Milestones in Drug Therapy MDT

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3 Milestones in Drug Therapy MDT Series Editors Prof. Michael J. Parnham, PhD Prof. Dr. J. Bruinvels Senior Scientific Advisor Sweelincklaan 75 PLIVA Research Institute Ltd NL-3723 JC Bilthoven Prilaz baruna Filipovića 29 The Netherlands HR Zagreb Croatia

4 TNF-alpha Inhibitors Edited by J.M. Weinberg and R. Buchholz Birkhäuser Verlag Basel Boston Berlin

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6 V Contents List of contributors Preface VII IX Patricia Malerich and Dirk M. Elston Introduction to TNF/pathophysiology of TNF Seth R. Stevens and Ting H. Chang History of development of TNF inhibitors Rahul Shukla and Ronald B. Vender Pharmacology of TNF inhibitors Jeffrey D. Greenberg and Mitsumasa Kishimoto Etanercept in rheumatology Noah Gratch and Andrew F. Alexis Etanercept in dermatology and off-label use Mihaela B. Taylor and Dahlia T. Lainer Infliximab in rheumatology Noah Scheinfeld Infliximab in dermatology, gastroenterology, and off-label use Harry D. Fischer Adalimumab in rheumatology Jennifer Clay Cather and Melodie Young Adalimumab in dermatology Jeffrey M. Weinberg A review of the safety of the tumor necrosis inhibitors infliximab, etanercept, and adalimumab Index

7 VII List of contributors Andrew F. Alexis, St. Luke s-roosevelt Hospital, 1090 Amsterdam Avenue Suite 11B, New York, NY 10025, USA; Ting H. Chang, Amgen, One Amgen Center Drive, MS 27-4-A, Thousand Oaks, CA 91320, USA; Jennifer Clay Cather, Baylor University Medical Center, Dallas, TX 75231, USA; Dirk M. Elston, Department of Dermatology, Geisinger Medical Center, 100 North Academy Ave, Danville, PA , USA; Harry D. Fischer, Rheumatology, Beth Israel Medical Center, Phillips Ambulatory Care Center, 10 Union Square East, Room 3d, New York, NY USA; Noah Gratch, Joan and Sanford Weill Medical College of Cornell University, New York, NY 10021, USA; Jeffrey D. Greenberg, NYU Hospital for Joint Diseases, 301 East 17th Street, Suite 1410, New York, NY 10003, USA; nyumc.org Mitsumasa Kishimoto, NYU Hospital for Joint Diseases, 301 East 17th Street, Suite 1410, New York, NY 10003, USA; yahoo.co.jp Dahlia T. Lainer, David Geffen School of Medicine, UCLA Medical Center and West Los Angeles VAMC, Los Angeles, CA 90095, USA; Patricia Malerich, Department of Dermatology, Geisinger Medical Center, 100 North Academy Ave, Danville, PA , USA; Noah Scheinfeld, Department of Dermatology, St. Luke s-roosevelt Hospital Center, 1090 Amsterdam Avenue, Suite 11D, New York, NY 10025, USA; Rahul Shukla, McMaster University and Dermatrials Research, 132 Young Street, Hamilton, ON, L8N 1V6, Canada; Seth R. Stevens, Amgen, One Amgen Center Drive, MS 27-1-D, Thousand Oaks, CA 91320, USA; Mihaela B. Taylor, David Geffen School of Medicine, UCLA Medical Center, Los Angeles, CA 90095, USA; Ronald B. Vender, McMaster University and Dermatrials Research, 132 Young Street, Hamilton, ON, L8N 1V6, Canada; dermatrials.com

8 VIII List of contributors Jeffrey M. Weinberg, Department of Dermatology, St. Luke s-roosevelt Hospital Center, 1090 Amsterdam Avenue, Suite 11D, New York, NY 10025, USA; Melodie Young, Baylor Health Care System, Dallas, TX 75231, USA;

