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ID PMID Title PublicationDate abstract
31755231 Inhibition of DNM1L and mitochondrial fission attenuates inflammatory response in fibrobla 2020 Jan Mitochondrial fission and fusion are important for mitochondrial function, and dynamin 1-like protein (DNM1L) is a key regulator of mitochondrial fission. We investigated the effect of mitochondrial fission on mitochondrial function and inflammation in fibroblast-like synoviocytes (FLSs) during rheumatoid arthritis (RA). DNM1L expression was determined in synovial tissues (STs) from RA and non-RA patients. FLSs were isolated from STs and treated with a DNM1L inhibitor (mdivi-1, mitochondrial division inhibitor 1) or transfected with DNM1L-specific siRNA. Mitochondrial morphology, DNM1L expression, cell viability, mitochondrial membrane potential, reactive oxygen species (ROS), apoptosis, inflammatory cytokine expression and autophagy were examined. The impact of mdivi-1 treatment on development and severity of collagen-induced arthritis (CIA) was determined in mice. Up-regulated DNM1L expression was associated with reduced mitochondrial length in STs from patients with RA and increased RA severity. Inhibition of DNM1L in FLSs triggered mitochondrial depolarization, mitochondrial elongation, decreased cell viability, production of ROS, IL-8 and COX-2, and increased apoptosis. DNM1L deficiency inhibited IL-1β-mediated AKT/IKK activation, NF-κBp65 nuclear translocation and LC3B-related autophagy, but enhanced NFKBIA expression. Treatment of CIA mice with mdivi-1 decreased disease severity by modulating inflammatory cytokine and ROS production. Our major results are that up-regulated DNM1L and mitochondrial fission promoted survival, LC3B-related autophagy and ROS production in FLSs, factors that lead to inflammation by regulating AKT/IKK/NFKBIA/NF-κB signalling. Thus, inhibition of DNM1L may be a new strategy for treatment of RA.
31712995 An Analysis of Real-World Data on the Safety of Etanercept in Older Patients with Rheumato 2020 Jan OBJECTIVE: The aim of this study was to use real-world data to evaluate potential interactions between age, treatment, and the risk of developing four adverse events (AEs) common in the elderly: congestive heart failure, serious infections, non-melanoma skin cancer, and interstitial lung disease. These AEs were identified as important in a prior age-based analysis (≤ 65 vs > 65 years) of etanercept- or placebo-treated patients with rheumatoid arthritis (RA) in controlled clinical trials. METHODS: Real-world data (1 January 2013 to 31 January 2018) were obtained from the IBM Watson Health MarketScan(®) Database. Patients were included if aged ≥ 18 years, enrolled for ≥ 1 year prior to RA diagnosis, and without any of the four AEs of interest prior to RA diagnosis or between RA diagnosis and first etanercept exposure. Logistic regression analysis was applied following propensity matching of patients receiving or not receiving etanercept based on age at diagnosis, age status at the beginning of observation (> 65 years or not), sex, geographic region, and follow-up duration. RESULTS: The overall cohort comprised 403,689 patients. The absolute risk of each of the four AEs increased with age. In propensity-matched cohorts, etanercept was associated with significantly higher odds of developing each of the four AEs (p < 0.001 for all). However, the relative risk of experiencing the four AEs in patients who received etanercept versus those who did not was similar between patients ≤ 65 years of age and those > 65 years of age. CONCLUSIONS: In patients with RA, the relative increase in etanercept-associated risk of experiencing congestive heart failure, serious infection, non-melanoma skin cancer, or interstitial lung disease was similar between elderly and non-elderly.
