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ID PMID Title PublicationDate abstract
31199818 Immunoglobulin G structure and rheumatoid factor epitopes. 2019 Antibodies are important for immunity and exist in several classes (IgM, IgD, IgA, IgG, IgE). They are composed of symmetric dimeric molecules with two antigen binding regions (Fab) and a constant part (Fc), usually depicted as Y-shaped molecules. Rheumatoid factors found in patients with rheumatoid arthritis are autoantibodies binding to IgG and paradoxically appear to circulate in blood alongside with their antigen (IgG) without reacting with it. Here, it is shown that rheumatoid factors do not react with native IgG in solution, and that their epitopes only become accessible upon certain physico-chemical treatments (e.g. heat treatment at 57 °C), by physical adsorption on a hydrophobic surface or by antigen binding. Moreover, chemical cross-linking in combination with mass spectrometry showed that the native state of IgG is a compact (closed) form and that the Fab parts of IgG shield the Fc region and thereby control access of rheumatoid factors and presumably also some effector functions. It can be inferred that antibody binding to pathogen surfaces induces a conformational change, which exposes the Fc part with its effector sites and rheumatoid factor epitopes. This has strong implications for understanding antibody structure and physiology and necessitates a conceptual reformulation of IgG models.
30403262 Evaluation of toxic retinopathy caused by antimalarial medications with spectral domain op 2019 Jan PURPOSE: To investigate the frequency of toxic retinopathy in patients with lupus erythematosus and rheumatoid arthritis with long-term use of chloroquine diphosphate or hydroxychloroquine through spectral domain optical coherence tomography and the outcomes of ophthalmological exams (visual acuity - Snellen's table, color vision test - Ishihara's table, fundoscopy, and retinography - red-free). METHODS: A cross-sectional study was carried out involving the ophthalmologic evaluation of patients using regular chloroquine diphosphate or hydroxychloroquine for a period of 1 year or longer. The patients completed a questionnaire on their opinions and treatment regularity. The same patients underwent ophthalmologic examination and spectral domain optical coherence tomography. RESULTS: The prevalence of toxic retinopathy caused by antimalarials was 4.15% (9 of 217 patients), 7.4% (4 of 54 patients) following chloroquine diphosphate usage, and 0.82% (1 of 121 patients) following hydroxychloroquine usage. Only patients with advanced stage maculopathy presented abnormalities during the ophthalmologic exam: the color vision test was altered in 11.1%, and visual acuity and fundoscopy were altered in 33.3%. Identification of early toxic retinopathy, detected in six patients, was possible using spectral domain optical coherence tomography. The mean duration of antimalarial drug usage among patients with toxic retinopathy was 10.4 years. Only 31% of the patients reported some symptoms during treatment, and although 24% were afraid to use the medication, they did so as prescribed. CONCLUSION: Use of spectral domain optical coherence tomography was essential for the diagnosis of early-stage antimalarial toxic retinopathy in patients with the following characteristics: asymptomatic, antimalarial use 7 days a week for a period of more than 5 years, and normal clinical ophthalmologic examination.
31783773 Associations between certolizumab pegol serum levels, anti-drug antibodies and treatment r 2019 Nov 29 OBJECTIVES: To identify a therapeutic target interval for certolizumab pegol drug levels and examine the influence of anti-drug antibodies in patients with inflammatory joint diseases. METHODS: Certolizumab pegol and anti-drug antibody levels were measured in serum samples collected after 3 months of certolizumab pegol treatment in 268 patients with inflammatory joint diseases (116 axial spondyloarthritis, 91 rheumatoid arthritis and 61 psoriatic arthritis) in the NOR-DMARD study. Treatment response was defined by Ankylosing Spondylitis Disease Activity Score Clinically important improvement in axial spondyloarthritis, European League Against Rheumatism good/moderate response in rheumatoid arthritis, and improvement in 28-joint Disease Activity Score of ≥ 0.6 in PsA. Serum drug levels and anti-drug antibodies were analysed using automated in-house assays. RESULTS: Certolizumab pegol serum levels varied considerably between individuals (median (IQR) 32.9 (17.3-43.9) mg/L). Certolizumab pegol level ≥ 20 mg/L was associated with treatment response for the total inflammatory joint disease population, with odds ratio (OR) 2.3 (95% CI 1.2-4.5, P = 0.01) and OR 1.9 (95% CI 1.0-3.5, P = 0.05) after 3 and 6 months of treatment, respectively. For individual diagnoses, this association was most consistent for axial spondyloarthritis, with OR 3.4 (95% CI 1.0-11.1, P < 0.05) and OR 3.3 (95% CI 1.0-10.8, P < 0.05), respectively. Certolizumab pegol level > 40 mg/L was not associated with any additional benefit for any of the diagnoses. Anti-drug antibodies were detected in 6.1% (19/310) of samples and were associated with low certolizumab pegol levels (P < 0.01). CONCLUSIONS: Serum certolizumab pegol levels 20-40 mg/L were associated with treatment response in inflammatory joint diseases. Our study is the first to show this association in axial spondyloarthritis and psoriatic arthritis patients. The results suggest a possible benefit of therapeutic drug monitoring in patients with inflammatory joint disease on certolizumab pegol treatment. TRIAL REGISTRATION: NCT01581294, April 2012.
