Download Public Health Relevance of Graves` Orbitopathy

ORIGINAL
ARTICLE
E n d o c r i n e
C a r e
Public Health Relevance of Graves’ Orbitopathy
Katharina A. Ponto, Sonja Merkesdal, Gerhard Hommel, Susanne Pitz,
Norbert Pfeiffer, and George J. Kahaly
Departments of Ophthalmology (K.A.P., S.P., N.P.), Medical Statistics (G.H.), and Medicine I (G.J.K.),
Johannes Gutenberg University Medical Centre, 55101 Mainz, Germany; and Division of Clinical
Immunology and Rheumatology (S.M.), Working Group for Health Economics and Clinical Epidemiology,
Hannover Medical School, 30625 Hannover, Germany
Context: Disfiguring proptosis and functional impairment in patients with Graves’ orbitopathy
(GO) may lead to impaired earning capacity and to considerable indirect/direct costs.
Objective: The aim of the study was to investigate the public health relevance of GO.
Design and Setting: This cross-sectional study was performed between 2005 and 2009 at a multidisciplinary university orbital center.
Patients: A total of 310 unselected patients with GO of various degrees of severity and activity
participated in the study.
Interventions: We conducted an observational study.
Main Outcome Measures: We measured work disability and sick leave as well as the resulting
indirect/direct costs of GO-specific therapies.
Results: Of 215 employed patients, 47 (21.9%) were temporarily work disabled, and 12 (5.6%) were
permanently work disabled. Five (2.3%) had lost their jobs, and nine (4.2%) had retired early. The mean
duration of sick leave was 22.3 d/yr. Compared with the German average of 11.6 d/yr, 32 (15%) patients
had taken longer sick leaves. The duration of sick leave correlated with the disease severity (P ⫽ 0.015),
and work disability correlated with diplopia (P ⬍ 0.001). Multivariable analysis identified diplopia as the
principal predictor for work disability (odds ratio, 1.7; P ⬍ 0.001). The average costs due to sick leave
and work disability ranged between 3,301€ (4,153$) and 6,683€ (8,407$) per patient per year. Direct
costs were 388 ⫾ 56€ (488 ⫾ 70$) per patient per year and per year were higher in sight-threatening
GO (1,185 ⫾ 2,569€; 1,491 ⫾ 3,232$) than in moderate-to-severe (373 ⫾ 896€; 469 ⫾ 1,127$; P ⫽ 0.013)
or in mild GO (332 ⫾ 857€; 418 ⫾ 1,078$; P ⫽ 0.016). Total indirect costs ranged between 3,318€
(4,174$) (friction cost method) and 6,738€ (8,476$) (human capital approach). Work impairment as well
as direct and indirect costs of GO significantly correlated with the scores of the internationally standardized and specific GO quality-of-life questionnaire.
Conclusions: Productivity loss and a prolonged therapy for GO incur great indirect and direct costs.
(J Clin Endocrinol Metab 98: 145–152, 2013)
t is a compelling proposition to analyze the costs caused
by diseases. In 2006 alone, direct disease-related costs
were approximately 254 billion € in Germany (http://
www.gbebund.de/oowa921-install/servlet/oowa/aw92/
dboowasys921.xwdevkit/xwd_init?gbe.isgbetol/xs_start_neu/
I
&p_aidi&p_aid87122444&nummer556&p_spracheD&p_
indsp399&p_aid98028304#SOURCES). From this total
amount, almost 2 billion € were spent on the treatment of thyroid disorders. Graves’ orbitopathy (GO) is the most common
extrathyroidal manifestation of autoimmune Graves’ disease
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2013 by The Endocrine Society
doi: 10.1210/jc.2012-3119 Received August 19, 2012. Accepted November 2, 2012.
First Published Online November 26, 2012
Abbreviations: AITD, Autoimmune thyroid disease; AP, appearance; EBM, Einheitlicher
Bewertungsmassstab; GO, Graves’ orbitopathy; GO-QOL, GO quality-of-life questionnaire; NTAD, nonthyroidal autoimmune disease; VF, visual functioning.
J Clin Endocrinol Metab, January 2013, 98(1):145–152
jcem.endojournals.org
145
146
Ponto et al.
Costs of Orbitopathy
(2), and the causal TSH receptor autoantibodies closely correlate with the clinical activity of GO (3, 4). Signs and symptoms
of GO include disfiguring proptosis and eyelid retraction, eye
motility disorders, and in the worst cases, corneal ulceration or
compressive optic neuropathy with a threat of vision loss (5).
Patients with GO are not only physically ill, but their quality of
life and working ability are also markedly impaired (6, 7). Specific treatment of GO includes immunosuppression and orbital
surgery (5, 8–10). Direct costs of illness due to these therapies
combined with costs caused by work disability and sick leave
may lead to a considerable health economic burden of GO that
isnotyetknown.Thusfar,nostudieshavebeenundertakeninto
the resulting health economic expenses caused by expensive
treatments and by the professional sequelae of GO. The objectives of the present study were to estimate the direct and indirect
costs in patients with GO as well as to correlate the clinical
findings with the degree of work impairment.
We hypothesized that direct costs would be higher in
patients with severe forms of the disease, e.g. in cases of
optic neuropathy and/or constant diplopia. Additionally,
we hypothesized that there would be correlations between
ophthalmic, endocrine, and serological parameters as well
as patients’ impairment due to GO regarding paid work.
