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The life-threatening eruptions of immune checkpoint inhibitor therapy
Journal Pre-proof The life-threatening rash of immune checkpoint inhibitor therapy
Emily L Coleman, Brianna Olamiju, Jonathan S Leventhal PII:
S0738-081X(19)30191-9
DOI:
https://doi.org/10.1016/j.clindermatol.2019.10.015
Reference:
CID 7401
To appear in:
Clinics in Dermatology
Please cite this article as: E.L. Coleman, B. Olamiju and J.S. Leventhal, The lifethreatening rash of immune checkpoint inhibitor therapy, Clinics in Dermatology(2019), https://doi.org/10.1016/j.clindermatol.2019.10.015
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© 2019 Published by Elsevier.
Journal Pre-proof Title: The life-threatening rash of immune checkpoint inhibitor therapy Authors: Emily L Coleman, BA, Brianna Olamiju, BA, Jonathan S Leventhal, MD Affiliations: Department of Dermatology, Yale University School of Medicine, New Haven, CT
Word Count: 3,509
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Figure Count: 6
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Disclosures/funding: Ms Coleman received funding from the NIH for her medical school
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research fellowship. The other authors have no relevant disclosures.
Corresponding author:
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Jonathan S Leventhal, MD
(203) 785 – 7637 (fax)
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(203) 785- 3442 (phone)
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15 York Street, LMP 5040, New Haven CT 06510
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[email protected]
Key Words: life-threatening cutaneous toxicities, severe cutaneous adverse reactions (SCAR), immune checkpoint inhibitor, Stevens-Johnson Syndrome, bullous pemphigoid, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, erythroderma, neutrophilic dermatoses, Sweet’s syndrome, sarcoidosis, dermatomyositis, lupus-like.
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Journal Pre-proof Abstract Immune checkpoint inhibitors (ICPi) have emerged as a new frontier of cancer therapy. While monoclonal antibodies to cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have revolutionized oncologic management, these agents may result in a spectrum of immune-related adverse events (irAE) of which dermatologic toxicities are among the most frequent. Prompt
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recognition and management of irAE is essential for dermatologists caring for the expanding
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population of cancer patients exposed to these drugs. Cutaneous toxicities may range from mild
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cases to severe and life-threatening presentations that may cause significant morbidity and
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mortality. This review provides an overview of severe cutaneous adverse reactions (SCARs) that may develop during ICPi therapy including Stevens-Johnson Syndrome (SJS), toxic epidermal
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necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute
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generalized exanthematous pustulosis (AGEP). In addition, immunobullous disorders, erythroderma, neutrophilic dermatoses, and cutaneous eruptions associated with systemic
Introduction
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manifestations are discussed.
Immune checkpoint inhibitors (ICPi) harness the immune system’s ability to combat cancer cells by inhibiting immune checkpoints that normally downregulate the immune response. These agents have revolutionized the treatment of cancer patients and are increasingly utilized in multiple solid organ and hematologic tumors. In fact, the discovery by James P. Allison and Tasuku Honjo of the two key proteins, cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1), respectively, resulted in their being awarded the 2018
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Journal Pre-proof Nobel Prize in Physiology or Medicine. The Nobel Assembly recognized this momentous paradigm shift in oncologic care as a result of these findings, for which monoclonal antibodies have been developed against CTLA-4, PD-1 and its ligand programmed cell death ligand 1 (PDL1). By upregulating the immune system, ICPi may lead to an array of immune-related adverse events (irAE), of which dermatologic reactions are among the most frequently encountered in up to 40% of patients.1
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Over the past several years, a variety of morphologic patterns of skin eruptions have
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emerged.2 While most cutaneous toxicities are mild and can be managed with local therapy, life-
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threatening reactions may occur which may result in disruption of cancer therapy, systemic
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corticosteroids, and hospitalization in the most severe cases. Early recognition of these severe cutaneous adverse reactions (SCARs) and prompt dermatologic management in a
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multidisciplinary fashion with oncologists is essential in reducing the morbidity and mortality
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associated with these toxicities. By distinguishing potentially life-threatening SCARs from more
cancer treatment.
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banal presentations, patients may avoid unnecessarily aggressive measures and interruption of
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This review provides an overview of the various morphologies of severe and lifethreatening reactions to ICPi, as well as cutaneous reactions associated with systemic disease. Cutaneous toxicities are graded on a schema proposed by the National Cancer Institute called “Common Terminology Criteria for Adverse Events” (CTCAE).3 The CTCAE is largely based on body surface area (BSA) of involvement and impact on patients’ quality of life (Figure 1). Understanding the grading criteria is important as it provides a framework guiding management. According to the CTCAE,
Grade 1 cutaneous toxicities involve less than 10% BS
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Grade 2 involve 10-30% BSA and/or impact instrumental activities of daily living
Grade 3 involve greater than 30% BSA and/or impact self-care activities of daily living
Grade 4 toxicities may include exfoliative dermatitis with life-threatening consequences and complications including extensive superinfection, fluid and electrolyte disturbance, and urgent intervention such as hospitalization, intravenous antibiotics or corticosteroids,
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or transfer to the burn unit.3,4
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CTLA-4 & PD-1/PD-L1 Inhibitors
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CTLA-4 is an immune checkpoint that downregulates T-cell activation.5 Ipilimumab and
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tremelimumab are the monoclonal antibodies to CTLA-4 most commonly used in clinical practice. Ipilimumab is approved for use in metastatic melanoma, and tremelimumab has
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demonstrated clinical activity against hepatocellular carcinoma.5,6 Cutaneous toxicities occur in
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approximately 50%-70% of patients on ipilimumab,7–9 the most common of which include maculopapular or morbilliform eruptions (10-50%), pruritus (<30%), and vitiligo-like
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hypopigmentation in patients with melanoma.2 Less commonly, dermatitis, lichenoid exanthema,
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photosensitivity, radiation dermatitis, and neutrophilic dermatoses may develop.2,10 Fortunately, potentially life-threatening SCARs rarely occur.5,11–15 In addition, cutaneous reactions with systemic manifestations may be seen including sarcoidosis, neutrophilic dermatoses, and druginduced connective tissue disorders.16–19 PD-1, and its ligand, PD-L1, constitute an immune checkpoint in peripheral tissues that tumors may hijack in an effort to escape immune surveillance.20 Monoclonal antibodies to PD-1 include nivolumab and pembrolizumab, which are indicated for use in a variety of tumors including melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma,
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Journal Pre-proof Hodgkin lymphoma, urothelial carcinoma, microsatellite instability-high cancer, advanced renal cell carcinoma, metastatic colorectal cancer, and hepatocellular carcinoma.21,22 Monoclonal antibodies to PD-L1 include atezolizumab, avelumab, and durvalumab, which are used in nonsmall cell lung cancer, Merkel cell carcinoma, and renal cell carcinoma.23–25 The overall rate of cutaneous toxicities to anti-PD-1 agents ranges from 34%-42%, with an increased frequency in combination anti-CTLA-4 therapy (58.5%-71.5%).1 The overall rate of dermatologic irAE to
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PD-L1 inhibitors is slightly less (approximately 15-20%).2 There are a wide range of skin
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reactions to PD-1/PD-L1 inhibitors, most commonly maculopapular or morbilliform eruptions,
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mucocutaneous lichenoid dermatitis, pruritus, and vitiligo-like leukoderma.2,26–28 In addition, psoriasis, Grover’s disease, acneiform eruptions, and sarcoidosis may occur.2,29–31 Higher grade
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toxicities include exfoliative dermatitis (SJS/TEN) and immunobullous disorders.32–45
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Figure 2 provides an algorithm for diagnosing potentially life-threatening rashes associated with
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ICPi based on morphologic presentation.
