AN OVERVIEW OF IBD PATIENTS ON BIOLOGICAL THERAPY AT RAIGMORE HOSPITAL

Gathered patient data on the biological medicines infliximab, adalimumab and vedolizumab.

DIPLOMA THESIS

to be awarded the academic degree

MAGISTRA DER PHARMAZIE

at Karl-Franzens-University Graz

written by: Angelika Sattler supervised by: Rhona Gunn, Head of Specialist Pharmaceutical Services at Raigmore Hospital, Inverness, Scotland

permitted by: Ao.Univ.-Prof. Mag.pharm. Dr.rer.nat. Astrid Ortner

submitted to: Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, Karl-Franzens-University Graz, Austria

Graz, 2018

Affidavit

I hereby confirm that the following diploma thesis entitled ”An overview of IBD patients on biological therapy at Raigmore Hospital" was written all by myself without any help and support of a third party. Further I confirm that I did not use any other sources than those indicated.

Graz, 27. April 2018

Angelika Sattler

I

Acknowledgements

First of all, I would like to thank Ao.Univ.-Prof. Mag.pharm. Dr.rer.nat. Astrid Ortner for offering me the opportunity to go to Scotland and do the project for my diploma thesis at Raigmore Hospital in Inverness. Furthermore, I would like to thank Ian Rudd, Director of Pharmacy, for the heartily welcome and making all possible in the first place.

Specials thanks go to my great supervisor Rhona Gunn, Head of Specialist Pharmaceutical Services at Raigmore Hospital, for her time and support during my stay and my research work at Raigmore Hospital.

Moreover, I would like to thank consultant gastroenterologist Lindsay Potts and lead advanced nurse IBD David Armour for giving me the possibility to work on this project and for their enthusiasms.

Last but not least, I would like to thank my parents for their encouraging love. Thank you for strengthen my decision to write my thesis abroad. I could not have done it without your support!

Dedicated to my beloved parents and grandparents.

II

Content

Affidavit ...... I

Acknowledgements ...... II

Abstract ...... VI

Kurzfassung ...... VII

1. Introduction ...... 1 1.1. Aetiology of IBD ...... 2 1.2. Epidemiology of IBD ...... 2 1.3. Crohn’s Disease ...... 3 1.3.1. Symptoms ...... 3 1.3.2. Classification ...... 4 1.3.3. Diagnosis ...... 4 1.4. Ulcerative Colitis ...... 5 1.4.1. Symptoms ...... 5 1.4.2. Classification ...... 5 1.4.3. Diagnosis ...... 7 1.5. Drug Therapy ...... 7 1.5.1. Aminosalicylates ...... 8 1.5.2. Corticosteroids ...... 9 1.5.3. Immunomodulators ...... 10 1.5.4. Antibiotics ...... 12 1.5.5. Biologicals ...... 12 1.6. Surgery ...... 12 1.7. Treatment pathway ...... 13 1.8. Remission ...... 14 1.8.1. Harvey-Bradshaw Index ...... 14 1.8.2. Faecal calprotectin ...... 15

2. Biological Therapy ...... 17

III

2.1. Monoclonal Antibodies ...... 18 2.2. TNFα- Inhibitors ...... 18 2.2.1. Antidrug- antibodies ...... 20 2.2.2. Infliximab ...... 20 2.2.3. Adalimumab ...... 21 2.3. Vedolizumab ...... 22 2.4. Biosimilars ...... 23

3. Research Question, Aim and Objectives ...... 25 3.1. Research Question ...... 25 3.2. Aim ...... 25 3.3. Objectives ...... 25

4. Methods ...... 26 4.1. Literature Review ...... 26 4.2. Research Methods ...... 26 4.2.1. Inclusion Criteria ...... 26 4.2.2. Exclusion Criteria ...... 27 4.2.3. Ethical consideration ...... 27 4.2.4. Sample Size ...... 27 4.3. Data Analysis ...... 27 4.3.1. Infliximab ...... 27 4.3.2. Adalimumab ...... 29 4.3.3. Vedolizumab ...... 30 4.3.4. Reason for switching treatment ...... 30 4.3.5. Investigations of duration and response ...... 31

5. Results ...... 33 5.1. Study Settings ...... 33 5.2. Infliximab ...... 33 5.2.1. Stopped Treatment ...... 34 5.2.2. Maintenance ...... 35 5.2.3. Switched biological ...... 36 5.3. Adalimumab ...... 36 5.3.1. Stopped treatment ...... 37 IV

5.3.2. Maintenance ...... 38 5.3.3. Switched biological ...... 39 5.4. Vedolizumab third-line treatment ...... 39 5.4.1. Stopped treatment ...... 40 5.4.2. Maintenance ...... 41 5.5. Vedolizumab second-line treatment ...... 42 5.5.1. Reason for switching ...... 43 5.5.2. Stopped treatment ...... 43 5.5.3. Maintenance ...... 44

6. Discussion ...... 45 6.1. Response rates ...... 45 6.2. Treatment duration ...... 47 6.3. Comparison with Literature ...... 48 6.4. Limitations ...... 50 6.5. Ongoing Work ...... 52 6.6. Future Work ...... 52 6.7. Recommendations ...... 53

7. Conclusion ...... 55

References ...... 56

List of Abbreviations ...... 66

List of Figures ...... 68

List of Tables ...... 68

Appendix ...... 70 A. HBI Score ...... 70 B. Patients total ...... 71 C. Reason for Switching ...... 81

V

Abstract

Introduction The number of patients suffering from Crohn’s Disease und Ulcerative Colitis is increasing in the last decades. Inflammatory Bowel Diseases (IBD) is used as the umbrella term for these diseases. Patients with severe IBD are treated with monoclonal antibodies, so-called biologicals. The biologicals infliximab, adalimumab and vedolizumab are some examples, which are on the market at the moment. Due to the improvements in therapies and the expiring patents, the interest according IBD treatment with biological drugs is increasing constantly.

Methods 232 patients who started biological therapy on infliximab, were investigated for this retrospective study. Data between 2005 and September 2017 were observed. The treatment duration and the state of health of the patients were investigated. Some patients had to switch to another biological drug, like adalimumab or vedolizumab. The reason for switching, as well as the state of health and the duration of treatment has been classified.

Results The biologicals infliximab and adalimumab show, as expected, the similar duration of treatment and remission rate. Whereas, vedolizumab shows different rates in remission according to second-line and third-line treatment.

Conclusion This study provides valuable information for possible future, prospective studies regarding IBD patients on biological therapy. Furthermore, recommendations were formulated.

VI

Kurzfassung

Einleitung In den letzten Jahrzehnten stieg die Anzahl der Erkrankten an Morbus Crohn und Colitis Ulcerosa, welche unter dem Sammelbegriff „entzündliche Darmerkrankungen“ geführt werden. Seit einigen Jahren werden schwere Fälle dieser Krankheiten mit monoklonalen Antikörpern, auch „Biologicals“ genannt, behandelt. Infliximab, Adalimumab und Vedolizumab sind einige der derzeit im Handel befindlichen monoklonalen Antikörper. Da sich diese Therapiemöglichkeiten fortwährend weiter entwickeln und schrittweise die Patente dieser Medikamente auslaufen oder schon ausgelaufen sind, wird diese Art der Therapie für entzündliche Darmerkrankungen immer bedeutender.