33273889 Prostanoid Receptor Subtypes and Its Endogenous Ligands with Processing Enzymes within Var 2020 A complex inflammatory process mediated by proinflammatory cytokines and prostaglandins commonly occurs in the synovial tissue of patients with joint trauma (JT), osteoarthritis (OA), and rheumatoid arthritis (RA). This study systematically investigated the distinct expression profile of prostaglandin E2 (PGE2), its processing enzymes (COX-2), and microsomal PGES-1 (mPGES-1) as well as the corresponding prostanoid receptor subtypes (EP1-4) in representative samples of synovial tissue from these patients (JT, OA, and RA). Quantitative TaqMan®-PCR and double immunofluorescence confocal microscopy of synovial tissue determined the abundance and exact immune cell types expressing these target molecules. Our results demonstrated that PGE2 and its processing enzymes COX-2 and mPGES-1 were highest in the synovial tissue of RA, followed by the synovial tissue of OA and JT patients. Corresponding prostanoid receptor, subtypes EP3 were highly expressed in the synovium of RA, followed by the synovial tissue of OA and JT patients. These proinflammatory target molecules were distinctly identified in JT patients mostly in synovial granulocytes, in OA patients predominantly in synovial macrophages and fibroblasts, whereas in RA patients mainly in synovial fibroblasts and plasma cells. Our findings show a distinct expression profile of EP receptor subtypes and PGE2 as well as the corresponding processing enzymes in human synovium that modulate the inflammatory process in JT, OA, and RA patients.
32337656 Tocilizumab-induced immunocomplex glomerulonephritis: a report of two cases. 2020 Nov We report here two cases of membranoproliferative glomerulonephritis that developed during treatment of rheumatoid arthritis with tocilizumab. In both cases, the initial findings were proteinuria and haematuria, followed by development of bilateral lower leg oedema. One of the patients was weakly positive for anti-nuclear antibody; both had hypocomplementaemia. The patients' renal impairment gradually resolved with discontinuation of tocilizumab followed by treatment with moderate doses of oral prednisolone. Pathological examination of renal biopsies resulted in diagnoses of immunocomplex glomerulonephritis and immunofluorescence staining revealed depositions of IgG, IgA, and IgM, accompanied by C3. Tocilizumab rarely induces autoimmune disorders; therefore, the underlying mechanism is unknown. One patient with immunocomplex glomerulonephritis that may have been associated with tocilizumab therapy for rheumatoid arthritis has been reported previously; that patient and our two are similar in their clinical courses and pathological findings. We conclude that such glomerulonephritis can occur during tocilizumab treatment, but this is rare. Clinicians should be aware of the possibility of paradoxical development of autoimmune diseases during tocilizumab therapy.
31836320 Anti-tumour necrosis factor-α therapy and recurrent or new primary cancers in patients wi 2020 Mar BACKGROUND: Safety of anti-tumour necrosis factor-α (TNFα) therapy in people with a history of cancer and with an immune-mediated disease is unknown. We aimed to assess the risk of recurrence of initial cancer or development of a new primary cancer after treatment with anti-TNFα therapy. METHODS: In this Danish, population-based cohort study we recruited adults (≥18 years) with inflammatory bowel disease (IBD), rheumatoid arthritis, or psoriasis and a primary cancer diagnosed between Jan 1, 1999 and Dec 31, 2016. Patients were recruited from the prospectively recorded Danish National Patient Registry and the Danish Cancer Registry. Participants were matched 1:10 between the treatment group who received anti-TNFα therapy and the control group (no anti-TNFα therapy) and we excluded individuals with a cancer diagnosed before their first anti-TNFα treatment (or before matching date for controls), individuals diagnosed with IBD, rheumatoid arthritis, or psoriasis after anti-TNFα initiation (or respective match date for controls), and individuals who received anti-TNFα with fewer than five matched controls. Using adjusted Cox proportional hazards regression, we estimated the primary outcome of development of recurrent or new primary cancer in patients who received anti-TNFα therapy compared with patients who did not receive this therapy, matched by sex, immune-mediated disease type, cancer type, and time from initial cancer diagnosis to first anti-TNFα registration. FINDINGS: Overall, 25 738 patients with immune-mediated disease and a history of cancer were identified. 434 patients who received anti-TNFα therapy after their initial cancer were matched to 4328 patients in the control group. During 18 752 person-years (median 5·6 years [IQR 2·8-7·9]) of follow up, 635 individuals developed recurrent or new primary cancer, 72 of whom had received anti-TNFα therapy and 563 of whom were in the control group. The median time between anti-TNFα treatment and recurrent or new primary cancer diagnosis was 2·8 years (IQR 1·7-5·4). The incidence of recurrent or new primary cancer development was 30·3 cases (95% CI 24·0-38·2) per 1000 person-years in the anti-TNFα treatment group and 34·4 cases (31·7-37·3) per 1000 person-years in the control group, yielding an adjusted hazard ratio of 0·82 (95% CI 0·61-1·11). INTERPRETATION: Use of anti-TNFα therapy was not associated with recurrent or new primary cancer development in patients with previous cancer. Timing of anti-TNFα therapy after an initial cancer diagnosis did not influence recurrent or new primary cancer development. This observation might guide clinical decision making among providers treating immune-mediated diseases with anti-TNFα medications. FUNDING: None.
