EXTENSIVE PERSONAL EXPERIENCE Dermopathy of Graves’ Disease (Pretibial Myxedema): Long-Term Outcome

Transcription

0013-7227/02/$15.00/0
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The Journal of Clinical Endocrinology & Metabolism 87(2):438 – 446
Copyright © 2002 by The Endocrine Society
EXTENSIVE PERSONAL EXPERIENCE
Dermopathy of Graves’ Disease (Pretibial Myxedema):
Long-Term Outcome
KARA M. SCHWARTZ, VAHAB FATOURECHI, DEBRA D. F. AHMED,
AND
GREGORY R. POND
From the Division of Endocrinology, Metabolism, Nutrition, and Internal Medicine (V.F.), Department of Dermatology
(D.D.F.A.), and Section of Biostatistics (G.R.P.), Mayo Clinic, Rochester, Minnesota 55905
Little is known about the long-term outcome of patients with
thyroid dermopathy, an extrathyroidal manifestation of
Graves’ disease. Also, it is not known to what degree treatment
promotes remission of the lesions. The present report supplies
information on the natural course of mild, untreated and severe, treated thyroid dermopathy. In this study, we report on
the outcomes of 178 patients seen at our institution between
January 1969 and November 1995 with thyroid dermopathy
who were followed up for an average of 7.9 yr. Nonpitting
edema was the most prevalent form of dermopathy (43.3%),
and the pretibial area was the region most commonly involved
(99.4%). The majority of patients with dermopathy had ophthalmopathy (97.0%). Topical corticosteroids were the most
commonly used treatment (53.9%). Patients with milder forms
of dermopathy (40.4%) did not receive any therapy for dermopathy. Twenty-six percent of the patients experienced
complete remission, 24.2% had moderate improvement (par-
tial remission), and 50.0% had no or minimal improvement of
their dermopathy at last follow-up. Patients who did not receive therapy experienced a significantly (P ⴝ 0.03) higher
rate of complete remission (34.7%) than those who received
local therapy (18.7%), although the combined complete and
partial remission rates were not significantly different for the
treated and untreated groups (P ⴝ 0.3). However, the treated
and untreated groups were not comparable because our practice is to use therapy for more extensive and severe cases. All
five cases of elephantiasis were in the treatment group and
were less likely to have remission because of the severity of
their skin condition. Patients receiving treatment were more
likely to have dermatologic consultation and histologic diagnosis (P < 0.001). The beneficial effect of topical corticosteroid therapy on long-term remission rates remains to be
determined. (J Clin Endocrinol Metab 87: 438 – 446, 2002)
L
OCALIZED MYXEDEMA, OR thyroid dermopathy, is
an infrequent manifestation of autoimmune thyroiditis
and, in particular, of Graves’ disease. It is characterized by
localized thickening of the skin (1, 2). Commonly localized
in the pretibial area, it is therefore often referred to as
pretibial myxedema (PTM). Various treatment modalities
have been employed, including topical and systemic corticosteroids, compression dressings, and local injections (3–7).
Moderate benefits of short-term topical corticosteroid therapy have been reported (3). We earlier reported a 10% complete remission rate after an average follow-up of 3.5 yr in a
study of 150 patients seen between 1969 and 1989 (1). Information is needed about the natural course and long-term
outcome of patients with this condition. Here we report on
a 26-yr experience (1969 –1995) with thyroid dermopathy. We
specifically present data on long-term outcome of mild, untreated and severe, treated groups in this disorder after analysis of the information obtained from the last clinical evaluation and the response of the patients to questionnaires
mailed in September 2000.
1989, who were subjects of a previous report (1), are included in the
present study. Additionally, we mailed questionnaires to all patients in
September 2000 to obtain current disease status and outcome information. Of 195 patients seen at the Mayo Clinic for PTM during this period,
178 were diagnosed for the first time at the Mayo Clinic between 1969
and 1995. (The remaining 17 patients had been diagnosed at this institution earlier.) The focus of this paper is the 178 patients with a new
diagnosis in the study period.
Clinical criteria for diagnosis
Diagnosis of PTM was made in all patients by the presence of the
typical clinical picture. The presentation included raised, waxy lesions
of the skin, usually in the pretibial area. The lesions were usually light
colored but could be flesh colored or yellowish brown. Hyperpigmentation and hyperkeratosis were also present in some cases, as was hyperhidrosis. The lesions were occasionally indurated and the hair follicles prominent so that the lesions had an orange peel (peau d’orange)
or pig skin appearance and texture. Dermopathy was classified into one
of the following four forms: nonpitting edema accompanied by typical
skin color changes, plaque, nodular, or elephantiasic (Fig. 1) (1). Endocrinologists usually performed the initial evaluation. More severe cases
and cases requiring confirmation were referred to dermatologists.
