1. A systematic review and meta-analysis: the effect of TSH suppressive
therapy on relapse rate on Graves’ disease treated patients
Gold Ekeanyanwu and Audrey Mercer
Department of Pharmacology, 29-39 Brunswick Square, London WC1N 1AX, UK
UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
Introduction
Method
Results
Conclusion
Graves’ disease is an autoimmune disorder caused by the
presence of specific antibodies stimulating the thyroid gland to
release an excess of thyroid hormones.
Figure 3. “Risk of bias summary”: authors’ judgements about
each risk of bias item for each included study. + meaning the
adequate, - meaning inadequate, and ? meaning unclear.
43 of records identified
through database searching
0 additional trials was
identified through other sources
18 records after duplicates were removed
18 records screened
5 records excluded
11 full text articles
assessed for eligibility
3 full text articles excluded
For not having the same
dose of ATD in both
groups
8 studies included in
qualitative analysis
8 studies included in
quantitative analysis
(meta-analysis)
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analysis flow chart
of the literature search.Figure 1. Preferred Reporting Items for
Systematic Reviews and Meta-Analysis
flow chart of the literature search.
Studyname Statistics for each study Odds ratio and 95% CI
Odds Lower Upper T4 Relative Relative
ratio limit limit Z-Value p-Value Treated Control weight weight
Glinoer et al (2001) 0.519 0.209 1.288 -1.415 0.157 23/ 42 28/ 40 22.97
Hashizumeet al (1991) 0.032 0.004 0.251 -3.274 0.001 1/ 60 17/ 49 9.53
Hoermannet al (2002) 0.672 0.374 1.206 -1.334 0.182 28/ 115 36/ 111 28.69
Mastorakos et a(2003)l 2.103 0.364 12.140 0.831 0.406 4/ 8 5/ 15 11.93
Rittmaster et al (1998) 0.978 0.492 1.945 -0.062 0.951 57/ 98 30/ 51 26.89
0.600 0.284 1.267 -1.339 0.180
0.01 0.1 1 10 100
Favours A Favours B
MetaAnalysis
Meta Analysis
Evaluation copy
Figure 4. Forest plot of 5 studies, comparing relapse between T4 treated group and control, Each study is represented with a square the
size of the square is proportional to the precision of the study. Studies were weighted by the inverse of the variance of their measure of effect
in that larger studies make higher contribution to the overall estimated result. The horizontal line drawn around each square was used
to represent the 95% confidence interval of that study. The aggregated Odds Ratio (0.600) of all studies is represented as a diamond at
the bottom with 95% CI, There was no statistically significant difference in rate of relapse between the T4 treated group and the
control (OR, 0.600; p=0.180)
Model Studyname Statistics for each study Relapsed / Total Odds ratio and 95%CI
Odds Lower Upper T3
ratio limit limit Z-Value p-Value treated Control
Wolfganget al(2000) 1.085 0.429 2.745 0.172 0.863 14/31 18/44
Pujolet al(1997) 1.338 0.386 4.637 0.459 0.646 12/19 13/23
Mastorakos et al(2003) 0.500 0.085 2.952 -0.765 0.444 2/ 12 5/ 15
Fixed 1.030 0.519 2.046 0.085 0.932
0.01 0.1 1 10 100
Favours A Favours B
Meta Analysis
Meta Analysis
Evaluation copy
Figure 5. Forest plot of 3 studies, comparing relapse between T3 treated group and control, The combined OR;1.030; 95% CI, 0.519-
2.416; ) of all 3 study is represented as a diamond at the bottom with 95% CI, There was no difference observed between the two
groups (OR, p=0.9322)
Study name Statistics for each study Sample size Hedges's g and 95% CI
Hedges's Standard Lower Upper TSH
g error Variance limit limit Z-Value p-ValueSuppressedControl
McLveretal(1996) 0.246 0.270 0.073 -0.283 0.776 0.912 0.362 25 29
Mastorakosetal(2003) -0.978 0.242 0.059 -1.452 -0.503 -4.039 0.000 38 37
Rittmasteretal(1998) 2.982 0.244 0.059 2.504 3.459 12.240 0.000 98 51
0.776 0.145 0.021 0.492 1.060 5.353 0.000
-4.00 -2.00 0.00 2.00 4.00
Favours A Favours B
MetaAnalysis
MetaAnalysis
Evaluation copy
Figure 6. Data was pooled from 3 studies for the mean time of relapse between the two groups. There was no statistical difference in
the time taken to relapse between the TSH suppressed group and the control, standard difference in mean (hedges’s g) was 0.750;
95% CI, -1.617-3.118; p=0.534.
