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ID PMID Title PublicationDate abstract
32896245 Endoplasmic reticulum stress perpetuated toll-like receptor signalling-mediated inflammati 2021 Jul OBJECTIVES: Multiple physiological and pathological conditions interfere with the function of the endoplasmic reticulum (ER). However, much remains unknown regarding the impact of ER stress on toll-like receptors (TLRs) -induced inflammatory responses in rheumatoid arthritis (RA). The aim of this study was to reveal the effects of ER stress and its regulator, X-box-binding protein-1 (XBP-1), on the inflammatory response of RA synovial fibroblasts (RASF) to different TLRs ligands. METHODS: ER stress was induced in RASF by incubating with thapsigargin (Tg). TLR2 ligand Pam3CSK4, TLR3 ligand PolyIC, TLR4 ligand LPS were used to stimulate the cells. Effects of ER stress on TLRs-induced inflammatory mediators were determined by using RT-PCR, qPCR and ELISA analysis. Western blots analysis was used to detected the signalling pathways in this process. For gene silencing experiment, control scrambled or XBP-1 specific siRNA were transfected into RASF. T helper (Th)1/Th17 cells expansion was determined by flow cytometry analysis, and IFN-γ/IL-17A production in supernatants were collected for ELISA assay. RESULTS: ER stress potentiated the expression of inflammatory cytokines, MMPs and VEGF in RASF stimulated by different TLRs ligands, which was companied with enhanced the activation of NF-κB and MAPKs signalling pathways. Silencing XBP-1 in RASF could dampen TLRs signalling-simulated inflammatory response under ER stress. Moreover, blockade of XBP-1 reduced the generation of Th1 and Th17 cells mediated by RASF, and suppressed the production of IFN-γ and IL-17A. CONCLUSIONS: Our findings suggest that ER stress and XBP-1 may function in conjunction with TLRs to drive the inflammation of RASF, and this pathway may serve as a therapeutic target for the disease.
33305638 Efficacy and safety of subcutaneous infliximab versus adalimumab, etanercept and intraveno 2021 Jan OBJECTIVES: There are few comparative data for tumor necrosis factor inhibitors in patients with rheumatoid arthritis (RA). METHODS: Historical data for reference product/biosimilar intravenous infliximab, or adalimumab and etanercept, were pooled and compared with phase 3 study results for a subcutaneous (SC) formulation of the infliximab biosimilar CT-P13, in a systematic review and meta-analysis (PROSPERO: CRD42019149621). RESULTS: The authors identified 13 eligible controlled trials that randomized over 5400 participants to prespecified treatments of interest. Comparison with pooled historical data suggested a numerical advantage for CT-P13 SC over intravenous infliximab for almost every prespecified efficacy outcome evaluated, including Disease Activity Score in 28 joints (C-reactive protein/erythrocyte sedimentation rate), Clinical/Simplified Disease Activity Index scores, American College of Rheumatology responses, and multiple measures of disease remission and low disease activity; for the majority of outcomes, there was no overlap in 95% confidence intervals between groups. A numerical advantage for CT-P13 SC was also observed for safety outcomes (adverse events, infections, and discontinuations). Similar, but less marked, trends were observed for comparison with historical efficacy and safety data for adalimumab/etanercept. CONCLUSION: CT-P13 SC offers an improved or similar benefit-to-harm ratio compared with infliximab (intravenous) and adalimumab/etanercept, for the treatment of moderate-to-severe RA.
33756160 BLK and BANK1 variants and interactions are associated with susceptibility for primary Sjà 2021 May BLK and BANK1 in primary Sjögren's syndrome (pSS) have scarcely been evaluated and the results are inconclusive. The aim of our study was to determine whether single nucleotide variants (SNVs) located within BLK or BANK1 are associated with susceptibility, clinical and serological features, and smoking in pSS. BLK rs13277113A/G, BANK1 rs10516487G/A and rs3733197G/A were genotyped in 203 cases and 424 controls using a TaqMan® SNP genotyping assay. The BLK rs13277113A allele showed association with pSS under the allelic (OR 1.35, p = 0.02), and recessive (OR 1.83, p = 0.003) model, while, BANK1 rs3733197G/A showed association under the dominant model (OR 2.90, p = 0.043). Interactions between BANK1 and BLK genotypes also showed association (OR 2.36, p < 0.0001). In addition, BLK rs13277113A/G was associated with protection against arthritis and BANK1 rs10516487G/A with both arthritis and keratoconjunctivitis sicca, meanwhile, BANK1 rs3733197G/A was associated with smoking in patients with pSS. This is the first study to describe an association between BLK and susceptibility to pSS in a Latin-American population. Our data also shows a first evidence of association between interactions of BLK and BANK1 in pSS, and association of BLK and BANK1with arthritis, keratoconjunctivitis sicca and smoking in patients with pSS.
