Adverse Reactions to Biologics

Transcription

1 Adverse Reactions to Biologics

2 Current Problems in Dermatology Vol. 53 Series Editors Peter Itin Basel Gregor B.E. Jemec Roskilde

3 Adverse Reactions to Biologics Volume Editors Lluís Puig Barcelona Wayne Gulliver St. John s, NL 25 figures, 24 in color, and 12 tables, 2018 Basel Freiburg Paris London New York Chennai New Delhi Bangkok Beijing Shanghai Tokyo Kuala Lumpur Singapore Sydney

4 Lluís Puig Hospital de la Santa Creu i Sant Pau Department of Dermatology Barcelona (Spain) Wayne Gulliver Faculty of Medicine Division of Medicine and Dermatology St. John s, NL (Canada) Library of Congress Cataloging-in-Publication Data Names: Puig Sanz, Lluís, editor. Gulliver, Wayne, editor. Title: Adverse reactions to biologics / volume editors, Lluís Puig, Wayne Gulliver. Other titles: Current problems in dermatology ; v Description: Basel ; New York : Karger, Series: Current problems in dermatology, ISSN ; vol. 53 Includes bibliographical references and index. Identifiers: LCCN ISBN (hard cover : alk. paper) ISBN (electronic version) Subjects: MESH: Skin Diseases--drug therapy Biological Products--adverse effects Biological Products--therapeutic use Classification: LCC RL110 NLM WR 650 DDC 616.5/06--dc23 LC record available at Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents and Index Medicus. Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Copyright 2018 by S. Karger AG, P.O. Box, CH 4009 Basel (Switzerland) Printed on acid-free and non-aging paper (ISO 9706) ISSN e-issn ISBN e-isbn

5 Contents VI Preface Puig, L. (Barcelona); Gulliver, W. (St. John s, NL) VII Introduction Biologics in Dermatology: Indications and Off-Label Usage Puig, L. (Barcelona); Gulliver, W. (St. John s, NL) 1 Adverse Reactions to Biologics in Psoriasis Lockwood, S.J.; Prens, L.M.; Kimball, A.B. (Boston, MA) 15 Clinical Trial and Registry Data Gooderham, M. (Peterborough, ON/Waterloo, ON/Kingston, ON); Papp, K. (Waterloo, ON) 28 Immunosuppression/Infections across Indications Al-Khalili, A.; Dutz, J.P. (Vancouver, BC) 37 The Immunogenicity of Biologic Therapies Garcês, S. (Indianapolis, IN); Demengeot, J. (Oeiras) 49 Paradoxical Reactions: Anti-Tumor Necrosis Factor Alpha Agents, Ustekinumab, Secukinumab, Ixekizumab, and Others Puig, L. (Barcelona) 64 Bullous Diseases Corbaux, C.; Joly, P. (Rouen) 70 Adverse Reactions of Antibody-Therapy for Primary Cutaneous Lymphomas: Rituximab, Brentuximab Vedotin, Alemtuzumab, and Mogamulizumab Saulite, I. (St. Gallen/Riga); Guenova, E. (St. Gallen/Zurich); Hoetzenecker, W. (St. Gallen/Linz) 82 Adverse Reactions to Biologics: Melanoma (Ipilimumab, Nivolumab, Pembrolizumab) Hwang, S.J.E.; Fernández-Peñas, P. (Sydney) 93 Skin Manifestations of Targeted Antineoplastic Therapy Sanmartín, O. (Valencia) 105 Author Index 106 Subject Index V

6 Preface In many areas of medicine, we still face the great challenge of finding therapies that will fulfill our patient s unmet needs. In dermatology, we have risen to the challenge on multiple fronts through advances in the understanding of both the genetics and immunopathogenesis of many inflammatory and malignant cutaneous disorders. This, combined with significant advances in targeted immunotherapy, has resulted in improved outcomes as these newer therapies are being used for both approved and off-label therapies for multiple chronic cutaneous disorders and multiple forms of skin cancer. As in dermatology, many other specialties also have patients benefiting from targeted therapy. Many of these therapies come with an adverse event profile that includes a range of cutaneous disorders. All of these therapies have an adverse event profile with a wide spectrum ranging from mild reactions such as upper respiratory tract infection or morbilliform drug eruption to life-threatening disorders that include severe infections, anaphylactic reactions or toxic epidermal necrolysis. As clinicians we always manage our patients on the basis of risk and benefit. Thus, we felt it would be important to gather a group of experts to evaluate the present state of knowledge with respect to adverse events to biologics used in patients with chronic cutaneous disorders or skin cancers, as well as biologics used by other specialties that significantly impact the skin. The expectation is that by truly understanding the risk of these targeted therapies, we will better manage our patients, resulting in significantly improved outcomes while striving to keep the risk to a minimum. We sincerely thank the authors for their valuable contribution in helping us understand the adverse reactions to biologics, and we know that many patients will benefit from the work as we disseminate this substantive body of information that we hope will have value to the practicing physician. Lluís Puig, Barcelona Wayne Gulliver, St. John s, NL VI

