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ID PMID Title PublicationDate abstract
26746234 Balancing benefits and risks of glucocorticoids in rheumatic diseases and other inflammato 2016 Feb PURPOSE: This consensus review article considers the question of whether glucocorticoid (GC) therapy is still relevant in the treatment of rheumatic diseases, with a particular focus on rheumatoid arthritis (RA), and whether its side effects can be adequately managed. Recent basic and clinical research on the molecular, cellular and clinical effects of GCs have considerably advanced our knowledge in this field. An overview of the subject seems appropriate. METHODS: This review is the result of a multidisciplinary expert working group, organised by European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. The recent literature was surveyed and the salient evidence synthetized. RESULTS: The pathophysiological basis of RA (and other inflammatory rheumatic diseases) now strongly implicates the adaptive immune system in addition to innate mechanisms. The molecular effect of GCs and differential GC sensitivity is better understood, although exploiting this knowledge is still in its infancy. The newer treatment strategies of early and aggressive control of RA have gr eatly improved clinical outcomes, but improvements are still possible. Newer targeted anti-inflammatory drugs have made an important impact, yet they too are associated with numerous side effects. DISCUSSION: Short durations of moderate doses of GCs are generally well tolerated and have a positive benefit/risk ratio. Patients should be assessed for fracture risk and bone preserving agents and be prescribed calcium and vitamin D supplementation. CONCLUSIONS: Within a strategy of a disease modifying approach to inflammatory disease, combination therapy including a GC is effective approach.
27958291 Sexual dimorphic function of IL-17 in salivary gland dysfunction of the C57BL/6.NOD-Aec1Ae 2016 Dec 13 Interleukin (IL)-17 is one of the critical inflammatory cytokines that plays a direct role in development of Sjögren's syndrome (SjS), a systemic autoimmune disease characterized by a progressive chronic attack against the exocrine glands. The expression levels of IL-17 are correlated with a number of essential clinical parameters such as focus score and disease duration in human patients. Significantly immunological differences of Th17 cells were detected at the onset of clinical disease in female SjS mice compared to males. To further define the role of IL-17 in SjS and elucidate its involvement in the sexual dimorphism, we examined the systemic effect of IL-17 by genetically ablating Il-17 in the C57BL/6.NOD-Aec1Aec2, spontaneous SjS murine model. The results indicate that IL-17 is a potent inflammatory molecule in the induction of chemoattractants, cytokines, and glandular apoptosis in males and females. Elimination of IL-17 reduced sialadenitis more drastically in females than males. IL-17 is highly involved in modulating Th2 cytokines and altering autoantibody profiles which has a greater impact on changing plasma cells and germinal center B cell populations in females than males. The result supports a much more important role for IL-17 and demonstrates the sexual dimorphic function of IL-17 in SjS.
26706891 Association of plasmacytoid dendritic cells with B cell infiltration in minor salivary gla 2016 Sep OBJECTIVES: Sjogren's syndrome (SS) is an autoimmune disease with features of both over-production of specific autoantibodies and organ-specific disorders, mainly sialadenitis and dacryoadenitis. However, little is known about the factors that contribute to lymphocytic infiltration of SS. METHODS: Minor salivary gland (MSG) tissue was obtained from 83 patients with primary SS (pSS) and 95 patients with secondary SS and examined pathologically, and correlation between infiltrated immune cells and histological features was evaluated. RESULTS: Plasmacytoid dendritic cells (pDCs) were increased in MSG of SS compared to Sicca syndrome. The density of pDCs was characteristically correlated with the accumulation of CXCL13(+)CD68(+) macrophages and CXCR5(+)CD19(+) B in the MSG of pSS. In vitro analysis indicated that Type I interferon (IFN) enhanced CXCL13 production by macrophages. Type I IFN was mainly expressed in pDCs and its expression was correlated with the accumulation of CXCL13(+) macrophages in the MSG of pSS. CONCLUSIONS: Our histological findings suggest the possible mechanism of type I IFN-CXCL13 axis during the pathological processes of acute/chronic salivary inflammation in SS; local production of type I IFN by pDCs, induction of CXCL13 production in macrophages by type I IFN, induction of accumulation of CXCR5(+)CD19(+) B cells by CXCL13 in the MSG.
