[New insights into the pathogenesis of ANCA-positive vasculitides]. / Vascularites ANCA-positives: données physiopathologiques récentes.

Recent studies provided new insights into the pathogenesis of vasculitides associated with antineutrophil cytoplasm antibodies (ANCA). They yield more information about the pathogenic role of ANCA, the initiation of the immune response against proteinase 3, the expression of ANCA target antigens on neutrophil surfaces, endothelial damage and the mechanisms of vasculitis associated with propylthiouracil. The pathogenic role of antimyeloperoxidase antibodies has been established in vitro and in vivo in animal models and in human. A pathogenic role for antiproteinase 3 antibodies has not yet been clearly established in vivo although it is well documented in vitro.

Titre and affinity of propylthiouracil-induced anti-myeloperoxidase antibodies are closely associated with the development of clinical vasculitis.

Substantial evidences suggested that propylthiouracil (PTU) could induced anti-myeloperoxidase (MPO) antibodies in sera from patients with hyperthyroidism, however, only a subgroup of the PTU-induced anti-MPO antibody positive patients developed clinical evident vasculitis. The aim of this study is to compare the titres and affinities of PTU induced anti-MPO antibodies in sera from patients with hyperthyroidism with and without clinical vasculitis. Anti-MPO antibody positive sera from patients diagnosed hyperthyroidism with (n = 13) and without (n = 14) clinical evident vasculitis were collected. The titre was determined by MPO-ELISA and expressed as logarithm value (lgT). The affinity constant (aK) of anti-MPO IgG was measured by antigen inhibition assay. The titre and aK values were compared between patients with and without vasculitis. In patients with vasculitis, the mean lgT of anti-MPO antibodies was 3.62 +/- 0.66; the median aK was 4.47 x 10(7)M(-1). In patients without vasculitis, the mean lgT was 2.54 +/- 0.29; the median aK was 0.14 x 10(7)M(-1), and both were significant lower than those in patients with vasculitis (t = 5.464; P = 0.000 & z = -4.373; P = 0.000, respectively). We concluded that the titre and affinity of anti-MPO antibodies might be associated with the development of clinical vasculitis in patients with PTU-induced ANCA.

Anti-myeloperoxidase antibodies in sera from patients with propylthiouracil-induced vasculitis might recognize restricted epitopes on myeloperoxidase molecule.

Myeloperoxidase (MPO) is one of the major target antigens of antineutrophil cytoplasmic antibodies (ANCA) in primary systemic vasculitis. It is known that propylthiouracil (PTU) could induce MPO-ANCA-positive vasculitis. The production of anti-MPO antibodies in patients with PTU-induced vasculitis may be different from that in patients with primary microscopic polyangiitis (MPA). One possible reason for this may be differences in epitope recognition. The aim of this study is to compare the epitopes of antibodies to MPO in sera from patients with PTU-induced vasculitis (n = 10) and MPA (n = 10). The sera were collected and used to inhibit monoclonal antibodies against human MPO (3D8 and 6B9) and affinity purified, horseradish peroxidase conjugated human anti-MPO antibodies (Pab1-HRP, Pab2-HRP) in a competitive inhibition enzyme-linked immunosorbent assay (ELISA) system using soluble human MPO as solid phase ligand. The Pab1-HRP and Pab2-HRP were affinity purified from plasma exchanges of a patient with PTU-induced vasculitis and a patient with MPA, respectively. The inhibition rates were evaluated and compared between the PTU and primary MPA groups. In the PTU group all 10 sera could inhibit 3D8: the average inhibition rate was 44.7% +/- 5.0%; 9/10 sera could inhibit 6B9: the average inhibition rate was 35.6% +/- 6.0%. However, in the MPA group all 10 sera could inhibit 3D8 and 6B9; the average inhibition rates were 68.4% +/- 16.1% (P < 0.01) and 62.2% +/- 17.2% (P < 0.01), respectively. Sera in both the PTU and MPA groups could inhibit Pab1-HRP and the inhibition rates were 81.4% +/- 9.4%versus 86.6% +/- 17.2% (P > 0.05). However, the average inhibition rate for Pab2-HRP in the MPA group was significantly higher than that in the PTU group (76.3% +/- 7.8%versus 58.9% +/- 15.5%, P < 0.01). We conclude that anti-MPO antibodies from patients with PTU-induced vasculitis and from patients with primary MPA could recognize more than one epitope on the native MPO molecule. Although the epitopes overlapped between the two groups, the epitopes of anti-MPO antibodies from patients with PTU-induced vasculitis might be more restricted.

