Crohn Disease: van Bodegraven AA

Hommes DW, Oldenburg B, van Bodegraven AA, van Hogezand RA, de Jong DJ, Romberg-Camps MJ, van der Woude J, Dijkstra G, Anonymous00077. · Academic Medical Centre, Amsterdam, the Netherlands. · Neth J Med. · Pubmed #16929083 links to  free full text

Abstract: Infliximab is an accepted induction and maintenance treatment for patients with Crohn's disease. The effectiveness of infliximab has been demonstrated for both active luminal disease and for enterocutaneous fistulisation. In addition, infliximab can be administered for extraintestinal symptoms of Crohn's disease, such as pyoderma gangrenosum, uveitis and arthropathy. Maintenance treatment with infliximab is effective and is regarded as safe as long as the necessary safety measures are heeded. Infusion reactions occur in 3 to 17% of the patients and are associated with the formation of antibodies to infliximab. A reduction in infusion reactions is possible by the concurrent administration of steroids and the use of immunosuppressants (azathioprine, 6-mercaptopurine, methotrexate). Furthermore, immunosuppressants increase the duration of the response to infliximab. For these reasons, the concomitant use of immunosuppressants with infliximab is recommended. Infections and most specifically tuberculosis need to be ruled out before infliximab is administered. Up to now, there are no indications for a connection between an increased risk for malignancies and treatment with infliximab.

de Boer NK, Derijks LJ, Keizer-Garritsen JJ, Lambooy LH, Ruitenbeek W, Hooymans PM, van Bodegraven AA, de Jong DJ. · Department of Gastroenterology and Hepatology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, the Netherlands. · J Clin Pharmacol. · Pubmed #17244769 No free full text.

Abstract: The proposed metabolic advantage of 6-thioguanine (6-TG) is the direct conversion into the pharmacologically active 6-thioguaninenucleotides (6-TGN). The authors assessed metabolic characteristics of 6-TG treatment in patients with Crohn's disease (N = 7) on therapy with 20 mg 6-TG. 6-thioguanine-monophosphate (6-TGMP), 6-thioguanine-diphosphate (6-TGDP), and 6-thioguanine-triphosphate (6-TGTP) were measured by high-performance liquid chromatography analysis in erythrocytes. Thiopurine S-methyltransferase activity and total 6-TGN levels were determined by standard methods. High interindividual variance in metabolite measurements was observed. Main metabolites were 6-TGTP (median = 531 pmol/8 x 10(8) red blood cells) and 6-TGDP (median = 199 pmol/8 x 10(8) red blood cells). Traces of 6-TGMP (median = 39 pmol/8 x 10(8) red blood cells) and 6-TG (2 patients) could be detected. 6-TGN levels correlated with 6-TGTP levels (r = 0.929, P = .003) and with the sum of separate nucleotides (r = 0.929, P = .003). No correlations were established between TPMT activity (median = 13 pmol/h/10(7)) and 6-TG metabolites. The 1-step metabolism of 6-TG still leads to high interindividual variance in metabolite concentrations. Total 6-TGN level monitoring may suffice for clinical practice.

Karimi O, Peña AS, van Bodegraven AA. · Laboratory of Immunogenetics, VUmc, Amsterdam, the Netherlands. · Drugs Today (Barc). · Pubmed #16193098 No free full text.

Abstract: Arthralgia is a common extraintestinal manifestation of inflammatory bowel disease (IBD). Alterations of the immunologic regulation in the gut may contribute to the pathogenesis of arthralgia. Probiotics (VSL#3) have proven effective in the treatment of pouchitis in patients with ileal pouch anal anastomosis after panproctocolectomy for ulcerative colitis both in maintaining remission and in preventing a flare-up without side effects. The aim of this study was to determine the safety and efficacy of VSL#3 in patients with quiescent IBD who suffered from arthralgia for more than two weeks. An open-label trial was conducted using VSL#3. Pre- and post-treatment joint pain intensity were measured on the Ritchie Articular Index and visual analog scale. Disease activity of the bowel was assessed by the Truelove-Witts and the Harvey-Bradshaw scores. Sixteen of 29 patients completed the trial; in 10 of the 16 patients a statistically significant improvement was documented by the Ritchie Articular Index. No one of the patients had a relapse of intestinal disease while on probiotics. These preliminary results suggest that the probiotic mixture VSL#3 may be an alternative treatment for arthralgia in patients with IBD without inducing exacerbation of the disease. Because probiotics may be effective in the treatment of IBD as well, our results suggest that patients with active disease and arthralgia may also derive benefit from this treatment. Proper randomized controlled studies are indicated.

van Bodegraven AA, Sloots CE, Felt-Bersma RJ, Meuwissen SG. · Department of Gastroenterology, Free University Hospital, Amsterdam, The Netherlands. · Dis Colon Rectum. · Pubmed #11786762 No free full text.