Study name Statistics for each study Odds ratio and 95% CI
Odds Lower Upper
ratio limit limit Z-Value p-Value
Glinoer et al 2000 32.143 3.747 275.750 3.164 0.002
Wilson et al (1990) 46.143 19.361 109.973 8.647 0.000
Docter et al (1986) 1.125 0.158 7.986 0.118 0.906
Mukrakami et al (1988) 36.186 1.821 719.085 2.353 0.019
McGregor et al (1980) 26.632 3.280 216.200 3.072 0.002
Takata et al (1980) 26.667 2.309 308.000 2.630 0.009
Zakranja et al (1980) 96.429 4.515 2059.526 2.925 0.003
Romaldini et al (1981) 2.885 0.954 8.720 1.877 0.061
Schleusener et al (1989) 2.589 1.699 3.945 4.428 0.000
Bliddal et al (1981) 4.278 0.798 22.928 1.697 0.090
Teng et al (1988) 10.286 2.565 41.240 3.290 0.001
deBruin et al (1988) 3.852 0.403 36.784 1.171 0.241
Young et al (1988) 2.407 0.831 6.976 1.618 0.106
Madec et al (1984) 5.029 1.575 16.055 2.727 0.006
Allanic et al (1990) 2.857 1.218 6.703 2.413 0.016
Wener et al (1991) 10.400 2.643 40.920 3.351 0.001
Weetman et al 0.958 0.323 2.841 -0.077 0.939
6.263 3.367 11.647 5.795 0.000
0.01 0.1 1 10 100
Favours A Favours B
Meta Analysis
Meta Analysis
Figure 7. Relapse between TR-ab positive patient and TR-ab negative patient at the end of ATD therapy, A previous meta-analysis (Feldt-
Rasmussen et al, 1994) was found during the search of references, their result was combined with one additional trial from this present
study. A total of 17 studies was pooled to obtain the effect of positive antibodies in the serum of patients after initial successful ATD
therapy. The rate of relapse was significantly higher in the TR-ab positive patient compared with patient with a negative TR-ab.
(OR, 6.932; 95% CI, 3.713-12.942; p=0.00)
-5 -4 -3 -2 -1 0 1 2 3 4 5
0.0
0.5
1.0
1.5
2.0
StandardError
Log odds ratio
Funnel Plot of Standard Error byLog odds ratio
Figure 8. Funnel plot of TR-ab as a predictor of relapse. This display
the studies included in this meta-analysis as a plot of effect size against
sample size (or some other measure of the extent to which the findings
could be affected by the play of chance). Because studies with a small
sample size have more chance variability than larger studies, the
expected picture is one of a symmetrical inverted funnel if the plot is
asymmetric, it indicates the presence of publication bias, meaning
that the meta-analysis may have not included all available trials.
• To investigate whether the suppression of TSH with
exogenous thyroid hormones (T4 & T3) reduce the odds of
relapse after successful treatment with ATD.
Aims
• Effect of Smoking on relapse rate
• Presence of tyrotropin receptor antibodies at the end of initial
treatment (ATD therapy) as a predictor of relapse
Secondary outcome measures
Intervention
Patients were treated with anti-thyroid drugs (20-60𝜇𝑔 of
methimazole or equivalent) until serum thyroid hormone
concentrations are within the corresponding reference ranges. They
were given thyroxine, tri-iodothyronin (50-100𝜇𝑔), if necessary, to
suppress serum TSH to undetectable concentrations (i.e. less than
0.04 mU/1) or a placebo.
• A meta-analysis was used to combine the
results of independent clinical trials to
obtain a quantitative estimate of the overall
effect of TSH suppressive therapy. This is
presented in the form of a forest plot. A
random effect model was used.
• Search database : Cochrane , PubMed,
EMBASE, Google scholar and HighWire
press. MeSH terms: “Graves' disease,”
“Thyroxine,” “Recurrence,” “Antithyroid
drugs,”
• Inclusion criteria: Randomised and Non-
randomised controlled trials; patients must
be initially made euthyroid with ATD; Same
dose of ATD used for both groups.
• A funnel plot was used to explore the risk of
publication bias
The data-analysis was carried out using Comprehensive meta-analysis software version 3.3.070 2014. , (2a) The program uses a
spreadsheet for data entry, but requires the user to identify specific columns to hold the study names and the effect size data. allows the
user to select the class of data entry types, the list of formats are arranged hierarchically. (2b) White columns are used for entering data.
Yellow columns display the computed effect size, This values are used in generating the plot, Depending on the nature of the study, the
result will be represented differently, (2c) Run analysis to generate the forest plot. The comparison between the two groups was performed
using odds ratio (OR) (The ratio of the odds of an event in one group (intervention group) to the odds of an event in another (e.g. the
control group)), with corresponding 95% confidence interval [CI], a random effect model is used. A p value <0.05 was considered
statistically significant.
(2a) (2b)
(2c)
• Prolonged administration of exogenous thyroid hormone to suppress
TSH level, does reduces the rate of recurrence of hyperthyroidism,
however this was not shown to be statically significant
• Presence of TR-ab in the serum after successful treatment with ATD
was the only parameter shown to reduce long term remission
Favours TSH Favours control
suppression
Favours T4 Favours control
Favours T3 Favours control
Favours TR-ab- Favours TR-ab+
Symptoms
Goitre high level of thyroid hormones
(T4) and (T3)
NervousnessHeat intolerance
TremorGraves’ opthalmopathy
(eyelid retraction)
Reference
1) Glinoer D, de Nayer P and Bex M (2001) 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 144(5): 475-483.
2) Hashizume K, Ichikawa K, Sakurai A, Suzuki S, Takeda T, Kobayashi M, Miyamoto T, Arai M and Nagasawa T (1991) 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 324(14): 947-953.
3) Hoermann R, Quadbeck B, Roggenbuck U, Szabolcs I, Pfeilschifter J, Meng W, Reschke K, Hackenberg K, Dettmann J, Prehn B, Hirche H and Mann K (2002) Relapse of Graves' disease after successful outcome of antithyroid drug therapy: results of a prospective randomized study on the use of levothyroxine. Thyroid 12(12): 1119-1128.
4) Mastorakos G, Doufas AG, Mantzos E, Mantzos J and Koutras DA (2003) T4 but not T3 administration is associated with increased recurrence of Graves' disease after successful medical therapy. J Endocrinol Invest 26(10): 979-984.