key: cord-0929930-jl4cxlw7 authors: Odorici, Giulia; Schenetti, Cecilia; Pacetti, Lucrezia; Schettini, Natale; Gaban, Alba; Mantovani, Lucia title: Acute generalized exanthematous pustulosis due to hydroxichloroquine date: 2022-04-23 journal: Dermatol Ther DOI: 10.1111/dth.15520 sha: 8ab144d3c4d3369b958a4ba99c292c92da0ff8e8 doc_id: 929930 cord_uid: jl4cxlw7 nan Acute generalized exanthematous pustulosis due to hydroxichloroquine Dear Editor, Hydroxichloroquine (HCQ) is a commonly used medication for various diseases such as malaria, rheumatoid arthritis, and systemic lupus erythematosus. Since 2019, due to the pandemic, its use has dramatically increased in patients with SARS-CoV-2 infection. 1 HCQ use is associated with a wide range of adverse reactions; among them, cutaneous reactions are commonly described. We report the case of a 74-year-old woman presenting with papules and macules on the neck rapidly spreading to the trunk and face with also erythema multiforme-like lesions and fever. The mucosae were not initially involved; Nikolsky sign was negative. Blood exams revealed neutrophilic leucocytosis (18.61 x 10 2 μl, normal values 2.00-7.50 10 2 μl) and increase of transaminanes (ALT 46 U/L, normal values <35 U/L). Repeated Covid-19 swabs were negative. A treatment with HCQ was started 20 days prior for osteoarthritis. Chronic drug history included omeprazole, atorvastatine, and ramipril+hydrochlorotiazide. Suspecting an adverse drug reaction to HCQ, the drug was immediately discontinued. Due to the pandemic the patient refused hospitalization, therefore a therapy with intramuscular methylprednisolone 60 mg/die was started. The rash kept spreading, involving new areas, including oral and vulvar mucosae, with a centrifugal extension; we also noticed pustules and erosions affecting symmetrically the neck and the trunk, developing upon confluent erythematous plaques ( Figure 1A) . A skin biopsy was performed from the abdomen. The histological examination revealed spongiosis, numerous neuthrophils scattered over epidermal and superficial derma, subcorneal, and intracorneal separations with neutrophils infiltration ( Figure 1B ). Based on the clinical and the hystopatological findings, a diagnosis of acute generalized exanthematous pustulosis (AGEP) was made. A progressive improvement in terms of clinical signs, symptoms and lab tests was observed. AGEP completely resolved in 40 days during which the steroid therapy was tapered. HCQ is an anti-malarian drug widely used in rheumatic and dermatologic diseases for its anti-inflammatory and immunosuppressive properties. Since 2019, due to the pandemic, its use has already involved millions of patients, who often receive no screening prior to starting the drug. HCQ is a generally well-tolerated medication, but short-term side effect can be observed (days to weeks, up to 2 months of treatment), the most common is gastrointestinal toxicity (nausea, abdominal pain, anorexia, and diarrhea). Rashes, followed by cutaneous hyperpigmentation, pruritus, Stevens-Johnson syndrome, and toxic epidermal necrolysis are described as common skin adverse effects. AGEP, urticaria, psoriasis, and drug reaction with eosinophilia and systemic symptoms are more rarely reported, and related to lower mean cumulative doses (e.g., less than 100 g). 2,3 AGEP is a severe cutaneous adverse reaction characterized by the sudden onset of numerous small, not follicular, sterile pustules on a base of edematous erythema. It is usually associated with high fever, peripheral neutrophilia, and an acute evolution. 4 The exact pathophysiology of AGEP is still not completely understood, but it is known that as a rare cause of AGEP, but in recent times, descriptions of HCQinduced AGEP have increased. 3 In case of HCQ-induced AGEP, the latency period appears to be longer (ranging from 4 to 30 days 6 ) than in antibiotics-related cases, and the eruption tends to be more serious and resistant to treatments. 7,8 A differential diagnosis could have been HCQ-induced generalized pustular figurate erythema (GPFE), which has been recently described in two patients with COVID-19; 9 however, our patient was febrile and the cutaneous presentation was more consistent with AGEP than GPFE. In our opinion, clinician should be aware of cutaneous skin adverse events, such as AGEP, associated with HCQ, which is still frequently used for various diseases. 10 Does hydroxychloroquine combat COVID-19? A timeline of evidence Acute generalized exanthematous pustulosis with erythema multiforme-like lesions induced by hydroxychloroquine in a woman with coronavirus disease 2019 (COVID-19) Toxicity of chloroquine and hydroxychloroquine following therapeutic use or overdose Acute generalized exanthematous pustulosis (AGEP): a review and update Acute generalized exanthematous pustulosis. Analysis of 63 cases Acute generalized exanthematous pustulosis induced by empiric hydroxychloroquine for presumed COVID-19 Hydroxychloroquine-induced acute generalized exanthematous pustulosis: an adverse reaction to keep in mind during COVID-19 pandemic Acute generalized exanthematous pustulosis with a focus on hydroxychloroquine: a 10-year experience in a skin hospital Generalized pustular figurate erythema first report in two COVID-19 patients on hydroxychloroquine Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial Honorarium, grant, or other form of payment were not given to anyone of the authors to produce the manuscript. All authors made substantive intellectual contributions to the published study and each author listed on the manuscript has seen and approved the submission of the manuscript. The authors have no conflicts of interest to disclose. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.