLE+RI patients is upregulated and may also serve as a potential biomarker for SLE+RI patient diagnosis and treatment.
32133009 A Comparison of Immunoglobulin Variable Region N-Linked Glycosylation in Healthy Donors, A 2020 N-linked glycans play an important role in immunity. Although the role of N-linked glycans in the Fragment crystallizable (Fc) region of immunoglobulins has been thoroughly described, the function of N-linked glycans present in Ig-variable domains is only just being appreciated. Most of the N-linked glycans harbored by immunoglobulin variable domain are of the complex biantennary type and are found as a result of the presence of N-linked glycosylation that most often have been introduced by somatic hypermutation. Furthermore, these glycans are ubiquitously present on autoantibodies observed in some autoimmune diseases as well as certain B-cell lymphomas. For example, variable domain glycans are abundantly found by anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) as well as by the B-cell receptors of follicular lymphoma (FL). In FL, variable domain glycans are postulated to convey a selective advantage through interaction with lectins and/or microbiota, whereas the contribution of variable domain glycans on autoantibodies is not known. To aid the understanding how these seemingly comparable phenomena contribute to a variety of deranged B-responses in such different diseases this study summarizes the characteristics of ACPA and other auto-antibodies with FL and healthy donor immunoglobulins, to identify the commonalities and differences between variable domain glycans in autoimmune and malignant settings. Our finding indicate intriguing differences in variable domain glycan distribution, frequency and glycan composition in different conditions. These findings underline that variable domain glycosylation is a heterogeneous process that may lead to a number of pathogenic outcomes. Based on the current body of knowledge, we postulate three disease groups with distinct variable domain glycosylation patterns, which might correspond with distinct underlying pathogenic processes.
32776324 Determination of tuberculin skin test for isoniazid prophylaxis in BCG vaccinated children 2020 Oct OBJECTIVE: The use of tumor necrosis factor inhibitors (anti-TNF) has a risk of activating latent tuberculosis infection (LTBI). This study was performed to investigate LTBI according to tuberculin skin test (TST) size and to determine the frequency of tuberculosis (TB) in bacillus Calmette-Guerin (BCG)-vaccinated children receiving anti-TNF treatment for rheumatological disease. MATERIALS AND METHODS: The study consisted of 559 children. Information on demographics, anti-TNF agents, TST size, and isoniazid (INH) prophylaxis was recorded. Patients (n = 254) with TST size ≥5 mm were divided into three groups according to TST size and INH prophylaxis: group 1, TST size 5 to 9 mm and no INH prophylaxis; group 2, TST size 5 to 9 mm with INH prophylaxis; and group 3, TST size ≥10 mm with INH prophylaxis. RESULTS: The 559 patients comprised 314 (56.3%) females and 245 (43.6%) males; they had a mean age of 13.1 ± 4.1 years. The mean TST size in all patients was 4.2 ± 4.7 mm. Group 1 consisted of 76 (29.9%) patients, group 2 consisted of 88 (34.6%) patients, and group 3 consisted of 90 (35.4%) patients. The mean TST sizes for the three groups were 6.8 ± 3.1 mm, 7.2 ± 3.2 mm, and 13.9 ± 2.8 mm, respectively. New TB was diagnosed in only two (0.35%) patients. Both of them were in group 3. CONCLUSIONS: A TST size of ≥10 mm in BCG-vaccinated children receiving anti-TNF treatment may distinguish children at high risk for reactivation of LTBI.
32006824 CD70-mediated CD27 expression downregulation contributed to the regulatory B10 cell impair 2020 Mar Regulatory B10 cells have been shown to exhibit impaired functions in autoimmune diseases. However, the underlying mechanism is still obscure. In the present study, we aimed to understand the regulatory characteristics of regulatory B10 cells and how these cells are involved in the development of rheumatoid arthritis (RA). Here, we chose CD19(+)CD24(hi)CD27(+) as the phenotype of regulatory B10 cells. We found that the frequencies of CD19(+)CD24(hi)CD27(+) regulatory B10 cells were decreased and that their IL-10-producing function was impaired in patients with RA compared with healthy controls (HCs). The impairment in CD19(+)CD24(hi)CD27(+) B10 cells was partially attributed to the decreased expression of CD27 induced by the upregulated CD70 expression on CD19 + B cells and CD4 + T cells. The proportion of CD19(+)CD24(hi)CD27(+) regulatory B10 cells could be restored by blocking the CD70-CD27 interaction with an anti-CD70 antibody. Furthermore, the CD70-CD27 interaction significantly elevated IL-10 expression and might compensate for the decreased number of CD19(+)CD24(hi)CD27(+) B cells. Hence, the CD70-CD27 interaction might play a critical role in the numerical and functional impairments of regulatory B10 cells, thus contributing to RA pathogenesis. In conclusion, the change in CD19(+)CD24(hi)CD27(+) regulatory B10 cells in RA was only a consequence, not the cause, of RA development, but the increased expression of CD70 might be the culprit.
