Macrophage-Stimulating 1 Polymorphism rs3197999 in Pediatric Patients with Inflammatory Bowel Disease.

Background and Objectives: Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), often necessitates long-term treatment and hospitalizations and also may require surgery. The macrophage-stimulating 1 (MST1) rs3197999 polymorphism is strongly associated with the risk of IBD but its exact clinical correlates remain under investigation. We aimed to characterize the relationships between the MST1 rs3197999 genotype and the clinical characteristics in children and adolescents with IBD within a multi-center cross-sectional study. Materials and Methods: Clinical data included serum C-reactive protein (CRP), albumin, activity indices (PUCAI, PCDAI), anthropometric data, pharmacotherapy details, surgery, and disease severity. Genotyping for rs3197999 was carried out using TaqMan hydrolysis probes. Results: The study included 367 pediatric patients, 197 with Crohn's disease (CD) (40.6% female; a median age of 15.2 years [interquartile range 13.2-17.0]) and 170 with ulcerative colitis (UC) (45.8% female; a median age of 15.1 years [11.6-16.8]). No significant relationships were found between MST1 genotypes and age upon first biologic use, time from diagnosis to biological therapy introduction, PUCAI, PCDAI, or hospitalizations for IBD flares. However, in IBD, the height Z-score at the worst flare was negatively associated with the CC genotype (p = 0.016; CC: -0.4 [-1.2-0.4], CT: -0.1 [-0.7-0.8], TT: 0.0 [-1.2-0.7)]). The TT genotype was associated with higher C-reactive protein upon diagnosis (p = 0.023; CC: 4.3 mg/dL [0.7-21.8], CT 5.3 mg/dL [1.3-17.9], TT 12.2 mg/dL [3.0-32.9]). Conclusions: This study identified links between MST1 rs3197999 and the clinical characteristics of pediatric IBD: height Z-score and CRP. Further studies of the associations between genetics and the course of IBD are still warranted, with a focus on more extensive phenotyping.

Subcutaneous Infliximab (CT-P13 SC) as Maintenance Therapy for Inflammatory Bowel Disease: Two Randomized Phase 3 Trials (LIBERTY).

BACKGROUND & AIMS: CT-P13 subcutaneous (SC), an SC formulation of the intravenous (IV) infliximab biosimilar CT-P13 IV, creates a unique exposure profile. The LIBERTY studies aimed to demonstrate superiority of CT-P13 SC vs placebo as maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Two randomized, placebo-controlled, double-blind studies were conducted in patients with moderately to severely active CD or UC and inadequate response or intolerance to corticosteroids and immunomodulators. All patients received open-label CT-P13 IV 5 mg/kg at weeks 0, 2, and 6. At week 10, clinical responders were randomized (2:1) to CT-P13 SC 120 mg or placebo every 2 weeks until week 54 (maintenance phase) using prefilled syringes. (Co-) primary end points were clinical remission and endoscopic response (CD) and clinical remission (UC) at week 54 (all-randomized population). RESULTS: Overall, 396 patients with CD and 548 patients with UC received induction treatment. At week 54 in the CD study, statistically significant higher proportions of CT-P13 SC-treated patients vs placebo-treated patients achieved clinical remission (62.3% vs 32.1%; P < .0001) and endoscopic response (51.1% vs 17.9%; P < .0001). In the UC study, clinical remission rates at week 54 were statistically significantly higher with CT-P13 SC vs placebo (43.2% vs 20.8%; P < .0001). Achievement of key secondary end points was significantly higher with CT-P13 SC vs placebo across both studies. CT-P13 SC was well tolerated, with no new safety signals identified. CONCLUSIONS: CT-P13 SC was more effective than placebo as maintenance therapy and was well tolerated in patients with moderately to severely active CD or UC who responded to CT-P13 IV induction. CLINICALTRIALS: gov, Numbers: NCT03945019 (CD) and NCT04205643 (UC).

Ustekinumab in paediatric patients with moderately to severely active Crohn's disease: UniStar study long-term extension results.

