Einar Oddsson

Subclinical intestinal inflammation: an inherited abnormality in Crohn’s disease relatives?

BACKGROUND & AIMS One approach to unraveling the genetics of complex inherited disease, such as Crohns disease, is to search for subclinical disease markers among unaffected family members. We assessed the possible presence, prevalence, and inheritance pattern of subclinical intestinal inflammation in apparently healthy relatives of patients with Crohns disease. METHODS A total of 49 patients with Crohns disease, 16 spouses, and 151 (58%) of 260 available first-degree relatives underwent a test for intestinal inflammation (fecal calprotectin concentration). The mode of inheritance was assessed from 36 index patients (by variance component analysis) when more than 50% of relatives were studied. RESULTS Fecal calprotectin concentrations in patients with Crohns disease (47 mg/L; confidence interval [CI], 27-95 mg/L) and relatives (11 mg/L; CI, 9-14 mg/L) differed significantly (P < 0.0001) from controls (4 mg/L; CI, 3-5 mg/L), whereas that of the spouses did not (4 mg/L; CI, 3-6 mg/L; P > 0.5). Fecal calprotectin concentration was increased in 49% of all relatives studied. The increased fecal calprotectin concentration among the relatives of the 36 index patients had an inheritance pattern that was most consistent with an additive inheritance pattern. CONCLUSIONS There is a high prevalence of subclinical intestinal inflammation in first-degree relatives of patients with Crohns disease that conforms best to an additive inheritance pattern. The genetic basis for this abnormality may represent a risk factor for Crohns disease.

Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen

BACKGROUND Selective inhibitors of cyclooxygenase (COX)-2 may provoke less gastric damage and platelet inhibition than conventional non-steroidal anti-inflammatory drugs. AIMS We compared the biochemical and gastrointestinal effects of nimesulide, a potent and selective COX-2 inhibitor, with naproxen which exhibits no selectivity. SUBJECTS Thirty six healthy volunteers were randomised to nimesulide 100 mg or naproxen 500 mg twice daily for two weeks in a double blind, crossover study with a washout between treatments. METHODS Gastrointestinal side effects were assessed by endoscopy, and by estimation of small intestinal absorption-permeability and inflammation. Comparisons were made between variables at the end of each treatment phase. RESULTS Nimesulide caused significantly less gastric injury using the modified Lanza score (p<0.001) as well as reduced duodenum injury (p=0.039). Nimesulide had lower visual analogue scores (VAS) for haemorrhage and erosive lesions in the stomach (p<0.001) and for mucosal injection in the duodenum (p=0.039). Naproxen increased excretion of calprotectin, a marker of intestinal inflammation (5.5 (1.2) to 12.1 (2.1) mg/l) while nimesulide had no effect (treatment difference p=0.03). Naproxen abolished platelet aggregation to arachidonic acid and suppressed serum thromboxane B2 (TXB2) by 98%, indices of COX-1 activity. In contrast, nimesulide had no significant effect on platelet aggregation, although it reduced serum TXB2 by 29%. Production of prostaglandin E2 and prostacyclin by gastric biopsies, also COX-1 dependent, was inhibited by naproxen, but not by nimesulide. COX-2 activity, determined as endotoxin induced prostaglandin E2 formation in plasma, was markedly suppressed by both treatments. INTERPRETATION Nimesulide has preferential selectivity for COX-2 over COX-1 in vivo at full therapeutic doses and induces less gastrointestinal damage than that seen with naproxen in the short term.

Does Sucralfate Prevent Short-Term NSAID Induced Damage to the Gastroduodenal Mucosa?

The objective of the study was to assess whether sucralfate can prevent or diminish short-term nonsteroidal anti-inflammatory drug (NSAID)-induced damage in the stomach and duodenum. Sixteen healthy subjects were randomly treated for 7 days with sucralfate 2 g b.d. or placebo in a double-blind cross-over manner. Naproxen 500 mg b.d. was given on days 3-7. Gastrointestinal endoscopy was performed before and after each treatment period. Mucosal damage was measured by counting erosions, submucosal hemorrhages or ulcers on a fixed point scale of 0-4 for stomach and duodenum separately. The mean posttreatment injury score in the stomach was 2.13 +/- 1.51 and 2.0 +/- 0.97 for the placebo and sucralfate periods, respectively (p = 0.72). The possibility of type II error was 7%. In the duodenum, the injury score was 1.69 +/- 1.08 and 1.06 +/- 0.93 for the placebo and sucralfate periods, respectively (p = 0.08). The possibility of type II error was 37%. Sucralfate has no efficacy as a prophylactic agent against short-term NSAID-induced gastroduodenal injury.