SUMMARY---5
CHAPTER 1: INTRODUCTION TO INFLAMMATORY BOWEL DISEASE---7
1. A brief history of IBD--- 7
2. Definition of IBD--- 8
3. Epidemiology and risk factors of IBD---9
3.1. Incidence and prevalence--- 9
3.2. Risk factors--- 9
3.2.1. Influence of gender and age---9
3.2.2. Influence of genetics--- 9
3.2.3. Influence of geographic environment---9
3.2.4. Influence of tobacco---12
3.2.5. Influence of microbiota and diet---12
3.2.6. Influence of other risk factors---12
4. Natural history of IBD--- 13
4.1. Crohn’s disease--- 13
4.2. Ulcerative colitis--- 14
4.3. IBD unclassified--- 14
5. IBD pathogenesis--- 15
5.1. Focus on the intestinal epithelium---15
5.2. Focus on the intestinal immune system and gut microbiota---17
5.3. Focus on the inflammatory response---18
6. Summary of the current paradigm of IBD pathogenesis---20
7. Current treatments used in IBD---21
7.1. A brief history of treatments and therapeutic goals---21
7.2. Use of steroids--- 22
7.3. Use of 5-ASA--- 22
7.4. Use of immunosuppressors---23
7.5. Use of next generation small molecules---23
7.6. Use of biotherapies--- 24
7.6.1. A brief history of biotherapies---24
7.6.2. The different drug classes currently used in IBD---25
7.6.2.1. Anti-TNF drugs--- 25
7.6.2.2. Anti-integrin drugs---25
7.6.2.3. Anti-IL12/23 drugs---26
7.6.2.4. Other biotherapies---27
7.6.3. Treatment strategies used in IBD---27
7.7. Surgery in IBD--- 28
8. Objectives in IBD--- 29
8.1. Objectives of this PhD thesis---29
8.1.1. First part: How to predict treatment response with biologics among patients with moderate-to-severe IBD?---30
8.1.2. Second part: Which genetic markers influence IBD severity?---31
CHAPTER 2: TREATMENT OPTIMIZATION BASED ON PHARMACOKINETICS 32
1. A brief history of biotherapy development---32
2. Introduction to the pharmacokinetics of biologic medicines---33
2.1. Description of the pharmacokinetics of biologics---33
2.2. Evaluation of the pharmacokinetics of biologics---34
2.3. Description of the immunogenicity of biologics---35
2.3.1. Definition and prevalence of immunogenicity in IBD---35
2.3.2. Mechanisms and clinical consequences of immunogenicity---36
2.3.3. Factors influencing immunogenicity---36
3. Primary nonresponse, secondary loss of response, and treatment optimization---37
3.1. Definitions--- 37
3.2. Primary nonresponse and loss of response with anti-TNF---37
3.3. Primary nonresponse and loss of response with vedolizumab and ustekinumab---38
4. Integration of pharmacokinetic studies in clinical practice: Therapeutic drug monitoring38 5. Working hypothesis--- 39
6. Aims of the work--- 40
7. Results--- 40
7.1. Early measurement of infliximab trough levels at induction---40
7.1.1. Retrospective study--- 40
7.1.1.1. Materials and methods---40
7.1.1.2. Results--- 43
7.1.1.3. Discussion--- 54
7.1.2. Prospective study---56
7.1.2.1. Materials and methods---56
7.1.2.2. Results--- 57
7.1.2.3. Discussion--- 60
7.2. Early measurement of vedolizumab trough levels at induction---61
7.2.1. Materials and methods---61
7.2.1.1. Study design--- 61
7.2.1.2. Study population--- 61
7.2.1.3. Data collection---61
7.2.1.4. Blood samples---62
7.2.1.5. Laboratory Methods---62
7.2.1.6. Statistical Analysis---63
7.2.1 Results--- 63
7.2.1.1 Study population--- 63
7.2.1.2 Early vedolizumab trough levels at induction for prediction of outcome and mucosal healing during maintenance---66
7.2.1.3 Impact of previous exposure to biologics on early vedolizumab trough levels at induction and outcome during maintenance---68
7.2.1.4 Predictive markers associated with vedolizumab trough levels at induction and outcome during maintenance---69
7.2.1.5 Impact of Immunomodulators on vedolizumab trough levels at induction and outcome during maintenance---71
7.2.1.6 Evolution of vedolizumab trough levels during maintenance---72
7.2.2 Discussion--- 72
7.3 Measurement of ustekinumab trough levels at induction and evaluation of its effectiveness in the Crohn’s disease population---75
7.3.1 Methods--- 75
7.3.1.1 Study design and population---75
7.3.1.2 Data collection and serum samples---75
7.3.1.3 Outcomes and parameters---76
7.3.1.4 Statistical methods---76
7.3.2 Results--- 77
7.3.2.1 Study Population---77
7.3.2.2 Clinical response and remission to ustekinumab---78
7.3.2.3 Evolution of biomarkers---80
7.3.2.4 Predictors of clinical response and remission at one year of follow-up---81
7.3.2.5 Pharmacokinetics of ustekinumab at induction---83
7.3.2.6 Evolution of arthralgia with ustekinumab---84