Methode Für diese retrospektive Studie wurden die Daten von insgesamt 232 PatientInnen im Zeitraum von 2005 bis September 2017 untersucht, welche ihre Therapie mit dem monoklonalen Antikörper Infliximab begonnen haben. Die Dauer der Behandlung und der Gesundheitszustand wurden erforscht. Einige PatientInnen mussten im Verlauf der Behandlung zu einem anderen monoklonalen Antikörper, Adalimumab oder Vedolizumab, wechseln. Hier wurden ebenfalls die Dauer der Therapie und der Gesundheitszustand ermittelt. Weiters wurde der Grund für den Wechsel des „Biologicals“ klassifiziert.

Ergebnisse Die Biologicals Infliximab und Adalimumab zeigen, wie erwartet, ähnliche Behandlungsdauer und Remissionsrate. Wo hingegen Vedolizumab starke Unterschiede in der Remissionsrate bei second-line und third-line Therapie aufwies.

Schlussfolgerung Diese Studie liefert wertvolle Informationen und Empfehlungen für zukünftige, prospektive Studien über PatientInnen mit entzündlichen Darmerkrankungen und der Behandlung mit Biologicals.

VII

1. Introduction

In the last decades, there a several diseases which are increasing due to the westernisation of the world. One of them are the so-called Inflammatory Bowel Diseases (IBD). There are two main different types of IBD, Ulcerative Colitis (UC) and Crohn’s Disease (CD). Both affect the gut by inflammation. The course of these diseases is classified by remission and relapse over many years and remain largely incurable. The difference of these two sorts of IBDs is related to their variety of inflammation. UC affects the large bowel and the mucosa, whereas CD concern the whole gut, including serosal surface. Although UC and CD are two different kind of diseases, the treatment is often very similar. [1]

This thesis gives an overview of both diseases, which are classified as IBD, and their different kind of treatment, including biological therapy. The ground breaking change in IBD treatment happened many years ago as the first biological, infliximab, was approved for the European market. The biologicals, which are used for IBD treatments, are monoclonal antibodies. Because of the product placement of the biosimilar from the biological infliximab, a cost-saving alternative to the original drug was available for treatment. Due to the fact that a biological has a very complex structure and is made out of biological sources, its replica, the so-called biosimilar, can never be identical to it. This is the reason that a biosimilar is not allowed be dedicated as a generic drug.

The retrospective study of this thesis aims to provide an insight into IBD treatment with the biological drugs infliximab, adalimumab and vedolizumab. Drug of the choice is still infliximab, because it is faster acting than adalimumab or vedolizumab and foremost, it still shows the best rate of response. However, some patients are suffering from treatment failure and therefore they have to change the biological medicine.

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1.1. Aetiology of IBD

IBDs can arise in children and adults, but the cause remains still unknown. But there is showing more and more evidence that UC and CD are related to an immune-mediated tissue damage like in other chronic inflammatory diseases. The tissue damage can be caused by genetic factors of weakness and environmental triggers or modifiers. An interaction because of the genetic polymorphism of proteins, with the microbial environment in the bowel, can also be a reason for IBDs. Molecular analysis shows a possibility of the correlation between abnormal or altered microbial composition in the gut and the occurrence of CD and UC. [2]

1.2. Epidemiology of IBD

“The incidence and prevalence of CD and UC is increasing in Europe. Estimated 0.3% of the European population suffers from IBD equalling 2.5–3 million persons.” [3]

As mentioned, the westernisation is one of the reasons the number of IBD patients is increasing. Westernisation is defined by high-income and is related to countries with western cultural heritage. This leads to the statement, that UC and CD are more common in western countries (Western Europe, North America, Australia, New Zealand) than in developing countries like Africa, Asia or South America. But the number of affected people is increasing in this developing countries either, because of the increasing influence of the Western World. [4] Studies show that migrants who are coming from low- to high-prevalence countries (western countries) are more likely to get involved with IBD while their immune system is still developing. That means, the impact is greater on younger people with migrational background. This is maybe caused due to vaccinations, treatments with antibiotics, commensal microbiota or exposure to enteric parameters. [5]

Due to these facts, Jewish and people from asian origin living in the United States of America and the United Kingdom are more often affected by IBD than those still living in their country of ethical origin. Beside the ethical background, UC and CD are more likely to occur in women compared to men. The main age to be affected is between 20-40 and 60-

2

80 years. One fact which also plays an important role related to IBDs, especially to CD is smoking. CD is much more negatively influenced by smoking than UC. Whereas country of origin, gender and lifestyle could be causing facts of this diseases, the social class plays no role in developing IBDs. [5]

1.3. Crohn’s Disease

CD was first described by the gastroenterologist Burrill Bernard Crohn and his colleagues Leon Ginzburg and Gordon Oppenheimer in the year 1932. [6] It is a chronic inflammation of the gastrointestinal tract. It can affect any part of the digestive system, from the mouth to the anus, but in particular the terminal ileum of the small intestine. The inflamed bowel wall is characterised by granulomas and fissuring ulcerations, which can lead to fibrosis, structuring and fistulas. The submucosal layer, which is affected the most, appears with oedema, fissures and gaps in its surface. This leads to fibrotic changes in the tissue of the submucosa related to its flexibility. The submucosa of the bowel gets inflexible and thicker as in common appearance. The course of disease can lead to several different complications and can affect the symptoms and the severity of disease. [7][8][9]

1.3.1. Symptoms

The main symptoms of CD are

- recurrent diarrhoea - colicky pain - weight loss - anorexia - fluid and electrolyte disorder - pyrexia - nausea - vomiting [7][8][9]

3

The diarrhoea in CD is not as bloody as in UC, because CD mainly affects the submucosal layer of the tissue and less the mucosal surface. Increasing severity of diarrhoea can increase the appearance of ulceration of the perianal skin. Depending on the severity of the disease, there may be formations of abscesses in the abdomen, fistulas and intestinal obstructions. The fistulas can penetrate different parts of the bowel, but also the bladder, vagina, urethra and the skin. Fistulas also appear in the ileum, so-called perianal fistulas. This tube-like passage can also cause diarrhoea because of malabsorption, bacterial overgrowth and abscess formation because of infection. Further complications can be, as mentioned above, secondary intestine inflammations plus Short Bowel Syndrome and Amyloidosis. Patients diseased by CD also have a higher risk of suffering from colon cancer. [7][8][9]

1.3.2. Classification

CD is classified by three different parameters. First of all, by the Montréal Classification (listed under 1.4.2.), related to appearance of the disease, and disease activity as well as respond rate to treatment. [10]

1.3.3. Diagnosis

The above-mentioned symptoms are one of the factors which are used to diagnose CD. Further additives are endoscopy and radiologic examination. [9]

“ECCO statement 3 For a reliable diagnosis of CD a minimum of two biopsies from five sites around the colon (including the rectum) as well as from the ileum should be obtained [EL5]” [10]

Making a biopsy is important to find more evidence for CD, like the above-quoted granulomas. Biopsy can also show focal crypt architectural abnormalities and different kinds of chronic inflammation. [10]

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1.4. Ulcerative Colitis

UC is, like CD, a chronic inflammation of the bowel, but it affects only the mucosa, from the colon and the rectum. This relapsing disease was first described in the year 1909, but it is still incurable and the up-to-date treatment is just palliative. [11]

1.4.1. Symptoms

The main symptom of UC is bloody diarrhoea with mucus. This is caused by the inflammation which affects the mucosal layer of the colon and rectum. Beside diarrhoea the patient may suffer on further symptoms like

- abdominal cramping - faecal incontinence - nocturnal incontinence, especially by severe daytime symptoms - weakness - anorexia - fatigability.[12]

1.4.2. Classification

According to the European Crohn’s and Colitis Organisation (ECCO) Guideline there are three different types of UC, as shown in Table 1, conferring to the location of the inflammation.