32126869 Association between thiopurine exposure and depression in patients with inflammatory bowel 2020 Oct BACKGROUND: Ras-related C3 botulinum substrate 1 (Rac1) is a member of the small molecule family Rho guanosine triphosphate (GTP)ases. Recent findings reveal epigenetic downregulation of Rac1 is a mechanism of depression. AIMS: The purpose of this study was to evaluate Rac1 as a therapeutic target for depression we examine the association between thiopurines, which inhibit Rac1, and the risk of depression among US veterans. METHODS: This study uses data spanning January 2000-May 2019, comparing thiopurine exposure (no exposure, less than one year, 1-2.9 years, 3-5 years, and greater than five years) in two separate cohorts, a rheumatoid arthritis cohort and inflammatory bowel disease cohort. We estimate the hazard of depression using a time dependent cox proportional hazards model. RESULTS: A total of 76,763 rheumatoid arthritis and 46,787 inflammatory bowel disease patients met all inclusion criteria. Patients exposed to thiopurines less than one year have a 27% (hazard ratio=1.272; 95% confidence interval=(1.038-1.559)) and 67% (hazard ratio=1.667 95% confidence interval=(1.501-1.850)) higher risk of depression in the rheumatoid arthritis and inflammatory bowel disease cohorts, respectively. In the inflammatory bowel disease cohort, we find the risk of depression is increased for up to five years of thiopurine exposure. CONCLUSION: These results provide evidence that Rac1 regulation is a viable therapeutic target for depression. Further research into therapeutics targeting Rac1 for the treatment of depression is warranted.
32868411 The Expression of P2X7 Receptor on Th1, Th17, and Regulatory T Cells in Patients with Syst 2020 Oct 1 P2X7 receptor (P2X7R) is highly expressed on immune cells, triggering the release of cytokines and regulating autoimmune responses. To investigate P2X7R surface expression on T helper (Th) 1, Th17, and regulatory T (Treg) cells in patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) and correlations with disease activity, 29 SLE and 29 RA patients and 18 healthy controls (HCs) were enrolled. We showed that SLE and RA patients had significantly higher levels of plasma cytokines (IFN-γ, IL-1β, IL-6, IL-17A, and IL-23), frequencies of Th1 and Th17 cells, and expression of P2X7R on Th1 and Th17 than HCs, and the Th17/Treg ratio was significantly increased, whereas Treg cell levels were significantly decreased. The Ca(2+) influx increase following BzATP stimulation was significantly higher in CD4(+)PBMCs from SLE and RA patients than in HCs. Blood levels of shed P2X7R were increased in SLE and RA patients. Furthermore, 28-joint Disease Activity Score and SLE Disease Activity Index score showed negative correlations with Treg cell levels and positive correlations with Th17/Treg ratio and Th17 cell P2X7R expression. Interestingly, Th17 cell P2X7R expression was closely correlated with IL-1β, C-reactive protein, the erythrocyte sedimentation rate, anticyclic citrullinated peptide Abs, albumin, and C4. These data indicate that increased Th17 cell P2X7R expression is functionally and positively related to disease activity and some inflammatory mediators in SLE and RA patients, and P2X7R could be critical in promoting the Th17 immune response and contributing to the complex pathogenesis of SLE and RA.
32879318 Analysis of chromatin organization and gene expression in T cells identifies functional ge 2020 Sep 2 Genome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T cells over 24 h, to identify functional enhancers regulating gene expression. We characterise changes in DNA interaction and activity dynamics that correlate with changes in gene expression, and find that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an example of T cell mediated disease, we demonstrate interactions of expression quantitative trait loci with target genes, and confirm assigned genes or show complex interactions for 20% of disease associated loci, including FOXO1, which we confirm using CRISPR/Cas9.
