International Journal of Cardiology 191 (2015) 11–12
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Ticagrelor-induced acute generalized exanthematous pustulosis☆ Ryan J. Maybrook a,⁎, Ryan Fischer b, Brent Deibert c, Ryan Gillihan c, Rachel Laarman b, Garth Fraga d, Daniel Aires b, Steven Gollub a a
University of Kansas Medical Center, Division of Cardiology, Kansas City, KS, United States University of Kansas Medical Center, Division of Dermatology, Kansas City, KS, United States University of Kansas School of Medicine, Kansas City, KS, United States d University of Kansas Medical Center, Department of Pathology and Laboratory Medicine, Kansas City, KS, United States b c
a r t i c l e
i n f o
Article history: Received 26 April 2015 Accepted 30 April 2015 Available online 1 May 2015 Keywords: Acute generalized exanthematous pustulosis Dual antiplatelet therapy Ticagrelor Clopidogrel P2Y12 antagonist
Reactions to antiplatelet drugs are not uncommon. With the proliferative use of dual antiplatelet therapy utilizing P2Y12 receptor inhibitors in the current era of medicine, a higher awareness is needed to identify such reactions. Various adverse reactions and side effects including exanthems and other hypersensitivity reactions are known to occur following the use of these agents [1]. We present a case in which the antiplatelet agent, ticagrelor, was given to a patient following coronary stent placement at the time of acute coronary syndrome. She then developed a diffuse, painful exanthem. Biopsy was performed and was consistent with acute generalized exanthematous pustulosis (AGEP). A discussion of AGEP and skin reactions to other antiplatelet agents follows. While cases of AGEP have been reported with clopidogrel, no cases have been previously reported with ticagrelor. A 65-year-old woman presented to the outpatient dermatology clinic with an extremely pruritic and painful generalized eruption of nine day duration that started two days after initiation of ticagrelor (Brilinta) for acute coronary syndrome. The patient had a history of significant coronary artery disease with a recent anterior wall ST elevation myocardial infarction (STEMI), end-stage renal disease on hemodialysis, ☆ Sources of support: None. ⁎ Corresponding author at: Division of Cardiovascular Diseases, University of Kansas Medical Center, 3901 Rainbow Boulevard, Room 1001 Eaton, MS 3006, Kansas City, KS 66160, United States. E-mail address: [email protected] (R.J. Maybrook).
http://dx.doi.org/10.1016/j.ijcard.2015.04.264 0167-5273/Published by Elsevier Ireland Ltd.
and diabetes mellitus. She underwent placement of two bare metal stents to the proximal and mid-left anterior descending artery, after which she was placed on ticagrelor 90 mg BID and aspirin 81 mg daily. Shortly after her eruption, ticagrelor was discontinued and clopidogrel was begun in its place in the outpatient setting. Physical exam showed generalized erythroderma with scattered sloughing, with accentuation on the abdomen and thighs. Several edematous plaques were studded with grouped pinpoint pustules (Fig. 1A and B). Importantly, no mucosal involvement of the eyes, oral mucosa, or genitalia was noted. Three biopsies were performed (Fig. 2), including pustular areas, and the patient was prescribed clobetasol ointment for symptomatic relief. She was admitted for excellent wound care given extensive dermatologic involvement. Admission labs revealed mild leukocytosis, with neutrophilic predominance and elevated eosinophils. Therefore, it was concluded that gross and histologic appearance was consistent with a diagnosis of acute generalized exanthematous pustulosis (AGEP). The patient received intravenous immunoglobulin (IVIg) on the night of the admission, but the IVIg was thought to have little impact on the course of treatment. The eruption improved over several days after discontinuation of ticagrelor, and the patient was subsequently discharged. The term, acute generalized exanthematous pustulosis, was originally introduced to the literature in 1980 by Beylot et al. [2]. AGEP is a rare cutaneous reaction characterized by a rapid, disseminated eruption of multiple non-follicular pustules generally beginning on the face and extending to the trunk and limbs. Mucosal involvement, usually oral, may be present in a minority