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Revista Española de Enfermedades Digestivas

versión impresa ISSN 1130-0108

Rev. esp. enferm. dig. vol.102 no.2 Madrid feb. 2010




Capsule endoscopy and nonsteroidal anti-inflammatory drugs (NSAID)-induced enteropathy - a bit of light in a long, dark tunnel

Cápsula endoscópica y enteropatía por antiinflamatorios no esteroideos (AINE): un poco de luz en un largo y oscuro túnel



J. Romero-Vázquez and J. M. Herrerías-Gutiérrez

Service of Digestive Diseases. University Hospital Virgen Macarena. Seville, Spain



For a long time non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, have been widely used in clinical practice for their analgesic, antipyretic, and anti-inflammatory effects.

These drugs' mechanism of action is unclear, but is overall based on an inhibition of cyclooxygenase, which blocks prostaglandin synthesis in inflamed areas. However, this inhibition is similarly seen at the gastrointestinal mucosa, where it brings about a disorder (1). Recent studies have shown that polymorphisms in CYP2C9, which metabolizes NSAIDs, modify the risk for gastroduodenal bleeding induced by these drugs, which would explain, at least partly, the high variability reported on the presence or absence of NSAID-induced lesions (2).

While awareness on NSAID-induced enteropathy is not new, as both clinical and necropsical evidence was available, the potential side effects on the small bowel (SB) were largely unknown as their study was performed using indirect radiographical methods or invasive procedures; the SB could not be totally reached by endoscopy, and large intestinal areas remained occult.

Therefore, we really have no detailed knowledge on the mechanism of action, risk factors, true prevalence of the disease (not only severe complications but also mild to moderate involvement), treatment, and prevention, and it was recently that we developed adequate tools for diagnosis.

In 2000 a non-invasive modality was launched for the complete study of the SB mucosa - capsule endoscopy (CE) (3). Its use has revolutionized the diagnostic-therapeutic algorithm for intestinal disease, and is currently considered the gold-standard technique for SB conditions.

Currently, its primary indication is the study of obscure gastrointestinal bleeding (OGIB) (4,5). Other indications approved by ASGE (American Society for Gastrointestinal Endoscopy) in 2006 include suspected Crohn's disease, SB tumors, follow-up of patients with polyposis syndromes, suspected refractory malabsorption syndromes, and NSAID-induced enteropathy.

Ever since its introduction we have a valid tool not only for diagnosis but also for research, hence human studies may now be developed to assess the prevalence, disease spectrum, severity, and prevention not only of NSAID-induced enteropathy but also of the impact of other drugs on the SB.

NSAIDs may cause on the SB a wide range of lesions: erosions, multiple ulcers, diaphragm-like strictures (likely a response to ulcer as derived from chronic NSAID ingestion) (6,7).

CE allowed to see that these lesions could be found on any SB segment in chronic NSAID users. Thus, Graham et al. (8) assessed NSAID-induced damage in patients with rheumatoid arthritis receiving NSAIDs for at least 3 months, and described that 71% had mucosal lesions in their SB. Later Sugimori et al. (9) used CE on patients with rheumatoid arthritis who had been on anti-rheumatic drugs or low-dose steroids for at least one year, and saw intestinal lesions in 81.3% of patients on NSAIDs and in 33.3% of those on other drugs, hence they concluded that other non-NSAID medications may also results in mucosal damage. Similarly, Kameda et al. (10) showed that 10.3% of patients undergoing CE or double-balloon enteroscopy for OGIB had mucosal lesions consistent with NSAID-induced enteropahy.

Probably aspirin (ASA), which undergoes no enterohepatic recirculation, would result in lower intestinal toxicity as compared to other NSAIDs. However, Leung et al. (11) demonstrated with CE mucosal lesions in the SB of patients receiving low-dose ASA, which has been then corroborated by other studies (12,13). These findings have led some authors to suggest a big-scale study to assess the real damage induced by ASA in the SB, given the high number of patients on such drug for cardiovascular disease or as chemoprevention.

When assessing NSAID-induced lesions in the SB a key challenge is the lack of homogeneous, standard terms from a diagnostic standpoint.

Thus, Hayashi et al. (14) defined with double-balloon endoscopy (DBE) criteria for NSAID-induced mucosal lesions in the SB: a) history of NSAID use; b) endoscopically found erosions, ulcers or diaphragm-like strictures; c) improvement in clinical signs and symptoms, and endoscopic findings following NSAID withdrawal; and d) exclusion of other mucosal damage causes (radiation enteritis, Crohn's disease, neoplasms, infection...). However, endoscopical improvement cannot be adequately assessed following NSAID cessation since many patients cannot fail to receive it because of chronic pain or antiplatelet therapy.

