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Tocilizumab in the treatment of rheumatoid arthritis and beyond.

Shetty A, Hanson R, Korsten P, Shawagfeh M, Arami S, Volkov S, Vila O, Swedler W, Shunaigat AN, Smadi S, Sawaqed R, Perkins D, Shahrara S, Sweiss NJ - Drug Des Devel Ther (2014)

Bottom Line: Treatment of RA has improved over the past decade.Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody against the IL-6 receptor and has been approved in many countries, including the United States, for the treatment of moderate to severe RA in patients who have not adequately responded to one or more disease-modifying antirheumatic drugs (DMARDs) or cannot tolerate other approved drug classes for RA.The aim of this review is to discuss the role of IL-6 in RA, and to provide an overview of the mode of action, pharmacokinetics, and safety of TCZ.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology, Pharmacy, Transplant, University of Illinois at Chicago, Chicago, IL, USA.

ABSTRACT
Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by joint pain, swelling, stiffness, and progressive destruction of the small joints of the hands and feet. Treatment of RA has improved over the past decade. With multiple cytokines well-known now to play a role in the pathogenesis of RA, including tumor necrosis factor alpha, interleukin (IL)-1β, and IL-6, many targeted biological treatments against these cytokines have emerged, changing the treatment of this disease. Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody against the IL-6 receptor and has been approved in many countries, including the United States, for the treatment of moderate to severe RA in patients who have not adequately responded to one or more disease-modifying antirheumatic drugs (DMARDs) or cannot tolerate other approved drug classes for RA. The aim of this review is to discuss the role of IL-6 in RA, and to provide an overview of the mode of action, pharmacokinetics, and safety of TCZ. Furthermore, efficacy studies of TCZ as both monotherapy and combination therapy will be evaluated. There have been several important clinical trials evaluating the efficacy and safety of TCZ in RA patients; this review summarizes this data from 14 key trials with emphasis on Phase III trials. Review of these trials provides strong evidence that its use, both as monotherapy and in combination with methotrexate or other DMARDs, is an effective treatment in reducing the signs and symptoms of RA. TCZ showed tolerable safety but care is required for its use since there are some important safety concerns including elevated liver enzymes, elevated low-density lipoprotein, infections, and gastrointestinal perforations. Additionally, given the efficacy of TCZ in the treatment of RA, this review discusses how TCZ may be beneficial in the treatment of other autoimmune diseases, spinal disease, cardiovascular disease, organ transplantation, and malignancies where elevated levels of IL-6 may play a role in the pathogenesis of these diseases.

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Related in: MedlinePlus

Functions of IL-6 in RA and blockage of IL-6 signal transduction by tocilizumab.Notes: Macrophages and fibroblasts produce IL-6, in addition to other proinflammatory cytokines including TNF-α, IL-1β, and IL-17. IL-6 is a pleiotropic proinflammatory cytokine with a variety of biologic effects regulating angiogenesis, bone metabolism, inflammation, immune suppression, autoantibody production, and production of CRP, which all contribute to the pannus formation seen in RA. Tocilizumab blocks these effects by binding to both the soluble and membrane-bound forms of the IL-6 receptor.Abbreviations: Auto-Abs, autoantibodies; CRP, C-reactive protein; IL, interleukin; mIL-6R, membrane bound IL6-receptor; RA, rheumatoid arthritis; RANKL, receptor activator of nuclear factor kappa-B ligand; RF, rheumatoid factor; sIL-6R, soluble IL-6 receptor; TH-17, T helper 17; TNF-α, tumor necrosis factor alpha; Tregs, regulatory T cells; VEGF, vascular endothelial growth factor.
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f1-dddt-8-349: Functions of IL-6 in RA and blockage of IL-6 signal transduction by tocilizumab.Notes: Macrophages and fibroblasts produce IL-6, in addition to other proinflammatory cytokines including TNF-α, IL-1β, and IL-17. IL-6 is a pleiotropic proinflammatory cytokine with a variety of biologic effects regulating angiogenesis, bone metabolism, inflammation, immune suppression, autoantibody production, and production of CRP, which all contribute to the pannus formation seen in RA. Tocilizumab blocks these effects by binding to both the soluble and membrane-bound forms of the IL-6 receptor.Abbreviations: Auto-Abs, autoantibodies; CRP, C-reactive protein; IL, interleukin; mIL-6R, membrane bound IL6-receptor; RA, rheumatoid arthritis; RANKL, receptor activator of nuclear factor kappa-B ligand; RF, rheumatoid factor; sIL-6R, soluble IL-6 receptor; TH-17, T helper 17; TNF-α, tumor necrosis factor alpha; Tregs, regulatory T cells; VEGF, vascular endothelial growth factor.

Mentions: IL-6 works through two differing signaling pathways, a membrane bound IL-6 receptor and a soluble IL-6 receptor. Normally, the IL-6 receptor binds to IL-6 and to a cell-surface glycoprotein called gp130, which is necessary for signal transduction. The gp130-mediated IL-6 signaling pathway works even for cells that do not express the membrane bound IL-6 receptor on their surface. IL-6 and the soluble IL-6 receptor are present in serum and synovial fluids and are seen in higher levels in patients with RA.14 All of these functions in which IL-6 mediates the systemic and articular features of RA make IL-6 blockade an attractive biologic target therapy for the treatment of RA (Figure 1).9


Tocilizumab in the treatment of rheumatoid arthritis and beyond.

