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Thrombophilia in inflammatory bowel disease may be due to several risk factors, such as a dysbalanced haemostasis with a hypercoagulative state, thrombocytosis, hyperfibrinogenaemia and hyperhomocysteinaemia. In addition, increased concentrations of lipoprotein (a), a modified form of low-density lipoprotein particles, have been associated with a higher risk of thrombotic vascular disease, probably due to inhibition of (local and endothelial) fibrinolysis. The mechanisms regulating the plasma concentration of lipoprotein (a) have not yet been elucidated completely, but genetic factors are involved. Dietary factors seem to play a minor role. In this issue of the journal, Koutroubakis et al. report that lipoprotein (a) concentration is elevated in patients with Crohn's disease, but not in patients with ulcerative colitis. Several other (apo)lipoproteins have a different pattern in patients with inflammatory bowel disease than in a control population of healthy subjects from Crete. These findings add up to the multifactorial nature of thrombophilia in inflammatory bowel disease patients, especially in patients with Crohn's disease, and give rise to speculations about the clinical significance of the observed different lipoprotein metabolism in patients with inflammatory bowel disease.

The Dutch national practice guideline 'Diagnosis and treatment of inflammatory bowel diseases (IBD) in adults' describes the multidisciplinary approach for adult patients with (suspected) IBD, recommended following analysis of the literature according to the principles of evidence based guideline development. Ulcerative colitis and Crohn's disease are associated with temporary or permanent extra-intestinal disorders: reactive inflammatory conditions, associated conditions, and those arising as a consequence of long standing, inflammatory, intestinal disease. Treatment is aimed first at the IBD disease process and subsequently at the specific extra-intestinal conditions if complaints persist. The fertility of women with IBD who have not been operated is comparable with those without this complaint. With the exception of methotrexate in both sexes and of sulfasalazine in men, none of the usual medicines for IBD is known to adversely influence fertility. Fertility decreases following abdominal surgery. IBD patients are advised to restrict onset of pregnancy to a longstanding, quiet phase of the disease (ideally1 year). The risk of complications during pregnancy is not elevated when IBD is in remission, but is increased during active disease. Nulliparae with an ileoanal pouch have approximately 50% long term risk of developing faecal incontinence; a planned full-term Caesarean section may be beneficial in such cases. Complicated perianal disease is similarly an indication for non-vaginal delivery. The life expectancy for patients with ulcerative colitis is normal, but is slightly lower in patients with Crohn's disease. These positive findings have not yet been incorporated into the practice of life insurance providers. The diversity of IBD patient health care and its delivery by many professionals places stringent requirements on the organisation of care by hospitals and those providing treatment. The transfer process from paediatric specialist to gastroenterologist affects both patients and parents deeply.

The Dutch national practice guideline 'Diagnosis and treatment of inflammatory bowel diseases (IBD) in adults' describes the multidisciplinary approach for adult patients with (suspected) IBD, recommended following analysis of the literature according to the principles of evidence based guideline development. The symptoms on first presentation of a patient with IBD are mainly connected with the localisation and severity of the disease and less with the resulting diagnosis 'Crohn's disease' or 'ulcerative colitis'. There is no test by which the diseases can be distinguished with certainty. Clinical course, ileocolonoscopy and histopathological investigation following biopsy form the 'gold standard' for diagnosis of IBD. The final diagnostic step is disease assessment according to the Montreal classification in order to enable unambiguous communication with medical professionals. The first aim of treatment is to treat and stabilise active disease (induction therapy); at the same time maintenance therapy is initiated. A step-up approach is recommended for both treatment aims. Surgical intervention is indicated if the medical treatment is ineffective, in case of intractable gastrointestinal bleeding, in clinically significant gastrointestinal stenosis due to fibrotic scar tissue, or if complications of the inflammation occur such as abscess, peritonitis, or complicated fistula formation. Nutrition and diet do not play a primary therapeutic role in treatment of adult patients with IBD. However, supportive nutritional care is warranted. Probiotics have a demonstrable effect in preventing pouchitis, but not in the treatment of IBD. Alternative medicine has no role to play in the treatment of IBD. The risk of developing colorectal carcinoma is slightly elevated in IBD patients. Therefore, endoscopic surveillance strategies, aimed at early detection of dysplasia, is indicated according to a schedule in which the frequency increases according to the time elapsed since first clinical signs of IBD.

