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Thesis

Reference

Precision Medicine in Inflammatory Bowel Disease

RESTELLINI, Sophie

Abstract

Inflammatory bowel diseases (IBD) are immune-mediated diseases with complex pathogenesis. IBD's course is heterogeneous, as is the response of patients to drugs, but physicians often take a “one size-fits-all” approach. Many patients do not respond to their first treatment, lose response, or suffer adverse events caused by medications. The need to manage patients individually, through precision medicine, is clear. Personalizing IBD treatment depends on determining which patients are at high risk of adverse complications, choosing the best therapy for each patient and optimizing treatment efficacy through tight and tailored monitoring. To change the natural course of disease, an individual's prognosis rather than their symptoms should guide therapy. This thesis outlines current knowledge of IBD pathogenesis and discusses the use of precision medicine to manage IBD patients, with the goal of improving the quality of clinical practice through targeted care.

RESTELLINI, Sophie. Precision Medicine in Inflammatory Bowel Disease. Thèse de privat-docent : Univ. Genève, 2021

DOI : 10.13097/archive-ouverte/unige:153049

Available at:

http://archive-ouverte.unige.ch/unige:153049

Disclaimer: layout of this document may differ from the published version.

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Clinical Medicine Section Department of Medicine

PRECISION MEDICINE IN INFLAMMATORY BOWEL DISEASE

Thesis submitted to the Faculty of Medicine of the University of Geneva

for the degree of Privat-Docent by

--- Sophie RESTELLINI

(Geneva) (2020)

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2 Acknowledgements

This thesis would not have been possible without the unconditional support of Professor Alan Barkun. I thank him for his confidence and his kindness. He showed me that

benevolent management was possible. I am eternally grateful for his guidance and hope to become as good a good mentor.

I express my deepest gratitude to Professor Laura Rubbia-Brandt for her mentorship and humanity. She has been an exceptional female role model.

I would like to thank my colleagues and friends, especially Thomas Agoritsas, Che-Young Chao, Laure Elkrief, Marc Girardin, Pascal Jullierat, Myriam Martel, Diana Ollo and my godmother Isabelle Morard. Working with them throughout my career and sharing their friendship has been a privilege.

I am sincerely grateful to the University of Geneva and especially to our Dean Pr Gem Gabay, and Vice-Deans Pr Jérome Pugin, Pr Alexandra Calmy and Pr Mathieu Nandaz. I intend to honor their trust and benevolence through my commitment to the University of Geneva.

This work could not have been completed without the Heads of my Academic and Clinical Departments, Professors Serge Ferrari and Pierre-Yves Martin, who have accompanied me with great kindness and support on this journey.

Of course, none of this would have been possible without my mentors: Professors Waqqas Afif; Alain Bitton; Talat Bessissow; Peter Lakatos; and, Pierre Michetti. I am proud to have learned both clinical and research aspects of inflammatory bowel disease from them. I thank them for their teaching and trust over the years and am grateful for everything they taught me.

I would like to thank my husband, Omar Kherad, from the bottom of my heart, for always believing in me and supporting me. He has been the best life partner I could ever wish for the past 10 years. I have saved my family for last, and thank them for their unconditional love, without which none of this would have been possible. Because of them I feel I am a happy and accomplished woman.

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I. Table of Contents

I. Abstract ... 4

II. Introduction ... 5

A. Inflammatory bowel diseases ... 5

1. Definition of inflammatory bowel disease ... 5

2. Clinical features... 8

3. Managing patients with inflammatory bowel disease: conventional and evolving immunomodulatory therapies ... 11

B. Precision medicine and its relevance to inflammatory bowel disease ... 15

1. General concept of precision medicine ... 15

2. Recent change of paradigms toward precision care in IBD ... 15

3. IBD clinic setting and use of technological tools for precision care ... 24

III. Article 1 ... 26

IV. Article 2 ... 43

V. Article 3 ... 50

VI. Article 4 ... 61

VII. Conclusion ... 70

A. Conclusion ... 70

B. Challenges on the horizon of personalized medicine in IBD ... 70

C. Research agenda ... 71

1. Theme A: Optimizing biologic medications toward precision care in IBD ... 71

2. Theme B: Setting up a pediatric transition program for precision care in IBD ... 71

VIII. References ... 78

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I. Abstract

Inflammatory bowel diseases (IBD) are immune-mediated diseases with complex

pathogenesis, characterized by a relapsing-remitting course and heterogeneous outcomes.

IBD’s effects on patient’s quality of life (QoL) can range from mild to severely debilitating, depending on frequency of flares, presence of concomitant extra-intestinal manifestations, penetrating complications, and treatment response. IBD care has changed greatly over the last two decades, particularly after the arrival of biologic treatments. The first of these treatments were tumor necrosis factor antagonist agents (anti-TNF-a), followed by therapies that targeted other pathways, e.g., inhibitors of leukocyte-trafficking molecules, anti-

inflammatory cytokines and JAKs inhibitors. IBD’s course is heterogeneous, as is the response of patients to drugs, but physicians often take a “one-size-fits-all” approach. Many patients do not respond to their first treatment, lose response, or suffer adverse events caused by medications. The need to manage patients individually, through precision medicine, is clear.

Personalizing IBD treatment depends on determining which patients are at high risk of adverse complications, choosing the best therapy for each patient, and controlling disease activity and proving QoL by optimizing treatment efficacy through tight and tailored

monitoring. If the patient’s response to therapeutic drugs is monitored to determine if they lose response (reactive strategy), this could provide valuable insight into the mechanisms that cause poor response and help to guide treatment decisions. New evidence also suggests that acting before the patient stops responding to a drug (proactive strategy) can prevent poor outcomes.

To change the natural course of disease, an individual’s prognosis rather than their

symptoms should guide therapy. Patients with poor prognosis should be treated with more aggressive therapies; patients with quiescent disease should be tightly controlled and their therapeutic drugs proactively monitored. Clinicians should look for and manage extra- intestinal complications since these are common and can significantly reduce a patient’s QoL. Based on the needs of the individual, preventive strategies like cancer surveillance, vaccinations, smoking cessation, evaluation of bone health and depression screening should also be adopted. Specialized IBD clinics should be established and made more accessible through telemedicine.

This thesis outlines current knowledge of IBD pathogenesis and discusses the use of precision medicine to manage IBD patients, with the goal of improving the quality of clinical practice through targeted care.

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II. Introduction

A. Inflammatory bowel diseases

1. Definition of inflammatory bowel disease

1.1 Epidemiology

Inflammatory bowel disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract, encompassing two major subtypes: Crohn’s disease (CD) and ulcerative colitis (UC).