27908305 Abatacept treatment of patients with primary Sjögren's syndrome results in a decrease of 2017 Mar OBJECTIVES: The aim of this study was to assess the histopathological changes in parotid gland tissue of primary Sjögren's syndrome (pSS) patients treated with abatacept. METHODS: In all 15 pSS patients included in the open-label Active Sjögren Abatacept Pilot (ASAP, 8 abatacept infusions) study parotid gland biopsies were taken before treatment and at 24 weeks of follow up. Biopsies were analysed for pSS-related histopathological features and placed in context of clini- cal responsiveness as assessed with EULAR Sjögren's syndrome disease activity index (ESSDAI). RESULTS: Abatacept treatment resulted in a decrease of germinal centres (GCs)/ mm2 (p=0.173). Number of GCs/mm2 at baseline was associated with response in the glandular domain of ESSDAI (Spearman ρ=0.644, p=0.009). Abatacept treatment did not reduce focus score, lymphoepithelial lesions, area of lymphocytic infiltrate, amount of CD21+ networks of follicular dendritic cells, and numbers of CD3+ T-cells or CD20+ B- cells. Number of IgM plasma cells/mm2 increased (p=0.041), while numbers of IgA and IgG plasma cells/mm2 were unaffected during abatacept treatment. CONCLUSIONS: Abatacept affects formation of GCs of pSS patients in parotid glands, which is dependent on co-stimulation of activated follicular-helper-T-cells. Herewith, local formation of (autoreactive) memory B-cells is inhibited. Presence of GCs at baseline predicts responsiveness to abatacept in the ESSDAI glandular domain.
25370295 Passive transfer of antibodies to the linear epitope 60 kD Ro 273-289 induces features o 2015 Apr Sjögren's syndrome (SS) is an autoimmune inflammatory disease that primarily affects the lacrimal and salivary glands causing dry eyes and mouth. Antibodies to Ro60 are observed frequently in patients with SS; however, the role of these antibodies in SS initiation and progression remains unclear. The sequence Ro60 273-289 (Ro274) is a known B cell epitope of Ro60 and antibodies to this epitope have been observed in a subset of SS patients and in animals immunized with Ro60 protein. Animals immunized with Ro274 linear peptide develop a Sjögren's-like illness. We hypothesized that passive transfer of anti-Ro274-specific immunoglobulin (Ig)G would induce a Sjögren's-like phenotype. To evaluate this hypothesis, we adoptively transferred affinity-purified Ro274 antibodies into naive BALB/c animals, then evaluated salivary gland histology, function and IgG localization 4 days post-transfer. At this time-point, there was no demonstrable mononuclear cell infiltration and salivary glands were histologically normal, but we observed a functional deficit in stimulated salivary flow of animals receiving Ro274 antibodies compared to animals receiving control IgG. Cellular fractionation and enzyme-linked immunosorbent assay revealed Ro274-specific antibodies in the nucleus and cytoplasmic fractions of isolated parotid salivary gland cells that was confirmed by immunohistochemistry. These data support the hypothesis that antibodies to Ro274 deposit in salivary glands can enter intact salivary gland cells and are involved in the dysregulation of salivary flow in SS.