Publisher Summary Inflammatory bowel diseases (IBD) are a group of chronic inflammatory disorders of the gastrointestinal tract of unknown origin; they comprise three main entities—ulcerative colitis (UC), Crohn's disease (CD), and indeterminate colitis. Indeterminate colitis represents a patient group that cannot be classified as either UC or CD, but which constitutes about 10% of IBD patients. The majority of these patients eventually develop the features of UC. CD and UC show variation in the individual clinical presentation and outcome that is most likely due to differences in genetic susceptibility, exposure to environmental factors, the commensal bacteria in the intestine, and the intestinal immune system. They also show major differences and it is not clear whether both disorders are related at the molecular level. However, more and more evidence is emerging that a dysregulated mucosal immune response underlies the chronic intestinal inflammation, potentially initiated by a dysfunctional intestinal barrier. Screening for IBD is performed in high-risk families or in the population at large. UC is diagnosed by a combination of characteristic clinical, endoscopic, and pathohistological findings. CD is diagnosed by the combination of characteristic clinical, endoscopic, and pathohistological findings.

Background Thioguanine has been used for the treatment of inflammatory bowel disease, in particular for patients who failed conventional thiopurine therapy. To date, thioguanine has been infrequently studied in ulcerative colitis. Aim To evaluate the tolerability, safety and efficacy of thioguanine in the treatment of ulcerative colitis. Methods A database analysis was performed on inflammatory bowel disease patients who had failed conventional thiopurine therapy and were treated with thioguanine. Rates and reasons for treatment failure were assessed. Laboratory values, abdominal ultrasonography, liver biopsy and endoscopic remission rates were evaluated. Results Forty-six patients were included and median treatment duration was 22 months (range 0.3–72.0). Nine patients failed thioguanine therapy: six due to adverse events, three due to therapy resistance. Concomitant treatment with aminosalicylates protected against thioguanine failure (hazard ratio (HR) 0.11, 95% CI 0.03–0.48). When performed, ultrasonography (n = 21) revealed no suspected therapy-related pathology in all but one patient, in whom hepatomegaly was observed. Liver histology (n = 12) predominantly revealed no abnormalities (n = 4) or non-specific regeneration (n = 4); none showed nodular regenerative hyperplasia. At follow-up, 40% of colonoscopies revealed endoscopic remission as compared with 10% at baseline (P = 0.180). Conclusions Long-term use of thioguanine appears to be well tolerated and relatively safe in ulcerative colitis patients who failed conventional thiopurine therapy.

Thiopurines such as azathioprine (AZA) and 6-mercaptopurine are frequently used for the treatment of inflammatory bowel diseases. Patients with low or absent thiopurine S-methyltransferase (TPMT) activity, resulting in high 6-thioguanine nucleotide levels, have an increased risk of developing leukopenia. Alternatively, certain viral infections could induce leukopenia. We present the case of an adult Crohn's disease patient with a parvovirus B19 infection and leukopenia during long-term AZA therapy. The uncomplicated long-term use of adequately-dosed AZA and stable non-toxic metabolite levels could not acknowledge TPMT deficiency as a primary cause of the leukopenia. parvovirus B19 was assumed to induce the leukopenia by restraining myeloid proliferation. In addition, AZA probably potentiated susceptibility to this viral infection and may have inhibited adequate immunological defense. Leukopenia during thiopurine therapy not explained by TPMT deficiency could be induced by parvovirus B19 infection and compels temporal but not permanent cessation of thiopurine therapy.

