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ID PMID Title PublicationDate abstract
31777801 Safety of Abatacept Versus Placebo in Rheumatoid Arthritis: Integrated Data Analysis of Ni 2019 Jun OBJECTIVE: To assess the safety of abatacept treatment in rheumatoid arthritis (RA) using integrated data from multiple clinical trials. METHODS: Data from nine double-blind, placebo-controlled studies of abatacept treatment (seven intravenous, two subcutaneous) in patients with RA were pooled, focusing on safety events in the double-blind treatment period of each study. Incidence rates (IRs) of adverse events (AEs) per 100 patient-years of exposure were calculated for abatacept- and placebo-treated patients. AEs in abatacept-treated patients were combined regardless of dose and formulation. RESULTS: In total, 2653 patients received abatacept and 1485 received placebo, with 2357 and 1254 patient-years of exposure, respectively. The mean (SD) durations of exposure in the abatacept and placebo groups were 10.8 (3.3) and 10.3 (3.5) months, respectively. The IRs (95% confidence interval [CI]) for serious AEs were 14.8 (13.3, 16.5) and 14.6 (12.5, 17.0) in the abatacept and placebo groups, respectively. Death occurred in 12 (0.5%) and 12 (0.8%) patients in the abatacept and placebo groups, respectively, and was most commonly caused by cardiac disorders. Malignancies were observed in 31 patients (1.2%) treated with abatacept (IR: 1.32 [95% CI: 0.90, 1.87]) versus 14 (0.9%; IR: 1.12 [0.61, 1.88]) who received placebo. Solid organ tumor was the most frequent malignancy reported in both groups (abatacept: 1.0%; IR: 1.11 [95% CI: 0.72, 1.62]; placebo: 0.8%; 0.96 [0.50, 1.67]). CONCLUSION: In this integrated analysis, the IRs of safety events in the abatacept and placebo groups were similar with no new safety concerns identified.
31625621 Free prednisolone pharmacokinetics predicted from total concentrations in patients with in 2020 Apr Prednisone is an anti-inflammatory drug widely used in internal medicine and rheumatology, but dosing remains empirical. The active metabolite of prednisone is free prednisolone. The aim of this work was to build a population pharmacokinetic (PK) model that can predict free prednisolone concentrations in patients with inflammatory/immunologic conditions.A total of 107 patients from the department of internal medicine of Cochin hospital provided 343 observations. Blood samples drawn for biological analyses were used for drug determination. Total plasma prednisolone concentrations were measured by liquid chromatography-mass spectrometry, and the data were modelled using Monolix. The pharmacokinetics was ascribed a one-compartment open model with three transit compartments standing for the absorption and metabolism process. The model used predicts free concentrations that served to derive total concentrations given published binding constants. Only size parameters influenced the pharmacokinetics. Free prednisolone CL(U) /F and V(U) /F, scaled allometrically on lean body weight, were, respectively, 26.7 L/h and 94.3 L for 50 kg LBW. CL(U) /F interindividual variability was 0.20. The additive and proportional residual variabilities were, respectively, 4.3 µg/L and 0.20. The results point out some dosing issues, that is the possibility of under- or over-dosage in thin or overweight patients respectively.
31179106 Acute exacerbation of interstitial lung diseases secondary to systemic rheumatic diseases: 2019 Apr Acute exacerbation (AE) is a possible manifestation of interstitial lung diseases (ILD) associated to very high mortality. It's defined as clinically significant respiratory deterioration with evidence of new widespread alveolar abnormalities on computed tomography scan. AE is better described in idiopathic pulmonary fibrosis (IPF) but also reported in ILD secondary to connective tissue diseases (CTD) and vasculitis. The main features and the real clinical impact of this severe complication in these patients are not well defined. Aim of our study was to prospectively investigate the incidence, clinical features and outcome of AE in a population of patients with ILD related to CTD and vasculitis. We consecutively enrolled all patients, with ILD secondary to rheumatic systemic diseases, referring to our multidisciplinary outpatient clinic for rare lung diseases. All patients were followed for at least 12 months (range, 12-36 months). At baseline, all patients underwent to a core set of laboratory investigations and periodically followed; data about demographic, disease onset, clinical, serological and therapeutic features were also recorded. AE occurred in 9/78 patients, with an incidence of 5.77/100 patients/year, and 5/9 patients died because of AE. The baseline value of DLCO was significantly associated to the risk of AE at Cox regression. In patients with ILD related to rheumatic systemic diseases AE can occur with an incidence similar to IPF. Rheumatologists should carefully consider this life-threatening complication as a possible natural course of all patients with ILD secondary to systemic rheumatic disease.
