Helicobacter pylori infection in rheumatoid arthritis: effect of drugs on prevalence and correlation with gastroduodenal lesions
N. Ishikawa,
T. Fuchigami1,
T. Matsumoto,
H. Kobayashi1,
Y. Sakai1,
H. Tabata,
N. Takubo2,
S. Yamamoto2,
M. Nakanishi3,
K. Tomioka4 and
M. Fujishima
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Divisions of
1 Gastroenterology,
3 Pathology and
4 Medical Laboratory and
2 Centre for Rheumatic Diseases, Matsuyama Red Cross Hospital, Ehime, Japan
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Abstract
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Objective. The aim of this study was to investigate the impact of Helicobacter pylori infection on clinical features in patients with rheumatoid arthritis (RA) under medication with non-steroidal anti-inflammatory drugs.
Methods. One hundred and eighty-four patients with RA were tested for the presence of H. pylori infection. Clinical features and gastroduodenal lesions were compared between H. pylori-positive and -negative patients.
Results. One hundred and thirteen patients were positive and 71 patients were negative for H. pylori. The age, severity of RA, prevalence of gastrointestinal symptoms and gastroduodenal lesions and the class of gastroprotective drugs were not different between the two groups. Reflux oesophagitis was less frequent and sulphasalazine was less frequently administered in the H. pylori-positive group.
Conclusions. The severity of RA, prevalence of gastroduodenal lesions other than reflux oesophagitis and the application of gastroprotective drugs do not seem to depend upon H. pylori infection in RA patients. Sulphasalazine may be protective against H. pylori infection.
KEY WORDS: Rheumatoid arthritis, Helicobacter pylori, Prevalence, Gastroduodenal lesion, Non-steroidal anti-inflammatory drugs.
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Introduction
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Since the identification of Helicobacter pylori in the stomach [1], this microorganism has been regarded as a causative factor in the formation of gastroduodenal mucosal lesions [2], and the eradication of H. pylori has been found to be effective for the treatment of such lesions [3]. As for the pathogenesis of gastroduodenal mucosal lesions, the role of non-steroidal anti-inflammatory drugs (NSAIDs) needs to be considered [4, 5].
The role of H. pylori in the pathogenesis of NSAID-induced gastrointestinal lesions remains controversial [611]. Although animal experiments and clinical investigations have suggested a synergistic effect of H. pylori on NSAID-induced gastropathy [6, 7], other investigations have demonstrated that there is no correlation between NSAIDs and H. pylori in the pathogenesis of gastroduodenal lesions [811].
Rheumatoid arthritis (RA) is a disease which requires the long-term use of NSAIDs. Because of this, patients with RA frequently develop gastroduodenal mucosal lesions. However, the correlation between H. pylori and gastroduodenal lesions in RA patients remains controversial [611]. In order to verify the impact of H. pylori infection on gastroduodenal lesions in patients with RA and to determine whether H. pylori infection has any significance with respect to the clinical features of RA, we investigated the prevalence of H. pylori in a large number of patients with RA who were being treated with NSAIDs.
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Patients and methods
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Subjects
During the period from February 1997 to March 1999, we treated 2510 patients with RA at our institution. Each patient satisfied the 1987 American Rheumatism Association criteria for RA [12]. Among these patients, 260 patients were selected regardless of clinical features, abdominal symptoms and medication. Informed consent for upper endoscopy was obtained from 211 patients, who were the subjects of the present investigation. The subjects comprised 8.4% among all the RA patients at our institution. Twenty-seven patients were not taking any NSAIDs, and accordingly were excluded from the investigation. The remaining 184 patients (87.2%) took a single oral dose of NSAID. There were 30 males and 154 females, and their ages at the time of investigation ranged from 27 to 86 yr, with a median of 59 years.