Over the past twenty years, IBD incidence has considerably increased, becoming a global public health problem; prevalence is estimated to be 0,3%.1,2 Up to 2 million Europeans and 1.6 million Americans suffer from IBD, making these regions and Oceania the zones of highest prevalence 1,3. Canada is one of the most affected country with approximately 29 per 100’000 person-years suffering from IBD and an incident cases per year of approximately 10’000.4 In Switzerland, about 0,41% of the population (12’000-15’000 adult patients) has been diagnosed with IBD. Data from the Swiss IBD cohort study (SIBDC) suggest that overall incidence continues to increase.5,6 The rising incidence of IBD in all newly industrialized countries result from Westernization of lifestyles.1,7

Figure 1. Age-standardized prevalence rate (per 100000 population) of IBD, both sexes, for 195 countries and territories, 2017 (published in GBD 2017 Inflammatory Bowel Disease Collaborators. Lancet Gastroenterol Hepatol 20208)

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6 1.2 Pathogenesis of inflammatory bowel disease

While the cause of IBD is still unclear, it seems to be produced by complex interactions between four pivotal factors: the genome; the exposome; the microbiome; and, the

immunome.9-13 Genetic susceptibility and environmental triggers lead to inappropriate and continuous immune response against the host microbiota, facilitated by disruption of the intestinal barrier. Below, I describe factors of IBD pathogenesis key to understanding therapeutic targets enabling personalized care of IBD patients.

1.2.1 The genome

Family history is a risk factor for developing IBD. People with relatives who suffer from IBD are at higher risk of developing the disease, suggesting a genetic predisposition.14 Relative risk of developing the disease is five-fold higher among first degree relatives of IBD patients.

15 The inheritable component seems stronger for CD; the concordance rate in monozygotic twins reaches 30-58%, while it is only 10-15% for UC. Patients with very early-onset IBD, who usually develop a more severe form of the disease, often report a positive family history.

Rare genetic variants that interfere with pathways, causing intestinal inflammation have been identified in this situation.16

IBD is a complex polygenic disorder driven by multiple common genetic polymorphisms. 17 Functional gene polymorphisms influence innate and adaptive immunity and regulation of the intestinal barrier. 18 Genome-wide association studies (GWASs) revealed more than 250 significant genetic risk loci, demonstrating its immense complexity.19,20,21 Up to 80-90% of GWASs-identified loci are noncoding variations, exerting pathogenic effects by modulating gene expression. Specific IBD loci are involved in biological processes like barrier function, microbial defense, innate and adaptative immune regulation, and autophagy. 22 Around 68%

of these loci are associated with both CD and UC, indicating that they have common

pathways of inflammation. 23 Some loci are different, contributing to the clinical, endoscopic, and histological discrepancies between the diseases. The first mutation thought to be associated with CD development was identified in the gene NOD2/CARD15, which revealed a peptidoglycan that modulates innate and adaptive immune responses, reinforcing the argument that the epithelial barrier is involved in mucosal homeostasis.9, 24 Many loci overlap with other inflammatory diseases, like psoriasis and spondylitis.20,23 While genetic testing is possible, it is not yet used to diagnose IBD since it can identify a person’s potential risk for IBD, but cannot predict if they will suffer from IBD - many people carry these genes but

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7 never develop IBD. IBD genetic studies must meet the challenge of translating these genetic discoveries into useful clinical tools.

1.2.2 The exposome

The incomplete concordance of IBD between monozygotic twins makes clear that genetics are not the only factors that influence the disease. 17,25 Several environmental risk factors (=exposome) may contribute to IBD pathogenesis, but study results are inconsistent and limited. Since the rate of IBD increases in newly industrialized countries with high migrant populations, the role of “westernization” of the environment may be central to disease development. The exposome mediates the pathogenesis of IBD through its effect on intestinal microbiota (microbiome).1,26,27,11

Environmental exposures continue over the life course, and many environmental factors have been associated with IBD including early life events (mode of delivery, breastfeeding, early exposition to antibiotics), exposure to pets and infections (the “hygiene hypothesis”), and smoking and diet. 28 Smoking is the most studied environmental IBD trigger. Tobacco smoking is particularly damaging for patients with CD, likely because the smoke is toxic to immune and mucus-producing cells, impairs autophagy, and changes the microbiome.11, 22,29-

31 Medications, like antibiotics, increase risk of developing IBD by changing the intestinal microbiome. The effect is more severe if antibiotics are administered early in life, when the microbiota helps shape immunity.32,33,34,35 Contraceptives, non-steroidal anti-inflammatory drugs and statins have also been incriminated.36,37 Diets rich in saturated fatty acids, processed food and red meats are also reported to increase IBD risk. High fiber diets, in contrast, may be protective and reduce CD risk by 40% due to their anti-inflammatory properties; colonic bacteria metabolize dietary fiber into light chain fatty acids. 38-40,37,41

1.2.3 The microbiome

IBD risk may also be influenced by the gut microbiome, which comprises all microorganisms, bacteria, viruses, protozoa, and fungi, and their collective genetic material present in the gastrointestinal tract. The microbiome establishes the connection between intestinal mucosa and the outside environment. In IBD patients, a decrease of microbiota diversity called

“dysbiosis” has been repeatedly reported. 42 In comparison to healthy people, those with IBD have fewer anti-inflammatory bacteria like Firmicutes and more bacteria with inflammatory capacities like Proteobacteria and Bacteroidetes in their microbiota. 43 Faecalibacterium prausnitzzi, a bacterium that produces short-chain fatty acids is also less common in the microbiota of IBD patients; this may inhibit epithelial cell growth and damage T regs cells.

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8 Lower counts of this bacteria were associated with higher ileal CD recurrence rate after surgery. 44,45 An increase of certain Proteobacteria, like E. coli, can affect the permeability of the intestine, reduce the diversity of the microbiota, and provoke inflammatory responses by regulating the expression of inflammatory genes. 46 IBD patients may also have more mucosa-associated bacteria. 47 Finally, augmentation of sulfate-reducing bacteria like Desulfovibrio can damage the intestinal barrier and activate mucosal inflammation by producing hydrogen-sulfate. 48 The microbiome is still a domain of intensive investigation and it is unclear if these associations are a cause or a consequence of IBD. Further study is required to identify the mechanisms that may reverse dysbiosis.

1.2.4 The immunome

Immune dysregulation plays a central role in IBD pathogenesis. The digestive tract is a crucial immunological interface. It preserves an immunologically complex balance between recognition and tolerance of commensal bacteria, antigens from food, self-antigens

(tolerogenic response), and pathogen identification (immunogenic response). 9 Several innate immune factors contribute to the persistence of inflammation like impairment of the intestinal barrier. Microbiome changes can cause inappropriate and continuing inflammation, epithelial neutrophil accumulation, defective antigen clearance by macrophages and

impaired conditioning of dendritic cells.9,49,50,13 Antigens that trigger inflammation are caught by antigen-presenting cells and intracellular degradation in the proteasomes exposes the epitope, the antigenic fraction that triggers a T cell mediated immune response. 13,51 The balance between effector T cells (TH1, TH2, TH17 and TH9) and regulatory T (Treg) cells is crucial to maintaining tolerance or promoting chronic inflammation. 50 T cells contribute to chronic intestinal inflammation and are a potential therapeutic target in IBD.