30451655 A single-arm, open-label study to assess the immunogenicity, safety, and efficacy of etane 2019 Jan OBJECTIVE: To evaluate the immunogenicity, safety, and efficacy of etanercept (ETN) manufactured using the serum-free, high-capacity manufacturing (SFHCM) process in patients with rheumatoid arthritis (RA). METHODS: In this global, multicenter, open-label, single-arm study (NCT02378506), 187 adult patients with moderate to severe RA received ETN 50 mg once weekly for 24 weeks manufactured using the SFHCM process. Immunogenicity (presence of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs)) was assessed at 12 and 24 weeks. Safety and efficacy were evaluated at 4, 12, and 24 weeks. RESULTS: Eight (4.5%) patients tested positive for ADA, and there were no NAbs detected at any time throughout the study. Ninety (48.1%) patients reported treatment-emergent adverse events (AEs), of which 27 (14.4%) reported injection-site reactions, and 43 (23.0%) reported infections. The majority of AEs were mild or moderate in severity, and the drug was well tolerated. Throughout the duration of the study (week 4 to week 24), there was a progressive increase in the American College of Rheumatology (ACR)-defined responses (ACR20: 55.9%-82.0%, ACR50: 16.1%-57.8%, and ACR70: 3.2%-26.7%) from baseline and the proportion of patients achieving low disease activity and remission, with a corresponding decrease in measures of disease activity. CONCLUSION: The immunogenicity, safety, and efficacy of ETN manufactured using the SFHCM process were similar to the current approved ETN formulation. ClinicalTrials.gov registration: NCT02378506.
30268770 The role of flavonoids in autoimmune diseases: Therapeutic updates. 2019 Feb Flavonoids are natural polyphenolic compounds which are included in a panoply of drugs and used to treat and/or manage human ailments such as metabolic, cardiovascular, neurological disorders and cancer. Thus, the purpose of this review is to emphasize the importance of flavonoids for the treatment of autoimmune diseases and put into the limelight of the scientific community several health-promoting effects of flavonoids which could be beneficial for the development of novel drugs from natural products. Despite available reviews on flavonoids targeting various disease conditions, a comprehensive review of flavonoids for autoimmune diseases is still lacking. To the best of our knowledge, this is the first attempt to review the potential of flavonoids for autoimmune diseases. The structure-activity relationship of flavonoids in this review revealed that the rearrangement and introduction of other functional groups into the basic skeleton of flavonoids might lead to the development of new drugs which will be helpful in relieving the painful symptoms of various autoimmune diseases.
30996811 Selective Inhibitors of T Cell Receptor Recognition of Antigen-MHC Complexes for Rheumatoi 2019 Apr 11 Autoreactive T cells specific to human collagen type II have a crucial role in the development of rheumatoid arthritis (RA) in the context of MHC class II allele HLA-DRB1-*04. The protein-protein interactions between the T cell receptor (TCR) and the type II collagen bound to the allele MHC of class II may thus represent the target for the development of new drugs against RA. In this study, a structure-based pharmacophore model for potential small molecule inhibitors was developed from protein-protein interface structure. The 3D model obtained was used for a virtual screening workflow, which resulted in three hits for experimental follow up. Three compounds have been identified that interfere with the TCR/collagenII-MHCII (K (i) values below 10 μM) and open up new possibilities in the treatment of RA.