Background: Dectin-1 is a pattern recognition receptor (PRR) expressed by myeloid cells that specifically recognizes b-1,3 glucan, a polysaccharide and major component of the fungal cell wall. Upon activation, dectin-1 signaling converges, similar to NOD2, on the adaptor molecule CARD9 which is associated with inflammatory bowel disease (IBD). An early stop codon polymorphism (c.714T.G) in DECTIN-1 results in a loss-of-function (p.Y238X) and impaired cytokine responses, including TNF-a, interleukin (IL)-1b and IL-17 upon in vitro stimulation with Candida albicans or b-glucan. The aim of the present study was to test the hypothesis that the DECTIN-1 c.714T.G (p.Y238X) polymorphism is associated with lower disease susceptibility or severity in IBD and to investigate the level of dectin-1 expression in inflamed and non-inflamed colon tissue of IBD patients. Methodology: Paraffin embedded tissue samples from non-inflamed and inflamed colon of IBD patients and from diverticulitis patients were immunohistochemically stained for dectin-1 and related to CD68 macrophage staining. Genomic DNA of IBD patients (778 patients with Crohn’s disease and 759 patients with ulcerative colitis) and healthy controls (n=772) was genotyped for the c.714T.G polymorphism and genotype-phenotype interactions were investigated. Principal Findings: Increased expression of dectin-1 was observed in actively inflamed colon tissue, as compared to noninflamed tissue of the same patients. Also an increase in dectin-1 expression was apparent in diverticulitis tissue. No statistically significant difference in DECTIN-1 c.714T.G allele frequencies was observed between IBD patients and healthy controls. Furthermore, no differences in clinical characteristics could be observed related to DECTIN-1 genotype, neither alone, nor stratified for NOD2 genotype. Conclusions: Our data demonstrate that dectin-1 expression is elevated on macrophages, neutrophils, and other immune cells involved in the inflammatory reaction in IBD. The DECTIN-1 c.714T.G polymorphism however, is not a major susceptibility factor for developing IBD. Citation: de Vries HS, Plantinga TS, van Krieken JH, Stienstra R, van Bodegraven AA, et al. (2009) Genetic Association Analysis of the Functional c.714T.G

Background: Tacrolimus is a potent immunomodulator that is effective in the systemic treatment of inflammatory bowel diseases (IBD). However, potential toxicity and systemic (side) effects after oral intake limit its use. We investigated the local applicability and Safety of tacrolimus for distal colitis. Methods: Patients; with refractory left-sided colitis or proctitis were treated for 4 weeks with a daily tacrolimus 2-4 mg enema or 2 mg suppository. Safety of local tacrolimus treatment was assessed by measurement of whole blood tacrolimus trough levels by monitoring liver and kidney function and blood glucose levels. Efficacy of treatment was assessed by comparing the disease activity index (DAI) in ulcerative colitis (UC) patients and endoscopic and histologic appearances before and after 4 weeks of treatment. Results: Nineteen patients with left-sided colitis (n = 7) or proctitis (n 12) were treated. Two patients with left-sided colitis had Crohn's disease (Cl)), the other 17 patients had UC. None of the patients developed side effects. Blood trough levels of tacrolimus were too low to induce systemic immune Suppression. Thirteen of 19 patients (3/5 left-sided UC, 0/2 left-sided CD, and 10/12 proctitis) showed clinical improvement of disease activity after 4 weeks of local tacrolimus treatment. Moreover, a significant improvement of histological appearance was observed in the suppository-treated group. Conclusions: This study demonstrates that local colonic application of tacrolimus 2-4 mg daily in patients with refractory distal colitis is Feasible, probably safe, and potentially efficacious, and therefore opens the need for a further, randomized trial.

Loss of bone mass and an increased risk of fractures is an issue of major concern for physicians treating inflammatory bowel disease patients. Multiple causes for decreased bone mass have been identified in the past, but the role of inflammation may be of pivotal importance. We here discuss the latest insights into the pathogenesis of inflammatory bowel disease-related bone loss and the implications for treatment.

In a report recently published in this journal (1), Reinshagen et al., who investigated 6-thioguanine nucleotide (6-TGN) concentrations in patients with inflammatory bowel disease (IBD), concluded that standard and adapted dosing of azathioprine led to identical 6-TGN concentrations and remission rates and that therapeutic drug monitoring of thiopurine therapy was of no clinical benefit in patients with a wild-type thiopurine S-methyltransferase ( TPMT ) genotype. As Reinshagen et al. point out, monitoring thiopurine metabolites is a more or less accepted method for assessing pharmacotherapeutic compliance. The use of monitoring to assess the achievement of therapeutic goals is still a matter of ongoing discussion, however, and the study conducted by Reinshagen et al. provides valuable data to inform this debate. Unfortunately, critical analytical problems still plague thiopurine research. Important differences exist in analytical procedures and reference values (2), and the stability of the thiopurine metabolites themselves is an issue as well. Few …