33436454 A comparison of faxed referrals and eConsult questions for rheumatology referrals: a descr 2021 Jan BACKGROUND: In Canada, wait times for access to specialized rheumatology services have increased, leading to new strategies to improve timely care; electronic consultations (eConsults) enable providers to ask specialists a clinical question using a secure platform, often reducing the need for a face-to-face visit. In this study, we sought to compare the types of referrals received through fax versus eConsult and to determine whether faxed referrals could be addressed using eConsult. METHODS: We conducted a descriptive study of consecutive faxed referrals sent to a tertiary care centre between Feb. 1 and Mar. 6, 2017, and a convenience sample of eConsults directed to rheumatology between Feb. 1, 2015, and Sept. 30, 2016, through the Champlain BASE eConsult Service, an Ontario-based service. We reviewed all referrals and categorized them by clinical content and question type. A rheumatologist with experience completing eConsult referrals assessed faxed referrals for their suitability to be answered through eConsults. Descriptive statistics were generated. RESULTS: We analyzed 300 consecutive faxed referrals and 300 (of 470) eConsult referrals. Faxed questions more often pertained to rheumatoid arthritis (32/300 [10.7%] v. 17/300 [5.7%]), systemic lupus erythematosus (24/300 [8.0%] v. 10/300 [3.3%]), and polyarthritis (30/300 [10.0%] v. 18/300 [6.0%]). eConsults more often addressed abnormal serology without joint symptoms (27/300 [9.0%] v. 8/300 [2.7%]) and gout (15/300 [5.0%] v. 4/300 [1.3%]). Faxed referrals were more likely to have no specific question (116/300 [38.7%]), and eConsults were more likely to have more than 1 question posed (99/300 [33.0%]) and a drug-related question (67/300 [22.3%]). The rheumatologist identified potential benefit from eConsult in 216/300 (72.0%) faxed referrals and 55/59 (93.2%) declined faxed referrals. INTERPRETATION: Despite differences in diagnosis between eConsults and faxed referrals, most faxed referrals showed the potential to be addressed through eConsult. Using eConsult may allow primary care providers to obtain answers to questions without requesting a face-to-face specialist referral, or provide support for patients awaiting face-to-face consultation.
34798945 Cardiovascular Health in Pediatric Rheumatologic Diseases. 2022 Feb Cardiovascular disease risk is evident during childhood for patients with juvenile systemic lupus erythematosus, juvenile dermatomyositis, and juvenile idiopathic arthritis. The American Heart Association defines cardiovascular health as a positive health construct reflecting the sum of protective factors against cardiovascular disease. Disease-related factors such as chronic inflammation and endothelial dysfunction increase cardiovascular disease risk directly and through bidirectional relationships with poor cardiovascular health factors. Pharmacologic and nonpharmacologic interventions to improve cardiovascular health and long-term cardiovascular outcomes in children with rheumatic disease are needed.
33863750 The shared susceptibility epitope of HLA-DR4 binds citrullinated self-antigens and the TCR 2021 Apr 16 Individuals expressing HLA-DR4 bearing the shared susceptibility epitope (SE) have an increased risk of developing rheumatoid arthritis (RA). Posttranslational modification of self-proteins via citrullination leads to the formation of neoantigens that can be presented by HLA-DR4 SE allomorphs. However, in T cell-mediated autoimmunity, the interplay between the HLA molecule, posttranslationally modified epitope(s), and the responding T cell repertoire remains unclear. In HLA-DR4 transgenic mice, we show that immunization with a Fibβ-74cit(69-81) peptide led to a population of HLA-DR4(Fibβ-74cit69-81) tetramer(+) T cells that exhibited biased T cell receptor (TCR) β chain usage, which was attributable to selective clonal expansion from the preimmune repertoire. Crystal structures of pre- and postimmune TCRs showed that the SE of HLA-DR4 represented a main TCR contact zone. Immunization with a double citrullinated epitope (Fibβ-72,74cit(69-81)) altered the responding HLA-DR4 tetramer(+) T cell repertoire, which was due to the P2-citrulline residue interacting with the TCR itself. We show that the SE of HLA-DR4 has dual functionality, namely, presentation and a direct TCR recognition determinant. Analogous biased TCR β chain usage toward the Fibβ-74cit(69-81) peptide was observed in healthy HLA-DR4(+) individuals and patients with HLA-DR4(+) RA, thereby suggesting a link to human RA.
