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      Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies

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          Abstract

          Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A better understanding of how the pathological mechanisms drive the deterioration of RA progress in individuals is urgently required in order to develop therapies that will effectively treat patients at each stage of the disease progress. Here we dissect the etiology and pathology at specific stages: (i) triggering, (ii) maturation, (iii) targeting, and (iv) fulminant stage, concomitant with hyperplastic synovium, cartilage damage, bone erosion, and systemic consequences. Modern pharmacologic therapies (including conventional, biological, and novel potential small molecule disease-modifying anti-rheumatic drugs) remain the mainstay of RA treatment and there has been significant progress toward achieving disease remission without joint deformity. Despite this, a significant proportion of RA patients do not effectively respond to the current therapies and thus new drugs are urgently required. This review discusses recent advances of our  understanding of RA pathogenesis, disease modifying drugs, and provides perspectives on next generation therapeutics for RA.

          Rheumatoid Arthritis: A preventable disease?

          The preclinical stages of rheumatoid arthritis (RA) represent a golden window for the development of therapies which could someday prevent the onset of clinical disease. The autoimmune processes underpinning RA usually begin many years before symptoms such as joint pain and stiffness emerge. Recent studies have identified some of the key cellular players driving these processes and begun to unpick how genetic and environmental risk factors combine to trigger them; they also suggest the existence of several distinct subtypes of RA, which require further exploration. Jiake Xu at the University of Western Australia in Perth and colleagues review current treatment strategies for RA and how such insights could ultimately lead to the earlier diagnosis of RA - as well as providing new opportunities for drug treatment and prevention through behavioral changes in high-risk individuals.

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          Most cited references 151

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          Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial.

          To evaluate the efficacy and safety of adalimumab (D2E7), a fully human monoclonal tumor necrosis factor alpha antibody, in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite treatment with MTX. In a 24-week, randomized, double-blind, placebo-controlled study, 271 patients with active RA were randomly assigned to receive injections of adalimumab (20 mg, 40 mg, or 80 mg subcutaneously) or placebo every other week while continuing to take their long-term stable dosage of MTX. The primary efficacy end point was the American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks. An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg, 40-mg, and 80-mg adalimumab plus MTX groups (47.8%, 67.2%, and 65.8%, respectively) than in the placebo plus MTX group (14.5%) (P < 0.001). ACR50 response rates with the 20-mg, 40-mg, and 80-mg adalimumab dosages (31.9%, 55.2%, and 42.5%, respectively) were significantly greater than that with placebo (8.1%) (P = 0.003, P < 0.001, and P < 0.001, respectively). The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response (26.9% and 19.2%, respectively) that was statistically significantly greater than that with placebo (4.8%) (P < 0.001 and P = 0.020). Responses were rapid, with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit (week 1). Adalimumab was safe and well tolerated; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events. The addition of adalimumab at a dosage of 20 mg, 40 mg, or 80 mg administered subcutaneously every other week to long-term MTX therapy in patients with active RA provided significant, rapid, and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo.
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            The pathogenesis of rheumatoid arthritis.

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              Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin.

              Autoimmunity is complicated by bone loss. In human rheumatoid arthritis (RA), the most severe inflammatory joint disease, autoantibodies against citrullinated proteins are among the strongest risk factors for bone destruction. We therefore hypothesized that these autoantibodies directly influence bone metabolism. Here, we found a strong and specific association between autoantibodies against citrullinated proteins and serum markers for osteoclast-mediated bone resorption in RA patients. Moreover, human osteoclasts expressed enzymes eliciting protein citrullination, and specific N-terminal citrullination of vimentin was induced during osteoclast differentiation. Affinity-purified human autoantibodies against mutated citrullinated vimentin (MCV) not only bound to osteoclast surfaces, but also led to robust induction of osteoclastogenesis and bone-resorptive activity. Adoptive transfer of purified human MCV autoantibodies into mice induced osteopenia and increased osteoclastogenesis. This effect was based on the inducible release of TNF-α from osteoclast precursors and the subsequent increase of osteoclast precursor cell numbers with enhanced expression of activation and growth factor receptors. Our data thus suggest that autoantibody formation in response to citrullinated vimentin directly induces bone loss, providing a link between the adaptive immune system and bone.
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                Author and article information

                Contributors
                jiake.xu@uwa.edu.au
                Journal
                Bone Res
                Bone Res
                Bone Research
                Nature Publishing Group UK (London )
                2095-4700
                2095-6231
                27 April 2018
                27 April 2018
                2018
                : 6
                Affiliations
                [1 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Department of Spine Surgery, Xiangya Hospital, , Central South University, ; No. 87, Xiangya Road, 410008 Changsha, China
                [2 ]ISNI 0000 0004 1936 7910, GRID grid.1012.2, School of Biomedical Sciences, Faculty of Health and Medical Sciences, , The University of Western Australia, ; Nedlands, Western Australia 6009 Australia
                [3 ]Musculoskeletal Health Network, Department of Health WA, 189 Royal Street, East Perth, WA 6004 Australia
                [4 ]ISNI 0000 0004 1936 7910, GRID grid.1012.2, School of Medicine, Faculty of Health and Medical Sciences, , The University of Western Australia, ; Nedlands, Western Australia 6009 Australia
                Article
                16
                10.1038/s41413-018-0016-9
                5920070
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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