Ulcerative Colitis: Peyrin-Biroulet L

Dubuquoy L, Rousseaux C, Thuru X, Peyrin-Biroulet L, Romano O, Chavatte P, Chamaillard M, Desreumaux P. · INSERM U795 ex E114, Clinique des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Swynghedauw, rue A Verhaeghe, F-59037 Lille Cedex, France. · Gut. · Pubmed #16905700 No free full text.

Abstract: The peroxisome proliferator activated receptor gamma(PPARgamma) is a nuclear receptor highly expressed in the colon and playing a key role in bacterial induced inflammation. Regulation of colon inflammation by this receptor has been well demonstrated in many experimental models of colitis but also in patients with ulcerative colitis, characterised by impaired expression of PPARgamma confined to their colon epithelial cells. Recent data showing that PPARgamma was the major functional receptor mediating the common aminosalicylate activities in inflammatory bowel diseases (IBD) have also reinforced the roles of this receptor in the control of intestinal inflammation. The aims of this review are to discuss the potential roles of PPARgamma in the physiopathology of IBD, as well as the emerging therapeutic strategies targeting this receptor.

Peyrin-Biroulet L, Bigard MA. · Service d'Hépato-gastro-entérologie, CHU Nancy-Brabois, allée du Morvan, 54511 Vandceuvre-lès-Nancy. · Rev Prat. · Pubmed #16052967 No free full text.

Abstract: The diagnosis of inflammatory bowel disease is sometimes difficult. The cardinal symptom of ulcerative colitis is bloody diarrhoea. The clinical characteristics of Crohn's disease are more heterogeneous, but typically include abdominal pain in the right lower quadrant, diarrhoea, weight loss and/or perianal disease. Extra intestinal (joint, cutaneaous and eye) manifestations can precede digestive symptoms and lead to the diagnosis of inflammatory bowel disease. The clinical course of these two diseases is unpredictable. The risk of colorectal cancer is significantly increased 8 years after diagnosis of pancolitis. Thus, regular surveillance by colonoscopy with random biopsies is recommended.

Peyrin-Biroulet L, Laclotte C, Roblin X, Bigard MA. · Department of Hepato-Gastroenterology, University Hospital of Nancy-Brabois, Allee du Morvan, 54 511 Vandoeuvre-les-Nancy, France. · World J Gastroenterol. · Pubmed #17511032 links to  free full text

Abstract: AIM: To evaluate the efficacy of adalimumab induction therapy in patients with ulcerative colitis who previously responded to infliximab and then lost response or became intolerant. METHODS: Ten patients with ulcerative colitis were enrolled in a 4-wk open-label trial. The patients received a loading dose of 160 mg adalimumab at wk 0 followed by 80 mg at wk 2. The primary efficacy measure was clinical improvement at wk 4, as defined by a decrease in clinical activity index (CAI) of more than 4. RESULTS: Four of 10 patients (40%) benefited from subsequent adalimumab therapy; one patient achieved remission (CAI<4) and 3 had clinical improvement at wk 4. 6 patients had no response (60%); 2 of 6 (33.3%) subsequently underwent colectomy. This was accompanied by a decrease in median CRP concentration from 16.8 mg/mL at baseline to 3.85 mg/mL at wk 4, excluding two patients who underwent colectomy after two infusions of adalimumab. Among the 6 patients with severe colitis (CAI>12) at baseline, none achieved remission and only one patient had clinical improvement at wk 4. CONCLUSION: The small advantage of adalimumab in patients with mild to moderate ulcerative colitis and lost response or intolerance to infliximab needs to be confirmed in randomised, double-blind, placebo-controlled trials.

