The Association Between Genetic Variants, Pharmacokinetics, and Infliximab Efficacy in Pediatric Patients With Crohn's Disease in China

Background: Infliximab is an effective therapy for Crohn's disease (CD). Early non-invasive predictors of disease remission allow for modification of treatments. The aim of this study was to investigate the associations between genetic variants, pharmacokinetics, and infliximab efficacy in pediatric patients with CD.Methods: This retrospective observational study included CD patients under infliximab therapy between August 2015 and December 2020. Information on demographics, laboratory tests, medication data, and disease activity index was collected. The trough levels of infliximab (TLI) and antibodies to infliximab (ATI) were measured at week 14, and reactive drug monitoring was performed during follow-up. Ten single-nucleotide polymorphisms involved in the NF-κB-mediated inflammatory response, pharmacokinetics, and therapeutic response to infliximab were genotyped.Results: A total of 62 pediatric CD patients were enrolled. The clinical remission (CR) rate was 69.4 and 63.2% at week 14 and week 30, respectively. TLI at week 14 was significantly independently associated with CR at week 14 and mucosal healing (MH) at week 30 (p = 0.007 and p = 0.025, respectively). The optimal TLI threshold level capable of distinguishing between the CR and non-CR groups was 2.62 μg/ml (p < 0.001, area under the curve = 0.79, sensitivity = 69.2%, specificity = 78.9%), while that capable of distinguishing between the MH and non-MH groups was 3.34 μg/ml (p < 0.001, area under the curve = 0.85, sensitivity = 78.6%, specificity = 79.4%). Rs3397 in TNFRSF1B was associated with time to ATI production in CD patients (p < 0.001).Conclusions: Higher TLI contributed to achieving MH. Genotyping rs3397 in TNFRSF1B may identify patients who are prone to generating immunogenicity to drugs.

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Exclusive Enteral Nutrition versus Infliximab in Inducing Therapy of Pediatric Crohn’s Disease

Gastroenterology Research and Practice ◽

10.1155/2017/6595048 ◽

2017 ◽

Vol 2017 ◽

pp. 1-4 ◽

Cited By ~ 4

Author(s):

Youyou Luo ◽

Jindan Yu ◽

Jingan Lou ◽

Youhong Fang ◽

Jie Chen

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Adverse Effects ◽

Enteral Nutrition ◽

Clinical Symptoms ◽

Activity Index ◽

Group Versus ◽

Disease Activity Index ◽

Mucosal Healing ◽

Exclusive Enteral Nutrition

Aim. To compare the effectiveness of exclusive enteral nutrition (EEN) and infliximab (IFX) therapy in pediatric Crohn’s disease (CD). Methods. In a prospective study of children initiating EEN or infliximab therapy for CD, we compared clinical outcomes using the pediatric Crohn’s disease activity index (PCDAI), growth improvement, endoscopic mucosal healing, and adverse effects. Data were measured at baseline and after 8 weeks of therapy. Results. We enrolled 26 children with CD; of whom, 13 were treated with infliximab, 13 with EEN. Clinical response (PCDAI) reduction ≥ 15 or final PCDAI ≤ 10 was achieved by 83.3% in the EEN group and 90.9% in the IFX group. Body mass index for age (BMIFA) z-scores were significantly increased in both groups (P<0.05). No significant differences were observed in PCDAI, height for age (HFA), or BMI recovery between two groups. Adverse effects were detected in 30.7% on infliximab and 0% on EEN. Mucosal healing was achieved in 71.4% cases in the EEN group versus 85.7% in the IFX group. Conclusion. EEN provided similar improvements as IFX in clinical symptoms, mucosal healing, and BMI. EEN therapy has less adverse effects when compared with IFX. This trial is registered with the Clinical Registration Number: ChiCTR-OON-17010834.

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Bovine lactoferrin and Crohn’s disease: a case study

Biochemistry and Cell Biology ◽

10.1139/bcb-2016-0107 ◽

2017 ◽

Vol 95 (1) ◽

pp. 133-141 ◽

Cited By ~ 4

Author(s):

David B. Alexander ◽

Masaaki Iigo ◽

Mohamed Abdelgied ◽

Keiji Ozeki ◽

Satoshi Tanida ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Activity Index ◽

