Therapy In IBD Research Articles

PWE-233 Single centre comparison of mortality, hospital recorded serious adverse events (SAE) and primary care recorded opportunistic infections (OI) in IBD patients treated with anti-TNF compared to thiopurines alone

IntroductionThe safety profile of anti-TNF therapy in IBD has been examined in previous case series, however these have been in tertiary centres, have not included a control cohort, or review...

P367 Compliance to the scheduled treatment with infliximab. Experience in a tertiary care hospital

Background: Scheduled infliximab infusions are effective inducing and maintaining remission in IBD. Compliance with the schedule is important to avoid infusional reactions and loss of response. The aim of this report is to assess the compliance to this treatment in our Unit. Methods: All infliximab infusions received in the IBD Day Care Centre of our hospital since its opening in March 2007 were recorded. Treatment schedule consists in an induction phase 0, 2, 6 weeks and maintenance every 8 weeks. Treatment intensification was prescribed following medical criteria. Infusion delay was defined when the interval between two maintenance doses exceeded 63 days (9 weeks) or when infusion was delayed more than 5 days from calculated date in the induction phase. Intervals when treatment was stopped due to pregnancy, “drug holidays” by medical criteria, etc were excluded. We define “non-adherent patient” when at least three doses and 25% of the total are delayed. Results: 128 patients received 1508 infliximab infusions in our hospital from March 2007 to October 2011. Mean number of infusions was 11.78 (SD 8.9). 60 patients (46.9%) were male and 68 (53.1%) female. The indication was Crohn’s disease in 98 patients (76.5%) and ulcerative colitis in 30 (23.4%). Age at start of the therapy was 39 years (SD 14.6 range 15 77). 74 patients (57.81%) had some dose delayed, being 1.73 the mean number of infusion delayed (SD 2.4). Mean delay was 11.97 days (SD 16.4 median 7 days). Only 19 (14.84%) patients had at least one interval between doses greater than 12 weeks. 13 patients were defined as non-adherent (10,15%) 8 male (53.3%) and 5 female. The type of disease was Crohn in 9 cases (69.2%) and ulcerative colitis in 4 (30.8%). Differences between adherent (AP) and non-adherent patients (NAP) were analyzed: there is no difference in gender or type of disease. Statistically significant differences were found in mean age at start of the therapy (39.44 SD 14.6 AP vs 25.67 SD 5.6 NAP, p < 0.001), number of doses received 11.78 SD 8.9 AP vs 19.15 SD 7.9, NAP p < 0.001), and time on therapy (202.25 SD 9.6 AP vs 99.3 SD 94.9 NAP, p < 0.001). There is no difference in treatment intensification need between both groups; 24 of 115 patients (20.8%) in adherent vs 3 of 13 (23%) in non-adherent (p =NS). Conclusions: Our patients have a good scheduled doses compliance on infliximab therapy in our Unit, even after years of treatment. Risk factors for poor compliance are young patients and need of prolonged therapy. P368 Routine practice of iron infusion therapy in IBD T. Iqbal1 *, G. Rogler2, C. Hoffman3, J. Stein4. 1University Hospital Birmingham, Gastroenterology, Birmingham, United Kingdom, 2University Hospital Zurich, Klinik fur Gastroenterologie und Hepatologie Department fur Innere Medizin, Zurich, Switzerland, 3Vifor Pharma Ltd., Glattbrugg, Switzerland, 4Interdisciplinary Crohn Colitis Centre Rhein Main, Frankfurt, Germany

P039 Serum MMPs 7 9 and their inhibitors during glucocorticoid and anti-TNF-alpha therapy in IBD