Anti-thyroid thioureylenes in the treatment of psoriasis.

Psoriasis is a common skin disorder associated with significant morbidity. Many agents are used in the medical management of this debilitating condition with the newer anti-cytokine agents being the most recent addition to the pharmacological armamentarium to battle the disorder. Cost concerns are very important with the newer "biologic" treatments costing in excess of 10,000 US dollars annually. The need for cheaper, orally administered agents is therefore imperative. This paper addresses the potential role of anti-thyroid thioureylenes, propylthiouracil and methimazole, in the treatment of psoriasis and reviews the possible mechanism of action of these drugs in this disorder. It is hypothesized that the beneficial effect of anti-thyroid thioureylenes in psoriasis is linked to their effect as anti-proliferative agents as reflected by significant decrease in markers of cellular proliferation such as proliferative cell nuclear antigen in biopsy specimens after treatment with these drugs. Propylthiouracil has been shown to bind to the hepatic T 3 receptor and it is possible that propylthiouracil (6-n-propyl-2-thiouracil) binding to the ligand-binding site normally occupied by T 3 impairs transcription by inactivating the effect of T 3 as well as by squelching retinoic X receptor heterodimer formation with other receptors of the steroid receptor superfamily such as the peroxisome proliferator-activated receptor, retinoic acid receptor and vitamin D receptors.

Leukocytoclastic vasculitis: a rare manifestation of propylthiouracil allergy.

OBJECTIVE: To report a case of leukocytoclastic vasculitis as a manifestation of propylthiouracil allergy. METHODS: We present the history, findings on physical examination, and results of laboratory evaluation in a 25-year-old woman. Associated reports from the literature are reviewed. RESULTS: The patient, with a history of Graves' disease, was referred for evaluation of a purpuric rash on the pinnas and buttocks bilaterally. Findings included exophthalmos and bilateral goiter with neck bruits. She was biochemically hyperthyroid. Biopsy of the skin lesions revealed leukocytoclastic vasculitis. Propylthiouracil therapy was discontinued, and prednisone was prescribed. Treatment with radioactive iodine resulted in appreciably diminished skin lesions and reduction in the size of the thyroid gland, but thyroxine and triiodothyronine levels increased. Administration of a second, higher dose of radioactive iodine with concomitant lithium carbonate resulted in clinical and biochemical improvement. Six months after initial assessment, the rash had resolved, and the patient's free thyroxine value had normalized, although the thyrotropin level was still suppressed. CONCLUSION: Leukocytoclastic vasculitis, although rarely seen as a manifestation of propylthiouracil allergy, has been reported in the medical literature and should be considered in the differential diagnosis of patients with a vasculitic rash. Treatment consists of discontinuation of the offending medication and administration of a corticosteroid and, occasionally, cyclophosphamide or plasmapheresis.

Preserved activation of thyrotropin receptor antibody to stimulate thyroid function despite long-term treatment in euthyroid patients with Graves' disease.

