Cutaneous Adverse Events Research Articles

The "Flolan Rash": An Impressively Asymptomatic and Non-Inflammatory Eruption Following Long-Term Epoprostenol Therapy

Epoprostenol (Flolan) is a last-resort intravenous medication for the treatment of severe pulmonary arterial hypertension (PAH). Cutaneous adverse events of Flolan are well-known by pulmonologists, though lacking in dermatologic literature. We report a near erythrodermic appearing, yet asymptomatic eruption lasting 10 years in a woman with end-stage PAH treated with long-term intravenous epoprostenol. Non-pruritic, blanching, erythematous papules coalescing to plaques surrounded by a hypopigmented halo encompassed her entire torso, as well as bilateral upper and lower extremities. Additional findings included bright red palms and soles associated with pain and tingling while walking. Laboratory workup revealed thrombocytopenia and a slightly elevated erythrocyte sedimentation rate (ESR); connective tissue disease markers were negative. Skin biopsies were, surprisingly, largely unremarkable without an inflammatory infiltrate. The patient was trialed on topical clobetasol ointment without effect. Her striking, yet asymptomatic and non-inflammatory eruption was thought due to long-term use of epoprostenol, a last-resort synthetic prostacyclin used to treat severe PAH. As her cutaneous findings were not bothersome, her dose of Flolan was not lowered and her lower extremity pain was treated with gabapentin. With this case, we aim to increase awareness of the impressive “Flolan rash”, a persistent erythematous eruption well-known by pulmonologists, yet scarcely described in dermatologic literature. Significant Finding: We report a striking, yet asymptomatic and non-inflammatory skin eruption lasting 10 years presumed due to long-term use of epoprostenol for end-stage pulmonary arterial hypertension. Meaning: Cutaneous adverse events of intravenous epoprostenol are well-known by pulmonologists, though lacking in dermatologic or primary care literature. The extensive body surface involvement, and near erythroderma, associated with Flolan necessitates awareness by patients, dermatologists, and other healthcare providers outside of the field of pulmonology. J Drugs Dermatol. 2022;21(11):1249-1251. doi:10.36849/JDD.6821.

SEVERE PAPULAR ECZEMA SKIN REACTION AFTER INTRAVENOUS IMMUNOGLOBULIN INFUSION IN PATIENT WITH CHRONIC LYMPHOCYTIC LEUKEMIA: A CASE REPORT

Hypogammaglobulinemia is a common finding in Chronic Lymphocytic Leukemia (CLL). Their etiology is multifactorial, due to disease-related immune defects and chemo-immunotherapy treatment as Rituximab. It is present in up to 85 % of patients at some point in their disease course. It is therefore important to monitor patients for the development of an antibody deficiency due to being susceptible to infections. Strategies to prevent infections in patients with secondary antibody deficiencies include replacement Immunoglobulin (Ig). However, nearly 6% develop skin reaction Ig associated, a rare adverse event reported only in case reports. A 64 years-old man was diagnosed with CLL in 2011. Despite treatment with Chlorambucil, in July 2013, the patient had therapeutic failure, so he switched to a 2nd-line regimen, with intravenous chemotherapy with cyclophosphamide, vincristine and prednisone for 2 cycles. In September 2013, due to disease progression, he was switched to a 3rd-line regimen with fludarabine and cyclophosphamide. In 2014, he presented an increase in the size of the cervical lymph nodes, so he used 8 cycles of Rituximab. After Rituximab-therapy, hypogammaglobulinemia was detected due to recurrent infections. Then, the patient received Ig monthly with pre-medication. Fifteen days after this Ig infusion, he developed an extensive pruritic, eczematous rash and lichenified skin lesions on the upper limbs. In the following months, 48 hours after the Ig infusion, he presented excoriated eczematous plaques located in the inguinal region and posterior thighs, with follicular pustules (delayed hypersensitivity reaction, type IV). Histological analysis of a skin biopsy specimen revealed subacute spongiotic dermatitis with intraepidermal microvesiculation. The lesions progressively regressed after stopping Ig infusions, oral prednisone, dapsone and topical application of tacrolimus and corticosteroids. Although the Rituximab used in the treatment of patients with CLL is capable of depleting the population of malignant lymphocytes, they lack specificity and further contribute to the significant immune dysfunction that predisposes these patients to a serious risk of infection. As such, the use of Ig therapy is increasing in the treatment of CLL. However, the severity of its rare adverse effects is often poorly recognized. Dermatologic adverse effects of Ig are rare and include urticaria, papules, eczema, pompholyx, lichenoid dermatitis, and desquamation. The underlying mechanism resulting in skin reactions following treatment with Ig is not clear. Most of these reactions develop within 2 weeks after immunoglobulin administration. The rash is managed with topical/systemic steroids and antihistamine treatment. These adverse events can also lead to cessation of therapy. This case report highlights the fact that cutaneous adverse effects of IgIV are more common than previously believed. Although the precise mechanism of this cutaneous eruption remains to be elucidated, its occurrence within days of Ig infusion, its characteristic distribution at onset, and its clinical course should be recognized by hematologists and dermatologists.

