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      Tocilizumab in the treatment of rheumatoid arthritis: an evidence-based review and patient selection

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          Abstract

          Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by articular and systemic manifestations, such as anemia, fatigue, osteoporosis, and increased risk for cardiovascular diseases. The pathogenesis of RA is driven by a complex network of proinflammatory cytokines, with a pivotal role of IL-6 and tumor necrosis factor (TNF). The management of RA has been dramatically changed during the last years by the introduction of a treat-to-target approach aiming to achieve an acceptable disease control. Nowadays, TNF inhibitors (TNFis) are the most frequently prescribed class of biologic therapies, but the significant proportion of patients experiencing the failure of a TNFi led to the development of alternative therapeutic options targeted on different pathways. Considering the increasing number of targeted therapeutic options for RA, there is a growing interest in the identification of potential predictors of clinical response to each available mechanism of action, with the aim to drive the management of the disease toward a personalized approach according to the concept of precision medicine. Tocilizumab (TCZ) is the first humanized anti-IL-6 receptor subunit alpha (anti-IL-6R) monoclonal antibody approved for the treatment of RA refractory to methotrexate or TNFis. TCZ inhibits both the cis- and trans-signaling cascades involving the Janus kinase-signal transducer and the activator of transcription pathway, playing a crucial role in modulating not only joint inflammation but also the previously mentioned extra-articular manifestations and comorbidities of RA, such as fatigue, anemia, bone loss, depression, type 2 diabetes, and increased cardiovascular risk. In this review, moving from pathogenetic insights and evidence-based clinical data from randomized controlled trials and real-life observational studies, we will discuss the drivers for the selection of patient candidates to receive TCZ, in order to clarify the current positioning of this drug in the treatment algorithm of RA.

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          Most cited references 102

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          TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.

          We describe de novo generation of IL-17-producing T cells from naive CD4 T cells, induced in cocultures of naive CD4 T cells and naturally occurring CD4+ CD25+ T cells (Treg) in the presence of TLR3, TLR4, or TLR9 stimuli. Treg can be substituted by TGFbeta1, which, together with the proinflammatory cytokine IL-6, supports the differentiation of IL-17-producing T cells, a process that is amplified by IL-1beta and TNFalpha. We could not detect a role for IL-23 in the differentiation of IL-17-producing T cells but confirmed its importance for their survival and expansion. Transcription factors GATA-3 and T-bet, as well as its target Hlx, are absent in IL-17-producing T cells, and they do not express the negative regulator for TGFbeta signaling, Smad7. Our data indicate that, in the presence of IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation of IL-17-producing T cells.
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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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              Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial.

              Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses. Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis. In this double-blind, randomised, placebo-controlled, parallel group phase III study, 623 patients with moderate to severe active rheumatoid arthritis were randomly assigned with an interactive voice response system, stratified by site with a randomisation list provided by the study sponsor, to receive tocilizumab 8 mg/kg (n=205), tocilizumab 4 mg/kg (214), or placebo (204) intravenously every 4 weeks, with methotrexate at stable pre-study doses (10-25 mg/week). Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20% improvement in both swollen and tender joint counts. The primary endpoint was the proportion of patients with 20% improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria (ACR20 response) at week 24. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00106548. The intention-to-treat analysis population consisted of 622 patients: one patient in the 4 mg/kg group did not receive study treatment and was thus excluded. At 24 weeks, ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo (120 [59%] patients in the 8 mg/kg group, 102 [48%] in the 4 mg/kg group, 54 [26%] in the placebo group; odds ratio 4.0 [95% CI 2.6-6.1], p<0.0001 for 8 mg/kg vs placebo; and 2.6 [1.7-3.9], p<0.0001 for 4 mg/kg vs placebo). More people receiving tocilizumab than those receiving placebo had at least one adverse event (143 [69%] in the 8 mg/kg group; 151 [71%] in the 4 mg/kg group; 129 [63%] in the placebo group). The most common serious adverse events were serious infections or infestations, reported by six patients in the 8 mg/kg group, three in the 4 mg/kg group, and two in the placebo group. Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis. F Hoffmann-La Roche, Chugai Pharmaceutical.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2019
                19 December 2018
                : 13
                : 57-70
                Affiliations
                [1 ]Department of Rheumatology, Gaetano Pini Institute, Milan, Italy, ennio.favalli@ 123456gmail.com
                [2 ]Department of Clinical Sciences and Health Community, University of Milan, Division of Rheumatology, Gaetano Pini Institute, Milan, Italy
                Author notes
                Correspondence: Ennio Giulio Favalli, Department of Rheumatology, Gaetano Pini Institute, Milan Via Gaetano Pini, 9 20122 Milan, Italy, Tel +39 25 829 6421, Email ennio.favalli@ 123456gmail.com
                Article
                dddt-13-057
                10.2147/DDDT.S150580
                6304084
                © 2019 Biggioggero 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.

                Categories
                Review

                Pharmacology & Pharmaceutical medicine

                real-life, efficacy, clinical trials, profiling, il-6

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