Ophthalmopathy was diagnosed on the basis of previously reported
criteria (8, 9). Eye status was defined as normal, mild, moderate, and
severe ophthalmopathy and ophthalmopathy associated with optic neuropathy (8, 9). The focus was on patients requiring surgical intervention.
No attempt was made to evaluate the outcome of ophthalmopathy in this
study.
Patients and Methods
We retrospectively reviewed the records of all patients who had a
discharge diagnosis of thyroid dermopathy or PTM between January 29,
1969, and November 15, 1995, at the Mayo Clinic. Patients seen before
Histologic criteria for dermopathy (Fig. 2)
Abbreviations: GAG, Glycosaminoglycans; OR, odds ratio; PTM,
pretibial myxedema.
Histologic confirmation was obtained by punch biopsy specimens
and hematoxylin and eosin and alcian blue-periodic acid-Schiff staining
438
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Schwartz et al. • Dermopathy of Graves’ Disease
J Clin Endocrinol Metab, February 2002, 87(2):438 – 446 439
FIG. 1. Thyroid dermopathy (localized myxedema) in five patients. A, Nonpitting edema form in pretibial area. B, Plaque form in pretibial area.
C, Nodular form in ankle and foot. D, Elephantiasic form. E, Occurrence of thyroid dermopathy in scar tissue.
in 62.3% of the patients. Classic histopathologic features were seen,
consisting of normal collagen in the papillary dermis and separation of
the collagen bundles by mucin. Mucin staining demonstrated abundant
diffuse mucin within the dermal fenestrations as large amounts of glycosaminoglycans (GAG) diffusely dispersed in the reticular part of the
dermis. Although there was infiltration of lymphocytes in the perivascular space and mast cells were moderately increased in number in
thyroid dermopathy, lymphocytic infiltration because of extensive GAG
accumulation and edema was not seen in all biopsy specimens and was
not a criterion for diagnosis.
or local functional problems were usually followed by endocrinologists,
and topical therapy was not initiated. Patients who received therapy
were generally treated with topical corticosteroids under occlusion or
compressive dressings. The applied treatment was nighttime dressing of
0.05% to 0.1% triamcinolone acetate in cream base under occlusion with
plastic film (Saran Wrap, Dow Chemical Co.). In some cases the cream
was applied three times daily. Each course of therapy usually lasted 2–10
wk. Therapy was continued or repeated for longer periods, depending
on clinical response (1). Compression was used in some patients and
consisted of athletic wraps or compression stockings, providing 20 – 40
mm Hg pressure.
Laboratory diagnostic criteria
Diagnosis of hyperthyroidism and hypothyroidism was made by
routine thyroid function tests, including measurement of TSH, serumfree T4, and total-serum T4. Thyroid-stimulating immunoglobulin was
measured in some patients who were seen after 1985 (5%) by a method
based on cAMP generation and was positive in all tested patients (1). The
number of patients was not adequate to evaluate the effect of the level
of thyroid-stimulating immunoglobulin on outcome of dermopathy.
Topical therapy
Topical treatment was initiated in the dermatology department, usually after histologic confirmation. Mild cases and cases without cosmetic
Evaluation of outcome
Complete remission was defined as absence of clinical dermopathy,
and mild improvement or partial remission was defined as flattening of
a plaque or nodule or reduction of edema. No improvement was defined
as worsening of clinical dermopathy or no change in the appearance of
the dermopathy. If the last relevant follow-up occurred at the patient’s
last Mayo Clinic visit, the patient’s dermopathy was classified as absent,
improved, unchanged, or worse on the basis of the physician’s documentation. The patient’s thyroid function status was noted as euthyroid
on no therapy, euthyroid on thyroid replacement, hypothyroid, or
hyperthyroid.
440
J Clin Endocrinol Metab, February 2002, 87(2):438 – 446
small numbers of patients in certain groups, Fisher’s exact test or the
rank-sum test was used in lieu of the chi-square or two-sample t test.
Logistic regression analysis was used to determine predictors of
outcome status. Because the severity of the disease was believed to be
different in patients who received treatment, compared with those who
did not, univariate and multivariate logistic regression models were
computed separately for each of these two groups. The odds ratio (OR)
and 95% confidence interval for the OR were computed. Expected time
until mild improvement (partial remission) or complete remission was
estimated using the Kaplan-Meier method.