Endoscopic examination
After we had obtained informed consent from each subject, upper gastrointestinal endoscopy was performed, regardless of gastrointestinal symptoms. Endoscopy was performed, using a forward-viewing instrument (Model GIF-Q20 or Q30; Olympus, Tokyo, Japan). During each endoscopic examination, a total of five biopsy specimens was obtained from gastroduodenal mucosa of normal appearance. We obtained two specimens from the greater curvature of the upper body, two from the antrum of the stomach and one from the second portion of the duodenum, using biopsy forceps (FB-24Q; Olympus, Tokyo). Two specimens, one from the antrum and the other from the greater curvature of the body, were processed for culture of H. pylori, while the other three specimens were used for histological investigations. All endoscopes were washed and sterilized with an automatic washing machine (EW20; Olympus) and the biopsy forceps were washed and soaked in 2% glutaraldehyde solution for 10 min prior to each examination.
Detection of H. pylori and amyloid deposits
Possible H. pylori infection was evaluated by culture, histological examination and anti-H. pylori antibody in the serum. In each patient, serum was obtained on the day of endoscopy, and anti-H. pylori antibody was measured with an enzyme-linked immunosorbent assay (ELISA) using the HM-CAP immunoassay kit (Kyowa Medex, Tokyo, Japan) [13]. An antibody titre above the cut-off value of 2.2 was considered to be positive.
Biopsy specimens for culture were homogenized in sterile saline before being inoculated onto the surface of Skirrow's agar medium (Nippon Becton Dickinson, Tokyo, Japan) and modified Skirrow's agar medium (H. pylori medium; Eiken Kagaku, Tokyo, Japan). This inoculation was performed within 2 h after sampling. The agar plates were incubated at 37°C for 7 days in a microaerophilic environment [14, 15]. The culture was considered to be positive for H. pylori if one or more colonies of Gram-negative bacteria positive for oxidase, catalase and urease were identified.
Biopsy specimens for histology were fixed in 10% formalin, embedded in paraffin and sectioned at 5 µm. These sections were stained with haematoxylineosin and modified Giemsa stain for histological detection of H. pylori.
Helicobacter pylori infection was determined to be positive when any two or all of serum antibody, culture and histology revealed positive results [16, 17]. Otherwise, the patients were regarded as negative for H. pylori. Patients with a positive result for only one test were determined to be negative for H. pylori as there might have been contamination and prior infection [16, 17].
Three sections from the two areas of the stomach and from the duodenum were stained with Congo red for possible amyloid deposits. The amyloid deposits were regarded as positive when green birefringence was observed under polarized microscopy.
Histological analysis of the background gastric mucosa
In the biopsy specimens obtained from the greater curvature of the upper body and from the antrum, the degree of atrophic change was recorded as none, mild, moderate or marked, according to the updated Sydney system [18]. In each case, the most marked degree of atrophic change among the two specimens was regarded as the representative grade of atrophy.
Assessment of clinical features
In each patient we evaluated age, gender, gastrointestinal symptoms, laboratory data and the duration and severity of RA at the time of endoscopy and therapy used for RA. Laboratory data at the time of endoscopy, including white blood cell count (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), albumin, haemoglobin, creatinine and rheumatoid factor (RF) were recorded. The stage of RA was assessed from the anatomical stage as determined by radiography [19].
Therapies used for RA were listed according to whether the medication had been administered before or after endoscopy. The medications were categorized into three groups: NSAIDs, corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs). The duration of NSAID treatment and the total dose of corticosteroid until endoscopy were also assessed. The DMARDs were classified according to the scheme used in our previous study [20]. The DMARDs were subdivided into anti-cancer drugs (ACDs) (methotrexate and cyclophosphamide), immunosuppressive drugs (ISDs) (azathioprine and mizoribine), gold compounds (GCs) (sodium aurothiomalate and auranofin), chelating agents (CAs) (penicillamine and bucillamine) and sulphasalazine (SASP).
Because there was variation in the indication of gastroprotective drugs among the referral physicians (e.g. gastrointestinal symptoms or use of NSAIDs), the groups of drugs administered at the time of endoscopy were also examined. The drugs were classified into histamine-2 (H2) receptor antagonists, proton pump inhibitors (PPI) and other mucosal protective drugs. The therapeutic regimen is summarized in Table 1
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Statistical analysis
Comparison between any two groups (H. pylori-positive and -negative groups; groups based on the use of gastroprotective drugs) was performed using the MannWhitney U-test, the
2 test or Fisher's exact probability test. P<0.05 was considered significant.
