Subcutaneous Infliximab in Refractory Crohn's Disease Patients: A Possible Biobetter?

Background: A subcutaneous formulation of infliximab (IFX-SC) approved to treat patients with inflammatory bowel disease may offer improved efficacy versus intravenous infliximab. Methods: Patients with refractory Crohn's disease (CD, n = 32) previously treated unsuccessfully with at least 2 biologics were treated with IFX-SC and followed from baseline at Week 0 (W0) to Week 30 (W30). The study's primary endpoint was the treatment's persistence at W30, while secondary goals included the analysis of serum infliximab trough levels (TL IFX), dynamics of anti-IFX antibodies (ATIs), and clinical, serum and fecal markers of CD activity during IFX-SC treatment. Results: Midterm treatment persistence with the continuation of treatment after W30 was 53%. TL IFX median values showed rapid, significant upward dynamics and exceeded 15.5 µg/mL at W30, whereas median ATI levels significantly declined. Among ATI-negative patients at W0 (n = 15), only one showed IFX immunogenicity with newly developed ATIs at W30. Among ATI-positive patients at W0, ATI seroconversion from ATI-positive to ATI-negative status was observed in 10 of 17 patients (58.8%). Patients who had continued IFX-SC treatment at W30 showed significant decreases in C-reactive protein (P = .0341), fecal calprotectin (P = .0002), and Harvey-Bradshaw index (P = .0029) since W0. Conclusions: Patients with refractory CD previously treated with at least 2 biologics exhibited clinically relevant improvement with IFX-SC, which showed less immunogenic potential than IFX-IV and highly stable TL IFX.

Real-Life Efficacy of Tofacitinib in Various Situations in Ulcerative Colitis: A Retrospective Worldwide Multicenter Collaborative Study.

BACKGROUND AND AIMS: Tofacitinib (TFB) appears to be effective in the treatment of ulcerative colitis (UC); however, available real-world studies are limited by cohort size. TFB could be an option in the treatment of acute severe ulcerative colitis (ASUC). We aimed to investigate efficacy and safety of TFB in moderate-to-severe colitis and ASUC. METHODS: This retrospective, international cohort study enrolling UC patients with ≥6-week follow-up period was conducted from February 1 to July 31, 2022. Indications were categorized as ASUC and chronic activity (CA). Baseline demographic and clinical data were obtained. Steroid-free remission (SFR), colectomy, and safety data were analyzed. RESULTS: A total of 391 UC patients (median age 38 [interquartile range, 28-47] years; follow-up period 26 [interquartile range, 14-52] weeks) were included. A total of 27.1% received TFB in ASUC. SFR rates were 23.7% (ASUC: 26.0%, CA: 22.8%) at week 12 and 41.1% (ASUC: 34.2%, CA: 43.5%) at week 52. The baseline partial Mayo score (odds ratio [OR], 0.850; P = .006) was negatively associated with week 12 SFR, while biologic-naïve patients (OR, 2.078; P = .04) more likely achieved week 52 SFR. The colectomy rate at week 52 was higher in ASUC group (17.6% vs 5.7%; P < .001) and decreased with age (OR, 0.94; P = .013). A total of 67 adverse events were reported, and 17.9% resulted in cessation of TFB. One case of thromboembolic event was reported. CONCLUSIONS: TFB is effective in both studied indications. TFB treatment resulted in high rates of SFR in the short and long terms. Higher baseline disease activity and previous biological therapies decreased efficacy. No new adverse event signals were found.

Serum TGF-ß1 and CD14 Predicts Response to Anti-TNF-α Therapy in IBD.