All tests were two sided, and a P value of less than 0.05 was considered statistically significant.
Results
Demographics
Of 178 patients, 36 (20.2%) were men and 142 (79.8%)
women. The mean age at diagnosis of PTM was 53.1 yr (range
14.3–79.6 yr). The average age for female patients was 52.9 yr
(range 14.3–79.6) and for male patients 54.1 yr (range 31.8 –
75.7 yr). One hundred sixty-two patients (91.0%) were classified as hyperthyroid, seven (3.9%) hypothyroid, and five
(2.8%) euthyroid; four (2.2%) were hypothyroid and then
became hyperthyroid during follow-up. At last known follow-up, 40 (22.5%) patients had died.
Therapy of thyroid dysfunction
FIG. 2. Photomicrograph of skin biopsy specimen from patient with
localized myxedema showing separation and fraying of connective
tissue fibers and edema. The epidermis (at top) is normal. (Hematoxylin and eosin, original magnification ⫻40.) [Reproduced with permission from Williams & Wilkins (Fatourechi et al., Ref. 1)].
Patient questionnaire
The patients were asked whether their thyroid-related skin condition
had returned entirely to normal (complete remission) or almost normal
(mild improvement or partial remission), was unchanged, or was worse
(no improvement). They were also asked whether they had received any
treatment for PTM (local corticosteroid cream, oral corticosteroid, cosmetic surgery, or other) since their last visit to the Mayo Clinic. They
were asked as well whether they had any skin problems in the legs
(including cosmetic concern, local discomfort, and difficulty in wearing
shoes or socks). Patients were also asked to indicate whether they were
taking thyroid hormone replacement therapy.
Of the 178 patients in the study, 40 were deceased at the time of survey
follow-up. Of the remaining 138 patients, 110 returned surveys (80%
response rate), 3 refused participation, 14 could not be contacted, and 11
had no response or had other exclusions.
Statistical methods
Descriptive statistics, such as the mean and sd for continuous variables and frequencies for categorical variables, were computed. Baseline
characteristics were compared among different groups with the chisquare test or two-sample t test when appropriate. When there were
Of the entire group, 110 patients (61.8%) received one
treatment with 131I, 43 patients (24.2%) had two treatments
with 131I, 18 (10.1%) received 3 or more such treatments, and
7 patients (3.9%) did not receive any 131I treatments. Twentyseven patients (15.2%) had undergone thyroidectomy. Fortytwo patients (23.6%) had been treated with a single course of
antithyroid agents, and one patient with 2 courses.
At last known status, 18 patients (10.1%) were euthyroid
on no therapy, 135 (75.8%) were euthyroid on T4 therapy, 7
(3.9%) were hypothyroid, and 14 (7.9%) were hyperthyroid;
the status of four patients was unknown. Including follow-up information obtained from the survey, the average
follow-up was 14 yr (median 12.5 yr) from the time of diagnosis of thyroid dysfunction.
Other systemic manifestations of Graves’ disease
Most patients (83.1%) were diagnosed with thyroid disease before the diagnosis of dermopathy. Only five patients
(3%) did not have any clinical evidence or history of ophthalmopathy. The remaining patients had significant eye disease at the time of diagnosis of dermopathy. Mild ophthalmopathy was present in 41%, moderate in 31%, and severe
in 15.2%; optic neuropathy was present in 9.4% of the patients with dermopathy. Additionally, the majority of patients (71.9%) were diagnosed with ophthalmopathy before
dermopathy. There was a high rate of rehabilitative eye surgery in the cohort, which included 46 eye muscle, 26 eyelid,
44 transantral orbital decompression, and 3 transfrontal decompression operations. Some required more than one corrective operation.
Thirty-one cases of acropachy were diagnosed (17.4%).
With the available information, it was not possible to assess
the outcome of acropachy.
Thyroid dermopathy
One hundred twenty-nine patients (72.5%) were first diagnosed with PTM at our institution. The remaining 49 patients were referred to our clinic with this diagnosis. Histologic confirmation of diagnosis was available in 104 patients
(58.4%). The area of skin involvement was pretibial in 166
(93.3%), pretibial and feet in 7 (3.9%), pretibial and upper
extremities in 2 (1.1%), and not documented in 1 patient. The
clinical form of PTM was nonpitting edema in 77 (43.3%),
plaque in 48 (27.0%), nodular in 33 (18.5%), elephantiasic in
5 (2.8%), and unclassifiable and/or unknown in 15 (8.4%).