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Life-threatening cutaneous reactions Immunobullous Disorders
Immunobullous disorders have been associated with anti-PD-1/PD-L1 therapy and may occur during combination anti-CTLA-4/PD-1 therapy as well.42 A recent analysis demonstrated that it occurs in approximately 1% of patients on ICPi.42 Patients typically manifest with clinical and histopathologic features of bullous pemphigoid (BP), although bullous lichenoid dermatitis, linear IgA bullous dermatosis, and erythema multiforme have been described.42,44,46,47 Notably, the latency of immunotherapy-associated bullous disorders appears to be longer than that of the
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Journal Pre-proof more common maculopapular or lichenoid reactions, with recent series demonstrating a 6-month mean latency after first infusion of immunotherapy.2,42 The clinical presentation may vary from scattered vesicles to widespread bullae and erosions with denuded skin and mucosal ulceration (Figure 3).42 Pruritus is a common feature and may precede the development of bullae. It is important to consider the diagnosis of prebullous pemphigoid in patients on ICPi with worsening pruritus refractory to conservative
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therapy. Histopathology, direct immunofluorescence (DIF) studies, and ELISA for BP180 should
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be obtained and are generally consistent with classical presentations of BP; however, atypical
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presentations with negative immunofluorescence and titers against BP180 have been reported.42
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Importantly, immunobullous disorders have been shown to frequently impact immunotherapy, often requiring temporary or permanent interruption and use of systemic
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therapy. Grade 1 eruptions may be treated with high potency topical steroids, and doxycycline
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with or without niacinamide.42 Grade 2 or 3 cases typically require systemic corticosteroids (0.51mg/kg/daily prednisone) with slow taper over a course of 1-2 months.4 ICPi therapy may be
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reinstituted at prednisone doses of 10 mg daily, but patients should be closely monitored for
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recurrence of skin disease. For patients with widespread bullae and denuded skin who are at-risk for life-threatening complications including superinfection, sepsis, and dehydration, hospitalization and intravenous corticosteroids 1-2mg/kg/daily is recommended.4 In addition, steroid-sparing agents, such as methotrexate and dapsone, as well as targeted biologic agents, such as omalizumab (in particular for patients with elevated IgE levels) and rituximab,b should be considered for recalcitrant cases.4,41,42,48
Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis
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Journal Pre-proof Maculopapular or morbilliform eruptions are common dermatologic irAE to ICPi (up to 25% during anti-CTLA-4 therapy, 15% during anti-PD-l therapy, <10% during anti-PD-L1 therapy),1 but in rare instances they may progress to exfoliative dermatitis. Acute SJS/TEN-like presentations may occur, as well. Fortunately, these grade 4 reactions occur in less than 1% of cases.49 Reports of SJS/TEN have been described in association with multiple ICPi including ipilimumab, nivolumab, and pembrolizumab.5,11,32–40,45,50 Most cases developed in patients
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treated for melanoma, although patients with follicular lymphoma, lung adenocarcinoma,
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nasopharyngeal carcinoma, and sarcomatoid renal cell carcinoma have also developed
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exfoliative dermatitis.32-40
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The clinical presentation generally resembles that of classical SJS/TEN. Fever and constitutional symptoms may precede skin lesions. Clinically, dusky macules or papules and
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occasionally atypical targetoid lesions rapidly manifest on the trunk and extremities, with
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associated mucosal involvement (ocular, oral, or anogenital sites). The skin is tender and may be associated with a positive Nikolsky sign (Figure 4), distinguishing SJS/TEN from a less
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concerning morbilliform or lichenoid eruption. Moist desquamation and skin sloughing with
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denuded red dermis follows. Based on BSA of denuded skin, cases may be delineated as SJS (<10%), SJS/TEN overlap (10-30%), or TEN (>30% BSA). The majority of cases associated with anti-PD-1 therapy began either after the first or second infusion; however, a few cases were of delayed reactions occurring after 5 and 9 cycles of pembrolizumab respectively.37,38 Three cases, all in association with nivolumab, were fatal.32– 34
Notably, some cases initially presented as a less severe morbilliform or lichenoid rash that
intensified over the course of weeks to months rather than an abrupt onset seen in classical
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Journal Pre-proof SJS/TEN. As such, clinicians should be cautious of maculopapular eruptions that fail to respond to standard therapy. The diagnosis of SJS/TEN may be rendered clinically and histopathologically. Biopsy of early lesions typically show scattered apoptotic keratinocytes in the basal epidermis, whereas more advanced lesions may show full-thickness epidermal necrosis or subepidermal bullae. Direct immunofluorescence studies (DIF) can help exclude immunobullous eruptions. Initial
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biopsy of two previously reported cases showed interface dermatitis that further progressed into
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full-thickness epidermal necrosis on subsequent biopsy.37,38 The differential diagnosis includes
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erythema multiforme major, disseminated fixed bullous drug eruption, staphylococcal scalded
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skin syndrome, and acute generalized exanthematous pustulosis (AGEP). Management of grade 4 exfoliative dermatitis includes discontinuation of the causative
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agent and immediate hospitalization with supportive care.4 Cancer patients often have multiple
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comorbidities and may be on numerous drugs that have also been associated with SJS/TEN (e.g. antibiotics, anti-seizure medications, and NSAIDS). Discontinuation of all unnecessary
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medications is prudent. Skin biopsy and DIF studies should be obtained to confirm the diagnosis
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and rule out a severe immunobullous disorder, as well as close monitoring of basic laboratory tests. Intravenous systemic corticosteroids (1-2mg/kg/daily) are recommended for grade 4 reactions with slow taper.4 Cyclosporine, or intravenous immunoglobulin, may be considered in corticosteroid unresponsive cases.4,38 Supportive care including hydration, nutritional support, and avoiding sources of infection (e.g. place venous catheters in areas of uninvolved skin) are aimed to limit associated complications such as dehydration, electrolyte imbalance, renal insufficiency and sepsis. Patients with extensive BSA involvement or life-threatening complications should be transferred to the ICU or burn unit. Consultation of specialists such as
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Journal Pre-proof ophthalmologists, urologists, and physical therapists should be considered in the appropriate clinical setting.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as druginduced hypersensitivity syndrome (DIHS), is a severe and potentially life-threatening reaction
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which may involve multiple organs. It is characterized by fever, rash, lymphadenopathy,
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eosinophilia, atypical leukocytosis, and abnormal liver function tests. Two cases of DRESS have
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been reported in association with anti-CTLA4 therapy, one of whom was also on anti-PD-1 therapy.12,13 Both patients presented with a diffuse maculopapular or morbilliform rash with
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peripheral eosinophilia and renal failure.12,13 One case also had hepatic involvement with
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transaminitis.13
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In general, DRESS may develop later than a classic morbilliform eruption with a typical range of onset of 2-8 weeks after initiation of the culprit drug. The cutaneous presentation is
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variable, but most patients present with a morbilliform eruption, and prominent facial edema is a
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hallmark sign.52 In addition, lymphadenopathy may be noted on physical examination. Other presentations may include urticarial, vesicular, pustular, purpuric, targetoid, and erythrodermic forms. The liver is the most common internal organ involved, although renal, cardiac, thyroid, pancreatic, and pulmonary inflammation may occur. The overall mortality from DRESS ranges 5-10%.52 The diagnosis of DRESS is based on the RegiSCAR criteria, although other criteria such as the Japanese Research Committee on Severe Cutaneous Adverse Reactions have been proposed. RegiSCAR criteria include: fever greater than 38.5 degrees Celsius, lymphadenopathy
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Journal Pre-proof in at least 2 sites, circulating atypical lymphocytes, peripheral eosinophilia, skin involvement greater than 50% BSA or suggestive of DRESS, biopsy suggestive of DRESS, and involvement of at least 1 organ.52 Histopathology may demonstrate features of several inflammatory conditions such as interface dermatitis, erythema multiforme, eczema, or AGEP. Laboratory evaluation to assess for systemic involvement should include CBC with differential and peripheral smear for atypical lymphocytes, basic metabolic panel and liver
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function tests, thyroid function, and baseline echocardiogram. Repeated monitoring of atypical
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laboratory findings is prudent to evaluate for disease progression and response to treatment.