Abstract: PURPOSE: Infliximab has been reported to improve fistulizing Crohn's disease. Moreover, prompt healing of mucosal ulcers has been described. Whether fistulas disappear or remainders of fistulas persist is unknown. This study documents fistulous tracts before and after infliximab therapy by means of hydrogen peroxide-enhanced endosonography METHODS: Eight patients with perianal, vaginal, or perineal fistulas were treated with a triplet of infliximab 5 mg/kg infusions. At baseline, and at Week 4 after the last infusion, fistulas were documented by local inspection, digital examination, and hydrogen peroxide-enhanced anal or vaginal endosonography. RESULTS: Patients with vaginal or perineal fistulas did not respond clinically to therapy, whereas patients with perianal fistulas improved considerably. However, in all patents remainders of fistulous tracts were demonstrated by endosonographic techniques. CONCLUSIONS: Short-term treatment of Crohn's disease-associated fistulas with infliximab does not induce disappearance of fistulous tracts, irrespective of therapeutic response.

Weersma RK, Stokkers PC, van Bodegraven AA, van Hogezand RA, Verspaget HW, de Jong DJ, van der Woude CJ, Oldenburg B, Linskens RK, Festen EA, van der Steege G, Hommes DW, Crusius JB, Wijmenga C, Nolte IM, Dijkstra G, Anonymous00042. · Department of Gastroenterology and Hepatology, University Medical Center Groningen and University of Groningen, P.O. Box 30001, 9700 RB Groningen, The Netherlands. · Gut. · Pubmed #18824555 No free full text.

Abstract: BACKGROUND: Crohn's disease and ulcerative colitis have a complex genetic background. We assessed the risk for both the development and severity of the disease by combining information from genetic variants associated with inflammatory bowel disease (IBD). METHODS: We studied 2804 patients (1684 with Crohn's disease and 1120 with ulcerative colitis) and 1350 controls from seven university hospitals. Details of the phenotype were available for 1600 patients with Crohn's disease and for 800 with ulcerative colitis. Genetic association for disease susceptibility was tested for the nucleotide-binding and oligomerisation domain 2 gene (NOD2), the IBD5 locus, the Drosophila discs large homologue 5 and autophagy-related 16-like 1 genes (DLG5 and ATG16L1) and the interleukin 23 receptor gene (IL23R). Interaction analysis was performed for Crohn's disease using the most associated single nucleotide polymorphism (SNP) for each locus. Odds ratios were calculated in an ordinal regression analysis with the number of risk alleles as an independent variable to analyse disease development and severity. RESULTS: Association with Crohn's disease was confirmed for NOD2, IBD5, DLG5, ATG16L1 and IL23R. Patients with Crohn's disease carry more risk alleles than controls (p = 3.85 x 10(-22)). Individuals carrying an increasing number of risk alleles have an increasing risk for Crohn's disease, consistent with an independent effects multiplicative model (trend analysis p = 4.25 x 10(-23)). Patients with Crohn's disease with a more severe disease course, operations or an age of onset below 40 years have more risk alleles compared to non-stricturing, non-penetrating behaviour (p = 0.0008), no operations (p = 0.02) or age of onset above 40 years (p = 0.028). CONCLUSION: Crohn's disease is a multigenic disorder. An increase in the number of risk alleles is associated with an increased risk for the development of Crohn's disease and with a more severe disease course. Combining information from the known common risk polymorphisms may enable clinicians to predict the course of Crohn's disease.