Therefore, we collected and evaluated clinical and cost
data from a group of 310 patients to perform a comprehensive cost-of-illness analysis for GO.
Patients and Methods
Patients
A total of 680 individuals (310 GO patients and 370 subjects
without GO) were included in a cross-sectional study at the multidisciplinary orbital center of the Johannes Gutenberg University Medical Centre, Mainz, Germany. All costing data were
collected within the endocrine outpatient clinic. Even if the study
design did not meet the requirements for a controlled study, the
groups without GO served as comparators for indirect costing
aspects.
Inclusion criteria for the GO group were a clinical overt GO
classified according to the Consensus Statement of the European
Group on Graves’ Orbitopathy (EUGOGO) (5). All GO patients
underwent a multidisciplinary assessment according to the recommendations of EUGOGO, and the clinical parameters were
correlated with information about GO-related work impairment. Furthermore, every patient answered the disease-specific
GO quality-of-life questionnaire (GO-QOL). We calculated the
GO-QOL scores for “appearance” (AP) and “visual functioning” (VF) (maximum score ⫽ 100) as previously reported, with
higher scores representing a better quality of life (6, 7).
The group of subjects without GO consisted of either healthy
subjects or patients with a benign nodular goiter, autoimmune
thyroid diseases (AITDs) without GO, or nonthyroidal autoimmune diseases (NTADs; e.g. rheumatoid arthritis). All informed
subjects gave their written consent. Exclusion criteria were a
missing signature and an uncertain diagnosis of GO. The pro-
J Clin Endocrinol Metab, January 2013, 98(1):145–152
tocol was consistent with the principles of the Declaration of
Helsinki. Because this study was observational and did not include any interventions aside from those commonly falling
within the daily routine and because none of the individualrelated data were passed to third parties, the Ethical Review
Committee of the Medical Association of the State Rhineland
Palatinate, Germany, decided that no approval was required.
German social security system
The German social security system is based on funding by the
compulsory health insurance companies, the social security pension insurance funds, and the state welfare (11, 12). During the
first 6 wk of sick leave, an unchanged basic salary is paid by the
employer. After wk 6 of a sick-leave period due to the same
disease within 3 yr, the health care payers provide approximately
80% of the current salary until wk 78. Before this limit is reached,
the patients are referred to rehabilitation if it is possible to provide treatment such that the patient may return to work. After a
maximum of 78 wk of sick leave, the income depends on the
judgment of work disability and on formal criteria of the social
security pension insurance fund or the labor office. Patients with
positive criteria of work disability receive a disability pension
provided by the social security pension insurance fund, and those
with positive criteria for unemployment compensation receive
payments from the state welfare. Patients not meeting any formal
criteria, such as a minimum duration of work and payment to the
compulsory insurance, receive state welfare at the bare subsistence level.
Cost assessment
Indirect costs comprise the domains of both disease-related
work disability and sick leave in employed patients. On the same
day, within a university joint thyroid-eye clinic, all patients were
interviewed by the endocrinologist about being on sick leave and
work disabled due to GO. The data were reported as work disability or sick leave status (work disability and sick leave due to
GO present or absent) and, in cases of sick leave, as the cumulative number of absent days due to GO certified by a physician.
Also, information was obtained regarding previous specific
therapies in all 310 GO patients. The average direct costs per year
were estimated by dividing the total costs by the duration of GO
in years. The following direct cost components were assessed:
costs from outpatient visits (endocrinologist and ophthalmologist), costs from medical therapy, costs from retrobulbar irradiation, and costs from surgery. Costs of thyroid-related therapies
were not calculated. Costs of outpatient treatment were gathered
according to the German Uniform Value Scale [Einheitlicher Bewertungsmassstab (EBM)] (http://www.kbv.de/8170.html). All
medical services approved for remuneration are listed in the
EBM. The translation of physical healthcare use units into monetary units was based on the EBM system (the monetary value of
each EBM point was 0.035€). Costs for medication were obtained from the so-called “Rote Liste,” the official catalog of
drugs in Germany (14). In-patient costs were calculated by ID
DIACOS, which is one of the leading code systems in Germany
(http://www.id-berlin.de).
To improve the transferability, all costs are stated in euros and
in U.S. dollars using the exchange rate of 1.258 on May 28, 2012.
Because the present cross-sectional study did not follow the patients over a longer period, we were not able to take into account
that the main part of the direct costs are incurred during the
J Clin Endocrinol Metab, January 2013, 98(1):145–152
jcem.endojournals.org
147
FIG. 1. Estimation of the indirect costs per patient and year based on the average gross income per month. The proportion of the daily income
that patients receive during the time not working is multiplied by the number of sick-leave days or, in case of work disability, by either the 58 d
(friction cost method) or the number of days per year (⫽365; human capital approach).
active phase of the disease, whereas indirect costs may continue
much longer and may potentially persist until the patient’s death.
We therefore calculated an average of direct costs per year,
whereas we calculated the “up-to-date” costs when dealing with
the indirect costs.
