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Case Report A CASE SERIES OF ALLOPURINOL-INDUCED TOXIC EPIDERMAL NECROLYSIS Harneet Ranu, Jackson Jiang, Pang Shiu Ming Abstract This is a case series of allopurinol-induced toxic epidermal necrolysis. Revisiting the indications of using allopurinol in asymptomatic hyperuricemia and a critical reappraisal of the safety profile of allopurinol is done in this article. The report is based on case presented at a tertiary hospital in Singapore. The aim of this study is to highlight the fatal consequences of the indiscriminate use of allopurinol. We report four cases of toxic epidermal necrolysis from allopurinol, three of which resulted in death. Our aim is to highlight that allopurinol in all these cases was not indicated and prescribed for asymptomatic hyperuricemia. The incidence and potentially severe and lethal consequences of allopurinol hypersensitivity syndrome and toxic epidermal necrolysis could be kept to a minimum by strictly adhering to the established indications of allopurinol treatment. Key Words: Allopurinol, hyperuricemia, toxic epidermal necrolysis Indian J Dermatol 2011:56(1):74-6
Introduction
was started on allopurinol for asymptomatic hyperuricemia. Ten days later, the patient developed painful blisters over the trunk that rapidly spread to involve more than 60% of her body involving her face, lips, eyes, oral and genital mucosa. [Figures 1 and 2] She was diagnosed as having toxic epidermal necrolysis which was confirmed by a skin biopsy, and she was given intravenous immunoglobulins (IVIG) 1 g/kg/day for 3 days. Blood work revealed a normal liver function and leukocytosis. Over the next couple of days, she developed low-grade fever. The erosions were slow to heal and cultures revealed secondary colonization with Pseudomonas and Candida. She also developed secondary pneumonia as seen on a chest X-ray which was treated with intravenous antibiotics. On day 21, she developed acute renal failure and severe sepsis with neutropenia and was managed by the infectious diseases physician. She continued to deteriorate despite intravenous antibiotics and specialized care at the burns unit. She died on day 25 of septicemic shock.
This study was conducted to highlight the indiscriminate usage of allopurinol that can sometimes result in catastrophic and lethal consequences. The aim of this study was to raise an awareness amongst medical practitioners who use allopurinol injudiciously for the treatment of asymptomatic hyperuricemia leading to potentially life threatening consequences to the patient. Toxic epidermal necrolysis is a commonly encountered condition at the Singapore General Hospital and most cases are due to allopurinol. This study was conducted to describe the rampant and frequently unjustified use of allopurinol resulting in toxic epidermal necrolysis. We report a case series of four cases linked to the unjustified use of allopurinol over the first 5 months of 2009. All four of these patients who developed TEN were elderly patients with comorbidities such as ischemic heart disease, hyperlipidemia, diabetes and hypertension. Three out of four patients died secondary to toxic epidermal necrolysis attributable to allopurinol.
Case 2
Case Reports
A 67-year-old Chinese man with ischemic heart disease, hypertension, hyperlipidemia and chronic atrial fibrillation had visited a general practitioner for a yearly health check up and found to have elevated uric acid levels. He was
Case 1 An 81-year-old Chinese lady with a past history of hypertension and diabetes mellitus was admitted for observation after a fall at home. During admission, her uric acid level was found to be raised at 945 µmol/L and she
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From the Dermatology unit, Block 6, Level 9, Singapore General Hospital, Singapore - 169 608, Singapore. Address for correspondence: Dr. Harneet Ranu, Dermatology unit, Block 6, Level 9, Singapore General Hospital, Outram Road, Singapore. E-mail:
[email protected] Indian Journal of Dermatology 2011; 56(1)
DOI: 10.4103/0019-5154.77557
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asymptomatic and suffered no symptoms of gout. Based on his uric acid levels alone, he was started on allopurinol by the general practitioner. Two weeks later, he was admitted to hospital with generalized painful blisters involving his face, trunk, limbs and mucosa, oral and genital. A skin biopsy confirmed toxic epidermal necrolysis. He was treated at the burns unit with prednisolone 1 mg/kg/ day and IVIG 1 g/kg/day for 5 days. His liver function was deranged twice that of normal and full blood count revealed leukocytosis. The total body surface area involved was 80%. He received specialized nursing care at the burns unit. The wounds became secondarily infected with Pseudomonas and were dressed with mepilex dressing and treated with intravenous antibiotics. Three weeks into the rash, he developed sudden hypotension and was found nonresponsive and pronounced dead after attempt to resuscitate him repeatedly failed. Cause of death still remains unclear.
Figure 1: Extensive erosions over the back of patient 1
Case 3 This is a 56-year-old Indonesian lady who was prescribed allopurinol by her general practitioner in Indonesia for back pain. According to her, uric acid levels tested in Indonesia were normal. Uric acid levels repeated at our hospital were normal. One month after taking allopurinol, she presented with generalized targetoid lesions over face, trunk and limbs, including tense blisters over the palms and soles, involving 30% of body surface area [Figure 3]. Toxic epidermal necrolysis was diagnosed by virtue of a skin biopsy. IVIG was commenced and the patient was nursed at the high dependency burns unit. Over the next 1 week, the epidermal detachment continued to progress to involve 70% of the body surface area. Herpes simplex type 1 was isolated from oral lesions and Candida from the buttocks and was treated with intravenous acyclovir and fluconazole. Her liver function showed cholestasis. An ultrasound and computerized tomography (CT) scan showed a pancreatic mass consistent with a pancreatic tumor. After a month of intensive treatment, the oral and cutaneous erosions healed and the patient was discharged well and opted for follow up in Indonesia for the pancreatic cancer.
