Prolonged Pustular Eruption From Hydroxychloroquine: An Unusual Case of Acute Generalized Exanthematous Pustulosis

Comment

Acute generalized exanthematous pustulosis is characterized by the sudden appearance of erythema and hundreds of sterile nonfollicular pustules, fever, and leukocytosis. Histologically, AGEP is composed of subcorneal and intraepidermal pustules, edema of the papillary dermis, and perivascular infiltrates of neutrophils and possible eosinophils. The pathogenesis of AGEP is thought to be due to the release of increased amounts of IL-8 by T cells, which attract and activate polymorphonuclear neutrophils.¹ Psoriasiform changes are uncommon. Clinically, AGEP is similar to pustular psoriasis but has shown to be its own distinct entity. Unlike patients with pustular psoriasis, patients with AGEP lack a personal or family history of psoriasis or arthritis, have a shorter duration of pustules and fever, and have a history of new medication administration. Other conditions to consider in the differential diagnosis include pustular psoriasis, subcorneal pustulosis, IgA pemphigus, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens-Johnson syndrome, and acute febrile neutrophilic dermatosis.

In AGEP, the average duration of medication exposure prior to onset varies depending on the causative agent. Antibiotics consistently have been shown to trigger symptoms after 1 day, whereas other medications, including HCQ, averaged closer to 11 days. Hydroxychloroquine is widely used to treat rheumatic and dermatologic diseases and has previously been reported to be a less common cause of AGEP³; however, a EuroSCAR study found that patients treated with HCQ were at a greater risk for AGEP.² Acute generalized exanthematous pustulosis usually follows a benign self-limiting course. Within days the eruption gradually evolves into superficial desquamation. Characteristically, removal of the offending agent typically leads to spontaneous resolution in less than 15 days. Resolution is generally without complications and, therefore, treatment is not always necessary. Death has been reported in up to 2% of cases.⁸ There are no known therapies that prevent the spread of lesions or further decline of the patient’s condition. Systemic corticosteroids often are used to treat AGEP with variable results.^1,5

Unique to our patient were recurring exacerbations of the cutaneous lesions beyond the typical 15 days for complete resolution. Even up to 40 days after discontinuation of medication, our patient continued to experience cutaneous symptoms. Other reported cases have not described patients with symptoms flaring or continuing for this extended period of time. A review of 7 external AGEP cases caused by HCQ (identified through a PubMed search of articles indexed for MEDLINE using the search terms acute generalized exanthematous pustulosis or eruption with hydroxychloroquine or plaquenil) showed resolution within 8 days to 3 weeks (Table).^3-6,8 One case report documented disease exacerbation on day 18 after tapering the methylprednisolone dose. This patient was then treated with cyclosporine and had a prompt recovery.⁵ One case of AGEP due to terbinafine reported continual symptoms for approximately 4 weeks after terbinafine discontinuation.⁹ Our patient’s continual symptoms beyond the typical 15 days may be due to the long half-life of HCQ, which is approximately 40 to 50 days. Systemic corticosteroids often are used to control severe eruptions in AGEP and were administered to our patient; however, their utility in shortening the duration or reducing the severity of the eruption has not been proven.

Conclusion

Hydroxychloroquine is a commonly used agent for dermatologic and rheumatologic conditions. The rare but severe acute adverse event of AGEP warrants caution in HCQ use. Correct diagnosis of AGEP with HCQ cessation generally is effective as therapy. Our patient demonstrated that not all cases of AGEP show rapid resolution of cutaneous symptoms after cessation of the drug. Hydroxychloroquine’s extended half-life of 40 to 50 days surpasses that of other medications known to cause AGEP and may explain our patient’s symptoms beyond the usual course.