Acute Generalized Exanthematous Pustulosis Associated with Ranolazine

Acute Generalized Exanthematous Pustulosis Associated With Ranolazine

Kurt Grelck, DO; Noelle Stewart, DO; Les Rosen, MD; Sean Sukal, MD

PRACTICE POINTS • Encountering an acute pustular reaction pattern should trigger the clinician to rule out acute generalized exanthematous pustulosis (AGEP). • Ranolazine, a new antianginal therapy, has been associated with AGEP. • Upon confirmation of AGEP, the patient’s recent medication history should be reviewed so the potential causative agent can be identified and withdrawn. copy Acute generalized exanthematous pustulosis of rapid onset on an erythematous base,2 often in (AGEP) is a potentially widespread, pustular, conjunction with fever, peripheral leukocytosis, and cutaneous eruption commonly associated with neutrophilia.3 Numerous drug therapies have been drug administration. We report a case of AGEP implicatednot in the etiology of AGEP, most commonly associated with the antianginal, anti-ischemic the β-lactam antibiotics, such as the penicillin deriv- agent ranolazine. The patient, an 83-year-old atives and cephalosporins.2 Typically, AGEP occurs man, had a validation score of 10 out of 12Do in soon after drug ingestion and resolves spontaneously, accordance with the EuroSCAR criteria (8-12 is shortly after the causative drug is discontinued. considered definitive), although it may have been Ranolazine is an antianginal, anti-ischemic medi- higher had blood work been performed prior to cation with an undetermined mechanism of action. diagnosis and treatment. After ranolazine was Its antianginal and anti-ischemic effects do not discontinued and a course of tapered oral pred- depend on reduced heart rate or blood pressure. At nisone was prescribed, the rash resolved with therapeutic levels, it inhibits the cardiac late sodium subsequent desquamation. current (INa), reducing the sodium-induced cal- Cutis.CUTIS 2015;96:E18-E21. cium overload in ischemic cardiac myocytes. Severe adverse reactions include angioedema; paresthesia; pancytopenia; and, in animal studies, tumorigenic- cute generalized exanthematous pustulosis ity.4 Herein we report a case of AGEP associated (AGEP) is a potentially widespread, pustular, with the use of ranolazine. cutaneous eruption. In 90% of cases, AGEP A 1,2 results from drug administration. It manifests as Case Report numerous subcorneal, nonfollicular, sterile pustules 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 Dr. Grelck is from Forefront Dermatology, Stevens Points, asymptomatic at the outset and became pruritic Wisconsin. Dr. Stewart is from Columbia Hospital, West Palm Beach, over time. For the last several years, the patient had Florida. Dr. Rosen is from Dermpath Diagnostics, Pompano Beach, been taking tamsulosin for benign prostatic hyper- Florida. Dr. Sukal is from the Sukal Skin Institute, Boca Raton, Florida. The authors report no conflict of interest. trophy and rosuvastatin for hyperlipidemia. Twelve Correspondence: Kurt Grelck, DO, 1809 Halstad Dr, Stevens Point, days prior to the exanthem, he had started taking WI 54482 ([email protected]). ranolazine for symptomatic ischemia until coronary

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angiography could be performed. He reported having evaluation, we discontinued ranolazine therapy and no associated fevers, chills, or malaise and had no prescribed the following tapered course of oral personal history of psoriasis, though he had a mater- prednisone: 60 mg daily for 4 days; 40 mg daily for nal history of the disorder. 3 days; 30 mg daily for 3 days; 20 mg daily for 3 days; Examination revealed numerous nonfollicular- 10 mg daily for 3 days; and 5 mg daily for 3 days). based pustules on diffuse erythematous patches Within a week after this regimen was initiated, the (Figure 1). There was no mucosal involvement rash showed improvement with eventual resolution and the skin was negative for the Nikolsky sign. and desquamation (Figure 4). Subsequently, the Spongiform intracorneal collections of neutrophils patient underwent successful angioplasty and mul- were visible on punch biopsy (Figures 2 and 3). tiple stent placement, which ultimately alleviated Periodic acid–Schiff stains for fungi were negative. his angina. The patient’s primary care physician had initiated a course of oral prednisone 5 mg daily, 3 days before Comment he presented to our outpatient dermatology clinic, Since its original description in 1968,5 AGEP has but it had little effect on the rash. Upon dermatologic been misdiagnosed and underreported. Due to its

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Figure 3. A cornified layer of epidermis with neutrophils, as visible on punch biopsy (H&E, original magni- fication ×630).

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

Figure 2. A punch biopsy showed spongiform intracorneal collections of neutrophils (H&E, original magnifica- Figure 4. Generalized desquamation following resolution ×200). tion of acute generalized exanthematous pustulosis.