of cases. It is often associated with fever and leukocytosis with neutrophilia during the acute phase [3,4]. In the majority of cases, a medication can be identified as the offending agent. More uncommon causes include infection, exposure to inorganic compounds such as mercury, and contrast agents [5]. The median time interval between drug exposure and development of symptoms is variable. An interval ranging from a few hours to 2–3 days for antibiotics and 1–3 weeks for non-antibiotic drugs has been reported [6]. The diagnosis of AGEP is suspected in a patient presenting with a characteristic exanthem within hours or days after starting a new drug. Histologic examination of a skin biopsy is generally necessary to confirm the diagnosis and rule out other similar widespread eruptions such as pustular psoriasis (von Zumbusch type), drug hypersensitivity syndrome (also referred to as DRESS [drug rash with eosinophilia and systemic symptoms]), or Stevens–Johnson syndrome/toxic epidermal necrolysis
12
R.J. Maybrook et al. / International Journal of Cardiology 191 (2015) 11–12
Fig. 1. (A) Grouped, non-follicular based pustule studding areas of edematous erythema on the chest and abdomen, surrounded by areas of superficial sloughing. (B) Non-follicular based pustule studding areas of edematous erythema on the proximal, lateral thigh.
(SJS/TEN) [4,5]. Since the gross morphologic appearance of AGEP is not pathognomonic, the histology is especially helpful to support the diagnosis. Typically, AGEP is a self-limiting disease and prompt withdrawal of the causative agent generally results in rapid resolution of the rash. Supportive care, including symptomatic treatment of pruritus and cutaneous inflammation, is often required. The eruption will generally resolve within four to ten days after withdrawal of the offending agent [3,5]. While used in some case reports, oral and/or intravenous systemic corticosteroids are usually not needed or recommended [6]. Ticagrelor, a reversible and non-competitive inhibitor at the P2Y12 platelet receptor, is commonly used following coronary stenting and in the treatment of acute coronary syndromes. While there are some welldocumented side effects of this agent, AGEP has never been described. In fact, no dermatologic reactions were reported in the initial ticagrelor trial [7]. This is in stark contrast to other currently utilized antiplatelet agents, such as clopidogrel (notably possessing a different mechanism of action compared to ticagrelor), which have well-described dermatologic hypersensitivity reactions [1]. Cases of AGEP have been previously reported with clopidogrel. In one case [8], clopidogrel was switched to ticlopidine with prompt resolution of the clinical manifestations of
AGEP. In another case [9], the clopidogrel was switched to ticagrelor. Other prior skin reactions reported with clopidogrel include type I hypersensitivity reaction with angioedema and urticaria [1] and SJS [10]. To date no cases of AGEP have been reported with prasugrel, another commonly used antiplatelet drug in the acute coronary syndrome setting. Dual antiplatelet therapy required following coronary stenting can usually be accomplished with the use of alternative antiplatelet medication. Desensitization has not been reported in the setting of antiplatelet drug-mediated AGEP. Furthermore, desensitization is mostly useful in cases of type 1 (immediate hypersensitivity) reactions, while AGEP appears to be driven by a T-cell mediated (delayed-type hypersensitivity) reaction [3]. To our knowledge, this is the first reported case of AGEP as a result of ticagrelor use. This case illustrates the need for prompt recognition of any significant dermatologic reaction following initiation of a new antiplatelet drug, cessation of the offending agent, and initiation of alternative antiplatelet drug in order to prevent stent thrombosis in a recently revascularized patient. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References
Fig. 2. Biopsy specimen demonstrated a large subcorneal pustule containing sheets of neutrophils (× 100, hematoxylin–eosin). The epidermis also contained microscopic spongiform pustules. There was a superficial dermal infiltrate of neutrophils and extravasated erythrocytes. Eosinophils were inconspicuous and vasculitis was absent.