OBJECTIVES: Our aim was to explore the diagnostic value of fasting citrulline concentrations to detect decreased intestinal energy absorption in patients with recently diagnosed celiac disease (CeD), refractory celiac disease (RCeD), and short bowel syndrome (SBS). Decreased intestinal energy absorption is regarded a marker of intestinal failure. METHODS: Fasting plasma citrulline concentrations were determined by high performance liquid chromatography (HPLC) in a prospective study of 30 consecutive adult patients (15 CeD, 9 RCeD, and 16 SBS) and 21 healthy subjects. Intestinal energy absorption capacity using bomb calorimetry was determined in all patients and healthy subjects and was regarded as the gold standard for intestinal energy absorption function. RESULTS: The mean fasting plasma citrulline concentration was lower in RCeD patients than in healthy subjects (28.5 ± 9.9 vs 38.1 ± 8.0 μmol/L, P < 0.05) and CeD patients (28.5 ± 9.9 vs 38.1 ± 6.4 μmol/L, P < 0.05), however, clearly within reference values. The mean intestinal energy absorption capcity was lower in SBS patients than in healthy subjects (64.3 ± 18.2 vs 90.3 ± 3.5%, P < 0.001), CeD patients (64.3 ± 18.2 vs 89.2 ± 3.4%, P < 0.001), and the RCeD group (64.3 ± 18.2 vs 82.3 ± 11.7%, P < 0.01). No relation was observed between fasting plasma citrulline concentration and intestinal energy absorption capacity (Pearson r = 0.09, P = 0.56). The area under the ROC curve for fasting plasma citrulline to detect decreased intestinal energy absorption capcity (i.e., < 85%) was 0.50. CONCLUSION: Fasting plasma citrulline concentrations have poor test characteristics for detection of decreased intestinal energy absorption capacity in patients with enterocyte damage.

Objective Haemostatic changes may be involved in the pathogenesis and progression of ulcerative colitis. We studied longitudinally inflammatory and haemostatic parameters in patients treated for severe ulcerative colitis. Design and setting We carried out a descriptive study of longitudinal blood measurements in patients with severe ulcerative colitis from one large regional hospital. Methods Nineteen patients with severe ulcerative colitis were assessed by an endoscopic score and a patient score at baseline. Patients were assessed by patient scores during treatment at scheduled intervals. At each visit, inflammatory and haemostatic parameters were determined. Results At baseline, the erythrocyte sedimentation rate, C-reactive protein, leucocyte and granulocyte count, thrombin-antithrombin complexes, prothrombin fragment 1+2, fibrinogen and degradation products of fibrinogen and fibrin were increased in patients when compared with controls, whereas albumin concentration and factor XIII activity were significantly lower. Antithrombin activity was normal. During treatment, the median patient score diminished significantly from 12 to 4.5 points after 2 weeks, decreased further to 4 points after 4 weeks and remained below 4 points throughout the remaining study period. Inflammation parameters returned to within the reference range in two patients after 4 weeks, whereas the coagulation markers prothrombin fragment 1+2 and thrombin-antithrombin complexes returned to normal values after 8 weeks and 24 weeks, respectively. In contrast with markers of inflammation, slightly increased concentrations of the degradation products of both fibrinogen and fibrin were found for almost 1 year, which indicated low-grade activation of coagulation and fibrinolysis. Conclusions These results are compatible with a condition of persistent hypercoagulation in patients with ulcerative colitis who are in clinical remission. Persistent hypercoagulation may contribute to the clinical course of ulcerative colitis.

Extraintestinal complications of inflammatory bowel disease (IBD) are often secondary to the underlying disease. Therefore, the first priority is to get active IBD into remission with medications, since surgery for IBD is not indicated for the treatment of extraintestinal complications. Symptoms of extraintestinal complications usually can be treated with simple agents; the treatment of patients with refractory symptoms and the use of more complex drug regimens should be done in cooperation with specialists on affected organ systems. Careful consideration of prescribed drugs is necessary because they may negatively influence the course of IBD.