Disease Activity Index ◽

Disease Recurrence ◽

Mucosal Healing ◽

University Hospital ◽

Bovine Lactoferrin ◽

Colonoscopic Examination

A 22-year-old male suffering from abdominal pain, repeated diarrhea, and weight loss visited the Digestive Disease Department of Nagoya City University Hospital on 19 December 2011. He was hospitalized and diagnosed with Crohn’s colitis. His Crohn’s Disease Activity Index (CDAI) was 415. Treatment by granulocyte apheresis, mesalazine, and adalimumab was started. His CDAI was 314 on 30 December and 215 on 5 January. A colonoscopic examination on 19 January showed almost complete remission in the transverse colon and marked remission in the rectum. Mesalazine therapy was stopped on 28 February, and the patient was instructed to self-inject 40 mg of adalimumab every other week. His CDAI was 50 on 10 April, indicating clinical remission. His last self-injection of adalimumab was on 24 April 2012, and he started taking 1 g of bovine lactoferrin (bLF) daily. His CDAI was 35 on 8 January 2013. He continued taking 1 g of bLF daily without any other treatment for Crohn’s disease. Laboratory blood tests on 7 September 2015 showed no sign of disease recurrence, and a colonoscopic examination on 23 October 2015 showed almost complete mucosal healing. This case indicates that ingestion of bLF to maintain Crohn’s disease in a remissive state should be further explored.

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Oral 5-Aminosalicyclic Acid Versus 6-Methylprednisolone in Active Crohn's Disease

Canadian Journal of Gastroenterology ◽

10.1155/1990/260563 ◽

1990 ◽

Vol 4 (7) ◽

pp. 446-451 ◽

Cited By ~ 19

Author(s):

Jürgen Schölmerich ◽

Harro Jenss ◽

Franz Hartmann ◽

Hanne Döpfer ◽

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Activity Index ◽

Area Under The Curve ◽

Disease Activity Index ◽

Entrance Examination ◽

Aminosalicylic Acid ◽

Double Blind ◽

Treatment Groups ◽

Starting Dose

The response to 5-aminosalicylic acid (5-ASA) in active Crohn's disease was studied in comparison to methylprednisolone in a 24 week randomized double-blind multicentre study. Sixty-two patients were included in the analysis. Thirty were treated with 500 mg 5-ASA qid and 32 with methylprednisolone (starting dose 48 mg for one week, then reduced weekly to 32, 24, 20, 16 and 12 mg with maintenance at 8 mg/day for the remaining 18 weeks). Mean age, earlier surgical intervention, localization of Crohn's disease and extraintestinal manifestations were not different in both groups. The Crohn's disease activity index (CDAI) and the van Hees index were not significantly different in both treatment groups at the entrance examination (median CDAI 232 in the 5-ASA group and 220 in the methylprednisolone group). According to the protocol, treatment was stopped due to insufficient efficacy in 73% of the patients receiving 5-ASA and in 34% of the patients receiving methylprednisolone (x2test P=0.0019). The area under the curve for the CDAl was significantly greater in 5-ASA (median 170) than in methylprednisolone (P≤0.007) (68). Eleven per cent of patients taking 5-ASA and 26% of patients taking methylprednisolone presented relevant side effects to treatment (not significant). It is concluded from these data that 5-ASA at the dose used in this study is not efficient in the treatment of active Crohn's disease. Considering recent studies in ulcerative colitis, a trial using a higher dose is indicated.

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Induction of Remission in Pediatric Crohn’s Disease Patients Assessed by the Mucosal Inflammation Noninvasive Index

Journal of Clinical Medicine ◽

10.3390/jcm10235613 ◽

2021 ◽

Vol 10 (23) ◽

pp. 5613

Author(s):

Roma Herman ◽

Paulina Dumnicka ◽

Stanisław Pieczarkowski ◽

Krzysztof Fyderek

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Induction Therapy ◽

Activity Index ◽

Disease Activity Index ◽

Fecal Calprotectin ◽

Mucosal Healing ◽

Mucosal Inflammation ◽

Exclusive Enteral Nutrition

Mucosal healing (MH) is the main therapeutic goal of Crohn’s disease (CD). The Mucosal Inflammation Noninvasive Index (MINI) appears to be a promising tool for distinguishing MH from its inflammation. This study aims to evaluate MINI in monitoring remissions induced by exclusive enteral nutrition (EEN) in pediatric CD patients. Out of 55 newly diagnosed CD children, 31 who completed 6–8 weeks of EEN were analyzed. Clinical and biochemical data, activity of CD assessed with the Pediatric Crohn’s Disease Activity Index (PCDAI) and MINI were compared within seven days pre- and post-EEN. Response to induction therapy was defined as a decrease of PCDAI by >12.5 points. The follow-up was performed up to 12 months after EEN termination. Out of 31 children who completed 6–8 weeks of EEN, eight required corticosteroids in addition to EEN. Twenty-four patients (77%) responded to induction therapy. In responders, MINI decreased from 19 (Q1:17; Q3:22) to 12 (Q1:6; Q3:14), p < 0.001. The diagnostic accuracy of post-EEN MINI and post-EEN fecal calprotectin (FC) for treatment failure were AUC: 0.899 (95%CI: 0.737–1.000) and 0.762 (95%CI: 0.570–0.954), respectively. In the follow-up of 25 patients (80.6%), the post-EEN MINI of ≥13 points predicted CD relapse (87.5% sensitivity; 64.7% specificity), while FC had no prognostic value. MINI allows for monitoring of EEN and is superior in predicting disease relapse to FC.