Background: Tumor necrosis factor-alpha (TNF-α) agonists revolutionized therapeutic algorithms in inflammatory bowel disease (IBD) management. However, approximately every third IBD patient does not respond to this therapy in the long term, which delays efficient control of the intestinal inflammation. Methods: We analyzed the power of serum biomarkers to predict the failure of anti-TNF-α. We collected serum of 38 IBD patients at therapy prescription and 38 weeks later and analyzed them with relation to therapy response (no-, partial-, and full response). We used enzyme-linked immunosorbent assay to quantify 16 biomarkers related to gut barrier (intestinal fatty acid-binding protein, liver fatty acid-binding protein, trefoil factor 3, and interleukin (IL)-33), microbial translocation, immune system regulation (TNF-α, CD14, lipopolysaccharide-binding protein, mannan-binding lectin, IL-18, transforming growth factor-ß1 (TGF-ß1), osteoprotegerin (OPG), insulin-like growth factor 2 (IGF-2), endocrine-gland-derived vascular endothelial growth factor), and matrix metalloproteinase system (MMP-9, MMP-14, and tissue inhibitors of metalloproteinase-1). Results: We found that future full-responders have different biomarker profiles than non-responders, while partial-responders cannot be distinguished from either group. When future non-responders were compared to responders, their baseline contained significantly more TGF-ß1, less CD14, and increased level of MMP-9, and concentration of these factors could predict non-responders with high accuracy (AUC = 0.938). Interestingly, during the 38 weeks, levels of MMP-9 decreased in all patients, irrespective of the outcome, while OPG, IGF-2, and TGF-ß1 were higher in non-responders compared to full-responders both at the beginning and the end of the treatment. Conclusions: The TGF-ß1 and CD14 can distinguish non-responders from responders. The changes in biomarker dynamics during the therapy suggest that growth factors (such as OPG, IGF-2, and TGF-ß) are not markedly influenced by the treatment and that anti-TNF-α therapy decreases MMP-9 without influencing the treatment outcome.

Association between ustekinumab therapy and changes in specific anti-microbial response, serum biomarkers, and microbiota composition in patients with IBD: A pilot study.

BACKGROUND: Ustekinumab, is a new therapy for patients with IBD, especially for patients suffering from Crohn's disease (CD) who did not respond to anti-TNF treatment. To shed light on the longitudinal effect of ustekinumab on the immune system, we investigated the effect on skin and gut microbiota composition, specific immune response to commensals, and various serum biomarkers. METHODOLOGY/PRINCIPAL FINDINGS: We recruited 11 patients with IBD who were monitored over 40 weeks of ustekinumab therapy and 39 healthy controls (HC). We found differences in the concentrations of serum levels of osteoprotegerin, TGF-ß1, IL-33, and serum IgM antibodies against Lactobacillus plantarum between patients with IBD and HC. The levels of these biomarkers did not change in response to ustekinumab treatment or with disease improvement during the 40 weeks of observation. Additionally, we identified differences in stool abundance of uncultured Subdoligranulum, Faecalibacterium, and Bacteroides between patients with IBD and HC. CONCLUSION/SIGNIFICANCE: In this preliminary study, we provide a unique overview of the longitudinal monitoring of fecal and skin microbial profiles as well as various serum biomarkers and humoral and cellular response to gut commensals in a small cohort of patients with IBD on ustekinumab therapy.

Skin microbiota signature distinguishes IBD patients and reflects skin adverse events during anti-TNF therapy.

Crohn's disease (CD) and ulcerative colitis (UC) are two forms of inflammatory bowel disease (IBD), where the role of gut but not skin dysbiosis is well recognized. Inhibitors of TNF have been successful in IBD treatment, but up to a quarter of patients suffer from unpredictable skin adverse events (SkAE). For this purpose, we analyzed temporal dynamics of skin microbiota and serum markers of inflammation and epithelial barrier integrity during anti-TNF therapy and SkAE manifestation in IBD patients. We observed that the skin microbiota signature of IBD patients differs markedly from healthy subjects. In particular, the skin microbiota of CD patients differs significantly from that of UC patients and healthy subjects, mainly in the retroauricular crease. In addition, we showed that anti-TNF-related SkAE are associated with specific shifts in skin microbiota profile and with a decrease in serum levels of L-FABP and I-FABP in IBD patients. For the first time, we showed that shifts in microbial composition in IBD patients are not limited to the gut and that skin microbiota and serum markers of the epithelium barrier may be suitable markers of SkAE during anti-TNF therapy.