Figure 2: Hemorrhagic cheilitis and mucositis seen in patient 1
Case 4 The fourth case is a 78-year-old Chinese lady who developed painful rashes over her eyes, face and oral mucosa, 3 weeks after being started on allopurinol by her physician for asymptomatically increased uric acid levels. She had underlying hypertension, dyslipidemia, ischemic heart disease and aortic stenosis. On admission, she had 50% body surface area involvement with severe facial and oropharnygeal involvement. Toxic epidermal necrolysis was confirmed by skin biopsy and IVIG 1 g/kg/day were instituted for 5 days. She was nursed at the burns unit. The epidermal detachment continued to progress, and after 1 week, it involved 90% of the body surface area. Her stay
Figure 3: Extensive denuded areas over buttocks of patient 3
was complicated by gram positive cocci bacteremia, and she was started on intravenous cloxacillin and ciprofloxacin. However, she developed overwhelming septicemia and disseminated intravascular coagulation resulting in death due to septicemic shock. 75
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Discussion
and toxic epidermal necrolysis most often present as a consequence of inappropriate treatment of asymptomatic hyperuricemia.[5,6] The incidence and potentially severe and lethal consequences of allopurinol hypersensitivity syndrome and toxic epidermal necrolysis could be kept to a minimum by strictly adhering to the established indications of allopurinol treatment. Some researchers believe that hyperuricemia is a risk factor for ischemic heart disease, and has been associated with diabetes mellitus, lipid abnormalities, hypertension and stroke. However, till date no direct role in the pathogenesis or outcome of these conditions has been confirmed.
Allopurinol is the first line drug for serum lowering therapy in gout and is approved by the US Food and Drug Administration (FDA). The Center for Pharmaceutical Administration, Health Sciences Authority (HSA) is the national agency that regulates medicinal and health-related products to safeguard public health. In addition to these four deaths, there have been 19 deaths reported in Singapore over the last 10 years as a result of TEN and allopurinol hypersensitivity syndrome. The US FDA has received a cumulative report of 23 cases of severe drug reactions to allopurinol over the period 2002–2009. Recently, HLA-B*5801 allele has been found to be an important genetic predisposition for severe cutaneous drug reactions in Han Chinese.
Alternative treatments are now emerging for the treatment of gout, including rasburicase[7] and febuxostat.[8-10] Febuxostat is a novel, potent, non-purine selective xanthine oxidase inhibitor. Clinical trials have demonstrated superior its ability to lower and maintain serum uric acid levels and is well tolerated. Febuxostat has been granted marketing authorization by the European Commission in early 2008 for the treatment of hyperuricemia and gout, and is the first major treatment alternative for gout in more than 40 years.
In a recent multinational study (Euro SCAR) of 379 patients with SJS and TEN by Halevy et al.,[1] allopurinol was found to be the most commonly associated drug causing StevensJohnson syndrome and toxic epidermal necrolysis in Europe and Israel. A daily dose greater than 200 mg was associated with higher risk than the lower doses. The risk was restricted to short-term use less than 8 weeks and co-medications did not appear to increase the risk.
References
Raised serum urate concentrations have been associated with insulin resistance, obesity, hypertension, dyslipidemia and atherosclerotic disease. For these reasons, urate lowering drugs were widely used in people with asymptomatic hyperuricemia in the past. No compelling evidence shows, however, that hyperuricemia causes cardiovascular disease which was previously thought.[2] About 5% of the population and a quarter of hospitalized patients are hyperuricemic. Most are asymptomatic and do not develop gout. In the Framingham study, 4.8% of the population was found to be hyperuricemic. Kelly estimated that 5–8% of the general population and up to 15% of hospitalized patients have elevated uric acid levels. Thus, allopurinol treatment for hyperuricemia alone would expose a large number of people to the drug with associated risks. Consequently, urate lowering agents should not be indicated and are not warranted in the treatment of asymptomatic hyperuricemia.[3] Long-term uric acid lowering therapy is indicated in gout with subcutaneous tophi, frequent attacks of gouty arthritis or urolithiasis. Uricosuric drugs are the first line for patients with decreased renal urate excretion. However, allopurinol is the most prescribed drug because of its efficacy, irrespective of the cause of the hyperuricemia, and due to its convenient once daily dosing. Therapeutic decisions have to take into account the imbalance between expected benefit and potential harm. In asymptomatic patients, therapeutic interventions must be effective in preventing complications or progression of disease with low risk of adverse events or deterioration of quality of life.[4] Treating asymptomatic hyperuricemia does not have clear benefits and our report shows the potential harm of this practice. Allopurinol hypersensitivity syndrome Indian Journal of Dermatology 2011; 56(1)
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