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Exp Clin Endocrinol Diabetes 2006; 114(8): 406-411
DOI: 10.1055/s-2006-924065
Article

© J. A. Barth Verlag in Georg Thieme Verlag KG · Stuttgart · New York

Impact of Smoking on the Course of Graves' Disease after Withdrawal of Antithyroid Drugs

B. Quadbeck 1 , U. Roggenbuck 2 , O. E. Janssen 1 , S. Hahn 1 , K. Mann 1 , R. Hoermann 3 , for the Basedow Study Group[*]
  • 1Division of Endocrinology, Department of Medicine, University of Duisburg-Essen, Germany
  • 2Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Germany
  • 3Department of Medicine I, Klinikum Lüdenscheid, Germany
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Publication History

Received: October 6, 2005 First decision: October 7, 2005

Accepted: December 28, 2005

Publication Date:
13 October 2006 (online)

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Abstract

Cigarette smoking has been reported to alter relapse rate in patients with Graves' disease (GD). However, the predictive effect of smoking in GD patients after withdrawal of antithyroid drug treatment (ATDT) is still controversial. A prospective multicenter trial has previously identified smoking as an independent risk factor for relapse. Based on this study, the present paper gives a more detailed analysis of the impact of smoking on the long-term course of GD after ATDT withdrawal. To this end, 86 smokers and 177 non-smokers were followed during two years after ATDT cessation. At the end of ATDT (visit 1) and four weeks later (visit 2) smokers had significant higher TSH receptor antibody (TRAb) levels than non-smokers (10.0 IU/L±1.6; mean±SEM vs. 6.4 IU/L±0.9; 11.0 IU/L±1.8 vs. 6.8 IU/L±0.8, p<0.01, respectively). During follow-up, Kaplan Meier analysis showed a significantly higher relapse rate in smokers than non-smokers. A subset of GD patients with TRAb levels >10 IU/L had the highest risk to develop relapse during follow-up. Among them, smokers more often relapsed than non-smokers irrespective of TRAb levels, p<0.01. Thus, in smokers with TRAb levels ≥10 IU/L the predictive values of a positive and negative test for relapse was 68% and 73%, respectively (specificity 95%). In conclusion, we identified two effects by which smoking alters the course of GD. First, smoking is implicated to elevate TRAb levels and therefore increase the risk for relapse during follow-up. Second, smoking is an independent risk factor to worsen the clinical course of both, GD patients with low and high immunological risk to experience relapse after a successful outcome of ATDT. Thus, our data suggest that smoking has modifying immunological consequences and an adverse impact on the course of GD after withdrawal of ATDT. Therefore, patients should be encouraged to stop smoking.