Cost valuation
In accordance with the German guidelines for socioeconomic
evaluation, productivity losses were assessed using the human
capital approach (16). Both the human capital approach and the
human capital approach with the addition of a friction cost period were measured, taking paid work into account (17). Using
a friction period means to count productivity losses only within
a limited period of time due to a patient’s productivity being
replaced assuming that no economy achieves full employment.
The friction period of 58 d, representing the mean time period
until a job reported by an employer to the employment office is
procured for a jobless person, was based on statistics from the
regional employment office. The time period until this new
worker is as productive as the person with GO who stopped
working is not included in the friction period. The friction
method aims at assessing productivity losses in more detail,
avoiding overestimation by shifting the focus from the patient to
a societal perspective.
In all patients, the number of days of lost productivity due to
work disability is cumulated. For the estimation according to the
human capital approach, the overall number of days since the
onset of work disability is applied; for the estimation according
to the friction cost approach, the overall number is truncated at
58 d. The sick leave days are evaluated as the cumulative number
of absent days due to GO certified by a physician. These physical
units (productivity losses) are then valuated by assuming that a
day of lost productivity costs society as much as the average daily
German wage estimated by population data. This approach implies that the marginal productivity equals the complete wage
costs of a person. The average wage is determined by dividing the
gross income of all gainfully employed citizens per year by the
total number of labor-force participants. Using the 2010 German
population data, costs of approximately 100€ per day of lost
productivity resulted (https://www-ec.destatis.de/csp/shop/sfg/
bpm.html.cms.cBroker.cls?cmspathstruktur,vollanzeige.csp
&ID1026655). The number of cumulative days of lost productivity due to either sick leave or work disability were therefore multiplied by 100€. In summary, costs for sick leave for
each gainfully employed patient were calculated using the following formula: sick leave days ⫻ (yearly income/365) ⫻ A.
The “A” factor depends on the degree of work impairment: A
is 1.0 for the first 6 wk of sick leave, it is 0.8 after that period,
and it decreases to 0.3 if patients receive a work disability
pension (Fig. 1). The yearly income data used for the calculations did not account for any additional expenditure by
employers (contributions to social insurance covered by employers, etc.)
Statistical analyses
Statistical analyses were performed using SPSS version
18 (Statistical Package for the Social Sciences, Chicago, IL), a
commercially available software package. Averages were reported with means and SD values. The ␹2 test and t test were used
for statistical analyses. A significant result was considered to be
P ⬍ 0.05. Finally, we investigated correlations of sick leave and
work disability with the possible confounders of sex, thyroid
function, and smoking behavior. All significant correlations of
the hypothesis testing were included in a binary logistic regression model for multivariable analysis (19).
Role of the funding source
The study had no external funding source.
Results
A total of 680 subjects, 141 (20.7%) males and 539
(79.3%) females, were enrolled in this study. Demo-
148
Ponto et al.
Costs of Orbitopathy
J Clin Endocrinol Metab, January 2013, 98(1):145–152
ysis of the correlation between GO severity and the duration of sick leave showed that four (40%), 21 (17%), and
seven (8%) patients with sight-threatening, moderate-tosevere, and mild GO, respectively, had taken more than
11.6 d/yr of sick leave (P ⫽ 0.015). Furthermore, patients
with optic neuropathy were nearly twice as likely to be
work disabled as patients without a compression of the
optic nerve (60 vs. 33%; P ⫽ 0.075). The frequency of
work disability was 23 of 110 (20.9%) in patients without
diplopia vs. 11 of 27 (41%), 25 of 58 (42%), and 14 of 20
(74%) in those with intermittent, inconstant, and constant
diplopia, respectively (P ⬍ 0.001). Nonsmokers were less
often work disabled than smokers (n ⫽ 37, 27%; vs. n ⫽
36, 46%; P ⫽ 0.006). Neither age, nor clinical activity of
GO, nor thyroid dysfunction correlated with work impairment (P ⫽ not significant).
The multivariable analysis of optic neuropathy, diplopia, and smoking with respect to work disability was performed using a binary logistic regression model. Optic
neuropathy and smoking were excluded from the analyses, whereas diplopia alone was sufficient to predict work
disability (odds ratio, 1.723; P ⬍ 0.001).
Indirect costs were estimated according to the
above-mentioned data on sick leave and work disability. The total yearly costs due to sick leave and work
disability averaged between 3,301€ (4,153$) and
6,683€ (8,407$) per patient (range, 0€, 0 –3,947 to 0€,
0 –24,228€; Table 2).
