American Journal of Therapeutics 22, e77–e83 (2015)

Challenges in Diagnosis, Management, and Treatment of Allopurinol-Induced DRESS Syndrome: Case Report and Literature Review Jincy Thankachen, MD, MS1 and Vikram Agarwal, MD, MPH2*

We describe the presentation, diagnosis, management, and treatment of a 62-year-old woman with a medical history of gout who presented with a maculopapular rash, facial and tongue edema. Her initial presentation, coupled with a history of recent allopurinol use for systematic relief, led to the diagnosis of allopurinol-induced drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, further confirmed by the RegiSCAR scoring criteria including a skin biopsy. The patient was initially treated conservatively but required systemic corticosteroid therapy as she developed severe multi-organ dysfunction. This article will highlight the challenges involved in diagnosing DRESS syndrome from other adverse cutaneous drug reactions, delayed systemic complications, and the need for evidence-based treatment modalities and regimens using the most recent published literature and analysis of case reports. Among treatment modalities, pulsed parenteral steroids show promise in a few case reports. We also discuss the newer alternative gout therapies since the mainstay of gout treatment, allopurinol, is potentially associated with morbidity and mortality risks as manifested in our patient with DRESS. Keywords: allopurinol, DRESS syndrome, gout

Drug rash with eosinophilia and systemic symptoms (DRESS) is a clinical syndrome characterized by cutaneous drug eruption, fever, pharyngitis, eosinophilia, and systemic symptoms (lymphadenopathy, hepatitis, interstitial nephritis, and/or carditis). DRESS syndrome along with Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are among the major adverse cutaneous drug reactions. These patients often have a similar history that includes the introduction of a new drug in the last 1–6 weeks, precipitating the condition. This article describes a patient with allopurinol-associated DRESS syndrome, and the

Departments of 1Medicine and 2Cardiovascular Diseases,St Luke’s Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY. The authors have no conflicts of interest to declare. *Address for correspondence: St Luke’s Roosevelt Hospital Center, 515 West, 59th St, New York, NY 10019. E-mail: vagarwal@post. harvard.edu

dilemmas in diagnosis and treatment of this potentially fatal condition. We also conducted a literature review to examine the features of other cases of DRESS syndrome associated with allopurinol use and highlight recent alternative therapies for gout.

CASE REPORT A 62-year-old African American woman presented to the emergency department with a 1-week history of pruritis followed by an erythematous maculopapular rash. The rash began at the neck and progressed down to her chest, arms, face, and lower extremities, with sparing of the palms and soles. She was sent home with oral diphenhydramine. Two days later, the patient returned to the emergency department with a worsening rash (Figure 1) along with tongue and facial edema (Figure 2). No lymphadenopathy was noted. Her medical history was significant for diabetes mellitus (type 2), hypertension, and gout. The patient had a gout flare-up about 3 weeks before and was

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prescribed allopurinol by her primary doctor. After taking the allopurinol for 2 days, she obtained symptomatic relief, and she stopped using it. She started noticing the rash 2 weeks after allopurinol discontinuation. She was a high school science teacher by profession. In the emergency room, she had an overall flat affect, talked in monosyllables, and exhibited inappropriate behavior, such as unexpected laughter. Her initial blood tests were notable for a mild acute kidney injury (blood urea nitrogen 5 23 mg/dL, creatinine 5 1.2 mg/dL), transaminitis [aspartate aminotransferase (AST) 5 34 U/L, alanine aminotransferase (ALT) 5 116 U/L, and alkaline phosphatase 5 198 U/L], normocytic normochromic anemia (hemoglobin 5 11.9 g/dL and hematocrit 5 35.9%), and marked hypereosinophilia (16%). The patient had no leukocytosis. Dermatology was consulted, and a skin biopsy from the right thigh was sent. Based on the characteristic skin findings and distribution, she was initially admitted to the intensive care unit for suspicion of a cutaneous drug reaction because of allopurinol use. Using the Naranjo algorithm, the likelihood of this case being a probable adverse drug reaction was high.1 There was concern for underlying SJS, although the Nikolsky sign was negative. Although she was not in respiratory distress and had no stridor on physical examination, indirect laryngoscopy revealed mild glottidis. She was hemodynamically stable and started on intravenous immunoglobulins (IVIGs) and supportive management. Immediately after the

