First episode of generalized pustular psoriasis or acute generalized exanthematous pustulosis? A case study

Dear Editors, Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction mostly associated with drugs and less commonly with infections.1 The clinical picture is characterized by the sudden appearance of pustules in a non-follicular pattern on an erythematous base localized in the folds.2, 3 Differentiating AGEP from the first episode of generalized pustular psoriasis (GPP) is often difficult.4 A 51-year-old woman presented with acute onset of predominantly intertriginous localized pustules on erythematous ground (Figure 1a). Three days earlier, she had received intravenous prednisolone and oral cetirizine for acute urticaria and a suspected allergic reaction to lemon juice. Personal and family history for atopic disease and psoriasis were negative. Two days later, she was taking oral prednisolone (40 mg) and ranitidine. In addition, she received 100 mg of oral prednisolone from a dermatologist for progressive erythema on her feet. The following day (day 0), pustules manifested. The patient had been taking bisoprolol and L-thyroxine for hypertension and autoimmune thyroiditis for many years. There were no present or past signs of infection. The next day, she presented at our clinic with multiple pustules on an erythematous base on the abdomen, mons pubis, groin, submammary, and neck. Blood examination showed leukocytosis (21,300/µl; normal range, 4,000–11,000/µl), elevated CRP (45 mg/dl; normal range, < 5 mg/l), an elevation of aspartate aminotransferase (56 U/l; normal range, ≤ 31), alanine aminotransferase (89 U/l; normal range, ≤ 34 U/l) and gamma GT (88 U/l; normal range, < 36 U/l). Since the AGEP score (EuroSCAR Study Group) reached 7/12 points, the diagnosis of AGEP was likely.2 The patient did not meet the ERASPEN diagnostic criteria for GPP, as these postulate either a duration of > 3 months or here we would need the sign for greater or equal >= (instead of just >) which we cannot find 1 relapse.5 Histologic examination revealed mild spongiosis, prominent subcorneal pustulosis, a superficial perivascular lymphocytic infiltrate admixed with some eosinophils and neutrophils (Figure 2). The diagnosis of AGEP, possibly triggered by prednisolone was made. Oral dexamethasone 8 mg twice daily was administered for 3 days. After dose reduction, lesions generalized with centrifugal spread, scaling, and central postinflammatory hyperpigmentation (Figure 1b). Dexamethasone dose was increased again, and upon subsequent attempts at dexamethasone dose reduction, skin lesions exacerbated again (Figure 1c), and at day 34 the patient presented with erythroderma, confluent erythematous macules and plaques with fine scaling. The suspected causative agent, prednisolone, had not been taken for several weeks, and erythematopustular flare-ups continued, now meeting the ERASPEN criteria for GPP. Thus, the original diagnosis of AGEP was revised. Subsequent genetic testing did not show a mutation in the IL36RN gene. Topical therapy with highly potent glucocorticoids was applied and systemic therapy with acitretin 40 mg per day was initiated, which resulted in significant improvement; dexamethasone was tapered off. Three weeks later (day 61), the patient showed typical psoriatic plaques on the elbows, and the diagnosis of psoriasis vulgaris was made, in addition to GPP. After 5 months, acitretin was discontinued. Psoriatic arthritis manifested and was treated with methotrexate for 2 years. There was no recurrence of skin lesions over the past 5 years. This case report exemplifies the problem of distinguishing AGEP from the first episode of GPP. Systematic reviews describe disease features and scoring systems for AGEP which can be used supportively and suggest trends, but none of the criteria can prove or exclude AGEP with certainty.2, 6, 7 The hypothesis that AGEP can be interpreted as a provoked abortive form of GPP therefore seems to us worthy of discussion. In this case, a reset of the provoked pathological immune reaction would have to be postulated, thus preventing a sustained manifestation of the disease. The two diseases – AGEP and GPP – could then be interpreted as ends of a spectrum with regard to their temporal dynamics. A comparison of molecular signatures in larger cohorts would be helpful to test this hypothesis. A first approach in this direction was made in a previous study that performed microarray analyses of skin of patients with the pustular skin diseases GPP, AGEP and palmoplantar pustulosis, and found that the three diseases shared many molecular alterations compared to healthy individuals, including an upregulation of IL36RN, IL8, and other genes affecting neutrophil chemoattraction, while there were also unique pathways enriched in each disease. Particularly in GPP there was a high number of differentially expressed genes, most of which (1797 out of 2151; 83.5%) were GPP specific, while in AGEP, 197 differentially expressed genes were identified, 0.5% of which were specific for AGEP.8 The association with medication use as a historically established differentiator between AGEP and GPP must also be considered with caution. Systemic corticosteroids (CS) are considered a trigger for both AGEP and GPP. In a recent literature case series of 297 patients on drug triggers for AGEP, systemic CS were reported as a rare cause with a prevalence of <1%,7 whereas several studies identified systemic CS as a frequent trigger of GPP (in up to 41.8% of cases).9-12 Thus, the probability of GPP triggered by CS appears to be higher than that of AGEP. With this case report, we aim to illustrate that (1) a clear distinction between AGEP and the first episode of GPP clinically and histologically may be virtually impossible, (2) a typical clinical picture of AGEP may also occur in GPP, and (3) ultimately only the observation of the further disease course can provide a definite diagnosis. Open access funding enabled and organized by Projekt DEAL. T.B. has been an advisor and/or received speakers' honoraria and/or received grants and/or participated in clinical trials of the following companies: Abbvie, ALK-Abello, Almirall, AstraZeneca, Bencard, Eli Lilly, Janssen- Cilag GmbH, Kiniksa, Leo Pharma GmbH, Mylan, Novartis, Sanofi, Philips, Biopharm, Thermo Fisher. R.M. has been an advisor and/or received speakers' honoraria and/or received grants and/or participated in clinical trials of the following companies: Abbvie, Almirall, Biogen IDEC GmbH, Boehringer-Ingelheim, Celgene, Janssen-Cilag GmbH, Leo Pharma GmbH, Lilly, MSD SHARP & DOHME GmbH, Novartis Pharma GmbH, Pfizer GmbH and UCB. M.P.S. has been an advisor and/or received speakers' honoraria and/or received grants and/or participated in clinical trials of the following companies: Abbvie, Almirall, Biogen, Boehringer-Ingelheim, Janssen-Cilag, Leo, Lilly, Novartis, UCB. N.R.K. reports no conflicts of interest.