Furthermore, work impairment and the resulting indirect costs correlated with answers of the GO-QOL. Patients who had been on sick leave due to GO within the
past year scored lower on the subscales VF and AP (VF,
65 ⫾ 25; and AP, 62 ⫾ 26) than those who were not (VF,
78 ⫾ 23; and AP, 80 ⫾ 22). Also, VF and AP were lower
(VF, 61 ⫾ 27; and AP, 66 ⫾ 26) in work-disabled subjects
than in those who had never been work disabled (VF, 80 ⫾
22; and AP, 77 ⫾ 23). Indirect costs were higher (15,419 ⫾
14,657€; 19,397 ⫾ 18,439$) in patients who were severely limited in their daily activities (VF ⬍ 59) than in
those who scored to be moderately limited (VF, 50 –75;
TABLE 1. Demographic and clinical data of the patients
with GO
n
Male/female
Age (yr), mean (SD)
Smokers
Graves’ disease
TSH receptor-autoantibodypositive
Thyroid function
Euthyroid
Hyperthyroid
Hypothyroid
Clinically active GO
Disease severity
Mild GO
Moderate-to-severe GO
Sight-threatening GO
Diplopia
Intermittent
Inconstant
Constant
Proptosis (mm), mean (SD)
Employed
Total
patients
310
215
51 (17)/259 (83) 32 (15)/183 (85)
48.6 (13.7)
45.1 (10.4)
98 (32)
79 (37)
290 (94)
200 (93)
216 (70)
154 (72)
223 (72)
75 (24)
12 (4)
129 (42)
152 (71)
54 (25)
9 (4)
81 (38)
111 (36)
176 (57)
23 (7)
166 (54)
41 (14)
87 (28)
38 (12)
19.0 (3.7)
84 (39)
121 (56)
10 (5)
105 (49)
27 (13)
58 (27)
20 (9)
19.0 (3.6)
Data are expressed as number (percentage) unless otherwise specified.
graphic data of the 310 patients with GO, of whom 215
were employed and at a working age, are illustrated in
Table 1. All GO patients gave information about the degree of work impairment due to GO, and the same data
were collected from the group of subjects without GO
(response rate, 100% for each group). Furthermore, the
data on previous specific therapies were available for all
patients with GO (response rate, 100%).
Work impairment and indirect costs
Of 215 employed patients with clinically overt GO, 47
(22%) were temporarily work disabled, and 12 (6%) were
permanently work disabled. Five (2%) had lost their jobs,
and nine (4%) had retired early due to their GO. The mean
duration of sick leave was 22.3 ⫾ 60.8 d/yr. Compared
with the German average of 11.6 d/yr, 32 (15%) of the
patients with GO had taken longer sick leaves. The analTABLE 2. Indirect costs in 215 employed patients with GO
Meanⴞ
Work disability
HCA
HCA ⫹ friction method
Sick leave
Total
HCA
HCA ⫹ friction method
Range
SD
Euros
U.S. dollars
Euros
U.S. dollars
4,086 ⫾ 5,986
666 ⫾ 975
2,652 ⫾ 6,933
5,140 ⫾ 7,530
878 ⫾ 1,227
3,336 ⫾ 8,722
0 –24,288
0 –3,947
0 –28,500
0 –30,554
0 – 4,965
0 –35,853
6,738 ⫾ 10,978
3,318 ⫾ 7,415
8,476 ⫾ 13,810
4,174 ⫾ 9,328
0 – 40,308
0 –30,433
0 –50,707
0 –38,2847
The human capital approach (HCA) and the human capital approach applying a friction cost period of 58 d (friction method) were performed.
Costs were given in euros and U.S. dollars (exchange rate 1.258, May 28, 2012).
J Clin Endocrinol Metab, January 2013, 98(1):145–152
jcem.endojournals.org
149
TABLE 3. Direct costs in patients with GO
Regular costs per patient
(mean ⴞ SD)
Therapy
Outpatient treatment
Ophthalmologist
Endocrinologist
Intravenous steroids (methylprednisolone, 6 wk 500 mg
weekly, followed by 6 wk 250 mg weekly)
Cyclosporine therapy (body weight adapted)
Orbital radiotherapy
Squint surgery
Eyelid surgery
Orbital fat resection
Orbital decompression
Euros
U.S. dollars
Frequency in 310
GO patients, n (%)
110 ⫾ 7.0
117 ⫾ 6.9
384 ⫾ 1.8
138 ⫾ 8.8
147 ⫾ 8.7
438 ⫾ 2.3
310 (100)
310 (100)
214 (69)
1,215 ⫾ 258.7
2,840 ⫾ 0
4,621 ⫾ 0
4,621 ⫾ 0
10,212 ⫾ 0
14,953 ⫾ 0
1,528 ⫾ 325.4
3,573 ⫾ 0
5,813 ⫾ 0
5,813 ⫾ 0
12,847 ⫾ 0
18,811 ⫾ 0
52 (17)
95 (31)
17 (6)
16 (5)
6 (2)
45 (15)
Costs were given in euros and U.S. dollars (exchange rate 1.258, May 28, 2012).
7,625 ⫾ 10,709€; 9,592 ⫾ 13,472$; P ⫽ 0.003) or mildly
limited (VF, ⬎75; 3,423 ⫾ 7,925€; 4,306 ⫾ 7,925$; P ⬍
0.001). On the other hand, indirect costs were higher
(9,788 ⫾ 12,796€; 12,313 ⫾ 16,097$) in those with a
moderately impaired self-consciousness (AP, 50 –75) than
in those with a mildly (AP, ⬎75; 4,353 ⫾ 8,518€; 5,576 ⫾
10,716$; P ⫽ 0.001) or severely (AP, ⬍50; 9,088 ⫾
12,804€; 11,433 ⫾ 16,107$; P ⬎ 0.05) impaired
self-consciousness.
Direct costs
All patients were followed within the university joint
thyroid-eye clinic by an ophthalmologist and an endocrinologist on a regular basis (at least four times per year).