Eshuis EJ, Bemelman WA, van Bodegraven AA, Sprangers MA, Bossuyt PM, van Milligen de Wit AW, Crolla RM, Cahen DL, Oostenbrug LE, Sosef MN, Voorburg AM, Davids PH, van der Woude CJ, Lange J, Mallant RC, Boom MJ, Lieverse RJ, van der Zaag ES, Houben MH, Vecht J, Pierik RE, van Ditzhuijsen TJ, Prins HA, Marsman WA, Stockmann HB, Brink MA, Consten EC, van der Werf SD, Marinelli AW, Jansen JM, Gerhards MF, Bolwerk CJ, Stassen LP, Spanier BW, Bilgen EJ, van Berkel AM, Cense HA, van Heukelem HA, van de Laar A, Slot WB, Eijsbouts QA, van Ooteghem NA, van Wagensveld B, van den Brande JM, van Geloven AA, Bruin KF, Maring JK, Oldenburg B, van Hillegersberg R, de Jong DJ, Bleichrodt R, van der Peet DL, Dekkers PE, Goei TH, Stokkers PC. · Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands. · BMC Surg. · Pubmed #18721465 links to  free full text

Abstract: BACKGROUND: With the availability of infliximab, nowadays recurrent Crohn's disease, defined as disease refractory to immunomodulatory agents that has been treated with steroids, is generally treated with infliximab. Infliximab is an effective but expensive treatment and once started it is unclear when therapy can be discontinued. Surgical resection has been the golden standard in recurrent Crohn's disease. Laparoscopic ileocolic resection proved to be safe and is characterized by a quick symptom reduction.The objective of this study is to compare infliximab treatment with laparoscopic ileocolic resection in patients with recurrent Crohn's disease of the distal ileum with respect to quality of life and costs. METHODS/DESIGN: The study is designed as a multicenter randomized clinical trial including patients with Crohn's disease located in the terminal ileum that require infliximab treatment following recent consensus statements on inflammatory bowel disease treatment: moderate to severe disease activity in patients that fail to respond to steroid therapy or immunomodulatory therapy. Patients will be randomized to receive either infliximab or undergo a laparoscopic ileocolic resection. Primary outcomes are quality of life and costs. Secondary outcomes are hospital stay, early and late morbidity, sick leave and surgical recurrence. In order to detect an effect size of 0.5 on the Inflammatory Bowel Disease Questionnaire at a 5% two sided significance level with a power of 80%, a sample size of 65 patients per treatment group can be calculated. An economic evaluation will be performed by assessing the marginal direct medical, non-medical and time costs and the costs per Quality Adjusted Life Year (QALY) will be calculated. For both treatment strategies a cost-utility ratio will be calculated. Patients will be included from December 2007. DISCUSSION: The LIR!C-trial is a randomized multicenter trial that will provide evidence whether infliximab treatment or surgery is the best treatment for recurrent distal ileitis in Crohn's disease. TRIAL REGISTRATION: Nederlands Trial Register NTR1150.

de Boer NK, van Bodegraven AA, de Graaf P, van der Hulst RW, Zoetekouw L, van Kuilenburg AB. · Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands. · Ther Drug Monit. · Pubmed #18520612 No free full text.

Abstract: There is an increased risk of developing bone marrow depression and infections during azathioprine therapy for inflammatory bowel disease. Patients with low or absent thiopurine S-methyltransferase (TPMT) activity have an increased risk of developing myelotoxicity. We describe a patient who developed pancytopenia combined with cytomegalovirus pneumonia after several years of azathioprine use. The bone marrow depression was probably caused by the viral infection, as all others causative factors were unlikely. Surprisingly, we observed grossly elevated TPMT activity (182 nmol/g/h) during the recovery phase, following the pancytopenic period. After complete recovery of the bone marrow suppression, TPMT activity returned to usual reference activity (43 nmol/g/h). This remarkable change in enzymatic activity of TPMT may be explained by differences in the age of red blood cells, as younger erythrocytes have a higher TPMT activity. Determination of a patient's TPMT status by phenotyping should therefore not be performed just after bone marrow depression or in cases of activated erythropoieses.

