R. Lana

Prevalence of mutations of the NOD2/CARD15 gene and relation to phenotype in Spanish patients with Crohn disease

Background: We assessed the prevalence of R702W, G908R, and L1007fs coding mutations in the NOD2/CARD15 gene and the genotype–phenotype relation in Spanish patients with Crohn disease. Methods: A cohort of 204 unrelated patients with Crohn disease and 140 healthy controls were studied. The phenotype was established before commencement of genotyping. Genotyping of the R702W, G908R, and L1007fs gene polymorphisms of NOD2/CARD15 was performed by two independent laboratories using different techniques. In the case of discordant results, specific sequencing of DNA strands was performed. Results: At least one mutation was present in 32.8% of patients compared to 10.7% in controls (OR = 4.08, 95% CI 2.21 to 7.50). In patients with Crohn disease, the frequency of R702W, G908R, and L1007fs carriers was 13.7%, 8.3%, and 14.2%, respectively. Compound heterozygotes and homozygotes occurred in 3.4% and 2.9% of patients and in none of the controls. The correlation of genotype–Vienna classification showed a significant association with ileal disease (RR = 1.61, 95% CI 1.21–2.15, P = 0.001) and an inverse association with colonic localization (RR = 0.29, 95% CI 0.11–0.80, P = 0.007). There was a significant association between G908R carriership and previous appendectomy, surgical interventions, and stricturing behavior. A gene‐dosage effect on phenotypic characteristics was not observed. Conclusions: In a Spanish population from Madrid, mutations of the NOD2/CARD15 gene were a marker of susceptibility to Crohn disease and were associated with ileal disease. Carriers of the G908R mutation showed a stricturing disease behavior, history of appendectomy, and surgical interventions over the course of the disease.

MDR1 polymorphisms and response to azathioprine therapy in patients with Crohn's disease.

Background To investigate the contribution of multidrug resistance 1 (MDR1) gene pharmacogenetics (G2677T/A and C3435T) to the efficacy of azathioprine in inducing remission in patients with Crohns disease (CD). Methods A cohort of 327 unrelated Spanish patients with CD recruited from a single center was studied. All patients were rigorously followed up for at least 2 years (mean time, 11.5 years). A case‐control analysis of MDR1 G2677T/A and C3435T SNPs and 2 loci haplotypes in 112 steroid‐dependent CD patients treated with azathioprine was performed. Patients were classified on the basis of response to azathioprine. Results A total 76 patients treated with azathioprine for longer than 3 months were included. Remission was achieved in 42 CD patients (55.3%). A higher frequency of the 2677TT genotype was found in nonresponders than in responders (17.65% versus 7.14%; OR = 2.8; 95% CI; 0.6–12.1; P = 0.11). Nonresponders to azathioprine were found to have a higher frequency of the 3435TT genotype than did CD patients who had achieved clinical remission (17.64% versus 4.76%; OR = 4.3; 95% CI, 0.8–22.8; P = 0.06). The 2677T/3435T haplotype was also more abundant in nonresponders (29.4% versus 20.2%), whereas the 2677G/3435C haplotype was more frequent in responders (58.3% versus 47.1%). Lack of response to azathioprine therapy in CD patients was 1.8‐fold greater in carriers of the 2677T/3435T haplotype than in carriers of the 2677G/3435C haplotype (OR = 1.8; 95% CI, 0.82–3.9; P = 0.14). Conclusions The results of our study indicate higher frequencies of the 2677TT and 3435TT genotypes and the 2677T/3435T haplotype in CD patients who did not respond to azathioprine. Additional replications in independent populations would confirm the real impact of these polymorphisms in response to azathioprine therapy. (Inflamm Bowel Dis 2007)

Mucosal healing for predicting clinical outcome in patients with ulcerative colitis using thiopurines in monotherapy

BACKGROUND Mucosal healing (MH) has emerged as a desirable treatment goal for patients with ulcerative colitis (UC). Currently little is known about the efficacy of using thiopurine immunosuppressants in monotherapy to achieve and maintain long-term MH in UC. This study analyzes the efficacy and the clinical impact of MH in patients with UC responded to thiopurine immunosuppressants in the long term. METHODS An open, observational, cohort study in 20 patients with UC had been in clinical remission in monotherapy with thiopurine immunosuppressants for at least 1 year. MH was assessed by endoscopy. The patients according to the Mayo Endoscopic Score (0 vs 1 and 2), were followed until the end of the study or patient relapse. (according to Truelove and Witts criteria). RESULTS Mean treatment time was 5.4 years. Twelve (60%) patients presented a Mayo Endoscopic Score of 0. A total of 18 patients were followed up for a median of 27.1 months. After endoscopy, 4 patients (22.2%) presented relapse, with a mean time of 27.5 months for a score ≥1 (95% CI; 18.2-36.8) versus 54.3 months for a score=0 (95% CI 47.2-61.3) (p=0.032). CONCLUSIONS This study shows the efficacy of thiopurine immunosuppressants in achieving mucosal healing in patients who respond to thiopurine immunosuppressants in the long term. We also observe the presence of endoscopy activity is not a rare event in this group of patients and is a predictor of early relapse.

