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GASTRODUODENAL LESIONS IN CHILDREN WITH JUVENILE RHEUMATOID ARTHRITIS
Claudio Len (1), Maria Odete E. Hilário (1), Elisabete Kawakami (2), Maria Teresa Terreri (1), Delia J. Becker (2), José Goldenberg (3) and Ulysses Fagundes Neto (2).
(1) Pediatric Rheumatology Unit, Division of Allergy, Clinical Immunology and Rheumatology, (2) Pediatric Endoscopy Unit, Division of Gastroenterology, Department of Pediatrics, (3) Division of Rheumatology, Department of Medicine, São Paulo Federal University - EPM, São Paulo, Brazil.
Address for correspondence:
Maria Odete E. Hilário, MD
Alameda dos Anapurus, 1370 Ap. 144
CEP 04087-004
São Paulo, SP, Brazil
FAX 5511-5701590
ABSTRACT; INTRODUCTION; METHODS; RESULTS; DISCUSSION; REFERENCES
Introduction. There are few studies about gastrointestinal abnormalities in patients with juvenile rheumatoid arthritis - probably due to the fact that this association is not frequently recognized. The aim of our study was to observe the prevalence of endoscopic gastroduodenal lesions in these patients.
Methods. Fourteen patients with juvenile rheumatoid arthritis, all of them using non-steroidal anti-inflammatory drugs associated or not with methotrexate, were assessed clinically and by endoscopy. Gastric antrum biopsy and Helicobacter pylori search were also performed.
Results. The mean age of the patients was 10.6y (7 boys). Abdominal pain was observed in 27% of them. Macroscopic endoscopic lesions were found in 43% and infection by H. pylori in 57%. The correlation between anemia and endoscopic abnormalities was statistically significant (p < 0.05).
Conclusion. Our data show that patients with juvenile rheumatoid arthritis have considerably susceptibility to gastroduodenal lesions, specially if they are using any drug association and present anemia.
Key words: juvenile rheumatoid arthritis - non-steroidal anti-inflammatory drugs - gastropathy
Abbreviations:
NSAID = |
non-steroidal antiinflammatory drugs |
RA = |
rheumatoid arthritis |
JRA = |
juvenile rheumatoid arthritis |
MTX = |
methotrexate |
The chronic use of non-steroidal antiinflammatory drugs (NSAID), corticosteroids and immunosuppressors by patients with rheumatic conditions can cause gastroduodenal lesions such as petechiae, erosion and ulceration, with or without bleeding.
It is known that adult patients with rheumatoid arthritis (RA) are more susceptible to the development of gastroduodenal lesions when compared to the general population, principally due to the chronic use of NSAID (3). Some review articles estimate that NSAID associated abdominal pain is present in 10% of juvenile rheumatoid arthritis (JRA) patients (1, 11). However, little is known about gastric lesions in these patients.
In a recent study, Mulberg et al (12) observed endoscopic lesions in 76% of 17 children with JRA and gastrointestinal complaints. This report showed that gastroduodenal lesions are not rare, and JRA patients should be investigated more carefully. Furthermore, the infection caused by the Helicobacter pylori is also a risk factor in the development of microscopic inflammation of the gastroduodenal mucosa of adults and children.
According to Oliveira et al (13), H. pylori gastroduodenal infection is very frequent in the Brazilian pediatric population, specially in children of low socio-economic level. In the Oliveira et al study, of the children aged between 9 and 11 years-old 48.8% presented serologic reaction to the bacteria, and most of the them were assymptomatic.
The aim of our study was to determine the prevalence of endoscopic gastrodueodenal lesions, as well as the presence of H. pylori infection in children with JRA being regularly treated with NSAID.
Fourteen patients diagnosed with JRA, according to the 1977 "American College of Rheumatology" criteria (2) were randomly selected in the period between February 1995 and March 1996, all having made use of NSAID for a minimum of 12 months. The patients were clinically evaluated as to the onset, duration and activity of the JRA, functional status, type of anti-rheumatic medication, presence of gastrointestinal symptoms and family history of peptic illness. The haemoglobin (Hb) level and the erythrocyte sedimentation rate (ESR) were analysed to determine the disease activity.
The patients were submitted to an endoscopic exam with a Pentax FG-24 endoscope, pediatric model, under conscious sedation (with midazolam 2 mg and mepheridine 1 mg/kg, intravenously) for children over 10 years old, and at the discretion of the anaesthetist for children less than 10 years old. A biopsy of the gastric antrum was performed, with the removal of two fragments, one for a rapid ureases test and the other for histologic study and H. pylori research with hematoxilin-eosin coloration and modified Giemsa. A biopsy of the duodenal mucosa was carried out on a patient suffering from chronic diarrhea and anemia (Table 1 - patient n# 3). All parents and patients were informed about the procedure, and all of them signed an informed consent. The patients with gastroduodenal lesions were treated with ranitidine 4 mg/kg/day b.i.d. for a period of 6 to 8 weeks. A triple therapy was prescribed for H.pylori, with subcitrate of coloidal bismuth 7 mg/kg/day, tinidazole 10 mg/kg/day b.i.d. and amoxilin 50 mg/kg/day t.i.d. during 14 days.
Statistical analysis : The clinical data was compared with endoscopic and histological finds, using the x2 test and the exact Fisher test. The significance level was considered for values of p < 0.05.
The mean age of the 14 patients (7 boys) was of 10.6y (5y - 16y). The mean age of the JRA onset was 6.8y (1.6y -15y) and the mean follow-up duration was 4.2y (1y - 12y). The onset type was polyarticular in 8 patients, pauciarticular in 5 and systemic in one. According the "American College of Rheumatology" functional classification (6), 2 patients were class I, 11 class II and one class IV.
