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DexamethasoneAntirheumatic properties hormonal effects and adverse reactions A 16 month study.

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Dexamethasone : Antirheumatic Properties, Hormonal
Effects and Adverse Reactions (A 16 Month Study)
By ROGER
L. BLACK,
WILLIAME. REEFE,JOHNR. DAVID,
KURTJ. BLOCH,
GEORGE
E. EHRLIMAND JOSEPH J. BUNIM
Dexamethasone has been administered
for 8 to 16 months (0.5 to 4.0 mg. daily),
with satisfactory antirheumatic response
in 20 of 27 patients with rheumatoid arthritis.
This compound has been found to be
the most potent anti-inflammatory corticosteroid thus far produced. It suppresses
ACTH and possibly thyroid-stimulating
hormone production by the anterior pituitary. Thyroid function, as measured by
radioactive iodine uptake, was reduced
in 11 of 19 patients during dexamethasone administration.
The most common side effect in this
group was striking weight gain-more
than 4 Kg. in 19 patients. Three patients
experienced pathologic fractures and one,
a peptic ulcer during dexamethasone
therapy. There were two deaths during
the period of study.
Dexamethasona esseva administrate durante 8 a 16 menses in dosages de 0,5 a
4,O mg per die con satisfacente responsas
antirheumatic in 20 de 27 patientes con
arthritis rheumatoide.
Esseva constatate que iste composito
es le plus potente corticosteroide antiinflammatori producite usque a iste tempore. Ill0 supprime le production de
ACTH e possibilemente de hormon thy.
roido-stimulatori in le pituitario anterior.
Le function thyroide, mesurate como
function del acceptation de iodo radioactive, esseva reducite in 11 de 19 patientes durante le administration de dexamethasona.
Le plus commun effect0 lateral in iste
gruppo esseva un frappante ganio de
peso. Isto amontava a plus que 4 kg in
19 del casos. Tres patientes experientiava
fracturas pathologic durante le c u s o de
dexamethasona. Un patiente habeva un
ulcere peptic. Duo mortes occurreva durante le period0 del studio.
I
N PRELIMINARY PUBLICATIONS,1~2
it was reported that dexamethasone
was the most potent anti-inflammatory corticosteroid thus far produced,
that it was free of certain undesirable side effects and, therefore, that it was
worthy of further investigation. This is a follow-up report on clinical, metabolic,
hormonal and adverse effects of dexamethasone administration in 27 patients
with rheumatoid arthritis treated for periods ranging from eight to 16 months.
CLINICAL
OBSERVATIONS
The series consists of 14 males and 13 females who ranged in age from seven
to 68 years and had had rheumatoid arthritis for one to 10 years (table 1).
Twenty patients exhibited seven or more of the features listed in the Revised
Diagnostic Criteria Classification of the American Rheumatism Association,s
From the National Institute of Arthritis and Metabolic Diseases, Ndionul Institutes of
Heulth, Bethesda, Md., and the Rheumdology S d e - G e o r g e t o w n Medtcol Division,
Georgetown Unloersity School of Aledicine, District of Columbia General Hospital, Washington, D. C .
112
113
DEXAMETHASONE
permitting a diagnosis of “classical” rheumatoid arthritis. The remaining seven
patients had five or more criteria, permitting the diagnosis of “definite” rheumatoid arthritis. None presented symptoms or findings listed among the
criteria for exclusion from the diagnosis of rheumatoid arthritis.
By American Rheumatism Association criteria, three patients were in Stage
I, five in Stage 11, 17 in Stage 111, and two in Stage IV. Twenty-two patients
had a positive bentonite flocculation test, and five a negative reaction. Subcutaneous nodules were present in 12 patients, each of whom had a positive
bentonite flocculation test.
Twenty-one of this group had received corticosteroids previously for three
months to six years, with inadequate control of symptoms. The remaining six
patients had received salicylates without sufficient relief.
The benefit achieved during dexamethasone therapy, as measured by indexes” shown in figure 1, was maintained over the entire period of observation
in most cases. The column at the left in each box (fig. 1 ) represents the total
of the scores for this group of patients prior to dexamethasone administration.
Improvement achieved at the time maintenance dose was established (within
the first six weeks) is reflected by the lower second columns in each box.
The status after eight to 16 months is represented by the third columns. Pain
on motion, tenderness, swelling and ring size all decreased, indicating progressive improvement in patient status. The range of motiont score was the
only parameter to show regression; a larger percentage deficit was found at
the latest observation period. Morning stiffness (shown as an average for all
patients) showed significant decrease in duration during dexamethasone
administration.
