The prevalence of duodenal lesions in patients with rheumatic diseases on chronic aspirin therapy

0016-5107/80/2601-0005$02.00/0 GASTROINTESTINAL ENDOSCOPY Copyright © 1980 by the American Society for Gastrointestinal Endoscopy

The prevalence of duodenal lesions in patients with rheumatic diseases on chronic aspirin therapy O. O. Lockard, Jr., MD K. J. Ivey, MD J. H. Butt, MD G. R. Silvoso, MD C. Sisk, MD S. Holt, MD Columbia, Missouri

Peroral endoscopy was performed in 56 patients with rheumatic disease who had been taking 8 or more aspirin tablets daily for more than 3 months yet who had no major gastrointestinal symptoms or history of peptic ulcer disease. Duodenal mucosal lesions were observed in 16 patients; 15 (27%) had erythema, 7 (13%) had erosions, and 2 (4%) had ulcers. The prevalence of duodenal lesions was the same in patients taking regular, buffered, or enteric-coated aspirin preparations. Patients with duodenal lesions were more likely to have associated gastric lesions. Aspirin has been epidemiologically implicated in the pathogenesis of peptic ulcer disease. 1 •2 Most studies have confirmed an association between aspirin ingestion and gastric ulcers,3-5 but the association between aspirin intake and duodenal ulceration has been controversiaI. 1 ,6-8 The effect of aspirin on the upper gastrointestinal tract in patients taking it chronically for rheumatic disease has also been controversial. 9 - 12 Prospective endoscopic studies of the upper gastrointestinal tract in patients with rheumatic disease are few. We have shown a definite association between aspirin and gastric ulcer in these patients. 13 ,14 The purpose of this study was to assess endoscopically the prevalence of duodenal lesions in patients who took aspirin over long periods for rheumatic diseases yet who had no major gastrointestinal symptoms or history of peptic ulcer disease,

METHODS All patients attending rheumatology clinics at the University of Missouri Medical Center and the Harry S, Truman Memorial Veterans Hospital, Columbia, Missouri, during a 6-month period were screened for chronic aspirin therapy. A detailed log of357 consecutive patients was kept; diagnosis, medications, and eligibility for study or reason for exclusion were recorded. Chronic aspirin therapy was defined as the ingestion of 8 or more 325 mg aspirin tablets daily for more than 3 months. Those with a history of peptic ulcer disease or major gastrointestinal

symptoms suggestive of active peptic ulcer disease were excluded, A group of 56 patients who took aspirin as their only anti-inflammatory medication was identified. Their medication included regular aspirin, buffered aspirin, and enteric-coated aspirin. The diagnoses in these 56 patients were rheumatoid arthritis in 35, osteoarthritis in 9, ankylosing spondylitis in 4, and psoriatic arthritis, systemic lupus erythematosis, scleroderma, and calcific tendinitis in 2 each. A group of 14 middle-aged control subjects was also identified. These subjects were taking no aspirin or antiinflammatory medications, had no major gastrointestinal symptoms or history of peptic ulcer disease, and had no rheumatic diseases. Endoscopy was performed by either of 2 fellows in gastroenterology and observed by either of 2 senior gastroenterologists. Olympus GIF-P2 panendoscopes were used for most of the examinations; an Olympus GIF-D3 panendoscope was employed in the rest. Care was taken to inspect each portion of the stomach and duodenum sequentially as the endoscope was advanced so as to exclude any artifacts of instrument trauma. Photographs of the lesions were obtained. Endoscopically visualized lesions were classified as erythema, erosion, or ulcer. Erythema was defined as a reddening of the mucosa or an area of mucosal petechiae. An

From the Department of Medicine, Divisions of Gastroenterology and Rheumatology, The Harry S. Truman Memorial Veterans Hospital and the University of Missouri, Columbia, Missouri. This work was supported in part by the Medical Research Service of the Veterans Administration and the Clinical Research Center, University of Missouri, Columbia, NIH Grant RROO287-12. Reprint requests: Kevin J. Ivey, MD, Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri 65212. VOLUME 26, NO. 1, 1980

