Clinical Manifestations and Management of Terbinafine-Induced Acute Generalized Exanthematous Pustulosis

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Introduction
Terbinafne is a commonly used antifungal drug whose mechanism of action includes inhibition of squalene epoxidase, preventing sterol biosynthesis in fungi, ultimately leading to cell death, and has been shown to be efective in the treatment of dermatophytes, including onychomycosis [1].Terbinafne, administered once daily, remains the best treatment option for patients with multiple comorbidities taking other prescription medications due to its minimal drug-drug interactions [2].
In a postmarketing surveillance study, the most common side efects of terbinafne were gastrointestinal (4.9%), such as nausea or diarrhea, and dermatological events (2.3%) [3].Te incidence of severe side efects was only 0.04%, including Stevens-Johnson syndrome, toxic epidermal necrolysis, subacute cutaneous lupus, and erythema multiforme [4].Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction characterized by the rapid formation of nonfollicular, sterile pustules on an erythematous base [5].Whereas knowledge of terbinafne and AEGP is largely based on case reports.AGEP can be a critical clinical condition and is rarely described, requires prompt diagnosis and treatment, and may be missed by the clinic.Te clinical characteristics of terbinafne-induced AGEP are unclear.Given that terbinafne is an important choice for dermatophyte infections, here we discussed the clinical features of terbinafne-induced AGEP, to provide a reference for clinical diagnosis and treatment.

Correlation Evaluation.
Te association of terbinafne with AGEP was assessed using the Naranjo scale [7].Te fnal score interpretations are stratifed into four categories, with a score of ≥9 considered "defnite," 5 to 8 "probable," 1 to 4 "possible," and ≤0 "doubtful."2.5.Statistical Analysis.Statistical analysis was performed using SPSS Statistics 22.0 (IBM, Armonk, NY, USA).Te count data are represented by n (%), and the continuous data are represented by the median value (minimum and maximum).

Treatment.
Te treatment and prognosis of terbinafneinduced AGEP are summarized in Table 3.

Discussion
AGEP has been attributed to a variety of causes, such as viral infections or allergy to mercury, while more than 90% of AGEP cases are caused by systemic drugs [8].Te most common drug classes that induced AGEP were beta-lactam antibiotics (25.9%), other antibiotics (20.8%), iodine contrast agents (7.3%), and corticosteroids (5.4%).Te most commonly involved drugs are amoxicillin, pristinamycin, and diltiazem [9].A multinational case-control study of AGEP showed that terbinafne was the most common drug after pristinamycin, ampicillin/amoxicillin, quinolones, (hydroxy) chloroquine, and sulphonamides [8].Te appearance time of AGEP varies with diferent drugs.AGEP was triggered after 1 day of antibiotic exposure [8].Te onset time of AGEP induced by diltiazem varied from 1 day to 3 weeks, while the average time of AGEP induced by hydroxychloroquine was 40 days [10,11].In contrast, terbinafne-induced AGEP had a longer incubation period, ranging from 1 to 77 days.Drug-induced AGEP resolved spontaneously within 15 days after discontinuation.Te resolution time of terbinafne-induced AGEP was longer, ranging from 2 days to 90.Tis long duration can be explained by the pharmacodynamic and pharmacokinetic properties of terbinafne.Terbinafne remains in sebaceousrich areas of the body for up to 15-20 days after stopping treatment [12].Te risks of severe acute adverse reactions (SCAAR) include genetic and nongenetic risk factors.Host factors include potential malignancies or systemic lupus erythematosus, as well as potential infections, such as tuberculosis and HIV.However, none of the above risk factors were found in terbinafne-induced AGEP.Although several patients had a positive history of psoriasis, EuroSCAR strongly recommended that AGEP be unrelated to the individual or family history of psoriasis [8].
Te mucocutaneous features of terbinafne-induced AGEP are characterized by sterile, nonfollicular pustules on an erythematous base with minimal mucosal involvement and are usually pruritic.Leukocytosis with an elevated neutrophil count  a represents the number of patients out of 32 on which information regarding this particular parameter was provided.b Median (minimum-maximum).