34344550 Multimodal rheumatologic complex treatment in patients with spondyloarthritis - a prospect 2021 Nov INTRODUCTION: Aim of this study was to prospectively assess the effects of multimodal rheumatologic complex treatment (MRCT), a special concept of in-patient physical treatment (PT) for treating spondyloarthritis (SpA), namely radiographic (r-) and non-radiographic (nr-) axial (ax-) SpA and psoriatic arthritis (PsA). METHODS: r-, nr-axSpA and PsA patients receiving a 16-day MRCT were eligible. MRCT was delivered to participants over 64 PT sessions of various modalities with a minimum of 1,400 min of treatment. Primary outcome was a change in pain levels measured on a numeric rating scale (NRS, 0 - 10) between baseline and discharge. Secondary outcomes were assessments of i) disease activity ii) functional disabilities iii) serum cytokine levels iv) analgesic usage v) patient global health assessment and patients' satisfaction with their therapeutic response to MRCT from baseline to discharge and over a 12-week follow-up. RESULTS: 50 patients completed the study and were analysed. Pain levels were improved significantly (p < 0.001, 95% confidence interval -2.25 to -0.8,). Further analyses revealed no influencing factors or relevant inter-group differences. Positive effects of MRCT lasted up to 12 weeks after discharge. Analgesic usage was reduced compared to baseline. Patient global health assessment continued to be improved throughout the whole follow-up. No MRCT-related harms were recorded. CONCLUSION: MRCT as a multimodal treatment concept with a strong emphasis on PT reduces pain in SpA meaningfully and facilitates reduced analgesic usage.
33741556 JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine s 2021 Jul OBJECTIVE: Janus kinase inhibitors (JAKinibs) are efficacious in rheumatoid arthritis (RA) with variable reported rates of adverse events, potentially related to differential JAK family member selectivity. Filgotinib was compared with baricitinib, tofacitinib and upadacitinib to elucidate the pharmacological basis underlying its clinical efficacy and safety. METHODS: In vitro JAKinib inhibition of signal transducer and activator of transcription phosphorylation (pSTAT) was measured by flow cytometry in peripheral blood mononuclear cells and whole blood from healthy donors and patients with RA following cytokine stimulation of distinct JAK/STAT pathways. The average daily pSTAT and time above 50% inhibition were calculated at clinical plasma drug exposures in immune cells. The translation of these measures was evaluated in ex vivo-stimulated assays in phase 1 healthy volunteers. RESULTS: JAKinib potencies depended on cytokine stimulus, pSTAT readout and cell type. JAK1-dependent pathways (interferon (IFN)α/pSTAT5, interleukin (IL)-6/pSTAT1) were among the most potently inhibited by all JAKinibs in healthy and RA blood, with filgotinib exhibiting the greatest selectivity for JAK1 pathways. Filgotinib (200 mg once daily) had calculated average daily target inhibition for IFNα/pSTAT5 and IL-6/pSTAT1 that was equivalent to tofacitinib (5 mg two times per day), upadacitinib (15 mg once daily) and baricitinib (4 mg once daily), with the least average daily inhibition for the JAK2-dependent and JAK3-dependent pathways including IL-2, IL-15, IL-4 (JAK1/JAK3), IFNγ (JAK1/JAK2), granulocyte colony stimulating factor, IL-12, IL-23 (JAK2/tyrosine kinase 2) and granulocyte-macrophage colony-stimulating factor (JAK2/JAK2). Ex vivo pharmacodynamic data from phase 1 healthy volunteers clinically confirmed JAK1 selectivity of filgotinib. CONCLUSION: Filgotinib inhibited JAK1-mediated signalling similarly to other JAKinibs, but with less inhibition of JAK2-dependent and JAK3-dependent pathways, providing a mechanistic rationale for its apparently differentiated efficacy:safety profile.