Key words

Autoimmunity - antibodies - Graves' disease

References

  • 1 Balazs C, Stenszky V, Farid NR. Association between Graves' ophthalmopathy and smoking.  Lancet. 1990;  336 754
    PubMedGoogle Scholar
  • 2 Banchereau J, Steinman RM. Dendritic cells and the control of immunity.  Nature. 1998;  392 245-252
    CrossrefPubMedGoogle Scholar
  • 3 Bartalena L, Martino E, Marcocci C, Bogazzi F, Panicucci M, Velluzzi F, Loviselli A, Pinchera A. More on smoking habits and Graves' ophthalmopathy.  J Endocrinol Invest. 1989;  12 733-737
    CrossrefPubMedGoogle Scholar
  • 4 Bartalena L, Marcocci C, Tanda ML, Manetti L, Dell'Unto E, Bartolomei MP, Nardi M, Martino E, Pinchera A. Cigarette smoking and treatment outcomes in Graves' ophthalmopathy.  Ann Intern Med. 1998;  22 632-635
    PubMedGoogle Scholar
  • 5 Burch HB, Wartofsky L. Graves'ophthalmopathy: current concepts regarding pathogenesis and management.  Endocr Rev. 1993;  14 747-793
    CrossrefPubMedGoogle Scholar
  • 6 Eckstein A, Quadbeck B, Mueller G, Rettenmeier AW, Hoermann R, Mann K, Steuhl P, Esser J. Impact of smoking on the response to treatment of thyroid associated ophthalmopathy.  Br J Ophthalmol. 2003;  87 773-776
    CrossrefPubMedGoogle Scholar
  • 7 Eckstein A, Quadbeck B, Tews S, Mann K, Krüger C, Mohr CH, Steuhl K-P, Esser J, Gieseler RK. Thyroid associated ophthalmopathy: evidence for CD4+ γδ T cells; de novo differentiation of RFD7+ macrophages, but not of RFD1+ dendritic cells; and loss of γδ and αβ T cell receptor expression.  Br J Ophthalmol. 2004;  88 803-808
    Google Scholar
  • 8 Ericsson UB, Lindgärde F. Effects of cigarette smoking on thyroid function and the prevalence of goitre, thyrotoxicosis and autoimmune thyroiditis.  J Intern Med. 1991;  229 67-71
    PubMedGoogle Scholar
  • 9 Feldt-Rasmussen U, Schleusener H, Carayon P. Meta-analysis evaluation of the impact of thyrotropin receptor antibodies on long term remission after medical therapy of Graves' disease.  J Clin Endocrinol Metab. 1994;  78 98-102
    CrossrefPubMedGoogle Scholar
  • 10 Garry PJ, Lashley DW, Owen GM. Automated measurement of urinary iodine.  Clin Chem. 1973;  19 950-953
    PubMedGoogle Scholar
  • 11 Geng Y, Savage SM, Johnson LJ, Seagrave J, Sopori ML. Effects of nicotine on the immune response I. Chronic exposure to nicotine impairs antigen receptor-mediated signal transduction in lymphocytes.  Toxicol Appl Pharmacol. 1995;  135 268-278
    CrossrefPubMedGoogle Scholar
  • 12 Geng Y, Savage SM, Razani-Boroujerdi S, Sopori ML. Effects of nicotine on the immune response. II. Chronic nicotine treatment induces T cell anergy.  J Immunol. 1996;  156 2384-2390
    PubMedGoogle Scholar
  • 13 George J, Levy Y, Shoenfeld Y. Smoking and immunity: an additional player in the mosaic of autoimmunity.  Scand J Immunol. 1997;  45 1-6
    CrossrefPubMedGoogle Scholar
  • 14 Glinoer D, de Nayer P, Bex M. Effects of L-thyroxine administration, TSH-receptor antibodies and smoking on the risk of recurrence in Graves' hyperthyroidism treated with antithyroid drugs: a double-blind prospective randomized study.  Eur J Endocrinol. 2001;  144 475-483
    Google Scholar
  • 15 Hashizume K, Ichikawa K, Sakurai A, Suzuki S, Takeda T, Kobayashi M, Miyamoto T, Arai M, Nagasawa T. Administration of thyroxine in treated Graves' disease. Effects on the level of antibodies to thyroid-stimulating hormone receptors and on the risk of recurrence of hyperthyroidism.  N Engl J Med. 1991;  324 947-953