OBJECTIVES: To assess the efficacy, safety, immunogenicity, and pharmacokinetics through 240 weeks of ustekinumab treatment in paediatric patients from the long-term extension (LTE) of the phase 1, double-blind UniStar trial. METHODS: Paediatric patients with moderately to severely active Crohn's disease (CD) were randomised 1:1 and stratified by body weight (<40 or ≥40 kg) to low- or high-dose intravenous ustekinumab followed by a subcutaneous maintenance dose at Week 8. At Week 16, patients were eligible to enter the LTE at the discretion of the investigator and continued maintenance dosing every 8 weeks up to Week 240. RESULTS: Of the 34 patients who entered the LTE, 25 patients with evaluable data completed Week 48, and 41.2% (14/34) achieved clinical remission at Week 48. Among the 24 patients with Week-0 C-reactive protein (CRP) levels ≥3 mg/L, 29.2% (7/24) achieved normalisation of CRP at Week 48, while imputing missing data as failures. Through Week 240, the most common adverse events were infections (n = 28) and gastrointestinal disorders (n = 26). The most common serious adverse event was worsening of CD (n = 6). Only one patient had detectable antibodies to ustekinumab. Median serum ustekinumab concentrations remained consistent through Week 48, were detectable through Week 224, and trended lower in patients <40 kg. CONCLUSIONS: Efficacy and pharmacokinetics through 1 year and safety and immunogenicity through 4 years of ustekinumab treatment in paediatric patients with CD were generally comparable to those previously reported in adults.

Combination biologic therapy in pediatric inflammatory bowel disease: Safety and efficacy over a minimum 12-month follow-up period.

OBJECTIVES: The severe course of inflammatory bowel diseases (IBDs) refractory to advanced therapies in children results in the search for new therapeutic methods. The aim of this study was to evaluate the efficacy and safety of dual therapy with biologics in a cohort of children with IBD. METHODS: Retrospective analysis of data from 29 children with a diagnosis of IBD, 19 with ulcerative colitis (66%), 10 with Crohn's disease (CD) (34%) qualified for dual biological therapy (DBT). The median age of patients was five (interquartile range [IQR], 1-15) years at diagnosis of IBD and 14 (IQR, 3-17) years at eligibility for dual therapy. Thirteen (45%) patients were treated with vedolizumab/adalimumab (VDZ + ADA), 13 (45%) with ustekinumab/adalimumab (UST + ADA), three (10%) with infliximab/vedolizumab (IFX + VDZ). RESULTS: Clinical remission was achieved in 13 (45%; seven UC and six CD) and 12 (41%; seven UC and five CD) Pediatric Weighted Crohn's Disease Activity Index (wPCDAI)/Pediatric Ulcerative Colitis Activity Index (PUCAI) patients after 4 and 12 months at the initiation of dual therapy. Clinical response based on wPCDAI/PUCAI was reported in 16 (55%; nine UC and seven CD) and 12 (41% seven UC and five CD) children after 4 and 12 months of follow-up, respectively. The median fecal calprotectin decreased significantly from 1240 µg/g (53-10,100) to 160 µg/g (5-2500; p = 0.004) between baseline and Month 4 and from 749 at baseline (57-10,100) to 17 (5-3110; p = 0.12) over 12 months. Moreover, 34% (six UC and four CD) of patients achieved endoscopic remission. CONCLUSIONS: DBT seems to be an effective alternative therapeutic option for patients with moderate and severe IBD.

Methylation of RUNX3 Promoter 2 in the Whole Blood of Children with Ulcerative Colitis.

Ulcerative colitis (UC) results from a complex interplay between the environment, gut microbiota, host genetics, and immunity. Runt-related transcription factor 3 (RUNX3) regulates Th1/Th2 balance and, thus, the synthesis of cytokines and inflammation. We aimed to analyze the dependence of RUNX3 promoter 2 (P2) methylation level on: age, sex, body mass index (BMI), C-reactive protein (CRP), serum albumin, disease duration, Pediatric Ulcerative Colitis Activity Index (PUCAI), the Paris classification, and exposure to medications. This multicenter, cross-sectional study recruited hospitalized children with UC. Methylation of RUNX3 P2 was measured with methylation-sensitive restriction enzymes in the whole blood DNA. Sixty-four children were enrolled, with a mean age of 14.5 ± 2.8 years. Half of them were female (51.6%), and the average BMI Z-score was -0.44 ± 1.14. The mean methylation of RUNX3 P2 was 54.1 ± 13.3%. The methylation level of RUNX3 P2 did not correlate with age, sex, nutritional status, CRP, albumin, PUCAI, or the extent of colitis (Paris E1-E4). RUNX3 P2 methylation did not differ between patients recruited within two and a half months of diagnosis and children who had UC for at least a year. Current or past exposure to biologics, immunosuppressants, or steroids was not associated with RUNX3 P2 methylation. Methylation of RUNX3 promoter 2 in whole blood DNA does not seem to be associated with the characteristics of UC in children.

