CASE REPORT
Acute Generalized Exanthematous Pustulosis Induced by Hydroxychloroquine: First Case Report in Canada and Review of the Literature Kristy Bailey, Daniel Mckee, Judy Wismer, and Neil Shear Background: Acute generalized exanthematous pustulosis (AGEP) is a rare drug eruption presenting with an acute, extensive formation of nonfollicular sterile pustules on an erythematous and edematous base. Typically, the rash is accompanied by fever and leukocytosis, with spontaneous resolution in , 15 days. The incidence of AGEP is estimated at one to five cases per million people per year. Only 18% of these are from nonantibiotics. Hydroxychloroquine (HCQ) is an antimalarial agent that is also used to treat various dermatologic and rheumatologic conditions. Objective: We report the first observation in Canada of a patient with AGEP induced by HCQ. Methods and Results: AGEP was diagnosed in a 48-year-old female who had been taking HCQ for 2 weeks and then developed a diffuse erythematous and edematous pustular eruption. Clinical and pathologic findings were consistent with a diagnosis of AGEP. The patient was treated with steroids and supportive measures. The rash resolved after 18 days and a complicated course in hospital. Conclusion: AGEP is a rare drug eruption, usually to antibiotics. We report the first case in Canada of AGEP as an adverse reaction to HCQ. Clinicians should keep in mind the possibility of this severe skin eruption. Contexte: La pustulose exanthe´mateuse aigue¨ ge´ne´ralise´e (PEAG) est une e´ruption rare, d’origine me´dicamenteuse, qui se manifeste par la formation e´tendue et aigue¨ de pustules ste´riles, non folliculaires, se de´veloppant sur un fond e´rythe´mateux et œde´mateux. Habituellement, l’e´ruption cutane´e, qui s’accompagne de fie`vre et de leucocytose, disparaıˆt d’elle-meˆme en moins de 15 jours. L’estimation de l’incidence de la PEAG est de 1 a` 5 cas pour un million de personnes, par anne´e; seuls 18% d’entre eux ne sont pas lie´s a` des antibiotiques. L’hydroxychloroquine (HCQ) est un antipaludique, mais elle sert aussi au traitement de diverses affections cutane´es et rhumatismales. Objectif: Il s’agit ici de la premie`re observation d’une patiente atteinte de PEAG provoque´e par l’HCQ, au Canada. Me´thode et re´sultats: Un diagnostic de PEAG a e´te´ pose´ chez une femme de 48 ans qui prenait de l’HCQ depuis 2 semaines et chez qui est apparue une e´ruption diffuse de pustules e´rythe´mateuses et œde´mateuses. Les signes cliniques et pathologiques e´taient compatibles avec ceux du diagnostic de PEAG. La patiente a e´te´ traite´e par les ste´roı¨des et des mesures d’appoint. L’e´ruption est disparue au bout de 18 jours, apre`s un se´jour a` l’hoˆpital pour des complications. Conclusions: La PEAG est une e´ruption rare, d’origine me´dicamenteuse, ge´ne´ralement attribuable aux antibiotiques. A e´te´ expose´ ici le premier cas de PEAG, au Canada, re´sultant d’une re´action de´favorable a` l’HCQ. Les cliniciens devraient se rappeler cette possibilite´ devant des cas graves d’e´ruption cutane´e.
CUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS (AGEP) is a rare pustular skin eruption often caused by an adverse drug reaction.1 A multinational
A
From the Departments of Dermatology and Plastic Surgery, McMaster University, Hamilton, ON, and the Department of Dermatology, University of Toronto, Toronto, ON. Address reprint requests: Kristy Bailey, MD, 86 Herkimer Street, Unit 44, Hamilton, ON L8P 2G7; e-mail: [email protected].
