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Peptic ulcer in rheumatoid patients on corticosteroid therapy. A clinical experimental and radiologic study

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Peptic Ulcer in Rheumatoid Patients on
Corticosteroid Therapy
A Clinical, Experimental and Radiologic Study
Rtj
WILLIAMH. KAMMERER,ROBERT
H. FREIBERCER
AND ABRAHAML. RIVELIS
An extensive study of the relationship
of peptic ulcer to adrenal steroid therapy
has led to the conclusion that certain
corticosteroids are responsible for gastric ulceration, probably as a result of
direct effects on the mucosa.
Peptic ulcer was observed radiographically in 31 per cent of patients with
rheumatoid arthritis receiving adrenal
steroids but in only 9 per cent of patients not treated and 5 per cent of
nonrheumatoid controls. Hydrochloric
acid and pepsin secretion were not influenced significantly by the administration of corticosteroids.
Un extense studio del relation inter
ulcere peptic e therapia adreno-stsroide
ha resultate in le conclusion que certe
corticosteroides es responsabile pro ulceration gastric, probabilemente in consequentia de effectos directe super le
mucosa.
Ulcere peptic esseva observate radiographicamente in 31 pro cento de patientes con arthritis rheumatoide qui recipeva steroides adrenal sed solmente in
9 pro cento de tal patientes qui non recipeva steroides adrenal e in 5 pro cento
de non-rheumatoide subjectos de controlo. Le secretion de acido hydrochloric
e de pepsina non esseva influentiate a
grados significative per le administration
de corticosteroides.
N
OT LONG after the introduction of cortisone and corticotropin for clinical use in 1950, reports began to appear on the occurrence of peptic
ulcer in patients receiving these substances. Since then, a large body of clinical and experimental data has accumulated on this subject, but the exact
role that corticosteroid therapy plays in the genesis of ulcer remains speculative and controversial.lS2Grey and his associates have long held the opinion that these hormones cause a sharp increase in free HCl acid and pepsin secretion, factors which they believe are responsible for the increased incidence of ~ l c e r . This
~ - ~ view has been supported by some and questioned by
others. Hirschowitze et al. have speculated that changes in the properties
or the rate of production, of gastric muciis may play a more important part in
the formation of these corticosteroid ulcers than the levels of pepsin or free
HCl. In an experimental study on Mann-Williamson dogs by Sandweiss,' who
used corticotropin and cortisone in doses comparable to those used in humans. no deleterious effects in the treated group over the control group
-
From the Hheunuitic Diseuse Ssctwn und Depurtment of Rdwlugy, Hospital for Specid
Surgeq and the Department of Medicine, Cornell Medical School, New York.
This study was aided by grants from the Research and Education Committee, Hospital
for Special Surgery; and the New York Chupter, Arthritis and Rheumatism Founrlation.
The prednisone and prednisolone (Meticorten and Meticdelone) used in this study
were generously supplied b y Schering Corporation. Triumcinolone wus made available
by the L,eder.k Company.
122
PEPTIC ULCER AFTER CORTICOSTEROID THERAPY
123
as to incidence of ulcer formation were found. Eleven of eighteen patients
with chronic gastric ulcer were purposefully treated by Forbess with corticotropin or cortisone. The three patients treated with corticotropin did not
mprove, but six of eight patients treated with cortisone healed, and none
was worse.
After the introduction of the metisteroids, prednisone and prednisolone,
the reported incidence of peptic ulcer in patients treated with these agents
was greater than it had been with the previously used corticosteroids, but
again, controversy has been widespread. In a study of 141 patients with
rheumatoid arthritis, 39 of whom received no hormone therapy while the
remainder were treated with hydrocortisone and prednisone in varying dosages, Boland9 concluded that the incidence of ulcer was higher in those
patients treated with prednisone than in those who received hydrocortisone.
The statistical validity of these studies, however, has been questioned by Brick.lo
It has even been questioned as to whether there is truly a higher incidence of
peptic ulcer in patients who received corticosteroids over those not so treated."
Henderson" found an incidence of only 5.3 per cent of ulcers in reviewing
data from 1,440 patients treated with cortisone. In a cooperative study conducted by the American Rheumatism Association'" on experience with cortisone in the treatment of 546 patients with rheumatoid arthritis, the incidence
of ulcer was 6.6 per cent. This reported incidence corresponds to the incidence of ulcer in the population at large. However, Howell and Ragan'*
reported 18 ulcers in 68 patients treated with cortisone for 5 to 30 months.
Kern, Clark and Lukers15 have recently reviewed their experience with 169
patients with rheumatoid arthritis who were treated with corticosteroids. In
this group, 7 of 124 patients who received corticosteroids developed a new
ulcer. Black, Yielding and BunimIs found six ulcers (16 per cent) in a group
of 39 patients receiving prednisone for two years. Two of these patients died
following gastrointestinal hemorrhage.
The present report deals with an experimental, clinical and radiographic
study, initiated in 1955, of the effects of corticosteroids on gastric secretion
and the occurrence of peptic ulcer in patients with rheumatoid arthritis who
were treated with such agents.
EXPERIMENTAL
STUDIES
Material and Methods
Subjects included 14 volunteer medical students and student nurses (ten women, four
men). All were healthy young adults with no history of gastrointestinal disease. Three
patients with rheumatoid arthritis who had developed peptic ulcer while on corticosteroid
therapy were also studied. All subjects were hospitalized during the 24 hour test periods.
