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W1220 What Factors Influence Adhesion to Therapy in Inflammatory Bowel Disease?
AGA Abstracts
after 3 yrs. Using the cut-off score, 56% of participants reported high levels and 20% reported low levels of adherence at both time points. Adherence improved in 11% and deteriorated in 12% across time. Reductions in adherence scores were correlated with increases in concerns about medication (r = -0.204, p <0.001) as measured by the Beliefs about Medication Questionnaire (BMQ), and with increases in the number of identified obstacles to adherence (r = -0.333, p <0.001). There was no significant relationship between adherence shifts and changes in beliefs about medication necessity, overuse, or potential harmfulness, or between medication adherence and patient-reported disease activity in either the previous 6 mo or 3 yr period. Increases in the use of medication reminders did not correlate with increases in medication adherence. Conclusions: Adherence behaviors were fairly stable over time, with the majority of participants maintaining a similar level across 3 yrs. Adherence to medication treatment remains a significant problem over time but does not appear to be as clearly related to disease activity as previously thought. Changes in adherence behaviour may be more related to the presence of obstacles in the environment. In addition, patient concerns about their medication were more strongly associated with changes in reported adherence behavior than recent disease activity. These findings suggest that patient beliefs about medications, the obstacles to medication use and the patients' usual pattern of adherence impacts more on adherence than disease activity.
group of patients, the methylated metabolites/ 6TGN ratio was significantly higher than in the mutated patients group (8.32 vs 1.05 respectively; p<0.05). 76% (13/17) of the patients with one or more mutation in the TPMT gene had a ratio below 2.13, in concordance with low or no TPMT activity. Discussion: We found a good correlation between TPMT genotype and the methylated metabolites/6TGN ratio. This allows to appreciate TPMT activity whether low (high 6-TGN levels) or high (low 6-TGN levels). These data have potential interest in the management of IBD patients under thiopurines. W1218 Periconceptional Use of Medication for Inflammatory Bowel Diseases in a Referral Center Zuzana Zelinkova, Peter Mensink, Jan Dees, Ernst J. Kuipers, Christien J. van der Woude Background: Inflammatory bowel diseases (IBD) affect patients in reproductive age. The information on the pregnancy-related safety of the most therapeutics used in IBD is however limited and little is known about the actual use of medication by IBD patients with active reproduction wish. Aim of the study: To determine patterns of medication use and therapeutic decisions in the periconceptional period in IBD patients in a referral center. Patients and methods: Between April 2007 and October 2008, pregnant IBD patients and IBD patients with active conception plans were recruited from the outpatient clinic of the gastroenterology department of academic hospital. The types of medication indicated for IBD and changes of the medication due to the active conception wish were noted. Results: In total 39 patients (average age 32 years; Crohn's disease/ulcerative colitis 25/14; 34 females) were included. Eleven patients (28%) had no medication, 25 used monotherapy (64%) and 3 patients (8%) used combination treatment. Eleven patients (28%) were on thiopurines; 6 (15%) patients received maintenance treatment with anti-tumor necrosis factor agents; 4 (10%) patients were using steroids (2 patients systemic steroids and 2 patients budesonide); 4 patients were on 5-aminosalicylates and 4 patients were using methotrexate. Because of the conception plans, 12 patients (31%) changed their medication in a following manner: stop/postpone methotrexate (4/1 patients), stop budesonide (2 patients), thiopurines (2 patients), 5-aminosalicylates (2 patients), infliximab (1 patient), ciproxine (1 patient) and stop of study medication (1 patient). The medication change was initiated by gastroenterologist (8 patients), general practitioner (1 patient), fertility specialist (1 patient). Two patients stopped their medication themselves. The changes of medications by physicians were motivated by fear for potential side-effects of the medication on the child (budesonide, thiopurines, infliximab and ciproxine) or known teratogenic potential (methotrexate). Conclusion: In a referral center, the majority of IBD patients with conception plans require medication for which limited information on the safety of the periconceptional use is available. The reproduction wish represents an important factor influencing the therapeutic strategy, as one third of these patients eventually change the medication due to their conception plans.
W1216 Disease Activity and pANCA Status Determine Early Response to Infliximab in Ulcerative Colitis Matthias Jürgens, Stephan Brand, Rüdiger P. Laubender, Maria Weidinger, Franziska Hartl, Julia Seiderer, Florian Beigel, Simone Pfennig, Cornelia Tillack, Fabian Schnitzler, Burkhard Göke, Thomas Ochsenkühn Background Infliximab (IFX; Remicade, Schering Plough), a chimeric monoclonal antibody targeting TNF-α, represents the first approved biological treatment for ulcerative colitis (UC). Recent studies could demonstrate the efficacy of IFX for induction and maintenance of remission in UC. In order to evaluate the response to IFX and remission rates in our single center UC cohort and to identify possible predictors for early response, we analyzed retrospectively the data of 90 UC patients treated with IFX. Methods All patients with moderate to severe UC (Lichtiger score CAI 5-18), refractory to immunosuppressive therapy or steroids and treated with IFX for at least 2 months between January 2005 and May 2008 were included into this study. Following induction therapy (week 0, 2, and 6), IFX infusions (5 mg/kg) were given every 8 weeks. For evaluation of disease activity, the CAI was calculated for each patient at each visit (Definitions for remission and clinical response: clinical remission: ≤ 4 points, clinical response: drop of ≥ 5 points). Results Overall, 90 patients were included into data analysis. Clinical response was observed in 50 patients (56%) with a decrease of mean CAI from 11.3 (range 5-18) before IFX to 3.8 points (range 0-9) after first infusion (mean decrease: 7.6, range 5-18). Fourty patients (44%) did not show significant clinical response to initial therapy (mean Δ of CAI 1.1; range -5-4). In 9 cases (10%; including 5 initial responders and 4 non-responders), infusion reactions appeared and treatment was stopped in 7 of these patients. Two patients with minor reactions were further treated with IFX (both initial responders). During IFX therapy, steroid treatment was stopped in 28 out of 42 patients (66.7%) with concomitant steroids at the onset of IFX therapy. Performing multivariate analysis for potential predictors of response, gender, presence of elevated ANCA serum levels, and severity of disease were found to influence the response. Nine patients (5 primary responders, 4 non-responders) experienced worsening of disease leading to colectomy. Additionally to colectomy and infusion reactions, the following adverse events were observed: worsening of pre-existing depression (n=1), delayed infusion reaction (n=1), viral respiratory infection (n=3), arthralgia (n=2), vomiting (n=4). Conclusion Patients with refractory UC benefit from IFX therapy. Severity of disease, gender and elevated serum levels of ANCA seem to modulate the response to IFX and could therefore be used to predict the likelihood of response to IFX before treatment. To clarify the long term outcome, studies in larger cohorts and long term follow-up will be necessary.