Attempts were made periodically to lower the maintenance dose of dexamethasone. Salicylate, either enteric-coated acetylsalicylic acid or a buffered
preparation, was added to the regimen of 13 patients (table 2 ) . Ten
of this group (77 per cent) tolerated a decrease averaging 1.8 mg. in the daily
dexamethasone dose. One of this group, after receiving her “final” maintenance dose for several months, tolerated complete withdrawal of corticosteroid during the fourth month of pregnancy. On the other hand, among the
14 patients not receiving salicylate, only two (14 per cent) tolerated a modest
decrease of 0.3 and 0.5 mg., respectively, in the maintenance dose. One other
tolerated slow tapering and discontinuation of the corticosteroid after 12
‘Complete indexes were obtained in 24 of the 27 cases. Pain on motion, tenderness and
swelling are rated for each joint on a scale of 1 to 3, and the patient’s individual score
represents the total for all his joints at the time measured. The ring size, measured with
standard jeweler’s rings, represents the total for the 10 proximal interphalangeal joints of
both hands. The range of motion is determined by measuring the passive range for each
joint (except the small joints of hands and feet and the spine) and expressing the total
number of degrees of motion found as a percentage of the total possible, according to a
standard norm. The percentage deficit is then taken as the score for the patient. Morning
stiffness is recorded as the number of hours between arising and the disappearance of stiffness.
, ! . 1 , jll .it ! ’!
tWe are indebted to Dr. David Fried and the Department of Physical Medicine and
Rehabilitation at the Clinical Center, National Institutes of Health, for range of motion
determinations.
~
114
BLACK, REEFE, DAVID, BLOCH, EHRLICH AND BUNIM
Table 1.-Composition of Series: Dexamethasone Administration for 8 to 16 Months;
27 Rheumtoid Arthritis Patients'
Ape distribution
Decade
Under29
30-39
40-49
50-59
80-69
Chsi6cstion
Duration of disease
No.pta.
Stage
No.pta.
Years
No.pta.
3
I
11
111
3
5
1-2
3-5
17
6-8
IV
2
9-10
8
8
9
2
8
8
7
1
Previous corticosteroid therapy
Duration
No. ~ta.
7
4
7
3
6
Over 3 yr.
2-3 yr.
1-2 yr.
Less than 1 yr.
None previously
'Males, 14, females, 13.
Table 2.-Administration
of Salicylate to Facilitate Lowering Daily
Maintenance Dose of Dexamethone
Case, Age. Sex
c. P., 57, M
I. D., 36, M
W. B., 50, M
E. B., 43, F
hi. Bl., 42, F
M. Bo., 38, F
c. s.,45, M
T. B., 68, M
I. M . , 49, M
W. T., 39, M
H. H., 36, F
G. Mc., 31, F
C. D., 16, F
Dexamethasone
original maintenance
dose (mg./day)
4
4
4
4
4
4
3.6
3.2
3
2.4
2
2
1
Salicylate added
( Gm./day )
3.6
2.4
3.6
3.6
4.5
4.5
6
3.6
4.5
2.4
3
3
2.4
Dexamethaeone
final maintenance
dose (mg./day)
4
4
1
0.5
3.5
3
1.5
4
1
1
1.5
1
0.5
months of therapy. Several previous attempts to decrease the dose had failed.
The improved functional status achieved by 20 patients was maintained
throughout the period of eight of 16 months of therapy (table 3).* Three severely handicapped patients, and nine with moderately impaired ability, improved to the point of complete functional capacity. The five remaining patients
in Classes 11, I11 and IV were more comfortable during dexamethasone therapy
but failed to improve in ability to perform daily tasks. Three of the five with
most severe impairment were receiving high maintenance doses of 3.5 to 4.0 mg.
daily, and two of these received supplementary salicylate. Although residual,
potentially reversible, idammatory changes seemed iesponsible for the continued impairment of function, a further increase in corticosteroid dosage
seemed imprudent.
The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
determinations showed a general trend toward normal values. Since corticosteroid dosage was adjusted to the minimum consistent with good control of
the disease and no attempt made at complete suppression, the laboratory values
were frequently in the abnormal range.
HORMONAL EFFECTS
Previously reported studies have shown that dexamethasone is 30 times
'One patient who died during tile fourth month of therapy, and another whose
dexamethasone was discontinued during pregnancy, were not included in this table.
115
DEXAMETHASONE
Table 3.-Functional Capacity of 25 Patients with Rheumatoid Arthritis Before and
After Dexamethasone Administration for Periods up to 16 Months
After 8 to 16 month8 of therapy
Before dexamethasone
Clans
~~
Class
1
I1
111
IV
0
-
-
-
-
10
9
1
-
-
11
2
6
3
-
4
1
1
1
1
Number of patients
I
Complete functional
capacity
I1 Capacity adequate, but
with discmmfort
111 Can perform few normal
activities
1V Incapacitated-wheel chair
or bedridden
more potent than prednisone in suppressing the pitnitary-adrenal axis in man.2
Aldosterone production was found to be independent of this pituitary effect.2
Since those studies were reported, we have had an opportunity to observe, in
addition, the effect of dexamethasone on thyroid function.