Clinical evaluation was conducted to ascertain whether thyrotropin receptor antibody (TRAb) in the normal range may still be involved in the regulation of thyroid function after prolonged treatment for Graves' disease. All patients (n = 33) were treated with antithyroid drugs for an average of 10.6 years and were under euthyroid conditions in which normal blood levels of tri-iodothyronine (T3) were significantly correlated with blood thyrotropin (TSH) levels, but not with titers of TRAb. A significant correlation was observed between TRAb titer and thyroid-stimulating antibody (TSAb) activity. In contrast, this correlation was not found in normal subjects. After administration of T3 (75 microg daily for 8 days), the patients showed increased levels of T3 with concomitant suppression of TSH levels. Under these conditions, linear regression analysis showed significant correlations of TRAb titer and TSAb activity with 24-h thyroid radioiodine uptake (r = 0.641 and 0.621 respectively, P < 0.01), in contrast to declining blood thyroxine levels. Moreover, the immunoglobulin G (IgG) of the patients precipitated to a greater extent than IgG from normal subjects a peptide consisting of the amino acid sequence near the terminus of the human TSH receptor. These findings indicated that TRAb at normal levels possessed significant unremitting activities on thyroid function despite long-term treatment in euthyroid patients with Graves' disease.

T cells ignore the parent drug propylthiouracil but are sensitized to a reactive metabolite generated in vivo.

The antithyroid drug propylthiouracil (PTU) is known to cause adverse immunological side effects, such as a lupus-like syndrome and vasculitic disorders. In vitro experiments have established that myeloperoxidase of activated neutrophils can oxidize PTU to the reactive intermediate propyluracil 2-sulfonate PTU-SO3-, and it has been proposed that PTU-SO3- might be responsible for the PTU-associated side effects. Here, using the direct popliteal lymph node assay (PLNA) in mice we found that PTU-SO3-, indeed, induced a T-cell-dependent primary PLN response, whereas the parent compound PTU failed to do so. As shown by adoptive transfer PLNA, splenic T cells of mice that had received four injections of PTU-SO3- mounted a specific secondary response to the reactive metabolite, but not to PTU. When homogenized peritoneal phagocytes, which had been incubated with PTU in vitro, were used as the antigen, a primary response in the direct PLNA was elicited, suggesting that the phagocytes contained the reactive metabolite. Moreover, T cells sensitized to the reactive metabolite PTU-SO3- were detected in mice that were undergoing long-term treatment with PTU plus an additional treatment with phorbol myristate acetate for stimulation of the oxidative metabolism of their phagocytic cells. Together, these findings support the concept that phagocytes oxidize PTU to its immunogenic metabolite, PTU-SO3-, which then, presumably via covalently binding to self-proteins, induces T cell sensitization.

Efecto de propiltiuracilo sobre la producción de anticuerpos antiseroalbúmina bovina en ratas / Effect of propylthiouracil the production bovine antiserum albumin antibodies in rat

Se presentan los resultados de un estudio realizado in vivo para evaluar el posible efecto inmunosupresor de pripiltiuracilo (PTU). Se utilizó seroalbúmina bovina (SAB) como inmunógeno, la cual se inyectó e a ratas en una dosis única de 5 mg. El PTU se administró en una dosis de 2,5 mg/24 horas durante 10 días. Los anticuerps se detectaron incubando el suero inmune con SAB-1 125. Se empleó polietilenglicol (10 g/dL) para separar el antígeno marcado libre. No encontramos una influencia significativa del PTU sobre la generación de anticuerpos anti SAB, resultado que no sustenta el efecto inmunosupresor de este antitiroideo. En los últimos años se ha estudiado esta característica de las tionamidas, pero los resultados han sido contradictorios

Efecto de propiltiuracilo sobre la producción de anticuerpos antiseroalbúmina bovina en ratas / Effect of propylthiouracil the production bovine antiserum albumin antibodies in rat

Se presentan los resultados de un estudio realizado in vivo para evaluar el posible efecto inmunosupresor de pripiltiuracilo (PTU). Se utilizó seroalbúmina bovina (SAB) como inmunógeno, la cual se inyectó e a ratas en una dosis única de 5 mg. El PTU se administró en una dosis de 2,5 mg/24 horas durante 10 días. Los anticuerps se detectaron incubando el suero inmune con SAB-1 125. Se empleó polietilenglicol (10 g/dL) para separar el antígeno marcado libre. No encontramos una influencia significativa del PTU sobre la generación de anticuerpos anti SAB, resultado que no sustenta el efecto inmunosupresor de este antitiroideo. En los últimos años se ha estudiado esta característica de las tionamidas, pero los resultados han sido contradictorios

Dose-dependent induction of anti-native DNA antibodies in cats by propylthiouracil.