30864525 Pharmacological Aspects and Potential Use of Phloretin: A Systemic Review. 2019 Over the past two decades, many researchers have concluded that a diet rich in polyphenolic compounds plays an important therapeutic role in reducing the risk of cancer, cardiovascular disease, inflammation, diabetes, and other degenerative diseases. Polyphenolic compounds have been reported to be involved in neutralization of reactive oxygen species and charged radicals, and have anticarcinogenic effects, hepatoprotective effects, low-glycaemic response, and other benefits. The benefits of fruits and vegetables may be partly attributable to polyphenolic compounds, which have antioxidant and free radical scavenging properties. Fruits such as apples contain a variety of phytochemicals, including (+)-catechin and (-)-epicatechin, phlorizin, phloretin quercetin, cyanidin-3-Ogalactoside, chlorogenic acid, and p-coumaric acid, all of which are strong antioxidants. Phloretin, a natural phenolic compound, is a dihydrochalcone, which is present in the apple. It exhibits a wide variety of activities such as antioxidative, anti-inflammatory, anti-microbial, anti-allergic, anticarcinogenic, anti-thrombotic, and hepatoprotective, besides being involved in the activation of apoptotic associated gene expression and signal transduction in molecular pathways. Despite a multitude of clinical studies, new efforts are needed in clinical research to determine the complete therapeutic potential of phloretin.
31197255 Macrophages are the primary effector cells in IL-7-induced arthritis. 2020 Jul Synovial macrophages are crucial in the development of joint inflammation and bone damage; however, the pathways that control macrophage remodeling in inflammatory M1 cells or bone-eroding osteoclasts are not fully understood. We determined that elevated IL-7R/CD127 expression is the hallmark of rheumatoid arthritis (RA) M1 macrophages and that these cells are highly responsive to interleukin-7 (IL-7)-driven osteoclastogenesis. We established that lipopolysaccharide (LPS), interferon-γ (IFNγ), and tumor necrosis factor-α (TNFα), the classic M1 macrophage mediators, enhance IL-7R expression in RA and murine macrophages. The local expression of IL-7 provokes arthritis, predominantly through escalating the number of F480(+)iNOS(+) cells rather than CD3(+) T cells. Ectopic LPS injection stabilizes IL-7-induced arthritis by increasing myeloid IL-7R expression, in part via IFNγ induction. Hence, in RAG-/- mice, IL-7-mediated arthritis is suppressed because of the reduction in myeloid IL-7R expression due to the lack of IFNγ. Moreover, the amelioration of IL-7-induced arthritis by anti-TNF therapy is due to a decrease in the number of cells in the unique F480(+)iNOS(+)IL-7R(+)CCL5(+) subset, with no impact on the F480(+)Arginase(+) cell or CD3(+) T cell frequency. Consistent with the preclinical findings, the findings of a phase 4 study performed with RA patients following 6 months of anti-TNF therapy revealed that IL-7R expression was reduced without affecting the levels of IL-7. This study shifts the paradigm by discovering that IL-7-induced arthritis is dependent on F480(+)iNOS(+)IL-7R(+)CCL5(+) cell function, which activates TH-1 cells to amplify myeloid IL-7R expression and disease severity.