Eflect on Thyroid Function
Earlier experience with ACTH and cortisone4J indicated that corticosteroids
decreased radioactive iodine uptake ( HA1 ) or accumulation gradient, lowered
serum protein-bound iodine concentration ( PBI ), ultimately decreased basal
metabolic rate (BMR) and, rarely, produced marked elevation of serum
cholesterol. Decreased thyroid uptake of RAI during corticosteroid administration was accompanied by increase in urinary excrction of an
dose.0 Administration of cortisone was also associated with a highly significant reduction
in rate of release of thyroid h ~ r m o n eThyroid-stimulating
.~
hormone (TSH) reversed these effects even when administered in the presence of high levels of
circulating adrenal cortico~teroids.~
Nevertheless, it has not yet been definitely
demonstrated that suppression of thyroid function in steroid-treated patients
results directly from reduction of TSH secretion.
Thyroid function studies were performed on 16 patients of the present series
and on three additional patients with rheumatoid arthritis receiving dexamethasone, three to nine months after the start of therapy. Figure 2 summarizes
the effect of various doses of dexamethasone on four parameters of thyroid
function. RAI uptake was reduced below 15 per cent in 24 hours in two of six
patients receiving 0.5 to 1.0 mg. of dexamethasone per day, three of five
patients receiving 1.5 to 2.0 mg. per day, four of six patients receiving 2.5 to
3.25 mg. per day, and both patients receiving 4.0 mg. dexamethasone per day.
The serum level of protein-bound iodine was found to be between 5.9 and
6.3 Pg. per cent in patients receiving 0.5 to 1.0 mg. dexamethasone, and tended
to be near or below the lower limit of normal (3.4 ug. per cent) in patients
receiving larger doses of dexamethasone. The PBI vdues in three patients were
markedly different from the rest; two patients receiving 3.5 and 3.0 mg. dexamethasone daily had a PBI of 7.8 pg. per cent and 9.0 ,ug.per cent,* and one
*It was later found that the PBI concentration was spuriously elevated by the ingestion of “cough medicine” containing potassium iodide.
116
BLACK, REEFE. DAVID, BLOCH, EHRLICH AND BUNIM
25
15-
Prw To
mOw.amlhosmm
After I Mo of
~osxomattlarcna
mAfter0to16Mos
of Dsiomelhasona
20
10
15
10
5
05
"
W
O
NW
O
l N TENERNSS
SWELLING
RING SIZE
%DEFICIT
MORNING STIFFNESS
R A M E OF MOTION (KXIRS-AVERAGE)
IN PATIENTS
THE EFFECT OF DEXAMETHASONE O N THYROID FUNCTION
WITH RHEUMATOID ARTHRITIS
P iI
BMR
CHOLESTEROL
-
300-
r
+I0 -
+5-
0-5
%
UPTAKE
IN
24 HRS.
%
205
-
270
-
255
-
-
i o -.
mg.
-15 -
__
.
240
-20 -25
-
-30 -35 -
1 1 i
23-
Wn,.
DEXAMETHASONE
OEXAMETHASONE
DEXAMETHASONE
DEXAMETHASONE
Fig. 1.-Dexamethasone therapy. Antirheumatic indexes in 24 rheumatoid
arthritis patients treated for 8 to 16 months.
Fig. 2.-The effect of dexamethasone on thyroid function in patients with
rheumatoid arthritis.
patient receiving 1.0 mg. dexamethasone had a PBI value of 1.2 pg. per cent
( E. B.) . There was no correlation between the dose of dexamethasone and the
basal metabolic rate, a wide range of BMR values being encountered at each
dose. However, 10 of 17 patients tested had a BMH of less than -10 per cent.
DEXAMETHASONE
117
Serum total cholesterol exceeded the upper limit of normal (250 mg. per cent)
in five patients. Again, there was no direct relation between the dose of
dexamethasone and the level of serum cholesterol. [n three of the five patients
with elevated serum cholesterol, the RAI uptake was below 15 per cent, PBI
at or below the lower limit of normal, and BMR at or below -15 per cent.
Intramuscular administration of thyroid-stimulating hormone, 10 U. per
day for three days, produced an increase in RAI uptake, PBI and BMR in patients J. R. and I. M., and a fall in serum cholesterol in patient I. M. There was
no change in thyroid function, however, following TSH administration in patient E. B. (fig. 3). The response of J. R. and I. M. is similar to that observed
in patients with hypothyroidism secondary to hypopituitarism. The response of
E. B. suggests primary hypothyroidism with completely inactive thyroid tissue. Thyroid function studies in this patient prior to dexamethasone administration and while she was receiving 15 mg. prednisone daily revealed an RAI
uptake of 13.6 per cent, PBI of 7.4 ,ug. per cent, BMR of 21.8 per cent, and
cholesterol of 290 mg. per cent. After 10 months of therapy with dexamethasone, RAI uptake was 0 per cent, PBI 1.2 pg. per cent, BMR -151 per cent,
and cholesterol 272 mg. per cent. However, the presence of elevated titers of
thyroglobulin antibodies ( determined with the use of thyroglobulin-coated,
tannic acid treated sheep erythrocytes ) prior to and during dexamethasone
administration ( 1:1250 and 1:6000, respectively) suggests that some process
destroying thyroid gland may be responsible for myxedema in this patient.