    CrossrefPubMedGoogle Scholar
  • 16 Hägg E, Asplund K. Is endocrine ophthalmopathy related to smoking?.  Br Med J (Clin Res Ed). 1987;  295 634-635
    CrossrefPubMedGoogle Scholar
  • 17 Hoermann R, Quadbeck B, Roggenbuck U, Szabolcs I, Pfeilschifter J, Meng W, Reschke K, Hackenberg K, Dettmann J, Prehn B, Hirche H, Mann K. Relapse of Graves' disease after successful outcome of antithyroid drug therapy: results of a prospective randomized study on the use of levothyroxine.  Thyroid. 2002;  12 1119-1128
    CrossrefPubMedGoogle Scholar
  • 18 Hofbauer LC, Mühlberg T, König A, Heufelder G, Schworm H-D, Heufelder AE. Soluble interleukin-1 receptor antagonist serum levels in smokers and nonsmokers with Graves' ophthalmopathy undergoing orbital radiotherapy.  J Clin Endocrinol Metab. 1997;  82 2244-2247
    CrossrefPubMedGoogle Scholar
  • 19 Kimball LE, Kulinskaya E, Brown B, Johnston C, Farid NR. Does smoking increase relapse rates in Graves' disease?.  J Endocrinol Invest. 2002;  25 152-157
    Google Scholar
  • 20 Lanzavecchia A, Sallusto F. Regulation of T cell immunity by dendritic cells.  Cell. 2001;  106 263-266
    CrossrefPubMedGoogle Scholar
  • 21 McIver B, Rae P, Beckett G, Wilkinson E, Gold A, Toft A. Lack of effect of thyroxine in patients with Graves' hyperthyroidism who are treated with an antithyroid drug.  N Engl J Med. 1996;  334 220-224
    CrossrefPubMedGoogle Scholar
  • 22 Melander A, Nordenskjold E, Lundh B, Thorell J. Influence of smoking on thyroid activity.  Acta Med Scand. 1981;  209 41-43
    PubMedGoogle Scholar
  • 23 Metcalfe RA, Weetman AP. Stimulation of extraocular muscle fibro-blasts by cytokines and hypoxia: possible role in thyroid-associated ophthalmopathy.  Clin Endocrinol (Oxf). 1994;  40 67-72
    Google Scholar
  • 24 Nedrebo BG, Holm PI, Uhlving S, Sorheim JI, Skeie S, Eide GE, Husebye ES, Lien EA, Aanderud S. Predictors of outcome and comparison of different drug regimens for the prevention of relapse in patients with Graves' disease.  Eur J Endocrinol. 2002;  147 583-589
    Google Scholar
  • 25 Nouri-Shirazi M, Guinet E. Evidence for the immunosuppressive role of nicotine on human dendritic cell functions.  Immunology. 2003;  109 365-373
    CrossrefPubMedGoogle Scholar
  • 26 Pfeilschifter J, Ziegler R. Smoking and endocrine ophthalmopathy: impact of smoking severity and current vs. lifetime cigarette consumption.  Clin Endocrinol (Oxf). 1996;  45 477-481
    Google Scholar
  • 27 Pfeilschifter J, Ziegler R. Suppression of serum thyrotropin with thyroxine in patients with Graves' disease: effects on recurrence of hyperthyroidism and thyroid volume.  Eur J Endocrinol. 1997;  136 81-86
    PubMedGoogle Scholar
  • 28 Prummel MF, Wiersinga WM. Smoking and risk of Graves' disease.  JAMA. 2003;  269 479-482
    PubMedGoogle Scholar
  • 29 Quadbeck B, Eckstein A, Tews S, Walz M, Hoermann R, Mann K, Gieseler R. Maturation of thyroidal dendritic cells in Graves' disease.  Scand J Immunol. 2002;  55 612-620
    CrossrefPubMedGoogle Scholar
  • 30 Quadbeck B, Hoermann R, Roggenbuck U, Hahn S, Mann K, Janssen OE. Sensitive thyrotropin and thyrotropin-receptor antibody determinations one month after discontinuation of antithyroid drug treatment as predictors of relapse in Graves' disease.  Thyroid. 2005;  15 1047-1054
    CrossrefPubMedGoogle Scholar
  • 31 Raber W, Kmen E, Waldhäusl W, Vierhapper H. Medical therapy of Graves' disease: effect on remission rates of methimazole alone and in combination with triiodothyronine.  Eur J Endocrinol. 2000;  142 117-124
