DOI: 10.1111/j.1468-3083.2011.04313.

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ORIGINAL ARTICLE

Cutaneous adverse drug reactions to allopurinol: 10 year observational survey of the dermatology department cagliari university (Italy)
L. Atzori,,* A.L. Pinna, L. Mantovani, C. Ferreli, M. Pau, M. Mulargia, N. Aste

Department of Dermatology, University of Cagliari, Cagliari, Italy Cattedra di Genetica Medica, University of Cagliari, Cagliari, Italy *Correspondence: L. Azori. E-mails: laura.atzori@libero.it; atzoril@unica.it

Abstract
Background Allopurinol is extensively prescribed for conditions associated with urate excess, despite being responsible for severe cutaneous adverse drug reactions (ADR). Objective A cross-sectional survey of allopurinol cases observed at the main Dermatology Department with inpatients facilities in southern Sardinia. (approx 560 836 inhabitants). Material and methods Data collection of all consecutive patients referred for ADR between 2001 and 2010. Causality assessment followed the WHO Collaborating Centre for Drug Monitoring criteria; illness severity score was adopted for toxic epidermal necrolysis (SCORTEN). Results Allopurinol was the culprit drug in 84 of 780 cutaneous ADR cases (10.7%; 8.4 cases year). Mean age was 74 years, 58% of the patients were female, 95% of patients required hospitalization. Clinical forms were maculo-papular eruptions (34 cases), Stevens-Johnson Syndrome Toxic Epidermal Necrolysis (31 cases), vasculitis (six cases), Drug Rash Eosinophilia and Systemic Symptoms (DRESS) (three cases), Acute Generalized Exanthematous Pustolosis (AGEP) (three cases), Pityriasis rosea-like eruption (three cases), lichenoid dermatitis (two cases), xed drug eruption (one case), erythroderma (one case). The indication for allopurinol prescription was asymptomatic hyper-uricemia in 95% of the patients. Twelve patients were under allopurinol dosage adjustment according to creatinine clearance. Final causality assessment was denite for 12% of the cases and probable for the remaining 88%. Full recovery was achieved in 88% of subjects; ten SJS TEN patients died (12% overall mortality; 32% mortality of the SJS TEN cases). Conclusion Considering the populations size of Southern Sardinia, is plausible that 1.5 100 000 Sardinian will be affected by allopurinol related ADR per year. Advanced age, and inappropriate allopurinol prescription were the main conditions affecting morbidity and mortality. Received: 4 February 2011; Accepted: 29 September 2011

Conicts of interest
None.

Funding sources
None.

Introduction
Severe skin adverse drug reactions (ADR) are a frequent cause of morbidity and mortality and allopurinol has been reported as one of the major responsable.15 This drug is a xanthine oxidase inhibThe authors state that the manuscript contains original unpublished work and it has not being submitted for publication elsewhere at the same time, neither as previous reports that might be regarded as redundant or duplicate publication of the same or very similar work.

itor and considered as rst choice therapy worldwide in the prevention and treatment of conditions with uric acid excess. Minor reactions presenting as skin rash are reported in about 2% of patients, while more severe reactions requiring drug discontinuation are rare (0.4%), but life-threatening.68 A reduction of adverse reactions incidence was suggested by adjusting the allopurinol doses in patients with impaired renal function.9 The recognition that oxypurinol, the main metabolite of allopurinol, may be the principal cause of delayed-type hypersensitivity10 and that

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Atzori et al.

oxypurinol concentrations are frequently elevated in patients with renal impairment has led to the widespread adoption of dosing guidelines, which advocate allopurinol dose reduction according to creatinine clearance. However, recent studies have suggested that adverse reactions, especially hypersensitive syndrome may occur even at low doses of allopurinol, which in turn fails to adequately treat hyperuricemia in gout.1113 As part of the activity of an intensive drug-surveillance programme, assessment of allopurinol cutaneous ADR frequency was judged a priority and a 10-year observational cross-sectional survey was conducted at the Dermatology Clinic of Cagliari University.

The case study was designed to collect as much information as possible on allopurinol skin ADR, and to extensively generate hypothesis which might be tested in future researches. The raw data are expressed in numbers and percentages, not statistically valuable in the absence of parameters, such as the number of prescriptions and the effective users of allopurinol, in the Sardinian population during the specied time period.