During the initial test period, the subject underwent gastric intubation for a 24 hour
period. The diet during this period consisted of liquid and semi-solid foods. Aspirations
were done hourly throughout the 24 hour period. During the first 2 hours of intubation
( during which food and fluids were withheld), continiious aspiration was performed;
the volume and viscosity of this aspirate was measured. All samples were analyzed for
free HCl by titration with N/10 Na OH, methyl orange being used as the indicator.
Viscosity was determined with an Ostwald viscometer, using the supernatant fluid from the
centrifuged specimen. The volunteer subjects then received hydrocortisone, prednisone
124
KAMMERER, FREIBEHGER AND Rn’ELIS
TABLE1.-Clinical Subjects
Week 2
Week 1
Volunteer
DIUU
Hydrocortisonr
1
Hydrocortisone
2
Hydrocortisone
3
Prednisone
4
Prednisone
6
Prednisone
6
l’rednisolone
7
Prednisolone
8
Prednisolone
9
Dose
30 mg./day
40 mg./day
60 mg./day
7.5 mg./day
10 mg./day
15 mg./day
7.5 mg./day
10 mg./day
15 mg./day
Drug
Prednisone
Prednisone
Prednisone
Hydrocortisone
Hydrocortisone
Hydrocortisone
Prednisolone AL ( OH ) :I
Prednisolone AL ( OH) 3
Prednisolone AL ( OH) 3
Prednisolone+ AL(OH)3
+
+
+
10
Prednisolone
7.6 mg./day
11
Prednisolone
10 mg./day
12
Predniaolone
16 mg./day
+ AL ( OH)
Prednisolone + AL ( OH)
13
14
Prednisone
Prednisone
7.5 mg./day
10 mg./day
Prednisolone
P redn isolone
Prednisolone
3
3
Dose
7.5 mg./day
10 mg./day
15 mg./day
30 mg./day
40 mg./day
60 mg./day
16 ml. 1~‘, hr. p-c.
% hr. & 1 hr. P.C.
I,$ hr. & 1 hr. P.C.
Probanthine 26 mg. a.e.
% hr. P.C. &
Pamine 2.5 mg. % hr. ax.
% hr. & 1 hr. P.C.
Pamine 2.5 mg.&, ’ hr. ax.
% hr. P.C. QC
Pamine 2.6 mg. qid
7.6 mg./day
10 -./day
+
+
or prednisolone in varying doses for five to seven days, and the gastric intubation was
repeated at the end of this time. A different corticosteroid was then administered for
five to seven days and the 24 hour gastric aspiration repeated. Medication was continued
unchanged during this period. Table 1 shows the schedule of dosage and the sequence
of the study. During each 24 hour test period, all of the urine excreted was collected and
analyzed for uropepsin hy the method of West.”* During the second test week, some of
the subjects received aluminium hydroxide and various anticholinergic agents in addition
to the corticosteroid.
Results
Figure 1 is a composite graph representing the hourly average level of
free HC1 in 6 subjects (volunteers 1-6, table 1) before and after the administration of hydrocortisone and prednisone in varying dosages. Figures
2 and 3 illustrate the average 24-hour level of free HC1 in each individual
subject before and after the administration of the various corticosteroids.
In the six subjects receiving hydrocortisone and prednisone alternately,
there was an average rise of 10 units of free HC1 secretion per hour over
basal levels in the 24 hour periods measured (fig. 2 ) . In the eight subjects
receiving prednisolone, there was no increase over basal levels, and in five
of these subjects the average hourly level of free HC1 was actually less
after one week of drug therapy than at basal level (fig. 3 ) . In this relatively
small sample, there is no clear-cut indication that the dose level of any of
the corticosteroids used had any bearing on the level of free HC1 secretion.
Figure 4 illustrates the average 2 hour total .volume of gastric secretion in
five subjects (volunteers 1 5 , table 1 ) after one week of hydrocortisone and
prednisone and in eight subjects (volunteers 7-14, table 1 ) after the use
of prednisolone and prednisolone plus aluminium hydroxide and anticholiner*Four uropepsin determinations were performed in the laboratory of the Department
of Gastroenterology, New York Hospital, through the cooperation of Dr. Marvin Sleisenger,
Director.
125
PEPTIC ULCER AFlT.R CORTICOSTEROID THERAPY
6 SUBJECTS
B A S A L LEVEL-
*--a
ONE WEEK OF HYOROCMISONE (20-40-60ng p day)
)(......9(
ONE WEEK OF PAEONISONE ( 7 & -10-15 mg p day)
UNITS
FREE
ncL
AVERAGE BASAL LEVEL
AVERAQE FREE ncL
AVERME FREE ncL
I
o
1
ml
I
I
I
s w ) i i e
noon
p-
-
31 UNITS FREE HCL
ONE WEEK HYDROCORTISONE
I ONE WEEK
PAEDNISONE
-
40
39
I
I
I
I
I
1
I
I
I
I
2
3
4
5
6
7
0
9 0 1 : 1 2 i
I
I
I
I
I
I
I
1
1
1
2
3
4
5
6
7
mn
FIG.1.-Hourly average levels of free HCl in 6 subjects before and after the administration of hydrocortisone and prednisone ( volunteers 1-6, t:ible 1 ).
0B A S A L
a
LEVEL
HYDROCORTISONE
PREDNISONE
-
FREE HCL
AVERAGE BASAL LEVEL
31 UNITS
AFTER ONE WEEK HYDROCORTlSONE * 40 UNITS
AFTER ONE WEEK PREDNISONE
39 UNITS
-
UNITS
FREE
AVERAGE
OF
24
nOURLY
MFWIATIONS 30
DAILY OOSAGt
SUBJECT
30MG.7.5 UO.
*I
X)M(L7.5 MQ,
4OMG.10 MG.
