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Several drugs have been associated with antineutrophil cytoplasmic antibodies (ANCA) positivity—namely, hydralazine, penicillamine, allopurinol, and propylthiouracil.1
Although propylthiouracil is often implicated in the induction of ANCA positive vasculitis,2,3 other antithyroid drugs, such as carbimazole and thiamazole, have been linked.4,5 Furthermore, ANCA positivity has been described in the course of Graves' disease without vasculitis.6
This study aimed at determining the frequency and specificity of ANCA in a series of patients with Graves' disease.
We retrospectively examined 35 serum samples from patients with Graves' disease. Diagnosis of the disease was based on typical signs and symptoms of hyperthyroidism, raised serum triiodothyronine and thyroxine, very low or undetectable thyroid stimulating hormone, and increased thyroid radioactive iodine uptake. All patients had been receiving treatment with carbimazole (30–45 mg) for at least two months. None of the patients were treated with propylthiouracil or any drug affecting the immune function. ANCA antibodies were determined by indirect immunofluorescence (IIF) on ethanol fixed granulocytes, as described elsewhere.7 Staining patterns were described as cANCA, when a diffuse granular cytoplasmic staining with central accentuation was seen, as pANCA, when a perinuclear pattern was observed, and as xANCA when a distinct, homogeneous, non-granular cytoplasmic staining pattern was seen. Autoantibodies against proteinase 3 and myeloperoxidase (MPO) were detected by enzyme linked immunosorbent assay (ELISA; Orgentec) as described elsewhere.8 Hospital Universitari Germans Trias I Pujol is a 553 bed hospital situated on the outskirts of Barcelona. It is a referral hospital serving a population of 700 000 inhabitants. The immunology laboratory is a reference centre.
ANCA (IIF) were detected in 21 (60%) of the serum samples. The titre ranged from 1/40 to 1/2560. The immunofluorescence staining pattern was as follows: nine (26%) pANCA, seven (20%) xANCA, and five (14%) cANCA. ELISA was positive in just one case (for MPO)—in the patient with an IIF titre of 1/2560.
Our results are very similar to those of Afeltra et al, who reported ANCA positivity by IIF in 6/21 (29%) patients with Graves' disease.6 The IIF staining pattern was aANCA in five cases and cANCA in one case. Anti-MPO antibodies were detected only in one (5%) of the patients. In our study ANCA were detected in 21 (60%) serum samples. The IIF staining patterns were more heterogeneous, but the ELISA results were similar.
Human MPO and human thyroid peroxidase (TPO) share global similarities which indicate that MPO and TPO are members of the same gene family. Therefore, it seems conceivable that MPO autoantibodies may cross react with TPO. Findings suggesting such a relationship were reported by Haapala et al, who found antibodies against both TPO and MPO in 19 patients, three with vasculitis and 16 with thyroid disorders.9
There is a need to determine the aetiopathogenetic role of ANCA antibodies in Graves' disease, the precise relation between ANCA and antithyroid drugs and, lastly, the antigens which are responsible for the ANCA positivity.
ANCA positivity in Graves' disease may be attributable to either antithyroid drugs (thiamazole or propylthiouracil) or to the disease itself.
This study was sponsored by a grant from the Catalan Society for Rheumatology.