32253242 Apolipoprotein E Triggers Complement Activation in Joint Synovial Fluid of Rheumatoid Arth 2020 May 15 We identified apolipoprotein E (ApoE) as one of the proteins that are found in complex with complement component C4d in pooled synovial fluid of rheumatoid arthritis (RA) patients. Immobilized human ApoE activated both the classical and the alternative complement pathways. In contrast, ApoE in solution demonstrated an isoform-dependent inhibition of hemolysis and complement deposition at the level of sC5b-9. Using electron microscopy imaging, we confirmed that ApoE interacts differently with C1q depending on its context; surface-bound ApoE predominantly bound C1q globular heads, whereas ApoE in a solution favored the hinge/stalk region of C1q. As a model for the lipidated state of ApoE in lipoprotein particles, we incorporated ApoE into phosphatidylcholine/phosphatidylethanolamine liposomes and found that the presence of ApoE on liposomes increased deposition of C1q and C4b from serum when analyzed using flow cytometry. In addition, posttranslational modifications associated with RA, such as citrullination and oxidation, reduced C4b deposition, whereas carbamylation enhanced C4b deposition on immobilized ApoE. Posttranslational modification of ApoE did not alter C1q interaction but affected binding of complement inhibitors factor H and C4b-binding protein. This suggests that changed ability of C4b to deposit on modified ApoE may play an important role. Our data show that posttranslational modifications of ApoE alter its interactions with complement. Moreover, ApoE may play different roles in the body depending on its solubility, and in diseased states such as RA, deposited ApoE may induce local complement activation rather than exert its typical role of inhibition.
32098857 Evaluation of hepatitis B virus in clinical trials of baricitinib in rheumatoid arthritis. 2020 Feb BACKGROUND: Reactivation of hepatitis B virus (HBV) replication is a well-recognised complication in patients receiving disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA). Limited data exist on HBV reactivation among patients with RA treated with janus kinase (JAK) inhibitors. The objective of the current study was to assess HBV reactivation in clinical trials of baricitinib, an oral selective JAK1 and JAK2 inhibitor in RA. METHODS: Data were integrated from four completed Phase 3 trials and one ongoing long-term extension (data up to 1 April 2017) in patients naïve to DMARDs or who had inadequate response (IR) to DMARDs including methotrexate (MTX)-IR and/or other conventional synthetic DMARD (csDMARD)-IR, or tumour necrosis factor inhibitors-IR. Within the clinical programme, baricitinib-treated patients may have received concomitant csDMARDs including MTX, or previous treatment with active comparators including MTX or adalimumab + MTX. At screening, all patients were tested for HBV surface antigen (HBsAg), core antibody (HBcAb) and surface antibody (HBsAb). Patients were excluded if they had (1) HBsAg+, (2) HBcAb+/HBsAb- (in Japan, could enrol if HBV DNA-) or (3) HBsAb+ and HBV DNA+. HBV DNA monitoring, following randomisation in the originating Phase 3 studies, was performed in Japan for patients with HBcAb+ and/or HBsAb+ at screening, and was later instituted globally for HBcAb+ patients in accordance with evolving guidance for HBV monitoring and management with immunomodulatory therapy. RESULTS: In total, 2890 patients received at least one dose of baricitinib in Phase 3 (6993 patient-years exposure). Of 215 patients with baseline serology suggestive of prior HBV infection (HbcAb+) who received a post-baseline DNA test, 32 (14.9%) were HBV DNA+ at some point following treatment initiation; 8 of 215 patients (3.7%) had a single quantifiable result (≥29 IU/mL). Of these eight patients, four met the definition of reactivation of HBV (HBV DNA level ≥100 IU/mL); baricitinib was permanently discontinued in four patients, and temporarily interrupted in two patients. No patient developed clinical evidence of hepatitis and in five of eight patients, antiviral therapy was not used. CONCLUSION: HBV reactivation can occur among RA patients treated with DMARDs, including baricitinib, with prior HBV exposure. Our data suggest that such patients should be monitored for HBV DNA during treatment and might be treated safely with the use of antiviral therapy as needed. The risk of HBV reactivation in patients with HBsAg treated with baricitinib is unknown.
33116155 Improvement of Certolizumab Fab' properties by PASylation technology. 2020 Oct 28 Certolizumab pegol is a Fab' antibody fragment for treatment of rheumatoid arthritis and Crohn's disease which is conjugated to a 40 kDa PEG molecule in order to increase the protein half-life. PEGylation may have disadvantages including immunogenicity, hypersensitivity, vacuolation, decreased binding affinity and biological activity of the protein. To overcome these problems, PASylation has been developed as a new approach. The nucleotide sequence encoding 400 amino acid PAS residues was genetically fused to the corresponding nucleotide sequences of both chains of certolizumab. Then, the bioactivity as well as physicochemical and pharmacokinetic properties of the recombinant PASylated expressed protein was assayed. Circular dichroism spectroscopy demonstrated that the random coil structure of PAS sequences did not change the secondary structure of the PASylated Fab' molecule. It was observed that PASylation influenced the properties of the Fab' molecule by which the hydrodynamic radius and neutralization activity were increased. Also, the antigen binding and binding kinetic parameters improved in comparison to the PEGylated Fab' antibody. Pharmacokinetic studies also showed prolonged terminal half-life and improved pharmacokinetic parameters in PASylated recombinant protein in comparison to the PEGylated and Fab' control molecules. The results reconfirmed the efficiency of PASylation approach as a potential alternative method in increasing the half-life of pharmaceutical proteins.