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Results
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Among the 184 patients, 113 were positive and 71 were negative for H. pylori. In the former group, 85 patients were positive for all the determinants and 28 patients were positive for two determinants. In the latter group, 54 patients were negative for all the determinants and 17 patients were positive for one determinant.
Comparison of clinical features between H. pylori-positive and -negative RA patients
Table 2
summarizes the comparison of clinical and endoscopic findings between H. pylori-positive and -negative patients. Age, gender and the incidence of gastrointestinal symptoms, such as epigastralgia, nausea and abdominal fullness at the time of endoscopy, were not different between the two groups. The incidence of gastroduodenal mucosal lesions was not different between the two groups, whereas that of reflux oesophagitis (8.5 vs 1.8%, P=0.038) was significantly higher in the H. pylori-negative group.
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TABLE 2. Age, gender, gastrointestinal symptoms and endoscopic findings in RA patients with and without H. pylori infection
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Table 3
compares the clinical features of RA. The duration of RA was not different between the H. pylori-positive and -negative groups. Similarly, the anatomical stage was not different between the two groups at the time of investigation. Laboratory parameters (WBC, ESR, CRP, albumin, haemoglobin, creatinine and RF) showed no difference between the two groups.
Comparison of medication between H. pylori-positive and -negative RA patients
Table 4
summarizes the medication used for RA and for antacid prescription. There was no difference with regard to the combination of drugs for the treatment of RA between the H. pylori-positive and -negative patients. The doses of NSAIDs and DMARDs were within the therapeutic range. The daily dose of corticosteroid ranged from 2.5 to 10 mg. At the time of endoscopy, each patient was treated with a single type of NSAID over a period of at least 2 months. No patient was treated with suppositories. The duration of NSAID intake was not different between the H. pylori-positive and -negative groups. There was no difference in the prescription of H2 receptor antagonists, PPIs and other mucosal protective drugs between the H. pylori-positive and -negative groups.
Table 5
compares details of the medications of corticosteroid and DMARDs between the H. pylori-positive and -negative groups. SASP was administered more frequently to the H. pylori-negative patients than to the positive patients (7.0 vs 0.9%, P=0.033), whereas the use of corticosteroid or other DMARDs, including GCs, was not different between the positive and negative patients.
Correlation among gastroprotective drugs, H. pylori and endoscopic findings
Table 6
indicates the correlation between classes of gastroprotective drugs and gastrointestinal symptoms, H. pylori infection and endoscopic findings. The H2 receptor antagonists included cimetidine (200800 mg/day), nizatidine (300 mg/day), ranitidine (150300 mg/day), famotidine (20 mg/day) and roxatidine acetate (150 mg/day). Lansoprazole (30 mg/day) was the only PPI prescribed. As shown in Table 6
, gastrointestinal symptoms, H. pylori infection and endoscopic findings were not different between patients who received and those who did not receive each of the gastroprotective drugs.
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TABLE 6. Gastrointestinal symptoms, H. pylori infection and endoscopic findings in RA patients receiving and not receiving gastroprotective drugs
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Histology and H. pylori infection
Table 7
shows a comparison of the histological findings from the biopsy specimens. Amyloid deposits were confirmed in 11 patients (6.0%). The incidence of amyloid deposits was not different between the H. pylori-positive and -negative groups. Mild, moderate and marked degrees of atrophy were more frequent in the H. pylori-positive group than in the negative group (P<0.001).
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Discussion
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The results of the present investigation indicate that H. pylori infection influenced neither the gastroduodenal mucosal lesions nor the clinical features of arthropathy in patients with RA under medication with NSAIDs. Although the overall prevalence of H. pylori infection in our patients (61.4%) appears to be low when compared with the prevalence in 1290 Japanese subjects [21], further studies are necessary to conclude whether the prevalence is actually low in subjects with RA. According to epidemiological and clinical investigations, the difference in the prevalence of H. pylori infection between RA patients and the general population is insignificant [22, 23].