32905628 Increased Induction Infliximab Clearance Predicts Early Antidrug Antibody Detection. 2021 Feb Treatment of patients with biologics such as infliximab may trigger development of antidrug antibodies, which are associated with faster drug clearance, reduced treatment efficacy, and increased risk of infusion-related reactions. The aim of this study was to identify predictors of baseline infliximab clearance and early antidrug antibody formation. Pharmacokinetic and pharmacokinetic/pharmacodynamic models for infliximab were developed using 21 178 observations from 859 patients from the PLANETRA (ClinicalTrials.gov identifier: NCT01217086) and PLANETAS (NCT01220518) studies in rheumatoid arthritis and ankylosing spondylitis, respectively, to address the specified aims. Infliximab pharmacokinetics were well described by a 2-compartment model with linear mean estimated baseline clearance of 0.26 L/day. Alongside increased body weight, serum C-reactive protein, and antidrug antibody concentrations and decreased serum albumin, elevated serum glucose levels predicted higher clearance. In patients with rheumatoid arthritis, baseline infliximab clearance and body weight were the only identified predictors of early antidrug antibody detection. The odds ratio for antidrug antibody detection for each 0.1 L/day increase in baseline infliximab clearance was 1.78 (95% confidence interval, 1.50-2.12); for each 10-kg increase in body weight, this was 1.19 (1.06-1.33). Here we describe increased serum glucose levels as a novel independent predictor of baseline infliximab clearance. Estimates of baseline infliximab clearance should be incorporated to guide dosing modifications and/or antidrug antibody prophylaxis in clinical practice.
34838728 Crystallographic landscape provides molecular insights into the modes of action of diverse 2022 Feb ROR-γt, the master regulator of Th-17 cells, is activated by the binding of small molecules at its orthosteric site, followed by the recruitment of co-activators or co-repressors in the ligand binding domain (LBD). Th-17 cells provide immune-dependent protection against cancers and pathogens. Their dysregulation causes inflammation and is therefore implicated in various autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and psoriasis. Consequently, there is enormous interest in the development of ROR-γt modulators, both agonist and inverse-agonists. Here, we review advances in the development of ROR-γt modulators that have been made over the past decade, focusing on the rich crystallography landscape for ROR-γt co-crystals that has delineated the relationship between the binding patterns of modulators and the resulting biological activities.
34592918 New horizons in the roles and associations of COX-2 and novel natural inhibitors in cardio 2021 Sep 30 Age-related cardiovascular disease is the leading cause of death in elderly populations. Coxibs, including celecoxib, valdecoxib, etoricoxib, parecoxib, lumiracoxib, and rofecoxib, are selective cyclooxygenase-2 (COX-2) inhibitors used to treat osteoarthritis and rheumatoid arthritis. However, many coxibs have been discontinued due to adverse cardiovascular events. COX-2 contains cyclooxygenase (COX) and peroxidase (POX) sites. COX-2 inhibitors block COX activity without affecting POX activity. Recently, quercetin-like flavonoid compounds with OH groups in their B-rings have been found to serve as activators of COX-2 by binding the POX site. Galangin-like flavonol compounds serve as inhibitors of COX-2. Interestingly, nabumetone, flurbiprofen axetil, piketoprofen-amide, and nepafenac are ester prodrugs that inhibit COX-2. The combination of galangin-like flavonol compounds with these prodrug metabolites may lead to the development of novel COX-2 inhibitors. This review focuses on the most compelling evidence regarding the role and mechanism of COX-2 in cardiovascular diseases and demonstrates that quercetin-like compounds exert potential cardioprotective effects by serving as cofactors of COX-2.
34137070 Anakinra for recalcitrant pyoderma gangrenosum. 2021 Dec Pyoderma gangrenosum (PG) is an autoinflammatory neutrophilic dermatosis characterized by rapidly enlarging, painful ulcers. Anakinra is a recombinant interleukin (IL)-1 receptor antagonist that blocks the activity of IL-1α and IL-1β by competitively inhibiting IL-1 binding to the IL-1 type 1 receptor. We present a series of two patients with recalcitrant PG, who had limited therapeutic options and multiple comorbidities and multiple previous treatment failures, who obtained 100% healing with anakinra. Compared with conventional first-line therapies for PG, the safety profile of anakinra may be preferable for patients with multiple comorbidities. Further research is needed to assess the safety and efficacy of anakinra for PG.
34843241 Discovery of a Novel Potent and Selective Calcium Release-Activated Calcium Channel Inhibi 2021 Dec 9 The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.