31601476 Complement C1q synergizes with PTX3 in promoting NLRP3 inflammasome over-activation and py 2020 Jan Excessive inflammatory cytokines play crucial roles in the pathogenesis of rheumatoid arthritis (RA), however, the underlying mechanism remains unclear. In this study, we demonstrated that pentaxin 3 (PTX3), an essential component of innate immunity, was elevated in RA and preferentially bound to CD14(+) monocytes. C1q promoted the binding and resulted in increased cell proliferation, activation and caspase-1-related late apoptotic cells (7-AAD(+)annexin V(+)), as well as enhanced release of inflammatory cytokines including TNF-α, IL-1β and IL-6. Serum from RA patients, compared with healthy controls, induced gasdermin D (GSDMD)-dependent pyroptosis in monocytes, and this ability was associated with disease activity. Moreover, PTX3 synergized with C1q to promote pyroptosis in RA-serum pre-incubated monocytes by coordinately enhancing NLRP3 inflammasome over-activation and inducing GSDMD cleavage, cell swelling with large bubbles, caspase-1-dependent cell death and inflammatory cytokine release including IL-6. On the other hand, IL-6 promoted PTX3 plus C1q-induced pyroptosis in both normal and RA serum pre-incubated monocytes. These findings collectively implicated an important role of IL-6 in driving PTX3 plus C1q-mediated pyroptosis in RA and shed lights on a potential new treatment strategy targeting pyroptosis-mediated persistent inflammatory cytokine release.
30152202 Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell-Deri 2019 Feb OBJECTIVE: Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross-reactivity. METHODS: IgG-secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full-length mAb (n = 93) and also as germline-reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mAb to promote osteoclastogenesis were investigated. RESULTS: Four unrelated anti-citrullinated protein autoantibodies (ACPAs), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA. The ACPAs recognized >3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients. The plasma cell-derived mAb were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay. CONCLUSION: These findings suggest that the high level of cross-reactivity among RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that RA is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints.
31323410 Clinical Analysis of Radiologic Measurements in Patients with Basilar Invagination. 2019 Nov OBJECTIVE: To investigate correlations between radiologic measurements and clinical outcomes in patients with basilar invagination (BI). METHODS: The medical records and radiologic data of 46 patients (27 women) who had undergone posterior atlantoaxial fusion or occipitocervical fusion for BI from January 2010 to June 2018 were retrospectively analyzed. Patients under 15 years old or with a polytraumatic, tumorous, or infectious pathology were excluded. The modified Ranawat method (MRM) and the Redlund-Johnell method (RJM) were used to obtain radiographic measurements of basilar invagination preoperatively, subacute postoperatively, and at 3-month and last follow-up. Visual analogue scale, Neck Disability Index, and Japanese Orthopedic Association (JOA) scores were also assessed. Correlations between MRM and RJM measurements and clinical outcomes were evaluated. RESULTS: Mean age of patients was 59.9 ± 16.5 years, mean body mass index was 23.5 ± 4.6 kg/m(2), and mean follow-up was 37.9 ± 23.8 months. Postoperative radiologic measurements increased about 36% of preoperative radiologic measurements. Subsidence at the C1-2 joint occurred in most patients at 3 months postoperatively, but clinical outcomes did not deteriorate. JOA scores were linearly correlated with percentage increases in both radiologic measurements subacute postoperatively (P < 0.05), but this significance was not maintained until the last follow-up. Occipital numbness and neuralgia were most common postoperative complications. One case of neurovascular injury and 3 cases of postoperative dysphagia occurred postoperatively. CONCLUSIONS: The subacute postoperative neurological outcomes of BI patients are significantly related to the amount of vertical reduction.
31600634 Effects of ticagrelor, empagliflozin and tamoxifen against experimentally-induced vascular 2019 Dec BACKGROUND: In the current investigation, the effects of the P2Y12 blocker ticagrelor, the sodium/glucose transporter-2-inhibitor empagliflozin, and the selective estrogen receptor modulator tamoxifen were examined against rheumatoid arthritis (RA)/diabetes mellitus (DM)-co-morbidity-induced defects in vascular reactivity. METHODS: After model setting, rats were allocated into a normal control, an RA/DM-co-morbidity, and three treatment groups receiving ticagrelor, empagliflozin and tamoxifen. Aorta tissue was isolated for enzyme-linked immunosorbent assay (ELISA) and western blot estimation of the pro-inflammatory molecules angiotensin-II (Ang-II) and endothelin-1 (ET-1), the adhesion molecules P-selectin and vascular cell adhesion molecule-1 (VCAM-1), the energy preserving molecule adenosine-5'-monophosphate-activated protein kinase (AMPK), and the anti-inflammatory molecule vasoactive intestinal peptide (VIP). Estimations of endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase (MMP)-2 were performed immunohistochemically, together with histopathological examination using hematoxylin and eosin and Masson trichrome staining. An in vitro study on rat aortic strips was conducted to assess aorta vasorelaxation. RESULTS: Ticagrelor, empagliflozin and tamoxifen significantly increased aorta tissue AMPK and eNOS and decreased Ang-II, ET-1, P-selectin, VCAM-1 and VIP levels compared with RA/DM-co-morbidity, coupled with improved acetylcholine vasorelaxation in vitro. CONCLUSION: Ticagrelor, empagliflozin and tamoxifen may correct vascular reactivity defects, where modulation of vascular AMPK, eNOS, Ang-II, ET-1, P-selectin, VCAM-1 and MMP-2 underline their protective effects.