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Table 1. Types of Ulcerative Colitis [13]

Term Distribution Description E1 Proctitis Involvement limited to the rectum [i.e. proximal extent of inflammation is distal to the recto-sigmoid junction] E2 Left-sided Involvement limited to the proportion of the colon distal to the splenic flexure [analogous to ‘distal’ colitis] E3 Extensive Involvement extends proximal to the splenic flexure, including pan-colitis

There are no gaps between the inflamed areas, it is constant and leads to lesions in the mucosa layer. Furthermore, mucosal haemorrhages can be developed with on following abscesses and the possibility to arise polyps. The affected tissue may become ulcerative and necrotic and with every flare the bowel wall will get thicker, and as by CD, will lose its flexibility. The flare of symptoms can last for only some days, but also for weeks or months. Whereas the timeframe of remission can be between months and decades. [12]

Furthermore, the ECCO Guidelines are listing the classification of disease activity, which are shown in table 2.

Table 2. Classification Disease Activity [13]

Mild Moderate Severe ‘in between mild and severe’ Bloody stools/ day < 4 4 or more if ≥ 6 and

Pulse < 90 bpm ≤ 90 bpm > 90 bpm or

Temperature < 37.5 °C ≤ 37.5 °C > 37.8°C

Haemoglobin > 11.5 g/dl ≥ 10.5 g/dl < 10.5 g/dl or

ESR < 20 mm/h ≤ 30 mm/h > 30 mm/h or

CRP Normal ≤ 30 mg/l > 30 mg/l

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A second classification of disease activity for UC, which is listed in the ECCO Guidelines, is the Montreal Classification and is shown in table 3.

Table 3. Montreal Classification [13]

S0 S1 S2 S3 Remission Mild Moderate Severe Stools/ day Asymptomatic ≤ 4 > 4 ≥ 6 and

Blood May be Present Present present Pulse All normal Minimal or no signs > 90 bpm or of systemic toxicity Temperature > 37.5°C or

Haemoglobin < 10.5 g/dl or

ESR > 30 mm/h

1.4.3. Diagnosis

“ECCO statement 3E A ‘gold standard’ for diagnosis of ulcerative colitis does not exist. It is established by clinical, laboratory, imaging, and endoscopic parameters, including histopathology. An infective cause should be excluded. Repeat endoscopy with histopathological review after an interval may be necessary if diagnostic doubt remains [EL5]” [13]

To diagnose UC, mainly the above-mentioned symptoms, and the classification because of the examined parameters are utilise.

1.5. Drug Therapy

The aim of medical treatment is the induction and maintenance of remission. This is important for the quality of life of every patient because IBDs are incurable.

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1.5.1. Aminosalicylates

5-Aminosalicylates, 5-ASA, are used for treating mild to moderate severe UC and mild to moderate severe CD. The first drug which contains 5-ASA was sulfasalazine (SPS). It is a prodrug. 5-ASA is linked by an azo bond to sulfapyridine. 5-ASA is released by bacterial action in the colon, as shown in figure 1. [15][16]

Figure 1. 5-ASA Release in the Colon; (i) Sulfasalazine, (ii) 5-ASA, (iii) Sulfapyridine [14]

There are now newer 5-ASA formulations, like mesalamine, which have a pH-depending release and are more gut specific. These formulations no longer contain sulfonamide. This and the fact that they are more gut specific explain the reduction of adverse effects. But also mesalamine may cause side effects like rush, headache, nausea, diarrhoea. The exact mode of action of mesalamine is still unknown. It may interrupt the mechanism of lipoxygenase and cyclooxygenase pathway. There is also the possibility that it increases the production of interleukin 1 (IL-1), interleukin 2 (IL-2) and the tumour necrosis factor (TNF) in the colonic mucosa. Mesalamine may also activates many different downstream effects and reduce the transcriptional activity of nuclear factor kappa B (NF-κB). These facts may explain the anti-inflammatory effect of mesalamine and its efficacy in IBD. Aminosacylates are able to induce and maintain remission in UC, whereas in CD there is no evidence for maintenance remission regarding these drugs. [15][16]

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1.5.2. Corticosteroids

Corticosteroids should only be used by flare of symptoms and only for a defined duration, usually not longer than 12 weeks. The aim treating with steroids should be well defined. These drugs were used for both, UC and CD, but only for patients with active disease, because they are not able to induce mucosal healing. Irrespective of the underlying pathogenesis, corticosteroids can be used on a wide range of inflammatory diseases because of their strong anti-inflammatory effects. The most common dosage forms of steroids are oral by tablet, like prednisolone or budesonide, or intravenous, like hydrocortisone or methylprednisolone. [17][18][19]

Table 4. Corticosteroids- Mechanism of Action [20]

Mechanisms of action Leukocytes Reduced migration, activation, survival Reduced activation of NF-κB

Phospholipase A2 inhibitor Reduce induction of COX-2 and inducible NOS Reduced production of cytokines and lipid mediators Increased kinin degradation Endothelial cells Reduce expression of adhesion molecules Reduced capillary permeability

The mechanisms in table 4 are related to the bindings of the corticosteroids with the intracellular glucocorticoid receptors.

The main problems of steroids are the occurring adverse effects. General side effects are cushingoid face, weight gain and dysphoria. Negative effects of the drug can also occur to the human metabolic process, be cardiovascular, affect the skin and the eyes. There is also an increased risk of suffering from osteoporosis and growth retardation in children. Due to these facts, there should be no long-term treatment with corticosteroids, like above- mentioned. [17][18][19]

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Stopping medical treatment with this kind of drugs should not happen suddenly. The dosage should be decreased step-by-step to avoid a flare-up of symptoms. Furthermore, steroids are very important hormones and by adding extra corticosteroids, the body reduces the own production. A sudden withdrawal leads to a lack of these, hence life- threatening symptoms may occur. [17][18][19]

1.5.3. Immunomodulators

There are three different types of immunomodulatory drugs: thiopurine, cyclosporine and methotrexate. [21] All immunomodulators, also called immunosuppressants, are considered for long-term treatment and are slow acting. Slow acting means, it can take several weeks to months until the drug develops its full value. Some patients have to take immunomodulators a life time. [22]

