Acute Generalized Exanthematous Pustulosis Associated With Ranolazine

Acute generalized exanthematous pustulosis (AGEP) is a potentially widespread, pustular, cutaneous eruption. In 90% of cases, AGEP results from drug administration.^1,2 It manifests as numerous subcorneal, nonfollicular, sterile pustules of rapid onset on an erythematous base,² often in conjunction with fever, peripheral leukocytosis, and neutrophilia.³ Numerous drug therapies have been implicated in the etiology of AGEP, most commonly the β-lactam antibiotics, such as the penicillin derivatives and cephalosporins.² Typically, AGEP occurs soon after drug ingestion and resolves spontaneously, shortly after the causative drug is discontinued.

Ranolazine is an antianginal, anti-ischemic medication with an undetermined mechanism of action. Its antianginal and anti-ischemic effects do not depend on reduced heart rate or blood pressure. At therapeutic levels, it inhibits the cardiac late sodium current (I_Na), reducing the sodium-induced calcium overload in ischemic cardiac myocytes. Severe adverse reactions include angioedema; paresthesia; pancytopenia; and, in animal studies, tumorigenicity.⁴ Herein we report a case of AGEP associated with the use of ranolazine.

Case Report

An 83-year-old man presented with a generalized rash of approximately 12 days’ duration. The patient reported that the small “pimple-like” bumps initially erupted on the back of the neck but gradually spread to the chest, back, and extremities. The lesions were asymptomatic at the outset and became pruritic over time. For the last several years, the patient had been taking tamsulosin for benign prostatic hypertrophy and rosuvastatin for hyperlipidemia. Twelve days prior to the exanthem, he had started taking ranolazine for symptomatic ischemia until coronary angiography could be performed. He reported having no associated fevers, chills, or malaise and had no personal history of psoriasis, though he had a maternal history of the disorder.

Examination revealed numerous nonfollicular-based pustules on diffuse erythematous patches (Figure 1). There was no mucosal involvement and the skin was negative for the Nikolsky sign. Spongiform intracorneal collections of neutrophils were visible on punch biopsy (Figures 2 and 3). Periodic acid–Schiff stains for fungi were negative.

Figure 1. Numerous nonfollicular-based pustules on diffuse erythematous patches.

Figure 2. A punch biopsy showed spongiform intracorneal collections of neutrophils (H&E, original magnification ×200).		Figure 3. A cornified layer of epidermis with neutrophils, as visible on punch biopsy (H&E, original magnification ×630).

The patient’s primary care physician had initiated a course of oral prednisone 5 mg daily, 3 days before he presented to our outpatient dermatology clinic, but it had little effect on the rash. Upon dermatologic evaluation, we discontinued ranolazine therapy and prescribed the following tapered course of oral prednisone: 60 mg daily for 4 days; 40 mg daily for 
3 days; 30 mg daily for 3 days; 20 mg daily for 3 days; 10 mg daily for 3 days; and 5 mg daily for 3 days). Within a week after this regimen was initiated, the rash showed improvement with eventual resolution and desquamation (Figure 4). Subsequently, the patient underwent successful angioplasty and multiple stent placement, which ultimately alleviated his angina.

Figure 4. Generalized desquamation following resolution of acute generalized exanthematous pustulosis.

Comment

Since its original description in 1968,⁵ AGEP has been misdiagnosed and underreported. Due to its rarity and clinical resemblance to more common pustular eruptions, such as exanthematous pustular psoriasis, the typical characteristics of AGEP were not clearly delineated until Beylot et al³ coined the term AGEP in 1980. Since that time, formalized criteria for the diagnosis and characterization of AGEP have been published.^1,2,6-8

Numerous drug therapies have been implicated in the etiology of AGEP, most commonly antimicrobial agents, such as β-lactam antibiotics. Many other drugs, however, also have been identified as potential causative agents,⁸ including but not limited to antifungal, anticonvulsant, and antihypertensive agents. Other less common etiologies include viral infections,^6,9-11 UV radiation, contrast media, heavy metal exposure (eg, to mercury), ingestion of urushiol (eg, in lacquered chicken), and spider bites.^2,8,12-16 Nevertheless, more than 90% 
of AGEP cases are attributed to drug exposure, with 80% of drug-induced cases believed to be caused 
by antibiotics.^1,8

The incidence of AGEP is estimated to be between 1 and 5 cases per million per year, using inclusion criteria from the EuroSCAR study, a multinational, case-controlled, pharmacoepidemiologic study of severe cutaneous adverse reactions.^8,16 The condition seems to affect males and females equally.^1,4 There are no reports of age or racial predilection.^1,6,17 It has been suggested that those with AGEP may have some form of psoriatic background.¹ Our patient had no personal history of inflammatory skin disease, although his mother had psoriasis.

The dermatitis presents as the sudden onset of a diffuse exanthematous eruption, which typically produces dozens to hundreds of sterile, nonfollicular, superficial pustules on an erythematous and possibly edematous base. Atypical presentations include target lesions, purpura, and vesicles. The reaction usually begins on the face or intertriginous areas of flexural surfaces and quickly disseminates. Patients may experience burning or pruritus. Acute generalized exanthematous pustulosis may involve mucous membranes but is usually limited to 1 location, most often the oral mucosa.^1,8,16,18 Systemic signs and symptoms include fever, lymphadenopathy, pharyngitis, and hepatosplenomegaly. Unlike most drug allergies that demonstrate eosinophilia, AGEP is associated with leukocytosis and neutrophilic predominance. Only 25% of affected patients exhibit eosinophilia.¹ Approximately 30% of patients in a retrospective analysis demonstrated abnormal renal function,² and there have been reports of mildly elevated transaminases.^8,19