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Acute generalized exanthematous pustulosis (AGEP) is a severe, usually drug-related reaction, characterized by an acute onset of mainly small non-follicular pustules on an erythematous base and spontaneous resolution usually within two weeks. Systemic involvement occurs in about 20% of cases. The course is mostly benign, and only in rare cases complications lead to life-threatening situations. Recent studies highlight the importance of genetic variations in interleukin-36 receptor antagonist gene (IL-36RN) in the pathogenesis of this disease. The physiopathology of AGEP remains unclear, but an involvement of innate and acquired immune cells together with resident cells (keratinocytes), which recruit and activate neutrophils via production of cytokines/chemokines such as IL-17, IL-36, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNFα) and chemokine (C-X-C motif) ligand 8 (CXCL8)/IL-8, has been postulated. Treatment is based on the removal of the causative drug, supportive care, infection prevention and use of potent topical or systemic steroids.

Acute generalized exanthematous pustulosis (AGEP) is a rare, acute, severe cutaneous adverse reaction mainly attributed to drugs, although other triggers, including infections, vaccinations, ingestion of various substances, and spider bites, have also been described. AGEP is characterized by the development of edema and erythema followed by the eruption of multiple punctate, non-follicular, sterile pustules and subsequent desquamation. AGEP typically has a rapid onset and prompt resolution within a few weeks. The differential diagnoses for AGEP are broad and include infectious, inflammatory, and drug-induced etiologies. Diagnosis of AGEP depends on both clinical and histologic criteria, as cases of overlap with other disease processes have been reported. Management includes removal of the offending drug or treatment of the underlying cause, if necessary, and supportive care, as AGEP is a self-limited disease. This review aims to provide an overview and update on the epidemiology, pathogenesis, reported precipitating factors, differentials, diagnosis, and management of AGEP.

Acute generalized exanthematous pustulosis (AGEP) is a serious and rare adverse reaction to clindamycin. This study investigated the clinical features of clindamycin-induced AGEP and provided reference for the prevention and treatment of AGEP. Case reports, case series and clinical studies of clindamycin-induced AGEP were collected by retrieving English and Chinese database from inception until May 31, 2024. Of the 35 patients included, 25 (71.4%) were female, and the median age was 57 years (1.6–88 years). The duration of AGEP onset is 2 days (range 0.04,13) after initial administration. The main clinical morphology of AGEP is a non-follicular pustular on an erythematous base, which may be accompanied by fever (54.3%) and pruritus (40.0%). These lesions mainly involved extremities and trunk. The median elevated neutrophil count was 13.3 × 10 9 /L (range 10.3, 31.4). Histologic features of AGEP are characterized by intracorneal, subcorneal, and/or intraepidermal pustules with papillary dermal edema containing neutrophilic, lymphocytic, andeosinophilic infiltrates. Patients gradually recovered after the withdrawal of clindamycin and supportive therapy with a median time of 9 days (range 2, 30). Clinicians should be aware of AGEP as a rare adverse effect of clindamycin. When clindamycin is prescribed, it should be stopped in time when AGEP occurs, and active systemic treatment should be given. AGEP is a self-limiting disease with a good prognosis.