Maiden et al. (15) classified capsule endoscopy findings seen in NSAID users into five categories: rough folds, denudated areas, red spots, mucosal breaks, and presence of blood. In turn, Graham et al. (8) established 4 categories: red spots, small erosions, big erosions, and ulcers.

Caunedo-Álvarez et al. developed a study - included in this issue of the Spanish Journal of Gastroenterology (16)- in 16 chronic NSAID users with osteoarthritis whom they compared to 17 non-NSAID users with similar disease (control group). They also assessed any relation between damage severity as evaluated with CE and gastroduodenal lesions as seen during upper GI endoscopy, and developed a 0-to-2 scale (0 = absence of lesions, 1 = red spots or petechiae, denudated areas and/or 1-5 mucosal breaks, and 2 = more than 5 mucosal breaks, stenosis or bleeding) to score intestinal involvement extent. Upon their analysis of results they reported that 75% of NSAID users had SB lesions, usually grade 1. Interestingly, 2 non-NSAID users (11.76%) also have SB lesions, grade 1 all of them. The study showed no association between NSAID-related enteropathy and gastroduodenopathy: gastroduodenal damage was not predictive of enteropathy severity.

The above study firstly introduced a simple scale for NSAID-related bowel damage assessment that allowed the recognition of lesions (usually mild to moderate) in 3 of 4 chronic users, which is consistent with data previously reported in the literature. It allows reflection on the fact that almost 12% of non-NSAID-using patients with osteoarthritis also had mucosal lesions in their SB, which prompts caution in assessing their presence in capsule endoscopy studies. Similarly, whether CE findings are clinically relevant and may result in symptoms such as bleeding, anemia or hypoalbuminemia should be debated, as well as factors conditioning that some patients do develop signs and symptoms related to chronic NSAID use whereas others have none or express tem subclinically. On the other hand, the above study found no relation between gastropathy and enteropathy presence or severity. Perhaps this may suggest a different mechanism of action in these segments, which would entail different risk groups, a doubtless appealing field for exploration.

Regarding the major endoscopic modalities currently available for the study of NSAID-related enteropathy there are seemingly no big differences in diagnostic yield, albeit CE seems to recognize a higher number of small erosions or red spots as compared to DBE (10,17). Overall, CE is recommended as initial diagnostic test, and DBE is used when therapy administration or biopsy collection is necessary.

Selective cyclooxigenase 2 (COX-2) inhibitors have been developed in recent years that showed a reduction in ulcer complications within the upper GI tract when compared to non-selective NSAIDs. However, studies available to this day on their potential "protective" effect on the intestinal mucosa are few. Thus, Hawkey et al. (18) conducted a study in healthy volunteers to examine whether CE-assessed mucosal lesions in the SB were also reduced. They compared lumiracoxib (a selective inhibitor) to naproxen + omeprazole and to placebo, and saw the selective COX-2 inhibitor was associated with fewer mucosal lesions as well as no increase in intestinal permeability or fecal calprotectin; differences versus the comparator arms were statistically significant. Subsequently, Maiden et al. (19) enrolled 40 healthy volunteers who underwent CE at baseline followed by the administration of delayed-release diclofenac for 14 days, and then an additional CE exam at study endpoint. Furthermore, they included 120 chronic NSAID users (for longer than 3 months) and 40 subjects on selective COX-2 inhibitors. Sixty healthy patients were used as controls. On analyzing results they concluded that CE demonstrates SB mucosal lesions in up to 68% of healthy volunteers on NSAIDs for a short time, whereas long-term NSAID usage and selective COX-2 inhibitors result in comparable SB damage (50-68%) with no statistically significant differences.

To assess the potential protective role of add-on prostaglandins (misoprostol) in NSAID regimens (diclofenac), Fujimori et al. (20) enrolled 34 healthy volunteers who underwent CE before and 14 days after treatment, and found a significantly reduced incidence of SB mucosal lesions in the combination group with add-on prostaglandin.

In summary, CE allows the study of NSAID-related enteropathy in a direct, safe, non-invasive manner, also assessing mucosal damage severity. Therefore, CE sheds some light into the thus-far dark tunnel of NSAID-related enteropathy.



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