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      Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis

      review-article
      1 , 2 , 1 , *
      Cells
      MDPI
      rheumatoid arthritis, autoimmunity, TNF, IL-6

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          Abstract

          Rheumatoid arthritis (RA) is an autoimmune disease that involves multiple joints bilaterally. It is characterized by an inflammation of the tendon (tenosynovitis) resulting in both cartilage destruction and bone erosion. While until the 1990s RA frequently resulted in disability, inability to work, and increased mortality, newer treatment options have made RA a manageable disease. Here, great progress has been made in the development of disease-modifying anti-rheumatic drugs (DMARDs) which target inflammation and thereby prevent further joint damage. The available DMARDs are subdivided into (1) conventional synthetic DMARDs (methotrexate, hydrochloroquine, and sulfadiazine), (2) targeted synthetic DMARDs (pan-JAK- and JAK1/2-inhibitors), and (3) biologic DMARDs (tumor necrosis factor (TNF)-α inhibitors, TNF-receptor (R) inhibitors, IL-6 inhibitors, IL-6R inhibitors, B cell depleting antibodies, and inhibitors of co-stimulatory molecules). While DMARDs have repeatedly demonstrated the potential to greatly improve disease symptoms and prevent disease progression in RA patients, they are associated with considerable side-effects and high financial costs. This review summarizes our current understanding of the underlying pathomechanism, diagnosis of RA, as well as the mode of action, clinical benefits, and side-effects of the currently available DMARDs.

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          Most cited references271

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          The NLRP3 inflammasome: molecular activation and regulation to therapeutics

          NLRP3 (NACHT, LRR and PYD domains-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase-1-dependent release of the proinflammatory cytokines, IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical basis of NLRP3 activation and regulation, and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.
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            Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis.

            Rheumatoid arthritis (RA) remains a significant unmet medical need despite significant therapeutic advances. The pathogenesis of RA is complex and includes many cell types, including T cells, B cells, and macrophages. Fibroblast-like synoviocytes (FLS) in the synovial intimal lining also play a key role by producing cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Rheumatoid FLS develop a unique aggressive phenotype that increases invasiveness into the extracellular matrix and further exacerbates joint damage. Recent advances in understanding the biology of FLS, including their regulation regulate innate immune responses and activation of intracellular signaling mechanisms that control their behavior, provide novel insights into disease mechanisms. New agents that target FLS could potentially complement the current therapies without major deleterious effect on adaptive immune responses.
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              Diagnosis and Management of Rheumatoid Arthritis

              Rheumatoid arthritis (RA) occurs in about 5 per 1000 people and can lead to severe joint damage and disability. Significant progress has been made over the past 2 decades regarding understanding of disease pathophysiology, optimal outcome measures, and effective treatment strategies, including the recognition of the importance of diagnosing and treating RA early.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                03 April 2020
                April 2020
                : 9
                : 4
                : 880
                Affiliations
                [1 ]Paul-Ehrlich-Institut, Vice President’s Research Group 1: Molecular Allergology, 63225 Langen (Hesse), Germany; Yen-Ju.Lin@ 123456pei.de
                [2 ]Paul-Ehrlich-Institut, Product Testing of Immunological Biomedicines, 63225 Langen (Hesse), Germany; Martina.Anzaghe@ 123456pei.de
                Author notes
                [* ]Correspondence: Stefan.Schuelke@ 123456pei.de ; Tel.: +49-6103-775209
                [†]

                These authors have contributed equally to this manuscript.

                Author information
                https://orcid.org/0000-0002-9674-5116
                Article
                cells-09-00880
                10.3390/cells9040880
                7226834
                32260219
                029509d9-64b4-425b-858a-982ef700e704
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 23 January 2020
                : 30 March 2020
                Categories
                Review

                rheumatoid arthritis,autoimmunity,tnf,il-6
                rheumatoid arthritis, autoimmunity, tnf, il-6

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