2. Clinical features

UC and CD are chronic relapsing and remitting diseases with variable evolution. These conditions have been associated with complications that greatly reduce QoL and increase anxiety and depression risk.52,53 IBD patients also have increased risk of mortality.54,55 Both conditions are more common in adults before middle-age, at 20-30 years for CD onset and 30-40 years for UC. Incidence peaks again between 50-60 years. About 25% of IBD cases are diagnosed in children under 18 years (pediatric-onset IBD).56 IBD affects men and women about equally; men are only slightly more likely to develop UC. In most studies, men

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9 make up about 60% of participants and women 40%. Men generally have worse outcomes than women, especially for UC. A study from Olmsted County, Minnesota, USA looked at colectomy rates and found that men were twice as likely to need colectomy than women, but could not offer a clear explanation.57 Several studies reported that men with UC are twice as likely to develop colorectal cancer.58 CD and UC share similarities, also differ in important ways.

2.1 CD manifestations

CD may occur in any part of the gastrointestinal tract, from the mouth to the anus. Healthy parts of the intestine may alternate with inflamed areas called skip lesions. CD is classed into four categories, by location (Montreal classification): in ileitis (L1), only the ileum is affected; in Crohn's colitis (L2), only the colon; in ileocolitis (L3), both the ileum and the colon are affected (most common form); and, in upper gastrointestinal CD (L4) only the stomach and the first part of the small intestine are inflamed. Inflammation in CD’s patients may extend through the entire thickness of the bowel wall (transmural inflammation) leading to possible serious complications including development of strictures and fistula formation, intra-abdominal abscesses and/or peritonitis.59,60 Up to 80% of patients with CD may have at least one surgery for the disease.59,61,62 Common symptoms of CD include diarrhea,

abdominal pain, and weight loss. Blood and mucus in the stool are present in up to 50% of patients with CD. In a cohort of newly diagnosed IBD patients, the two most commonly reported symptoms at presentation were fatigue and abdominal pain.63

2.2 UC manifestations

UC is limited to the rectum and colon; inflammation occurs only in the mucosal layer of the intestine. Usual presentation is continuous inflammation with an ascending gradient from the rectum to the proximal colon. Ulcerative colitis is typed by the area of the colon affected (Montreal classification): in proctitis (E1), inflammation is limited to the rectum; in left-sided colitis (E2) the rectum is affected as far as the splenic flexure; and in pancolitis or extensive colitis (E3) the entire colon is affected. UC causes inflammation and ulceration in the large intestine, leading to loose stools or diarrhea, hematochezia or blood in stools, and bowel urgency. In a cohort of newly diagnosed IBD patients with UC, bloody bowel movements and diarrhea were the two predominant symptoms at presentation. 63 About 10-15% of patients with UC will undergo proctocolectomy either for refractory colitis or because they develop colorectal cancer,64 but the arrival of new therapies seems to be decreasing these

numbers.65 About 10% of IBD cases exhibit features of both CD and UC; this is called indeterminate colitis (IC).

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10 2.3 Extraintestinal manifestations

IBD is a systemic immune disorder not limited to the gut that can cause “extraintestinal manifestation” (EIM) in multiple other organs. The pathogenesis of EIM has not been fully described. It is unclear whether EIM is a direct product of the inflammatory process in the gut or a consequence of shared genetic background impaired leading to impaired immune responses to environmental factors. Several mechanisms have been proposed, including aberrant lymphocyte homing, upregulation of tumor necrosis factor, and cross-reactive antigen presentation.66 A recent cohort study showed that EIM occur frequently; about 50%

of IBD patients develop an EIM at some point, which drastically reduces their QoL.67,66 The definition of EIM is not uniform, so EIMs are classified by pathogenesis into immune- mediated manifestations caused by the same processes that drive inflammation in the gut, 68 and non-immune-mediated IBD-associated complications like vein and arterial diseases (venous thromboembolism, ischemic heart disease, cerebral vascular disease, peripheral arterial disease), osteoporosis, anemia, and nutrient deficiency that are the result of inflammatory complications on the body.69 EIMs can also be categorized as “specific” (the same disease as IBD but located outside the gut), “reactive” (shares pathogenic

mechanisms with IBD but has different histo-morphological characteristics), ”associated”

(EIMs more frequently observed in IBD than in controls, with an unclear pathogenic link), and “treatment induced” (appearing after IBD treatments introduction). 68

Multiple organ systems can be involved, but musculoskeletal (arthritis type 1 or 2 and spondylarthropathy), ophthalmic (episcleritis and uveitis), dermatological (pyoderma gangrenosum, erythema nodosum, and stomatitis) and hepatobiliary disorders (non- alcoholic fatty liver disease NAFLD, primary sclerosing cholangitis (PSC)) are more

frequent.70,71 The most common EIMs at presentation are joint pain (20% in CD; 14% in UC) and oral ulcerations (13% in CD; 6% in UC),72 which may or may not be linked to disease activity. Erythema nodosum, episcleritis, and type 1 arthritis are typically associated with intestinal disease; spondylarthropathy and type 2 arthritis do not correlate with intestinal inflammation. The correlation between pyoderma gangrenosum or uveitis is still not clear. 66 Looking for EIMs is necessary to personalize care because (i) EIMs strongly affect morbidity and mortality, (ii) EIMs can indicate ongoing intestinal disease activity even if patients are asymptomatic, (iii) EIMs usually appear after IBD diagnosis (median of 92 months), but precede IBD diagnosis in 25% of patients, as highlighted in a prospective work of the Swiss IBD cohort study.73 Clinicians should screen for underlying IBD in patients with EIMs to speed diagnosis. To provide the best care a close collaboration between specialists is key to success.

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3. Managing patients with inflammatory bowel disease:

conventional and evolving immunomodulatory therapies

3.1 Goals of IBD treatments

The goal of treatment in IBD has shifted over the years, from treating symptoms to controlling inflammation to achieving remission. IBD experts of the International Organization for the Study of IBD (IOIBD) group have defined therapeutic goals by consensus. They underlined the need for objective parameters of remission beyond the absence of symptoms of disease activity to assess response/remission. They also suggested targets for the management of IBD patients, to avoid the risk of long-term disease complications cause by bowel inflammation. The main targets in CD are clinical remission, defined by patient-reported outcome measures (PROMs) like resolution of abdominal pain and altered bowel habit from disease activity, and endoscopic remission or “mucosal healing,” defined as resolution of ulceration at ileocolonoscopy or resolution of findings of inflammation from cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. In UC, the targets are clinical remission, defined as resolution of rectal bleeding and altered bowel habit related to the disease activity, and endoscopic remission, defined as mucosal healing, indicated by a Mayo endoscopy score of 0 or 1. Together, clinical and endoscopic remission define “deep remission,” which improves QoL, reduces need for hospitalization and surgery, and lowers colorectal cancer risk.74

Changing the treatment goal and targeting both clinical and endoscopic remission could change the course of the disease and slow its progress.