The possible interaction of NSAIDs with H. pylori in the pathogenesis of gastroduodenal mucosal lesions is still a matter of discussion. Although Chan et al. [6] and Taha et al. [7] suggested the prophylactic value of H. pylori eradication in NSAID-induced gastropathy, contradictory results have been demonstrated in several articles [811]. Four major articles state that H. pylori infection did not influence the endoscopic grade of gastroduodenal mucosal lesions in long-term NSAID users, although in one of these studies dyspeptic symptoms were found more frequently in H. pylori-positive patients [8]. In the present investigation, the incidence and types of gastroduodenal lesions and dyspeptic symptoms were not different between the H. pylori-positive and -negative groups. It thus seems likely that H. pylori does not contribute to the pathogenesis of gastroduodenal lesions in patients who are under medication with NSAIDs. In contrast, although a report [24] suggested that H. pylori infection had no role to play in the pathogenesis of reflux oesophagitis, recent investigations have confirmed that the organism prevents this type of oesophagitis [25, 26]. Indeed, the patients in our investigation uniformly received NSAIDs, and there was a significant negative correlation between H. pylori infection and the prevalence of reflux oesophagitis. These observations suggest that H. pylori infection is protective against reflux oesophagitis in patients undergoing long-term treatment with NSAIDs.
In a preliminary report, Zentilin et al. [27] reported the effect of H. pylori eradication on the severity of arthropathy in patients with RA. According to their results, the analogue score for RA and morning stiffness had improved 4 months after H. pylori eradication in RA patients who were infected with H. pylori. In the present investigation, however, there were no differences in the clinical severity of RA between H. pylori-positive and -negative patients. Although there remains the possibility that medications intended to eradicate H. pylori may have had a therapeutic effect on arthropathy in the patients, as reported by Zentilin et al. [27], H. pylori infection does not seem to be closely associated with the severity of RA.
Mizokami et al. [11] reported that anti-rheumatic drugs had no effect on the prevalence of H. pylori in patients with RA. However, the suppressive effect of GCs on H. pylori infection in RA patients has been reported [28, 29]. In contrast, our present investigation indicates that, among various DMARDs, SASP was the only drug that was prescribed more frequently in H. pylori-negative patients than in positive patients. Even though an in vitro study confirmed that gold sodium thiomalate suppresses H. pylori [30], controversial results have been presented in clinical investigations [11, 3133]. There remains the possibility that GCs act bacteriostatically against H. pylori, but our results suggest that GCs do not decrease the prevalence of H. pylori infection in patients with RA.
In chronic inflammatory bowel disease (IBD), SASP has been confirmed to be suppressive against H. pylori infection. El-Omar et al. [34] and Parente et al. [35] demonstrated a significantly lower prevalence of H. pylori in IBD patients treated with SASP when compared with the general population. Although SASP has not yet been proven to have any direct antibacterial effect on H. pylori, our results conform to the clinical observations found in IBD patients.
Our histological analysis revealed that patients with positive H. pylori findings had greater mucosal atrophy than those with negative H. pylori findings. This result seems to be compatible with the large amount of data for non-RA patients. Because amyloidosis is a life-threatening complication in RA [36, 37], we investigated the possible role of H. pylori in amyloidosis. However, we found the prevalence of gastrointestinal amyloidosis in H. pylori-positive and -negative patients to be equal. Thus, H. pylori does not seem to be closely associated with the development of gastrointestinal amyloidosis in RA patients.
In conclusion, our findings show that H. pylori infection does not seem to be associated with disease activity and gastroduodenal mucosal lesions in patients with RA under medication with NSAIDs. Although SASP may affect the prevalence of H. pylori infection in RA, there seems to be no evidence to suggest the necessity for H. pylori eradication in patients with RA undergoing long-term NSAID treatment.
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Acknowledgments
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The English was revised by Miss K. Miller (Royal English Language Centre, Fukuoka, Japan).
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Notes
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Correspondence to: N. Ishikawa, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan 
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Submitted 16 March 2000;
Accepted 20 July 2001