9 IX Preface Over the last decade, the advent of biologic agents has greatly revolutionized therapeutic medicine in the management of chronic inflammatory diseases, such as rheumatoid arthritis, Crohn s disease, and psoriasis. Elucidation of the complex web of cytokine network and the roles of these cytokines in the pathogenesis of inflammatory disorders provided one of the key catalysts for the advancement of targeted biologic therapy in autoimmune and inflammatory diseases. TNF-α is known to play a crucial role in the pathogenesis of many chronic inflammatory diseases. Elevated levels of TNF-α have been demonstrated in Crohn s disease, psoriasis, psoriatic arthritis, and rheumatoid arthritis, suggesting a role for TNF-α in their pathogenesis. Although TNF-α plays a critical role in the activation of innate and acquired immune responses, the persistence of the immune response and inappropriate production of TNF-α can produce pathological changes resulting from chronic inflammation and tissue damage. The purpose of this volume is to provide a comprehensive overview of the development, pharmacology, efficacy, and safety of the currently available TNF-α inhibitors etanercept, infliximab, and adalimumab. The initial three chapters of the volume provide a background on the field on TNF-α and its inhibition. Chapter 1 provides an introduction to TNF and reviews the pathophysiology of this cytokine. Chapter 2 then presents the history of the development of TNF inhibitors. The pharmacology of these agents is reviewed in Chapter 3. The next segment of the volume provides an in-depth evaluation of the applications and efficacy of each of the individual TNF-inhibitors. Chapter 4 reviews the use of etanercept in rheumatology, while Chapter 5 surveys the use of this drug in dermatology and off-label applications. Chapter 6 evaluates the use of infliximab in rheumatology, and Chapter 7 reviews its use in dermatology, gastroenterology, and as an off-label agent. Finally, Chapters 8 and 9 discuss the use of adalimumab, respectively, in rheumatology and dermatology. The final chapter of the book reviews the safety of all three agents, as the TNF inhibitors share a common set of safety concerns. These drugs have proven very safe, compared with traditional agents, but proper knowledge of their safety issues is necessary for their optimal usage. The use of biologic agents is truly an evolving field. In this volume, an outstanding group of authors have provided the most recent clinical data, encompassing proper applications, efficacy, and safety. We hope that you will find the information useful in the scope of your research or practice. We urge you, however, to keep abreast of this field after reading this volume, as the flow of new information is constant. Jeffrey M. Weinberg Robin Buchholz New York, January 2006

10 TNF-alpha Inhibitors Edited by Jeffrey M. Weinberg and Robin Buchholz 2006 Birkhäuser Verlag/Switzerland 1 Introduction to TNF/pathophysiology of TNF Patricia Malerich and Dirk M. Elston Department of Dermatology, Geisinger Medical Center, Danville, PA, USA Introduction to basic cell to cell communication and cytokines The complex organization of cellular functions in the human body requires a precise interplay of activity. Cell to cell communications must be sent and received in an efficient system. When the distance over which a signal must travel is greater then an intracellular space, soluble polypeptide factors called cytokines are employed as messenger proteins [1]. Cytokines are small proteins released by cells that trigger specific effects on target cells equipped to respond. Cytokines can be broadly categorized as primary and secondary cytokines. Primary cytokines, such as IL-1 and Tumor Necrosis Factor alpha (TNF-α), are considered part of the innate immune system and can independently initiate inflammatory cascades in human tissues. Secondary cytokines are produced later in the cascade, after the primary cytokines. They have a more limited range of activity. TNF- local and systemic effects TNF-α is an example of a primary cytokine and the model for a family of proteins classified by the diverse biologic activities they produce as well as the similarity of their receptor molecules. TNF-α is a multidimensional cytokine with effects on cellular metabolism, antiviral activities, coagulation processes, growth regulation of cells and insulin response. In this text, we will focus on the broad range of TNF-α effects on inflammation and immunity. TNF-α was named based on the observed ability to stimulate necrosis of malignant tumors, but was soon found to be an important mediator of cutaneous inflammation. T cells that recognize peptides bound to major histocompatibility complex (MHC) class II molecules have two types: inflammatory CD4 T cells (Th1) and helper CD4 T cells (Th2). Most antimicrobial responses are Th1 responses, involving a characteristic array of cytokines including TNF-α, IL-12, IL-2, IL-6, IL-8, and IFN-gamma. In contrast, Th2 responses are involved in atopy and allergic reactivity as well as the response to some parasites. Typical Th2 cytokines include IL-4, IL-5, IL-9, and IL-13.

11 2 P. Malerich and D.M. Elston Although the evolutionary advantage of a Th1 inflammatory response may be resistance to infections, TNF-α expression is induced in the course of most inflammatory responses in the skin, and many of these inflammatory responses produce pain, itch and suffering. Control of Th1 responses through modification of cytokine activity has dramatically altered the approach to the treatment of a wide range of inflammatory skin disorders. The recognition of psoriasis as a TNF-α-mediated inflammatory disease was pivotal in the development of biological agents for the treatment of psoriasis. TNF-α also plays a pivotal role in psoriatic arthritis, Crohn s disease, and a range of cutaneous inflammatory disorders [2]. Psoriasis is a hyperproliferative disorder, with the proliferation being driven by a complex cascade of inflammatory mediators. Effective therapeutic agents appear to influence the disease primarily by their effects on the inflammatory cascade. Although the interplay of cytokines is complex, the main signal for development of a Th1 response may be interleukin 12 [3, 4]. Some agents used to treat psoriasis have been shown to affect IL-12, and antibodies specifically targeting this cytokine appear promising as antipsoriatic drugs [5]. Most of the effective biological agents that are currently available target TNF-α, and these agents have proved highly effective in managing severe psoriasis. A shift in the balance from a predominantly Th1 response to a predominantly Th2 response is associated with improvement in psoriasis [6]. Reduced expression of anti-inflammatory cytokines such as IL-1RA and IL-10 has been found in psoriatic plaques, but the antipsoriatic effect of IL-10 may be related to effects on peripheral blood leukocytes rather than a direct effect on keratinocytes [7 9]. Polymorphisms of IL-19 and 20 genes may play a role in the pathogenesis of psoriasis [10]. Polymorphisms for the IL-10 gene predispose towards psoriasis, and a response to therapy is correlated with rising levels of IL-10 mrna expression [11]. Available biologic agents target CD2-positive lymphocytes, CD-11a and TNF-α, and specific targets for therapy include TNF-α, LFA-1/ICAM-1 binding, and LFA-3/CD2 binding. New agents may target other cytokines, including IL-12 and IL-15. IL-15 promotes recruitment of inflammatory cells in psoriasis, as well as angiogenesis, and the production of additional cytokines [12]. An IL-15 monoclonal antibody appears promising in a mouse model of psoriasis [13]. As most of the currently available agents target TNF-α, a thorough understanding of its function and interactions is critical. This will be the major focus of this chapter. Interaction of TNF-α with other cytokines TNF-α induction of cytokine cascades can begin and maintain inflammation. This is evidenced by stimulated release of interleukin-1, interleukin-2, interleukin-6, interleukin-8, granulocyte-macrophage colony-stimulating factor,