3.2 Conventional therapies in IBD

Understanding of the mechanisms that cause IBD to develop has improved over the last twenty years, leading to significant advances in effective IBD treatment.75 Choice of treatment depends on location and severity, drug efficacy, desire to minimize adverse effects, and the preferences of the patient. The treatment has 2 phases: the induction of response/remission followed by a maintenance period during which therapy should be continued to prevent relapse.

3.2.1 Aminosalicylates

Aminosalicylates, also known as 5-aminosalicylic acid (5-ASA) or mesalazine, can be used to induce and maintain remission in mild to moderate UC, but are not an effective

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12 therapeutic option in CD.76 5-ASA’s can be delivered orally or to the rectum with enemas, foam, or suppositories, acting as a topical anti-inflammatory. Administering oral and rectal therapy together potentiates the effect of the drug.

3.2.2. Corticosteroids

Corticosteroids are usually used to induce remission in mild to moderate IBD which requires rapid symptom management. They are not considered as a maintenance therapy because they often cause high rate of long-term side effects and do not prevent relapse. Usually, patients are slowly tapered of steroids and introduced to corticosteroid-sparing drugs for long term management.77 For mild to moderate CD with disease located in the ileum and/or ascending colon Budesonide, an oral steroid, can be used to induce response. This

formulation of steroids is substantially metabolized in the first pass, leading to low systemic bioavailability that limits its systemic toxicity and lead to a selected effect on the GI tract.

More recently a multi-matrix (MMX) budesonide formulation was developed to induce response in UC when 5-ASA therapy was insufficient.

3.2.3 Immunomodulators

IBD patients who failed 5-ASA treatment or have become dependent on corticosteroids can be treated with immunomodulators agents like thiopurines (azathioprine and 6-

mercapropurine) and methotrexate. Thiopurines can be used to maintain remission in CD and UC. Because it takes up to 6 months before patients see an effect, they cannot be used for induction or for steroids non-responder patients.78,79 Thiopurines can also be associated with serious adverse events. The enzyme thiopurine S-methyltransferase (TPMT) is

responsible for the metabolism of thiopurines. Polymorphism of this enzyme is common and can trigger accumulation of toxic metabolites linked to bone marrow suppression or

hepatotoxicity.80 TPMT activity should be assessed before thiopurine treatment is started and patients with no, or low, TPMT activity should not be treated with this enzyme.8182 Other adverse events like pancreatitis, allergic reaction, infection, and increased risk of cancer, especially in elderly patients (lymphoma, non-melanoma skin cancers, urinary tract cancers), have been reported for thiopurines.83

Methotrexate can be an alternative immunomodulator to azathioprine for CD induction and maintenance treatment but is ineffective in treating UC. Remission is usually induced by administering intramuscular injections of 25mg/week of methotrexate followed by

15mg/week po for maintenance. Folic acid supplements are required because methotrexate inhibits the enzyme dihydrofolate reductase, producing a state of effective folate deficiency.

Taking folic acid also improves some of the side effects of the drug 84,85 which include

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13 nausea and vomiting, hepatotoxicity, bone marrow suppression, and pulmonary fibrosis.

Methotrexate is teratogenic in women and can cause azoospermia in men.

Immunomodulator monotherapy has lost its appeal, given its limited efficacy and side-effect profile, but it still plays an important role in “combotherapies”. Combining azathioprine and infliximab, an anti-tumor necrosis factor alpha (anti-TNFα) agent, improves disease control and reduces immunogenicity of the anti-TNFα.86,87 The latest guidelines recommend combining thiopurine at start of therapy with infliximab to induce remission in patients with moderate-to-severe CD non-responders to conventional therapy, but the effects of

combination with other biologic treatment are still uncertain. 88

3.3 Biologic treatments and small molecules in IBD

Dysregulation of the immune system in IBD patients stimulates production of proinflammatory cytokines like tumor necrosis factor (TNF)-α, which plays a key role in the pathogenesis of the disease and adhesion molecules. In the early 2000s, targeting those cytokines led to the development of TNF inhibitors. Infliximab, a chimeric monoclonal antibody between murine and human amino-acid sequences, was the first approved for both induction and maintenance of CD and UC. This revolutionized IBD management after the pivotal ACCENT and ACT trials were published.89,90 Since then, we have added an increasing array of biologic and small- molecule therapies to our medical arsenal,91 including newer drugs directed at inflammatory cytokines and leukocyte-trafficking molecules. Among these treatments approved for CD and UC are vedolizumab, which blocks the interaction between an integrin on the surface of gut- specific lymphocytes and a receptor on the vascular endothelium of the intestinal tract (α4β7 and MAdCAM-1, respectively), and ustekinumab, which is directed against the common p40 subunit of interleukin IL-12/23. A newer promising UC treatment strategy blocks the JAK/STAT signaling pathway. The latest accepted drug, tofacitinib, is also a promising target, since many cytokines activate JAK signaling during inflammatory response. Several other molecules in this category are in the last phases of investigation for CD treatments (filgotinib, upadacitinib etc.). These new therapeutic options are valuable because they open alternative pathways to therapy if one treatment fails. Many new pathways are in the pipeline, e.g., a sphingosine1- phosphate receptor modulator (a selective small molecule agonist for G protein-coupled S1P receptor [S1P1]), leads to internalization of the S1P1 receptor on the surface of C-C chemokine receptor type 7 positive lymphocytes, trapping these lymphocytes in lymph nodes.92

Patients should have a pre-immunosuppression screening that includes, at minimum, a tuberculosis and hepatitis B check, and should be counseled about lymphoma risk, and asked about vaccination status and personal or family cancer history.93

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14 Many biologics have demonstrated therapeutic effects in IBD treatment but despite dramatic progress over the last few years, IBD therapies are far from sufficient. At the individual level, the first biologic treatment seems to be most effective and patients often have a diminished response to second-line biologics.94,95 Up to 30% of all patients newly diagnosed with IBD do not reach clinical remission and mucosal healing with their first anti-TNFa therapy (primary non-responders),96 and many stop responding to drugs every year (secondary non- responders)97. The annual risk of secondary non-response rate varies from 13% per patient year for infliximab (IFX)98 to 20% for adalimumab.99 Newer biologics targeting different inflammatory pathways pose the same problems as anti-TNF agents since many patients do not respond but there are few before-and-after comparison with anti-TNFa therapy. In 2019, the results of the VARSITY trial, the first head-to-head randomized controlled trial between biologic agents with different modes of action in IBD, were published.100 VARSITY compared the efficacy and safety of intravenous vedolizumab and subcutaneous adalimumab in patients with moderate-to-severe active ulcerative colitis. Head-to-head trials comparing other treatment options like etrolizumab (a monoclonal antibody against β7 integrin) and infliximab or ustekinumab and adalimumab are ongoing, with results expected in the next 5 years. These results might dramatically change our clinical practice.