7.3.2.7 Adverse events---84
7.3.3 Discussion--- 85
7.4 Impact of different wash-out periods on biologic pharmacokinetics---87
7.4.1 Materials and methods--- 87
7.4.1.1 Study design--- 87
7.4.1.2 Study population--- 87
7.4.1.3 Data Collection and definitions---87
7.4.1.4 Blood samples---88
7.4.1.5 Laboratory Methods---88
7.4.1.6 Statistical Analysis---88
7.4.2 Results--- 88
7.4.2.1 Study population--- 88
7.4.2.2 Impact of wash-out on pharmacokinetics during induction---91
7.4.2.3 Pharmacokinetic levels at induction according to biologic used as first-line or second-line treatment--- 93
7.4.2.4 Evolution of anti-infliximab antibodies during vedolizumab induction---93
7.4.2.5 Impact of wash-out on clinical outcomes---95
7.4.2.6 Impact of wash-out on safety---97
7.4.3 Discussion--- 98
8 Summary of results--- 99
9 Perspectives--- 100
9.1 Short-term perspectives--- 100
9.2 Long-term perspectives--- 100
CHAPTER 3: INVESTIGATION OF GENE MARKERS IN SEVERE IBD---101
1. State of the art of IBD genetics---101
1.1. A brief history of IBD genetics---101
1.2. From the genetics of susceptibility to the genetics of disease severity---103
1.3. Studying healthy cohorts in order to understand the genetics of IBD severity---106
2. Clinical evaluation of severe IBD---107
2.1. Severity in Crohn’s Disease---108
2.2. Severity in Ulcerative Colitis---108
3. Working hypothesis--- 110
4. Aims--- 110
5. Materials and methods--- 110
5.1. GEOCODE Cohort--- 110
5.1.1. Characteristics of the GEOCODE cohort---110
5.1.2. Conditions of stimulation of whole blood cell cultures---112
5.1.2.1. Stimulation using Toll like receptor agonists---112
5.1.2.2. Stimulation using T cell receptor antagonists---114
5.1.2.3. Process for stopping Toll like receptor and T cell receptor stimulation---114
5.2. Techniques used for evaluating levels of cytokine production---114
5.3. Techniques used for evaluating hormones, immunophenotyping, and viral serologies 115 5.4. Techniques used for DNA and RNA extraction---116
5.4.1. DNA extraction--- 116
5.4.2. RNA extraction--- 116
5.5. Techniques used for genotyping---116
5.6. Statistical analysis--- 117
5.6.1. Descriptive analysis---117
6. Results--- 117
6.1. Description of the GEOCODE cohort---117
6.1.1. Generalities--- 117
6.1.2. Description of subject characteristics at baseline---118
6.1.3. Description of endocrine status at baseline---119
6.1.4. Description of immune status at baseline---119
6.1.4.1. Inter-variability of the immune system---121
6.1.4.2. Influence of viral serologies on the immune system---122
6.1.4.3. Inter-variability of CRP levels---122
6.2. Characteristics of the cytokine response---123
6.2.1. Inter-variability of the cytokine response---123
6.2.1.1. Inter-variability of the cytokine response following Toll like receptor stimulation--- 123
6.2.1.2. Inter-variability of the cytokine response following T cell receptor stimulation 125 6.2.1.3. Inter-variability of the cytokine response with hydrocortisone---126
6.2.2 Correlations of the levels of cytokine production---130
6.2.2.1 Influence of duration of stimulation---130
6.2.2.2 Influence of the type of stimulation on cytokine response---131
6.2.3 Hierarchical clustering of cytokine production---133
6.2.4 Definition of immunotypes---135
6.2.5 Influence of phenotype characteristics, immune, and endocrine status on cytokine response--- 135
6.2.5.1 Influence of subject characteristics on cytokine response---135
6.2.5.2 Influence of endocrine status on cytokine response---136
6.2.5.3 Influence of immune status on cytokine response---136
6.2.5.4 Influence of viral serologies on cytokine response---137
7 Summary and overall discussion of results---137
7.1 Summary and discussion of section 6.1 study population---137
7.2 Summary and discussion of section 6.2 cytokine response---138
8 Perspectives--- 139
8.1 Short-term perspectives--- 139
8.2 Medium-term perspectives---140
8.3 Long-term perspectives--- 141
CHAPTER 4: GENERAL DISCUSSION AND PERSPECTIVES---142
1. Discussion of treatment optimization based on pharmacokinetics---142
2. Discussion of research of gene markers of severe IBD---143
3. Perspectives for future research---144
REFERENCES---147
ANNEX A: LIST OF PUBLICATIONS---167
A.1 Publications related to this thesis---167
Peer-reviewed journal articles--- 167
Peer-reviewed conference abstracts---167
Book chapter--- 168
A.2 Publications unrelated to this thesis---168
Peer-reviewed journal articles--- 168
Peer-reviewed conference abstracts---168
