Capsule endoscopic diagnosis of nonsteroidal antiinflammatory drug-induced enteropathy.

BACKGROUND: Case reports have linked nonsteroidal antiinflammatory drugs (NSAIDs) to a variety of lesions in the small and large bowel including bleeding, protein loss, strictures, increased intestinal permeability, and NSAID enteropathy. We here review the use of wireless capsule endoscopy to quantitate and assess the nature of the small bowel damage caused by NSAIDs when taken short term and in patients on long-term NSAIDs and COX-2 inhibitors. METHODS: Forty healthy volunteers underwent a baseline capsule endoscopy. After taking diclofenac slow-release 75 mg twice a day for a total of 14 days, both investigations were repeated. A further 120 patients on long-term NSAIDs (more than 3 months) and 40 on COX-2 inhibitors underwent a capsule endoscopy study. Sixty healthy patients acted as controls. Small bowel damage was categorized and quantitated. RESULTS: Short-term diclofenac: Capsule endoscopy demonstrated new pathology in 27 (68%) of subjects. The most common lesions were mucosal breaks, seen in 16 (40%), which were seen to be bleeding in 2 (5%). Long-term NSAIDs: The main pathology was related to mucosal breaks (29%); 3% had free luminal blood and 2% had strictures. The damage seen in 50% of patients on selective COX-2 inhibitors did not differ significantly (P<0.5) from that seen with NSAIDs. CONCLUSIONS: Capsule endoscopy demonstrates evidence of macroscopic injury to the small intestine, in up to 68% of volunteers, resulting from 2 weeks ingestion of slow-release diclofenac. Long-term use of NSAIDs and COX-2 inhibitors causes comparable small bowel damage (50%-68%).

Long-term effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective agents on the small bowel: a cross-sectional capsule enteroscopy study.

BACKGROUND & AIMS: Nonsteroidal anti-inflammatory drug (NSAID) gastropathy is sufficiently important as to warrant co-administration of misoprostol or proton pump inhibitors or a switch to selective cyclooxygenase (COX)-2 inhibitors. However, the serious ulcer outcome studies suggested that 40% of the clinically significant gastrointestinal bleeding originated more distally, presumably from NSAID enteropathy. We used capsule enteroscopy to study small-bowel damage in patients on long-term NSAIDs and COX-2-selective agents. METHODS: Sixty healthy volunteers acted as controls. One hundred twenty and 40 patients on long-term NSAIDs and COX-2 selective agents, respectively, underwent a capsule enteroscopy study. Small-bowel damage was categorized and quantitated. RESULTS: Sixty-two percent of patients on conventional NSAIDs were abnormal, which differed significantly (P < .001) from controls. The main pathology related to reddened folds (13%), denuded areas (39%), and mucosal breaks (29%). Two percent had diaphragm-like strictures and 3% had bleeding without an identifiable lesion. The damage, seen in 50% of patients on selective COX-2 inhibitors (reddened folds, 8%; denuded areas, 18%; and mucosal breaks, 22%), did not differ significantly (P > .5) from that seen with NSAIDs. CONCLUSIONS: Long-term NSAIDs and COX-2-selective agents cause comparable small-bowel damage. This suggests an important role for COX-2 in the maintenance of small-bowel integrity. The results have implications for strategies that aim to minimize the gastrointestinal damage in patients requiring anti-inflammatory analgesics.

Genetic aspects of intestinal permeability in inflammatory bowel disease.

There is a long-standing belief that disruption of the intestinal barrier function may lead to systemic and local intestinal disease. The role of increased intestinal permeability in Crohn's disease is reviewed here. What is not in doubt is that intestinal permeability in patients with Crohn's disease is increased proportional to disease activity; it can be used to predict clinical relapse of disease and prognosis; and a small proportion of first-degree relatives have increased intestinal permeability. This last finding has been subject to much speculation. In particular it has been suggested that it represents a genetically determined abnormality. If so it might play an important pathogenic process in the disease. However this permeability change in relatives does not conform to a classical inheritance pattern and in some studies it is found in the patients' spouses. This suggests an environmental cause for the changes. However proponents of an environmental factor have been singularly inactive in attempting to identify this agent(s). In view of recent research it seems likely that the increased intestinal permeability in relatives of Crohn's patients may be secondary to sub-clinical intestinal inflammation. This inflammation conforms to an inherited additive trait. The genetic basis for this inflammation is being studied.

Selective white cell apheresis reduces relapse rates in patients with IBD at significant risk of clinical relapse.