Results
Of 780 consecutive patients affected by cutaneous ADR, allopurinol was the culprit drug in 84 cases (10.7%), with a mean incidence of 8.4 cases year. Distribution of cases over the period of intensive monitoring is illustrated in Fig. 1. Mean age of the total sample was 74 year-old, ranging from 62 to 96 years; 50 (59%) patients were female. For reasons of the extension of the eruption and severity of symptoms, hospitalization was required in 81 (96%) patients. Clinical forms are described and listed by frequency in Table 1. Main reactions were maculo-papular eruptions, closely followed by the spectrum of Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). The drug rash with eosinophilia and systemic symptom (DRESS) resulted less frequent than expected, but only denite cases following the REGISCAR scoring were considered. Diagnostic challenge was represented by several reactions simulating more common dermatitis, such as the Pityriasis rosealike eruption and the lichenoid dermatitis. Some examples are shown in the gures: progression from severe maculo-papular reaction towards SJS TEN syndrome (Figs 2 and 3), as well as peculiar features, such as red-purple hue, groin and genital regions involvement. Peculiar reactions, such as acute generalized exanthematous pustolosis (AGEP), and confusing features, such as the presence of detachment area intermingled with a micro-pustular eruption, mucositis without skin detachment (Figs 46) or suspected vasculitis required biopsy and histological examination, as well as blood analysis for the nal assessment. The 31 (37%)

Materials and methods

From January 2001 until December 2010, all patients reporting allopurinol cutaneous adverse reactions were investigated at the Dermatology Department at Cagliari University (Italy). The Local Ethic Committee authorized the study, part of a more general investigation on Cutaneous ADR (N1880-25 04 01). Cases were selected among all patients affected by cutaneous ADR observed in the same period of time. All patients agreed to participate in the study and allopurinol cutaneous ADRs were recorded on magnetic support, including hospitalized and out-patients. Attention was paid not to duplicate cases. The diagnostic criteria followed the World Health Organization (WHO) Collaborating Centre for Drug Monitoring recommendations and included clinical features, circumstantial evidence, time relationships between taking the drug and rash onset, and exclusion of alternative diagnoses. For this purpose, accurate allergic and pharmacologic anamnesis, as well as a history of previous reactions to drugs were obtained from the patients and general practitioners. When allopurinol was not the principle drug suspected, the observation was excluded from the study. Routine blood and instrumental examinations were performed in all cases. A skin biopsy was performed in doubtful cases, when the histological examination was considered necessary for the differential diagnosis, and in all the suspected DRESS cases. Determination of HLA-B*5801 carriers is an examination only recently accessible in our University Genetic Laboratory and was performed in a minority of patients affected by SJS-TEN syndrome, recruited between 2005 and 2010. HLA-genotyping was performed by polymerase chain reaction amplication and reverse hybridization using sequence-specic oligonucleotide probes and sequence-specic primers (PCR-SSO PCR-SSP). Information on co-morbidity, indications for allopurinol administration, and eventual dosage adjustment on the basis of creatinine clearance were the main variables of interest. Evolution of the reaction and treatment performed were also recorded. For severe cutaneous ADR, additional information was collected adopting the REGISCAR criteria for DRESS and the illness severity score for toxic epidermal necrolysis (SCORTEN).1419 Final causality assessment followed the WHO Collaborating Centre for Drug Monitoring criteria.20 Mortality was calculated on the total sample (overall mortality) and specically in the severe cutaneous ADR subgroup.

Figure 1 Annual distribution of the allopurinol cutaneous adverse reactions observed at the Dermatology Department of Cagliari University.

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Cutaneous adverse reactions to allopurinol

Table 1 Allopurinol cutaneous adverse reactions: clinical manifestations ordered by frequency in a 10 year period
Clinical form Males Females 10 24 12 19 Number of cases (%) 34 (40) 31 (37) 18 (21) 4 (4.7) 9 (10.7) 33 30 21 6 (7.1) 3 (3.5) 3 (3.5) 6 (7.1) 1 (1.2) 3 (3.5) Number of hospitalized patient (%) 34 (40) 31 (37)

Maculo-papular eruption Severe cutaneous ADR StevensJohnson syndrome (SJS) Overlap SJS TEN Toxic epidermal necrolysis (TEN) Cutaneous vasculitis Pityriasis rosea-like eruption Drug rash with eosinophilia and systemic symptom (DRESS) Acute generalized exanthematous pustolosis (AGEP) Lichenoid dermatitis Fixed drug eruption Erytroderma Total

Figure 3 Same patient 24 h later: dramatic evolution into a TEN case.