DOI 10.2310/7750.2013.12105 # 2013 Canadian Dermatology Association
414
case-control study estimated the incidence of AGEP at one to five cases per million people yearly.1 AGEP is characterized by an acute onset of numerous small, nonfollicular pustules on an erythematous background. Patients typically have fever ($ 38uC) with leukocytosis (neutrophil count $ 7.0 3 109/L), and spontaneous resolution usually occurs within 15 days.1 Typical histopathologic features include spongiform subcorneal and/or intraepidermal pustules, marked papillary edema, and polymorphous perivascular infiltrates with neutrophils and exocytosis of some eosinophils.2
Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 6 (November/December), 2013: pp 414–418
AGEP Induced by Hydroxychloroquine
Antibiotics are the most common causative agents of AGEP;3 however, there are rare case reports of non– antibiotic-induced AGEP.4 In a recent literature review by Paradisi and colleagues, only 16 cases of hydroxychloroquine (HCQ)-induced AGEP were reported worldwide over 14 years between January 1993 and December 2007.5 HCQ is classified as an antimalarial medication that acts as an immunosuppressive agent by entering the lysosome of antigen-presenting cells and raising the pH.6 This is thought to cause decreased intracellular processing and subsequent decreased immune cell functioning.7 HCQ also has antiinflammatory properties and is thought to act by blocking the activation of Toll-like receptors on plasmacytoid dendritic cells.8 These two properties have led to the use of HCQ in the treatment of various dermatologic and rheumatic disorders. This article describes the first case of AGEP induced by HCQ in Canada.
Case Report A 48-year-old white female patient with a 20-year history of untreated, mild systemic lupus erythematosus (SLE) developed discoid lupus on the scalp. The lesions persisted despite topical steroids, and she was started on HCQ 200 mg daily. Fourteen days later, the patient developed a pruritic rash on her face and neck. Over the next 2 days, she developed widespread erythema, scale, and studded pustules covering more than half of her body surface area (Figure 1). She had palmar erythema with greenish yellow pustules and swelling of the digits (Figure 2). She had prominent facial
Figure 1. Numerous nonfollicular, studded, and partially confluent pustules on an erythematous background on the back.
Figure 2. Diffuse erythema and edema on the palms with yellowgreen pustules, some coalescing into lakes of pus.
involvement and no mucosal involvement. She complained of chills, skin pain, lethargy, generalized aches, and nonspecific joint pain. She was found to be febrile, with a temperature of 38.2uC. She had a high white blood cell count with a left shift (neutrophil count 14.7 3 109/L). Her septic workup, including a chest radiograph, blood cultures, urine cultures, and other routine laboratory findings, was negative. At this time, a pustular drug reaction to HCQ or pustular psoriasis was suspected. The patient had no personal or family history of psoriasis. Three punch biopsies and swabs of the pustules were taken. The patient was started on intravenous methylprednisolone, and HCQ was discontinued. Cefazolin was started empirically with suspicion of bacterial skin superinfection. She continued to be febrile, with a rising leukocytosis. Cefazolin was replaced by piperacillin/tazobactam and vancomycin. Methylprednisolone was discontinued. The patient began to improve clinically, and her skin showed evidence of desquamation and healing on her hands and arms. Three days later, the patient developed pustules along the lateral and dorsal aspect of her tongue (Figure 3). Her lower legs and dorsal feet became edematous, with scattered large bullae on an erythematous to violaceous base (Figure 4). The allergy and immunology team did not suspect angioedema, and the infectious disease team did not suspect an antibiotic reaction. The worsening of her eruption and mucosal involvement was thought to be secondary to steroid withdrawal. Oral prednisone was therefore started at a dose of 50 mg daily. Antibiotics were continued.
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exocytosis of neutrophils with a perivascular and mixed infiltrate of lymphocytes, some neutrophils, and eosinophils in the upper dermis. There was no parakeratosis to suggest psoriasis. The patient was discharged home on a tapering dose of oral corticosteroid. She was followed in the dermatology clinic, and her skin lesions continued to resolve.
Discussion
Figure 3. Pustules on the lateral and dorsal body of the tongue with perioral crusting and facial erythema and edema.