32189513 Natural History of 321 Flatfoot Reconstructions in Adult Acquired Flatfoot Deformity Over 2021 Jun The purpose of this study was to report the natural history, demographics, and mechanisms of requirement for additional surgery in patients undergoing flatfoot reconstruction for adult acquired flatfoot. A total of 321 consecutive patients undergoing flatfoot reconstruction over a 14-year period were included (2002-2016). All procedures were performed by a senior orthopaedic foot and ankle surgeon at our institution. Demographic data, operative reports, clinic notes, and radiographs were available for review. Statistical analysis included calculation of relative risk (RR) ratios. The majority of patients were female (83.2%,) and most patients were overweight with a body mass index greater than 25 kg/m(2) (56.4%). Patient comorbidities included diabetes (13.7%) and rheumatoid arthritis (3.7%). Additional surgery was required for 54 patients (16.8%). The most common reasons for additional surgery were the following: painful calcaneal hardware (57.4%), conversion to triple arthrodesis (16.7%), and wound healing complications (9.1%). An increased risk of need for additional surgery was associated with female gender (RR = 3.4; P = .0005), smoking status (RR = 1.9; P = .0081), and age (<60 years of age; RR = 1.8; P = .042). Although retrospective, the results provide insight into the natural history of this procedure. Clinicians may use these data to appropriately counsel patients who are at increased risk of requirement for additional surgery, such as smokers, women, and patients <60 years old, regarding treatment options.Levels of Evidence: Level IV.
32228715 Cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA-4-Ig) suppresses Staphylococcus aureu 2020 Mar 30 BACKGROUND: Cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA-4-Ig) competes with CD28 for binding CD80/CD86 on antigen-presenting cells (APCs) to limit T cell activation. B cells are believed to be important APCs in the pathogenesis of autoimmune diseases and express CD80/CD86 after activation; however, relatively little is known about the effect of CTLA-4-Ig on B cells. This study tested the impact of CTLA-4-Ig on human B cell responses. METHODS: Human blood B cells were purified from healthy donors and activated in the presence of CTLA-4-Ig or the L6-Ig control protein in vitro. RT-q-PCR and immunofluorescence staining were performed to detect activation marker expression. ELISA was conducted to measure cytokine secretion. The CD80/CD86 levels on the surface of the memory B cells in the blood of 18 patients with rheumatoid arthritis (RA) were detected using immunofluorescence staining. RESULTS: CTLA-4-Ig suppressed the expression of Staphylococcus aureus (SAC)-induced CD80, CD86, TNFA, and IL6 in human B cells at the transcriptional level. Furthermore, CTLA-4-Ig concomitantly decreased SAC-induced CD80/CD86 surface expression on and TNF-α and IL-6 secretion from B cells. On the other hand, T cell-dependent (TD) stimulation-induced B cell activation, proliferation, plasma cell differentiation, and antibody secretion were not affected by CTLA-4-Ig. As expected, TD stimulation-induced surface CD80 was hindered by CTLA-4-Ig. Notably, a blockade of CD80/CD86 on the surface of the memory B cells was observed in the patients with RA after abatacept (CTLA-4-Ig) treatment. In a portion of the RA patients, restoration of CD80/CD86 staining on the surface of the memory B was detected starting in the 3rd month of abatacept treatment. Interestingly, the surface levels of CD80/CD86 on the patients' memory B cells positively correlated with disease activity. CONCLUSIONS: We found that CTLA-4-Ig directly suppressed SAC-induced B cell activation in vitro. Obstruction of CD80 and CD86 on the surface of the memory B cells was detected in the RA patients after abatacept treatment. Blocking CD80/CD86 on B cells by CTLA-4-Ig may hinder T cell activation and associated with the disease activity of RA in vivo. Our findings indicate that CTLA-4-Ig may regulate humoral responses by modulating B cell activation and interfering T cell-B cell interaction.
