High Prevalence of Antineutrophil Cytoplasmic Antibody Positivity in Childhood Onset Graves’ Disease Treated with Propylthiouracil

Abstract

Propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA)-related vasculitis and nephritis were recently reported in about 30 patients with hyperthyroidism. The objective of this study was to clarify the prevalence of ANCA and the relationship between ANCA and thyroid antibodies in children with Graves' disease. Titers of myeloperoxidase (MPO)-ANCA in sera of 51 patients with childhood onset Graves' disease (16 before treatment, 25 and 10 treated with PTU and methimazole, respectively) were measured by enzyme-linked immunosolvent assay. Antithyroglobulin antibodies (TGAbs) and antithyroperoxidase antibodies (TPOAbs) were also measured by RIA in 25 PTU-treated patients. No patients had clinical manifestations of vasculitis and nephritis. MPO-ANCA was positive in 6.7% of patients before treatment and in 64.0% of those treated with PTU and in none of those treated with methimazole. MPO-ANCA had a significantly positive correlation with TGAbs (P < 0.05) and no significant correlation with TPOAbs. These findings show the high prevalence of the MPO-ANCA positivity in PTU-treated childhood onset Graves' disease, suggesting that PTU may not be preferred as the first line for the treatment of children with Graves' disease. The significant correlation between MPO-ANCA and TGAbs indicates that the severity of Graves' disease may be a factor responsible for the MPO-ANCA positivity. The cross-reactivity between MPO-ANCA and TPOAbs may not play a role in the high prevalence of MPO-ANCA in the patients exposed to PTU.

A comparison of antineutrophil cytoplasmic antibody prevalence in patients treated and untreated for hyperthyroidism

“…A high frequency of ANCA positivity has been reported in patients receiving treatment with antithyroid medication [22,27,29]. Both antithyroid drugs may lead to asymptomatic ANCA positivity, but PTU is the agent which causes most frequent ANCA positivity [22,23,29].…”

Antineutrophil cytoplasmic antibodies in patients with Graves? disease: association of antimyeloperoxidase autoantibodies with propylthiouracil therapy

“…Sato et al 19 and Wada et al 21 reported that none of the MPO-ANCA-positive Graves'-disease patients developed ANCA-associated disorders. An intriguing hypothesis is that MPO-ANCA may be pathogenic only in patients with a synergistic inflammatory event, such as an infection that induces priming of PMN, or with a certain immunological background which may determine disease susceptibility.…”

“…However, the percentage of MPO-ANCA-positive patients did not correlate with the duration of PTU treatment in patients in this study. Sato et al 19 showed that 16 (64%) of 25 childhood-onset Graves'-disease patients receiving PTU were MPO-ANCA-positive. Gunton et al 20 and Wada et al 21 also described a significant incidence of MPO-ANCApositive sera in patients treated with PTU.…”

“…These results are almost in agreement with recent reports by other workers. 18,19 An important question is when do MPO-ANCA appear in the Graves'-disease patients during PTU therapy. Since sera before PTU treatment or serial serum samples after PTU treatment were not available in our MPO-ANCApositive patients at the time of this investigation, it is difficult to determine when patients became MPO-ANCApositive.…”

ANCA-associated vasculitides—lessons from the adult literature

“…However, no such link has been found in adult patients with AASV [21]. Environmental factors, such as propylthiouracil in MPA, may act as a disease trigger in susceptible children [22,23]. Infection, particularly with Staphylococcus aureus, has also been linked to WG, with nasal carriage in WG patients being associated with disease relapse [24] and clearance with cotrimoxazole reducing the risk of relapse [25].…”