Acute Generalized Exanthematous Pustulosis Associated With Ranolazine

In the EuroSCAR study, for reasons that were not apparent, symptoms developed within 
24 hours of exposure to triggering antibiotics, whereas the median time to rash onset in response to 
non–anti-infective agents was 11 days.⁸ This finding is consistent with the delayed onset of symptoms experienced by our patient after initiating ranolazine therapy.

The differential diagnosis of AGEP primarily includes pustular psoriasis, subcorneal pustulosis, pustular folliculitis, DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome, bullous impetigo, and occasionally erythema multiforme and toxic epidermal necrolysis, with the latter typically characterized by more mucous membrane involvement.²⁰ Biopsy does not always support a definitive diagnosis; clinical correlation is often necessary. Because of the EuroSCAR study, Sidoroff et al⁸ devised a clinical validation score based on morphology (presence of pustules and erythema, distribution, and eventual desquamation), histopathology (presence of intraepidermal pustules, spongiosis, and papillary edema), and disease course (duration of symptoms, neutrophilia, fever, acute onset, and time to resolution). A definitive score is 8 to 12 (out of 12), and our patient’s score was 10; the score may have been higher had blood work been performed, but by the time the diagnosis was made the patient’s condition had improved enough to make laboratory workup unnecessary.

Several theories have been proposed to explain the pathophysiology of AGEP. Some hold that the causative agent induces the formation of antigen-antibody complexes, thereby activating the complement system, which in turn produces neutrophil chemotaxis.^3,21 A more recent theory suggests that drug exposure causes drug-specific CD4 and CD8 cells to migrate into dermal and epidermal layers of the skin.¹⁷ Both T cells and keratinocytes express IL-8, which attracts polymorphonuclear leukocytes, causing them to accumulate in the dermis and then the epidermis. The different clinical presentations of AGEP may be attributed to other cytokines and interleukins that T cells express during this process. In the epidermis, CD8 cells kill keratinocytes, causing focal necrosis and prompting the formation of subcorneal vesicles filled primarily with CD4 cells. CD4 and CD8 cells are then localized to the dermis where neutrophils enter the vesicles, transforming them into sterile pustules.^6,16,17

Acute generalized exanthematous pustulosis has been characterized as a type IV delayed hypersensitivity reaction, with affected patients often demonstrating positive patch testing or a history of prior sensitization to the perpetrating agent.^18,19,21 Although there have been reports of positive patch testing for certain drugs, the unknown sensitivity and specificity of such testing as well as preparation-dependent variables may limit the diagnostic utility of this approach.²¹ The additional risk for inducing AGEP by patch testing the suspected drug also is a consideration. Due to our patient’s definitive clinical validation score, we did not perform this test.²¹

The AGEP eruption is typically self-limited and tends to resolve within 4 to 10 days after cessation of the triggering agent. Postpustular desquamation often occurs upon resolution of the primary lesions. Treatment usually involves discontinuation of the suspected causative agent and the use of antihistamines, antipyretics, topical corticosteroids, and emollients. Although there are reports of AGEP responsiveness to oral and intravenous steroids, such treatment rarely is required.^8,16,22 
We prescribed a tapered course of oral prednisone due to our patient’s imminent need for angioplasty.

Conclusion

This case of AGEP induced by ranolazine is notable. Given the potential widespread use of this antianginal medication and the severity of this potential adverse reaction, it is important for clinicians to recognize AGEP, discontinue ranolazine if determined to be a causative agent, and then initiate an appropriate alternative antianginal therapy.