Necrotizing vasculitis secondary to propylthiouracil presenting as purpura fulminans

K. E. J. Park, D. R. Chipps and E. M. Benson

Department of Diabetes and Endocrinology, Level 2, ICP & MR, Westmead Hospital, Hawkesbury Road, Westmead, NSW 2145, Australia

SIR, We report the occurrence of antineutrophil cytoplasmic antibody (ANCA)-positive cutaneous vasculitis in a woman with active Graves' disease being treated with propylthiouracil (PTU), presenting as purpura fulminans. A 35-yr-old Caucasian female presented with rapid onset of haemorrhagic skin lesions (Fig. 1Go) involving her lower limbs and both ears associated with severe burning pain. Her past history included Graves' disease and hepatitis C virus (HCV) infection due to long-term i.v. drug use, though she denied being a current user. Medications on presentation included PTU 200 mg t.d.s., methadone 110 mg daily and clonazepam 2 mg b.d. In addition, she had been taking roxithromycin 150 mg b.d. for the 5 days prior to presentation, for an upper respiratory tract infection. The Graves' disease was diagnosed in 1992 and its management had been difficult, largely due to non-compliance. Having relapsed following an ablative course of radioactive iodine (550 MBq), she was recommenced on PTU at 300 mg/day in August 1995. This was subsequently increased to 600 mg/day until she presented in January 1996.



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FIG. 1.  Rapid onset haemorrhagic skin lesions involving the lower limbs (left) and both ears (right).

 
Examination revealed an afebrile normotensive female with exophthalmos and a diffuse non-tender goitre. There were large areas of livedo and tender, non-raised haemorrhagic areas covering most of her left lateral thigh with similar lesions seen elsewhere on the lower limbs as well as both ears. These lesions doubled in size over the next 12 h with areas of haemorrhage and necrosis. Moderate splenomegaly was also present.

Diagnostic possibilities considered initially were purpura fulminans, vasculitis related to PTU, bacterial endocarditis and HCV-related cryoglobulinaemia. Investigations including full blood count, electrolytes and renal function were normal. Coagulation studies showed prothrombin time 17 s [reference range (RR=11–18)], APTT 42 s (RR 25–36), TT 16 s (RR 11–15) and D-Dimer was positive (1.00–2.00 mg/l). Protein C antigen (Ag), protein S Ag, activated thrombin III, activated protein C resistance and factor V DNA analysis were all normal. She had a weak IgM anticardiolipin antibody, but no IgG anticardiolipin antibody, and a lupus anticoagulant was not detected. Thyroid function tests showed thyroid stimulating hormone (TSH) <0.1 uU/ml (RR 0.10–4.00), FT4 7.5 pmol/l (RR 11.5–25.1) and FT3 5.7 pmol/l (RR 3.4–7.2). Liver function tests revealed an elevated alkaline phosphatase at 256 U/l (RR 30–115) and gamma glutamyl transferase at 209 U/l (RR 5–30). ESR was 50 mm/h (RR 0–20) and CRP was 113 mg/l (RR 0–6). Urine analysis showed microscopic haematuria and grew Escherichia coli. A throat swab grew ß-haemolytic Streptococcus and a sputum culture grew Haemophilus influenzae. Further investigation revealed past hepatitis A and B infection (HAV, HBV), and HCV IgG specific antibodies were detected. Antibodies to HIV 1 and HIV 2 were negative. Cryoglobulins were not detected. Three sets of blood cultures were negative. Transoesophageal echocardiogram was normal. Biopsies of the skin lesions were obtained and all medications were ceased except the methadone.

Skin biopsy showed severe acute vasculitis involving small and larger vessels with polymorph infiltration within the vessel walls and leucocytoclasis. There was extensive intravascular thrombosis associated with infarction of the dermis and epidermis. Immunofluorescent studies on the skin biopsy demonstrated significant IgM, C3 and fibrinogen, and a trace of C1q in the walls of medium-sized vessels. Immunological studies revealed a positive p-ANCA titre >1:640, IgG antibody against lactoferrin and IgM antibody against myeloperoxidase; however, PR3 antibodies were not detected. Anti-endothelial antibodies were tested on human umbilical vein cells, but were not detected. She had a speckled ANA titre 1:40, and an unidentified precipitin line was detected by counterimmunoelectrophoresis on rabbit thymus.