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Management of DRESS includes withdrawal of the culprit drug, and systemic corticosteroids as
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in other SCARs (oral prednisone 0.5-1mg/kg/daily for milder presentations; intravenous methylprednisolone 1-2mg/kg/daily for severe presentations). Importantly, steroids should be
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slowly tapered over at least 6-8 weeks to reduce the risk of rebound. Of the reported cases of
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disease.12,13
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DRESS associated with ICPi, intravenous or oral corticosteroids effectively managed the
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Neutrophilic Drug eruptions (AGEP, CSVV, Neutrophilic Dermatoses) Neutrophilic drug eruptions including acute generalized exanthematous pustulosis (AGEP), cutaneous small vessel vasculitis (CSVV), and neutrophilic dermatoses (Sweet’s syndrome and pyoderma gangrenosum) have been associated with ICPi. AGEP has been described in two patients on anti-CTLA4 therapy, one of which was on combination therapy with a PD-1 inhibitor.15,49 AGEP is characterized by the acute development of fever and hundreds of nonfollicular pustules on an erythematous base with an associated neutrophilia, and usually develops with 48 to 72 hours of beginning a new drug.53 The pustules
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Journal Pre-proof in AGEP may be pruritic and tend to favor truncal and intertriginous sites.53 Severe cases may involve the mucous membranes and internal organs including the kidneys, lungs, and liver. Overlap with DRESS and SJS/TEN may rarely occur. The overall mortality is less than 5%, and death usually results from disseminated intravascular coagulation or severe organ dysfunction.53 The diagnosis of AGEP may be rendered clinically and histopathologically, with biopsy demonstrating dermal papillary edema, neutrophilic and eosinophilic perivascular infiltrate, and
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intraepithelial and/or subcorneal pustules. Management of AGEP like other SCARs includes
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withdrawal of the culprit drug, and systemic corticosteroids (oral prednisone 0.5-1mg/kg/daily
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for lower BSA involvement and intravenous methylprednisolone 1-2 mg/kg/daily for higher BSA involvement).4 Vigilant skin care and close monitoring for secondary infections is essential.
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Neutrophilic dermatoses, such as Sweet’s syndrome and pyoderma gangrenosum-like
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ulcers, have been reported in association with anti-CTLA-4 therapy and anti-PD-1
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therapy.16,18,54,55 Also known as acute febrile neutrophilic dermatosis, Sweet’s syndrome is commonly associated with systemic symptoms including fever, malaise, and arthralgias or
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arthritis.56 In addition, ocular, pulmonary, renal, hepatic, neurologic, and gastrointestinal
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involvement may occur. Lesions are classically tender erythematous plaques that may vesiculate and are generally distributed on the head, neck, and upper extremities. Pyoderma gangrenosum typically manifests with a pustule on an inflamed base that progresses to an ulcer with an undermined violaceous border. Of the cases associated with ICPi therapy, discontinuation of the causative drug and management with systemic corticosteroids with or without dapsone effectively managed the neutrophilic dermatosis.16–18,54 Notably, one patient showed that lesions of Sweet’s did not recur after readministration of nivolumab after temporary interruption.54 Diagnosis of Sweet’s syndrome is based on the following major criteria: abrupt onset of typical
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Journal Pre-proof cutaneous lesions and histologic features of Sweet’s syndrome (neutrophilic infiltrate, with occasional leukocytoclasia without vasculitis).56 Minor criteria include association with a known trigger, fever and constitutional symptoms, leukocytosis, and prompt response to systemic corticosteroids. While systemic corticosteroids are the mainstay therapy, steroid-sparing options include dapsone and colchicine. Cutaneous small vessel vasculitis (CSVV) with palpable purpura and ulcerative lesions
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on the bilateral lower extremities has been reported in a patient on combination
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ipilimumab/nivolumab therapy.57 The patient’s immunotherapy was held, and he was treated
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with systemic corticosteroids and dapsone. CSVV manifests with purpuric macules and papules
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on the lower extremities, while upper extremity and extensor involvement may occur. More widespread presentations with hemorrhagic bullae and pustules may occur. The differential
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diagnosis includes CSVV due to other medications, infections, or malignancy, Henoch-
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Schönlein purpura or IgA vasculitis, urticarial vasculitis and ANCA-associated vasculitis. Medium-sized and large vessel vasculitis should be considered in the setting of livedo racemosa,
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retiform purpura, subcutaneous nodules and ulcers. Biopsy and DIF may help confirm the
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diagnosis, while a comprehensive review of systems should be performed to evaluate for internal organ involvement. Basic laboratory evaluation including a complete blood count (CBC), basic metabolic functions, urinalysis, and liver function tests should be obtained. Low grade presentations may be managed by observation and topical steroids, while extensive skin disease and internal organ involvement may require systemic corticosteroids. Colchicine and dapsone are steroid-sparing alternatives.
Erythrodermic papulosquamous eruptions (Psoriasis, PRP-like)
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Journal Pre-proof The development of psoriasis and exacerbation of existing psoriasis has been associated with the use of anti-PD-1/PD-L1 agents.29 Severe cases of psoriasis including widespread pustular (Figure 5) and erythrodermic presentations and psoriatic arthritis may occur, as well as erythrodermic pityriasis rubra pilaris-like eruption.29,58 We reported one case of PRP-like erythroderma due to pembrolizumab which presented with diffuse orange-red plaques and a waxy palmarplantar keratoderma (Figure 6).58 The patient was responsive to topical steroids and
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acitretin; however, treatment with pembrolizumab was discontinued due to the severity of the
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eruption with > 70% BSA involvement. Idiopathic PRP may be treated with methotrexate,
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acitretin, or biologic agents including TNF-alpha inhibitors and IL-12/23 inhibitors. Use of
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biologic agents in cancer patients should be reserved for severe and recalcitrant cases due to their immunomodulatory properties. The differential diagnosis of erythroderma includes drug
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eruptions (morbilliform eruption with >80% involvement), primary dermatoses that progressed
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to erythroderma (e.g. psoriasiform, seborrheic dermatitis, atopic dermatitis), paraneoplastic erythroderma, dermatomyositis with PRP-like features, immunobullous dermatoses, and
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cutaneous T-cell lymphoma. Biopsy for histopathology, DIF, and flow cytometry studies may be
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helpful in ruling out other entities in the differential diagnosis. Care must be taken in the management of patients with erythroderma due to the possibility of thermal dysregulation, dehydration, and electrolyte disturbance. Treatment is geared towards the underlying cause. Symptomatic relief may be provided with open-wet dressings and topical corticosteroids or topical camphor-menthol. In the case of severe erythrodermic psoriasiform or pityriasiform eruptions due to ICPi, phototherapy, acitretin, and methotrexate have been used.29 Biologic agents should be considered for recalcitrant cases. Patients should be closely monitored for recrudescence if ICPi therapy is readministered.