25955801 Comparison of structural allograft and traditional autograft technique in occipitocervical 2015 Aug OBJECT The authors' objectives were to compare the rate of fusion after occipitoatlantoaxial arthrodesis using structural allograft with the fusion rate from using autograft, to evaluate correction of radiographic parameters, and to describe symptom relief with each graft technique. METHODS The authors assessed radiological fusion at 6 and 12 months after surgery and obtained radiographic measurements of C1-2 and C2-7 lordotic angles, C2-7 sagittal vertical alignments, and posterior occipitocervical angles at preoperative, postoperative, and final follow-up examinations. Demographic data, intraoperative details, adverse events, and functional outcomes were collected from hospitalization records. Radiological fusion was defined as the presence of bone trabeculation and no movement between the graft and the occiput or C-2 on routine flexion-extension cervical radiographs. Radiographic measurements were obtained from lateral standing radiographs with patients in the neutral position. RESULTS At the University of Utah, 28 adult patients underwent occipitoatlantoaxial arthrodesis between 2003 and 2010 using bicortical allograft, and 11 patients were treated using iliac crest autograft. Mean follow-up for all patients was 20 months (range 1-108 months). Of the 27 patients with a minimum of 12 months of follow-up, 18 (95%) of 19 in the allograft group and 8 (100%) of 8 in the autograft group demonstrated evidence of bony fusion shown by imaging. Patients in both groups demonstrated minimal deterioration of sagittal vertical alignment at final follow-up. Operative times were comparable, but patients undergoing occipitocervical fusion with autograft demonstrated greater blood loss (316 ml vs 195 ml). One (9%) of 11 patients suffered a significant complication related to autograft harvesting. CONCLUSIONS The use of allograft in occipitocervical fusion allows a high rate of successful arthrodesis yet avoids the potentially significant morbidity and pain associated with autograft harvesting. The safety and effectiveness profile is comparable with previously published rates for posterior C1-2 fusion using allograft.
26345380 Effects of dexamethasone, celecoxib, and methotrexate on the histology and metabolism of b 2015 OBJECTIVE: To investigate the long-term effects of three antiarthritics, namely dexamethasone, celecoxib, and methotrexate on the histology and metabolism of intact bone tissue in rats. METHODS: Thirty-two 12-week-old healthy female Sprague Dawley rats were randomly allocated into four groups: 1) control (saline, daily); 2) dexamethasone (2 mg/kg, twice weekly); 3) celecoxib (50 mg/kg, daily); and 4) methotrexate (0.5 mg/kg, twice weekly). The drugs were administered to the rats for 12 weeks and the animals were weighed on a weekly basis. The femurs and lumbar vertebrae were harvested for bone mineral density and bone mechanical properties analyses. The proximal tibiae were processed for bone histomorphometry and micro-computed tomography analyses. RESULTS: The following results were obtained: 1) dexamethasone strongly inhibited bone formation rate accompanied with a decrease in bone mineral density and bone biomechanical properties; 2) celecoxib stimulated bone resorption, leading to a decrease of bone mass and femur biomechanic properties; and 3) methotrexate caused bone loss and bone quality deterioration to a lesser extent due to the increase of the bone turnover rate on the proximal tibial metaphysis of the rats. CONCLUSION: This study provides a comparative profile of the long-term effects of clinical doses of celecoxib, methotrexate, and dexamethasone on intact skeletons of the rats. The results indicate that the three antiarthritics have varying degrees of side effects on bone metabolism, and these findings will help physicians to learn more about the potential effects of antiarthritics on bone metabolism.
26422345 Total knee arthroplasty after osseous ankylosis of the knee joint. 2015 OBJECTIVE: A knee fusion is associated with considerable restrictions, including the inability to sit properly, use public transportation, and climb stairs. The purpose of this study is to report and discuss our cases of spontaneous ankylosed knees which were taken down and underwent total knee arthroplasty (TKA). METHODS: Six patients who experienced spontaneous ankylosis of the knee undergoing conversion to TKA between 2003-2012 were enrolled retrospectively in this study. The etiology was childhood pyogenic arthritis in 2 patients, intraarticular fractures in 2, gunshot in 1, and juvenile rheumatoid arthritis in 1. The clinical data were recorded with the use of the Hospital for Special Surgery (HSS) knee rating system, Western Ontario and McMaster Questionnaire (WOMAC), and Visual Analog Scale (VAS), preoperatively and postoperatively at final follow-up. RESULTS: The average follow-up time was 86 months (range: 22-126 months). At the final follow-up, the average range of active flexion was 85° (range: 75-95°). Postoperative average HSS knee rating system was improved from 19.5 (range: 18-22) to 57.49 (range: 46-80), WOMAC was improved from 39.75 (range: 36.4-43) to 62.41 (range: 50.8-74.5). VAS was improved from 9.5 (range: 7-9) to 2.8 (range: 2-4). A pyogenic infection developed in 2 patients; 1 was managed by debridement, and 1 was managed by arthrodesis 2 years later. CONCLUSION: The ability to walk and sit in a normal fashion is of great importance for patients. With good preoperative planning and careful handling, gratifying results are possible with TKA.