Endocrinologists usually made the initial diagnosis, and 116
patients (65.2%) received diagnostic confirmation by a
dermatologist.
Initial treatment of thyroid dermopathy
Seventy-two patients (40.4%) received no specific therapy
for their thyroid dermopathy, and 96 patients (53.9%) were
treated by topical corticosteroids alone or in combination
with other treatments. In 81.0% of those treated by topical
corticosteroids, the agents were applied under occlusion.
Only six patients received local corticosteroid injections, and
one patient underwent surgical excision.
Baseline characteristics of the treated and untreated
groups were different in the frequency of extreme forms of
dermopathy, such as the elephantiasic form, which was
present only in the treated group. The treated group also had
more dermatologic referrals, which resulted in a higher rate
of biopsy confirmation (P ⬍ 0.001). Treated patients were
diagnosed with PTM later after the diagnosis of hyperthyroidism (P ⫽ 0.04) (Table 1). Patients who were treated were
slightly older and were more likely to be male, although
neither variable approached statistical significance (Table 1).
After having received the initial treatment only, 16 patients
(16.7%) had no or minimal improvement and 20 (20.8%) had
moderate improvement on subsequent short-term follow-up
examination. Only one had complete remission.
Subsequent therapy and long-term follow-up of thyroid
dermopathy (Tables 2 and 3)
The average length of follow-up for dermopathy was 7.9
yr (range 0 –30.4 yr, median 5.4 yr), with follow-up ending at
patient death, complete remission, or the patient’s last
known follow-up (with a Mayo Clinic physician or by questionnaire). Eighty-two (46.1%) of the 178 patients did not
receive any topical corticosteroid treatments, 81 (45.5%) received one course of treatment, 12 (6.7%) received two
courses, and 3 (1.7%) received three or more courses. Duration of corticosteroid therapy was quite variable, the shortest
duration being 5 d and the longest 8 yr. The majority had
therapy for less than 1.5 yr; however, one patient reported
using continuous local therapy for 2.3 yr and another for 8
yr. Of the 96 patients who received topical corticosteroid
treatments, 50 (52.1%) had no or minimal improvement at
last known follow-up (17 have since died), 26 (27.1%) had
moderate improvement (six have since died), and 20 (20.8%)
had complete remission (three have since died). Twenty-one
patients (11.8%) received compressive dressing treatment. Of
these, 14 received topical steroid therapy at some time (before, after, or simultaneously with the compressive dressings). Eleven patients received local corticosteroid injection
(Tables 2 and 3). Nine patients received systemic corticosteroids for treatment of severe dermopathy.
Forty-six patients (25.8%) had complete remission, with an
average time to complete remission of 8.8 yr (range 0.3–30.4
yr). Forty-three patients (24.2%) had moderate improvement
but not complete remission at last known follow-up (nine
have since died). At last known follow-up, 89 patients
(50.0%) had no or minimal improvement (27 have died). Of
these patients, 23 still had a cosmetic concern about their legs,
TABLE 1. Baseline clinical characteristics of patients who received therapy for dermopathy at any time compared with patients who
never received therapy
Variable
Female (%)
Thyroid condition (%)
Hyperthyroid
Hypothyroid
Euthyroid
Hypothyroid then hyperthyroid
Initial Dx at Mayo Clinic (%)
Dx by histologic exam (%)
Clinical form (%)
Nonpitting edema
Nodular
Plaques
Elephantiasic
Unclassifiable
Acropachy (%)
Ophthalmopathy (%)
Mean (SD) age at PTM Dx (yr)
Mean (SD) time before PTM Dx and when
hyperthyroidism Dx was made (yr)
Received initial
treatment
Received no initial
treatment
78.1
82.2
90.5
5.7
2.9
1.0
72.4
75.3
91.8
1.4
2.7
4.1
69.9
42.4
48.0
18.0
28.0
5.0
1.0
17.1
96.2
53.4 (13.5)
4.2 (5.8)
43.3
22.4
29.9
0.0
4.5
17.8
98.6
52.7 (10.1)
3.7 (7.0)
P
0.50
0.26a
0.71
⬍0.001
0.21a
Dx, diagnosis.
a
Fisher’s exact test.
b
Rank-sum test.