31191532 Discrepancy of Serological and Molecular Patterns of Circulating Epstein-Barr Virus Reacti 2019 Primary Sjögren's syndrome (pSS) is characterized by B cell hyperactivation, production of autoantibodies and increased risk of B cell lymphomas. Serological profile of Epstein-Barr virus (EBV) reactivation and increase EBV DNA levels in exocrine glands are observed in pSS, but whether these abnormalities are accompanied with disturbed systemic EBV control or have any association with pSS activity remains to be investigated. In this observational study, we initially explored anti-EBV antibodies and cell-free DNA in 395 samples from a cross-sectional plasma collection of pSS patients included in ASSESS French national cohort. Results were assessed in relation with disease activity. Further, to assess cell-associated EBV DNA we organized a case-control study including 20 blood samples from pSS patients followed in University Hospital Center of Montpellier. Results were compared with matched controls. Robust response against EBV early antigen (EA) was observed in pSS patients with anti-SSA/B (Sjögren's syndrome A and B) and anti-SSA autoantibodies compared to anti-SSA/B negatives (P < 0.01 and P = 0.01, respectively). Increased beta-2 microglobulin, kappa and lambda light chains, and immunoglobulin G levels were more frequently observed in anti-EA seropositive pSS subjects compared to anti-EA negative subjects (P < 0.001; P = 0.001; P = 0.003, respectively). Beta-2 microglobulin was independently associated with anti-EA positivity in multivariate analysis (P < 0.001). Plasma cell-free EBV DNA and EBV cellular reservoir was not different between pSS patients and controls. We conclude that serological evidence of EBV reactivation was more frequently observed and more strongly associated with anti-SSA/B status and B cell activation markers in pSS. However, serological profile of EBV reactivation was not accompanied by molecular evidence of systemic EBV reactivation. Our data indicated that EBV infection remains efficiently controlled in the blood of pSS patients.
31365341 Rituximab levels are associated with the B cell homeostasis but not with the clinical resp 2019 Apr OBJECTIVE: To study the levels of rituximab (RTX) and anti-RTX antibodies (ARAs) in patients with rheumatoid arthritis (RA) at 30, 90, and 180 days after the first infusion, in relation to clinical and serological parameters and B cell homeostasis. METHODS: Thirty-four patients with RA who failed to respond to anti-tumor necrosis factor therapy received RTX. At baseline, 4, 12, and 24 weeks after the first infusion of RTX, we performed a clinical assessment and determined the levels of RTX, ARAs, B cells, rheumatoid factors, anti-cyclic citrullinated peptide antibodies, immunoglobulins, and complements. RESULTS: RTX levels varied widely among patients. No ARAs were detected during the follow-up. Patients with lower levels of RTX presented with higher decreases in erythrocyte sedimentation rate, immunoglobulins, and complement 6 months after the first infusion. Patients with higher levels of RTX showed a higher B cell depletion at 90 days but an earlier B cell recovery than those with lower levels of RTX. No differences in clinical response were observed between the two groups at 6 months after starting the treatment. CONCLUSION: Our findings suggest that RTX levels in the serum of patients with RA are related to B cell homeostasis and the severity of immunological parameters but not to the clinical response at 6 months.
31129176 Respective contribution of cytosolic phospholipase A2α and secreted phospholipase A(2) II 2019 Aug Phospholipase A(2)s (PLA(2)) play a key role in generation of eicosanoids. Cytosolic PLA(2)α (cPLA(2)α) is constitutively expressed in most cells, whereas IIA secreted PLA(2) (sPLA(2)-IIA) is induced during inflammation and is present at high levels in the synovial fluid of rheumatoid arthritis patients. In mice, both cPLA(2)α and sPLA(2)-IIA have been implicated in autoimmune arthritis; however, the respective contribution of these two enzymes to the pathogenesis and production of eicosanoids is unknown. We evaluated the respective role of cPLA(2)α and sPLA(2)-IIA with regard to arthritis and eicosanoid profile in an in vivo model of arthritis. While arthritis was most severe in mice expressing both enzymes, it was abolished when both cPLA(2)α and sPLA(2)-IIA were lacking. cPLA(2)α played a dominant role in the severity of arthritis, although sPLA(2)-IIA sufficed to significantly contribute to the disease. Several eicosanoids were modulated during the course of arthritis and numerous species involved sPLA(2)-IIA expression. This study confirms the critical role of PLA(2)s in arthritis and unveils the distinct contribution of cPLA(2)α and sPLA(2)-IIA to the eicosanoid profile in arthritis.