[1] A.N. Cheema, et al., Characterization of clopidogrel hypersensitivity reactions and management with oral steroids without clopidogrel discontinuation, J. Am. Coll. Cardiol. 58 (14) (2011) 1445–1454. [2] C. Beylot, P. Bioulac, M.S. Doutre, Acute generalized exanthematic pustuloses (four cases) (author's transl), Ann. Dermatol. Venereol. 107 (1–2) (1980) 37–48. [3] S. Peermohamed, R.M. Haber, Acute generalized exanthematous pustulosis simulating toxic epidermal necrolysis: a case report and review of the literature, Arch. Dermatol. 147 (6) (2011) 697–701. [4] T.C. Kostopoulos, et al., Acute generalized exanthematous pustulosis: atypical presentations and outcomes, J. Eur. Acad. Dermatol. Venereol. 29 (2) (2015) 209–214. [5] A.A. Hammerbeck, N.H. Daniels, J.P. Callen, Ioversol-induced acute generalized exanthematous pustulosis: a case report, Arch. Dermatol. 145 (6) (2009) 683–687. [6] A. Sidoroff, et al., Acute generalized exanthematous pustulosis (AGEP)—a clinical reaction pattern, J. Cutan. Pathol. 28 (3) (2001) 113–119. [7] L. Wallentin, et al., Ticagrelor versus clopidogrel in patients with acute coronary syndromes, N. Engl. J. Med. 361 (11) (2009) 1045–1057. [8] J.C. Ellerbroek, M.G. Cleveland, Clopidogrel-associated acute generalized exanthematous pustulosis, Cutis 87 (4) (2011) 181–185. [9] C.A. Ulman, et al., Acute generalized exanthematous pustulosis induced by clopidogrel, Int. J. Dermatol. 53 (10) (2014) e461–e462. [10] Y.J. Jeung, et al., Comparison of the causes and clinical features of drug rash with eosinophilia and systemic symptoms and Stevens–Johnson syndrome, Allergy Asthma Immunol. Res. 2 (2) (2010) 123–126.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Ticagrelor-induced acute generalized exanthematous pustulosis☆ Ryan J. Maybrook a,⁎, Ryan Fischer b, Brent Deibert c, Ryan Gillihan c, Rachel Laarman b, Garth Fraga d, Daniel Aires b, Steven Gollub a a
University of Kansas Medical Center, Division of Cardiology, Kansas City, KS, United States University of Kansas Medical Center, Division of Dermatology, Kansas City, KS, United States University of Kansas School of Medicine, Kansas City, KS, United States d University of Kansas Medical Center, Department of Pathology and Laboratory Medicine, Kansas City, KS, United States b c
a r t i c l e
i n f o
Article history: Received 26 April 2015 Accepted 30 April 2015 Available online 1 May 2015 Keywords: Acute generalized exanthematous pustulosis Dual antiplatelet therapy Ticagrelor Clopidogrel P2Y12 antagonist
Reactions to antiplatelet drugs are not uncommon. With the proliferative use of dual antiplatelet therapy utilizing P2Y12 receptor inhibitors in the current era of medicine, a higher awareness is needed to identify such reactions. Various adverse reactions and side effects including exanthems and other hypersensitivity reactions are known to occur following the use of these agents [1]. We present a case in which the antiplatelet agent, ticagrelor, was given to a patient following coronary stent placement at the time of acute coronary syndrome. She then developed a diffuse, painful exanthem. Biopsy was performed and was consistent with acute generalized exanthematous pustulosis (AGEP). A discussion of AGEP and skin reactions to other antiplatelet agents follows. While cases of AGEP have been reported with clopidogrel, no cases have been previously reported with ticagrelor. A 65-year-old woman presented to the outpatient dermatology clinic with an extremely pruritic and painful generalized eruption of nine day duration that started two days after initiation of ticagrelor (Brilinta) for acute coronary syndrome. The patient had a history of significant coronary artery disease with a recent anterior wall ST elevation myocardial infarction (STEMI), end-stage renal disease on hemodialysis, ☆ Sources of support: None. ⁎ Corresponding author at: Division of Cardiovascular Diseases, University of Kansas Medical Center, 3901 Rainbow Boulevard, Room 1001 Eaton, MS 3006, Kansas City, KS 66160, United States. E-mail address: [email protected] (R.J. Maybrook).