W1219 Appropriateness of Therapy for Active Crohn's Disease: Results of a Multidisciplinary International Expert Panel (EPACT II) Pierre F. Michetti, Pascal Juillerat, Christian Mottet, Valérie Pittet, Miquel Angel Gassull, Franz Josef Heil, Jean-Jacques Gonvers, John-Paul Vader, Florian Froehlich, Christian P. Felley Introduction: The development of novel therapies and the increasing number of trials testing management strategies for luminal Crohn's disease (CD) have not filled all the gaps in our knowledge. Thus, in clinical practice, many decisions for CD patients need to be taken without high quality evidence. For this reason, a multidisciplinary European expert panel followed the RAND method to develop explicit criteria for the management of individual patients with active, steroid-dependent (ST-D) and steroid-refractory (ST-R) CD. Methods: Twelve international experts convened in Geneva, Switzerland in December 2007, to rate explicit clinical scenarios, corresponding to real daily practice, on a 9-point scale according to the literature evidence and their own expertise. Median ratings were stratified into three categories: appropriate (7-9), uncertain (4-6) and inappropriate (1-3). Results: Overall, panelists rated 296 indications pertaining to mild-to-moderate, severe, ST-D, and ST-R CD. In anti-TNF naïve patients, budesonide and prednisone were found appropriate for mildmoderate CD, and infliximab (IFX) when those had previously failed or had not been tolerated. In patients with prior success with IFX, this drug with or without co-administration of a thiopurine analog was favored. Other anti-TNFs were appropriate in case of intolerance or resistance to IFX. High doses steroids, IFX or adalimumab were appropriate in severe active CD. Among 105 indications for ST-D or ST-R disease, the panel considered appropriate the thiopurine analogs, methotrexate, IFX, adalimumab and surgery for limited resection, depending on the outcome of prior therapies. Anti-TNFs were generally considered appropriate in ST-R. Conclusion: Steroids, including budesonide for mild-to-moderate CD, remain first-line therapies in active luminal CD. Anti-TNFs, in particular IFX with respect to the amount of available evidence, remain second-line for most indications. Thiopurine analogs are preferred to anti-TNFs when steroids are not appropriate, except when anti-TNFs were previously successful. These recommendations are available online (www.epact.ch). A prospective evaluation of these criteria in a large database in Switzerland in underway to validate these criteria.
W1217 Methylated Metabolites/6-TGN Ratio and TPMT Genotype in the Pharmacological Monitoring of IBD Patients Under Thiopurines Xavier Fonrose, Alain A. Chartier, Nicolas Mathieu, Nicole Jourdil, Germain Bessard, Bruno L. Bonaz Thiopurine drugs, Azathioprine (AZA) and 6-mercaptopurine (6-MP), are widely used in the treatment of inflammatory bowel diseases (IBD). AZA/6-MP are pro-drugs requiring intracellular activation by a multi-enzymatic process involving 1) xanthine oxidase, which converts AZA/6-MP into inactive metabolites, 2) hypoxanthine phosphoribosyl transferase, which converts AZA/6-MP into thioinosine monophosphate (TIMP) then metabolized into 6-tioguanine nucleotides (6-TGN) that possess immune modifier activity, 3) thiopurine methyltransferase (TPMT), which converts thiopurines into methylated metabolites (6-MMP and 6-MeTIMP). TPMT has a genetic polymorphism. The methylated metabolites/6TGN ratio is considered to be related to the degree of TPMT activity. Aim: To investigate the correlation between TPMT genotype and the methylated metabolites/6TGN ratio. Methods: We retrospectively analyze the data of 179 IBD patients. 6-TGN, methylated metabolites levels and major TPMT genetic variants (*1, *2, *3A,*3B, *3C) were extracted from our laboratory database. Results: The median 6-TGN level was 241 pmoles / 8.10x8 RBCs (range: 10-944). 42% of the 6-TGN levels were in the presumed therapeutic range (235 - 450 pmoles / 8.10x8 RBCs) described by some authors. The median methylated metabolite levels were 1369 pmoles / 8.10x8 RBCs (range: 41-72,752). The median methylated metabolites/ 6TGN ratio was 6.46 (interquartile range: 2.13 - 21.30). According to the distribution of the ratio, patients were separated into three groups: patients with high (ratio above 21.30), normal (ratio between 2.13 and 21.30), and low or no (ratio below 2.13) TPMT activity respectively. Patients with a high TPMT activity had lower values of 6-TGN levels compared to patients with normal TPMT activity (182 vs 234 pmoles / 8.10x8 RBCs; p<0.05). Patients with a ratio below 2.13 and no TPMT mutation had higher 6-TGN levels than patients with a normal TPMT activity (317 vs 234 pmoles / 8.10x8 RBCs; p<0.05). As for TPMT genotype, none of the three tested mutations was detected in 90.5% (162/179) of the patients. In this
AGA Abstracts
W1220 What Factors Influence Adhesion to Therapy in Inflammatory Bowel Disease? Fernando Bermejo, Antonio López-San Román, Alicia Algaba, Jose Antonio Carneros, Paz Valer, Silvia García-Garzón, Sandra Sánchez Prudencio, Belén Piqueras, Ivan Guerra, Fernando García Durán, Esperanza Tomás, Jose L. Rodriguez Aims: Inflammatory bowel disease (IBD) is a clinical condition associated with a high risk of deficient adhesion to therapy. Our aim was to analyze the degree of adhesion to treatment in a specialized IBD Clinic, and to study which factors could influence it Methods: A total of 107 consecutive patients were included during a three-month period. With previous