24618265 Risk of high-grade cervical dysplasia and cervical cancer in women with systemic inflammat 2015 Jul BACKGROUND: Previous studies have suggested a potential risk of cervical cancer in patients with systemic inflammatory diseases (SID) such as inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE). OBJECTIVES: To assess the risk of high-grade cervical dysplasia, a surrogate endpoint for cervical cancer and cervical cancer, in women with SID, including IBD, psoriasis, rheumatoid arthritis (RA) or SLE, compared with the risk in women without SID. METHODS: Using US insurance data (2001-2012), we conducted a cohort study of 133,333 women with SID, based on two or more diagnoses and one or more dispensed prescription for disease-specific treatment, and 533,332 women without SID. High-grade cervical dysplasia and cervical cancer was defined by a validated algorithm with a positive predictive value of ≥81%. RESULTS: Over the mean follow-up of 2.1 years, the crude incidence rate of high-grade cervical dysplasia and cervical cancer per 100,000 person-years was the highest at 141.1 in SLE and the lowest at 82.2 in psoriasis among women with SID, and 73.4 in women without SID. The multivariable HR adjusted for potential confounders was 1.07 (95% CI 0.79 to 1.45) in IBD, 0.96 (95% CI 0.73 to 1.27) in psoriasis, 1.49 (95% CI 1.11 to 2.00) in RA and 1.53 (95% CI 1.07 to 2.19) in SLE. Multivariable HRs were increased, but not statistically significant, in IBD, RA and SLE with baseline use of systemic immunosuppressive drugs or steroids. CONCLUSIONS: The risk of high-grade cervical dysplasia and cervical cancer was 1.5 times higher in women with RA and SLE than in those without SID. The risk may be increased in IBD with use of systemic immunosuppressive drugs or steroids.
27982031 Harnessing the natural inhibitory domain to control TNFα Converting Enzyme (TACE) activit 2016 Dec 16 Dysregulated activity of A Disintegrin And Metalloproteinase 17 (ADAM17)/TNFα Converting Enzyme (TACE) is associated with inflammatory disorders and cancer progression by releasing regulatory membrane-tethered proteins like TNFα, IL6R and EGFR ligands. Although specific inhibition of TACE is thought to be a viable strategy for inflammatory disorders and for malignancies treatment, the generation of effective inhibitors in vivo has been proven to be challenging. Here we report on the development of a protein inhibitor that leverages the endogenous modulator of TACE. We have generated a stable form of the auto-inhibitory TACE prodomain (TPD), which specifically inhibits in vitro and cell-surface TACE, but not the related ADAM10, and effectively modulated TNFα secretion in cells. TPD significantly attenuated TACE-mediated disease models of sepsis, rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), and reduced TNFα in synovial fluids from RA patients. Our results demonstrate that intervening with endogenous ADAM sheddase modulatory mechanisms holds potential as a general strategy for the design of ADAM inhibitors.
27478398 Rapid Growth of Lung Nodules due to Combined Pulmonary Vasculitis, Silicoanthracosis, and 2016 Background. Silicoanthracosis is a pneumoconiosis due to occupational inhalation of silica and carbon dusts. Clinically, it can be associated with vasculitis or rheumatoid arthritis. In association with these diseases, silicoanthracosis can present within the lung with multiple pulmonary nodules which, as a differential diagnosis, can mimic metastatic disease or multiple abscesses. Case Presentation. We present the case of a 62-year old former pit worker with pulmonary nodules, chondrocalcinosis due to calcium pyrophosphate deposition (CPPD), and a history of renal cancer. Within a short period of time, pulmonary nodules grew rapidly. Thoracoscopically, the resected lung specimen revealed silicoanthracosis associated with small-to-medium-size vasculitis in the presence of antineutrophil cytoplasmatic autoantibodies (c-ANCA). Conclusion. Pulmonary silicoanthracotic lesions on the base of ANCA-associated vasculitis and CPPD arthritis can rapidly grow. A mutual correlation between silicoanthracosis, ANCA-associated vasculitis, and CPPD seems possible. Apart from this, consideration of metastatic disease should be obligatory in patients with a history of cancer at the same time being immunosuppressed.
