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      Drug Design, Development and Therapy (submit here)

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      Spotlight on mavrilimumab for the treatment of rheumatoid arthritis: evidence to date


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          The introduction of biological therapies into clinical practice has dramatically modified the natural history of chronic inflammatory diseases, such as rheumatoid arthritis (RA). RA is a systemic autoimmune disease that causes articular damage and has a great negative impact on patients’ quality of life. Despite the wide spectrum of available biological treatments, ~30% of RA patients are still unresponsive, resulting in high disability and increased morbidity and mortality. In the last few decades, the scientific knowledge on RA pathogenesis vastly improved, leading to the identification of new proinflammatory molecules as potential therapeutic targets. Several in vitro and in vivo studies showed that granulocyte-macrophage colony-stimulating factor (GM-CSF), known to be a hematopoietic factor, is also one of the proinflammatory cytokines involved in macrophage activation, crucial for the pathogenic network of RA. Mavrilimumab, a human monoclonal antibody targeting the subunit α of GM-CSF receptor, was recently developed as a competitive antagonist of GM-CSF pathway and successfully adopted in human trials for mild to moderate RA. Mavrilimumab phase I and phase II studies reported an overall good efficacy and safety profile of the drug, and these encouraging results promoted the initiation of worldwide phase III studies. In particular, 158-week results of phase II trials did not show long-term lung toxicity, addressing the major concern about this target of pulmonary alveolar proteinosis development. However, further clinical studies conducted in larger RA populations are needed to confirm these promising results. This review summarizes the biological role of GM-CSF in RA and the preclinical and clinical data on mavrilimumab and other monoclonal antibodies targeted on this pathway as an alternative therapeutic option in RA patients who are unresponsive to conventional biological drugs.

          Most cited references69

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          Colony-stimulating factors in inflammation and autoimmunity.

          Although they were originally defined as haematopoietic-cell growth factors, colony-stimulating factors (CSFs) have been shown to have additional functions by acting directly on mature myeloid cells. Recent data from animal models indicate that the depletion of CSFs has therapeutic benefit in many inflammatory and/or autoimmune conditions and as a result, early-phase clinical trials targeting granulocyte/macrophage colony-stimulating factor and macrophage colony-stimulating factor have now commenced. The distinct biological features of CSFs offer opportunities for specific targeting, but with some associated risks. Here, I describe these biological features, discuss the probable specific outcomes of targeting CSFs in vivo and highlight outstanding questions that need to be addressed.
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            The pathogenesis of rheumatoid arthritis.

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              Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial.

              Tumor necrosis factor (TNF) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti-TNF monoclonal antibody, to inhibit the progression of structural joint damage, reduce the signs and symptoms, and improve physical function in patients with active RA receiving concomitant treatment with methotrexate (MTX). In this multicenter, 52-week, double-blind, placebo-controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to receive adalimumab 40 mg subcutaneously every other week (n = 207), adalimumab 20 mg subcutaneously every week (n = 212), or placebo (n = 200) plus concomitant MTX. The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]). At week 52, there was statistically significantly less radiographic progression, as measured by the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean +/- SD change 0.1 +/- 4.8) or 20 mg weekly (0.8 +/- 4.9) as compared with that in the placebo group (2.7 +/- 6.8) (P < or = 0.001 for each comparison). In addition, there were statistically significant changes in the components of the TSS. At week 24, ACR20 responses were achieved by 63% and 61% of patients in the adalimumab 40 mg every other week and 20 mg weekly groups, respectively, versus 30% of patients in the placebo group (P < or = 0.001 for each comparison). At week 52, ACR20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg every other week and 20 mg weekly, respectively, versus 24% of patients taking placebo (P < or = 0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo (mean change in HAQ score -0.59 and -0.61, respectively, versus -0.25; P < or = 0.001 for each comparison). A total of 467 patients (75.4%) completed 52 weeks of treatment. Adalimumab was generally well tolerated. Discontinuations occurred in 22.0% of adalimumab-treated patients and in 30.0% of placebo-treated patients. The rate of adverse events (both serious and nonserious) was comparable in the adalimumab and placebo groups, although the proportion of patients reporting serious infections was higher in patients receiving adalimumab (3.8%) than in those receiving placebo (0.5%) (P < or = 0.02), and was highest in the patients receiving 40 mg every other week. In this 52-week trial, adalimumab was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                13 January 2017
                : 11
                : 211-223
                [1 ]Department of Clinical Sciences and Health Community, University of Milan, Division of Rheumatology, Gaetano Pini Institute
                [2 ]Department of Rheumatology, Gaetano Pini Institute, Milan, Italy
                Author notes
                Correspondence: Ennio Giulio Favalli, Department of Rheumatology, Gaetano Pini Institute, Milan, Via Gaetano Pini, 9, Milan 20122, Italy, Tel +39 02 5829 6421, Fax +39 02 5829 6315, Email ennio.favalli@ 123456gmail.com
                © 2017 Crotti et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.


                Pharmacology & Pharmaceutical medicine
                rheumatoid arthritis,gm-csf,mavrilimumab,monoclonal antibody,biologic drugs


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