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importantly, 3/4 patients have reached sustained remission (CDAI<150) through long-term anti-MAP treatment; 1 patient remains in clinical and histological normality for over 4 years on anti-MAP without either infliximab or anti-inflammatory medications. The remaining patient experienced marked clinical improvement but has not yet received treatment long enough to achieve numerical remission. Conclusions: 1) CDAI scores and CD-related symptoms markedly improved in all 4 patients 2) Previous CD treatments, including infliximab, were able to be terminated without relapse whilst on anti-MAP 3) Anti-MAP may be an effective rescue therapy for patients who failed infliximab treatment and supports a bacterial etiology of CD. 1. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Lancet. 2002;359(9317):1541-9 2. Kaplan G, Hur C, Korzenik J, et al. Aliment Pharma & Ther. 2007;26(11-12):1509-1520 3. Borody TJ, Leis S, Warren EF, et al. Dig and Liv Dis. 2002;34(1):29-38 4. Selby W, Pavli P, Crotty B, et al. Gastroenterology. 2007;132(7):2313-2319 W1223 Clinical Experience with Adalimumab in a Multicenter Swiss Cohort of Patients with Crohn's Disease Cristina Nichita, Marc Stelle, Stephan R. Vavricka, Ali Abdou El-Wafa, Philippe De Saussure, Alex Straumann, Gerhard Rogler, Pierre F. Michetti Background : Adalimumab ( ADA) is a fully human monoclonal antibody which binds with a high affinity and specificity to tumor necrosis factor (TNFα). Controlled clinical trials have demonstrated its efficacy and safety in the treatment of moderate-to-severe Crohn's disease (CD). However, long term experience with ADA in real-life clinical practice has rarely been reported. Objective: to assess the long term effectiveness and the safety of ADA in a multicenter cohort of patients with moderate-to-severe CD. Methods: Fifty five patients (21 men, 34 women), mean age 37.5 years (±11.4 years), median disease duration 12.7 years ( range 1-41 years) were treated with ADA and followed up over a period of 52 weeks (range 12-96 weeks, median 50 weeks). Thirty eight patients had previously been treated with infliximab (IFX). The ADA induction regimen was 160/80 mg in 31 patients and 80/ 40 mg in 24 patients. The clinical evolution during treatment was evaluated with the HarveyBradshaw Index (HBI) at week (W) 4-6, 12, 24 and 52. Patients were classified in three categories : remission (HBI < 4 pts) , response (reduction HBI > 3 pts) and non response. Results: On week 4-6, a response was demonstrated in 83.6 % patients and remission was obtained in 52.7%. The remission was maintained in 89.6% and 72.4% of the patients at W12 and W24, respectively. In per protocol analysis at W52, half of patients were still in response and half had stopped ADA : 5/19 because of adverse events and 14/19 because of no response or loss of response. Thirteen patients (23.6%) needed a dose escalation after a mean interval of 7 months (range 1-24 month). The response rate at W4-6 was not influenced by gender, smoking status, disease duration, localisation of disease, previous surgery, previous IFX treatment, the first month total ADA dose, or the first month ADA dose divided by body weight. Interestingly, however, the remission rate at W4-6 was significantly higher in patients intolerant (78.9%) to IFX, as compared to those who had lost response to IFX (42.1%; p=0.02). Overall ADA was well tolerated, 54.5% patients didn't report any side effects. The most common side effect was pain at the injection site (10.9%), followed by asthenia (9%) and infections (7.2%). Conclusion : ADA was effective and safe in clinical practice as induction and maintenance therapy for patients with moderate-to-severe CD.
W1221 Side Effects of Azathioprine in the Treatment of Chronic Inflammatory Bowel Disease Eleonora V. Avallone, Roberta Pica, Claudio Cassieri, Aurora De Carolis, Paolo Paoluzi, Piero Vernia AIM: Azathioprine (AZA) is frequently used in inflammatory bowel disease (IBD) for inducing and maintaining remission, sparing the use of steroids. The treatment must be withdrawn in 15% of patients due to the occurrence of adverse events, often related to the genetic background of the patients. Side effects are dose-independent (allergic reactions, idiosyncrasies) or dose-dependent (myelotoxicity, hepatitis, cancer). Aim of this study has been to investigate the prevalence of adverse effects, type and time of onset of AZA in a large series of Italian IBD patients, from a single centre. MATERIALS AND METHODS: Two thousand and fourteen consecutive IBD out-patients, referred to our Institution, were retrospectively studied. AZA was prescribed to 297 patients, 137 (46.1%) affected by ulcerative colitis (UC) and 160 (53.9%) by Crohn's disease (CD). One hundred and sixty-one (54.2%) were male and 136 (45.8%) female (average age of 32.38 +/- 13.33 SD years, range 10-75 y.). RESULTS: Seventy-seven patients (26%) discontinued the treatment due to side effects, 39 with UC, and 38 with CD, with a respective prevalence of 28.5 % and 23,7%. The side effects was classified as dose independent 14.6% and dose dependent 13.9% in UC patients (one patient died due to severe leucopenia) and dose independent 10% and 13.7% dose dependent in CD patients. Side effects were observed after a mean period of 14.5 +/- 20.3 SD months (range 0.5-123 m.). One hundred and fifty-three patients (51.5%) are still under treatment with AZA. The dose was reduced in 20 patients (13.1%) following the occurrence of mild side effects (3.9% dose independent and 9.2% dose dependent), 133 (86.9%) are still under treatment at full dosage. Thirty-six patients (12.1%) stopped therapy after obtaining stable remission, while 24 (8.1%), due to treatment failure. CONCLUSIONS: The prevalence of side effects leading to the withdrawal of AZA treatment was higher (26%) than that usually reported (15%). This higher prevalence may be attributed to genetic factors (prevalence of the phenotypic expression of the TPMT gene or other enzymes involved in AZA metabolism). The differing cut-off levels of leucocyte/lymphocyte considered at risk and leading to the suspension of treatment or reduction of dosage may also be responsible for discordance. Eleven percent of patients showed dose dependent effects 12 months from the onset of therapy, casting doubt on the adherence to the treatment schedule, at least in a subset of patients. Nonetheless this observation prompts prolonging clinical and biochemical controls over the usual six-month period.
