Clinical Cases in Psoriasis [2nd ed. 2019] 978-3-030-18771-2, 978-3-030-18772-9

Table of contents :
Front Matter ....Pages i-xi
34-Year-Old with Widespread Redness and Scaly Skin (Michael P. Lee, Kevin K. Wu, Jashin J. Wu)....Pages 1-7
13-Year-Old with Red, Scaly Rash (Michael P. Lee, Kevin K. Wu, Jashin J. Wu)....Pages 9-15
22-Year-Old with Red, Scaly Spots After Strep Throat Infection (Michael P. Lee, Kevin K. Wu, Jashin J. Wu)....Pages 17-22
25-Year-Old with Hair Flakes and Scaly Spots on Scalp (Michael P. Lee, Kevin K. Wu, Jashin J. Wu)....Pages 23-29
36-Year-Old with Nail Deformities (Michael P. Lee, Kevin K. Wu, Jashin J. Wu)....Pages 31-37
22-Year-Old Male with Pink Plaques on the Face (Kevin K. Wu, Michael P. Lee, Jashin J. Wu)....Pages 39-44
36-Year-Old Female with Bright Red Plaques on the Labia Majora (Kevin K. Wu, Michael P. Lee, Jashin J. Wu)....Pages 45-51
67-Year-Old with Thick Plaques on the Palms (Kevin K. Wu, Michael P. Lee, Jashin J. Wu)....Pages 53-59
61-Year-Old Male with Joint Stiffness (Kevin K. Wu, Michael P. Lee, Jashin J. Wu)....Pages 61-69
The Non-compliant Psoriasis Patient (Kevin K. Wu, Michael P. Lee, Jashin J. Wu)....Pages 71-78
36-Year-Old Severely Obese Male with Worsening Psoriasis (Deeti J. Pithadia, Kelly A. Reynolds, Jashin J. Wu)....Pages 79-86
26-Year-Old Female with Worsening Psoriasis Who Is Planning Pregnancy (Deeti J. Pithadia, Kelly A. Reynolds, Jashin J. Wu)....Pages 87-93
31-Year-Old Female with Psoriasis on Adalimumab with Loss of Effect (Deeti J. Pithadia, Kelly A. Reynolds, Jashin J. Wu)....Pages 95-102
A 53-Year-Old Female with Psoriasis and Breast Cancer (Kelly A. Reynolds, Deeti J. Pithadia, Jashin J. Wu)....Pages 103-108
79-Year-Old Male with Psoriasis and a History of Melanoma In Situ (Kelly A. Reynolds, Deeti J. Pithadia, Jashin J. Wu)....Pages 109-115
Pneumococcal Vaccine for 67-Year-Old Male on Adalimumab (Kelly A. Reynolds, Deeti J. Pithadia, Jashin J. Wu)....Pages 117-122
47-Year-Old Given BCG Vaccine as a Child (Michael P. Lee, Kevin K. Wu, Jashin J. Wu)....Pages 123-129
45-Year-Old with Psoriasis Started on Adalimumab (Michael P. Lee, Kevin K. Wu, Jashin J. Wu)....Pages 131-138
46-Year-Old with Psoriasis and Chronic Hepatitis C (Kevin K. Wu, Michael P. Lee, Jashin J. Wu)....Pages 139-145
HIV Infection in a 58-Year-Old Male with Psoriasis (Kevin K. Wu, Michael P. Lee, Jashin J. Wu)....Pages 147-152
Back Matter ....Pages 153-157

Citation preview

Clinical Cases in Dermatology Series Editor: Robert A. Norman

Jashin J. Wu Editor

Clinical Cases in Psoriasis Second Edition

Clinical Cases in Dermatology Series Editor Robert A. Norman Tampa, FL, USA

This series of concise practical guides is designed to facilitate the clinical decision-making process by reviewing a number of cases and defining the various diagnostic and management decisions open to clinicians. Each title is illustrated and diverse in scope, enabling the reader to obtain relevant clinical information regarding both standard and unusual cases in a rapid, easy to digest format. Each focuses on one disease or patient group, and includes common cases to allow readers to know they are doing things right if they follow the case guidelines. More information about this series at http://www.springer. com/series/10473

Jashin J. Wu Editor

Clinical Cases in Psoriasis Second Edition

Editor

Jashin J. Wu Founder and CEO Dermatology Research and Education Foundation Irvine, CA USA

Clinical Cases in Dermatology ISBN 978-3-030-18771-2    ISBN 978-3-030-18772-9 (eBook) https://doi.org/10.1007/978-3-030-18772-9 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To my loving wife Stephanie, who understands and allows my pursuits as an academic dermatologist. To my son Conrad, who I hope grows to be a man of maturity, wisdom, intellect, and strength. To my parents Shin Wu, M.D., and Jane Joaquin-Wu, M.D., who installed in me the value of hard work and perseverance, thank you for all that you have given me. Jay

Acknowledgements

The editors would like to thank Grant Weston and others at Springer for all of their steady support over the 6-month period of writing, revising, and editing this book. We acknowledge the patients who allowed their photos to be used for educational purposes like this and also for giving us inspiration in developing our strategies to treat their severe psoriasis.

Contents

1

34-Year-Old with Widespread Redness and Scaly Skin���������������������������������������������������������������    1 Michael P. Lee, Kevin K. Wu, and Jashin J. Wu

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13-Year-Old with Red, Scaly Rash�����������������������������    9 Michael P. Lee, Kevin K. Wu, and Jashin J. Wu

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22-Year-Old with Red, Scaly Spots After Strep Throat Infection���������������������������������������   17 Michael P. Lee, Kevin K. Wu, and Jashin J. Wu

4

25-Year-Old with Hair Flakes and Scaly Spots on Scalp���������������������������������������������������������������   23 Michael P. Lee, Kevin K. Wu, and Jashin J. Wu

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36-Year-Old with Nail Deformities ���������������������������   31 Michael P. Lee, Kevin K. Wu, and Jashin J. Wu

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22-Year-Old Male with Pink Plaques on the Face�����   39 Kevin K. Wu, Michael P. Lee, and Jashin J. Wu

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36-Year-Old Female with Bright Red Plaques on the Labia Majora�����������������������������������������������������   45 Kevin K. Wu, Michael P. Lee, and Jashin J. Wu

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67-Year-Old with Thick Plaques on the Palms���������   53 Kevin K. Wu, Michael P. Lee, and Jashin J. Wu ix

x

9

Contents

61-Year-Old Male with Joint Stiffness�����������������������   61 Kevin K. Wu, Michael P. Lee, and Jashin J. Wu

10 The Non-compliant Psoriasis Patient�������������������������   71 Kevin K. Wu, Michael P. Lee, and Jashin J. Wu 11 36-Year-Old Severely Obese Male with Worsening Psoriasis���������������������������������������������   79 Deeti J. Pithadia, Kelly A. Reynolds, and Jashin J. Wu 12 26-Year-Old Female with Worsening Psoriasis Who Is Planning Pregnancy ���������������������������������������   87 Deeti J. Pithadia, Kelly A. Reynolds, and Jashin J. Wu 13 31-Year-Old Female with Psoriasis on Adalimumab with Loss of Effect���������������������������   95 Deeti J. Pithadia, Kelly A. Reynolds, and Jashin J. Wu 14 A 53-Year-Old Female with Psoriasis and Breast Cancer �������������������������������������������������������  103 Kelly A. Reynolds, Deeti J. Pithadia, and Jashin J. Wu 15 79-Year-Old Male with Psoriasis and a History of Melanoma In Situ ���������������������������  109 Kelly A. Reynolds, Deeti J. Pithadia, and Jashin J. Wu 16 Pneumococcal Vaccine for 67-Year-Old Male on Adalimumab �����������������������������������������������������������  117 Kelly A. Reynolds, Deeti J. Pithadia, and Jashin J. Wu 17 47-Year-Old Given BCG Vaccine as a Child�������������  123 Michael P. Lee, Kevin K. Wu, and Jashin J. Wu

Contents

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18 45-Year-Old with Psoriasis Started on Adalimumab �����������������������������������������������������������  131 Michael P. Lee, Kevin K. Wu, and Jashin J. Wu 19 46-Year-Old with Psoriasis and Chronic Hepatitis C����������������������������������������������������������������������� 139 Kevin K. Wu, Michael P. Lee, and Jashin J. Wu 20 HIV Infection in a 58-Year-Old Male with Psoriasis�����������������������������������������������������������������  147 Kevin K. Wu, Michael P. Lee, and Jashin J. Wu Index���������������������������������������������������������������������������������������  153

Chapter 1 34-Year-Old with Widespread Redness and Scaly Skin Michael P. Lee, Kevin K. Wu, and Jashin J. Wu

Case A 34-year-old male, with a history of scaly plaques since 18-years-old, presented with generalized erythema and fine scaling of his skin. He had been on adalimumab for almost a year with suboptimal results. The patient had previously failed treatment with etanercept and methotrexate 20  mg weekly used in conjunction with other biologics. Treatment with infliximab appeared to be most effective for 5 years, but lost efficacy towards the end. Phototherapy for the patient was not attempted due to scheduling issues with his work. He also endorsed hand and right knee pain in the mornings. Patient had never had a biopsy performed nor did he have M. P. Lee Eastern Virginia Medical School, Norfolk, VA, USA K. K. Wu Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_1

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any history of malignancy. He is a former smoker and drinks alcohol socially. On physical examination, face, neck, chest, abdomen, back, arms, legs, buttocks, and groin had well-defined erythematous scaly plaques. His palms and soles were clear. The affected body surface area was 95%. Based on the clinical case description, what is the most likely diagnosis? 1. Atopic dermatitis 2 . Pityriasis rubra pilaris 3. Erythrodermic psoriasis 4. Seborrheic dermatitis 5. Cutaneous T cell lymphoma

Diagnosis Erythrodermic psoriasis

Discussion Erythrodermic psoriasis (EP) is a rare, life-threatening variant of psoriasis characterized by widespread redness, itching, pain, and scaly skin. It is the least common subtype of psoriasis occurring in less than 3% of patients, has a variable age of onset, and appears to favor males [1, 2]. Erythrodermic psoriasis typically encompasses more the 75% of the total body surface area and can also be associated with pustules and exfoliation of skin, resulting in loss of its many protective functions. Symptoms may develop rapidly over several days or gradually over weeks. With impaired skin function, patients with EP may experience dehydration, infections, hypothermia, and death from sepsis if not properly treated [3]. The pathogenesis of erythrodermic psoriasis is still under investigation. There is evidence, however, pointing to a prominent role of T lymphocytes interactions with macrophages, and it has been demonstrated that the ratio of Th1/Th2

Chapter 1.  34-Year-Old with Widespread Redness…

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response was significantly lower in EP compared to patients with psoriasis [4]. Patients with EP were also found to have significantly higher levels of interleukin-4 and interleukin-10 compared to both psoriasis patients and healthy controls. It is imperative to gather a detailed history and perform a thorough exam in order diagnosis EP and initiate appropriate management. EP should be considered when a patient presents with erythema of 75% or more of body surface area involvement and skin features of psoriasis with other causes of erythroderma less likely. Patient history will usually reveal personal or family history of psoriasis, and exam may demonstrate other features consistent with psoriasis including plaques, arthralgias, and nail disease. Skin biopsy will most frequently show histological features supporting psoriasis such as hyper- and parakeratosis along with a thickened stratum spongiosum layer and reduced granular layer.

Treatment Due to the uncommon nature of EP and limited high quality studies for disease management, treatment recommendations are derived mostly from case reports and case series. Initial management typically involves correcting any fluid or electrolyte abnormalities, treatment of infections, and hypothermia prophylaxis. After stabilization, the US National Psoriasis Foundation has advocated use of systemic medications as first line therapies including cyclosporine or infliximab. Both of these medications have demonstrated rapid onset of action for EP [5]. Other appropriate therapies include methotrexate and acitretin, although these medications typically work slower. Cyclosporine is a calcineurin inhibitor that blocks T-cell activation by preventing transcription of interleukin-2. Due to its rapid onset of action, it is recommended for unstable cases of EP and is given orally in doses of 4–5 mg/kg per day until remission. A case series of 33 subjects demonstrated that 67% of patients had complete remission within 3 months

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of using cyclosporine [6]. Infliximab, a soluble anti-TNF-­ alpha antibody, also boasts a rapid onset of action that leads to decreased T-cell infiltration in erythrodermic psoriasis. It is given as the standard regimen for psoriasis where a 5 mg/ kg dose is administered at 0, 2, 6 weeks, followed by every 8 weeks. An open-label, single site study showed 40% of patients achieving a 90% reduction in PASI and 20% of patients achieving a 75% reduction in PASI at 14  weeks of treatment [7]. Combination treatment using one of these systemic medications along with a topical therapy has been shown to be effective and is also frequently necessary to achieve remission [5]. Methotrexate and acitretin can also be used as alternative first line therapies, although they have demonstrated a slower onset of action. Methotrexate is usually administered on a weekly schedule with folic acid supplementation. A retrospective study showed a good response in 94% of patients with EP [8]. Acitretin, a vitamin A derivative, is typically given in doses of 25 to 50  mg per day, but effect is not apparent for at least 3  months [9]. Newer biologic medications including ustekinumab, ixekizumab, and secukinumab for the treatment of erythrodermic psoriasis show promising preliminary results [10–12]. Particularly ustekinumab has been demonstrated to be safe and associated with significant improvements of Psoriasis Area and Severity Index scores after 4  weeks of therapy [13]. However, data is currently limited to small studies and case reports and further investigation is needed before routine recommendation of use. There are no head to head comparisons of the recommended rapid onset first line therapies. Treatments should be selected on an individual basis, taking into consideration side effect profiles. Cyclosporine commonly causes nephrotoxicity and hypertension, and infliximab is contraindicated during active infections. While treatment options for EP have greatly increased in the past several years, there is a need for additional controlled trials to better characterize the pathology of the disease and understand the role of each medication.

Chapter 1.  34-Year-Old with Widespread Redness…

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The patient from the clinical scenario was started on cyclosporine along with clobetasol topical spray and tacrolimus ointment for affected areas. Patient was counseled on risks of cyclosporine use including increased risk of lymphoma, cancer recurrence, hypertension, and impaired kidney function. He was to follow up in 1 month and was also referred to rheumatology to evaluate for possible psoriatic arthritis.

Key Points • Erythrodermic psoriasis is a rare, life-threatening variant of psoriasis that presents with generalized erythema, itching, pain, and scaly skin. It typically involves greater than 75% of surface body area. • Due to disruption of a large area of the protective skin barrier, patients with EP are prone to dehydration, electrolyte abnormalities, impaired thermoregulation, and infections. • After stabilization and correction of any associated complications, first line treatments for EP include cyclosporine or infliximab, as they act rapidly to treat the disease. Acitretin and methotrexate can also be considered, although they have a slower onset of action.

References 1. Boyd AS, Menter A.  Erythrodermic psoriasis. Precipitating factors, course, and prognosis in 50 patients. J Am Acad Dermatol. 1989;21(5 Pt 1):985–91. 2. Lebwohl M.  Psoriasis. Lancet. 2003;361(9364):1197–204. https:// doi.org/10.1016/S0140-6736(03)12954-6. 3. Green MS, Prystowsky JH, Cohen SR, Cohen JI, Lebwohl MG.  Infectious complications of erythrodermic psoriasis. J Am Acad Dermatol. 1996;34(5. Pt 2):911–4. 4. Zhang P, Chen HX, Duan YQ, Wang WZ, Zhang TZ, Li JW, Tu YT. Analysis of Th1/Th2 response pattern for erythrodermic psoriasis. J Huazhong Univ Sci Technolog Med Sci. 2014;34(4):596– 601. https://doi.org/10.1007/s11596-014-1322-0.

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5. Rosenbach M, Hsu S, Korman NJ, Lebwohl MG, Young M, Bebo BF Jr, Van Voorhees AS, National Psoriasis Foundation Medical Board. Treatment of erythrodermic psoriasis: from the medical board of the National Psoriasis Foundation. J Am Acad Dermatol. 2010;62(4):655–62. https://doi.org/10.1016/j. jaad.2009.05.048. 6. Management of erythrodermic psoriasis with low-dose cyclosporin. Studio Italiano Multicentrico nella Psoriasi (SIMPSO). Dermatology. 1993;187(Suppl 1):30–7. https://doi. org/10.1159/000247289. 7. Poulalhon N, Begon E, Lebbe C, Liote F, Lahfa M, Bengoufa D, Morel P, Dubertret L, Bachelez H.  A follow-up study in 28 patients treated with infliximab for severe recalcitrant psoriasis: evidence for efficacy and high incidence of biological autoimmunity. Br J Dermatol. 2007;156(2):329–36. https://doi. org/10.1111/j.1365-2133.2006.07639.x. 8. Haustein UF, Rytter M.  Methotrexate in psoriasis: 26 years’ experience with low-dose long-term treatment. J Eur Acad Dermatol Venereol. 2000;14(5):382–8. 9. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, Gottlieb AB, Koo JY, Lebwohl M, Lim HW, Van Voorhees AS, Beutner KR, Bhushan R. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol. 2009;61(3):451–85. https://doi.org/10.1016/j.jaad.2009.03.027. 10. Pescitelli L, Dini V, Gisondi P, Loconsole F, Piaserico S, Piccirillo A, Stinco G, Errichetti E, Talamonti M, Tripo L, Volpi W, Prignano F.  Erythrodermic psoriasis treated with ustekinumab: an Italian multicenter retrospective analysis. J Dermatol Sci. 2015;78(2):149–51. https://doi.org/10.1016/j. jdermsci.2015.01.005. 11. Saeki H, Nakagawa H, Ishii T, Morisaki Y, Aoki T, Berclaz PY, Heffernan M.  Efficacy and safety of open-label ixekizumab treatment in Japanese patients with moderate-to-severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis. J Eur Acad Dermatol Venereol. 2015;29(6):1148–55. https:// doi.org/10.1111/jdv.12773.

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12. Weng HJ, Wang TS, Tsai TF. Clinical experience of secukinumab in the treatment of erythrodermic psoriasis: a case series. Br J Dermatol. 2018;178(6):1439–40. https://doi.org/10.1111/ bjd.16252. 13. Saraceno R, Talamonti M, Galluzzo M, Chiricozzi A, Costanzo A, Chimenti S. Ustekinumab treatment of erythrodermic psoriasis occurring after physical stress: a report of two cases. Case Rep Dermatol. 2013;5(3):254–9. https://doi.org/10.1159/000348645.

Chapter 2 13-Year-Old with Red, Scaly Rash Michael P. Lee, Kevin K. Wu, and Jashin J. Wu

Case 13-year-old female presented with red, scaly rash for several years. Patient had previously been prescribed topical creams with mild improvement of symptoms. She denied any joint stiffness or pain. Patient had a significant family history of psoriasis in her paternal uncles and aunts. She was brought in to clinic by her mother and is currently in eighth grade. With the exception of obesity, the patient was otherwise healthy and denied any recent illness, sore throat, or sick contacts. On physical examination, erythematous scaly papules and plaques were visualized on scalp, face, neck, chest, abdomen, extremities, and back. Patient deferred exam of breasts, groin, buttocks, and bilateral upper hips. The lesions appeared M. P. Lee Eastern Virginia Medical School, Norfolk, VA, USA K. K. Wu Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_2

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worse on the back and greater than 10% of the body surface area was affected. Based on the clinical case description, what is the most likely diagnosis? 1. Atopic dermatitis 2 . Severe pediatric psoriasis 3. Pityriasis rosea 4. Contact dermatitis 5. Pityriasis rubra pilaris

Diagnosis Severe pediatric psoriasis

Discussion Pediatric psoriasis can have profound impacts on both a child’s physical and psychological health [1]. As in adults, the incidence of psoriasis in children has more than doubled since the 1970 and may be attributed to the rising prevalence of obesity [2]. Studies revealed that children with psoriasis were significantly more likely to be obese, and those with greater psoriasis severity had higher risks of obesity [3]. Children with psoriasis may also be at higher risk for other components of metabolic syndrome, including diabetes and dyslipidemia. Other comorbidities associated with pediatric psoriasis include hypertensive disease, arthritis, and psychological disorders, conveying the importance of prompt diagnosis and treatment in children. Pediatric psoriasis presents similarly to adult psoriasis, but lesions may differ in their distribution. Pediatric psoriasis most commonly involves the scalp, face, extensor regions, and postauricular areas. The disease is characterized by well demarcated erythematous scaly papules and plaques that have a cycle of remission and relapsing. Severity can range greatly from a few scattered lesions to involving an extensive

Chapter 2.  13-Year-Old with Red, Scaly Rash

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body surface area. The major variants of pediatric psoriasis are the same as in adult psoriasis: plaque, guttate, pustular, and erythrodermic. There appears to be a stronger genetic component in pediatric psoriasis compared to adult psoriasis [4]. The most common predisposing risk factor for earlyonset disease involves the human leukocyte antigen Cw6 or PSOR1 [5].

Treatment Prior to initiating treatment, it is important to determine the severity of psoriasis in the pediatric patient. Patients with psoriasis involving less than 10% body surface area can often be treated with topical medications including corticosteroids, vitamin D analogs, and calcineurin inhibitors. For moderate to severe disease involving more than 10% body surface area or disease that does not respond adequately to topical medications, phototherapy or systemic agents are often employed. Corticosteroids remain the mainstay of therapy for mild to moderate pediatric psoriasis. Medium-potency topical corticosteroids are typically used for areas such as the trunk, scalp, and extremities, while use of low-potency topical corticosteroids are reserved for sensitive areas such as the face and genitals. Reduced erythema and plaque thickness may be seen in 2–4 weeks. Lesions on the trunk or extremities that do not respond to medium-potency corticosteroids can be treated with high-potency corticosteroids, but caution should be used as risk of skin atrophy increases with prolonged use. Therefore, treatment with high-potency corticosteroids should be administered in a 2 weeks on and 2 weeks off cycle. Pediatric patients also experience enhanced absorption of topical medications, which exposes them to higher risks of developing side effects and needs to be considered when devising treatment regimen [6]. Topically administered vitamin D analogs including calcipotriol and calcitriol have demonstrated efficacy in pediatric patients with psoriasis with minimal adverse side effects. They

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can be utilized as monotherapy or alternated with topical steroids to reduce steroid exposure in a 2 weeks on 2 weeks off fashion. Vitamin D analogs can also be used for sensitive areas of the skin such as face and intertriginous areas, with calcitriol appearing to cause less irritation than calcipotriol [7]. However, they have a relatively slow onset of action and require 6–8 weeks of treatment for adequate benefit. Etanercept is often employed as a first line treatment in pediatric psoriasis cases that are refractory to topical treatment. It is typically administered as 0.8 mg/kg once weekly up to a maximum dose of 50 mg. In a study of 211 children with moderate to severe plaque psoriasis, more children treated with etanercept achieved a 75% reduction in Psoriasis Area and Severity Index (PASI) score compared to placebo [8]. Ustekinumab may also be used as a first line treatment for more severe cases of psoriasis. Patients in a study that received two dose, standard dose, or half dose regimens of ustekinumab were more likely to achieve a PASI75 compared to children on placebo [9]. Etanercept and ustekinumab represent the only treatments approved by the US FDA for treatment of psoriasis in children at least 4  years old and 12 years old, respectively. Methotrexate is also an appropriate systemic agent for moderate to severe pediatric psoriasis. It can be initiated as a 0.3 mg/kg dose given weekly and increased weekly to a maximum of 25 mg. Methotrexate has demonstrated efficacy and safety for treatment of pediatric psoriasis. A study showed that one third of children achieved PASI75 after 24  weeks of initiating treatment [10]. Once adequate improvement of symptoms has been achieved, patients should be tapered to a lower maintenance dose to reduce risk of adverse effects, including gastrointestinal distress and upper respiratory infections. Narrow band ultraviolet B (UV-B) phototherapy is an effective and well-tolerated treatment for moderate to severe pediatric psoriasis. 51% of patients in a retrospective study demonstrated complete remission of lesions, while PASI75 was seen in 41% of the children after a mean treatment

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time of 3  months [11]. Psoralen with UV-A phototherapy (PUVA) can be considered but is rarely used in children due to long term toxicity. Short term side effects from phototherapy include erythema, pruritus and blistering while long term effects include DNA damage leading to possible carcinogenesis. The patient and her mother were counseled on psoriasis and genetic nature of the disease along with its remitting and relapsing course. As her psoriasis was refractory to previous treatment, other options for moderate to severe psoriasis were discussed including narrowband UV-B phototherapy and methotrexate. Patient and her mother opted for UV-B phototherapy 2–3 times weekly. Risks of treatment, including skin damage and DNA damage leading to possible skin cancer, were discussed, and patient was to follow up in clinic in 3 months.

Key Points • Pediatric psoriasis incidence has doubled since 1970, possibly due to the increasing prevalence of obesity. • The mainstay of treatments for mild to moderate pediatric psoriasis include topical medications such as corticosteroids and vitamin D analogs. • For moderate to severe psoriasis refractory to topical medications, systemic agents such as etanercept, ustekinumab, methotrexate or narrowband UV-B phototherapy may be used.

References 1. Parisi R, Symmons DP, Griffiths CE, Ashcroft DM, Identification, Management of Psoriasis & Associated ComorbidiTy Project Team. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133(2):377–85. https://doi.org/10.1038/jid.2012.339.

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2. Tollefson MM, Crowson CS, McEvoy MT, Maradit Kremers H. Incidence of psoriasis in children: a population-based study. J Am Acad Dermatol. 2010;62(6):979–87. https://doi.org/10.1016/j. jaad.2009.07.029. 3. Paller AS, Mercy K, Kwasny MJ, Choon SE, Cordoro KM, Girolomoni G, Menter A, Tom WL, Mahoney AM, Oostveen AM, Seyger MM.  Association of pediatric psoriasis severity with excess and central adiposity: an international cross-­ sectional study. JAMA Dermatol. 2013;149(2):166–76. https:// doi.org/10.1001/jamadermatol.2013.1078. 4. Raychaudhuri SP, Gross J.  A comparative study of pediatric onset psoriasis with adult onset psoriasis. Pediatr Dermatol. 2000;17(3):174–8. 5. Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, Gudjonsson JE, Li Y, Tejasvi T, Feng BJ, Ruether A, Schreiber S, Weichenthal M, Gladman D, Rahman P, Schrodi SJ, Prahalad S, Guthery SL, Fischer J, Liao W, Kwok PY, Menter A, Lathrop GM, Wise CA, Begovich AB, Voorhees JJ, Elder JT, Krueger GG, Bowcock AM, Abecasis GR, Collaborative Association Study of Psoriasis. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet. 2009;41(2):199–204. https://doi.org/10.1038/ng.311. 6. Silverberg NB. Update on pediatric psoriasis, Part 2: Therapeutic management. Cutis. 2010;86(4):172–6. 7. Shah KN. Diagnosis and treatment of pediatric psoriasis: current and future. Am J Clin Dermatol. 2013;14(3):195–213. https://doi. org/10.1007/s40257-013-0026-8. 8. Paller AS, Siegfried EC, Langley RG, Gottlieb AB, Pariser D, Landells I, Hebert AA, Eichenfield LF, Patel V, Creamer K, Jahreis A, Etanercept Pediatric Psoriasis Study Group. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med. 2008;358(3):241–51. https://doi. org/10.1056/NEJMoa066886. 9. Landells I, Marano C, Hsu MC, Li S, Zhu Y, Eichenfield LF, Hoeger PH, Menter A, Paller AS, Taieb A, Philipp S, Szapary P, Randazzo B.  Ustekinumab in adolescent patients age 12 to 17 years with moderate-to-severe plaque psoriasis: results of the randomized phase 3 CADMUS study. J Am Acad Dermatol. 2015;73(4):594–603. https://doi.org/10.1016/j.jaad.2015.07.002. 10. van Geel MJ, Oostveen AM, Hoppenreijs EP, Hendriks JC, van de Kerkhof PC, de Jong EM, Seyger MM. Methotrexate in pediatric plaque-type psoriasis: long-term daily clinical prac-

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tice results from the Child-CAPTURE registry. J Dermatolog Treat. 2015;26(5):406–12. https://doi.org/10.3109/09546634.201 4.996515. 11. Pavlovsky M, Baum S, Shpiro D, Pavlovsky L, Pavlotsky F. Narrow band UVB: is it effective and safe for paediatric psoriasis and atopic dermatitis? J Eur Acad Dermatol Venereol. 2011;25(6): 727–9. https://doi.org/10.1111/j.1468-3083.2010.03832.x.

Chapter 3 22-Year-Old with Red, Scaly Spots After Strep Throat Infection Michael P. Lee, Kevin K. Wu, and Jashin J. Wu

Case A 22-year-old female presented with acute onset numerous red, scaly spots over her entire body that appeared 8 days ago. Patient reported she had a throat infection with positive strep culture 3  weeks prior and was treated with clindamycin and medrol-pack. She had previously experienced similar symptoms 3  years ago after a positive strep throat infection. She was treated at the time with clobetasol prescribed by a dermatologist. Patient endorsed generalized itchiness but denied any fever, nausea, vomiting, diarrhea, joint pain, or weight changes. She had no known family history of psoriasis or skin cancer.