C-Reactive Protein/Albumin Ratio at Diagnosis of Pediatric Inflammatory Bowel Disease: A Retrospective Multi-Center Study.

BACKGROUND This study aimed to evaluate the C-reactive protein-to-albumin (CRP/albumin) ratio at diagnosis of pediatric inflammatory bowel disease (IBD). MATERIAL AND METHODS Serum CRP/albumin ratio was calculated for patients with Crohn's disease (CD; n=186) and ulcerative colitis (UC; n=159) aged 3-18 years. RESULTS Patients with CD differed in CRP/albumin ratio at diagnosis in groups with quiescent, mild, moderate, and severe disease (P=0.011). CRP/albumin ratio at diagnosis was significant in differentiating patients with severe CD from quiescent disease at diagnosis (area under the curve (AUC)=0.94, odds ratio (OR)=63.4, 95% confidence interval (CI) 7.1-569.1, P<0.0001). CRP/albumin ratio at diagnosis could moderately differentiate penetrating from non-penetrating disease behavior in CD at diagnosis (AUC=0.73, OR=6.3, 95% CI 2.0-19.3, P<0.001). Furthermore, CRP/albumin ratio at diagnosis weakly differentiated IBD patients in need of biological treatment in a step-up procedure (AUC=0.58, OR=2.1, 95% CI 1.3-3.4, P=0.022) and in need of surgery (AUC=0.63, OR=3.1, 95% CI 1.4-7.2, P=0.006). For the IBD, CRP/albumin ratio at diagnosis was weakly correlated with age at first immunosuppressive treatment (rho=0.20, P=0.018), time from diagnosis to first biological treatment (rho=-0.37, P<0.001), days spent in hospital (rho=0.26, P=0.007), number of severe relapses (rho=0.31, P=0.001), and Pediatric Crohn's Disease Activity Index (rho=0.38, P=0.002). CONCLUSIONS The present findings add to previous studies carried out in adult patients and show that the CRP/albumin ratio at diagnosis was not significantly associated with the course of either CD or UC in children. However, CRP/albumin ratio could differentiate patients with severe CD from those with quiescent disease.

Pharmacokinetics, Pharmacodynamics, and Safety of Etrolizumab in Children With Moderately to Severely Active Ulcerative Colitis or Crohn's Disease: Results from a Phase 1 Randomized Trial.

BACKGROUND: Etrolizumab, a humanized anti-ß7 antibody, has not been studied in children. Here, we evaluate the pharmacokinetics, pharmacodynamics, and safety of etrolizumab in children with inflammatory bowel disease. METHODS: Patients age 4 to 17 years with moderately to severely active ulcerative colitis or Crohn's disease were randomized 1:1 to receive 1.5mg/kg of etrolizumab subcutaneously every 4 weeks (q4w) or 3.0mg/kg every 8 weeks (q8w) for 16 weeks in this open-label phase 1 trial. Pharmacokinetics, pharmacodynamics, safety, and efficacy were assessed. RESULTS: Of the 24 patients treated, 21 completed the study. In the groups of 1.5mg/kg q4w and 3.0mg/kg q8w, respectively, mean (SD) maximum concentration (Cmax) was 9.8 (4.86) µg/mL and 18.1 (6.25) µg/mL; and mean (SD) area under the curve within a dosing interval (AUCtau) was 167 (86.9) and 521 (306) µg·day/mL after the last dose. The Cmax increased dose proportionally. The AUC over an 8-week period was slightly higher in the 3.0mg/kg q8w dose group. Median half-life was similar for both dosing regimens. Median numbers of free ß7high gut-homing T and B cell subsets declined below 10% of baseline, confirming ß7 target engagement and complete/near-complete receptor occupancy. Adverse events were consistent with the safety profile in adults. Approximately 60% of patients achieved a clinical response. CONCLUSIONS: Etrolizumab showed a dose-proportional increase in Cmax and a slightly greater than dose-proportional increase in AUCtau. Both regimens achieved complete/near-complete ß7 receptor occupancy, with a similar relationship to concentration as adults. Etrolizumab was well tolerated and demonstrated clinical activity in children.

Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Crohn's Disease.

BACKGROUND: Mirikizumab is a humanized monoclonal antibody targeting interleukin 23p19 with demonstrated efficacy in psoriasis and ulcerative colitis. We investigated the safety and efficacy of mirikizumab in patients with moderate-to-severe Crohn's disease (CD). METHODS: Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12. RESULTS: At Week 12, endoscopic response was significantly higher by the predefined 2-sided significance level of 0.1 for all mirikizumab groups compared with PBO (200 mg: 25.8%, 8/31, 95% confidence interval [CI], 10.4-41.2, P = .079; 600 mg: 37.5%, 12/32, 95% CI, 20.7-54.3, P = .003; 1000 mg: 43.8%, 28/64, 95% CI, 31.6-55.9, P < .001; PBO: 10.9 %, 7/64, 95% CI, 3.3-18.6). Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C and SC groups, respectively. Frequencies of adverse events (AE) in the mirikizumab groups were similar to PBO. Through Week 52, frequencies of treatment-emergent AEs were similar across all groups. Frequencies of serious AE and discontinuations due to AE were higher in the nonrandomized maintenance cohort. CONCLUSION: Mirikizumab effectively induced endoscopic response after 12 weeks in patients with moderate-to-severe CD and demonstrated durable efficacy to Week 52. A detailed summary can be found in the Video Abstract. ClinicalTrials.gov, Number: NCT02891226.

HLA-DQA1*05 Associates with Extensive Ulcerative Colitis at Diagnosis: An Observational Study in Children.

The human leukocyte antigen (HLA) allele group HLA-DQA1*05 predisposes to ulcerative colitis (UC) and is associated with the development of antibodies against infliximab in patients with inflammatory bowel disease (IBD). Therefore, we hypothesized that the presence of HLA-DQA1*05 correlates with characteristics of pediatric IBD. Within a multi-center cohort in Poland, the phenotype at diagnosis and worst flare was established and HLA-DQA1*05 status was assessed enabling genotype-phenotype analyses. HLA-DQA1*05 was present in 221 (55.1%) out of 401 children with IBD (UC n = 188, Crohn's disease n = 213). In UC, the presence of HLA-DQA1*05 was moderately associated with a large extent of colonic inflammation at diagnosis (E4 55% more frequent in HLA-DQA1*05-positive patients, p = 0.012). PUCAI at diagnosis (p = 0.078) and the time from UC diagnosis to the first administration of biologic treatment (p = 0.054) did not differ depending on HLA-DQA1*05 status. The number of days of hospitalization for exacerbation was analyzed in 98 patients for whom sufficient follow-up was available and did not differ depending on HLA-DQA1*05 carriership (p = 0.066). HLA-DQA1*05 carriers with CD were less likely to present with both stenosing and penetrating disease (B2B3, p = 0.048) and to have active disease proximal to the ligament of Treitz (L4a) at the worst flare (p = 0.046). Future research focusing on explaining and preventing anti-TNF immunogenicity should take into account that ADA may develop not only as an isolated reaction to anti-TNF exposure but also as a consequence of intrinsic differences in the early course of UC.

Genetic Variants of DMBT1 and SFTPD and Disease Severity in Paediatric Inflammatory Bowel Disease-A Polish Population-Based Study.

Deleted in malignant brain tumours 1 protein (DMBT1) and surfactant protein D (SFTPD) are antimicrobial peptides previously linked to inflammatory bowel disease (IBD) susceptibility. This study attempts to link the most potential IBD-associated polymorphisms in DMBT1 and SFTPD with the disease severity in children. A total of 406 IBD patients (Crohn's disease (CD) n = 214 and ulcerative colitis (UC) n = 192) were genotyped using hydrolysis probe assay. Clinical expression was described by disease activity scales, albumin and C-reactive protein levels, localisation and behaviour (Paris classification), systemic steroid, immunosuppressive, biological, and surgical treatment, number of exacerbation-caused hospitalisations, relapses and nutritional status. IBD patients with the risk genotype (AA) in DMBT1 rs2981804 had more frequent biological treatment (AA: vs. AG/GG; p = 0.012), concomitant diseases (AA vs. AG vs. GG; p = 0.015) and cutaneous manifestations (AA vs. AG/GG, p = 0.008). In UC, rs2981804 genotypes might be linked with albumin concentrations at diagnosis (AA vs. AG vs. GG; p = 0.009). In CD, DMBT1 rs2981745 was significantly associated with the number of severe relapses per year of disease (p = 0.020) and time-to-immunosuppression (p = 0.045). SFTPD was seemingly found to be associated with age at first immunosuppression in IBD (CC vs. CT vs. TT; p = 0.048). In conclusion, selected polymorphisms of DMBT1 and SFTPD might be associated with some disease severity measures in children with IBD. However, the magnitude of associations and their clinical relevance might be minor.