33264602 Succinyl-CoA Ligase Deficiency in Pro-inflammatory and Tissue-Invasive T Cells. 2020 Dec 1 Autoimmune T cells in rheumatoid arthritis (RA) have a defect in mitochondrial oxygen consumption and ATP production. Here, we identified suppression of the GDP-forming β subunit of succinate-CoA ligase (SUCLG2) as an underlying abnormality. SUCLG2-deficient T cells reverted the tricarboxylic acid (TCA) cycle from the oxidative to the reductive direction, accumulated α-ketoglutarate, citrate, and acetyl-CoA (AcCoA), and differentiated into pro-inflammatory effector cells. In AcCoA(hi) RA T cells, tubulin acetylation stabilized the microtubule cytoskeleton and positioned mitochondria in a perinuclear location, resulting in cellular polarization, uropod formation, T cell migration, and tissue invasion. In the tissue, SUCLG2-deficient T cells functioned as cytokine-producing effector cells and were hyperinflammatory, a defect correctable by replenishing the enzyme. Preventing T cell tubulin acetylation by tubulin acetyltransferase knockdown was sufficient to inhibit synovitis. These data link mitochondrial failure and AcCoA oversupply to autoimmune tissue inflammation.
33060659 Quantitative bone single photon emission computed tomography analysis of the effects of du 2020 Oct 15 Effects of long-term bisphosphonate (BP) administration on the metabolism of healthy bone and the concomitant changes in imaging are unclear. Hence, we aimed to retrospectively investigate the effects of long-term BP administration on the intact parietal bone using the standardised uptake value (SUV) derived from single photon emission computed tomography (SPECT). We enrolled 29 patients who had odontogenic infection, osteoporosis, bone metastasis cancer, or rheumatoid arthritis, and classified them into BP-naïve: A (14 patients) and BP-treated: B, < 4 years (7 patients) and C, ≥ 4 years (8 patients) groups. We measured the maximum bilateral SUV (SUVmax) of the parietal bone using quantitative bone SPECT software. There were significant differences in the duration of BP administration and SUVmax of the parietal bone among the diseases (P < 0.0001 and P = 0.0086, respectively). There was a positive correlation between the duration of BP administration and SUVmax of the parietal bone (r(s) = 0.65, P = 0.0002). The SUVmax was significantly different between A and B (P = 0.02) and between A and C (P = 0.0024) groups. This is the first report on the correlation between long-term BP administration and the SUVmax of the parietal bone using the quantitative bone SPECT analysis.
33237483 Evaluation of the impact of age and adiposity on a multi-biomarker disease activity score 2021 Jun PURPOSE: We assessed the impact of adjustment of the multi-biomarker disease activity score (MBDA) for age, sex, and leptin, over the range of age and adiposity, and assessed relationships with clinical disease activity. METHODS: Patients with RA, ages 18-75 years, were recruited from clinical practices and completed whole-body DXA to quantify fat mass indices (FMI, kg/m(2)). FMI Z-scores were calculated based on distributions in a reference population. Descriptive statistics described relationships between age, FMI Z-score, and the original MBDA and adjusted MBDA (aMBDA). Swollen joint counts (SJC) and the clinical disease activity index (CDAI) were assessed over MBDA categories. RESULTS: There were 104 participants (50% female) with mean (SD) age of 56.1 (12.5) and body mass index (BMI) of 28.8 (6.9). Older age was associated with higher MBDA scores in men. The aMBDA was not associated with age. The original MBDA score was associated with FMI Z-score among women (Rho = 0.42, p = 0.002) but not men. The aMBDA was not associated with FMI Z-score in either women or men. The aMBDA score was lower than the original MBDA in the highest quartile of FMI in women and was higher in the lowest FMI quartiles in women and men. CDAI, SJC, and radiographic scores were similar across activity categories for the original MBDA score and aMBDA. CONCLUSIONS: The aMBDA demonstrated reduced associations with adiposity, particularly among women. The aMBDA may be less likely to overestimate disease activity in women with greater adiposity and to underestimate disease activity in men and women with lesser adiposity. Key Points • Leptin adjustment of the MBDA score reduces the influence of adiposity, particularly among women. • Leptin adjustment results in significantly higher estimated disease activity in thin men and women. • The adjusted and unadjusted score correlate similarly with clinical disease activity measures.
