Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-11-23
2001-08-14
Saunders, David (Department: 1644)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007400, C435S007930, C435S007940, C435S007950, C435S973000, C436S506000, C436S512000
Reexamination Certificate
active
06274329
ABSTRACT:
This application is a national stage filing under 35 USC 371 from PCT/EP98/01401, filed Mar. 11, 1998.
The invention relates to a novel method for the determination of autoantibodies which are directed against thyroid autoantigens and are referred to below in short as “thyroid autoantibodies”.
Among the diseases which are associated with disturbances of the normal function and/or with microscopically or optically perceptible changes of the thyroid, those which have the character of autoimmune diseases play an important role. The most well known thyroid diseases, which must be counted as autoimmune diseases, are in particular Graves' disease, Hashimoto's thyroiditis and primary hypothyroidism. Atrophic autoimmune thyroiditis, primary myxoedema, asymptomatic thyroiditis, postpartal thyroiditis and neonatal hypothyroidism may be mentioned as further such diseases, different designations being used for identical diseases or diseases of the same type, depending on the clinical picture.
The differential diagnosis demonstrating that the observed thyroid disease is one of the autoimmune diseases is based on the detection of autoantibodies in the patient. In many cases, the detection of these autoantibodies therefore permits the distinction of autoimmune diseases from other thyroid diseases by differential diagnosis (cf. Pfannenstiel, P. & Saller, B. in “Schilddrusenkrankheiten—Diagnose und Therapie” [Thyroid diseases—Diagnosis and Therapy], Berliner Medizinische Verlagsanstalt, 1993; or Ziegler, R., Pickardt, C. R., Willig, R.-P. in “Rationelle Diagnostik in der Endokrinologie” [Rational diagnosis in endocrinology], Georg Thieme Verlag, 1993). The known autoantibodies occurring in the case of thyroid autoimmune diseases belong to three different types which differ in the thyroid proteins acting as autoantigens. The three thyroid autoantigens are the TSH receptor, thyroperoxidase (TPO, identical to the earlier so-called microsomal antigen) and thyroglobulin (Tg) (Dawe, K., Hutchings, P., Champion, B., Cooke, A., Roitt, I., “Autoantigens in Thyroid diseases”, Springer Semin. Immunopathol. 14, 285-307, 1993). Autoantibodies against the TSH receptor occur specifically in Graves' disease but not in other autoimmune diseases of the thyroid (Pfannenstiel & Saller, loc. cit.). In addition, autoantibodies against the other two autoantigens, i.e. against TPO and Tg, are also detectable with relatively low sensitivity in many cases in Graves' disease. For the diagnosis of Graves' disease, however, the detection of autoantibodies against TPO and/or Tg does not play a major role in view of the relevance and specificity of the detection of autoantibodies against the TSH receptor.