M. P. Lee Eastern Virginia Medical School, Norfolk, VA, USA K. K. Wu Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_3

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On physical examination, 3–5 mm erythematous, teardrop-­ shaped papules and plaques, some with thin adherent scales, were visualized over her body in a generalized distribution sparing the palms and soles. The affected body surface area was 5%. Based on the clinical case description, what is the most likely diagnosis? 1. Pityriasis rosea 2 . Pemphigus foliaceus 3. Guttate psoriasis 4. Small plaque parapsoriasis 5. Tinea corporis

Diagnosis Guttate psoriasis

Discussion Guttate psoriasis commonly presents in adults younger than 30 years old following a group A beta-hemolytic streptococci throat infection. It is characterized by numerous small, erythematous, teardrop-like papules and plaques with fine scale. “Guttate” refers to the teardrop appearance of the lesions and may appear as an initial presentation or exacerbation of chronic plaque psoriasis. Guttate psoriasis classically involves the extremities and trunk, and pruritus is a common symptom. Variations in reported prevalence of guttate psoriasis is closely correlated with epidemics of invasive streptococci infections [1]. Other less commonly associated risk factors include viral or fungal infections and medications such as TNF inhibitors [2, 3]. Although a combination of genetic and environmental variables contribute to the disease course, the pathogenesis of guttate psoriasis is still not fully understood. There is an observed association with guttate psoriasis and a positive

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HLA-Cw∗0602, and it is believed that the streptococcal M-protein binds to the HLA and stimulates a T-cell response in patients with psoriasis [4]. In a case-control study of 143 patients with guttate psoriasis, those who were positive for HLA-Cw∗0602 were more likely to have a positive streptococcal throat culture than patients who were negative for the HLA-Cw∗0602 [5]. Diagnosis of guttate psoriasis is based on clinical examination with skin biopsy if there are any uncertainties. Histology of guttate psoriasis typically displays epidermal hyperplasia with parakeratosis, acanthosis, and a decreased granular layer. Findings are consistent with and resemble plaque psoriasis. The differential diagnosis include pityriasis rosea, tinea corporis, secondary syphilis, and pemphigus foliaceus. Fortunately, guttate psoriasis has a good prognosis, and the most common course is spontaneous remission over weeks to months [6].

Treatment Due to the good prognosis and possibility of spontaneous remission, patients with guttate psoriasis may abstain from treatment. However, many patients choose to undergo treatment due to aesthetic concerns, and first line therapies include topical agents and phototherapy. The choice of treatment should be tailored to the individual patient, as there are limited studies focused on guttate psoriasis management. Ultraviolet (UV) phototherapy has been indicated as first-­ line therapy and may accelerate the clearance of lesions in guttate psoriasis. The treatment is relatively safe and can treat large surface areas using broadband UV-B, narrowband UV-B, or psoralen plus UV-A phototherapy. Studies have shown that narrowband UV-B therapy is more effective in patients with plaque-type psoriasis and is, therefore, generally used in the treatment of guttate lesions [7]. In a randomized trial, psoralen plus UV-A phototherapy was significantly more effective than narrowband UV-B, but strict photoprotection after treatment

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made this choice of therapy less favorable among patients [8]. In general, phototherapy is an appealing choice of management compared to other forms of therapy due to its ease of use and effectiveness over large surface areas. Although multiple topical agents including corticosteroids and vitamin D analogs have been evaluated for chronic plaque psoriasis, none of them have been specifically studied for treatment of guttate psoriasis. Guttate psoriasis can often be widespread, making application of the ointment or cream over a large area impractical. Therefore, it is recommended that topical treatments be used in conjunction with phototherapy in patients with numerous lesions [9]. Corticosteroid therapy also confers the risk of skin atrophy with prolonged usage, further limiting its treatment for large surface areas. Systemic treatment and antibiotics have also been utilized in the treatment of guttate psoriasis. Typically, systemic treatments with medications including cyclosporine, acitretin, methotrexate, or biologics are used for guttate psoriasis refractory to previously mentioned first line therapies. Although these treatments have shown efficacy in plaque psoriasis, there are few high-quality studies specifically studying their use in guttate psoriasis. Cyclosporine, however, has been recommended as second-line because its intermittent use falls in line with the short lived cases of guttate psoriasis and can therefore be an appropriate treatment [10]. While biologic medications have been increasingly utilized for the treatment of plaque psoriasis, their role in guttate psoriasis has not been well established as studies are limited to case reports. One report has described ustekinumab induced remission of recalcitrant guttate psoriasis, but further studies are necessary [11]. The often transient nature of guttate psoriasis is not conducive for biologic use. Intermittent use of biologics may cause patients to develop neutralizing antibodies, reducing efficacy of future use if required [12]. Antibiotic therapy has also been proposed as a potential management option because of the well-known association of guttate psoriasis with streptococcal infection. Antibiotics along with tonsillectomy can reduce known risk factors of recurrent streptococcus infections, but is ineffective in treat-

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ing psoriasis and there is currently insufficient data to support an established practice guideline [13]. The patient from the clinical scenario was started on a combination of clobetasol ointment and desonide cream for affected areas. She was also started on NB-UVB phototherapy three times a week and counseled on risks of skin damage along with DNA damage leading to possible skin cancer. Patient was to follow up in 2 months to assess outcomes of treatment.

Key Points • Guttate psoriasis is a variant of psoriasis with acute onset characterized by numerous small, erythematous, teardrop-­ shaped papules and plaques with fine scale. • The majority of guttate psoriasis begins with an inciting factor, most commonly streptococcal pharyngitis. Other causes include viral infections, fungal infections, and medication use. • Narrowband UV-B phototherapy is considered first line treatment for guttate psoriasis due to its effectiveness over large areas of involvement and due to the transient nature of the disease.

References 1. McFadden JP, Baker BS, Powles AV, Fry L.  Psoriasis and streptococci: the natural selection of psoriasis revisited. Br J Dermatol. 2009;160(5):929–37. https://doi. org/10.1111/j.1365-2133.2009.09102.x. 2. Costa-Romero M, Coto-Segura P, Suarez-Saavedra S, Ramos-­Polo E, Santos-Juanes J. Guttate psoriasis induced by infliximab in a child with Crohn’s disease. Inflamm Bowel Dis. 2008;14(10):1462– 3. https://doi.org/10.1002/ibd.20450. 3. Ito T, Furukawa F. Psoriasis guttate acuta triggered by varicella zoster virus infection. Eur J Dermatol. 2000;10(3):226–7. 4. Holm SJ, Sakuraba K, Mallbris L, Wolk K, Stahle M, Sanchez FO.  Distinct HLA-C/KIR genotype profile associates with guttate psoriasis. J Invest Dermatol. 2005;125(4):721–30. https://doi. org/10.1111/j.0022-202X.2005.23879.x.

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5. Mallbris L, Wolk K, Sanchez F, Stahle M. HLA-Cw∗0602 associates with a twofold higher prevalence of positive streptococcal throat swab at the onset of psoriasis: a case control study. BMC Dermatol. 2009;9:5. https://doi.org/10.1186/1471-5945-9-5. 6. Pfingstler LF, Maroon M, Mowad C. Guttate psoriasis outcomes. Cutis. 2016;97(2):140–4. 7. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, Gottlieb A, Koo JY, Lebwohl M, Lim HW, Van Voorhees AS, Beutner KR, Bhushan R.  Guidelines of care for the management of psoriasis and psoriatic arthritis: section 5. Guidelines of care for the treatment of psoriasis with phototherapy and photochemotherapy. J Am Acad Dermatol. 2010;62(1):114–35. https://doi.org/10.1016/j.jaad.2009.08.026. 8. Yones SS, Palmer RA, Garibaldinos TT, Hawk JL. Randomized double-blind trial of the treatment of chronic plaque psoriasis: efficacy of psoralen-UV-A therapy vs narrowband UV-B therapy. Arch Dermatol. 2006;142(7):836–42. https://doi.org/10.1001/ archderm.142.7.836. 9. Chalmers RJ, O’Sullivan T, Owen CM, Griffiths CE. A systematic review of treatments for guttate psoriasis. Br J Dermatol. 2001;145(6):891–4. 10. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, Gottlieb AB, Koo JY, Lebwohl M, Lim HW, Van Voorhees AS, Beutner KR, Bhushan R.  Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol. 2009;61(3):451–85. https://doi.org/10.1016/j.jaad.2009.03.027. 11. Brummer GC, Hawkes JE, Duffin KC.  Ustekinumab-induced remission of recalcitrant guttate psoriasis: a case series. JAAD Case Rep. 2017;3(5):432–5. https://doi.org/10.1016/j. jdcr.2017.06.015. 12. Levin EC, Gupta R, Brown G, Malakouti M, Koo J.  Biologic fatigue in psoriasis. J Dermatolog Treat. 2014;25(1):78–82. https:// doi.org/10.3109/09546634.2013.826341. 13. Owen CM, Chalmers RJ, O’Sullivan T, Griffiths CE. A systematic review of antistreptococcal interventions for guttate and chronic plaque psoriasis. Br J Dermatol. 2001;145(6):886–90.

Chapter 4 25-Year-Old with Hair Flakes and Scaly Spots on Scalp Michael P. Lee, Kevin K. Wu, and Jashin J. Wu

Case 25-year-old female, with a history of polycystic ovary syndrome, presented with persistent hair flakes along with scaly spots on scalp and behind the ears for 4 years. Patient also has had lesions around her nasolabial folds but denied any other areas of involvement. She was previously treated with fluocinonide solution, which has been effective in clearing the lesions, but symptoms have always relapsed. Patient denied any family history of psoriasis. On physical examination, focal areas of thick white plaques were visualized on scalp (Fig.  4.1) and posterior to ears affecting about 2% of body surface area. Brown velvety M. P. Lee Eastern Virginia Medical School, Norfolk, VA, USA K. K. Wu Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_4

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Figure 4.1 Mildly erythematous patches and thick white plaques with fine overlying scale were present along the anterior hairline

plaques were also observed on the posterior neck. No facial lesions were noted and the rest of the skin exam was declined by patient. Based on the clinical case description, what is the most likely diagnosis? 1. 2 . 3. 4. 5.

Seborrheic dermatitis Tinea capitis Atopic dermatitis Pediculosis capitis Scalp psoriasis

Diagnosis Scalp psoriasis

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Discussion Scalp psoriasis is a manifestation of plaque psoriasis that involves the scalp and can extend to surrounding regions including forehead, posterior neck, and ears [1]. It can present in the absence of or alongside plaque psoriasis or other variants of psoriasis of the body. The scalp is often the first manifestation in patients with psoriasis due vulnerability to Malassezia infection, damage from ultraviolet light, and Koebner response from frequent manipulation and styling of hair [2]. Scalp psoriasis is diagnosed clinically and should be strongly suspected in patients with a personal or family history of psoriasis. Skin biopsy can be utilized for uncertain cases. Mild cases of scalp psoriasis present with a dry and flaky scalp with associated pruritus. Moderate to severe forms of scalp psoriasis present with more prominent, well-­demarcated plaques that can be easily palpated. Diagnosis of scalp psoriasis may be challenging as conditions that involve the scalp can appear similar. Seborrheic dermatitis is a very common disease of the scalp that shares many similar features. The plaques in scalp psoriasis, however, are better defined and with white-silver flakes, in contrast to the oily, yellow flakes of seborrheic dermatitis. Seborrheic dermatitis is also seen more on the face of patients with oily skin. Other differential diagnoses include autoimmune conditions that may present similarly to scalp psoriasis. Discoid lupus erythematous (DLE) is an inflammatory skin condition that presents with scaly plaques on the scalp, nose, cheeks, ears, and extremities. Unlike alopecia from psoriasis, alopecia that from DLE is typically scarring, and hair growth does not resume with clearance of the lesions. Dermatomyositis is an inflammatory skin disease that also presents with progressive muscle weakening. It can present with pink scaly plaques on the scalp with involvement of the extensor surfaces of the arms and hands. Tinea capitis and atopic dermatitis should be strongly considered in children, as these diseases occur commonly in this population.

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Treatment The scalp is a highly visible location and significant embarrassment or aesthetic concern may accompany patients suffering from scalp psoriasis compelling them to seek treatment. The presence of hair on the scalp can make treatments challenging or difficult to apply, and typically patient preference is taken into consideration to improve compliance with therapy. The primary topical agents used include corticosteroids as recommended by the US National Psoriasis Foundation. Topical corticosteroids therapy has been shown to cause a rapid and marked improvement within 2 weeks of beginning treatment [1, 3]. As with long term use of any topical steroids, side effects such as skin atrophy, folliculitis, and telangiectasias need to be considered. Topical vitamin D analogs, such as calcipotriol, may also be used for scalp psoriasis. They generally have a slower onset of action than topical corticosteroids, and their side effect profile includes erythema, dryness, and itching. A systematic review, however, has demonstrated that topical corticosteroids are more effective than topical vitamin d analogs [4]. Combined treatment with both vitamin D analogs and topical corticosteroids can be considered in patients refractory to monotherapy and has been shown to reduce the risk of side effects when medications are stopped [5, 6]. Preferred drug vehicle for scalp psoriasis include gels, foams, or solutions depending on patient preference. Less appealing vehicles include ointments and creams, as they are greasy and difficult to apply to the scalp [7]. Other possible treatments for scalp psoriasis include tar shampoo preparations, dithranol, and tazarotene. Evidence is limited on the effectiveness of these treatments on the scalp. Tar derivatives have multiple mechanisms of action including anti-inflammatory, antibacterial, and anti-fungal, but due to the smell may be unappealing to patients. Salicylic acid can be prescribed in conjunction with topical treatments due to its keratolytic effect. However, adding another topical medication may complicate treatment regimens leading to decreased

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compliance [3]. Phototherapy is not effective in treating scalp psoriasis due to the densely packed hair follicles preventing UV light reaching the skin surface. Complete involvement of the scalp represents an affected 9% of total body surface area. Biologic agents including adalimumab, infliximab, etanercept, and ustekinumab have been effective in severe scalp psoriasis and have been shown to significantly improve Psoriasis Scalp Severity Index scores (PSSI) [8]. Infliximab exhibited the greatest efficacy with a 74% reduction in PSSI at week 4 [8]. A recent study also showed secukinumab as a well-tolerated and efficacious treatment with a 90% reduction in PSSI at 12 weeks [9]. Other effective systemic medication include methotrexate and acitretin. Methotrexate, however, can cause hepatotoxicity when used long term and acitretin can exacerbate the hair loss experienced in scalp psoriasis when used [2]. Therefore, these medications should be carefully considered and employed when other regions of the body are affected by psoriasis. The patient from the clinical scenario was started on clobetasol 0.05% topical solution twice daily for 2 weeks on and 2 weeks off cycle, repeating as necessary for rash. She was also started on adjunctive coal tar 12.5% shampoo therapy. Of note, the patient also had a history of seborrheic dermatitis and was prescribed desonide 0.05% topical cream for 2 weeks on and 2 weeks off cycle, using as necessary. The brown velvety papules on posterior neck were diagnosed as acanthosis nigricans, and patient was counseled on etiology and weight loss.

Key Points • Scalp psoriasis is a manifestation of psoriasis that can extend beyond hair margins to surrounding regions including forehead, posterior neck, and ears. • The diagnosis of scalp psoriasis may be challenging, as many other diseases involving the scalp present with scaly plaques (seborrheic dermatitis being the most common).

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• Potent topical corticosteroids are first line therapies for scalp psoriasis and can be used in conjunction with other treatments (e.g. tar shampoo) to increase effectiveness.

References 1. Crowley J. Scalp psoriasis: an overview of the disease and available therapies. J Drugs Dermatol. 2010;9(8):912–8. 2. Kircik LH, Kumar S. Scalp psoriasis. J Drugs Dermatol. 2010;9(8 Suppl ODAC Conf Pt 2):s101–5. 3. Chan CS, Van Voorhees AS, Lebwohl MG, Korman NJ, Young M, Bebo BF Jr, Kalb RE, Hsu S. Treatment of severe scalp psoriasis: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2009;60(6):962–71. https://doi.org/10.1016/j. jaad.2008.11.890. 4. Schlager JG, Rosumeck S, Werner RN, Jacobs A, Schmitt J, Schlager C, Nast A.  Topical treatments for scalp psoriasis. Cochrane Database Syst Rev. 2016;(2):CD009687. https://doi. org/10.1002/14651858.CD009687.pub2. 5. Gooderham M, Debarre JM, Keddy-Grant J, Xu Z, Kurvits M, Goodfield M. Safety and efficacy of calcipotriol plus betamethasone dipropionate gel in the treatment of scalp psoriasis in adolescents 12–17 years of age. Br J Dermatol. 2014;171(6):1470–7. https://doi.org/10.1111/bjd.13235. 6. Luger TA, Cambazard F, Larsen FG, Bourcier M, Gupta G, Clonier F, Kidson P, Shear NH. A study of the safety and efficacy of calcipotriol and betamethasone dipropionate scalp formulation in the long-term management of scalp psoriasis. Dermatology. 2008;217(4):321–8. https://doi.org/10.1159/000155642. 7. Mason AR, Mason JM, Cork MJ, Hancock H, Dooley G. Topical treatments for chronic plaque psoriasis of the scalp: a systematic review. Br J Dermatol. 2013;169(3):519–27. https://doi.org/10.1111/ bjd.12393. 8. Fotiadou C, Lazaridou E, Sotiriou E, Kyrgidis A, Apalla Z, Ioannides D.  Scalp psoriasis and biologic agents: a retrospective, comparative study from a tertiary psoriasis referral centre. J Eur Acad Dermatol Venereol. 2016;30(12):2091–6. https://doi. org/10.1111/jdv.13780.

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9. Bagel J, Duffin KC, Moore A, Ferris LK, Siu K, Steadman J, Kianifard F, Nyirady J, Lebwohl M.  The effect of secukinumab on moderate-to-severe scalp psoriasis: results of a 24-week, randomized, double-blind, placebo-controlled phase 3b study. J Am Acad Dermatol. 2017;77(4):667–74. https://doi.org/10.1016/j. jaad.2017.05.033.

Chapter 5 36-Year-Old with Nail Deformities Michael P. Lee, Kevin K. Wu, and Jashin J. Wu

Case 36-year-old postpartum female presented with nail deformities that started 15 months ago. Patient had a history of red, scaly lesions but was otherwise healthy. She denied any joint pain, tenderness, or recent trauma to her fingers. Patient at the time was nursing and would finish in 1 month. On physical examination, there was pitting in her fingernails and onycholysis with separation and breakage (Fig. 5.1). Nail plate thickening and subungual debris were noted. Erythematous indurated, scaly papules and plaques were also visualized on bilateral arms and legs, abdomen, scalp, and ears. Eight percent of body surface area was affected. Based on the clinical case description, what is the most likely diagnosis for her nail pathology? M. P. Lee Eastern Virginia Medical School, Norfolk, VA, USA K. K. Wu Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_5

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Figure 5.1  Fingernail pitting and onycholysis with separation and breakage

1. Onychomycosis 2 . Koilonychia 3. Yellow nail syndrome 4. Nail psoriasis 5. Paronychia congenita

Diagnosis Nail psoriasis

Discussion Nail psoriasis is a common manifestation in patients with psoriasis. It is characterized by pitting, onycholysis, subungual hyperkeratosis, and nail discoloration. 78.3% of patients with nail psoriasis also have cutaneous psoriasis plaques on the

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body, and 86% of patients with psoriatic arthritis have nail psoriasis [1, 2]. The higher occurrence with psoriatic arthritis may be related to the adjacent location of the nails to the interphalangeal joints and can be used as a predictor of psoriatic arthritis disease [3]. Nail psoriasis can also be an isolated finding of psoriasis, and diagnosis is important for proper management [4]. Nail disease has been correlated to both the severity of psoriatic skin disease and the length of time since psoriasis diagnosis [5]. The disease can be painful for patients and debilitating for their daily routine or professional work. The clinical presentation of nail psoriasis is associated with the anatomic location of disease in the nail and onychodystrophy will vary depending on the affected unit. The disease is characterized by inflammation of the nail bed and/or matrix, which is responsible for producing the nail plate. The proximal nail matrix forms the dorsal nail plate, while the distal matrix forms the ventral plate. Pitting presents as depressions in the top layers of the nail plate, where length of the pit can indicate the amount of time the nail matrix has been under inflammation [4]. If the nail bed is affected, subungual hyperkeratosis will result and present as yellow, lubricous nails where excessive proliferation can lead to onycholysis [4]. There is an increased risk of infection with onycholysis due to the separation of the nail plate allowing infectious agents to colonize [4]. Diagnosis of nail psoriasis is largely clinical. Most patients with nail psoriasis have a strong personal or family history of psoriasis. Biopsy is usually not necessary. If onychomycosis is a possibility, periodic acid-Schiff staining, potassium hydroxide testing, or culture can be done to diagnose.

Treatment Many treatment options exist for nail psoriasis. The goal of treatment is to improve the function and appearance of the nails. Severity of disease, number of nails involved, associated symptoms, and level of impairment are factors used to guide

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management. The Nail Psoriasis Severity Index (NAPSI) can also be utilized to assess the severity of disease as well as the response to treatment [6]. To use the NAPSI scoring system, the nail is divided into four quadrants, with each quadrant assigned a score of 1 for presence of nail matrix psoriasis and 1 for nail bed involvement. The maximum score is 8 per nail, which gives a total score of 160 for all nails, and higher scores correlate to higher severity of disease. The NAPSI, however, is infrequently used in clinical practice and most often used for clinical research. First-line therapy involves topical corticosteroids or topical vitamin D analogs either as monotherapy or combination treatment. High potency topical corticosteroids combat the inflammation seen in nail psoriasis. Adverse effects from long term steroid use include cutaneous atrophy and bone resorption also known as ‘disappearing digit’ [7]. Steroids can be used in conjunction with topical vitamin D analogs such as calcipotriol, which has the added effect of immunomodulation to reduce hyperkeratosis, onycholysis, and discoloration. The combination of the two may have improved efficacy for some patients and should be considered on an individual basis [8]. Studies, however, are still lacking, and one study found no difference between using calcipotriol monotherapy and combination therapy with betamethasone [9]. Tazarotene is a third generation retinoid that can also be used as first line treatment in mild symptoms of nail psoriasis. A randomized, controlled trial using tazarotene therapy 0.1% gel nightly for 24 weeks in 31 patients saw a significant difference in reduction of onycholysis compared to the control group [10]. It is applied once daily with occlusive dressing, but prolonged use can lead to skin erythema and irritation. Patients should apply topical medications to the nail plate, hyponychium and nail folds and occlusive dressing can be used to increase absorption. Topical tacrolimus can considered as second line treatment for nail psoriasis. Tacrolimus is a calcineurin inhibitor that blocks T-cell activation by preventing interleukin-2 transcription. In a study of 21 patients with nail psoriasis, each

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participant had one hand randomly selected to receive topical tacrolimus 0.1%, while the other hand was used as a control. After 12  weeks of treatment, the mean reduction in NAPSI score was significantly greater in the treatment hand than the control hand [11]. It is typically given once daily to the periungual skin. The US National Psoriasis Foundation has recommended systemic agents for moderate to severe nail disease refractory to topical agents. TNF inhibitors such as adalimumab and etanercept have demonstrated efficacy for nail psoriasis and have been recommended as first line therapy [12]. Ustekinumab has also been shown to be effective for severe nail psoriasis and approached a 50% reduction in NAPSI by 24 weeks [13]. A RCT using ixekizumab in the treatment of fingernail psoriasis showed significant improvements by week 12, with continued improvements through week 60 and more than 50% of patients achieving complete resolution [14]. Apremilast, approved by the FDA in 2014 for plaque psoriasis, can be considered as second line therapy for severe cases through its reduction of TNF-alpha levels [12]. A 52 week RCT using apremilast showed a 43.6% reduction in NAPSI at week 32 and a 60.2% reduction at week 52 [15]. It has a relatively safe profile with side effects of headache and diarrhea [15]. Other second line medications that have been recommended by the National Psoriasis Foundation include methotrexate and infliximab [12]. As with all systemic medications, however, these come with increased risks that must be balanced with potential benefits. Treatment using these agents should be reserved for those with debilitating nail psoriasis or along with diffuse skin and joint involvement. Finally, proper hand and foot care should be emphasized to minimize nail psoriasis symptoms. Any trauma to the nails including biting or manicures should be avoided, as trauma may exacerbate the disease. Nails should be frequently trimmed, moisturizer should be applied to the nails, and protective gloves should be used when handling liquids or chemicals.

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The patient from the clinical scenario was started on fluocinolone 0.05% topical ointment twice daily. Once she finished nursing, she was instructed to add calcipotriene 0.005% topical cream at night. The patient was scheduled for follow up in 2 months to assess treatment efficacy.

Key Points • Nail psoriasis is a common disease involving the nail bed and/or nail matrix and often occurs in patients suffering from psoriasis. • Nail psoriasis is highly associated with psoriatic arthritis and can be used as a predictor of disease. • First line treatments for nail psoriasis include topical corticosteroids and/or topical vitamin D analogs along with topical tazarotene. Refractory cases can be treated with biologics, but extent of disease must be considered due to increased risks of adverse effects.

References 1. Salomon J, Szepietowski JC, Proniewicz A.  Psoriatic nails: a prospective clinical study. J Cutan Med Surg. 2003;7(4):317–21. https://doi.org/10.1007/s10227-002-0143-0. 2. Tan ES, Chong WS, Tey HL.  Nail psoriasis: a review. Am J Clin Dermatol. 2012;13(6):375–88. https://doi. org/10.2165/11597000-000000000-00000. 3. Langenbruch A, Radtke MA, Krensel M, Jacobi A, Reich K, Augustin M.  Nail involvement as a predictor of concomitant psoriatic arthritis in patients with psoriasis. Br J Dermatol. 2014;171(5):1123–8. https://doi.org/10.1111/bjd.13272. 4. Jiaravuthisan MM, Sasseville D, Vender RB, Murphy F, Muhn CY. Psoriasis of the nail: anatomy, pathology, clinical presentation, and a review of the literature on therapy. J Am Acad Dermatol. 2007;57(1):1–27. https://doi.org/10.1016/j.jaad.2005.07.073. 5. Armesto S, Esteve A, Coto-Segura P, Drake M, Galache C, Martinez-Borra J, Santos-Juanes J. [Nail psoriasis in individuals with psoriasis vulgaris: a study of 661 patients]. Actas Dermosifiliogr. 2011;102(5):365–72. https://doi.org/10.1016/j. ad.2011.02.007.

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6. Rich P, Scher RK.  Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis. J Am Acad Dermatol. 2003;49(2):206–12. 7. Wolf R, Tur E, Brenner S. Corticosteroid-induced ‘disappearing digit’. J Am Acad Dermatol. 1990;23(4. Pt 1):755–6. 8. Rigopoulos D, Gregoriou S, Daniel Iii CR, Belyayeva H, Larios G, Verra P, Stamou C, Kontochristopoulos G, Avgerinou G, Katsambas A.  Treatment of nail psoriasis with a two-­compound formulation of calcipotriol plus betamethasone dipropionate ointment. Dermatology. 2009;218(4):338–41. https://doi. org/10.1159/000202179. 9. Tosti A, Piraccini BM, Cameli N, Kokely F, Plozzer C, Cannata GE, Benelli C.  Calcipotriol ointment in nail psoriasis: a controlled double-blind comparison with betamethasone dipropionate and salicylic acid. Br J Dermatol. 1998;139(4):655–9. 10. Scher RK, Stiller M, Zhu YI. Tazarotene 0.1% gel in the treatment of fingernail psoriasis: a double-blind, randomized, vehicle-­ controlled study. Cutis. 2001;68(5):355–8. 11. De Simone C, Maiorino A, Tassone F, D’Agostino M, Caldarola G.  Tacrolimus 0.1% ointment in nail ­ psoriasis: a randomized controlled open-label study. J Eur Acad Dermatol Venereol. 2013;27(8):1003–6. https://doi.org/10.1111/j.1468-3083.2012.04642.x. 12. Crowley JJ, Weinberg JM, Wu JJ, Robertson AD, Van Voorhees AS, National Psoriasis F. Treatment of nail psoriasis: best practice recommendations from the Medical Board of the National Psoriasis Foundation. JAMA Dermatol. 2015;151(1):87–94. https://doi.org/10.1001/jamadermatol.2014.2983. 13. Rich P, Bourcier M, Sofen H, Fakharzadeh S, Wasfi Y, Wang Y, Kerkmann U, Ghislain PD, Poulin Y, investigators P. Ustekinumab improves nail disease in patients with moderate-­ to-­severe psoriasis: results from PHOENIX 1. Br J Dermatol. 2014;170(2):398–407. https://doi.org/10.1111/bjd.12632. 14. van de Kerkhof P, Guenther L, Gottlieb AB, Sebastian M, Wu JJ, Foley P, Morita A, Goldblum O, Zhang L, Erickson J, Ball S, Rich P. Ixekizumab treatment improves fingernail psoriasis in patients with moderate-to-severe psoriasis: results from the randomized, controlled and open-label phases of UNCOVER-3. J Eur Acad Dermatol Venereol. 2017;31(3):477–82. https://doi.org/10.1111/ jdv.14033. 15. Nguyen CM, Leon A, Danesh M, Beroukhim K, Wu JJ, Koo J.  Improvement of nail and scalp psoriasis using apremilast in patients with chronic psoriasis: phase 2b and 3, 52-week randomized, placebo-controlled trial results. J Drugs Dermatol. 2016;15(3):272–6.

Chapter 6 22-Year-Old Male with Pink Plaques on the Face Kevin K. Wu, Michael P. Lee, and Jashin J. Wu

Case A 22-year-old male presented with pink plaques on the scalp and face. This patient previously used selenium sulfide concentrated shampoos on both the scalp and face with modest benefit. Symptoms included mild burning. He denied a family history of psoriasis. On physical examination, pink indurated plaques were noted on the scalp, upper forehead, bilateral pre-auricular areas, and bilateral post-auricular areas (Fig.  6.1). Total affected body surface area was 3%. Onycholysis of multiple fingernails bilaterally was also noted. Based on the case description, what is the diagnosis?

