A 65-year-old man with a history of coronary artery disease, myocardial infarction, hypertension, hypereosinophilic syndrome, and chronic hepatitis B presented with a pruritic, generalized rash 3 weeks after initiating amlodipine for refractory hypertension. Physical examination demonstrated widespread indurated pink-red papules coalescing into plaques over the trunk, extremities, face, and scalp. Laboratory evaluation, including complete blood count, metabolic panel, and peripheral flow cytometry, was unremarkable. A skin biopsy revealed vacuolar interface change with a perivascular lymphocytic and granulomatous infiltrate containing eosinophils, consistent with an interstitial granulomatous drug reaction (IGDR). Amlodipine was discontinued and he was initiated on high-dose systemic and high-potency topical corticosteroids. Within 1 week, he experienced significant improvement in pruritus and had not developed any new lesions. Prednisone was successfully tapered without recrudescence of his rash. IGDR is an uncommon hypersensitivity reaction that is most associated with broadly prescribed cardiovascular medications such as calcium channel blockers (CCB) and statins. IGDR rests along a spectrum of reactive granulomatous dermatitides that are triggered by medications, autoimmune diseases, malignancies, or other underlying conditions. Recognition of IGDR by history, exam, and pathology is important for cardiologists and other prescribing clinicians, as its clinical presentation differs from more common drug exanthems as it can develop weeks to months after starting a CCB and can persist long after it is withdrawn. This case underscores the importance of maintaining vigilance for drug eruptions in patients presenting with new rashes while on antihypertensive therapy.
Clinical Vignette
A 65-year-old male with a history of idiopathic hypereosinophilic syndrome (on mepolizumab), chronic hepatitis B (on tenofovir), hyperlipidemia, coronary artery disease, prior anterior wall myocardial infarction with spontaneous reperfusion, and hypertension presented to the emergency department with a rapidly progressive, intensely pruritic, generalized rash. The rash began 5 days prior, first appearing on his upper and lower extremities and then involving the trunk, face, and scalp. He denied fever, weight loss, arthralgias, or systemic symptoms. He had started amlodipine 3 weeks prior for refractory hypertension despite taking metoprolol and valsartan. He otherwise denied any new medications or dose changes to existing medications. Physical examination revealed widespread indurated pink-red papules coalescing into plaques over the extremities, trunk, face, and scalp ( Figures 1 , 2 and 3 ). Standard labs including a complete blood count, complete metabolic panel, and peripheral flow cytometry were unremarkable.
Rash at presentation, consisting of indurated pink-red papules and plaques distributed across the face. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Rash at presentation, distributed across the trunk and extremities.
Rash at presentation, demonstrating the indurated pink-red papules and plaques on the flank. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Question 1: What is the Best Initial Step in the Management of This Patient?
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A.
Start systemic corticosteroids
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B.
Perform a skin punch biopsy
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C.
Obtain autoimmune serologies and neoplastic work-up
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D.
Empirically discontinue all antihypertensive medications
Question 1 Answer: B
A new, diffuse rash that erupts within a few weeks of starting a new medication should prompt a comprehensive evaluation, including a detailed medication timeline, review of systems, and often, a skin biopsy (B). In doing so, it is crucial to exclude severe cutaneous drug reactions associated with rapid and significant morbidity and mortality, including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). This patient’s rash is inconsistent with SJS/TEN, which is characterized by skin pain rather than pruritus, prominent mucosal involvement, dusky targetoid lesions, and epidermal necrosis/detachment. DRESS is a delayed hypersensitivity reaction with an onset of 2 to 6 or more weeks, which overlaps with this patient’s timeline. However, DRESS presents with systemic features (fever, facial edema), hematologic abnormalities (eosinophilia, atypical lymphocytes), and visceral involvement (transaminitis, acute interstitial nephritis), which were not seen. The benign, skin limited morbilliform drug eruptions (MDE) are the most common drug rashes and present as a blanching erythematous macules and papules that appear within days (often 5–14 days) of exposure and fade rapidly after withdrawal without sequalae.
As our patient’s history and exam is inconsistent with SJS/TEN, DRESS, and MDE, histopathology is essential for distinguishing among the other possibilities. Therefore, a punch biopsy was obtained. Histopathologic examination revealed patchy vacuolar interface degeneration and superficial to mid dermal perivascular lymphocytic and loosely granulomatous inflammation with eosinophils ( Figure 4 ). Altogether, the clinical and histopathologic features were consistent with a diagnosis of interstitial granulomatous drug reaction (IGDR).
