Katarina Mitrova

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.

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.

Disease activity is an important factor for indeterminate interferon-γ release assay results in children with inflammatory bowel disease.

Background: Interferon-&ggr; release assay (IGRA) is widely used for screening of latent tuberculosis (TB) before and during biological therapy (BT). An indeterminate result of IGRA represents a limitation in the management of inflammatory bowel disease (IBD). Data on factors influencing IGRA results are scarce in children. The aim of the study was to identify factors influencing IGRA results in children with IBD. Methods: Seventy-two children with IBD (59 Crohn disease, 11 ulcerative colitis, 2 IBD-unclassified) indicated for BT were tested for TB infection (history, TB skin test, chest radiograph, IGRA; QuantiFERON—TB Gold in tube [QFT]) and consecutively retested using QFT in 1-year intervals. Results: We recorded 165 results of QFT (3% positive, 87% negative, and 10% indeterminate results). During follow-up we identified 4 conversions of negative QFT to positivity (3%) and 4 reversions (4%). Patients with indeterminate results of QFT had significantly lower actual weight-for-height z score (P = 0.022), higher platelet count (P = 0.00017), and lower levels of serum albumin (P = 0.015) compared with patients with positive or negative QFT. Indeterminate QFT was associated with corticosteroid treatment, BT, and disease activity, but not with treatment by immunomodulators. In a subanalysis of patients with Crohn disease alone, Pediatric Crohns Disease Activity Index was identified as single independent risk factor for indeterminate results (P = 0.00037). Conclusions: Although corticosteroid treatment is traditionally considered to be the main risk factor for indeterminate results of IGRA, the disease activity of IBD has even more profound effects on the results.

Infliximab Biosimilar (Remsima™) in Therapy of Inflammatory Bowel Diseases Patients: Experience from One Tertiary Inflammatory Bowel Diseases Centre.

Background: The evidence on the efficacy and safety of biosimilar infliximab (IFX) in patients with inflammatory bowel diseases (IBD) is sparse. Methods: Consecutive IBD patients visiting our centre were included. One cohort composed of prospectively followed patients who were switched from original to biosimilar IFX between January and March 2015. The second cohort included retrospectively assessed anti-tumor necrosis factor α-naïve patients who started therapy between January 2015 and January 2016. Disease activity was assessed using standard clinical indices, endoscopic evaluation, and laboratory parameters (blood count, C-reactive protein (CRP) and fecal calprotectin (FC)). Trough levels and anti-drug antibodies (ATIs) were also measured. Patients were evaluated 56 weeks (W56) after switch and at week 14 (W14) and week 46 (W46) in the naïve cohort. Results: Seventy-four IBD patients were switched to biosimilar IFX and 119 naïve patients newly initiated therapy with the preparation. Disease activity remained stable in a majority of switched patients (remission at week 0 (W0) vs. W56: 72.2 vs. 77.8%; median difference of both Harvey-Bradshaw index and Simple Clinical Colitis Activity Index between W0 and W56 was 0). When W0 and W56 were compared, no significant difference in CRP (4.3 ± 8.0 vs. 3.3 ± 3.8 mg/l; p = 0.89) and FC (135 ± 153 vs. 199 ± 225 µg/g; p = 0.17) was observed. In total, 92% of Crohns disease (CD) and 83% of ulcerative colitis (UC) patients responded to induction therapy (W14) with biosimilar IFX. At W46, the response rate was 86% in CD and 64% in UC. Moreover, half of UC patients experienced mucosal healing at W14 and improvement of perianal disease occurred in 95% of CD at W46. In this cohort, clear steroid-sparing effect was observed. No increase in immunogenicity was found in switched patients (ATI positivity: 9.5 vs. 6.0%, p = 0.54) and the type and frequency of adverse events were comparable to the original preparation in both cohorts. Conclusion: Switching of IBD patients from original to biosimilar IFX is effective and safe.

Frequency and characteristics of infusion reactions during biosimilar infliximab treatment in inflammatory bowel diseases: results from Central European nationwide cohort

ABSTRACT Background: Safety data of the ‘real life’ use of an infliximab biosimilar, CT-P13 in inflammatory bowel disease (IBD) are still lacking. Our aim was to assess the frequency and characteristics of infusion reactions during CT-P13 therapy in 13 Hungarian and 1 Czech IBD centres. Methods: Clinical and safety data was registered at fixed appointments. Trough levels and anti-drug antibody (ADA) concentration were measured by ELISA. Association between demographic, clinical, laboratory parameters and infusion reaction rates were evaluated statistically. Results: Three hundred and eighty-four IBD patients were included. Twenty-eight Hungarian IBD patients (9.6%) developed infusion reaction during the treatment, 64.3% of them was previously exposed to anti TNF therapy. No infusion reaction occurred in the Czech population. CT-P13 therapy had to be stopped in 17 patients who developed infusion reaction and was switched to adalimumab in 12 patients. However in 39.3% of patients developing infusion reaction CT-P13 therapy was continued with the use of premedication. Cumulative ADA positivity rates were 8.7%, 19.3%, and 28.0% at weeks 0, 14, and 30. Previous anti-TNF-alpha exposure (30% vs. 3.1%, p < 0.001, OR 6.3 (2.7–14.6)) and ADA positivity (32.6% vs. 4.1%, p < 0.001, OR 19(5–73)) during the induction therapy were predictive factors for infusion reactions. Conclusions: Patients with previous exposure to anti-TNF-alpha and ADA positivity during the induction therapy were more likely to develop infusion reactions.

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.

Development of High‐Sensitive ELISA Method for Detection of Adipophilin Levels in Human Colostrum and Breast Milk

To develop and validate high‐sensitive (hs) ELISA method for detection of adipophilin (adipose differentiation‐related protein, ADRP) in human breast milk (BM) and to analyze adipophilin levels in BM during 12 months of lactation.

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.