CAMPYLOBACTER PYLORI ASSOCIATED GASTRITIS IN PATIENTS WITH RHEUMATOID ARTHRITIS TAKING NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

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1 British Journal of Rheumatology 1988;27: CAMPYLOBACTER PYLORI ASSOCIATED GASTRITIS IN PATIENTS WITH RHEUMATOID ARTHRITIS TAKING NONSTEROIDAL ANTI-INFLAMMATORY DRUGS BY R. UPADHYAY 1, A. HOWATSON 2, A. McKINLAY 1, B. J. Z. DANESH 1, R. D. STURROCK 3 AND R. I. RUSSELL 1 x Gastroenterology Unit, 2 Department of Pathology, and ^Centre for Rheumatic Diseases, Royal Infirmary, Glasgow G31 2ER, UK SUMMARY Fifty-two patients with rheumatoid arthritis taking nonsteroidal anti-inflammatory drugs were studied in order to assess the carriage rate of Campylobacterpylori () with reference to dyspeptic symptoms, endoscopic appearance and antral histology. All patients were interviewed using a standard gastrointestinal symptom scoring questionnaire and underwent endoscopy at which two antral biopsies were obtained. Sections were examined for the presence and severity of gastritis and of. Forty-four of 52 patients (85%) had histological evidence of gastritis. Twenty-six of 44 (59%) patients with gastritis were positive for. Twenty-six of 28 patients with 'active' (polymorph infiltration) chronic gastritis were positive for (p < 0.002). Sixteen of 26 bacteria-positive patients had gastrointestinal symptoms compared with eight of 26 bacteria-negative patients (p < 0.05) and this may have therapeutic implications. There was no correlation between the presence of organisms and the appearances at endoscopy. KEY WORDS: 'Active' chronic gastritis, Prevalence, Dyspepsia, Endoscopy. UPPER gastrointestinal disease such as gastritis and peptic ulceration is a common finding in patients with rheumatoid arthritis [1]. Various factors including the use of nonsteroidal antiinflammatory drugs (NSAIDs) have been incriminated as aetiological factors. Recent interest in Campylobacter pylori () and its association with active chronic gastritis and peptic ulceration prompted us to examine its possible role in patients with rheumatoid arthritis (RA) taking NSAIDs. Our aim was to determine the carriage rate of in patients with RA and to examine the relationship of this feature to gastrointestinal symptoms, endoscopic appearance and histological findings. SUBJECTS AND METHODS Fifty-two patients (18 male, 34 female; age range years; mean age 52.8) with definite or classical RA were studied. These included 38 subjects randomly selected from the rheumatology out-patient clinic irrespective of dyspeptic symptoms and 14 consecutive patients referred for endoscopy over the same period. The reasons for endoscopic referral were dyspepsia in six and iron deficiency anaemia in eight. Informed consent was obtained and all the patients were interviewed prior to endoscopy Submitted 8 May; revised version accepted 28 August Address correspondence to Dr. R. Upadhyay. using a standardized gastrointestinal symptom scoring questionnaire (Table I). Patients with a gastrointestinal symptom score of more than 5 were defined as symptomatic. This was based on two factors: (i) A score of 3 was the lowest positive score in the chart (Table I), implying occasional, mild and transient symptoms such as are widely prevalent in the healthy population, (ii) The median score for the entire study group was 5, more than which reflected a symptom of moderate severity, duration or frequency or alternatively, more than one symptom. Patients underwent an upper gastrointestinal endoscopy which was performed by one operator (R.U.). The endoscopic appearance was noted and two biopsies of gastric antrum were obtained. All specimens were taken from the greater curve within 5 cm of the pylorus. Sec- TABLEI GASTROINTESTINAL SYMPTOM SCORE CHART: NAUSEA, VOMITING, ABDOMINAL PAIN AND HEARTBURN WERE EACH SCORED ACCORDING TO THE CHARACTERISTICS CHARTED BELOW Timing Short period <2 h Frequency Occasional Some days Severity Mild Moderate Score >2h Most days Severe "Every day Very severe 113