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Sarcoidosis Cutaneous and systemic sarcoidosis have been reported during anti-PD-1/PD-L1 therapy, anti-CTLA-4 therapy, or combination anti-CTLA-4/PD-1 therapy.2,30,31 Both new onset and exacerbation of existing disease may occur. Cutaneous lesions may manifest similarly to classical sarcoidosis with periorificial papules, annular plaques, subcutaneous lesions, or
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involvement of previous scar sites.30,31 While cutaneous disease is not life-threatening it may be
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a sign of underlying systemic involvement, in particular pulmonary disease. Clinicians should
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consider sarcoidosis in cancer patients who develop hilar lymphadenopathy while on ICPi
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therapy. Biopsy of pulmonary lymphadenopathy should be obtained when possible to avoid misdiagnosis for progression of underlying malignancy. Other organs may be involved including
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the eyes, bones, kidney, spleen, nervous system, and joints.30,31 In general, most reported cases of
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cutaneous and systemic sarcoidosis have responded to systemic corticosteroids with resumption
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of immunotherapy. In addition, hydroxychloroquine may be effectively used.31
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Graft versus host disease (GVHD)
Immunotherapy is increasingly used in the treatment of hematologic malignancy, and anti-PD-1 agents are approved for Hodgkin’s lymphoma. There exists a significant risk for graft versus host disease (GVHD) before and after allogeneic hematopoietic stem cell transplantation (HSCT), with significantly increased risk of GVHD-related morbidity and mortality in this population.59 Clinically, acute GVHD resembles a maculopapular or morbilliform eruption. Severe presentations (grade 4) resemble TEN. Chronic GVHD may have a variety of manifestations
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Journal Pre-proof including lichenoid, morpheaform/sclerodermoid, eczematous, ichthyosiform, and dyspigmentation. The major differential diagnosis for acute GVHD is a morbilliform drug eruption, viral exanthem, and toxic erythema of chemotherapy in the setting of conventional chemotherapy administration. In one study, the use of ICPi in hematologic malignancy before allogeneic HSCT resulted in high incidence of hyper-acute (7%), acute (56%), and chronic (29%) GVHD.59 Administration
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of ICPi after allogeneic-HSCT showed high efficacy but also increased the risk of GVHD (14%
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acute, 9% chronic).59 Life-threatening and fatal cases with cutaneous and systemic involvement
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have been reported, necessitating extreme caution and surveillance with the use of ICPi before or
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after HSCT.60 The management of life-threatening GVHD in the context of immunotherapy includes discontinuation of the ICPi and systemic immunosuppression with prednisone or other
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immunomodulatory agents (e.g. cyclosporine, mycophenolate mofetil, tacrolimus) in a multi-
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disciplinary fashion with hematology.
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Exacerbation of autoimmune disease and connective tissue disorders
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The exacerbation of existing autoimmune disease is a significant concern for patients on ICPi. One study demonstrated that 27% of patients on ipilimumab developed a flare in their autoimmune disorder requiring systemic corticosteroids.61 These included patients with rheumatoid arthritis, psoriasis, polymyalgia rheumatica, ulcerative colitis, inflammatory arthritis, and sarcoidosis.61 Another series of immunotherapy-associated psoriasis demonstrated that 71% of patients had a prior history psoriasis that flared on treatment.29 Other reports of autoimmune skin disorders that flared on ICPi included subacute cutaneous lupus erythematosus, and BP.28,62
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Journal Pre-proof The development of new onset connective tissue disease may also occur. One case of dermatomyositis developed during anti-CTLA-4 therapy for metastatic melanoma.19 The patient had hallmark signs including a photodistributed eruption with periorbital edema, Gottron’s papules of the dorsal hands, and nailfold telangiectasias.19 He was also found to have elevated muscle enzymes and severe myopathy requiring the use of wheelchair. Treatment with ipilimumab was discontinued, and the patient was managed with intravenous corticosteroids.19 In
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addition, new onset cutaneous lupus-like reactions have been described (lesions presenting as
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edematous plaques mimicking tumid lupus, but histopathology demonstrating interface
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dermatitis),63 as well as lupus nephritis with the use of ICPi.64
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Although a minority of patients with underlying autoimmune disease will flare during ICPi, a thorough history should be obtained to identify those with existing disease in order to
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closely monitor them while on immunotherapy. For patients who develop new onset
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rheumatologic disease or exacerbation of existing disease, a review of systems and directed
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Conclusions
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laboratory workup should be performed to evaluate for systemic complications.
Potentially life-threatening cutaneous toxicities may develop during ICPi and may be a significant source of morbidity and mortality in cancer patients. A diversity of morphologic reactions has been observed including SCARs such as SJS/TEN, DRESS, and AGEP. In addition, immunobullous disorders, erythroderma, neutrophilic dermatoses, sarcoidosis, connective tissue disorders, and exacerbation of autoimmune disease may occur. These potentially life-threatening toxicities often necessitate treatment interruption or cessation and use of systemic corticosteroids and supportive care. As such, recognition of the ever-expanding
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Journal Pre-proof spectrum of dermatologic irAE is essential for dermatologists caring for cancer patients, in order to distinguish life-threatening reactions earlier from more banal toxicities. Prompt dermatologic management in a multidisciplinary fashion with oncologists may reduce the morbidity and mortality associated with these rashes.
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Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol. 2014;71:161-169.
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Nayar N, Briscoe K, Fernandez Penas P. Toxic Epidermal Necrolysis-like Reaction With Severe Satellite Cell Necrosis Associated With Nivolumab in a Patient With Ipilimumab Refractory Metastatic Melanoma. J Immunother. 2016;39:149-152. Ito J, Fujimoto D, Nakamura A, et al. Aprepitant for refractory nivolumab-induced
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course of pembrolizumab therapy. J Oncol Pharm Pract. August 2018:1078155218791314. doi:10.1177/1078155218791314 Saw S, Lee HY, Ng QS. Pembrolizumab-induced Stevens-Johnson syndrome in non-
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melanoma patients. Eur J Cancer. 2017;81:237-239. Haratake N, Tagawa T, Hirai F, Toyokawa G, Miyazaki R, Maehara Y. Stevens-Johnson
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2018. doi:10.1016/j.jtho.2018.05.031 Liniker E, Menzies AM, Kong BY, et al. Activity and safety of radiotherapy with anti-PD1 drug therapy in patients with metastatic melanoma. Oncoimmunology. 2016;5:e1214788. 41.
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Naidoo J, Schindler K, Querfeld C, et al. Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting PD-1 and PD-L1. Cancer Immunol Res.
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Immunomodulatory Effects. Case Rep Dermatol. 2018;10:1-6. Sowerby L, Dewan AK, Granter S, Gandhi L, LeBoeuf NR. Rituximab Treatment of Nivolumab-Induced Bullous Pemphigoid. JAMA dermatology. 2017;153:603-605. 49.
Wang P-F, Chen Y, Song S-Y, et al. Immune-Related Adverse Events Associated with Anti-PD-1/PD-L1 Treatment for Malignancies: A Meta-Analysis. Front Pharmacol. 2017;8:730.