The next day, the mucosal lesions had resolved and some of the bullae had opened, leaving erosions. All swabs of the pustules were negative, and all antibiotics were held. Over the next 4 days, the edema, erythema, and pustules began to resolve. Extensive superficial desquamation ensued over her entire body surface. All three biopsy reports were consistent with a diagnosis of AGEP. There were intraepidermal collections of neutrophils as well as subcorneal collections. There was edema of the papillary dermis, some spongiosis, and
Figure 4. Dorsal aspect of the feet with dusky erythema, edema, purpura, and a large bulla just proximal to the fifth metatarsophalangeal joint.
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Several different drugs have been implicated as the causative agent for AGEP. Antibiotics are the most common cause.3,9 Other rare causes include nonantibiotic medications, infections, contact dermatitis, and mercury hypersensitivity. A multinational case-control study covering a population base of 100 million people in six countries reported 97 cases of AGEP over 4 years.4 Only 7 of these cases were due to HCQ.4 Our literature search of PubMed using the terms acute generalized exanthematous pustulosis and hydroxychloroquine revealed only 17 Englishlanguage4,5,10–16 and 15 French-language17–22 case reports worldwide of HCQ causing AGEP from 1963 to the present. Of these cases, 26 were from Europe, 3 from Asia, 1 from South America, and 2 from North America. Both North American cases were from the United States. Based on our search, our patient is the first case of HCQ-induced AGEP reported in Canada. HCQ is a 2-[{4-[(7-chloroquinolin-4-yl)amino]pentyl} (ethyl)amino]ethanol that is excreted renally, with a half-life of 1 to 2 months.2 It was first used as an antimalarial agent. Due to its antiinflammatory and immunosuppressant properties described above, HCQ is now also being used to treat SLE, rheumatoid arthritis,23 polymorphous light eruption, atrophoderma of Perini and Pasini, juvenile chronic arthritis, and hepatic sarcoidosis.4 The most common adverse reaction is nausea and mild diarrhea. Cutaneous side effects are rare. It has been reported that only 3% of patients have discontinued HCQ due to adverse cutaneous reactions.24 HCQ can also worsen existing psoriasis and porphyria. Rarely, HCQ can cause StevensJohnson syndrome or toxic epidermal necrolysis (TEN).25,26 There have been reports of an AGEP-TEN overlap drug eruption.27,28 There is only one report of an AGEP-TEN overlap from HCQ administration.16 We describe a similar case that initially presented with features of AGEP and then developed mucosal lesions, dusky erythema, edema, and bullae on the lower legs and feet—features more consistent with TEN. A repeat biopsy was not performed. It can be argued that our case was solely AGEP and that the withdrawal of steroids provoked a flare in the eruption.
Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 6 (November/December), 2013: pp 414–418
AGEP Induced by Hydroxychloroquine
Edema of the face, purpura, vesicles, blisters, erythema multiforme–like lesions, and mucous membrane involvement have all also been described in cases of AGEP.3 Onset of TEN after administration of the causative agent ranges from a few days to 1 month. Our patient had an onset reaction time of 14 days. AGEP is typically regarded as having a rapid onset, within 1 day of treatment. However, a recent multinational case-control study of AGEP showed two different timing patterns.4 For antibiotic exposure, the median time to onset of AGEP was 1 day. For all other nonantibiotic medications, including HCQ, the median treatment duration prior to the onset of AGEP was 11 days, with a range of 4 to 30 days. From our literature search described above, all 32 cases reported timing of the reaction between 722 and 22 days.20 A recent multicenter, double– blinded, randomized, controlled trial of HCQ concentrationresponse relationships in rheumatoid arthritis reported a maximum blood concentration of HCQ at 5 to 6 weeks of treatment.29 This supports the clinical finding of a slow onset of AGEP after administration of HCQ. Eighteen days after the initial onset of the rash, and a complicated course in hospital, our patient had resolving skin lesions and was discharged home. The role of patch testing in drug eruptions is still under investigation. It has been estimated that 58% of AGEP patients will have positive patch tests. AGEP was reinduced in one of the patients.30 Patch testing was offered and declined by our patient. The labeling of HCQ has recently been changed to include AGEP among the potential adverse reactions listed. A recent review of AGEP reported that 2% of cases led to death. 17 Clinicians should be aware when prescribing HCQ that AGEP or an AGEP-TEN overlap picture can occur and it is essential to discontinue the medication as soon as possible if a pustular eruption occurs.