Usefulness of Colon Assessment by Magnetic Resonance Enterography in Pediatric Patients with Inflammatory Bowel Disease-Retrospective Case Series.

BACKGROUND: Magnetic resonance enterography (MRE) is an excellent way to study the small bowels. During such an examination, the colon is also seen within the field of study. The aim of this study was to evaluate the effectiveness of MRE in detecting characteristics of active inflammatory bowel disease (IBD) in the colon, in comparison to different features seen in colonoscopies. METHODS: This retrospective study was conducted with 41 children. Features of active inflammation we considered were wall thickening; contrast enhancement; incorrect signal in the DWI sequence in the MRE; and presence of ulceration, erosion, erythema, spontaneous bleeding and a decrease of the vascular pattern seen in colonoscopy. The colon was divided into six segments: caecum, ascending, transverse, descending, sigmoid and rectum. RESULTS: The sensitivity of MRE was, on average, 50-75%, and as high as 92-100%, depending on the segment. The most important feature for which there was the most dependencies was ulceration. In the analysis of intestinal wall thickness, the AUC value >0.8 was detected as ulceration (segments: cecum, ascending, descending colon, sigmoid), spontaneous bleeding (ascending colon and sigmoid) and decreased vascular pattern (ascending, transverse, descending colon). CONCLUSIONS: Evaluation of qualitative structural changes in MRE distinguishes patients with inflammation in colonoscopy from patients without lesions, with high diagnostic accuracy, albeit higher specificity than sensitivity.

Safety and Effectiveness of Vedolizumab for the Treatment of Pediatric Patients with Very Early Onset Inflammatory Bowel Diseases.

Background: Vedolizumab (vedo) is effective for induction and maintenance of remission in adults with inflammatory bowel disease (IBD). Pediatric data are still limited, especially for the youngest children with very early onset disease (VEO-IBD). The aim of this study was to assess the safety and efficacy of vedo in VEO-IBD. Methods: We performed a retrospective review of pediatric IBD patients with VEO-IBD (defined as aged <6 years) receiving vedo. Data on demographics, disease behavior, activity, and previous treatments/surgeries were collected. Disease activity was assessed using the pediatric Crohn's disease (CD) activity index (PCDAI) for CD or pediatric ulcerative colitis (UC) activity index (PUCAI) for UC. Primary outcome was clinical response after induction therapy with vedolizumab (4th dose week). It was defined as a decrease in PCDAI of at least 12.5 points between baseline and 4th dose week for CD, and a decrease in PUCAI of at least 20 points between baseline and this time for UC. Descriptive statistics were performed to analyze the data. Results: The study included 16 patients with VEO-IBD who have received vedo: 4/16 (25%) with CD, and 12/16 (75%) with UC at the median age of diagnosis 33.7 months (6.6 months-4.5 years). Median age at vedo initiation was 6.5 years (2.2-16.5 years). Among the analyzed individuals, 56.25% had failed more than one anti-tumor necrosis factor (TNF) alfa agent. Clinical response at 4th dose week was observed in 9/16 (56.3%) patients: mean baseline PCDAI score was 34.4 ± 1.9 and 10.6 ± 1.8 after induction therapy with vedo, while PUCAI score was 26 ± 6 vs. 18 ± 8, respectively. There was improvement in patients' nutritional state: at baseline 2/16 (12.5%) children had body mass index (BMI) below 1 percentile and no child had such BMI after induction therapy with vedo. No infusion reactions or serious adverse events/infections were reported. Conclusion: Vedolizumab is safe and effective in the medical management of pediatric patients with VEO-IBD.

Intestinal Microbiota in Common Chronic Inflammatory Disorders Affecting Children.