Fecal Microbiome Changes and Specific Anti-Bacterial Response in Patients with IBD during Anti-TNF Therapy.

Inflammatory bowel diseases (IBD) are chronic disorders of the gastrointestinal tract that have been linked to microbiome dysbiosis and immune system dysregulation. We investigated the longitudinal effect of anti-TNF therapy on gut microbiota composition and specific immune response to commensals in IBD patients. The study included 52 patients tracked over 38 weeks of therapy and 37 healthy controls (HC). To characterize the diversity and composition of the gut microbiota, we used amplicon sequencing of the V3V4 region of 16S rRNA for the bacterial community and of the ITS1 region for the fungal community. We measured total antibody levels as well as specific antibodies against assorted gut commensals by ELISA. We found diversity differences between HC, Crohn's disease, and ulcerative colitis patients. The bacterial community of patients with IBD was more similar to HC at the study endpoint, suggesting a beneficial shift in the microbiome in response to treatment. We identified factors such as disease severity, localization, and surgical intervention that significantly contribute to the observed changes in the gut bacteriome. Furthermore, we revealed increased IgM levels against specific gut commensals after anti-TNF treatment. In summary, this study, with its longitudinal design, brings insights into the course of anti-TNF therapy in patients with IBD and correlates the bacterial diversity with disease severity in patients with ulcerative colitis (UC).

A novel postgraduate endoscopic course using a large animal model of secondary Crohn's disease stricture.

BACKGROUND: The increasing complexity of advanced endoscopic techniques places a high demand on the endoscopist's expertise. Thus, live porcine models have been more frequently used for training. We briefly describe a hands-on postgraduate endoscopic course regarding a novel method of treatment of anastomotic strictures in a porcine model. METHODS: The porcine model of Crohn's disease anastomotic stricture with two artificial side-to-side ileo-colonic anastomoses was used. Participants performed endoscopic stricturotomy under supervision at one of two equipped endoscopic stations. Available animals were endoscopically re-examined 3 months after the course. RESULTS: Twelve anastomoses were prepared for the course. Eleven circumferential stricturotomies together with horizontal cut and clip placement were conducted. All anastomoses were passable for the scope after the procedure, and no case of perforation or bleeding occurred. All anastomoses available for re-examination remained passable for the endoscope after 3 months. CONCLUSION: We successfully organised the first endoscopic hands-on course for the training of endoscopic stricturotomy on a large animal model.

Novel porcine model of Crohn's disease anastomotic stricture suitable for evaluation and training of advanced endoscopic techniques.

BACKGROUND AND AIMS: Currently, treatment options in postsurgical recurrence of stricturing Crohn's disease (CD) are limited. However, development of new invasive endoscopic techniques in clinical practice has safety constraints. The aim of this study was to create a large animal model of anastomotic stricture with CD properties to enable development of new techniques and training. METHODS: A side-to-side ileocolonic anastomosis was created in a modified Roux-en-Y manner with bowel continuity preserved. Two weeks after surgery, we began endoscopic submucosal injections of phenol/trinitrobenzenesulfonic acid solution. This solution was injected every 2 weeks in each quadrant of the anastomosis until development of a stricture. The anastomosis site was assessed endoscopically 2 weeks after the last application (baseline) and then every 2 months until month 6. Endoscopically nonpassable strictures were treated with balloon dilation, endoscopic stricturotomy, and stent placement to confirm the feasibility of such interventions. RESULTS: Nineteen minipigs were included with no postoperative adverse events. After a mean of 4.4 ± .7 injection sessions with 10.5 ± 3.0 mL of the solution, anastomotic strictures were created in 16 pigs (84.2%). Mean diameter of the strictures at baseline was 11.6 ± 2.2 mm. The strictures were inflamed, and the endoscope could not pass. Follow-up was successfully completed in 15 animals (79.0%) with the mean deviation from the initial diameter in every measurement of -.02 ± 2.26 mm (P = .963) and a mean final diameter of 11.7 ± 3.4 mm. The histopathologic evaluation revealed the presence of submucosal fibrosis, chronic inflammation, and microgranulomas. All strictures were amenable to endoscopic therapeutic interventions. CONCLUSIONS: We developed a novel, reproducible porcine model of anastomotic stricture with histologically verified changes mimicking CD and stable diameter for more than 6 months. It is suitable for further endoscopic interventions.