30976734 Pyrolytic carbon humeral head in hemi-shoulder arthroplasty: preliminary results at 2-year 2019 Mar BACKGROUND: In patients with osteoarthritis (OA) and an intact rotator cuff, hemi-shoulder arthroplasty (HSA) can be a viable option as it offers the advantage of keeping the native glenoid intact. However, glenoid erosion has frequently been reported. The aim of this study was to report preliminary clinical results of HSA with a new pyrolytic carbon (pyrocarbon) humeral head. METHODS: This prospective multicenter study included a continuous series of 65 patients who underwent pyrocarbon HSA in 5 centers. RESULTS: At the time of analysis, 1 patient was lost to follow-up, 3 patients underwent revision, and 61 patients were evaluated at a mean follow-up of 25.9 ± 3.3 months. The mean age at index surgery was 57.9 ± 13.3 years. The indications were primary glenohumeral OA in 37 patients, osteonecrosis in 11, secondary OA in 11, and rheumatoid arthritis in 2. The mean Constant score increased from 31.0 ± 15.8 points at baseline to 74.6 ± 17 points at last follow-up. Radiographic analyses showed that 86% of glenoids remained unchanged whereas 14% evolved slightly. CONCLUSIONS: Pyrocarbon HSA grants improvement in pain and function in patients with primary OA or secondary OA after instability but at a lower level in patients with post-traumatic sequelae (secondary OA or osteonecrosis). These preliminary clinical and radiologic results are encouraging, although they need to be confirmed by longer-term follow-up observations.
31740402 Agonist-induced 4-1BB activation prevents the development of Sjӧgren's syndrome-like sial 2020 Mar 1 Activation of costimulatory receptor 4-1BB enhances T helper 1 (Th1) and CD8 T cell responses in protective immunity, and prevents or attenuates several autoimmune diseases by increasing Treg numbers and suppressing Th17 or Th2 effector response. We undertook this study to elucidate the impact of enforced 4-1BB activation on the development of Sjögren's syndrome (SS)-like sialadenitis in non-obese diabetic (NOD) model of this disease. An anti-4-1BB agnostic antibody was intraperitoneally injected to female NOD mice aged 7 weeks, prior to the disease onset that occurs around 10-11 weeks of age, 3 times weekly for 2 weeks, and the mice were analyzed for SS pathologies at age 11 weeks. The salivary flow rate was markedly higher in the anti-4-1BB-treated NOD mice compared to the IgG-treated controls. Anti-4-1BB treatment significantly reduced the leukocyte infiltration of the submandibular glands (SMGs) and the levels of serum antinuclear antibodies. Flow cytometric analysis showed that the percentages of CD4 T cells, Th17 cells and plasmacytoid dendritic cells among SMG leukocytes were markedly reduced by anti-4-1BB treatment, in conjunction with a reduction in SMG IL-23p19 mRNA levels and serum IL-17 concentrations. Although the proportion of Tregs and IL-10 mRNA levels in SMGs were not altered by 4-1BB activation, IL-10 mRNA levels in salivary gland-draining lymph nodes and serum IL-10 concentrations were both markedly increased. While anti-4-1BB treatment did not affect the amount of Th1 cells and IFNγ mRNA in the SMGs, it increased these measurables in salivary gland-draining lymph nodes. Hence, agonistic activation of 4-1BB impedes the development of SS-like sialadenitis and hyposalivation.