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erosion was defined as a flat, 2-dimensional lesion without depth. An ulcer was defined as a 3-dimensional, "punched out" lesion showing depth. The data were analyzed by a biomedical statistician utilizing a test of equality of proportions of 2 independent populations. 15

mg/dl with buffered aspirin, and 12.8 mg/dl with entericcoated aspirin. As patients were fasted before endoscopy, the average time from the last aspirin dose until the serum salicylate levels were drawn was slightly in excess of 12 hours. Using previous data on the serum half-life of salicylates in patients with rheumatic arthritis,16 the usual serum salicylate levels in these groups may be extrapolated to have been between 20 and 25 mg/dl. There was no statistically significant difference among the aspirin preparations with respect to frequency of duodenal erythema, erosions, or ulceration. The lack of difference in the occurrence rates of duodenal lesions among the aspirin preparations is in sharp contrast to the findings in the stomachs of these patients ( Table III). The frequency of gastric ulcer was higher in patients taking either regular or buffered aspirin than in those taking enteric-coated aspirin. When patients taking regular or buffered aspirin are combined, the relative frequency of gastric ulcer is significantly higher than in patients taking enteric-coated aspirin. In contrast, the frequency of duodenal lesions was similar for all 3 preparations. Both regular and buffered aspirin produced significantly more gastric erosions and ulcers than they produced duodenal erosions and ulcers. On the other hand, there was no significant difference in the occurrence rates of erosions and ulcers in the stomach as compared to the duodenum in those patients taking enteric-coated aspirin. When the 16 patients with duodenal lesions are compared to the 34 without duodenal lesions, they are found to have a higher frequency of gastric lesions. Gastric erythema was noted in 88% of patients with duodenal lesions

RESULTS The average age of the control group was 41 years, with a range of 35 to 51 years. The male to female ratio in the control group was 1:1. The average age of the patients with rheumatic diseases was 53 years, with a range of 30 to 79 years. The male to female ratio was 3:1 among the patients with rheumatic diseases. The average duration of endoscopy in control patients was 20.1 ± 2.2 (SEM) minutes compared to 17.7 ± 1.1 (SEM) minutes in the patients with rheumatic disease, a difference which is not statistically significant. To assess variability between endoscopists, 29 endoscopic examinations were performed without discussion between the 2 observers during the procedure. Findings were subsequently compared. There was no qualitative disagreement in classifying lesions as erythema, erosion, or ulcer. Sixteen of 56 patients taking aspirin for rheumatic disease were found to have duodenal lesions. Some subjects had more than one type of lesion. The prevalence of the several lesions is shown in Table I. The data were also analyzed according to the type of aspirin used by the patients ( Table II). Analysis of the average daily aspirin dosage revealed no statistically significant difference among the groups. Patients on regular aspirin took an average of 12 tablets per day, patients on buffered aspirin took an average of 13 tablets per day, and patients on enteric-coated aspirin took an average of 12 tablets per day. Analysis of serum salicylate levels drawn the morning of endoscopy failed to reveal any statistically significant differences among the groups; the mean serum salicylate level was 10.6 mg/dl in patients taking regular aspirin, 9.5

Table III.

Comparison of frequencies of gastric and duodenill lesions according to type of aspirin ingested. regular aspirin

(n Gastric erosion Gastric ulcer Duodenal erosion Duodenal ulcer

Table I.

Frequencies of duodenal lesions in asymptomatic patients taking aspirin for rheumatic diseases compared with normal control subjects.

Erythema Erosion Ulcer

patients taking aspirin (n = 56)

control subjects

27% 13%* 4%

7% 0% 0%

(n = 14)

= 20)

buffered aspirin

(n

= 14)

enteric-coated aspirin

(n

= 22)

35%*

71%t

18%

20%*

29%**

5%

10%

14%

14%

0%

7%

5%

* P < 0.05 for gastric lesions compared to duodenal lesions for regular aspirin t P < 0.05 for gastric erosion compared to duodenal erosions for buffered aspirin •• P - 0.066 for gastric ulcer compared to duodenal ulcer for buffered aspirin

• P < 0.05 compared to normal controls

Table II.