A determination of anti-TPO autoantibodies and anti-Tg autoantibodies is carried out in particular when autoimmune thyroiditis is suspected. In autoimmune thyroiditis of the Hashimoto type and in atrophic autoimmune thyroiditis, anti-TPO autoantibodies are very frequently present, but no autoantibodies against the TSH receptor. Frequently, the occurrence of anti-TPO autoantibodies is accompanied by anti-Tg autoantibodies, but there are cases where exclusively anti-Tg autoantibodies, but not anti-TPO autoantibodies, are detectable (Meng, W. in “Schilddrusenerkrankungen” [Thyroid diseases], Gustav Fischer Verlag, 1992; Pfannenstiel & Saller, loc. cit.; Ziegler et al., loc. cit.). Since there are therefore cases of autoimmune thyroiditis where no anti-TPO autoantibodies are detectable, the determination of anti-Tg autoantibodies is recommended in addition to the determination of anti-TPO autoantibodies (Feldt-Rasmussen, U. “Analytical and clinical performance goals for testing autoantibodies to thyroperoxidase, thyroglobulin, and thyrotropin receptor”, Clinical Chemistry 42:1, 160-163, 1996). Whereas, apart from autoimmune thyroiditis of the Hashimoto type, there are further thyroid clinical pictures which constitute autoimmune diseases and in which anti-TPO or anti-Tg autoantibodies may be increased (primary myxoedema, asympotomatic thyroiditis, postpartal thyroiditis, neonatal hypothyroidism), there is only one indication in which anti-TPO autoantibodies do not occur alongside anti-Tg autoantibodies and are recommended for measurement, namely thyroid carcinoma (Feldt-Rasmussen, loc. cit.). In the case of thyroid carcinoma, large amounts of thyroglobulin are released from the thyroid cells, resulting in the formation of autoantibodies against Tg. Usually, thyroglobulin (Tg) is therefore determined for the detection of a thyroid carcinoma. However, the Tg determination may be disturbed by the presence of anti-Tg autoantibodies, and a so-called recovery measurement must therefore be carried out to back up the results of the measurements for the Tg determination. For confirming the findings in the case of a disturbed Tg detection, it may be of interest in specific cases to test the corresponding biological sample for the presence of anti-Tg autoantibodies.
The dominant method for the determination of autoantibodies when autoimmune thyroiditis is suspected is the determination of anti-TPO autoantibodies. The reliability of such determinations with respect to their diagnostic sensitivity is however under discussion (Haagen, U. & Bergmann, A., “Besondere Aspekte der Qualitatssicherung der Komponente Autoantigen bei Fertigreagenzien fur die Schilddrusenautoimmundiagnostik” [Particular aspects of the quality assurance of the component autoantigen in ready-to-use reagents for thyroid autoimmune diagnosis], Abstract from the “Jahrestagung der Sektion Schilddruse der Deutschen Gesellschaft fur Endokrinologie” [Annual Meeting of the Thyroid Section of the German Society for Endocrinology], Nov. 23-25, 1995, Hanover, pages 15-22): In the case of specific immunological assay methods for anti-TPO autoantibodies the antigen TPO is used as an assay component in a form in which all epitopes recognized by autoantibodies may not be present, it being possible in particular for conformational epitopes to be absent. This may be the case if a recombinant antigen produced by genetic engineering is used, if the antigen has been purified and hence conformationally stressed, if the antigen is immobilized directly on a solid phase and/or if the antigen is labelled under rigid conditions. Depending on the assay design it is also possible that specific significant anti-TPO autoantibodies are not detected (Mariotti, S., et al., “False negative results observed in anti-thyroid peroxidase autoantibody determination by competitive radioimmunoassays using monoclonal antibodies”, Eur. J. Endocrinol. 130, 552-558, 1994).
Since cases are therefore known in which the sole determination of anti-TPO autoantibodies gives a false negative result, it is advisable to carry out an additional second determination, namely of anti-Tg autoantibodies, to confirm the diagnosis.
In spite of the advantages of an additional anti-Tg determination, the increasing pressure of costs in the health sector has led to discussions in which it has been suggested that an additional anti-Tg determination in the diagnosis of Hashimoto's thyroiditis be dispensed with although it is recognized that the danger of false diagnoses will be increased as a result (Nordyke, R. A. et al., “The superiority of antimicrosomal over antithyroglobulin antibodies for detecting Hashimoto's thyroiditis”, Arch. Intern. Med. 153, 862-865, 1993).
Under these circumstances, it is the object of the present invention to provide a method for the determination of thyroid autoantibodies for the differential diagnosis of thyroid diseases, which method on the one hand requires only the relatively little effort of an individual determination but has a diagnostic sensitivity which reduces the risk of false negative results, at least compared with the determination of only one type of autoantibodies, and furthermore to provide at least one possibility for the successful technical implementation of such a method.
This object is achieved by a
B.R.A.H.M.S. Diagnostica GmbH
DeCloux Amy
Pillsbury & Winthrop LLP
Saunders David
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