Cats receiving propylthiouracil (PTU) develop antinuclear antibodies (ANA) and an immune-mediated disease syndrome characterized by anorexia, lymphadenopathy, weight loss, and Coombs-positive hemolytic anemia. Investigation of the ANA specificity indicated that the predominant ANA activity consistent of anti-native DNA (nDNA) antibodies. The formation of anti-nDNA antibodies and immune-mediated disease syndrome appeared to be dose-dependent, even in cats in which a response had been induced on 4 prior occasions. These results supply further evidence that PTU-induced autoimmunity is not the result of a simple drug allergy. Rather, it appears that PTU induces a lupus-like syndrome, including the hallmark sign of systemic lupus erythematosus, anti-nDNA antibodies.

Agranulocytosis induced by propylthiouracil: evidence of a drug dependent antibody reacting with granulocytes, monocytes and haematopoietic progenitor cells.

A patient with agranulocytosis and myeloid marrow hypoplasia following a second exposure to propylthiouracil (PTU) was studied for antibodies against mature blood cells and bone marrow precursor cells. During the acute phase of the agranulocytosis, significant growth inhibition of the myeloid committed progenitor cells (CFU-GM) was found following incubation with complement, indicating the presence of in-vivo cell bound cytotoxic antibodies. Using immunofluorescence and complement dependent cytotoxicity techniques it was demonstrated that acute phase and recovery phase sera contained circulating antibodies, reactive not only with differentiated granulocytes and monocytes but also with myeloid and erythroid (BFU-E/CFU-E) progenitor cells. Complement dependent lysis of the progenitor cells was facilitated by preincubation with PTU. These results indicate that the agranulocytosis was mediated by a PTU dependent antibody that affected both mature blood cells and bone precursor cells.

In vitro immunoreactivity to propylthiouracil, methimazole, and carbimazole in patients with Graves' disease: a possible cause of antithyroid drug-induced agranulocytosis.

Studies of in vitro immunoreactivity to propylthiouracil (PTU), methimazole (MMI), and carbimazole (CARB), as assessed by peripheral blood lymphocyte transformation and 2 antibody tests, were carried out in 12 patients with Graves' hyperthyroidism who had developed agranulocytosis during treatment with PTU (11 patients) or CARB (1 patient) from 1 week to 10 yr earlier. Significant lymphocyte transformation responses to antithyroid drugs (stimulation indices greater than mean +/- 2 SD for normal subjects) were found in 5 of 6 patients tested, in 1 patient to PTU only, in 3 patients to MMI only, and in 1 patient to both PTU and MMI, but in none of 10 patients currently being treated with PTU who did not develop agranulocytosis. Circulating antibodies causing neutrophil agglutination in the presence of antithyroid drugs were demonstrated, using the indirect Coombs test, in 5 of 7 patients tested, in 2 patients to PTU only, in 3 patients to CARB only and in 1 patient (the only one tested with MMI) to PTU and MMI. Lymphocyte transformation and antibody tests to PTU were both carried out in 6 patients. Of these, both tests were positive in one patient, both negative in 3 patients, and 1 negative and 1 positive in 2 patients. In the 1 patient in whom both tests were carried out with CARB (patient 3), tests were negative, whereas in the 1 patient in whom both tests were carried out with MMI (patient 3), 1 test was positive, whereas the other was negative. Thus, in patients in whom both tests were carried out using the same drug, correlation between lymphocyte transformation responses and the detection of neutrophil antibodies was found in 5 of 6 cases. Antibodies reactive with neutrophils were also detected in 2 of the 5 patients tested using an enzyme-linked immunosorbent assay. In this test antibodies to PTU or MMI were not demonstrated. Possible mechanisms for the neutrophil depression in relation to these findings are discussed. It is concluded that patients with Graves' disease may be prone to develop this complication of antithyroid drug therapy because of underlying immunological abnormalities.