Hadithi M, Cazemier M, Meijer GA, Bloemena E, Felt-Bersma RJ, Mulder CJ, Meuwissen SG, Pena AS, van Bodegraven AA. · Department of Gastroenterology, VUmc University Medical Center, Amsterdam, PO Box 7057, Amsterdam 1007 MB, The Netherlands. · World J Gastroenterol. · Pubmed #18506923 links to  free full text

Abstract: AIM: To describe the characteristics of Dutch patients with chronic inflammatory bowel disease (IBD) first diagnosed above 60 years of age-a disease also known as old-age colitis (OAC) and to highlight a condition that has a similar appearance to IBD, namely segmental colitis associated with diverticular disease (SCAD). METHODS: A retrospective longitudinal survey of patient demographic and clinical characteristics, disease characteristics, diagnostic methods, management and course of disease was performed. The median follow-up period was 10 years. RESULTS: Of a total of 1100 IBD patients attending the Department of Gastroenterology, 59 (5%) [median age 82 years (range 64-101); 25 male (42%)] were identified. These patients were diagnosed with ulcerative colitis (n = 37, 61%), Crohn's disease (n = 14, 24%), and indeterminate colitis (n = 8, 15%). Remission was induced in 40 (68%) patients within a median interval of 6 mo (range 1-21) and immunosuppressive therapy was well tolerated. Histological evaluation based on many biopsy samples and the course of the disease led to other diagnosis, namely SCAD instead of IBD in five (8%) patients. CONCLUSION: OAC is not an infrequent problem for the gastroenterologist, and should be considered in the evaluation of older patients with clinical features suggestive of IBD. Extra awareness and extensive biopsy sampling are required in order to avoid an erroneous diagnosis purely based on histological mimicry of changes seen in SCAD, when diagnosing IBD in the presence of diverticulosis coli.

Zhernakova A, Festen EM, Franke L, Trynka G, van Diemen CC, Monsuur AJ, Bevova M, Nijmeijer RM, van 't Slot R, Heijmans R, Boezen HM, van Heel DA, van Bodegraven AA, Stokkers PC, Wijmenga C, Crusius JB, Weersma RK. · Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands. · Am J Hum Genet. · Pubmed #18439550 links to  free full text

Abstract: The two main phenotypes of inflammatory bowel disease (IBD)--Crohn's disease (CD) and ulcerative colitis (UC)--are chronic intestinal inflammatory disorders with a complex genetic background. Using a three-stage design, we performed a functional candidate-gene analysis of innate immune pathway in IBD. In phase I, we typed 354 SNPs from 85 innate immunity genes in 520 Dutch IBD patients (284 CD, 236 UC) and 808 controls. In phase II, ten autosomal SNPs showing association at p < 0.006 in phase I were replicated in a second cohort of 545 IBD patients (326 CD, 219 UC) and 360 controls. In phase III, four SNPs with p < 0.01 in the combined phase I and phase II analysis were genotyped in an additional 786 IBD samples (452 CD, 334 UC) and 768 independent controls. Joint analysis of 1851 IBD patients (1062 CD, 789 UC) and 1936 controls demonstrated strong association to the IL18RAP rs917997 SNP for both CD and UC (p(IBD) 1.9 x 10(-8); OR 1.35). Association in CD is independently supported by the Crohn's disease dataset of the Wellcome Trust Case Control Consortium (imputed SNP rs917997, p = 9.19 x 10(-4)). In addition, an association of the CARD9 rs10870077 SNP to CD and UC was observed (p(IBD) = 3.25 x 10(-5); OR 1.21). Both genes are located in extended haplotype blocks on 2q11-2q12 and 9q34.3, respectively. Our results indicate two IBD loci and further support the importance of the innate immune system in the predisposition to both CD and UC.

Borm ME, van Bodegraven AA, Mulder CJ, Kraal G, Bouma G. · Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. · Genes Immun. · Pubmed #18340358 No free full text.

Abstract: The mechanism by which mutations in NOD2 predispose to Crohn's disease (CD) is incompletely understood. In mice, NOD2 has been found to function as a negative regulator of Toll-like receptor 2 (TLR2) signaling. In contrast, studies in humans so far showed no negative regulatory interaction between NOD2 and TLR2, and in fact suggest a synergistic effect between the two. Here, we show that this interaction is dose dependent. Adding low doses of muramyl dipeptide (MDP) to TLR2 primed monocytes results in a significant increase in cytokine production, whereas adding higher doses of MDP led to a striking downregulation of the responses. This downregulation by high-dose MDP does not occur in monocytes from NOD2-deficient patients. The inhibitory role of NOD2 at high concentrations of MDP implicates a safety mechanism to prevent exaggerated antibacterial immune responses in the gut to high or perpetuating bacterial load. This regulatory mechanism is lost in NOD2-deficient CD patients.

