scholarly journals A Quick and Painless Reminder: The Pharmacotherapy of Rheumatoid Arthritis in Primary Practice

2018 ◽  
Vol 60 (2) ◽  
pp. 38-42
Author(s):  
Linda Brand ◽  
De Wet Wolmarans ◽  
Sarel J. Brand
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cell ◽  
Bone Erosion ◽  
Synovial Fibroblasts ◽  
Pathological Features ◽  
Cell Infiltrate ◽  
Immune Disorder ◽  
Synovial Hyperplasia ◽  
Role Players ◽  
Primary Practice

Rheumatoid arthritis, an auto-immune disorder, is characterized by chronic inflammation of the joints, synovial hyperplasia and bone erosion. These pathological features are promoted by a synovial microenvironment featuring B-cell and T-cell infiltrate, synovial fibroblasts and an intricate network of pro-inflammatory cellular messengers – prominent molecular role-players that represent critical targets in the pharmacotherapy of the disease. This review offers a brief overview of the etiopathology of rheumatoid arthritis while focussing on the practical aspects of methotrexate and glucocorticoid use that are of relevance for primary practice.

Synoviocytes-derived Interleukin 35 Potentiates B Cell Response in Patients with Osteoarthritis and Rheumatoid Arthritis

2017 ◽  
Vol 45 (4) ◽  
pp. 563-573 ◽  
Author(s):  
Ngar-Woon Kam ◽  
Dehua Liu ◽  
Zhe Cai ◽  
Wah-Yan Mak ◽  
Chun-Kwok Wong ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Flow Cytometry ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Synovial Fibroblasts ◽  
B Cell Activation ◽  
Qrt Pcr ◽  
Tnf Α ◽  
Factor Α

Objective.Elevated expression of interleukin 35 (IL-35) is associated with autoimmune disease, including rheumatoid arthritis (RA). The present study was undertaken to determine the functional interaction among IL-35, B cells, and stromal cells residing in the synovium of patients with RA and osteoarthritis (OA).Methods.IL-35 (EBI-3/p35) expression was investigated in RA and OA synovium using quantitative real-time PCR (qRT-PCR) and immunohistochemistry. IL-35 receptor (IL-35R) expression on B cells dissociated from synovium and periphery of patients with RA, OA, and healthy donor controls (HC) was determined by flow cytometry. The degree of B cells activation after IL-4 and/or IL-35 stimulation was measured by flow cytometry and qRT-PCR. Synovial fibroblasts (SF) purified from RA and OA synovium were cocultured with peripheral HC B cells in the presence/absence of tumor necrosis factor-α (TNF-α) and with/without anti-IL-35–blocking antibodies.Results.EBI-3/p35 transcripts were expressed in close proximity to B cells residing in RA and OA synovium. IL-35R subunits, gp130 and IL-27Rα, but not IL-12Rβ2, were expressed in B cells extracted from the synovium and periphery of patients with RA/OA. Notably, RA synovium expressed the highest level of IL-27Rα on their cell surface. IL-35 induced proliferation and IgG production in HC B cells. Cocultures of HC B cells with RASF, but not OASF, exhibited significantly elevated B cells activation. TNF-α–induced, RASF-dependent secretion of IgG in B cells is partly IL-35–dependent.Conclusion.To our knowledge, for the first time we demonstrated that synovial/peripheral B cells expressed IL-35R and were responsive to IL-35 stimulation. SF residing in RA synovium can be linked to B cell activation and maintenance in RA synovium through IL-35.

scholarly journals Antcin K Inhibits TNF-α, IL-1β and IL-8 Expression in Synovial Fibroblasts and Ameliorates Cartilage Degradation: Implications for the Treatment of Rheumatoid Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
David Achudhan ◽  
Shan-Chi Liu ◽  
Yen-You Lin ◽  
Chien-Chung Huang ◽  
Chun-Hao Tsai ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cytokine Production ◽  
Bone Erosion ◽  
Interleukin 1 ◽  
Synovial Fibroblasts ◽  
Nuclear Factor Κb ◽  
Cartilage Degradation ◽  
Signaling Cascades ◽  
Necrosis Factor Alpha ◽  
Tnf Α