Adverse Cutaneous Drug Reaction Following Granulocyte Colony-Stimulating Factor Administration in Nasopharynx Cancer Patient with Febrile Neutropenia: A Case Report

Introduction: Several side effects may occur during cancer treatment such as myelosuppression following systemic chemotherapy, which is mainly manifested as neutropenia and is associated with increased infection risk. Febrile neutropenia is associated with a worse prognosis. Granulocyte colony-stimulating factor (G-CSF) may be given prophylactically before chemotherapy in selected cases or as adjuvant therapy in febrile neutropenia. G-CSF administration may be associated with several side effects, including skin manifestation. More rarely, G-CSF administration may induce acute febrile neutrophilic dermatosis is which known as a Sweet syndrome. Case Presentation: A 63-year-old man with nasopharyngeal cancer stage III on chemotherapy and radiotherapy came to our emergency department with a chief complaint of fever, coughing, and shortness of breath. He was diagnosed with community-acquired pneumonia and febrile neutropenia. His white blood cell (WBC) count was 200/mm3 . On the third day of hospitalization and G-CSF administration, he developed a rash and had skin desquamation mainly on his head including the scalp, face, lips, upper trunk, arms, and the surface of both hands. His follow-up laboratory result was WBC 8300/mm3 with a neutrophil count of 87%. Presumable Sweet syndrome diagnosis with differential diagnosis of other drug eruption reactions was made. Systemic and topical were administered, and G-CSF was stopped. Significant improvement was observed. Conclusions: G-CSF administration in febrile neutropenic cancer is generally safe; however, several adverse events may occur. Cutaneous adverse events following G-CSF administration should be recognized and treated accordingly. Sweet syndrome is rare but should be recognized as a possible G-CSF-induced drug skin complication.

Management of cutaneous toxicities under amivantamab (anti MET and anti EGFR bispecific antibody) in patients with metastatic non-small cell lung cancer harboring EGFR Exon20ins: towards a proactive, multidisciplinary approach

Contexte.The Epidermal Growth Factor Receptor (EGFR) is mutated in 10–15% of patients with lung adenocarcinoma. At metastatic stage EGFR tyrosine kinase inhibitors (TKIs) are used front line for patients harboring targetable mutations. Novel anti-EGFR therapies are being developed. Amivantamab is a bispecific anti-EGFR and anti-MET antibody with expected skin toxicities. ObjectiveWe developed here guidelines for prevention and treatment of cutaneous toxicities under amivantamab according to our experience at Institut Curie. Materiel & MethodThe first patients with metastatic lung cancer harboring EGFR Exon20ins mutation, included in the phase 1 CHRYSALIS trial and cured at Institute Curie from November 1st 2019 until December 31st 2021 were selected for this work. Retrospectively, all cutaneous adverse events were registered and classified according to the CTCAE 6.0 classification, and actions we implemented to minimize and treat these adverse events were collected. We then developed guidelines based on these datas. ResultsA total of seven patients started amivantamab as monotherapy. The two most frequent dermatological adverse events were: acneiform rash and paronychia (100 % of patients). Other adverse events presented by the patients were reported: modification of hair growth with hypertrichosis in 50 % of men (n = 1/2) and hirsutism in 80 % of women (n = 4/5); skin abrasion of the scalp in 71 % (n = 5/7); and skin fissure in 57 % (n = 4/7). We recommend first a rigorous inspection of the skin and teguments to determine the risk rate to have dryer skin under treatment; second a prevention of paronychia/acneiform rash/and skin fissures with prophylactic tetracycline, skin moisturizing, and hygienic measures starting at least 14 days before treatment initiation; third a particular attention to the psychological impact of skin toxicities with access to psychological support. ConclusionWe propose here guidelines for the management of dermatological toxicities under amivantamab with a multidisciplinary approach for the proactive management of cutaneous toxicities with a focus on preventive actions.