The 14 patients were using the following NSAID: indomethacin (n=7), naproxen (n=5), piroxicam (n=1). One patient received intra-articular corticosteroid. Three patients were also using oral corticosteroids, 8 were using methotrexate (MTX) and one cyclosporine.
Macroscopic endoscopic lesions were observed in 6/14 patients (43%), most frequently in girls (4:2): enanthematous gastritis of the antrum in 2, erosive gastritis of the antrum in one, inflammatory gastric polyp, erosive gastritis of the antrum and duodenitis in one, nodular gastritis of the antrum in one and gastric ulcer in one patient (Table 1). Infection by H.pylori was present in 8/14 patients (57.1%), 5 of them (62.5%) with endoscopic lesions (active superficial chronic gastritis); there was no statistical difference between the presence or absence of H.pylori and the endoscopic findings. Only one patient with gastric ulcer (# 4) presented satisfactory adherence to the treatment against H.pylori, and his endoscopic control was normal, without H.pylori (Table 1).
A 16 years-old girl suffering from chronic diarrhea, was submitted to a duodenal biopsy that showed subtotal villous atrophy (Grade IV) (Table 1).
The clinical and endoscopic findings of the 8 patients without endoscopic lesions are presented in Table 2.
Abdominal pain was observed in 4/14 patients (27%), two of them presenting endoscopic lesion. The relationship between the endoscopic findings and the existence of pain was not statistically significant. Family history of peptic illness was found in only 2 patients, one with endoscopic lesion. Anemia with hemoglobin levels below 10 mg/dl was detected in 4 patients, and endoscopic lesions in 3 of them (75%). This correlation was statistically significant (p < 0.05).
It was not possible to correlate the type of drug to the presence of the endoscopic lesion. Gastropathy was always observed when indomethacin was associated to other NSAID (Table 1). MTX was used in 5 of 6 patients with lesion, but this drug was always associated to NSAID (Table 1).
In our study, all patients were evaluated by endoscopic examination, presenting or not abdominal complaints. We observed macroscopic gastroduodenal lesions in 6 of the 14 JRA patients (43%), who regularly used NSAID, but only 2/6 (33,3%) were symptomatic. In Mulberg, et al study (12), all the JRA patients were using NSAID (n = 17) and were refered for evaluation of abdominal pain, anemia or melena. These authors observed gastropathy by endoscopic examination in 13 of 17 JRA patients (76.4%) using NSAID. This frequency of endoscopic findings in this study is higher, probably because all of the patients were symptomatic.
In a recent retrospective study that included medical records of 702 JRA, Keenan et al (7) observed only 5 with clinically significant gastropathy, as defined by Roth and Bennet (15), all of them with barium swallow or endoscopy alterations. These 5 patients were using NSAID, and the treatment of the gastropathy included antacids, H2 blockers and/or sulcrafate. These authors conclude that the number of children with JRA who experience clinically significant gastropathy appears to be low. It is important to emphasize that the authors did not report the number of patients with abdominal pain or anemia, and some of them would probably present endoscopic lesions, despite the presence of significant gastropathy.
One aspect to be considered is the real frequency of endoscopic findings related to the use of NSAID, which could be overestimated by the frequence of H.pylori infection. Recently, H.pylori has been highly associated with recurrent peptic ulcer disease (4). Other studies including JRA patients have not detected the presence or serological evidence of the bacteria (5,12). In our study, H.pylory was present in 57.1% of the patients, but we could not associate its presence with the endoscopic findings (gastroduodenal lesions).
We observed anemia (Hb levels below 10 mg) in 3/6 patients that were using NSAID and presented gastroduodenal lesions (# 3, 4 and 6 - Table 1), 2 of them with normal ESR values. It is probably that in these patients the asymptomatic gastointestinal hemorrhage was an important determinant of the anemia. Among the patients who did not present endoscopic abnormalities, one had high ESR (125 mm) and anemia. In this case, the anemia was probably caused by the high inflammatory pattern of the arthritis. Due to the small number of patients, we coud not determine the exact relationship between anemia and endoscopic lesions.
The association between celiac disease and JRA has been reported by some authors (8,9). Lepore et al (8) studied 119 patients with juvenile chronic arthritis, and found 4 patients with antiendomysium antibodies. In 3 of these patients (2.5%), intestinal biopsy showed villous atrophy, and only one patient presented improvement of the articular disease and nutritional status after gluten-free diet. In our study, the patient with subtotal villous atrophy did not present any improvement after we started specific diet (gluten-free).
MTX has being administered with greater frequency to children with JRA, mainly in cases of agressive and rapid progression to osteoarticular erosion (14). This drug acts as an antifolate and may cause mucosal lesions at any point in the digestive tract, from the oral cavity to the large intestine. McKendry and Dale (10) studied 144 adult patients with rheumatoid arthritis using MTX, and observed that 50.7% presented gastrointestinal symptoms, which were more frequent in older patients. In our study, the patient that was using MTX as the sole drug and 4/7 patients that were using MTX and NSAID presented macoscopic gastroduodenal lesions (Tables 1 and 2). These data are significative, but do not allow us to associate MTX to gastrointestinal abnormalities.
In conclusion, our data show that patients with JRA (with or without gastroduodenal complaints) have considerable susceptibility to gastroduodenal lesions, and should be evaluated carefully, specially if they are using any kind of drug association and present anemia, with or without high ESR values. Prospective studies with larger samples are necessary to evaluate the action of different NSAID and the risk factors in the pediatric population.