30284646 Imbalance of circulating Tfr/Tfh ratio in patients with rheumatoid arthritis. 2019 Feb Follicular helper T(Tfh) cells and follicular regulatory T(Tfr) cells are critical for the development and maintenance of germinal center and humoral immune responses. Accumulating evidence has demonstrated that the dysregulation of either Tfh or Tfr cells contributes to the pathogenesis of autoimmune diseases. The aim of this study was to examine the numbers of Tfh and Tfr cells in patients with rheumatoid arthritis (RA). Twenty-four patients with RA patients and 20 health controls (HCs) were enrolled in this study. We analyzed the numbers of Tfh (CD4(+) CXCR5(+) PD-1(hi)) cells and Tfr (CD4(+) CXCR5(+)CD127(lo)) cells in 24 RA patients via flow cytometry. The level of the soluble PD-1 and its ligands (sPD-L1 and sPDL-2) were examined by ELISA. Flow cytometry revealed that both circulating Tfh and Tfr cells were increased in RA patients compared with HCs. More importantly, the ratio of Tfr/Tfh was decreased, indicating a disruption of the balance between Tfh and Tfr. The Tfr/Tfh ratio was inversely correlated with level of serum CRP, ESR, RF, anti-CCP, IgG and DAS28 index. We also found that the serum level of sPD-1 was significantly elevated in the RA patients, which was positively correlated with CRP, ESR and the number of Tfh cells. These results indicate that an imbalance of circulating Tfr and Tfh cells may be involved in the immunopathogenesis of RA and may provide novel insight for the development of RA therapies.
30430682 Use of tumor necrosis factor-alpha inhibitors during pregnancy among women who delivered l 2019 Mar PURPOSE: To describe the use of tumor necrosis factor-alpha inhibitors (TNFis) among pregnancies ending in a live birth and with a diagnosis of ankylosing spondylitis (AS), Crohn's disease (CD), juvenile idiopathic arthritis (JIA), psoriasis (PsO), psoriatic arthritis (PsA), rheumatoid arthritis (RA), or ulcerative colitis (UC). METHODS: We identified pregnancies among women aged 15 to 54 years between 01/01/2004 and 09/30/2015 from 16 health plans participating in Sentinel. We inferred indication using ICD-9-CM codes in the 183-day period before conception. We assessed proportion of infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab by calendar year, indication, and maternal age, and compared them to proportions in an age-matched, indication-matched, and date-matched non-pregnant cohort. RESULTS: Among 19 681 pregnancies with at least one chronic inflammatory condition, 2990 (15.2%) received a TNFi. In both pregnancies and matched non-pregnant cohort, TNFi use was highest (34.4%; 55.8%) for PsA patients and lowest (6.2%; 13.4%) for PsO patients. Etanercept was most frequently used among AS/JIA/PsA/PsO/RA patients, while infliximab was the preferred TNFi for CD/UC patients. Except for infliximab and certolizumab, TNFi use during pregnancy decreased after the first trimester. Pregnancies among older pregnant women (45-54 years) were more likely to be treated compared with the matched non-pregnant cohort. CONCLUSION: There was a preference for etanercept among pregnancies with AS/JIA/PsA/PsO/RA, despite the availability of other TNFis. Decline in TNFi use after the first trimester may be related to the desire to reduce TNFis transplacental transfer and to minimize infection risk to the fetus or baby associated with live vaccine immunizations after birth.