35518061 Metabolomics study of the therapeutic mechanism of a Chinese herbal formula on collagen-in 2019 Jan 25 Wenjinghuoluo (WJHL) prescription, the typical rheumatoid arthritis (RA) treatment compound in traditional Chinese medicine, shows favorable efficacy. The precise mechanism of WJHL on RA therapy is yet to be elucidated. This study aimed to determine the metabolic biomarkers in the early onset of RA and evaluate the regulation effect of WJHL on metabolite levels. Multivariate statistical analysis identified 93 biomarkers by precise MS/MS. These biomarkers played an important role in the regulation of key metabolic pathways associated with collagen-induced arthritis (CIA). A total of 68 biomarkers were related to the treatment of CIA by WJHL therapy. In addition, pathway analysis results showed six and three significant related pathways according to corresponding differential metabolites before and after WJHL therapy. Finally, disease and function prediction of ingenuity pathway analysis indicated that lipid metabolism, small molecule biochemistry, and carbohydrate metabolism were associated functions of WJHL therapy on CIA. Furthermore, top analysis-ready molecules of up-regulated thiamine and down-regulated arachidonic acid maybe the most related metabolites of WJHL therapy on CIA. The present work indicates that a metabolomics platform provides a new insight into understanding the mechanisms of action of natural medicines, such as WJHL.
31470415 Timing metabolism in cartilage and bone: links between circadian clocks and tissue homeost 2019 Aug 1 The circadian system in mammals is responsible for the temporal coordination of multiple physiological and behavioural processes that are necessary for homeostasis. In the skeleton, it has long been known that metabolic functions of chondrocytes, osteoblasts and osteoclasts exhibit intrinsic circadian rhythms. In addition, results from animal models reveal a close connection between the disruption of circadian rhythms and skeletal disorders such as rheumatoid arthritis, osteoarthritis and osteoporosis. In this review, we summarise the latest insights into the genetic and biochemical mechanisms linking cartilage and bone physiology to the circadian clock system. We also discuss how this knowledge can be utilised to improve human health.
30930186 Management of acute-stage chikungunya disease: Contribution of ultrasonographic joint exam 2019 Jul OBJECTIVE: Chikungunya (CHIKV) is an arbovirus that causes acute, debilitating polyarthritis. Its diagnosis can be difficult for clinicians not used to managing joint diseases or detecting synovitis. Joint Doppler ultrasonography (DUS) is a simple, non-invasive examination, able to visualize synovitis. Its diagnostic and prognostic value in rheumatoid arthritis is well-established. METHODS: Patients with serologically proven acute arbovirosis where included. Clinical examination and joint count were performed (DAS score). Ultrasound examination was performed by another clinician - experienced in joint DUS - who also performed ultrasound joint score. Joints were examined by DUS in B-mode looking for: subcutaneous infiltration, effusion, tenosynovitis, erosion and Doppler signal. RESULTS: In our experience, joint DUS is able to detect effusions in 92.8% of painful joints, with 28.3% of the effusions emitting a high-power Doppler signal. No erosion was observed. Subcutaneous inflammatory infiltration of the ankles (aseptic cellulitis) was found in 28.6% of patients. CONCLUSION: Joint DUS is able to detect objective signs responsible for joint pain, which can be useful for practitioners not accustomed to this type of pathology. It also makes possible distinction between articular and periarticular manifestations.