Koslowski MJ, Kübler I, Chamaillard M, Schaeffeler E, Reinisch W, Wang G, Beisner J, Teml A, Peyrin-Biroulet L, Winter S, Herrlinger KR, Rutgeerts P, Vermeire S, Cooney R, Fellermann K, Jewell D, Bevins CL, Schwab M, Stange EF, Wehkamp J. · Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany. · PLoS One. · Pubmed #19221600 links to  free full text

Abstract: Reduced expression of Paneth cell antimicrobial alpha-defensins, human defensin (HD)-5 and -6, characterizes Crohn's disease (CD) of the ileum. TCF-4 (also named TCF7L2), a Wnt signalling pathway transcription factor, orchestrates Paneth cell differentiation, directly regulates the expression of HD-5 and -6, and was previously associated with the decrease of these antimicrobial peptides in a subset of ileal CD. To investigate a potential genetic association of TCF-4 with ileal CD, we sequenced 2.1 kb of the 5' flanking region of TCF-4 in a small group of ileal CD patients and controls (n = 10 each). We identified eight single nucleotide polymorphisms (SNPs), of which three (rs3814570, rs10885394, rs10885395) were in linkage disequilibrium and found more frequently in patients; one (rs3814570) was thereby located in a predicted regulatory region. We carried out high-throughput analysis of this SNP in three cohorts of inflammatory bowel disease (IBD) patients and controls. Overall 1399 healthy individuals, 785 ulcerative colitis (UC) patients, 225 CD patients with colonic disease only and 784 CD patients with ileal involvement were used to determine frequency distributions. We found an association of rs3814570 with ileal CD but neither with colonic CD or UC, in a combined analysis (allele positivity: OR 1.27, 95% CI 1.07 to 1.52, p = 0.00737), which was the strongest in ileal CD patients with stricturing behaviour (allele frequency: OR 1.32, 95% CI 1.08 to1.62, p = 0.00686) or an additional involvement of the upper GIT (allele frequency: OR 1.38, 95% CI 1.03 to1.84, p = 0.02882). The newly identified genetic association of TCF-4 with ileal CD provides evidence that the decrease in Paneth cell alpha-defensins is a primary factor in disease pathogenesis.

Chen M, Peyrin-Biroulet L, Xia B, Guéant-Rodriguez RM, Bronowicki JP, Bigard MA, Guéant JL. · Inserm, U724, Laboratory of Cellular and Molecular Pathology in Nutrition, Faculty of Medicine, Nancy-Université, Nancy- Vandoeuvre, France. · BMC Med Genet. · Pubmed #18700049 links to  free full text

Abstract: BACKGROUND: The association of genetic polymorphisms related to metabolism of homocysteine with inflammatory bowel disease has been evidenced in Crohn disease and remains an open question in ulcerative colitis. We evaluated the association of the polymorphisms of MTHFR, MTR, MTRR and TCN2 genes with ulcerative colitis in Central China. METHODS: 168 patients were genotyped for these polymorphisms and compared to 219 matched controls. RESULTS: Methionine synthase 2756G allele frequency was higher in ulcerative colitis than in controls 0.15 (95% C.I. 0.11-0.19) vs 0.09 (95% C.I. 0.07 - 0.12), (P = 0.0137) and predicted ulcerative colitis risk in logistic regression, with an Odds ratio at 1.8 (95% C.I. 1.15-2.84). Methylenetetrahydrofolate reductase 677TT genotype was 2.7-fold more prevalent in individuals with pancolitis than in those with left colitis or proctitis, with respective percentages of 27.3 (95% C.I.16.4-42.0) and 10.5 (95% C.I. 6.3-17.1) (P = 0.0123). The carriage of 677TT or 677CT/1298AC genotypes of methylenetetrahydrofolate reductase was more frequent in cases with pancolitis than in subjects with left colitis or proctitis (P = 0.0048), with an Odds ratio adjusted by age and sex at 3.3 (95% C.I. 1.4-7.9), P = 0.0084) in logistic regression. CONCLUSION: Methionine synthase and methylenetetrahydrofolate reductase are genes of vitamin B12 and folate cellular metabolism associated respectively with risk and extent of ulcerative colitis, at least in Central China. This finding may open new insights, particularly for the potential interest in treating patients carrying the 677TT MTHFR genetic trait and a deficit in folate.