Five other patients with abnormal thyroid functions had no demonstrable
antibodies to thyroglobulin.”
Five patients in this series had had thyroid function studies performed while
they were receiving 16-a methylprednisone (MK-log), and two of these
were also studied while receiving prednisone (fig. 4).8Patient J. R. had an
increase in RAI uptake while receiving 16-(Ymethylprednisone; however, on
dexamethasone it again declined below normal limits. Following the change
from 16-(Ymethylprednisone to dexamethasone in approximately equivalent
antirheumatic doses, four other patients also had a decline in RAI uptake.
In both J. R. and I. M., serum PBI concentration decreased following 16-01
methylprednisone administration, as compared to the values obtained during
prednisone administration. However, there was no significant change in PBI
in four other patients who received dexamethasone following a course of 16-or
methylprednisone. One patient, F. M., showed an unexplained rise in PBI to
5.9 p g . per cent while on dexamethasone. The BMR tended to decrease
in all five patients while they were receiving dexamethasone, but only F. M.
and I. M. showed a significant change.
Comment.-The interpretation of the observed changes in thyroid function
during dexamethasone administration is made difficult by the paucity of
studies prior to the start of therapy, the simultaneous administration of
salicylate in some cases, the knowledge that abnormal thyroid function occurs in “untreated” rheumatoid patients, and the almost complete absence
of clinical signs and symptoms of hypothyroidism in these patients.
*We are indebted to Dr. Howard Goodman of the National Heart Institute for the thyroid
antibody determinations.
118
BLACK, IIEEFE, DAVID, BLOCH, EHRLICH AND BUNIM
CHANGES IN THYROID FUNCTION FOLLOWING T.S.H. ADMINISTRATION IN PATIENTS TREATED WITH DEXAMETHASONE
PBI
RAI
Before
Before
After
50
After
40
%
30
PQ%
UPTAKE 20
24 HRS.
10
2
0
0
CHOLESTEROL
BMR
Before
Before
After
After
0
mq%
300
-30
-40
r -----
I
200
J.R.; Denornethasone I.Omg dolly M
I. M.; Denomethosone 3.01110 dally fb-A
E.B.8 Doxometharone O.5mg dolly M
COMPARISON OF THE EFFECT OF EQUIVALENT ANTIRHEUMATIC DOSES OF
PREONISONE, 16-a-METHYL-PREDNISONE AND DEXAMETHASONE ON THYROID FUNCTION
Prtdnirone
16-a-MelhylPrtdnlsone
Dexanuthaone
%
x
24 HRS.
Prtdniront
10
l6-a-Udhyl-
Dtaomtlhasone
Predniront
*27%
16-a-MethylPrednlranc
Dtxametharw
PBI
Alcq 7
.
4.0
-- -----
3.0
- -- - - - - - -
-
-40
-
J.R.
I.M.
CCI
H.H.
L_1
F.M.
M.B.
M.S.
Fig. 3.-Changes in thyroid function following TSH administration in patients
treated with dexamethasone.
Fig. 4.-Comparison of the effect of equivalent antirheumatic doses of 16-amethyl-prednisone and dexamethasone on thyroid function.
DEXAMETHASONE
119
As was mentioned, administration of ACTH and cortisone, as well as prednisone,' may be associated with laboratory changes indicative of hypothyroidism.
Since many patients in our series had received other corticosteroids prior to
dexamethasone, we may assume that some already had suppression of thyroid
function.
The administration of large doses of salicylate (6.0 to 9.0 Gm. daily) to
euthyroid patients was found to increase BMR, reduce serum concentration
of PBI and reduce thyroid uptake and rate of release of RAI.9 Exogenous TSH
increased RAI uptake, elevated serum PBI concentration, and accelerated release of 113' despite the maintenance of serum salicylate levels of 35 to 51 mg./
100 rn1.l" Nine patients in our series received 2.5 to 6.0 Gm. of salicylate daily
in addition to dexamethasone. There was no significant difference, however,
in thyroid function of patients receiving dexamethasone plus salicylate and
those receiving dexamethasone alone.
Wolfson et alS5found that nine of 18 patients with rheumatoid arthritis
had serum concentrations of PBI below the normal limit, and six of 13 patients
had an RAI uptake below normal, prior to corticosteroid therapy. However, in
the absence of information concerning salicylate intake of these patients, it is
uncertain whether these data reflect the thyroid status of completely untreated rheumatoid patients. Short et al." reported that about 25 per cent of
patients with rheumatoid arthritis had a BMR below -10 per cent, but other
thyroid function studies were not performed.
Wolfson et a1.j remarked that the diagnosis of hypothyroidism was unusually
difficult in corticosteroid-treated patients. They felt that the usual symptoms
were either absent or well hidden beneath the manifestations of the primary
disease being treated, or obscured by the often striking effects of ACTH and
cortisone. In our series we encountered few symptoms and signs indicative of
hypothyroidism, even in those patients with markedly abnormal laboratory
determinations. Only two such patients were treated for hypothyroidism-I.