12

3 (3.5)

3 (3.5)

11 10 10 34 50

2 (2.4) 1 (1.2) 1 (1.2) 84

0 0 1 (1.2) 81 (96.4)

patients affected by severe cutaneous adverse reactions (SJS TEN patients) were also evaluated following the illness severity score for toxic epidermal necrolysis (SCORTEN),1416 whose results are reported in Table 2. Lesion onset generally occurred 24 weeks after drug intake, but referral to a dermatologist occurred 23 weeks later. Prodromic u-like symptoms were reported by 24 (28%) patients; fever at referral was present in a minority of cases (16 patients; 19%). Peripheral blood eosinophilia (exceeding 0.45 109 L (450 lL; only three patients had value >0.7 109 L) was the most frequent haematological alteration (56 cases; 66%), followed by a slight

Figure 4 Atypical wide spread target lesions on the abdomen in a 82 year-old lady, nally diagnosed as SJS.

Figure 2 Allopurinol maculo-papular eruption at the moment of referral.

anaemia and lymphocytosis (45 cases; 53%); slight renal impairment (62 cases; 74%) and hepatic enzymes elevation (36 cases; 43%; only three patients with value >two folds the normal). An history of chronic renal impairment prior to the ADR development was positive in 59 cases (70%), and there was not a relevant worsening during the reaction course. Only three patients had an acute renal and hepatic involvement, persistent behind drug discontinuation and accompanied by hypereosinophilia, atypical lymphocytes, lymph nodes enlargement in more than two stations, fever. Cutaneous biopsy also suggested the nal diagnosis of DRESS (more than ve points at the REGISCAR scoring). The remaining four patient with a slight acute renal involvement were elderly, with a diffuse maculo-papular eruption (two cases) and cutaneous vasculitis (two cases), whose creatinine values rapidly recover after simple saline infusion. The HLA sequence-based typing conrmed the presence of HLA B*5801 in all the 18 patients affected by SJS TEN syndrome that were tested. Considering the HLA B*5801 allele frequency (28 1822; 1.5%) in the European populations data bank available on dbMHC (http://www.ncbi.nlm.nih.gov/projects/mhc/ihwg.cgi),

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Table 3 Indication to allopurinol administration and concomitant chronic renal insufciency in the studied population
Indication to allopurinol administration Number of cases (%) Chronic renal insufciency (%) 55 (65.4) 3 (3.5) 1 (1.2) Adjustment of dosage according to creatinine clearance 12 (14.3%) 0 0

Asymptomatic hyper-uricemia Gout Secondary hyper-uricemia

80 (95.3) 3 (3.5) 1 (1.2)

Table 4 Concomitant diseases in the studied population

Concomitant diseases Hypertensive heart disease Chronic renal failure Diabetes mellitus Chronic obstructive bronchopathy Other chronic heart diseases Lymphoma (nal stage) Number of cases (%) 68 (81) 59 (70.2) 36 (43) 12 (14.2) 7 (8.3) 1 (1.2)

Figure 5 Red purple diffuse erythema, rapidly evolved in a micro-pustules eruption, with areas of detachment and genital involvement. Histology conrmed the diagnosis of AGEP.

Figure 6 Severe mucositis in a DRESS case.

Table 2 Distribution of the SJS TEN cases on the basis of the SCORTEN score evaluation, following Bastuji-Garin et al.17
SCORTEN score (mortality risk %) 01 (3.2) 2 (12.1) 3 (35.8) 4 (58.3) >5 (90) Number of cases 0 6 10 5 10 Type of treatment Supportive treatment Supportive treatment + IVIg Supportive treatment + IVIg Transferred to intensive care unit Final outcome Recovered Recovered Recovered Deceased

there was a highly signicant increase of the carrier frequency in the allopurinol patients (18 18; 100%, P < 0.0000, OR = 65.07 (30.66138.09).

