Dear Editors, A 38-year-old woman developed a severe purpuric rash, which was diagnosed as propylthiouracil (PTU) induced vasculopathy. She had longstanding thyroid issues and was diagnosed with Graves' disease in 2014. She denied any alcohol or recreational drug use. Her regular medications included 3-monthly intramuscular medroxyprogesterone (150 mg/ml), propranolol (40 mg twice daily) commenced in 2019, and mirtazapine (15 mg at night) commenced three months ago. She had documented drug reactions to ibuprofen, carbimazole and PTU which all caused a nondescript rash reaction. She was previously documented to have received PTU in 2017 and 2020, and in both instances developed a rash. The patient was initially admitted to the intensive care unit for 2 weeks due to a thyroid storm triggered by a gastrointestinal illness. She was managed with PTU (200 mg 4–6 hourly), dexamethasone (4 mg daily), iodine 5% solution (0.5 mL three times a day), propranolol (80 mg four times a day) and magnesium replacement. Upon discharge, she was prescribed 300 mg propylthiouracil and 40 mg propranolol twice daily, and her mirtazapine was reinitiated. Five days later, she represented with a non-pruritic, maculopapular rash on her face, torso and upper limbs. A dermatological consultation was sought, with advice to cease the PTU; however, it was considered clinically important to continue the medication. She was advised to adopt photoprotection measures, use antihistamines as needed, apply topical corticosteroids, and discontinue mirtazapine. Two weeks later, she represented with a non-blanching, confluent purpuric rash with hemorrhagic bullae that had spread to her abdomen, lower limbs and helices (Figure 1). Propylthiouracil was discontinued after 33 days of use, and she was transferred to a tertiary center for urgent multidisciplinary evaluation, including input from dermatology, rheumatology, and reconstructive surgery. Investigations revealed an elevated ANA titer (1:640, speckled pattern), elevated MPO-ANCA IgG (54 U/ml; reference < 20 U/ml), and a low-titer atypical c-ANCA (1:40) without elevation of PR3-ANCA IgG (15 U/ml; reference < 20 U/ml). Inflammatory markers were mildly elevated (ESR 40 mm/h; CRP 48 mg/l). The ENA and anti-double stranded DNA results were unremarkable and her cryoglobulins were negative. The C3 and C4 complement components, coagulation profile and thrombosis screen (lupus anticoagulant, anti-cardiolipin antibodies, beta-2-glycoprotein, protein C and S, antiphospholipid antibodies) were unremarkable. Routine blood counts, biochemistry, and renal function were within normal limits. Four biopsies were taken from the abdomen, left arm and bilateral thighs. Histopathology showed necrosis of the superficial epidermis and the presence of red blood cells and fibrin in the underlying dermis with minimal surrounding inflammation (Figure 2). Given the small number of neutrophils present, these inflammatory changes were not sufficient to indicate vasculitis. Overall, the biopsies demonstrated features of an occlusive vasculopathy without evidence of a primary vasculitis. The patient was managed with a regime of immunosuppression (500 mg methylprednisolone daily, 1 g rituximab once and 60 mg prednisolone daily), infection prophylaxis and surgical debridement of necrotic skin involving removal of 45% of her total body surface area. Moreover, given her chronic difficulty with thyroid function, she underwent thyroidectomy. In total, the patient underwent four debridement procedures, including split-thickness skin grafting and application of a biodegradable temporizing matrix, and received burn care at a tertiary burns center. At review 4 months after the initial debridement, she continued to show good clinical progress. Propylthiouracil is a known trigger of ANCA-associated disease, and early withdrawal should be considered when clinically appropriate. Although the exact pathomechanism remains unclear, it is thought to involve immune-modulating effects of the drug.1 PTU-induced autoimmune disease most commonly demonstrates features of vasculitis.2-4 Depending on disease severity, management for PTU-induced vasculitis may range from simply ceasing PTU to using systematic corticosteroids and other immunosuppressant agents. Given that only a few cases of PTU-induced vasculopathy have been reported, no standard treatment protocol has been developed for these cases.5, 6 Instead, it has been suggested that management protocols for cases of primary cutaneous vasculopathy should be adopted including consideration of anticoagulation.5 In this case, the patient did not receive anticoagulation treatment during her initial admission for thyroid storm or in her subsequent admission for vasculopathy. While anticoagulation was considered in this patient, it was not initiated, as she responded to initial treatment under the presumed diagnosis of vasculitis. Furthermore, anticoagulation was avoided due to concerns about bleeding risk in the context of extensive necrotic skin involvement and the need for multiple surgical debridements. This case of propylthiouracil-induced vasculopathy underscores the need to recognize this rare adverse effect, its clinical features, and to distinguish it from PTU-induced vasculitis. The authors would like to thank Dr David James, Dr Fiona Tang, and Dr Rohan Mortimore for their assistance with the histopathologic assessment and preparation of the microscopic images. Open access publishing facilitated by The University of Queensland, as part of the Wiley - The University of Queensland agreement via the Council of Australian University Librarians. None.
Dwivedi et al. (Thu,) studied this question.