D'Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman H, De Vos M, van Deventer S, Stitt L, Donner A, Vermeire S, Van de Mierop FJ, Coche JC, van der Woude J, Ochsenkühn T, van Bodegraven AA, Van Hootegem PP, Lambrecht GL, Mana F, Rutgeerts P, Feagan BG, Hommes D, Anonymous00044, Anonymous00045. · Imelda Gastrointestinal Clinical Research Centre, Bonheiden, Belgium. · Lancet. · Pubmed #18295023 No free full text.

Abstract: BACKGROUND: Most patients who have active Crohn's disease are treated initially with corticosteroids. Although this approach usually controls symptoms, many patients become resistant to or dependent on corticosteroids, and long exposure is associated with an increased risk of mortality. We aimed to compare the effectiveness of early use of combined immunosuppression with conventional management in patients with active Crohn's disease who had not previously received glucocorticoids, antimetabolites, or infliximab. METHODS: We did a 2-year open-label randomised trial at 18 centres in Belgium, Holland, and Germany between May, 2001, and January, 2004. We randomly assigned 133 patients to either early combined immunosuppression or conventional treatment. The 67 patients assigned to combined immunosuppression received three infusions of infliximab (5 mg/kg of bodyweight) at weeks 0, 2, and 6, with azathioprine. We gave additional treatment with infliximab and, if necessary, corticosteroids, to control disease activity. 66 patients assigned to conventional management received corticosteroids, followed, in sequence, by azathioprine and infliximab. The primary outcome measures were remission without corticosteroids and without bowel resection at weeks 26 and 52. Analysis was by modified intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00554710. FINDINGS: Four patients (two in each group) did not receive treatment as per protocol. At week 26, 39 (60.0%) of 65 patients in the combined immunosuppression group were in remission without corticosteroids and without surgical resection, compared with 23 (35.9%) of 64 controls, for an absolute difference of 24.1% (95% CI 7.3-40.8, p=0.0062). Corresponding rates at week 52 were 40/65 (61.5%) and 27/64 (42.2%) (absolute difference 19.3%, 95% CI 2.4-36.3, p=0.0278). 20 of the 65 patients (30.8%) in the early combined immunosuppression group had serious adverse events, compared with 19 of 64 (25.3%) controls (p=1.0). INTERPRETATION: Combined immunosuppression was more effective than conventional management for induction of remission and reduction of corticosteroid use in patients who had been recently diagnosed with Crohn's disease. Initiation of more intensive treatment early in the course of the disease could result in better outcomes.

de Boer NK, Jarbandhan SV, de Graaf P, Mulder CJ, van Elburg RM, van Bodegraven AA. · Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands. · Am J Gastroenterol. · Pubmed #16771965 No free full text.

Abstract: INTRODUCTION: The use of azathioprine (AZA) in the treatment of autoimmune diseases during pregnancy are believed to be relatively safe, particularly taking into account the potential risks for mother and fetus should the underlying disease become active due to withdrawal of this thiopurine. However, essential evidence on the safety of AZA use during pregnancy is lacking. The determination of the intrauterine exposure to maternal AZA use may provide additional and crucial insights into the safety and teratogenicity of this drug. METHODS: We describe three patients with Crohn's disease and autoimmune hepatitis who were treated with AZA throughout all trimesters of their pregnancies. Thiopurine metabolites (6-thioguaninenucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP)) were measured in the red blood cells (RBC) of mother and infant directly after delivery. RESULTS: The 6-TGN concentration was slightly lower in the RBC of the infant than the mother. No 6-MMP could be detected in the infant. CONCLUSION: The placenta forms a (relative) barrier to AZA and its metabolites. Intrauterine exposure to 6-TGN may be minimized by careful therapeutic drug monitoring of the mother during pregnancy.

de Boer NK, Mulder CJ, van Bodegraven AA. · Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, the Netherlands. · Neth J Med. · Pubmed #16397313 links to  free full text