27717524 STA-21, a STAT-3 inhibitor, attenuates the development and progression of inflammation in 2017 Feb We set out to investigate the influence of STA-21, a dynamic STAT-3 inhibitor, on the expansion and progression of rheumatoid arthritis (RA), and to determine its potential mechanisms of action in a mouse model of collagen antibody-induced arthritis (CAIA). To this end, arthritis was induced via intravenous (IV) injection of Balb/c mice with a cocktail of antibodies directed against type II collagen (1.5μg/mouse, IV), followed by lipopolysaccharide (LPS) at a dose of (25μg/mouse, i.p.) on day 3. Mice were then left untreated or were simultaneously treated with STA-21 (0.5mg/kg, i.p., once daily for 2 weeks) followed by evaluation for clinical and histological features of arthritic inflammation and flow cytometric analysis of cytokines and transcription factors in peripheral blood. STA-21 enhanced the clinical course of arthritis in CAIA mice and decreased CD8(+)RORγt(+) and CD8(+)IL-21(+) cells while inducing the production of CD8(+)Foxp3(+) cells. Furthermore, STA-21 prevented the production of TNF-α and IL-6 in peripheral blood and increased IL-27 production by CD14(+) cells. Moreover, STA-21 not only regulates Th1/Th2 serum cytokine levels but also the mRNA and protein expression of key factors including NF-κB p65, RORγt, T-bet, IL-4, GATA-3, JAK1, Stat3, and IL-21. Thus, administration of the Stat3 inhibitor STA-21 inhibits cellular signaling pathways and downstream activation of key transcription factors previously shown to play key roles in the pathogenesis of RA. Therefore, these data suggest that STA-21 could be considered as a potential treatment for patients with RA.
26604432 Collagen Induced Arthritis in DBA/1J Mice Associates with Oxylipin Changes in Plasma. 2015 Oxylipins play important roles in various biological processes and are considered as mediators of inflammation for a wide range of diseases such as rheumatoid arthritis (RA). The purpose of this research was to study differences in oxylipin levels between a widely used collagen induced arthritis (CIA) mice model and healthy control (Ctrl) mice. DBA/1J male mice (age: 6-7 weeks) were selected and randomly divided into two groups, namely, a CIA and a Ctrl group. The CIA mice were injected intraperitoneally (i.p.) with the joint cartilage component collagen type II (CII) and an adjuvant injection of lipopolysaccharide (LPS). Oxylipin metabolites were extracted from plasma for each individual sample using solid phase extraction (SPE) and were detected with high performance liquid chromatography/tandem mass spectrometry (HPLC-ESI-MS/MS), using dynamic multiple reaction monitoring (dMRM). Both univariate and multivariate statistical analyses were applied. The results in univariate Student's t-test revealed 10 significantly up- or downregulated oxylipins in CIA mice, which were supplemented by another 6 additional oxylipins, contributing to group clustering upon multivariate analysis. The dysregulation of these oxylipins revealed the presence of ROS-generated oxylipins and an increase of inflammation in CIA mice. The results also suggested that the collagen induced arthritis might associate with dysregulation of apoptosis, possibly inhibited by activated NF-κB because of insufficient PPAR-γ ligands.