Frequencies of duodenal lesions according to type of aspirin ingested.·

Erythema Erosion Ulcer

regular aspirin (n = 20)

buffered aspirin (n = 14)

enteric-coated aspirin

25% 10% 0%

21% 14% 7%

32% 14%t 5%

(n

= 22)

controls

(n -14)

7% 0% 0%

• None of the differences among preparations compared to each other approach statistical significance. to control

t P < 0.05 compared 6

GASTROINTESTINAL ENDOSCOPY

compared with 70% in those without such lesions (P = 0.054); the frequency of gastric erosions was 63% in those with duodenal lesions compared with 30% in those without (P < 0.05); the frequency of gastric ulcers was 31% in patients with duodenal lesions compared with only 9% in those without duodenal lesions (P < 0.05).

DISCUSSION Our study indicates that patients with rheumatic disease on chronic aspirin therapy have a high prevalence of duodenal lesions. Even though our patients were without major gastrointestinal symptoms, 13% were found to have duodenal erosions and 4% were found to have duodenal ulcers. The type of aspirin preparation, whether regular, buffered, or enteric-coated, had no effect on the frequency of duodenal lesions, the occurrence rates of duodenal lesions with the different aspirin preparations being statistically indistinguishable. In contrast is the finding that enteric-coated aspirin produced fewer gastric lesions than regular or buffered aspirin. 13 ,14 Enteric-coated aspirin, therefore, may be preferable because of this characteristic. Also, the difference in endoscopic findings agrees with a previous report describing less fecal occult blood loss in patients with rheumatoid arthritis given enteric-coated aspirin as compared to regular aspirin. 17 Insofar as the average daily dose and the serum salicylate levels were comparable among the 3 preparations, the difference in the distribution of lesions suggests that the direct effects of aspirin on the gastric mucosa are important. The finding that enteric-coated aspirin produced fewer ulcers and erosions in the stomach than regular and buffered aspirin but produced equivalent lesions in the duodenum would suggest that the site of injury may "shift" more distally with delayed release of the aspirin. 1B Furthermore, the occurrence of gastric erosions or ulcer with enteric-coated aspirin suggests either premature breakdown of tablets in the stomach or gastric reflux of aspirin. Both duodenal ulcer patients and volunteers are reported to display such reflux. 19•2o A major problem in studies such as this is the selection of ideal controls. Ideal controls for this study would be patients with identical rheumatic diseases, with the identical degree of arthritic disease activity, but on no therapy. This is impossible. All our patients had severe disease, and none could be deprived of drugs, even for short periods of time. In unpublished prospective endoscopic studies in over 50 normal volunteers under the age of 35 years, we have yet to find a single duodenal erosion. Nor did we find erosions or ulcers in any of the 14 middle-aged volunteers reported here. Nevertheless, our control group was not strictly age- and sex-matched. It is possible that the greater age and maleness in our patients predisposed to more duodenal ulcer disease. This is unlikely to be the only factor involved. For example, in a prospective endoscopic study, we found that 55% of normal healthy young male and female volunteers, 21 to 30 years old, given regular aspirin, 8 tablets daily for 2 weeks, developed multiple duodenal erosions/ 1 similar to those seen in the rheumatic disease patients. Our observations indicate that an appreciable number of patients on chronic aspirin therapy for rheumatic disease

VOLUME 26, NO. 1, 1980

have duodenal lesions, even though they lack symptoms usually associated with peptic ulcer disease. Lack of symptoms in the presence of peptic ulcer disease has been observed by other investigators. 22 This suggests that occurrence rates of duodenal disease, when the diagnosis is made in such patients on the basis of symptoms, may seriously underestimate the frequency of these lesions.

ACKNOWLEDGMENT The authors acknowledge the assistance of Drs. W. N. Baskin, W. Tatum, and P. A. MacKercher in the early parts of this study.

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