1.5.3.1. Thiopurines

The aim of these drugs is to induce and maintenance steroid-free remission in IBD patients, but are also used as combination therapy with corticosteroids. Azathioprine is a prodrug und needs to be converted in 6-mercaptopurine. Both, azathioprine (AZA) and 6- mercaptopurine (6-MP) are used as drugs. 6-MP undergoes enzymatic conversion, which consists of three enzymatic pathways like the thiopurine methyltransferase (TPMT), to release the active metabolites 6-thioguanine nucleotide (6-TGN) and 6- methylmercaptopurine (6-MMP). [21][23] 6-TGN is considered to be the metabolite with therapeutically impact, whereas 6-MMP is related to hepatoxicity and myelotoxicity. Between 30-50% of all patients have to discontinue their thiopurine therapy because of side effects and lack of efficacy. [24] Due to this two problems, the so-called therapeutic drug monitoring is very important. By measuring 6-TGN and 6-MMP it is possible to make a statement about non-respondent or adverse effects. Side effects can be nausea, vomiting, headache, arthralgia, fever, rash and abdominal pain. [21][23] The immunosuppressive effect of 6-TGN may be related to its similarity to purine guanine. Because of this similarity it bounds in the leukocytes’ DNA, inhibits the DNA synthesis and

10 blocks the downstream process of the T-cell proliferation. The entire course of effectiveness is not developed yet, but there is also the possibility that thiopurines are able to inhibit genes which cause immune- and inflammation reactions. [24]

1.5.3.2. Cyclosporine

Cyclosporine is used in severe active UC and is also known as a powerful immunosuppressant. It is not often used in CD because it requires quite a high dosage and other additive treatments, for example TNF inhibitors. Cyclosporine blocks the activation of T-cells by inhibiting interleukin-2 (IL-2) transcription, thus function and proliferation of T-cells are inhibited. Cyclosporine increases the risk of infections, it can cause hypertension, kidney damages and hepatoxicity. Due to the low dosage used in IBD treatment, the risk of serious adverse effects is very low. [25][26][27]

1.5.3.3. Methotrexate

Methotrexate, also an immunosuppressive drug, is used as monotherapy and in combination with biologicals. It can be used either for induction or maintenance steroid- free remission in patients with IBD. In combination therapy with biologicals, more precisely with anti-TNF agents, the same result like treatment with AZA/6-MP can be expected. The rate of immunogenicity is decreased and the trough level of the biological is increased. [28][29][30] Secondary actions of this drug include nausea, vomiting, fatigue, diarrhoea, leukopenia, liver fibrosis, hypersensitivity pneumonitis, and teratogenicity. These side effects occur due to the fact that methotrexate inhibits the enzyme of the folic acid metabolism. To reduce the likeliness of adverse effects, oral folic acid should be given. The drug also stimulates anti-inflammation and immunomodulatory effects by inhibiting further folate-dependent enzymes. [28][29][30] In higher dose, methotrexate inhibits RNA, DNA and protein syntheses by inhibiting the dihydrofolate reductase. Methotrexate offers a high safety and is a cheap alternative to treat people with CD or UC. [28][29][30]

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1.5.4. Antibiotics

Antibiotics do not have a big impact in IBD treatment. Sometimes they are used to treat CD or are given after surgery to prevent relapse. [31]

1.5.5. Biologicals

Biologicals are an immuno-target treatment for patients with CD and UC. After introducing this kind of medicine, the treatment for IBD has entirely changed. The number of hospitalisation, surgery and steroid treatment has decreased whereas the quality of life, the number of patients with mucosal healing and clinical remission is increasing. [32]

1.6. Surgery

One of the aims of medical treatment, in particularly biological therapy, is to avoid surgery. Nevertheless, almost 80% of all CD patients have to undergo surgery, not only because of treatment failure. Another reason for surgery may be complications like stricture, abscess, fistula, haemorrhage or malignant transformation. CD cannot be cured by surgical investigations, whereas UC can.[33][34]

Patients suffering from CD as well as of UC need surgery in some stage of their course of disease. The main types of operations are

- Colectomy with/without pouch reconstruction - Right hemicolectomy - Small bowel resection - Stricturoplasty [35]

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1.7. Treatment pathway

Before treating with biological medicine, most of the patients face a long pathway of medical treatment. This kind of drug treatment is called the step-up treatment and is shown in figure 2.

The first step of medical treatment is to start the patient on 5-ASA (or sulfasalazine SPS). If there is no response, an additional treatment with corticosteroids may be required. UC patients who suffer from mild to moderate disease should be treated in this way. Patients affected by CD might also need a course of antibiotics in addition to 5-ASA and steroids. Budesonide is used as the steroid of choice. Patients who respond well to treatment with steroids should switch to an immunomodulator, for example thiopurines (AZA/6-MP) or methotrexate (MTX), as a long-term therapy with steroids is not recommended due to several adverse effects. Furthermore, patients without positive response to corticosteroids should also be treated with immunomodulators. [36][37] If neither induction nor maintenance of remission could be achieved with the previous mentioned treatment pathway, biological therapy should be considered. Biologicals can be combined with immunomodulator to achieve better response rate. [36][37]

Figure 2. Step-Up Treatment [36]

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1.8. Remission

Remission is defined by the disappearance of any kind of symptoms or signs of a disease. It can be temporary or permanent. [38] The aim of IBD treatment is steroid-free clinical remission. Remission can be interrupted by relapse. Clinical relapse in UC, for instance, is defined by recurrence of rectal bleeding, increased stool frequency and abdominal cramping. [12] All confirmed by endoscopy. Endoscopy is an inversive intervention and requires a hospital for its performance. It is essential for diagnosing and defining relapse, but it is not a preferred tool for observing maintenance therapy in CD and UC. Remission is not easy to define. There a several, non-invasive, parameters which can be used to define the state of health of the patient. The Harvey-Bradshaw Index (HBI), for example, is a subjective alternative to define remission. Whereas clinical markers, such as the faecal calprotectin (FC), are generally objective. The combination of subjective and objective values should be used to define the clinical conditions of the patient.

1.8.1. Harvey-Bradshaw Index

The Harvey-Bradshaw Index (HBI) is a simplified version of the Crohn’s Disease Activity Index. It is used to classify the activity of the disease. [39] Usually the HBI will be assessed at the hospital on the day the biological is administered. The index consists of five subgroups:

- general well-being - abdominal pain - number of liquid stools per day - abdominal mass - extraintestinal manifestations [39]

The questions regarding this five groups are related to the patient’s symptoms the weeks before assessment. [39]

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A HBI score < 5 demonstrates inactive disease (remission), whereas a score ≥ 5 shows active disease. [39] The form to investigate the HBI is shown in the Appendix. [39]

1.8.2. Faecal calprotectin

FC is a reliable biomarker for defining inflammation in the gut. It is a calcium- binding protein and consist of almost 60% of neutrophilic cytosol and is found in monocytes as well as in macrophages. The high level of calprotectin in stool, at persisting inflammation, is related to the gathering of neutrophils in the inflamed mucosa. An elevated level of FC correlates with disease activity. [40][41] The protein remains stable up to 7 days at room temperature and is resistant against enzymatic degradation, which makes it easy to measure. The patient can take a stool sample at home and submit it via post to the laboratory, where the level of calprotectin will be quantified. The intake of nonsteroidal anti-inflammatory drugs may decrease the level of expressed FC and should be avoided or reduce to minimum. This reliable biomarker is also used for monitoring gut inflammation during biological maintenance. The normal range of FC for a healthy persons is situated < 50 µg/g. [40][41] First, FC was used to distinguish between IBD and Irritable Bowel Syndrome (IBS). The difference between these two clinical pictures is, that in IBS there is rarely any elevation in the FC level and this syndrome cannot be treated with any medication. [41]

For people with IBD the level of this laboratory value may be elevated, depending on their remission/inflammation status and severity of disease. The classification of the FC levels is shown in table 5.