Extracts from Taiwan’s traditional medicinal mushroom, Antrodia cinnamomea, exhibit anti-inflammatory activities in cellular and preclinical studies. However, this paper is the first to report that Antcin K, a triterpenoid isolated from A. cinnamomea, inhibits proinflammatory cytokine production in human rheumatoid synovial fibroblasts (RASFs), which are major players in rheumatoid arthritis (RA) disease. In our analysis of the mechanism of action, Antcin K inhibited the expression of three cytokines (tumor necrosis factor alpha [TNF-α], interleukin 1 beta [IL-1β] and IL-8) in human RASFs; cytokines that are crucial to RA synovial inflammation. Notably, incubation of RASFs with Antcin K reduced the phosphorylation of the focal adhesion kinase (FAK), phosphoinositide 3-kinase (PI3K), protein kinase B (AKT) and nuclear factor-κB (NF-κB) signaling cascades, all of which promote cytokine production in RA. Intraperitoneal injections of Antcin K (10 mg/kg or 30 mg/kg) attenuated paw swelling, cartilage degradation and bone erosion, and decreased serum levels of TNF-α, IL-1β, IL-8 in collagen-induced arthritis (CIA) mice; in further experiments, IL-6 levels were similarly reduced. The inhibitory effects of Antcin K upon TNF-α, IL-1β and IL-8 expression in human RASFs was achieved through the downregulation of the FAK, PI3K, AKT and NF-κB signaling cascades. Our data support clinical investigations using Antcin K in RA disease.

scholarly journals FLICE-inhibitory protein expression in synovial fibroblasts and at sites of cartilage and bone erosion in rheumatoid arthritis

2002 ◽  
Vol 46 (6) ◽  
pp. 1512-1518 ◽  
Author(s):  
J�rg Schedel ◽  
Renate E. Gay ◽  
Peter Kuenzler ◽  
Christian Seemayer ◽  
Beat Simmen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Protein Expression ◽  
Bone Erosion ◽  
Synovial Fibroblasts ◽  
Inhibitory Protein

scholarly journals A BAFF/APRIL-dependent TLR3-stimulated pathway enhances the capacity of rheumatoid synovial fibroblasts to induce AID expression and Ig class-switching in B cells

2011 ◽  
Vol 70 (10) ◽  
pp. 1857-1865 ◽  
Author(s):  
Michele Bombardieri ◽  
Ngar-Woon Kam ◽  
Fabia Brentano ◽  
Ken Choi ◽  
Andrew Filer ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
B Cell ◽  
Cell Survival ◽  
Cell Activation ◽  
Cytidine Deaminase ◽  
Synovial Fibroblasts ◽  
Dermal Fibroblasts ◽  
Class Switching ◽  
B Cell Survival

ObjectivesTo dissect the role of toll-like receptor (TLR) signalling and B cell survival/proliferating factors in the crosstalk between rheumatoid arthritis synovial fibroblasts (RASF) and B cells.MethodsRASF, rheumatoid arthritis dermal fibroblasts (RADF) and osteoarthritis synovial fibroblasts (OASF) were analysed for the expression of B cell survival/proliferating factors BAFF and APRIL in resting conditions and upon stimulation with TLR2/TLR3/TLR4 ligands. Unswitched IgD+ B cells were co-cultured with RASF/OASF/RADF in the presence/absence of TLR ligands and with/without BAFF/APRIL blocking antibodies. Activation-induced cytidine deaminase (AID) mRNA expression, Iγ-Cμ and Iα-Cμ circular transcripts (CTs; markers of ongoing class-switching to IgG and IgA) and IgM/A/G production were measured to assess functional activation of B cells.ResultsTLR3 and to a lesser extent TLR4, but not TLR2 stimulation, induced up to ∼1000-fold BAFF mRNA and increased soluble BAFF release. APRIL was less significantly regulated by TLR3. Resting and TLR3-stimulated RASF released higher levels of BAFF/APRIL compared with RADF. TLR3 stimulation of RASF but not RADF in co-culture with B cells strongly enhanced AID expression, Iγ-Cμ and Iα-Cμ CTs and class-switching to IgG/IgA. Blockade of BAFF/APRIL signalling completely inhibited TLR3-induced, RASF-dependent expression of AID, CTs and the secretion of IgG/IgA.ConclusionsRASF produce high levels of BAFF and APRIL constitutively and in response to TLR3 stimulation. These factors are critical in directly modulating AID expression, class-switch recombination and IgG/IgA production in IgD+ B cells. Overall, this work highlights a novel and fundamental role for the TLR3/B cell survival factor axis in sustaining B cell activation in the rheumatoid arthritis synovium.