The incidence and prevalence rate of chronic inflammatory disorders is on the rise in the pediatric population. Recent research indicates the crucial role of interactions between the altered intestinal microbiome and the immune system in the pathogenesis of several chronic inflammatory disorders in children, such as inflammatory bowel disease (IBD) and autoimmune diseases, such as type 1 diabetes mellitus (T1DM) and celiac disease (CeD). Here, we review recent knowledge concerning the pathogenic mechanisms underlying these disorders, and summarize the facts suggesting that the initiation and progression of IBD, T1DM, and CeD can be partially attributed to disturbances in the patterns of composition and abundance of the gut microbiota. The standard available therapies for chronic inflammatory disorders in children largely aim to treat symptoms. Although constant efforts are being made to maximize the quality of life for children in the long-term, sustained improvements are still difficult to achieve. Additional challenges are the changing physiology associated with growth and development of children, a population that is particularly susceptible to medication-related adverse effects. In this review, we explore new promising therapeutic approaches aimed at modulation of either gut microbiota or the activity of the immune system to induce a long-lasting remission of chronic inflammatory disorders. Recent preclinical studies and clinical trials have evaluated new approaches, for instance the adoptive transfer of immune cells, with genetically engineered regulatory T cells expressing antigen-specific chimeric antigen receptors. These approaches have revolutionized cancer treatments and have the potential for the protection of high-risk children from developing autoimmune diseases and effective management of inflammatory disorders. The review also focuses on the findings of studies that indicate that the responses to a variety of immunotherapies can be enhanced by strategic manipulation of gut microbiota, thus emphasizing on the importance of proper interaction between the gut microbiota and immune system for sustained health benefits and improvement of the quality of life of pediatric patients.

Apolipoprotein E variants correlate with the clinical presentation of paediatric inflammatory bowel disease: A cross-sectional study.

BACKGROUND: It has been suggested that apolipoprotein E (APOE) polymorphisms are associated with the risk of developing inflammatory bowel disease (IBD) and the early age of disease onset. However, there are no reports regarding the relationship with clinical characteristics and disease severity. AIM: To summarise that APOE polymorphisms are associated with the risk of developing IBD and the early age of disease onset. METHODS: In total, 406 patients aged 3-18 with IBD (192 had ulcerative colitis and 214 had Crohn's disease) were genotyped using the TaqMan hydrolysis probe assay. Clinical expression was described at diagnosis and the worst flare by disease activity scales, albumin and C-reactive protein levels, localisation and behaviour (Paris classification). Systemic steroid intake with the total number of courses, immunosuppressive, biological, and surgical treatment with the time and age of the first intervention were determined. The total number of exacerbation-caused hospitalisations, the number of days spent in hospital due to exacerbation, the number of relapses, and severe relapses were also estimated. RESULTS: Ulcerative colitis patients with the APOEε4 allele had lower C-reactive protein values at diagnosis (P = 0.0435) and the worst flare (P = 0.0013) compared to patients with the APOEε2 allele and genotype APOEε3/ε3. Crohn's disease patients with the APOEε2 allele scored lower on the Pediatric Crohn's Disease Activity Index at diagnosis (P = 0.0204). IBD patients with APOEε2 allele spent fewer days in the hospital due to relapse (P = 0.0440). CONCLUSION: APOE polymorphisms are associated with the risk of developing IBD and the clinical expression of IBD. However, the clinical relevance of the differences identified is rather modest.

Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease.

BACKGROUND & AIMS: This study compared pharmacokinetics, symptomatic and endoscopic efficacy, safety, and immunogenicity of a subcutaneous formulation of the infliximab biosimilar CT-P13 (CT-P13 SC) vs intravenous CT-P13 (CT-P13 IV) in patients with inflammatory bowel disease (IBD). METHODS: This randomized, multicenter, open-label, parallel-group, phase 1 study enrolled tumor necrosis factor inhibitor-naïve patients with active ulcerative colitis (total Mayo score 6-12 points with endoscopic subscore ≥2) or Crohn's disease (Crohn's Disease Activity Index 220-450 points) at 50 centers. After CT-P13 IV induction at Week (W) 0/W2, patients were randomized (1:1) to receive CT-P13 SC every 2 weeks (q2w) from W6 to W54 or CT-P13 IV every 8 weeks from W6 to W22. At W30, all patients receiving CT-P13 IV switched to CT-P13 SC q2w until W54. The primary endpoint was noninferiority of CT-P13 SC to CT-P13 IV for observed predose CT-P13 concentration at W22 (Ctrough,W22), concluded if the lower bound of the 2-sided 90% confidence interval (CI) for the ratio of geometric least-squares means exceeded 80%. RESULTS: Overall, 66 and 65 patients were randomized to CT-P13 SC and CT-P13 IV, respectively. The primary endpoint of noninferiority was met with a geometric least-squares means ratio for Ctrough,W22 of 1154.17% (90% CI 786.37-1694.00; n = 59 [CT-P13 SC]; n = 57 [CT-P13 IV]). W30/W54 clinical remission rates were comparable between arms. Other efficacy, safety, and immunogenicity assessments were also broadly comparable between arms, including after switching. CONCLUSIONS: The pharmacokinetic noninferiority of CT-P13 SC to CT-P13 IV, and the comparable efficacy, safety, and immunogenicity profiles, support the potential suitability of CT-P13 SC treatment in IBD. ClinicalTrials.gov ID: NCT02883452.