Biosimilars: concept, current status, and future perspectives in inflammatory bowel diseases.

The inflammatory bowel diseases (IBD), which consist of Crohn's disease and ulcerative colitis, are chronic, incurable immunemediated inflammatory disorders of the intestine. As IBD incidence continues to increase globally and its mortality is low, prevalent cases of IBD are rapidly increasing, thereby leading to a substantial increase in health care costs. Although the introduction of biologic agents for IBD management has revolutionized the armamentarium of IBD therapy, the high cost of this therapy is concerning. With the expirations of patents for existing biologic agents (originals), biosimilars with cheaper costs have been highlighted in the field of IBD. Despite concerns regarding their short- and long-term efficacy, safety, immunogenicity, and interchangeability, increasing evidence via prospective observations and phase III or IV clinical trials, which aim to prove the "biosimilarity" of biosimilars to originals, has partly confirmed their efficacy, safety, and interchangeability. Additionally, although patients and physicians are reluctant to use biosimilars, a positive budget impact has been reported owing to their use in different countries. In the near future, multiple biosimilars with lower costs, and efficacy and safety profile similar to originals, could be used to treat IBD; thus, further consideration and knowledge dissemination are warranted in this new era of biosimilars.

The efficacy of a non-leaching antibacterial central venous catheter - a prospective, randomized, double-blind study.

BACKGROUND: Antimicrobial coatings of central venous catheters (CVC) have the potential to reduce the risk of infectious complications. The aim of this study was to examine the efficacy of a catheter with a non-leaching antimicrobial coating against catheter colonization and bloodstream infections (BSI). METHODS: The study was conducted in two centers using a prospective, randomized, double-blind and controlled design (680 intensive care patients; a protective CVC (Certofix® protect) or a standard CVC (Certofix®). Primary objectives were the rates of catheter colonization and BSI in the two groups. Other baseline demographics, APACHE II score, insertion site, location of CVC placement (ICU or theatre), indwelling time and length of ICU stay were comparable for both groups. RESULTS: While the rate of catheter colonization between the coated and uncoated CVC (17.4% vs. 18.7%, P=0.7477) and the rate of microbiologically confirmed catheter associated infections were similar (1.4% vs. 1.9%, P=0.7521), the coated CVC showed a significantly lower incidence of BSI (2.0% vs. 6.5%, P=0.0081) and a significantly lower mean incidence of BSI per 1000 catheter days (3.2 vs. 8.3, P=0.0356). CONCLUSION: The non-leaching antibacterial coating of the protective catheter was effective in reducing the incidence of BSI but not the rate of catheter colonization. However, the incidence of BSI is a better surrogate marker for the risk of developing clinical signs of infection suggesting that use of the non-leaching protective catheter is effective in this regard. Trial number: ClinicalTrials.gov (ID: NCT00555282), https://clinicaltrials.gov/show/NCT00555282.

Infliximab biosimilar CT-P13 therapy is effective in maintaining endoscopic remission in ulcerative colitis - results from multicenter observational cohort.

BACKGROUND: CT-P13, the first biosimilar monoclonal antibody to infliximab (IFX), has previously been confirmed to be efficacious in inducing mucosal healing in ulcerative colitis (UC) patients. The aim of this study was to evaluate the efficacy of CT-P13 therapy in maintaining mucosal healing in UC. METHODS: CT-P13 trough levels, antibody positivity, serum inflammatory markers as CRP level, fecal calprotectin at weeks 14 and 54, concomitant steroid and azathioprine therapy at the time of induction therapy and at weeks 14 and 54, previous use of anti TNF drug and the need of dose intensification as possible predictive factors for mucosal healing at week 54 were evaluated in this prospective study. RESULTS: 61 patients had already completed the 54-week treatment period. Mucosal healing was shown in 65.5 % and 62.1 %, complete mucosal healing was present in 31% and 38 % at week 14 and 54, respectively. The median values of CRP, leukocytes, thrombocytes, and albumin showed significant difference between baseline and week 54. Serum antibody positivity was proved in 6.5 % and 19.7 % of cases at week 14 and 54, respectively. CONCLUSION: Our study confirmed the long-term efficacy of CT-P13 therapy on mucosal healing in UC.