FIGURE 1. Initial presentation to the emergency department illustrates an erythematous maculopapular rash over the arms, with sparing of the palms. No superficial swelling, blistering, cellulitic, or desquamative changes are seen. American Journal of Therapeutics (2015) 22(3)

Thankachen and Agarwal

FIGURE 2. Facial edema is manifested here as lip swelling with blistering noted in the upper lip. No exfoliative changes or chelosis. Tongue swelling and erythema are also part of the initial presentation in the emergency department. Although not seen here, there was evidence of mild glottidis through indirect laryngoscopy.

initiation of IVIGs, she started experiencing rigors, fevers, and cough. Despite symptomatic management, her fevers persisted, ranging from 102 to 103.9°F. IVIGs were discontinued. Two days after admission, the skin biopsy results returned negative for SJS. It showed a mixed cell infiltrate with numerous eosinophils. Based on the constellation of symptoms along with the biopsy findings, the patient was diagnosed with DRESS syndrome. Using the RegiSCAR criteria, she scored a 6, indicating a definite case of DRESS syndrome.4 With supportive management, there was marked improvement of her skin and mucosal involvement, and the patient was transferred to the medical floor. However, the patient’s kidney function (blood urea nitrogen/ creatinine 5 53/2.9 mg/dL) and liver function (AST/ ALT 5 164/333 U/L and alkaline phosphatase 5 361 U/L) progressively worsened. The patient’s flat affect and inappropriate emotional responses continued to persist. Viral cultures, blood cultures, and urine cultures were all negative. Seven days after hospital admission, the patient’s metabolic profile displayed low albumin (2.3 g/dL), and an abnormal coagulation panel [international normalized ratio (INR) 5 1.6], all indicating signs of impending liver failure. In view of the worsening laboratory abnormalities, the patient was started on www.americantherapeutics.com

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Age Allopurinol (yrs)/ dose (mg/d)/ RegiSCAR sex duration (d) score*

Organs involved

HHV-6 status

Treatment (name/route/dose (mg))

Complications/ recurrence

Duration (d)

100/X

4

Skin, liver, renal

X

Steroids/IV/X

3

61/F

200/X

2

X

Steroids/IV/X

X

Caloguiri et al14

70/M

300/X

3

2ve

None

60/F

300/39

5

Potassium sodium citrate/ PO/200 Prednisone/PO/10–30

10

Sukuki et al15

Skin, renal, hematological Skin, respiratory, renal Skin, liver

Retroperitoneal hematoma, myocardial infarction Unknown

11

Masaki et al16

51/M

X/23

4

Skin, liver, brain

+ve

Chan et al17

X/M

X/21

3

Skin, liver

X

Prednisolone/IV/20 Prednisone/PO/40 Prednisone/PO/X

Yes with reintroduction of allopurinol None

X/M

X/21

3

Skin, liver

X

Prednisone/PO/X

X

Hamanaka et al18 44/M

100/X

4

Skin, liver, renal

X

30

83/M 52/F 63/M 80/M

100/1 200/9 X/X 300/42

Yoshikawa et al19 Guttierez-Macias et al20 43/F 300/3, 200/20 Chao et al21

2 2 3 4

Skin, renal Skin, liver Liver Skin, liver, brain

X X +ve X

Hydrocortisone sodium succinate/topical/200 Betamethasone/PO/X Prednisone/PO/X Steroids/X/X Prednisone/PO/60

6

X

Methylprednisolone/IV/20; prednisolone/PO/5

Shalom et al22 Suzuki et al23

X/7 X/X

4 4

Skin, liver, hematological, renal, lungs Skin, liver, renal Skin, liver

X +ve

X/X X/21 300/X

4 5 4

Prednisone/PO/40 Prednisolone/PO/0.75 mg/kg Prednisolone/PO/1 mg/kg None Methylprednisone/IV/60

