Martin Kolar

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.

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.

Dymanics of matrix-metalloproteinase 9 after brain trauma – results of a pilot study

BACKGROUND Secondary brain injury contributes to poor outcome for patients sustaining brain trauma. Matrix metalloproteinase-9 (MMP-9) is a potential marker, as well as effector of secondary brain injury. This enzyme degrades components of extracellular matrix, and thus it can contribute to blood-brain barrier disruption. METHODS We studied dynamics of MMP-9 in jugular venous blood of 15 patients sustaining either an isolated head injury or a head injury as a part of major trauma, and requiring intensive care (Glasgow Coma Scale <8 at the time of admission). Blood samples were taken at the 1st, 3rd and 5th day, levels of MMP-9 in plasma were assessed using ELISA. Outcome quality was assessed at the time of discharge from our hospital. FINDINGS Our results show an increase of MMP-9 levels on the 1st day after the brain trauma, followed by a drop on the 3rd day and a rise on day 5. This biphasic time-course was observed in all patients, but no statistically significant differences between each group (major trauma vs. isolated brain trauma, good outcome vs. poor outcome) were found. CONCLUSIONS Initially increased MMP-9 levels in the 1st posttraumatic day is probably related to transient blood-brain barrier dysruption. The decrease of MMP-9 levels observed on the 3rd day can be explained by restoration of blood-brain barrier integrity and its reduced permeability. The second rise of MMP-9 levels observed in the 5th day probably indicates a developing secondary brain injury during which MMP-9 is produced in the brain as a part of an inflammatory response. RESULTS of our study suggest that MMP-9 could play an important role in pathogenesis of secondary brain injury.

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.