10 MGlO MG.
P4
P2
P 5
60
0 3
P b
FIG.!?.-Average 24 hour levels of free HCl in 8 subjects before and after the administration of hydrocortisone and prednisone.
gic agents. In the five subjects receiving prednisone and hydrocortisone,
there was a significant rise in the 2 hour volume, but this did not occur in
the subjects receiving prednisolone. The marked variation of the basal level
126
KAMMERER, FREIBERGER AND RIVELIS
-
FREE HCL
LEVEL
AVERAGE BASAL LEVEL 38 UNITS
PREDN~SOLONE AFTER ONE W E K PREDNISOLONE. 37 UNITS
0 BASAL
-
UNITS
II
so
FREE
AVERAGE
OF
24
nouRLi
ASPIRATIONS
30
20
DAlUI
DOSAGE
10
75YO.
L5 YO.
SUBJECT
P7
010
my^.
ISYG.
ISYG.
7.5~0.
IOYO.
P I1
t 9
PI2
0 13
0
1
4
FIG. 3.-Average 24 hour levels of free HC1 in 8 subjects before and after the administration of prednisolone.
between the group treated with prednisone and the group treated with prednisolone is, however, significant and may reflect an unpredictable difference
in the chance selection of the volunteers.
Viscosity determination showed a decrease in relative viscosity over basal
levels with all agents used (fig. 5 ) .
Owing to errors in collection, it was possible to measure uropepsin excretion in only three of the six subjects receiving hydrocortisone and prednisone and in four of the eight subjects receiving prednisolone (fig. 6). In
the hydrocortisone-prednisone group, there was a decrease in uropepsin excretion over the control level while in the prednisolone-treated group, there
was a slight increase.
The administration of aluminium hydroxide and anticholinergic agents in
varying dosage resulted in a lower average free HC1 secretion in six subjects receiving prednisolone (fig. 7). Prednisolone alone was administered
the first week. During the second week, prednisolone plus the antacid medication was given.
Figures 8 and 9 illustrate the hourly levels of free HC1 in two patients
with rheumatoid arthritis who developed gastric ulcer while on corticosteroid
therapy. The ulcer was still present in each instance when these studies were
made. The patient who received prednisolone (fig. 9 ) had lower levels for
free HC1 after one week of treatment than prior to treatment.
These analyses would seem to indicate that after the administration of
corticosteroids in varying dosage for one week:
1. There was a moderate decrease in viscosity of gastric secretion with
all three corticosteroids used.
127
PEPTIC ULCER AFTER CORTICOSTEXOID THERAPY
700
-
600 -
BASAL
LEVEL
500-
ILDNISOU))(E
+
TOTAL
ALIDHI,
GEL
AND
ANTIKKlNERGlC
AGENTS
2
FIG.4.-Two hour total volume of gastric secretion in 5 subjects before and after the
administration of hydrocortisone and prednisone and in 18 different subjects before and
after the administration of prednisolone and prednisolone plus aluminium hydroxide and
anticholinergic agents.
2. There was no significant change in 24 hour uropepsin excretion in the
subjects tested.
3. There was an average increase of 10 units of free HCl per hour over
basal levels in the 24 hour analyses of six subjects receiving hydrocortisone
or prednisone. This increase was not correlated in a quantitative way with
the dosage of drug used. No increase in free HC1 occurred in the eight
subjects receiving prednisolone, but this may be related to difference in the
sex composition or to the other variants in the two groups.
4. The 2 hour total volume of gastric secretion in five subjects who received hydrocortisone or prednisone showed an average increase over basal
levels.
CLINICUAND RADIOLUGICSTUDIES
Clinical Materials
Over a 12 month period, x-ray examinations of the upper gastrointestinal
tract were obtained in 117 patients with rheumatoid arthritis who were
being maintained on corticosteroid therapy. These patients were about
equally divided between those attending the arthritis clinic of the Hospital For Special Surgery and those who were private patients of one
of the authors (W.H.K.). In addition, a group of rheumatoid patients who
had never received such therapy or who had not had corticosteroid treatment
For a six month period before examination was also examined radiologically.
188
KAMMERER, FREIBERGER AND RIVELTS
120110-
100.
90-
IASAL
.EVEL
6 SUB
80-
6 SUBJECTS
VISCOSITY
IN
SECONDS
1
BASAL
LEVEL
J ECTS)
PAEDIlSOLONl
70'
PRED7k-15
ISOLONI
mg/doy
'k-I5
60
ng#day
-+
\NTACID$
AND
50
L1(TUHOLI
NERGIC
AGENTS
40
30
20
10
FIG.5.-Relative viscosity of gastric secretion in a two hour specimen in 6 subjects
before and after the administration of hydrocortisone and prednisone and in 6 different
subjects before and after the administration of prednisolone and prednisolone plus aluminium
hydroxide and anticholinergic agents (viscosity H,O = 73-76 seconds).
0.75
0 BASAL
M W 2 4 HR
(AVERAGE)
LEVEL
HYDROCORTISONE
0.50
PREDNISOLONE
0.25
# SUBJECTS
3
4
FIG.6.-Uropepsin excretion in 3 subjects before and after the administration of hydrocortisone and prednisone and in 4 different subjects before and after the administration
of prednisolone.
PEPTIC ULCER AFTER CORTICOSTEROID THERAPY
FREE
129
P
R
E
D
N
’O-
HiL
AVERAGE
I
S
OF
2024
HOURLY
ASPIRATIONS
0
L
0
N
E
10-
.