NOD2/CARD15: geographic differences in the Spanish population and clinical applications in Crohn's disease

Crohn’s disease (CD) is a genetically complex disease in which both genetic susceptibility and environmental factors play key ro les in the development of the disorder. NOD2/CARD15 muta tions are associated with CD. NOD2 encodes for a protein that is an intracellular receptor for a bacterial product (muramyl dipeptide), though the exact functional consequences of these mutations remain the subject of debate. NOD2/CARD15 mutations are as sociated with ileal CD, with stricturing behavior, and possibly with a more complicated course of CD. NOD2/CARD15 mutations associated with CD have demonstrated heterogeneity across eth nicities and populations throughout the world, with regional varia tions across Europe and Spain. However, “NOD2/CARD15 testing” is not yet ready for use in the clinical setting. One of the reasons is that we know that these genetic variants increase the risk of disease only marginally, and many healthy individuals carry the risk alleles, At present it is not recommended to screen first-degree relatives, because we do not have the ability to prevent the disease at the present time.

Diagnostic and treatment recommendations on perianal Crohn's disease

Treatment of perianal fistulas in Crohns disease should be defined on an individual basis. A combined medical and surgical approach is the optimal treatment. Adequate management of perianal fistula disease is based on the presence or absence of active proctitis, anatomic location, and fistula type. Furthermore, the presence of perianal abscesses must be ruled out. This evaluation includes digital rectal examination, endoscopy, and examination under anesthesia combined with pelvic magnetic resonance imaging or anorectal endoscopy ultrasonography findings.

Polymorphisms in the interleukin-10 gene and relation to phenotype in patients with ulcerative colitis

BACKGROUND AND OBJECTIVES Interleukin-10 (IL-10) has a key role in regulating mucosal inflammation in inflammatory bowel disease. In our population of Spanish ulcerative colitis (UC) patients, we have previously demonstrated that two polymorphisms (IL-10.G14 microsatellite allele and homozygous for the -1082G allele (guanine at position -1082)) in the IL-10 gene were susceptibility markers for disease. No data exist regarding the relationship of these IL-10 polymorphisms with phenotypic subpopulations in UC. Therefore, this study sought to examine the contribution of IL-10 polymorphisms to phenotypical variability in UC. MATERIAL AND METHODS A cohort of 215 Spanish unrelated patients with UC recruited in a single center was studied. All patients were rigorously phenotyped and followed for at least 3 years (mean time: 11.8 years). The clinical phenotype was established before genotyping. Genotyping was performed using polymerase chain reaction (PCR) assays. RESULTS Patients with UC included 129 (60%) men and 89 (40%) women. Mean age at diagnosis was 38 years, with a range of 8-83. Disease extent included 127 (59.1%) left-side patients and 88 (40.9%) extensive patients. Neither UC phenotype variable was associated with the presence of susceptibility polymorphisms (10G14 microsatellite and -1082G allele). CONCLUSIONS In Madrids Spanish population of UC patients, the carrying of the ILG14 microsatellite or -1082G polymorphism in the IL-10 gene was not associated with phenotype of disease.

Accidental ingestion of unusual metallic foreign body

interest that goes to the emergency department coming from the dentist s consultation. During the endodontic treatment she has ingested accidentally one of the metallic instruments (dental screwdriver) with which the intervention was being made. She refers sharp body sensation at epigastrium. Abdominal radiograph is made in which is appraised in the gastric camera a metallic object of great size with a sharp edge (Fig. 1). Before the perforation risk, emergent endoscopic removal is made without complications in spite of the size of this object (Fig. 2). The ingestion of foreign bodies supposes a frequent consultation in the emergency department and it is the second cause of accomplishment of emergency upper flexible (1). The most frequent location is in the esophagus and although until 90% of the foreign bodies they are eliminated spontaneously recommends its precocious endoscopic removal once identified to avoid complications (perforation, hemorrhage, aspiration, pneumomediastinum, mediastinitis). When the foreign bodies are in the stomach is possible to be had an expectant attitude except the characteristics of the object are susceptible to cause complications, as it is our case when being a metallic instrument with a sharp edge that can produce a perforation in its progression by digestive tract (2). The flexible fibroendoscopy has demonstrated to be a safe and effective technique for the removal of foreign bodies, reason why it is exceptional to resort to the use of rigid endoscopy or surgery (3,4).