Nadezda Machkova

Infliximab trough levels may predict sustained response to infliximab in patients with Crohn's disease

BACKGROUND AND AIMS Over 10% of Crohns disease (CD) patients annually lose response to infliximab. Infliximab trough levels (TL), concomitant immunosuppressants and endoscopic healing were proposed as predictors of favourable infliximab outcome. We assessed infliximab TL measured after induction therapy as predictors of sustained clinical response. Furthermore, we tried to identify other predictors of long-term benefit of infliximab therapy. METHODS We included CD patients treated with infliximab between October 2007 and March 2010 who responded to 3-dose induction followed by maintenance therapy and in whom blood samples taken at treatment week 14 or 22 were available in blood bank. Sustained response to infliximab was defined as absence of treatment failure due to loss of response or drug intolerance. RESULTS Eighty four patients were included. Sustained response to infliximab was observed in 47 (56%) patients during a median follow-up of 25 months (14-37). Infliximab TL>3μg/ml were associated with a decreased risk of treatment failure (HR 0.34; 95% CI: 0.16-0.75), whereas the presence of antibodies against infliximab and need for corticosteroids increased this risk (HR 4.34; 95% CI: 1.51-12.5 and HR 2.49, 95% CI: 1.08-5.73, respectively). No impact of concomitant thiopurines was observed, although patients receiving thiopurines had higher infliximab TL than those without immunomodulators (5.51 vs. 0.71μg/ml; p=0.01). CONCLUSION During a median follow up of 2 years sustained response to infliximab was observed in slightly more than half of CD patients. Infliximab TL>3μg/ml at the start of maintenance regime were predicative of sustained response to infliximab.

Impact of Anti–Tumor Necrosis Factor Alpha Antibodies Administered to Pregnant Women With Inflammatory Bowel Disease on Long-term Outcome of Exposed Children

Background:Prenatal exposure to anti–tumor necrosis factor &agr; (TNF-&agr;) antibodies seems to be safe for fetal development. Data on long-term outcome of exposed children are missing. Our aim was to assess long-term postnatal development of children exposed to anti–TNF-&agr; during pregnancy. Methods:Consecutive children aged ≥12 months exposed to anti-TNFs prenatally for maternal inflammatory bowel disease in 3 centers in the Czech Republic were enrolled. Data on psychomotor development, infections, antibiotics, vaccination, and allergy were retrospectively obtained from mothers, treating pediatricians, and childrens vaccination cards. Furthermore, standardized laboratory tests on humoral and cellular immunity were performed. Results:Twenty-five children exposed to biologicals were included (median age, 34 mo; range, 14–70 mo). All children had normal growth, and all but 1 had normal psychomotor development. Majority (80%) experienced at least 1 infection (mainly respiratory), and 60% of infants received antibiotics, 32% of those within the first year of life. Vaccination was undertaken according to vaccination protocol to 23 infants (92%). Fifteen children also had tuberculosis vaccination without serious complication. Immunological investigation was performed with 17 children (68%). Cellular immunity was normal in all infants, and 7 children had mild decrease in IgA and/or IgG immunoglobulins without clinical significance. All children had a detectable serologic response to vaccination. Conclusions:Exposure to anti–TNF-&agr; antibodies seems to be safe for growth and psychomotor development of children, although clinical significance of relatively high frequency of infections and antibiotic use among infants remains questionable because of the lack of a control group. Continuous follow-up of exposed children is absolutely warranted.

Pregnancy and newborn outcome of mothers with inflammatory bowel diseases exposed to anti-TNF-α therapy during pregnancy: three-center study