OBJECTIVE: In healthy conditions, factors inducing or inhibiting coagulation and factors inducing or inhibiting fibrinolysis are in balance. In ulcerative colitis, hypercoagulation is presumed, which may explain part of the clinical features of this disease. Therapy strategies affecting hemostasis may improve the course of ulcerative colitis. This study was conducted to evaluate the balance of coagulation and fibrinolysis in the course of treatment of active ulcerative colitis. METHODS: Patients with active ulcerative colitis were studied by serial determination of markers of the coagulation cascade (thrombin-antithrombin complexes and fibrin degradation products [FbDP]) and the fibrinolytic cascade (fibrinogen degradation products [FgDP]). Parameters of inflammation were also measured (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], albumin, platelet count, and fibrinogen). Disease activity was assessed by endoscopic and histopathological scores. Follow-up measurement was performed in the course of treatment at the third or fourth month after baseline. Measurements were compared with healthy controls. RESULTS: Thirty-three patients and 22 healthy controls were included. During active ulcerative colitis, inflammatory parameters (CRP, ESR, platelet count) and hemostatic parameters (thrombin-antithrombin complexes, fibrinogen, FgDP, and FbDP) were elevated in comparison with healthy controls. Albumin was decreased and antithrombin-III remained unchanged. During treatment, disease activity decreased significantly endoscopically and histopathologically (p < 0.001). CRP, ESR, platelet count, and fibrinogen also decreased significantly. The hemostatic balance, expressed as the ratio between the plasmin-dependent generation of FgDP and coagulation-dependent generation of FbDP, increased from 0.69 to 1.12 during treatment, mainly because of a decrease of FbDP. In healthy controls, this ratio was 1.33. CONCLUSIONS: The coagulation and fibrinolytic cascades were activated in active ulcerative colitis, with a hemostatic imbalance in favor of coagulation. This hypercoagulability persisted in 20% (7/33) of patients with ulcerative colitis in remission. The decrease of FbDP and the increase in the FgDP/FbDP ratio during reconvalescence of ulcerative colitis showed that the coagulation cascade was more activated than the fibrinolytic cascade in active disease.

Inflammatory bowel disease (IBD), in particular Crohn's disease refractory to conventional therapy, fistulizing Crohn's disease and chronic active ulcerative colitis, generally respond well to anti-tumor necrosis factor (TNF) therapy. However, serious side effects do occur, necessitating careful monitoring of therapy. Potential side effects of anti-TNF therapy include opportunistic infections, which show a higher incidence when concomitant immunosuppression is used. Furthermore, antibody formation against anti-TNF is associated with decreased efficacy and an increased frequency of infusion reactions. The hypothesis of a slightly increased risk of lymphomas in IBD patients treated with anti TNF-therapy is debatable, since most studies lack the specific design to properly address this issue. Alarmingly, the occurrence of hepatosplenic T-cell lymphomas coincides with combined immunosuppressive therapy. Despite the potential serious side effects, anti-TNF therapy is an effective and relatively safe treatment option for refractory IBD. Future research is needed to answer important questions, such as the long-term risk of malignancies, safety during pregnancy, when to discontinue and when to switch anti-TNF therapy, as well as to determine the balance between therapeutic and toxic effects.

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 NOD2deficient CD patients. Genes and Immunity (2008) 9, 274–278; doi:10.1038/gene.2008.9; published online 13 March 2008

Contains fulltext : 69534.pdf (Publisher’s version ) (Open Access) 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.

Mesalazine is a safe drug, although adverse events may be seen in a minority of patients. This applies also to pregnant women and children. The role of mesalazine in combination therapy to improve efficacy and concomitant drug pharmacokinetics, or in chemoprevention against inflammatory bowel disease (IBD)-related colonic carcinoma has not yet been completely elucidated. Therapeutic success of mesalazine may be optimized by a combination of high dose and low frequency of dosage to improve compliance. Therefore, due to its superior safety profile and pharmacokinetic characteristics, mesalazine is preferable to sulphasalazine. This paper reviews the literature concerning mechanisms of action, indications and off-label use, pharmacokinetic properties and formulations, therapeutic effi cacy, compliance, paediatric indications, chemoprevention, and safety issues and adverse event profi le of mesalazine treatment versus sulphasalazine. It also highlights these controversies in order to clarify the potential benefi ts of mesalazines in IBD therapy and evidence for its use.

INFLIXIMAB FOR TREATMENT OF PERINEAL METASTATIC CROHN'S DISEASE. Klaas van der Linde, Maarten A. Meijssen, Ad A. van Bodegraven, Ruud A. van Hogezand, Stephan J. Marks, Daan W. Hommes, Sander 1. van Deventer, Univ Hosp Rotterdam, Rotterdam, Netherlands; Westeinde Hosp, The Hague, Netherlands; Free Univ Hosp, Amsterdam, Netherlands; Leiden Univ Med Ctr, Leiden, Netherlands; Centocor B V, Leiden, Netherlands; Acad Med Ctr, Amsterdam, Netherlands.