Mechanisms underlying primary non-response are multifactorial and include disease aspect and characteristics and treatment strategy-related factors. The “one size- fits-all” approach is not appropriate for a many patients and the need to personalize care in IBD patients is high.

Clinicians should choose the right drug at the right time for the right patient, and shift their approach from “reactive” management driven by disease complications to “proactive”

management with the goal of preventing disease complications.

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B. Precision medicine and its relevance to inflammatory bowel disease

1. General concept of precision medicine

Precision medicine refers to a medical model in which medical decisions are tailored to an individual person based on predicted risk of disease or response to a treatment, and to all medical information gathered to date, including knowledge of the genome and possibly other individual data like proteomics (the entire repertoire of proteins in a given biological fluid), the metabolome (profile of small molecules in a sample), the epigenome (all the modifications induced by the environment on our genome), and the microbiome (complex expression of all the germs which constitute or are present in our organism in different tissues). 101

This individualized approach has already been used in other fields like oncology where, for example, patients with breath cancer who expressed HER2 could benefit from a monoclonal antibody treatment called trastuzumab that targets HER2.102

2. Recent change of paradigms toward precision care in IBD

Patients with IBD follow different disease courses; everyone has a unique and unpredictable phenotype. Some patients can have a very mild disease, but over a 10-year period up to 53% of patients with CD will developed narrowing or penetrating disease and up to 19% of patients with UC will require colectomy. 103,104 This variability reinforces the idea that a unique approach will be suboptimal for a significant proportion of patients, especially those with aggressive factors. These patients have a “window of opportunity” for effective

treatment that should not be missed because delays may lead to intestinal damage with irreversible consequences.105

Precision medicine is a relatively new concept in IBD and comprises a model of care in which an individual’s phenotypes and genotypes are characterized so the physician can tailor treatment to the patient and deliver it at the appropriate time.106,107 Precision medicine can be applied before treatment begins, when biomarkers are used to determine the best treatment for a patient. It can also be applied after treatment start, with tight and

personalized monitoring of disease activity and treatment efficacity to improve QoL and prevent adverse drug events and long-term complications. Finally, precision strategies in this field improve medical adherence and follow-up,notably through developing an IBD-

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16 specialized clinic with multidisciplinary care and a telemedicine system. With precision medicine, it may be possible to lower the burden of healthcare costs related to biologic drugs that are a large driver of increased healthcare expenditure.5

2.1 Step-up versus top-down strategy

In 2004, D’Haens at al. demonstrated the advantages of starting IBD treatment with a combination of immunomodulators and biological therapy and then de-escalating as appropriate (top-down strategy); there was more beneficial than the standard of care that started with steroids and then stepped up to immunomodulators, followed by biologics if necessary (step-up strategy). The study showed that the top down strategy significantly raised clinical remission rates without steroids. In 2010, the pivotal SONIC trial reported that combining immunomodulator and IFX was more effective than immunomodulator or IFX alone to achieve corticosteroid-free remission (56.8% for combined therapy; 30% for immunomodulators alone; 44% for IFX alone) and mucosal healing (44% for combined therapy; 16,5% for immunomodulators alone; 30% for IFX alone).86 In 2015, the REACT study reported that an early treatment combination for CD patients was more effective than conventional management for controlling risk of major adverse outcomes like serious disease-related adverse events, hospitalizations, or surgery (27.7% for combined therapy;

35.1% for conventional management, p = 0.0003).108

In traditional step-up strategy or accelerated step-up approach, which reactively escalates medications in response to disease flares, undertreatment of more severe patients is unavoidable, and this increases the likelihood of developing complications. But a top-down strategy risks overtreating patients who might have remained stable without complications on milder and less expensive drugs. Though step-up strategy was unaffordable in some healthcare settings, biosimilar drugs have recently been shown to be safe and effective, and are to 40% cheaper, significantly decreasing health care costs. The European Crohn’s and Colitis Organization (ECCO) recommend early top-down strategy for treating selected patients with high-risk factors of complicated disease, since they will benefit most from early diagnosis and treatment that modifies the course of the disease.

2.2 Treat to target and tight monitoring

“Treat to target” and “tight monitoring” recently became the standard of care in IBD follow-up and refer to using predefined outcome measures (clinical, biochemical and/or endoscopic)

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17 as goals to optimize therapy. Inspired by evidence in other specialties, notably from the rheumatology literature, the IOIBD group published the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) recommendations with the objective of delineating a

“treat to target” approach to obtain clinical and endoscopic remission in IBD.58,61,109In parallel, there was growing evidence in the IBD literature that endoscopic healing was associated with improved clinical and long-term outcomes.110,111 The STRIDE

recommendations include targeting improvement in clinical and endoscopic outcomes and also incorporate patient-reported outcome measures (PROMs). Choosing these measures of improvement and PROMs might improve IBD treatment outcomes more than treatment based on symptom-derived scales. Also mucosal healing was considered the sole target endpoint to reach in recent drugs trials112, all newly designed and recently published clinical trials in IBD have moved toward complex outcomes goals encompassing PROMs,

biochemicals and endoscopic improvements.113 STRIDE recommends using biomarkers like CRP and fecal calprotectin (FCP) to monitor response but there was no consensus on how to use them until the results of the CALM trial were published. In this study, Colombel et al.

tested the efficacy of tight control management based on 3-monthly biomarkers versus conventional management, which used Crohn’s Disease Activity Index on clinical (CDAI) and endoscopic outcomes in moderate to severe CD.114 CALM demonstrated that a significantly higher number of patients achieved mucosal healing in the “tight control” group than in conventional arm. The same group of authors published in 2019 follow-up data that showed that patients who achieved mucosal healing in the first year of treatment were less likely to have disease progression over a median of 3 years, including less likelihood of hard outcomes like hospitalization and surgery.115 The utility of monitoring based on biomarkers was also highlighted by a recent systematic review showing that two consecutive elevated FCP tests predicted disease relapse within the next 2 to 3 months.116 It is also possible to use monitoring to assess the possibility of de-escalation. Louis E and al. highlighted this in the prospective STORI trial that followed 115 CD patients on combination therapy. Anti-TNF was discontinued in these patients after at least 6 months of corticosteroid-free clinical remission, resultingin frequent relapse. These biomarkers can elevate 4 months before clinical symptoms of relapse appear.117

2.3 Personalized approach to predicting disease course and guiding choice of treatment for individual patients

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18 Early detection of IBD patients who may be prone to developing a severe form of the

disease is a most difficult challenge. But there are clinical predictors that may predict an unfavorable disease course and help physicians tailor IBD management (Table 1).