scholarly journals POS0388 INTERLEUKIN 40 (IL-40) IS UP-REGULATED IN RHEUMATOID ARTHRITIS (RA) AND ASSOCIATED WITH DISEASE ACTIVITY, LEVELS OF AUTOANTIBODIES AND CHEMOKINES

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 424.1-424
Author(s):  
A. Navrátilová ◽  
L. Andres Cerezo ◽  
H. Hulejova ◽  
V. Becvar ◽  
D. Tegzová ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
Synovial Fluid ◽  
Disease Activity ◽  
B Cell ◽  
Synovial Tissue ◽  
Lupus Erythematosus ◽  
Synovial Fibroblasts ◽  
Clinical Activity

Background:Interleukin 40 (IL-40) is newly identified B cell - associated cytokine implicated in humoral immune responses and in B cell development. As B cells play a pivotal role in autoimmunity, we aimed to investigate the function of IL-40 in rheumatoid arthritis (RA).Objectives:The aim of our study was to determine the function of IL-40 in RA.Methods:IL-40 expression in the synovial tissue was determined by immunohistochemistry and immunofluorescence (n=4-5). IL-40 was analysed in the serum/synovial fluid of patients with RA (n=69), systemic lupus erythematosus (SLE; n=69), osteoarthritis (OA; n=44), and in healthy controls (HC; n=25). Given the association of IL-40 with B cells, we analysed the effect of rituximab therapy on the serum IL-40 in 19 patients with RA after 16 and 24 weeks of the therapy. The clinical activity of patients with RA was assessed according to the 28 joint count Disease Activity Score (DAS28). Levels of C-reactive protein (CRP) and autoantibodies were measured by routine laboratory techniques. In vitro experiments were performed in RA synovial fibroblasts (n=9). Levels of cytokines and inflammatory mediators were determined in serum, synovial fluid and supernatants using ELISA or multiplex immunoassay.Results:IL-40 was overexpressed in RA synovial tissue compared to OA, particularly by synovial fibroblasts and immune cells such as B and T lymphocytes, macrophages and neutrophils. The levels of IL-40 were significantly higher in the synovial fluid of RA patients compared to OA (33.2 (6.6-68.9) vs. 0.7 (0.1-2.4) ng/ml; p<0.0001). In addition, IL-40 was increased in the serum of RA patients compared to SLE, OA or HC (4.8 (1.7-24.9) vs. 1.4 (1.0-1.9), 1.6 (0.6-3.1) or 1.5 (0.7-2.7) ng/ml; p<0.0001 for all) and decreased after 16 (p<0.01) and 24 weeks (p<0.001) in a subgroup of rituximab treated patients with RA. IL-40 levels in RA patients correlated with autoantibodies rheumatoid factor (IgM) and anti-citrullinated protein antibody (ACPA) in the serum (p<0.0001 and p<0.01) as well as in the synovial fluid (p<0.0001 and p<0.001). IL-40 in RA synovial fluid was also significantly associated with DAS28 (p<0.05), synovial fluid leukocyte count (p<0.01), number of swollen joints (p<0.05) and neutrophil attractants IL-8 (p<0.01) and MIP-1α (p<0.01). RA synovial fibroblasts exposed to recombinant IL-40 increased secretion of IL-8 (p<0.01), MCP-1 (p<0.05) and MMP-13 (p<0.01) compared to unstimulated cells in in vitro conditions.Conclusion:Our results show for the first time that IL-40 is elevated in RA and decreases following B-cell depletion therapy. The association of IL-40 with autoantibodies and chemokines may imply its potential involvement in RA development. Moreover, IL-40 up-regulates the secretion of chemokines and MMP-13 by synovial fibroblasts, indicating its role in the regulation of inflammation and tissue destruction in RA.Acknowledgements:Supported by MHCR 023728 a SVV 260 523Disclosure of Interests:None declared

