Periodic Reporting for period 4 - PIBD-SETQuality (Paediatric Inflammatory Bowel Diseases Network for Safety, Efficacy, Treatment and Quality improvement of care)
Reporting period: 2020-01-01 to 2021-06-30
The incidence, particularly of paediatric onset Inflammatory Bowel Diseases (PIBD, Crohn’s disease (CD) and ulcerative colitis (UC)) has risen in recent decades. A research gap at present involves identification of strategies to maximise therapeutic effectiveness without increasing risks from the treatment. Our goals are:
- Development of an accessible and feasible risk-stratified treatment algorithm for new onset paediatric IBD (based on an existing inception cohort) and validation of this algorithm in a new independent inception cohort
- Generation of a homogenized high-powered and secured data base to collect and analyse longterm real world data of children with IBD (inception cohort) in a prospective registry designed to analyze effectiveness and safety signals and correlate them to individual risk factors (genetic, immunological and microbiological)
- Design and performance of a risk algorithm-based prospective large-scale multicenter randomized clinical trial (RCT). For the first time a RCT will be based on a stratification of patients into high versus low risk groups for early complicated/relapsing disease based on predictors at presentation in order to provide optimal therapy (further optimized by drug monitoring), and using different treatment strategies in each arm.
- Development of an accessible and feasible risk-stratified treatment algorithm for new onset paediatric IBD (based on an existing inception cohort) and validation of this algorithm in a new independent inception cohort
- Generation of a homogenized high-powered and secured data base to collect and analyse longterm real world data of children with IBD (inception cohort) in a prospective registry designed to analyze effectiveness and safety signals and correlate them to individual risk factors (genetic, immunological and microbiological)
- Design and performance of a risk algorithm-based prospective large-scale multicenter randomized clinical trial (RCT). For the first time a RCT will be based on a stratification of patients into high versus low risk groups for early complicated/relapsing disease based on predictors at presentation in order to provide optimal therapy (further optimized by drug monitoring), and using different treatment strategies in each arm.
In CD (WP1), the previously established risk algorithm indicating high calprotectin levels, PCDAI >5 and or elevated CRP levels at week 12 as positive predictors for relapse are currently revalidated in the inception cohort. It allows to categorize patients in low, moderate or high risk.
For UC (WP2), 190 children with UC of the inception cohort were extracted and independently analysed: 190 children were completed at least 1 year of follow-up (age 12.9±3.7 98 [52%] male), 76 (40%) patients received induction therapy with 5-ASA, 61 (32%) with oral corticosteroids (CS), 34 (18%) with intravenous CS and 19 (10%) others. steroid-free remission (SFR) at 12 months was achieved in 118 (62%) patients and SSFR was achieved in 64 (34%) patients. Acute severe colitis (ASC) occurred in 33 (17%) patients during the first year from diagnosis, 3 (2%) of whom underwent colectomy during the same hospitalization, and another 1 by 10 months from hospitalization. 87 (46%) patients escalated to IMM, and 76 (40%) to anti-TNF. Despite the fact that 1/5 of children with new-onset of UC required admission for ASC during the first year of diagnosis, still most children achieved SFR at 12 months.
Biologic sampling for the pharmacological analyses within the RCT (WP4) are completed and samples were transferred for analyses by end of RP4 (analyses are underway); in the same line all Health economic and quality of life questionnaires (WP8) are completed.
The PIBD Cloud database is functional and underuse since 2017. 696 patients (77% of the planned recruitment) were included in the inception cohort by 06/2021. Follow-up of these patients will be the basis of the independent validation of the risk algorithms of WP 1 and WP2. First analyses on safety events are completed.