0.91
0.65
0.69
0.04b
442
TABLE 2. Final follow-up status of patients with various patterns of initial therapy for dermopathy
Initial treatment
No. of patients
No/minimal improvement,
no. (%)
Moderate improvement,
no. (%)
Complete remission,
no. (%)
None/observationa
Topical corticosteroids alone
Compressive dressings alone
Topical corticosteroids and compressive
dressings
Topical corticosteroids and otherb
Compressive dressings and otherb
Topical corticosteroids, compressive dressings,
and otherb
Surgical excision
Topical corticosteroids and corticosteroid
injection
72
75
5
9
32 (44.4)
40 (53.3)
5 (100.0)
5 (55.6)
15 (20.8)
21 (28.0)
0
1 (11.1)
1
3
2
0
2 (66.7)
1 (50.0)
0
0
1 (50.0)
1 (100.0)
1 (33.3)
0
1
6
0
3 (50.0)
1 (100.0)
2 (33.3)
0
1 (16.7)
25 (34.7)
14 (18.7)
0
3 (33.3)
a
One patient had unknown last follow-up status.
Other treatments included antibiotics for local infection, tretinoin, “hot cream,” salicylic acid, ammonium lactate lotion, and vacuum pump
therapy for swelling.
b
TABLE 3. Final follow-up status for observation vs. treatment groups administered any time during disease course
a
Initial treatment
No. of
patients
No/minimal
improvement,
no. (%)
Moderate
improvement,
no. (%)
Complete
remission,
no. (%)
None/observationa
Topical corticosteroids
Compressive dressings
Corticosteroid injection
72
96
21
11
32 (44.4)
50 (52.1)
13 (61.9)
4 (36.4)
15 (20.8)
26 (27.1)
3 (14.3)
4 (36.4)
25 (34.7)
20 (20.8)
5 (23.8)
3 (27.3)
One patient had unknown last follow-up status.
FIG. 3. Percentage of patients who had complete remission according
to treatment group (Kaplan-Meier method).
FIG. 4. Combined percentage of patients who had partial or complete
remission according to treatment group (Kaplan-Meier method).
21 had local discomfort, and 10 had difficulty in wearing
shoes or socks. The rate of complete remission increased with
time, both for the treated group and for the no-therapy
group.
Using the Kaplan-Meier estimate, a 50% complete remission rate was achieved after 17 yr in patients who were
untreated, but only 27% of patients treated with any treatment had complete remission at that point (Fig. 3). When
partial remission and complete remission rates were combined, at 17-yr follow-up, 60% of the untreated group had
partial or complete remission (Fig. 4), whereas the rate for the
treated group was 50%. Patients who were not treated had
a higher rate of complete remission than did treated patients
(P ⫽ 0.03). No statistically significant difference was found
between treated and untreated groups in the proportion of
patients having combined complete plus partial remission
(P ⫽ 0.30) as their final outcome.
As stated above, treated patients were believed to have
worse disease. Results of univariate logistic regression analysis are shown for patients who received treatment at any
time (Table 4) and for patients who never received any treatment (Table 5). Of patients who received treatment at any
time, those with a longer follow-up (OR ⫽ 1.04, P ⬍ 0.037),
those who had transantral orbital decompression surgery
(OR ⫽ 2.97, P ⬍ 0.01) and those who had eye surgery for
Graves’ eye disease other than transantral orbital decom-
TABLE 4. Predictors of final outcome status for patients receiving treatment at any timea
Variable
OR
Sex (F vs. M)
Age
Duration of follow-up
Acropachy (yes vs. no)
Hyperthyroid (yes vs. no)
Duration of thyroid disease before PTM diagnosis
Transantral orbital decompression surgery (yes vs. no)
Eye surgery, excluding transantral orbital (yes vs. no)
Local corticosteroid therapy (yes vs. no)
Systemic corticosteroid therapy (yes vs. no)
1.83
1.01
1.04
1.15
0.26
1.08
2.97
2.51
2.18
1.27
95% confidence interval for
OR estimate
(0.72,
(0.98,
(1.00,
(0.45,
(0.08,
(0.99,
(1.29,
(1.14,
(0.54,
(0.46,
4.67)
1.04)
1.09)
2.94)
0.89)
1.17)
6.82)
5.53)
8.74)
3.45)
P
0.20
0.43
0.037
0.78
0.032
0.078
0.010
0.022
0.27
0.65
a
In a multivariate logistic regression model with a stepwise selection procedure (P ⬍ 0.05), transantral orbital decompression surgery and
hyperthyroidism are the only two predictors to enter the model.