(6WBJECTS)
_ _
FIG.7.-Average free HC1 secretion in 24 hours in 6 subjects after the administration
of prednisolone for one week and the administration of prednisolone plus aluminium hydroxide and anticholinergic agents during the second week.
Finally, a group of nonrheumatoid patients was examined for control purposes. Patients were selected for these last two groups by attempting to
“match them with those in Group I according to age, sex, and duration and
severity of disease.
Results
The results of these examinations are shown in table 2. Of the 117 patients
with rheumatoid arthritis receiving corticosteroid therapy, peptic ulcer was
demonstrated in 36, an incidence of 31 per cent. Of these, four represented
reactivation of an old ulcer while 32 were new ulcers. Among the rheumatoid
patients not receiving corticosteroid therapy, there were three ulcers, an
incidence of 9 per cent, while in the nonrheumatoid patients, questionable
ulceration was observed in two patients. Of the 36 ulcers observed in the
patients treated with corticosteroids, 31 were gastric and 5 duodenal, a
ratio of gastric to duodenal ulcer of 6 to 1. Of the five patients developing
duodenal ulcers, one was a male and four were females.
The possibility that any study of t h i s nature might be weighted in favor
of those patients presenting gastrointestinal symptoms, unless all patients on
corticosteroid therapy were examined, must be appreciated. It was impossible to be certain that all clinic patients on such therapy were examined,
but in the attempt to prevent the element of selection from influencing the
results, all of the rheumatoid patients who were treated with corticosteroids
and seen by one of the authors were subjected to roentgenographic examination. These totaled 74 patients, and ulcer was demonstrated in 21 (31 per
130
KAMMERER, FREIBERGER AND RIVELIS
O--*
%--X
BASAL LEVEL
AFTER 6 DAYS PRWNISONE lOm9 (I
.
BASAL AVERAGE
ds
AFTER 7 MYS PREDNISONE lOmg (I day
&(OH), Bcc m hr. B Ihr. p.c. and
PROBANTHINE 15mg tld O.C.
+
I3 UNITS FREE HCL
AFTER 6 DAYS PREDNISONE = 34UNITS FREE HCL
AFfER 7 WYS PREDNISONE
AL(OH1,ANO
PROBANTHINE 2 5 UNITS FREE HCL
+
0
6ol
I
I
I
;’\\
\
\
FIG. 8.-Hourly levels of free HCI in a 50 year old woman with rheumatoid arthritis
who had developed a gastric iilcer while on prednisone (the ulcer was still active when
these studies were inadc 1.
TABLE
2.-Results of Gustrointmtinul X - R U ~ JExuniiriutioti in
Nonrhercmutoid Putiertk
Total
(I
Group of Rheiiniutoid and
Location
of Ulcer
Developed
Peptic Ulcer
Numbcr
‘/c
Gastric
Duodenal
117
36
31vc
31
5
Rheumai?id Patients:
Nonc0rti::osteroid therapy
33
3
9%
2
1
Nonrhenmatoid Patients:
( Miscellaneous Orthopedic
Conditions )
37
2(?)
5 Yo
2
0
Rheiimstoid Patients:
Corticosteroid Therapy
Of the 5 patients developing diiodennl ulcer while on corticosteroids 2 were nien and .3
women.
cent), exactly the same kcidence found in the remainder of the group.
Thus it would appear that if any unplanned selection of patients had occurred, it did not distort the true incidence. The difference in incidence of
ulcer in the group treated with corticosteroids and in the other two groups was
131
PEPTIC ULCER AFTEH CORTICOSTEROID THERAPY
60-
.---.
BASAL LEVEL
50-
AFTER 6 DAYS PREDNISOLONE IOmw'doy
40.
30,
20
10
mn
am
FIG.9.-Free HCI levels in a 52 year old woinan with rheumatoid arthritis who had
developed a gastric ulcer while on prednisolonc (the ulcer was still active when these
studies were made ).
TABLE
3.-Age and Sex of Pntients with Rheirniutoid Arthritis Receicing Corticosterokls
Devehped
Peptic
Ulcer
Developed
Peptic Ulcer
Age
Men
No.
1s-30
4
31-40
41-50
51-60
61-70
71-80
0
0
3
5
9
0
Total
1
22
2
2
0
6
%
Women
1
No.
11
1
1127%
24
40
12"
J
14
4
5
3
95
30
2770
%
1
}26,
32%
striking and, subjected to statistical analysis, was found to be of unquestioned significance.
Age and Sex.-It will be noted in table 3 that 6 of 22 males and 30 of 95
females developed ulcer. The incidence in the two sexes is relatively the
same, which is in sharp contrast to the far greater frequency of spontaneous
132
KAMMERER, FREIBERGER AND I U V E I J S
TABLE4.--Uuration
of Arthritis
Corticostcroid Therapr
Number of
Developed
Patients
Ulcer
l.eura
Under One
1-2
2-5
1
"1
16
34
20
21
18
8
8
117
36
6-10
11-15
16-20
Over Twenty
Totid
4
1""
5l
34%
Nmtcorticosteroid Therapy
Number of
Developed
Patients
Ulcer
0
0
2
2
1
11
8
6
1
1
0
4
0
0
33
3
ulcer in males. The incidence was greatest between the ages of 40 to 70
with no significant difference between the sexes.
Durution of Disease.-It is apparent (table 4 ) that among the patients
treated with corticosteroids, ulcer occtured as frequently in those whose arthritis had existed less than 10 years as in those who had the disease for
longer than 10 years. Among the patients not treated with steroids, the
three ulcers that occurred were in patients who had arthritis for less than
10 years.
Duration of Treatment.-Analysis of the data (table 5) indicates that duration of corticosteroid treatment seems to have relatively slight effect upon
the development of peptic ulcer.