Background: Ulcerative colitis is one of the most common diseases of large intestine in human. It is indicative of increased expression of NO-synthases, predominantly of iNOS, and COX-2. L-arginine is the substrate for nitric oxide, and also for L-ornithine which is the precursor for the synthesis of collagen and polyamines. Purpose of the research was to study the effect of blockage of COX-2 activity with celecoxib combined with injection of L-arginine on the cytoprotective and metabolic processes under experimental ulcerative colitis. Methods: UC was modeled by 1ml of 4% acetic acid injected into rats’ large intestine. In the MMLI were determined: area and degree of destructive changes (histologically), parameters of NO-synthase system, content of TBA products, activity of SOD, catalase and concentration of L-arginine in the plasma of blood Results: The development of UC was accompanied by the destructive changes in the MMLI, enhanced processes of LP, increased content of NO, and considerable activation of iNOS. Histological investigations revealed disorders of mucous barrier of the MMLI, destructive changes of its components, presence of edema, deep erosions, infiltration of lymphocytes. Blocking COX-2 by celecoxib in case of experimental colitis caused reduction of the area of ulcerogenic lesions to 54.9±14.1mm2. Activity of general NOS reduced by 57% (p < 0.01), of iNOS by 58% (p < 0.01), NO content decreased by 29%, and content of TBA products decreased by 20%. Introduction of of L-arginine in case of experimental colitis caused reduction of the area of ulcerogenic lesions to 41.5±28.7mm2. Activity of general NOS reduced by 57% (p < 0.01), of iNOS by 54% (p < 0.01), NO content decreased by 29%, and content of MDA decreased by 20%. In combined action of introduction of L-arginine with the blockage of COX-2 by celecoxib, area of MMLI lesions considerably decreased and was 37.5±25.5mm2 (p < 0.01). Activity of general NOS diminished to the norm and activity of iNOS by 74% (p < 0.01). Content of MDA and catalase was at the level of intact animals. Conclusions: Combined blockage of COX-2 and introduction of L-arginine as determined in our investigations, strengthened their effects and tended to reduce iNOS activity, content of nitric oxide decreased, lipoperoxiation processes and activity of SOD in the MMLI diminished. This provides substantiation for new approaches to the treatment of ulcerative colitis and for development of the drugs capable of combined effect on iNOS and COX-2

P368 Routine practice of iron infusion therapy in IBD

P368 Routine practice of iron infusion therapy in IBD

Therapeutic drug monitoring of thiopurine metabolites in adult thiopurine tolerant IBD patients on maintenance therapy

Background and aimsTherapeutic drug monitoring of active metabolites of thiopurines, azathioprine and 6-mercaptopurine, is relatively new. The proposed therapeutic threshold level of the active 6-thioguanine nucleotides (6-TGN) is ≥235pmol/8×108 erythrocytes. The aim of this prospective cross-sectional study was to compare 6-TGN levels in adult thiopurine tolerant IBD patients with an exacerbation with those in remission, and to determine the therapeutic 6-TGN cut-off level. MethodsHundred IBD patients were included. Outcome measures were thiopurine metabolite levels, calculated therapeutic 6-TGN cut-off level, CDAI/CAI scores, thiopurine dose and TPMT enzyme activity. ResultsForty-one patients had an exacerbation, 59 patients were in remission. In 17% of all patients 6-TGN levels were compatible with non-compliance. The median 6-TGN levels were not significantly different between the exacerbation and remission group (227 versus 263pmol/8×108 erythrocytes, p=0.29). The previous reported therapeutic 6-TGN cut-off level of 235pmol/8×108 erythrocytes was confirmed in this study. Twenty-six of the 41 patients (63%) with active disease had 6-TGN levels below this threshold and 24 of 59 IBD patients (41%) in clinical remission (p=0.04). ConclusionsThiopurine non-compliance occurs frequently both in active and quiescent disease. 6-TGN levels below or above the therapeutic threshold are associated with a significant higher chance of IBD exacerbation and remission, respectively. These data support the role of therapeutic drug monitoring in thiopurine maintenance therapy in IBD to reveal non-compliance or underdosing, and can be used as a practical tool to optimize thiopurine therapy, especially in case of thiopurine non-response

Cytomegalovirus disease, haemophagocytic syndrome, immunosuppression in patients with IBD: ‘A cocktail best avoided, not stirred’

We report two cases of cytomegalovirus (CMV) viraemia resulting in severe pneumonitis and associated haemophagocytic syndrome manifesting in patients with inflammatory bowel disease, on stable doses of azathioprine in clinical remission. In both cases, azathioprine was withdrawn at time of hospital presentation and after delays in diagnosis; intravenous ganciclovir was then administered, with resultant rapid improvement of haematological and clinical parameters. Following recovery, immunomodulators were not recommenced given patient aversion and the theoretical risk of CMV reactivation, albeit the evidence for this approach is limited. CMV-related haemophagocytic syndrome and organ dysfunction, in the context of immunomodulator therapy in IBD are rare but life-threatening, and thus requires further investigation and discussion.