scholarly journals The Mechanisms Underlying Chronic Inflammation in Rheumatoid Arthritis from the Perspective of the Epigenetic Landscape

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Yasuto Araki ◽  
Toshihide Mimura
Keyword(s):  
Rheumatoid Arthritis ◽  
Joint Destruction ◽  
Synovial Fibroblasts ◽  
Cell Types ◽  
Epigenetic Mechanisms ◽  
Synovial Hyperplasia ◽  
Genetic And Environmental Factors ◽  
Inflammatory Autoimmune Disease ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that is characterized by synovial hyperplasia and progressive joint destruction. The activation of RA synovial fibroblasts (SFs), also called fibroblast-like synoviocytes (FLS), contributes significantly to perpetuation of the disease. Genetic and environmental factors have been reported to be involved in the etiology of RA but are insufficient to explain it. In recent years, accumulating results have shown the potential role of epigenetic mechanisms, including histone modifications, DNA methylation, and microRNAs, in the development of RA. Epigenetic mechanisms regulate chromatin state and gene transcription without any change in DNA sequence, resulting in the alteration of phenotypes in several cell types, especially RASFs. Epigenetic changes possibly provide RASFs with an activated phenotype. In this paper, we review the roles of epigenetic mechanisms relevant for the progression of RA.

scholarly journals Proteasome inhibition restored the reduced expression of fibroblast growth factor receptor 3 in rheumatoid arthritis synovial fibroblasts

2020 ◽  
Author(s):  
Michel Neidhart ◽  
Emmanuel Karouzakis ◽  
Sandro Fucentese ◽  
Oliver Distler ◽  
Astrid Jüngel
Keyword(s):  
Rheumatoid Arthritis ◽  
Proteasome Inhibitors ◽  
Growth Factor Receptor ◽  
Synovial Fibroblasts ◽  
Dna Demethylation ◽  
Proteasome Activity ◽  
Signal Pathways ◽  
20S Proteasome ◽  
Fibroblast Growth ◽  
Synovial Hyperplasia

Abstract Background. Synovial hyperplasia is a hallmark of rheumatoid arthritis (RA). This might be associated with an imbalance of growth-promoting and apoptotic pathways, among them fibroblast growth factors (FGFs) and their receptors (FGFRs) . The aim was to investigate differences in FGFRs and to explore the factors that might explain the differences between RA and osteoarthritis (OA) synovial fibroblasts. Methods. To assess FGFRs expression, immunohistochemistry, flow cytometry and RT-qPCR were performed. The cells were treated with TNFa, FGF2, a demethylation agent, PKA-mimics or inhibitors, hypoxia-mimics or proteasome inhibitors. Proliferation was measured using the CCK8 assay and 20S proteasome activity by a fluorescent assay. Results. In RA, FGFR3 protein was decreased in the synovial lining layer (p<0.005) and in cultured RA synovial fibroblasts (RASF) (n=10, p < 0.01). Transcription was unchanged and DNA demethylation decrease its expression. Exposure to TNFa or FGF2 had no effect on FGFR3. PKA-modulation and hypoxia-mimics induced transient changes only. Most interesting, in RASF, the proteasome inhibitor MG-132 restored FGFR3 expression (p<0.001) to levels measured in normal or OA synovial fibroblasts. MG-132 abolished the enhanced proliferative response of RASF to FGF2 (p<0.005). Increased 20S proteasome activity correlated (r=- 0.63, p<0.05) with decreased expression of FGFR3. Conclusions. The expression of FGFR3 is reduced in RA partially due to an increased degradation in proteasomes. This leads to an imbalance in the FGF-related signal pathways and may contribute to synovial hyperplasia. Proteasome inhibitors could represent a novel therapeutic strategy in RA, particularly to prevent synovial hyperplasia.