32243486 A novel indomethacin/methotrexate/MMP-9 siRNA in situ hydrogel with dual effects of anti-i 2020 Apr 21 Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammatory cell infiltration, and cartilage and bone disruption, which ultimately leads to loss of joint function. Current treatments for RA only focus on anti-inflammatory activity but neglect to prevent further damage to articular cartilage and bone. Here we attempted to co-deliver indomethacin (IND), methotrexate (MTX) and a small-interfering RNA targeting MMP-9 using an in situ hydrogel loaded with PEI-SS-IND-MTX-MMP-9 siRNA nanoparticles (D/siRNA-NGel) to treat RA synergistically and comprehensively. IND, MTX and MMP-9 siRNA were able to escape from the endosome and down-regulate the expression of MMP-9 and inflammatory cytokines of Raw-264.7 cells. After intra-articular injection in arthritic mice, the D/siRNA-NGel effectively relieved joint swelling and significantly reduced the expression of TNF-α, IL-6 and MMP-9 in the ankle fluid, knee joint fluid and plasma of RA mice without causing any side effects. Most importantly, the co-delivery system restored the morphological parameters of the ankle joints close to normal. The D/siRNA-NGel could achieve good anti-inflammatory activity and reverse cartilage disruption through a synergistic effect between chemical drugs and MMP-9 siRNA. This co-delivery system should have promising applications in the treatment of rheumatoid arthritis and other metabolic bone diseases which cause serious bone erosion.
31712132 High LDL levels lessen bone destruction during antigen-induced arthritis by inhibiting ost 2020 Jan Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by severe joint inflammation and bone destruction as the result of increased numbers and activity of osteoclasts. RA is often associated with metabolic syndrome, whereby elevated levels of LDL are oxidized into oxLDL, which might affect osteoclastogenesis. In this study, we induced antigen-induced arthritis (AIA) in Apoe(-/-) mice, which spontaneously develop high LDL levels, to investigate the effects of high LDL/oxLDL levels on osteoclast differentiation and bone destruction. Whereas basal levels of bone resorption were comparable between naive WT and Apoe(-/-) mice, induction of AIA resulted in a significant reduction of bone destruction in Apoe(-/-) mice as compared to WT controls. In line with that, the TRAP(+) area on the cortical bone was significantly decreased. The absence of Apoe did affect neither the numbers of CD11b(+)Ly6C(high) and CD11b(-)/Ly6C(high) osteoclast precursors (OCPs) in the BM of naïve mice nor their in vitro osteoclastogenic potential as indicated by comparable mRNA expression of osteoclast markers. Addition of oxLDL, but not LDL, to pre-osteoclasts from day 3 and mature osteoclasts from day 6 of osteoclastogenesis strongly reduced the number of TRAP(+) osteoclasts and their resorptive capacity. This coincided with a decreased expression of various osteoclast markers. Interestingly, oxLDL significantly lowered the expression of osteoclast-associated receptor (Oscar) and the DNAX adaptor protein-12 encoding gene Tyrobp, which regulate the immunoreceptor tyrosine-based activation motif (ITAM) co-stimulation pathway that is strongly involved in osteoclastogenesis. Collectively, our findings suggest that under inflammatory conditions in the joint, high LDL levels lessen bone destruction during AIA, probably by formation of oxLDL that inhibits osteoclast formation and activity through modulation of the ITAM-signaling.
31918027 Understanding the immunopathogenesis of autoimmune diseases by animal studies using gene m 2020 Mar Autoimmune diseases are clinical syndromes that result from pathogenic inflammatory responses driven by inadequate immune activation by T- and B-cells. Although the exact mechanisms of autoimmune diseases are still elusive, genetic factors also play an important role in the pathogenesis. Recently, with the advancement of understanding of the immunological and molecular basis of autoimmune diseases, gene modulation has become a potential approach for the tailored treatment of autoimmune disorders. Gene modulation can be applied to regulate the levels of interleukins (IL), tumor necrosis factor (TNF), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), interferon-γ and other inflammatory cytokines by inhibiting these cytokine expressions using short interfering ribonucleic acid (siRNA) or by inhibiting cytokine signaling using small molecules. In addition, gene modulation delivering anti-inflammatory cytokines or cytokine antagonists showed effectiveness in regulating autoimmunity. In this review, we summarize the potential target genes for gene or immunomodulation in autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD) and multiple sclerosis (MS). This article will give a new perspective on understanding immunopathogenesis of autoimmune diseases not only in animals but also in human. Emerging approaches to investigate cytokine regulation through gene modulation may be a potential approach for the tailored immunomodulation of some autoimmune diseases near in the future.