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Assessment of a new score for capsule endoscopy in pediatric Crohnʼs disease (CE-CD)

Endoscopy International Open ◽

10.1055/a-1522-8723 ◽

2021 ◽

Vol 09 (10) ◽

pp. E1480-E1490

Author(s):

Salvatore Oliva ◽

Silvio Veraldi ◽

Salvatore Cucchiara ◽

Giusy Russo ◽

Alessandra Spagnoli ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Capsule Endoscopy ◽

Pediatric Patients ◽

Activity Index ◽

Pediatric Population ◽

Disease Activity Index ◽

Mucosal Inflammation ◽

Predictive Score ◽

Noninvasive Markers

Abstract Background and study aims Two scores have been implemented to standardize capsule endoscopic (CE) findings in patients with Crohn’s disease (CD): Lewis score (LS) and Capsule Endoscopy Crohnʼs Disease Activity Index (CECDAI). Both have limitations and are not well validated in the pediatric population. The aim of our study was to assess a new score (capsule endoscopy – Crohn’s disease index, CE-CD) in pediatric patients with CD and to compare it to preexisting scores. Patients and methods This was a double-center, retrospective study involving pediatric subjects with CD who underwent CE. Correlation analyses between CE-CD, endoscopy scores and noninvasive markers of disease activities were performed. The ability of different CE scores to predict clinical and endoscopic outcomes was evaluated with regression and survival analyses. Results A total of 312 subjects were analyzed. The CE-CD score showed a moderate (Pearson’s r = 0.581, P < 0.001) and strong (r = 0.909, P < 0.001) association with LS and CECDAI, respectively. CE-CD was a statistically significant predictor of hospitalization (hazard ratio [HR]1.061), treatment escalation (HR 1.062), steroid therapy (HR 1.082), clinical (HR 1.064) and endoscopic (HR 1.060) relapse over the twenty-four months (P < 0.001). Subjects with mucosal inflammation according to CE-CD (CE-CD ≥ 9) had worse outcomes compared to patients without inflammation (CE-CD < 9) (Log rang test < 0.001). Conclusions The CE-CD score is a simple, reliable, reproducible, and predictive score for evaluation of small bowel inflammation in pediatric patients with CD. Prospective validation is needed to confirm the applicability of this new index in clinical practice.

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Anti-Mycobacterial Antibiotic Therapy Induces Remission in Active Paediatric Crohn’s Disease

Microorganisms ◽

10.3390/microorganisms8081112 ◽

2020 ◽

Vol 8 (8) ◽

pp. 1112 ◽

Cited By ~ 1

Author(s):

Gaurav Agrawal ◽

Harrison Hamblin ◽

Annabel Clancy ◽

Thomas Borody

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Antibiotic Therapy ◽

Clinical Remission ◽

Activity Index ◽

Disease Activity Index ◽

Mucosal Healing ◽

Paediatric Patients ◽

Endoscopic Remission ◽

Paediatric Crohn’S Disease

Crohn’s disease is increasing in incidence and prevalence in younger people and is of a particularly aggressive nature. One emerging treatment targets Mycobacterium avium paratuberculosis (MAP), an organism implicated in the causation of Crohn’s disease. This study reviewed a cohort of paediatric patients with active Crohn’s disease treated with Anti-Mycobacterial Antibiotic Therapy (AMAT). Sixteen paediatric patients, the majority of whom had failed conventional immunosuppressive therapy, were treated with AMAT. Endoscopic remission was scored using the Simple Endoscopic Score for Crohn’s Disease and clinical remission was assessed using the Weighted Paediatric Crohn’s Disease Activity Index (wPCDAI). Inflammatory blood markers were also routinely recorded. Patients were followed up clinically and endoscopically during treatment after an average of two months (range 1–6) and 17 months (range 2–49), respectively. A significant reduction in both scores assessing clinical improvement (p < 0.001) and mucosal healing (p < 0.0078) was observed at these timepoints; 47% of patients had achieved clinical remission and 63% endoscopic remission. Haemoglobin and serum inflammatory markers normalised for more than 50% of the cohort by six months of treatment. No adverse effects were reported throughout treatment. This is the first report of Anti-Mycobacterial Antibiotic Therapy offering a safe and efficacious therapy for paediatric patients with Crohn’s disease. Further larger randomised studies are required in order to validate these findings.

