Propylthiouracil (PTU) is usually the first choice for the treatment of hyperthyroidism, but it has serious side effects such as hepatitis, cholestatic jaundice, splenomegaly and lupus-like syndrome, in addition to mild and common side effects like granulocytopenia, pruritus, urticaria and maculopapular or papular eruption. Antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis is another serious side effect. A 14-year-old female receiving PTU treatment for hyperthyroidism was referred to our clinic with fever, cough and dyspnea. The PTU dosage was first decreased but pericardial, dermal and joint involvement ascribed to PTU developed later and the drug was discontinued. ANCA-positive vasculitis due to PTU was considered when tests revealed an ANCA-positive state. We suggest that severe multisystemic vasculitis due to PTU should be considered during PTU usage.

We present a case who developed vasculitis with pleural, pericardial, cutaneous and joint involvement while being treated with PTU.

Table I: Clinical and Laboratory Findings of the Case at Admission and Follow-up

The patient presented again three months later with palpitations, dyspnea and chest pain. The physical examination findings were: temperature 37ºC and apical heart beat 122/min. Laboratory findings were: ESR 60 mm/hr and CRP (++). Echocardiography showed minimal mitral insufficiency due to papillary muscle dysfunction secondary to hypertrophy. Thyroid function test showed a high fT3 and suppressed TSH (Table I). The repeated ultrasonography revealed increased thyroid volume. The result of the fine needle aspiration biopsy of the thyroid was consistent with lymphocytic thyroiditis. Autoimmunity test results were: antinuclear antibody (ANA): negative, antidouble strand ANA (anti dsANA): negative, immunoglobulins: normal, and pANCA positive [antimyeloperoxidase antibody (anti MPO Ab): 176 RU/ml (0-20), antiproteinase antibody (anti PR3 Ab): 5.3 RU/ml (0-20)]. The results of the follow-up TFT six months later (on the 14th month of PTU treatment) were consistent with hypothyroidism, and L-thyroxine (LT4) was added to the drug regimen.

The patient was seen at the 22^nd month of PTU treatment with fever, malaise and sore throat followed by a rash. The rash had started on the auricular helix and cheeks and spread to the chest and distal extremities and showed irregular margins, crustiness in places, and necrotic centers; ecchymosis was present, with the biggest lesion measuring 12x8 cm. She also had bilateral arthritis of the ankles (Fig. 1). A skin biopsy from the rash site was consistent with leukocytoclastic vasculitis with no immune deposits. PTU was stopped and methimazole started. In addition, methyl prednisolone 60 mg/day was started for the vasculitis and arthritis. On follow-up a month later, the TFT results were euthyroid and the skin lesions and arthritis had resolved. She continues to take steroids on alternate days, now on the 27^th day of follow-up, and the pANCA (anti MPO Ab: 113.9 RU/ml) is still positive.

Fig. 1: Photographs of the patient demonstrating rash on the auricular helix and cheeks spreading to the distal extremities. The rash on the lower extremities was crusty in places and there were necrotic centers. Ecchymosis was present, with the biggest lesion measuring 12x8 cm.

Clinical and laboratory findings at admission and follow-up are given in Table I.

Propylthiouracil-associated vasculitis frequently causes arthritis and this can sometimes be the initial finding. Joint involvement can vary from arthralgia of moderate intensity to severe synovitis and can take the form of a migratory polyarthritis of the small and large joints[13]. Our case had arthritis starting from the ankles and extending to the interphalangeal joints of both hands.

Extracutaneous findings of PTU-associated hypersensitivity vasculitis include conjunctivitis, pharyngitis, cholestatic jaundice, hepatitis, hepatosplenomegaly, pleural effusion, pneumonia, respiratory failure, cardiomegaly, arrhythmia, pericarditis, hematological findings (leukopenia, anemia, thrombocytopenia), glomerulonephritis, and renal failure[1,2,4,5,7-15]. The extracutaneous findings of our case were arthritis, pleural effusion, pericarditis, rash and anemia. Some ANCA-positive patients using PTU can develop vasculitis between the first week to the 13^th year of treatment[7,16]. However, patients have been reported with the findings limited to the skin and no renal involvement. The ones who may develop ANCA-positive PTU vasculitis should be under close observation for possible nephritis[11,17].

Autoimmune thyroid disease patients not receiving thionamides have been studied for ANCA positivity, and rates of 28.5% for Graves disease and 9% for Hashimoto thyroiditis have been reported[18]. Another study looked at the ANCA positivity rate among the groups treated with PTU and methimazole and reported 37% among those receiving PTU, while the methimazole group was negative[19].

While an improvement is observed in the vasculitic skin lesions following PTU discontinuation in most cases, those with severe renal failure or multiple organ involvement may require months of high-dose steroid treatment[20]. In our case, the skin lesions and arthritis resolved completely within 10 days once the PTU was stopped and steroid treatment started. In case of severe multisystem involvement accompanying PTU vasculitis, other treatment modalities used are cyclophosphamide, azathioprine and plasmaph eresis[7,13,17,21,22].

In conclusion, PTU is a rare cause of vasculitis and the hypersensitivity reaction, which typically consists of acral purpuric skin lesions and various degrees of internal organ involvement. We want to emphasize with this report that serious hypersensitivity vasculitis should be kept in mind and that PTU should be chosen with caution when children are treated for hyperthyroidism.