BACKGROUND: We assessed whether selective granulocyte and monocyte/macrophage adsorption apheresis maintained clinical remission in asymptomatic inflammatory bowel disease (IBD) patients at significant risk of clinical relapse. METHODS: Sixty asymptomatic patients (age 18-70 years) with IBD (in clinical remission) with fecal calprotectin over 250 microg/g (which defines those at risk of clinical relapse with >80% specificity and sensitivity) were recruited for this open-label, prospective, randomized, controlled study. Twenty-nine underwent selective leukocytapheresis, undergoing 5, once weekly, out-patient sessions. Thirty-one had unchanged maintenance treatment and acted as controls. Follow-up for a clinical relapse was 6 months. The secondary outcome variable was the time to relapse. RESULTS: The number of patients who remained in clinical remission at 6 months was significantly lower in controls (32.3%) than in the apheresis (72.4%) group (P = 0.0023, Fisher's exact test). The time to first relapse was significantly earlier in the control group (99 +/- 73 days) as compared with the apheresis group (161 +/- 44 days) (log-rank test; P = 0.0004). Mild and transient headache was reported by 16 of the 29 (55%) for up to 3 hours, but no serious side effects were observed. CONCLUSIONS: This study represents a new approach to the treatment of IBD by targeting a group of asymptomatic patients for treatment who are at significant risk of relapse based on high fecal calprotectin concentrations. Selective leukocytapheresis significantly reduced the number of, and increased the time to, clinical relapse in these patients without serious side effects.

Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease.

BACKGROUND & AIMS: It has been variably suggested that nonselective NSAIDs and cyclooxygenase (COX)-2 selective inhibitors aggravate or ameliorate clinical disease activity in patients with inflammatory bowel disease. We assessed the effect of these drugs in patients with inflammatory bowel disease (n = 209) and the possible mechanisms. METHODS: First, patients with quiescent Crohn's disease and ulcerative colitis received the non-NSAID analgesic acetaminophen (n = 26) and the conventional NSAIDs naproxen (n = 32), diclofenac (n = 29), and indomethacin (n = 22) for 4 weeks. The Harvey-Bradshaw index was used to define relapse. Second, to assess the mechanism of relapse, intestinal inflammation was quantitated (fecal calprotectin) before and during treatment (20 patients/group) with acetaminophen, naproxen (topical effect, COX-1 and -2 inhibitor), nabumetone (COX-1 and -2 inhibitor), nimesulide (selective COX-2 inhibitor), and low-dose aspirin (selective COX-1 inhibition). RESULTS: Nonselective NSAIDs were associated with a 17%-28% relapse rate within 9 days of ingestion. No patient had an early relapse on acetaminophen, nimesulide, or aspirin, whereas those on naproxen and nabumetone (20%) experienced relapse. These clinical relapses were associated with escalating intestinal inflammatory activity. CONCLUSIONS: NSAID ingestion is associated with frequent and early clinical relapse of quiescent inflammatory bowel disease, and the mechanism appears to be due to dual inhibition of the COX enzymes. Selective COX-2 inhibition with nimesulide and COX-1 inhibition with low-dose aspirin appear to be well-tolerated in the short-term.

A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy.

BACKGROUND & AIMS: Conventional acidic nonsteroidal anti-inflammatory drugs frequently cause small bowel inflammation. Diagnosis is largely based on assay of surrogate markers of inflammation in stool, such as fecal calprotectin. However, stool markers are not widely available and the precise nature of this inflammation is uncertain. We used wireless capsule enteroscopy to quantitate and assess the nature of the small bowel damage caused by nonsteroidal anti-inflammatory drugs when taken on a short-term basis. METHODS: Forty healthy volunteers underwent a baseline capsule enteroscopy and fecal calprotectin test. After taking diclofenac slow-release 75 mg twice a day (with omeprazole 20 mg twice a day for gastroprotection) for a total of 14 days, both investigations were repeated. RESULTS: After drug treatment, 30 subjects (75%) had increased repeat fecal calprotectin concentrations above the upper limit of normal. Capsule enteroscopy showed new pathology in 27 subjects (68%). The commonest lesions were mucosal breaks, seen in 16 (40%), which were seen to be bleeding in 2 (5%); reddened folds in 14 (35%); petechiae or red spots in 13 (33%); denuded mucosa in 8 (20%); and blood in the lumen without a visualized source in 3 (8%). Fifteen of the 27 subjects had more than one lesion concurrently. CONCLUSIONS: This study provides both biochemical and direct evidence of macroscopic injury to the small intestine in 68%-75% of volunteers resulting from 2 weeks' ingestion of slow-release diclofenac.