In a subcohort of n=92 patients recruited to the inception cohort, biomaterial was collected for immunological analysis of WP9. These analyses are completed for all patients: heterogeneity in the frequency of TIGIT+CD38+ effector T cells was detected at time of diagnosis. Around 50% of CD patients had strongly reduced frequencies of inhibitory TIGIT+CD38+ effector T cells (TIGITlow patients) compared to UC patients and age-matched healthy controls. TIGITlow CD patients needed earlier anti-TNF treatment with 73% of patients receiving anti-TNF within 1 year versus 36% for CD patients with normal frequencies of TIGIT+CD38+ effector T cells. Fewer TIGITlow CD patients had sustained corticosteroid free remission and more TIGITlow CD patients did not reach remission within 6 months or had a disease relapse within 1 year. Reduced frequencies of TIGIT+CD38+ effector T cells associated with active inflammation as frequencies restored to normal after 3 months of induction therapy. Phenotypic characterization of TIGITnegCD38+ effector T cells in CD patients at diagnosis showed an inflammatory profile enriched in Ki67, reflecting recent proliferation, and high expression of chemokine receptors associated with inflammatory non-classical T helper-1 IFN-γhighIL-17low producing cells. In agreement, high frequencies of TIGITnegCD38+ effector T cells correlated with high plasma IFN-γ concentrations.
Analyses in parallel on plasma samples of 36 patients revealed that CD and UC/IBD-U patients shared increased abundance of 17 proteins amongst which interleukin-6 and oncostatin-M. Increased abundance of the Th1 cytokine interferon-γ was strictly associated with CD while Th17-associated interleukin-17A was significantly more abundant in UC/IBD-U. Hierarchical clustering of plasma protein profiles discriminated 2 clusters of UC patients with different clinical disease activity and disease extent. In CD, 3 patient clusters were identified. CD#3 patients had lower clinical disease activity, lower C-reactive protein and higher blood albumin concentrations. Clusters CD#1 and CD#2 had comparable clinical parameters. CD#1 patients had higher abundance of 14 proteins associated with neutrophil function and interferon-γ signaling while CD#2 patients had a marked increase in frequencies of activated (HLA-DR+) memory Th cells. The 3 CD clusters responded differently to therapy with CD#1 patients exhibiting more modulated proteins and greater fold changes, CD#2 patients showing intermediate modulation and CD#3 patients exhibiting only a few changes. Further in-depth immunological analyses are currently ongoing.
For the genetic analyses (WP11) of patients developing rare complications, 4 patients were analysed, and DNA of 5 more patients extracted. WES allowed identifying a mutation of XIAP in each of the 2 patients developing HLH, so far, no disease causing mutation was seen in the patient with B cell lymphoma nor in the patient with Hodgkin lymphoma (WES in trios).
For UC (WP2), 190 children with UC of the inception cohort were extracted and independently analysed: 190 children were completed at least 1 year of follow-up (age 12.9±3.7 98 [52%] male), 76 (40%) patients received induction therapy with 5-ASA, 61 (32%) with oral corticosteroids (CS), 34 (18%) with intravenous CS and 19 (10%) others. steroid-free remission (SFR) at 12 months was achieved in 118 (62%) patients and SSFR was achieved in 64 (34%) patients. Acute severe colitis (ASC) occurred in 33 (17%) patients during the first year from diagnosis, 3 (2%) of whom underwent colectomy during the same hospitalization, and another 1 by 10 months from hospitalization. 87 (46%) patients escalated to IMM, and 76 (40%) to anti-TNF. Despite the fact that 1/5 of children with new-onset of UC required admission for ASC during the first year of diagnosis, still most children achieved SFR at 12 months.
Biologic sampling for the pharmacological analyses within the RCT (WP4) are completed and samples were transferred for analyses by end of RP4 (analyses are underway); in the same line all Health economic and quality of life questionnaires (WP8) are completed.
The PIBD Cloud database is functional and underuse since 2017. 696 patients (77% of the planned recruitment) were included in the inception cohort by 06/2021. Follow-up of these patients will be the basis of the independent validation of the risk algorithms of WP 1 and WP2. First analyses on safety events are completed.
