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Acute generalized exanthematous pustulosis induced by piroxicam: A case report Y. Cherif, Moez Jallouli, M. Mseddi1, H. Turki1, Z. Bahloul
ABSTRACT
Departments of Internal Medicine, and 1Dermatology, Hedi Chaker University Hospital, Sfax, Tunisia
Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous reaction characterized by an acute episode of sterile pustules over erythematous‑edematous skin. The main triggering drugs are antibiotics, mainly beta‑lactam and macrolides. Non‑steroid anti‑inflammatory drugs may rarely be responsible. We describe a case of a woman with AGEP, who presented with generalized pustulosis lesions after the use of piroxicam for renal colic. The diagnosis was confirmed by the clinical and histological correlations and the dermatosis resolved after withdrawal of the drug.
Received: 27‑06‑2013 Revised: 30‑07‑2013 Accepted: 21‑01‑2014 Correspondence to: Dr. Moez Jallouli, E‑mail: [email protected]
KEY WORDS: Acute generalized exanthematous pustulosis, adverse drug reactions, piroxicam, pustulosis
Introduction Cutaneous adverse drug reactions are estimated to be about 30% of all adverse drug reactions and observed in 2‑3% of hospitalized patients.[1] The cutaneous drug reaction shows various clinical features and mechanisms.[1,2] Acute generalized exanthematous pustulosis (AGEP) is a generalized pustular eruption that is primarily drug‑induced in probably more than 90% of case.[3] In a few cases infections including cytomegalovirus [4] and parvovirus B19, [5] chlamydia and mycoplasma pneumoniae[6,7] have been suspected. A spider bite was recently implicated as a possible cause of AGEP in three patients.[8] Although various drugs have been implicated in this condition, there are no reported cases of AGEP caused by oral oxicams in the current literature. We report here a case of AGEP induced by piroxicam. Case Report This was a case report of a 61‑year‑old female patient who was admitted to internal medicine department for renal colic. She had no history of psoriasis or any other skin disorder. The patient had a history of longstanding arterial hypertension for 3 years treated with captopril, indapamide, nifedipine and diabetes mellitus for 3 years treated with glibenclamide, Access this article online Website: www.ijp‑online.com
Quick Response Code:
DOI: 10.4103/0253-7613.129332
232 Indian Journal of Pharmacology | April 2014 | Vol 46 | Issue 2
glimepiride and dyslipidemia treated with simvastatin. She was given oral piroxicam 20 mg/day by her primary care physician for treatment of renal colic. There were no other medications prior to starting piroxicam. At 4 days after starting oral piroxicam, she developed a generalized itchy eruption consisting of multiple papules that sometimes coalesced to larger and scaly plaques, on a background of widespread erythema with associated multiple 2‑3 mm pustules [Figure 1]. The mucus membranes, palms and soles were spared. Nikolsky’s sign was negative. The remaining physical examination was normal. Her white blood cell count was 10.8 × 103/mm3, with a 6.42 × 103/mm3 neutrophil count. The remaining laboratory tests performed were within the normal range: creatinine 61.1 µmol/l, erythrocyte rate sedimentation at 30 mm/h, C‑reactive protein 19.48 mg/l and Figure 1: Multiple papules and pustules that coalesced to larger and scaly plaques
Cherif, et al.: Piroxicam induced exanthematous pustulosis
her liver function tests were: Aspartate transaminase 38 U/ml, bilirubin 9 µmol/l and alkaline phosphatase 88 U/ml. A skin biopsy specimen revealed well‑developed subcorneal pustules associated with epidermal spongiosis. Scattered neutrophils as well as eosinophils were noted within the dermis (According to the EuroSCAR score, the most of criteria have been met by our patient who had a score of 9). Within a week of piroxicam withdrawal, the patient’s lesions gradually began clearing. The patient remained on the same therapies for her arterial hypertension, diabetes mellitus and dyslipidemia. Discussion AGEP is a rare pustular severe cutaneous adverse reaction that generally presents with an acute edematous erythema and small non‑follicular sterile pustules mostly beginning in folds or face and within hours becomes diffuse. Skin symptoms are almost always accompanied by fever (≥38°C) and leukocytosis with a high neurophil count (≥7000/μl). Other skin symptoms such as marked edema of the face, purpura, blisters and vesicles have been described.