Endocrine Journal 2003, 80 (1), 45-89 Practical Treatment with Minimum Maintenance Dose of Anti- Thyroid Drugs for Prediction of Remission in Graves’ Disease ‘Taxv KASHIWAI, You HIDAKA, Toru TAKANO, Ke-ta TATSUMI, Yuxixo IZUMI, ‘Yuxr SHIMAOKA, Hisato TADA, Keiko TAKEOKA AND Nosuyuxt AMINO Department of Laboratory Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan Abstract. Although many researchers have reported clinical and laboratory parameters for prediction of remission in Graves’ disease during or after ani-thyroid drug therapy, there is no reliable one to assure the complete remission. ‘We prospectively examined a practical therapy with minimum maintenance dose of anti-thyroid drugs for prediction of remission in Graves’ disease. Fifty-seven patients with Graves’ disease were treated with antithyroid drugs atthe inital dose of 30 mg/day of methimazole (MMI) or 300 me/day of propylthiouracil (PTU). Then, doses were grad- wally decreased, and finally discontinued when the patients were able to maintain euthyroid (normal FT4 and TSH) for at least 6 months with the minimum maintenance dose (MMI S mg every other day or PTU SO mg every other day). After discontinuation of drugs, FT4, FT3, TSH and TSH-binding inhibitory immunoglobulin (TBI) were measured every one t0 two months for the fist 6 months and every 3-4 months for the next 18 months to confirm Continuous remission. After 2 years of drug cessation, 46 (81%) of $7 patients were in remission and the other 11 pa- tients had relapsed into thyrotoxicosis, At the time Of drug discontinuation, the serum concentration of FT, FTs and TSH, titers of anti-thyroglobulin antibodies and antithyroid microsomal antibodies, goiter size were not éifer- ent between the remission and relapse groups. At the time of drug cessation, the activites of TBI and thyroid Stimulating antibodies (TSAb) overlapped between the {wo groups, although they were significantly lower in the remission group than inthe relapse group (p<0.01). Forty percent (/10) of TBII positive patients and 719% (23/32) lof TSAb positive patients continued to be in remission. On the other hand, thyrotoxicosis relapsed in 5 (11%) of 47 ‘TBI negative and 2 (8%) of 25 TSAb negative patients. These data indicate that minimum maintenance therapy to -eep euthyroid (normal FT4 and TSH) for 6 months isa practical measure for 81% prediction of remission in Graves’ disease. The measurement of TBIL or TSAb gave litle additional information for predicting remission TSH receptor antibody (Endocrine Journal 80: 45-49, 2003) Key words; Graves’ disease, Anti-thyroid drug, Treatment, Remission, An ANTITHYROID drugs (ATD), such as methimazole (MMI) and propylthiouracil (PTU), have long been used for the drug therapy of Graves’ disease. A. ‘major clinical problem of ATD therapy is that there is no reliable way to predict the remission [1, 2]. Many clinical and laboratory parameters, such as ‘TRH test [3, 4], T3 suppression test [5-7], goiter size [8, 9], technetium-99m thyroid uptake [10], serum thyroglobulin [11], T3/T4 ratio [12] or FT3/FT4 ra- Received: August 5, 2002 ‘Accepted: November 12, 2002 Correspondence to: Nobuyuki AMINO, M.D., Department of Laboratory Medicine, Osaka University Graduate School of “Medicine D2, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan tio [13], have been examined for prediction of remis- sion. However, the actual remission rate in the pa- tients evaluated with one of the above markers was between 60 and 80%. Antithyroid autoantibodies, especially TBII and TSAb, which are the main patho- genic factor causing Graves’ thyrotoxicosis, have also been reported as predictive parameters [8, 9, 14] Using these parameters many studies reported that remission was predicted in about 80% of the pa- tients, On the contrary, some other studies reported ‘TBI or TSAb was not a good marker for predicting remission (15, 16], although it was useful for predict- ing the relapse of thyrotoxicosis. Combining the parameters mentioned above, the remission rate im- proved to 80 to 90%, Some parameters for cellular“ KASHIWAT eal immunity have been reported to be more useful for prediction of remission [9], but not suitable for clini- cal use. The measurement of many parameters at the same time is not practical, especially for cost: effectiveness. Several studies reported that the re- mission rate was improved by long-term ATD treat- ment compared with short-term treatment [17, 18], although there are controversial reports (19, 20]. In cases with intractable disease, the long-term adminis- tration of ATD for 8-21 years has been recommend- ed [21]. In this study we prospectively examined for the practical measure of prediction of remission with minimum maintenance therapy using ATD. Materials and Methods Patients We studied 57 patients (mean age, 48.1 years old; 13 men and 44 women) with Graves’ disease who attended our thyroid clinic. The ATD therapy was started with MMI 30 mg/day or PTU 300 mg/day and then ATD dose was decreased to 20 mg/day or 200 mg/day, respectively when serum FT4 and FT3 values decreased into normal range. ATD dose was further decreased gradually (15 mg—>10 mg->5 mg) when serum FT4 and TSH were kept in normal for 3 to 6 months or when TSH value was increased over, normal range. Lastly patients were kept in eu. thyroid on the minimum maintenance dose (MMI 5 mg every other day or PTU $0 mg every other day) Finally, we discontinued ATD medication when their serum FT4 and TSH had been kept at normal for six months. This observation period of six months with. minimum maintenance dose was decided based on our previous study that up to 80% of patients relapsed into Graves’ thyrotoxicosis within 6 months after cessation of ATD (9). During minimum main- tenance therapy, serum FT4, FT3, TSH and TBIL were measured every month for at least 6 months. After discontinuation of ATD, FT4, FT3, TSH and ‘TBII were measured every 1-2 months for the first 6 ‘months and every 3-4 months for the next 18 months to confirm continuous remission. When patients had increased thyroid hormones and/or suppressed TSH during minimum maintenance therapy, the ATD dose was increased and we repeated the pro- tocol of minimum maintenance therapy. During the two year observation period, they were considered to have a relapse,of thyrotoxicosis when they had in- creased thyroid hormones and suppressed TSH. We regarded the patients as being in remission when they Kept euthyroid (normal FT4, FT3 and TSH) for at least 2 years. Informed consent was obtained from all patients. Measurements The serum levels of FT4 and FT3 were measured using commercial radioimmunoassay kits (FT4: Eiken Chemical Co. Ltd., Tokyo, Japan. FT3: Ortho-Clinical Diagnostics, Amersham, UK) as previously described [22]. The serum TSH was measured by SPAC-S TSH kit (Daiichi Radioisotope Laboratory Ltd., Tokyo, Japan) (February 1991- June 1993), Berilux TSH (Hoechst Japan, Tokyo, Japan) (July 1993-June 1995), Ab bead TSH kit EIKEN (Fiken Immunochemical Laboratory, Tokyo, Japan) (July 199S-April 1999) and ECLusys TSH (Boehringer Mannheim, Roche Diagnostics K.K., Penzberg, Germany) (May 1999-now). The lower detection limit in each kit was 0.05, 0.04, 0.05 and 0.02 xU/ml, respectively. The normal reference range in each kit was 0.6-5.4, 0.6-3.7, 0.5-3.7 and 0.4-3.8 uU/ml, respectively. Anti-thyroglobulin antibody (TGPA) and anti-thyroid microsomal anti- body (MCPA) were measured by particle aggregation assay. TBIL was measured using a commercial kit (TRAD; Baxter Travenol Co., Japan) and the cut-off value was 12% [22]. TSAb activity was measured by the activity to induce cAMP release from the rat thyroid cell line FRTL-S as previously described. The normal cut-off value was below 140% [22] Statistical analysis For the comparison of various parameters between the groups of remission and relapse, the Mann- Whitney U test was used. A p value below 0.05 was considered significant. Results Of $7 patients with Graves’ disease, 46 (80.7%) patients maintained euthyroid for at least 2 yearsPRACTICAL TREATMENT FOR GRAVES’ DISEASE a after drug cessation and were considered to be in re- mission. The remaining 11 (19.3%) patients relapsed into thyrotoxicosis within 2 years. Nine of them relapsed within 8 months after withdrawal of ATD. The relapse time after discontinuation