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Kardaun SH, Sekula P, Valeyrie-Allanore L, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol. 2013;169:1071-1080. Szatkowski J, Schwartz RA. Acute generalized exanthematous pustulosis (AGEP): A
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Figure Legend
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Figure 1: Guide to grading and managing rashes associated with immune checkpoint inhibitors. Adapted from the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) and American Society of Clinical Oncology Clinical Practice Guideline.3,4 Figure 2: Algorithm for diagnosing potentially life-threatening rashes associated with immune checkpoint inhibitors based on morphological presentation. Figure 3: Bullous pemphigoid associated with anti-PD-1 therapy manifesting with widespread urticarial plaques, tense bullae, and erosions requiring hospitalization and intravenous
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Journal Pre-proof corticosteroids. Figure 4: Morbilliform eruption that progressed over the course of weeks to a SJS-like presentation with dusky lesions that resulted in erosions and desquamation of skin with a positive Nikolsky sign. Figure 5: Widespread pustular, plaque, and palmarplantar psoriasis associated with psoriatic arthritis during anti-PD-1 therapy, treated with phototherapy with narrowband ultraviolet
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B and methotrexate.
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Figure 6: Acute PRP-like erythrodermic eruption manifesting with orange-red plaques and waxy
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keratoderma, treated with topical steroids and acitretin.
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Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Emily L Coleman, Brianna Olamiju, Jonathan S Leventhal PII:
S0738-081X(19)30191-9
DOI:
https://doi.org/10.1016/j.clindermatol.2019.10.015
Reference:
CID 7401
To appear in:
Clinics in Dermatology
Please cite this article as: E.L. Coleman, B. Olamiju and J.S. Leventhal, The lifethreatening rash of immune checkpoint inhibitor therapy, Clinics in Dermatology(2019), https://doi.org/10.1016/j.clindermatol.2019.10.015
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© 2019 Published by Elsevier.
Journal Pre-proof Title: The life-threatening rash of immune checkpoint inhibitor therapy Authors: Emily L Coleman, BA, Brianna Olamiju, BA, Jonathan S Leventhal, MD Affiliations: Department of Dermatology, Yale University School of Medicine, New Haven, CT
Word Count: 3,509
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Figure Count: 6
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Disclosures/funding: Ms Coleman received funding from the NIH for her medical school
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research fellowship. The other authors have no relevant disclosures.
Corresponding author:
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Jonathan S Leventhal, MD
(203) 785 – 7637 (fax)
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(203) 785- 3442 (phone)
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15 York Street, LMP 5040, New Haven CT 06510
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[email protected]
Key Words: life-threatening cutaneous toxicities, severe cutaneous adverse reactions (SCAR), immune checkpoint inhibitor, Stevens-Johnson Syndrome, bullous pemphigoid, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, erythroderma, neutrophilic dermatoses, Sweet’s syndrome, sarcoidosis, dermatomyositis, lupus-like.
1
Journal Pre-proof Abstract Immune checkpoint inhibitors (ICPi) have emerged as a new frontier of cancer therapy. While monoclonal antibodies to cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have revolutionized oncologic management, these agents may result in a spectrum of immune-related adverse events (irAE) of which dermatologic toxicities are among the most frequent. Prompt
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recognition and management of irAE is essential for dermatologists caring for the expanding
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population of cancer patients exposed to these drugs. Cutaneous toxicities may range from mild
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cases to severe and life-threatening presentations that may cause significant morbidity and
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mortality. This review provides an overview of severe cutaneous adverse reactions (SCARs) that may develop during ICPi therapy including Stevens-Johnson Syndrome (SJS), toxic epidermal
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necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute
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generalized exanthematous pustulosis (AGEP). In addition, immunobullous disorders, erythroderma, neutrophilic dermatoses, and cutaneous eruptions associated with systemic
Introduction
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manifestations are discussed.
Immune checkpoint inhibitors (ICPi) harness the immune system’s ability to combat cancer cells by inhibiting immune checkpoints that normally downregulate the immune response. These agents have revolutionized the treatment of cancer patients and are increasingly utilized in multiple solid organ and hematologic tumors. In fact, the discovery by James P. Allison and Tasuku Honjo of the two key proteins, cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1), respectively, resulted in their being awarded the 2018
2
Journal Pre-proof Nobel Prize in Physiology or Medicine. The Nobel Assembly recognized this momentous paradigm shift in oncologic care as a result of these findings, for which monoclonal antibodies have been developed against CTLA-4, PD-1 and its ligand programmed cell death ligand 1 (PDL1). By upregulating the immune system, ICPi may lead to an array of immune-related adverse events (irAE), of which dermatologic reactions are among the most frequently encountered in up to 40% of patients.1
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Over the past several years, a variety of morphologic patterns of skin eruptions have
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emerged.2 While most cutaneous toxicities are mild and can be managed with local therapy, life-
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threatening reactions may occur which may result in disruption of cancer therapy, systemic
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corticosteroids, and hospitalization in the most severe cases. Early recognition of these severe cutaneous adverse reactions (SCARs) and prompt dermatologic management in a
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multidisciplinary fashion with oncologists is essential in reducing the morbidity and mortality
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associated with these toxicities. By distinguishing potentially life-threatening SCARs from more
cancer treatment.
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banal presentations, patients may avoid unnecessarily aggressive measures and interruption of
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This review provides an overview of the various morphologies of severe and lifethreatening reactions to ICPi, as well as cutaneous reactions associated with systemic disease. Cutaneous toxicities are graded on a schema proposed by the National Cancer Institute called “Common Terminology Criteria for Adverse Events” (CTCAE).3 The CTCAE is largely based on body surface area (BSA) of involvement and impact on patients’ quality of life (Figure 1). Understanding the grading criteria is important as it provides a framework guiding management. According to the CTCAE,
Grade 1 cutaneous toxicities involve less than 10% BS
3
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Grade 2 involve 10-30% BSA and/or impact instrumental activities of daily living
Grade 3 involve greater than 30% BSA and/or impact self-care activities of daily living
Grade 4 toxicities may include exfoliative dermatitis with life-threatening consequences and complications including extensive superinfection, fluid and electrolyte disturbance, and urgent intervention such as hospitalization, intravenous antibiotics or corticosteroids,
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or transfer to the burn unit.3,4
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CTLA-4 & PD-1/PD-L1 Inhibitors
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CTLA-4 is an immune checkpoint that downregulates T-cell activation.5 Ipilimumab and
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tremelimumab are the monoclonal antibodies to CTLA-4 most commonly used in clinical practice. Ipilimumab is approved for use in metastatic melanoma, and tremelimumab has
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demonstrated clinical activity against hepatocellular carcinoma.5,6 Cutaneous toxicities occur in
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approximately 50%-70% of patients on ipilimumab,7–9 the most common of which include maculopapular or morbilliform eruptions (10-50%), pruritus (<30%), and vitiligo-like
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hypopigmentation in patients with melanoma.2 Less commonly, dermatitis, lichenoid exanthema,
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photosensitivity, radiation dermatitis, and neutrophilic dermatoses may develop.2,10 Fortunately, potentially life-threatening SCARs rarely occur.5,11–15 In addition, cutaneous reactions with systemic manifestations may be seen including sarcoidosis, neutrophilic dermatoses, and druginduced connective tissue disorders.16–19 PD-1, and its ligand, PD-L1, constitute an immune checkpoint in peripheral tissues that tumors may hijack in an effort to escape immune surveillance.20 Monoclonal antibodies to PD-1 include nivolumab and pembrolizumab, which are indicated for use in a variety of tumors including melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma,
4
Journal Pre-proof Hodgkin lymphoma, urothelial carcinoma, microsatellite instability-high cancer, advanced renal cell carcinoma, metastatic colorectal cancer, and hepatocellular carcinoma.21,22 Monoclonal antibodies to PD-L1 include atezolizumab, avelumab, and durvalumab, which are used in nonsmall cell lung cancer, Merkel cell carcinoma, and renal cell carcinoma.23–25 The overall rate of cutaneous toxicities to anti-PD-1 agents ranges from 34%-42%, with an increased frequency in combination anti-CTLA-4 therapy (58.5%-71.5%).1 The overall rate of dermatologic irAE to
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PD-L1 inhibitors is slightly less (approximately 15-20%).2 There are a wide range of skin
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reactions to PD-1/PD-L1 inhibitors, most commonly maculopapular or morbilliform eruptions,
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mucocutaneous lichenoid dermatitis, pruritus, and vitiligo-like leukoderma.2,26–28 In addition, psoriasis, Grover’s disease, acneiform eruptions, and sarcoidosis may occur.2,29–31 Higher grade
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toxicities include exfoliative dermatitis (SJS/TEN) and immunobullous disorders.32–45
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Figure 2 provides an algorithm for diagnosing potentially life-threatening rashes associated with
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ICPi based on morphologic presentation.