65/M 77/F

53/F Descamps et al24 40/M Hassan et al25 73/M

Skin, renal, vasculitis Skin, pancreas, liver Skin, respiratory, renal, liver

+ve

2ve 2ve

2 3 days with taper X

14 X X Few days

Myocardial infarction Myocardial infarction None None None Unknown Death

BID/14, TID/14 Unknown with taper X X

/2 Unknown

X

/Skin None Unknown

BID/2

(Continued on next page)

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American Journal of Therapeutics (2015) 22(3)

84/F

Frackowiak et al13

Allopurinol and DRESS Syndrome

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Table 1. Summary of allopurinol-associated DRESS case reports.

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*RegiSCAR scoring criteria for DRESS syndrome with score of 2–3 5 possible case, 4–5 5 probable case, and .5 5 definite case.4 yrs, years; mg, milligrams; d, day; mg/d, milligrams/day; BID, twice daily; F, female; IV, intravenous; M, male; PO, oral; TID, 3 times daily; X, unknown/not specified; +ve, positive; 2ve, negative.

X 30 Steroids/X/X Dexamethasone/PO/8; dexchlorpheniramine/ PO/6 X 2ve Skin, liver, renal Skin, vasculitis, liver 5 3 X/90 100/75 70/M 54/M Yaylaci et al26 Ben Fredj et al27

Duration (d) Treatment (name/route/dose (mg)) HHV-6 status Organs involved Age Allopurinol (yrs)/ dose (mg/d)/ RegiSCAR score* sex duration (d)

Table 1. (Continued) Summary of allopurinol-associated DRESS case reports.

Death None

Thankachen and Agarwal Complications/ recurrence

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American Journal of Therapeutics (2015) 22(3)

oral prednisone (1 mg$kg21$d21). Three days after the initiation of steroids, the patient’s liver and kidney function started improving. In addition, there was a marked improvement in the patient’s speech and affect. She was gradually tapered off the oral steroids over a period of 6 weeks, and her follow-up laboratory tests and neurological examination have been normal at 3 months.

DISCUSSION DRESS is an idiosyncratic hypersensitivity response, characterized by a maculopapular erythematous eruption that typically develops 3–6 weeks after initiation of the culprit drug. It was first introduced in 1996 by Bocquet et al.2 The pathophysiology of DRESS syndrome remains unclear, but a defect in detoxification of the causative drug, immunological imbalance, and infections such as human herpes virus type 6 (HHV-6) have been proposed as possible underlying causative mechanisms. Reactivation of HHV-6 has also been suggested to be associated with a more severe form of DRESS.2,3 A scoring criteria, the RegiSCAR scoring system, was recently proposed to help differentiate DRESS syndrome from other severe adverse cutaneous drug reactions.4 In a recent review, 171 cases of DRESS syndrome have been reported in literature that fit the criteria.4 The organ systems are usually involved in a stepwise fashion and in order of frequency, which include the skin, liver, kidneys, lungs, heart, and, more rarely, central nervous system, thyroid, pancreas, colon, muscle, and serosa.3 Despite having clearly defined markers, the diagnosis of DRESS is challenging on multiple levels. The biggest challenge is posed by the dermatological involvement, with significant overlap in the presentations of maculopapular erythematous drug eruptions, such as SJS/TEN, acute generalized exanthematous pustulosis, and DRESS. All patients present with erythematous macules and plaques, often symmetric in distribution, and can also involve oral and genital areas. The timing of skin manifestations is also challenging regarding diagnosis as both DRESS and SJS/ TEN overlap, although SJS is usually within 1–3 weeks, and DRESS occurs within 6 weeks of drug initiation.5,6 There is no pathognomonic pattern of skin rash for DRESS.4 Some clinical signs distinguishing DRESS apart from other maculopapular drug eruptions includes systemic symptoms and negative Nikolski sign. Skin biopsy is the gold standard. Subepidermal bullae are seen in SJS/TEN, and eosinophilic infiltrate is seen in DRESS. However, relying solely on skin biopsy findings can delay diagnosis. www.americantherapeutics.com