Disease Time frame Predictor of unfavorable course Crohn’s

disease

Within 5 years of diagnosis Age < 40 yo

Need for steroids in first flare Perianal disease

Upper gastrointestinal lesions Ileocolonic lesions

Within 10 years of diagnosis Age < 40 yo

Upper gastrointestinal lesions Stricturing and penetrating behavior Terminal ileal lesions

Ulcerative colitis

Within 5 years of diagnosis Younger age Female gender Within 10 years of diagnosis Younger age

Female gender

Fewer systemic symptoms Extensive colitis

Non-smoking status

Table 1: Clinical parameters that predict unfavorable inflammatory bowel disease course (adapted from Borg-Bartolo, et al. F1000Res. 2020 118)

In CD, early onset diagnosis, extensive disease, deep ulcerations, upper gastrointestinal involvement, smoking, and penetrating phenotypes (strictures and fistulae), or steroids use at diagnosis are associated with poorer prognosis.In UC, early onset diagnosis and

extensive colitis are poor prognostic factors. The presence of extraintestinal manifestations, especially primary sclerosing cholangitis and non-smoking status, predict risk of pouchitis after ileal pouch anal anastomosis.119,120,121 These clinical criteria are helpful but not sufficient to permit accurate prediction of disease severity in individuals.

The paradigm has shifted from a reliance on clinical predictors toward using biomarkers to identify patients at risk of complicated disease and to tailoring treatment algorithms based on disease course. For example, positivity of Anti-Saccharomyces Cerevisiae Antibodies

(ASCA) or newly discovered antibodies like CBir1, Anti-OmpC antibody or anti-I2 in CD

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19 correlate to a higher risk of penetrating disease.122,123 If treatment failure can be predicted, patients’ therapy can be switched early, increasing the likelihood and cost-effectiveness of recapturing response. The thiopurine methyltransferase (TPMT) genotype is now the most accurate at predicting adverse events from azathioprine. Low and intermediate TPMT activity significantly increase risk of adverse events like myelosuppression in patients receiving thiopurines for IBD. For biologic treatments, multiple factors are associated with higher clearance of the drug, including high body weight, low albumin level, low hemoglobin, and high inflammatory burden reflected by biomarkers. 124 A recent multicenter, prospective, observational cohort study called PANTS for “Personalized Anti-TNF Therapy in Crohn’s Disease Study” reported that, in 1610 patients, low drug concentration level at Week 14 was associated with PNR and non-remission at Week 54. Obesity at baseline (for adalimumab) and smoking (for infliximab) were associated with non-remission at Week 54 and

immunogenicity.125 Even if these biomarkers indicate a risk of a complicated disease evolution, their role in everyday clinical care is not yet well-defined and no study has identified adequate predictors for IBD treatment response that physicians can use in clinics to treat patients with precision medicine.

Some endoscopic findings can predict the course of the disease and help physicians choose among treatments, e.g., deep ulcerations are predictors of worse CD outcomes.126 Multiple markers can be combined to predict the course of disease. The Inflammatory Bowel South- Eastern Norway (IBSEN) cohort described four factors associated with higher risk of colectomy in UC patients: i) extent of disease; ii) age (<40 years); iii) need for systemic steroids; iv) CRP (⩾30 mg/l); and, erythrocyte sedimentation rate (⩾30 mm/h) at diagnosis.104

IBD prognosis is very unpredictable and improved techniques for identifying specific predictors of disease evolution would be welcome. In clinical practice, there is currently no available markers potentially used as predictors for better drug selection before initiating the therapy. Ongoing head-to-head trials are comparing different biologics and their results may improve our algorithms for treating IBD.100 Today, the choice of adequate treatment is based on assessing multiple factors like disease activity, size and location of mucosal lesions, anatomic distribution and load of inflammation (local or systemic), prior hospitalizations or surgery, postoperative complications, and presence of extraintestinal manifestations and previous treatment response. Other essential considerations include the impact of the disease on the patient’s QoL and treatment preference.

(21)

20 2.4. Defining personalized targets for treatment and follow-up strategy once

treatment has begun:

Patients and physician may define remission differently; the first takes a subjective

approach, but the second benefits from added objective measures. For many years, patients were defined as “in remission” if they had few or no IBD symptoms. Earlier studies were based only on subjective parameters and analyzed predictive factors of therapeutic response by comparing responders to non-responders after therapy start. Later studies of IBD patient management included objective parameters. The goal of IBD treatment is now a composite of clinical remission, biochemical remission with a normalized C-reactive protein (CRP) and fecal calprotectin (FCP), and endoscopic remission or mucosal healing (visual healing of the intestinal mucosa).61 Clinical, biochemical and endoscopic monitoring of response/remission under treatment should be incorporated into the follow-up process for patients with IBD.

2.4.1 Clinical criteria for remission

Patients are focused on the goal of clinical remission. There are CD and UC disease activity indices like the Crohn’s Disease Activity Index (CDAI) and the pMayo score. 127 But

symptoms correlate poorly with endoscopy, especially in CD, where IBD symptoms and other conditions not related to inflammation overlap, e.g., irritable bowel syndrome, bile salt diarrhea, steatorrhea, bacterial overgrowth, and scarring tissue. The correlation between clinical remission and endoscopic findings may be closer in UC. 128 Often, assessments based only on symptoms while patient started treatment are insufficiently precise for decision making.

2.4.2 Biologic criteria for remission

The response rate to IFX seems significantly higher after induction treatment in patients with a higher level of CRP (>5 mg/l) than for patients with a normal value before treatment (76%

vs 46%; p = 0.004). 129 Early normalization of CRP reportedly correlate with sustained long- term response, without need for therapeutic adjustment (p < 0.001).130,131 FCP is also an interesting measure for IBD follow-up in clinics. Biochemical remission monitored by FCP correlates strongly with mucosal healing; sensitivity and specificity are about 80%.132 Normalizing FCP to a value less than 100 µg/g after induction therapy with anti-TNFa is more likely to result in sustained clinical remission after 12 months than if the post-induction level remains elevated (88% versus 38%; p < 0.0001).133 When patients are in remission, an increase in FCAL levels can predict a relapse.134,117

(22)

21 Biological parameters are useful tools in managing IBD, but abnormalities in any one of them should not, by themselves, indicate the need to change therapies.

2.4.3 Endoscopic criteria for remission

The target of endoscopic healing is sometimes difficult to reach. Endoscopic remission in CD has been defined using different thresholds for the simple endoscopic score for CD (SES- CD) or the CD Endoscopic Index of Severity (CDEIS) score; remission may also be defined as complete absence of ulceration, which may or not consider aphthae. A less strict

measure of endoscopic healing is required for endoscopic response, for which the standard is a 50% reduction of the baseline SES-CD score.135 In UC, endoscopic remission is defined in most studies as a Mayo score of 0 (no lesion) or 1 (mild erythema and friability). But a recent study evaluating relapse risk based on the degree of mucosal healing showed that patients whose endoscopic Mayo score was 1 were at higher risk of relapse (36.6%) than those whose score was 0 (9.4%; p < 0.001).106 The highest rate of endoscopic remission is now obtained with biologic treatments.136,137,138 Histologic healing seems to be of major prognostic importance and may become in a near future an additional target to reach. Some authors demonstrated that UC patients had a significantly higher rate of relapse if they had microscopic inflammation that with patients who had no infiltration109 but more research is required to determine the precise role of histologic remission in IBD patients.