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Life-threatening cutaneous reactions Immunobullous Disorders
Immunobullous disorders have been associated with anti-PD-1/PD-L1 therapy and may occur during combination anti-CTLA-4/PD-1 therapy as well.42 A recent analysis demonstrated that it occurs in approximately 1% of patients on ICPi.42 Patients typically manifest with clinical and histopathologic features of bullous pemphigoid (BP), although bullous lichenoid dermatitis, linear IgA bullous dermatosis, and erythema multiforme have been described.42,44,46,47 Notably, the latency of immunotherapy-associated bullous disorders appears to be longer than that of the
5
Journal Pre-proof more common maculopapular or lichenoid reactions, with recent series demonstrating a 6-month mean latency after first infusion of immunotherapy.2,42 The clinical presentation may vary from scattered vesicles to widespread bullae and erosions with denuded skin and mucosal ulceration (Figure 3).42 Pruritus is a common feature and may precede the development of bullae. It is important to consider the diagnosis of prebullous pemphigoid in patients on ICPi with worsening pruritus refractory to conservative
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therapy. Histopathology, direct immunofluorescence (DIF) studies, and ELISA for BP180 should
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be obtained and are generally consistent with classical presentations of BP; however, atypical
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presentations with negative immunofluorescence and titers against BP180 have been reported.42
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Importantly, immunobullous disorders have been shown to frequently impact immunotherapy, often requiring temporary or permanent interruption and use of systemic
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therapy. Grade 1 eruptions may be treated with high potency topical steroids, and doxycycline
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with or without niacinamide.42 Grade 2 or 3 cases typically require systemic corticosteroids (0.51mg/kg/daily prednisone) with slow taper over a course of 1-2 months.4 ICPi therapy may be
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reinstituted at prednisone doses of 10 mg daily, but patients should be closely monitored for
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recurrence of skin disease. For patients with widespread bullae and denuded skin who are at-risk for life-threatening complications including superinfection, sepsis, and dehydration, hospitalization and intravenous corticosteroids 1-2mg/kg/daily is recommended.4 In addition, steroid-sparing agents, such as methotrexate and dapsone, as well as targeted biologic agents, such as omalizumab (in particular for patients with elevated IgE levels) and rituximab,b should be considered for recalcitrant cases.4,41,42,48
Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis
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Journal Pre-proof Maculopapular or morbilliform eruptions are common dermatologic irAE to ICPi (up to 25% during anti-CTLA-4 therapy, 15% during anti-PD-l therapy, <10% during anti-PD-L1 therapy),1 but in rare instances they may progress to exfoliative dermatitis. Acute SJS/TEN-like presentations may occur, as well. Fortunately, these grade 4 reactions occur in less than 1% of cases.49 Reports of SJS/TEN have been described in association with multiple ICPi including ipilimumab, nivolumab, and pembrolizumab.5,11,32–40,45,50 Most cases developed in patients
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treated for melanoma, although patients with follicular lymphoma, lung adenocarcinoma,
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nasopharyngeal carcinoma, and sarcomatoid renal cell carcinoma have also developed
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exfoliative dermatitis.32-40
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The clinical presentation generally resembles that of classical SJS/TEN. Fever and constitutional symptoms may precede skin lesions. Clinically, dusky macules or papules and
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occasionally atypical targetoid lesions rapidly manifest on the trunk and extremities, with
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associated mucosal involvement (ocular, oral, or anogenital sites). The skin is tender and may be associated with a positive Nikolsky sign (Figure 4), distinguishing SJS/TEN from a less
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concerning morbilliform or lichenoid eruption. Moist desquamation and skin sloughing with
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denuded red dermis follows. Based on BSA of denuded skin, cases may be delineated as SJS (<10%), SJS/TEN overlap (10-30%), or TEN (>30% BSA). The majority of cases associated with anti-PD-1 therapy began either after the first or second infusion; however, a few cases were of delayed reactions occurring after 5 and 9 cycles of pembrolizumab respectively.37,38 Three cases, all in association with nivolumab, were fatal.32– 34
Notably, some cases initially presented as a less severe morbilliform or lichenoid rash that
intensified over the course of weeks to months rather than an abrupt onset seen in classical
7
Journal Pre-proof SJS/TEN. As such, clinicians should be cautious of maculopapular eruptions that fail to respond to standard therapy. The diagnosis of SJS/TEN may be rendered clinically and histopathologically. Biopsy of early lesions typically show scattered apoptotic keratinocytes in the basal epidermis, whereas more advanced lesions may show full-thickness epidermal necrosis or subepidermal bullae. Direct immunofluorescence studies (DIF) can help exclude immunobullous eruptions. Initial
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biopsy of two previously reported cases showed interface dermatitis that further progressed into
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full-thickness epidermal necrosis on subsequent biopsy.37,38 The differential diagnosis includes
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erythema multiforme major, disseminated fixed bullous drug eruption, staphylococcal scalded
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skin syndrome, and acute generalized exanthematous pustulosis (AGEP). Management of grade 4 exfoliative dermatitis includes discontinuation of the causative
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agent and immediate hospitalization with supportive care.4 Cancer patients often have multiple
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comorbidities and may be on numerous drugs that have also been associated with SJS/TEN (e.g. antibiotics, anti-seizure medications, and NSAIDS). Discontinuation of all unnecessary
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medications is prudent. Skin biopsy and DIF studies should be obtained to confirm the diagnosis
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and rule out a severe immunobullous disorder, as well as close monitoring of basic laboratory tests. Intravenous systemic corticosteroids (1-2mg/kg/daily) are recommended for grade 4 reactions with slow taper.4 Cyclosporine, or intravenous immunoglobulin, may be considered in corticosteroid unresponsive cases.4,38 Supportive care including hydration, nutritional support, and avoiding sources of infection (e.g. place venous catheters in areas of uninvolved skin) are aimed to limit associated complications such as dehydration, electrolyte imbalance, renal insufficiency and sepsis. Patients with extensive BSA involvement or life-threatening complications should be transferred to the ICU or burn unit. Consultation of specialists such as
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Journal Pre-proof ophthalmologists, urologists, and physical therapists should be considered in the appropriate clinical setting.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as druginduced hypersensitivity syndrome (DIHS), is a severe and potentially life-threatening reaction
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which may involve multiple organs. It is characterized by fever, rash, lymphadenopathy,
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eosinophilia, atypical leukocytosis, and abnormal liver function tests. Two cases of DRESS have
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been reported in association with anti-CTLA4 therapy, one of whom was also on anti-PD-1 therapy.12,13 Both patients presented with a diffuse maculopapular or morbilliform rash with
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peripheral eosinophilia and renal failure.12,13 One case also had hepatic involvement with
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transaminitis.13
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In general, DRESS may develop later than a classic morbilliform eruption with a typical range of onset of 2-8 weeks after initiation of the culprit drug. The cutaneous presentation is
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variable, but most patients present with a morbilliform eruption, and prominent facial edema is a
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hallmark sign.52 In addition, lymphadenopathy may be noted on physical examination. Other presentations may include urticarial, vesicular, pustular, purpuric, targetoid, and erythrodermic forms. The liver is the most common internal organ involved, although renal, cardiac, thyroid, pancreatic, and pulmonary inflammation may occur. The overall mortality from DRESS ranges 5-10%.52 The diagnosis of DRESS is based on the RegiSCAR criteria, although other criteria such as the Japanese Research Committee on Severe Cutaneous Adverse Reactions have been proposed. RegiSCAR criteria include: fever greater than 38.5 degrees Celsius, lymphadenopathy
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Journal Pre-proof in at least 2 sites, circulating atypical lymphocytes, peripheral eosinophilia, skin involvement greater than 50% BSA or suggestive of DRESS, biopsy suggestive of DRESS, and involvement of at least 1 organ.52 Histopathology may demonstrate features of several inflammatory conditions such as interface dermatitis, erythema multiforme, eczema, or AGEP. Laboratory evaluation to assess for systemic involvement should include CBC with differential and peripheral smear for atypical lymphocytes, basic metabolic panel and liver
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function tests, thyroid function, and baseline echocardiogram. Repeated monitoring of atypical
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laboratory findings is prudent to evaluate for disease progression and response to treatment.
