Allopurinol-induced Sweet’s syndrome

Abstract

Sweet’s syndrome, or acute febrile neutrophilic dermatosis, is an uncommon severe cutaneous condition, not previously associated with allopurinol therapy. We describe the case of an 87-year-old woman with hyperuricemia who developed classic Sweet’s syndrome manifestations 8 days after being treated with allopurinol. Patient’s symptoms included fever, painful edema in the hands and lower limbs with non-pruritic erythematous plaques topped by pus-filled skin blisters, right eye conjunctivitis, splenomegaly and joint pain. At the emergency department, blood tests showed neutrophilic leukocytosis, inflammatory state and altered liver function. During hospitalization, she received unsuccessful treatments with two different antibiotics (namely ceftriaxone and levofloxacin), while treatment with intravenous methylprednisolone produced a rapid clinical remission of symptoms, cutaneous lesion pain improvement, normalization of her body temperature and her blood values returned to normal. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship between the patient’s development of Sweet’s syndrome and allopurinol therapy. Because the signs and symptoms of Sweet’s syndrome resemble an infectious process, the correct diagnosis may be delayed and inappropriate treatment regimen with antibiotics may often precede glucocorticoid therapy.

Introduction

Sweet’s syndrome, or acute febrile neutrophilic dermatosis, is an uncommon, severe cutaneous condition, characterized by the abrupt development of painful, tender, erythematous plaques, fever greater than 38°C, and a nodular perivascular neutrophilic dermal infiltrate without evidence of vasculitis on histologic examination.^1–3 Extracutaneous manifestations of Sweet’s syndrome commonly include joint or ocular disorders (i.e. arthralgia, conjunctivitis, scleritis, and iritis), but may also involve lymph nodes, spleen, bones, liver, or lung.⁴

It commonly develops in association with other systemic disorders or identifiable triggers, including underlying malignancies, autoimmune disorders, pregnancy, antecedent vaccination, inflammatory bowel disease, or infections.^4,5

Sweet’s syndrome in the course of drug administration remains a rare phenomenon, although a wide variety of molecules have been cited in literature as possible causative agents.

We herein report a case of Sweet’s syndrome in a patient with hyperuricemia treated with allopurinol.

Case presentation

An 87-year-old Caucasian woman affected by type 2 diabetes mellitus, obesity, arterial hypertension, osteoporosis, and arthritis at both knees was being chronically treated with valsartan/hydrochlorothiazide 80/12.5 mg daily, metformin 2 g daily, acetylsalicylic acid 100 mg daily, lansoprazole 30 mg daily, and alendronate/cholecalciferol 70 mg + 5600 IU weekly. Because of the increase of her blood uric acid (6.2 mg/dl [normal range, 2.4–5.7 mg/dL]), she was then prescribed allopurinol at a dose of 300 mg daily for 2 weeks.

Eight days after allopurinol initiation, the patient developed fever (39–40°C), painful edema in the hands and lower limbs with non-pruritic erythematous plaques topped by pus-filled skin blisters, right eye conjunctivitis, and joint pain. Her general practitioner prescribed desloratadine 2.5 mg daily and cefpodoxime proxetil 400 mg daily. Two days later, because of the unremitting fever and rapid worsening of dermatological symptoms, the patient decided to discontinue allopurinol therapy, suspecting its potential involvement in the adverse reaction occurred. Seven days after allopurinol suspension, the patient sought medical care at the emergency department because of the persistence of symptoms. On examination, she was found to have right eye conjunctivitis, skin lesions with slightly raised red-purple plaques on her lower limbs varying in size from a few millimeters to 2–3 cm, and several plaques were coalescent into larger lesions – some of them extending to the trunk and neck. The lesions were often covered by whitish pus-filled lesions. Painful, brown nodules were observed on the distal phalanx of the fifth finger of the right hand and the third toe of the left foot. Blood tests showed neutrophilic leukocytosis (neutrophils, 20.58 × 10³/µL [normal range, 1.9–8 × 10³/µL]), an inflammatory state (C-reactive protein, 427 mg/L [normal range, 0.1–5 mg/L], erythrocyte sedimentation rate (ESR) 106 mm/h [normal range, 1.0–14 mm/h]), and altered liver function (total bilirubin, 1.26 mg/dL [normal range, 0–1.20 mg/dL], conjugated, direct bilirubin 0.54 mg/dL [normal range, 0.00–0.30 mg/dL], with gamma-GT values doubling the upper limit of the normal range). Culture of pus samples were negative for bacterial, fungal, and mycobacterial organisms. No evidence of vasculitis was present. An enlargement of the spleen was also observed.