TABLE 5. Predictors of final outcome status for patients receiving no treatment at any timea
a
Variable
OR
Sex (F vs. M)
Age
Duration of follow-up
Acropachy (yes vs. no)
Hyperthyroid (yes vs. no)
Duration of thyroid disease before PTM diagnosis
Transantral orbital decompression surgery (yes vs. no)
Eye surgery, excluding transantral orbital (yes vs. no)
1.15
0.99
1.00
1.60
1.62
1.02
2.18
1.21
95% confidence interval for
OR estimate
(0.37,
(0.95,
(0.95,
(0.50,
(0.32,
(0.96,
(0.75,
(0.49,
3.54)
1.03)
1.06)
5.09)
8.09)
1.09)
6.40)
2.99)
P
0.81
0.90
0.89
0.43
0.56
0.53
0.15
0.68
In a multivariate logistic regression with a stepwise selection procedure, no predictor entered the model at the P ⫽ 0.05 level of significance.
pression surgery (OR ⫽ 2.51, P ⬍ 0.02) all had a significantly
better final outcome. Hyperthyroid patients had worse
(OR ⫽ 0.26, P ⬍ 0.03) final outcome than did patients who
were not hyperthyroid. Although the difference is not statistically significant, patients who received corticosteroid
therapy, local (OR ⫽ 2.18, P ⬍ 0.27) or systemic (OR ⫽ 1.27,
P ⬍ 0.6), had a better final outcome than those who received
other treatment for dermopathy. In a multivariate logistic
regression analysis using a stepwise selection procedure, the
only predictor of improved outcome in the treatment group
was a history of transantral orbital decompression and eye
muscle surgery for ophthalmopathy (Table 4).
Among patients who did not receive treatment for PTM,
no variable was a statistically significant predictor of final
outcome status. Although the difference was not statistically
significant, patients who received transantral orbital decompression surgery (OR ⫽ 2.18, P ⬍ 0.15) or any other eye
surgery (OR ⫽ 1.2, P ⬍ 0.6) had a better final outcome. The
reason for the better outcome in patients who had eye surgery is not completely clear, and the clinical relevance remains questionable. However, there were more patients with
systemic corticosteroid therapy in this group, and these patients usually had more frequent clinic visits and longer
follow-up.
Discussion
Cause of thyroid dermopathy
About 0.5– 4.3% of patients with a history of thyrotoxicosis
have thyroid dermopathy, and 15% of patients with severe
Graves’ ophthalmopathy have this cutaneous manifestation
(2). The hallmark finding on biopsy specimens from these
skin lesions is increased levels of GAG in the reticular, but
not the papillary, dermis (2), with hyaluronic acid concentrations often 6 to 16 times higher in these lesions than in
normal skin (10). This increased deposition apparently results from increased fibroblast stimulation, but the cause of
this stimulation, although of autoimmune origin, is not yet
clear.
It has been speculated that the thyroid-stimulating hormone receptor antibody plays a role (11, 12). Heat shock
protein (13), IL-1, and TGF-␤ (14) have also been implicated
in PTM, although their roles are not clearly defined. Whatever the cause of the increased GAG production, accumulation of GAG leads to the characteristic skin lesions associated with thyroid dermopathy. Specifically, the hyaluronic
acid expands the dermal tissue and causes fluid to accumulate. It may also cause compression or occlusion of small local
lymphatics and thereby increase the dermal edema (4). These
manifestations, as mentioned previously, are most commonly found in the pretibial area, a fact that several researchers have attempted to explain. Schermer et al. (15)
suggested that the stasis of venous blood and the daily physical trauma to the lower extremities might stimulate mucin
deposition. Rapoport et al. (16) also proposed that dependent
edema may play a role, causing the slower return of lymph
from the lower legs and increasing the half-life of fibroblaststimulating cytokines locally. Other research indicates that
fibroblasts in different regions of the body may have different
characteristics and mechanisms of regulation (10).
However, other evidence suggests that deposition of GAG
may not be just a local phenomenon. Wortsman et al. (17)
found, on the basis of preradial skin biopsies, that preradial
GAG deposition might occur commonly in patients with
Graves’ disease, although this result was not found in an-
444
other study (18). Salvi et al. (19), using ultrasonography,
found increased pretibial skin thickness in 33% of patients
with autoimmune thyroid disease, suggesting that dermopathy may be much more prevalent at the subclinical level
than is diagnosed. Thus, increased deposition of GAG may
occur throughout the body without clinical manifestations.