Abstract: Azathioprine is a frequently used immunosuppressant for managing inflammatory bowel disease (IBD). In recent years the hepatotoxic profile of thiopurines has been recognised. We report the case of a 40-year-old man with Crohn's disease treated with azathioprine. After taking azathioprine (2.2 mg/kg daily) for two years, his liver function tests were found to be elevated. Moreover, a myelodepression was established as platelet and leucocytes counts were lowered. The 6-thioguaninenucleotide level was 738 picomoles/8 x 10(8) per red blood cell, which is well above the proposed upper limit of efficacy and associated with an increased risk of developing a myelodepression. Genotyping of the enzyme thiopurine methyltransferase revealed no mutant alleles. The ultrasonography and CT scan showed signs of portal hypertension (spleen 17 cm and widened splenic vein). A liver biopsy was performed and an incomplete septal liver cirrhosis was found. An upper endoscopy revealed oesophageal varices (grade 2 to 3). Autoimmune and viral liver diseases were ruled out by laboratory parameters. After cessation of therapy, all laboratory parameters normalised. Therefore, azathioprine is believed to be the causative factor for inducing the liver cirrhosis. Continuous monitoring of patients taking thiopurines is mandatory. The role of 6-thioguaninenucleotide levels in inducing myelotoxicity and hepatotoxicity is discussed.

Borm ME, van Bodegraven AA, Mulder CJ, Kraal G, Bouma G. · Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. · Int J Immunogenet. · Pubmed #16313306 No free full text.

Abstract: Nuclear factor kappaB (NF-kappaB) designates a group of critical transcription factors involved in a variety of immunologic and/or inflammatory processes. Conceivably, genes involved in the NF-kappaB pathway make interesting candidate genes for chronic inflammatory disorders, including the inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC). In two mouse models of colitis, strong linkage has been observed with a locus on chromosome 3 that harbours the Nfkb1 gene. In addition, a polymorphism in the promoter region of the human NFKB1 gene was found to be associated with susceptibility to UC. In this study, we searched to confirm this previously found association in IBD in a different population. Allele and genotype frequencies of the -94 ins/delATTG polymorphism were determined in 266 unrelated Dutch Caucasian IBD patients (127 UC, 139 CD), and 155 matched healthy controls. The allele frequency of the deletion was significantly higher in UC patients (P = 0.019), but not in CD patients, compared to healthy controls, and the UC patients homozygous for the -94 ATTG deletion had a younger age of onset. Our findings confirm the previously found association between this polymorphism and susceptibility to UC in an independent study population and adds further evidence for the role of this gene in disease susceptibility.

de Boer NK, de Graaf P, Wilhelm AJ, Mulder CJ, van Bodegraven AA. · Gastroenterology and Hepatology, VU University Medical Centre, The Netherlands. · Aliment Pharmacol Ther. · Pubmed #16128683 links to  free full text

Abstract: BACKGROUND: Tioguanine (thioguanine) has been proposed as a rescue thiopurine for azathioprine or mercaptopurine intolerant inflammatory bowel disease patients. The use of tioguanine leads to high 6-tioguaninenucleotide (6-thioguaninenucleotide) levels in red blood cells but, contra-intuitively, these have yet not been associated with an increased risk of myelotoxicity. AIM: To assess the role of 6-tioguaninenucleotide concentrations in developing myelotoxicity during tioguanine treatment. METHODS: Database analysis of 25 patients treated with tioguanine. Clinical findings and laboratory parameters were related to 6-tioguaninenucleotide levels. RESULTS: One patient developed a myelodepression (21 mg TG/day for 3 months and 6-tioguaninenucleotide 714 pmol/8 x 10(8) red blood cells). 6-Tioguaninenucleotide levels varied greatly between individuals (mean 6-tioguaninenucleotide level 621 pmol/8 x 10(8) red blood cells, s.d. 340 pmol/8 x 10(8) red blood cells and range 34-1653 pmol/8 x 10(8) red blood cells). The TG dosages (mean 20.6 mg/day and median 20 mg/day) did not correlate with 6-tioguaninenucleotide levels (r = 0.31, N.S.). High 6-tioguaninenucleotide levels (>450 pmol/8 x 10(8) red blood cells) did not effect haemoglobin concentrations (mean 8 mmol/L), peripheral leucocyte (mean 7.5 x 10(9)/L) or platelet counts (mean 298 x 10(9)/L). No correlations were established between laboratory parameters, type of disease and 6-tioguaninenucleotide level. CONCLUSION: High 6-tioguaninenucleotide levels in erythrocytes (>450 pmol/8 x 10(8)) during TG treatment compared to azathioprine or mercaptopurine treatment are not indicative for (developing) myelotoxicity.

van der Linde K, Boor PP, van Bodegraven AA, de Jong DJ, Crusius JB, Naber TH, Kuipers EJ, Wilson JH, de Rooij FW. · Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. · Dig Liver Dis. · Pubmed #15843082 No free full text.