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Allopurinol and DRESS Syndrome

The importance of a thorough drug history cannot be overemphasized. Prompt recognition and withdrawal of the causative drug is essential along with supportive treatment. Initial testing should include a complete blood count with differential count and peripheral blood smear, comprehensive metabolic panel with liver enzymes, and urinalysis. Patients with suspected DRESS should be admitted for multiple critical factors. Special emphasis must be placed on subtle changes in mentation, which can indicate central nervous system involvement, as in our case. Angioedema is another potentially fatal complication, with 1 published case report of allopurinol-induced DRESS syndrome, requiring an emergent surgical airway.7 Discontinuation of the drug, administering topical hydrocortisone, oral H1 and H2 receptor antagonists often result in a transient improvement in drug rash, hypereosinophilia, liver enzymes, and renal function. But after days into the course of treatment, renal and liver function can deteriorate. Monitoring liver function is crucial because the most common cause of mortality in patients with DRESS syndrome is hepatic failure.2 Liver and renal function studies need to be trended till normalization and periodically assessed as relapse has occurred after completion of treatment.4 Along with long-term follow-up, family members of patients with DRESS syndrome need to be addressed as it has also been described in familial aggregations.2 Prognostic factors in DRESS have been studied, and 5 independent factors associated with increased mortality rate have been identified: heart rate .90 bpm, white blood cells .12,000, respiratory rate .20 per minute, gastrointestinal bleeding, and coagulopathy.11 DRESS in conjunction with systemic inflammatory response syndrome (SIRS) also worsened outcomes.11 Other manifestations of DRESS include pulmonary and cardiac complications. Eosinophilic pneumonitis has been implicated in respiratory decline and chest x-ray and chest computed tomography are necessary in these patients.6 Another fatal and underrecognized condition is myocarditis occurring immediately to a delay of 4 months after the initial diagnosis of DRESS.12 These patients need a baseline electrocardiography and echocardiography. Myocarditis can occur as acute necrotizing eosinophilic resulting in biventricular failure and pericardial effusion. The mortality rate with acute necrotizing eosinophilic is greater than 50% with a survival of only 3–4 days.12 There are no randomized controlled trials comparing supportive care alone versus addition of systemic steroids. The rapid decline in systemic function is the reasoning behind the use of corticosteroids as the mainstay of treatment in DRESS. The typical steroid dose include 0.5 mg.kg21 of oral prednisone daily and may control both cutaneous and visceral features of DRESS www.americantherapeutics.com

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syndrome, but the response often is suboptimal, and rapid tapering has been shown to lead to relapse of systemic symptoms.8,9 There are also no trials establishing therapeutic regimens and often clinicians base regimens on their experiences. There have been a few recent case reports substantiating the use of pulsed steroids in DRESS. Natkunarajah et al9 performed a pilot study looking at the efficacy of pulsed intravenous methylprednisolone. There was complete recovery in 9 of 10 patients with DRESS syndrome, when pulsed IV methylprednisolone was given for 3 consecutive days (along with topical steroid for skin changes), followed by a 30-day tapering course of oral prednisone. There is also recent data from pediatric literature highlighting pulsed steroids in the setting of failed immunoglobulin therapy. Kocaoglu et al28 highlight 2 pediatric case reports where pulsed steroids were given with successful resolution of symptoms. In both cases, parenteral pulse corticosteroid therapy was administered as 30 mg/kg (maximum 1 g) for 3 days, followed by a 2-week course of prednisone (1 mg$kg21$d21) with rapid recovery of liver function studies and resolution of symptoms.28 There are major side effects associated with prolonged exposure to systemic corticosteroids and include acute psychosis, increased risk of infection, decreased glucose tolerance, and cardiac arrhythmias. IVIGs is indicated in SJS/TEN, whereas very little data is published in relation to DRESS. One previous case has been described of a woman with DRESS who developed severe postoperative infection and required administration of IVIGs rather than steroids.10 Her skin eruption and systemic manifestations improved after 7 days of IVIGs administration. Allopurinol-induced DRESS syndrome has been reported in about 0.4% of patients taking allopurinol for hyperuricemia and gout.13 In addition, the death rate in these patients is higher than that described in DRESS cases because of other drugs.4 Impaired renal function and the use of thiazide diuretics, which favor accumulation of the allopurinol metabolite, oxypurinol, often coexist in patients developing DRESS syndrome. A systematic review of allopurinol-associated DRESS cases reported in the literature was carried out by searching PubMed–MEDLINE between January 1997 and August 2013. The MESH search terms were, “Allopurinol”, “Oxypurinol” and “Drug hypersensitivity syndrome”. Publications were limited to English language. Twenty cases of allopurinolassociated DRESS cases based on the RegiSCAR criteria were analyzed (Table 1). Publications were excluded from analysis when they displayed data group summaries and results were not assigned to a specific patient. Cases represented males and females, ages ranging from 40 to 84 years, allopurinol American Journal of Therapeutics (2015) 22(3)