Abstract Objective. Substantial number of women with inflammatory bowel disease (IBD) conceives while on anti-TNF-α therapy. The aim was to assess the safety and efficacy of anti-TNF-α treatment during pregnancy and to analyze relationship of neonatal and maternal anti-TNF-α levels at delivery with gestational age at the last exposure. Material and methods. Women with IBD exposed to anti-TNF-α therapy during pregnancy were included. Data on anti-TNF-α treatment, disease activity, concomitant medication, pregnancy and newborn outcome were recorded. Anti-TNF-α levels from cord blood were assessed by ELISA. Results. Forty-one pregnancies (27 Crohns disease; 14 ulcerative colitis) were exposed to infliximab (IFX; 32) and adalimumab (ADA; 9). Ten (24%) women had active disease at conception and 31 (76%) were in remission with 3 patients experiencing relapse during pregnancy. Anti-TNF-α therapy started prior to and after conception in 32 and 9 women, respectively. There were 34 (83%) live births (median birth weight 3145 g) of which 28 were at-term and 6 preterm deliveries. Five (12%) pregnancies ended in spontaneous and two in therapeutic abortion. No congenital malformations except for one case of hip dysplasia were observed. Similarly, no serious perinatal complication occurred. IFX cord levels measured in 11 children positively correlated with gestational week at the last drug administration and maternal levels at delivery, while no such correlation was found in case of ADA. Conclusions. The results confirm that anti-TNFs are effective and safe during pregnancy. A positive correlation between IFX cord levels and gestational week of last exposure as well as maternal serum levels was observed.

Discontinuation of anti-tumor necrosis factor therapy in inflammatory bowel disease patients: a prospective observation.

Abstract Background: Discontinuation of anti-TNF therapy in patients with inflammatory bowel diseases (IBD) in remission remains a controversial issue. The aims of our study were to assess the proportion of patients who relapse after cessation of biological treatment, and to identify potential risk factors of disease relapse. Methods: Consecutive IBD patients who discontinued anti-TNF therapy in steroid-free clinical and endoscopic remission were prospectively followed. Multiple logistic regression and Cox proportional-hazards models were used to assess the predictors of disease relapse. Results: Seventy-eight IBD patients (Crohns disease, CD 61; ulcerative colitis, UC 17) were included and followed for a median of 30 months (range 7–47). A total of 32 (53%) CD patients and nine (53%) UC patients relapsed by the end of the follow-up with a median time to relapse of 8 months (range 1–25) in CD patients and 14 months (range 4–37) in UC patients, respectively. The cumulative probabilities of maintaining remission at 6, 12, and 24 months were 82%, 59%, and 51% in CD patients, and 77%, 77%, and 64% in UC patients, respectively. Survival of CD patients who were in deep remission (clinical and endoscopic healing; faecal calprotectin <150 mg/kg; CRP ≤5 mg/l) was not better compared with those who did not fulfill these criteria. In multivariate models, only colonic CD protected patients from disease relapse. Conclusions: Approximately half of the IBD patients relapsed within 2 years after anti-TNF discontinuation. In CD patients, no difference between those who were or were not in deep remission was found. Colonic localization protected patients from relapse.

P360 Infliximab trough levels may predict sustained response to infliximab in patients with Crohn's disease: A single cohort study

P360 Infliximab trough levels may predict sustained response to infliximab in patients with Crohn’s disease: A single cohort study M. Bortlik1 *, D. Duricova2, K. Malickova3, A. Komarek4, N. Machkova5, E. Bouzkova6, L. Hrdlicka6, M. Lukas7. 1Iscare Lighthouse, IBD Centre, Prague, Czech Republic, 2Charles University, IBD Clinical and Research Centre, Prague, Czech Republic, 3Charles University, Institute of Clinical Biochemistry and Laboratory Diagnostics, Prague, Czech Republic, 4Faculty of Mathematics and Physics, Charles University, Department of Probability and Mathematical Statistics, Prague, Czech Republic, 5IBD Clinical And Research Center Iscare, Gastroenterology, Prague, Czech Republic, 6Charles University, IBD Clinical and Research Centre, Iscare, Prague, Czech Republic, 7Clinical Centre Isacre Lighthouse, IBD Clinical and Research Centre, Prague, Czech Republic

Tu1141 Mucosal Healing of Small Bowel Crohn's Disease After Anti-TNFα Therapy Assessed by Capsule Endoscopy