30137540 Is joint pain in patients with arthralgia suspicious for progression to rheumatoid arthrit 2019 Jan 1 OBJECTIVES: The development of RA includes a phase of arthralgia preceding clinical arthritis. The aetiology of symptoms of arthralgia is unclear. Since subclinical joint inflammation is expected to be causally related to pain, we aimed to study associations between subclinical MRI-detected inflammation and pain in patients with arthralgia suspicious for progression to RA. METHODS: Unilateral MRIs of the wrist, MCP (2-5) and MTP (1-5) joints of 325 patients who fulfilled the EULAR definition of arthralgia suspicious for progression to RA were scored by two readers on subclinical inflammation (synovitis, bone marrow oedema and tenosynovitis). Associations between MRI-detected inflammation and overall pain severity at patient level (measured using the visual analogue scale), as well as with local joint tenderness, were studied. Analyses were stratified for ACPA. RESULTS: At patient level, synovitis (β = 0.10, P = 0.048) and tenosynovitis (β = 0.11, P = 0.026) associated with the visual analogue scale pain. Of the 1620 imaged joints, 447 (28%) were tender. MRI-detected synovitis associated independently with joint tenderness in all patients (odds ratio 1.74, P < 0.001), and in the ACPA-negative stratum (odds ratio 1.96, P < 0.001). In the ACPA-positive stratum only bone marrow oedema (osteitis) was independently associated with tenderness (odds ratio 2.39, P = 0.005). Sensitivity analyses in patients who developed inflammatory arthritis during follow-up (n = 61) revealed similar associations. Subclinical inflammation was present in 51% of tender joints and 39% of non-tender joints. CONCLUSION: In patients with arthralgia suspicious for progression to RA, MRI-detected subclinical inflammation is associated with overall pain and local joint tenderness. However, the association is partial, indicating that subclinical inflammation is not the sole explanation of the arthralgia.
31196979 Cartilage-binding antibodies induce pain through immune complex-mediated activation of neu 2019 Aug 5 Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.
31651120 Importance of 14-3-3eta, anti-CarP, and anti-Sa in the diagnosis of seronegative rheumatoi 2019 Oct 24 BACKGROUND/AIM: Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation. The study aimed to assess serum 14-3-3eta, anti-CarP, and anti-Sa in seronegative RA (SNRA) patients who were treatment-naïve as well as in healthy subjects. This is the first study in the literature to examine these autoantibodies together in SNRA patients. MATERIALS AND METHODS: Forty-five treatment-naïve SNRA patients and 45 healthy subjects were recruited. Drugs change the levels of autoantibodies; therefore, patients who took any medication had been excluded from our study. Anti-carbamylated protein, anti-Sa, and 14-3-3eta were measured by using three different ELISA kits. RESULTS: Median serum concentration of healthy controls in 14-3-3eta was 0.02 (0.02–0.27) ng/mL. Median serum concentration of SNRA patients in 14-3-3eta was 1.00 (0.48–1.28) ng/mL. Data were analyzed with Mann–Whitney U tests; the P-value was <0.001 in 14-3-3eta. Receiver operating characteristic (ROC) curve analysis showed that 14-3-3eta in SNR compared to healthy controls had a significant (P < 0.001) area under the curve (AUC) of 0.90 (95% confidence interval, 0.83–0.96). At a cutoff of ≥0.33 ng/mL, the ROC curve yielded a sensitivity of 88.9%, a specificity of 82.2%, a positive predictive value of 83.3%, and a negative predictive value of 88.1%. CONCLUSION: We found that 14-3-3eta can be used as a diagnostic marker in SNRA.
31061053 Trends in the costs of drugs launched in the UK between 1981 and 2015: an analysis of the 2019 May 5 OBJECTIVES: To investigate the trend in the launch price of new drugs for five common health conditions. DESIGN: Cross-sectional study using data on new drugs launched in the UK between 1981 and 2015 for hypertension, asthma, rheumatoid arthritis, schizophrenia and colorectal cancer. DATA AND SOURCES: All drugs marketed in the UK between 1981 and 2015 (inclusive), and licensed specifically for the treatment of one of the five chosen conditions were included in the study. Newly launched medicines and their launch prices were identified by hand-searching all editions of the British National Formulary in addition to searching the websites of relevant regulatory agencies (European Medicines Agency and Medicines and Healthcare products Regulatory Agency). The launch price in UK pounds for a 28-day supply of each medicine at a typical or usual maintenance dose was adjusted for the effects of general inflation using the gross domestic product deflator series. RESULTS: 104 drugs were included in our study with a mean inflation-adjusted 28-day launch price of £288 (SD £678). The launch price of new drugs varied significantly across the five conditions, with drugs for hypertension having the lowest mean price (£27) and drugs for colorectal cancer having the highest mean price (£1590) (p<0.001). There were large increases in launch prices across the study period, but the magnitude and pattern was markedly different between therapeutic areas. Biological drugs represented 13.5% of all included drugs and had a significantly higher launch price than non- biological drugs (£1233 vs £141, p<0.001). 22.1% of included drugs were first-of-kind and had a significantly higher launch price than follow-on drugs (£768 vs £151) (p<0.0001). CONCLUSION: Drugs prices continue to increase across different therapeutic areas. This has some association with novelty, but, it is not clear if this increase in price is associated with medical benefits.
