RHODE ISLAND M EDICAL J OURNAL 18 Newer Treatment Strategies for Autoimmune Diseases EDWARD V. LALLY, MD GUEST EDITOR E. Lally, MD 19 Targeted Immunomodulatory Therapy: An Overview ASHLEY L. LEFEBVRE, PharmD, CDOE LAURA MCAULIFFE, PharmD: PGY2 23 Systemic Lupus Erythematosus: A. Lefebvre, PharmD A Review of the Clinical Approach to Diagnosis and Update on Current Targeted Therapies JOANNE SZCZYGIEL CUNHA, MD KATARZYNA GILEK-SEIBERT, MD J. Cunha, MD 28 Pemphigus: Pathogenesis to Treatment K. Gilek-Siebert, MD CHRISTOPHER DIMARCO, MD 32 Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP): C. DiMarco, MD Clinical Features, Diagnosis, and Current Treatment Strategies JACQUES REYNOLDS, DO GEORGE SACHS, MD, PhD G. Sachs, MD, PhD KARA STAVROS, MD 36 Autoimmune Cytopenias: Diagnosis & Management CHRISTIAN P. NIXON, MD, PhD JOSEPH D. SWEENEY, MD C. Nixon, MD, PhD ADVANCES IN AUTOIMMUNE DISEASES Newer Treatment Strategies for Autoimmune Diseases EDWARD V. LALLY, MD GUEST EDITOR 18 18 EN In contemporary parlance, autoimmune disease has been syndromes and can more readily allow for immunotherapy used as a designation for a variety of chronic inflammatory directed at specific pathways (“targeted therapies”). disorders that are characterized by the presence of auto- In this issue of the Rhode Island Medical Journal, we antibodies. This rubric has been applied to diseases whose review four inflammatory syndromes traditionally consid- etiologies are not infectious, neoplastic or degenerative in ered to be autoimmune in nature. By the above definition, nature. The autoantibody profile may simply include a pos- two of these (SLE, pemphigus) would be viewed as auto- itive antinuclear antibody (ANA) test or it may be further antibody-mediated but the other two (cytopenias, CIDP) defined by autoantibodies with specific identifiable auto- both likely fit the criteria even though the demonstration antigens. By this description, autoimmune disease encom- of specific autoantibodies in these disorders has been elu- passes a wide variety of disorders manifesting as chronic sive. Other immunologically-mediated diseases (rheumatoid inflammation confined to a tissue or organ or as a systemic arthritis, multiple sclerosis, inflammatory bowel disease, inflammatory disease. Although, this nosology may serve myasthenia gravis, and autoimmune thyroid and liver dis- to define syndromes that may be amenable to specific anti- ease) should also be viewed as autoimmune in nature. There inflammatory or immunosuppressive treatments, it has not have been significant developments in immunomodulatory served to advance our understanding of the etiology of these therapy as reviewed in the introductory article by Lefebvre diseases, nor does it imply that the autoantibodies them- and McAuliffe. There is convincing evidence that the dis- selves directly participate in the pathogenesis of the disease. eases listed in this review article are characterized by While these diseases may be “immunologically-mediated”, antigen-driven T-Cell activation and subsequent pro-inflam- there is often very little evidence that these autoantibodies matory cytokine generation. However, effective strategies actually are involved in the disease pathogenesis. to abrogate T-cell activation and block resultant cytokines A stricter definition of autoimmune disease would or cytokine receptors have outpaced the ability to identify include the stipulation, that not only should autoantibodies specific triggering antigens or subsequent autoantibodies be present, but that there is evidence to support the notion that are pathogenic. Nonetheless, the advent of such sophis- that they actually participate in the etiopathogenesis of the ticated targeted therapies will undoubtedly improve man- disorder. This definition adds a more rational framework agement and outcomes for immunologically-mediated for understanding autoimmune disease. It also allows for a diseases, some, but not all, of which should be considered better characterizing of the immunopathogenesis of these auto-immune in nature. Author Edward V. Lally, MD, is Professor of Medicine, and Director, Division of Rheumatology, Rhode Island Hospital and The Alpert Medical School of Brown University. WWW.RIMED.ORG | RIMJ ARCHIVES | DECEMBER WEBPAGE DECEMBER 2016 RHODE ISLAND MEDICAL JOURNAL 18 ADVANCES IN AUTOIMMUNE DISEASES Targeted Immunomodulatory Therapy: An Overview ASHLEY L. LEFEBVRE, PharmD, CDOE; LAURA MCAULIFFE, PharmD 19 22 EN ABSTRACT species of the mAB (i.e. human, mouse, chimeric, etc.). The Monoclonal antibodies and other biologic response mod- suffix “-mab” is common to most mABs.3 ifiers have allowed for targeted drug therapy in manag- ing various autoimmune diseases. A number of immune pathways have