Urticaria relapse after mRNA COVID-19 vaccines in patients affected by chronic spontaneous urticaria and treated with antihistamines plus omalizumab: A single-center experience.

Urticaria is a disease characterized by wheals and/or angioedema. Chronic spontaneous urticaria (CSU) occurs for longer than 6 weeks and appears independently of any identifiable exogenous stimulus. During the vaccination campaign for Coronavirus disease 2019 (COVID‐19) pandemic, several cutaneous adverse events have been described, among which urticaria lasting less than 6 weeks (acute urticaria, AU). AU due to vaccines can be IgE or non‐IgE mediated; the former typically develop within 4 h of drug exposure, the latter occurs later and the mechanism is unclear. In this retrospective study we analyzed the frequency and clinical characteristics of urticaria occurring after COVID‐19 vaccine (post‐vaccination urticaria relapse) in adult CSU patients treated with antihistamine and omalizumab, and in clinical remission.

Sirolimus-Induced Rash in a Kidney Transplant Patient.

Sirolimus is an inhibitor of the mammalian target of rapamycin, which is used in kidney transplant immunosuppression. The clinical spectrum of cutaneous adverse events associated with sirolimus use varies, with maculopapular rash being an uncommon side effect very rarely reported in the literature. We present the case of a 78-year-old male renal transplant recipient who developed a diffuse maculopapular pruritic rash after starting sirolimus. This case report demonstrates that maculopapular rash is an uncommon sirolimus-related side effect that must be identified promptly so the medication can be discontinued and rash progression prevented.LEARNING POINTSAcneiform dermatitis, folliculitis, onychopathy, oral ulcers, rash and stomatitis are all common dermatological side effects of sirolimus.The occurrence of a diffuse pruritic maculopapular rash associated with sirolimus use is rare, but an important differential to keep in mind.Sirolimus cessation is required in case of diffuse pruritic maculopapular rash.

Dermatology evaluation for cutaneous immune-related adverse events is associated with improved survival in cancer patients treated with checkpoint inhibition

Dermatology evaluation for cutaneous immune-related adverse events is associated with improved survival in cancer patients treated with checkpoint inhibition

Factors Affecting Adverse Events after Venous Malformation Sclerotherapy

PurposeTo evaluate factors that contribute to adverse events (AEs) after embolization of venous malformations (VMs) using sclerosing agents. Materials and MethodsA retrospective review of patients who underwent direct puncture embolization of VMs with a sclerosing agent and adjunctive techniques, also termed as sclerotherapy, from 2016 to 2021 was performed. Three-hundred one embolizations in 137 patients (median age, 19.0 years; interquartile range, 12.8–31.5 years) were evaluated. The VM characteristics and embolization details were analyzed. Anticoagulation was also evaluated based on D-dimer levels. Cutaneous and noncutaneous AEs were analyzed. The AEs were categorized using Society of Interventional Radiology guidelines. ResultsVMs involving tissue planes were subcutaneous (n = 104), intramuscular (n = 84), and combined (n = 113). Overlying skin involvement was observed in 56% of the patients. Sodium tetradecyl sulfate was mainly used (83%). Periprocedural anticoagulation was used in 9% of the patients. Most AEs were minor (30/301, 9.7%), and only 1.7% (5/301) were major (21 cutaneous and 14 noncutaneous AEs). Age below 18 years (odds ratio, 4.4502; 95% confidence interval, 1.5607–12.6890; P = .0052) and overlying skin involvement (odds ratio, 7.1794; 95% confidence interval, 1.6226–31.7656; P = .0094) were factors associated with cutaneous AEs. All noncutaneous AEs developed in patients with intramuscular VMs; however, this association was not statistically significant. There was no severe hematologic AE or permanent consequence. ConclusionsThe overall AE rate after VM embolization was 11.6%; however, major AEs were rare (1.7%). Cutaneous AEs were associated with young age and overlying skin involvement. All noncutaneous AEs developed in patients with intramuscular VMs.