K. K. Wu Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA M. P. Lee Eastern Virginia Medical School, Norfolk, VA, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_6

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Figure 6.1  Pink indurated plaques on the upper forehead and scalp

1. Seborrheic dermatitis 2 . Atopic dermatitis 3. Psoriasis including facial psoriasis 4. Lupus tumidus erythematous

Answer Psoriasis including facial psoriasis

Discussion Facial psoriasis affects an estimated 17–29% of patients diagnosed with psoriasis, and most patients with facial psoriasis also have plaques elsewhere on the body [1, 2]. Facial psoriasis presents with indurated, scaly, well-defined, and pruritic plaques on the forehead, ears and other areas of the face. These plaques often appear less prominent than classic pso-

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riasis plaques. Presentation of psoriasis lesions elsewhere in addition to the face aids in the diagnosis of facial psoriasis [3]. Facial psoriasis is categorized based upon the locational distribution of the plaques. The three categories of facial psoriasis include centrofacial, peripherofacial, and mixed [2]. Centrofacial psoriasis is likely the most severe form of facial psoriasis, as this variant is associated with higher total-body PASI score, need for more extensive treatment, and younger age of onset [4]. The presence of facial psoriasis regardless of category has been associated with greater risk of nail involvement, pruritus, hospitalization due to psoriasis, and Koebner response (development of psoriasis lesions in areas of cutaneous trauma) [3, 5]. The visible nature of facial psoriasis causes significant psychosocial distress [6]. Facial psoriasis has been associated with a decrease in self-confidence and problems acquiring employment [7]. Identification and treatment of facial psoriasis is vital to improving both the medical and psychosocial outcomes of patients affected. Differential diagnoses of facial plaques include seborrheic dermatitis, atopic dermatitis, and lupus erythematosus tumidus. Seborrheic dermatitis typically causes yellow plaques with greasier scales, contrasting with the pink/red plaques with drier, silvery scales caused by psoriasis [8]. Atopic dermatitis may also present with pruritic and erythematous plaques. Lupus erythematosus tumidus produces red plaques as well, but these plaques tend not to scale [9].

Treatment Facial psoriasis is often recurrent and treatment-resistant. For isolated facial psoriasis or facial psoriasis that does not clear with systemic therapy, first-line agents include topical vitamin D analogs (e.g. calcipotriene, calcitriol), low-potency topical corticosteroids, tacrolimus ointment, pimecrolimus cream, and crisaborole ointment [2, 10]. Tacrolimus, pimecrolimus and crisaborole are used off-label for facial psoriasis. The thin

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and sensitive skin of the face is particularly prone to side-­ effects from corticosteroids such as skin atrophy, telangiectasia, glaucoma, acne, and perioral dermatitis [3, 11]. Therefore, high-potency topical corticosteroids on the face is not recommended. Low-potency (class 5–6) topical corticosteroids may be used but not for more than 2 consecutive weeks. Calcineurin inhibitors are successful in treating facial psoriasis but not in treating psoriasis elsewhere on the body [11]. This is due to the inability of these agents to penetrate the thicker plaques of psoriasis on the body. In contrast, the thinner plaques of facial psoriasis allow for adequate penetration of calcineurin inhibitors. Use of topical tacrolimus ointment twice daily has been shown to be efficacious for facial psoriasis in randomized controlled studies [12]. Patients experienced significant reductions in erythema, induration, and severity of facial lesions with tacrolimus. Pimecrolimus cream is also efficacious for facial psoriasis. However, a temporary burning sensation has been reported in patients using pimecrolimus cream [11]. Topical vitamin D analogs (e.g. calcipotriene and calcitriol) are also successful in treatment of facial psoriasis. These agents are attractive because they are generally well-­ tolerated. However, they may cause facial irritation and erythema, which may lead to poor medication compliance [7]. In multiple case reports, crisaborole, a PDE-4 inhibitor, has been shown to be safe and effective for treatment of facial psoriasis [10]. Side-effects of crisaborole include burning or stinging of the skin on the site of application [13]. For his facial psoriasis, the patient was started on desonide 0.05% cream, a low potency topical corticosteroid, to affected areas of the face twice daily for 2 weeks on and 2 weeks off, repeating the cycle as needed. For scalp psoriasis, the patient was started on fluocinonide 0.05% topical solution, a high potency topical corticosteroid, twice daily for 2 weeks on and 2 weeks off, repeating the cycle as needed. The patient was also instructed to begin rotating tar and salicylic acid shampoos every 2 weeks for his scalp psoriasis.

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Key Points • Facial psoriasis presents with pruritic, erythematous, indurated, and well-demarcated plaques on the face. • Facial psoriasis causes significant psychosocial issues. • Facial psoriasis is often treatment-resistant and recurring. • Topical vitamin D analogs, topical calcineurin inhibitors, and crisaborole are first-line treatments for isolated facial psoriasis; low-potency topical corticosteroids may also be used in 2 weeks on, 2 weeks off cycles. • Avoid high-potency topical corticosteroids on the face due to risk of side-effects.

References 1. Canpolat F, Cemil BC, Eskioglu F, Akis HK. Is facial involvement a sign of severe psoriasis? Eur J Dermatol. 2008;18(2):169–71. https://doi.org/10.1684/ejd.2008.0363. 2. van de Kerkhof PC, Murphy GM, Austad J, Ljungberg A, Cambazard F, Duvold LB.  Psoriasis of the face and flexures. J Dermatolog Treat. 2007;18(6):351–60. https://doi. org/10.1080/09546630701341949. 3. Young Park J, Hyun Rim J, Beom Choe Y, Il Youn J. Facial psoriasis: comparison of patients with and without facial involvement. J Amer Acade Dermatol. 2004;50:582–4. 4. Woo SM, Choi JW, Yoon HS, Jo SJ, Youn JI.  Classification of facial psoriasis based on the distributions of facial lesions. J Am Acad Dermatol. 2008;58(6):959–63. https://doi.org/10.1016/j. jaad.2008.02.006. 5. Kim KH, Ahn JY, Park MY, Youn JI.  Relation between the Peripherofacial psoriasis and scalp psoriasis. Ann Dermatol. 2016;28(4):422–6. https://doi.org/10.5021/ad.2016.28.4.422. 6. Beattie PE, Lewis-Jones MS. A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br J Dermatol. 2006;155(1):145– 51. https://doi.org/10.1111/j.1365-2133.2006.07185.x.

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7. Ortonne JP, Humbert P, Nicolas JF, Tsankov N, Tonev SD, Janin A, et al. Intra-individual comparison of the cutaneous safety and efficacy of calcitriol 3 microg g(-1) ointment and calcipotriol 50 microg g(-1) ointment on chronic plaque psoriasis localized in facial, hairline, retroauricular or flexural areas. Br J Dermatol. 2003;148(2):326–33. 8. Naldi L, Rebora A.  Clinical practice. Seborrheic dermatitis. N Engl J Med. 2009;360(4):387–96. https://doi.org/10.1056/ NEJMcp0806464. 9. Choonhakarn C, Poonsriaram A, Chaivoramukul J.  Lupus erythematosus tumidus. Int J Dermatol. 2004;43(11):815–8. https:// doi.org/10.1111/j.1365-4632.2004.02073.x. 10. Lee EB, Lebwohl MG, Wu JJ. Treatment of psoriasis with crisaborole. J Dermatolog Treat. 2018;30:1–2. https://doi.org/10.1080/ 09546634.2018.1480747. 11. Jacobi A, Braeutigam M, Mahler V, Schultz E, Hertl M. Pimecrolimus 1% cream in the treatment of facial psoriasis: a 16-week open-label study. Dermatology. 2008;216(2):133–6. https://doi.org/10.1159/000111510. 12. Lebwohl M, Freeman AK, Chapman MS, Feldman SR, Hartle JE, Henning A, Tacrolimus Ointment Study G.  Tacrolimus ointment is effective for facial and intertriginous psoriasis. J Am Acad Dermatol. 2004;51(5):723–30. https://doi.org/10.1016/j. jaad.2004.07.011. 13. Paller AS, Tom WL, Lebwohl MG, Blumenthal RL, Boguniewicz M, Call RS, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75(3):494–503 e496. https:// doi.org/10.1016/j.jaad.2016.05.046.

Chapter 7 36-Year-Old Female with Bright Red Plaques on the Labia Majora Kevin K. Wu, Michael P. Lee, and Jashin J. Wu

Case A 36-year-old female presented to the clinic with a 25-year history of erythematous and scaly rashes on the back, scalp, and genitals. The patient was using clobetasol cream for these rashes, which helped. The patient denied nail deformities, joint pain, or joint stiffness. She was otherwise healthy with no chronic medical issues, no allergies, and no use of other medications. The patient did not drink alcohol or smoke. She had no family history of psoriasis or melanoma. On physical exam, there were bright, erythematous, scaly, and indurated plaques on the back and scalp. On genital skin K. K. Wu Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA M. P. Lee Eastern Virginia Medical School, Norfolk, VA, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_7

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exam, bright red and erythematous plaques with mild scaling were noted on the bilateral labia majora. Total affected body surface area was 0.25%. Based on the clinical case description, what is the most likely diagnosis of the rash on the genitals? 1. Tinea cruris 2 . Fixed drug eruption 3. Candidal intertrigo 4. Genital psoriasis 5. Erythrasma

Answer Genital psoriasis

Discussion Genital psoriasis is found in up to 40% of psoriasis patients. It is more common in men but may also affect women [1, 2]. More than 60% of psoriasis patients report ever experiencing genital psoriasis [3]. This disease manifests in bright, erythematous, well-defined plaques in the genital region. In contrast with psoriasis on the body, plaques of genital psoriasis are thinner and produce minimal scaling [4]. However, scales can appear in keratinized areas of the genitalia, including the penile shaft, scrotum, and labia majora. When scaling is present, removal of these scales often causes the Auspitz phenomenon (bleeding at site of scale removal) [4]. In males, genital psoriasis most commonly involves the shaft of the penis, followed by the scrotum and the glans penis. In females, genital psoriasis most commonly involves the labia majora, followed by the perineum and labia minora. Patients with genital psoriasis often present with concomitant scalp, flexural, and nail involvement of psoriasis [3]. Genital psoriasis patients experience burning, pruritus, pain, and dyspareunia at the site of lesions. Women experience dyspareu-

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nia more often than men, especially with vulvar involvement of disease [3, 5]. Genital psoriasis causes significant psychosocial stress, discomfort, and embarrassment [6]. The location of the lesions may be detrimental to sex life, as these patients report a significant decrease in their level of sexual activity. In addition, partaking in sexual activity may worsen disease severity via the Koebner phenomenon [3, 4]. Patients with genital psoriasis report significantly greater rates of depression. Women with vulvar involvement of genital psoriasis report greater rates of depression than those without vulvar involvement [3, 5]. Differential diagnoses of plaques on the genitals include genital psoriasis, fixed drug eruptions, erythrasma, candida intertrigo, and tinea cruris. Genital psoriasis is the most common inflammatory condition affecting the genitals of males. Fixed drug eruptions are reactions to medications that present with erythematous, dusky, well-demarcated, and possibly bullous lesions that may be painful and pruritic [6]. Erythrasma presents with well-defined, pink to brown patches with fine scaling and superficial fissures. Wood’s lamp test is positive in both erythrasma and fixed drug eruptions. Candidal intertrigo presents with erythematous plaques with scaling and superficial satellite papules/pustules. Tinea cruris presents with erythematous, well-defined plaques with central clearing. Some patients may present with multiple etiologies causing their genital rash (e.g. candida or tinea infection superimposed onto psoriasis plaques), and all etiologies must be treated in these cases. If a penile plaque is treatment-­ resistant, the patient should be evaluated for squamous cell carcinoma in situ [6]. Diagnosis of genital psoriasis is often delayed. Patients often will not report genital psoriasis to their healthcare provider, likely due to embarrassment. In addition, clinicians often neglect examining the genital region during physical exams. Clinicians must strive to create an open discussion about genital involvement of psoriasis in order to appropriately counsel and treat these patients, thus improving their

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quality of life. In a population-based questionnaire study of patients with genital psoriasis, patients reported that it would be beneficial for physicians to inquire about sexual functioning [2].

Treatment Similar to the face, axilla, intertriginous areas, and neck, the thin and sensitive skin of the genitals is particularly prone to side-effects from high-potency topical corticosteroids. Therefore, first-line treatment of genital psoriasis includes topical calcineurin inhibitors, lower-potency topical corticosteroids, topical vitamin D analogues (e.g. calcipotriene, calcitriol), and crisaborole. For long-term management, topical calcineurin inhibitors and vitamin D analogues are preferred. Lowerpotency corticosteroid should be tapered down after 2–4 weeks of application in order to reduce the risk of side-­effects [7]. Ointments are generally avoided in the genital region due to their thick consistency, which may cause discomfort. Topical calcineurin inhibitors such as tacrolimus ointment and pimecrolimus cream are effective treatments for genital psoriasis [8, 9]. Genital skin is thin, allowing for greater penetration of these medication. Side-effects of topical tacrolimus ointment include burning and folliculitis when applied to the genital region [10]. Side-effects of pimecrolimus cream includes pruritus and burning after application. Topical vitamin D analogs such as calcipotriene and calcitriol are also effective for genital psoriasis [10]. Calcipotriene and calcitriol are generally well-tolerated. However, ­calcipotriene may cause irritant contact dermatitis in some patients. Calcitriol may cause erythema on the site of application but has lower risk of skin irritation than calcipotriene [10]. Combination treatment with a low-dose topical corticosteroid and a topical vitamin D analog may decrease risk of side-effects and increase effectiveness of both therapies [6]. In multiple case reports, crisaborole, a PDE-4 inhibitor has been shown to be safe and efficacious for genital psoriasis

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[11]. Side-effects of crisaborole include burning or stinging of the skin on the site of application [12]. Systemic treatments such as biologics may be considered if there is significant body surface area involvement. In a phase IIIb randomized controlled study, ixekizumab significantly reduced pruritus and skin involvement of patients with genital psoriasis [13]. Patients receiving ixekizumab also reported an increase in sexual activity. The patient was treated with tacrolimus ointment twice per day to affected regions of the genitals, clobetasol solution twice per day for scalp psoriasis, and clobetasol cream twice per day for body psoriasis.

Key Points • Genital psoriasis presents with thin, erythematous, well-­ defined plaques with minimal scaling. • Patients may experience severe discomfort, psychosocial issues, and embarrassment, which may hinder discussion with clinicians and delay care. • First-line treatments include calcineurin inhibitors, topical vitamin D analogs, low-potency (class 5–6) corticosteroids, and crisaborole. High-potency corticosteroids should be avoided due to higher risks of side-effects in this region.

References 1. Meeuwis KA, de Hullu JA, de Jager ME, Massuger LF, van de Kerkhof PC, van Rossum MM. Genital psoriasis: a questionnaire-­ based survey on a concealed skin disease in the Netherlands. J Eur Acad Dermatol Venereol. 2010;24(12):1425–30. https://doi. org/10.1111/j.1468-3083.2010.03663.x. 2. Meeuwis KA, de Hullu JA, van de Nieuwenhof HP, Evers AW, Massuger LF, van de Kerkhof PC, van Rossum MM.  Quality of life and sexual health in patients with genital psoriasis. Br J Dermatol. 2011b;164(6):1247–55. https://doi. org/10.1111/j.1365-2133.2011.10249.x.

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3. Ryan C, Sadlier M, De Vol E, Patel M, Lloyd AA, Day A, et al. Genital psoriasis is associated with significant impairment in quality of life and sexual functioning. J Am Acad Dermatol. 2015;72(6):978–83. https://doi.org/10.1016/j.jaad.2015.02.1127. 4. Meeuwis KA, de Hullu JA, Massuger LF, van de Kerkhof PC, van Rossum MM. Genital psoriasis: a systematic literature review on this hidden skin disease. Acta Derm Venereol. 2011a;91(1):5–11. https://doi.org/10.2340/00015555-0988. 5. Zamirska A, Reich A, Berny-Moreno J, Salomon J, Szepietowski JC.  Vulvar pruritus and burning sensation in women with psoriasis. Acta Derm Venereol. 2008;88(2):132–5. https://doi. org/10.2340/00015555-0372. 6. Buechner SA.  Common skin disorders of the penis. BJU Int. 2002;90(5):498–506. 7. Kalb RE, Bagel J, Korman NJ, Lebwohl MG, Young M, Horn EJ, et al. Treatment of intertriginous psoriasis: from the medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2009;60(1):120–4. https://doi.org/10.1016/j.jaad.2008.06.041. 8. Bissonnette R, Nigen S, Bolduc C.  Efficacy and tolerability of topical tacrolimus ointment for the treatment of male genital psoriasis. J Cutan Med Surg. 2008;12(5):230–4. https://doi. org/10.2310/7750.2008.07055. 9. Rallis E, Nasiopoulou A, Kouskoukis C, Roussaki-Schulze A, Koumantaki E, Karpouzis A, Arvanitis A. Successful treatment of genital and facial psoriasis with tacrolimus ointment 0.1%. Drugs Exp Clin Res. 2005;31(4):141–5. 10. Liao YH, Chiu HC, Tseng YS, Tsai TF. Comparison of cutaneous tolerance and efficacy of calcitriol 3 microg g(-1) ointment and tacrolimus 0.3  mg g(−1) ointment in chronic plaque psoriasis involving facial or genitofemoral areas: a double-blind, randomized controlled trial. Br J Dermatol. 2007;157(5):1005–12. https:// doi.org/10.1111/j.1365-2133.2007.08201.x. 11. Lee EB, Lebwohl MG, Wu JJ. Treatment of psoriasis with crisaborole. J Dermatolog Treat. 2018;30:1–2. https://doi.org/10.1080/ 09546634.2018.1480747. 12. Paller AS, Tom WL, Lebwohl MG, Blumenthal RL, Boguniewicz M, Call RS, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75(3):494–503 e496. https:// doi.org/10.1016/j.jaad.2016.05.046.

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13. Ryan C, Menter A, Guenther L, Blauvelt A, Bissonnette R, Meeuwis K, et  al. Efficacy and safety of ixekizumab in a randomized, double-blinded, placebo-controlled phase IIIb study of patients with moderate-to-severe genital psoriasis. Br J Dermatol. 2018;179:844–52. https://doi.org/10.1111/bjd.16736.

Chapter 8 67-Year-Old with Thick Plaques on the Palms Kevin K. Wu, Michael P. Lee, and Jashin J. Wu

Case A 67-year-old female presented with a 3-year history of persistent, pruritic, red, thick plaques on the bilateral palms. The patient also had a history of psoriatic arthritis, which improved with adalimumab. However, her plaques persisted despite treatment with adalimumab. Treatment with etanercept and methotrexate also failed to treat her plaques. Her chronic medical issues included hypertension and hypercholesterolemia. On physical examination, there were red, scaly, indurated papules and plaques on the bilateral palms, soles, elbows, and knees, with a total body surface area involvement of 6% (Figs. 8.1 and 8.2). Both plantar surfaces of the

K. K. Wu Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA M. P. Lee Eastern Virginia Medical School, Norfolk, VA, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_8

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Figure 8.1 Erythematous, scaly, indurated papules and plaques were present on the palmar surfaces of both hands

Figure 8.2 Erythematous, scaly, indurated papules and plaques were also present on the dorsal surfaces of both hands. No onycholysis or onychodystrophy was noted

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feet were clear. No lichenification, pustules, desquamation, wrinkling, or fissures were noted. No onycholysis or onychodystrophy was noted. Based on the clinical case description, what is the most appropriate topical treatment for this patient? 1. Triamcinolone 0.5% cream 2 . Hydrocortisone 2.5% cream 3. Pimecrolimus cream 4. Clobetasol 0.05% ointment 5. Tacrolimus cream

Answer Clobetasol 0.05% ointment

Discussion 12–16% of psoriasis patients are affected with palmar-plantar psoriasis [1]. Palmar-plantar psoriasis presents with well-­ demarcated, erythematous, scaly, thick plaques on the palms and soles. The lesions may become pustular [2]. Although the palms and soles only add up to 5% of the total body surface area (characterized as mild disease with PASI scoring), palmar-­ plantar psoriasis causes profound decrements to quality of life [2, 3]. When the hands are affected, activities of daily living become extremely difficult and painful. When the soles are affected, walking may become unbearably painful. A survey-based population study of 317 patients found that those with palmar-plantar psoriasis reported significantly greater physical distress and disability than those with just plaque psoriasis [4]. Interestingly, palmar-plantar psoriasis patients did not report higher psychosocial stress than those

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with plaque psoriasis possibly because the lesions may be easily disguised. However, these patients may avoid h ­ andshaking due to embarrassment [2, 4]. Relieving pain and discomfort leads to significant treatment satisfaction in palmar-plantar psoriasis [4]. Therefore, treatments should aim to reduce pain and discomfort, even if the lesions are not completely resolved.

Treatment For mild cases of palmar-plantar psoriasis, alternating topical corticosteroids with topical vitamin D analogs (e.g. calcipotriene, calcitriol) may be effective. Due to the thickened stratum corneum on palmar and plantar skin, high-potency topical corticosteroids may be necessary for effective treatment. Using occlusive tools such as gloves and plastic wraps may aid in the absorption of the medication. For severe cases of palmar-plantar psoriasis or cases with greater than 10% body surface area involvement, systemic treatments with retinoids, cyclosporine, apremilast, methotrexate, or biologics may be considered. Systemic treatments may even be considered for palmar-plantar psoriasis with BSA less than 10%, as cases are often recurrent and resistant to topical therapies. Acitretin is effective in reducing pain symptoms of palmar-­ plantar psoriasis, leading to high patient satisfaction rates. However, acitretin may not completely resolve the lesions. Side-effects of acitretin such as oral mucosal dryness and increase in blood lipid levels are dose-dependent. Therefore, it is unnecessary to increase the dose of acitretin to resolve lesions if the patient is reporting significant reductions in pain and discomfort [5]. Methotrexate is another effective systemic medication in treatment of palmar-plantar psoriasis. In a randomized prospective study comparing acitretin and methotrexate, both medications significantly improved psoriasis lesions [3]. Side-­ effects of methotrexate include nausea, vomiting, and changes in liver function tests. Supplementing with 1–5 g of folic acid per day may reduce the risk of side-effects.

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Cyclosporine is highly effective in resolving resistant plaques. However, its extensive side-effect profile limits its use for chronic management of palmar-plantar psoriasis.Apremilast has also been found to significantly improve palmar-­plantar psoriasis. Side-effects of apremilast include headache, upper respiratory infection, and gastrointestinal upset. Biologic therapies such as ustekinumab, secukinumab, and ixekizumab have been shown to significantly improve palmar-­ plantar psoriasis when compared to placebo [6–10]. TNF inhibitors should be avoided, as they may paradoxically induce palmar-plantar psoriasis. Some patients started on TNF inhibitors reported a transformation of palmar-plantar psoriasis to pustular palmar-plantar psoriasis [11–15]. This finding may possibly be due to an imbalance of TNF-α and IFN-α molecules in genetically susceptible patients [13]. Other effective treatment options include ultraviolet therapy, bath psoralen plus ultraviolet A, and tar-based soaps. Recalcitrant cases of pustular palmar-plantar psoriasis may be treated with oral or topical dapsone [16]. The patient was treated with acitretin 25  mg a day and clobetasol 0.05% ointment twice a day on affected areas for 2  weeks on and 2  weeks off, with the cycle repeated as needed. During her 6-week follow-up, the patient reported clearance of her palmar-plantar psoriasis after 2  weeks of treatment. On examination, her palms, soles, and elbows were clear, but a few red, scaly, and indurated papules were noted on the right knee. The patient was ecstatic with her results.

Key Points • Palmar-plantar psoriasis has a profound occupational impact on patients. • Mild cases should be treated with high-potency topical corticosteroids. Consider systemic treatments such as retinoids, methotrexate, cyclosporine, apremilast, or certain biologics (e.g. ustekinumab, secukinumab, and ixekizumab) for severe cases.

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• Avoid TNF inhibitors, as they may paradoxically induce palmar-plantar psoriasis.

References 1. Merola JF, Li T, Li WQ, Cho E, Qureshi AA. Prevalence of psoriasis phenotypes among men and women in the USA. Clin Exp Dermatol. 2016;41(5):486–9. https://doi.org/10.1111/ced.12805. 2. Farley E, Masrour S, McKey J, Menter A.  Palmoplantar psoriasis: a phenotypical and clinical review with introduction of a new quality-of-life assessment tool. J Am Acad Dermatol. 2009;60(6):1024–31. https://doi.org/10.1016/j.jaad.2008.11.910. 3. Janagond AB, Kanwar AJ, Handa S.  Efficacy and safety of systemic methotrexate vs. acitretin in psoriasis patients with significant palmoplantar involvement: a prospective, randomized study. J Eur Acad Dermatol Venereol. 2013;27(3):e384–9. https://doi. org/10.1111/jdv.12004. 4. Pettey AA, Balkrishnan R, Rapp SR, Fleischer AB, Feldman SR.  Patients with palmoplantar psoriasis have more physical disability and discomfort than patients with other forms of psoriasis: implications for clinical practice. J Am Acad Dermatol. 2003;49(2):271–5. 5. Ortiz NE, Nijhawan RI, Weinberg JM. Acitretin. Dermatol Ther. 2013;26(5):390–9. https://doi.org/10.1111/dth.12086. 6. Au SC, Goldminz AM, Kim N, Dumont N, Michelon M, Volf E, et  al. Investigator-initiated, open-label trial of ustekinumab for the treatment of moderate-to-severe palmoplantar psoriasis. J Dermatolog Treat. 2013;24(3):179–87. https://doi.org/10.3109/095 46634.2012.672710. 7. Bissonnette R, Poulin Y, Guenther L, Lynde CW, Bolduc C, Nigen S.  Treatment of palmoplantar psoriasis with infliximab: a randomized, double-blind placebo-controlled study. J Eur Acad Dermatol Venereol. 2011;25(12):1402–8. https://doi. org/10.1111/j.1468-3083.2011.03984.x. 8. Gottlieb A, Sullivan J, van Doorn M, Kubanov A, You R, Parneix A, et al. Secukinumab shows significant efficacy in palmoplantar psoriasis: results from GESTURE, a randomized controlled trial. J Am Acad Dermatol. 2017;76(1):70–80. https://doi.org/10.1016/j. jaad.2016.07.058.

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9. Menter A, Warren RB, Langley RG, Merola JF, Kerr LN, Dennehy EB, et  al. Efficacy of ixekizumab compared to etanercept and placebo in patients with moderate-to-severe plaque psoriasis and non-pustular palmoplantar involvement: results from three phase 3 trials (UNCOVER-1, UNCOVER-2 and UNCOVER-3). J Eur Acad Dermatol Venereol. 2017;31(10):1686–92. https://doi.org/10.1111/jdv.14237. 10. Paul C, Reich K, Gottlieb AB, Mrowietz U, Philipp S, Nakayama J, et  al. Secukinumab improves hand, foot and nail lesions in moderate-to-severe plaque psoriasis: subanalysis of a randomized, double-blind, placebo-controlled, regimen-finding phase 2 trial. J Eur Acad Dermatol Venereol. 2014;28(12):1670–5. https:// doi.org/10.1111/jdv.12359. 11. Brown G, Wang E, Leon A, Huynh M, Wehner M, Matro R, et al. Tumor necrosis factor-alpha inhibitor-induced psoriasis: systematic review of clinical features, histopathological findings, and management experience. J Am Acad Dermatol. 2017;76(2):334– 41. https://doi.org/10.1016/j.jaad.2016.08.012. 12. Collamer AN, Battafarano DF. Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: clinical features and possible immunopathogenesis. Semin Arthritis Rheum. 2010;40(3):233– 40. https://doi.org/10.1016/j.semarthrit.2010.04.003. 13. Raposo I, Torres T.  Palmoplantar psoriasis and palmoplan tar pustulosis: current treatment and future prospects. Am J Clin Dermatol. 2016;17(4):349–58. https://doi.org/10.1007/ s40257-016-0191-7. 14. Shmidt E, Wetter DA, Ferguson SB, Pittelkow MR. Psoriasis and palmoplantar pustulosis associated with tumor necrosis factor-­ alpha inhibitors: the Mayo Clinic experience, 1998 to 2010. J Am Acad Dermatol. 2012;67(5):e179–85. https://doi.org/10.1016/j. jaad.2011.05.038. 15. Wollina U, Hansel G, Koch A, Schonlebe J, Kostler E, Haroske G.  Tumor necrosis factor-alpha inhibitor-induced psoriasis or psoriasiform exanthemata: first 120 cases from the literature including a series of six new patients. Am J Clin Dermatol. 2008;9(1):1–14. 16. Sheu JS, Divito SJ, Enamandram M, Merola JF.  Dapsone therapy for pustular psoriasis: case series and review of the literature. Dermatology. 2016;232(1):97–101. https://doi. org/10.1159/000431171.