[3] Additional systemic manifestations include mild eosinophilia, lymphadenopathy, acute renal failure and a mild elevation of liver enzymes.[1,3,9] The multinational epidemiological case‑control study on severe cutaneous adverse reactions (EuroSCAR‑project) has developed and used the well‑defined EuroSCAR group criteria to establish the diagnosis of AGEP.[3] The accuracy of the EuroSCAR group criteria has been validated.[3,9] It allots 0, 1 or 2 points for each of 4 variables of morphology, −10, 0, 1, 2 or 3 for each of 5 variables of histological findings. In addition, it assigns −4, −2, 0 or 1 for each of 5 items of the disease’s course. Its involved items yield causality levels of definite with a scale at 8‑12 points, probable (5‑7 points), possible (1‑4 points) and excluded AGEP (0 point).[3] The range of the score is between −18 and 12. In our case, the EuroSCAR score was 9 and therefore, the case was specified as definite AGEP. Histological findings show subcorneal and/or intraepidermal pustules, with pronounced edema in the papillary dermis and a perivascular infiltrate of neutrophils and eosinophils.[3] A wide spectrum of cutaneous diseases or reactions is associated with pustular eruptions. [10] However, the chief differential diagnosis would include pustular psoriasis.[3,11] Most cases of AGEP have been attributed to drug reactions.[3] Roujeau et al.[12] found that 87% of cases resulted from drug reactions. Studies show that antibiotics were the most common drugs implicated (75%), with no attributes to non‑steroidal anti‑inflammatory drugs (NSAIDs). Furthermore, there is an increasing number of cases caused by anti‑fungals.[1,3,11] A study done by Chang et al.[9] analyzed 16 cases of AGEP with a relatively low association with systemic drugs (62.5%), there was no case of causative NSAIDs. There have been few cases implicating NSAIDs,[1] including ibuprofen,[13] diclofenac,[1,11] topical bufexamac, naproxen and phenylbutazone. [11] As corticosteroids are commonly used in the treatment of severe AGEP; they nevertheless, may trigger severe and rare AGEP.[14]
In this case, the clinical presentation and histology of a skin biopsy were consistent with AGEP. Resolution began without further use of piroxicam, which advocates the diagnosis in retrospect. The other medications (nifedipine, captopril, indapamide, glibenclamide, glimepiride and simvastatin) were continued. This association could have been strengthened by performing patch test with piroxicam.[11] Due to the self‑limited and benign course of this disease, treatment is usually not necessary except for symptomatic therapy and withdrawal of the culprit drug.[8] Some cases have been treated with intravenous hydrocortisone, oral prednisolone or methylprednisolone or topical agents alone.[9,10] Drugs like infliximab were used in an over lop of AGEP‑toxic epidermal necrolysis.[10] In our case, the withdrawal of piroxicam was sufficient to resolve all clinical features in only 1 week. References 1. Turk BG, Gunaydin A, Ertam I, Ozturk G. Adverse cutaneous drug reactions among hospitalized patients: Five year surveillance. Cutan Ocul Toxicol 2013;32:41‑5. 2. Wedi B. Definitions and mechanisms of drug hypersensitivity. Expert Rev Clin Pharmacol 2010;3:539‑51. 3. Sidoroff A, Halevy S, Bavinck JN, Vaillant L, Roujeau JC. Acute generalized exanthematous pustulosis (AGEP) – A clinical reaction pattern. J Cutan Pathol 2001;28:113‑9. 4. Haro‑Gabaldón V, Sánchez‑Sánchez‑Vizcaino J, Ruiz‑Avila P, Gutiérrez‑Fernández J, Linares J, Naranjo‑Sintes R. Acute generalized exanthematous pustulosis with cytomegalovirus infection. Int J Dermatol 1996;35:735‑7. 5. Calistru AM, Lisboa C, Cunha AP, Bettencourt H, Azevedo F. Acute generalized exanthematous pustulosis to amoxicillin associated with parvovirus B19 reactivation. Cutan Ocul Toxicol 2012;31:258‑61. 