Serum Soluble IL2-Receptor is Increased in a Subpopulation of Crohns Disease Patients, Who Respond to Open Label Use of Ustekinumab, a Human Monoclonal Antibody to IL-12/23p40

for relapse of the individual patient. Results: Of the 34 patients enrolled in this trial 26 patients (14 CD, 12 UC) were evaluable for the per protocol analysis. After completion of the 12 weeks treatment phase 14 out of 26 (53.9%) patients were in remission off corticosteroids (complete responders). Another 9 (34.6%) patients were in remission at a corticosteroid dose equal or lower than their individual threshold dose (partial responders). In total, vidofludimus met the primary endpoint in 88.5% of patients (complete and partial response). Response rates did not differ between Crohn's disease and ulcerative colitis. Vidofludimus was well tolerated, no drug-related serious adverse events were observed. Conclusions: This trial provides first evidence of clinical efficacy of vidofludimus in patients with Crohn's disease and ulcerative colitis. Considering the favorable safety and tolerability profile vidofludimus may have potential as a novel future remission maintenance therapy in IBD. These data substantiate the relevance of IL-17 suppression in IBD as a promising and innovative therapeutic approach.

High Dose Vitamin D Therapy in Paediatric IBD

High Dose Vitamin D Therapy in Paediatric IBD

Azathioprine maintenance therapy in IBD:medium term outcomes from a nurse-delivered IBD monitoring service at a district general hospital

IntroductionAzathioprine is widely acknowledged as the benchmark therapy for maintenance of remission in IBD. Published long term outcome data from the district general hospital setting are limited.MethodsA prospective data base...

Higher Weight Based Doses of Adalimumab Reduces Risk of Surgery at 6 Months

Purpose: Anti-TNFα therapy has demonstrated efficacy in the treatment of moderate-severe Crohn's disease (CD). Both infliximab (IFX) and adalimumab (ADA) have similar rates of remission and response, however both their mode of administration and dosing strategy are different. Whereas IFX is prescribed as a weight based regimen of 5mg/kg or 10 mg/kg infusion, ADA is given subcutaneously in fixed dosing fashion, independent of patient's weight. No study has controlled for weight and its possible effect on remission rates or need for surgical intervention after induction with ADA. Hypothesis: Weight is an important factor in inducing remission in Crohn's disease, and induction regimens with a higher mg/kg dose of ADA are more likely to result in decreased need for surgery. Methods: The Consortium on Outcomes of Biologic Therapy in IBD (COBI) is a prospectively compiled database of patients treated for CD between July 2002 and September 2009 with anti-TNF therapy. A retrospective analysis was performed to determine the effect of induction dosing mg/kg on our primary endpoint, the need for surgical intervention at 6 months time. Both Univariate and Multivariate Analysis were performed. Secondary outcomes were remission and response rates as measured by Harvey Bradshaw Index (HBI). Results: There were 78 patients who received ADA therapy for CD. Of those, only 58 had sufficient data regarding weight, HBI, and surgery to be included in analysis. The mean age for initiation of ADA was 34 years (range 12-73, 56% female). The induction dose was calculated as the mg of ADA received over the 4 week induction period. The range of ADA dosing was 1.73-7.8 mg/kg. There was an association between lower ADA concentration during induction and need for surgical intervention at 6 months (OR 0.49, 95% CI: 0.28-0.84). This held significance in both univariate and multivariate analysis (p=0.009). Initial HBI scores were correlated with need surgical intervention but the study was not powered to detect impact of weight based dosing on remission rates. Conclusion: ADA at higher mg/kg dosing during the induction period of 4 weeks was correlated with a decreased need for surgical intervention at 6 months. The optimal dosing regimen for ADA has been previously described at 160 mg/80 mg, however heavier patients may warrant even higher induction dosing given a likely lower serum concentration in these heavier patients. Trough levels are not commercially available, and existing data has not been stratified by weight. This study demonstrates that a weight based regimen may lead to optimization of ADA. A prospective study where mg/kg dosing is correlated with serum concentration is warranted. Disclosure: Dr Scherl - Speaker's Bureau: Abbott.

W1340 A Novel Approach for Gene Therapy in IBD

W1340 A Novel Approach for Gene Therapy in IBD

W1326 Effect of Initial Medical Treatment and Maintenance Therapy on Patients With Crohn's Disease and Perianal Lesions in Korea

and suspect types were 4(7.4%), 23(42.6%), 27(50.0%) patients, respectively. The median dosage of corticosteroid was 0.58mg/kg (0.39-1.20). There were 25(46.3%) cases with complete remission, 23(42.6%) with partial remission, and 6(11.1%) patients showed no response to corticosteroid therapy after 1 month post-treatment. Three months after the treatment, 22(40.7%) showed prolonged response, 25(46.3%) showed steroid dependency, 3(5.6%) showed refractoriness and 4 (7.4%) received operation respectively. At 1 year, there were 26(48.1%) patients in prolonged response, 19(35.2%) in corticosteroids dependency, and 4(7.4%) that received operation. The cumulative probability of surgery was 17.5% and 49.1% at 1 and 3 years, respectively. Prolonged response at three months was independently associated with decreased risk of surgery in the long-term (P=0.009, HR 0.176, CI 0.0480.649). Conclusions: Short-term response rate to initial corticosteroid therapy in IBD was high, however the responses showed a decreasing tendency along with time. Prolonged response at three month was associated with decreased risk of surgery in the long-term.