32301420 Ultrasound measurement of muscle thickness at the proximal forearm in a rheumatologic sett 2020 Sep OBJECTIVES: To provide a detailed description of the ultrasound (US) scanning protocol to measure the muscle thickness in the forearm and to test its feasibility and interobserver reliability. METHODS: Four rheumatologists trained in musculoskeletal US carried out the examinations in 45 subjects (30 consecutively enrolled patients and 15 healthy subjects). Each of the four rheumatologists took two measurements of each forearm (radial muscle thickness and ulnar muscle thickness) and the time needed to complete the bilateral US assessment was recorded. RESULTS: The mean time required to acquire all measurements in each subject was less than four minutes. We found an excellent interobserver reliability of the proposed scanning protocol, with an intraclass correlation coefficient (ICC) among the four sonographers of 0.97 (CI 0.95-0.98) for the right ulnar muscle thickness, an ICC of 0.97 (CI 0.94-0.98) for the left ulnar muscle thickness, an ICC of 0.93 (CI 0.89-0.96) for the right radial muscle thickness and an ICC of 0.95 (CI 0.91-0.97) for the left radial muscle thickness. CONCLUSIONS: The results of this study provide evidence in favour of interobserver reliability and feasibility of US measurement of the forearm muscle thickness.
31312844 Long-term safety of sarilumab in rheumatoid arthritis: an integrated analysis with up to 7 2020 Feb 1 OBJECTIVE: Sarilumab is a human monoclonal antibody that blocks IL-6 from binding to membrane-bound and soluble IL-6 receptor-α. We assessed the long-term safety of sarilumab in patients from eight clinical trials and their open-label extensions. METHODS: Data were pooled from patients with rheumatoid arthritis who received at least one dose of sarilumab in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; combination group) or as monotherapy (monotherapy group). Treatment-emergent adverse events (AEs) and AEs and laboratory values of special interest were assessed. RESULTS: 2887 patients received sarilumab in combination with csDMARDs and 471 patients received sarilumab monotherapy, with mean exposure of 2.8 years and 1.7 years, maximum exposure 7.3 and 3.5 years, and cumulative AE observation period of 8188 and 812 patient-years, respectively. Incidence rates per 100 patient-years in the combination and monotherapy groups, respectively, were 9.4 and 6.7 for serious AEs, 3.7 and 1.0 for serious infections, 0.6 and 0.5 for herpes zoster (no cases were disseminated), 0.1 and 0 for gastrointestinal perforations, 0.5 and 0.2 for major adverse cardiovascular events, and 0.7 and 0.6 for malignancy. Absolute neutrophil counts <1000 cells/mm3 were recorded in 13% and 15% of patients, respectively. Neutropenia was not associated with increased risk of infection or serious infection. Analysis by 6-month interval showed no signal for increased rate of any AE over time. CONCLUSION: The long-term safety profile of sarilumab, either in combination with csDMARDs or as monotherapy, remained stable and consistent with the anticipated profile of a molecule that inhibits IL6 signalling.