M. and E. B. In I. M., reduction in dose of dexamethasone from 3.0 to 0.5 mg.
daily led to a rise in RAI uptake to 23 per cent, an increase in BMR to the
normal range, and a fall in serum cholesterol to 355 mg. per cent after three
weeks on the lower dose. Serum concentration of PRI remained abnormal.
Patient E. B. received 75 pg. of triiodothyronine; serum cholesterol promptly
decreased to within normal limits and BMR increased. Her somnolence and
fatigue diminished appreciably, and no increase in corticosteroid dosage was
required to control joint symptoms.
E8ect on Carbohydrate Metabolism
The relatively modest effect of dexamethasone on glycogen deposition in
rats1'J3 suggested at first that this corticosteroid might exercise decreased
diabetogenic properties in patients receiving therapeutic doses. Indeed, preliminary clinical studies supported this possibility.2
Serial glucose utilization rate ( GUR ) determinations according to the
method of Amatuzio et al." were performed at three month intervals
during dexamethasone administration on 22 subjects in this series. Similar
120
BLACK, REEFE, DAVID, BLOCH, EHRLICH AND BUNIM
determinations were made on 13 of these while they were receiving older
steroids prior to institution of dexamethasone therapy. Five patients listed in
table 4 showed progressive impairment of glucose utilization during the administration of dexamethasone in doses of 0.5 to 4.0 mg. daily. One of these
patients had normal, and another only moderately impaired, function while
receiving a related steroid, 16-a methylprednisone. One had had borderline
function while taking triamcinolone. The other two had been receiving aspirin
only, prior to dexamethasone, and both had normal function when first studied.
Six other patients, not included in table 4, had diabetic or borderline GUR's
throughout the period of the study. Another group of six continued to have
normal rates.
The remaining five patients are of interest. All exhibited diabetic rates prior
to dexamethasone administration, four receiving prednisone in doses of 18 to
24 mg. daily, and one, aspirin only. Three of the five were given dexamethasone,
3.0 to 4.0 mg. daily, and the others 1.0 and 2.0 mg., respectively. All five showed
improvement in glucose utilization with normal rates after three to 12 months
of dexamethasone administration.
None of the 27 patients in this study had elevated fasting blood glucose
levels or glucosuria.
Comment.-As pointed out in a recent review by Frawley and associates,'j
corticosteroid effect upon carbohydrate metabolism can be measured by at
least two parameters in man-glucosuria and anti-insulin. Bastenie and coworkers'6 have demonstrated that although impairment of carbohydrate
metabolism occurs almost universally early in the course of corticosteroid
administration, in most cases function returns to normal in the face of continued corticosteroid therapy. It has been suggested by Fajans and ConnI7
that the islets of Langerhans may respond with increased function to the hyperglycemic effect of the adrenal corticosteroids. Hyperplasia and hypertrophy
Table I.-Patients
Showing Zncreasing lmpairment of the Glucose Utilization
Rate during Dexamethasone Administration
Glucose utilization rate9
Case
J. R.
I. Y.
M. Bl.
N. A.
C. D.
Dexamethasone
daily
Previous therapy
maintenance
daily dose
dose (mg.)
16-Methylprednisone
8 mg.
16-Methslprednisone
8 mg.
Aspirin
3.6 Gm.
Triamcinobne
8 mg.
Aspirin
3.6 Gm.
0.5
3.0-1.0
4.0-3.6
3.5
1.0-0.5
During dexamethaaone administration
Prior to dexamethasone
Normal
(0GTT)t
Borderline
(2.6)
%Borderline
(2.6 J
-
1-3 mo.
Diabetic
(2.4)
4-8 mo.
7-9 mo.
10-12 mo.
Borderline
(2.7)
-
Diabdic
(1.7)
Normal
Normal
Diabetic
(3.0)
(2.9)
(1.9)
Diabetic
(1.9)
Normal
(3.4)
Diabetic
(2.8)
-
Diabetic
(2.2)
*Glucose utilization rates were determined by the method of Amatuzio e t al." The K values in parentheses represent the rate of disappearance of administered glucose (excees above fasting level) in per
cent disappearing per minute.
Normal
2.87 to 4.86
Borderline 2.46 to 2.91
Diabetic less than 2.46
tOGTT = Oral Glucose Tolerance Test.
$Dashes indicate procedure not performed.
DEXAMETHASONE
121
of the islet cells have been observed by H o u s ~ a y ’in~ animals experiencing
corticosteroid suppression of carbohydrate metabolism. Hence, the development of a diabetic state secondary to glucocorticoid excess is probably related
directly to the individual‘s capacity to increase insulin production.’;
Dexamethasone has been compared to triamcinolone and to hydrocortisone
in terms of anti-insulin effect in a diabetic patient.‘!’ Dexamethasone, 3 mg.
daily, produced a greater increase in insulin requirement (40to 180 U.) than
either prednisone, 30 mg. daily (40 to 100 U.) or triamcinolone, 20 mg. daily
(40 to 120 U.).