The patient was treated intravenously with methylprednisolone 40 mg, ranitidine hydrochloride 50 mg, levofloxacin 500 mg, paracetamol 1 g, and lysine acetylsalicylate 500 mg. Ceftriaxone sodium 1 g and enoxaparin sodium 6000 IU were also administered. After 24 h, the patient experienced dyspnea and tachyarrhythmia. The electrocardiographic evaluation revealed high frequency atrial flutter/fibrillation. Computed tomography (CT) of the thorax showed right basal pleural effusion while echocardiogram showed a mild left ventricular hypertrophy, dilated left atrium, and first degree diastolic dysfunction. The patient was therefore administered a 300 mg bolus of amiodarone hydrochloride intravenously for 20 min followed by a 24-h infusion of amiodarone 750 mg in glucose 5%. She was then transferred to the department of internal medicine for additional evaluations. Teicoplanin 400 mg daily and meropenem 2 g daily were administered because of suspected bacterial endocarditis with septic embolism.

At the time of referral, her medical history was unremarkable for malignancies, or presence of respiratory infections. In addition, the levels of the main tumor markers (CA 125, CA 15-3, CA 19-9, CEA) were within the normal ranges. She had no past history of drug allergies/reactions or family history of similar skin problems; she denied drugs/complementary or alternative medicines use.

During hospitalization, on the basis of the clinical picture, a diagnosis of Sweet’s syndrome was made and the therapy with methylprednisolone 40 mg daily intravenously was continued. The patient showed a rapid clinical remission of symptoms, with cutaneous lesion pain improvement and normalization of her body temperature within 24 h. The other symptoms (vesicular-pustular lesions, conjunctivitis, myocardial sinus rhythm, pleural effusion, splenomegaly, poliarthralgia) progressively resolved and also her blood values returned to normal (neutrophils 6.29 × 10 ³/L; uric acid 4.8 mg/dL, C-reactive protein 4.8 mg/L, ESR 43 mm/h). The patient was discharged 4 weeks later, with a prescription of prednisone 16 mg/day to be gradually tapered off till its definitive discontinuation.

Discussion

Little is known about the pathophysiology of Sweet’s syndrome, although a hypersensitivity reaction is thought to play a role,⁶ given its prompt response to corticosteroid therapy.² Several drugs have also been implicated in the pathogenesis of Sweet’s syndrome; the best documented evidence exists for granulocyte colony-stimulating factor, all-trans retinoic acid, vaccines, and tetracyclines.^2,7 Other frequently reported drugs are trimethoprim/sulfamethoxazole, quinolones, nitrofurantoin, clindamycin, oral contraceptives, hydralazine, furosemide, clozapine, diazepam, lenalidomide, imatinib, abacavir, azathioprine, bortezomib, celecoxib, and adalimumab.^2,8–10 The average duration from the administration of drug to the onset of skin lesions was found to be approximately 5–7 days in most cases.^6,11

Dermatological complications related to allopurinol therapy are common and may occur in up to 10–15% of cases; these include maculopapular eruption, pruritus, rash, and, more rarely, Stevens-Johnson syndrome and toxic epidermal necrolysis (less than 1%).¹² However, a Medline search did not reveal any documented case report of Sweet’s syndrome related to allopurinol or to concurrent medications the patient was taking.

In our patient, the observed symptoms are consistent with a diagnosis of Sweet’s syndrome,^5,6 namely: (1) painful erythematous plaques or nodules of sudden onset; (2) pyrexia greater than 38°C; (3) temporal relation between the drug ingestion and clinical presentation; and (4) rapid response to systemic corticosteroid therapy following several unsuccessful antibiotic treatments. The non-dermatological clinical manifestations typical of Sweet’s syndrome observed during hospitalization were poliarthralgias, ears and lips pustules, conjunctivitis of the right eye, hepatic serum enzyme abnormalities, atrial flutter, pleural effusion, splenomegaly. The suspect of allopurinol-induced Sweet’s syndrome is also well-supported by the temporal relationship with allopurinol intake (the patient had being treated with concurrent medications for years), and prompt response to glucocorticoid therapy.^2,5 In addition, alternative causes of Sweet’s syndrome, including malignancies, infections, inflammatory or autoimmune diseases were excluded, and a potential, synergistic role of concomitant drugs is very unlikely, basing on available literature.¹³ The Naranjo probability scale for causality assessment scored 6 for the described event, indicating a probable association between the adverse reaction and the consumption of allopurinol.¹⁴ This score was confirmed after applying an expanded Naranjo scale with specific criteria for Sweet’s syndrome developed by Thompson and Montarella.²

Conclusions

Clinicians should be aware of the potential for a drug induced cause of Sweet’s syndrome. Because the signs and symptoms of Sweet’s syndrome (fever, leukocytosis, and skin rash) resemble an infectious process, an inappropriate treatment with antibiotics could be initiated while the correct glucocorticoid therapy delayed.