http://dx.doi.org/10.1016/j.ijcard.2015.04.264 0167-5273/Published by Elsevier Ireland Ltd.
and diabetes mellitus. She underwent placement of two bare metal stents to the proximal and mid-left anterior descending artery, after which she was placed on ticagrelor 90 mg BID and aspirin 81 mg daily. Shortly after her eruption, ticagrelor was discontinued and clopidogrel was begun in its place in the outpatient setting. Physical exam showed generalized erythroderma with scattered sloughing, with accentuation on the abdomen and thighs. Several edematous plaques were studded with grouped pinpoint pustules (Fig. 1A and B). Importantly, no mucosal involvement of the eyes, oral mucosa, or genitalia was noted. Three biopsies were performed (Fig. 2), including pustular areas, and the patient was prescribed clobetasol ointment for symptomatic relief. She was admitted for excellent wound care given extensive dermatologic involvement. Admission labs revealed mild leukocytosis, with neutrophilic predominance and elevated eosinophils. Therefore, it was concluded that gross and histologic appearance was consistent with a diagnosis of acute generalized exanthematous pustulosis (AGEP). The patient received intravenous immunoglobulin (IVIg) on the night of the admission, but the IVIg was thought to have little impact on the course of treatment. The eruption improved over several days after discontinuation of ticagrelor, and the patient was subsequently discharged. The term, acute generalized exanthematous pustulosis, was originally introduced to the literature in 1980 by Beylot et al. [2]. AGEP is a rare cutaneous reaction characterized by a rapid, disseminated eruption of multiple non-follicular pustules generally beginning on the face and extending to the trunk and limbs. Mucosal involvement, usually oral, may be present in a minority of cases. It is often associated with fever and leukocytosis with neutrophilia during the acute phase [3,4]. In the majority of cases, a medication can be identified as the offending agent. More uncommon causes include infection, exposure to inorganic compounds such as mercury, and contrast agents [5]. The median time interval between drug exposure and development of symptoms is variable. An interval ranging from a few hours to 2–3 days for antibiotics and 1–3 weeks for non-antibiotic drugs has been reported [6]. The diagnosis of AGEP is suspected in a patient presenting with a characteristic exanthem within hours or days after starting a new drug. Histologic examination of a skin biopsy is generally necessary to confirm the diagnosis and rule out other similar widespread eruptions such as pustular psoriasis (von Zumbusch type), drug hypersensitivity syndrome (also referred to as DRESS [drug rash with eosinophilia and systemic symptoms]), or Stevens–Johnson syndrome/toxic epidermal necrolysis
12
R.J. Maybrook et al. / International Journal of Cardiology 191 (2015) 11–12
Fig. 1. (A) Grouped, non-follicular based pustule studding areas of edematous erythema on the chest and abdomen, surrounded by areas of superficial sloughing. (B) Non-follicular based pustule studding areas of edematous erythema on the proximal, lateral thigh.