The particular corticosteroid in use at the time ulcer was demonstrated
is shown in table 6. The majority was receiving prednisone (or prednisolone)
when roentgenographic diagnosis of ulcer was made. However, we do not
conclude that these data indicate that prednisone is more ulcerogenic than
cortisone or hydrocortisone. The majority of these patients had been receiving corticosteroid therapy for long periods; cortisone and hydrocortisone had been used before the metisteroids were employed in most of these
patients. All of the steroids used may have contributed to the pathogenesis
of the ulcer, so that these data may simply represent summation of treatment. We feel that any glucocorticoid has potential ulcerogenic properties,
TABLE5.--Corticosteroid Therupy
Duration of
Treatment (months)
Number of
Patients
Developed
Peptic
Ulcer
Less Than Six
1
0
1
6-12
13-24
6
16
}26%
25-36
37-48
21
3
3
1
0"
}29,
49-60
61-72
73-90
5
12
47
4
16
Total
117
36
9
1
1.3:3
PEPL‘IC ULCER A W E R CORTICOSTEROID THERAPY
TABLE6
Corticoeteroid Therapy
l h r a tion
Drug in Use at Time of
Treatment
period
(months)
Total Duration
Corticosteroids
No. of Patients
3-12
13-24
25-36
37-48
49-60
61-72
73-90
16
I1
9
5
12
47
Totd
117
7
Prednisone
No.
Dvlpd.
of Pts.
Ulcer
X-%Y
Triamcinolone
No.
Dvlpd.
of Pts.
Ulcer
Cortieone
No.
Dvlpd.
of Pts.
Ulcer
14
55
17
1
1
8
18
6
25
2
2
2
1
1
88
32
25
2
4
2
but whether one or another is more potent in this respect has not been definitely established.
Dosage of Corticosteroids.-The doses employed at the time ulcer was
demonstrated are listed in table 7. Dosage is divided into small, moderate
and large. For the patients treated with cortisone, hydrocortisone and
triamcinolone, the data are too meager to be of statistical significance. In
the group treated with prednisone, it appears that ulcer occurred more frequently among those patients receiving a larger daily dose.
The relationship of the severity of arthritis and the incidence of ulcer
is difficult to determine because there is no dependable or uniform system
of classification of disease severity in respect to rheumatoid arthritis. When
possible, severity has been classified according to the American Rheumatism
Association recommended classification of “Stage of Disease.”18 ( By this
means, it was found that among those patients who had moderately severe
(Stage 3) or severe rheumatoid arthritis (Stage 4),ulcer was found twice as
frequently compared to those patients with milder disease (Stages 1 or 2).
In those patients who had active ulcers, gastrointestinal distress was not
by any means a common accompaniment, regardless of how severe the ulcer
appeared radiologically. Ten patients with ulcer had few or no ulcer symptoms. Two patients with perforation had no prior gastrointestinal sympTABLE7.-Dosage of Corticosteroids
Dose
mn./day
Number
of Patients
50 mg.
or Less
Over 50 mg.
2
2
1
1
Predriisone
2.5-7.5 mg.
10-15 mg.
Above 15 mg.
21
61
6
1
27
3
Triamcinolone
4-8 mg.
10-14 mg.
Above 14 nig.
8
14
1
1
3
0
Cortieosteroid
Cortisone
Hydrocortisone
Developed
Ulcer
134
KAMMERER, FREIBERGER AND RII’ELIS
tomatology. Even when gastrointestinal distress did occur, it was found to
vary widely in its characteristics and seldom assumed the classic pattern
associated with noniatrogenic peptic ulcer.
The usual complications of peptic ulcer have been encountered in this
group. There were four patients who had gross bleeding manifested by
either hematemesis or melena, and 3 whose stools were persistently positive
for occnlt blood. One of these patients is of great interest in that she had
;I demonstrated gastric ulcer with hematemesis occurring on three different
occasions, each time while receiving a different corticosteroid-hydrocortisone,
prednisone and triamcinolone successively. Healing of the ulcer was demonstrated in each instance before another corticosteroid was administered; however, healing has not taken place four months after the last hemorrhage,
which occurred while taking triamcinolone, even though the use of corticosteroids had been promptly discontinued.
Five patients had acute abdominal distress and three required operation.
In two instances of ulcer (one gastric, one duodenal), acute perforation of
the ulcer occurred. In the third instance, a diverticulum of the colon had
ruptured. This patient was found to have a nonperforating gastric ulcer at
the time of the operation. In the two other patients there was subsidence of
pain and signs of an “acute abdomen” during continuation of conservative
therapy, and they were not subjected to surgery.
When ulcer was demonstrated treatment usually consisted of withdrawal
of the corticosteroid and the institution of an antacid and anticholinergic
dietary regimen, sometimes with, sometimes without, hospitalization. Healing of the ulcer has occurred in as short a period as 3 weeks but in some
instances has been delayed for many months. One patient’s ulcer has not
healed after discontinuance of drug for over one year, although there has
been gradual reduction in size of the ulcer. This patient has had negative
chymotrypsin lavage studies, persistently negative stools for occult blood and
remains in good health with no gastrointestinal symptoms.
The evidence is not convincing that an anti-ulcer regimen has substantially influenced healing of the ulcers in these patients. Indeed, several patients developed ulcer while on a modified ulcer regimen.