been exploited in the development of CYTOKINE-DIRECTED THERAPIES targeted immunomodulatory therapies, including cyto- TNFα Inhibitors kine-directed therapies such as tumor necrosis factor-al- Tumor necrosis factor-alpha (TNFα) is a cell-signaling pro- pha and interleukins, integrins, B-cells, and co-stimulation tein, or cytokine, that induces cell proliferation and differ- modulators. With new targeted therapies in the pipe- entiation through its interaction with TNF receptors on cell line, more options are becoming available for treatment surfaces. TNFα plays a role early in many inflammatory of autoimmune diseases. immune processes. It is produced primarily by macrophages, KEYWORDS: monoclonal antibodies, biologic response but also by monocytes, B-cells, and other tissues. Activa- modifiers, immunomodulatory therapy tion of TNFα also leads to the secretion of interleukin (IL)-1 and IL-6, both proinflammatory cytokines. Dysregulation of TNFα can lead to the development of various autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), ankylosing spondilitis, and psoriasis.4 For INTRODUCTION instance, in IBD, TNFα secretion leads to the stimulation of With major advances in genetic sequencing and biomedi- endothelial cells to express adhesion molecules, facilitating cal research, targeted therapy with monoclonal antibodies migration of various white blood cells into inflamed tissue.5 (mABs) has emerged as a successful strategy for managing TNFα inhibitor therapies are recombinant IgG mABs that autoimmune diseases. Treatment with mABs has the advan- essentially serve as decoy TNF receptors. They bind to TNFα tage of modifying specific immune pathways as opposed to molecules and prevent their interaction with TNF receptors, other non-specific therapies. The first mAB (muromonab ultimately leading to suppression of the immune system and CD3) was developed from mice and approved in 1986 to inflammatory responses. Examples of TNFα inhibitors are prevent rejection of a kidney transplant.1 However, this adalimumab and etanercept, with the latter possessing a lon- first generation of mABs was not well-tolerated due to for- ger half-life due to its dimeric nature. The goal of treatment eign recognition of the murine components by the patient’s with TNFα inhibitor therapy is to reduce inflammation and immune system.2 severity of symptoms, with the hope of achieving improved Since then, different approaches to producing chimeric quality of life. (part mouse, part human) and fully humanized mABs have been discovered, rendering mABs less immunogenic. One Interleukins such approach to producing mABs is from hybridomas, Interleukins are a large class of cytokines responsible for var- formed from the fusion of B-lymphocytes and immortal ious immune responses, including inflammatory response myeloma cells.1 The B-lymphocytes are obtained from the mediation, lymphocyte growth and differentiation, and spleens of mice after they have been immunized against a immune cell chemotaxis, which can be implicated in auto- specific antigenic determinant, or epitope.1 The hybridomas immune diseases. Interleukin-17A (IL-17A), produced largely are cultured, leading to the generation of polyclonal antibod- by T-helper 17 cells (Th17), acts directly on keratinocytes ies. The polyclonal culture is screened for the desired anti- to stimulate various pro-inflammatory processes in plaque body activity and then cloned.1 psoriasis.6 Interleukin-12 (IL-12) and interleukin-23 (IL-23) The World Health Organization has policies for nomen- have been implicated in the production and development of clature of mABs.3 The structure is composed of four parts: Th17 cells, leading to psoriatic plaques and joint inflamma- the prefix, substem-A, substem-B, and suffix. Substem-A tion in psoriatic arthritis.7 In RA, IL-6 is released directly by indicates the nature of the target of the mAB, such as tumor synovial cells and macrophages into the synovium causing or cardiovascular. Substem-B indicates the originating inflammation and destruction.8 WWW.RIMED.ORG | RIMJ ARCHIVES | DECEMBER WEBPAGE DECEMBER 2016 RHODE ISLAND MEDICAL JOURNAL 19 ADVANCES IN AUTOIMMUNE DISEASES Monoclonal antibodies targeting interleukins are directed notice and produce antibodies, present “self” antigens, and at cytokines involved in the production of interleukin, the produce various cytokines implicated in the disease process. interleukin itself, or receptors at which interleukin exerts Monoclonal antibodies directed at B-cells are generally its effect. Ustekinumab was developed against the p40 sub- focused at B-cell depletion. The primary agent used for unit of both IL-12 and -23, both important in differentiation B-cell depletion in autoimmune diseases is rituximab,