BACKGROUND:Inflammatory bowel disease (IBD) patients have an increased risk of osteoporosis related fractures. Necessity of bone density measurement in IBD patients is not clearly defined, however, the risk of fracture increases among them. Fracture Risk Assessment Tool (FRAX) score computes the 10-years probability of the major osteoporotic fractures and particularly hip fracture. Clinical FRAX (c-FRAX) does not include the bone mineral density (BMD) measurement. We aimed to compare the value the c-FRAX to FRAX enhanced with dual x-ray absorptiometry (DEXA) (bmd-FRAX) in IBD patients. METHODS:169 consecutive IBD patients (128 Crohns disease (CD) and 41 ulcerative colitis (UC); female/male: 88/81) were included into the study. Mean age of the patients was 35.9±11.7 years, 7.6% of them was postmenopausal women. FRAX-scores were calculated with the online tool using a Hungarian algorithm. Bone mineral density measurements were performed by DEXA. Calculations were performed using SPSS statistics 15.0 software. RESULTS:In patients under 40 the c-FRAX score regardingmajor osteoporotic fracture riskwas significantly higher compared to bmd-FRAX (1,9±1,1 vs. 1,4±0,8, p,0,01). The same difference was observed computing the probability of hip fractures (c-FRAX: 0,4±0,7 vs. bmd-FRAX: 0,3±0,5; p ,0,05). In a subgroup analysis the fracture risks have not differed in CD vs. UC patients. Major fracture risk c-FRAX and bmd-FRAX were 3,0±3,4% es 2,4±2,7% in CD and 3.4±3.4% and 2.5±2.4% in UC patients (non-significant (NS)). Clinical FRAX and bmd-FRAX showing hip fracture risk were 0.8±1.5% and 0.6±1.4% in CD and 0.8±1.3% and 0.4±0.7% in UC, respectively (NS). We did not observe any correlation between FRAX scores and calcium intake, physical activity, severity, extentand duration of the disease. Subgroup analysis regarding steroid use and body mass index has not been performed due to the FRAX system included in these parameters. CONCLUSION:Guidelines regarding IBD associated osteoporosis advise to perform the DEXA measurements in patients with some special risk factors for bone loss. In our study the fracture risk according to FRAX scores completed with DEXA were lower than clinical FRAX especially in patients younger than 40 years. Our results suggest that DEXA enhanced FRAX may have an advantageous role in preventing over medicating young IBD patients.

Sa1958 No Difference in Immunogenicity of the Original and Biosimilar Infliximab in Patients With Inflammatory Bowel Disease: Short-Term Results

Background: Biosimilar infliximab (IFX) seems to have similar efficacy and safety to original preparation in patients with inflammatory bowel diseases (IBD) who are naïve to anti-TNFa therapy. However, the evidence on switching from original to biosimilar preparation is very sparse. Aim: Our aim was to evaluate efficacy and safety of switching from original to biosimilar preparation IFX in patients with Crohn ′s disease (CD) and ulcerative colitis (UC). Methods: Consecutive patients with CD and UC on maintenance IFX treatment at our center who were switched from original to biosimilar IFX during a period from January to March 2015 were included. Patients were followed prospectively in regular intervals coincident with infusion applications. At each visit disease activity was registered using HarveyBradshaw index (HBI) for CD and Simple clinical colitis activity index (SCCAI) for UC; blood sample taken for analysis of blood count, biochemistry and IFX pharmacokinetics (trough levels, TL and anti-drug antibodies, ATI) and stool sample obtained for measurement of fecal calprotectin (FC). Furthermore, adverse events were registered. All patients were evaluated at week 24 (W24) of treatment with biosimilar IFX. Results: Seventy-four patients with IBD, 56 with CD and 18 with UC, were switched to biosimilar IFX after mean time of 3±2.2 years on original preparation. Almost half of individuals (34, 46%) were on concomitant azathioprine and one patient had systemic corticosteroids. Majority of patients, 51 (69%) were at the time of switch (week 0, W0) in clinical remission, 16 (22%) had mild to moderate active disease and 4 (5%) individuals had severe disease activity. Comparing W0 and W24, no significant difference in C-reactive protein levels (4.3±8.0 mg/L vs. 3.6±4.5; p=0.78) and FC (135±153 μg/g vs. 226±297; p=0.44) was observed. Likewise, no increase in immunogenicity was found (IFX TL: 3.4±3.8 μg/mL vs. 3.8±3.3, p=0.23; ATI positivity: 9.5% vs. 10%, p=0.79). Furthermore, disease activity was stable until the end of follow-up (remission at W0 vs. W24: 72% vs. 78%). Three patients discontinued IFX treatment up to W22 due to loss of response (n=1), adverse event (n=1) and low grade dysplastic lesion in colon (1 UC patients). None patient experienced infusion reaction and the frequency and type of adverse events were similar to that observed during treatment with original IFX. Conclusion: Based on our results switching of IBD patients from original to biosimilar IFX is effective and safe. Importantly, no increase in immunogenicity was observed. Acknowledgement: The study was supported by IBD-COMFORT foundation.