26653716 Reduced physical activity in children and adolescents with Juvenile Idiopathic Arthritis d 2015 Dec 10 BACKGROUND: Vascular health is of concern in patients with Juvenile Idiopathic Arthritis (JIA) since Rheumatoid Arthritis (RA) epidemiologically has a well-described association with premature development of atherosclerosis. Chronic inflammation with persisting systemic circulating inflammatory proteins may be a cause of vascular damage, but general physical inactivity could be an important contributor. Pain and fatigue are common complaints in patients with JIA and may well lead to an inactive sedentary lifestyle. For this reason we assessed the physical activity (PA) objectively in patients with moderate to severe Juvenile Idiopathic Arthritis (JIA) in comparison with gender and age matched healthy schoolchildren, and looked for associations between PA and features of JIA. METHODS: One hundred thirty-three patients, 7-20 years of age, participated. Disease activity, disability, functional ability, and pain were assessed and PA was measured by accelerometry through 7 days and compared to PA in age- and gender-matched healthy schoolchildren. RESULTS: We found a significantly lower level of PA in patients compared to gender- and age-matched healthy schoolchildren both in average activity (counts per minute, cpm) (475.6 vs. 522.7, p = 0.0000018) and in minutes per day spent with cpm >1500 (67.9 vs. 76.4, p = 0.0000014), with cpm >2000 (moderate physical activity) (48.4 vs. 52.8, p = 0.0001, and with cpm >3000 (high physical activity) (24.7 vs. 26.5, p = 0.00015). A negative association (β = -0.213, p = 0.014) between active disease in weight bearing joints and high physical activity remained the only significant association between disease related factors and PA. Of the girls 19% and of the boys 45% (vs. 39% and 61% in the reference group) met standards set by Danish Health Authorities for daily PA in childhood. CONCLUSION: Children and adolescents with JIA are less physically active than their healthy peers and less active than recommended for general health by the Danish Health Authorities. This is not explained by pain or objective signs of inflammation. When inflammation has been curbed, restoration of an active healthy lifestyle should be highly prioritized.
27556049 Effect of N-Feruloylserotonin and Methotrexate on Severity of Experimental Arthritis and o 2016 Rheumatoid arthritis (RA) is a chronic inflammatory disease, leading to progressive destruction of joints and extra-articular tissues, including organs such as liver and spleen. The purpose of this study was to compare the effects of a potential immunomodulator, natural polyphenol N-feruloylserotonin (N-f-5HT), with methotrexate (MTX), the standard in RA therapy, in the chronic phase of adjuvant-induced arthritis (AA) in male Lewis rats. The experiment included healthy controls (CO), arthritic animals (AA), AA given N-f-5HT (AA-N-f-5HT), and AA given MTX (AA-MTX). N-f-5HT did not affect the body weight change and clinical parameters until the 14th experimental day. Its positive effect was rising during the 28-day experiment, indicating a delayed onset of N-f-5HT action. Administration of either N-f-5HT or MTX caused reduction of inflammation measured as the level of CRP in plasma and the activity of LOX in the liver. mRNA transcription of TNF-α and iNOS in the liver was significantly attenuated in both MTX and N-f-5HT treated groups of arthritic rats. Interestingly, in contrast to MTX, N-f-5HT significantly lowered the level of IL-1β in plasma and IL-1β mRNA expression in the liver and spleen of arthritic rats. This speaks for future investigations of N-f-5HT as an agent in the treatment of RA in combination therapy with MTX.
26934991 MicroRNA-20a negatively regulates expression of NLRP3-inflammasome by targeting TXNIP in a 2016 Dec OBJECTIVES: Rheumatoid arthritis (RA) is a heterogenic and systemic autoimmune disease characterized by synovitis and joint structural damage. However, the pathogenesis of RA is still obscure. It has been reported microRNA-20a (miRNA-20a) was significantly associated with the regulation of pro-inflammatory cytokines release in RA FLS. The purpose of this study was to explore the function and underlying mechanisms of miRNA-20a on NLRP3-inflammasome in adjuvant-induced arthritis (AA) fibroblast-like synoviocytes (FLSs) in vitro. METHODS: In this study, using a combination of Western blotting, Q-PCR, and ELISA analysis, we investigated the influence and function of miRNA-20a on NLRP3-inflammasome by targeting TXNIP in AA FLSs. RESULTS: In the present study, the expression of NLRP3-inflammasome was significant up-regulated in AA model in vitro. Our study indicated that silence of NLRP3 down-regulated the expression of NLRP3-inflammasome and the secretion of IL-1β and MMP-1. Moreover, over-expression of miR-20a decreased formation of NLRP3-inflammasome, including NLRP3, ASC and caspase-1, and suppressed the secretion of IL-1β and MMP-1, along with down-regulated the expressions of TXNIP in primary FLSs isolated from AA. With the combined use of prediction programs and luciferase assay, the rat TXNIP mRNA 3'UTR predicted to be targeted by miR-20a. Similarly, inhibitor TXNIP expression by TXNIP-siRNA markedly repressed formation of NLRP3-inflammasome and the secretion of IL-1β and MMP-1. CONCLUSION: Taken together, these results indicate that miR-20a may play a pivotal role in the NLRP3-inflammasome by targeted inhibit TXNIP expression in AA FLSs.