The glucosuric effect of dexamethasone has also been compared to that of
other corticosteroids. Frawley*5found dexamethasone in dosage of 3 mg. daily
equivalent to cortisone 100 mg. daily and hydrocortisone 80 mg. daily in the
production of glucosuria in a diabetic patient. Slater et a1.,2O also studying a
diabetic patient, found a similar ratio in that dexamethasone, 2.4 mg. daily,
produced glucosuria comparable to that produced by cortisone, 90 mg. daily.
These studies clearly indicate that dexamethasone, early in its course of administration, causes impairment of carbohydrate metabolism in man. Our
observations have been concerned with the effects of long-term dexamethasone
administration, as manifested by changes in the glucose utilization rate (GUR)
and fasting blood glucose levels. It is difficult to explain with certainty conflicting results in the two groups of five patients who “converted” their CUR’S
(normal to diabetic and diabetic to normal, respectively). The dosage range
of dexamethasone in the two groups was nearly equal, being, in fact, somewhat
less in the group showing impairment. The factor of diet might be considered,
but nine of the 10 were consistently studied as inpatients while on a standard
hospital diet, consisting of more than 300 Gin. of carbohydrate daily. The degree of activity also influences the GUR, inactive patients tending to show
more impaired rates.21 Paradoxically, the most inactive of these 10 patients
were in the group which converted to normal GUR’s. Two patients in this group
showed no change in functional ability, and the other three improved only by
one class. None was in remission. On the other hand, in the group showing ;I
diabetic tendency, four of the five improved to a Full functional capacity, two
showing an increase of two functional classes. It appears then that the conversions in GUR’s were not related to change in physical activity. The hypoglycemic eflect of acetylsalicylate has been demonstrated by Hecht and
GoldneP in diabetic and nondiabetic patients. Glucose tolerance curves
obtained after the administration of acetylsalicylate were parallel to but lower
than the pre-treatment curves. This would suggest that in these cases the glucose utilization rate was not changed. In our patients, no consistent relationship existed between alteration in the salicylate regimen and the glucose
utilization rate.
Since neither fasting hyperglycemia nor glucosriria was demonstrated in
this group of 27 patients, it appears that none suffered exhaustion of the
“insulin-producing reserve” even after receiving therapeutic doses of dexamethasone for eight to 10 months. The variability in extent of the “reserve” in
different patients and at different times in the same patient was reflected by
different degrees of impairment of the GUR.
122
BLACK,
REEFE, DAVID, BLOCH, EHRLICH AND BUNIM
SIDE EFFECTS
The incidence of side effects in this group is listed in table 5. Twenty-five
of the 27 patients developed facial rounding, a “buffalo hump,” and in some instances, striae. These symptoms developed early-usually between one nncl
three weeks after the start of dexamethasone. In one patient who previously
exhibited facial rounding while taking 80 to 30 mg. of prednisone daily, this
manifestation disappeared during the first month of dexamethasone administration, 1.0mg. daily. It is of interest that two patients, each on a 2 mg. daily dose
of dexamethasone, developed side effects including facial rounding, increased
appetite, restlessness and profuse sweating between m e and two weeks after
beginning the corticosteroid, even though the dose was insufficient to suppress
the arthritic symptoms.
Weight gain not related to edema formation was one of the most disturbing
side effects. The marked increase in appetite resulted in strikingly increased
caloric intake in most patients when an unrestricted diet was available after
discharge from the hospital. Within three to six months after the start of
therapy, 19 patients (nine men and 10 women) gained over 4 Kg. in weight.
Although in a few cases this gain was desirable, in most the end result was a
grossly oversized face and abdomen. Of the nine patients gaining over 9 Kg.,
only two were later successful in curbing their appetite enough to lose 3 and
5 Kg., respectively.
Other side effects included restlessness and/or jnsoinnia in 11, hirsutism in
10, increased sweating in nine and a mood change with increasing irritability
in four. No patient became psychotic. Eleven patients developed petechiae
and/or spontaneous ecchymoses. One patient showed this side effect within the
Table 5.--Side Efiects Appearing during the Adminktratwn of Dexamethasone
to 27 Patients with Rheumatoid Arthritis for Periods of 8 to 16 Months
_______
Facial rounding and/or “buffalo hump”. .
Appetite increase. . . . . . . . . . . . . . . . . . . . . .
Weight gain over 4 Kg.. ...............................
Petechiae and/or ecchymoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Restlessness and insomnia.
Hirsutism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Increased sweating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Edema ................................................
Mood change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Epigastric p a i n ’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Fractures after mild trauma., . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
vertebrae ................. 2
fibula . . . . . . . . . . . .
19
11
11
10
9
8
4
. .4. . .
3
. 1
Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Peptic ulcer! . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1
‘One patient had a peptic ulcer prior t o dexamethasone administration.
tTwenty-two patients had repeated radiologic examination of the gastrointestinal tract
during dexamethasone therapy.