Chapter 9 61-Year-Old Male with Joint Stiffness Kevin K. Wu, Michael P. Lee, and Jashin J. Wu

Case A 61-year-old male presented for follow-up for his psoriasis and psoriatic arthritis. He had been on secukinumab for the past 2.5  months, and his last dose was today. He reported a lack of improvement of his psoriasis and psoriatic arthritis with secukinumab. He was previously on adalimumab and etanercept with minimal improvement of his symptoms. He requested to switch to another medication. He stated that his joint stiffness was worse in the mornings and improved with activity. He denied any fever, illness, trauma, weakness, or numbness/tingling in extremities. He denied any family history of psoriasis or psoriatic arthritis. On physical examination, erythematous, indurated, thick, scaly papules and plaques were noted on the dorsal hands, K. K. Wu Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA M. P. Lee Eastern Virginia Medical School, Norfolk, VA, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_9

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arms, and legs. Total body surface area involvement was 5%. No onycholysis or onychodystrophy was noted. On musculoskeletal examination, decreased range of motion with tenderness in the wrist and shoulder joints was noted. Mild swelling and tenderness was noted on the metacarpophalangeal joints bilaterally. Lower extremity joint examination revealed no abnormalities. Based on the case description, which of the following is the best treatment to switch the patient to? 1. Intra-articular joint injections 2 . Physical therapy 3. Non-steroidal anti-inflammatory drugs 4. Ixekizumab 5. Apremilast

Answer Ixekizumab

Discussion Psoriatic arthritis (PsA) is a chronic, inflammatory, seronegative spondyloarthropathy. PsA tends to occur 10–12  years after the initial diagnosis of psoriasis [1]. However, 14–20% of patients may experience PsA before or simultaneously with their initial skin symptoms [2]. Psoriatic arthritis occurs in 19.7% of psoriasis patients [3]. Patients with greater psoriatic skin involvement have greater risk of developing PsA.  However, the severity of arthritis does not necessarily correlate with the severity of skin disease [4]. Up to 39% of patients with PsA are carriers of the HLA-B27 allele, which is also associated with ankylosing spondylitis, inflammatory bowel disease, and reactive arthritis [5]. Symptoms of PsA include tenderness, stiffness, and reduced range of motion of affected joints. Although any joint may be

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affected, PsA has a predilection toward the distal joints of the upper and lower extremities. Axial, wrist, knee, and ankle joints are also commonly involved. Distribution of joint involvement may vary considerably between different patients. Symptoms of PsA are classically worse after periods of inactivity (e.g. in the mornings or after long car/air travel) with gradual improvement with activity. Dactylitis (inflammation of the entire finger or toe, causing “sausage-fingers”) and enthesitis (inflammation of the attachment sites of tendons and ligaments that insert into the bone) occur in up to 50% of PsA patients [6]. Psoriatic nail abnormalities (e.g. onycholysis, onychodystrophy) are associated with the development of PsA. In a questionnaire study of 1511 patients, psoriatic nail changes were found in 68.6% of PsA patients [7]. 40–60% patients with PsA may eventually develop destructive and dystrophic arthritis if PsA is left untreated [8]. PsA patients develop profound physical limitations and severely reduced quality of life if not appropriately treated. Radiographs of PsA patients classically reveal spur formation and pencil-in-cup deformity. Joint space narrowing, joint erosions, joint lysis, and spondylitis may also be seen on radiographs. The presence of dactylitis may indicate a greater degree of radiographic joint damage [9]. Differential diagnoses include osteoarthritis and rheumatoid arthritis. Dactylitis and enthesitis would not be seen in these two diseases. Rheumatoid arthritis classically spares the distal interphalangeal joints, and osteoarthritis tends to worsen with activity and improve with rest. Psoriatic nail abnormalities may also aid in guiding the diagnosis of PsA. Because psoriasis typically presents years before PsA symptoms occur, dermatologists are in a position to screen for symptoms early on in the disease process. Irreversible joint damage begins 2 years after PsA onset, and early detection and treatment of PsA may improve long-term outcomes [10]. Dermatologists should screen psoriasis patients for PsA symptoms at every visit and make appropriate referrals to rheumatology.

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Treatment Treatments for PsA include non-steroidal anti-inflammatory drugs (NSAIDs) for mild disease and oral or injectable disease-­ modifying drugs for moderate-to-severe disease. However, NSAIDs may not be preferred in patients with active psoriatic skin disease, as they are associated with psoriasis flares and increased risk of cardiovascular disease [11]. Systemic corticosteroids should be avoided in psoriasis patients, as both use of and withdrawal from systemic corticosteroids may precipitate psoriasis flares [12, 13]. Both European League Against Rheumatism (EULAR) and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) guidelines for management of PsA recommend conventional synthetic disease-modifying rheumatic drugs (DMARDs) (e.g. methotrexate, cyclosporine, leflunomide) as initial therapy after failure of NSAIDs [14, 15]. Biologic (e.g. TNF, IL-17, IL-12/23 inhibitors) or targeted synthetic (e.g. apremilast) DMARDs are recommended after failure of conventional synthetic DMARDs. However, early biologic DMARD use is recommended in patients with active enthesitis and/or dactylitis. The first biologic DMARD prescribed would usually be a TNF inhibitor, as TNF inhibitors have the largest body of evidence supporting their use in PsA. If the TNF inhibitor fails or is not clinically appropriate, an IL-12/23 or IL-17 inhibitor may be considered. TNF inhibitors are effective in treating both psoriasis and PsA.  TNF inhibitors have been shown to reduce synovitis, joint damage, dactylitis, enthesitis, and axial disease [16, 17]. In a double-blinded randomized controlled clinical trial (ADEPT), adalimumab was found to be efficacious in both reducing symptoms and inhibiting structural damage of PsA [18]. In 48-week open-label extension of the trial, adalimumab continued to demonstrate sustained inhibition of radiographic disease progression. Other TNF inhibitors such as etanercept and infliximab also significantly reduced both the symptoms and radiographic disease progression of PsA in randomized controlled trials (Sherry et al. 2010; Antoni et al.

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2005). However, infliximab is dosed intravenously, which may be undesirable and inconvenient for patients. Many patients do not sustain a long-term response to TNF inhibitors and may need to switch to other agents [19, 20]. Other biologics such as IL-17A and IL-12/23 inhibitors can be effective in treating PsA after failure of TNF inhibitors [15]. In randomized controlled trials, ustekinumab (PSUMMIT 1 and 2), secukinumab (FUTURE 1 and 2), and ixekizumab (SPIRIT-P1 and P2) were all found to be effective in improving symptoms and reducing radiographic joint damage from PsA [21–25]. However, patients who previously received TNF inhibitors experienced lower response rates with secukinumab than TNF inhibitor naïve patients. In contrast, ixekizumab was very effective for both groups of PsA patients. Other treatments of PsA include methotrexate, leflunomide, apremilast, and cyclosporine. Limited evidence supports methotrexate for treatment of PsA.  A randomized controlled trial found no significant improvement of any rheumatology-related response indices in PsA in patients receiving methotrexate. However, patients on methotrexate did report improvement in subjective symptom assessments. Evidence for reduction of radiographic joint disease progression on methotrexate was inconclusive. Many biologic trials allowed for concomitant use of methotrexate during the course of the studies, and most found no significant difference in response rate in those receiving combination treatment versus those receiving biologics alone [26]. In randomized controlled trials, patients on apremilast reported modest improvement of PsA symptoms including enthesitis and dactylitis [27]. However, evidence of reduction in radiographic joint disease progression was inconclusive. Cyclosporine is infrequently used for treatment of PsA due to its extensive side-effect profile and lack of efficacy [28]. Cyclosporine should only be used short-term due to its side-effects and should not be utilized for long-term maintenance treatment of PsA. The patient was switched from secukinumab to ixekizumab. At 6-month follow-up, the patient reported significant

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improvement in both his psoriasis and psoriatic arthritis. However, he reported new erythematous, scaly, indurated papules and plaques in the groin for 3 months which did not improve with topical nystatin. The rash was diagnosed as inverse psoriasis, and the patient was treated with topical tacrolimus.

Key Points • Presentation and severity of PsA can vary significantly from patient to patient. • Dermatologists are in a unique position to screen for early signs of PsA and prevent permanent joint damage and disability. • Efficacy of biologics (e.g. TNF inhibitors, IL-17 inhibitors, and IL-12/23 inhibitor) for treatment in PsA is well-­ documented. Clinically significant improvements in symptoms, quality of life, and radiographic joint disease progression can be achieved with biologic treatments. • Methotrexate and apremilast are second-line agents for PsA.  They have not been shown to inhibit radiographic joint disease progression in PsA.

References 1. Gottlieb AB, Mease PJ, Mark Jackson J, Eisen D, Amy Xia H, Asare C, Stevens SR. Clinical characteristics of psoriatic arthritis and psoriasis in dermatologists’ offices. J Dermatolog Treat. 2006;17(5):279–87. https://doi.org/10.1080/09546630600823369. 2. Chang CA, Gottlieb AB, Lizzul PF.  Management of psoriatic arthritis from the view of the dermatologist. Nat Rev Rheumatol. 2011;7(10):588–98. https://doi.org/10.1038/nrrheum.2011.125. 3. Alinaghi F, Calov M, Kristensen LE, Gladman DD, Coates LC, Jullien D, et al. Prevalence of psoriatic arthritis in patients with psoriasis: a systematic review and meta-analysis of observational and clinical studies. J Am Acad Dermatol. 2018;80:251–265.e19. https://doi.org/10.1016/j.jaad.2018.06.027.

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4. Cohen MR, Reda DJ, Clegg DO. Baseline relationships between psoriasis and psoriatic arthritis: analysis of 221 patients with active psoriatic arthritis. Department of Veterans Affairs Cooperative Study Group on Seronegative Spondyloarthropathies. J Rheumatol. 1999;26(8):1752–6. 5. Queiro R, Morante I, Cabezas I, Acasuso B.  HLA-B27 and psoriatic disease: a modern view of an old relationship. Rheumatology (Oxford). 2016;55(2):221–9. https://doi. org/10.1093/rheumatology/kev296. 6. Helliwell P.  Psoriasis and psoriatic arthritis: an integrated approach. Berlin: Springer; 2005. 7. Reich K, Kruger K, Mossner R, Augustin M. Epidemiology and clinical pattern of psoriatic arthritis in Germany: a prospective interdisciplinary epidemiological study of 1511 patients with plaque-type psoriasis. Br J Dermatol. 2009;160(5):1040–7. https:// doi.org/10.1111/j.1365-2133.2008.09023.x. 8. Gladman DD, Antoni C, Mease P, Clegg DO, Nash P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis. 2005;64(Suppl 2):ii14–7. https://doi.org/10.1136/ ard.2004.032482. 9. Brockbank JE, Stein M, Schentag CT, Gladman DD. Dactylitis in psoriatic arthritis: a marker for disease severity? Ann Rheum Dis. 2005;64(2):188–90. https://doi.org/10.1136/ard.2003.018184. 10. Mease PJ, Armstrong AW.  Managing patients with psoriatic disease: the diagnosis and pharmacologic treatment of psoriatic arthritis in patients with psoriasis. Drugs. 2014;74(4):423–41. https://doi.org/10.1007/s40265-014-0191-y. 11. Chou R, Helfand M, Peterson K, Dana T, Roberts C.  Drug class review: cyclo-oxygenase (COX)-2 inhibitors and non-­ steroidal anti-inflammatory drugs (NSAIDs): final report update 3. Portland (OR); 2006. 12. Brodell RT, Williams L.  A corticosteroid-induced flare of psoriasis. How to control or, better yet, avoid. Postgrad Med. 1999;106(7):31–2. https://doi.org/10.3810/pgm.1999.12.813. 13. Mrowietz U, Domm S.  Systemic steroids in the treat ment of psoriasis: what is fact, what is fiction? J Eur Acad Dermatol Venereol. 2013;27(8):1022–5. https://doi. org/10.1111/j.1468-3083.2012.04656.x. 14. Coates LC, Gossec L, Ramiro S, Mease P, van der Heijde D, Smolen JS, et  al. New GRAPPA and EULAR recommendations for the management of psoriatic arthritis. Rheumatology

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(Oxford). 2017;56(8):1251–3. https://doi.org/10.1093/ rheumatology/kew390. 15. Gossec L, Smolen JS, Ramiro S, de Wit M, Cutolo M, Dougados M, et  al. European League Against rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis. 2016;75(3):499–510. https://doi.org/10.1136/ annrheumdis-2015-208337. 16. Gossec L, Smolen JS, Gaujoux-Viala C, Ash Z, Marzo-Ortega H, van der Heijde D, et al. European League Against rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies. Ann Rheum Dis. 2012;71(1):4–12. https://doi.org/10.1136/annrheumdis-2011-200350. 17. Ritchlin CT, Kavanaugh A, Gladman DD, Mease PJ, Helliwell P, Boehncke WH, et  al. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis. 2009;68(9):1387–94. https://doi. org/10.1136/ard.2008.094946. 18. Mease PJ, Gladman DD, Ritchlin CT, Ruderman EM, Steinfeld SD, Choy EH, et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005;52(10):3279–89. https://doi.org/10.1002/art.21306. 19. Alwawi EA, Krulig E, Gordon KB.  Long-term efficacy of biologics in the treatment of psoriasis: what do we really know? Dermatol Ther. 2009;22(5):431–40. https://doi. org/10.1111/j.1529-8019.2009.01259.x. 20. Gniadecki R, Kragballe K, Dam TN, Skov L.  Comparison of drug survival rates for adalimumab, etanercept and infliximab in patients with psoriasis vulgaris. Br J Dermatol. 2011;164(5):1091– 6. https://doi.org/10.1111/j.1365-2133.2011.10213.x. 21. Kavanaugh A, McInnes IB, Mease PJ, Hall S, Chinoy H, Kivitz AJ, et al. Efficacy of subcutaneous secukinumab in patients with active psoriatic arthritis stratified by prior tumor necrosis factor inhibitor use: results from the randomized placebo-controlled FUTURE 2 study. J Rheumatol. 2016;43(9):1713–7. https://doi. org/10.3899/jrheum.160275. 22. Kavanaugh A, Mease PJ, Reimold AM, Tahir H, Rech J, Hall S, et al. Secukinumab for long-term treatment of psoriatic arthritis: a two-year followup from a phase III, randomized, double-­ blind placebo-controlled Study. Arthritis Care Res (Hoboken). 2017;69(3):347–55. https://doi.org/10.1002/acr.23111.

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23. Kavanaugh A, Ritchlin C, Rahman P, Puig L, Gottlieb AB, Li S, et  al. Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-­ blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials. Ann Rheum Dis. 2014;73(6):1000–6. https://doi.org/10.1136/ annrheumdis-2013-204741. 24. Rahman P, Puig L, Gottlieb AB, Kavanaugh A, McInnes IB, Ritchlin C, et  al. Ustekinumab treatment and improvement of physical function and health-related quality of life in patients with psoriatic arthritis. Arthritis Care Res (Hoboken). 2016;68(12):1812–22. https://doi.org/10.1002/acr.23000. 25. van der Heijde D, Gladman DD, Kishimoto M, Okada M, Rathmann SS, Moriarty SR, et  al. Efficacy and safety of Ixekizumab in patients with active psoriatic arthritis: 52-week results from a phase III Study (SPIRIT-P1). J Rheumatol. 2018;45(3):367–77. https://doi.org/10.3899/jrheum.170429. 26. Combe B, Behrens F, McHugh N, Brock F, Kerkmann U, Kola B, Gallo G.  Comparison of etanercept monotherapy and combination therapy with methotrexate in psoriatic arthritis: results from 2 clinical trials. J Rheumatol. 2016;43(6):1063–7. https://doi. org/10.3899/jrheum.151290. 27. Kavanaugh A, Mease PJ, Gomez-Reino JJ, Adebajo AO, Wollenhaupt J, Gladman DD, et al. Longterm (52-week) results of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis. J Rheumatol. 2015;42(3):479–88. https://doi.org/10.3899/jrheum.140647. 28. Salvarani C, Macchioni P, Olivieri I, Marchesoni A, Cutolo M, Ferraccioli G, et al. A comparison of cyclosporine, sulfasalazine, and symptomatic therapy in the treatment of psoriatic arthritis. J Rheumatol. 2001;28(10):2274–82.

Chapter 10 The Non-compliant Psoriasis Patient Kevin K. Wu, Michael P. Lee, and Jashin J. Wu

Case A 46-year-old male with a long history of poorly managed psoriasis presented for follow-up of psoriasis and psoriatic arthritis. He had been using adalimumab 40 mg every week and cyclosporine 100 mg twice a day. Last month, the patient briefly stopped cyclosporine due to fear of liver toxicity. His psoriasis flared, so he restarted cyclosporine 3 weeks ago. Of note, this patient had an extensive history of self-­discontinuing treatment against medical advice, despite counseling and reassurance during visits and phone calls. The patient had worked for United Parcel Service for 28 years, and he worked Monday through Friday from 6 p.m. to 4 a.m. He noted that his work schedule hindered his ability to keep up with his

K. K. Wu Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA M. P. Lee Eastern Virginia Medical School, Norfolk, VA, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_10

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medication regimen. He requested a medication that required less frequent dosing. On physical examination, erythematous, scaly, indurated papules and plaques were noted diffusely on the scalp, bilateral arms, bilateral legs, chest, abdomen, and back. Approximately 50% of his total body surface area was affected. No nail or joint abnormalities were noted. Which is the best treatment recommendation for this patient? 1. Continue adalimumab and cyclosporine 2 . UVB phototherapy 3. Methotrexate 4. Apremilast 5. Ustekinumab

Answer Ustekinumab

Discussion Treatment compliance refers to patient behavior that results in the following of instructions provided by their healthcare provider. In a population-based study of psoriasis patients, 39% of patients reported that they did not comply with the treatment regimen recommended by their clinician [1]. A systematic review found that psoriasis patient noncompliance with topical corticosteroid preparations may be as high as 88.3% [2]. Variables that influence noncompliance include the provider-patient relationship, cost of the medication, patient beliefs about their condition and medications, and side-effects of medications. Patient noncompliance may often be unintentional, and patients may misunderstand the medication directions or simply forget to take their doses. Maximizing compliance is essential in treating psoriasis. Psoriasis is associated with a host of physical and psychiatric

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co-morbidities, including cardiovascular disease, metabolic syndrome, psoriatic arthritis, diabetes, depression, anxiety, obesity, and suicidality [3]. Some comorbidities such as suicidality has been specifically linked with psoriasis disease severity [4, 5]. Treatment of psoriasis with biologics have been shown to decrease depressive symptoms in randomized clinical trials [6, 7]. There is growing belief that treating psoriasis with medications may reduce risk of the cardiovascular comorbidities, and this theory is being actively investigated [8, 9]. Compliance to an effective psoriasis treatment regimen may not only improve symptoms of psoriasis but also possibly reduce the risk of the associated comorbidities. Therefore, it is paramount to ensure patient compliance in order to improve patient outcomes. Clinicians play an active role in ensuring patient compliance. In a questionnaire survey of 26 dermatologists and 50 psoriasis patients regarding treatment with oral systemic medications, patients reported that the clinician should have spent more time explaining their treatment regimens [10]. One-third of the patients did not know how to appropriately use their treatments, one-third of patients was under the impression that their psoriasis would improve within 1–2  weeks, and more than half of the patients discontinued their treatments due to lack of perceived efficacy. Clinicians must set appropriate expectations and spend adequate time educating the patient on their diagnoses and treatment regimens to minimize noncompliance. Numerous studies investigated specific characteristics of noncompliant psoriasis patients, including age, psoriasis severity, distribution of psoriasis lesions, demographic factors, and psychiatric comorbidities. In a survey-based study of psoriasis treatment compliance, non-compliers were significantly younger, had younger age of onset of psoriasis, and had greater disease severity than compliers [1]. The evidence is less consistent in regards to gender, marital status, smoking, and employment. There is a positive association between higher level of education and treatment compliance [11, 12]. Depression was also significantly associated with noncompliance in psoriasis patients [13]. Distribution of psoriasis

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lesions has a significant impact on compliance, as those with facial lesions and with greater body surface area involvement were paradoxically less likely to be compliant with their treatments [12]. This finding may be due to feelings of resignation or having “had enough” and losing hope on treatment options for their psoriasis [13].

Treatment Treatment-related factors have a profound influence on psoriasis patient compliance. For example, fear of side-effects significantly reduces patient compliance to a medication [14]. In contrast, the actual occurrence of side-effects has less of an impact. The duration of treatment also influences patient compliance; patients treated with a medication for long term, as opposed to less than 2 months, are significantly more likely to comply with their treatment regimen [12, 15, 16]. Patients are also more likely to comply with a medication with a rapid onset of action and quick process of administration [17]. Some preparations of topical medications such as ointments may cause undesirable cosmetic and tactile properties, reducing patient compliance with these medications. In a survey of 120 patients on treatment preferences in psoriasis, 44% preferred systemic treatments, 26% preferred creams, 17% preferred ointments, 3% preferred phototherapy, and 10% reported no preference [1]. Most patients preferred injectable agents over oral systemic agents, likely due to the lower frequency of administration [18]. Treatment regimens with higher frequency of dosing are associated with patient noncompliance [19]. Two studies found that ustekinumab had a higher patient compliance rate than both adalimumab or etanercept [20, 21]. Data on other biologics such as etanercept, infliximab, and adalimumab is limited and less consistent [22, 23]. First-line treatments for moderate-to-­ severe psoriasis patients with a history of noncompliance include biologics with infrequent maintenance dosing: ustekinumab (every 12  weeks), tildrakizumab (every

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12 weeks), guselkumab (every 8 weeks), secukinumab (every 4 weeks), and ixekizumab (every 4 weeks). Ustekinumab and tildrakizumab may be particularly favorable to patients because they have the least frequent dosing regimen. The patient was started on ustekinumab as monotherapy for his psoriasis. At 4-month follow-up, skin examination found significant clearance of psoriasis lesions. Approximately 2% of the total body surface area was involved. He did not report any adverse effects and was very happy with his new regimen.

Key Points • Compliance refers to the following of treatment instructions set by the healthcare provider. • Compliance is greatest when using treatments with less frequent dosing, more rapid onset of action, and fewer perceived side effects. • Ustekinumab and tildrakizumab only require every 12-week dosing, making them favorable choices for noncompliant patients. • Compliance with topical therapies is low due to cosmetic properties, tactile properties, lower efficacy, and frequency of application.

References 1. Richards HL, Fortune DG, O’Sullivan TM, Main CJ, Griffiths CE. Patients with psoriasis and their compliance with medication. J Am Acad Dermatol. 1999;41(4):581–3. 2. Svendsen MT, Andersen F, Hansen J, Johannessen H, Andersen KE.  Medical adherence to topical corticosteroid preparations prescribed for psoriasis: a systematic review. J Dermatolog Treat. 2017;28(1):32–9. https://doi.org/10.1080/09546634.2016.1178375. 3. Menter MA, Armstrong AW, Gordon KB, Wu JJ. Common and not-so-common comorbidities of psoriasis. Semin Cutan Med Surg. 2018;37(2S):S48–51. https://doi.org/10.12788/j.sder.2018.011.

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4. Kurd SK, Troxel AB, Crits-Christoph P, Gelfand JM. The risk of depression, anxiety, and suicidality in patients with psoriasis: a population-based cohort study. Arch Dermatol. 2010;146(8):891– 5. https://doi.org/10.1001/archdermatol.2010.186. 5. Rapp SR, Exum ML, Reboussin DM, Feldman SR, Fleischer A, Clark A.  The physical, psychological and social impact of psoriasis. J Health Psychol. 1997;2(4):525–37. https://doi. org/10.1177/135910539700200409. 6. Langley RG, Feldman SR, Han C, Schenkel B, Szapary P, Hsu MC, et al. Ustekinumab significantly improves symptoms of anxiety, depression, and skin-related quality of life in patients with moderate-to-severe psoriasis: results from a randomized, double-­ blind, placebo-controlled phase III trial. J Am Acad Dermatol. 2010;63(3):457–65. https://doi.org/10.1016/j.jaad.2009.09.014. 7. Menter A, Augustin M, Signorovitch J, Yu AP, Wu EQ, Gupta SR, et  al. The effect of adalimumab on reducing depression symptoms in patients with moderate to severe psoriasis: a randomized clinical trial. J Am Acad Dermatol. 2010;62(5):812–8. https://doi.org/10.1016/j.jaad.2009.07.022. 8. Mehta NN, Shin DB, Joshi AA, Dey AK, Armstrong AW, Duffin KC, et  al. Effect of 2 psoriasis treatments on vascular inflammation and novel inflammatory cardiovascular biomarkers: a randomized placebo-controlled trial. Circ Cardiovasc Imaging. 2018;11(6):e007394. https://doi.org/10.1161/ CIRCIMAGING.117.007394. 9. Wu JJ, Sundaram M, Cloutier M, Gauthier-Loiselle M, Guerin A, Singh R, Ganguli A.  The risk of cardiovascular events in psoriasis patients treated with tumor necrosis factor-alpha inhibitors versus phototherapy: an observational cohort study. J Am Acad Dermatol. 2018;79(1):60–8. https://doi.org/10.1016/j. jaad.2018.02.050. 10. Choi CW, Kim BR, Ohn J, Youn SW. The advantage of cyclosporine a and methotrexate rotational therapy in long-term systemic treatment for chronic plaque psoriasis in a real world practice. Ann Dermatol. 2017;29(1):55–60. https://doi.org/10.5021/ ad.2017.29.1.55. 11. Gokdemir G, Ari S, Koslu A.  Adherence to treatment in patients with psoriasis vulgaris: Turkish experience. J Eur Acad Dermatol Venereol. 2008;22(3):330–5. https://doi. org/10.1111/j.1468-3083.2007.02425.x.

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12. Zaghloul SS, Goodfield MJ. Objective assessment of compliance with psoriasis treatment. Arch Dermatol. 2004;140(4):408–14. https://doi.org/10.1001/archderm.140.4.408. 13. Zalewska A, Miniszewska J, Chodkiewicz J, Narbutt J.  Acceptance of chronic illness in psoriasis vulgaris patients. J Eur Acad Dermatol Venereol. 2007;21(2):235–42. https://doi. org/10.1111/j.1468-3083.2006.01912.x. 14. Brown KK, Rehmus WE, Kimball AB.  Determining the relative importance of patient motivations for nonadherence to topical corticosteroid therapy in psoriasis. J Am Acad Dermatol. 2006;55(4):607–13. https://doi.org/10.1016/j.jaad.2005.12.021. 15. Atkinson MJ, Sinha A, Hass SL, Colman SS, Kumar RN, Brod M, Rowland CR.  Validation of a general measure of treatment satisfaction, the treatment satisfaction questionnaire for medication (TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes. 2004;2:12. https://doi. org/10.1186/1477-7525-2-12. 16. Uhlenhake EE, Kurkowski D, Feldman SR.  Conversations on psoriasis—what patients want and what physicians can provide: a qualitative look at patient and physician expectations. J Dermatolog Treat. 2010;21(1):6–12. https://doi. org/10.3109/09546630903085328. 17. Fouere S, Adjadj L, Pawin H.  How patients experience psoriasis: results from a European survey. J Eur Acad Dermatol Venereol. 2005;19(Suppl 3):2–6. https://doi. org/10.1111/j.1468-3083.2005.01329.x. 18. Augustin M, Holland B, Dartsch D, Langenbruch A, Radtke MA.  Adherence in the treatment of psoriasis: a systematic review. Dermatology. 2011;222(4):363–74. https://doi. org/10.1159/000329026. 19. Vangeli E, Bakhshi S, Baker A, Fisher A, Bucknor D, Mrowietz U, et  al. A systematic review of factors associated with non-­ adherence to treatment for immune-mediated inflammatory diseases. Adv Ther. 2015;32(11):983–1028. https://doi.org/10.1007/ s12325-015-0256-7. 20. Clemmensen A, Spon M, Skov L, Zachariae C, Gniadecki R.  Responses to ustekinumab in the anti-TNF agent-naive vs. anti-TNF agent-exposed patients with psoriasis vulgaris. J Eur Acad Dermatol Venereol. 2011;25(9):1037–40. https://doi. org/10.1111/j.1468-3083.2010.03914.x.

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21. Umezawa Y, Nobeyama Y, Hayashi M, Fukuchi O, Ito T, Saeki H, Nakagawa H.  Drug survival rates in patients with psoriasis after treatment with biologics. J Dermatol. 2013;40(12):1008–13. https://doi.org/10.1111/1346-8138.12353. 22. Esposito M, Gisondi P, Cassano N, Ferrucci G, Del Giglio M, Loconsole F, et  al. Survival rate of antitumour necrosis factor-alpha treatments for psoriasis in routine dermatological practice: a multicentre observational study. Br J Dermatol. 2013;169(3):666–72. https://doi.org/10.1111/bjd.12422. 23. Gniadecki R, Kragballe K, Dam TN, Skov L.  Comparison of drug survival rates for adalimumab, etanercept and infliximab in patients with psoriasis vulgaris. Br J Dermatol. 2011;164(5):1091– 6. https://doi.org/10.1111/j.1365-2133.2011.10213.x.