34645184 [Correlation between serum CCL20 level and disease severity in patients with rheumatoid ar 2021 Feb 6 Objective: To investigate the correlation between serum CCL20 level and disease severity in patients with rheumatoid arthritis (RA). Methods: From July 2018 to July 2019, a cross-sectional study was conducted in the Department of Rheumatology and Immunology, the Third Affiliated Hospital of Southern Medical University. The observation group consisted of 105 outpatients and inpatients diagnosed with RA, while the control group was 90 healthy people with age and gender matched physical examination in the Third Affiliated Hospital of Southern Medical University. According to Steinbroker classification, RA patients were divided into Steinbroker grade 2 group (n=35), Steinbroker grade 3 group (n=38) and steinbroker grade 4 group (n=32); according to DAS28 score, RA patients were divided into remission group (DAS28<2.6)(n=39), mild active group (DAS28 2.6-3.2)(n=25), moderate active stage group (DAS28 3.2-5.1)(n=20) and severe active stage group (DAS28 ≥ 5.1)(n=21). The levels of chemokine ligand 20 (CCL20), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were detected by ELISA. The levels of CCL20 in each group were compared, and the correlation between CCL20 and other indicators was analyzed. The receiver operating characteristic (ROC) curve of CCL20 in diagnosis of RA was analyzed to explore the correlation between CCL20 and disease severity of RA patients. Results: Compared with the normal control group, the serum CCL20 level in RA patients was significantly increased [(48.1±16.7) pg/ml vs (17.6±5.9) pg/ml, t=19.39, P<0.001]. In addition, serum CCL20 in steinbroker grade 4 group was significantly higher than that in Steinbroker grade 3 group [(59.5±10.1) pg/ml vs (47.4±17.5) pg/ml, t=3.472, P<0.001], and the serum CCL20 level in steinbroker grade 3 group was significantly higher than that in steinbroker grade 2 group [(47.4±17.5) pg/ml vs (38.4±14.6) pg/ml, t=2.370, P<0.001], CCL20 level in steinbroker grade 2 group was significantly higher than that in normal control group [(38.4±14.6) pg/ml vs (17.6±5.9) pg/ml, t=7.738, P<0.001]. In addition, serum CCL20 level was significantly positively correlated with steinbroker score (r=0.505, P<0.001); CCL20 level in active RA patients was significantly higher than that in remission RA patients [(57.2±13.2) pg/ml vs (32.7±8.9) pg/ml, t=10.31, P<0.001]. The serum CCL20 level in severe activity group was significantly higher than that in moderate activity group [(60.6±10.9) pg/ml vs (51.7±16.2) pg/ml, t=0.212, P=0.040], and the serum CCL20 level in moderate activity group was significantly higher than that in mild activity group [(51.7±16.2) pg/ml vs (40.5±18.6) pg/ml, t=0.217, P=0.037]. In addition, there was a significant positive correlation between serum CCL20 level and DAS28 score (r=0.451, P<0.001). In addition, serum CCL20 level was positively correlated with serum CRP (r=0.332, P<0.001). According to the ROC curve, the specificity of steinbroker grade 2 group was 0.53, and the sensitivity was 0.74, AUC was 0.659; the sensitivity of steinbroker grade 3 group was 0.78, and the specificity was 0.69, AUC was 0.734; the sensitivity of mild vs medium stage was 0.64, and the specificity was 0.70, AUC was 0.699; the sensitivity of medium stage vs severe stage was 0.57, and the specificity was 0.68,AUC was 0.678. Conclusion: Serum CCL20 level in RA patients is significantly increased and positively correlated with disease severity, which may be used as a marker to observe and evaluate the progression of RA.