DEXAMETHASONE
123
first two weeks of dexamethasone therapy, but in the others this first appeared between the fourth and fifteenth week of treatment.
Since metabolic studies‘ revealed no sodium retention, edema was a surprising finding in eight of these 27 patients. The edema was pitting and involved the feet, ankles and lower legs. Although the edema seemed related to
cardiac and/or venous disease in one case, and to inflammatory process in the
ankles or tarsal joints in three others, there were four in whom these factors
could not be evoked. All eight of these patients showed ecchymoses. No patient without ecchymoses became edematous. Although these two phenomena,
edema and ecchymoses, may occur coincidentally, it is possible that interference
with normal capillary integrity during dexamethasone administration may account for edema formation.
One patient (D. S . ) developed hypertension. His blood pressure prior to
dexamethasone administration ranged around 15O/OO. Four months later,
on a maintenance dose of 3 mg., his blood pressure was 174/112, and the hypertension persisted throughout his subsequent coiirsc.
A mild acneform eruption was observed in five patients. Incidental findings
included lichen planus-like lesions of the oral mucosa in three and spontaneous
rupture of the extensor tendons in the hands of two other patientsz3
Pathologic fractures occurred in three men, aged 36, 46 and 49, with rheumatoid arthritis of over four years’ duration. Two sustained compression
fractures of the vertebrae, while the third had a fracture of the fibula. None
had previous fractures, although all had received other corticosteroids for one
to five years prior to this study. These three men wcre among the five patients
receiving the highest maintenance doses of dexamethasone, 3.5 to 4.0 mg. daily.
Figure 5 shows the radiologic appearance of the spine of patient W. B. before
and after vertebral fractures.
All fractures occurred during the first three month period of study. Serum
calcium remained normal, but the alkaline phosphatase rose in two patients
following vertebral compression. Since all the patients with severe osteoporosis
had normal serum alkaline phosphatase, the rise in the patients with fractures
was thought to be related to the repair process.
Change in linear height was observed in two patients of this group and in
six prednisone-treated patients of another series who sustained spontaneous
vertebral compression. Six of the eight from the two groups who experienced
vertebral fractures lost 1 to 2% inches in height. This is in contrast to the
total variation of *% inch noted in the dexamethasone-treated patients who
did not develop a vertebral fracture during the eight to 16 months of observation. This small variation was probably due to changes in posture occurring
with alteration in activity of the patients’ arthritis.
Epigastric pain was noted by four of the 27 patients while they were receiving dexamethasone. One of these had had a demonstrable gasfric ulcer
while taking 20 mg. of prednisone daily. This patient failed to show healing
despite an anti-ulcer regimen while receiving dexamethasone, 4 mg., and
buffered aspirin, 3.6 Gm., daily. A subtotal gastric resection was performed
three months after dexamethasone therapy was begun.
124
BLACK, REEFE, DAVID, BLOCH, EHRLTCH AND BUNIM
Fig. 5.-(A) Radiograph of lumbar spine (patient W. B.) while receiving prednisone, 20 to 25 mg. daily prior to dexamethasone administration. ( B ) Radiograph
of lumbar spine (patient W. B.) during third month of dexarnethasone administration, 4 mg. daily.
Stool examinations for occult blood ( benzidine test) were performed in
series of three or more daily collections at three month intervals, as shown in
table 6. During these periods the patients were recei\-ing a standnrd hospital
diet which included meat. Eight of 11 patients receiving dexamethasone and
salicylate therapy showed positive tests on one or more occasions. However,
only one of the seven patients receiving desamethasone alone showed occult
blood in his stools. This patient had a history of a gastric ulcer one month before dexamethasone was started. Healing was demonstrated radiologically
prior to the first dose of dexamethasone. Salicylate therapy has been shown
to cause bleeding from the gastrointestinal tract of a degree sufficient to produce positive tests for occult
In our cases the presence of occult blood
in the stools is better correlated with salicylate therapy than with dexamethasone administration.
Radiographic esamination of the gastrointestinal tract was performed at
three to six months intervals in 22 of these 27 patients regardless of the
presence or absence of symptoms or of occult blood in the stools. One patient
was found to have an asymptomatic gastric ulcer in the fourth month of
dexamethasone administration.
There were two deaths in this group. One was that of a 57 year old male
with rheumatoid arthritis and heart disease, who died following extensive
thrombophlebitis of both femoral veins which had required inferior vena caval
ligation. Postmortem examination showed bilateral femoral thrombophlebitis,
and pericarditis and valvulitis consistent with rheumatoid heart disease.
125
DEXAMETHASONE
Table 6.-Occurrence
of Occult Blood in the Stools of Rheumatoid Arthritis Patients
Receiving Dexamethasone and Salicylate Therapy Compared to
Dexamethasone Therapy Alone
Occult Blood in Stools*
Case
c. P.
I. D.
M. B1.
h.1. Bo.
H. H.
c. s.