Table 5. FC-Level Classification [40][42]

severity of disease FC µg/g normal < 50 µg/g quiescent disease, relapse unlikely < 100 µg/g inflammation possible 100- 250 µg/g active disease > 250 µg/g

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FC level between 100- 250 µg/g is the most difficult range to interpret. There may be a relapse in the near future either there may be no active disease at all. Patients, who are considered to be in this range, have a decreased likelihood to suffer from a flare of symptoms in the next six months. But the possibility of a relapse is still increased. A result > 250 µg/g means an active disease. People above this upper limit should be reassessed by their consultants, intervention is necessary. The patient is suffering from active disease with all its consequences. [40][42]

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2. Biological Therapy

Biological medicine became more and more important in the last years. Compared to other medical treatments, biologicals can introduce and maintain mucosal healing and not just antagonize the symptoms. [32] Beside IBD, biologicals are used to treat serious and chronic diseases like diabetes, autoimmune diseases and cancer. The so-called biologicals are produced out of several biological sources, e.g. living cells or organisms. The variety of biologicals is widespread, they can be different in size and structural complexity. However, most of them are made of proteins. The protein has to be linked to an active substance of choice. Therefore highly developed cell systems and recombinant DNA technology is used. Because of the advanced manufacturing process, the European Union (EU) imposed strict requirements for this process. The biologicals which are used in IBD treatment are made out of monoclonal antibodies, but biologicals can be simpler proteins like insulin, a growth hormone, or proteins of intermediate complexity like coagulation factors. [43]

Figure 3. Examples Biological Medicines EU [43]

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2.1. Monoclonal Antibodies

Monoclonal antibodies are complex biological macromolecules, created by a monoclonal cell line. According to their complex structure, monoclonal antibodies have a wide range of size, charge variants, many different post translational modification, like a variety of glycosylation patterns. Furthermore, they have long half-lives, N and C terminal heterogeneity and may cause immunogenicity. These antibodies are immunoglobulins or fragments of it, produced by recombinant DNA technology, hybridoma technology, B- lymphocyte immortalization or other technologies such as genetically engineered animal and have a specificity for a certain target ligand. A monoclonal antibody is built of two light and two heavy polypeptide chains which are linked by di-sulphide bonds. The specificity of an antibody is related to its so-called Fab part where the binding region is located. The Fc part can interact with several receptors and may lead to immune effector functions. Because of these determining factors, every monoclonal antibody presents a unique profile. [44][45]

2.2. TNFα- Inhibitors

TNFα (tumor necrosis factor alpha) is mainly produced by monocytes, macrophages and T- lymphocytes. It is a pleiotropic cytokine which plays an important role in the response of the immune system related to inflammatory reactions. The cytokine binds to receptors on lymphoid cells and activates the so-called NF-kB, nuclear factor kappa B, by activating signalling cells. The activation of NF-kB leads to an upregulation in the expression of cytokines like interleukin-1 (IL-1) and interleukin-6 (IL-6). According to these two cytokines, inflammation and cell survival will be induced. In the gut tissue of IBD patients, NF-kB has high activity. On this ground there is an unhealthy upregulation in expression and secretion of cytokines in the inflamed bowel.[46]

TNFα influences the pathogeneses of several autoimmune inflammatory diseases, like IBD. To suppress the effect of TNFα and block the expression of inflammatory genes, TNFα- inhibitors are used. These inhibitors are monoclonal antibodies which are binding on two different types of TNFα, the transmembrane and the soluble one, to interfere the interaction between TNFα and its receptor. As a result, the receptor cannot get activated,

18 which is located on endothelial, immune and inflammatory cells. Therefore, a stimulation of inflammation, cytotoxicity and cell adhesion is not possible. By binding TNFα, the inhibitor neutralizes the proinflammatory effect of it. [47] While treatment with TNFα-inhibitors, the body may generate antibodies against this drug, so-called antidrug antibodies. This immunogenicity is a result of formation of an immune complex, which obstructs the interaction between the inhibitor and TNFα its self. This may lead to a lower serum through level in the blood, up to a subtherapeutic level. Creating antidrug antibodies may also increase the potential of side effects. [47] Reactions are the main adverse effects of anti-TNFα treatment.

Main characteristics of TNFα inhibitors infliximab and adalimumab are shown in table 6.

Table 6. Characteristics Infliximab Adalimumab [47]

infliximab adalimumab Structure monoclonal antibody monoclonal antibody Fully human no yes Ligand sTNF, mTNF sTNF, mTNF Weight (kDa) 150 150 Half-life (days) 8-10 10-14 Approved indications CD, UC, RA, PsA, AS CD, UC, RA, PsA, AS Reverse signaling high high Apoptosis high high Dosage 5 mg/kg 40 mg Administration intravenous subcutaneous Frequency (weeks) Induction 0, 2, 6; 2 maintenance 8

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2.2.1. Antidrug- antibodies

Many patients are losing response to their biological therapy after a period of time. This secondary non-response can be caused by the formation of antidrug antibodies as an immune response regarding to biological therapy. Also reactions can be caused because of the antidrug antibodies.[48]

Antidrug antibodies bind at the TNF-α inhibitors and form a complex. Due to this complex, the biological cannot bind at its target, TNF-α, and cannot develop its full therapeutic value, respectively will be neutralized. Furthermore, TNF-α remains active and increases the inflammation in the gut. Because of the complex formation of antidrug antibodies and biological, its therapeutic role is decreased and may leads to increased clearance of the drug which can lead to low serum drug level. Due to the limitation of pharmacodynamics and pharmacokinetics of the biological, the activity of IBD can be influenced and the patient may experience a flare of active disease. After developing antidrug antibodies, stopping or switching treatment should be considered. Due to the immunogenicity, as a result of the antibody formation, the patient may be treated without any benefit, or may experience, as mentioned above, several kind of reactions. [48]

2.2.2. Infliximab

Infliximab was the first TNFα- inhibitor which got licensed by regulatory agencies. It is a chimeric monoclonal antibody composed of constant human and variable murine regions. It is administered intravenously, every 8 weeks. During induction phase it is given at week 0, 2, 6, 8. [47][49] The optimal therapeutically range of drug level, to achieve the best treatment results, is situated between 3-7 μg/ml. [50] The trade name of the biological infliximab is Remicade©. There are several biosimilars, for example Remsima© and Inflectra©, which are also applied at Raigmore Hospital.

Contraindicated for infliximab are patients who experienced hypersensitivity to this drug before. Further contraindications are severe infections like sepsis, abscesses and

20 opportunistic infections or tuberculosis. Patients with moderate to severe heart failure are contraindicated as well. [51]

Very common adverse effects, defined by one or more patients out of ten, regarding to infliximab are as following:

- viral infection - headache - upper respiratory tract infection, sinusitis - abdominal pain, nausea - infusion-related reaction, pain [50][51]

2.2.3. Adalimumab

Adalimumab is a fully humanized monoclonal antibody manufactured by recombinant DNA technologies and, like infliximab, an anti-TNFα drug. It is administered fortnightly subcutaneous. [47] A serum concentration > 5 μg/mL correlates with good response to the biological adalimumab. [52] A drug level ≤ 5 μg/mL can be considered as subtherapeutic level. The patent protection for adalimumab is valid until 2018, so there is no biosimilar on the market at the moment. The trade name of the biological adalimumab is Humira©.