Indication to allopurinol administration (Table 3) was asymptomatic hyper-uricemia in the vast majority of the patients. The single case of secondary hyper-uricemia was due to a nal stage lymphoma. Concomitant diseases (Table 4), preceding the allopurinol ADR of several years were very frequent and related to patient age, ranging from hypertensive or chronic heart disease to diabetes mellitus, and chronic obstructive bronchopathy. Fifty percentage of the patients presented three conditions at the same time. Only 10 (12%) patients were taking just one drug prior to allopurinol being prescribed. All other patients were on three to more drugs daily. Concomitant drugs had not been changed in the month prior to the skin ADR, and were not discontinued or reduced in dosage, with no apparent inuence on the eruption recovery. Chronic renal insufciency was the second most frequent co-morbidity and only 12 patients (14.3%) were under allopurinol dosage adjustment according to creatinine clearance. Ten (12%) patients reported previous use of allopurinol with some kind of transitory or mild reaction, and were considered as exposed to an involuntary rechallenge. Final causality assessment classied as denite, 12% of the cases (involuntary rechallenge), and as probable, the remaining 88%. The main therapeutic measures were drug discontinuation, antihistamine administration, supportive care in all cases, while general corticosteroids (0.5 mg prednisone or equivalent) were used in non-responsive severe eruptions and DRESS. Intravenous immunoglobulines (IVIg) 2 g kg were administered in 15 SJS TEN patients, with a SCORTEN index of 34 (Table 2). Patients with a low SCORTEN were excluded from this kind of therapy as recovery is frequent with simple supportive care.

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Patients with SCORTEN values 5 were excluded, as mortality risk would have had negatively affected the drug efcacy judgment. Considering the total case study, complete recovery was seen in 88% of the cases. Hospitalization time ranged from 7 to 43 days. Ten (12%) patients affected by SJS TEN syndrome, with SCORTEN values 5 (Table 2), unfortunately died, despite the efforts of the local intensive care unit, where the patients had been immediately moved from the dermatology ward. All the patients treated with IVIg recovered completely. Mild sequelae, such as hyper-pigmentation and adnexial atrophy were present in about half of the patients treated with high dose IVIg and in all the patients who survived with supportive care. Mortality can be estimated at 12%, overall and 32%, considering the SJS TEN population. All DRESS cases recovered, but after a long period exceeding the 6 weeks.

Discussion
Adverse cutaneous reactions to allopurinol are frequent, often severe especially in elderly and medicated patients.25 Prescriptions have increased worldwide in the last decade, especially under the boost of low-cost generic drugs, because it remains the most effective, economic, orally administered treatment for all the conditions characterized by urate excess. An intensive cutaneous ADR monitoring has been in place at our Dermatology Clinic since 1995, which is the reference public institution with inpatients facilities for the approximate 560 836 inhabitants in Southern Sardinia (data from the Italian National Statistics Institute (ISTAT), updated the 31 10 2009). Considering this catchments area and the 10-year period of observation, the mean annual frequency of 8.4 cases suggests a forecast of 1.5 100 000 inhabitants at risk of allopurinol skin ADR per year, and in particular 5.5 million inhabitants could manifest SJS TEN syndrome, with its consequent high mortality risk. Allopurinol induced DRESS 7,8,1416 was quite uncommon in our experience (3.5%; 0.3 cases per year, 0.5 cases million inhabitants), although eosinophilia, diffuse lymphadenopathy and transitory renal hepatic impairment were frequent in several other cases. Extremely restricted criteria in the diagnosis of DRESS1416 have been adopted at our centre: especially regarding the worsening of chronic renal insufciency, the assessment of acute renal hepatic impairment, the skin rash evaluation, including skin biopsy and time to recover. Therefore, only denite cases have been considered and underestimation is plausible, but our experience highlight that eventual possible DRESS cases do recover without major concern, when the drug is timely withdrawn. Medical major concern is the evolution of unrecognized and undervalued cutaneous rashes into DRESS. In our opinion, a correct intensive surveillance programme in elderly medicated patients taking allopurinol is the nal clue to avoid this risk. Susceptibility to such an idiosyncratic reaction, as well as to SJS TEN syndrome is thought to be genetically determined. The polymorphisms of the genes involved in allopurinol, and its metabolite oxypurinol, detoxication are under investigation world-wide. The role of HLA-B*5801 allele in predisposing to allo-