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rarity and clinical resemblance to more common 24 hours of exposure to triggering antibiotics, pustular eruptions, such as exanthematous pustular whereas the median time to rash onset in response to psoriasis, the typical characteristics of AGEP were non–anti-infective agents was 11 days.8 This find- not clearly delineated until Beylot et al3 coined the ing is consistent with the delayed onset of symp- term AGEP in 1980. Since that time, formalized cri- toms experienced by our patient after initiating teria for the diagnosis and characterization of AGEP ranolazine therapy. have been published.1,2,6-8 The differential diagnosis of AGEP primarily Numerous drug therapies have been implicated includes pustular psoriasis, subcorneal pustulosis, in the etiology of AGEP, most commonly antimi- pustular folliculitis, DRESS (drug reaction with crobial agents, such as β-lactam antibiotics. Many eosinophilia and systemic symptoms) syndrome, other drugs, however, also have been identified bullous impetigo, and occasionally erythema multi- as potential causative agents,8 including but not forme and toxic epidermal necrolysis, with the latter limited to antifungal, anticonvulsant, and antihy- typically characterized by more mucous membrane pertensive agents. Other less common etiologies involvement.20 Biopsy does not always support a include viral infections,6,9-11 UV radiation, contrast definitive diagnosis; clinical correlation is often media, heavy metal exposure (eg, to mercury), necessary. Because of the EuroSCAR study, Sidoroff ingestion of urushiol (eg, in lacquered chicken), et al8 devised a clinical validation score based on and spider bites.2,8,12-16 Nevertheless, more than 90% morphology (presence of pustules and erythema, dis- of AGEP cases are attributed to drug exposure, with tribution, and eventual desquamation), histopathol- 80% of drug-induced cases believed to be caused ogy (presence of intraepidermal pustules, spongiosis, by antibiotics.1,8 and papillary edema), and disease course (duration The incidence of AGEP is estimated to be of symptoms, neutrophilia, fever, acute onset, and between 1 and 5 cases per million per year, using time to resolution).copy A definitive score is 8 to 12 (out inclusion criteria from the EuroSCAR study, a of 12), and our patient’s score was 10; the score may multinational, case-controlled, pharmacoepidemi- have been higher had blood work been performed, ologic study of severe cutaneous adverse reactions.8,16 but by the time the diagnosis was made the patient’s The condition seems to affect males and females conditionnot had improved enough to make laboratory equally.1,4 There are no reports of age or racial pre- workup unnecessary. dilection.1,6,17 It has been suggested that those with Several theories have been proposed to explain AGEP may have some form of psoriatic background.1 the pathophysiology of AGEP. Some hold that the Our patient had no personal history of inflammatoryDo causative agent induces the formation of antigen- skin disease, although his mother had psoriasis. antibody complexes, thereby activating the comple- The dermatitis presents as the sudden onset of ment system, which in turn produces neutrophil a diffuse exanthematous eruption, which typically chemotaxis.3,21 A more recent theory suggests that produces dozens to hundreds of sterile, nonfollicular, drug exposure causes drug-specific CD4 and CD8 superficial pustules on an erythematous and possi- cells to migrate into dermal and epidermal layers of bly edematous base. Atypical presentations include the skin.17 Both T cells and keratinocytes express target lesions, purpura, andCUTIS vesicles. The reaction IL-8, which attracts polymorphonuclear leukocytes, usually begins on the face or intertriginous areas of causing them to accumulate in the dermis and then flexural surfaces and quickly disseminates. Patients the epidermis. The different clinical presentations may experience burning or pruritus. Acute general- of AGEP may be attributed to other cytokines and ized exanthematous pustulosis may involve mucous interleukins that T cells express during this process. membranes but is usually limited to 1 location, most In the epidermis, CD8 cells kill keratinocytes, caus- often the oral mucosa.1,8,16,18 Systemic signs and ing focal necrosis and prompting the formation of symptoms include fever, lymphadenopathy, phar- subcorneal vesicles filled primarily with CD4 cells. yngitis, and hepatosplenomegaly. Unlike most drug CD4 and CD8 cells are then localized to the dermis allergies that demonstrate eosinophilia, AGEP is where neutrophils enter the vesicles, transforming associated with leukocytosis and neutrophilic pre- them into sterile pustules.6,16,17 dominance. Only 25% of affected patients exhibit Acute generalized exanthematous pustulosis has eosinophilia.1 Approximately 30% of patients in a been characterized as a type IV delayed hyper- retrospective analysis demonstrated abnormal renal sensitivity reaction, with affected patients often function,2 and there have been reports of mildly demonstrating positive patch testing or a history of elevated transaminases.8,19 prior sensitization to the perpetrating agent.18,19,21 In the EuroSCAR study, for reasons that Although there have been reports of positive patch were not apparent, symptoms developed within testing for certain drugs, the unknown sensitivity