W1224 Appropriate Infliximab Infusion Dosage and Monitoring: Results of a Consensus Meeting of Rheumatologists, Dermatologists and Gastroenterologists Hilbert S. de Vries, Martijn G. van Oijen, Wietske Kievit, Rieke J. Driessen, Elke M. de Jong, Marjonne C. Creemers, Dirk J. De Jong Background:Infliximab (IFX) is currently indicated and reimbursed for rheumatoid arthritis, ankylosing spondylitis, Crohn's disease (both adult and pediatric), ulcerative colitis, psoriatic arthritis and plaque psoriasis. National and international guidelines and consensus statements on the use of IFX, have been developed for each of three medical specialities: rheumatology, dermatology and gastroenterology, mostly based on clinical studies and expert opinion. Objective:To prepare consensus on the dosage and monitoring of IFX in all patients with chronic inflammatory disorders in order to achieve optimal care. Methods:In July 2008, a consensus meeting was held by an expert panel from the medical specialties of dermatology, rheumatology and gastroenterology from a large university hospital in The Netherlands. From each department, a clinical researcher and an clinician participated, both selected by their (research) experience with IFX. International, national and local guidelines on the use of IFX were reviewed and compared, in order to achieve inter-specialty consensus regarding dosage and infusion monitoring. Results: Differences exist between the guidelines recommended dosage of IFX for each indication (e.g. 3 mg/kg for RA and 5 mg/kg for CD). However, head-to-head studies comparing 3 mg/kg and 5 mg/kg in patients with CD and RA have not been performed. Loss of response to IFX is a common problem within the three medical specialties. One of the findings of the consensus panel is that none of the guidelines from each specialty gives indicators how and when to choose for dosage adjustment or frequency intensification. Monitoring of vital signs (blood pressure, pulse, temperature) during infusion with IFX is common in clinical practice based on recommendations from clinical trials. It is also recommended by some guidelines. However, the consensus panel agreed that routine measurement of vital signs should not be performed since the development of acute infusion reactions is rather recognizable by clinical symptoms than by changes in vital signs, based on our observations (de Vries et al. J Clin Gastroenterol 2008). Conclusion:In the opinion of the consensus panel, the optimal concentration of IFX needs to be established using head-to-head studies. The consensus panel agreed that patient who initially responded to IFX, but lost response to their current dose and interval, are eligible for frequency intensification. Others should be treated with dosage increasement. In addition, based on the results from the department of gastroenterology, the consensus panel agreed that routine measurement of vital signs is not warranted in any patient receiving IFX.
W1222 Anti-MAP Rescues Anti-TNF Failures for Over 4 Years Thomas J. Borody, Sahisha Ketheeswaran, Sharyn Leis On an ITT basis, 74% of Crohn's disease (CD) patients go into remission on infliximab with 42% not responding at all.1 In responders the long-term efficacy of infliximab is limited by loss of response over time.2 Growing evidence suggests that prolonged anti-Mycobacterium avium paratuberculosis (anti-MAP) combination therapy can improve CD in a significant number of patients for many years.3,4 Aim: To examine the efficacy of anti-MAP rescue therapy in CD patients who have failed multiple infliximab treatments. Methods: Patients with severe, active CD who had undergone anti-MAP rescue therapy following infliximab failure, were included in this retrospective analysis. Patients had previously received multiple courses of infliximab (3-30 courses). Originally patients had longstanding symptoms of diarrhoea, rectal bleeding, abdominal pain, urgency, malaise and fatigue. Anti-MAP therapy consisted of rifabutin, clarithromycin and clofazimine, (initially adding ciprofloxacin or ethambutol), commenced as a ramp-up schedule with doses not exceeding 600mg/d, 1g/d, 100mg/d, and 1g/d, or 400mg/d respectively. Effectiveness of treatment was determined by a marked fall in Crohn's Disease Activity Index (CDAI) from baseline values, symptomatic and endoscopic improvement. Results: All 4 patients (2M, 2F; aged 20-56y) achieved sustained response (CDAI reduction >100) by 11 weeks of anti-MAP therapy. Markers of inflammation, CRP levels and ESR, also decreased considerably from baseline levels in 4/ 4 patients. Concomitant medications were reduced without symptomatic relapse. More
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consent and in all privacy, patients filled up an anonymous survey with demographic data (age, gender, study level, working status, personal status), data concerning the disease (type of IBD, year of diagnosis, number of hospital admissions, IBD-related surgical procedures), data about therapy (drug, dose, interval), self-applied adhesion declaration and self-medication. An activity index was calculated on the spot (Harvey-Bradshaw/Truelove) Results: Mean age was 41.3±11 years, 60% were women. The number of years since IBD diagnosis was 8±7; 64% were Crohn's disease (71% inactive), 36% ulcerative colitis (70% inactive). A 66% was treated with aminosalicylates, 51% with immunosuppressors, 8% with glucocorticoids. A 66% needed an IBD-related hospital admission in the past, and 17% any IBD-related surgical procedure. A 69% (95%CI: 60-77%) showed some type of non-adhesion. A 66% (57-75%) acknowledged dome degree of involuntary non-adhesion: either forgetting to take their dose (63%) or being careless about having taken it (27%). A 16% (9-22%) showed some kind of voluntary non-adhesion: interrupting the therapy when feeling better (13%) or when feeling worse (6%). A 25% (17-33%) forgot at least a dose a week (mean weekly number of forgotten doses 1.6), and the most frequent cause was to be away form home when they were supposed to take the medication. This was more frequent under mesalazine therapy (30%) than with azathioprine (17%) (p=n.s.). A multivariate analysis identified as risk factors for a lower adhesion the dosing in three or more takes a day (OR 3; 95%CI 1.1-8.4; p= 0.03) and feeling little informed about their disease (OR 4.9; 95%CI 1.1-23.8; p=0.04). On the other hand, immunomodulator therapy was a predictive factor for better adhesion (OR 0.29; 95%CI 0.11-0.74; p=0.01). The concordance between patient recall and clinical records was complete in 86%, whereas in 10.3% the patients did not accurately remember the dose and in 3.7% there was confusion about the drug taken. A 9% acknowledged self-medication during flares Conclusions: In our setting, adhesion to therapy in IBD patients is not satisfactory. Patients treated with immunosuppressors have better adhesion. Optimizing the information on the disease and giving the medication in one or two daily doses could enhance therapeutic adhesion
after 3 yrs. Using the cut-off score, 56% of participants reported high levels and 20% reported low levels of adherence at both time points. Adherence improved in 11% and deteriorated in 12% across time. Reductions in adherence scores were correlated with increases in concerns about medication (r = -0.204, p <0.001) as measured by the Beliefs about Medication Questionnaire (BMQ), and with increases in the number of identified obstacles to adherence (r = -0.333, p <0.001). There was no significant relationship between adherence shifts and changes in beliefs about medication necessity, overuse, or potential harmfulness, or between medication adherence and patient-reported disease activity in either the previous 6 mo or 3 yr period. Increases in the use of medication reminders did not correlate with increases in medication adherence. Conclusions: Adherence behaviors were fairly stable over time, with the majority of participants maintaining a similar level across 3 yrs. Adherence to medication treatment remains a significant problem over time but does not appear to be as clearly related to disease activity as previously thought. Changes in adherence behaviour may be more related to the presence of obstacles in the environment. In addition, patient concerns about their medication were more strongly associated with changes in reported adherence behavior than recent disease activity. These findings suggest that patient beliefs about medications, the obstacles to medication use and the patients' usual pattern of adherence impacts more on adherence than disease activity.