Abstract: BACKGROUND AND AIMS: Interleukin-10 is an anti-inflammatory and immunomodulatory cytokine. Interleukin-10 deficient mice are prone to develop chronic colitis. Administration of recombinant human interleukin-10 has been proposed to have a beneficial effect in a subgroup of patients with Crohn's disease. Recently, we found an interleukin-10 Gly15Arg mutation in a family with Crohn's disease which is associated with reduced interleukin-10 secretion by in vitro stimulated monocytes and lymphocytes. We hypothesised that this interleukin-10 mutation plays a role in maintaining the inflammatory process in Crohn's disease in some families. PATIENTS AND METHODS: We evaluated interleukin-10 Gly15Arg in 379 patients with Crohn's disease, and 75 unrelated healthy controls. Also, first degree family members of interleukin-10 Gly15Arg carriers were evaluated. Additionally, mutation carriers and their relatives were evaluated for CARD15 R702W, G908R, and 1007fs. RESULTS: Two patients with Crohn's disease were heterozygous for the interleukin-10 Gly15Arg mutation. No homozygotes were found. The Gly15Arg mutation was not observed in the controls. In first degree family members of the Crohn's disease-affected interleukin-10 Gly15Arg carriers, the mutation was found in Crohn's disease-affected as well as in their apparently healthy individuals. All family members carried one or two CARD15 mutation(s). CONCLUSION: The interleukin-10 Gly15Arg mutation is rare in patients with Crohn's disease, and is not associated with the disease in the Netherlands.

Wierdsma NJ, van Bodegraven AA. · VU Medisch Centrum, 0B 115, Postbus 7057, 1007 MB Amsterdam. · Ned Tijdschr Geneeskd. · Pubmed #15751315 No free full text.

Abstract: Two adult patients, men aged 43 and 45 years, with Crohn's disease, complicated by high-output small-bowel-stomy and short-bowel syndrome due to several intestinal resections, presented with extreme weight loss. Although both patients followed a high-calorie diet combining solid foods and enteral nutrition by nasogastric tube, containing 16,000 kJ and 21,000 kJ, respectively, weight loss continued. Faecal fat excretion and basal metabolic rate were determined, but these could not explain the caloric deficit. Therefore, faecal bomb calorimetry, a measurement of total faecal energy content, was also performed, revealing a considerably higher faecal energy loss than had been calculated from faecal fat excretion; this indicates that faecal carbohydrate loss plays an important supplementary role. A stable weightwas achieved in both patients by prescribing extra food. Therefore, faecal fat excretion is an insufficient indicator of total faecal calorie loss in patients with high-output stomata and short-bowel syndrome. Bomb calorimetry may be considered as a tool to determine the remaining absorptive capacity in short-bowel patients.

Xia B, Crusius JB, Wu J, Zwiers A, van Bodegraven AA, Peña AS. · Department of Gastroenterology, Wuhan University Zhongnan Hospital, Wuhan, China. · Clin Exp Immunol. · Pubmed #12605697 links to  free full text

Abstract: Signal transducer and activator of transcription 6 (STAT6) is a key transcription factor involved in interleukin 4 (IL-4) and IL-13-mediated Th2 response. The STAT6 gene is located on chromosome 12q13.3-14.1 (IBD2 region) and is therefore a positional and functional candidate gene for study in inflammatory bowel disease. We investigated the G2964A polymorphism in the 3' untranslated region of the STAT6 gene in Dutch patients with inflammatory bowel disease and healthy controls. The G2964A polymorphism in the STAT6 gene was genotyped in 141 unrelated Dutch Caucasian patients with ulcerative colitis, 183 patients with Crohn's disease and 173 healthy individuals by PCR and the amplification-created restriction site method. Patients with Crohn's disease were classified according to the Vienna classification and the patients with ulcerative colitis were classified with the age at onset, extent of disease and colectomy. We did not find significant differences in genotype and allele frequencies of the G2964A polymorphism in the STAT6 gene between ulcerative colitis, Crohn's disease and healthy controls. Subgroups of the patients with Crohn's disease classified according to the Vienna classification and those with ulcerative colitis classified according to age of onset, disease extension and colectomy did not differ in the distribution of this polymorphism. The STAT6 G2964A gene polymorphism is not involved in the overall susceptibility or in determining the phenotype of IBD.