6. Lim CS, Lim SL. Acute generalized exanthematous pustulosis associated with asymptomatic Mycoplasma pneumoniae infection. Arch Dermatol 2009;145:848‑9. 7. Manzano S, Guggisberg D, Hammann C, Laubscher B. Acute generalized exanthematous pustulosis: First case associated with a Chlamydia pneumoniae infection. Arch Pediatr 2006;13:1230‑2. 8. Davidovici BB, Pavel D, Cagnano E, Rozenman D, Halevy S, EuroSCAR, et al. Acute generalized exanthematous pustulosis following a spider bite: Report of 3 cases. J Am Acad Dermatol 2006;55:525‑9. 9. Chang SL, Huang YH, Yang CH, Hu S, Hong HS. Clinical manifestations and characteristics of patients with acute generalized exanthematous pustulosis in Asia. Acta Derm Venereol 2008;88:363‑5. 10. Peermohamed S, Haber RM. Acute generalized exanthematous pustulosis simulating toxic epidermal necrolysis: A case report and review of the literature. Arch Dermatol 2011;147:697‑701. 11. Speeckaert MM, Speeckaert R, Lambert J, Brochez L. Acute generalized exanthematous pustulosis: An overview of the clinical, immunological and diagnostic concepts. Eur J Dermatol 2010;20:425‑33. 12. Roujeau JC, Bioulac‑Sage P, Bourseau C, Guillaume JC, Bernard P, Lok C, et al. Acute generalized exanthematous pustulosis. Analysis of 63 cases. Arch Dermatol 1991;127:1333‑8. 13. Rastogi S, Modi M, Dhawan V. Acute localized exanthematous pustulosis (ALEP) caused by Ibuprofen. A case report. Br J Oral Maxillofac Surg 2009;47:132‑4. 14. Ziemssen T, Bauer A, Bär M. Potential side effect of high‑dose corticosteroid relapse treatment: Acute generalized exanthematous pustulosis (AGEP). Mult Scler 2009;15:275‑7. Cite this article as: Cherif Y, Jallouli M, Mseddi M, Turki H, Bahloul Z. Acute generalized exanthematous pustulosis induced by piroxicam: A case report. Indian J Pharmacol 2014;46:232-3. Source of Support: Nil. Conflict of Interest: No.
Indian Journal of Pharmacology | April 2014 | Vol 46 | Issue 2 233
Copyright of Indian Journal of Pharmacology is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Acute generalized exanthematous pustulosis induced by piroxicam: A case report Y. Cherif, Moez Jallouli, M. Mseddi1, H. Turki1, Z. Bahloul
ABSTRACT
Departments of Internal Medicine, and 1Dermatology, Hedi Chaker University Hospital, Sfax, Tunisia
Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous reaction characterized by an acute episode of sterile pustules over erythematous‑edematous skin. The main triggering drugs are antibiotics, mainly beta‑lactam and macrolides. Non‑steroid anti‑inflammatory drugs may rarely be responsible. We describe a case of a woman with AGEP, who presented with generalized pustulosis lesions after the use of piroxicam for renal colic. The diagnosis was confirmed by the clinical and histological correlations and the dermatosis resolved after withdrawal of the drug.
Received: 27‑06‑2013 Revised: 30‑07‑2013 Accepted: 21‑01‑2014 Correspondence to: Dr. Moez Jallouli, E‑mail: [email protected]
KEY WORDS: Acute generalized exanthematous pustulosis, adverse drug reactions, piroxicam, pustulosis
Introduction Cutaneous adverse drug reactions are estimated to be about 30% of all adverse drug reactions and observed in 2‑3% of hospitalized patients.[1] The cutaneous drug reaction shows various clinical features and mechanisms.[1,2] Acute generalized exanthematous pustulosis (AGEP) is a generalized pustular eruption that is primarily drug‑induced in probably more than 90% of case.[3] In a few cases infections including cytomegalovirus [4] and parvovirus B19, [5] chlamydia and mycoplasma pneumoniae[6,7] have been suspected. A spider bite was recently implicated as a possible cause of AGEP in three patients.[8] Although various drugs have been implicated in this condition, there are no reported cases of AGEP caused by oral oxicams in the current literature. We report here a case of AGEP induced by piroxicam. Case Report This was a case report of a 61‑year‑old female patient who was admitted to internal medicine department for renal colic. She had no history of psoriasis or any other skin disorder. The patient had a history of longstanding arterial hypertension for 3 years treated with captopril, indapamide, nifedipine and diabetes mellitus for 3 years treated with glibenclamide, Access this article online Website: www.ijp‑online.com