26756335 A Novel Triazolopyridine-Based Spleen Tyrosine Kinase Inhibitor That Arrests Joint Inflamm 2016 Autoantibodies and the immunoreceptors to which they bind can contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). Spleen Tyrosine Kinase (Syk) is a non-receptor tyrosine kinase with a central role in immunoreceptor (FcR) signaling and immune cell functionality. Syk kinase inhibitors have activity in antibody-dependent immune cell activation assays, in preclinical models of arthritis, and have progressed into clinical trials for RA and other autoimmune diseases. Here we describe the characterization of a novel triazolopyridine-based Syk kinase inhibitor, CC-509. This compound is a potent inhibitor of purified Syk enzyme, FcR-dependent and FcR-independent signaling in primary immune cells, and basophil activation in human whole blood. CC-509 is moderately selective across the kinome and against other non-kinase enzymes or receptors. Importantly, CC-509 was optimized away from and has modest activity against cellular KDR and Jak2, kinases that when inhibited in a preclinical and clinical setting may promote hypertension and neutropenia, respectively. In addition, CC-509 is orally bioavailable and displays dose-dependent efficacy in two rodent models of immune-inflammatory disease. In passive cutaneous anaphylaxis (PCA), CC-509 significantly inhibited skin edema. Moreover, CC-509 significantly reduced paw swelling and the tissue levels of pro-inflammatory cytokines RANTES and MIP-1α in the collagen-induced arthritis (CIA) model. In summary, CC-509 is a potent, moderately selective, and efficacious inhibitor of Syk that has a differentiated profile when compared to other Syk compounds that have progressed into the clinic for RA.
26429698 Fc Receptor-mediated Effector Function Contributes to the Therapeutic Response of Anti-TNF 2016 Jan BACKGROUND AND AIMS: Anti-tumour necrosis factor [TNF] monoclonal antibodies [infliximab, adalimumab] induce complete mucosal healing in a proportion of patients with Crohn's disease whereas a TNF receptor fusion protein [etanercept] is not effective and the anti-TNF F[ab']2 fragment [certolizumab] shows a very low rate of complete mucosal healing. In contrast, all four TNF-neutralising drugs have demonstrated efficacy in the treatment of rheumatoid arthritis. These observations suggest that factors other than neutralisation of TNF may contribute to clinical outcomes in Crohn's disease. Here we tested the hypothesis that Fc receptor [FcR]-mediated effects may contribute to the therapeutic response of anti-TNF antibodies in inflammatory bowel disease. METHODS: We modified an IgG2c mouse anti-TNF antibody that binds the high-affinity FcRs to generate an IgG1 isotype with strongly diminished binding. We examined the therapeutic effects of both antibodies in the T cell transfer model of inflammatory bowel disease and the collagen-induced arthritis model. RESULTS: The IgG2c anti-TNF antibody prevented colonic inflammation in the T cell transfer model of colitis, whereas the IgG1 anti-TNF did not. Conversely, both the IgG2c and IgG1 anti-TNFs were similarly effective in reducing the severity of articular inflammation in mouse collagen-induced arthritis. CONCLUSION: These data support the concept that the mechanism of action for TNF-neutralising drugs may differ across immune-mediated diseases and, potentially, between therapeutics within a particular disease. Our data suggest a specific role of Fc-mediated immune regulation in the resolution of intestinal inflammation by anti-TNF monoclonal antibodies.