    CrossrefPubMedGoogle Scholar
  • 32 Rendl J, Seybold S, Borner W. Urinary iodide determined by paired-ion reversed-phase HPLC with electrochemical detection.  Clin Chem. 1994;  40 908-913
    PubMedGoogle Scholar
  • 33 Richmond I, Pritchard GE, Ashcroft T. Distribution of gamma delta T-cells in the bronchial tree of smokers and non-smokers.  J Clin Pathol. 1993;  46 926-930
    PubMedGoogle Scholar
  • 34 Rittmaster RS, Abbott EC, Douglas R, Givner ML, Lehmann L, Reddy S, Salisbury SR, Schlossberg AH, Tan MH, York SE. Effect of methimazole, with or without L-thyroxine, on remission rates in Graves' disease.  J Clin Endocrinol Metab. 1998;  83 814-818
    CrossrefPubMedGoogle Scholar
  • 35 Sepkovic DW, Haley JN, Wynder EL. Thyroid activity in cigarette smokers.  Arch Intern Med. 1984;  144 501-503
    CrossrefPubMedGoogle Scholar
  • 36 Schleusener H, Schwander J, Fischer C, Holle R, Holl G, Badenhoop K, Hensen J, Finke R, Bogner U, Mayr WR. et al . Prospective multicentre study on the prediction of relapse after antithyroid drug treatment in patients with Graves' disease.  Acta Endocrinol (Copenh). 1989;  120 689-701
    PubMedGoogle Scholar
  • 37 Schott M, Morgenthaler NG, Fritzen R, Feldkamp J, Willenberg HS, Scherbaum WA, Seissler J. Levels of autoantibodies against human TSH receptor predict relapse of hyperthyroidism in Graves' disease.  Horm Metab Res. 2004;  36 92-96
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Shine B, Fells P, Edwards OM, Weetman AP. Association between Graves' ophthalmopathy and smoking.  Lancet. 1990;  335 1261-1263
    CrossrefPubMedGoogle Scholar
  • 39 Tamai H, Hayaki I, Kawai K, Komaki G, Matsubayashi S, Kuma K, Kumagai LF, Nagataki S. Lack of effect of thyroxine administration on elevated thyroid stimulating hormone receptor antibody levels in treated Graves' disease patients.  J Clin Endocrinol Metab. 1995;  80 1481-1484
    CrossrefPubMedGoogle Scholar
  • 40 Tellez M, Cooper J, Edmonds C. Graves' ophthalmopathy in relation to cigarette smoking and ethnic origin.  Clin Endocrinol (Oxf). 1992;  36 291-294
    PubMedGoogle Scholar
  • 41 Vitti P, Rago T, Chiovato L, Pallini S, Santini F, Fiore E, Rocchi R, Martino E, Pinchera A. Clinical features of patients with Graves' disease undergoing remission after antithyroid drug treatment.  Thyroid. 1997;  7 369-375
    CrossrefPubMedGoogle Scholar
  • 42 Vestergaard P. Smoking and thyroid disorders - a meta-analysis.  Eur J Endocrinol. 2002;  146 153-161
    Google Scholar
  • 43 Weetman AP. Autoimmune thyroid disease: propagation and progression.  Eur J Endocrinol. 2003;  148 1-9
    CrossrefPubMedGoogle Scholar
  • 44 Winsa B, Mandahl A, Karlsson FA. Graves' disease, endocrine ophthalmopathy and smoking.  Acta Endocrinol (Copenh). 1993;  128 156-160
    PubMedGoogle Scholar
  • 45 Zimmermann-Belsing T, Nygaard B, Rasmussen AK, Feldt-Rasmussen U. Use of the 2nd generation TRAK human assay did not improve prediction of relapse after antithyroid medical therapy of Graves' disease.  Eur J Endocrinol. 2002;  146 173-177
    CrossrefPubMedGoogle Scholar

1 See Acknowledgements for list of members.

Correspondence

Beate QuadbeckM.D. 

Division of Endocrinology·Department of Medicine·University of Duisburg-Essen

Hufelandstraße 55

45122 Essen

Germany

Phone: +49/20/17 23 28 21

Fax: +49/20/17 23 59 76

Email: beate.quadbeck@uni-essen.de

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