Dermatologic Terapy
Dermatologic Terapy 5 (>8.0 × 10 9 /L) and fever (≥38 °C) were another feature of terbinafne-induced AGEP.During AGEP resolution, some patients have desquamation of the afected area.It is reported that up to 20% of AGEP elderly patients have visceral organ involvement, the most common of which are the liver, kidney, and lung [13].In patients with terbinafne-induced AGEP, liver involvement manifested only as elevated aspartate aminotransferase and alanine aminotransferase [14].Renal involvement manifests as elevated creatinine and acute prerenal failure [15,16].After discontinuation of terbinafne and supportive care, liver enzymes and renal function returned to normal levels.
Te diagnosis of AGEP relies on clinical and histology.Te diferential diagnosis of generalized pustular eruptions can be difcult due to the similar clinical and histopathologic features of AGEP and generalized pustular psoriasis (GPP).AGEP difers from GPP mainly in drug exposure, no relapse, faster recovery time after discontinuation, and no personal and family history of psoriasis.One patient started terbinafne and initially showed a generalized outbreak of AGEP, but later seemed closer to the pustular psoriasis (PP) [17].Te typical pathological manifestations of AGEP are the formation of subcorneal and/or intraepidermal cavernous pustules, marked edema of the papillary dermis, perivascular infltration of neutrophils, and eosinophil exocytosis in some patients.Terbinafne-induced AGEP conforms to the above characteristics.
Patch and in vitro tests have confrmed that AGEP is a delayed-type hypersensitivity reaction mediated by T lymphocytes [18,19].Te possible mechanism of AEGP is the activation of specifc CD4+ and CD8 + T lymphocytes through antigen-presenting cells after pathogenic factors (mainly drugs) come into contact with the body.Activated lymphocytes rapidly proliferate and migrate into the dermis and epidermis.Activated CD8 T cells release perforin and granzyme B, which, through interaction with Fas ligands, induce apoptosis of intraepidermal keratinocytes, resulting in tissue destruction and intraepidermal blistering form [20]. Specifc CD4 + T lymphocytes release a large amount of neutrophil chemokine CXCL8, which chemotactic neutrophils into blisters and eventually form sterile pustules.[21] In addition, T17 cells may also play a role in the pathogenesis of AGEP.IL-17, a potent pro-infammatory cytokine capable of recruiting neutrophils, can also synergize with CXCL8, released by keratinocytes to promote pustule formation.[22] Individuals with IL-36RN mutations may be at increased risk of developing AGEP.Mutations in the IL36RN gene lead to an uncontrolled IL-36 pathway, which further leads to increased production of IL-6, IL-8, IL-1α, and IL-1β, and may predispose to pustules [23].Navarini et al. studied the IL36RN gene mutation in AGEP and found that the IL36RN gene mutation in AGEP patients was signifcantly higher than that in the control group (1.6% vs. 0.4%) [24].Tese results suggest that patients with mutations in the IL36RN gene are susceptible to AGEP.
fAGEP and GPP are difcult to distinguish, which is particularly important when choosing a therapy.Identifcation and immediate withdrawal of suspected medications remain the most important measures in the management of AGEP patients [5].However, there is still no consensus on the optimal treatment regimen for AGEP.Antibiotics should be avoided unless there are clear and signifcant signs of infection [25].Antiseptic solutions prevent infection, moisturizers and emollients can help restore the skin barrier, and topical corticosteroids can relieve itching and infammation [5,26].Most AGEP cases clear rapidly with systemic corticosteroids, but severe or refractory cases may require other systemic treatments such as cyclosporine, infiximab, and intravenous immune globulin [26].To date, the therapeutic value of glucocorticoids in AGEP remains questionable.In one patient, pustules worsened with oral steroids but improved with intravenous steroids [27].Further research is needed on which treatment regimen is more efective for AGEP.Interleukin 17 may be a therapeutic target for AGEP [28].Although AGEP is usually self-limiting and has a good prognosis, re-exposure of terbinafne may lead to re-occurrence of AGEP, so patients must be advised to avoid re-exposure [29].

Conclusion
Terbinafne-induced AGEP is a rare cutaneous adverse reaction.Te development of impetigo during the administration of terbinafne should consider the possibility of AGEP.Terbinafne discontinuation is the mainstay of treatment for AGEP.Te prognosis is good after discontinuation.

Figure 1 :
Figure 1: Flow chart of study selection process for reported cases of terbinafne-induced acute generalized exanthematous pustulosis.
Te following information was extracted from each patient: gender, age, country, past medical history, concomitant medications, drug dose, time of onset, clinical features of AGEP eruptions, laboratory tests, skin biopsy, treatment, and prognosis.2.3.AGEP Diagnosis.AGEP diagnosis is made by the modifed EuroSCAR scoring system

Table 3 )
. Six patients (18.8%) scored between 5 and 8 by the European Study of Severe Cutaneous Adverse Reactions (EuroSCAR), indicating a probable AGEP diagnosis and 26 patients had a score ≥9, indicating a defnite AGEP diagnosis.
a represents the number of patients out of 32 on which information regarding this particular parameter was provided.b

Table 2 :
Clinical features, laboratory tests, and skin biopsies of 32 patients with terbinafne-induced acute generalized exanthematous pustulosis.