Chapter 11 36-Year-Old Severely Obese Male with Worsening Psoriasis Deeti J. Pithadia, Kelly A. Reynolds, and Jashin J. Wu

Case A 36-year-old male with a 2-year history of psoriasis, hypertension, and class 3 obesity (172.4 kg; BMI 54.5) presents for flaring of psoriasis. He previously failed treatment with ­cyclosporine 5 mg twice each day and has been taking adalimumab 40 mg every other week for the past 4 months. He has noticed minimal improvement with adalimumab and desires re-­evaluation of his treatment regimen. He admits to a 15 kg weight gain in the past 6  months. He denies injection site reactions, fever, cough, dyspnea, hemoptysis, night sweats,

D. J. Pithadia Medical College of Georgia, Augusta University, Augusta, GA, USA K. A. Reynolds University of Cincinnati, College of Medicine, Cincinnati, OH, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_11

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headaches, edema, muscle weakness, tingling, numbness, or joint pain. His sister has psoriasis controlled with topical corticosteroids. On physical examination, the patient is morbidly obese. Erythematous, scaly, indurated papules and plaques are visible on the scalp, face, neck, bilateral arms, bilateral legs, and abdomen (Fig.  11.1). He defers exam of the groin and buttocks. Approximately 40% of examined body surface area is affected. Based on the patient’s history and physical examination, what is the best treatment option? 1. Continue adalimumab as prescribed 2 . Increase adalimumab to 40 mg weekly 3. Switch to etanercept 4. Switch to infliximab 5. Switch to apremilast

Figure 11.1  Large, erythematous, well-demarcated plaque with fine micaceous scale on the abdomen

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Treatment Switch to infliximab

Discussion Compared to the general population, children and adults with psoriasis have higher prevalence of metabolic risk factors, including increased body weight, adiposity, elevated waist circumference, dyslipidemia, and type II diabetes [1, 2]. A correlation between obesity, defined as body mass index (BMI) greater than 30, and psoriasis was initially reported by a 1986 study of nearly 160,000 individuals [3]. Since then, many investigations of this association have been pursued, and in 2007 the International Psoriasis Council affirmed the relationship in a review of over 10,000 patients from these studies [4]. Subsequent studies have observed a correlation between obesity and severity of psoriasis. In an analysis of over 4000 patients with psoriasis, the overlap between prevalence of obesity and mild, moderate, and severe psoriasis was 14%, 34%, and 66%, respectively [5]. The pathophysiology of the relationship between obesity and psoriasis has not been fully elucidated, though it has been found that elevated BMI can predict psoriasis development. In a cohort of nearly 9000 individuals initially unaffected with psoriasis followed over a 14-year period, incidence of psoriasis correlated with increasing BMI [6]. It is hypothesized that systemic inflammation induced by obesity may bring on and worsen psoriatic skin findings [7]. Overexpression of tumor necrosis factor (TNF)-alpha is known to occur in adipose tissue of obese patients [8]. Likewise, TNF-alpha upregulation has been demonstrated in psoriatic lesions, and drug-­induced inhibition of TNF has proven to be effective in treating psoriasis. Others claim that inflammation from psoriasis may predispose to the development of obesity, though

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evidence is limited [9]. Moreover, social stigma and psychological burden associated with psoriasis may lead to increased alcohol intake, reduced physical activity, and increased saturated fat consumption, leading to weight gain [10]. Obese patients with psoriasis have poorer adherence to therapy than their counterparts with normal BMI, leading to further worsening of cutaneous symptoms [11]. Many studies have found that psoriasis patients with obesity have reduced response to standard doses of drug therapy. A large cohort study found the odds ratio for reaching 75% improvement in Psoriasis Area and Severity Index (PASI) scores at follow-up in normal-BMI patients compared to obese patients to be 0.73 at 8  weeks and 0.62 at 16  weeks. These results were consistent among different types of systemic therapy at standard doses, including psoralen and ultraviolet A (PUVA), acitretin, cyclosporine, methotrexate, and various biologics [12]. Therefore, weight-based dose adjustment may be warranted to ensure adequate therapy in overweight and obese patients. Ustekinumab, a IL-12/23 inhibitor, is among few psoriasis biologics that incorporates weight into dosing. For patients who weigh over 100 kg, the dose is doubled from the typical 45–90  mg, making it a reasonable treatment option for obese patients. Data from the phase III PHOENIX 1 and PHOENIX 2 trials showed improved response with increasing dose of ustekinumab with increasing body weight, irrespective of height [13]. A smaller and more recent study conducted in Japan found that BMI negatively correlates with reduction of PASI scores with use of a consistent dose of ustekinumab, while body weight regardless of height does not [14]. Infliximab is the only widely used biologic for psoriasis that utilizes true weight-based dosing. The standard prescription is 5 mg/kg per dose, making it a superior option for patients who are obese or overweight. Furthermore, infliximab has been uniquely proven to have consistent efficacy when uniform dosing is utilized across a range of BMIs [15]. The additional simplicity and cost-effectiveness of dosing that it affords makes it among the best treatment options

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for patients with moderate-to-severe psoriasis and obesity. An effective non-biologic treatment option for obese patients with mild psoriasis is PUVA, since the dose of psoralen can be weight-adjusted. However, large body habitus results in increased proximity to phototherapy bulbs during treatment, leading to elevated risk for phototherapy-induced erythema [16]. Weight reduction may also reduce severity of psoriatic skin lesions in overweight and obese patients. One randomized controlled trial of 60 psoriasis patients with BMI greater than 27 found that participants issued a low-calorie diet leading to mean weight loss of 15.4 kg had significantly improved PASI scores and Dermatology Quality of Life Index scores [17]. Another study showed improved response to cyclosporine therapy in obese patients co-managed with a low-calorie diet that led to body weight reduction [18]. Psoriasis patients who undergo bariatric surgery have been documented to have improvement in cutaneous symptoms [19]. Following gastric bypass, suppression of appetite is mediated by dramatic increases in glucagon-like peptide-1, an incretin shown to have anti-inflammatory effects that may alleviate psoriasis [20]. According to the National Psoriasis Foundation, there is insufficient evidence to formulate a uniform treatment algorithm for obese psoriasis patients [9]. Nonetheless, a multidisciplinary approach should be utilized, which involves working with the patient’s primary care physician to control both psoriasis and metabolic disease. When determining a therapeutic regimen, it is important to consider the metabolic side effect profile of each drug utilized. Methotrexate and cyclosporine may augment risk of hepatic and renal toxicity, and acitretin has increased risk of hypertriglyceridemia and hypercholesterolemia [22]. The phosphodiesterase-4 inhibitor apremilast has been found to be associated with significant weight loss [21], a favorable side effect in obese patients. However, patient weight correlates inversely with PASI improvement when using apremilast, and weightbased dosing is not available [22].

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This patient was switched from adalimumab to infliximab therapy. He also began a diet and exercise regimen under guidance by his primary care doctor. At follow-up 2 months later, he had lost 15 pounds and his body surface area involvement decreased to 1%.

Key Points • Psoriasis is associated with obesity, a relationship that is likely mediated by underlying systemic inflammation present in both disorders. • The most effective therapies for psoriasis in obese patients are those with weight-based dosing regimens as well as PUVA. Infliximab is the simplest and most cost-effective biologic to use since its efficacy at a uniform dose is consistent across multiple BMIs. • In obese patients, it is critical to avoid therapies with adverse effects that can exacerbate metabolic disease, including methotrexate, cyclosporine, and acitretin.

References 1. Fernández-Armenteros JM, Gómez-Arbonés X, Buti-Soler M, et al. Psoriasis, metabolic syndrome and cardiovascular risk factors. A population-based study. J Eur Acad Dermatol Venereol. 2019;33(1):128–35. 2. Paller AS, Mercy K, Kwasny MJ, et  al. Association of pediatric psoriasis severity with excess and central adiposity: an international cross-sectional study. JAMA Dermatol. 2013;149(2):166– 76. https://doi.org/10.1001/jamadermatol.2013.1078. 3. Lindegård B.  Diseases associated with psoriasis in a general population of 159,200 middle-aged, urban, native Swedes. Dermatologica. 1986;172(6):298–304. 4. Sterry W, Strober BE, Menter A. Obesity in psoriasis: the metabolic, clinical and therapeutic implications. Report of an interdisciplinary conference and review. Br J Dermatol. 2007;157(4):649–55. https://doi.org/10.1111/j.1365-2133.2007.08068.x.

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5. Langan SM, Seminara NM, Shin DB, et al. Prevalence of metabolic syndrome in patients with psoriasis: a population-based study in the United Kingdom. J Invest Dermatol. 2012;132(3 Pt 1):556–62. https://doi.org/10.1038/jid.2011.365. 6. Danielsen K, Wilsgaard T, Olsen AO, Furberg AS.  Overweight and weight gain predict psoriasis development in a population-­ based cohort. Acta Derm Venereol. 2017;97(3):332–9. https://doi. org/10.2340/00015555-2530. 7. Bremmer S, Van voorhees AS, Hsu S, et al. Obesity and psoriasis: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2010;63(6):1058–69. 8. Hotamisligil GS, Arner P, Caro JF, et  al. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409–15. https://doi. org/10.1172/JCI117936. 9. Herron MD, Hinckley M, Hoffman MS, et  al. Impact of obesity and smoking on psoriasis presentation and management. Arch Dermatol. 2005;141(12):1527–34. https://doi.org/10.1001/ archderm.141.12.1527. 10. Sathyanarayana Rao TS, Basavaraj KH, Das K.  Psychosomatic paradigms in psoriasis: psoriasis, stress and mental health. Indian J Psychiatry. 2013;55(4):313–5. https://doi. org/10.4103/0019-5545.120531. 11. Højgaard P, Glintborg B, Kristensen LE, Gudbjornsson B, Love TJ, Dreyer L.  The influence of obesity on response to tumour necrosis factor-α inhibitors in psoriatic arthritis: results from the DANBIO and ICEBIO registries. Rheumatology (Oxford). 2016;55(12):2191–9. https://doi.org/10.1093/rheumatology/ kew326. 12. Naldi L, Addis A, Chimenti S, et al. Impact of body mass index and obesity on clinical response to systemic treatment for psoriasis. Evidence from the Psocare project. Dermatology (Basel). 2008;217(4):365–73. https://doi.org/10.1159/000156599. 13. Lebwohl M, et  al. Impact of weight on the efficacy and safety of ustekinumab in patients with moderate to severe psoriasis: rationale for dosing recommendations. J Am Acad Dermatol. 2010;63:571–9. 14. Yanaba K, Umezawa Y, Ito T, et  al. Impact of obesity on the efficacy of ustekinumab in Japanese patients with psoriasis: a retrospective cohort study of 111 patients. Arch Dermatol Res. 2014;306(10):921–5. https://doi.org/10.1007/s00403-014-1495-1.

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15. Reich K, Menter A, Plotnick M, Guzzo C, Li S, Gottlieb AB.  Consistency of infliximab response across subgroups of patients with psoriasis: integrated results from randomized controlled clinical trials. Psoriasis Forum. 2007;13:21–6. 16. Gisondi P, Del Giglio M, Girolomoni G.  Considerations for systemic treatment of psoriasis in obese patients. Am J Clin Dermatol. 2016;17(6):609–15. https://doi.org/10.1007/ s40257-016-0211-7. 17. Jensen P, Zachariae C, Christensen R, et  al. Effect of weight loss on the severity of psoriasis: a randomized clinical study. JAMA Dermatol. 2013;149(7):795–801. https://doi.org/10.1001/ jamadermatol.2013.722. 18. Gisondi P, Del Giglio M, Di Francesco V, Zamboni M, Girolomoni G.  Weight loss improves the response of obese patients with moderate-to-severe chronic plaque psoriasis to low-dose cyclosporine therapy: a randomized, controlled, investigator-blinded clinical trial. Am J Clin Nutr. 2008;88(5):1242–7. https://doi. org/10.3945/ajcn.2008.26427. 19. Sako EY, Famenini S, Wu JJ.  Bariatric surgery and psoriasis. J Am Acad Dermatol. 2014;70(4):774–9. 20. Faurschou A, Zachariae C, Skov L, Vilsbøll T, Knop FK. Gastric bypass surgery: improving psoriasis through a GLP-1-dependent mechanism? Med Hypotheses. 2011;77(6):1098–101. https://doi. org/10.1016/j.mehy.2011.09.011. 21. Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015;73(1):37–49. 22. Vujic I, Herman R, Sanlorenzo M, et al. Apremilast in psoriasis— a prospective real-world study. J Eur Acad Dermatol Venereol. 2018;32(2):254–9. https://doi.org/10.1111/jdv.14598.

Chapter 12 26-Year-Old Female with Worsening Psoriasis Who Is Planning Pregnancy Deeti J. Pithadia, Kelly A. Reynolds, and Jashin J. Wu

Case A 26-year-old female with a 2-year history of diffuse-body psoriasis presents for worsening of psoriasis over the past 4 months. Her current regimen consists of low to high potency, topical corticosteroids depending on the area of the body affected, as well as ultraviolet B phototherapy. She would like to become pregnant with her first child within the next few months. She has never used systemic therapies and fears the effects they may have if she were to conceive. She denies other medical conditions. She denies fever, chills, night sweats, edema, cough, dyspnea, joint pain, or nail changes. D. J. Pithadia Medical College of Georgia, Augusta University, Augusta, GA, USA K. A. Reynolds University of Cincinnati, College of Medicine, Cincinnati, OH, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_12

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On physical examination, she is well-nourished and in no acute distress. Total body skin examination shows erythematous, scaly, indurated papules and plaques diffusely, covering 20% of the body surface area. Based on the patient’s history, what is the best treatment recommendation for this patient? 1. Continue topical corticosteroid therapy and ultraviolet phototherapy 2. Continue ultraviolet phototherapy and discontinue topical corticosteroid therapy 3. Begin topical tazarotene 4. Begin adalimumab 5. Begin certolizumab pegol

Treatment Begin certolizumab pegol

Discussion Hormonal changes that occur during pregnancy may promote onset, worsening, or even improvement of psoriasis in many pregnant women. Data from nine retrospective studies found that 37% of patients experience improvement of psoriasis in pregnancy while 18% experience worsening of disease. This may be attributed to variations in estrogen levels. Higher-than-average third-trimester estriol levels were observed in those with improved symptoms and lowerthan-­average levels were detected in those with worsened symptoms [1]. Many women also experience psoriasis exacerbation following delivery, with body surface area involvement increasing significantly by 6  weeks post-partum. This effect is attributed to increased levels of prolactin [2]. Obesity, smoking, and depression are among the greatest independent risk factors for increasing severity of psoriasis during pregnancy [3].

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Numerous studies have demonstrated poor neonatal outcomes in pregnant women with inadequately controlled psoriasis, including recurrent abortion, preterm labor, premature rupture of membranes, pregnancy-induced hypertensive diseases, and neonatal macrosomia and growth restriction [4, 5]. Pregnant women in the third trimester are at particularly increased risk for developing pustular psoriasis (impetigo herpetiformis), a severe and generalized form associated with significantly increased maternal and neonatal morbidity and mortality. Though it generally resolves following delivery, post-partum anticipatory guidance for these patients is crucial due to frequent recurrence of disease with subsequent pregnancies and use of hormonal contraceptives [6]. Ideally, women should plan pregnancy when their psoriasis is in remission or when they are responsive to therapies known to be safe for the fetus. Emollients and moisturizers are the lowest-risk agents and a good firstline option for patients with very mild but bothersome scaling. Low to moderate potency topical corticosteroids have been considered the mainstay for pregnant patients with mild psoriasis as well as those planning pregnancy due to their insignificant effect on neonatal outcomes. High potency steroids should be avoided in the first trimester due to their association with low birth weight [7]. Narrowband ultraviolet B (UVB) phototherapy may be utilized for more extensive psoriasis. Common adverse effects include erythema, pruritus, and melasma. Photodegradation of folate may also occur, particularly in patients with lighter skin, leading to increased risk of neural tube defects in the fetus if supplementation is inadequate [8]. Some systemic treatments may be utilized in patients with severe or refractory psoriasis, though caution must be utilized since the risk of these therapies may outweigh the benefit [3]. Cyclosporine is FDA pregnancy category C, and most studies of its safety involve animal models and pregnant organ transplant recipients. These studies demonstrate

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potential for placental transfer leading to low birth weight and prematurity, as well as maternal hypertensive diseases and diabetes [9, 10]. Tumor necrosis factor (TNF) inhibitors are the most commonly utilized biologic medications in severe, refractory psoriasis in pregnancy. They are considered safe in the first 5 months of pregnancy but should be discontinued by 22 weeks due to evidence of transplacental transport beginning at this time [11]. Data regarding specific neonatal outcomes caused by placental transfer of this class of drugs is inconsistent. Some case reports and studies report minimal adverse fetal effects caused by this class [12], while others describe spontaneous abortions, stillbirths, low birth weight, and impaired immunity [13]. VACTERL-spectrum abnormalities have been reported with etanercept use, though this is controversial since many of the women studied were also taking other medications proven to be teratogenic [14, 15]. Due to inconclusive evidence, TNF inhibitors should be used with caution and at the lowest doses possible. In March 2018, certolizumab pegol (CZP) became FDA-­ approved for patients moderate-to-severe plaque psoriasis who are candidates for systemic therapy. Based on findings from three phase 3 randomized, controlled studies, utilizing 200 mg or 400 mg of CZP biweekly provides clinically significant benefit to psoriasis patients. The drug also has a safety profile comparable to that of previously approved TNF inhibitors [16, 17]. Unlike other biologics within its class, this therapy does not contain the fragment crystallizable (Fc) receptor known to mediate placental transfer. The CRIB study investigated placental transfer of CZP during the third trimester in pregnant women being treated with CZP for rheumatologic disease. Only 3 of 15 umbilical cord samples collected had measurable CZP levels, and none of the infants had significantly quantifiable plasma drug levels from birth to 8 weeks of life. This provides evidence that, unlike other biologics such as TNF inhibitors, CZP treatment results in minimal third-trimester in-utero fetal exposure [18]. Another study that analyzed over 1000 pregnancies with maternal exposure to CZP discovered no increased incidence of

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t­ eratogenicity or fetal death compared to the general population [19]. Based upon this evidence, CZP is a superior biologic therapy for women with moderate-to-severe psoriasis anticipating pregnancy who are refractory to topical steroid and UVB treatment. Regardless of choice of therapy, close follow-up and co-management of the disorder with the patient’s obstetrician increases likelihood of positive outcomes for both the mother and the infant. Psoriasis therapies considered pregnancy category X include methotrexate and vitamin A derivatives. Methotrexate may cause premature fetal death by inducing spontaneous abortion, and it hence requires discontinuation for 3 months before attempting to conceive. The topical vitamin A derivative tazarotene and systemic acitretin are also absolutely contraindicated in pregnancy, and use of either therapy requires two forms of active contraception in all women of childbearing age. This patient was advised to begin CZP treatment, given her desire to conceive with moderate-to-severe psoriasis refractory to topical steroids and phototherapy. She was educated about the risks of uncontrolled psoriasis and high-­ potency topical steroids in pregnancy. She was also informed of the potential risks of CZP therapy. She ultimately discontinued topical corticosteroids and began CZP before becoming pregnant.

Key Points • The first-line treatment for pregnant patients with mild psoriasis include low to moderate potency topical corticosteroids. UVB phototherapy may also be utilized as a second-­line treatment. • Certolizumab pegol is a novel TNF inhibitor that does not cross the placenta and is considered the safest biologic for a fetus in patients with moderate-to-severe psoriasis. • Cyclosporine and other TNF inhibitors may be utilized in severe cases psoriasis in pregnancy, but they should be used conservatively due to insufficient evidence of their safety.

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References 1. Murase JE, Chan KK, Garite TJ, Cooper DM, Weinstein GD. Hormonal effect on psoriasis in pregnancy and post partum. Arch Dermatol. 2005;141(5):601–6. 2. Ceovic R, Mance M, Bukvic mokos Z, Svetec M, Kostovic K, Stulhofer buzina D.  Psoriasis: female skin changes in various hormonal stages throughout life—puberty, pregnancy, and menopause. Biomed Res Int. 2013;2013:571912. 3. Vena GA, Cassano N, Bellia G, Colombo D.  Psoriasis in pregnancy: challenges and solutions. Psoriasis (Auckl). 2015;5:83–95. 4. Cohen-Barak E, Nachum Z, Rozenman D, Ziv M.  Pregnancy outcomes in women with moderate-to-severe psoriasis. J Eur Acad Dermatol Venereol. 2011;25(9):1041–7. 5. Lima XT, Janakiraman V, Hughes MD, Kimball AB.  The impact of psoriasis on pregnancy outcomes. J Invest Dermatol. 2012;132(1):85–91. 6. Trivedi MK, Vaughn AR, Murase JE.  Pustular psoriasis of pregnancy: current perspectives. Int J Women’s Health. 2018;10:109–15. 7. Chi CC, Lee CW, Wojnarowska F, Kirtschig G.  Safety of topical corticosteroids in pregnancy. Cochrane Database Syst Rev. 2009;3:CD007346. 8. Park KK, Murase JE.  Narrowband UV-B phototherapy during pregnancy and folic acid depletion. Arch Dermatol. 2012;148(1):132–3. 9. Mason RJ, Thomson AW, Whiting PH, et  al. Cyclosporine-­ induced fetotoxicity in the rat. Transplantation. 1985;39(1):9–12. 10. Paziana K, Del Monaco M, Cardonick E, et al. Ciclosporin use during pregnancy. Drug Saf. 2013;36(5):279–94. 11. Johansen CB, Jimenez-Solem E, Haerskjold A, Sand FL, Thomsen SF.  The use and safety of TNF inhibitors during pregnancy in women with psoriasis: a review. Int J Mol Sci. 2018;19(5):pii: E1349. 12. Raja H, Matteson EL, Michet CJ, Smith JR, Pulido JS. Safety of tumor necrosis factor inhibitors during pregnancy and breastfeeding. Transl Vis Sci Technol. 2012;1(2):6. 13. Weber-Schoendorfer C, Oppermann M, Wacker E, et  al. Pregnancy outcome after TNF-α inhibitor therapy during the first trimester: a prospective multicentre cohort study. Br J Clin Pharmacol. 2015;80(4):727–39.

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14. Carter JD, Valeriano J, Vasey FB.  Tumor necrosis factor-alpha inhibition and VATER association: a causal relationship. J Rheumatol. 2006;33(5):1014–7. 15. Carter JD, Ladhani A, Ricca LR, Valeriano J, Vasey FBA. Safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the Food and Drug Administration database. J Rheumatol. 2009;36(3):635–41. 16. Gottlieb AB, Blauvelt A, Thaçi D, et al. Certolizumab pegol for the treatment of chronic plaque psoriasis: results through 48 weeks from 2 phase 3, multicenter, randomized, double-blinded, placebo-controlled studies (CIMPASI-1 and CIMPASI-2). J Am Acad Dermatol. 2018;79(2):302–314.e6. 17. Lebwohl M, Blauvelt A, Paul C, et  al. Certolizumab pegol for the treatment of chronic plaque psoriasis: results through 48 weeks of a phase 3, multicenter, randomized, double-blind, etanercept- and placebo-controlled study (CIMPACT). J Am Acad Dermatol. 2018;79(2):266–276.e5. 18. Mariette X, Förger F, Abraham B, et al. Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study. Ann Rheum Dis. 2018;77(2):228–33. 19. Clowse MEB, Schuerele AE, Chambers C, et  al. Pregnancy outcomes after exposure to certolizumab pegol: updated results from a pharmacovigilance safety database. Arthritis Rheumatol. 2018;70:1399–407.

Chapter 13 31-Year-Old Female with Psoriasis on Adalimumab with Loss of Effect Deeti J. Pithadia, Kelly A. Reynolds, and Jashin J. Wu

Case A 31-year-old female with a 5-year history of psoriasis presents for routine dermatology follow-up. She has been treated with adalimumab 40 mg every other week for the past 4 years. She had been satisfied with the efficacy of her long-term adalimumab therapy, but she recently feels that her psoriasis is beginning to flare again despite no changes in treatment regimen and consistent adherence to therapy. She reports increased stress from school and her endeavor to open a D. J. Pithadia Medical College of Georgia, Augusta University, Augusta, GA, USA K. A. Reynolds University of Cincinnati, College of Medicine, Cincinnati, OH, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_13

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­ usiness after graduation. She has been smoking one pack b per day for 5 years. She denies fever, chills, weight loss, cough, hemoptysis, dyspnea, edema, muscle weakness, numbness, and tingling. On physical examination, she is well-developed and in no acute distress. Skin examination shows scaly, erythematous, indurated papules covering 8% of her body surface area, mostly localized to the bilateral legs. At follow-up 3 months ago, skin involvement was 0.5% of body surface area. Which of the following is the best next step in management of this patient? 1. Add topical steroids 2 . Switch to phototherapy 3. Add methotrexate to regimen 4. Increase adalimumab frequency to 40 mg every week 5. Continue adalimumab 40 mg every other week

Treatment Add methotrexate to regimen

Discussion Failure of response to biologic therapy is a common source of frustration in patients with moderate-to-severe psoriasis. Some patients do not respond to therapy from time of induction, an experience commonly referred to as primary non-­response. This has been found to occur in 10–30% of patients treated with tumor necrosis factor (TNF) inhibitors [1], which is the most frequently utilized class of biologics for psoriasis. Though there lacks a true consensus regarding the time frame at which this phenomenon should be evaluated, there is some agreement among trials that it should not be assessed prior to 8–14 weeks of therapy with TNF inhibitor, depending on the exact drug used [2, 3]. Factors cited by one retrospective study to increase the likelihood of primary non-­response include

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female gender, elevated baseline Psoriasis Area and Severity and Index (PASI) score (>15), and lack of comorbid psoriatic arthritis [4]. Secondary loss-of-response, which also has no established definition, is generally considered to involve diminished efficacy of treatment following successful initial response despite no changes in regimen. This has been observed in 24–46% of patients on TNF inhibitors [1]. There is also no standard time frame at which loss-of-­response may be evaluated, though it is generally considered to range from 12 weeks to 12  months following initiation of therapy and may vary based on length of induction period of each biologic [4, 5]. The best-known factor contributing to secondary non-­ response to biologics is the development of anti-drug antibodies (ADAs), which causes a phenomenon known as immunogenicity. These antibodies attenuate effects of biologics by interfering with their binding site, neutralizing their active constituent, or possibly even forming immune complexes that hasten drug clearance [6]. Generally, decreasing immunogenicity is observed with increasing concentration of human components of the monoclonal antibodies that compose biologics [7]. The development of ADAs has been observed in response to most commonly utilized TNF inhibitors, including adalimumab, infliximab, etanercept, and ­certolizumab pegol, as well as to each of the approved interleukin-17 (IL-17) inhibitors and ustekinumab [8–11]. ADAs formed against many of these biologics have been shown to decrease serum drug concentrations, leading to subsequent increases in PASI scores [8]. However, anti-­etanercept antibodies do not have neutralizing effects, and therefore no significant declines in trough levels have been observed with persistent use of etanercept [12]. This may partially be attributed to etanercept being a fully-human antibody, especially given that treatment with fully-human secukinumab and brodalumab also cause development of only non-neutralizing antibodies that do not affect clinical outcomes [9]. However, this explanation is insufficient given that adalimumab and ustekinumab, which are also fully-­human, are highly susceptible to inactivation by ADAs. It has also been proposed that

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etanercept’s unique structure causes ADAs to bind to regions that do not interfere with TNF binding and hence do not alter drug efficacy [8]. The best management option for secondary treatment failure is immunosuppressant therapy, which may decrease ADA levels. Methotrexate has significant evidence for preventing immunogenicity in numerous autoimmune disorders, including psoriasis [13]. In a 2010 study that analyzed concentrations of antibodies against adalimumab in psoriasis patients, although only 3 of 29 patients utilized concomitant methotrexate, none of the patients using methotrexate developed antibodies [10]. A variety of other prospective and retrospective studies analyzing the effects of methotrexate on antibody formation and clinical response to adalimumab, infliximab, and etanercept have also shown favorable results [14–16]. Methotrexate use has also been shown to treat existing immunogenicity by mediating clearance of formed antibodies [17]. A case series has reported additional PASI score improvement following adjunctive treatment with methotrexate in two patients who were successfully managed with ustekinumab [18]. This effect may be attributed to decreased levels of ADAs. Methotrexate, however, holds life-threatening risks of hepatotoxicity, aplastic anemia, and pulmonary fibrosis. It is also classified as pregnancy category X and should be discontinued at least 3 months prior to conceiving [19]. Women of childbearing age must utilize reliable contraception during treatment. Other agents used to decrease immunogenicity include azathioprine, fumaric acid, hydroxyurea, and retinoids [20]; however, like methotrexate, each has dangerous effects that must be considered prior to prescribing. Switching to another biologic in a different class may also be an effective method of management in those who are unresponsive to or poor candidates for concomitant therapy [21]. Increasing the dose of the same drug is unlikely to restore clinical response in patients with very high levels of ADAs [2]. Other potential etiologies for biologic failure and lossof-­response include sub-therapeutic dosing, delayed drug

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response, and non-compliance to therapy. For psoriasis specifically, psychological stress, obesity, alcohol abuse, smoking, and bacterial and viral infections have also been implicated [22–24]. Patients with sub-therapeutic drug levels with limited development of serum ADAs may be managed by increasing dose intensity or frequency [2]. In patients with negative ADAs and adequate-to-elevated serum drug trough levels, it is acceptable to continue treatment without dose changes for 24 weeks total with periodic monitoring for improvement in PASI scores. If this fails, they may be switched to another biologic with a different mechanism of action [24]. In spite of the above algorithm specific to ADA levels, evidence of the clinical utility of ADA measurement in psoriasis is limited. Most data that promotes measuring ADA levels are from studies of patients with inflammatory bowel disease and rheumatoid arthritis [25, 26]. One study specific to psoriasis found that current assays for anti-adalimumab antibodies have poor specificity in relation to PASI score changes [27]. Additionally, there is currently no standardized method of setting personalized target trough levels for each biologic, which may pose a challenge for adjusting drug levels using therapeutic monitoring [2]. Given this information, in patients with loss of response to biologics following prolonged successful treatment course, it is reasonable to add a non-biologic immunosuppressive therapy to the regimen without measuring ADA or trough levels. Concurrent lifestyle changes may also be recommended, and further laboratory evaluation can be performed in patients who remain unresponsive. The patient was advised to add methotrexate to her current regimen of adalimumab. She was counseled on the adverse effects of the medication and elected to get an intrauterine device for contraception. She also began exercising for stress relief and cut back to using three cigarettes per day. At follow-up 3 months later, skin involvement decreased to 0.5% of body surface area.

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Key Points • Loss of response to biologics in psoriasis is frequently caused by development of anti-drug antibodies (ADAs), which decrease levels of active drug in the serum. • Patients experiencing loss-of-response to biologics following prolonged efficacy can be initially managed with addition of a non-biologic immunosuppressant such as methotrexate to lower ADAs. Increasing the dose or frequency of biologic therapy or switching to a different biologic within or outside the same class may also be considered. • Co-management of metabolic, environmental, and psychosocial factors that aggravate psoriasis may improve efficacy of biologic therapy.