P492 Impact of anti-TNFa therapy of inflammatory bowel disease during pregnancy on long-term outcome of exposed children

Methods:Aquestionnaire including 6 main questions and a basic section with regard to personal information was sent to all gastroenterologists in Switzerland. Results: The vast majority of all Swiss GI specialists (90%) use a thiopurine as the first step up strategy after steroids and not anti-TNF(7.5%) or combo-therapy (2.5%) up front. While 41.2% of all Swiss gastroenterologists state to have no specific preference for any TNF-inhibitor, IFX is the favourite anti-TNF agent in 47.1% (ADA 10.9% and CTZ 0.8%). IFX is even significantly more preferred in those seeing less than 30 IBD patients per year (57.4%; >30. Pat 36.2%, p = 0.02). To address LOR the most preferred strategy is shortening the interval of anti-TNF administration in 49.5% of doctors (mean 5.4 on a scale from 1 to 6; lowest and highest agreement, respectively), followed by increasing the dose (5.0), switching the TNF-inhibitor (4.9), add a thiopurine (3.9), initiate a full re-induction (3.6), add prednisone (3.5), refer to surgery (3.5) and add methotrexate (2.9). In case of prolonged remission on combo therapy Swiss gastroenterologists stop one drug after a mean of 15.7 month (with a fairly wide range from 6 to 48 month). The thiopurine is stopped first in most cases (50.8%; TNF-inhibitor first 40%, only 4.2% continue both therapies, stop both at the same time 1.7%, other 3.3%). Conclusions: In the case of LOR dose intensification prior to switching of the TNF-inhibitors is most often used among Swiss gastroenterologists. Regarding step-up and de-escalation strategies GI specialists in Switzerland still mainly apply a conventional step-up with thiopurines. In the case of prolonged remission, stopping the immunosuppressant first is preferred.

Predictors of Sustained Response to Infliximab in Patients With Crohn's Disease: A Single Cohort Study

Background and Aims: The three anti-TNF agents infliximab (IFX), adalimumab (ADA) and certolizumab pegol (CZP) have demonstrated similar efficacy in induction and maintenance of response and remission in Crohns disease (CD) treatment. Given the comparability of these drugs, patients preferences may influence the choice of the product. However, data on patients preferences for choosing anti-TNF agents are lacking. We therefore aimed to assess the CD patients appraisal to select the drug of his choice and to identify factors guiding this decision. Methods: A prospective survey among anti-TNF-naive CD patients was performed. Patients were provided a description of the three anti-TNF agents focusing on indication, application mode (s.c. vs. i.v.), application time intervals, setting of application (hospital vs. private practice vs. patients home), average time to apply the medication per month, typical side effects, and the scientific evidence of efficacy and safety available for every drug. Patients answered a questionnaire consisting of 17 questions, covering demographic, disease-specific, and medication data. Results: Hundred patients (47f/53m, mean age 45±16 years) completed the questionnaire. Disease duration was 5 years in 62% of patients. Disease location was ileal in 33%, colonic in 40%, and ileocolonic in 27%. Disease phenotype was inflammatory in 68%, stenosing in 29%, and internally fistulizing in 3% of patients. Additionally, 20% had perianal fistulizing disease. Patients were already treated with the following drugs: mesalamines 61%, budesonide 44%, prednisone 97%, thiopurines 78%, methotrexate 16%. In total, 30% had already heard about IFX, 20% about ADA, and 11% about CZP. Thirty-six percent voted for treatment with ADA, 28% for CZP, and 25% for IFX, whereas 11% were undecided. The following factors influenced the patients decision for choosing a specific anti-TNF drug (several answers possible): side effects 76%, physicians recommendation 66%, application mode 54%, efficacy experience 52%, time to spend for therapy 27%, patients recommendations 21%, interactions with other medications 12%. The single most important factor for choosing a specific anti-TNF was (1 answer): side effect profile 35%, physicians recommendation 22%, efficacy experience 21%, application mode 13%, patients recommendations 5%, time spent for therapy 3%, interaction with other medications 1%. Conclusions: The majority of patients preferred anti-TNF syringes to infusions. The safety profile of the drugs and the physicians recommendation are major factors influencing the patients choice for a specific anti-TNF drug. Patients issues about safety and lifestyle habits should be taken into account when prescribing specific anti-TNF formulations.