31557796 Mesenchymal Stem Cells Extract (MSCsE)-Based Therapy Alleviates Xerostomia and Keratoconju 2019 Sep 25 Sjogren's syndrome (SS) is an autoimmune disease that manifests primarily in salivary and lacrimal glands leading to dry mouth and eyes. Unfortunately, there is no cure for SS due to its complex etiopathogenesis. Mesenchymal stem cells (MSCs) were successfully tested for SS, but some risks and limitations remained for their clinical use. This study combined cell- and biologic-based therapies by utilizing the MSCs extract (MSCsE) to treat SS-like disease in NOD mice. We found that MSCsE and MSCs therapies were successful and comparable in preserving salivary and lacrimal glands function in NOD mice when compared to control group. Cells positive for AQP5, AQP4, α-SMA, CK5, and c-Kit were preserved. Gene expression of AQP5, EGF, FGF2, BMP7, LYZ1 and IL-10 were upregulated, and downregulated for TNF-α, TGF-β1, MMP2, CASP3, and IL-1β. The proliferation rate of the glands and serum levels of EGF were also higher. Cornea integrity and epithelial thickness were maintained due to tear flow rate preservation. Peripheral tolerance was re-established, as indicated by lower lymphocytic infiltration and anti-SS-A antibodies, less BAFF secretion, higher serum IL-10 levels and FoxP3(+) T(reg) cells, and selective inhibition of B220(+) B cells. These promising results opened new venues for a safer and more convenient combined biologic- and cell-based therapy.
31421154 Immune modulation by rebamipide in a mouse model of Sjogren's syndrome via T and B cell re 2019 Oct Rebamipide is a gastroprotective drug used widely in the treatment of gastritis and gastric ulcers. It has also been shown to improve dry eye and dry mouth, two major symptoms of Sjogren's syndrome (SS). However, little is known about the effects of rebamipide on T and B cell regulation in SS. In this study, we used a NOD/ShiLtJ mouse model of SS to examine the ability of rebamipide to ameliorate disease development by modulating T and B cells. Our results show that the oral administration of rebamipide suppressed SS progression and the level of inflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor-α, and IL-17, in the salivary glands and spleen of NOD/ShiLtJ mice. Rebamipide treatment also increased the number of ex vivo CD19+CD25+Foxp3+ regulatory B cells and CD19+CD5+CD1d + IL-10+ cells in NOD/ShiLtJ mice. In vitro, rebamipide suppressed IL-6 and IL-17 production by Th17 cells in splenic CD4+ cells from the mice. Thus, rebamipide may be effective in controlling the immune imbalance between pathogenic immune cells and regulatory cells, resulting in fundamental improvement in patients with SS.
31068931 Elevated CCL19/CCR7 Expression During the Disease Process of Primary Sjögren's Syndrome. 2019 Primary Sjögren's syndrome (pSS) is a common chronic autoimmune disease characterized by a high prevalence of autoantibodies and lymphocyte-mediated exocrine gland damage. To enhance our understanding of the mechanisms underlying the progression of the disease and to discover potential biomarkers for the early diagnosis of pSS, we applied RNA sequencing to compare the gene expression patterns in minor salivary glands between pSS patients and non-pSS. A total of 293 differentially expressed genes (DEGs) were detected in pSS vs. non-pSS (FDR < 0.05, fold changes > 2). Of these DEGs, 285 (97.26%) were up-regulated, with most being involved in immune system activation, especially in the formation of the immunological synapse. Significantly elevated CCL19/CCR7 expression in the salivary gland was found to be related to anti-Sjögren's syndrome-related antigen A (SSA) antibody and IgG levels in pSS patients, which was further confirmed in a larger cohort. Up-regulated gene expression showed strong discriminatory accuracy in identifying pSS with area under the curve of 0.98 using receiver operating characteristic curve analysis. In conclusion, gene expression changes in pSS include strong markers of immunological activation and have good discriminatory power in identifying patients with pSS.