Adalimumab holds the same contraindications as infliximab. [53]

Very common adverse effects regarding to adalimumab are as following:

- respiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral) - leukopenia (including neutropenia and agranulocytosis), anaemia - lipids increased - headache 21

- abdominal pain, nausea and vomiting - elevated liver enzymes - rash (including exfoliative rash) - musculoskeletal pain - injection site reaction (including injection site erythema) [53]

2.3. Vedolizumab

Vedolizumab is a welcome alternative to the well-established anti-TNFα treatment in IBD. Although, drugs like infliximab and adalimumab have changed the treatment of CD and UC in a very positive way, some patients cannot benefit of them. Either they are primary non- responders, have secondary loss of response, are intolerant, or have had serious adverse effects, e.g. infusion-related or paradox immune-inflammatory reactions. [54]

Vedolizumab is a full humanized, gut-specific immunoglobulin G1 (IgG1) and inhibits the α4β7 integrin. α4β7 Integrin is an adhesion molecule, located on the surface of activated lymphocytes. This molecule binds to the mucosal addressin cell adhesion molecule 1 (MAdCAM-1), which is characteristically expressed in gut-associated lymphoid tissue. This bond leads to immigration of the activated lymphocytes from the systemic circulation and further to inflammation of the gut. The mechanism of action of vedolizumab is based on blocking the binding-side on α4β7 integrin so it cannot get connected to its target, MAdCAM-1. Because of its high gut-specificity this drug presents a much lower risk of systemic infections or reactions than other biologicals. [55] There are no vedolizumab biosimilars available yet. The trade name of the current vedolizumab drug is Entyvio©.

Hypersensitivity related to vedolizumab is listed as a contraindication for this drug. Also contraindicated are severe infections such as cytomegalovirus, listeriosis, sepsis and tuberculosis. Furthermore opportunistic infections as progressive multifocal leukoencephalopathy are listed as a contraindication. [55]

22

Very common adverse effects regarding to vedolizumab are as following:

- nasopharyngitis - headache - arthralgia [56]

2.4. Biosimilars

“A biosimilar is a biological medicine highly similar to another already approved biological medicine (the ‘reference medicine’). Biosimilars are approved according to the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicines.” [57]

A biosimilar is not allowed to be considered as a generic medicine, because of the wide range of variability in nature and the intricate manufacturing process. Therefore, an exact replication of a biological medicine is not possible due to the fact that it is produced by biological sources. The natural variability and the complex manufacturing of biological drugs do not allow an exact replication of the molecular microheterogeneity. [43]

Infliximab was the first monoclonal antibody which got licensed as a biosimilar in 2013. The launch of this biosimilar means a lot of potential economical savings for health care systems in several countries. In 2015, the Healthcare Improvement Scotland developed a national prescribing framework for biosimilar medicines, following a request of the NHS Scotland directors of pharmacy. [58]

This framework contains following prescribing principals:

- Promote safe introduction of biosimilar medicines - Promote prescriber confidence - Encourage a consistent approach across NHS Scotland - Support National Procurement

23

- Support the view of Scottish Medicines Consortium policy on biosimilar medicines - Recognise the potential savings that can be achieved within NHS Scotland by the use of biosimilar medicines [58]

The framework also contains suggestions regarding gastroenterology, therefore also IBD treatment is concerned. Each new patient of future biological therapy should be considered for induction with biosimilar medicine. Patients on biological maintenance therapy may be considered for a switch to a biosimilar too. The decision of the treatment choice should be made by the treating clinician. [58]

24

3. Research Question, Aim and Objectives

3.1. Research Question

What is the clinical outcome of IBD patients on the biological drugs infliximab, adalimumab and vedolizumab.

3.2. Aim

The aim of this retrospective study is to obtain data on how many patients needed to switch or stop their biological therapy. Furthermore, this research work aims at identifying reasons for switching or stopping the biological therapy and to survey on how long patients have been on each biological. This work also investigates on the patients’ state of health while on maintenance therapy.

3.3. Objectives

- Conduct literature research about IBD, in particular CD and UC - Carry out literature research about IBD treatment in general - Carry out literature research about biological medicine and biological treatment - Gather patient information on SCI Store at NHS Intranet - Integrate the gathered patient details in the provided data sheet - Collocate patient data according to their course of treatment - Determine objective criteria to measure the clinical outcome - Classify the reason for switching therapy - Define each reason for switching - Analyse the collected data by the defined conditions - Carry out a final meeting to discuss the results with the involved pharmacist and gastroenterologist - Formulate recommendations for potential future work

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4. Methods

4.1. Literature Review

The databases EMBASE, MEDLINE, Google Scholar and PubMed were used to carry out a literature review. Manual literature research was conducted at the Highland Health Science Library in Inverness. Also the homepages of the European Crohn’s and Colitis Organisation (ECCO), the European Medicine Agency (EMA), and the World Health Organization (WHO) and electronic Medicines Compendium (eMC) were reviewed.

4.2. Research Methods

All relevant papers and articles, which were found in the above-mentioned databases were searched through by hand. Every patient letter, of patients on biological therapy, which was found on Scottish Care Information (SCI) Store at the NHS Intranet, concerning IBD treatment, was reviewed carefully by hand. The sensitivity of the correspondences was always guaranteed. All relevant information about the biological course of treatment were registered in an Excel sheet. The new gathered data were compared to the provided data sheet and equilibrated.

4.2.1. Inclusion Criteria

- People suffering from IBD, in particular Crohn’s Disease and Ulcerative Colitis - Male and female - Patients who started their biological therapy on infliximab and were anti-TNFα Naïve - Patients switched from infliximab to adalimumab and further on to vedolizumab - Patients switched from infliximab to vedolizumab - Patients of all age (children and adults)

26

4.2.2. Exclusion Criteria

- People who were not anti-TNFα Naïve before starting with infliximab - Patients switched from infliximab to golimumab - Patients switched from adalimumab to golimumab - Patients switched from adalimumab to ustekinumab - Patients who started their first biological treatment with vedolizumab

4.2.3. Ethical consideration

This study is a retrospective study and the patients data, which were used in the analysis, were exclusively based on hospital records of Raigmore Hospital, Inverness. No formal approval of the Ethics committee was needed.

4.2.4. Sample Size

The sample size was limited by the number of IBD patients, treated with biologicals at Raigmore Hospital, Inverness and the above-listed inclusion and exclusion criteria.

4.3. Data Analysis

All gathered data were enlisted in an Excel sheet and compared to the provided data collection. The patients data were sorted by the course of treatment. First, every patient who has ever been or still is on infliximab treatment was listed in a sheet. The main criteria for this project is that the first biological therapy for IBD is infliximab. After establishing the list of every infliximab patient who was anti-TNFα Naïve and started the treatment after 2005, the data sheet was divided in subgroups.

4.3.1. Infliximab

First subgroup involves all patient who had stopped their infliximab treatment and received no further biological therapy. The reason for stopping the therapy was investigated.

27

The second group is related to patients who are still on infliximab maintenance therapy and their up-to-date clinical conditions. To define the up-to-date condition of the patients on maintenance therapy the HBI, as subjective value, and the FC level, as an objective value, were used.

