Low doses of antithyroid drugs (ATD) for extended periods may be an alternative for Graves' disease (GD) patients who relapse after a course of ATD.
Methods:
Patients with GD relapse (n = 238) after discontinuation of ATD therapy for 12–24 months were retrospectively analyzed in a nonrandomized study. Radioiodine (RAI) treatment and L-thyroxine replacement was used in 114 patients, and a low dose of methimazole (MMI; 2.5–7 mg/daily) was used in 124 patients. Thyroid dysfunction, Graves' ophthalmopathy (GO) evolution, quality of life (QoL), and body weight were evaluated during the follow-up.
Results:
The mean follow-up was 80.8 ± 35.3 months for the RAI group, and 71.3 ± 40.3 months for the low-dose MMI group. No notable side effects were observed in either group. Thyroid dysfunction was predominant in the RAI group (p < 0.001), and euthyroidism was more common in the MMI group (p < 0.001). GO deterioration was mainly evaluated by clinical activity score (CAS)—it was higher in the RAI group (p < 0.0005) over all periods of follow-up. Multivariate logistic analysis showed that RAI treatment was associated with no improvement in CAS during follow-up (24 months: OR = 3.51 [CI 1.02–12.03], p < 0.05; 36 months: OR = 8.46 [CI 1.47–48.58], p < 0.05; 48 months: OR = 19.52 [CI 1.70–223.10], p < 0.05; 60 months: OR = 21.1 [CI 1.5–298], p < 0.05). Kaplan–Meier survival analysis confirmed this finding (p < 0.0003). Assessment of QoL using the Short Form Health Survey's 36 parameters in stable euthyroid patients (at least six months) was similar in both groups. The RAI group patients gained more weight (p < 0.005), particularly after 24 months of follow-up.
Conclusions:
The use of low doses of MMI is efficient and safe, and offers better outcomes for GO than RAI treatment. Prolonged low doses of MMI may be an alternative choice for relapsed GD patients, particularly for GO patients or for patients who refuse a definitive treatment.
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References
1.
BahnRS, BurchHB, CooperDS, GarberJR, GreenleeMC, KleinI, LaurbergP, McDougallIR, MontoriVM, RivkeesSA, RossDS, SosaJA, StanMN; American Thyroid Association; American Association of Clinical Endocrinologists. 2011. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid, 17:456–520.
2.
GlinoerD, HeschD, LagasseR, LaurbergP. 1987. The management of hyperthyroidism due to Graves' disease in Europe in 1986. Results of an international survey. Acta Endocrinol Suppl (Copenh), 285:3–23.
3.
RomaldiniJH. 1997. Case selection and restrictions recommended to patients with hyperthyroidism in South America. Thyroid, 7:225–228.
4.
NagayamaY, IzumiM, NagatakiS. 1989. The management of hyperthyroidism due to Graves' disease in Japan in 1988. The Japan Thyroid Association. Endocrinol Jpn, 36:299–314.
5.
BurchHB, BurmanKD, CooperDS. 2012. A 2011 survey of clinical practice patterns in the management of Graves' disease. J Clin Endocrinol Metab, 97:4549–4558.
6.
CooperDS. 2005. Antithyroid drugs. N Engl J Med, 352:905–917.
7.
WatanabeN, NarimatsuH, NohJY, YamaguchiT, KobayashiK, KamiM, ItoK, ItoK. 2012. Antithyroid drug-induced hematopoietic damage: a retrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves' disease. J Clin Endocrinol Metab, 97:E49–53.
8.
AbrahamP, AvenellA, McGeochSC, ClarkLF, BevanJS. 2010. Antithyroid drug regimen for treating Graves' hyperthyroidism. Cochrane Database Syst Rev CD003420.
9.
Abraham-NordlingM, TorringO, HambergerB, LundellG, TallstedtL, CalissendorffJ, GöranWallin. 2005. Graves' disease: a long-term quality-of-life follow up of patients randomized to treatment with antithyroid drugs, radioiodine, or surgery. Thyroid, 15:1279–1286.
10.
BiondiB, KahalyGJ. 2010. Cardiovascular involvement in patients with different causes of hyperthyroidism. Nat Rev Endocrinol, 6:431–443.
11.
SlingerlandDW, BurrowsBA. 1979. Long-term antithyroid treatment in hyperthyroidism. JAMA, 242:2408–2410.
12.
AziziF, AtaieL, HedayatiM, MehrabiY, SheikholeslamiF. 2005. Effect of long-term continuous methimazole treatment of hyperthyroidism: comparison with radioiodine. Eur J Endocrinol, 152:695–701.
13.
LegerJ, GelwaneG, KaguelidouF, BenmeradM, AlbertiC. French Childhood Graves' Disease Study Group. 2012. Positive impact of long-term antithyroid drug treatment on the outcome of children with Graves' disease: national long-term cohort study. J Clin Endocrinol Metab, 97:110–119.
14.
LaurbergP, BermanDC, AndersenS, Bulow PedersenI. 2011. Sustained control of Graves' hyperthyroidism during long-term low-dose antithyroid drug therapy of patients with severe Graves' orbitopathy. Thyroid, 21:951–956.
15.
ElbersL, MouritsM, WiersingaW. 2011. Outcome of very long-term treatment with antithyroid drugs in Graves' hyperthyroidism associated with Graves' orbitopathy. Thyroid, 21:279–283.
16.
MouritsMP, PrummelMF, WiersingaWM, Koornneef. 1997. Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy. Clin Endocrinol (Oxf), 47:9–14.
17.