of drugs was not related to the activities of TSAD at the time of drug cessation (data not shown). Clinical and labor- atory data at the time of ATD discontinuation was shown in Table 1. Values of FT4, FT3, TSH and titers of TGPA or MCPA, and goiter size were not different between the two groups. The duration of ATD treatment was not different in the two groups. There were obvious overlaps of TBII or TSAb ac- tivities at the time of drug cessation between the remission and relapse groups (Fig. 1), although there were significant differences between the two. The remission rate was 89% (42/47) for TBII negative patients and 92% (23/25) for TSAb negative ones. However, 40% (4/10) of TBII positive patients and 71% (23/32) of TSAb positive patients maintained remission after ATD cessation (Fig. 1). All patients with TBIT more than 30% and/or TSAb more than 2000% relapsed into thyrotoxicosis. Discussion At the present time the most useful parameters for predicting remission of Graves’ disease are believed to be TBI and/or TSAb in combination with or without several other markers. The predictive value is reported to be 80 to 90% [8, 9, 14, 15] In th study, the remission rate for TBII and/or TSAb negative patients was similar to that in the previous reports. However, without these markers, the remis- sion rate of the patients in this study, wherein ATD treatment was simply discontinued after 6 month therapy with minimum maintenance dose, was 81%, which was not so different from those mentioned above. According to our protocol, ATD was discontinued even when TBI and/or TSAb antibodies were posi- tive, and acutually TBII was positive in 16% (10/37) and TSAb was positive in 56% (32/37) of the pa- tients at the time of ATD cessation. The high activ- ity of TSAb at the end of treatment has been report ed to be useful for prediction of relapse [6-9] rather than remission. In our result, higher TSAb activity of more than 2000% was indicative of relapse. However, positive TSAb was not useful for predic- tion of relapse, since 71% of TSAb positive patients kept in remission. This means that about 70% of, patients would have to futilely continue ATDs, if disappearance of TSAb was defined as a marker of, ATD discontinuation. Thus, TBII and/or TSAb ‘measurement cannot be recommended for prediction of remission, because it gives only a slightly more reli- able guarantee than our simple practical approach. In order to obtain the satisfactory condition of normal FT4 and TSH for at least 6 months under @ minimum maintenance dose, it took considerable time in this study. However, the shortest duration Table 1. Clinical and laboratory data at the time of cessation of anti-thyroid drugs in patients with Graves” disease Total (9=57) _ Remission ( Relapse (n= 11) ‘Age (years) 4.12102 4884102 4492101 Male/Female 13/44 134 110 FTS (g/d) 1.172017 Li7£0.16 1520.19 FTS (e/a) 3.782 0.52, 3.7620. 3.89+0.47 TSH (uU/mb) 1.964 1.11 2.06 = 1.14 1.46 £0.84 TBI (%%) 9.1109 6325.1 20.94 18.8" TSAb (0) S492 1185 186 #157 2066 +2150" TGPA (2%100) 3274212 3.302220 3.004 141 MCPA (2100) 5.634287 5582251 5.884 2.42 Goiter size em) 3684056 3.69 0.56 3.69 £0.63, Duration of treatment (months) _71.0237.7 __—73.5+38.8 60.32322 Data indicate meat 28D. Significantly different from remission group at p<0.01 (*),8 KASHIWAL etal A p<0.01 TBII (%) Remission casio)” ERY Fig. 1. ‘TBIL (A) and TSAb (B) at end of anti-thyroid drug treatment, p<0.01 Remission Relapse (a=40) uel) ‘TBI and TSAb in remission group was significantly low compared with those in relapse group. Gray zone indicates normal range. of drug administration was 12 months in this study, Therefore we could apply this protocol to every pa- tient and easily controllable patients would accord- ingly have a shorter period of drug therapy. On the other hand, intractable cases would require longer duration of more than 8 years, as in the cases report- ed by Shizume [21] ‘We are now using a sensitive TSH assay from which the normal value of serum TSH is clearly measurable, hence we do not need the TRH test for evaluation of complete euthyroid condition. 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