The costs of the GO-specific therapies are illustrated in
Table 3. Mean direct costs per patient and year were 388 ⫾
56€ (488 ⫾ 70$). Analyses of correlations between the
direct costs and the clinical feature showed a correlation
with disease severity, but not with diplopia. Direct costs
per year were higher in sight-threatening GO (1,185 ⫾
2,569€; 1,491 ⫾ 3,232$) than in moderate-to-severe
(373 ⫾ 896€; 469 ⫾ 1,127$; P ⫽ 0.013) or in mild GO
(332 ⫾ 857€; 418 ⫾ 1,078$; P ⫽ 0.016).
Direct costs also correlated with answers of the GOQOL. Direct costs were higher (597 ⫾ 1,342€; 751 ⫾
1,688$) in patients who were severely limited in their daily
activities (VF, ⬍59) than in those who scored as moderately limited (VF, 50 –75; 367 ⫾ 1,002€; 462 ⫾ 1,261$;
P ⬎ 0.05) or mildly limited (VF, ⬎75; 298 ⫾ 872€; 375 ⫾
1,097$; P ⬎ 0.05). On the other hand, direct costs were
higher (609 ⫾ 1,306€; 766 ⫾ 1,643$) in those with a
moderately impaired self-consciousness (AP, 50 –75) than
in those with a mildly (AP, ⬎75; 298 ⫾ 872€; 375 ⫾
1,097$; P ⫽ 0.026) or severely (AP, ⬍50; 327 ⫾ 728€;
411 ⫾ 916$; P ⬎ 0.05) impaired self-consciousness.
Public health relevance
To evaluate the public health relevance of GO, we estimated the costs of GO within the German population of 82
million people (http://www.destatis.de/jetspeed/portal/cms/
Sites/destatis/Internet/DE/Presse/pm/2010/01/PD10_028_
12411,templateIdrenderPrint.psml ). If approximately 40%
of patients with Graves’ disease have clinically overt GO and
if the prevalence of Graves’ disease is at least 0.5%, there will
be 410,000 GO patients in Germany (21–23). Direct costs of
GO would then be a total of 159,080,000€ (200,122,640$)
per year, whereas the indirect costs would average between
1,360,380,000€ (1,711,358,040$) and 2,762,580,000€
(3,475,325,640$) per year.
Work disability and sick leave in subjects without
GO
Overall, 132 of 167 patients with AITD without GO,
61 of 81 healthy subjects, 49 of 63 patients with goiter,
and 41 of 59 patients with NTAD were at a working age
and employed. A higher prevalence of work disability was
noted in GO patients than in healthy subjects, in patients
with either Graves’ disease or Hashimoto’s thyroiditis
without eye involvement, and in patients with nonthyroidal autoimmune diseases or benign goiter (Table 4; P ⬍
0.001).
Discussion
Disfiguring proptosis, diplopia, and optic neuropathy in
GO necessitate a long-standing immunosuppressive and
surgical therapy and lead to work limitations. To the best
of our knowledge, the costs of GO have not been evaluated
thus far. Within the present study of 310 unselected patients with various degrees of GO, the rate of work disability and the duration of sick leave were correlated with
150
Ponto et al.
Costs of Orbitopathy
J Clin Endocrinol Metab, January 2013, 98(1):145–152
TABLE 4. Indirect costs in persons without GO
Indirect costs
per patient
Work disability
HCA
FCA
Sick leave
Total
HCA
FCA
Healthy
Benign
nodular goiters
AITD
Other autoimmune diseases
Euros
U.S. dollars
Euros
U.S. dollars
Euros
U.S. dollars
Euros
U.S. dollars
888 ⫾ 2,997
145 ⫾ 488
1,253 ⫾ 2,435
1,117 ⫾ 3,770
182 ⫾ 614
1,576 ⫾ 3,063
1,198 ⫾ 3,390
195 ⫾ 552
753 ⫾ 1,008
1,507 ⫾ 4,265
245 ⫾ 694
947 ⫾ 1,268
1,198 ⫾ 3,390
195 ⫾ 552
3,041 ⫾ 1,420
1,507 ⫾ 4,265
245 ⫾ 694
3,826 ⫾ 1,786
1,982 ⫾ 4,154
232 ⫾ 677
3,041 ⫾ 1,420
2,493 ⫾ 5,226
292 ⫾ 852
3,826 ⫾ 1,786
2,142 ⫾ 4,669
1,398 ⫾ 2,700
2,695 ⫾ 5,874
1,759 ⫾ 3,397
4,239 ⫾ 1,420
3,236 ⫾ 6,849
5,333 ⫾ 1,786
4,071 ⫾ 8,616
4,239 ⫾ 1,420
3,236 ⫾ 6,849
5,333 ⫾ 1,786
4,071 ⫾ 8,616
7,130 ⫾ 13,005
826 ⫾ 1,287
8,970 ⫾ 16,360
1,039 ⫾ 1,619
Data are expressed as mean ⫾ SD. The human capital approach (HCA) and the human capital approach applying a friction cost period of 58 d (FCA
method) were performed. Costs were given in euros and U.S. dollars (exchange rate 1.258, May 28, 2012).
the clinical features in these patients and compared with
work impairment in 370 persons without GO. Furthermore, a cost estimate was performed to calculate the direct
and indirect costs for GO.
Healthy subjects and patients with goiter, AITD, or
NTAD were less often work disabled than GO patients.