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dose range from 100 to 300 mg daily (if mentioned) with allopurinol treatment duration varying from days to weeks, and multi-organ involvement. Most case reports did not incorporate HHV-6 serology. Treatment regimens mostly included systemic corticosteroids. There was variability between oral and intravenous administration and dosing ranging from 5 to 60 mg daily or weight-based regimens. There was no standard treatment duration, but among the case reports treated with steroids for more than 2 weeks, recurrence and/or systemic complications were reported less. Alternatives to allopurinol have been suggested, such as potassium sodium citrate, febuxostat, and rasburicase.13,14 Febuxostat has been reported to have a safer adverse effect profile compared with allopurinol, especially in patients with renal failure.14 The CONFIRMS trial concluded that febuxostat at 80 mg daily was superior to allopurinol at 300 mg daily in lowering uric acid.30 Even decreased dosing of febuxostat at 40 mg daily was still more efficacious than allopurinol at regular dosing (300 mg daily) and lower (200 mg daily) for those with renal impairment. In animals other than primates, uric acid is dissolved into allantoin, a soluble form through the enzyme uricase. However, the use of rasburicase can impose challenges such as parenteral administration and risk of anaphylactic reactions.14 There has been recent work in creating a rasburicase-entrapped transdermal patch using mesoporous silica in helping increase patient compliance and administration.31 In 2010, a parenteral polyethylene glycol–conjugated uricase, pegloticase, was approved by the Food and Drug Administration for the treatment of gout. Pegloticase is given as a biweekly infusion and enzymatically catalyzes the oxidation of uric acid to allantoin. Adverse effects of pegloticase include anaphylaxis, infusion reactions, gout flares, and exacerbation of congestive heart failure. At present, substantial expense compromises its costeffectiveness as an initial approach.29 In summary, allopurinol-induced DRESS syndrome has a complex etiology, including possible HHV-6 coinfection. Diagnosis should be based on the RegiSCAR scoring criteria that emphasize the commonality of liver and renal involvement, and syndrome resolution can take longer than other adverse cutaneous drug reactions. The multi-organ nature of DRESS along with the patient’s clinical picture and laboratory values may necessitate other tests/imaging modalities. Recurrence of DRESS has been reported after completion of treatment. Periodic follow-up of these patients is critical. Our review of case reports suggests that long-term steroid therapy seems to decrease the incidence of systemic complications and/or recurrence, but evidence-based treatment regimens are lacking. Finally, further development of affordable alternatives to allopurinol American Journal of Therapeutics (2015) 22(3)

Thankachen and Agarwal

is needed. This case report highlights the challenges in management and treatment of DRESS syndrome, especially in allopurinol-associated DRESS syndrome, where the mortality rate secondary to multi-organ failure is the highest and requires diligence in improving clinical outcomes.

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American Journal of Therapeutics (2015) 22(3)

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Challenges in Diagnosis, Management, and Treatment of Allopurinol-Induced DRESS Syndrome: Case Report and Literature Review.

We describe the presentation, diagnosis, management, and treatment of a 62-year-old woman with a medical history of gout who presented with a maculopa...
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