Subjective Psychophysical Experiences in the Course of Inflammatory Bowel Disease-A Comparative Analysis Based on the Polish Pediatric Crohn's and Colitis Cohort (POCOCO).

No gold standard is available to evaluate subjective psychophysical experiences in pediatric inflammatory bowel disease (IBD). We aimed to assess pain, anxiety, and limitations in social activities at diagnosis and the worst flare of the disease in relation to clinical expression, treatment and IBD severity. A total of 376 children completed the survey (Crohn's disease (CD) n = 196; ulcerative colitis (UC) n = 180). The questionnaire included 12 questions regarding pain, anxiety, and social activity, all assessed at recruitment and retrospectively at diagnosis and worst flare using a numeric rating scale. Patients that had ever been treated with systemic glucocorticosteroids scored higher in pain (p < 0.001), anxiety (p = 0.015), and social activity domains (p < 0.016) at worst flare, and the answers correlated with the number of steroid courses (p < 0.0392). The perception of social activity limitations also correlated independently with the number of immunosuppressants (p < 0.0433) and biological agents (p < 0.0494). There was no difference in retrospective perception of pain, anxiety and social activity limitations between CD and UC patients at diagnosis and the worst flare. The level of limitations in social activity correlated with hospitalisations due to relapse, days spent in the hospital, number of relapses, and severe relapses with the strongest association of rho = 0.39 (p = 0.0004). Subjective and retrospective perception of pain, anxiety, and limitations in social activity differs depending on therapy, correlates with treatment modalities, and severity measures such as hospitalisations.

Reproduction and Pregnancy in Inflammatory Bowel Disease - Management and Treatment Based on Current Guidelines.

Inflammatory bowel diseases (IBD) affect mainly young population. Therefore, fertility and pregnancy are important clinical issues to be considered. Generally, fertility in IBD patients is not decreased either in males or females when compared to a healthy population. Moreover, drugs used for IBD treatment do not significantly affect fertility in humans. However, prolonged treatment with sulphasalazine may reduce semen quality and cause reversible infertility. Since the disease course and a risk of pregnancy-related complications depend mainly on disease activity at the time of conception, female patients with IBD should plan their pregnancy during a remission phase. Methotrexate, mycophenolate mofetil and thalidomide are strongly contraindicated during pregnancy. Other medications used for IBD seem to be safe provided that they are administered with caution. In 2015, European Crohn's and Colitis Organisation (ECCO) published its Consensus on Reproduction and Pregnancy in IBD. However, management of IBD during the reproductive age and during pregnancy still remains controversial, since evidence-based data come mostly from retrospective studies. The aim of this paper was to discuss the issue of reproduction and pregnancy in IBD patients based on current ECCO guidelines and literature.

The Course of Ulcerative Colitis After Pediatric Liver Transplantation for Sclerosing Cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) and autoimmune sclerosing cholangitis (ASC) are often associated with ulcerative colitis (UC). The impact on the course of UC remains unclear, and up-to-date evidence in pediatric populations is scarce. The aim of the study was to analyze the course of UC in pediatric patients transplanted owing to PSC or ASC. MATERIAL AND METHODS: We retrospectively reviewed data from children with PSC/ASC and UC who underwent orthotopic liver transplantation (OLT). In all patients UC diagnosis was based on clinical presentation, endoscopy, and histology. RESULTS: Seventeen patients (9 female) with PSC or ASC underwent OLT from deceased donors at a median age of 16.8 years (range = 11.5-18.2 years). In 15 patients, UC was diagnosed before OLT (median age of diagnosis = 10.6 years; range = 6.6-18.0 years), and 2 patients developed UC after OLT. Ten patients (59%) presented with pancolitis on initial endoscopy. Disease activity was severe in 9 patients (53%) and most patients improved after initial treatment with steroids. Before OLT only 2 patients (13%) had severe disease activity. After OLT, 4 patients developed flares of the disease. These patients were successfully treated and remained in remission at the end of the posttransplant follow-up period (median = 3.76 years; range = 0.4-15.5 years). None of the patients developed colorectal cancer or underwent colectomy during 3.7 years of post-OLT follow-up. CONCLUSION: In our experience, the course of UC was not aggravated by OLT for PSC, and UC did not adversely affect patient or graft survival.