Acknowledgment Financial disclosure of authors and reviewers: None reported.
References 1. Sidoroff A, Halevy S, Bavinck JN, et al. Acute generalized exanthematous pustulosis (AGEP)—a clinical reaction pattern. J Cutan Pathol 2001;28:113–9, doi:10.1034/j.1600-0560.2001. 028003113.x. 2. Burrows NP, Russell Jones RR. Pustular drug eruptions: a histopathological spectrum. Histopathology 1993;22:569–73, doi: 10.1111/j.1365-2559.1993.tb00178.x.
3. Roujeau JC, Bioulac-Sage P, Bourseau C, et al. Acute generalized exanthematous pustulosis: analysis of 63 cases. Arch Dermatol 1991;127:1333–8, doi:10.1001/archderm.1991.01680080069004. 4. Sidoroff A, Dunant A, Viboud C, et al. Risk factors for acute generalized exanthematous pustulosis (AGEP)—results of a multinational case-control study (EuroSCAR). Br J Dermatol 2007;157: 989–96, doi:10.1111/j.1365-2133.2007.08156.x. 5. Paradisi A, Bugatti L, Sisto T, et al. Acute generalized exanthematous pustulosis induced by hydroxychloroquine: three cases and a review of the literature. Clin Ther 2008;30:930–40, doi: 10.1016/j.clinthera.2008.05.014. 6. Ohkuma S, Poole B. Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc Natl Acad Sci U S A 1978;75:3327–31, doi: 10.1073/pnas.75.7.3327. 7. Hurst NP, French JK, Gorjatschko L, et al. Chloroquine and hydroxychloroquine inhibit multiple sites in metabolic pathways leading to neutrophil superoxide release. J Rheumatol 1988;15:23–7. 8. Katz SJ, Russell AS. Re-evaluation of antimalarials in treating rheumatic diseases: re-appreciation and insights into new mechanisms of action. Curr Opin Rheumatol 2011;23:278–81, doi:10.1097/ BOR.0b013e32834456bf. 9. Gebhardt M, Lustig A, Bocker T, et al. Acute generalized exanthematous pustulosis (AGEP): manifestation of drug allergy to propicillin. Contact Dermatitis 1995;33:204–5, doi:10.1111/ j.1600-0536.1995.tb00553.x. 10. Friedman SJ. Pustular psoriasis associated with hydroxychloroquine. J Am Acad Dermatol 1987;16:1256–7, doi:10.1016/S01909622(87)80021-X. 11. Lotem M, Ingber A, Segal R, Sandbank M. Generalized pustular drug rash induced by hydroxychloroquine. Acta Derm Venereol 1990;70:250–1. 12. Assier-Bonnet H, Saada V, Bernier M, et al. Acute generalized exanthematous pustulosis induced by hydroxychloroquine. Dermatology 1996;193:70–1, doi:10.1159/000246211. 13. Evans CC, Bergstresser PR. Acute generalized exanthematous pustulosis precipitated by hydroxychloroquine. J Am Acad Dermatol 2004;50:650–1, doi:10.1016/S0190-9622(03)02733-6. 14. Martins A, Lopes LC, Paiva Lopes MJ, Rodrigues JC. Acute generalized exanthematous pustulosis induced by hydroxychloroquine. Eur J Dermatol 2006;16:317–8. 15. Park JJ, Yun SJ, Lee JB, et al. A case of hydroxychloroquine induced acute generalized exanthematous pustulosis confirmed by accidental oral provocation. Ann Dermatol 2010;22:102–5, doi:10.5021/ad.2010.22.1.102. 16. Lateef A, Tan KB, Lau TC. Acute generalized exanthematous pustulosis and toxic epidermal necrolysis induced by hydroxychloroquine. Clin Rheumatol 2009;28:1449–52, doi:10.1007/s10067-0091262-4. 17. Saissi EH, Beau-Salinas F, Jonville-Bera AP, et al. [Drugs associated with acute generalized exanthematic pustulosis]. Ann Dermatol Venereol 2003;130:612–8. 18. Degos R, Touraine R, Civatte J, et al. [Erythroderma with appearance of pustular psoriasis during a case of Duhring’s disease treated with hydroxychloroquine]. Bull Soc Fr Dermatol Syphiligr 1963;70:129–34. 19. Assier H, Auffret N, Beltzer-Garelly E, et al. [Acute generalized exanthematous pustulosis induced by hydroxychloroquine]. Ann Dermatol Venereol 1993;120:848–50.