The association of Graves’ disease with collagen disorders or
markers of collagen disorders, including elevated levels of
antinuclear antibody, supports the theory that connective
tissue may be involved systemically as part of the autoimmune disease (20). The discovery of increased urinary GAG
levels in patients with Graves’ disease also fits with this
paradigm (21). Thus, the skin of the entire body may have a
propensity to develop localized myxedema, but this only
appears clinically in regions with additional mechanical
(gravitational forces) or anatomic (site-specific differences in
fibroblasts) factors. In fact, localized myxedema has been
documented outside the pretibial region. Cases have been
reported involving the shoulders, upper back, upper extremities, and pinnae (22). In our study, two patients had dermopathy of the upper extremities. When dermopathy occurs
in these unusual locations, there is often a history of trauma.
Though the causes of dermopathy are debated, its development follows a predictable pattern. Generally, thyrotoxicosis develops first, followed by ophthalmopathy and finally
dermopathy in patients who have all of these manifestations
(1, 23). The results of our study were consistent with this
pattern, with 83% of patients having had thyroid disease
before the development of dermopathy and 72% having had
ophthalmopathy before PTM. In 17%, thyroid acropachy was
diagnosed, involving soft tissue swelling of the hands and
feet with characteristic radiographic features (1, 5). In this
study and in our previous report, almost 80% of the patient
population were women and more than 90% of patients were
hyperthyroid. Nonpitting edema was the most frequent form
of dermopathy. In the present study, 3% of our patients did
not have a diagnosis of clinical ophthalmopathy. A diagnosis
of PTM in the absence of ophthalmopathy is always questionable. However, some of these patients may have had
mild eye disease at an earlier time that was never diagnosed.
Pretibial myxedema has several typical clinical appearances. Nonpitting edema is the most common. This too was
confirmed by the present study. However, raised plaques
and nodules also often occurred in our patients. Rarely, patients present with an elephantiasic form consisting of nodules and lymphedema, five patients having had this extreme
form in the present study.
Therapy of thyroid dermopathy
The treatment of dermopathy is usually symptomatic.
Generally, PTM is only of cosmetic concern, but a case of
peroneal nerve trapping has been reported (24), and associated lower extremity swelling can make shoes difficult to
wear. In our study, 10 patients had such a problem, and 21
complained of local discomfort.
Local therapies. Therapy for thyroid dermopathy has variable
success. Given the relatively benign nature of this problem,
topical corticosteroids are more likely to be used than systemic therapy (1). Strengths of topical corticosteroids range
from midpotency steroids, such as fluocinolone acetonide
(3), to high-potency steroids, such as clobetasole propionate
(25). Topical corticosteroids have had their absorption further enhanced with hydrocolloid (25) or plastic wrap occlusive dressings. Duration of these treatments varies. In general, occlusion is applied for at least 12 h each day. A trial of
4 – 6 wk may be reasonable but must be followed carefully to
watch for signs of adverse effects from the topical steroids
(e.g. atrophy, telangiectasis, and ecchymoses). Additionally,
compression has been useful, especially when lymphatic involvement is suspected (4, 5). Ideally, compression consists
of athletic wraps or compression stockings, providing 20 – 40
mm Hg pressure.
In a study by Kriss et al. (3), all 11 patients treated with 0.2%
fluocinolone acetonide cream under occlusion experienced
“favorable dermatologic responses” within 4 – 6 wk, but attempts at achieving long-term remission were unsuccessful
because of undesirable side effects. However, it is unclear
whether this favorable response corresponds to the “partial
remission” classification used in our study. In our study, we
had a 47.9% partial or complete remission rate among more
severe cases treated with corticosteroids at any time, compared with a 55.6% partial or complete remission rate among
patients with milder disease who did not receive any treatment. Patients with more severe dermopathy are more likely
to receive local corticosteroids, whereas patients with mild
disease are more likely to receive no treatment at all. The
long-term outcome appears to be better in milder cases despite the absence of therapy.
Twelve percent of our patients received compressive
dressings in combination with local corticosteroids. The
23.8% complete remission rate in these patients exceeds that
with use of topical corticosteroids alone.
In addition, intralesional octreotide injection has recently
shown promise in the treatment of PTM but needs further
study (26, 27). No patients in our study underwent this
therapy. Surgical excision (28) has been reported. However,
surgical intervention is not advised because of the high rates
of recurrence (29). Intralesional corticosteroids, such as triamcinolone acetonide, have also been used with some success (7). The use of intralesional steroid injections is losing
favor, despite a few favorable reports (6, 7), because of their
tendency to cause lumpy-appearing skin and the frequent
recurrence of disease after treatment (2, 7). Only 6.2% of
patients in our study received corticosteroid injections; their
remission rate was 27.3%, greater than that for patients receiving topical corticosteroids or compressive dressings.
