MiR-346 and TRAb as Predicative Factors for Relapse in Graves’ Disease Within One Year

Abstract

Despite the efficacy and safety, antithyroid drug (ATD) therapy for Graves’ disease (GD) is associated with a high risk of relapse, especially within the first year. The inability to predict whether and when relapse may occur is a major problem for ATD therapy. This study was aimed to investigate potential predicative factors for GD patients after ATD withdrawal. Consecutive patients newly diagnosed with GD and treated with ATD [methimazole (MMI)] were enrolled in this study. Univariate and multivariate Cox proportional hazard analyses were used for the analysis of predicative parameters for GD relapse after MMI withdrawal. Kaplan-Meier survival analysis and log-rank test were utilized for presenting the risk of relapse. Of the 103 patients included, 67 (65.0%) remained in remission and 36 (35.0%) had a relapse within 1 year after the MMI withdrawal. The multivariate analysis suggested significant predictive factors for GD relapse: patients with higher miR-346 expressions (≥median value) at diagnosis and at cessation, and lower TRAb levels at cessation. MiR-346 at diagnosis and cessation, and TRAb at cessation could serve as predictive factors for GD relapse within 1 year after drug withdrawal.

Key words

MiR-346 - TRAb - Graves’ disease - antithyroid drugs

• References

• 1 Langenstein C, Schork D, Badenhoop K, Herrmann E. Relapse prediction in Graves disease: Towards mathematical modeling of clinical, immune and genetic markers. Rev Endocr Metab Disord 2016; DOI: DOI: 10.1007/s11154-016-9386-8.
• 2 Brent GA. Clinical practice. Graves’ disease. N Engl J Med 2008; 358: 2594-2605
• 3 Burch HB, Burman KD, Cooper DS, Hennessey JV. A 2013 survey of clinical practice patterns in the management of primary hypothyroidism. J Clin Endocrinol Metab 2014; 99: 2077-2085
• 4 Villagelin D, Romaldini JH, Santos RB, Milkos AB, Ward LS. Outcomes in Relapsed Graves’ Disease Patients Following Radioiodine or Prolonged Low Dose of Methimazole Treatment. Thyroid 2015; 25: 1282-1290
• 5 Romaldini JH. Case selection and restrictions recommended to patients with hyperthyroidism in South America. Thyroid 1997; 7: 225-228
• 6 Cooper DS. Antithyroid drugs. N Engl J Med 2005; 352: 905-917
• 7 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
• 8 O’Connell RM, Rao DS, Chaudhuri AA, Baltimore D. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 2010; 10: 111-122
• 9 Bernecker C, Lenz L, Ostapczuk MS, Schinner S, Willenberg H, Ehlers M, Vordenbaumen S, Feldkamp J, Schott M. MicroRNAs miR-146a1, miR-155_2, and miR-200a1 are regulated in autoimmune thyroid diseases. Thyroid 2012; 22: 1294-1295
• 10 Hiratsuka I, Yamada H, Munetsuna E, Hashimoto S, Itoh M. Circulating MicroRNAs in graves’ disease in relation to clinical activity. Thyroid 2016; 26: 1431-1440
• 11 Chen J, Tian J, Tang X, Rui K, Ma J, Mao C, Liu Y, Lu L, Xu H, Wang S. MiR-346 regulates CD4(+)CXCR5(+) T cells in the pathogenesis of Graves’ disease. Endocrine 2015; 49: 752-760
• 12 Liu X, Shi B, Li H. Valuable predictive features of relapse of Graves’ disease after antithyroid drug treatment. Ann Endocrinol (Paris) 2015; 76: 679-683
• 13 Cappelli C, Gandossi E, Castellano M, Pizzocaro C, Agosti B, Delbarba A, Pirola I, De Martino E, Rosei EA. Prognostic value of thyrotropin receptor antibodies (TRAb) in Graves’ disease: a 120 months prospective study. Endocr J 2007; 54: 713-720
• 14 Allahabadia A, Daykin J, Holder RL, Sheppard MC, Gough SC, Franklyn JA. Age and gender predict the outcome of treatment for Graves' hyperthyroidism. J Clin Endocrinol Metab 2000; 85: 1038-1042
• 15 Eckstein AK, Lax H, Losch C, Glowacka D, Plicht M, Mann K, Esser J, Morgenthaler NG. Patients with severe Graves’ ophthalmopathy have a higher risk of relapsing hyperthyroidism and are unlikely to remain in remission. Clin Endocrinol (Oxf) 2007; 67: 607-612
• 16 Weetman AP, McGregor AM. Autoimmune thyroid disease: further developments in our understanding. Endocr Rev 1994; 15: 788-830
• 17 Antonelli A, Ferrari SM, Corrado A, Di Domenicantonio A, Fallahi P. Autoimmune thyroid disorders. Autoimmun Rev 2015; 14: 174-180
• 18 Wang PW, Chen IY, Juo SH, Hsi E, Liu RT, Hsieh CJ. Genotype and phenotype predictors of relapse of graves’ disease after antithyroid drug withdrawal. Eur Thyroid J 2013; 1: 251-258
• 19 Hoermann R, Quadbeck B, Roggenbuck U, Szabolcs I, Pfeilschifter J, Meng W, Reschke K, Hackenberg K, Dettmann J, Prehn B, Hirche H, Mann K. Basedow Study G. 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
• 20 Tun NN, Beckett G, Zammitt NN, Strachan MW, Seckl JR, Gibb FW. Thyrotropin Receptor Antibody Levels at Diagnosis and After Thionamide Course Predict Graves’ Disease Relapse. Thyroid 2016; 26: 1004-1009
• 21 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
• 22 Zhu C, Ma J, Liu Y, Tong J, Tian J, Chen J, Tang X, Xu H, Lu L, Wang S. Increased frequency of follicular helper T cells in patients with autoimmune thyroid disease. J Clin Endocrinol Metab 2012; 97: 943-950