Post-operatively, both elevation of FCP and early endoscopic anastomotic recurrence are associated with increased risk of recurrence and indicate a need to adapt treatment quickly.

2.5 Personalizing monitoring response to therapy with pharmacogenetics, therapeutic drug monitoring, and pharmacokinetics

Therapeutic drug monitoring (TDM) is the measurement of drug levels (trough or peak) and detection of anti-drug antibody concentrations (ADA). There is growing evidence that this tool has a pivotal role in daily clinical practice, helping physicians personalize and optimize care of IBD patients. Of patients with IBD, 30% are primary non-responders (PNR) to biologic treatment, and up to 50% of those who initially respond to a drug are secondary non-responders (SLR) in whom the treatment loses efficacy.139,140 PNR and SLR can be due to either pharmacokinetic (PK) or pharmacodynamic (PD) problems. PK problems are associated with inadequate drug exposure, often because the patient develops ADA, but PD issues are typically associated with inflammatory process unrelated to the targeted

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22 immunoinflammatory pathway. 141 To optimize the use of treatments, pharmacokinetic measurements of anti-TNFa are frequently used to manage IBD in the induction and maintenance phases.

2.5.1 TDM to assess drug response

Many studies suggested that serum concentrations of IFX and ADA significantly correlate with mucosal healing in patients with IBD. 142 Multiple pivotal trials demonstrated that infliximab, adalimumab, golimumab, and certolizumab pegol concentrations were higher in patients who achieved clinical and endoscopic remission than in non-responders.The target cutoffs varied between studies, drugs, and timing of dosage (induction or maintenance period). 141 The utility of this tool is less clear for non-anti-TNFa biologics, but some studies have found a correlation between low serum concentrations of vedolizumab and

ustekinumab and lower patient response rates. 143

2.5.2 TDM to optimize patient losing response (reactive strategy)

About 37% of patients treated with IFX lose clinical remission over time, as do 18.2% treated with adalimumab; a recent meta-analysis reported annual risk at about 13% for IFX and 24.4% for adalimumab.98,144 TDM helps manage PNR and SLR by revealing the underlying mechanism of non-response, so physicians can decide whether to optimize the current drug (by increasing dose, shortening the interval of administration or associate a concomitant immunomodulatory drug) or switch to another therapeutic class. This “reactive“ strategy is more cost-effective than empiric dose escalation.99,145 Several algorithms are available to help clinicians make the best therapeutic decision based on the patient’s PK/PD.146,147 In summary, patients with a low drug concentration, and who do not have ADA can benefit from increasing the dose, but patients with low drug concentration and high ADA levels should be switched to another TNFa antagonist against which they have no ADA yet;

patients with a high drug concentration and no ADA should be switched to another therapeutic class because their disease is not mainly driven along this inflammatory pathway. Experts recommend reactive TDM for all agents, both for PNR and SLR patients.141

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23 Figure 2. Algorithm for using reactive therapeutic drug to monitor IBD patients for secondary loss of response to TNF antagonists. Published in Ma C et al. Curr Treat Options

Gastroenterol. 2019. 148

2.5.3 TDM to prevent patients from losing response (proactive strategy)

Preliminary data suggest that patients with clinical response/remission can also benefit from implementing TDM strategy before they become symptomatic (proactive strategy).141 The primary objective is to avoid loss of response by maintaining optimal anti-TNF

concentrations, reducing risk of adverse events and possibly costs by implementing a de- escalation strategy in patients with supratherapeutic drug concentrations.

Three important studies evaluated the role of routine proactive TDM. TAXIT and TAILORIX, two randomized control trials, compared anti-TNF dosing based on proactive TDM with dosing based on clinical features. TAXIT found a reduced relapse rate in the proactive TDM group, and modest cost savings. TAILORIX found no significant benefit of systematic proactive TDM overdosing, based on clinical features, but its study design prevented

researchers from drawing firm conclusions. In a recent retrospective study, Papamichael and al. compared patients with IBD who were proactively monitored for drugs (titrated to a target concentration) to those who were reactively monitored (titration performed after loss of response) and found proactive monitoring was associated with better clinical outcomes (greater drug durability, less surgery or hospitalization, and lower risk of immunogenicity to IFX).149 In 2019, The first prospective randomized controlled trial of proactive TDM was published: the PAILOT study (Paediatric Crohn’s disease Adalimumab-Level-based

(25)

24 Optimisation Treatment) achieved its primary end point of sustained corticosteroid-free clinical remission.150 PAILOT included 78 biological-naïve children with CD who responded to adalimumab induction therapy and were then randomized to either proactive dose optimization or reactive testing. The proportion of patients with corticosteroid-free clinical remission was significantly higher in the proactive group (82%; n=31) than in the reactive TDM group (48%; n=19; p=002), providing more evidence that proactive TDM is more useful than standard dosing and reactive TDM.

A recent consensus among experts is that it is appropriate to order drug/antibody concentration testing at least once a year and at the end of induction for maintenance patients on any anti-TNFa.141

2.5.4 TDM to monitor drug de-escalation or withdrawal

Anti-TNFa TDM was also associated with reduced costs especially when de-escalating IFX dose in patients with IBD. 151,152 When patients reach clinical and endoscopic remission, proactive TDM can help reduce the amount of the drug in people with supratherapeutic drug levels, which is necessary for their safety and lowers costs. 153 TAXIT proved this strategy effective: drug de-escalation was implemented in CD patients with clinical remission and high IFX TL (>7 µg/ml) by reducing their dose or extending the interval between two infusions; 93% of patients (72 patients) were in normal range after their dose was reduced and clinical outcome was unchanged. Using pharmacokinetic parameters may also be appropriate for patients whose CD is in clinical remission and who may be candidates for anti-TNF withdrawal. In the STORI trial, IFX TL was measured before IFX was halted, with the novel finding that TL above 4.5 µg/ml predicted relapse.117 Patients with higher TL at time of IFX discontinuation were more prone to relapse, which suggests that these patients still need anti-TNF to maintain a level of drug concentration that keeps them in clinical remission.

3. IBD clinic setting and use of technological tools for precision care

Most recent publications highlight significant gaps in the implementation of quality of care parameters for IBD.154,155 The IBD McGill University Health Center and other similar clinics have shown that a specialized multifaceted structure based primarily on dedicated IBD- specialists, IBD-nurses, and available referral specialist, can implement the processes that

(26)

25 improve IBD patient outcomes. Rapid access pathways to the IBD center optimize resources and allow physicians to quickly make therapeutic decisions and prevent unplanned

emergency room visits for most patients.156 Telemedicine, including telemonitoring, teleconsulting and tele-education assists patients whose IBD can flare unpredictably and need continuous medication to improve or maintain their health.106 Some countries, like the Netherlands, Denmark, or Spain have already adopted their own IBD care program using a remote communication system for IBD; these have shown positive long-term outcomes improving medical adherence through better communication between patients and

healthcare providers and increasing QoL. 157These models reduce indirect costs including transport to hospitals and loss of working hours, saving the public money.