32039569 Evaluation of Financial Conflicts of Interest Among Physician-Authors of American College 2020 Sep OBJECTIVE: Clinical practice guidelines (CPGs) underpin patient care, and ideally authors of these guidelines would be free from outside influence. However, it has been shown many times that authors of professional society CPGs receive large sums of money from industry drug companies, creating financial conflicts of interest. This study investigated industry payments catalogued in the Open Payments Database (OPD) that have been received by authors of the American College of Rheumatology (ACR) CPGs. METHODS: Guidelines on the ACR web site that were published during or after August 2014 were used to retrieve the list of authors. All general, research, associated research, and ownership payments reported on the OPD between the date of publication of the CPG and 12 months prior were extracted in a parallel and blinded manner by 2 investigators. RESULTS: Of the 89 US-based physician-authors from the 5 ACR CPGs identified within the study timeframe, 56 (62.9%) had received at least 1 payment according to OPD records. These 56 authors had received a median of $522 (interquartile range $119-2,500), which, combined, was a total of $9,728,751. Nineteen authors had received at least 1 industry payment relevant to the CPG recommendations, for a median amount of $748 and a total of $1,961,362 in relevant payments. Of the total relevant payments received, a significant proportion was undisclosed (for ACR CPGs during or after August 2014, undisclosed payments were $699,561, or 35.7% of the total). CONCLUSION: Fewer than one-half of the US-based physician-authors of ACR CPGs during or after August 2014 had received guideline-relevant industry payments. Nonetheless, a substantial proportion of the money received was not disclosed. Conflict of interest disclosure is a bare minimum requirement, and more permanent solutions may include divestiture or inclusion of more nonconflicted authors.
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.
31850514 Presence, function, and regulation of IL-17F-expressing human CD4(+) T cells. 2020 Apr The pro-inflammatory cytokine IL-17A has been implicated in the immunopathology of inflammatory arthritis. IL-17F bears 50% homology to IL-17A and has recently been suggested to play a role in inflammation. We investigated the induction and cytokine profile of IL-17F(+) CD4(+) T cells, and how IL-17F may contribute to inflammation. Upon culture of healthy donor CD4(+) T cells with IL-1β, IL-23, anti-CD3, and anti-CD28 mAb, both IL-17A and IL-17F-expressing cells were detected. In comparison to IL-17A(+) IL-17F(-) CD4(+) T cells, IL-17F(+) IL-17A(-) and IL-17A(+) IL-17F(+) CD4(+) T cells contained lower proportions of IL-10-expressing and GM-CSF-expressing cells and higher proportions of IFN-γ-expressing cells. Titration of anti-CD28 mAb revealed that strong co-stimulation increased IL-17F(+) IL-17A(-) and IL-17A(+) IL-17F(+) CD4(+) T cell frequencies, whereas IL-17A(+) IL-17F(-) CD4(+) T cell frequencies decreased. This was partly mediated via an IL-2-dependent mechanism. Addition of IL-17A, IL-17F, and TNF-α to synovial fibroblasts from patients with inflammatory arthritis resulted in significant production of IL-6 and IL-8, which was reduced to a larger extent by combined blockade of IL-17A and IL-17F than blockade of IL-17A alone. Our data indicate that IL-17A and IL-17F are differentially regulated upon T cell co-stimulation, and that dual blockade of IL-17A and IL-17F reduces inflammation more effectively than IL-17A blockade alone.
32999492 Revisiting the cardiovascular risk of hydroxychloroquine in RA. 2020 Dec Cardiac toxicity can be induced by hydroxychloroquine, especially when used in combination with azithromycin. Interest in hydroxychloroquine and azithromycin as potential therapies for COVID-19 has renewed concerns about the possible cardiovascular risk these drugs present to patients with rheumatoid arthritis.
33327323 Arthroscopic treatment of a lipoma arborescens of the elbow: A case report. 2020 Dec 11 INTRODUCTION: Lipoma Arborescens is a rare pathology that mainly affects the knee. Occurrences in the elbow are even more uncommon and mainly involve the bicipitoradial bursa. CASE'S DESCRIPTION: We describe the case of a 54-year-old patient known for rheumatoid arthritis, who consulted for chronic elbow pain associated with swelling and limited extension. DIAGNOSIS: The diagnosis of a lipoma arborescens of the elbow involving the whole joint was made using magnetic resonance imaging and confirmed during arthroscopy. INTERVENTIONS: After a failed nonoperative treatment consisting in intra-articular cortisone injections and physiotherapy, the patient underwent arthroscopic synovectomy and arthrolysis. OUTCOME: At 1-year follow-up, he reported no pain, satisfactory range of motion, and major improvements in clinical scores. CONCLUSION: This is the first illustrated case report about lipoma arborescens involving the whole elbow joint. Even though it is a rare disease, awareness of its presentation, imaging patterns, and treatment options is therefore important for clinicians, radiologists, and surgeons. In this case, arthroscopic treatment resulted in satisfactory and long-lasting pain relief and functional results. It may be considered as a safe and effective option in case of failed nonoperative measures.