Fifteen patients with ulcer continued to receive corticosteroid treatment,
but the corticosteroid they had been using was replaced by triamcinolone
in relatively comparable doses. In this group, healing was demonstrated in
eight patients; the ulcer was unchanged or worse in five (in one of the
latter, severe hematemesis occurred) and in two patients the status of the
ulcer has not yet been determined. In four patients prednisone was continued after demonstration of ulcer and in three, healing of the ulcer has
occurred, while in one, the ulcer has remained relatively unchanged over
ii period of 18 months. Corticosteroid treatment has been resumed in two
patients who underwent a gastric resection and in one patient after repair
of a ruptured duodenal ulcer with no reactivation of ulcer over R period
of three, four, and two years respectively.
It is of great interest that the occurrence of gastric ulcer has been demon-
PEP n
(
:ULCXR AFTER COHTICOSTEROID THERAPY
135
strated in four patients who had achlorhydria after histamine stimulation.
Two patients demonstrated such achlorhydria on two different occasions.
The ulcer in three of these patients has healed completely and in one has
decreased over 50 per cent in three weeks’ time.
There have been three deaths in the entire group. Two of these occurred
following surgery (in one patient for ruptured gastric ulcer and in one for
a ruptured diverticulum of the colon). The third death was probably due
to amyloidosis (no autopsy) in a patient whose gastric ulcer had healecl
prior to death and who was continuing to take corticosteroid therapy at
the time of death.
Radiologic Data
From the roentgenographic standpoint, two features have been impressive: 1.) the preponderant occurrence oi gastric rather than duodenal ulcer
and 2 . ) some unusual aspects of these corticosteroid ulcers in comparison
to the usual spontaneous ulcer.
The location of the ulcers was most unusual: 30 were in the antrum of the
stomach, 5 in the duodenum and 1 in the pyloric canal. Figures 10 to 27
are illustrative of the typical findings.
While it cannot be said that the corticosteroid ulcer has any typical
roentgen appearance, there were some rather consistently unusual features.
Many ulcers were shallow and surrounded by a smooth zone of thickened
stomach wall, apparently caused by inflammatory edema. The ulcer was
flexible on palpation and frequently the peristaltic waves passed through the
base of the ulcer without interruption. In many cases the base of the ulcer
was so flexible that one had the impression that one was looking at and
palpating a diverticulum. One explanation for this finding may be that
there is a lack of fibrous scar tissue at the base of the ulcer crater. In these
cases there was a lack of spasni and irritability. The above findings were
present in approximately 50 per cent of the demonstrated ulcers. A few
of the ulcers showed considerable fibrosis and rigidity of the stomach wall
and in two cases the possibility of antral carcinoma was seriously considered,
though subsequent study proved the contrary.
Discussion
In a total of over 5,000 yearly radiologic examinations of the upper gastrointestinal tract at the New York Hospital, the ratio of gastric to duodenal
ulcer was 1:lO. (The ratio is less in women than men.) Further, only a few
of these gastric ulcers are located in the antrum. Of the 31 gastric ulcers
demonstrated in this series, eight projected at the greater curvature side
of the antrum. The occurrence of noniatrogenic benign greater curvature
ulcer is extremely rare in the experience of most radiologists.
One possible explanation for the wide discrepancy in reported incidence
of peptic ulcer in patients on corticosteroid treatment is the often encountered,
unusual radiologic features of these ulcers. Unless the radiologist is alert to
these variations, he may very well overlook some of them.
136
LAMhlEREH, FREIBERGER AND HIVELlS
FIG.10.-T. G., 44 year old female. 10/19/56, greater curvature u l e r visualized on x-ray.
This patient had been on corticosteroid therapy for 7 years. She was given prednisone (10
mg. daily from 1954 on.
FIG.11.-Same patient as in figure 10. On 2/15/57the ulcer was decreased in size. Prednisone was continued a t 7.5 mg. (1. day.
FIGS.12 AND 13.-X-ray demonstriitions of lesser curvature ulcer in R.R., a 56 year old
female (7/25/55). This patient had been taking prednisone ( 10 nig. daily) for 22 months.
FIG.14.-Saine patient as in figures 12 and 13. One year later the ulcer was still present,
hut smaller. Corticosteroid administration had been continued.
FIG. 15.-R.D., 56 year old femalr. Large grcatcr ciirvature ulcer seen on x-ray taken
3/11/57. This patient had been on corticosteroid therapy for 6 years; in 1955 she begau
taking prednisone ( 10 my. (1. day ) . On 3.i 11,‘57 the drug wils changed to triamcinolone. On
5/1/57 she was diagnosed as having an “acute” abdomen ( with possible perforation).
FIG. 16-Very large, probably penetrating, greater curvature gastric ulcer in an 11 year
old girl. The patient, not included in oiir scries, hnd bren on a high dosage of cortisone for
juvenile rheumatoid arthritis.
SUMMARY
From information gained in the study of gastric secretion in volunteers
hefore and after the administration of viuious corticosteroids, it \vould appear improbable that any of the factors studied were sufficiently altered
rI.:pTIcULCER AFTER co~ricosmRomTHERAPY
137
FIG. 17.-L.C., a 70 year old female, who
had been taking prednisone (12.5 mg. daily)
for 1% years at the time her very flexible and
quite shallow ulcer was seen on x-ray.
FIG.18.-Same patient as in figure 17. Triaincinolone had been substituted for prednisonc.
The ulcer persisted to September, 1957.
FIGS.19 AND 20.-S.K., a 58 year old female, on prednisone for t w o years (15 ing.
q. day). The x-rays are illustrative of rapid change in size of the ulcer over a short period
of time.
to be of significance in the genesis of peptic ulcer. This would seem to be
particularly true of the role of pepsin and free HCl. Certainly the occurrence of ulcer in 4 subjects with histamine achlorhydria would lend support
to this view. Furthermore, if the factors of increased free HCl and pepsin
were chiefly responsible, one would expect a larger incidence of duodenal
rather than gastric ulceration.