34130151 Nicotinamide mononucleotide-elicited NAMPT signaling activation aggravated adjuvant-induce 2021 Sep Supplement of nicotinamide mononucleotide (NMN), the direct precursor of nicotinamide adenine dinucleotide (NAD(+)) has gained prominence due to the significant anti-aging potentials of nicotinamide phosphoribosyltransferas (NAMPT)/NAD(+) signaling. Because over-expression of NAMPT is deeply implicated in inflammatory arthritis, we investigated the effects of NMN supplement on rats with adjuvant-induced arthritis (AIA). Tested rats were given oral treatment of NMN at 200 mg/kg/day for 25 days. Arthritis score and body weight were periodically recorded. Clinical outcomes were evaluated based on arthritic manifestations, ELISA analysis and histological examination. T cells subsets were analyzed by flow cytometry. Expressions of protein and mRNA were assessed by immunoblotting and PCR methods, respectively. Levels of CD172a, CD43, and NAMPT in peripheral blood mononuclear cells (PBMCs) were investigated by immunofluorescence approach. Obtained results were further validated by experiments in vitro. Generally, NMN exacerbated AIA severity in rats. It deteriorated MMP3-controlled tissues damages, and altered immune profile by increasing Th17/Treg cells ratio. The up-regulation of NAMPT in PBMCs from NMN-treated rats was confirmed by both immunofluorescence and PCR experiments, which was synchronized with significant increase in iNOS, MCP-1, IL-1β expression. NMN-primed AIA PBMCs were potent in up-regulating MCP-1, IL-1β, MMP3 and p-JNK expression in synovioblast. NMN stimulus barely affected Th17 cells count in in vitro cultured splenocytes, but it greatly potentiated the capability of AIA monocytes in inducing IL-17α secretion and Th17 cells differentiation in the co-cultured splenocytes. It suggested that long-term NMN supplement could exacerbate inflammatory arthritis by reshaping the immune milieu through the up-regulation of NAMPT.
34862310 Incidence of COVID-19 in patients treated with infliximab compared with patients treated w 2021 Dec OBJECTIVE: To determine whether patients with inflammatory autoimmune diseases treated with rituximab (RTX) have more severe forms of COVID-19 compared with patients treated with anticytokine therapies, such as Tumour Necrosis Factor (TNF) inhibitors. METHODS: We included all patients who were on either RTX or infliximab (IFX) in two Swiss cantons during the first wave of the COVID-19 pandemic. We collected self-reported symptoms compatible with COVID-19, PCR-confirmed diagnoses of COVID-19 and the evolution of COVID-19 infections. We computed the raw and propensity score-adjusted incidence of COVID-19 by treatment group. RESULTS: 190 patients were enrolled, of whom 121 (64%) were in the RTX group and 69 (36%) were in the IFX group. Twenty-one patients (11%) reported symptoms compatible with COVID-19 (RTX: 10, IFX: 11, p=0.14). Among patients with COVID-19 symptoms, four developed severe forms of the disease, with life-threatening pulmonary manifestations requiring intensive mechanical ventilation (RTX: 4 of 10, IFX: 0 of 11, Fisher's exact test p=0.04). The incidence rate of COVID-19 symptoms was 0.73 (95% CI 0.39 to 1.37) cases per 1000 patient-days on RTX vs 1.52 (95% CI 0.82 to 2.85) cases per 1000 patient-days on IFX (crude p=0.10, adjusted p=0.07). The incidence rate of severe COVID-19 was 0.28 (95% CI 0.08 to 0.7.2) cases per 1000 patient-days on RTX compared with null on IFX (95% CI 0.0 to 0.44) (p=0.13). A replication in an independent validation cohort confirmed these findings, with consistent results in the Swiss Clinical Quality Management registry. CONCLUSION: While the incidence of symptoms compatible with COVID-19 was overall similar in patients receiving RTX or IFX, the incidence of severe COVID-19 tended to be higher in the RTX group.
34335612 Mechanism of Immunoregulatory Properties of Vasoactive Intestinal Peptide in the K/BxN Mic 2021 The K/BxN mouse model of rheumatoid arthritis (RA) closely resembles the human disease. In this model, arthritis results from activation of autoreactive KRN T cells recognizing the glycolytic enzyme glucose-6-phosphate isomerase (GPI) autoantigen, which provides help to GPI-specific B cells, resulting in the production of pathogenic anti-GPI antibodies that ultimately leads to arthritis symptoms from 4 weeks of age. Vasoactive intestinal peptide (VIP) is a neuropeptide broadly distributed in the central and peripheral nervous system that is also expressed in lymphocytes and other immune cell types. VIP is a modulator of innate and adaptive immunity, showing anti-inflammatory and immunoregulatory properties. Basically, this neuropeptide promotes a shift in the Th1/Th2 balance and enhances dedifferentiation of T regulatory cells (Treg). It has demonstrated its therapeutic effects on the collagen-induced arthritis (CIA) mouse model of RA. In the present hypothesis and theory article, we propose that the immunoregulatory properties of VIP may be due likely to the inhibition of T cell plasticity toward non-classic Th1 cells and an enhanced follicular regulatory T cells (Tfr) activity. The consequences of these regulatory properties are the reduction of systemic pathogenic antibody titers.