Additionally, patients with moderate or severe GO took
sick leave more often than subjects without GO as well as
the German average. In addition, work impairment correlated with the clinical parameters of GO. As hypothesized, patients with diplopia and with severe GO took
more sick leave and were more often work disabled than
those without diplopia and with mild or moderate GO. In
contrast, the clinical activity score did not correlate with
the degree of work impairment. A possible explanation is
that patients in the active and acute phase of the disease
had not been work disabled thus far and therefore had not
taken more sick leave at the time of data acquisition. Because smoking is a risk factor for GO, smokers were also
more often work disabled (24, 25). Sex and thyroid dysfunction did not confound the correlations.
Disease severity increased not only the indirect but also
the direct costs. As hypothesized, the direct costs were
higher in patients with optic neuropathy, most probably
because these patients often require high-dosage immunosuppression and several surgical procedures. Work impairment with the resulting indirect cost as well as the
direct costs correlated with disease-specific quality of life
measured with the GO-QOL. Patients who were work
disabled or on sick leave due to GO scored lower on subscales AP and VF. Furthermore, direct as well as indirect
costs were higher in patients severely limited in their daily
activities (low VF scores). Regarding the AP score, the
direct and indirect costs were higher in those with a moderately impaired self-consciousness than in those with
higher or lower AP scores. One reason for that might be
that patients tend to focus more on functional aspects of
the disease than on their self-perception during the active
phase of the disease.
There is only one study dealing with direct costs of GO,
namely with the costs of orbital radiotherapy (26). Within
this study, the costs of orbital radiotherapy and of treatment during the first year after therapy were calculated
(5,007 vs. 4,465€ in the sham-irradiated group). The
costs of radiotherapy in The Netherlands (2,779€) were
comparable to those in Germany (2,840€). Further
studies of the costs of thyroid disorders in Germany
dealt with benign nodular goiters, most likely because
of their higher prevalence in a country with a historically low iodine intake. Regarding hyperthyroidism, the
costs of radioactive iodine therapy and thyroid surgery
have been compared (27).
Conversely, there are numerous studies on the direct
and indirect costs of other diseases. Several studies have
investigated the economic burden of visual impairment
and blindness in the United States (28 –31). These studies
showed that refractive errors, age-related macular degeneration, cataracts, diabetic retinopathy, and primary
open-angle glaucoma incur immense costs. Furthermore,
an increasing linear trend in the indirect costs of glaucoma as disease severity worsened was shown (32). As
in glaucoma, vision field defects may also occur in GO.
Nevertheless, the most common and most burdensome
signs and symptoms of GO are cosmetic disfigurement
and diplopia. Therefore, none of these mostly age-related disorders can be compared with GO. It has also
been shown that dry eye syndrome and strabismus incur
indirect costs (33, 34). Even if the rate of dry eye symptoms and diplopia is high in patients with GO, these
symptoms do not occur in isolation, but rather as a part
of a complex of symptoms (35, 36).
In Germany, indirect costs average 5,019€ per patient
in 306,736 diabetics and 3,691€ per person in the average
population (1). However, the most convincing data from
studies on disease-related costs addressed the costs associated with rheumatoid arthritis (13, 15, 17, 18). Using the
same methods for cost calculation as the present study,
these studies showed that active stages of rheumatoid ar-
J Clin Endocrinol Metab, January 2013, 98(1):145–152
thritis are associated with impaired earning capacity (13,
15). Similar to patients with these rheumatic diseases, patients with GO also experience cosmetic disfigurement
and functional limitations. Nevertheless, rheumatoid arthritis takes a chronic and relapsing course and causes
permanent damage. In contrast, GO is often self-limited or
can be improved or at least stabilized.
The present study has some limitations. First, we
looked at patients at the multidisciplinary orbital center of
a single institution. These patients had been referred to a
specialized center due to their above-average disease severity. Therefore, a relatively high percentage of subjects
with optic neuropathy were noted. Second, the present
cost estimation is based on German costing data and is
therefore not applicable to countries with different social
security systems. Because the systems are at least partly
comparable, the costs of GO might be similar at least
among the European countries. Third, one should consider that the present data are not based on precise calculations but rather on an estimation of costs. A model for
estimating direct and indirect costs of GO should optimally have taken into account that the disease has a finite
active phase usually lasting 1–2 yr and that direct costs are
incurred during this period and sometimes for a little longer when multiple rehabilitative surgical procedures are
carried out. Indirect costs may continue for much longer
and may persist until the patient’s death. Because the present study had a cross-sectional design, this could not be
taken into account. Instead, a calculation of the average
direct cost per year and of the “up-to-date” indirect costs
was performed. Nevertheless, this approach most probably leads to an underestimation of the costs. Also, data are
missing regarding the patients’ social background and
coping strategies. Furthermore, the present data were derived from the patients themselves and may therefore differ from administrative data. In line with this, Merkesdal
et al. (20) investigated the validity of patient-reported productivity losses, and this study comparing the patient and
insurer data on overall productivity costs showed that patients reported their productivity losses adequately.
Therefore, even as an estimate only, the present data are
most likely the most detailed record on the costs of GO
that are available as yet.
In conclusion, for the first time, this study in a large
collective of patients with GO clearly demonstrates the
economic consequences and the public health relevance
of GO.
Acknowledgments
Address all correspondence and requests for reprints to: Prof.