2 114 BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXVII NO. 2 t # FiciHRE Endoscopic biopsy of antral mucosa showing large numbers of Campylobacter pylori (arrows). Ncutrophil polymorphs arc present within the epithelium. (Crcsyl violet: X2580) tions were stained with cresyl violet and haematoxylin and eosin stain and examined by a single histopathologist (A. H.) in a blind fashion. Sections displaying bacteria with a spiral morphology confined to the gastric mucous layer were considered positive for (Fig.). The degree and severity of the inflammatory response was also assessed (Table II). RESULTS Forty-four of 52 patients (85%) had histological evidence of gastritis. Twenty-six of 44 patients (59%) with gastritis were positive for C. pylori and all these had 'active' chronic gastritis, activity being indicated by polymorph infiltration of the mucosa. Only two patients with 'active' chronic gastritis had no demonstrable C. pylori (Table III). The prevalence of in different age groups is shown in Table IV and 62% of positive patients had a gastrointestinal symptom score of 5 or more compared with 31% of bacteria-negative patients (p < 0.05) (Table V). There was no correlation between the endoscopic appearance and presence of (Table VI). No correlation was found between the presence of and the ingestion of any particular NSAID. TABLE II HISTOLOOICAL ASSESSMENT OF INFLAMMATION (i) Chronic inflammatory cells (ii) Acute inflammatory ecus (iii) Ulceration I Few superficial plasma cells II $ III Plasma cells extending throughout the full thickness of the lamina prop rid I Few/occasional polymorphs in the lamina propria n t Ill Extensive polymorphs in the lamina propria with infiltration of glands/crypts Present or absent TABLE III Campylobacter pylori IN RELATION TO GASTRIC ANTRAL HISTOLOGY absent present No. of patients Normal 'Active' Chronic chronic gastritis gastritis p < by two-tailed Fisher's exact probability test. DISCUSSION The results show that histological evidence of gastritis is a common finding in patients with RA

3 UPADHYAY ETAL.: CAMPYLOBACTER PYLORI ASSOCIATED GASTRITIS 115 TABLE IV Campylobacter pylori STATUS IN RELATION TO DIFFERENT AGE GROUPS Age groups (years) ^ No. of patients positive negative Total no. of patients TABLE V Campylobacter pylori STATUS IN RELATION TO GASTROINTESTINAL SYMPTOMS Symptom score >5 Symptom score ^5 Total no. of patients present absent Total 16(62%)* 8(31%) (38%) 18 (69%) * X 2 = 4.95; p < 0.05 (chi squared test). TABLE VI Campylobacter pylori STATUS IN RELATION TO ENDOSCOPIC APPEARANCE Normal Gastritis/ duodenitis Erosion Ulcer Total no. of patients present absent taking NSAID. The patients could be divided into those positive for and who invariably had 'active' (polymorph infiltration) chronic gastritis and those who were negative for C. pylori and in whom polymorph infiltration was rarely seen. The association of with 'active' chronic gastritis and noniatrogenic peptic ulcer has been reported by many observers [2-8]. However, there are few previous data relating to NSAID users and our study suggests that the presence of is a commonfindingin RA patients taking NSAID. The study group did represent patients attending hospital and the results may not be applicable to RA subjects in the community. The prevalence rate of 50% may be no more than expected in the general population and recent evidence has suggested that there is an age-related increase in C, pylori infection in the normal population reaching about 50% in those over 50 years of age [9]. We stratified our results according to different age groups (Table IV) in order to identify any difference from the normal population. It is of interest that a higher proportion (13/21) of the under-50 age group were positive. Conversely, fewer of those over 50 years of age were bacteria positive (13/31). However, the numbers in each individual age range were too small for identification of significant differences. It would appear that the overall prevalence of amongst patients with RA does not differ from that of the general population. Patients with RA have a high incidence of hypochlorhydria [10] which in turn may lead to overgrowth by various organisms. It may therefore be arguable whether histological identification alone is adequate to confirm in RA. During the course of our study, culture for became established in our Bacteriology Department and an excellent correlation could be demonstrated between histological appearances and culture of the organism. Ideally, the present study should have included a control group comprising RA patients who were not taking NSAID. This would have enabled us to assess whether the presence of was related to the NSAID therapy. Inclusion of such a control group, however, is practically impossible because patients attending hospital are invariably receiving NSAID. The clinical significance of.c- pylori remains unclear. Langenberg etal. [11] found that six of 25 asymptomatic medical students had chronic gastritis in association with. In our study, upper gastrointestinal symptoms were significantly associated with. Previously there was sparse evidence that gastritis causes symptoms [12], but upper gastrointestinal symptoms have recently been correlated with gastroduodenitis, as evidenced by the presence of mucosal neutrophils [13, 14]. Our own findings would be in broad agreement with this. Our results may have important therapeutic implications regarding the treatment of dyspepsia in patients taking NSAID. Treatment of nonulcer dyspepsia by standard agents such as H2 antagonists and antacids is unsatisfactory [15]. If the organism has a causal role in the symptoms of such patients then bismuth preparations or antibiotics, either alone or in combination, may prove more effective. Previous studies have

