Peptic ulcer in rheumatoid patients on corticosteroid therapy. A clinical experimental and radiologic studyкод для вставкиСкачать
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.