The third subgroup includes all patient who had to switch from infliximab to adalimumab as further biological therapy because of well-defined reasons. Those reasons were defined by the consultant and as a result of this project divided in four different classes.

Moreover, as the fourth subgroup, the quantity of patients who switched from infliximab to vedolizumab were specified. The same parameters to identify clinical outcome, as at the other subgroups, were used to determine reasons for switching treatment and clinical outcome.

The four different motives for switching biological therapy were defined during data analysis due to the resulting evidence of this research work:

- primary non-responder - secondary non- responder - reaction - clinical decision

Patients with a low level of both, FC (< 100 µg/g) and HBI Score (<5) were defined as in remission. Patients on infliximab maintenance with an intermediate level of FC and a HBI Score under 5 were defined to respond to treatment. Patients with intermediate level of FC (100 µg/g >FC< 250 µg/g) and high HBI Score (>5) were defined as patients with an active disease. Patients with a low HBI Score (<5) but an increased FC level (>250µg/g) were defined as patients with an active disease/ relapse/flare. Patients with an HBI Score over 5 and a low FC level (< 100 µg/g) were defined to respond to treatment. 28

The above-listed definition of the disease activity is shown in table 7. For patients with no FC or HBI Score data, the intermediate level of these values was used.

Table 7. Definition Disease Activity FC [µg/g] HBI Score remission < 100 < 5 respond 100- 250 < 5 < 100 > 5 active disease 100- 250 > 5 > 250 < 5

4.3.2. Adalimumab

The adalimumab subgroup was divided in further subsections, following the same categories as infliximab:

- stopped adalimumab treatment without on-following biological therapy - still on adalimumab (maintenance therapy) - switched from adalimumab to vedolizumab

As above-mentioned, also the reason for stopping, current state of health on maintenance therapy and motive of switching were surveyed. For defining the clinical state-of health of adalimumab patients in maintenance therapy, only the FC level can be used. Because of the self-administration of adalimumab, which is done at home, the HBI Score cannot be investigated. For patients with no FC level, the average level of all patients on adalimumab maintenance was used.

29

4.3.3. Vedolizumab

The remaining patients, who switched to vedolizumab were split in two remaining groups:

- still on vedolizumab (maintenance therapy) - stopped treatment

These two groups were determined on the same conditions as the afore said categories, the clinical condition of the patients and the reason for stopping. After stopping vedolizumab, no further investigation in relation to the patient’s treatment was made. To define remission in patients on vedolizumab maintenance therapy, same frame conditions as by defining remission in infliximab patients were used. For patients with the latest FC level investigated before starting the biological vedolizumab, only the HBI score was utilised for defining remission/ response.

4.3.4. Reason for switching treatment

There are several reasons for switching the biological, which were defined by a consultant at the time of switching. The categorisation into four groups was conducted within the scope of this research work by the research student.

4.3.4.1. Primary non-responder

The primary non-responder is a patient, whom state of health is not improving after finishing the induction phase on biological therapy and starting maintenance treatment.

4.3.4.2. Secondary non- responder

A secondary non-responder is defined as a patient, whom response to a biological therapy is decreasing after a certain time of treatment. The so-called loss of response may be caused by subtherapeutic drug level and/or developing antibodies to the biological, which is a monoclonal antibody in this case. In addition, increased drug clearance or other factors which reduce the level of circulating drug, can be a reason for triggering subtherapeutic drug level. [52][59] 30

4.3.4.3. Reaction

The category “reaction” is used as an umbrella term for all kind of reactions which can be a result of biological treatment. E.g. rash, psoriasis, all kind of anaphylaxis, delayed infusion-reactions.

4.3.4.4 Clinical decision

The term clinical decision is utilised when the reason of switching therapy was not well- defined or not possible to find out.

4.3.5. Investigations of duration and response

The duration of every biological therapy was elicited in months and an average of it was calculated. If the duration of treatment was not available, because of some issues, the average duration was used for these patients. The issues were:

- no exact start date of the treatment was known - no exact stop date of the treatment was known

The number of patients with CD and UC were defined, as well as the total number of patients on each biological.

The rate of response on every biological medicine, i.e. infliximab, adalimumab and vedolizumab, by ascertaining the percentage of patients on remission of each biological was defined. Therefore, each patient on remission was compared to the total of patients on the related biological medicine. Remission was defined by FC and the HBI Score, no matter the treatment was stopped because of the state of health or the patient is still on maintenance therapy. For patients, where no FC level or HBI Score was available, the average of all patients in the same category was used.

31

Infliximab was used as Remicade©, Remsima© and Inflectra©. No difference was made whatever biological or biosimilar was used. This decision was made regarding to the definition of the European Union concerning biosimilars (see chapter 2.4. Biosimilars)

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5. Results

5.1. Study Settings

To conduct this retrospective study, 232 patients (125 male, 107 female) who started infliximab treatment and were anti-TNFα Naïve, were surveyed. The patients started their treatment between 2005, no precise date available, and September 2017. The examination of the patient data took place at the Raigmore Hospital in Inverness, Scotland, between September and November 2017. Of the 232 patients, 75 suffered on Ulcerative Colitis, whereas 155 were affected by Crohn’s Disease. Furthermore, there was one patient with inflammatory bowel disease- unclassified (IBD-U) and one with Pouchitis, which were classified as others. The percentage distribution male/female is 53,9%/46,1% and UC/CD/Others is 32,3%/66,8%/0,9%. The numbers and percentages of infliximab patients are shown in table 8.

Table 8. Infliximab Patients Total

Disease Patients n % CD 155 66,8 UC 75 32,3 others 2 0,9

5.2. Infliximab

The infliximab patients were divided in different groups:

- stopped infliximab - maintenance - switched to adalimumab, vedolizumab

The distribution of the patients in each group is shown in figure 4.

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Figure 4. Infliximab Patients

5.2.1. Stopped Treatment

Of 232 patients 37 patients stopped their infliximab treatment ( n=11 UC/n=26 CD- n=20 male/n=17 female). Two stopped because of remission, 12 as a result of subtherapeutic drug level. 21 patients stopped infliximab treatment due to subtherapeutic level and development of antibodies. The two remaining patients, classified as others, stopped because of brain inflammation and no response. The percentage distribution is shown in figure 5. All 37 ex-biological patients did not receive further biological treatment.

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Figure 5. Reason for Stopping Infliximab Treatment (%)

Stopping treatment in the groups subtherapeutic level and antibodies was carried out due to remission.

5.2.2. Maintenance

90 patients are still on infliximab therapy, the so-called maintenance treatment. 31 of the 90 patients have UC whereas 58 have CD. The proportion between male and female is 64,4% and 35,6% (male n=58/female n=32). 44 were defined to be in remission, 12 responding to treatment and 34 are still suffering from active disease. The percentage distribution is shown in figure 6.

Figure 6. Infliximab Maintenance (%)

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5.2.3. Switched biological

From the 232 patients on infliximab therapy, 78 switched to adalimumab. 25 switched to vedolizumab, the so-called second-line therapy of vedolizumab. Two patients had to be excluded from on following investigation because their follow-up treatment was neither adalimumab nor vedolizumab, but golimumab.