30676860 High dose hepatitis B vaccine is not effective in patients using immunomodulatory drugs: a 2019 In patients undergoing immunotherapy, the quality of the immune response is reduced, which may negatively affect the efficacy of vaccination. This study was conducted in order to evaluate the efficacy of the hepatitis B virus (HBV) vaccine in patients using immunomodulators. Seronegative patients for HBV who were using biological agents, were included in the study. The vaccination was administered on the standard schedule in 3 doses of 20 or 40 µg/ml. Eighty-two patients (52%) were males and the mean age of all patients was 44,8 ± 10,3 years. Among these 109 patients, 83 had psoriasis, 12 had Crohn's disease, six had rheumatoid arthritis, three had ulcerative colitis, three had hydradenitis supurativa, one had Behcet's disease and one had ankylosing spondylitis. The biological agents that were being used by these patients were adalimumab (62), ustekinumab (25), infliximab (12), etanercept (9) and golimumab (1). Seventy-three of the patients were vaccinated with a dose of 20 µg/ml and 36 with 40 µg/ml. The anti-HBs titers of fifty-eight (53.2%) patients were above 10 mIU/ml. The antibody response rate was lowest in infliximab-users (16.7%) (p = 0.007), which was followed by adalimumab (48.4%), and higher protection rates were achieved in patients using ustekinumab and etanercept (72% and 88.9%, respectively; p < 0.05). The HBV vaccine response rate in patients using immunomodulators was significantly lower than that in immunocompetent patients. Furthermore, high dose vaccination did not increase the response rate. Clinicians should take into account administering HBV vaccination before treatment with biological agent in patients who have negative HBV serology.
31199978 Lipidoid-polymer hybrid nanoparticles loaded with TNF siRNA suppress inflammation after in 2019 Sep Rheumatoid arthritis (RA) is a common autoimmune disease, which is characterized by painful chronic inflammation in the joints, and novel safe and efficacious treatments are urgently needed. RNA interference (RNAi) therapy based on small interfering RNA (siRNA) is a promising approach for silencing specific genes involved in inflammation. However, delivery of siRNA to the target site, i.e. the cytosol of immune cells, is a challenge. Here, we designed lipid-polymer hybrid nanoparticles (LPNs) composed of lipidoid and poly(DL-lactic-co-glycolic acid) loaded with a therapeutic cargo siRNA directed against the proinflammatory cytokine tumor necrosis factor (TNF), which plays a key role in the progression of RA. We compared their efficacy and safety with reference lipidoid-based stable nucleic acid lipid particles (SNALPs) in vitro and in vivo. Cryogenic transmission electron microscopy, atomic force microscopy and small-angle X-ray scattering revealed that the mode of loading of siRNA in lamellar structures differs between the two formulations. Thus, siRNA was tightly packed in LPNs, while LPNs displayed lower adhesion than SNALPs. The LPNs mediated a higher TNF silencing effect in vitro than SNALPs in the RAW 264.7 macrophage cell line activated with lipopolysaccharide. For both types of delivery systems, macropinocytosis was involved in cellular uptake. In addition, clathrin-mediated endocytosis contributed to uptake of SNALPs. LPNs loaded with TNF siRNA mediated sequence-specific suppression of inflammation in a murine experimental arthritis model upon intra-articular administration. Hence, the present study demonstrates that LPN-mediated TNF knockdown constitutes a promising approach for arthritis therapy of TNF-mediated chronic inflammatory conditions.