George J. Kahaly, Department of Medicine I, Johannes Guten-
jcem.endojournals.org
151
berg University Medical Centre, Langenbeckstrasse 1, 55101
Mainz, Germany. E-mail: [email protected].
No funding was obtained for this study or for writing this
paper.
Parts of the material were presented (oral presentation)
September 13, 2011, at the Congress of the European Thyroid
Association, Krakow, Poland.
Disclosure Summary: The authors have nothing to declare.
References
1. Köster I, von Ferber L, Ihle P, Schubert I, Hauner H 2006 The cost
burden of diabetes mellitus: the evidence from Germany—the
CoDiM study. Diabetologia 49:1498 –1504
2. Bartalena L 2011 The dilemma of how to manage Graves’ hyperthyroidism in patients with associated orbitopathy. J Clin Endocrinol Metab 96:592–599
3. Lytton SD, Ponto KA, Kanitz M, Matheis N, Kohn LD, Kahaly GJ
2010 A novel thyroid stimulating immunoglobulin bioassay is a
functional indicator of activity and severity of Graves’ orbitopathy.
J Clin Endocrinol Metab 95:2123–2131
4. Ponto KA, Kanitz M, Olivo PD, Pitz S, Pfeiffer N, Kahaly GJ 2011
Clinical relevance of thyroid-stimulating immunoglobulins in
Graves’ ophthalmopathy. Ophthalmology 118:2279 –2285
5. Wiersinga WM, Perros P, Kahaly GJ, Mourits MP, Baldeschi L,
Boboridis K, Boschi A, Dickinson AJ, Kendall-Taylor P, Krassas GE,
Lane CM, Lazarus JH, Marcocci C, Marino M, Nardi M, Neoh C,
Orgiazzi J, Pinchera A, Pitz S, Prummel MF, Sartini MS, Stahl M, von
Arx G 2006 Clinical assessment of patients with Graves’ orbitopathy: the European Group on Graves’ Orbitopathy recommendations
to generalists, specialists and clinical researchers. Eur J Endocrinol
155:387–389
6. Ponto KA, Hommel G, Pitz S, Elflein H, Pfeiffer N, Kahaly GJ 2011
Quality of life in a German Graves’ orbitopathy population. Am J
Ophthalmol 152:483– 490.e1
7. Ponto KA, Pitz S, Pfeiffer N, Hommel G, Weber MM, Kahaly GJ
2009 Quality of life and occupational disability in endocrine orbitopathy. Dtsch Arztebl Int 106:283–289
8. Mourits MP, Bijl H, Altea MA, Baldeschi L, Boboridis K, Currò N,
Dickinson AJ, Eckstein A, Freidel M, Guastella C, Kahaly GJ, Kalmann R, Krassas GE, Lane CM, Lareida J, Marcocci C, Marino M,
Nardi M, Mohr Ch, Neoh C, Pinchera A, Orgiazzi J, Pitz S, Saeed P,
Salvi M, Sellari-Franceschini S, Stahl M, von Arx G, Wiersinga WM
2009 Outcome of orbital decompression for disfiguring proptosis in
patients with Graves’ orbitopathy using various surgical procedures.
Br J Ophthalmol 93:1518 –1523
9. Bartalena L, Marcocci C, Tanda ML, Piantanida E, Lai A, Marinò
M, Pinchera A 2005 An update on medical management of Graves’
ophthalmopathy. J Endocrinol Invest 28:469 – 478
10. Zang S, Ponto KA, Kahaly GJ 2011 Clinical review: intravenous
glucocorticoids for Graves’ orbitopathy: efficacy and morbidity.
J Clin Endocrinol Metab 96:320 –332
11. Simon M 2009 The health care system in Germany. An introduction
in the pattern and functionality. [Das Gesundheitssystem in
Deutschland. Eine Einführung in Struktur und Funktionsweise.] 1st
ed. Bern, Switzerland: Huber; 2009
12. Klever-Deichert G, Gerber A, Stock S, Lüngen M 2006 The German
health care system. In: Lauterbach KW, Stock S, Brunner H, eds.
Gesundheitsoekonomie. Lehrbuch für Mediziner und andere Gesundheitsberufe. Bern, Switzerland: Huber; 73–100
13. Merkesdal S, Huelsemann JL, Mittendorf T, Zeh S, Zeidler H, Ruof
J 2006 Productivity costs of rheumatoid arthritis in Germany. Cost
composition and prediction of main cost components. Z Rheumatol
65:527–534
152
Ponto et al.