purinol severe cutaneous adverse reactions is still a controversial point in literature, especially in European studies.2123 Our experience in this eld is recent and preliminary, but HLA B*5801 was positive in all the SJS TEN patients (18 18) in whom the essay was performed. The comparison with the allele frequency in the general European population, according to the dbMHC database, conrmed a strong association, similar to what has been reported in Han Chinese patients.20 Furthermore, association of this peculiar HLA allele with natural killer cells function and cytotoxic response 24,25 might represent a missing link to the understanding of the complex allopurinol capacity to induce skin lesions. Experimental studies had demonstrated signicant T lymphocyte inltration of the affected tissue 26 and positive interferon gamma tests on patients lymphocytes.27 Probably, certain components of the immune system are affected differently by allopurinol, with a nal disequilibrium predisposing to drug reactions. Recent investigations have suggested that allopurinol directly inhibits the lymphocytes enzyme purine nucleoside phosphorylase 28 and an alteration of CD4 CD8 rate has been documented under chronic treatment with allopurinol, affecting the CD4 component. An augmented antibody response, with IgM deposits and circulating immune complexes 29 is probably secondary to altered interactions with the B cells.7 The allopurinol metabolite, oxypurinol has a marked ability to stimulate lymphocytes compared with control groups.7,10,30,31 The concomitant release of several mediators from eosinophils and or activation of neutrophils might be important for the clinical evolution of lesions, with appearance of pustules,28 or aggravation of skin detachment, as well as internal organ involvement in DRESS.7 Considering the spectrum of clinical manifestations and the severity of the skin involvement, our survey is characterized by a high incidence of severe reactions, requiring hospitalization and close monitoring for eventual progression towards SJS TEN syndrome. A certain selection of cases might have affected the study, as patients with very mild reactions are not normally referred to our specialized centre, being cared after by the general practitioner. The incidence of severe manifestations is probably low compared with the millions of persons receiving the drug, but taking together our results with prior studies, the use of allopurinol for asymptomatic hyper-uricemia should be avoided.712 Our experience is emblematic of the incongruous prescription of allopurinol: only four patients had primary indications for the treatment. A careful evaluation of the ADR risk should be performed in every patient: advanced age and number of medications (more than three drugs), including thiazide diuretics, which have been implicated in a reduction of allopurinol elimination.30 Although performed only in a minority of patients, dosage adjustment on the basis of renal function9 resulted ineffective in preventing ADR occurrence. Our experience conrms the opinion of several authors regarding the futility of this preventive measure. Cutaneous ADR treatment relies on prompt discontinuation of the drug, and supportive care.2,3234 DRESS cases responded well

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to corticosteroids, especially the renal functionality, but complete recover required a period of 69 weeks. Our limited experience with high dose IVIg in SJS TEN syndrome was encouraging: rapid improvement and full recovery was seen in all the 15 patients treated, with a SCORTEN index of 34, and a consequent mortality risk of 30-60%. Given the absence of validated therapies, the prole of IVIg in an hospital settings is promising and effective.3537 Furthermore, transfer to the intensive care units was extremely ineffective in ameliorating the recovery rate in our experience. The SCORTEN index was very helpful to evaluate prognosis.

Conclusion
Awareness of iatrogenic skin reaction is necessary to suspect diagnosis, and avoid any delay in taking the decision to discontinue the responsible drug, which remains the main therapeutic option. Allopurinol is a worldwide marketed drug, economical and effective, but inappropriate prescription is an increasing problem affecting morbidity and mortality. Clear indication for allopurinol should be checked and the patient monitored closely for the appearance of adverse reactions. Severe skin reactions might not be prevented by dosage adjustment according to the creatinine clearance rate and referral to an experienced dermatologist is recommended to avoid life-threatening conditions.

Acknowledgement
We thank Dr Barry Mark Wheaton for the linguistic assistance.

References
1 Hunziker T, Kunzi UP, Braunschweig S et al. Comprehensive hospital monitoring (CMDH): adverse skin reactions, a 20-year survey. Allergy 1997; 52: 388393. 2 Wolkenstein P, Revuz J. Drug-induced severe skin reactions. Incidence, management and prevention. Drug Saf 1995; 13: 5668. 3 Lin MS, Dai YS, Pwu RF et al. Risk estimates for drugs suspected of being associated with Stevens-Johnson syndrome and toxic epidermal necrolysis: a case-control study. Intern Med J 2005; 35: 188190. 4 Halevy S, Ghislain PD, Mockenhaupt M et al. Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. JAAD 2008; 58: 2532. 5 Russmann S, Lauterburg B. Life-threatening adverse effects of pharmacologic antihyperuricemic therapy. Ther Umsch 2004; 61: 575 577. 6 Mockenhaupt M, Viboud C, Dunant A et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol 2008; 128: 3544. 7 Arellano F, Sacristan JA. Allopurinol hypersensitivity syndrome: a review. Ann Pharmacother 1993; 27: 337343. 8 Begon E, Roujeau JC. Drug hypersensitivity syndrome: DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms). Ann Dermatol Venereol 2004; 131: 293297. 9 Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufciency. Am J Med 1984; 76: 4756. 10 Emmerson BT, Hazelton RA, Frazer IH. Some adverse reactions to allopurinol may be mediated by lymphocyte reactivity to oxypurinol. Arthritis Rheum 1988; 31: 436440.