27807194 Therapeutic Targeting of the G-CSF Receptor Reduces Neutrophil Trafficking and Joint Infla 2016 Dec 1 G-CSF is a hemopoietic growth factor that has a role in steady state granulopoiesis, as well as in mature neutrophil activation and function. G-CSF- and G-CSF receptor-deficient mice are profoundly protected in several models of rheumatoid arthritis, and Ab blockade of G-CSF also protects against disease. To further investigate the actions of blocking G-CSF/G-CSF receptor signaling in inflammatory disease, and as a prelude to human studies of the same approach, we developed a neutralizing mAb to the murine G-CSF receptor, which potently antagonizes binding of murine G-CSF and thereby inhibits STAT3 phosphorylation and G-CSF receptor signaling. Anti-G-CSF receptor rapidly halted the progression of established disease in collagen Ab-induced arthritis in mice. Neutrophil accumulation in joints was inhibited, without rendering animals neutropenic, suggesting an effect of G-CSF receptor blockade on neutrophil homing to inflammatory sites. Consistent with this, neutrophils in the blood and arthritic joints of anti-G-CSF receptor-treated mice showed alterations in cell adhesion receptors, with reduced CXCR2 and increased CD62L expression. Furthermore, blocking neutrophil trafficking with anti-G-CSF receptor suppressed local production of proinflammatory cytokines (IL-1β, IL-6) and chemokines (KC, MCP-1) known to drive tissue damage. Differential gene expression analysis of joint neutrophils showed a switch away from an inflammatory phenotype following anti-G-CSF receptor therapy in collagen Ab-induced arthritis. Importantly, G-CSF receptor blockade did not adversely affect viral clearance during influenza infection in mice. To our knowledge, we describe for the first time the effect of G-CSF receptor blockade in a therapeutic model of inflammatory joint disease and provide support for pursuing this therapeutic approach in treating neutrophil-associated inflammatory diseases.
27196292 CP-25 attenuates the inflammatory response of fibroblast-like synoviocytes co-cultured wit 2016 Aug 2 ETHNOPHARMACOLOGICAL RELEVANCE: Total glucosides of paeony (TGP) is the first anti-inflammatory immune regulatory drug approved for the treatment of rheumatoid arthritis in China. A novel compound, paeoniflorin-6'-O-benzene sulfonate (code CP-25), comes from the structural modification of paeoniflorin (Pae), which is the effective active ingredient of TGP. The aim of the present study is to investigate the effect of CP-25 on adjuvant arthritis (AA) fibroblast-like synoviocytes (FLS) co-cultured with BAFF-activated CD4(+) T cells and the expression of BAFF-R in CD4(+) T cells. METHODS: The mRNA expression of BAFF and its receptors was assessed by qPCR. The expression of BAFF receptors in CD4(+) T cells was analyzed by flow cytometry. The effect of CP-25 on AA rats was evaluated by their joint histopathology. The cell culture growth of thymocytes and FLS was detected by cell counting kit (CCK-8). The concentrations of IL-1β, TNF-α, and IL-6 were measured by Enzyme-linked immunosorbent assay (ELISA). RESULTS: The mRNA expression levels of BAFF and BAFF-R were enhanced in the mesenteric lymph nodes of AA rats, TACI expression was reduced, and BCMA had no change. The expression of BAFF-R in CD4(+) T cells was also enhanced. CP-25 alleviated the joint histopathology and decreased the expression of BAFF-R in CD4(+) T cells from AA rats in vivo. In vitro, CP-25 inhibited the abnormal cell culture growth of BAFF-stimulated thymocytes and FLS. In the co-culture system, IL-1β, IL-6 and TNF-α production was enhanced by FLS co-cultured with BAFF-activated CD4(+) T cells. Moreover, BAFF-stimulated CD4(+) T cells promoted the cell culture growth of FLS. The addition of CP-25 decreased the expression of BAFF-R in CD4(+) T cells and inhibited the cell culture growth and cytokine secretion ability of FLS co-cultured with BAFF-activated CD4(+) T cells. CONCLUSION: The present study indicates that CP-25 may repress the cell culture growth and cytokine secretion ability of FLS, and its inhibitory effects might be associated with its ability to inhibit the expression of BAFF-R in CD4(+) T cells in a co-culture. These observations might provide a scientific basis for the development of new drugs for the treatment of autoimmune diseases by CP-25.