7 Introduction Biologics in Dermatology: Indications and Off-Label Usage The use of biologics in dermatology has been the subject of some recent excellent reviews [1 3] and highlights the number of cutaneous disorders for which these targeted therapeutics are both indicated for use or being used off-label. As well, of interest to the dermatologist, a significant number of biologics which have been developed for non-dermatological use have been associated with a multitude of cutaneous adverse events. It is, therefore, imperative that the dermatologist be familiar with adverse events associated with biological agents used in dermatological and nondermatological diseases. As dermatologists, we were first introduced to biologics about 14 years ago with the marketing authorization of alefacept, an immunoglobulin G1 (IgG1) recombinant dimeric fusion protein targeting LFA-3 [2] and indicated for the treatment of moderate-to-severe psoriasis. The primary endpoint of a 75% improvement in the psoriasis area severity index was achieved in approximately 20% patients, with some noted to have a lasting response of up to 1 year [2]. In 2016, ixekizumab, a humanized IgG4 antibody that neutralizes IL-17A, was approved by the FDA for the treatment of moderate-to-severe psoriasis [1]. Approximately 89% of ixekizumab-treated patients achieve PASI 75 improvement. The adverse event profiles of both molecules, while different, are acceptable. Today multiple biologics have been approved and are indicated for the treatment of moderate-to-severe chronic plaque psoriasis, and have efficacy and safety profiles that allow continuous use with a risk-benefit ratio that is acceptable to the regulators. This was not the case in the past, and in 2009 efalizumab was voluntarily withdrawn from the market when the severe but rare side effect of progressive multifocal leukoencephalopathy (PML) was observed. In 2017, dermatologists have a multitude of options to treat moderate-to-severe psoriasis and these include drugs that target tumor necrosis factor (TNF), namely etanercept, infliximab, and adalimumab. In addition to the approved indication of moderate-to-severe psoriasis, adalimumab is also approved for the treatment of hidradenitis suppurativa (HS). As well, TNF antagonists have been used off-label in the treatment of pyoderma gangrenosum, chronic spontaneous urticaria, urticarial vasculitis, and atopic dermatitis [1]. The anti-il-12/23 molecule ustekinumab is also approved for the treatment of moderate-tosevere chronic plaque psoriasis and has also been used off-label in the treatment of HS [1]. In , we saw the arrival of anti-il-17s including secukinumab and ixekizumab, again both approved for the treatment of moderate-tosevere psoriasis. It is theorized that IL-17 may play a role in other inflammatory skin disorders such as HS, and the expectation is that drugs targeting IL-17 will also be explored for this indication [4]. VII