group of patients, the methylated metabolites/ 6TGN ratio was significantly higher than in the mutated patients group (8.32 vs 1.05 respectively; p<0.05). 76% (13/17) of the patients with one or more mutation in the TPMT gene had a ratio below 2.13, in concordance with low or no TPMT activity. Discussion: We found a good correlation between TPMT genotype and the methylated metabolites/6TGN ratio. This allows to appreciate TPMT activity whether low (high 6-TGN levels) or high (low 6-TGN levels). These data have potential interest in the management of IBD patients under thiopurines. W1218 Periconceptional Use of Medication for Inflammatory Bowel Diseases in a Referral Center Zuzana Zelinkova, Peter Mensink, Jan Dees, Ernst J. Kuipers, Christien J. van der Woude Background: Inflammatory bowel diseases (IBD) affect patients in reproductive age. The information on the pregnancy-related safety of the most therapeutics used in IBD is however limited and little is known about the actual use of medication by IBD patients with active reproduction wish. Aim of the study: To determine patterns of medication use and therapeutic decisions in the periconceptional period in IBD patients in a referral center. Patients and methods: Between April 2007 and October 2008, pregnant IBD patients and IBD patients with active conception plans were recruited from the outpatient clinic of the gastroenterology department of academic hospital. The types of medication indicated for IBD and changes of the medication due to the active conception wish were noted. Results: In total 39 patients (average age 32 years; Crohn's disease/ulcerative colitis 25/14; 34 females) were included. Eleven patients (28%) had no medication, 25 used monotherapy (64%) and 3 patients (8%) used combination treatment. Eleven patients (28%) were on thiopurines; 6 (15%) patients received maintenance treatment with anti-tumor necrosis factor agents; 4 (10%) patients were using steroids (2 patients systemic steroids and 2 patients budesonide); 4 patients were on 5-aminosalicylates and 4 patients were using methotrexate. Because of the conception plans, 12 patients (31%) changed their medication in a following manner: stop/postpone methotrexate (4/1 patients), stop budesonide (2 patients), thiopurines (2 patients), 5-aminosalicylates (2 patients), infliximab (1 patient), ciproxine (1 patient) and stop of study medication (1 patient). The medication change was initiated by gastroenterologist (8 patients), general practitioner (1 patient), fertility specialist (1 patient). Two patients stopped their medication themselves. The changes of medications by physicians were motivated by fear for potential side-effects of the medication on the child (budesonide, thiopurines, infliximab and ciproxine) or known teratogenic potential (methotrexate). Conclusion: In a referral center, the majority of IBD patients with conception plans require medication for which limited information on the safety of the periconceptional use is available. The reproduction wish represents an important factor influencing the therapeutic strategy, as one third of these patients eventually change the medication due to their conception plans.
W1216 Disease Activity and pANCA Status Determine Early Response to Infliximab in Ulcerative Colitis Matthias Jürgens, Stephan Brand, Rüdiger P. Laubender, Maria Weidinger, Franziska Hartl, Julia Seiderer, Florian Beigel, Simone Pfennig, Cornelia Tillack, Fabian Schnitzler, Burkhard Göke, Thomas Ochsenkühn Background Infliximab (IFX; Remicade, Schering Plough), a chimeric monoclonal antibody targeting TNF-α, represents the first approved biological treatment for ulcerative colitis (UC). Recent studies could demonstrate the efficacy of IFX for induction and maintenance of remission in UC. In order to evaluate the response to IFX and remission rates in our single center UC cohort and to identify possible predictors for early response, we analyzed retrospectively the data of 90 UC patients treated with IFX. Methods All patients with moderate to severe UC (Lichtiger score CAI 5-18), refractory to immunosuppressive therapy or steroids and treated with IFX for at least 2 months between January 2005 and May 2008 were included into this study. Following induction therapy (week 0, 2, and 6), IFX infusions (5 mg/kg) were given every 8 weeks. For evaluation of disease activity, the CAI was calculated for each patient at each visit (Definitions for remission and clinical response: clinical remission: ≤ 4 points, clinical response: drop of ≥ 5 points). Results Overall, 90 patients were included into data analysis. Clinical response was observed in 50 patients (56%) with a decrease of mean CAI from 11.3 (range 5-18) before IFX to 3.8 points (range 0-9) after first infusion (mean decrease: 7.6, range 5-18). Fourty patients (44%) did not show significant clinical response to initial therapy (mean Δ of CAI 1.1; range -5-4). In 9 cases (10%; including 5 initial responders and 4 non-responders), infusion reactions appeared and treatment was stopped in 7 of these patients. Two patients with minor reactions were further treated with IFX (both initial responders). During IFX therapy, steroid treatment was stopped in 28 out of 42 patients (66.7%) with concomitant steroids at the onset of IFX therapy. Performing multivariate analysis for potential predictors of response, gender, presence of elevated ANCA serum levels, and severity of disease were found to influence the response. Nine patients (5 primary responders, 4 non-responders) experienced worsening of disease leading to colectomy. Additionally to colectomy and infusion reactions, the following adverse events were observed: worsening of pre-existing depression (n=1), delayed infusion reaction (n=1), viral respiratory infection (n=3), arthralgia (n=2), vomiting (n=4). Conclusion Patients with refractory UC benefit from IFX therapy. Severity of disease, gender and elevated serum levels of ANCA seem to modulate the response to IFX and could therefore be used to predict the likelihood of response to IFX before treatment. To clarify the long term outcome, studies in larger cohorts and long term follow-up will be necessary.