34051316 Diagnosing muscle disease in a cohort of classic dermatomyositis patients seen at a rheuma 2022 Mar BACKGROUND: Existing criteria to improve the probability of capturing dermatomyositis (DM) include muscle biopsy but little is known about whether less invasive diagnostic procedures may be just as useful. OBJECTIVE: We aimed to determine whether skin biopsy, electromyography, or magnetic resonance imaging of the involved muscle could be done in lieu of muscle biopsy. METHODS: Two hundred and seventy-five patients were reviewed to investigate the presence of cutaneous and muscle disease, their timing in relation to diagnosis, and results of skin biopsies, muscle biopsies, magnetic resonance imaging, and electromyography. RESULTS: Of the cases with findings consistent with DM on muscle biopsy, 65% were in agreement with diagnostic features on electromyography or magnetic resonance imaging. Results of skin and muscle biopsies supported DM in 67% of patients who underwent both procedures. LIMITATIONS: A limited number of patients had muscle biopsies. CONCLUSION: In the presence of DM-specific skin findings, less invasive procedures may be sufficient to diagnose DM and guide its management.
32415262 IRAK4 inhibition: a promising strategy for treating RA joint inflammation and bone erosion 2021 Sep Flares of joint inflammation and resistance to currently available biologic therapeutics in rheumatoid arthritis (RA) patients could reflect activation of innate immune mechanisms. Herein, we show that a TLR7 GU-rich endogenous ligand, miR-Let7b, potentiates synovitis by amplifying RA monocyte and fibroblast (FLS) trafficking. miR-Let7b ligation to TLR7 in macrophages (MΦs) and FLSs expanded the synovial inflammatory response. Moreover, secretion of M1 monokines triggered by miR-Let7b enhanced Th1/Th17 cell differentiation. We showed that IRAK4 inhibitor (i) therapy attenuated RA disease activity by blocking TLR7-induced M1 MΦ or FLS activation, as well as monokine-modulated Th1/Th17 cell polarization. IRAK4i therapy also disrupted RA osteoclastogenesis, which was amplified by miR-Let7b ligation to joint myeloid TLR7. Hence, the effectiveness of IRAK4i was compared with that of a TNF inhibitor (i) or anti-IL-6R treatment in collagen-induced arthritis (CIA) and miR-Let7b-mediated arthritis. We found that TNF or IL-6R blocking therapies mitigated CIA by reducing the infiltration of joint F480(+)iNOS(+) MΦs, the expression of certain monokines, and Th1 cell differentiation. Unexpectedly, these biologic therapies were unable to alleviate miR-Let7b-induced arthritis. The superior efficacy of IRAK4i over anti-TNF or anti-IL-6R therapy in miR-Let7b-induced arthritis or CIA was due to the ability of IRAK4i therapy to restrain the migration of joint F480(+)iNOS(+) MΦs, vimentin(+) fibroblasts, and CD3(+) T cells, in addition to negating the expression of a wide range of monokines, including IL-12, MIP2, and IRF5 and Th1/Th17 lymphokines. In conclusion, IRAK4i therapy may provide a promising strategy for RA therapy by disconnecting critical links between inflammatory joint cells.
34264363 [Answering epidemiologic rheumatologic questions by cooperation with the large population- 2022 Mar This article presents how, based on the availability of new imaging methods and medications, objectives regarding the rheumatic disease axial spondyloarthritis (axSpA) have developed over the course of more than two decades into a rheumatologic research group. During recent years, cooperation with the Study of Health in Pomerania (SHIP) cohort has given rise to new fundamental aspects. This involved intensive cooperation between the Ruhr University Bochum (Rheumazentrum Ruhrgebiet) and the Greifswald University Hospital (Community Medicine research collective). The design of the SHIP cohort was published 10 years ago and the cohort approach presented in the Bundesgesundheitsblatt, which also described central methodologic questions in detail. In 2014, a cooperation project between the Ruhr Rheumatology Center/Ruhr University Bochum and the SHIP Department of Clinical and Epidemiologic Research (Klinisch-Epidemiologische Forschung, KEF; SHIP-KEF) was established, which has already resulted in publication of interesting results in high-ranking journals. In order to stress the potential of such corporations, important contents thereof are presented herein, with a focus on MRI and consideration of historical aspects.