References 1. Ding NS, Hart A, De Cruz P. Systematic review: predicting and optimising response to anti-TNF therapy in Crohn’s disease— algorithm for practical management. Aliment Pharmacol Ther. 2016;43(1):30–51. 2. Roda G, Jharap B, Neeraj N, Colombel JF.  Loss of response to anti-TNFs: definition, epidemiology, and management. Clin Transl Gastroenterol. 2016;7:e135. 3. Ben-Horin S, Kopylov U, Chowers Y.  Optimizing anti-TNF treatments in inflammatory bowel disease. Autoimmun Rev. 2014;13(1):24–30. 4. De Simone C, Caldarola G, Maiorino A, et al. Clinical predictors of nonresponse to anti-TNF-α agents in psoriatic patients: a retrospective study. Dermatol Ther. 2016;29(5):372–6. 5. Orlando A, Renna S, Rizzuto G, Orlando E, Affronti M, Cottone M.  Selective use of combination therapy in patients with infliximab-­resistant inflammatory bowel disease: data from a tertiary referral center. Clin Gastroenterol Hepatol. 2016;14(6):914. 6. Sethu S, Govindappa K, Alhaidari M, et  al. Immunogenicity to biologics: mechanisms, prediction and reduction. Arch Immunol Ther Exp. 2012;60:331–44. 7. Boehncke WH, Brembilla NC.  Immunogenicity of biologic therapies: causes and consequences. Expert Rev Clin Immunol. 2018;14(6):513–23.

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8. Moots RJ, Xavier RM, Mok CC, et al. The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: results from a multinational, real-world clinical practice, non-interventional study. PLoS One. 2017;12(4):e0175207. 9. Chiu HY, Chu TW, Cheng YP, Tsai TF.  The association between clinical response to ustekinumab and immunogenicity to ustekinumab and prior adalimumab. PLoS One. 2015;10(11):e0142930. 10. Thomas LW, Lee EB, Wu JJ.  Systematic review of anti-drug antibodies of IL-17 inhibitors for psoriasis. J Dermatol Treat. 2019;30(2):110–6. 11. Jani M, Isaacs JD, Morgan AW, et  al. High frequency of antidrug antibodies and association of random drug levels with efficacy in certolizumab pegol-treated patients with rheumatoid arthritis: results from the BRAGGSS cohort. Ann Rheum Dis. 2017;76(1):208–13. 12. Vincent FB, Morand EF, Murphy K, Mackay F, Mariette X, Marcelli C.  Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective. Ann Rheum Dis. 2013;72(2):165–78. 13. Farhangian ME, Feldman SR. Immunogenicity of biologic treatments for psoriasis: therapeutic consequences and the potential value of concomitant methotrexate. Am J Clin Dermatol. 2015;16(4):285–94. 14. Dalaker M, Bonesrønning JH.  Long-term maintenance treatment of moderate-to-severe plaque psoriasis with infliximab in combination with methotrexate or azathioprine in a retrospective cohort. J Eur Acad Dermatol Venereol. 2009;23(3):277–82. 15. Gottlieb AB, Langley RG, Strober BE, Papp KA, Klekotka P, Creamer K.  A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis. Br J Dermatol. 2012;167(3):649–57. 16. Philipp S, Wilsmann-Theis D, Weyergraf A, Rotterdam S, Frambach Y, Gerdes S. Combination of adalimumab with traditional systemic antipsoriatic drugs—a report of 39 cases. J Dtsch Dermatol Ges. 2012;10(11):821–37. 17. Jani M, Barton A, Warren RB, Griffiths CE, Chinoy H. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology (Oxford). 2014;53(2):213–22.

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18. Jayasekera PS, Parslew RA, Al-Sharqi A. Recapturing adequate control of psoriasis by additional immunosuppressive agents alongside ustekinumab. JAAD Case Rep. 2016;2(4):310–4. 19. Hackmon R, Sakaguchi S, Koren G.  Effect of methotrexate treatment of ectopic pregnancy on subsequent pregnancy. Can Fam Physician. 2011;57(1):37–9. 20. Rønholt K, Iversen L. Old and new biological therapies for psoriasis. Int J Mol Sci. 2017;18(11):pii: E2297. 21. Bracke S, Lambert J. Viewpoint on handling anti-TNF failure in psoriasis. Arch Dermatol Res. 2013;305(10):945–50. 22. Adışen E, Uzun S, Erduran F, Gürer MA. Prevalence of smoking, alcohol consumption and metabolic syndrome in patients with psoriasis. An Bras Dermatol. 2018;93(2):205–11. 23. Fry L, Baker BS. Triggering psoriasis: the role of infections and medications. Clin Dermatol. 2007;25(6):606–15. 24. Berg M, Svensson M, Brandberg M, Nordlind K.  Psoriasis and stress: a prospective study. J Eur Acad Dermatol Venereol. 2008;22(6):670–4. 25. Jani M, Chinoy H, Warren RB, et  al. Clinical utility of random anti-tumor necrosis factor drug-level testing and measurement of antidrug antibodies on the long-term treatment response in rheumatoid arthritis. Arthritis Rheumatol. 2015;67(8):2011–9. 26. Afif W, Loftus EV, Faubion WA, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody c­ oncentrations in patients with inflammatory bowel disease. Am J Gastroenterol. 2010;105(5):1133–9. 27. Lombardi G, Perego S, Sansoni V, Diani M, Banfi G, Altomare G. Anti-adalimumab antibodies in psoriasis: lack of clinical utility and laboratory evidence. BMJ Open. 2016;6(12):e011941.

Chapter 14 A 53-Year-Old Female with Psoriasis and Breast Cancer Kelly A. Reynolds, Deeti J. Pithadia, and Jashin J. Wu

Case A 53-year-old pre-menopausal female with long-standing severe psoriasis and psoriatic arthritis presents to clinic to discuss treatment options in light of a recent breast cancer diagnosis. Her psoriasis had been well-controlled on e­ tanercept for the past few years. She was diagnosed with stage 1A invasive ductal carcinoma (estrogen receptor positive, progesterone receptor-positive, human epidermal growth factor receptor-2 negative) and underwent lumpectomy and sentinel node biopsy 4 weeks ago. She is scheduled for 6 weeks of whole-breast external beam radiation. She plans to start tamoxifen therapy after she has completed radiotherapy. K. A. Reynolds University of Cincinnati College of Medicine, Cincinnati, OH, USA D. J. Pithadia Medical College of Georgia, Augusta University, Augusta, GA, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_14

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On exam, she is obese and well-appearing with scattered red, scaly, indurated papules and plaques involving 8% of her total body surface area. In the upper outer quadrant of the left breast, 2 small, well-healing linear scars are noted. What is the best treatment option for this patient? A. Discontinue etanercept and begin treatment with topical corticosteroids. B. Discontinue etanercept and switch to treatment with acitretin. C. Discontinue etanercept and begin treatment with methotrexate. D. Discontinue etanercept and switch to adalimumab. E. Continue etanercept as prescribed.

Treatment Discontinue etanercept and switch to treatment with acitretin.

Discussion Patients with psoriasis have been shown to have an increased risk of developing certain kinds of cancer, including lymphoma, non-melanoma skin cancer, and lung cancer; however, there has been no proven association between psoriasis and breast cancer [1]. While many cohort studies have evaluated the link between psoriasis and incidence of cancer [1–4], relatively few have evaluated the challenges of managing psoriasis in patients with an active cancer diagnosis. Given the complex interplay between inflammation, immunosuppression, and carcinogenesis, there is a theoretical possibility that psoriasis or its therapies may hinder cancer treatment, accelerate tumor progression, or worsen outcomes. Despite this hypothetical risk, little is known about how psoriasis therapies may impact cancer because patients with an active cancer diagnosis are typically excluded from clinical trials for immunomodulatory therapies [5, 6].

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Biologics, methotrexate, and cyclosporine are generally discontinued in patients with psoriasis who are undergoing chemotherapy due to increased risk of infection, cytopenia, and poorer outcomes in general [5–7]. The oral retinoid acitretin, however, is a non-immunosuppressant systemic medication that has been shown to be an effective treatment for severe psoriasis [8]. Based on a large retrospective cohort study, acitretin has not been associated with an increased risk of cancer [9]. Further, since it does not suppress the immune system, it theoretically should not interfere with cancer treatment or worsen outcomes. Acitretin has been associated with severe birth defects and requires the use of dual contraceptive therapies in all women of childbearing age [8], but all contraceptives containing progesterone or estrogen are relatively contraindicated in patients with hormonally responsive cancers [10]. Tamoxifen is frequently used as adjuvant therapy in patients with hormonally responsive breast cancer, and while it does have antiestrogenic effects, it is not considered to be an effective method of birth control when used as monotherapy [10]. The copper-intrauterine device (IUD) is a highly effective method of birth control, and given its absence of hormonal components, it is considered to be a safe contraceptive option in patients with breast cancer [10]. In patients with a past history of successfully treated breast cancer, observational studies suggest that biologic and immunosuppressant therapies do not result in cancer recurrence [11–13]. Consequently, the American College of Rheumatology guidelines recommend that, with careful consideration of the tumor type, treatment received, and prognosis, any biologic therapy can be safely used in patients with a history of solid malignancy [7]. Starting any biologic agent in a patient with a history of cancer should be preceded by a conversation with the patient’s oncologist with his or her explicit approval of the treatment. Interestingly, the complex etiological relationship between psoriasis and cancer may be bidirectional. A retrospective cohort study found that patients with breast cancer are at an

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increased risk of developing psoriasis in the 12  years after their cancer diagnosis compared to matched controls (HR = 1.17; 95% CI = 1.07–1.28) [14]. The authors concluded that the risk was treatment-specific, with higher incidence of psoriasis in patients who underwent radiotherapy (HR = 2.44; 95% CI = 1.44–4.12) [14].A few cases reporting paraneoplastic-­ type psoriasifom eruptions in patients with breast cancer also exist in the literature [15, 16]. This has been attributed to upregulation of psoriasin, a protein that is overexpressed in psoriatic keratinocytes that has also been identified as a poor prognostic marker in ductal carcinoma [15]. There have also been a few case reports of psoriasis remission with tamoxifen therapy [17, 18]. Female sex hormones have been purported to stimulate the immune system, whereas the antiestrogenic effects of tamoxifen have been theorized to reduce hormonally-induced autoimmune responses [17]. The risks and benefits of continuing biologic therapy in the setting of active cancer were discussed with the patient. She chose to discontinue etanercept. After two negative urine pregnancy tests were obtained, the patient was switched to acitretin. She agreed to the placement of a copper IUD by her gynecologist. She was given anticipatory guidance on the potential worsening of her psoriasis with radiotherapy.

Key Points • Acitretin is an oral synthetic retinoid that does not result in immunosuppression and is therefore a reasonable therapeutic option for patients with moderate-to-severe psoriasis in the setting of an active cancer diagnosis. Two forms of contraception are required in women of childbearing age who are using this medication. • Radiotherapy has been associated with worsening of psoriasis symptoms in patients with breast cancer. However, the antiestrogenic effects of tamoxifen may result in symptom improvement.

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• The current ACR guidelines state that biologic and immunosuppressant therapies are safe in patients with previously treated malignancy, but not in patients who are actively receiving chemotherapy.

References 1. Chiesa Fuxench ZC, Shin DB, Ogdie Beatty A, Gelfand JM. The risk of cancer in patients with psoriasis: a population-based cohort study in the health improvement network. JAMA Dermatol. 2016;15(3):282–90. 2. Hannuksela-Svahn A, Pukkala E, Laara E, et  al. Psoriasis, its treatment, and cancer in a cohort of Finnish patients. J Invest Dermatol. 2000;114:587–90. 3. Brauchli YB, Jick SS, Miret M, et al. Psoriasis and risk of incident cancer: an inception cohort study with a nested case-control analysis. J Invest Dermatol. 2009;129:2604–12. 4. Chen YJ, Wu CY, Chen TJ, Shen JL, Chu SY, Wang CB, Chang YT.  The risk of cancer in patients with psoriasis: a population-based cohort study in Taiwan. J Am Acad Dermatol. 2011;65(1):84–91. 5. Elandt K, Aletaha D. Treating rheumatic patients with a malignancy. Arthritis Res Ther. 2011;13:223. 6. Zogala RJ, Goutsouliak K, Suarez-Almazor ME.  Management considerations in cancer patients with rheumatoid arthritis. Oncology. 2017;31(5):374–80. 7. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68:1–26. 8. Treating psoriasis: systemic medications: Soriatane|National Psoriasis Foundation. Psoriasis.org. https://www.psoriasis.org/ about-psoriasis/treatments/systemics/soriatane. Published 2018. 9. Reddy SP, Martires K, Wu JJ. The risk of melanoma and hematologic cancers in patients with psoriasis. J Am Acad Dermatol. 2017;76:639–47. 10. Zerden ML. Selecting the right contraception method for cancer patients. OB Gyn News. Published; 2015. 11. Dixon WG, Watson KD, Lunt M, Mercer LK, Hyrich KL, Symmons DP. Influence of anti-tumor necrosis factor therapy on

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cancer incidence in patients with rheumatoid arthritis who had a prior malignancy: results from British Society for Rheumatology Biologics Register. Arthritis Care Res. 2010;62:755–63. 12. Strangfeld A, Hierse F, Rau R, Burmester GR, Krummel-­ Lorenz B, Demary W, Listing J, Zink A.  Risk of incidence or recurrent malignancies among patients with rheumatoid arthritis exposed to biologic therapy in German biologics register RABBIT.  Arthritis Res Ther. 2010;12:R5. https://doi. org/10.1186/ar2904. 13. Raaschou P, Frisell T, Askling J. TNF inhibitor therapy and risk of breast cancer recurrence in patients with rheumatoid arthritis: a nationwide cohort study. Ann Rheum Dis. 2015;74:2137–43. 14. Yang H, Brand JS, Li J, Ludvigsson JF, Ugalde-Morales E, Chiesa F, Hall P, Czene K. Risk and predictors of psoriasis in breast cancer patients: a Swedish population based cohort study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer symposium; 2017 Dec 5–9; San Antonio, TX.  Philadelphia (PA): AACR. Cancer Res. 2018;78(4 Suppl):Abstract nr P6-12-24. 15. Madsen P, Rasmussen H, Leffers H, et  al. Molecular cloning occurrence and expression of a novel partially secreted protein ‘psoriasin’ that is highly up-regulated in psoriatic skin. J Invest Dermatol. 1991;97:701–12. 16. Hughes BR, Cotterill JA. The relationship of psoriasis to malignancy: a clinical report. Clin Exp Dermatol. 1993;18:41–4. 17. Boyd A, King L. Tamoxifen-induced remission of psoriasis. J Am Acad Dermatol. 1999;41(5):887–9. 18. Ferrari VD, Jirillo A.  Psoriasis and tamoxifen therapy: a case report. Tumori. 1996;82(3):262.

Chapter 15 79-Year-Old Male with Psoriasis and a History of Melanoma In Situ Kelly A. Reynolds, Deeti J. Pithadia, and Jashin J. Wu

Case A 79-year-old male with a 2-year history of mild inverse psoriasis presents to clinic to establish care and discuss treatment options. He is currently using calcitriol ointment and topical steroids with minimal improvements noted. His last dermatologist also recommended methotrexate, which was effective for a few weeks until the patient discontinued it. Dermatological history is also significant for melanoma in situ, which was removed 1 year ago via excisional biopsy. Follow-up visits with his previous dermatologist have shown no signs of recurrence.

K. A. Reynolds University of Cincinnati College of Medicine, Cincinnati, OH, USA D. J. Pithadia Medical College of Georgia, Augusta University, Augusta, GA, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_15

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The patient denies any previous use of immunosuppressant medications or exposure to phototherapy. He denies a history of excessive sun exposure. He reports no family history of skin cancer or psoriasis. On exam, the patient is noted to have well-demarcated scaly erythematous plaques involving his intergluteal cleft, intertriginous fold, and perianal folds, affecting approximately 3% of his body surface in total. Mild psoriasiform lesions are also noted around his nasolabial folds, posterior auricular folds, and submandibular area. On his upper back, there is a 3  cm well-healed scar at the site of his previous excisional biopsy, with no surrounding abnormalities or evidence of recurrence. Based on the case description, what is the best recommendation for this patient? . Continue current topical regimen. A B. Begin treatment with psoralen and ultraviolet A (PUVA) therapy. C. Begin treatment with acitretin. D. Discontinue topical regimen and begin treatment with adalimumab. E. Discontinue topical regimen and begin treatment with infliximab.

Treatment Begin treatment with acitretin.

Discussion The association between psoriasis and various types of cancer, including non-melanoma skin cancer, lymphoma, lung cancer, pharyngeal cancer, and some urothelial tumors, have been reported in multiple cohort studies [1–4]; however, the relationship between psoriasis and melanoma is less well-­ characterized. Some retrospective studies have reported a significant relationship between melanoma and psoriasis, even

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after adjusting for age and exposure to phototherapy [5]. Other population studies, on the other hand, have reported no significant increased risk of melanoma in patients with psoriasis [1–4, 6], while still others have proposed a lower risk [7]. Both chronic inflammation as well as immunosuppressant therapies have been implicated in the pathogenesis of melanoma in patients with autoinflammatory disease. It has been purported that chronic inflammation may predispose patients to weakened immune surveillance and increased susceptibility to carcinogenesis [7]. There is a significantly increased incidence of melanoma in patients with inflammatory bowel disease (IBD), which may be of particular significance given the pathophysiologic parallels between psoriasis and IBD and the recent discovery that the psoriasis and IBD have shared susceptibility gene loci [8, 9]. The pro-inflammatory cytokine milieu that is characteristic of psoriasis may also contribute to tumorogenesis [10]. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-12/23, IL-17, IL-22, IL-23, interferon (IFN) -alpha, IFN-gamma, and granulocyte monocyte-colony stimulating factor (GM-CSF) have all been shown to be upregulated in psoriasis skin and are correlated with the clinical features of psoriasis [11]. Increased TNF-alpha and IL-17 have been shown to activate genes coding for melanoma mitogens ex  vivo [10]. IFN-­ gamma has been shown to counteract this effect by promoting a strong immune response protecting against immunogenic melanoma cells [12]. This cytokine environment is often purposely disrupted with biologics and other immunosuppressant therapies, which may also disrupt the cytokine network involved in cancer immunosurveillance [10]. Studies have linked TNF inhibitors infliximab, golimumab, etanercept, and adalimumab with increased incidence of melanoma [13]. Certolizumab pegol, interestingly, does not confer increased risk, and therefore may be a reasonable therapeutic option in patients with severe psoriasis and a high risk of melanoma [13]. Based on pooled safety data, the risk of malignancy with ustekinumab at 5 years is considered comparable to the general US population [14], although there have been a few case reports of

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melanoma with ustekinumab treatment [15–17]. Integrated safety data for ixekizumab suggests that malignancy risk is comparable to etanercept, but more long-term safety data are required for agents targeting the IL-17/23 axis [18]. A large retrospective cohort study examined other systemic psoriasis medications including methotrexate, cyclosporine, and acitretin, and concluded that the risk of melanoma is not increased by these therapies [19]. There have been no reports of melanoma with acitretin use, and since acitretin is widely used as a photoprotectant in patients at risk for nonmelanoma skin cancers, it may be a good option for at-risk patients with moderate psoriasis [19]. An Australian study concluded there was a three-fold increased risk of melanoma in patients with rheumatoid arthritis (RA) treated with methotrexate compared to the general population. However, since it did not compare the risk of melanoma in patients treated with methotrexate to those treated with other therapies for RA, the independent risk conferred by methotrexate cannot be definitively concluded by this study [20]. Retrospective and prospective cohort studies have confirmed an increased risk of melanoma in psoriasis patients with a history of psoralen and ultraviolet A (PUVA) therapy. This risk is directly correlated with the amount of exposure and may be further increased with the concurrent use of other immunosuppressive therapies [19, 21, 22]. Narrowband ultraviolet B (UVB) phototherapy, on the other hand, has been shown to have no significant carcinogenic potential [23–26]. However, despite the evidence supporting the safety of UVB phototherapy with regard to incident melanoma, there may be a medicolegal risk in recommending phototherapy to patients with a history of melanoma. In general, topical agents including corticosteroids, calcineurin inhibitors (tacrolimus, pimecrolimus) and vitamin D analogs (calcitriol, calcipotriol and tacalcitol) have no associated increased risk of melanoma, and therefore may be used in patients with mild psoraisis [19, 27, 28].

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The patient was advised to begin therapy with acitretin and to return to clinic for a full-body skin check. If the patient’s symptoms are refractory to treatment with acitretin, the patient may be a candidate for treatment with certolizumab pegol.

Key Points • An increased risk of melanoma in patients with psoriasis has been purported to be in part due to the chronic inflammatory nature of as well as certain treatment options, although the pathophysiology is not totally understood. • Topical therapies and acitretin have no reports of melanoma associated with their use and should be considered first-line therapies for mild-to-­ moderate psoriasis in patients with a history of melanoma. • The TNF inhibitors infliximab, golimumab, etanercept, and adalimumab have been shown to increase the risk of melanoma in patients with psoriasis, whereas certolizumab pegol confers no increased risk. Certolizumab pegol may be a reasonable treatment option for patients with a history of melanoma with moderate-to-severe psoriasis.

References 1. Hannuksela-Svahn A, Pukkala E, Laara E, et  al. Psoriasis, its treatment, and cancer in a cohort of finnish patients. J Invest Dermatol. 2000;114:587–90. 2. Brauchli YB, Jick SS, Miret M, et  al. Psoriasis and risk of incident cancer: an inception cohort study with a nested case-control analysis. J Invest Dermatol. 2009;129:2604–12. 3. Fuxench C, et al. The risk of cancer in patients with psoriasis: a population-based cohort study in the health improvement network. JAMA Dermatol. 2016;152(3):282–90. 4. Chen YJ, Wu CY, Chen TJ, Shen JL, Chu SY, Wang CB, Chang YT.  The risk of cancer in patients with psoriasis: a popula-

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tion-based cohort study in Taiwan. J Am Acad Dermatol. 2011;65(1):84–91. 5. Bhattacharya T, Nardone B, Rademaker A, Martini M, Amin A, Al-Mudaimeagh HM, Kiguradze T, Schneider D, West DP.  Co-existence of psoriasis and melanoma in a large urban academic centre population: a cross-sectional retrospective study. J Eur Acad Dermatol Venereol. 2016;30:83–5. 6. Lee MS, Lin RY, Chang YT, et  al. The risk of developing non-­ melanoma skin cancer, lymphoma and melanoma in patients with psoriasis in Tai- wan: a 10-year, population-based cohort study. Int J Dermatol. 2012;51:1454–60. 7. Megna M, Napolitano M, Balato N, et al. Psoriasis in melanoma patients: a prospective pilot study. G Ital Dermatol Venereol. 2017;152(2):109. 8. Kappelman MD, Farkas DK, Long MD, et  al. Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-­based cohort study with 30 years of follow-up evaluation. Clin Gastroenterol Hepatol. 2014;12:265–73.e1. 9. Ellinghaus D, Ellinghaus E, Nair RP, et al. Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. Am J Hum Genet. 2012;90:636–47. 10. Wang CQ, Akalu YT, Suarez-Farinas M, et  al. IL-17 and TNF synergistically modulate cytokine expression while suppressing melanogenesis: potential relevance to psoriasis. J Invest Dermatol. 2013;133:2741–52. 11. Baliwag J, Barnes DH, Johnston A.  Cytokines in psoriasis. Cytokine. 2015;73(2):342–50. 12. Wang S, Zhou M, Lin F, et al. Interferon-c induces senescence in normal human melanocytes. PLoS One. 2014;9(3):e9323. 13. Nardone B, Hammel JA, Raisch DW, Weaver LL, Schneider D, West DP.  Melanoma associated with TNF-alpha inhibitors: a Research on Adverse Drug events And Reports (RADAR) Project. Br J Dermatol. 2014;170(5):1170–2. 14. Papp KA, Griffiths CEM, Gordon K, et  al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5-years of follow-up. Br J Dermatol. 2013;168:844–54. 15. da Silva FR, de Souza CLF, Steiner D.  Amelanotic melanoma during the use of ustekinumab for severe psoriasis. J Am Acad Dermatol. 2017;76:AB38. 16. Ustekinumab. First report of malignant melanoma: case report. Reactions Weekly. 2012;1389:41.

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17. Ehmann LM, Tillack-Schreiber C, Brand S, Wollenberg A. Malignant melanoma during ustekinumab therapy of Crohn’s disease. Inflamm Bowel Dis. 2012;18:E199–200. 18. Strober B, Leonardi C, Papp KA, et  al. Short and long-term safety outcomes with ixekizumab from 7 clinical trials in psoriasis: etanercept comparisons and integrated data. J Am Acad Dermatol. 2017;76:432–440.e17. 19. Reddy SP, Martires K, Wu JJ. The risk of melanoma and hematologic cancers in patients with psoriasis. J Am Acad Dermatol. 2017;76:639–47. 20. Buchbinder R, Barber M, Heuzenroeder L, Wluka AE, Giles G, Hall S, Harkness A, Lewis D, Littlejohn G, Miller MH, Ryan PF, Jolley D.  Incidence of melanoma and other malignancies among rheumatoid arthritis patients treated with methotrexate. Arthritis Rheum. 2008;59(6):794–9. 21. Stern RS, Nichols KT, Vakeva LH.  Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study. N Engl J Med. 1997;336(15):1041–5. 22. Whitmore SE, Morison WL. Melanoma after PUVA therapy for psoriasis. N Engl J Med. 1997;337:502–3. 23. Hearn RM, Kerr AC, Rahim KF, Ferguson J, Dawe RS. Incidence of skin cancers in 3867 patients treated with narrow-band ultraviolet B phototherapy. Br J Dermatol. 2008;159:931–5. 24. Archier E, Devaux S, Castela E, et  al. Carcinogenic risks of Psoralen UV-A therapy and Narrowband UV-B therapy in chronic plaque psoriasis: a systematic literature review. J Eur Acad Dermatol Venereol. 2012;26:22–31. 25. Naldi L.  Malignancy concerns with psoriasis treatments using phototherapy, methotrexate, cyclosporin, and biologics: facts and controversies. Clin Dermatol. 2010;28:88–92. 26. Lee E, Koo J, Berger T. UVB phototherapy and skin cancer risk: a review of the literature. Int J Dermatol. 2005;44:355–60. 27. De Haes P, Garmyn M, Verstuyf A, et al. 1,25-Dihydroxyvitamin D3 and analogues protect primary human keratinocytes against UVB-induced DNA damage. J Photochem Photobiol B. 2005;78:141–8. 28. Hui RL, Lide W, Chan J, Schottinger J, Yoshinaga M, Millares M.  Association between exposure to topical tacrolimus or pimecrolimus and cancers. Ann Pharmacother. 2009;43:1956–63.

Chapter 16 Pneumococcal Vaccine for 67-Year-Old Male on Adalimumab Kelly A. Reynolds, Deeti J. Pithadia, and Jashin J. Wu

Case A 67-year-old male smoker with psoriasis presents to clinic for pneumococcal vaccination. His psoriasis symptoms have been well controlled on biweekly adalimumab for the past few months. His dermatology history is also significant for basal cell carcinoma on his left lower eyelid removed 3  years ago via excisional biopsy. He has not previously received a pneumococcal vaccine. On exam, he is afebrile and well-­appearing, with scattered erythematous, indurated, scaly papules and plaques involving his bilateral lower extremities. Approximately 0.5% of his total body surface area is affected.

K. A. Reynolds University of Cincinnati College of Medicine, Cincinnati, OH, USA D. J. Pithadia Medical College of Georgia, Augusta University, Augusta, GA, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_16

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What is the best course of action for this patient? A. Administer 13-valent pneumococcal conjugate vaccine (PCV13) today, followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) in 8 weeks. B. Administer PPSV23 today, followed by PCV13 vaccination in 1 year. C. Administer both PCV13 and PPSV23 at this visit. D. No vaccines are indicated for this patient at this time. E. Discontinue adalimumab, then vaccinate with either PCV13 or PPSV23 in 6 months.

Next Step Administer 13-valent pneumococcal conjugate vaccine (PCV13) today, followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) in 8 weeks.