Shetty A, Hanson R, Korsten P, Shawagfeh M, Arami S, Volkov S, Vila O, Swedler W, Shunaigat AN, Smadi S, Sawaqed R, Perkins D, Shahrara S, Sweiss NJ - Drug Des Devel Ther (2014)

Functions of IL-6 in RA and blockage of IL-6 signal transduction by tocilizumab.Notes: Macrophages and fibroblasts produce IL-6, in addition to other proinflammatory cytokines including TNF-α, IL-1β, and IL-17. IL-6 is a pleiotropic proinflammatory cytokine with a variety of biologic effects regulating angiogenesis, bone metabolism, inflammation, immune suppression, autoantibody production, and production of CRP, which all contribute to the pannus formation seen in RA. Tocilizumab blocks these effects by binding to both the soluble and membrane-bound forms of the IL-6 receptor.Abbreviations: Auto-Abs, autoantibodies; CRP, C-reactive protein; IL, interleukin; mIL-6R, membrane bound IL6-receptor; RA, rheumatoid arthritis; RANKL, receptor activator of nuclear factor kappa-B ligand; RF, rheumatoid factor; sIL-6R, soluble IL-6 receptor; TH-17, T helper 17; TNF-α, tumor necrosis factor alpha; Tregs, regulatory T cells; VEGF, vascular endothelial growth factor.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3974690&req=5

f1-dddt-8-349: Functions of IL-6 in RA and blockage of IL-6 signal transduction by tocilizumab.Notes: Macrophages and fibroblasts produce IL-6, in addition to other proinflammatory cytokines including TNF-α, IL-1β, and IL-17. IL-6 is a pleiotropic proinflammatory cytokine with a variety of biologic effects regulating angiogenesis, bone metabolism, inflammation, immune suppression, autoantibody production, and production of CRP, which all contribute to the pannus formation seen in RA. Tocilizumab blocks these effects by binding to both the soluble and membrane-bound forms of the IL-6 receptor.Abbreviations: Auto-Abs, autoantibodies; CRP, C-reactive protein; IL, interleukin; mIL-6R, membrane bound IL6-receptor; RA, rheumatoid arthritis; RANKL, receptor activator of nuclear factor kappa-B ligand; RF, rheumatoid factor; sIL-6R, soluble IL-6 receptor; TH-17, T helper 17; TNF-α, tumor necrosis factor alpha; Tregs, regulatory T cells; VEGF, vascular endothelial growth factor.
Mentions: IL-6 works through two differing signaling pathways, a membrane bound IL-6 receptor and a soluble IL-6 receptor. Normally, the IL-6 receptor binds to IL-6 and to a cell-surface glycoprotein called gp130, which is necessary for signal transduction. The gp130-mediated IL-6 signaling pathway works even for cells that do not express the membrane bound IL-6 receptor on their surface. IL-6 and the soluble IL-6 receptor are present in serum and synovial fluids and are seen in higher levels in patients with RA.14 All of these functions in which IL-6 mediates the systemic and articular features of RA make IL-6 blockade an attractive biologic target therapy for the treatment of RA (Figure 1).9

Bottom Line: Treatment of RA has improved over the past decade.Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody against the IL-6 receptor and has been approved in many countries, including the United States, for the treatment of moderate to severe RA in patients who have not adequately responded to one or more disease-modifying antirheumatic drugs (DMARDs) or cannot tolerate other approved drug classes for RA.The aim of this review is to discuss the role of IL-6 in RA, and to provide an overview of the mode of action, pharmacokinetics, and safety of TCZ.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology, Pharmacy, Transplant, University of Illinois at Chicago, Chicago, IL, USA.

ABSTRACT
Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by joint pain, swelling, stiffness, and progressive destruction of the small joints of the hands and feet. Treatment of RA has improved over the past decade. With multiple cytokines well-known now to play a role in the pathogenesis of RA, including tumor necrosis factor alpha, interleukin (IL)-1β, and IL-6, many targeted biological treatments against these cytokines have emerged, changing the treatment of this disease. Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody against the IL-6 receptor and has been approved in many countries, including the United States, for the treatment of moderate to severe RA in patients who have not adequately responded to one or more disease-modifying antirheumatic drugs (DMARDs) or cannot tolerate other approved drug classes for RA. The aim of this review is to discuss the role of IL-6 in RA, and to provide an overview of the mode of action, pharmacokinetics, and safety of TCZ. Furthermore, efficacy studies of TCZ as both monotherapy and combination therapy will be evaluated. There have been several important clinical trials evaluating the efficacy and safety of TCZ in RA patients; this review summarizes this data from 14 key trials with emphasis on Phase III trials. Review of these trials provides strong evidence that its use, both as monotherapy and in combination with methotrexate or other DMARDs, is an effective treatment in reducing the signs and symptoms of RA. TCZ showed tolerable safety but care is required for its use since there are some important safety concerns including elevated liver enzymes, elevated low-density lipoprotein, infections, and gastrointestinal perforations. Additionally, given the efficacy of TCZ in the treatment of RA, this review discusses how TCZ may be beneficial in the treatment of other autoimmune diseases, spinal disease, cardiovascular disease, organ transplantation, and malignancies where elevated levels of IL-6 may play a role in the pathogenesis of these diseases.

Show MeSH
Related in: MedlinePlus