Fecal zonulin is elevated in Crohn's disease and in cigarette smokers.

OBJECTIVES: Human zonulin is a protein that increases permeability in the epithelial layer of the small intestine by reversibly modulating the intercellular tight junctions. There is not sufficient information available about zonulin's participation in inflammatory bowel diseases (IBD). The aim of this study was therefore to investigate fecal and serum zonulin in IBD patients and its relation to the disease localization, behavior and smoking status. DESIGN AND METHODS: Forty IBD patients and forty healthy persons were examined for fecal and serum zonulin concentrations by competitive ELISA (DRG International Inc). Values were correlated to IBD type, localization and behavior, and smoking. RESULTS: Serum and fecal zonulin were significantly higher in patients with Crohn's disease compared to ulcerative colitis (p = 0.038 for fecal zonulin, and p = 0.041 for serum zonulin concentrations). No association of serum or fecal zonulin was found with respect to IBD localization and behavior. The only difference was found with respect to smoking. Both the IBD cohort and healthy smokers showed significantly higher fecal zonulin levels (median 203 ng/mL) compared to non-smokers (median 35.8 ng/mL), p < 0.001. CONCLUSIONS: Fecal and serum zonulin levels are elevated in patients with active Crohn's disease but not with ulcerative colitis. High fecal zonulin levels in smokers irrespective of IBD point to the significant and undesirable up-regulation of gut permeability in cigarette smokers.

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

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.

Efficacy of Infliximab Biosimilar CT-P13 Induction Therapy on Mucosal Healing in Ulcerative Colitis.

INTRODUCTION: CT-P13 is the first biosimilar to infliximab that has been approved for the same indications as its originator infliximab. No data are available on the effect of infliximab biosimilar on mucosal healing. The aim of this study was to evaluate the efficacy of CT-P13 induction therapy on mucosal healing in patients with ulcerative colitis [UC]. PATIENTS AND METHODS: UC patients, who received CT-P13 therapy from its local introduction at three Hungarian and one Czech inflammatory bowel disease centres, were prospectively enrolled. Sigmoidoscopy was performed after the end of the induction therapy at week 14. Mucosal healing was defined as Mayo endoscopic subscore 0 or 1. Complete mucosal healing was defined as Mayo endoscopic subscore 0. Trough level of CT-P13 was measured at week 14. RESULTS: Sixty-three UC patients who underwent CT-P13 induction therapy were enrolled in the study. Indication for the therapy was acute, severe flare up and chronic, refractory activity in 24 and 39 patients, respectively. Cumulative clinical response and steroid-free remission at week 14 were achieved in 82.5% and 47.6% of the patients, respectively. Sigmoidoscopy revealed steroid-free mucosal healing in 47.6% of the patients, and complete mucosal healing was present in 27%. Mayo endoscopic subscore decreased significantly at week 14 compared to baseline. Trough levels of infliximab correlated with mucosal healing. CONCLUSION: This is, to our knowledge, the first study examining the efficacy of CT-P13 induction therapy on mucosal healing in UC. The results indicate that mucosal healing is achieved in two-thirds of UC patients by the end of the induction treatment with CT-P13.

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

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 (Crohn's 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.

Salting out in organic solvents: a new route to carbon nanotube bundle engineering.

In this study we investigate salt effects on bundle formation of carbon nanotubes (CNTs) dispersed in an organic solvent, N-methyl-2-pyrrolidone (NMP). Addition of NaI salt leads to self-assembly of CNTs into well-recognizable bundles. It is possible to control the size of the CNT bundles by varying the salt concentration.

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.