Martin Lukas

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.

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.

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.

Role of interventional inflammatory bowel disease in the era of biological therapy: a position statement from the Global Interventional IBD Group

Interventional (or therapeutic) inflammatory bowel disease (IBD) endoscopy has an expanding role in the treatment of disease and surgical adverse events. Endoscopic therapy has been explored and used in the management of strictures, fistulas/abscesses, colitis-associated neoplasia, postsurgical acute or chronic leaks, and obstructions. The endoscopic therapeutic modalities include balloon dilation, stricturotomy, stent placement, fistulotomy, fistula injection and clipping, sinusotomy, EMR, and endoscopic submucosal dissection. With a better understanding of the disease course of IBD, improved long-term impact of medical therapy, and advances in endoscopic technology, we can foresee interventional IBD becoming an integrated part of the multidisciplinary approach to patients with complex IBD.

Combination of endoscopic treatment – septectomy and stricturotomy in the afferent ileal limb of the ileal pouch

Endoscopic therapy of inflammatory bowel disease associated complications, such as stricture and fistula, has become an adjunct to medical and surgical treatment [1, 2]. Here we describe the case of a patient with ulcerative colitis and ileal pouch-anal anastomosis (IPAA) with complex stricture, which was successfully treated with a combined endoscopic stricturotomy and septectomy (▶Video1). The patient was a 68-year-old woman with a diagnosis of ulcerative colitis since 1997. She underwent a subtotal colectomy in 2000 and IPAA in 2001. Since her surgery, she suffered from recurrent episodes of pouchitis, which were successfully treated with antibiotics. In 2016, she developed an ano-vaginal fistula, which was treated by ano-rectal advancement flap. In 2017 the patient’s symptoms worsened, and she had 10 bowel movements daily along with abdominal pain, bloating, and early satiety. In January, 2018, the pouch endoscopy showed mucosal edema, erosions, and erythema in the pouch body. About 5 cm above the ileal inlet into the pouch there was a moderate narrowing of the lumen along with a septum (▶Fig. 1 a), which a regular gastroscope could not traverse. The septum was thought to result from a full-thickness bowel wall bridge. As a first step, a guidewire was inserted to verify the position of the septum. Then, the septum was cut with an isolated-tip (IT) knife alongside the guidewire (▶Fig. 1b), and the stump of the septum was resected using a polypectomy snare (▶Fig. 1 c). The remaining stricture was then treated by IT knife stricturotomy (▶Fig. 1d). Subsequently, three endoscopic clips were placed along the incised edges of the stricture to maintain luminal patency and to prevent bleeding and perforation. Finally, the afferent limb was successfully intubated. The traditional approach to treatment of bowel strictures in patients with IBD involves endoscopic balloon dilation (EBD) or surgery. An “interventional IBD” approach extends the therapeutic armamentarium by several other techniques, such as stricturotomy, fistulotomy, and sinusotomy [3]. An endoscopic stricturotomy with needle-knife or IT knife seems to carry a higher efficacy, a lower risk of perforation, but a higher risk of bleeding than endoscopic balloon dilation [4]. Endoscopic septectomy, resection of the stump of the septum, stricturotomy, and clip placement were used to treat our patient, with no immediate or delayed complications. To the best of our knowledge, this is the first report of the combination of four endoscopic techniques used to treat a patient with IBD surgery-related complication. However, randomized controlled studies should be carried out to properly assess the endoscopic techniques described.

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.