Dermatology: Practical and Conceptual Research Letter | Dermatol Pract Concept. 2023;13(2):e2023130 1 Sorafenib-Induced Acute Generalized Exanthematous Pustulosis Andrea Cortese1,2, Saverio Pancetti3, Tiziana Pressiani4, Francesco Toso1,2, Giovanni Fiorillo1,2, Antonio Costanzo1,2, Riccardo Giovanni Borroni1,2 1 Dermatology, Humanitas Research Hospital – IRCCS, Rozzano (MI), Italy 2 Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy 3 Pathology, Humanitas Research Hospital - IRCCS, Rozzano (MI), Italy 4 Oncology, Humanitas Research Hospital - IRCCS, Rozzano (MI), Italy Key words: sorafenib, acute generalized exanthematous pustulosis, severe cutaneous adverse reaction; tyrosin-kinase inhibitors Citation: Cortese A, Pancetti S, Pressiani T, et al. Sorafenib-Induced Acute Generalized Exanthematous Pustulosis. Dermatol Pract Concept. 2023;13(2):e2023130. DOI: https://doi.org/10.5826/dpc.1302a130 Accepted: November 17, 2022; Published: April 2023 Copyright: ©2023 Cortese et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Andrea Cortese, MD, Dermatology, Humanitas Research Hospital – IRCCS, Via A. Manzoni 56, 20089 Rozzano (MI), Italy. E-mail: andreacortese08@gmail.com Introduction Acute generalized exanthematous pustulosis (AGEP) is a se- vere cutaneous adverse reaction (SCAR), with an incidence rate between 1 and 5 cases per million per year. Clinically, AGEP is characterized by the abrupt onset of edematous erythema and widespread small sterile pustules. Fever with leukocytosis generally accompany cutaneous findings and mucous membrane may also be affected; the mortality rate of AGEP is up to 5%. The main differential diagnosis of AGEP with generalized pustular psoriasis is often challenging [1]. Case Presentation A 62-year-old man with HBV-related chronic hepatitis was referred to our Dermatology Unit for the acute onset of skin and mucosal lesions associated with fever, 7 days since the start of oral sorafenib 400 mg twice daily. for radia- tion therapy-refractory stage IV hepatocellular carcinoma. Past medical history was negative for psoriasis. On physi- cal examination, numerous disseminated tiny non-follicular pustules were observed overlying confluent erythematous macules on his trunk and limbs, involving about 75% of the body surface area (Figure 1). Furred tongue and desqua- mation of the lips were also present. Body temperature was 38.5 °C. No enlarged lymph nodes or hepatosplenomegaly were noticed. Complete blood count showed leukocytosis with relative neutrophilia (80%, normal range 50%-75%); serum bilirubin level was increased (3.0 mg/dL, normal range 0.3-1.2 mg/dL). Blood and skin cultures resulted negative. Histological examination of a skin biopsy showed multifo- cal spongiosis in the epidermis, with intraepidermal pustules containing fibrin and neutrophils. In the superficial dermis, a mixed inflammatory infiltrate composed of scattered neutro- phils and lymphocytes was present (Figure 2). According to the validation score of the EuroSCAR study group [2], a diagnosis of acute generalized exanthematous pustulosis (AGEP) was made; using the Naranjo scale [3] the 2 Research Letter | Dermatol Pract Concept. 2023;13(2):e2023130 skin reaction collected six points and was considered proba- bly relate” to sorafenib (Figure 3), so the drug was discontin- ued with steady improvement in the following days. Conclusions Sorafenib is an oral multi-kinase inhibitor that mainly tar- gets C-RAF, B-RAF, vascular endothelial growth factor (VEGF) receptors, and platelet-derived growth factor recep- tor (PDGFR). The drug is approved for the treatment of both unresectable hepatocellular carcinoma and advanced renal cell carcinoma. Up to 60% patients treated with sorafenib experience cutaneous adverse events, including hand-foot skin reactions, maculo-papular exanthem, pruritus, alopecia, subungual splinter hemorrhages, seborrheic dermatitis-like eruption and erythema multiforme [4]. AGEP has been Most commonly associated with aminopenicillins, quinolones, chloroquine and sulphonamides, and to our knowledge only three cases of sorafenib-induced pustular reactions were Figure 1. Confluent erythematous macules on his trunk and limbs, involving about 75% of the body surface area, d with overlying disseminated tiny non-follicular pustules. Figure 2. Intraepidermal pustule containing fibrin and neutrophils; in the superficial dermis, a mixed inflammatory infiltrate composed scattered neutrophils and lymphocytes was present. Research Letter | Dermatol Pract Concept. 2023;13(2):e2023130 3 published: one of them defined as acute localized exanthem- atous pustulosis (ALEP) [5], while two reported as AGEP [6,7]. These evidence may suggest an increasing incidence of sorafenib-induced AGEP due to the relatively recent intro- duction use of this kinase-inhibitor. 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Naranjo Adverse Drug Reaction Probability Scale. # Naranjo Questions Yes No Do not know 1. Are there previous conclusive reports on this reaction? 1 0 0 2. Did the adverse event occur after the suspected drug was administered? 2 -1 0 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? 1 0 0 4. Did the adverse reaction reappear when the drug was readministered? 2 -1 0 5. Are there alternative causes (other than the drug) that could have on their own cause the reaction? -1 2 0 6. Did the reaction reappear when a placebo was given? -1 1 0 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? 1 0 0 8. Was the reaction more severe when the does was increased or less severe when the dose was decreased? 1 0 0 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 1 0 0 10. Was the adverse event confirmed by any objective evidence? 1 0 0