In a subcohort of n=92 patients recruited to the inception cohort, biomaterial was collected for immunological analysis of WP9. These analyses are completed for all patients: heterogeneity in the frequency of TIGIT+CD38+ effector T cells was detected at time of diagnosis. Around 50% of CD patients had strongly reduced frequencies of inhibitory TIGIT+CD38+ effector T cells (TIGITlow patients) compared to UC patients and age-matched healthy controls. TIGITlow CD patients needed earlier anti-TNF treatment with 73% of patients receiving anti-TNF within 1 year versus 36% for CD patients with normal frequencies of TIGIT+CD38+ effector T cells. Fewer TIGITlow CD patients had sustained corticosteroid free remission and more TIGITlow CD patients did not reach remission within 6 months or had a disease relapse within 1 year. Reduced frequencies of TIGIT+CD38+ effector T cells associated with active inflammation as frequencies restored to normal after 3 months of induction therapy. Phenotypic characterization of TIGITnegCD38+ effector T cells in CD patients at diagnosis showed an inflammatory profile enriched in Ki67, reflecting recent proliferation, and high expression of chemokine receptors associated with inflammatory non-classical T helper-1 IFN-γhighIL-17low producing cells. In agreement, high frequencies of TIGITnegCD38+ effector T cells correlated with high plasma IFN-γ concentrations.
Analyses in parallel on plasma samples of 36 patients revealed that CD and UC/IBD-U patients shared increased abundance of 17 proteins amongst which interleukin-6 and oncostatin-M. Increased abundance of the Th1 cytokine interferon-γ was strictly associated with CD while Th17-associated interleukin-17A was significantly more abundant in UC/IBD-U. Hierarchical clustering of plasma protein profiles discriminated 2 clusters of UC patients with different clinical disease activity and disease extent. In CD, 3 patient clusters were identified. CD#3 patients had lower clinical disease activity, lower C-reactive protein and higher blood albumin concentrations. Clusters CD#1 and CD#2 had comparable clinical parameters. CD#1 patients had higher abundance of 14 proteins associated with neutrophil function and interferon-γ signaling while CD#2 patients had a marked increase in frequencies of activated (HLA-DR+) memory Th cells. The 3 CD clusters responded differently to therapy with CD#1 patients exhibiting more modulated proteins and greater fold changes, CD#2 patients showing intermediate modulation and CD#3 patients exhibiting only a few changes. Further in-depth immunological analyses are currently ongoing.
For the genetic analyses (WP11) of patients developing rare complications, 4 patients were analysed, and DNA of 5 more patients extracted. WES allowed identifying a mutation of XIAP in each of the 2 patients developing HLH, so far, no disease causing mutation was seen in the patient with B cell lymphoma nor in the patient with Hodgkin lymphoma (WES in trios).
The following important impacts form are expected :
Significantly decreasing treatment related risks (infections, new immune-mediated diseases and tumours/cancers) in the paediatric population
Establishing novel and/or more effective treatment schemes for healthcare interventions in the paediatric population
Focussing PIBD-SETQuality on PIBD patients targets the most severe patients early in their lives and disease progression and can lead to major benefits in the short, medium and long term.
- Identification and improved treatment of patients at most risk of severe disease progression will have major impacts on improved health, well being, and quality of life of the individual. These will be demonstrated within both the RCT and the registry data.
- Improved health for an individual also benefits their family both in terms of psycosocial and economic outcomes, by the ability to lead ‘normal’ lives, retaining full employment and reducing stresses.
- Impact to the local health economy by identifying effective and safe treatments directed at the patients who will most benefit from them with improved utilisation of scarce resources (benefit translatable across all of Europe and beyond).
- Improving health and reducing side effects of treatment leads to improved school attendance, educational achievement and job prospects (benefit the broader economy and improvement of the productivity and carers.)
Significantly decreasing treatment related risks (infections, new immune-mediated diseases and tumours/cancers) in the paediatric population
Establishing novel and/or more effective treatment schemes for healthcare interventions in the paediatric population
Focussing PIBD-SETQuality on PIBD patients targets the most severe patients early in their lives and disease progression and can lead to major benefits in the short, medium and long term.
- Identification and improved treatment of patients at most risk of severe disease progression will have major impacts on improved health, well being, and quality of life of the individual. These will be demonstrated within both the RCT and the registry data.
- Improved health for an individual also benefits their family both in terms of psycosocial and economic outcomes, by the ability to lead ‘normal’ lives, retaining full employment and reducing stresses.
- Impact to the local health economy by identifying effective and safe treatments directed at the patients who will most benefit from them with improved utilisation of scarce resources (benefit translatable across all of Europe and beyond).
- Improving health and reducing side effects of treatment leads to improved school attendance, educational achievement and job prospects (benefit the broader economy and improvement of the productivity and carers.)