12 Introduction to TNF/pathophysiology of TNF 3 transforming growth factor and interferon-γ [14 16]. TNF-α may also be involved in apoptosis of aging lymphocytes [17]. An understanding of the complex relationship of cytokines is critical to the development of agents to modify their effects on inflammation and cellular proliferation. Endothelial cells TNF-α initiates inflammation by changes in the local vasculature. Endothelial cells treated with TNF-α demonstrate increased production of vasodilators such as prostaglandin and nitric oxide. The resulting increase in tissue perfusion serves to increase the concentration of inflammatory cells in the area. TNF-α amplifies endothelial cell surface L selectins, E-selectins and P-selectins, and ICAM-1, in turn encouraging tethering, rolling and adhesion of arriving leukocytes [18, 19]. Endothelial cells also begin to secrete cytokines that assist in activation of leukocytes as well as furthering their migration. TNF-α induces vascular endothelial growth factor aiding in vascular permeability, leukocyte migration and creating new vessel networks but the interplay of these factors is complex [20]. The extravasation of activated leukocytes is an active and multifaceted process that coincides with the nonspecific movement of fluid out of the vessel through the altered vessel wall. Vascular leakage helps to form a matrix that can be used by leukocytes for extended migration, while induction of matrix metalloproteinases results in destruction of the extracellular matrix. These leukocyte behaviors are intimately associated with the inflammatory response in psoriasis and represent targets for therapy. Neutrophils TNF-α enhances accumulation of neutrophils through stimulation of expression of IL-8. Neutrophils may be the major source of IL-8 within psoriatic skin lesions, with autocrine secretion resulting in microabscess and pustule formation [21]. Macrophages TNF-α is major activator of macrophages, increasing nitric oxide production, proinflammatory cytokines and chemokine production. TNF-α upregulates macrophage inflammatory protein-3 alpha (CCL20) and it s receptor in psoriasis [22]. It also acts to upregulate expression of vascular endothelial growth factor and heme oxygenase-1 [20].

13 4 P. Malerich and D.M. Elston Keratinocytes TNF-α regulates not only inflammatory responses but also cell motility, cell cycle activity, and apoptosis. The result is increased proliferation of keratinocytes. Interactions with keratinocytes involve an array of chemokines induced by TNF-α. The sum includes promotion of proliferation, and tissue repair by inducing basement membrane components and collagen-degrading proteases. TNF-α induces actin cytoskeleton regulators and integrins, resulting in enhanced keratinocyte motility and attachment [23]. Joint and bone changes TNF-α stimulates bone and proteoglycan resorption through actions of inflammatory molecules such as prostaglandins and leukotrienes. Cartilage synthesis is not only inhibited but formed cartilage is destroyed by collagenase proteins. TNF-α stimulates neutrophils and fibroblasts to produce a variety of enzymes including collagenase and matrix metalloproteinase that have direct roles in tissue and joint damage [24, 25]. Systemic effects All the members of the class of cytokines represented by TNF-α are capable of initiating a systemic acute phase reaction. TNF-α treated hepatocytes display an increase in acute phase proteins resulting in systemic effects, such as fever and shock. TNF-α can create tissue and vascular injury by increasing pro-coagulant proteins such as tissue factor and at the same time decreasing anticoagulant proteins. Therefore, TNF-α has been thought to play a prominent role in systemic diseases in which the major component is chronic inflammation, including graft versus host disease, bacterial septic shock, and AIDS proliferation of Kaposi s sarcoma cells [26, 27]. TNF and the basic molecular makeup The TNF-α protein belongs to a trimeric domain protein family, which consists of 18 genes mapped to chromosome position 7p21 that encodes 20 proteins [28]. TNF-α exists in a membrane bound nonglycosylated form and in a soluble form. The soluble and membrane bound forms of TNF-α are both biologically dynamic, differentiated by their affinities for receptors. TNF-α-converting enzyme (TACE) or TNF-α-converting activity (TACA) produces TNF-α by cleaving a 233-amino acid precursor protein and also creates the soluble 17-kDa TNF-α by cleaving the 26-kDa transmembrane TNF-α [29]. As the TNF-α monomers are shed from the cell membrane, they combine into