4 116 BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXVII NO. 2 shown that treatment with these agents can lead to eradication of the organism, resolution of gastritis and relief of symptoms [16, 17]. Whether this will prove to be the case in patients taking NSAID remains to be seen. REFERENCES 1. Sun DC, Roth SH, Mitchell CS. Upper gastrointestinal disease in rheumatoid arthritis. Am J Dig Dis 1974;19: Warren JR. Unidentified curved bacilli on gas- trie epithelium in active chronic gastritis. Lancet 1983;i: Marshall B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1983 ;i: Lambert JR, Hansky J, Eaves ER, Korman MG, Pinkard K, Medley G. Campylobacter like organisms (CLO) in human stomach. Gastroenterology 1985;88: Steer HW. The gastro-duodenal epithelium in peptic ulceration. J Pathol 1985;146: McNulty CAM, Watson DM. Spiral bacteria of the gastric antrum. Lancet 1984;i: Rollason TP, Stone J, Rhodes JM. Spiral organisms in endoscopic biopsies of human stomach. / Clin Pathol 1984;37: Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984;i: Graham DY, Klein PD, Opekun AR, el al. Epidemiology of Campylobacter pyloridis infection. Gastroenterology 1987;92: De Whitee TJ, Geerdink PJ, Lamers CB, Boerbooms AM, Van Der Korst JK. Hypochlorhydria and hypergastrinaemia in rheumatoid arthritis. Ann Rheum Dis 1979;38: Langenberg ML, Tytgat GNJ, Schipper MEI, Rietra PJGM, Zanen HC. Campylobacterlike organisms in the stomach of patients and healthy individuals. Lancet 1984;i: Talley NJ. The pathogenesis of non-ulcer dyspepsia. MedJAust 1985;143: Greenlaw R, Sheahan DG, DeLuca V, Miller D, Myersen D, Myersen P. Gastroduodenitis: a broader concept of peptic ulcer disease. Dig Dis Sci 1980;25: Toukan AU,,Kamal MF, Amr SS, Arnaout MA, Abu-Romneh AS. Gastroduodenal inflammation in patients with non-ulcer dyspepsia. Dig Dis Sci 1985;30: Nyren O, Adami HO, Bates S, et al. Absence of therapeutic benefit from antacids or cimetidine in non-ulcer dyspepsia. N EnglJ Med 1986;314: Langenberg ML, Rauws EAJ, Schipper MEI. The pathogenic role of Campylobacter pyloridis studied by attempts to eliminate these organisms. Campylobacter III: Proceedings of the Third International Workshop on Campylobacter Infections. London: Public Health Laboratory Service, 1985; McNulty CAM, Gearty JC, Crump B, et al. Campylobacter pyloridis and associated gastritis: investigator blind, placebo controlled trial of bismuth salicylate and erythromycin ethylsuccinate. Br Med J 1986;293:645-9.

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