(SJS/TEN) [4,5]. Since the gross morphologic appearance of AGEP is not pathognomonic, the histology is especially helpful to support the diagnosis. Typically, AGEP is a self-limiting disease and prompt withdrawal of the causative agent generally results in rapid resolution of the rash. Supportive care, including symptomatic treatment of pruritus and cutaneous inflammation, is often required. The eruption will generally resolve within four to ten days after withdrawal of the offending agent [3,5]. While used in some case reports, oral and/or intravenous systemic corticosteroids are usually not needed or recommended [6]. Ticagrelor, a reversible and non-competitive inhibitor at the P2Y12 platelet receptor, is commonly used following coronary stenting and in the treatment of acute coronary syndromes. While there are some welldocumented side effects of this agent, AGEP has never been described. In fact, no dermatologic reactions were reported in the initial ticagrelor trial [7]. This is in stark contrast to other currently utilized antiplatelet agents, such as clopidogrel (notably possessing a different mechanism of action compared to ticagrelor), which have well-described dermatologic hypersensitivity reactions [1]. Cases of AGEP have been previously reported with clopidogrel. In one case [8], clopidogrel was switched to ticlopidine with prompt resolution of the clinical manifestations of
AGEP. In another case [9], the clopidogrel was switched to ticagrelor. Other prior skin reactions reported with clopidogrel include type I hypersensitivity reaction with angioedema and urticaria [1] and SJS [10]. To date no cases of AGEP have been reported with prasugrel, another commonly used antiplatelet drug in the acute coronary syndrome setting. Dual antiplatelet therapy required following coronary stenting can usually be accomplished with the use of alternative antiplatelet medication. Desensitization has not been reported in the setting of antiplatelet drug-mediated AGEP. Furthermore, desensitization is mostly useful in cases of type 1 (immediate hypersensitivity) reactions, while AGEP appears to be driven by a T-cell mediated (delayed-type hypersensitivity) reaction [3]. To our knowledge, this is the first reported case of AGEP as a result of ticagrelor use. This case illustrates the need for prompt recognition of any significant dermatologic reaction following initiation of a new antiplatelet drug, cessation of the offending agent, and initiation of alternative antiplatelet drug in order to prevent stent thrombosis in a recently revascularized patient. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References
Fig. 2. Biopsy specimen demonstrated a large subcorneal pustule containing sheets of neutrophils (× 100, hematoxylin–eosin). The epidermis also contained microscopic spongiform pustules. There was a superficial dermal infiltrate of neutrophils and extravasated erythrocytes. Eosinophils were inconspicuous and vasculitis was absent.
[1] A.N. Cheema, et al., Characterization of clopidogrel hypersensitivity reactions and management with oral steroids without clopidogrel discontinuation, J. Am. Coll. Cardiol. 58 (14) (2011) 1445–1454. [2] C. Beylot, P. Bioulac, M.S. Doutre, Acute generalized exanthematic pustuloses (four cases) (author's transl), Ann. Dermatol. Venereol. 107 (1–2) (1980) 37–48. [3] S. Peermohamed, R.M. Haber, Acute generalized exanthematous pustulosis simulating toxic epidermal necrolysis: a case report and review of the literature, Arch. Dermatol. 147 (6) (2011) 697–701. [4] T.C. Kostopoulos, et al., Acute generalized exanthematous pustulosis: atypical presentations and outcomes, J. Eur. Acad. Dermatol. Venereol. 29 (2) (2015) 209–214. [5] A.A. Hammerbeck, N.H. Daniels, J.P. Callen, Ioversol-induced acute generalized exanthematous pustulosis: a case report, Arch. Dermatol. 145 (6) (2009) 683–687. [6] A. Sidoroff, et al., Acute generalized exanthematous pustulosis (AGEP)—a clinical reaction pattern, J. Cutan. Pathol. 28 (3) (2001) 113–119. [7] L. Wallentin, et al., Ticagrelor versus clopidogrel in patients with acute coronary syndromes, N. Engl. J. Med. 361 (11) (2009) 1045–1057. [8] J.C. Ellerbroek, M.G. Cleveland, Clopidogrel-associated acute generalized exanthematous pustulosis, Cutis 87 (4) (2011) 181–185. [9] C.A. Ulman, et al., Acute generalized exanthematous pustulosis induced by clopidogrel, Int. J. Dermatol. 53 (10) (2014) e461–e462. [10] Y.J. Jeung, et al., Comparison of the causes and clinical features of drug rash with eosinophilia and systemic symptoms and Stevens–Johnson syndrome, Allergy Asthma Immunol. Res. 2 (2) (2010) 123–126.
![[Acute generalized exanthematous pustulosis].](/assets/img/hold.png)