596 Increased Risk of Surgery After Attenuation of Anti-TNFα Therapy for Crohn's Disease

Background: The rate of intestinal resection among patients with Crohn's disease may be as high as 80% after 20 years of disease. By inducing mucosal healing and achieving high remission rates, TNFα antagonists reduce hospitalizations and steroid requirement. Early combination treatment with azathioprine (AZA) and anti-TNFα achieves higher remission rates than either infliximab (IFX) or AZA alone. It is presumed that IFX, adalimumab (ADA) and certolizumab (CZP) will also impact on the need for surgery. However, many patients attenuate response or flare during therapy, requiring re-induction or switch among antiTNFs. When this fails, surgery becomes necessary. The goal of our study was to identify risk factors for surgery in the setting of biologic therapy. Methods: The Consortium on Outcomes of Biologic Therapy in IBD (COBI) is a prospectively compiled database of 147 patients treated for Crohn's disease between July 2002 and September 2009 with anti-TNFα medications (for a total of 366 patient-years of therapy). We performed a retrospective analysis to determine the incidence and risk of TNFα antagonist attenuation of response or need for surgical intervention. Both univariate and multivariate analyses were performed. Results: In our cohort, 63% of patients were either re-induced with (16/93, 17%) or switched to a second TNFα antagonist (77/93, 83%). Surgery had been performed in 38% of these patients prior to anti-TNFα therapy. The mean age at the start of the first anti-TNFα was 33.5 (± 15.2) years; mean duration of disease 9.2 (± 9) years and mean duration of initial anti-TNFα treatment 36.1 (±31.2) months. There were 82, 9 and 2 patients initially started on IFX, ADA and CZP respectively; the second agent used was IFX, ADA and CZP in 1, 55 and 21 patients respectively. There were 31 patients (33%) who underwent surgery within 6 months of failing the initial regimen. Patients treated with anti-TNFα therapy for longer periods (>30 months) had increased odds of surgery (OR 3.22, 95% CI 1.03-10.06). Conclusion: Despite the efficacy of the TNFα antagonists, nearly 2/3 of patients required either re-induction or switch within the class, with surgery necessary in nearly 1/3 of those patients. Patients on long-term anti-TNFα therapy before switching had a greater risk for surgery. Earlier intervention with primary anti-TNFα therapy may decrease secondary loss of response and intestinal resection rates. Further studies are warranted to determine antiTNFα optimization strategies and whether attenuation is less likely among different antiTNFα agents.

W1322 The Practice of North-American Gastroenterologists in Treating IBD Patients With C.Difficile: Antibiotics Alone or Combined Antibiotics-Immunomodulators?

and suspect types were 4(7.4%), 23(42.6%), 27(50.0%) patients, respectively. The median dosage of corticosteroid was 0.58mg/kg (0.39-1.20). There were 25(46.3%) cases with complete remission, 23(42.6%) with partial remission, and 6(11.1%) patients showed no response to corticosteroid therapy after 1 month post-treatment. Three months after the treatment, 22(40.7%) showed prolonged response, 25(46.3%) showed steroid dependency, 3(5.6%) showed refractoriness and 4 (7.4%) received operation respectively. At 1 year, there were 26(48.1%) patients in prolonged response, 19(35.2%) in corticosteroids dependency, and 4(7.4%) that received operation. The cumulative probability of surgery was 17.5% and 49.1% at 1 and 3 years, respectively. Prolonged response at three months was independently associated with decreased risk of surgery in the long-term (P=0.009, HR 0.176, CI 0.0480.649). Conclusions: Short-term response rate to initial corticosteroid therapy in IBD was high, however the responses showed a decreasing tendency along with time. Prolonged response at three month was associated with decreased risk of surgery in the long-term.