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20. Bonnetblanc JM, Combeau A, Dang PM. [Hydroxychloroquine PUVA therapy photoinduced acute generalized exanthematous pustulosis]. Ann Dermatol Venereol 1995;122:604–5. 21. Fain O, Stirnemann J, Kettaneh A. [Acute generalized exanthematous pustulosis included by hydroxychloroquine during lupus]. Rev Prat 2010;60:20. 22. Djennane M, Tablit I, Billhot M, et al. [Acute generalized exanthematic pustulosis induced by hydroxychloroquine: case report]. Rev Med Interne 2010;31:e7–8. 23. Wallace DJ. The history of antimalarials. Lupus 1966;5 Suppl 1: S2–3. 24. Salido M, Joven B, D’Cruz DP, et al. Increased cutaneous reactions to hydroxychloroquine (Plaquenil) possibly associated with formulation change: comment on the letter by Alarco´n. Arthritis Rheum 2002;46:3392–6, doi:10.1002/art.10565. 25. Callaly EL, FitzGerald O, Rogers S. Hydroxychloroquine-associated, photo-induced toxic epidermal necrolysis. Clin Exp Dermatol 2008;33:572–4, doi:10.1111/j.1365-2230.2008.02704.x.
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26. Murphy M, Carmichael AJ. Fatal toxic epidermal necrolysis associated with hydroxychloroquine. Clin Exp Dermatol 2001;26: 457–8, doi:10.1046/j.1365-2230.2001.00857-3.x. 27. Meiss F, Helmbold P, Meykadeh N, et al. Overlap of acute generalized exanthematous pustulosis and toxic epidermal necrolysis: response to antitumour necrosis factor-alpha antibody infliximab: report of three cases, J Eur Acad Dermatol Venereol 2007;21:717–9. 28. Goh TK, Pang SM, Thirumoorthy T, et al. Acute generalised exanthematous pustulosis and toxic epidermal necrolysis induced by carbamazepine. Singapore Med J 2008;49:507–10. 29. Munster T, Gibbs JP, Shen D, et al. Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis. Arthritis Rheum 2002;46:1460–9, doi:10.1002/art.10307. 30. Barbaud A, Collet E, Milpied B, et al. A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions. Br J Dermatol 2013;168:555–62, doi:10.1111/bjd.12125.