Acute generalized exanthematous pustulosis (AGEP) is a rare but severe cutaneous adverse reaction characterized by the abrupt onset of non-follicular sterile pustules on an erythematous and edematous background. These pustules typically appear within 24 to 48 hours after exposure to the causative drug, often localized to the face, trunk, and intertriginous area. Herein we firstly reported a 56-year-old man with severe plaque psoriasis who developed metamizole-induced AGEP during a clinical trial for BEBT-305 (HSP90 inhibitor) that was successfully treated with Secukinumab. A 56-year-old man with a 40-year history of severe plaque psoriasis developed fever and self-administered metamizole. Within a few days, a progressive eruption appeared and worsened until hospital admission with a baseline PASI score of 50.3 three weeks later. The rash was characterized by diffuse erythema, intense pruritus and severe desquamation. Additionally, he developed edema in the lower extremities, and dense pustules appeared on his neck, inner thighs, and abdomen. The patient had no history of systemic treatment for psoriasis and had only used topical agents with limited benefit prior to presentation. Previously, the patient was enrolled in the \"Heat shock proteins 90 inhibitors BEBT-305 Clinical Trial (CTR20222218)\". The patient took BEBT-305-200 mg orally daily for one month with no adverse effect. The patient had no prior medical history and no known drug allergies. Further tests and examination showed a high white blood cell count and C-reactive protein, abnormal liver function. The IL36RN and CARD14 gene tests were negative. A diagnosis of AGEP was made, allowing for the administration of Secukinumab 300 mg by subcutaneous injection. Sustained improvements were seen 1 week after the first dose of subcutaneous injection with the PASI score decreased to 11.8. Of note, there was resolution of the pustules and most erythema. After discharge, the patient received monthly injections of secukinumab 300 mg for seven months. PASI 100 response was achieved at 7 months. All skin lesions have cleared, with no recurrence to date. This case is the first case in which metamizole-induced AGEP with a history of psoriasis has been successfully treated with Secukinumab. Biologics should be considered in patients with AGEP, especially those with a history of psoriasis. This can benefit both diseases.

Adverse cutaneous drug reactions are recognized as being major health problems worldwide causing considerable costs for health care systems. Most adverse cutaneous drug reactions follow a benign course; however, up to 2 % of all adverse cutaneous drug eruptions are severe and life-threatening. These include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Physicians should be aware of specific red flags to rapidly identify these severe cutaneous drug eruptions and initiate appropriate treatment. Besides significant progress in clinical classification and treatment, recent studies have greatly enhanced our understanding in the pathophysiology of adverse cutaneous drug reactions. Genetic susceptibilities to certain drugs have been identified in SJS/TEN patients, viral reactivation in DRESS has been elucidated, and the discovery of tissue resident memory T cells helps to better understand the recurrent site-specific inflammation in patients with fixed drug eruption.

Cutaneous adverse drug reactions are unpredictable and include various different skin conditions of varying degrees of severity. The most concerning are usually referred to as severe cutaneous adverse reactions (SCARs) and include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DiHS) or hypersensitivity syndrome (HSS), Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). All are delayed type IV hypersensitivity reactions in which a T-cell-mediated drug-specific immune response is responsible for causing the disease. Nonetheless, specific T-cell subpopulations develop in response to certain environmental conditions and produce cytokines that orchestrate the various phenotypes. Cytotoxic T lymphocytes (CTLs), T-helper type 1 (Th1), Th2, Th17, and regulatory T cells (Treg), among other T-cell subpopulations, participate in the development of SCAR phenotypes. Cell subpopulations belonging to the innate immune system, comprising natural killer cells, innate lymphoid cells, monocytes, macrophages and dendritic cells, can also participate in shaping specific immune responses in various clinical conditions. Additionally, tissue-resident cells, including keratinocytes, can contribute to epidermal damage by secreting chemokines that attract pro-inflammatory immunocytes. The final phenotypes in each clinical entity result from the complex interactions between a variety of cell lineages, their products, soluble mediators and genetic and environmental factors. Although the pathophysiology of these reactions is not fully understood, intensive research in recent years has led to major progress in our understanding of the contribution of certain cell types and soluble mediators to the variability of SCAR phenotypes.

During the past decade, major advances have been made in the accurate diagnosis of severe cutaneous adverse reactions (SCARs) to drugs, management of their manifestations, and identification of their pathogenetic mechanisms and at-risk populations. Early recognition and diagnosis of SCARs are key in the identification of culprit drugs. SCARS are potentially life threatening, and associated with various clinical patterns and morbidity during the acute stage of Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reactions with eosinophilia and systemic symptoms, and acute generalised exanthematous pustulosis. Early drug withdrawal is mandatory in all SCARs. Physicians' knowledge is essential to the improvement of diagnosis and management, and in the limitation and prevention of long-term sequelae. This Seminar provides the tools to help physicians in their clinical approach and investigations of SCARs.