Neutrophilic dermatosis with necrobiotic changes as an unusual manifestation after the first shot of a COVID‐19 mRNA vaccine together with a high fever and liver injury

Coronavirus disease 19 (COVID‐19) mRNA vaccines sometimes cause various skin rashes. We report an unusual case of erythema nodosum‐like nodules with vesicular and pustular papules, which arose after the first shot of a COVID‐19 mRNA vaccine. A skin biopsy showed marked neutrophilic infiltration with necrobiotic changes throughout the dermis and subcutis. Immunohistochemically, CD8+ cells were much more common than CD4+ cells in the dense neutrophilic infiltrates. Many CD68+ macrophages were present around the CD8+ cells. No cases of neutrophilic dermatosis with necrobiotic changes have been reported. Thus, our findings should be added to the cutaneous adverse effects of the vaccines.

35264 Cutaneous immune-related adverse events occurrence among melanoma subtypes: A multi-institutional cohort study

Background: Immune checkpoint inhibitors (ICI) revolutionized treatment of advanced melanoma, but are associated with significant toxicities. Cutaneous immune-related adverse events (cirAEs) are the most common. Despite this, the association of cirAEs on morbidity and mortality remains underexplored. Here, we examine the impact of melanoma subtype on cirAE onset and survival among ICI recipients in a multi-institutional, retrospective cohort study. Methods: We identified 765 metastatic melanoma patients in the Mass General Brigham Healthcare System who received ICI treatment between December 2011 and May 2020. CirAE development was determined through manual chart abstraction. Multivariate time-series regressions were used to assess relationships between primary melanoma subtypes (acral, mucosal, and non-acral/non-mucosal cutaneous melanomas-controls), cirAE development, and survival, adjusting for age at ICI initiation, sex, race/ethnicity, ICI-type, and Charleston Comorbidity Index. Results: 241 patients (31.5%) developed a cirAE. The mean time to cirAE onset after ICI initiation was longer for acral melanoma patients compared with controls (15.6 vs. 3.6 months, P < .001). After covariate adjustment, acral melanoma patients were significantly less likely to develop a cirAE (HR = 0.42 P = .038) compared with controls. Mucosal melanoma patients were more likely to develop a cirAE compared with controls, but this association did not reach significance after covariate adjustment (HR = 1.38, P = .125). CirAE presence was protective from mortality (HR = 0.74, P = .049) for all patients. Additionally, metastatic melanoma patients with acral (HR = 2.13, P = .001) or mucosal (HR = 1.90, P < .001) primaries exhibited the worst survival. Conclusion: This study demonstrates significant differences in cirAE development and survival among melanoma subtypes and can inform clinicians when counseling melanoma patients.

34193 Psoriasiform eruption after treatment with pembrolizumab

Immune checkpoint inhibitors, such as the programmed cell death protein 1 (PD-1) inhibitors, are gaining popularity in the treatment of several types of cancer, and function by stimulating the immune system’s antitumor activity. Immune-related adverse events are common following the use of immune checkpoint inhibitors with rash being the most frequent complaint. Herein, we present the case of a 67-year-old woman with a history of plaque psoriasis and metastatic squamous cell carcinoma of the lung who presented with widespread well-defined erythematous scaly plaques following a dose increase of pembrolizumab (a PD-1 inhibitor).While cutaneous adverse events are common with the use of PD-1 inhibitors, they most frequently manifest as morbilliform eruptions.

35172 Cutaneous reactions to PD-1 inhibitors

Background: Programmed cell death 1 (PD-1) inhibitors have changed the landscape of management of advanced malignancies. However, they are often associated with cutaneous adverse effects that may prevent patients from completing treatment. Common adverse effects include morbilliform and psoriasiform rash, bullous pemphigoid-like eruptions, and dyspigmentation.