These studies indicate that there is no question that the incidence of
peptic ulcer is far greater in patients with rheumatoid arthritis under treatment with corticosteroids than that in patients with rheumatoid arthritis not
so treated, or in the population at large. One of the most comprehensive clinical surveys of the incidence of ulcer in the U. S.laindicates that those afflicted
in any one annual survey will vary from 1 to 3 per cent of the population
over 20 years of age. However, it will be realized that these figures of
over-all incidence actually mean little in comparison to the high incidence
in the group reported here occurring over a relatively short period of time.
In a well documented study from England20 it was calculated that the
expectation rate of developing a new peptic ulcer in men was 0.327 per cent
per year between the ages of 35 and 64. Using this anticipated rate and the
number of man-years of treatment it is found that in the group of patients
reported here the risk of developing an ulcer while on corticosteroid therapy
is increased in man by a ratio of 15 to 1 and in woman by a ratio of 43 to 1.
(The latter is calculated on the basis of an overall incidence in women onehalf that of men.)
Two factors stand out in this study as having a bearing upon the develop-
KAMMERER, EIREIBERGER AND RIVELIS
FIG.21.-R.S., a 66 year old female, on
corticosteroids for 7 years. This patient had
been taking prednisone (15 mg. q. day) for
21 months when her ulcer was demonstrated
roentgenographically.
FIG. 22.-Same patient as in figure 21. R.S.
had changed to triamcinolone with persistence
of her ulcer but decrease in its size.
FIG.23.-M. B., a 56 year old female, had
been taking prednisone (15 mg. q. day) when
her ulcer was first visualized.
FIGS.24 ANII 25.-Same patient as in figure
23. After one year the nlcer was still present.
Triamcinolone had been substituted for prednisone. Histamine achlorhydria was present.
FIG.26.-N.S., a 56 year old female, had been taking prednisone for 22 months (15 mg.
q. day) when her ulcer was visualized.
FIG.27.-Sanie patient a s in figure 26. Notc persistence of the ulcer. The corticosteroid
had been changed to triaincinolone ( 8 mg. q. day ) ,
ment of dcer, i.e., the dosage of corticosteroid and the severity of the arthritis.
The risk of developing ulcer would seem to be sharply increased in those
patients with severe disease receiving large daily doses of corticosteroids.
These data may be statistically misleading in that patients with severe disease are more likely to be receiving larger doses of drug, so that it is difficult to be certain a s to which of the two factors is more important in
increasing the risk of ulcer. In our experimental study, the dosage of corticosteroids did not appear to have any significant bearing on the various factors
of gastric secretion. This might point to severity of disease a s being more
important in the genesis of ulcer. It would appear wise, however, to avoid
the temptation to use larger closes of corticosteroids in those patients with
severe disease; if larger doses are used ;is a calculated risk, carefnl observation of the patient for any untoward gastrointestinal symptoms or signs
is imperative.
Unfortrmately, there is no reliable method of detecting ulcer except by
PEPTIC ULCER AFTER CORTICOSTEROID THERAPY
139
roentgenographic examination, Frequently, these ulcers are completely
“silent,” often up to the time of perforation or hemorrhage. Stool examination for occult blood is also unreliable, as we have seen large ulceration
with negative stool examinations. Thus, it becomes a question of how often
x-ray examination should be carried out. Certainly it should be done if
questioning reveals any change in digestive habits regardless of how bizarre
or atypical these may be. In the absence of symptoms, it would seem wise
to do an upper gastrointestinal roentgenographic series every 12 to 18
months on all patients on prolonged corticosteroid treatment, although this
is an arbitrary and far from satisfactory solution of the problem.
When ulcer occurs, the decision is often difficult as to what course to
pursue in respect to continuation of corticosteroids. At times the rheumatoid
arthritis is of such severity that withdrawal of the drug will result in transforming a relatively self-sustaining individual into a bed-ridden or wheelchair cripple. On the other hand, the possibility of catastrophic complications
such as hemorrhage or perforation looms large and the death rate following
these complications in this group is alarming. We have continued the use
of the corticosteroid as a calculated risk in some patients in whom ulcer has
been demonstrated, but only after the patient is thoroughly acquainted with
the risk and enters into the decision. The use of a bland diet with frequent
feedings is, perhaps, the most important therapeutic measure in these patients from the standpoint of avoiding irritation of the gastric mucosa. It
appears doubtful whether the addition of antacids or anticholinergic agents
adds much protection. Also, we feel there is no good evidence that the use
of these latter agents acts in a prophylactic way in protection against the
development of ulcer, and they may simply lull the physician into a false
sense of security. Upon withdrawal of corticosteroids, the rate of healing
does not seem to be affected by the intensity of the anti-ulcer regimen
followed.
The hope that the newer corticosteroids, triamcinolone and delta 1,6 methyl
hydrocortisone,* might be less ulcerogenic has not been born out by our
experience to date.
SUMMARY
1. In fourteen normal volunteers given hydrocortisone, prednisone and
prednisolone in varying dosage and sequence for two weeks, analysis of
various factors of gastric secretion does not indicate changes in secretion of
free HC1 or pepsin that would appear to be of significance in the genesis
of peptic ulcer.
2. Radiologic examination of the upper gastrointestinal tract in 117 rheumatoid patients treated with corticosteroids has revealed the occurrence of
‘Since these data were collected, one patient receiving delta l,6 methyl hydrocortisone
( Medrol-Upjohn) has developed a large gastric ulcer. Gastrointestinal x-ray prior to
administering the drug was negative. Ten weeks later, a gastrointestinal series demonstrated a greater curvature ulcer.