11 Dalbeth N, Stamp L. Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events. Semin Dial 2007; 20: 391395. 12 Chao J, Terkeltaub R. A critical reappraisal of allopurinol dosing, safety, and efcacy for hyperuricemia in gout. Curr Rheumatol Rep 2009; 11: 135140. 13 Vazquez-Mellado J, Morales EM, Pacheco-Tena C, Burgos-Vargas R. Relation between adverse events associated with allopurinol and renal function in patients with gout. Ann Rheum Dis 2001; 60: 981983. 14 Bocquet H, Bagot M, Roujeau JC. Drug induced pseudolymphoma and drug hypersensitivity syndrome (DRSSS). Semin Cutan Med Surg 1996; 15: 250257. 15 Kardaun SH, Sidoroff A, Valeyrie-Allanore L et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist. Br J Dermatol 2007; 156: 609611. 16 Cacoub P, Musette P, Descamps V et al. The DRESS syndrome: a literature review. Am J Med 2011; 124: 588597. 17 Bastuji-Garin S, Fouchard N, Bertocchi M et al. SCORTEN: a severity of illness score for toxic epidermal necrolysis. J Invest Dermatol 2000; 115: 149153. 18 Guegan S, Bastuji-Garin S, Poszepczynska-Guigne E et al. Performance of the SCORTEN during the rst ve days of hospitalization to predict the prognosis of epidermal necrolysis. J Invest Dermatol 2006; 126: 272 276. 19 Trent JT, Kirsner RS, Romanelli P, Kerdel FA. Use of SCORTEN to accurately predict mortality in patients with toxic epidermal necrolysis in the United States. Arch Dermatol 2004; 140: 890892. 20 International drug monitoring: the role of national centres. Report of the WHO meeting. World Health Organ Rep Series 1972; 498: 125. 21 Tassaneeyakul W, Jantararoungtong T, Chen P et al. Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics 2009; 19: 704709. 22 Hung SI, Chung WH, Liou LB et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A 2005; 102: 41344139. 23 Lonjou C, Borot N, Sekula P et al. A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to ve high-risk drugs. Pharmacogenet Genomics 2008; 18: 99107. 24 Draghi M, Yawata N, Gleimer M et al. Single-cell analysis of the human NK cell response to missing self and its inhibition by HLA class I. Blood 2005; 105: 20282035. 25 Chung WH, Hung SI. Genetic markers and danger signals in StevensJohson syndrome and Toxic epidermal Necrolysis. Allergol Int 2010; 59: 325332. 26 Braden GL, Warzynski MJ, Golightly M, Ballow M. Cell-mediated immunity in allopurinol-induced hypersensitivity. Clin Immunol Immunopathol 1994; 70: 145151. 27 Halevy S, Cohen AD, Livni E. The diagnostic role of the in vitro druginduced interferon-gamma release test in Stevens-Johnson syndrome. Int J Dermatol 1999; 38: 835840. 28 Britschgi M, Pichler WJ. Acute generalized exanthematous pustulosis, a clue to neutrophil-mediated inammatory processes orchestrated by T cells. Curr Opin Allergy Clin Immunol 2002; 2: 325331. 29 Lockard O Jr, Harmon C, Nolph K, Irvin W. Allergic reaction to allopurinol with cross-reactivity to oxypurinol. Ann Intern Med 1976; 85: 333335. 30 Hamanaka H, Mizutani H, Nouchi N et al. Allopurinol hypersensitivity syndrome: hypersensitivity to oxypurinol but not allopurinol. Clin Exp Dermatol 1998; 23: 3234. 31 Young JL Jr, Boswell RB, Nies AS. Severe allopurinol hypersensitivity. Association with thiazides and prior renal compromise. Arch Intern Med 1974; 134: 553558.

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Cutaneous adverse reactions to allopurinol

32 Garcia-Doval I, LeCleach L, Bocquet H et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol 2000; 136: 323 327. 33 Schneck J, Fagot JP, Sekula P et al. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol 2008; 58: 3340. 34 Harr T, French LE. Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis 2010; 5: 39.

35 Trent J, Halem M, French LE, Kerdel F. Toxic epidermal necrolysis and intravenous immunoglobulin: a review. Semin Cutan Med Surg 2006; 25: 9193. 36 Prins C, Kerdel FA, Padilla RS et al. Toxic epidermal necrolysis-intravenous immunoglobulin. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol 2003; 139: 2632. 37 Viard I, Wehrli P, Bullani R et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 1998; 282: 490493.

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