Severe cutaneous adverse reactions (SCARs), which include Stevens–Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (also known as drug-induced hypersensitivity syndrome), acute generalized exanthematous pustulosis, and generalized bullous fixed drug eruption, are life-threatening conditions. The pathogenesis of SCARs involves T cell receptors recognizing drug antigens presented by human leukocyte antigens, triggering the activation of distinct T cell subsets. These cells interact with keratinocytes and various immune cells, orchestrating cutaneous lesions and systemic manifestations. Genetic predisposition, impaired drug metabolism, viral reactivation or infections, and heterologous immunity influence SCAR development and clinical presentation. Specific genetic associations with distinct SCAR phenotypes have been identified, leading to the implementation of genetic screening before prescription in various countries to prevent SCARs. Whilst systemic corticosteroids and conventional immunomodulators have been the primary therapeutic agents, evolving strategies, including biologics and small molecules targeting tumour necrosis factor, different cytokines, or Janus kinase signalling pathways, signify a shift towards a precision management paradigm that considers individual clinical presentations.Severe cutaneous adverse reactions (SCARs) are a group of adverse reactions characterized by severe skin eruptions and varying degrees of systemic involvement. In this Primer, Hung et al. summarize current knowledge of epidemiology and mechanisms of SCARs and discuss diagnosis, treatment and quality of life of patients. They also highlight outstanding research questions.

Acute generalized exanthematous pustulosis (AGEP) is a rare severe cutaneous adverse reaction usually caused by drugs. The annual incidence is one to five cases per million. It is characterized by an acute febrile episode, accompanied by numerous small primarily non-follicular, sterile pustules arising within large areas of edematous erythema. There have been several case reports to date of AGEP following exposure to antifungals. Terbinafine is most commonly implicated in AGEP. We report a case of 7-year-old boy who developed AGEP shortly after commencing oral fluconazole for Tinea capitis. To our knowledge, this is the fourth reported case of AGEP due to fluconazole.

Neutrophilic dermatoses are a group of conditions characterized by the accumulation of neutrophils in the skin and clinically presenting with polymorphic cutaneous lesions, including pustules, bullae, abscesses, papules, nodules, plaques and ulcers. In these disorders, the possible involvement of almost any organ system has lead to coin the term ‘neutrophilic diseases’. Neutrophilic diseases have close clinicopathological similarities with the autoinflammatory diseases, which present with recurrent episodes of inflammation in the affected organs in the absence of infection, allergy and frank autoimmunity. Neutrophilic diseases may be subdivided into three main groups: (1) deep or hypodermal forms whose paradigm is pyoderma gangrenosum, (2) plaque-type or dermal forms whose prototype is Sweet’s syndrome and (3) superficial or epidermal forms among which amicrobial pustulosis of the folds may be considered the model. A forth subset of epidermal/dermal/hypodermal forms has been recently added to the classification of neutrophilic diseases due to the emerging role of the syndromic pyoderma gangrenosum variants, whose pathogenesis has shown a relevant autoinflammatory component. An increasing body of evidence supports the role of pro-inflammatory cytokines like interleukin (IL)-1-beta, IL-17 and tumour necrosis factor (TNF)-alpha in the pathophysiology of neutrophilic diseases similarly to classic monogenic autoinflammatory diseases, suggesting common physiopathological mechanisms. Moreover, mutations of several genes involved in autoinflammatory diseases are likely to play a role in the pathogenesis of neutrophilic diseases, giving rise to regarding them as a spectrum of polygenic autoinflammatory conditions. In this review, we focus on clinical aspects, histopathological features and pathophysiological mechanisms of the paradigmatic forms of neutrophilic diseases, including pyoderma gangrenosum, Sweet’s syndrome, amicrobial pustulosis of the folds and the main syndromic presentations of pyoderma gangrenosum. A simple approach for diagnosis and management of these disorders has also been provided.