140
KAMMERER, FREIBERGER AND RIVELIS
peptic ulcer in 36 (31 per cent). In a group of rheumatoid patients not
treated with corticosteroids and in nonrheumatoid controls, the incidence of
ulcer was 9 per cent and 5 per cent respectively.
3. The only factors that appear to be of significance in patients who
develop ulcer while on corticosteroid therapy are the daily dosage of steroid
and the severity of the arthritis, with more ulcers occurring in those patients
receiving larger amounts of steroid and in the group with severe arthritis.
4. The demonstration of ulcer in the antrum of the stomach and a large
number on the greater curvature of the stomach are the most important features in the roentgenograms.
5. We speculate that in certain individuals, corticosteroids may have an
effect upon local tissue resistance, in this case the gastric mucosa. This would
appear to be a more likely explanation of the high incidence of ulcer than any
change in gastric secretion induced by these agents.
SUMMARY
8. Forbes, J.: Inadvisabiliity of giving
1. Kirsner, J. B., Kassriel, R. S. and Palmer, W. L.: Peptic ulcer: Review of
ACTH to patients with gastric ulcer;
recent literature pertaining to etiolLancet 2:555457, 1952.
9. Boland, E. W.:Prednisone and predniogy, pathogenesis and certain clinical
solone therapy in rheumatoid araspects. Advances Int. Med. 8:41,
thritis. J.A.M.A. 160:613-621, 1956.
2 . Gastroenterology Research Group: Is
there a relationship between peptic 10. Brick, I. B.: Drugs for arthritis. J.A.M.A.
160~13,1956.
ulcer and the adrenal glands? Am.
11. Meltzer, L. E., Bockman, A. D., DunsJ. Dig. Dis. 2:3, 1957.
3. Spiro, H. M., Reifenstein, R. W. and
more, A. and Cohen, A.: The incidence of peptic ulcer formation among
Gray, S . J.: The effect of adrenopatients on long-term prednisone thercorticotrophic hormone upon uropepapy. Read at Ninth International Consin excretion. J. Lab. & Clin. Med.
gress on Rheumatic Diseases, June
35:899-910, 1950.
23-28, 1957, Toronto, Canada.
4. Gray, S . J., Benson, J. A., Jr., Reifenstein, R. W. and Spiro, H. M.: 12. Henderson, E.: New developments in
steroid therapy of rheumatic diseases.
Chronic stress and peptic ulcer. I.
J. Med. SOC. New Jersey. 52:609,
Effect of corticotropin (ACTH) and
1955.
cortisone on gastric secretion. J.A.M.A.
13. Experience with Cortisone in the man147:1529-1537, 1951.
agement of rheumatoid arthritis. Re5. -, Ramsey, C. and Reifenstein, R. W.:
port of a cooperative study conducted
Hormonal influences upon the stomby a committee of the American Rheuach; Am. J. Gastroenterol. ,24244matism Association. Ann. Rheomat.
252, 1955.
Dis. 14:4, 1955.
6. Hirschowitz, B. I., Streeten, D. H. P.,
Pollard, H. M. and Boldt, H.A., Jr.: 14. Howell, D. S. and Ragan, C.: The
course of rheumatoid arthritis during
Role of gastric secretions in activafour years of induced hyperadrenaltion of peptic ulcers by corticotropin.
ism. ( I H A ) . Medicine 35.43, 1956.
J.A.M.A. 157~27,1955.
7. Sandweiss, 1). J., Scheinberg, S. R., 15. Kern, F. Jr., Clark, M. and Lubens, J.:
Peptic ulceration occurring during
Saltzstein, H. C.: Effects of adrenotherapy for rheumaotid arthritis. Gascorticotrophic hormone ( ACTH) on
troenterology 33:1, July 1957.
peptic ulcer. 11. Experimmtal studies
on Mann-Williamson dogs. Gastroen- 16. Black, R. L., Yielding, K. L. and Bunim,
J. J.: Observations on new synthetic
terology 27:617-624, 1954.
PEPTIC ULCER AFTER CORTICOSTEROID THERAPY
141
anti-rheumatic steroids and critical
teria in rheumatoid arthritis. J.A.M.A.
140:659, 1949.
evaluation of prednisone therapy in
rheumatoid arthritis. J. Chron. Dis. 5: 19. Ivy, A, c., Grossman, M. I. and Bath1957.
rach, W. H.: Peptic ulcer. Philadel17. West, P. M., Ellis, F. W. and Scott,
phia, Blakiston, 1950, p. 605.
B. L.: A simplified method for determining h e excretion rate of wopep- 20. Doll, R. and Jones, F. A.: Occupational
sin. J. Lab. Clin. Med. 39:159, 1952.
factors in the etiology of gastric and
IS. Steinbrocker, O., Traeger, C. H. and
duodenal ulcers. Med. Res. Council
Special Report Series, No. 276, 1951.
Batterman, R. C.: Therapeutic cri-
William H . Kammerer, M.D., Attending Physician, Hospital
For Special Surgery; Assistant Attending Physician, New
k'ork Hospital; Assistant Professor of Clinical Medicine,
Cornell Medical School, New York, N.Y.
Robert H . Freiberger, M .D., Director, Department of Roentgenology, Hospital For Special Surgery; Assistant Professor
of Clinical Radiology, Cornell Medical School, New York,
N.Y.
Abraham L. Riuelis, M.D., Research Fellow in Rheumutic
Disease, Hospital For Special Surgery, New York, N.Y.
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