Costs of Orbitopathy
14. 2010 Rote Liste. Buchausgabe: Arzneimittelinformationen für
Deutschland (einschliesslich EU-Zulassungen und bestimmter Medizinprodukte). Frankfurt: Rote Liste Service GmbH
15. Zirkzee EJ, Sneep AC, de Buck PD, Allaart CF, Peeters AJ, Ronday
HK, Westedt ML, le Cessie S, Vliet Vlieland TP 2008 Sick leave and
work disability in patients with early arthritis. Clin Rheumatol 27:
11–19
16. Graf von der Schulenburg JM, Greiner W, Jost F, Klusen N, Kubin
M, Leidl R, Mittendorf T, Rebscher H, Schoeffski O, Vauth C,
Volmer T, Wahler S, Wasem J, Weber C; Hanover Consensus Group
2008 German recommendations on health economic evaluation:
third and updated version of the Hanover Consensus. Value Health
11:539 –544
17. Merkesdal S, Ruof J, Huelsemann JL, Schoeffski O, Maetzel A, Mau
W, Zeidler H 2001 Development of a matrix of cost domains in
economic evaluation of rheumatoid arthritis. J Rheumatol 28:657–
661
18. Huscher D, Merkesdal S, Thiele K, Zeidler H, Schneider M, Zink A
2006 Cost of illness in rheumatoid arthritis, ankylosing spondylitis
and systemic lupus erythematosus in Germany. Ann Rheum Dis
65:1175–1183
19. Schneider A, Hommel G, Blettner M 2010 Linear regression analysis: part 14 of a series on evaluation of scientific publications. Dtsch
Arztebl Int 107:776 –782
20. Merkesdal S, Ruof J, Huelsemann JL, Mittendorf T, Handelmann S,
Mau W, Zeidler H 2005 Indirect cost assessment in patients with
rheumatoid arthritis (RA): comparison of data from the health economic patient questionnaire HEQ-RA and insurance claims data.
Arthritis Rheum 53:234 –240
21. Putta-Manohar S, Perros P 2010 Epidemiology of Graves’ orbitopathy. Pediatr Endocrinol Rev 7(Suppl 2):182–185
22. Daumerie C 2010 Epidemiology. In: Wiersinga WM, Kahaly GJ,
eds. Graves’ orbitopathy—a multidisciplinary approach, questions
and answers. 2nd revised edition. Basel, Switzerland: Karger; 33–39
23. Jacobson DL, Gange SJ, Rose NR, Graham NM 1997 Epidemiology
and estimated population burden of selected autoimmune diseases
in the United States. Clin Immunol Immunopathol 84:223–243
24. Stan MN, Bahn RS 2010 Risk factors for development or deterioration of Graves’ ophthalmopathy. Thyroid 20:777–783
25. Cawood TJ, Moriarty P, O’Farrelly C, O’Shea D 2007 Smoking and
J Clin Endocrinol Metab, January 2013, 98(1):145–152
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
thyroid-associated ophthalmopathy: a novel explanation of the biological link. J Clin Endocrinol Metab 92:59 – 64
Prummel MF, Terwee CB, Gerding MN, Baldeschi L, Mourits MP,
Blank L, Dekker FW, Wiersinga WM 2004 A randomized controlled
trial of orbital radiotherapy versus sham irradiation in patients with
mild Graves’ ophthalmopathy. J Clin Endocrinol Metab 89:15–20
Kahaly GJ, Dietlein M 2002 Cost estimation of thyroid disorders in
Germany. Thyroid 12:909 –914
Frick KD, Kymes SM, Lee PP, Matchar DB, Pezzullo ML, Rein DB,
Taylor HR 2010 The cost of visual impairment: purposes, perspectives, and guidance. Invest Ophthalmol Vis Sci 51:1801–1805
Frick KD, Gower EW, Kempen JH, Wolff JL 2007 Economic impact
of visual impairment and blindness in the United States. Arch Ophthalmol 125:544 –550
Rein DB, Zhang P, Wirth KE, Lee PP, Hoerger TJ, McCall N, Klein
R, Tielsch JM, Vijan S, Saaddine J 2006 The economic burden of
major adult visual disorders in the United States. Arch Ophthalmol
124:1754 –1760
Smith TS, Frick KD, Holden BA, Fricke TR, Naidoo KS 2009 Potential lost productivity resulting from the global burden of uncorrected refractive error. Bull World Health Organ 87:431– 437
Traverso CE, Walt JG, Kelly SP, Hommer AH, Bron AM, Denis P,
Nordmann JP, Renard JP, Bayer A, Grehn F, Pfeiffer N, Cedrone C,
Gandolfi S, Orzalesi N, Nucci C, Rossetti L, Azuara-Blanco A, Bagnis A, Hitchings R, Salmon JF, Bricola G, Buchholz PM, Kotak SV,
Katz LM, Siegartel LR, Doyle JJ 2005 Direct costs of glaucoma and
severity of the disease: a multinational long term study of resource
utilisation in Europe. Br J Ophthalmol 89:1245–1249
Mertzanis P, Abetz L, Rajagopalan K, Espindle D, Chalmers R,
Snyder C, Caffery B, Edrington T, Simpson T, Nelson JD, Begley C
2005 The relative burden of dry eye in patients’ lives: comparisons
to a U.S. normative sample. Invest Ophthalmol Vis Sci 46:46 –50
Gürdal C, Saraç O, Genç I, Kýrýmlýoðlu H, Takmaz T, Can I 2011
Ocular surface and dry eye in Graves’ disease. Curr Eye Res 36:8 –13
Beauchamp GR, Black BC, Coats DK, Enzenauer RW, Hutchinson
AK, Saunders RA, Simon JW, Stager Jr DR, Stager Sr DR, Wilson
ME, Zobal-Ratner J, Felius J 2005 The management of strabismus
in adults—III. The effects on disability. J AAPOS 9:455– 459
Lyons CJ, Rootman J 2010 Strabismus in Graves’ orbitopathy. Pediatr Endocrinol Rev 7(Suppl 2):227–229