JenkinsonC, CoulterA, WrightL. 1993. Short form 36 (SF36) health survey questionnaire: normative data for adults of working age. BMJ, 306:1437–1440.
VaismanF, CoeliCM, WardLS, GrafH, CarvalhoG, MontenegroRJr, VaismanM. 2013. How good is the levothyroxine replacement in primary hypothyroidism patients in Brazil? Data of a multicentre study. J Endocrinol Invest, 36:485–488.
20.
HollowellJG, StaehlingNW, FlandersWD, HannonWH, GunterEW, SpencerCA, BravermanLE. 2002. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab, 87:489–499.
21.
BiondiB, WartofskyL. 2014. Treatment with thyroid hormone. Endocr Rev, 35:433–512.
BriesacherBA, AndradeSE, FouayziH, ChanKA. 2008. Comparison of drug adherence rates among patients with seven different medical conditions. Pharmacotherapy, 28:437–443.
24.
McCrudenDC, HilditchTE, ConnellJM, McLellanAR, RobertsonJ, AlexanderWD. 1987. Duration of antithyroid action of methimazole estimated with an intravenous perchlorate discharge test. Clin Endocrinol (Oxf), 26:33–39.
25.
LaurbergP, WallinG, TallstedtL, Abraham-NordlingM, LundellG, TorringO. 2008. TSH-receptor autoimmunity in Graves' disease after therapy with anti-thyroid drugs, surgery, or radioiodine: a 5-year prospective randomized study. Eur J Endocrinol, 158:69–75.
26.
PedroAB, RomaldiniJH, TakeiK. 2011. Changes of serum cytokines in hyperthyroid Graves' disease patients at diagnosis and during methimazole treatment. Neuroimmunomodulation, 18:45–51.
27.
BartalenaL. 2011. The dilemma of how to manage Graves' hyperthyroidism in patients with associated orbitopathy. J Clin Endocrinol Metab, 96:592–599.
28.
VannucchiG, CampiI, CovelliD, DazziD, CurroN, SimonettaS, RatigliaR, Beck-PeccozP, SalviM. 2009. Graves' orbitopathy activation after radioactive iodine therapy with and without steroid prophylaxis. J Clin Endocrinol Metab, 94:3381–3386.
29.
BartalenaL, MarcocciC, BogazziF, ManettiL, TandaML, Dell'UntoE, Bruno-BossioG, NardiM, BartolomeiMP, LepriA, RossiG, MartinoE, PincheraA. 1998. Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N Engl J Med, 338:73–78.
30.
BartalenaL, MarcocciC, BogazziF, PanicucciM, LepriA, PincheraA. 1989. Use of corticosteroids to prevent progression of Graves' ophthalmopathy after radioiodine therapy for hyperthyroidism. N Engl J Med, 321:1349–1352.
31.
EgleUT, KahalyGJ, PetrakF, HardtJ, BatkeJ, BestJ, RothenbacherM. 1999. The relevance of physical and psychosocial factors for the quality of life in patients with thyroid-associated orbitopathy (TAO). Exp Clin Endocrinol Diabetes, 107:S168–1671.
32.
KahalyGJ, HardtJ, PetrakF, EgleUT. 2002. Psychosocial factors in subjects with thyroid-associated ophthalmopathy. Thyroid, 12:237–239.
33.
TerweeC, WakelkampI, TanS, DekkerF, PrummelMF, WiersingaW. 2002. Long-term effects of Graves' ophthalmopathy on health-related quality of life. Eur J Endocrinol, 146:751–757.
34.
Vigario PdosS, VaismanF, CoeliCM, WardL, GrafH, CarvalhoG, JúniorRM, VaismanM. 2013. Inadequate levothyroxine replacement for primary hypothyroidism is associated with poor health-related quality of life—a Brazilian multicentre study. Endocrine, 44:434–440.
35.
BiondiB, PalmieriEA, KlainM, SchlumbergerM, FilettiS, LombardiG. 2005. Subclinical hyperthyroidism: clinical features and treatment options. Eur J Endocrinol, 152:1–9.
36.
Abraham-NordlingM, WallinG, TraiskF, BergG, CalissendorffJ, HallengrenB, HednerP, LantzM, NyströmE, AsmanP, LundellG, TörringO; Thyroid Study Group of TT. 96. 2010 Thyroid-associated ophthalmopathy; quality of life follow-up of patients randomized to treatment with antithyroid drugs or radioiodine. Eur J Endocrinol, 163:651–657.
37.
LjunggrenJG, TorringO, WallinG, TaubeA, TallstedtL, HambergerB, LundellG. 1998. Quality of life aspects and costs in treatment of Graves' hyperthyroidism with antithyroid drugs, surgery, or radioiodine: results from a prospective, randomized study. Thyroid, 8:653–659.
38.
NakamuraH, MiyauchiA, MiyawakiN, ImagawaJ. 2013. Analysis of 754 cases of antithyroid drug-induced agranulocytosis over 30 years in Japan. J Clin Endocrinol Metab, 98:4776–4783.
39.
JanssonS, BergG, LindstedtG, MichanekA, NystromE. 1993. Overweight—a common problem among women treated for hyperthyroidism. Postgrad Med J, 69:107–111.
40.
Al-AdsaniH, HofferLJ, SilvaJE. 1997. Resting energy expenditure is sensitive to small dose changes in patients on chronic thyroid hormone replacement. J Clin Endocrinol Metab, 82:1118–1125.
41.
KnudsenN, LaurbergP, RasmussenLB, BulowI, PerrildH, OvesenL, JørgensenT. 2005. Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. J Clin Endocrinol Metab, 90:4019–4024.