W1219 Appropriateness of Therapy for Active Crohn's Disease: Results of a Multidisciplinary International Expert Panel (EPACT II) Pierre F. Michetti, Pascal Juillerat, Christian Mottet, Valérie Pittet, Miquel Angel Gassull, Franz Josef Heil, Jean-Jacques Gonvers, John-Paul Vader, Florian Froehlich, Christian P. Felley Introduction: The development of novel therapies and the increasing number of trials testing management strategies for luminal Crohn's disease (CD) have not filled all the gaps in our knowledge. Thus, in clinical practice, many decisions for CD patients need to be taken without high quality evidence. For this reason, a multidisciplinary European expert panel followed the RAND method to develop explicit criteria for the management of individual patients with active, steroid-dependent (ST-D) and steroid-refractory (ST-R) CD. Methods: Twelve international experts convened in Geneva, Switzerland in December 2007, to rate explicit clinical scenarios, corresponding to real daily practice, on a 9-point scale according to the literature evidence and their own expertise. Median ratings were stratified into three categories: appropriate (7-9), uncertain (4-6) and inappropriate (1-3). Results: Overall, panelists rated 296 indications pertaining to mild-to-moderate, severe, ST-D, and ST-R CD. In anti-TNF naïve patients, budesonide and prednisone were found appropriate for mildmoderate CD, and infliximab (IFX) when those had previously failed or had not been tolerated. In patients with prior success with IFX, this drug with or without co-administration of a thiopurine analog was favored. Other anti-TNFs were appropriate in case of intolerance or resistance to IFX. High doses steroids, IFX or adalimumab were appropriate in severe active CD. Among 105 indications for ST-D or ST-R disease, the panel considered appropriate the thiopurine analogs, methotrexate, IFX, adalimumab and surgery for limited resection, depending on the outcome of prior therapies. Anti-TNFs were generally considered appropriate in ST-R. Conclusion: Steroids, including budesonide for mild-to-moderate CD, remain first-line therapies in active luminal CD. Anti-TNFs, in particular IFX with respect to the amount of available evidence, remain second-line for most indications. Thiopurine analogs are preferred to anti-TNFs when steroids are not appropriate, except when anti-TNFs were previously successful. These recommendations are available online (www.epact.ch). A prospective evaluation of these criteria in a large database in Switzerland in underway to validate these criteria.
W1217 Methylated Metabolites/6-TGN Ratio and TPMT Genotype in the Pharmacological Monitoring of IBD Patients Under Thiopurines Xavier Fonrose, Alain A. Chartier, Nicolas Mathieu, Nicole Jourdil, Germain Bessard, Bruno L. Bonaz Thiopurine drugs, Azathioprine (AZA) and 6-mercaptopurine (6-MP), are widely used in the treatment of inflammatory bowel diseases (IBD). AZA/6-MP are pro-drugs requiring intracellular activation by a multi-enzymatic process involving 1) xanthine oxidase, which converts AZA/6-MP into inactive metabolites, 2) hypoxanthine phosphoribosyl transferase, which converts AZA/6-MP into thioinosine monophosphate (TIMP) then metabolized into 6-tioguanine nucleotides (6-TGN) that possess immune modifier activity, 3) thiopurine methyltransferase (TPMT), which converts thiopurines into methylated metabolites (6-MMP and 6-MeTIMP). TPMT has a genetic polymorphism. The methylated metabolites/6TGN ratio is considered to be related to the degree of TPMT activity. Aim: To investigate the correlation between TPMT genotype and the methylated metabolites/6TGN ratio. Methods: We retrospectively analyze the data of 179 IBD patients. 6-TGN, methylated metabolites levels and major TPMT genetic variants (*1, *2, *3A,*3B, *3C) were extracted from our laboratory database. Results: The median 6-TGN level was 241 pmoles / 8.10x8 RBCs (range: 10-944). 42% of the 6-TGN levels were in the presumed therapeutic range (235 - 450 pmoles / 8.10x8 RBCs) described by some authors. The median methylated metabolite levels were 1369 pmoles / 8.10x8 RBCs (range: 41-72,752). The median methylated metabolites/ 6TGN ratio was 6.46 (interquartile range: 2.13 - 21.30). According to the distribution of the ratio, patients were separated into three groups: patients with high (ratio above 21.30), normal (ratio between 2.13 and 21.30), and low or no (ratio below 2.13) TPMT activity respectively. Patients with a high TPMT activity had lower values of 6-TGN levels compared to patients with normal TPMT activity (182 vs 234 pmoles / 8.10x8 RBCs; p<0.05). Patients with a ratio below 2.13 and no TPMT mutation had higher 6-TGN levels than patients with a normal TPMT activity (317 vs 234 pmoles / 8.10x8 RBCs; p<0.05). As for TPMT genotype, none of the three tested mutations was detected in 90.5% (162/179) of the patients. In this
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W1220 What Factors Influence Adhesion to Therapy in Inflammatory Bowel Disease? Fernando Bermejo, Antonio López-San Román, Alicia Algaba, Jose Antonio Carneros, Paz Valer, Silvia García-Garzón, Sandra Sánchez Prudencio, Belén Piqueras, Ivan Guerra, Fernando García Durán, Esperanza Tomás, Jose L. Rodriguez Aims: Inflammatory bowel disease (IBD) is a clinical condition associated with a high risk of deficient adhesion to therapy. Our aim was to analyze the degree of adhesion to treatment in a specialized IBD Clinic, and to study which factors could influence it Methods: A total of 107 consecutive patients were included during a three-month period. With previous