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Management of DRESS includes withdrawal of the culprit drug, and systemic corticosteroids as
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in other SCARs (oral prednisone 0.5-1mg/kg/daily for milder presentations; intravenous methylprednisolone 1-2mg/kg/daily for severe presentations). Importantly, steroids should be
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slowly tapered over at least 6-8 weeks to reduce the risk of rebound. Of the reported cases of
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disease.12,13
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DRESS associated with ICPi, intravenous or oral corticosteroids effectively managed the
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Neutrophilic Drug eruptions (AGEP, CSVV, Neutrophilic Dermatoses) Neutrophilic drug eruptions including acute generalized exanthematous pustulosis (AGEP), cutaneous small vessel vasculitis (CSVV), and neutrophilic dermatoses (Sweet’s syndrome and pyoderma gangrenosum) have been associated with ICPi. AGEP has been described in two patients on anti-CTLA4 therapy, one of which was on combination therapy with a PD-1 inhibitor.15,49 AGEP is characterized by the acute development of fever and hundreds of nonfollicular pustules on an erythematous base with an associated neutrophilia, and usually develops with 48 to 72 hours of beginning a new drug.53 The pustules
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Journal Pre-proof in AGEP may be pruritic and tend to favor truncal and intertriginous sites.53 Severe cases may involve the mucous membranes and internal organs including the kidneys, lungs, and liver. Overlap with DRESS and SJS/TEN may rarely occur. The overall mortality is less than 5%, and death usually results from disseminated intravascular coagulation or severe organ dysfunction.53 The diagnosis of AGEP may be rendered clinically and histopathologically, with biopsy demonstrating dermal papillary edema, neutrophilic and eosinophilic perivascular infiltrate, and
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intraepithelial and/or subcorneal pustules. Management of AGEP like other SCARs includes
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withdrawal of the culprit drug, and systemic corticosteroids (oral prednisone 0.5-1mg/kg/daily
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for lower BSA involvement and intravenous methylprednisolone 1-2 mg/kg/daily for higher BSA involvement).4 Vigilant skin care and close monitoring for secondary infections is essential.
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Neutrophilic dermatoses, such as Sweet’s syndrome and pyoderma gangrenosum-like
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ulcers, have been reported in association with anti-CTLA-4 therapy and anti-PD-1
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therapy.16,18,54,55 Also known as acute febrile neutrophilic dermatosis, Sweet’s syndrome is commonly associated with systemic symptoms including fever, malaise, and arthralgias or
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arthritis.56 In addition, ocular, pulmonary, renal, hepatic, neurologic, and gastrointestinal
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involvement may occur. Lesions are classically tender erythematous plaques that may vesiculate and are generally distributed on the head, neck, and upper extremities. Pyoderma gangrenosum typically manifests with a pustule on an inflamed base that progresses to an ulcer with an undermined violaceous border. Of the cases associated with ICPi therapy, discontinuation of the causative drug and management with systemic corticosteroids with or without dapsone effectively managed the neutrophilic dermatosis.16–18,54 Notably, one patient showed that lesions of Sweet’s did not recur after readministration of nivolumab after temporary interruption.54 Diagnosis of Sweet’s syndrome is based on the following major criteria: abrupt onset of typical
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Journal Pre-proof cutaneous lesions and histologic features of Sweet’s syndrome (neutrophilic infiltrate, with occasional leukocytoclasia without vasculitis).56 Minor criteria include association with a known trigger, fever and constitutional symptoms, leukocytosis, and prompt response to systemic corticosteroids. While systemic corticosteroids are the mainstay therapy, steroid-sparing options include dapsone and colchicine. Cutaneous small vessel vasculitis (CSVV) with palpable purpura and ulcerative lesions
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on the bilateral lower extremities has been reported in a patient on combination
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ipilimumab/nivolumab therapy.57 The patient’s immunotherapy was held, and he was treated
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with systemic corticosteroids and dapsone. CSVV manifests with purpuric macules and papules
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on the lower extremities, while upper extremity and extensor involvement may occur. More widespread presentations with hemorrhagic bullae and pustules may occur. The differential
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diagnosis includes CSVV due to other medications, infections, or malignancy, Henoch-
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Schönlein purpura or IgA vasculitis, urticarial vasculitis and ANCA-associated vasculitis. Medium-sized and large vessel vasculitis should be considered in the setting of livedo racemosa,
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retiform purpura, subcutaneous nodules and ulcers. Biopsy and DIF may help confirm the
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diagnosis, while a comprehensive review of systems should be performed to evaluate for internal organ involvement. Basic laboratory evaluation including a complete blood count (CBC), basic metabolic functions, urinalysis, and liver function tests should be obtained. Low grade presentations may be managed by observation and topical steroids, while extensive skin disease and internal organ involvement may require systemic corticosteroids. Colchicine and dapsone are steroid-sparing alternatives.