31244929 Imaging fibrosis in inflammatory diseases: targeting the exposed extracellular matrix. 2019 In a variety of diseases, from benign to life-threatening ones, inflammation plays a major role. Monitoring the intensity and extent of a multifaceted inflammatory process has become a cornerstone in diagnostics and therapy monitoring. However, the current tools lack the ability to provide insight into one of its most crucial aspects, namely, the alteration of the extracellular matrix (ECM). Using a radiolabeled platelet glycoprotein VI-based ECM-targeting fusion protein (GPVI-Fc), we investigated how binding of GPVI-Fc on fibrous tissue could uncover the progression of several inflammatory disease models at different stages (rheumatoid arthritis, cutaneous delayed-type hypersensitivity, lung inflammation and experimental autoimmune encephalomyelitis). Methods: The fusion protein GPVI-Fc was covalently linked to 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and subsequently labeled with (64)Cu. We analyzed noninvasively in vivo (64)Cu-GPVI-Fc accumulation in murine cutaneous delayed-type hypersensitivity, anti-glucose-6-phosphate isomerase serum-induced rheumatoid arthritis, lipopolysaccharide-induced lung inflammation and an experimental autoimmune encephalomyelitis model. Static and dynamic Positron Emission Tomography (PET) of the radiotracer distribution was performed in vivo, with ex vivo autoradiography confirmation, yielding quantitative accumulation and a distribution map of (64)Cu-GPVI-Fc. Ex vivo tissue histological staining was performed on harvested samples to highlight the fusion protein binding to collagen I, II and III, fibronectin and fibrinogen as well as the morphology of excised tissue. Results: (64)Cu-GPVI-Fc showed a several-fold increased uptake in inflamed tissue compared to control tissue, particularly in the RA model, with a peak 24 h after radiotracer injection of up to half the injected dose. Blocking and isotype control experiments indicated a target-driven accumulation of the radiotracer in the case of chronic inflammation. Histological analysis confirmed a prolonged accumulation at the inflammation site, with a pronounced colocalization with the different components of the ECM (collagen III and fibronectin notably). Binding of the fusion protein appeared to be specific to the ECM but unspecific to particular components. Conclusion: Imaging of (64)Cu-GPVI-Fc accumulation in the ECM matrix appears to be a promising candidate for monitoring chronic inflammation. By binding to exposed fibrous tissue (collagen, fibronectin, etc.) after extravasation, a new insight is provided into the fibrotic events resulting from a prolonged inflammatory state.
30893553 Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Se 2019 Apr 11 Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.
31245305 Dynamic Alterations in the Gut Microbiota of Collagen-Induced Arthritis Rats Following the 2019 Rheumatoid arthritis (RA) is a common autoimmune disease linked to chronic inflammation. Dysbiosis of the gut microbiota has been proposed to contribute to the risk of RA, and a large number of researchers have investigated the gut-joint axis hypothesis using the collagen-induced arthritis (CIA) rats. However, previous studies mainly involved short-term experiments; very few used the CIA model to investigate changes in gut microbiota over time. Moreover, previous research failed to use the CIA model to carry out detailed investigations of the effects of drug treatments upon inflammation in the joints, hyperplasia of the synovium, imbalance in the ratios of Th1/Th2 and Th17/Treg cells, intestinal cytokines and the gut microbiota following long-term intervention. In the present study, we carried out a 16-week experiment to investigate changes in the gut microbiota of CIA rats, and evaluated the modulatory effect of total glucosides of paeony (TGP), an immunomodulatory agent widely used in the treatment of RA, after 12 weeks of administration. We found that taxonomic differences developed in the microbial structure between the CIA group and the Control group. Furthermore, the administration of TGP was able to correct 78% of these taxonomic differences, while also increase the relative abundance of certain forms of beneficial symbiotic bacteria. By the end of the experiment, TGP had reduced body weight, thymus index and inflammatory cell infiltration in the ankle joint of CIA rats. Furthermore, the administration of TGP had down-regulated the synovial content of VEGF and the levels of Th1 cells and Th17 cells in CIA rats, and up-regulated the levels of Th2 cells and Treg cells. The administration of TGP also inhibited the levels of intestinal cytokines, secretory immunoglobulin A (SIgA) and Interferon-γ (IFN-γ). In conclusion, the influence of TGP on dynamic changes in gut microbiota, along with the observed improvement of indicators related to CIA symptoms during 12 weeks of administration, supported the hypothesis that the microbiome may play a role in TGP-mediated therapeutic effects in CIA rats. The present study also indicated that the mechanism underlying these effects may be related to the regulation of intestinal mucosal immunity remains unknown and deserves further research attention.