Association of pre-existing drug allergies with cutaneous immune-related adverse events among patients on immune checkpoint inhibitor therapy

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31789 Scleroderma associated with immune checkpoint inhibitor durvalumab

As the use of immune checkpoint inhibitors (ICI) in cancer treatment regimens continues to rise, so has the incidence of immune-related cutaneous adverse events (irCAEs). Among irCAEs, ICI-induced scleroderma and systemic sclerosis (SSc) are rare and poorly understood. We present a case of progressive and debilitating scleroderma-like changes in a 78-year-old female being treated with durvalumab (anti-PD-L1) for squamous cell carcinoma of the lung. After 12 treatments, the patient started to develop painful skin thickening, fibrosis, and erosions of the hands, ankles, feet, and ankles that subsequently worsened after treatment completion. A full-thickness biopsy confirmed the diagnosis of fibrosing dermatitis. Laboratory values were significant for a positive homogenous ANA (1:320) and an elevated C-reactive protein. The patient’s scleroderma proceeded to involve most of her trunks, arms, and legs despite treatment with hydroxychloroquine, systemic corticosteroids, mycophenolate mofetil, intravenous immunoglobulin, and apremilast. There have been less than 10 cases of limited cutaneous and diffuse cutaneous sclerosis reported in the literature following treatment with anti-PD-1 agents. To our knowledge, this is the first case of scleroderma following anti-PD-L1 therapy. As in this patient, ICI-induced scleroderma can be recalcitrant and can significantly impact quality of life. Patients on ICIs should be carefully examined for scleroderma-like changes as early recognition and treatment initiation could reduce disease severity and lead to improved tolerance to ICIs.

33907 A retrospective chart review of management strategies for lichenoid eruptions associated with immune-checkpoint inhibitor therapy from a single institution

Immune checkpoint inhibitors (ICI) and their associated immune related cutaneous adverse events (irCAEs) are continuing to become a mainstay of cancer treatment regimens. While most rashes are mild and easily manageable, severe or persistent rashes like lichenoid dermatoses can significantly impact quality of life and may require ICI cessation. Lichenoid dermatoses currently have no management guidelines beyond the use of topical or oral steroids. Our study is the first large-scale retrospective chart review to characterize ICI-induced lichenoid eruptions, their treatments, and associated tumor response. We used natural language processing and our institutional medical record to identify 119 patients with lichenoid eruptions on ICI therapy. Of those, 108 rashes were characterized as lichenoid dermatitis and fifteen as lichenoid mucositis. Most patients presented with a diffuse distribution (86%, 101/117), with pruritus in lichenoid dermatoses (82%, 89/108) and pain in lichenoid mucositis (80%, 12/15). Successful treatments for lichenoid dermatitis included topical steroids (81%, 88/108), oral antihistamines (21%, 23/108), and oral steroids (15%, 16/108). Of lichenoid dermatitis patients, 21% (23/108) either did not respond to treatment (7) or required oral steroids (16). Approximately 28% of patients who had lichenoid dermatitis had a dose impact on their ICI because of the irCAE,which is significantly greater than the average 5-10% dose impact of most irCAEs. This descriptive study highlights the importance of lichenoid dermatitis and the need for more effective nonsteroidal management strategies.

32950 Autoantibody profiles of bullous immune-related cutaneous adverse events from immune checkpoint blockade may present with atypical or typical antibody serologies

Background: With immune checkpoint blockade (ICB) now standard of care in a multitude of cancer types, immune-related cutaneous adverse events (ircAEs) negatively impact quality of life and frequently lead to treatment interruptions. Autoimmune bullous ircAEs have been found to be overrepresented in patients treated with anti-PD1 antibodies when compared with matched controls. Furthermore, although cases of bullous ircAEs have been reported, no extensive characterization based on a larger cohort has been undertaken.