She was commenced on fragmin 5000 U b.d., to reduce the progressive skin infarction, and methylprednisolone 500 mg b.d. for 3 days followed by prednisolone 75 mg daily. Within 24 h, the progression of the skin lesions ceased. Over the week, areas of infarcted skin broke down, but skin grafts were not required. In view of the risk of this presentation being related to PTU, the patient was not rechallenged with PTU, but rather underwent thyroidectomy. The steroids were rapidly tapered over 2 months. Eighteen months after the initial presentation, the patient was well, the p-ANCA was negative and lactoferrin antibodies were no longer detectable.

This patient's appearance on presentation was consistent with purpura fulminans. However, urgent skin biopsy showed clear evidence of vasculitis with associated thrombosis, and coagulation studies suggested minor intravascular coagulation only. Purpura fulminans is a rare form of purpura characterized by sudden onset of fever, prostration, anaemia and symmetrical massive ecchymoses, usually of the lower extremities. In adults, it usually follows a systemic infectious process. Laboratory values are consistent with disseminated intravascular coagulation as well as decreased levels of fibrinogen, and factors V and VIII, but vasculitis is not seen on biopsy.

PTU was thought to be the causative agent of the vasculitis in our patient. The relationship of p-ANCA to HCV infection is not yet well defined. Chronic HCV infection is associated with various skin disorders, including leucocytoclastic vasculitis [1]. In these cases, vasculitis is associated with cryoglobulinaemia [1, 2], although a single case of p-ANCA-positive leucocytoclastic vasculitis has been reported in a patient with HCV infection and undetectable cryoglobulins [3]. However, the rapid recovery from disease in the presence of ongoing HCV infection suggests that this was not the cause of the vasculitis in our patient [4].

The pathogenesis of PTU-induced vasculitis remains unknown, although it has been hypothesized that PTU serves as an MPO substrate for free radical production [5]. Dolman et al. [6] reported six patients with p-ANCA-positive vasculitis associated with PTU treatment. In these cases, p-ANCA was directed against human neutrophil elastase, proteinase-3 or myeloperoxidase, but p-ANCA against lactoferrin was not examined. More recently, Kitahara et al. [5] described a patient with PTU-induced vasculitis in which p-ANCA was positive against multiple determinants including lactoferrin, whereas in our patient there was an IgG anti-lactoferrin antibody and an IgM anti-myeloperoxidase antibody, but no proteinase-3 antibodies. It is not clear whether ANCA has a direct pathogenic role in the development of PTU-associated vasculitis or is merely an epiphenomenon. On withdrawal of PTU, clinical improvement was associated with a fall in the ANCA titre, as seen in our patient. ANCA is not detectable in those receiving PTU without vasculitic complications [6].

This case serves to highlight that cutaneous vasculitis can present as purpura fulminans, highlighting the need for histology in such cases.

References

  1. Daoud MS, Gibson LE, Daoud S et al. Chronic hepatitis C and skin diseases: A review. Mayo Clin Proc 1995;70:559–63.[ISI][Medline]
  2.  Durand JM, Kaplanski G, Richard MA et al. Cutaneous vasculitis in a patient infected with hepatitis C virus. Detection of hepatitis C virus RNA in the skin by polymerase chain reaction. Br J Dermatol 1993;128:359–60.
  3.  Manna R, Todaro L, Latteri M et al. Leukocytoclastic vasculitis associated with hepatitis C virus antibodies. Br J Rheumatol 1997;36:124–5.[ISI][Medline]
  4.  Theilmann L, Gmelin K, Kallinowski B et al. Prevalence of antibodies to hepatitis C virus in sera from patients with systemic necrotizing vasculitis. Nephron 1991;57:482.[ISI][Medline]
  5.  Kitahara T, Hiromura K, Maezawa A et al. Case of propylthiouracil-induced vasculitis associated with ANCA; review of literature. Clin Nephrol 1997;47:336–40.[ISI][Medline]
  6.  Dolman KM, Gans RO, Vervaat TJ et al. Vasculitis and anti-neutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy. Lancet 1993;342:651–2.[ISI][Medline]
Accepted 25 January 1999