Quick Response Code:
DOI: 10.4103/0253-7613.129332
232 Indian Journal of Pharmacology | April 2014 | Vol 46 | Issue 2
glimepiride and dyslipidemia treated with simvastatin. She was given oral piroxicam 20 mg/day by her primary care physician for treatment of renal colic. There were no other medications prior to starting piroxicam. At 4 days after starting oral piroxicam, she developed a generalized itchy eruption consisting of multiple papules that sometimes coalesced to larger and scaly plaques, on a background of widespread erythema with associated multiple 2‑3 mm pustules [Figure 1]. The mucus membranes, palms and soles were spared. Nikolsky’s sign was negative. The remaining physical examination was normal. Her white blood cell count was 10.8 × 103/mm3, with a 6.42 × 103/mm3 neutrophil count. The remaining laboratory tests performed were within the normal range: creatinine 61.1 µmol/l, erythrocyte rate sedimentation at 30 mm/h, C‑reactive protein 19.48 mg/l and Figure 1: Multiple papules and pustules that coalesced to larger and scaly plaques
Cherif, et al.: Piroxicam induced exanthematous pustulosis
her liver function tests were: Aspartate transaminase 38 U/ml, bilirubin 9 µmol/l and alkaline phosphatase 88 U/ml. A skin biopsy specimen revealed well‑developed subcorneal pustules associated with epidermal spongiosis. Scattered neutrophils as well as eosinophils were noted within the dermis (According to the EuroSCAR score, the most of criteria have been met by our patient who had a score of 9). Within a week of piroxicam withdrawal, the patient’s lesions gradually began clearing. The patient remained on the same therapies for her arterial hypertension, diabetes mellitus and dyslipidemia. Discussion AGEP is a rare pustular severe cutaneous adverse reaction that generally presents with an acute edematous erythema and small non‑follicular sterile pustules mostly beginning in folds or face and within hours becomes diffuse. Skin symptoms are almost always accompanied by fever (≥38°C) and leukocytosis with a high neurophil count (≥7000/μl). Other skin symptoms such as marked edema of the face, purpura, blisters and vesicles have been described.[3] Additional systemic manifestations include mild eosinophilia, lymphadenopathy, acute renal failure and a mild elevation of liver enzymes.[1,3,9] The multinational epidemiological case‑control study on severe cutaneous adverse reactions (EuroSCAR‑project) has developed and used the well‑defined EuroSCAR group criteria to establish the diagnosis of AGEP.[3] The accuracy of the EuroSCAR group criteria has been validated.[3,9] It allots 0, 1 or 2 points for each of 4 variables of morphology, −10, 0, 1, 2 or 3 for each of 5 variables of histological findings. In addition, it assigns −4, −2, 0 or 1 for each of 5 items of the disease’s course. Its involved items yield causality levels of definite with a scale at 8‑12 points, probable (5‑7 points), possible (1‑4 points) and excluded AGEP (0 point).[3] The range of the score is between −18 and 12. In our case, the EuroSCAR score was 9 and therefore, the case was specified as definite AGEP. Histological findings show subcorneal and/or intraepidermal pustules, with pronounced edema in the papillary dermis and a perivascular infiltrate of neutrophils and eosinophils.[3] A wide spectrum of cutaneous diseases or reactions is associated with pustular eruptions. [10] However, the chief differential diagnosis would include pustular psoriasis.[3,11] Most cases of AGEP have been attributed to drug reactions.[3] Roujeau et al.[12] found that 87% of cases resulted from drug reactions. Studies show that antibiotics were the most common drugs implicated (75%), with no attributes to non‑steroidal anti‑inflammatory drugs (NSAIDs). Furthermore, there is an increasing number of cases caused by anti‑fungals.[1,3,11] A study done by Chang et al.[9] analyzed 16 cases of AGEP with a relatively low association with systemic drugs (62.5%), there was no case of causative NSAIDs. There have been few cases implicating NSAIDs,[1] including ibuprofen,[13] diclofenac,[1,11] topical bufexamac, naproxen and phenylbutazone. [11] As corticosteroids are commonly used in the treatment of severe AGEP; they nevertheless, may trigger severe and rare AGEP.[14]