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importantly, 3/4 patients have reached sustained remission (CDAI<150) through long-term anti-MAP treatment; 1 patient remains in clinical and histological normality for over 4 years on anti-MAP without either infliximab or anti-inflammatory medications. The remaining patient experienced marked clinical improvement but has not yet received treatment long enough to achieve numerical remission. Conclusions: 1) CDAI scores and CD-related symptoms markedly improved in all 4 patients 2) Previous CD treatments, including infliximab, were able to be terminated without relapse whilst on anti-MAP 3) Anti-MAP may be an effective rescue therapy for patients who failed infliximab treatment and supports a bacterial etiology of CD. 1. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Lancet. 2002;359(9317):1541-9 2. Kaplan G, Hur C, Korzenik J, et al. Aliment Pharma & Ther. 2007;26(11-12):1509-1520 3. Borody TJ, Leis S, Warren EF, et al. Dig and Liv Dis. 2002;34(1):29-38 4. Selby W, Pavli P, Crotty B, et al. Gastroenterology. 2007;132(7):2313-2319 W1223 Clinical Experience with Adalimumab in a Multicenter Swiss Cohort of Patients with Crohn's Disease Cristina Nichita, Marc Stelle, Stephan R. Vavricka, Ali Abdou El-Wafa, Philippe De Saussure, Alex Straumann, Gerhard Rogler, Pierre F. Michetti Background : Adalimumab ( ADA) is a fully human monoclonal antibody which binds with a high affinity and specificity to tumor necrosis factor (TNFα). Controlled clinical trials have demonstrated its efficacy and safety in the treatment of moderate-to-severe Crohn's disease (CD). However, long term experience with ADA in real-life clinical practice has rarely been reported. Objective: to assess the long term effectiveness and the safety of ADA in a multicenter cohort of patients with moderate-to-severe CD. Methods: Fifty five patients (21 men, 34 women), mean age 37.5 years (±11.4 years), median disease duration 12.7 years ( range 1-41 years) were treated with ADA and followed up over a period of 52 weeks (range 12-96 weeks, median 50 weeks). Thirty eight patients had previously been treated with infliximab (IFX). The ADA induction regimen was 160/80 mg in 31 patients and 80/ 40 mg in 24 patients. The clinical evolution during treatment was evaluated with the HarveyBradshaw Index (HBI) at week (W) 4-6, 12, 24 and 52. Patients were classified in three categories : remission (HBI < 4 pts) , response (reduction HBI > 3 pts) and non response. Results: On week 4-6, a response was demonstrated in 83.6 % patients and remission was obtained in 52.7%. The remission was maintained in 89.6% and 72.4% of the patients at W12 and W24, respectively. In per protocol analysis at W52, half of patients were still in response and half had stopped ADA : 5/19 because of adverse events and 14/19 because of no response or loss of response. Thirteen patients (23.6%) needed a dose escalation after a mean interval of 7 months (range 1-24 month). The response rate at W4-6 was not influenced by gender, smoking status, disease duration, localisation of disease, previous surgery, previous IFX treatment, the first month total ADA dose, or the first month ADA dose divided by body weight. Interestingly, however, the remission rate at W4-6 was significantly higher in patients intolerant (78.9%) to IFX, as compared to those who had lost response to IFX (42.1%; p=0.02). Overall ADA was well tolerated, 54.5% patients didn't report any side effects. The most common side effect was pain at the injection site (10.9%), followed by asthenia (9%) and infections (7.2%). Conclusion : ADA was effective and safe in clinical practice as induction and maintenance therapy for patients with moderate-to-severe CD.
W1221 Side Effects of Azathioprine in the Treatment of Chronic Inflammatory Bowel Disease Eleonora V. Avallone, Roberta Pica, Claudio Cassieri, Aurora De Carolis, Paolo Paoluzi, Piero Vernia AIM: Azathioprine (AZA) is frequently used in inflammatory bowel disease (IBD) for inducing and maintaining remission, sparing the use of steroids. The treatment must be withdrawn in 15% of patients due to the occurrence of adverse events, often related to the genetic background of the patients. Side effects are dose-independent (allergic reactions, idiosyncrasies) or dose-dependent (myelotoxicity, hepatitis, cancer). Aim of this study has been to investigate the prevalence of adverse effects, type and time of onset of AZA in a large series of Italian IBD patients, from a single centre. MATERIALS AND METHODS: Two thousand and fourteen consecutive IBD out-patients, referred to our Institution, were retrospectively studied. AZA was prescribed to 297 patients, 137 (46.1%) affected by ulcerative colitis (UC) and 160 (53.9%) by Crohn's disease (CD). One hundred and sixty-one (54.2%) were male and 136 (45.8%) female (average age of 32.38 +/- 13.33 SD years, range 10-75 y.). RESULTS: Seventy-seven patients (26%) discontinued the treatment due to side effects, 39 with UC, and 38 with CD, with a respective prevalence of 28.5 % and 23,7%. The side effects was classified as dose independent 14.6% and dose dependent 13.9% in UC patients (one patient died due to severe leucopenia) and dose independent 10% and 13.7% dose dependent in CD patients. Side effects were observed after a mean period of 14.5 +/- 20.3 SD months (range 0.5-123 m.). One hundred and fifty-three patients (51.5%) are still under treatment with AZA. The dose was reduced in 20 patients (13.1%) following the occurrence of mild side effects (3.9% dose independent and 9.2% dose dependent), 133 (86.9%) are still under treatment at full dosage. Thirty-six patients (12.1%) stopped therapy after obtaining stable remission, while 24 (8.1%), due to treatment failure. CONCLUSIONS: The prevalence of side effects leading to the withdrawal of AZA treatment was higher (26%) than that usually reported (15%). This higher prevalence may be attributed to genetic factors (prevalence of the phenotypic expression of the TPMT gene or other enzymes involved in AZA metabolism). The differing cut-off levels of leucocyte/lymphocyte considered at risk and leading to the suspension of treatment or reduction of dosage may also be responsible for discordance. Eleven percent of patients showed dose dependent effects 12 months from the onset of therapy, casting doubt on the adherence to the treatment schedule, at least in a subset of patients. Nonetheless this observation prompts prolonging clinical and biochemical controls over the usual six-month period.