scholarly journals IL-40: A New B Cell-Associated Cytokine Up-Regulated in Rheumatoid Arthritis Decreases Following the Rituximab Therapy and Correlates With Disease Activity, Autoantibodies, and NETosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Adela Navrátilová ◽  
Lucie Andrés Cerezo ◽  
Hana Hulejová ◽  
Viktor Bečvář ◽  
Michal Tomčík ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
Disease Activity ◽  
B Cell ◽  
Synovial Tissue ◽  
Lupus Erythematosus ◽  
Synovial Fibroblasts ◽  
Tissue Destruction ◽  
Humoral Immune ◽  
B Cell Homeostasis

BackgroundInterleukin 40 (IL-40) is a newly identified B cell-associated cytokine implicated in humoral immune responses and B cell homeostasis. As B cells play a pivotal role in autoimmunity, we investigated the function of IL-40 in rheumatoid arthritis (RA).MethodsIL-40 expression was determined in the synovial tissue from RA and osteoarthritis (OA) patients. IL-40 was analysed in the serum/synovial fluid of patients with RA (n=50), systemic lupus erythematosus (SLE, n=69), OA (n=44), and healthy controls (HC, n=50). We assessed the changes of IL-40 levels in RA patients following the B cell depletion by rituximab (n=29) or after the TNF inhibition by adalimumab (n=25). We examined the relationship between IL-40, disease activity, autoantibodies, cytokines, and NETosis markers. Effect of IL-40 on synovial fibroblasts was determined.ResultsIL-40 was overexpressed in RA synovial tissue, particularly by synovial lining and infiltrating immune cells. The levels of IL-40 were up-regulated in the synovial fluid of RA versus OA patients (p&lt;0.0001). Similarly, IL-40 was increased in the serum of RA patients compared to HC, OA, or SLE (p&lt;0.0001 for all) and decreased after 16 and 24 weeks (p&lt;0.01 and p&lt;0.01) following rituximab treatment. No significant effect of adalimumab on IL-40 was observed. IL-40 levels in RA patients correlated with rheumatoid factor-IgM and anti-cyclic citrullinated peptides (anti-CCP) in the serum (p&lt;0.0001 and p&lt;0.01), as well as in the synovial fluid (p&lt;0.0001 and p&lt;0.001). Synovial fluid IL-40 was also associated with disease activity score DAS28 (p&lt;0.05), synovial fluid leukocyte count (p&lt;0.01), neutrophil attractants IL-8 (p&lt;0.01), MIP-1α (p&lt;0.01), and markers of neutrophil extracellular traps externalization (NETosis) such as proteinase 3 (p&lt;0.0001) and neutrophil elastase (p&lt;0.0001). Synovial fibroblasts exposed to IL-40 increased the secretion of IL-8 (p&lt;0.01), MCP-1 (p&lt;0.05), and MMP-13 (p&lt;0.01) compared to the unstimulated cells.ConclusionsWe show the up-regulation of IL-40 in RA and its decrease following B cell depleting therapy. The association of IL-40 with autoantibodies, chemokines, and markers of NETosis may imply its potential involvement in RA development. Moreover, IL-40 up-regulates the secretion of chemokines and MMP-13 in synovial fibroblasts, indicating its role in the regulation of inflammation and tissue destruction in RA.

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