Xia B, Crusius JB, Wu J, Zwiers A, van Bodegraven AA, Peña AS. · Dept. of Gastroenterology, Wuhan University Zhongnan Hospital, Wuhan, People's Republic of China. · Scand J Gastroenterol. · Pubmed #12465728 No free full text.

Abstract: BACKGROUND: Inflammatory bowel diseases (IBDs) are characterized by chronic intestinal inflammation as a result of an exaggerated T-cell response. CTLA4, a receptor of activated T cells, has an inhibitory function in regulating T-cell activation. Since CTLA4 gene polymorphisms have been associated with several autoimmune diseases, the aim was to study these gene polymorphisms in patients with IBD in two different populations. METHODS: The C-318T polymorphism in the promoter region and A+49G polymorphism in exon I of the CTLA4 gene were investigated by a PCR-SSP method. We studied 139 unrelated patients with ulcerative colitis (UC), 163 patients with Crohn disease (CD) and 174 healthy controls of Dutch Caucasian origin as well as 35 patients with UC and 62 healthy controls from the Chinese Han population. RESULTS: No significant differences in the distribution of allele, genotype and haplotype frequencies were observed between C-318T and A+49G gene polymorphisms and IBD in Dutch Caucasians and UC in the Chinese Han population. Although the haplotypes of the C-318T and A+49G polymorphisms were distributed differently between Dutch Caucasian and Chinese Han populations, there were no differences in the subgroups of patients with CD classified according to age, localization and behaviour in the Vienna classification and in those with UC classified according to age at onset, disease extension and presence of colectomy in the Dutch patients. However, the CTLA4-318 genotype CC was more frequent in patients with CD over 40 years (93%) than in younger patients (74%) (P = 0.045). CONCLUSION: C-318T and A+49G CTLA4 gene polymorphisms and their haplotypes are not associated in Dutch Caucasian patients with IBD and in Chinese patients with UC.

Murillo L, Crusius JB, van Bodegraven AA, Alizadeh BZ, Peña AS. · Department of Gastroenterology and Laboratory of Immunogenetics, Vrije Universiteit Medical Centre, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. · Immunogenetics. · Pubmed #11976792 No free full text.

Abstract: An insertion mutation at nucleotide 3020 (3020insC) in the CARD15 gene, originally reported as NOD2, has been strongly associated with Crohn's disease. The CARD15 G2722C missense mutation was also shown to be associated with this disease. We studied 130 Dutch Crohn's disease patients, with a median follow up of 9.2 years, in relation to the Vienna classification, and 152 ethnically matched healthy controls. We confirm reports that the CARD15 3020insC mutation increases the susceptibility to Crohn's disease, but we do not confirm this relationship for CARD15 G2722C. Our findings suggest that these mutations are not a marker of a particular form of Crohn's disease according to the Vienna classification. Whether the CARD153020insC and CARD15 G2722C mutations are responsible for a different etiopathogenic mechanism in a subgroup of patients remains to be studied.

van de Scheur MR, van der Waal RI, van Bodegraven AA, Völker-Dieben HJ, Starink TM, van der Waal I. · Department of Dermatology, University Hospital Vrije Universiteit/ACTA, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. · J Clin Gastroenterol. · Pubmed #11960070 No free full text.

Abstract: Crohn's disease can be accompanied by extraintestinal manifestations. The authors report on a 39-year-old patient who presented with cheilitis granulomatosa as the first manifestation of Crohn's disease. Four years later, intestinal Crohn's disease was diagnosed. One year afterward, acute loss of visual acuity from optic neuropathy developed as another rare extraintestinal manifestation of Crohn's disease.

van Bodegraven AA, Meuwissen SG. · Department of Gastroenterology, Academic Hospital Free University, Amsterdam, The Netherlands. · Ital J Gastroenterol Hepatol. · Pubmed #10425570 No free full text.

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Bouma G, van Bodegraven AA, van Waesberghe JH, Mulder CJ, Pieters-van den Bos IC. · No affiliation provided · Am J Gastroenterol. · Pubmed #19352337 No free full text.

This publication has no abstract.

Ouburg S, Mallant-Hent R, Crusius JB, van Bodegraven AA, Mulder CJ, Linskens R, Peña AS, Morré SA. · No affiliation provided · Gut. · Pubmed #15710998 links to  free full text

This publication has no abstract.