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and specificity of such testing as well as preparation- (AGEP)-results of a multinational case-control study dependent variables may limit the diagnostic utility (EuroSCAR) [published online ahead of print September of this approach.21 The additional risk for inducing 13, 2007]. Br J Dermatol. 2007;157:989-996. AGEP by patch testing the suspected drug also is a 9. Rouchouse B, Bonnefoy M, Pallot B, et al. Acute general- consideration. Due to our patient’s definitive clinical ized exanthematous pustular dermatitis and viral infec- validation score, we did not perform this test.21 tion. Dermatologica. 1986;173:180-184. The AGEP eruption is typically self-limited and 10. Naides SJ, Piette W, Veach LA, et al. Human parvovirus tends to resolve within 4 to 10 days after cessation of B19-induced vesiculopustular skin eruption. Am J Med. the triggering agent. Postpustular desquamation often 1988;84:968-972. occurs upon resolution of the primary lesions. Treatment 11. Feio AB, Apetato M, Costa MM, et al. Acute generalized usually involves discontinuation of the suspected caus- exanthematous pustulosis due to Coxsackie B4 virus [in ative agent and the use of antihistamines, antipyretics, Portuguese]. Acta Med Port. 1997;10:487-491. topical corticosteroids, and emollients. Although there 12. Goh TK, Pang SM, Thirumoorthy T, et al. Acute gen- are reports of AGEP responsiveness to oral and intra- eralised exanthematous pustulosis and toxic epidermal venous steroids, such treatment rarely is required.8,16,22 necrolysis induced by carbamazepine. Singapore Med J. We prescribed a tapered course of oral prednisone due to 2008;49:507-510. our patient’s imminent need for angioplasty. 13. Ofuji S, Yamamoto O. Acute generalized exanthematous pustulosis associated with a human parvovirus B19 infec- Conclusion tion. J Dermatol. 2007;34:121-123. This case of AGEP induced by ranolazine is notable. 14. Davidovici BB, Pavel D, Cagnano E, et al. Given the potential widespread use of this antiangi- Acute generalized exanthematous pustulosis following nal medication and the severity of this potential a spider bite:copy report of 3 cases. J Am Acad Dermatol. adverse reaction, it is important for clinicians to 2006;55:525-529. recognize AGEP, discontinue ranolazine if deter- 15. Park YM, Park JG, Kang H, et al. Acute generalized mined to be a causative agent, and then initiate an exanthematous pustulosis induced by ingestion of lacquer appropriate alternative antianginal therapy. chicken. Br J Dermatol. 2000;143:230-232. 16. notHammerbeck AA, Daniels NH, Callen JP. REFERENCES Ioversol-induced acute generalized exanthematous 1. Roujeau JC, Bioulac-Sage P, Bourseau C, et al. Acute pustulosis: a case report. Arch Dermatol. 2009;145:683-687. generalized exanthematous pustulosis. analysis of 63 cases.Do 17. Halevy S. Acute generalized exanthematous pustulosis. Arch Dermatol. 1991;127:1333-1338. Curr Opin Allergy Clin Immunol. 2009;9:322-328. 2. Sidoroff A, Halevy S, Bavnick JN, et al. Acute generalized 18. Kim HJ, Jung KD, Lee KT, et al. Acute generalized exanthematous pustulosis (AGEP)–a clinical reaction pat- exanthematous pustulosis caused by diltiazem [pub- tern. J Cutan Pathol. 2001;28:113-119. lished online ahead of print February 28, 2011]. Ann 3. Beylot C, Bioulac P, Doutre MS. Acute generalized exan- Dermatol. 2011;23:108-110. thematic pustuloses (four cases) [in French]. Ann Dermatol 19. Speck LM, Wilkerson MG, Perri AJ, et al. Acute general- Venereol. 1980;107:37-48. ized exanthematous pustulosis caused by terazosin hydro- 4. Ranexa [package insert]. FosterCUTIS City, CA: Gilead Sciences, chloride. J Drugs Dermatol. 2008;7:395-397. Inc; December 2013. 20. Sidoroff A. Acute generalized exanthematous pustulosis 5. Baker H, Ryan TJ. Generalized pustular psoriasis. a clini- (AGEP). UpToDate Web site. http://www.uptodate.com cal and epidemiological study of 104 cases. Br J Dermatol. /contents/acute-generalized-exanthematous-pustulosis 1968;80:771-793. -agep?source=search_result&search=agep&selected 6. Guevara-Gutierrez E, Uribe-Jimenez E, Diaz-Canchola M, et al. Title=1~85. Updated March 18, 2015. Accessed Acute generalized exanthematous pustulosis: report of 12 cases October 6, 2015. and literature review. Int J Dermatol. 2009;48:253-258. 21. Mashiah J, Brenner S. A systemic reaction to patch test- 7. Chang SL, Huang YH, Yang CH, et al. Clinical mani- ing for the evaluation of acute generalized exanthematous festations and characteristics of patients with acute gen- pustulosis. Arch Dermatol. 2003;139:1181-1183. eralized exanthematous pustulosis in Asia. Acta Derm 22. Ibrahimi O, Gunawardane N, Sepehr A, et al. Venereol. 2008;88:363-365. Terbinafine-induced acute generalized exanthematous 8. Sidoroff A, Dunant A, Viboud C, et al. Risk factors pustulosis (AGEP) responsive to high dose intravenous for acute generalized exanthematous pustulosis corticosteroid. Dermatol Online J. 2009;15:8.

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