33521 Two cases of oral baricitinib associated papular eruption on face

Background: Janus kinase (JAK) inhibitors reduce inflammation by interrupting JAK-STAT pathway and are used for various disease. However, cutaneous adverse effects including reactivation of herpes simplex virus, herpes zoster, disseminated molluscum contagiosum, and acneiform eruptions were reported. In addition, few cases of granulomatous inflammation after JAK inhibitor use have been reported recently. Methods: Patient 1, a 40-year-old woman, presented with erythematous papules on periorbital and perioral area for 13 months. She had been taking prednisolone and hydroxychloroquine for rheumatoid arthritis (RA) for 1 year, but symptoms were not controlled. Thus, oral baricitinib was administered. After 2 months, facial lesions appeared. Patient 2, a 64-year-old woman, presented with erythematous papules on face developed 2 weeks ago. She has been taking baricitinib for RA because of inadequate response to methotrexate. Facial eruption occurred 4 months after initiation of baricitinib. Results: For patient 1, histopathologic examination showed dense dermal infiltration of lymphocytes, histiocyte and few plasma cells, which implicated granulomatous dermatitis. Doxycycline and topical gentamycin/prednicarbate were given and the lesions showed response. Patient 2 showed improvement after treatment with doxycycline, topical metronidazole, and topical ivermectin. However, lesions aggravated 7 months after doxycycline cessation with continuous baricitinib use. Conclusion: Although JAK inhibitors are known to be effective for the treatment of granulomatous diseases like sarcoidosis, granulomatous drug eruption has been reported. In our cases, facial skin lesions appeared 2 and 4 months after starting baricitinib, respectively. Our cases imply that dermatologists should be aware of the potential association between JAK inhibitors and cutaneous eruption.

33521 Two cases of oral baricitinib associated papular eruption on face

Background: Janus kinase (JAK) inhibitors reduce inflammation by interrupting JAK-STAT pathway and are used for various disease. However, cutaneous adverse effects including reactivation of herpes simplex virus, herpes zoster, disseminated molluscum contagiosum, and acneiform eruptions were reported. In addition, few cases of granulomatous inflammation after JAK inhibitor use have been reported recently. Methods: Patient 1, a 40-year-old woman, presented with erythematous papules on periorbital and perioral area for 13 months. She had been taking prednisolone and hydroxychloroquine for rheumatoid arthritis (RA) for 1 year, but symptoms were not controlled. Thus, oral baricitinib was administered. After 2 months, facial lesions appeared. Patient 2, a 64-year-old woman, presented with erythematous papules on face developed 2 weeks ago. She has been taking baricitinib for RA because of inadequate response to methotrexate. Facial eruption occurred 4 months after initiation of baricitinib. Results: For patient 1, histopathologic examination showed dense dermal infiltration of lymphocytes, histiocyte and few plasma cells, which implicated granulomatous dermatitis. Doxycycline and topical gentamycin/prednicarbate were given and the lesions showed response. Patient 2 showed improvement after treatment with doxycycline, topical metronidazole, and topical ivermectin. However, lesions aggravated 7 months after doxycycline cessation with continuous baricitinib use. Conclusion: Although JAK inhibitors are known to be effective for the treatment of granulomatous diseases like sarcoidosis, granulomatous drug eruption has been reported. In our cases, facial skin lesions appeared 2 and 4 months after starting baricitinib, respectively. Our cases imply that dermatologists should be aware of the potential association between JAK inhibitors and cutaneous eruption.

34568 What a headache: Erenumab-provoked urticarial drug eruption

Erenumab is a calcitonin gene-related peptide receptor antagonist monoclonal antibody indicated for migraine prophylaxis in treatment resistant patients first approved in 2018. In the pivotal trials, the only reported cutaneous adverse effect was injection site pain. Here, we report a 40-year-old Caucasian woman who presented with a polymorphic eruption of the extremities and trunk that initially presented in the days following her first injection of erenumab. The eruption was urticarial on the trunk and papulosquamous on the extremities.

33263 Rare cutaneous adverse effects of botulinumtoxin A: A review

Among trained injectors there are few, but increasing reports of adverse effects of botulinumtoxin A (BTX A). While there are many reports of adverse effects due to diffusion or misplacement of BTX A, we report 3 rare phenomena that are much less prevalent in the literature and unrelated to user technique: linear depressions, circular depressions and silicone granulomas. There appears to be 2 variants of cutaneous depression after BTX A injection: 1 with well-defined circular depressions and one that appears more linear, following orientation of the frontalis muscle.