The 2020 SARS-Covid-19 crisis has catalyzed implementation of telemedicine in most centers and feedback from caregivers and patients has been positive.158 Telemedicine has limits, because it requires patients and caregivers to self-manage, cannot substitute for clinical examinations in some cases, raises confidentiality issues, and insurers may not cover or reimburse remote care services.

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26

III. Article 1

CLINICAL PARAMETERS CORRELATE WITH ENDOSCOPIC ACTIVITY OF ULCERATIVE COLITIS: A SYSTEMATIC REVIEW

Restellini S, Chao C-Y, Martel M, Barkun A, Kherad O, Seidman E, Wild G, Bitton A, Afif W, Bessissow T, Lakatos P-L

Clinical Gastroenterology and Hepatology 2019;17:1265–1275. doi:10.1016/j.cgh.2018.12.021

This was systematic review of published literature on the correlation between patient reported clinical symptoms and endoscopic disease activity in ulcerative colitis.

We reviewed 23 studies (1 randomized trial, 22 observational studies) and included 3’320 patients with ulcerative colitis.

The study assessed correlation between clinical indices and endoscopic disease activity based on the following parameters: sensitivity; specificity; correlation coefficients; and, area under the receiver operator curve.

The study found:

Composite clinical measures, including rectal bleeding and stool frequency, were moderately to strongly correlated with endoscopic disease activity. Absence of rectal bleeding more successfully identified patients with inactive disease that did

normalizing stool frequency.

Therefore:

The clinical symptoms reported by ulcerative colitis patients may help physicians decide which patients to prioritize for endoscopic disease activity assessment, which is especially useful in resource limited settings.

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IV. Article 2

HARMONIZATION OF QUALITY OF CARE IN AN IBD CENTER IMPACTS DISEASE OUTCOMES: IMPORTANCE OF STRUCTURE,

PROCESS INDICATORS AND RAPID ACCESS CLINIC

Reinglas J, Restellini S, Gonczic, L, Kurtic Z, Verdon C, Nene S, Kohen R, Afif W, Bessissow T, Wild G, Seidman E, Bitton A, Lakatos P.L,c,

Digestive and Liver Disease 51 (2019) 240-345, doi: 10.1016/j.dld.2018.11.013

This study evaluated the quality of care pre- and post-referral and during follow-up at the tertiary IBD center at McGill, Canada, based on quality of care indicators (QIs) validated by groups of international experts. The study also measured the effects of implementing a rapid access clinic (RAC) to improve healthcare services in IBD. This retrospective review of 1’357 consecutive patients who presented at an outpatient visit captured disease characteristics, biochemistry, imaging and endoscopy data, changes in medications, and vaccination profiles.

We found that:

- The MUHC IBD center harmonized objective monitoring and accelerated treatment pathways were applied at referral and during follow-up.

- Implementing a quality of care strategy and establishing a rapid access IBD clinic reduced undesirable outcomes like steroid dependency, ER visits, emergency hospitalizations and surgeries.

This study was the first to comprehensively evaluate real life structure, process and outcome indicators on care delivery in a real-world setting, and to suggest that personalized strategies like tight monitoring strongly emphasized objective patient (re)evaluation, timely access, and accelerated treatment strategy at referral and during follow-up, showing the objective benefit of implementing rapid access clinics.

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V. Article 3

SCREENING FOR NONALCOHOLIC FATTY LIVER DISEASE IN

INFLAMMATORY BOWEL DISEASES: A COHORT STUDY USING TRANSIENT ELASTOGRAPHY

Saroli Palumbo C *, Restellini S *, Chao C-Y, Aruljothy A, Lemieux C, Wild G, Afif W, Lakatos P-L, Bitton A, Cocciolillo S, Ghali P, Bessissow T, Sebastiani G

*co-first author

Inflamm Bowel Dis, 25 (1), 124-133 2019 Jan 1: doi: 10.1093/ibd/izy200

This study was a prospective evaluation of prevalence and risk factors of inflammatory bowel disease (IBD) patients who have non-alcoholic fatty liver disease (NAFLD) and associated liver fibrosis in patients and are at risk from chronic inflammation, hepatotoxic drugs, and alteration of their gut microbiota.

We assessed 384 IBD patients with transient elastography (TE) and the controlled attenuation parameter (CAP). Presence of NAFLD was defined as CAP ≥248 dB/m and significant liver fibrosis (stage 2 or higher out of 4) was defined as a TE measurement of ≥7.0 kPa. Predictors of NAFLD and significant liver fibrosis were determined by logistic regression analysis.

We found:

- 32.8% of patients had NAFLD and 12.2% had significant liver fibrosis.

- Independent predictors of NAFLD were older age (adjusted odds ratio [aOR], 1.45;

95% confidence interval [CI], 1.15-1.82), higher body mass index (BMI; aOR, 1.31; 95%

CI, 1.20-1.42), and higher triglycerides (aOR, 1.45; 95% CI, 1.01-2.09).

- Significant liver fibrosis was independently predicted by older age (aOR, 1.38; 95% CI, 1.12-1.64) and higher BMI (aOR, 1.14; 95% CI, 1.07-1.23).

Therefore:

Since NAFLD seems to be highly prevalent in IBD, evaluating metabolic comorbidities could help physicians decide which patients to screen further and which interventions might be most appropriate for individual patients.

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VI. Article 4

THERAPEUTIC DRUG MONITORING GUIDES THE MANAGEMENT OF CROHN’S PATIENTS WITH SECONDARY LOSS OF RESPONSE TO

ADALIMUMAB

Restellini S, Chao C-Y, Lakatos P.L, Aruljothy A, Haya A, Kherad O, Bitton A, Wild G, Afif W, Bessissow T

Inflammatory Bowel Diseases. 2018 July, 24 (7): 1531-38.doi: 10.1093/ibd/izy044

This study tested whether empiric dose escalation of adalimumab in Crohn’s disease patients who lost response improved clinical outcomes more than tailored treatment adjustment based on monitoring therapeutic drugs (TDM).

We retrospectively analyzed 104 patients who had lost response to adalimumab and compared composite remission outcome (defined as Harvey Bradshaw Index <5, C-reactive protein <5mg/L, fecal calprotectin <250µg/g and simple endoscopy score for Crohn’s disease

<3) at 3, 6 and 12 months in those patients whose dose was empirically guided to those whose dose was guided by TDM.

This study demonstrated that:

- Empiric dose escalation did not improve clinical outcome irrespective of baseline serum adalimumab trough level.

- Empiric escalation resulted in inappropriate adjustments in some patients, including 9.6% of those with high titer of anti-adalimumab antibodies.

Therefore:

Personalized treatment that adjusts doses based on therapeutic drug monitoring reduces unnecessary increases in doses and does not compromise treatment outcomes, demonstrating it is an appropriate treatment strategy.

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