In this case, the clinical presentation and histology of a skin biopsy were consistent with AGEP. Resolution began without further use of piroxicam, which advocates the diagnosis in retrospect. The other medications (nifedipine, captopril, indapamide, glibenclamide, glimepiride and simvastatin) were continued. This association could have been strengthened by performing patch test with piroxicam.[11] Due to the self‑limited and benign course of this disease, treatment is usually not necessary except for symptomatic therapy and withdrawal of the culprit drug.[8] Some cases have been treated with intravenous hydrocortisone, oral prednisolone or methylprednisolone or topical agents alone.[9,10] Drugs like infliximab were used in an over lop of AGEP‑toxic epidermal necrolysis.[10] In our case, the withdrawal of piroxicam was sufficient to resolve all clinical features in only 1 week. References 1. Turk BG, Gunaydin A, Ertam I, Ozturk G. Adverse cutaneous drug reactions among hospitalized patients: Five year surveillance. Cutan Ocul Toxicol 2013;32:41‑5. 2. Wedi B. Definitions and mechanisms of drug hypersensitivity. Expert Rev Clin Pharmacol 2010;3:539‑51. 3. Sidoroff A, Halevy S, Bavinck JN, Vaillant L, Roujeau JC. Acute generalized exanthematous pustulosis (AGEP) – A clinical reaction pattern. J Cutan Pathol 2001;28:113‑9. 4. Haro‑Gabaldón V, Sánchez‑Sánchez‑Vizcaino J, Ruiz‑Avila P, Gutiérrez‑Fernández J, Linares J, Naranjo‑Sintes R. Acute generalized exanthematous pustulosis with cytomegalovirus infection. Int J Dermatol 1996;35:735‑7. 5. Calistru AM, Lisboa C, Cunha AP, Bettencourt H, Azevedo F. Acute generalized exanthematous pustulosis to amoxicillin associated with parvovirus B19 reactivation. Cutan Ocul Toxicol 2012;31:258‑61. 6. Lim CS, Lim SL. Acute generalized exanthematous pustulosis associated with asymptomatic Mycoplasma pneumoniae infection. Arch Dermatol 2009;145:848‑9. 7. Manzano S, Guggisberg D, Hammann C, Laubscher B. Acute generalized exanthematous pustulosis: First case associated with a Chlamydia pneumoniae infection. Arch Pediatr 2006;13:1230‑2. 8. Davidovici BB, Pavel D, Cagnano E, Rozenman D, Halevy S, EuroSCAR, et al. Acute generalized exanthematous pustulosis following a spider bite: Report of 3 cases. J Am Acad Dermatol 2006;55:525‑9. 9. Chang SL, Huang YH, Yang CH, Hu S, Hong HS. Clinical manifestations and characteristics of patients with acute generalized exanthematous pustulosis in Asia. Acta Derm Venereol 2008;88:363‑5. 10. Peermohamed S, Haber RM. Acute generalized exanthematous pustulosis simulating toxic epidermal necrolysis: A case report and review of the literature. Arch Dermatol 2011;147:697‑701. 11. Speeckaert MM, Speeckaert R, Lambert J, Brochez L. Acute generalized exanthematous pustulosis: An overview of the clinical, immunological and diagnostic concepts. Eur J Dermatol 2010;20:425‑33. 12. Roujeau JC, Bioulac‑Sage P, Bourseau C, Guillaume JC, Bernard P, Lok C, et al. Acute generalized exanthematous pustulosis. Analysis of 63 cases. Arch Dermatol 1991;127:1333‑8. 13. Rastogi S, Modi M, Dhawan V. Acute localized exanthematous pustulosis (ALEP) caused by Ibuprofen. A case report. Br J Oral Maxillofac Surg 2009;47:132‑4. 14. Ziemssen T, Bauer A, Bär M. Potential side effect of high‑dose corticosteroid relapse treatment: Acute generalized exanthematous pustulosis (AGEP). Mult Scler 2009;15:275‑7. Cite this article as: Cherif Y, Jallouli M, Mseddi M, Turki H, Bahloul Z. Acute generalized exanthematous pustulosis induced by piroxicam: A case report. Indian J Pharmacol 2014;46:232-3. Source of Support: Nil. Conflict of Interest: No.
Indian Journal of Pharmacology | April 2014 | Vol 46 | Issue 2 233
Copyright of Indian Journal of Pharmacology is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