Erythrodermic papulosquamous eruptions (Psoriasis, PRP-like)
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Journal Pre-proof The development of psoriasis and exacerbation of existing psoriasis has been associated with the use of anti-PD-1/PD-L1 agents.29 Severe cases of psoriasis including widespread pustular (Figure 5) and erythrodermic presentations and psoriatic arthritis may occur, as well as erythrodermic pityriasis rubra pilaris-like eruption.29,58 We reported one case of PRP-like erythroderma due to pembrolizumab which presented with diffuse orange-red plaques and a waxy palmarplantar keratoderma (Figure 6).58 The patient was responsive to topical steroids and
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acitretin; however, treatment with pembrolizumab was discontinued due to the severity of the
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eruption with > 70% BSA involvement. Idiopathic PRP may be treated with methotrexate,
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acitretin, or biologic agents including TNF-alpha inhibitors and IL-12/23 inhibitors. Use of
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biologic agents in cancer patients should be reserved for severe and recalcitrant cases due to their immunomodulatory properties. The differential diagnosis of erythroderma includes drug
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eruptions (morbilliform eruption with >80% involvement), primary dermatoses that progressed
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to erythroderma (e.g. psoriasiform, seborrheic dermatitis, atopic dermatitis), paraneoplastic erythroderma, dermatomyositis with PRP-like features, immunobullous dermatoses, and
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cutaneous T-cell lymphoma. Biopsy for histopathology, DIF, and flow cytometry studies may be
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helpful in ruling out other entities in the differential diagnosis. Care must be taken in the management of patients with erythroderma due to the possibility of thermal dysregulation, dehydration, and electrolyte disturbance. Treatment is geared towards the underlying cause. Symptomatic relief may be provided with open-wet dressings and topical corticosteroids or topical camphor-menthol. In the case of severe erythrodermic psoriasiform or pityriasiform eruptions due to ICPi, phototherapy, acitretin, and methotrexate have been used.29 Biologic agents should be considered for recalcitrant cases. Patients should be closely monitored for recrudescence if ICPi therapy is readministered.
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Sarcoidosis Cutaneous and systemic sarcoidosis have been reported during anti-PD-1/PD-L1 therapy, anti-CTLA-4 therapy, or combination anti-CTLA-4/PD-1 therapy.2,30,31 Both new onset and exacerbation of existing disease may occur. Cutaneous lesions may manifest similarly to classical sarcoidosis with periorificial papules, annular plaques, subcutaneous lesions, or
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involvement of previous scar sites.30,31 While cutaneous disease is not life-threatening it may be
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a sign of underlying systemic involvement, in particular pulmonary disease. Clinicians should
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consider sarcoidosis in cancer patients who develop hilar lymphadenopathy while on ICPi
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therapy. Biopsy of pulmonary lymphadenopathy should be obtained when possible to avoid misdiagnosis for progression of underlying malignancy. Other organs may be involved including
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the eyes, bones, kidney, spleen, nervous system, and joints.30,31 In general, most reported cases of
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cutaneous and systemic sarcoidosis have responded to systemic corticosteroids with resumption
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of immunotherapy. In addition, hydroxychloroquine may be effectively used.31
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Graft versus host disease (GVHD)
Immunotherapy is increasingly used in the treatment of hematologic malignancy, and anti-PD-1 agents are approved for Hodgkin’s lymphoma. There exists a significant risk for graft versus host disease (GVHD) before and after allogeneic hematopoietic stem cell transplantation (HSCT), with significantly increased risk of GVHD-related morbidity and mortality in this population.59 Clinically, acute GVHD resembles a maculopapular or morbilliform eruption. Severe presentations (grade 4) resemble TEN. Chronic GVHD may have a variety of manifestations
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Journal Pre-proof including lichenoid, morpheaform/sclerodermoid, eczematous, ichthyosiform, and dyspigmentation. The major differential diagnosis for acute GVHD is a morbilliform drug eruption, viral exanthem, and toxic erythema of chemotherapy in the setting of conventional chemotherapy administration. In one study, the use of ICPi in hematologic malignancy before allogeneic HSCT resulted in high incidence of hyper-acute (7%), acute (56%), and chronic (29%) GVHD.59 Administration
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of ICPi after allogeneic-HSCT showed high efficacy but also increased the risk of GVHD (14%
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acute, 9% chronic).59 Life-threatening and fatal cases with cutaneous and systemic involvement
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have been reported, necessitating extreme caution and surveillance with the use of ICPi before or
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after HSCT.60 The management of life-threatening GVHD in the context of immunotherapy includes discontinuation of the ICPi and systemic immunosuppression with prednisone or other
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immunomodulatory agents (e.g. cyclosporine, mycophenolate mofetil, tacrolimus) in a multi-
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disciplinary fashion with hematology.
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Exacerbation of autoimmune disease and connective tissue disorders
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The exacerbation of existing autoimmune disease is a significant concern for patients on ICPi. One study demonstrated that 27% of patients on ipilimumab developed a flare in their autoimmune disorder requiring systemic corticosteroids.61 These included patients with rheumatoid arthritis, psoriasis, polymyalgia rheumatica, ulcerative colitis, inflammatory arthritis, and sarcoidosis.61 Another series of immunotherapy-associated psoriasis demonstrated that 71% of patients had a prior history psoriasis that flared on treatment.29 Other reports of autoimmune skin disorders that flared on ICPi included subacute cutaneous lupus erythematosus, and BP.28,62
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Journal Pre-proof The development of new onset connective tissue disease may also occur. One case of dermatomyositis developed during anti-CTLA-4 therapy for metastatic melanoma.19 The patient had hallmark signs including a photodistributed eruption with periorbital edema, Gottron’s papules of the dorsal hands, and nailfold telangiectasias.19 He was also found to have elevated muscle enzymes and severe myopathy requiring the use of wheelchair. Treatment with ipilimumab was discontinued, and the patient was managed with intravenous corticosteroids.19 In
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addition, new onset cutaneous lupus-like reactions have been described (lesions presenting as
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edematous plaques mimicking tumid lupus, but histopathology demonstrating interface
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dermatitis),63 as well as lupus nephritis with the use of ICPi.64
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Although a minority of patients with underlying autoimmune disease will flare during ICPi, a thorough history should be obtained to identify those with existing disease in order to
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closely monitor them while on immunotherapy. For patients who develop new onset
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rheumatologic disease or exacerbation of existing disease, a review of systems and directed
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Conclusions
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laboratory workup should be performed to evaluate for systemic complications.
Potentially life-threatening cutaneous toxicities may develop during ICPi and may be a significant source of morbidity and mortality in cancer patients. A diversity of morphologic reactions has been observed including SCARs such as SJS/TEN, DRESS, and AGEP. In addition, immunobullous disorders, erythroderma, neutrophilic dermatoses, sarcoidosis, connective tissue disorders, and exacerbation of autoimmune disease may occur. These potentially life-threatening toxicities often necessitate treatment interruption or cessation and use of systemic corticosteroids and supportive care. As such, recognition of the ever-expanding
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Journal Pre-proof spectrum of dermatologic irAE is essential for dermatologists caring for cancer patients, in order to distinguish life-threatening reactions earlier from more banal toxicities. Prompt dermatologic management in a multidisciplinary fashion with oncologists may reduce the morbidity and mortality associated with these rashes.
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Figure Legend
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Figure 1: Guide to grading and managing rashes associated with immune checkpoint inhibitors. Adapted from the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) and American Society of Clinical Oncology Clinical Practice Guideline.3,4 Figure 2: Algorithm for diagnosing potentially life-threatening rashes associated with immune checkpoint inhibitors based on morphological presentation. Figure 3: Bullous pemphigoid associated with anti-PD-1 therapy manifesting with widespread urticarial plaques, tense bullae, and erosions requiring hospitalization and intravenous
24
Journal Pre-proof corticosteroids. Figure 4: Morbilliform eruption that progressed over the course of weeks to a SJS-like presentation with dusky lesions that resulted in erosions and desquamation of skin with a positive Nikolsky sign. Figure 5: Widespread pustular, plaque, and palmarplantar psoriasis associated with psoriatic arthritis during anti-PD-1 therapy, treated with phototherapy with narrowband ultraviolet
of
B and methotrexate.
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Figure 6: Acute PRP-like erythrodermic eruption manifesting with orange-red plaques and waxy
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na
lP
re
-p
keratoderma, treated with topical steroids and acitretin.
25
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6