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Acute Generalized Exanthematous Pustulosis Induced by Hydroxychloroquine: First Case Report in Canada and Review of the Literature Kristy Bailey, Daniel Mckee, Judy Wismer, and Neil Shear Background: Acute generalized exanthematous pustulosis (AGEP) is a rare drug eruption presenting with an acute, extensive formation of nonfollicular sterile pustules on an erythematous and edematous base. Typically, the rash is accompanied by fever and leukocytosis, with spontaneous resolution in , 15 days. The incidence of AGEP is estimated at one to five cases per million people per year. Only 18% of these are from nonantibiotics. Hydroxychloroquine (HCQ) is an antimalarial agent that is also used to treat various dermatologic and rheumatologic conditions. Objective: We report the first observation in Canada of a patient with AGEP induced by HCQ. Methods and Results: AGEP was diagnosed in a 48-year-old female who had been taking HCQ for 2 weeks and then developed a diffuse erythematous and edematous pustular eruption. Clinical and pathologic findings were consistent with a diagnosis of AGEP. The patient was treated with steroids and supportive measures. The rash resolved after 18 days and a complicated course in hospital. Conclusion: AGEP is a rare drug eruption, usually to antibiotics. We report the first case in Canada of AGEP as an adverse reaction to HCQ. Clinicians should keep in mind the possibility of this severe skin eruption. Contexte: La pustulose exanthe´mateuse aigue¨ ge´ne´ralise´e (PEAG) est une e´ruption rare, d’origine me´dicamenteuse, qui se manifeste par la formation e´tendue et aigue¨ de pustules ste´riles, non folliculaires, se de´veloppant sur un fond e´rythe´mateux et œde´mateux. Habituellement, l’e´ruption cutane´e, qui s’accompagne de fie`vre et de leucocytose, disparaıˆt d’elle-meˆme en moins de 15 jours. L’estimation de l’incidence de la PEAG est de 1 a` 5 cas pour un million de personnes, par anne´e; seuls 18% d’entre eux ne sont pas lie´s a` des antibiotiques. L’hydroxychloroquine (HCQ) est un antipaludique, mais elle sert aussi au traitement de diverses affections cutane´es et rhumatismales. Objectif: Il s’agit ici de la premie`re observation d’une patiente atteinte de PEAG provoque´e par l’HCQ, au Canada. Me´thode et re´sultats: Un diagnostic de PEAG a e´te´ pose´ chez une femme de 48 ans qui prenait de l’HCQ depuis 2 semaines et chez qui est apparue une e´ruption diffuse de pustules e´rythe´mateuses et œde´mateuses. Les signes cliniques et pathologiques e´taient compatibles avec ceux du diagnostic de PEAG. La patiente a e´te´ traite´e par les ste´roı¨des et des mesures d’appoint. L’e´ruption est disparue au bout de 18 jours, apre`s un se´jour a` l’hoˆpital pour des complications. Conclusions: La PEAG est une e´ruption rare, d’origine me´dicamenteuse, ge´ne´ralement attribuable aux antibiotiques. A e´te´ expose´ ici le premier cas de PEAG, au Canada, re´sultant d’une re´action de´favorable a` l’HCQ. Les cliniciens devraient se rappeler cette possibilite´ devant des cas graves d’e´ruption cutane´e.
CUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS (AGEP) is a rare pustular skin eruption often caused by an adverse drug reaction.1 A multinational
A
From the Departments of Dermatology and Plastic Surgery, McMaster University, Hamilton, ON, and the Department of Dermatology, University of Toronto, Toronto, ON. Address reprint requests: Kristy Bailey, MD, 86 Herkimer Street, Unit 44, Hamilton, ON L8P 2G7; e-mail: [email protected].
DOI 10.2310/7750.2013.12105 # 2013 Canadian Dermatology Association
414
case-control study estimated the incidence of AGEP at one to five cases per million people yearly.1 AGEP is characterized by an acute onset of numerous small, nonfollicular pustules on an erythematous background. Patients typically have fever ($ 38uC) with leukocytosis (neutrophil count $ 7.0 3 109/L), and spontaneous resolution usually occurs within 15 days.1 Typical histopathologic features include spongiform subcorneal and/or intraepidermal pustules, marked papillary edema, and polymorphous perivascular infiltrates with neutrophils and exocytosis of some eosinophils.2
Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 6 (November/December), 2013: pp 414–418
AGEP Induced by Hydroxychloroquine
Antibiotics are the most common causative agents of AGEP;3 however, there are rare case reports of non– antibiotic-induced AGEP.4 In a recent literature review by Paradisi and colleagues, only 16 cases of hydroxychloroquine (HCQ)-induced AGEP were reported worldwide over 14 years between January 1993 and December 2007.5 HCQ is classified as an antimalarial medication that acts as an immunosuppressive agent by entering the lysosome of antigen-presenting cells and raising the pH.6 This is thought to cause decreased intracellular processing and subsequent decreased immune cell functioning.7 HCQ also has antiinflammatory properties and is thought to act by blocking the activation of Toll-like receptors on plasmacytoid dendritic cells.8 These two properties have led to the use of HCQ in the treatment of various dermatologic and rheumatic disorders. This article describes the first case of AGEP induced by HCQ in Canada.