Insolation and Disease Severity in Paediatric Inflammatory Bowel Disease-A Multi-Centre Cross-Sectional Study.

This study was to investigate whether the clinical course of inflammatory bowel disease (IBD) in a Polish paediatric cohort fits a seasonal pattern and depends on insolation. Two hundred and fourteen patients diagnosed with Crohn's disease (CD) and 192 with ulcerative colitis (UC) aged from 3 to 18 years, were recruited in seven centres of similar latitude. The seasons were defined as winter (December-February), spring (March-May), summer (June-August), autumn (September-November). The year was also divided depending on insolation threshold (3.0 kWh/m2/day). Patients diagnosed with IBD when the isolation was >3 kWh/m2/day had poorer nutritional status than those diagnosed while insolation was below threshold (lower standardised BMI at diagnosis (-0.81 ([-1.34]-[-0.03]) vs. -0.52 ([-1.15]-0.15); p = 0.0320) and worst flare (-0.93 ([-1.37]-[-0.05]) vs. -0.66 ([-1.23]-0.17); p = 0.0344), with the need for more frequent biological treatment (45.5% vs. 32.7%, p = 0.0100). Patients diagnosed in winter were significantly younger at diagnosis (11.4 vs. 13.0; padj = 0.0180) and first immunosuppressive treatment (11.3 vs. 13.3; padj = 0.0109) than those diagnosed in other seasons. CD patients diagnosed in months with higher insolation spent more days in hospital than those diagnosed in months with lower insolation [4.6 (1.8-11.8) vs. 2.9 (1.3-6.2); p = 0.0482]. CD patients diagnosed in summer had significantly more concomitant diseases. In patients with CD, the occurrence of the worst flare was more frequent in autumn. Furthermore, the season of birth was associated with Pediatric Crohn's Disease Activity Index at worst flare and earlier surgery. In conclusion, several clinical parameters are associated with insolation, the season of diagnosis and season of birth in the clinical course of Crohn's disease.

Randomized, Ascending Dose, Phase 2 Study of KHK4083, an Anti-OX40 Monoclonal Antibody, in Moderately Active Ulcerative Colitis.

Background: OX40 (CD134) plays a role in the maintenance of late T-cell proliferation and survival. KHK4083 is a monoclonal antibody directed against OX40. We aimed to assess the safety and preliminary efficacy of KHK4083 in patients with moderately active ulcerative colitis (UC). Methods: In this multicenter, double-blind, parallel-group, phase 2 study, patients with moderately active UC patients were randomized to ascending doses of intravenous KHK4083 (1, 3, or 10 mg/kg) or placebo every 2 weeks for 12 weeks. The primary endpoint was safety. The primary efficacy end point was the change from baseline in mean modified Mayo endoscopy subscore at week 12. Treatment with KHK4083 or placebo was continued every 4 weeks for up to 52 weeks in responders. Results: Long-term treatment with KHK4083 was well tolerated, with treatment-related adverse events being predominantly transient mild-to-moderate infusion-related reactions. Exploratory analysis of biopsy samples showed the virtually complete elimination of OX40+ cells in colon mucosa after 12 weeks of KHK4083 treatment. There were no significant differences between any of the randomized KHK4083 dose groups and placebo for the mean change in Mayo endoscopy subscore from baseline to week 12. Conclusions: KHK4083 can be safely administered intravenously at doses up to 10 mg/kg every 2 or 4 weeks for up to 52 weeks. Proof of pharmacodynamic action was confirmed by depletion of the elevated levels of the OX40+ cells associated with UC at all tested doses. Clinical response and mucosal healing (endoscopic improvement) in this population was not correlated with ablation of OX40+ T cells.