8 The search for new therapies for treating moderate-to-severe chronic plaque psoriasis continues with other anti-il-17 monoclonal antibodies just approved (brodalumab) or under development (e.g. bimekizumab) [1]. New targets including IL-23 have been identified and drugs targeting IL-23 including guselkumab (just approved by the FDA), and tildrakizumab and others under development, such as risankizumab and mirikizumab [1]. With the significant number of biologics on the market for the treatment of moderate-to-severe chronic plaque psoriasis, it is important that we understand the common, unique, and severe adverse events associated with each of these therapies. To this end Lockwood et al. [pp. 1 14], Gooderham et al. [pp ], Al-Khalili et al. [pp ] discuss adverse reactions to biologics used in psoriasis. The information contained in these chapters will also be relevant to biologics such as adalimumab when indicated for the treatment of HS as well as for the biologics used offlabel for a multitude of cutaneous disorders, as previously mentioned. It is extremely satisfactory to know that the vast majority of patients receiving biologic therapy for the treatment of chronic plaque psoriasis achieve 75% or greater improvement in the cutaneous signs and symptoms of psoriasis, and a significant improvement is also observed in the patient s quality of life. Furthermore, it is reassuring to note that based on clinical trials and extensive registry data, these drugs are often well-tolerated and safe, and their side effect profile can be predicted on the basis of our understanding of immunopathogenesis of psoriasis, psoriasis animal models, and human populations with similar cytokine deficiencies. As cytokines are important molecules in the host response to infection, it is impressive that the risk of infection with biologic therapy in chronic plaque psoriasis is small, but as we see in the chapter Al-Khalili et al. [pp ] special consideration must be given to granulomatous infections, viral hepatitis, human immunodeficiency virus, and fungal infections, as well as to the perioperative management of those patients. As these molecules are foreign proteins, they elicit an immune response. This immune response may have little or no consequence as in the production of non-neutralizing antibodies. On the other end of the spectrum, anti-drug antibodies as described by Garcês and Demengeot [pp ] can result in unwanted consequences including immune complex formation, alterations in pharmacokinetics, and reduction of drug efficacy as well as potentially increasing the risk of significant adverse events, such as drug hypersensitivity type reactions. It is therefore imperative that we understand the immunogenicity of our biologic therapies because of its potential impact on response to treatment and the adverse event profile. Puig [pp ] reviews the paradoxical reactions to biologic therapies, a phenomenon that could be potentially related to the unique pathogenesis of psoriasis in a small subset of patients, coupled with the immunogenicity of biologics used to treat psoriasis. These paradoxical reactions range anywhere from worsening of the chronic plaque psoriasis being treated to the induction of other forms of psoriasis, such as palmoplantar pustular psoriasis, generalized pustular psoriasis, or erythrodermic psoriasis. Some or all of these events have been observed with all of the biologics presently on the market for the treatment of chronic plaque psoriasis. When it comes to immune bullous disorders, we have no approved biologic treatment, but Corbaux and Joly [pp ] discuss rituximab and other anti-cd20 targeting molecules that are used for treating immune bullous disorders. The other potential target for treating immune bullous disorders include IgE, so it is not surprising that the anti-ige monoclonal antibody omalizumab, which is approved for the treatment of asthma and chronic spontaneous urticaria, has been used off-label in patients with bullous pem- VIII Puig Gulliver

9 phigoid. Rituximab and the other anti-cd20 targeting molecules are also used off-label in multiple inflammatory skin disorders including dermatomyositis, systemic lupus erythematosus, graft-versus-host disease, and cutaneous B-cell lymphoma [1]. Omalizumab has also been used off-label in the treatment of atopic dermatitis [3]. Although these molecules are generally considered safe, significant adverse events including infections, PML, and severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been associated with rituximab, while omalizumab can run the risk of inducing anaphylaxis. Along with the advances in treating inflammatory disorders of the skin, significant progress has been made in treating cutaneous malignancies, especially melanoma and cutaneous lymphoma. Hwang and Fernández-Peñas [pp ] discuss the biologics ipilimumab, a human monoclonal IgG1, and tremelimumab, a human monoclonal IgG2 that target cytotoxic T-lymphocyte antigen-4. These drugs can lead to improved survival, but are associated with multiple cutaneous adverse events ranging from vitiligo to toxic epidermal necrolysis, which is associated with significant mortality and morbidity. Multiple cutaneous toxicities have also been reported with this class of drugs, and it is important for the clinician to recognize these eruptions as some of them can require dose adjustment or discontinuation of therapy. Another class of melanoma therapy includes monoclonal antibodies that target programmed cell death-1 (PD-1) and other checkpoint inhibitors. These include nivolumab and pembrolizumab, both showing improvements in response rate in the 30 40% range, with a lasting response in many patients. These drugs are also being used off-label for recurrent or metastatic squamous cell carcinoma of the head and neck, as well as for advanced Merkel cell carcinoma. Again drugs that target PD-1 are associated with multiple cutaneous adverse events ranging from pruritus, eczema, and psoriasis to severe vesiculobullous reactions. Disorders of pigmentation have also been observed. In recent trials, anti-cytotoxic T-lymphocyte antigen-4 and anti-pd-1 therapies have been combined, again with a significant number of patients developing cutaneous toxicities. P rimary cutaneous B- or T-cell lymphomas have also seen advances in treatment through the development of monoclonal antibodies, as outlined by Saulite et al. [pp ]. They may be helpful in advanced stages of primary cutaneous lymphomas where aggressive polychemotherapy is associated with significant adverse events and low rates of complete remission. Monoclonal antibodies for the treatment of primary cutaneous lymphomas have a broad clinical spectrum of potential toxicities, as they not only target the tumor cells, but also normal B- and T-cells and their precursors. Rituximab, a mouse-human monoclonal antibody targeting CD20, is the mainstay of treatment for cutaneous B-cell lymphomas, while brentuximab, mogamulizumab, and alemtuzumab are used for cutaneous T-cell lymphoma. Rituximab is used off-label for immune bullous disorders and can be associated with infusion reactions, tumor lysis syndrome as well as life-threatening mucocutaneous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis. Other important adverse events to be recognized include transient hematological alterations and various infections including PML, a rare but often fatal infection caused by the JC virus. Monoclonal antibodies used for treating cutaneous T-cell lymphomas include brentuximab, a CD30-directed monoclonal chimeric Ig1 antibody that is associated with infusion reactions, tumor lysis syndrome, and severe mucocutaneous reactions. Significant toxicity has also been noted in other systems ranging from neurologic, pulmonary, herpetic, and renal manifestations. Transient neutropenia and serious and sometimes fatal infections can also be associated with this therapy. Alemtuzumab, the humanized Introduction Biologics in Dermatology: Indications and Off-Label Usage IX