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Achieving Target Infliximab Drug Concentrations Improves Blood and Fecal Neutrophil Biomarkers in Crohn’s Disease

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa241 ◽

2020 ◽

Cited By ~ 1

Author(s):

Ruben J Colman ◽

Yi-Ting Tsai ◽

Kimberly Jackson ◽

Brendan M Boyle ◽

Joshua D Noe ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Activity Index ◽

Disease Activity Index ◽

Mucosal Healing ◽

Mucosal Inflammation ◽

Operating Characteristics ◽

Cut Points ◽

Peripheral Blood Neutrophil ◽

Drug Concentrations

Abstract Background The neutrophil fecal biomarkers, calprotectin (FCP) and lactoferrin (LCT), and peripheral blood neutrophil CD64 surface receptor (nCD64) are biomarkers for mucosal inflammation in inflammatory bowel disease (IBD). Although FCP has been evaluated as a biomarker for mucosal healing, cut points for LCT and nCD64 are less known. We aimed to identify the cut points for LCT and nCD64 that were associated with FCP remission, with a secondary aim to evaluate the relationship between biochemical outcomes and infliximab (IFX) trough concentrations. Methods We analyzed FCP, LCT, and nCD64 before and after IFX induction in a pediatric Crohn’s disease (CD) cohort study. Week-14 FCP biomarker remission was defined as FCP <250 µg/g, with clinical response defined as a weighted Pediatric Crohn’s Disease Activity Index <12.5 or Δ>17.5 improvement. Predictive outcomes were calculated by receiver operating characteristics (ROCs). Results Among 56 CD patients, ROC analysis identified an infusion 4 LCT <8.06 (area under the receiver operator characteristics [AUROC], 0.934, P < 0.001) and nCD64 <6.12 (AUROC, 0.76, P = 0.02) as the ideal cut points for week-14 FCP biomarker remission. End of induction IFX-trough of >9.4 µg/mL (AUROC, 0.799, P = 0.002) and >11.5 µg/mL (AUROC, 0.835, P = 0.003) were associated with a FCP <250 and FCP <100, respectively. We found patients achieving end of induction trough >5 µg/mL had a median FCP improvement (dose 1 to dose 4) of 90% compared with a median of 35% with levels <5 µg/mL (P = 0.024) with a similar median reduction in nCD64 (48% vs 20%, P = 0.031). Conclusions This study establishes cut points in neutrophil stool and blood biomarkers for both biochemical remission and therapeutic trough levels following induction therapy. Further studies that evaluate pharmacodynamic biomarker targets for endoscopic and histologic healing are warranted.

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Outcomes of Passable and Non-passable Strictures in Clinical Trials of Crohn’s Disease: A Post-hoc Analysis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab045 ◽

2021 ◽

Author(s):

Neeraj Narula ◽

Emily C L Wong ◽

Parambir S Dulai ◽

John K Marshall ◽

Jean-Frederic Colombel ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Activity Index ◽

Disease Activity Index ◽

Symptom Improvement ◽

Logistic Regression Models ◽

Post Hoc Analysis ◽

Endoscopic Remission ◽

Post Hoc ◽

The Impact

Abstract Background and Aims There is paucity of evidence on the reversibility of Crohn’s disease [CD]-related strictures treated with therapies. We aimed to describe the clinical and endoscopic outcomes of CD patients with non-passable strictures. Methods This was a post-hoc analysis of three large CD clinical trial programmes examining outcomes with infliximab, ustekinumab, and azathioprine, which included data on 576 patients including 105 with non-passable strictures and 45 with passable strictures, as measured using the Simple Endoscopic Score for Crohn’s Disease [SES-CD]. The impact of non-passable strictures on achieving clinical remission [CR] and endoscopic remission [ER] was assessed using multivariate logistic regression models. CR was defined as a Crohn’s Disease Activity Index [CDAI] <150, clinical response as a CDAI reduction of ≥100 points, and ER as SES-CD score <3. Results After 1 year of treatment, patients with non-passable strictures demonstrated the ability to achieve passable or no strictures in 62.5% of cases, with 52.4% and 37.5% attaining CR and ER, respectively. However, patients with non-passable strictures at baseline were less likely to demonstrate symptom improvement compared with those with passable or no strictures, with reduced odds of 1-year CR (adjusted odds ratio [aOR] 0.17, 95% CI 0.03–0.99, p = 0.048). No significant differences were observed between patients with non-passable strictures at baseline and those with passable or no strictures in rates of ER [aOR 0.82, 95% CI 0.23–2.85, p = 0.751] at 1 year. Conclusions Patients with non-passable strictures can achieve symptomatic and endoscopic remission when receiving therapies used to treat CD, although they are less likely to obtain CR compared with patients without non-passable strictures. These findings support the importance of balancing the presence of non-passable strictures in trial arms.

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