Case Report A 48-year-old white female patient with a 20-year history of untreated, mild systemic lupus erythematosus (SLE) developed discoid lupus on the scalp. The lesions persisted despite topical steroids, and she was started on HCQ 200 mg daily. Fourteen days later, the patient developed a pruritic rash on her face and neck. Over the next 2 days, she developed widespread erythema, scale, and studded pustules covering more than half of her body surface area (Figure 1). She had palmar erythema with greenish yellow pustules and swelling of the digits (Figure 2). She had prominent facial
Figure 1. Numerous nonfollicular, studded, and partially confluent pustules on an erythematous background on the back.
Figure 2. Diffuse erythema and edema on the palms with yellowgreen pustules, some coalescing into lakes of pus.
involvement and no mucosal involvement. She complained of chills, skin pain, lethargy, generalized aches, and nonspecific joint pain. She was found to be febrile, with a temperature of 38.2uC. She had a high white blood cell count with a left shift (neutrophil count 14.7 3 109/L). Her septic workup, including a chest radiograph, blood cultures, urine cultures, and other routine laboratory findings, was negative. At this time, a pustular drug reaction to HCQ or pustular psoriasis was suspected. The patient had no personal or family history of psoriasis. Three punch biopsies and swabs of the pustules were taken. The patient was started on intravenous methylprednisolone, and HCQ was discontinued. Cefazolin was started empirically with suspicion of bacterial skin superinfection. She continued to be febrile, with a rising leukocytosis. Cefazolin was replaced by piperacillin/tazobactam and vancomycin. Methylprednisolone was discontinued. The patient began to improve clinically, and her skin showed evidence of desquamation and healing on her hands and arms. Three days later, the patient developed pustules along the lateral and dorsal aspect of her tongue (Figure 3). Her lower legs and dorsal feet became edematous, with scattered large bullae on an erythematous to violaceous base (Figure 4). The allergy and immunology team did not suspect angioedema, and the infectious disease team did not suspect an antibiotic reaction. The worsening of her eruption and mucosal involvement was thought to be secondary to steroid withdrawal. Oral prednisone was therefore started at a dose of 50 mg daily. Antibiotics were continued.
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exocytosis of neutrophils with a perivascular and mixed infiltrate of lymphocytes, some neutrophils, and eosinophils in the upper dermis. There was no parakeratosis to suggest psoriasis. The patient was discharged home on a tapering dose of oral corticosteroid. She was followed in the dermatology clinic, and her skin lesions continued to resolve.
Discussion
Figure 3. Pustules on the lateral and dorsal body of the tongue with perioral crusting and facial erythema and edema.
The next day, the mucosal lesions had resolved and some of the bullae had opened, leaving erosions. All swabs of the pustules were negative, and all antibiotics were held. Over the next 4 days, the edema, erythema, and pustules began to resolve. Extensive superficial desquamation ensued over her entire body surface. All three biopsy reports were consistent with a diagnosis of AGEP. There were intraepidermal collections of neutrophils as well as subcorneal collections. There was edema of the papillary dermis, some spongiosis, and
Figure 4. Dorsal aspect of the feet with dusky erythema, edema, purpura, and a large bulla just proximal to the fifth metatarsophalangeal joint.