However, since some patients received more than one mode
of therapy, additional benefits from local corticoid injection
cannot be determined.
Systemic immunomodulatory therapy. Immunomodulation such
as systemic corticosteroids (30) and cytotoxic therapy (31) have
also produced improvement in patients with PTM, but because
of their side effects these agents are rarely used unless required
for therapy of associated ophthalmopathy. High-dose iv
immunoglobulin treatment (32) and plasmapheresis (33, 34)
have also been used to treat PTM in a few patients and have led
to improvement or remission of the condition (33).
Outcome of local therapy. In our previous report (1), involving
fewer patients and a shorter follow-up, we found that 38%
of patients experienced partial remission of their dermopathy and only 8% had complete remission. However, in the
present study with longer follow-up, 24% had partial remission and 26% complete remission. This result suggests that
with longer follow-up more patients will experience complete remission of their dermopathy. In fact, the untreated
patients with 17 yr of follow-up had a 50% complete remission rate (Fig. 3).
There was no statistically significant difference in complete plus partial remission rate between the local therapy
and the no-therapy groups. The trend of better outcome in
the untreated group is likely related to the severity of the
cases of dermopathy, those with more severe disease receiving treatment more often than those with milder dermopathy. Combined partial or complete remission rate gradually
increased with time, to 70% in the group with no treatment
and 58% in the treated group 25 yr after the diagnosis of PTM
(Fig. 4). Patients with more severe dermopathy would logically be expected to have a lower rate of complete remission
than those with milder disease. Thus, if patients with severe
dermopathy are those receiving topical corticosteroids, compressive dressings, or intralesional corticosteroid injections,
the long-term efficacy of these treatments is difficult to evaluate from the present study because they cannot be compared with the no-therapy group.
Conclusion and recommendations
The present study supplies information about the natural
course of treated and untreated thyroid dermopathy, but
there are some limitations. The treated and untreated groups
were not comparable. Half of patients with thyroid dermopathy experienced significant improvement or complete disappearance of PTM lesions after long-term follow-up. The
difference in outcome, in terms of combined complete and
partial remission, between treated severe cases and nontreated mild cases was not significant, but the nontreated
mild group had a tendency for better outcome. This could be
related to the severity of the treated cases, and we cannot
conclude that treatment in severe cases does not improve
long-term outcome. Although the previous and present reports suggest short-term benefits from topical corticosteroid
therapy in thyroid dermopathy, the effect of short-term initial topical therapy on long-term benefits remains to be determined. For a definitive conclusion, randomized clinical
trials may be necessary to determine which treatments for
thyroid dermopathy promote long-term remission. But such
long-term randomized trials may not be feasible because of
the rarity of the condition. Short-term study may not be
indicative of long-term results because of the occurrence of
remission often years after termination of therapy. Meanwhile, to achieve better outcomes, new modes of therapy are
needed.
At present, immunomodulation such as with systemic corticosteroid therapy, iv Ig, and octreotide are used for severe
cases of Graves’ ophthalmopathy (9). This therapy, directed
at ophthalmopathy, is likely to result in improvement of
associated dermopathy. For these patients, local corticoste-
roid therapy under occlusion may offer additional help. If
there is edema, especially in elephantiasic cases, compression can be added to local corticosteroid therapy. Mild cases
of dermopathy can be observed, or they can be treated with
local corticosteroids if there is cosmetic concern or local discomfort. Optimum local corticosteroid therapy is usually
4 – 8 wk and can be extended to 1 yr, depending on response.
Trauma to dependent and other areas of skin should be
avoided. Surgical excision is not recommended, and local
corticosteroid injection is not advised at the present time.
Evidence for benefits of systemic or local octreotide therapy
is inadequate.
Acknowledgments
Received June 3, 2001. Accepted October 29, 2001.
Address all correspondence and requests for reprints to: Dr. V. Fatourechi, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905.
This work was supported in part by the Richard F. Emslander Clinical
Investigator Award. K.M.S. is a student at Mayo Medical School.
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EXTENSIVE PERSONAL EXPERIENCE Dermopathy of Graves’ Disease (Pretibial Myxedema): Long-Term Outcome

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