10 monoclonal antibody directed at CD52, can also be associated with infusion reactions, hematological toxicity, infections, and autoimmunity. Mogamulizumab, a humanized monoclonal antibody targeting CCR4, has a similar side effect profile, including infusion reactions, mucocutaneous reactions such as Stevens-Johnson syndrome, as well as other severe adverse events including angioimmunoblastic T-cell lymphoma. Although relatively rare, cutaneous lymphomas are still a significant challenge, and new therapeutic strategies are certainly welcome. In addition to the medications that are used for treating cutaneous inflammatory disorders and malignancies, many of the newer target anticancer therapies are associated with a multitude of cutaneous reactions, so it is important that the dermatologist be familiar with these common and diverse cutaneous adverse events as outlined by Sanmartín [pp ]. EGFR inhibitors, multikinase inhibitors as well as SMO inhibitors are known to cause diverse cutaneous disorders ranging from papulopustular and seborrheic eruptions to nail fold inflammation, xerosis and morbilliform eruptions, to name just a few. As dermatologists we are able to recognize these cutaneous manifestations and in many cases offer therapy that may symptomatically improve the eruption. Although this text is quite comprehensive with respect to biologics presently used in patients with a multitude of skin disorders, we have not covered all molecules or all cutaneous disorders. For example, when it comes to atopic dermatitis, dupilumab a monoclonal antibody targeting the α subunit of interleukin-4 receptor has been approved by the FDA for the treatment of moderate-to-severe atopic dermatitis. Other molecules that target IL-5, 13 and 31 are also being investigated [1]. We also know that many molecules including rituximab, omalizumab, anakinra, ustekinumab, etanercept, and apremilast have been used off-label in the treatment of atopic dermatitis and other forms of eczema [1]. As the number of biologics for dermatological disorders continue to increase, our knowledge of their adverse event profiles will expand, and by understanding both the risk and the benefit of these newer therapies, we will be able to better manage our patients. The same holds true in any other specialties for which newer targeted therapies are being developed. It is expected that many of these molecules will have an impact on the patient s skin and that our knowledge of the cutaneous adverse events will be important in helping us to co-manage these patients. Lluís Puig, Barcelona Wayne Gulliver, St. John s, NL References 1 Veilleux MS, Shear NH: Biologics in patients with skin diseases. J Allergy Clin Immunol 2017; 139: Leonardi CL, Romiti R, Tebbey PW: Ten years on: the impact of biologics on the practice of dermatology. Dermatol Clin 2015; 33: Fernandez JM, MD, Fernandez AP, Lang DM: Biologic therapy in the treatment of chronic skin disorders. Immunol Allergy Clin North Am 2017; 37: Clinics Review Articles, Dermatologic Clinics, Hidradenitis Suppurativa, January 2016, vol. 34. X Puig Gulliver