Discussion Patients who are on biologic or immunosuppressant therapies for psoriasis may be immunocompromised and consequently have an increased risk of infection. A population-based cohort study in Taiwan demonstrated that patients using topical therapies for psoriasis are two-times more likely to be hospitalized for pneumonia than patients without psoriasis, compared to 2.54 times the risk in patients on systemic therapies like biologics, methotrexate, and cyclosporine [1]. Vaccines are important tools for pneumococcal infection prevention, but immunosuppressant therapies have been theorized to affect patients’ ability to mount an appropriate immune response to vaccine antigens [2, 3]. Tumor necrosis factors (TNFs) comprise a superfamily of cytokines that play an important role in the autoimmune pathophysiology of psoriasis as well as in active immunity [4–7]. Adalimumab is a fully human anti-TNF monoclonal antibody that neutralizes the effects of TNF by preventing

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interaction with its receptors [8]. By preventing the binding of TNF to its receptors on immune-modifying cells, adalimumab and other TNF inhibitors interfere at multiple points along inflammatory cascades, resulting in their therapeutic suppression of autoinflammation as well as a concurrent suppression of protective immune responses [9]. Two types of pneumococcal vaccines are commonly used in the United States to protect against invasive pneumococcal disease: a 13-valent conjugated vaccine (PCV13) and a 23-valent polysaccharide vaccine (PPSV23). Per the Center for Disease Control (CDC) recommendations, PCV13 is recommended in all infants at 2, 4, 6, and 12–15 months [10]. The CDC also recommends another dose of PCV13 followed by one dose of PPSV23 for all adults 65 years of age as well as for patients who are immunocompromised due to immunosuppressant medications or chronic conditions like asplenia, diabetes mellitus, chronic obstructive pulmonary disease, chronic heart failure, or renal disease. For immunocompromised patients, the recommended interval between PCV13 and PPSV23 vaccinations is 8 weeks, compared to 1 year for immunocompetent patients. In severely immunocompromised patients, revaccination with PPSV23 may be indicated every 5 years [10]. In general, a host’s response to a vaccine is dependent on the nature and dose of the antigen as well as the immunogenic capacity of the host [11]. The differences between PCV13 and PPSV23 are the breadth of coverage and composition. PPSV23 contains antigens from 23 common serotypes of Streptococcus pneumoniae, whereas PCV13 contains 13 antigens. Twelve of the 13 serotypes in PCV13 are also contained in PPSV23. While both vaccines are of comprised of polysaccharide chains from the S. pneumoniae capsule, PCV13 conjugates these polysaccharides to a protein [12]. The addition of the protein improves the immunogenicity of the PCV13 by producing a T-cell dependent response, whereas unconjugated polysaccharide capsule antigens elicit a T-cell independent antibody response [12]. Despite the theoretical impairment of immunogenicity with TNF inhibition, most studies have concluded that

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­ neumococcal vaccines are safe and effective in patients on p these medications [13]. Still, some clinicians and researchers recommend immunization prior to the start of immunosuppressant therapy to ensure sufficient immunological protection [13, 14]. A randomized controlled study by Kaine et al. concluded that there was no difference in immunogenic response to PPSV23 in patients receiving adalimumab compared to placebo [6]. Another study compared anti-pneumococcal antibody titer levels after vaccination with PPSV23 in patients on etanercept or infliximab to patients on other disease-­modifying medications. Both groups mounted clinically significant humoral responses to PPSV23, but patients on TNF inhibitors had lower mean antibody titers against all S. pneumoniae serotypes tested [14]. Methotrexate has been shown to reduce pneumococcal immune response, both when used in combination with TNF inhibitors and as monotherapy, but this effect was not significantly different from the response mounted by healthy controls [15]. Adequate pneumococcal immune responses have also been documented in patients treated with other biologics including alefacept [2], tofacitinib [16], etanercept [4], ustekinumab [17], and ixekizumab [18]. In a parallel-group randomized study, patients treated with secukinumab were found to have the same antibody response to meningococcal and influenza vaccines as healthy controls, but secukinumab’s specific effect on pneumococcal vaccine efficacy has not been studied [19]. More studies are needed to assess newer biologics’ effects on vaccination efficacy, including brodalumab and the new interleukin-23 inhibitors. The patient was administered the PCV13 vaccine and scheduled for PPSV23 vaccination in 8 weeks.

Key Points • Patients on immunosuppressant or biological medications for psoriasis are considered to have a higher risk of infection, especially pneumonia.

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• The CDC recommends pneumococcal vaccination with PCV13 followed by PPSV23 after 8 weeks in pneumococcal-­ naïve, iatrogenically immunocompromised patients. • Therapeutic TNF inhibition may result in lower mean antibody titers after pneumococcal vaccination, but does not significantly affect patients’ ability to mount a protective immune response.

References 1. Kao L-T, Lee C-Z, Liu S-P, Tsai M-C, Lin H-C.  Psoriasis and the risk of pneumonia: a population-based study. PLoS One. 2014;9(12):e116077. 2. Lynde C, Krell J, Korman N, Mathes B.  Immune response to pneumococcal polysaccharide vaccine in adults with chronic plaque psoriasis treated with alefacept. J Am Acad Dermatol. 2011;65:799–806. 3. Salinas GF, De Rycke LD, Barendregt B, Parmarta JE, Hreggvidstdottir H, Cantaert T, van der Burg M, Tak PP, Baeten D. Anti-TNF treatment blocks the induction of T cell-dependent humoral responses. Ann Rheum Dis. 2013;72:1037–43. 4. Baliwag J, Barnes DH, Johnston A.  Cytokines in psoriasis. Cytokine. 2015;73(2):342–50. 5. Mease PJ, Ritchlin CT, Martin RW, et al. Pneumococcal vaccine response in psoriatic arthritis patients during treatment with etanercept. J Rheumatol. 2004;31:1356–61. 6. Kaine JL, Kivitz AJ, Birbara C, Luo AY. Immune responses following administration of influenza and pneumococcal vaccines to patients with rheumatoid arthritis receiving adalimumab. J Rheumatol. 2007;34(2):272–9. 7. Aggarwal BB.  Signaling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol. 2003;3:745–56. 8. Salfeld J, Kaymakcalan Z, Tracey D, Robert A, Kamen R.  Generation of fully human anti-TNF antibody D2E7 [abstract]. Arthritis Rheum. 1998;41(Suppl):S57. 9. Croft M. The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol. 2009;9:271–85. 10. Pneumococcal Disease|Vaccines—PCV13 and PPSV23|CDC. CDC.gov. https://www.cdc.gov/pneumococcal/vaccination.html. Published 2018. Accessed August 31, 2018.

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11. Plotkin SA, Orenstein WA, Offit PA.  Vaccines. 5th ed. Philadelphia: Saunders; 2008. p. 17–36. 12. Hayward S, Thompson LA, McEachern A.  Is 13-valent Pneumococcal Conjugate Vaccine (PCV13) combined with 23-valent Pneumococcal Polysaccharide Vaccine (PPSV23) superior to PPSV23 alone for reducing incidence or severity of pneumonia in older adults? A Clin-IQ.  J Patient-centered Res Rev. 2016;3(2):111–5. 13. Visser LG.  TNF-alpha antagonists and immunization. Curr Infect Dis Rep. 2011;13:243–7. 14. Elkayam O, Caspi D, Reitblatt T, Charboneau D, Rubins JB. The effect of tumor necrosis factor blockade on the response to pneumococcal vaccination in patients with rheumatoid arthritis and ankylosing spondylitis. Semin Arthritis Rheum. 2004;33:283–8. 15. Kapetanovic MC, Saxne T, Sjöholm A, et al. Influence of methotrexate, TNF blockers and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis. Rheumatology. 2006;45:106–11. 16. Winthrop KL, Korman N, Abramovits W, et al. T-cell-mediated immune response to pneumococcal conjugate vaccine (PCV-13) and tetanus toxoid vaccine in patients with moderate-to-severe psoriasis during tofacitinib treatment. J Am Acad Dermatol. 2018;78:1149–55. 17. Brodmerkel C, Wadman E, Langley RG, et al. Immune response to pneumococcus and tetanus toxoid in patients with moderate-­ to-­ severe psoriasis following long-term ustekinumab use. J Drugs Dermatol. 2013;12:1122. 18. Gomez E, Bishop J, Jackson K, Muram T, Phillips D, Wilhelm S. 434 Treatment with ixekizumab does not interfere with the efficacy of tetanus and pneumococcal vaccines in healthy subjects. J Invest Dermatol. 2017;137:S266. 19. Chioato A, Noseda E, Stevens M, Gaitatzis N, Kleinschmidt A, Picaud H.  Treatment with the interleukin-17A-blocking antibody secukinumab does not interfere with the efficacy of influenza and meningococcal vaccinations in healthy subjects: results of an open-label, parallel-group, randomized single-center study. Clin Vaccine Immunol. 2012;19:1597–602.

Chapter 17 47-Year-Old Given BCG Vaccine as a Child Michael P. Lee, Kevin K. Wu, and Jashin J. Wu

Case 47-year-old male, with an extensive history of psoriasis on his whole body for many years, presented with persistent erythematous plaques on bilateral lower legs. He had previously been on multiple medications for his psoriasis including methotrexate and acitretin. For the past 2–3  years, patient had been on etanercept 50 mg twice weekly. His psoriasis had mildly improved, but he continued to experience lesions on the legs, arms, and trunk. His last etanercept injection was the previous week. Patient had no history of psoriatic arthritis or injection site reactions. He denied any fevers, chills, night sweats, cough, hemoptysis, shortness of breath, leg edema, weakness, or numbness in the extremities. Of note, patient is Filipino and received the BCG vaccine as a child. M. P. Lee Eastern Virginia Medical School, Norfolk, VA, USA K. K. Wu Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_17

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On physical examination, a total body skin check was performed with erythematous, scaly indurated papules and plaques visualized mostly on the bilateral lower legs and some on arms and trunk. The affected body surface area was approximately 6%. Based on the clinical case description, what is the best treatment recommendation for this patient? 1. Start adalimumab 2 . Start topical steroids 3. Start rifampin and isoniazid 4. Start topical calcineurin inhibitor 5. Continue etanercept

Treatment Start adalimumab

Discussion TNF-alpha is an inflammatory cytokine that plays an important role in the pathogenesis of psoriasis and is often the target of therapy in the treatment of moderate to severe psoriasis involving more than 5% body surface area [1]. TNF-­alpha is also crucial in inhibiting viral replication and maintaining granulomas in tuberculosis (TB) infections [2]. While TNF inhibitors have been successful in treating psoriasis, careful testing for latent and active tuberculosis infections is necessary, as incidence of TB infections have gone up with TNF inhibitor use [3]. Mycobacterium tuberculosis is responsible for the transmission of TB infections through aerosolized inhalation. An inadequate pulmonary immune response that is unable to clear the mycobacterium via macrophages results in infection. The CDC estimates that one fourth of the world is infected with 1.7 million TB related deaths each year. In 2016, the United States experienced 9272 new TB cases, a 3.6% decrease from 2015.

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Patients with latent TB infection are mostly asymptomatic as Mycobacterium are contained within granulomas, which prevents further replication of the bacteria and disease progression [4]. Reactivation of latent TB from decreased host defenses can lead to extrapulmonary spread of the bacterium to multiple organ systems including the vertebra and kidney [4]. Risk factors for reactivation are multifactorial and include age, bacterial load, and immune compromise. TNF-­ alpha works on increasing phagocytic activity of macrophages and the formation of granulomas. Thus, use of TNF inhibitors can increase the risk of TB infections [3]. All TNF inhibitors increase the risk of tuberculosis, although adalimumab and infliximab confer the highest risk [5, 6]. Prior to initiating a TNF inhibitor for psoriasis treatment, a thorough history and physical exam should be performed to rule out any TB infection. Epidemiologic risk factors should be taken into consideration along with performing a purified protein derivative (PPD) skin test or interferon gamma release assay (IGRA) [7]. Patients with a positive PPD or IGRA should be followed up with a chest plain film to rule out active TB [7]. Patients with a positive PPD or IGRA and negative plain film reading have a diagnosis of latent TB infection (LTBI). Those with epidemiologic risk factors of TB exposure such as birth or travel to endemic area, occupation in homeless shelter or prison, occupation in healthcare settings, or contact with a patient with known active TB should be tested initially using IGRA as recommended by the CDC [8]. Patients that have received BCG vaccine should also be initially tested with IGRA [8]. IGRA is preferred as initial screening test, as it is more sensitive and can be completed in one visit. It is also unnecessary to know a patient’s Bacille Calmette-Guérin (BCG) vaccine history, which can cause a false positive PPD.  Interestingly, there have been a few reported cases of patients developing psoriatic skin lesions following BCG vaccine [9, 10]. For patients without risk factors for TB exposure and have not received the BCG vaccine, PPD skin test is a reasonable alternative test [8].

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Treatment Patients with latent or active TB must be properly treated prior to initiating biologic therapy. For LTBI, 9  months of isoniazid in conjunction with vitamin B6, 4  months of rifampin, or 12  weeks of isoniazid plus rifapentine are the recommended treatments by the CDC [11]. Those with active TB must defer biologic therapy and be referred to a specialist for treatment using standard multidrug therapy of rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE). Without proper screening or treatment of TB infections, potentially life threatening infections can occur for patients treated with TNF inhibitors. Adalimumab, etanercept, and infliximab all contain black box warnings for risk of disseminated and extrapulmonary tuberculosis. From 1998 to 2002 there were 54 cases per 100,000 people of infliximab associated TB infection and 28 cases per 100,000 people of etanercept associated TB infections in the United States [12]. Regarding adalimumab, a 5-year observational registry study demonstrated 18 cases of TB infection with 3 being active TB [13]. These cases highlight the importance of thorough evaluation for TB risk factors and appropriate screening for LTBI.  Patients with LTBI should not be started on TNF inhibitor therapy without receiving TB prophylaxis. There are alternative treatments that are safe in the setting of TB infection. Narrowband ultraviolet B (NB-UVB) has been demonstrated to be effective for psoriasis affecting more than 10% body surface area and is not associated with TB reactivation [14]. Screening for TB is therefore unnecessary and therapy can be administered safely. Other topical medications including corticosteroids, vitamin D analogs, and calcineurin inhibitors have also not been shown to increase risk of TB reactivation, although these treatments may be difficult to use in patients with psoriasis affecting more than 10% body surface area [14]. Ustekinumab, an immunomodulator that works by blocking IL-12/IL-23, can also be considered as low risk for reactivation of TB. Safety data from five studies using ustekinumab showed 167 of 3177 patients having latent TB infection, but

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no cases of active TB were reported while patients were simultaneously receiving ustekinumab and isoniazid treatment [15]. Ixekizumab and secukinumab, which act through inhibiting IL-17, have also not been shown to increase the risk of TB reactivation as seen from multiple studies [15–17]. However, both of these medications have been mandated by the FDA to include warnings of TB infection as cytokines play a vital role in immune response. The patient from the clinical scenario previously received the BCG vaccine as a child. He was thoroughly examined and screened for history of tuberculosis and risk factors. Given his persistent psoriatic lesions on etanercept, treatment was switched to adalimumab 40  mg every other week. He was counseled to go to the emergency department if he experienced any symptoms of fever, cough, and hemoptysis.

Key Points • Immunosuppressive therapy such as TNF inhibitors increase the risk of tuberculosis infection. • Patients should be screened for latent tuberculosis infection with a PPD skin test or IGRA. Those who have previously received BCG vaccine should have an IGRA due to the chance of false positives. • Patients diagnosed with latent TB and are at high risk of reactivation should either begin TB treatment prior to starting any immunosuppressive therapy or consider other safer forms of psoriasis treatment.

References 1. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, Gottlieb AB, Koo JY, Lebwohl M, Lim HW, Van Voorhees AS, Beutner KR, Bhushan R.  Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol. 2009;61(3):451–85. https://doi.org/10.1016/j.jaad.2009.03.027.

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2. Fotiadou C, Lazaridou E, Ioannides D.  Safety of anti-­ tumour necrosis factor-alpha agents in psoriasis patients who were chronic hepatitis B carriers: a retrospective report of seven patients and brief review of the literature. J Eur Acad Dermatol Venereol. 2011;25(4):471–4. https://doi. org/10.1111/j.1468-3083.2010.03754.x. 3. Keane J. TNF-blocking agents and tuberculosis: new drugs illuminate an old topic. Rheumatology (Oxford). 2005;44(6):714–20. https://doi.org/10.1093/rheumatology/keh567. 4. Getahun H, Matteelli A, Chaisson RE, Raviglione M.  Latent Mycobacterium tuberculosis infection. N Engl J Med. 2015;372(22):2127–35. https://doi.org/10.1056/NEJMra1405427. 5. Brassard P, Kezouh A, Suissa S.  Antirheumatic drugs and the risk of tuberculosis. Clin Infect Dis. 2006;43(6):717–22. https:// doi.org/10.1086/506935. 6. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM.  Tuberculosis associated with infliximab, a tumor necrosis factor alpha-­neutralizing agent. N Engl J Med. 2001;345(15):1098–104. https://doi. org/10.1056/NEJMoa011110. 7. Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, Vinh DC.  Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003;3(3):148–55. 8. Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K, IGRA Expert Committee; Centers for Disease Control and Prevention (CDC). Updated guidelines for using interferon gamma release assays to detect Mycobacterium t­uberculosis infection—United States, 2010. MMWR Recomm Rep. 2010;59(RR-5):1–25. 9. Koca R, Altinyazar HC, Numanoglu G, Unalacak M.  Guttate psoriasis-like lesions following BCG vaccination. J Trop Pediatr. 2004;50(3):178–9. https://doi.org/10.1093/tropej/50.3.178. 10. Takayama K, Satoh T, Hayashi M, Yokozeki H.  Psoriatic skin lesions induced by BCG vaccination. Acta Derm Venereol. 2008;88(6):621–2. https://doi.org/10.2340/00015555-0496. 11. Centers for Disease Control and Prevention. Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep. 2011;60(48):1650–3.

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12. Wallis RS, Broder M, Wong J, Beenhouwer D.  Granulomatous infections due to tumor necrosis factor blockade: correction. Clin Infect Dis. 2004;39(8):1254–5. https://doi.org/10.1086/424455. 13. Menter A, Thaci D, Papp KA, Wu JJ, Bereswill M, Teixeira HD, Rubant S, Williams DA.  Five-year analysis from the ESPRIT 10-year postmarketing surveillance registry of adalimumab treatment for moderate to severe psoriasis. J Am Acad Dermatol. 2015;73(3):410–419 e416. https://doi.org/10.1016/j. jaad.2015.06.038. 14. Doherty SD, Van Voorhees A, Lebwohl MG, Korman NJ, Young MS, Hsu S, National Psoriasis F. National Psoriasis Foundation consensus statement on screening for latent tuberculosis infection in patients with psoriasis treated with systemic and biologic agents. J Am Acad Dermatol. 2008;59(2):209–17. https://doi. org/10.1016/j.jaad.2008.03.023. 15. Tsai TF, Ho V, Song M, Szapary P, Kato T, Wasfi Y, Li S, Shen YK, Leonardi C, Phoenix PAP, Japanese Ustekinumab Study Group. The safety of ustekinumab treatment in patients with moderate-to-severe psoriasis and latent tuberculosis infection. Br J Dermatol. 2012;167(5):1145–52. https://doi. org/10.1111/j.1365-2133.2012.11142.x. 16. Griffiths CE, Reich K, Lebwohl M, van de Kerkhof P, Paul C, Menter A, Cameron GS, Erickson J, Zhang L, Secrest RJ, Ball S, Braun DK, Osuntokun OO, Heffernan MP, Nickoloff BJ, Papp K, UNCOVER-2 and UNCOVER-3 investigators. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015;386(9993):541–51. https:// doi.org/10.1016/S0140-6736(15)60125-8. 17. van de Kerkhof PC, Griffiths CE, Reich K, Leonardi CL, Blauvelt A, Tsai TF, Gong Y, Huang J, Papavassilis C, Fox T. Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol. 2016;75(1):83–98 e84. https://doi. org/10.1016/j.jaad.2016.03.024.

Chapter 18 45-Year-Old with Psoriasis Started on Adalimumab Michael P. Lee, Kevin K. Wu, and Jashin J. Wu

Case A 45-year-old male with a history of psoriasis presented for follow up consultation for systemic psoriasis therapies. Patient’s psoriasis had been stable on acitretin 25 mg once daily, but he continued to have lesions over his body that have never cleared. He understood he could increase the dose to twice daily for improvement, but he was worried about possible side effects such as dry, cracked skin on the lips and feet. Patient was willing to try and initiate longterm adalimumab at the visit for better clearance of lesions. He was a previous smoker and from Mexico. He denied any fever, night sweats, cough, hemoptysis, shortness of breath, M. P. Lee Eastern Virginia Medical School, Norfolk, VA, USA K. K. Wu Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_18

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leg edema, muscle weakness, headache, tingling or numbness in the extremities. Previous hepatitis B testing was reactive for anti-HBc and negative for remainder of the panel. On physical examination, a total body skin check was performed with erythematous, scaly indurated papules and plaques visualized on the trunk, legs, and arms. The affected body surface area was approximately 15%. Based on the clinical case description, what is the best treatment recommendation prior to starting adalimumab for this patient? 1. Methotrexate for 2 months 2 . Topical corticosteroid and calcipotriol for 2 months 3. Entecavir for 2 months 4. Narrowband ultraviolet-B phototherapy for 2 months 5. Cyclosporine for 2 months

Treatment Entecavir for 2 months

Discussion Systemic psoriasis therapies are used for the treatment of moderate to severe psoriasis, typically with debilitating disease or involving more than 5% body surface area [1]. TNF-­ alpha is an inflammatory cytokine that plays an important role in the pathogenesis of psoriasis and has been the target of therapy utilizing biologic agents such as adalimumab, infliximab, and etanercept. TNF-alpha response is also crucial in maintaining granulomas in tuberculosis infections and in inhibiting viral replication along with aiding in viral clearance [2, 3]. While TNF inhibitors have proved successful in treating psoriasis, it is important to determine a patient’s predisposition to infection by testing for risk factors such as hepatitis B status [2].

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Active hepatitis B infection is dependent on viral replication and a patient’s immune response. Patients that are subjected to immunosuppression through medications are at increased risk of infection or reactivation of previous disease. A sudden rise in hepatitis B dsDNA along with an elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are the first signs of infection. Active infection while on immunosuppressive therapy can also lead to interruptions in treating the underlying disease such as psoriasis. If left untreated, the disease course can lead to fulminant hepatic failure and death [4]. Evaluation of a patient’s hepatitis B serum markers can determine the likelihood of developing an active infection. The presence of hepatitis B surface antigen (HBsAg) establishes a diagnosis with 6  months being the cutoff between acute or chronic infection [5]. Typically, HBsAg appears in a patient’s serum between 1 and 10 weeks after an acute exposure to hepatitis B virus and before any elevation in ALT or AST. The prevalence of HBsAg varies among countries with high prevalence defined as greater than 8% and low prevalence as 2%. In developed countries such as the United States, the prevalence is higher in those who immigrated from high risk countries or engaging in high risk behaviors [6]. The presence of hepatitis B surface antibody (HBsAb) signifies that the patient is either immune to infection from previous exposure or received a vaccine and is not actively infected. With acute exposure to hepatitis B virus, the appearance of HBsAb follows the disappearance of HBsAg and confers long term immunity. HBsAb, however, may be undetectable for a while even after surface antigens disappear, known as a window period where neither HBsAb or HBsAg are detected [5]. During this window period, hepatitis B core antigen antibody (anti-HBc) can be detected and a diagnosis can be made [5]. Patients that are HBsAg negative, HBsAb positive, and anti-HBc positive can be classified as having previous exposure to hepatitis B virus and have subsequently recovered without active infection. The risk of reactivation for these patients has been shown to be very low [7].

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The American Gastroenterological Association currently recommends testing patients for any evidence of hepatitis B infection prior to starting immunosuppressive therapy [8]. Along with testing for HBsAg, HBsAb, and anti-HBc status, liver function tests are also recommended. Patients that exclusively test positive for HBsAb can be started on immunosuppressive therapy such as TNF inhibitors as these patients are immune and have not previously been infected. If in addition to HBsAb positivity, a patient also tests positive for anti-HBc, this signifies a recovery from a previous hepatitis B infection and the patient does not currently have an active infection. These patients have a low risk of reactivation and do not need to be started on antivirals before TNF inhibitors, but discussion with hepatologist is recommended [7]. If a patient tests negative for all three markers, this denotes that the patient has never previously been infected nor is he immune. TNF inhibitors can be safely administered to these patients, but hepatitis B vaccination is recommended before starting immunosuppressive therapy [5]. Patients that are positive for HBsAg and anti-HBc may be in an acute or chronic state of infection. These patients should undergo further testing and have quantitative anti-HBc IgM and hepatitis B DNA measurements taken to establish infection status. It is recommended these patients are started on antiviral medication such as entecavir or tenofovir and should also be monitored by a hepatologist [7].

Treatment For patients with moderate to severe psoriasis and known hepatitis B infection, special care and safety needs to be taken into consideration when selecting a non-topical treatment, mainly to determine if the agent can exacerbate existing viral liver disease or promote viral replication. Although the immunosuppressive effects of UV light have not been specifically evaluated for risk of viral reactivation, UV-B phototherapy has generally been considered to be safe in patients with confirmed hepatitis B [9].

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Biologic agents may also be considered for moderate to severe psoriasis in the setting of concomitant hepatitis B. Under close monitoring and collaboration with a gastroenterologist, IL-12/23 inhibitor ustekinumab or IL-17 inhibitors secukinumab, and ixekizumab may be utilized as first line therapies {Kaushik, 2018 #362}. Ustekinumab treatment in psoriasis patients with coexisting hepatitis B has been demonstrated to be safe, but patients may also benefit from antiviral prophylactic therapy to decrease likelihood of reactivation [10, 11]. Safety data on interleukin-17 inhibitors such as secukinumab and ixekizumab are limited to case reports, but are thought to not substantially increase risk of hepatitis B reactivation due to their mechanism of action [12]. The risk of interleukin-23 inhibitors guselkumab and tildrakizumab reactivating HBV infection is currently unknown due to studies excluding patients with active HBV infection. However, due to their mechanism of action, they are not believed to increase the risk. Other biologic agents such as TNF inhibitors are considered second line agents for coexisting hepatitis B infection and generally should be managed with a hepatologist [11]. It is recommended that antiviral therapy be initiated prior to starting TNF inhibitor therapy and patients should have close laboratory monitoring of liver function tests. Antiviral prophylaxis should be started at least 2–4 weeks before initiation of TNF inhibitor treatment and continue for 3–6 months even after discontinuing TNF inhibitor treatment [2]. Due to his hepatitis B panel, the patient from the clinical scenario had been started on entecavir 0.5 mg once daily for 2 months prior to his consultation visit for initiating adalimumab. Patient was started on adalimumab 80 mg at week 1, 40 mg at week 2, and 40 mg every other week with potential risks discussed including TB or hepatitis reactivation. He was to follow up in 1 month for liver function panel testing.

Key Points • Immunosuppressive therapy such as TNF-alpha inhibitors increase the risk of hepatitis B reactivation.

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• Treatments for patients with psoriasis and coexisting hepatitis B include phototherapy, ustekinumab, and interleukin-­17 inhibitors, with TNF inhibitors considered second line therapy. • Patients should be screened for hepatitis B prior to initiating immunosuppressive therapy by analyzing HBsAg, HBsAB, and anti-HBc status. Serologic marker HBsAg

Result −

HBsAb

−

Anti-HBc

−

HBsAg

−

HBsAb

+

Anti-HBc

+

HBsAg

−

HBsAb

+

Anti-HBc

−

HBsAg

+

HBsAb

−

Anti-HBc

+

Anti-HBc IgM

+

HBsAg

+

HBsAb

−

Anti-HBc

+

Anti-HBc IgM

−

HBsAg

−

HBsAb

−

Anti-HBc

+

Hepatitis B status Susceptible to infection

Immunity due to prior infection

Immunity due to vaccination

Acute infection

Chronic infection

Status uncertain: 1.  Recovery from infection 2.  False positive anti-HBc 3.  Chronic infection 4.  Resolution of acute infection

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References 1. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, Gottlieb AB, Koo JY, Lebwohl M, Lim HW, Van Voorhees AS, Beutner KR, Bhushan R. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol. 2009;61(3):451–85. https://doi.org/10.1016/j.jaad.2009.03.027. 2. Fotiadou C, Lazaridou E, Ioannides D.  Safety of anti-­ tumour necrosis factor-alpha agents in psoriasis patients who were chronic hepatitis B carriers: a retrospective report of seven patients and brief review of the literature. J Eur Acad Dermatol Venereol. 2011;25(4):471–4. https://doi. org/10.1111/j.1468-3083.2010.03754.x. 3. Xie X, Li F, Chen JW, Wang J.  Risk of tuberculosis infection in anti-TNF-alpha biological therapy: from bench to bedside. J Microbiol Immunol Infect. 2014;47(4):268–74. https://doi. org/10.1016/j.jmii.2013.03.005. 4. Gupta S, Govindarajan S, Fong TL, Redeker AG.  Spontaneous reactivation in chronic hepatitis B: patterns and natural history. J Clin Gastroenterol. 1990;12(5):562–8. 5. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560–99. https://doi. org/10.1002/hep.29800. 6. Nelson NP, Easterbrook PJ, McMahon BJ.  Epidemiology of hepatitis B virus infection and impact of vaccination on disease. Clin Liver Dis. 2016;20(4):607–28. https://doi.org/10.1016/j. cld.2016.06.006. 7. Motaparthi K, Stanisic V, Van Voorhees AS, Lebwohl MG, Hsu S, Medical Board of the National Psoriasis Foundation. From the Medical Board of the National Psoriasis Foundation: recommendations for screening for hepatitis B infection prior to initiating anti-tumor necrosis factor-alfa inhibitors or other immunosuppressive agents in patients with psoriasis. J Am Acad Dermatol. 2014;70(1):178–86. https://doi.org/10.1016/j. jaad.2013.08.049.

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8. Reddy KR, Beavers KL, Hammond SP, Lim JK, Falck-Ytter YT, American Gastroenterological Association Institute. American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology. 2015;148(1):215–9; quiz e216–217. https://doi.org/10.1053/j. gastro.2014.10.039. 9. Strober B, Berger E, Cather J, Cohen D, Crowley JJ, Gordon KB, Gottlieb A, Horn EJ, Kavanaugh AF, Korman NJ, Krueger GG, Leonardi CL, Menter A, Schwartzman S, Sobell JM, Young M. A series of critically challenging case scenarios in moderate to severe psoriasis: a Delphi consensus approach. J Am Acad Dermatol. 2009;61(1 Suppl 1):S1–S46. https://doi.org/10.1016/j. jaad.2009.03.017. 10. Chiu HY, Chen CH, Wu MS, Cheng YP, Tsai TF. The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C.  Br J Dermatol. 2013;169(6):1295– 303. https://doi.org/10.1111/bjd.12461. 11. Navarro R, Vilarrasa E, Herranz P, Puig L, Bordas X, Carrascosa JM, Taberner R, Ferran M, Garcia-Bustinduy M, RomeroMate A, Pedragosa R, Garcia-Diez A, Dauden E.  Safety and effectiveness of ustekinumab and antitumour necrosis factor therapy in patients with psoriasis and chronic viral hepatitis B or C: a r­ etrospective, multicentre study in a clinical setting. Br J Dermatol. 2013;168(3):609–16. https://doi.org/10.1111/bjd.12045. 12. Bevans SL, Mayo TT, Elewski BE. Safety of secukinumab in hepatitis B virus. J Eur Acad Dermatol Venereol. 2018;32(3):e120–1. https://doi.org/10.1111/jdv.14608.