30925056 Novel Pyrazolo[4,3- d]pyrimidine as Potent and Orally Active Inducible Nitric Oxide Syntha 2019 Apr 25 In order to discover novel anti-inflammatory agents for treatment of arthritis and based on preliminary structure-activity relationships, four series (A-D) of total 90 new pyrazolo[4,3- d]pyrimidine compounds were designed and synthesized. All the compounds have been tested for their anti-inflammatory activities by inhibiting of LPS-induced NO production. A clear structure-activity relationship has been concluded step by step, and finally 3,4,5-trimethoxystyryl-1 H-pyrazolo[4,3- d]pyrimidine was found to be the most active scaffold. Among them, compound D27 was discovered as the most potent anti-inflammatory agent (IC(50) = 3.17 μM) with low toxicity and strong inhibitory of NO release (IR = 90.4% at 10 μM). This compound also showed potent inhibition of iNOS with IC(50) value of 1.12 μM. Preliminary mechanism studies indicated that it could interfere with the stability and formation of active dimeric iNOS. The anti-inflammatory effect of this compound was determined by adjuvant-induced arthritis in rat model. We believe these findings would further support the study of rational design of more efficient iNOS inhibitors in the future.
31606410 The role of α7nAChR in controlling the anti-inflammatory/anti-arthritic action of galanta 2019 Dec OBJECTIVE: The evolution of the "cholinergic anti-inflammatory pathway" and the fact that the α 7 subunit of the nicotinic acetylcholine receptor (α7nAChR) is present in the spleen, joint and on the surface of lymphocytes, opened up the prospective in this study of targeting the α7nAChR by the anticholinesterase and cholinergic drug, galantamine, to control inflammation in rheumatoid arthritis (RA). METHODS: Twelve-adjuvant arthritic rats were exposed to the selective α7nAChR blocker methylcaconitine citrate 15 min before galantamine treatment. As control, six adjuvant arthritic rats were treated with galantamine and six others were untreated. After five days TNF-α levels were assessed in spleen and joints, while reduced glutathione was measured in blood and joint tissue. In the second part, magnetically sorted CD4 + T cells from peripheral blood mononuclear cells of RA patients and healthy donors were used to sort CD4 + CD25 - primary T cells (Tresp) and CD4 + CD25 + CD127low Tregs. The suppressive function of Tregs was investigated after incubation with galantamine using flow cytometry. Cell culture supernatants were analyzed for TNF-α and IL-10 levels after three days incubation period of Tregs with Tresp. The effect of galantamine on Tregs was then blocked by α-Bungarotoxin and the same assay has been repeated. RESULTS & CONCLUSION: Selective α7nAChR blockade interrupted the anti-inflammatory effect of galantamine in the spleen and joints of arthritic rats. In healthy donors, galantamine could strengthen the suppressive activity of Tregs; while in RA patients it did not modulate the function of Tregs significantly. Further studies are necessary to investigate whether modulation of the cholinergic nervous system, especially α7nAChR, could have impact on the disturbed immune system in RA, which may open up a new treatment option of autoimmune diseases.
31192747 Additive immunosuppressive effect of leflunomide and hydroxychloroquine supports rationale 2019 Jul Objective: Effective treatment for primary Sjögren's syndrome (pSS) is not available. pSS immunopathology involves a variety of immune-cells and dysregulated pathways; targeting several pathways instead of only one could therefore be effective. Treatment with leflunomide (LEF) and hydroxychloroquine (HCQ) might be successful given their unique immunosuppressive properties. We aimed to study the in vitro effects of LEF, HCQ and their combination on T- and B-cell proliferation, cytokine and immunoglobulin production by activated PBMCs. Methods: PBMCs of six healthy individuals and nine pSS patients were stimulated with superantigen and TLR9 agonist to mimic the hallmark features. LEF, HCQ and their combinations were tested at clinically observed concentrations and proliferation, cytokine and immunoglobulin production were measured. Results: TCR/TLR9 activation of PBMCs induced strong proliferation of T and B-cells and production of CXCL13, IFN-α, IFN-γ, IgG and IgM. LEF dose-dependently inhibited all measured parameters, where HCQ potently and dose-dependently decreased B cell proliferation, CXCL13, IFN-α, IgG and IgM production. At different concentration combinations, HCQ and LEF inhibited several immune hallmark features more potently than each single compound. Conclusion: A combination of LEF and HCQ at clinically applicable concentrations additively inhibits immune activation, supporting a potential implementation of this drug combination in pSS treatment.