W. B.
I. M.
W. T.
E. B.
C. D.
Dexamethasone
maintenance
dose (mg./day)
4
4
3.5
3
1.5
1.5
1
1
1
0.5
0.5
Salicylate
maintenance
doee (Gm./day)
Dexamethasone and Salicylate
Prior to
dexarnethasonet
0
3.6
2.4
4.5
4.5
3.0
6.0
3.6
4.5
2.4
3.6
2.4
2t
2
0
0
0
0
0
0
1
1
1-3 mo.
4-6 mo.
'7-9 mo.
0
2
0
-
-
1
1
0
0
0
2
05
0
0
2
2
1
O§
0
0
2
1
0
0
1
0
1
0
0
1
1
0
PATIENTS RECEIVING DEXAMETHASONE ONLY
D. S.
N. A.
P. Be.
P. Ba.
V. R.
F.M.
3
3
2
1
1
0
0
0
0
0
0
2
0
1
0
0.5
0
0
R.T.
0.5
0
0
0
0
0
0
1
0
0
0
0
0
0
0
0
0
0
0
"Benzidine test for occult blood. Stools examined in series of 3 or more specimens driring
each period.
0 = all negative.
1 = occasionally positive.
2 z frequently positive.
tPatient had an active gastric ulcer. Gastric resection done 3 months after dexamethasone
therapy started.
ISorne patients received salicylate occasionally.
§Patient not on salicylate at this time.
There was no evidence of infection or septicemia. The other patient, while at
home on a dose of 3.5 mg. of dexamethasone, became acutely ill with shortness of breath and weakness. He was admitted to another hospital under the
care of another physician. The daily dosage was abruptly reduced from 3.5
to 1.5 mg. and ACTH and DOCA were supplemented. The patient died on
the tenth hospital day. Unfortunately the cause of death could not be clearly
established .
SUMMARY
Dexamethasone was administered for eight to 16 months in daily divided
doses of 0.5 to 4.0 mg. with satisfactory antirheumatic response in 20 of 27
patients with rheumatoid arthritis. Five of the 27, although rendered more
comfortable, failed to improve in functional status.
This compound has been found to be the most potent anti-inflammatory
126
BLACK, REEFE, DAVID, BLOCH, EHRLICH AND BUNIM
corticosteroid thus far produced. It suppresses ACTH production by the anterior pituitary. Thyroid function, iis measured by H,4I uptake, was reduced in
11 of 19 patients. This suppression could be reversed by exogenous TSH administration during continued steroid therapy. No direct evidence has been
presented, however, to demonstrate that pituitary secretion of TSH is suppressed by dexamethasone. Dexamethasone caused impairment of carbohydrate metabolism in 11 of 22 cases, as reflected in abnormal glucose utilization rates on repeated determinations. In no patient, however, was elevation
of fasting blood glucose level or glucosuria observed.
The most annoying side effect in this group was striking weight gain-over
4 Kg. in 19 patients. The greatest gain was 18 Kg. Pathologic fractures occurred in three patients. Only one patient developed a peptic ulcer during
dexamethasone therapy. Psychosis did not occur.
When dexamethasone was combined with salicylnte therapy, it was possible
to effect substantial reduction of steroid dosage in 77 per cent of the patients so
treated. On the other hand, occult blood in the stools was found in eight of 11
patients receiving combined therapy, but in only one of seven patients taking
dexamethasone alone. One gastric ulcer was found thus far among 22 patients
who have received periodic radiologic examinations. There were two deaths
during the period of the study.
Gradual withdrawal of dexamethasone was possible in two of our cases, after
seven and 12 months, respectively, at a 2 mg. dosage level, without the appearance of adrenal insufficiency or recurrence of arthritis.
Further observations are necessary to ascertain the effect of long-term administration of dexamethasone on pituitary function and the incidence of
serious side effects.
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DEXAMETHASONE
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Roger L. Bkck, M.D., Senior Znuestigator, National Tnstitute
of Arthritis a d Metaboltc Diseases, Bethesda, Md.; Clinical
Assistant Professor of Medicine, Georgetown Uniuersity,
Washington, D . C .
Willicini E . Reefe, M.D., Co-Director, Rheumcrtology Seruice
-Georgetozun Alrclical Division, D . C . General Hos-pitd,
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John R . Dazjid, M.D., Clinical Associate, National Institute of
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128
BLACK, REEFE, DAVID, BLOCH, FHRLICH AND BUNIM
Kurt J . Bloch, M.D., Senior Investigator, National Institute o f
Arthritis and Metabolic Diseases, Bethesda, Md.
George E . Ehrlich, M.D., Trainee, National lnstitute of Arthritis and Metabolic D i s m m , Bethesda, Md.
Joseph 1. Bunim, M.D., Clinical Director, National Zmtitute of
Arthritis and Metabolic Diseases, Bethesda, Md .; Associate
Professor o f Medicine, Johns Hopkins Uniuersity, Baltimore,
Md.; Clinical Professor of Medicine, Georgetown University
School of Medicine, Washington, D. C.
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