Ulcerative colitis: failed tacrolimus-infliximab or surgery? authors’ reply

Sirs, Oresland’s surgical comments1 concerning our study2 as well as essentially all trials on pharmacological therapy in IBD are well taken. We agree that the current medical armamentarium suffers from the lack of long-term solutions. We also share his concern that unremitting efforts with the sequential use of different immunosuppressives may render patients more susceptible to infections and increase perioperative risks if the proper timing of a surgical intervention is missed. The one-out-of-four remission rate following infliximab upon tacrolimus failure is clearly unsatisfactory. Moreover, a significant fraction of the approximate quarter of patients responding to infliximab following tacrolimus failure may well have to be operated ultimately in the further course of disease. However, being physicians, we have to take into account patients’ preferences when discussing treatment options and in general patients’ preference is to retain their colon until all other options have failed. As a matter of fact, Oresland’s view is the ex-post view. The trial was undertaken to test the possibility that a substantial proportion of patients refractory to tacrolimus would benefit from a TNF-antibody. This sequence of treatments, if the clinical conditions allow, makes good sense as the half-life of tacrolimus is much shorter and, after stopping, the risk of a combined and likely additive immunosuppression would be minimized. This is different when applying infliximab with its long half-life first and ciclosporin second, resulting in severe infectious complications because of triple or quadruple immunosuppression.3 Unfortunately, ex-post, it appears that the tacrolimus refractory cohort is a negative selection and as a rule exhibits cross-refractoriness to anti-TNF, although the mechanisms of action are quite different. Therefore, we emphasized in the final sentence of our report that ‘the risks and benefits (of immunosuppression) have to be weighed carefully against the risks and benefits of proctocolectomy’.2 Hence, the trial was justified to help estimate the potential benefit vs. risk of infliximab following tacrolimus, and the benefit turned out to be limited. Declaration of personal and funding interests: None.

Gastrointestinal and liver adverse effects of drugs used for treating IBD

Drugs used for treating inflammatory bowel disease are known to have a number of gastrointestinal and liver adverse effects. 5-ASA products are relatively safe and have few adverse events. In contrast sulfasalazine has side effects in 11-40% of treated patients including fatigue, nausea, abdominal pain and diarrhoea. Glucocorticoids can induce or propagate peptic ulcers and upper GI bleeding especially in combination with NSAIDs. Thioguanins may have severe gastrointestinal side effects including gastrointestinal complaints (in up to 12%), hepatotoxicity (up to 4%) and pancreatitis (1%). Nodular regenerative hyperplasia (NRH) is an important potential side effect of thiopurine therapy especially in men with Crohn's disease after ileocecal resection. NRH may ultimately lead to portal hypertension. A major concern of methotrexate therapy in IBD besides myelosuppression and pulmonary fibrosis is hepatotoxicity. 5mg of folic acid substitution per week potentially decreases gastrointestinal side effects by 80% without interfering with the efficacy of methotrexate. Besides renal dysfunction, tremor, hirsutism, hypertension and gum hyperplasia cyclosporine is known to have a number of gastrointestinal side effects that occur with less frequency such as diarrhoea (up to 8%) nausea and vomiting (up to 10%) and hepatotoxicity in 1-4%. Rare gastrointestinal adverse events are gastritis and peptic ulcers. Paying attention to these potential deleterious side effects is mandatory for physicians treating IBD patients.

S1105 Psoriasis and Eczema Skin Lesions Associated with TNF-Blockade Therapy in IBD: Natural History and Clinical Characteristics

S1105 Psoriasis and Eczema Skin Lesions Associated with TNF-Blockade Therapy in IBD: Natural History and Clinical Characteristics

Granulocyte–monocyte apheresis for the treatment of ulcerative colitis—is this the end of the road?

The pathogenesis of ulcerative colitis involves activated granulocytes, monocytes and macrophages. Apheresis has been suggested as a safe and effective treatment for ulcerative colitis. This Practice Point commentary discusses the findings and limitations of a multicenter, randomized, sham-controlled trial by Sands and colleagues, who investigated the efficacy of leukocyte apheresis in patients with moderate-to-severe ulcerative colitis. The results of this trial show no significant difference in outcomes between sham-treated and apheresis-treated patients. Rates of clinical remission, clinical response, endoscopic remission and response, and changes in Mayo score and Quality of Life score were similar between sham-treated and apheresis-treated patients. These findings contradict the results of previous studies, and serve to emphasize the importance of performing rigorous and appropriately designed clinical trials with established end points to determine the efficacy of therapy in IBD. The same standard of rigorous evaluation must be applied to new devices as is applied to pharmaceutical products.

Use of combination therapy in IBD

Use of combination therapy in IBD

Why are cytokines targeted for biological therapy in IBD?

Why are cytokines targeted for biological therapy in IBD?