W1224 Appropriate Infliximab Infusion Dosage and Monitoring: Results of a Consensus Meeting of Rheumatologists, Dermatologists and Gastroenterologists Hilbert S. de Vries, Martijn G. van Oijen, Wietske Kievit, Rieke J. Driessen, Elke M. de Jong, Marjonne C. Creemers, Dirk J. De Jong Background:Infliximab (IFX) is currently indicated and reimbursed for rheumatoid arthritis, ankylosing spondylitis, Crohn's disease (both adult and pediatric), ulcerative colitis, psoriatic arthritis and plaque psoriasis. National and international guidelines and consensus statements on the use of IFX, have been developed for each of three medical specialities: rheumatology, dermatology and gastroenterology, mostly based on clinical studies and expert opinion. Objective:To prepare consensus on the dosage and monitoring of IFX in all patients with chronic inflammatory disorders in order to achieve optimal care. Methods:In July 2008, a consensus meeting was held by an expert panel from the medical specialties of dermatology, rheumatology and gastroenterology from a large university hospital in The Netherlands. From each department, a clinical researcher and an clinician participated, both selected by their (research) experience with IFX. International, national and local guidelines on the use of IFX were reviewed and compared, in order to achieve inter-specialty consensus regarding dosage and infusion monitoring. Results: Differences exist between the guidelines recommended dosage of IFX for each indication (e.g. 3 mg/kg for RA and 5 mg/kg for CD). However, head-to-head studies comparing 3 mg/kg and 5 mg/kg in patients with CD and RA have not been performed. Loss of response to IFX is a common problem within the three medical specialties. One of the findings of the consensus panel is that none of the guidelines from each specialty gives indicators how and when to choose for dosage adjustment or frequency intensification. Monitoring of vital signs (blood pressure, pulse, temperature) during infusion with IFX is common in clinical practice based on recommendations from clinical trials. It is also recommended by some guidelines. However, the consensus panel agreed that routine measurement of vital signs should not be performed since the development of acute infusion reactions is rather recognizable by clinical symptoms than by changes in vital signs, based on our observations (de Vries et al. J Clin Gastroenterol 2008). Conclusion:In the opinion of the consensus panel, the optimal concentration of IFX needs to be established using head-to-head studies. The consensus panel agreed that patient who initially responded to IFX, but lost response to their current dose and interval, are eligible for frequency intensification. Others should be treated with dosage increasement. In addition, based on the results from the department of gastroenterology, the consensus panel agreed that routine measurement of vital signs is not warranted in any patient receiving IFX.
W1222 Anti-MAP Rescues Anti-TNF Failures for Over 4 Years Thomas J. Borody, Sahisha Ketheeswaran, Sharyn Leis On an ITT basis, 74% of Crohn's disease (CD) patients go into remission on infliximab with 42% not responding at all.1 In responders the long-term efficacy of infliximab is limited by loss of response over time.2 Growing evidence suggests that prolonged anti-Mycobacterium avium paratuberculosis (anti-MAP) combination therapy can improve CD in a significant number of patients for many years.3,4 Aim: To examine the efficacy of anti-MAP rescue therapy in CD patients who have failed multiple infliximab treatments. Methods: Patients with severe, active CD who had undergone anti-MAP rescue therapy following infliximab failure, were included in this retrospective analysis. Patients had previously received multiple courses of infliximab (3-30 courses). Originally patients had longstanding symptoms of diarrhoea, rectal bleeding, abdominal pain, urgency, malaise and fatigue. Anti-MAP therapy consisted of rifabutin, clarithromycin and clofazimine, (initially adding ciprofloxacin or ethambutol), commenced as a ramp-up schedule with doses not exceeding 600mg/d, 1g/d, 100mg/d, and 1g/d, or 400mg/d respectively. Effectiveness of treatment was determined by a marked fall in Crohn's Disease Activity Index (CDAI) from baseline values, symptomatic and endoscopic improvement. Results: All 4 patients (2M, 2F; aged 20-56y) achieved sustained response (CDAI reduction >100) by 11 weeks of anti-MAP therapy. Markers of inflammation, CRP levels and ESR, also decreased considerably from baseline levels in 4/ 4 patients. Concomitant medications were reduced without symptomatic relapse. More
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consent and in all privacy, patients filled up an anonymous survey with demographic data (age, gender, study level, working status, personal status), data concerning the disease (type of IBD, year of diagnosis, number of hospital admissions, IBD-related surgical procedures), data about therapy (drug, dose, interval), self-applied adhesion declaration and self-medication. An activity index was calculated on the spot (Harvey-Bradshaw/Truelove) Results: Mean age was 41.3±11 years, 60% were women. The number of years since IBD diagnosis was 8±7; 64% were Crohn's disease (71% inactive), 36% ulcerative colitis (70% inactive). A 66% was treated with aminosalicylates, 51% with immunosuppressors, 8% with glucocorticoids. A 66% needed an IBD-related hospital admission in the past, and 17% any IBD-related surgical procedure. A 69% (95%CI: 60-77%) showed some type of non-adhesion. A 66% (57-75%) acknowledged dome degree of involuntary non-adhesion: either forgetting to take their dose (63%) or being careless about having taken it (27%). A 16% (9-22%) showed some kind of voluntary non-adhesion: interrupting the therapy when feeling better (13%) or when feeling worse (6%). A 25% (17-33%) forgot at least a dose a week (mean weekly number of forgotten doses 1.6), and the most frequent cause was to be away form home when they were supposed to take the medication. This was more frequent under mesalazine therapy (30%) than with azathioprine (17%) (p=n.s.). A multivariate analysis identified as risk factors for a lower adhesion the dosing in three or more takes a day (OR 3; 95%CI 1.1-8.4; p= 0.03) and feeling little informed about their disease (OR 4.9; 95%CI 1.1-23.8; p=0.04). On the other hand, immunomodulator therapy was a predictive factor for better adhesion (OR 0.29; 95%CI 0.11-0.74; p=0.01). The concordance between patient recall and clinical records was complete in 86%, whereas in 10.3% the patients did not accurately remember the dose and in 3.7% there was confusion about the drug taken. A 9% acknowledged self-medication during flares Conclusions: In our setting, adhesion to therapy in IBD patients is not satisfactory. Patients treated with immunosuppressors have better adhesion. Optimizing the information on the disease and giving the medication in one or two daily doses could enhance therapeutic adhesion