416
Several different drugs have been implicated as the causative agent for AGEP. Antibiotics are the most common cause.3,9 Other rare causes include nonantibiotic medications, infections, contact dermatitis, and mercury hypersensitivity. A multinational case-control study covering a population base of 100 million people in six countries reported 97 cases of AGEP over 4 years.4 Only 7 of these cases were due to HCQ.4 Our literature search of PubMed using the terms acute generalized exanthematous pustulosis and hydroxychloroquine revealed only 17 Englishlanguage4,5,10–16 and 15 French-language17–22 case reports worldwide of HCQ causing AGEP from 1963 to the present. Of these cases, 26 were from Europe, 3 from Asia, 1 from South America, and 2 from North America. Both North American cases were from the United States. Based on our search, our patient is the first case of HCQ-induced AGEP reported in Canada. HCQ is a 2-[{4-[(7-chloroquinolin-4-yl)amino]pentyl} (ethyl)amino]ethanol that is excreted renally, with a half-life of 1 to 2 months.2 It was first used as an antimalarial agent. Due to its antiinflammatory and immunosuppressant properties described above, HCQ is now also being used to treat SLE, rheumatoid arthritis,23 polymorphous light eruption, atrophoderma of Perini and Pasini, juvenile chronic arthritis, and hepatic sarcoidosis.4 The most common adverse reaction is nausea and mild diarrhea. Cutaneous side effects are rare. It has been reported that only 3% of patients have discontinued HCQ due to adverse cutaneous reactions.24 HCQ can also worsen existing psoriasis and porphyria. Rarely, HCQ can cause StevensJohnson syndrome or toxic epidermal necrolysis (TEN).25,26 There have been reports of an AGEP-TEN overlap drug eruption.27,28 There is only one report of an AGEP-TEN overlap from HCQ administration.16 We describe a similar case that initially presented with features of AGEP and then developed mucosal lesions, dusky erythema, edema, and bullae on the lower legs and feet—features more consistent with TEN. A repeat biopsy was not performed. It can be argued that our case was solely AGEP and that the withdrawal of steroids provoked a flare in the eruption.
Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 6 (November/December), 2013: pp 414–418
AGEP Induced by Hydroxychloroquine
Edema of the face, purpura, vesicles, blisters, erythema multiforme–like lesions, and mucous membrane involvement have all also been described in cases of AGEP.3 Onset of TEN after administration of the causative agent ranges from a few days to 1 month. Our patient had an onset reaction time of 14 days. AGEP is typically regarded as having a rapid onset, within 1 day of treatment. However, a recent multinational case-control study of AGEP showed two different timing patterns.4 For antibiotic exposure, the median time to onset of AGEP was 1 day. For all other nonantibiotic medications, including HCQ, the median treatment duration prior to the onset of AGEP was 11 days, with a range of 4 to 30 days. From our literature search described above, all 32 cases reported timing of the reaction between 722 and 22 days.20 A recent multicenter, double– blinded, randomized, controlled trial of HCQ concentrationresponse relationships in rheumatoid arthritis reported a maximum blood concentration of HCQ at 5 to 6 weeks of treatment.29 This supports the clinical finding of a slow onset of AGEP after administration of HCQ. Eighteen days after the initial onset of the rash, and a complicated course in hospital, our patient had resolving skin lesions and was discharged home. The role of patch testing in drug eruptions is still under investigation. It has been estimated that 58% of AGEP patients will have positive patch tests. AGEP was reinduced in one of the patients.30 Patch testing was offered and declined by our patient. The labeling of HCQ has recently been changed to include AGEP among the potential adverse reactions listed. A recent review of AGEP reported that 2% of cases led to death. 17 Clinicians should be aware when prescribing HCQ that AGEP or an AGEP-TEN overlap picture can occur and it is essential to discontinue the medication as soon as possible if a pustular eruption occurs.
Acknowledgment Financial disclosure of authors and reviewers: None reported.
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Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 6 (November/December), 2013: pp 414–418
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