Oussalah A, Laclotte C, Chevaux JB, Bensenane M, Babouri A, Serre AA, Boucekkine T, Roblin X, Bigard MA, Peyrin-Biroulet L. · Inserm, U724, and Department of Hepato-Gastroenterology, University Hospital of Nancy, Vandoeuvre-les-Nancy, France. · Aliment Pharmacol Ther. · Pubmed #18652603 No free full text.

Abstract: BACKGROUND: Adalimumab may be effective in inducing remission in patients with mild-to-moderate ulcerative colitis who had secondary failure to infliximab. AIM: To evaluate long-term efficacy and safety of adalimumab in patients with ulcerative colitis who previously responded to infliximab, and then lost response or became intolerant. METHODS: We report our single-centre experience in 13 patients. The patients received a loading dose of 160 mg of adalimumab subcutaneously in week 0, followed by 80 mg at week 2 and then 40 mg every other week starting at week 4. The primary efficacy measure was the proportion of patients on adalimumab therapy during the study. RESULTS: Median duration of follow-up was 42 weeks (range, 10-100). The mean number of adalimumab infusions was 21 (range, 5-50). The probability of maintaining adalimumab was 92.3%, 84.6%, 60.6% and 32.5% at 1, 3, 6 and 23 months respectively. Six of 13 patients (46.2%) underwent colectomy during the study. No serious toxicities occurred in the study. CONCLUSION: Adalimumab is well-tolerated and may be effective in maintaining clinical remission in a subgroup of patients with ulcerative colitis and lost response or intolerance to infliximab, potentially avoiding colectomy in about half of the patients.

Peyrin-Biroulet L, Colombel JF. · No affiliation provided · Nat Rev Gastroenterol Hepatol. · Pubmed #19575022 No free full text.

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Hejazi R, Colombel JF, Peyrin-Biroulet L. · No affiliation provided · Gastroenterol Clin Biol. · Pubmed #18387427 No free full text.

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Roblin X, Peyrin-Biroulet L, Biroulet LP, Phelip JM, Nancey S, Flourie B. · Department of Gastroenterology, CHU Grenoble, Grenoble, France. · Am J Gastroenterol. · Pubmed #19086961 No free full text.

Abstract: BACKGROUND AND AIMS: A therapeutic level of 6-thioguanine nucleotides (6-TGN) has been reported in inflammatory bowel disease (IBD) patients under azathioprine (AZA). We investigated the threshold value of 6-TGN that may be predictive of AZA refractoriness and its impact on safety profile. METHODS: Patients with normal thiopurine methyltransferase (TPMT) activity (7.5-14 U/mL erythrocytes), suffering from steroid-dependent or active IBD despite AZA use for at least 6 months, were prospectively included. Clinical efficacy, adverse events, and thiopurine metabolite levels were recorded at baseline, 1 month after each dose escalation, and thereafter every 3 months. RESULTS: Fifty-five patients were included (43 with Crohn's disease, 12 with ulcerative colitis). After a mean follow-up of 12 months, 31 patients (56.3%) did not reach clinical remission despite a gradual increase in AZA dose and 6-TGN level of >400 pmol/8 x 10(8) erythrocytes, and were considered refractory to AZA (sensitivity 45%, specificity 100%). Adverse events occurred more frequently in these patients than in responders (42%vs 25%, respectively, P= 0.02). Among 55 patients, 15 cases of myelotoxicity associated with elevated levels of total methylated metabolites (14,500 pmol/8 x 10(8) erythrocytes vs 5,230 pmol/8 x 10(8) erythrocytes in patients without myelotoxicity, P= 0.03) were observed. Patients with total methylated metabolites of >11,100 pmol/8 x 10(8) erythrocytes had an increased risk of developing myelotoxicity (odds ratio [OR] 11.0, 95% confidence interval [CI] 1.1-250, P= 0.05). CONCLUSION: A 6-TGN level of >400 pmol/8 x 10(8) erythrocytes in IBD patients with normal TPMT activity and steroid-dependent or active disease despite an optimal AZA regimen may predict refractoriness to this drug. Furthermore, high levels of methylated derivatives are associated with an increased risk of myelotoxicity.