Chapter 19 46-Year-Old with Psoriasis and Chronic Hepatitis C Kevin K. Wu, Michael P. Lee, and Jashin J. Wu

Case A 46-year-old male with a history of psoriasis and hepatitis C due to IV drug use presented to the clinic to discuss treatment options. The patient discontinued topical clobetasol for his psoriasis because he felt the medication was causing him pain. He was unable to starting phototherapy due to his busy schedule. He had been treated with calcitriol ointment in the past with beneficial results and would like a refill. He denied joint stiffness or pain. The patient worked in a hospital setting. On skin examination, there were scaly, erythematous, indurated papules and plaques on the bilateral dorsal hands, elbows, and legs. His affected BSA was 8%. Abdominal K. K. Wu Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA M. P. Lee Eastern Virginia Medical School, Norfolk, VA, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_19

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examination did not reveal any tenderness, distension, or organomegaly. Based on the case description, what is the best treatment recommendation for this patient’s psoriasis? 1. 2 . 3. 4. 5.

Methotrexate Coal Tar Ixekizumab Acitretin Apremilast

Treatment Apremilast

Discussion Hepatitis C virus (HCV) infection is the most common blood-borne infection in the U.S., affecting 2.4 million people in 2016 [1]. Chronic HCV infection may lead to end-stage liver disease, cirrhosis, and hepatocellular carcinoma. HCV infection has been shown to increase the risk of a psoriasis diagnosis. TNF-alpha is a mutual cytokine in HCV and psoriasis, and HCV infection may trigger psoriasis due to overproduction of TNF-alpha [2]. Interestingly, the blood levels of HCV antibodies are correlated to psoriasis severity in psoriasis patients with concomitant HCV [3]. Lesional and non-­ lesional biopsies from psoriasis patients with HCV have higher mRNA levels of the inflammatory cytokines ­IFN-­gamma, TLR9, and cathelicidin than biopsies from psoriasis patients without HCV [4]. Treatment of psoriasis patients with concomitant HCV is challenging, as many psoriasis treatments are potentially hepatotoxic, immunosuppressive, or both, which are generally contraindications for HCV patients [5–7]. In addition, treatment of HCV with interferon therapy such as pegylated interferon and interferon alfa may exacerbate psoriasis.

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Treatment The National Psoriasis Foundation (NPF) suggests topical therapies such as topical corticosteroids, vitamin D analogues, and calcineurin inhibitors as first-line treatment for psoriasis patients with concomitant HCV [5]. Ultraviolet B (UVB) phototherapy, which exerts local effects confined to the skin, may also be used in HCV-positive patients. Importantly, UVB phototherapy has no association with reactivation of HCV infections [5, 8]. In addition to the NPF’s recommended therapies, we recommend apremilast as another first-line therapy for treatment of psoriasis with concomitant HCV [9]. Apremilast is unique in that it does not target a single cytokine, but instead works in restoring the balance of pro-inflammatory and anti-­ inflammatory mediators [10]. The mechanism of action of apremilast is less immunosuppressive than traditional psoriasis therapies. TNF inhibitors such as etanercept and adalimumab may be used as second-line therapies for psoriasis patients with concomitant HCV [11]. Literature on TNF inhibitors for treatment of this population is limited. However, prior case studies of TNF inhibitor use in psoriasis patients with concomitant HCV found that etanercept and adalimumab may be reasonably safe and efficacious [11, 12]. Most HCV patients using TNF inhibitors sustained stable viral and hepatic outcomes throughout the studies, despite theoretical risk of HCV reactivation. However, there is insufficient data to assess the long-term safety of TNF inhibitors in HCV patients. Some studies have reported benefit from using TNF inhibitors in combination with HCV therapy such as interferon and ribavirin [5]. For example, Zein et  al. found that patients treated with a combination of etanercept and standard HCV therapy (interferon alfa-2b and ribavirin) had significantly lower virologic response and fewer side-effects from their treatments [13]. It is believed that TNF inhibition leads to an enhanced peripheral T-cell response to antigens and also enhances the effect of interferon-alpha on HCV [12].

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Cyclosporine use in this population is controversial [11]. Cyclosporine has demonstrated anti-viral activity in patients with HCV by blocking cellular cyclophilin B, a regulator of HCV RNA polymerase [14]. However, cyclosporine has also been associated with recurrence and progression of hepatitis C, leading to liver fibrosis and cirrhosis [11]. If cyclosporine is used, patients will require antiviral therapy and regular monitoring of LFTs and viral titers. There is limited data on the use of ustekinumab, an IL-12/23 inhibitor, for treatment of psoriasis with concomitant HCV. In a case series of 20 psoriasis patients with concomitant HCV, patients on ustekinumab exhibited no aggravation of HCV [15]. However, in one study of four HCV patients treated with at least two ustekinumab injections, one patient experienced HCV reactivation [16]. More studies are needed to understand the risk of HCV reactivation before ustekinumab can be recommended as a treatment option for psoriasis patients with concomitant HCV. Several psoriasis treatments should be avoided or used cautiously in psoriasis patients with concomitant HCV. For example, methotrexate is absolutely contraindicated in patients with HCV because it is associated with liver damage and druginduced hepatitis [11]. Acitretin may cause hepatotoxicity and should be used cautiously in patients with pre-­existing liver disease [8, 11]. Psoriasis patients with concomitant HCV on acitretin should undergo routine liver enzyme labs to monitor for hepatotoxicity. There is currently limited literature supporting the use of IL-17 inhibitors in psoriasis patients with concomitant HCV; therefore, these agents should be used with caution [11]. There is currently no data on the use of IL-23 inhibitors in patients with psoriasis and concomitant HCV [11]. Prior to beginning systemic therapy in this population, the dermatology provider should consult and maintain communication with a hepatologist [8]. The patient must be evaluated by the hepatologist to determine the extent of liver disease and assess whether the patient has an indication for antiviral treatments. Unfortunately, there are currently no randomized controlled trials evaluating the safety and efficacy of treatments

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for psoriasis with concomitant HCV. The evidence supporting the use of the aforementioned therapies consist mainly of case reviews and case reports. The patient was started on apremilast for his psoriasis. At three-month follow-up, his psoriasis was clearing up and becoming less scaly. His total BSA was 1.5%.

Key Points • HCV infection may trigger psoriasis. • Standard HCV treatments such as interferon and ribavirin may lead to or exacerbate psoriasis. • First-line treatments for psoriasis patients with concomitant HCV include phototherapy, topical therapies, and apremilast. • TNF inhibitors may be used as second-line therapy for psoriasis with concomitant HCV.

References 1. CDC. Viral hepatitis statistics and surveillance. 2016. Retrieved from United States. 2. Imafuku S, Naito R, Nakayama J.  Possible association of hepatitis C virus infection with late-onset psoriasis: a hospital-based observational study. J Dermatol. 2013;40(10):813–8. https://doi. org/10.1111/1346-8138.12240. 3. Gabr SA, Berika MY, Alghadir AH. Apoptosis and clinical severity in patients with psoriasis and HCV infection. Indian J Dermatol. 2014;59(3):230–6. https://doi.org/10.4103/0019-5154.131377. 4. Chun K, Afshar M, Audish D, Kabigting F, Paik A, Gallo R, Hata T. Hepatitis C may enhance key amplifiers of psoriasis. J Eur Acad Dermatol Venereol. 2017;31(4):672–8. https://doi.org/10.1111/ jdv.13578. 5. Frankel AJ, Van Voorhees AS, Hsu S, Korman NJ, Lebwohl MG, Bebo BF Jr, et  al. Treatment of psoriasis in patients with hepatitis C: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2009;61(6):1044–55. https:// doi.org/10.1016/j.jaad.2009.03.044.

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6. Kim GW, Jwa SW, Song M, Kim HS, Kim BS, Kim MB, Ko HC.  Extensive psoriasis induced by pegylated interferon alfa-2a and ribavirin in the treatment of chronic hepatitis C.  Ann Dermatol. 2013;25(4):479–82. https://doi.org/10.5021/ ad.2013.25.4.479. 7. Taylor C, Burns DA, Wiselka MJ. Extensive psoriasis induced by interferon alfa treatment for chronic hepatitis C. Postgrad Med J. 2000;76(896):365–7. 8. Bonifati C, Lora V, Graceffa D, Nosotti L. Management of psoriasis patients with hepatitis B or hepatitis C virus infection. World J Gastroenterol. 2016;22(28):6444–55. https://doi.org/10.3748/ wjg.v22.i28.6444. 9. Reddy SP, Shah VV, Wu JJ.  Apremilast for a psoriasis patient with HIV and hepatitis C.  J Eur Acad Dermatol Venereol. 2017;31(11):e481–2. https://doi.org/10.1111/jdv.14301. 10. Schafer P.  Apremilast mechanism of action and applica tion to psoriasis and psoriatic arthritis. Biochem Pharmacol. 2012;83(12):1583–90. https://doi.org/10.1016/j.bcp.2012.01.001. 11. Kaushik SB, Lebwohl MG. CME Part II psoriasis: which therapy for which patient focus on special populations and chronic infections. J Am Acad Dermatol. 2018;80:43–53. https://doi. org/10.1016/j.jaad.2018.06.056. 12. Brunasso AM, Puntoni M, Gulia A, Massone C. Safety of anti-­ tumour necrosis factor agents in patients with chronic hepatitis C infection: a systematic review. Rheumatology (Oxford). 2011;50(9):1700–11. https://doi.org/10.1093/rheumatology/ ker190. 13. Zein NN. Etanercept as an adjuvant to interferon and ribavirin in treatment-naive patients with chronic hepatitis C virus infection: a phase 2 randomized, double-blind, placebo-controlled study. J Hepatol. 2005;42(3):315–22. 14. Heck JA, Meng X, Frick DN. Cyclophilin B stimulates RNA synthesis by the HCV RNA dependent RNA polymerase. Biochem Pharmacol. 2009;77(7):1173–80. https://doi.org/10.1016/j. bcp.2008.12.019. 15. Navarro R, Vilarrasa E, Herranz P, Puig L, Bordas X, Carrascosa JM, et  al. Safety and effectiveness of ustekinumab and antitumour necrosis factor therapy in patients with psoriasis and

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chronic viral hepatitis B or C: a retrospective, multicentre study in a clinical setting. Br J Dermatol. 2013;168(3):609–16. https:// doi.org/10.1111/bjd.12045. 16. Chiu HY, Chen CH, Wu MS, Cheng YP, Tsai TF. The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C.  Br J Dermatol. 2013;169(6):1295– 303. https://doi.org/10.1111/bjd.12461.

Chapter 20 HIV Infection in a 58-Year-Old Male with Psoriasis Kevin K. Wu, Michael P. Lee, and Jashin J. Wu

Case A 58-year-old male with a 2-year history of psoriasis and a 10-year history of HIV presented for follow-up care of his psoriasis. He was previously treated with methotrexate resulting in complete clearance of his skin but ultimately ­discontinued the medication due to liver enzyme elevation, diarrhea, and stomach ache. He was then started on apremilast but discontinued it due to inefficacy. He is unable to try phototherapy due to his work schedule. Review of systems was unremarkable, and the patient has no AIDS-defining conditions. On physical examination, there were several pink, round plaques with thick white scale on the bilateral upper and K. K. Wu Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA M. P. Lee Eastern Virginia Medical School, Norfolk, VA, USA J. J. Wu (*) Founder and CEO, Dermatology Research and Education Foundation, Irvine, CA, USA © Springer Nature Switzerland AG 2019 J. J. Wu (ed.), Clinical Cases in Psoriasis, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-18772-9_20

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lower extremities. Approximately 3% of the BSA was affected. Based on the case description, which of the following is the best treatment for this patient? 1. 2 . 3. 4. 5.

Methotrexate Infliximab Cyclosporine Ustekinumab Acitretin

Treatment Acitretin

Discussion Skin diseases are among the most common manifestations of human immunodeficiency virus (HIV) infection. Although the prevalence of psoriasis in the HIV-infected population is similar to that of the general population, psoriasis has a propensity to be more severe and treatment-refractory in patients with concomitant HIV [1]. Psoriasis in HIV patients may also present at any degree of severity during any stage of the HIV infection [2]. However, more severe psoriasis is correlated with worsening HIV-mediated immunosuppression. Psoriasis may be the first manifestation of HIV infection in some patients. Therefore, those with new-onset psoriasis may benefit from HIV testing [3, 4]. Psoriasis patients at risk for ­infection or with treatment-refractory disease may also benefit from HIV testing [5]. Although HIV-infected patients may present with any subtype of psoriasis, the most common subtypes include plaque, guttate, inverse, and erythrodermic psoriasis [6]. Multiple subtypes of psoriasis may be present in the same patient. HIV-positive psoriasis patients are more likely to have significant psoriatic arthritis when compared to HIV-­

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negative psoriasis patients [6]. Histological examination of skin specimens from HIV-infected psoriasis patients classically shows elevated plasma cells [4]. Treatment of HIV-infected psoriasis patients poses a unique challenge, as HIV-associated psoriasis is paradoxically a T-lymphocyte mediated disease in the setting of T-lymphocyte depletion [6]. Many psoriasis treatments are immunosuppressive and can potentially lead to severe complications in HIV patients [4]. Interestingly, psoriasis may improve in HIV patients that begin antiretroviral therapy and replenish T-lymphocyte counts [3].

Treatment In general, HIV patients with psoriasis should be treated with agents that have minimal to no immunosuppressive properties, which limits the treatment options for these patients. First-line therapy for psoriasis with concomitant HIV includes phototherapy, which lacks systemic properties. Topical agents such as corticosteroids, vitamin D analogues, a combination of corticosteroids and vitamin D analogues (e.g. betamethasone dipropionate with calcipotriol), or topical calcineurin inhibitors may also be used as first-line therapy with or without phototherapy [6]. Based on the World Health Organization (WHO) guidelines, any HIV patient, regardless of CD4 count or the presence of an AIDS-defining illness, should start on antiretroviral therapy [7]. In addition to treating HIV, antiretroviral therapies have been shown to reduce the severity of psoriasis in HIV patients [6]. If phototherapy, topical treatments, and antiretroviral therapies are unsuccessful in treating psoriasis patients with concomitant HIV, second-line treatments include acitretin, apremilast, TNF inhibitors, and ustekinumab [6, 8]. However, acitretin may interfere with some antiretroviral drugs. Apremilast, a phosphodiesterase-4 inhibitor, is safe and well-­ tolerated in psoriasis patients with HIV. Side-effects of apremilast include nausea, diarrhea, weight loss, and upper respiratory tract infections [9].

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Biologic agents should be considered in HIV-positive psoriasis patients with refractory psoriasis or debilitating psoriatic arthritis. Specifically, ustekinumab and TNF inhibitors such as etanercept, adalimumab, and infliximab have been deemed safe and effective in psoriasis patients with concomitant HIV in multiple case studies [8]. One case study found that etanercept treatment in a patient with HIV led to complete clearance of pustular psoriasis [10]. In a case study of an HIV-positive psoriasis patient treated with IL-12/23 inhibitor ustekinumab, the patient tolerated the medication well, and his CD4 count increased from 429  cells/mL at baseline to 480 cells/mL 7 months after initiating ustekinumab [11]. Methotrexate and cyclosporine should be avoided in psoriasis patients with concomitant HIV due to the risk of opportunistic infections [8]. Methotrexate may worsen HIV disease severity and may also lead to leucopenia and opportunistic infections [12]. Cyclosporine may inhibit activation of CD4 lymphocytes via calcineurin inhibition, which may theoretically be beneficial in HIV patients because T-cell activation is needed for HIV replication [13]. A number of case reports found that cyclosporine was effective and tolerable in a psoriasis patient with concomitant HIV [14]. However, further data supporting the use of cyclosporine in psoriasis with concomitant HIV is limited. Due its known immunosuppressive effects and limited literature supporting its use, cyclosporine should also be avoided in this population. Psoriasis patients with HIV treated with immunosuppressant medications should be managed in collaboration with infectious disease specialists for monitoring of CD4 counts and viral load and prevention of opportunistic infections. In some cases, infectious disease specialists may recommend prophylaxis to prevent opportunistic infections in these patients [13]. Unfortunately, there are currently no randomized controlled trials evaluating the safety and efficacy of treatments for psoriasis with concomitant HIV. The evidence supporting the use of the aforementioned therapies consist mainly of case reviews and case reports.

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The patient was treated with acitretin and topical betamethasone dipropionate alternating with topical tacrolimus. At 3-month follow-up, the patient experienced improvement of his psoriasis lesions, and his total affected BSA was 1%.

Key Points • Psoriasis prevalence in HIV patients is similar to that of the general population. However, HIV patients with psoriasis may have more severe and treatment-refractory disease. • All HIV patients should start antiretroviral therapy regardless of CD4+ count or presence of AIDS-defining illnesses. • First-line treatments for psoriasis with concomitant HIV include phototherapy and topical therapies. Second-line treatments include TNF inhibitors, ustekinumab, acitretin, and apremilast. • Methotrexate and cyclosporine should be avoided due to the risk of opportunistic infection.

References 1. Hsu S, Papp KA, Lebwohl MG, Bagel J, Blauvelt A, Duffin KC, et al. Consensus guidelines for the management of plaque psoriasis. Arch Dermatol. 2012;148(1):95–102. https://doi.org/10.1001/ archdermatol.2011.1410. 2. Mallon E, Bunker CB.  HIV-associated psoriasis. AIDS Patient Care STDs. 2000;14(5):239–46. https://doi. org/10.1089/108729100317696. 3. Bartlett BL, Khambaty M, Mendoza N, Tremaine AM, Gewirtzman A, Tyring SK, Tyring SK.  Dermatological management of human immunodeficiency virus (HIV). Skin Therapy Lett. 2007;12(8):1–3. 4. Montazeri A, Kanitakis J, Bazex J. Psoriasis and HIV infection. Int J Dermatol. 1996;35(7):475–9.

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5. Armstrong AW, Aldredge L, Yamauchi PS.  Managing patients with psoriasis in the busy clinic: practical tips for health care practitioners. J Cutan Med Surg. 2016;20(3):196–206. https://doi. org/10.1177/1203475415623508. 6. Menon K, Van Voorhees AS, Bebo BF Jr, Gladman DD, Hsu S, Kalb RE, et  al. Psoriasis in patients with HIV infection: from the medical board of the National Psoriasis Foundation. J Am Acad Dermatol. 2010;62(2):291–9. https://doi.org/10.1016/j. jaad.2009.03.047. 7. WHO. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. 2015. 8. Kaushik SB, Lebwohl MG. CME Part II psoriasis: which therapy for which patient focus on special populations and chronic infections. J Am Acad Dermatol. 2018;80:43–53. https://doi. org/10.1016/j.jaad.2018.06.056. 9. Yiu ZZ, Warren RB. Novel oral therapies for psoriasis and psoriatic arthritis. Am J Clin Dermatol. 2016;17(3):191–200. https:// doi.org/10.1007/s40257-016-0179-3. 10. Mikhail M, Weinberg JM, Smith BL.  Successful treatment with etanercept of von Zumbusch pustular psoriasis in a patient with human immunodeficiency virus. Arch Dermatol. 2008;144(4):453–6. https://doi.org/10.1001/archderm.144.4.453. 11. Paparizos V, Rallis E, Kirsten L, Kyriakis K. Ustekinumab for the treatment of HIV psoriasis. J Dermatolog Treat. 2012;23(6):398– 9. https://doi.org/10.3109/09546634.2011.579085. 12. Kalb RE, Strober B, Weinstein G, Lebwohl M.  Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference. J Am Acad Dermatol. 2009;60(5):824–37. https://doi. org/10.1016/j.jaad.2008.11.906. 13. Morar N, Willis-Owen SA, Maurer T, Bunker CB. HIV-associated psoriasis: pathogenesis, clinical features, and management. Lancet Infect Dis. 2010;10(7):470–8. https://doi.org/10.1016/ S1473-3099(10)70101-8. 14. Jacobson SK, Calne RY, Wreghitt TG. Outcome of HIV infection in transplant patient on cyclosporin. Lancet. 1991;337(8744):794.

Index

A Acitretin, 4, 105 hepatitis C virus, 142 human immunodeficiency virus infected psoriasis patients, 149 melanoma, 112 palmar-plantar psoriasis, 56 pregnancy, 91 scalp psoriasis, 27 Active hepatitis B infection, 133 Adalimumab, 95, 98, 117 psoriatic arthritis, 64 Adequate pneumococcal immune responses, 120 Alanine aminotransferase (ALT), 133 American College of Rheumatology guidelines, 105 American Gastroenterological Association, 134 Antibiotic therapy, 20 Anti-drug antibodies (ADAs), 97 Antiretroviral therapy, HIV infected psoriasis patients, 149 Apremilast hepatitis C virus, 141 human immunodeficiency virus infected psoriasis patients, 149

nail psoriasis, 35 obesity, 83 palmar-plantar psoriasis, 57 psoriatic arthritis, 65 Aspartate aminotransferase (AST), 133 B Bacille Calmette-Guérin (BCG) vaccine, 125 Bath psoralen plus ultraviolet A, 57 Biologics, 105 agents, 27 failure, 98 Body mass index (BMI), 81 Breast cancer biologic therapy, 106 retrospective cohort study, 105 Brodalumab, 97 C Calcineurin inhibitors, facial psoriasis, 42 Calcipotriene, genital psoriasis, 48 Calcipotriol nail psoriasis, 34 scalp psoriasis, 26

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Calcitriol genital psoriasis, 48 ointment, 109 Candidal intertrigo, 47 Centrofacial psoriasis, 41 Certolizumab pegol (CZP), 111 pregnancy, 90 Clobetasol cream, 45 palmar-plantar psoriasis, 57 scalp psoriasis, 27 Compliance comorbidities, 73 physical examination, 72 treatment, 72, 74–75 Copper-intrauterine device (IUD), 105 Corticosteroids, 11, 20 scalp psoriasis, 26 Crisaborole, 42 genital psoriasis, 48 Cyclosporine, 3, 4, 20, 105 hepatitis C virus, 142 HIV infected psoriasis patients, 150 obesity, 83 palmar-plantar psoriasis, 57 pregnancy, 89 psoriatic arthritis, 65 D Dactylitis, 63 Depression, 73 Dermatomyositis, 25 Disappearing digit, 34 Discoid lupus erythematous (DLE), 25 Disease-modifying rheumatic drugs (DMARDs), 64 E Enthesitis, 63 Erythrasma, 47 Erythrodermic psoriasis (EP)

diagnosis, 2 pathogenesis, 2 phototherapy, 1 physical examination, 2 treatment, 3 Etanercept, 12, 98 psoriasis, 123 European League Against Rheumatism (EULAR), 64 F Facial psoriasis diagnosis, 39 differential diagnoses, 41 identification and treatment, 41 physical examination, 39 treatment, 41–42 types, 41 visible nature, 41 Female sex hormones, 106 Fingernail pitting, 32 First-line therapy, 34 Fluocinonide solution, 23 G Genital psoriasis causes, 47 diagnosis, 46, 47 differential diagnoses, 47 disease manifests, 46 in females, 46 in men, 46 physical exam, 45 treatment, 48–49 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), 64 Guselkumab, compliance, 75 Guttate psoriasis clinical examination, 19

Index diagnosis, 18 pathogenesis, 18 physical examination, 18 systemic treatments, 20 treatment, 19

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L Latent TB infection (LTBI), 125 Leflunomide, psoriatic arthritis, 65 Loss-of-response, 98

H HCV, see Hepatitis C virus (HCV) Hepatitis B serum markers, 133 Hepatitis B surface antibody (HBsAb), 133 Hepatitis C virus (HCV) infection, 140 skin examination, 139 treatment, 140–143 Hepatotoxicity, 142 Human immunodeficiency virus (HIV) infected psoriasis patients, 147 histological examination, 149 physical examination, 147 treatment, 148–151

M Melanoma, immunosuppressant therapies, 111 Methotrexate, 4, 12, 98, 105 hepatitis C virus, 142 HIV infected psoriasis patients, 150 obesity, 83 palmar-plantar psoriasis, 56 pneumococcal infection, 120 psoriatic arthritis, 65 scalp psoriasis, 27 Mildly erythematous patches, 24 Mild psoriasiform lesions, 110 Mycobacterium tuberculosis, 124, 125

I IL-17 inhibitors, psoriatic arthritis, 64 Immunogenicity, 97 Immunosuppressant therapy, 98 Infliximab, 4, 98 obesity, 82 psoriatic arthritis, 65 Interferon gamma release assay (IGRA), 125 Interleukin-17 inhibitors, 135 Interleukin-23 inhibitors, 135 International Psoriasis Council, 81 Ixekizumab, 127, 135 compliance, 75 genital psoriasis, 49 melanoma, 112 palmar-plantar psoriasis, 57 psoriatic arthritis, 65

N Nail deformities, 31 Nail psoriasis characteristics, 32 clinical presentation, 33 diagnosis, 33 pathology, 31 physical examination, 31 treatment, 33 Nail Psoriasis Severity Index (NAPSI), 34 Narrowband ultraviolet B (NB-UVB) phototherapy, 12, 112, 126 National Psoriasis Foundation (NPF), 83, 141 Non-steroidal anti-inflammatory drugs (NSAIDs), psoriatic arthritis, 64

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O Obesity pathophysiology, 81 physical examination, 80 treatment, 80 Occlusive tools, 56 Oral retinoid acitretin, 105 P Palmar-plantar psoriasis chronic medical issues, 53 physical distress and disability, 55 physical examination, 53 treatment, 55–57 PDE-4 inhibitor, 42 genital psoriasis, 48 Pediatric psoriasis adult, 10 children, 10 diagnosis, 10 physical examination, 9 treatment, 11 variants, 11 Penile plaque, 47 Phototherapy, human immunodeficiency virus infected psoriasis patients, 149 Pimecrolimus cream, 42 Pink indurated plaques, 39 13-valent pneumococcal conjugated vaccine (PCV13), 119 23-valent pneumococcal polysaccharide vaccine (PPSV23), 119 Pneumococcal vaccines, 119 PCV13, 119 PPSV23, 119 Polycystic ovary syndrome (PCOS), 23 Pregnancy emollients and moisturizers, 89 hormonal changes, 88 risk factors, 88

third trimester, 89 Primary non-response, 96 PsA, see Psoriatic arthritis (PsA) Psoralen and ultraviolet A (PUVA) therapy, 83, 112 Psoriasis immunosuppressant therapies, 118 and melanoma, 110 pathogenesis, 124 physical examination, 124, 132 treatment, 134 Psoriasis Area and Severity Index (PASI), 82, 83, 97 Psoriasis Scalp Severity Index scores (PSSI), 27 Psoriatic arthritis (PsA) differential diagnoses, 63 occurence, 62 radiographs, 63 symptoms, 62 treatment, 62, 64 Psoriatic nail abnormalities, 63 R Red, scaly spots, 9, 17 Retinoids, palmar-plantar psoriasis, 56 Rheumatoid arthritis (RA), 112 S Scalp psoriasis diagnosis, 24 differential diagnoses, 25 physical examination, 23 treatment, 26–27 Secukinumab, 97, 127, 135 compliance, 75 palmar-plantar psoriasis, 57 pneumococcal infection, 120 psoriatic arthritis, 65 Skin diseases, 148 Streptococcus pneumoniae, 119 Systemic inflammation, obesity, 81 Systemic psoriasis therapies, 132

Index T Tamoxifen, 105 Tar-based soaps, 57 Tazarotene, 34 pregnancy, 91 Thick white plaques, 24 Tildrakizumab, compliance, 75 Tinea cruris, 47 TNF-alpha, 124 psoariasis, 132 Topical agents, HIV infected psoriasis patients, 149 Topical calcineurin inhibitors, genital psoriasis, 48 Topical steroids, 109 Topical tacrolimus, 34 ointment, facial psoriasis, 42 Topical treatments, HIV infected psoriasis patients, 149 Topical vitamin D analogs, 26, 42 genital psoriasis, 48 Tuberculosis (TB), 124 screening, 126 treatment, 126 Tumor necrosis factor (TNF) inhibitors hepatitis C virus, 141 HIV infected psoriasis patients, 149 obesity, 81 palmar-plantar psoriasis, 57 pregnancy, 90 psoriasis, 118, 125 psoriatic arthritis, 64 TNF-alpha, 124 psoariasis, 132

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U Ultraviolet B (UVB) phototherapy, 19 hepatitis C virus, 141 palmar-plantar psoriasis, 57 pregnancy, 89 US National Psoriasis Foundation, 35 Ustekinumab, 126 compliance, 75 hepatitis C virus, 142 HIV infected psoriasis patients, 149 melanoma, 111 obesity, 82 palmar-plantar psoriasis, 57 psoriasis, 135 psoriatic arthritis, 65 V 13-Valent pneumococcal conjugated vaccine (PCV13), 119 23-Valent pneumococcal polysaccharide vaccine (PPSV23), 119 Vitamin D analogs, 20, 34 HIV infected psoriasis patients, 149 W Weight reduction, 83 Worsening diffuse-body psoriasis, 87 physical examination, 88 treatment, 88