The reasons and percentage of patients switching from infliximab were as subsequently listed: primary non responder (n=14), secondary non responder (n=28), reaction (n=20) and clinical decision (n=16). The percentage distribution is shown in figure 7.

Figure 7. Reason for Switching from Infliximab to Adalimumab (%)

5.3. Adalimumab

The adalimumab patients were also divided in different groups:

- stopped adalimumab - maintenance - switched to vedolizumab

The distribution of the patients in each group is shown in figure 8 .

36

Figure 8. Adalimumab Patients

78 of all 232 infliximab patients switched from infliximab to adalimumab. 28 (36%) patients are men, 50 women (64,1%). 14 UC patients and 63 who are affected by CD. 1 was defined as others. Two patients had to be excluded from on following investigation because their follow up treatment was either ustekinumab or golimumab.

5.3.1. Stopped treatment

10 stopped biological therapy on adalimumab and received no further biological treatment. One patient stopped therapy due to remission. The others 9 stopped for various reasons. Three of this nine stopped after the experience of reactions, six due to clinical decision. The percentage distribution is shown in figure 9. 37

Figure 9. Reason for Stopping Infliximab Treatment (%)

5.3.2. Maintenance

39 patients are on maintenance therapy. 14 of the 39 patients on adalimumab maintenance are in remission regarding their FC level (FC < 100 µg/g). 9 responding to treatment without being in remission and 16 are having an active disease. The percentages are shown in figure 10.

Figure 10. Maintenance Adalimumab (%)

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5.3.3. Switched biological

27 (35%) of all patients who switched to adalimumab were switched to vedolizumab (UC 18,5%; CD 77,8%; other 3,7%).

8 were primary non-responder, 5 were secondary non-responder, 4 had any kind of reactions and 10 switched due to clinical decision, as shown in figure 11.

Figure 11. Reason for Switching from Adalimumab to Vedolizumab (%)

5.4. Vedolizumab third-line treatment

The third-line vedolizumab patients were divided in different groups:

- stopped vedolizumab - maintenance

The distribution of the patients in each group is shown in figure 12.

39

Figure 12. Vedolizumab Third-Line Patients

27 (34,6%) of the 78 adalimumab patients had to switch to vedolizumab. 9 (33,3%) patients were male, 18 (66,7%) female.

5.4.1. Stopped treatment

6 (22,2%) patients stopped the treatment with vedolizumab. These six patients suffer from CD, one is male and five are female.

One stopped because of a primary non-response, five due to clinical decision. One of the patients who stopped because of clinical decision will restart biological therapy on vedolizumab. The percentages are shown in figure 13. 40

Figure 13. Reason for Stopping Treatment on Third-Line Vedolizumab (%)

5.4.2. Maintenance

21 of vedolizumab patients are still on this therapy. 5 (23,8%) UC, 16 (71,4%) CD and one (4,8%) other. The proportion male/female is 8 (38,1%) male, 13 (61,9%) female.

12 of the 21 patients on maintenance are in remission, whereas 4 suffer from active disease. Four patients are responding to treatment with vedolizumab and one patient has not started the therapy yet. Percentages of the patients distribution are shown in figure 14.

Figure 14. Maintenance Third-Line Vedolizumab (%)

41

5.5. Vedolizumab second-line treatment

25 patients of all 232 infliximab patients switched directly to vedolizumab, so-called second-line therapy. This concerned 68% UC and 32% CD patients. These 10,8% were never treated with adalimumab.

The second-line vedolizumab patients were divided in different groups:

- stopped vedolizumab - maintenance

The distribution of the patients in each group is shown in figure 15.

Figure 15. Vedolizumab Second-Line Patients

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5.5.1. Reason for switching

5 patients were primary non-responder to infliximab, 9 were secondary non responder, 1 had a reaction and 10 switched due to clinical decision from infliximab to vedolizumab. The percentages are shown in figure

Figure 16. Reason for Switching from Infliximab to Vedolizumab (%)

5.5.2. Stopped treatment

27 have stopped treatment. One because of primary non-response, one because of secondary non-response and 5 due to clinical decision, as shown in figure 17.

Figure 17. Reason for Stopping Treatment on Second-Line Vedolizumab (%)

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5.5.3. Maintenance

18 (72%) are still on this biological medicine. 9 patients are in remission, 7 suffer from an active disease or a flare. One patient responds to vedolizumab and one patient has just started the treatment and no data are available. The percentage distribution is shown in figure 18.

Figure 18. Maintenance Second-Line Vedolizumab (%)

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6. Discussion

6.1. Response rates

All 232 patients of this retrospective investigation were TNF-α Naïve before they started biological therapy with infliximab. A major part of patients, about 40%, either stopped infliximab or on maintenance therapy, are in remission or respond to the biological drug infliximab.

78 patients of all 232, switched from infliximab to adalimumab because of well-defined reasons, which are listed in the section “4.3.4. Reason for switching treatment”

31% of all adalimumab patients, on maintenance therapy or stopped, respond to the biological or are in remission.

27 of the 78 adalimumab patients moved forward to vedolizumab. The reasons for switching were investigated, as above-mentioned.

60% of all vedolizumab patients, who were all treated with infliximab and adalimumab in the first place, respond to the treatment or are in remission.

25 patients of all 232 infliximab patients switched directly to vedolizumab, the so-called second-line therapy. 40% of all the 25 patients, who never received adalimumab, respond to this biological drug or are in remission.

The number of patients on each treatment is shown in table 9.

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Table 9. Biological Patients Total

Infliximab Adalimumab Vedolizumab Infliximab- Vedolizumab Total 232 78 27 25 Stopped 37 10 6 7 Maintenance 90 39 21 18 Switched 78 27 - - Exclude 2 2 - - Switched to 25 vedolizumab

The above mentioned percentage distribution of response and remission rate is shown in figure 19 below.

Figure 19. Response/ Remission Rate of all Patients (%)

The variation in response rate according vedolizumab third- and second-line therapy was surprising and need further investigation in the future. No explanation was found in the final meeting with the involved pharmacist and gastroenterologist.

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6.2. Treatment duration

All patients who stopped infliximab, were treated around 30 months (median= 30 months) before this drug was stopped and receiving no further biological treatment. Before switching to adalimumab or vedolizumab, the patients were 16 months (median= 16 months) on infliximab maintenance therapy.

Adalimumab patients received this drug 16 months (median= 16 months) before they had to stop. The average duration of adalimumab treatment before patients switched to vedolizumab was 17 months (median= 17 months).

Before vedolizumab therapy was stopped, second-line as well as third-line, patients were treated with this biological about 6,5 months (median= 5 months). At the endpoint of this study, with November 2017, the average duration of vedolizumab maintenance therapy was 15 months (median= 12months).

Figure 20. Median Duration of Biological Therapy in Months

Infliximab and adalimumab show pretty similar results according to the length of treatment before therapy was stopped or switched. This may be explained by the fact that both biosimilars are TNF-α inhibitors and have the same profile regarding their effects. In the past, there was lack of knowledge that biological therapy can be stopped if

47 the patient is in remission. This explains the different treatment duration of infliximab before stopping therapy (30 months) and the other treatments with TNF-α inhibitors, which all show the same results.

The best data provide the vedolizumab group regarding the treatment duration. But these data are not as reliable as from the other two groups, as the average duration of the treatment is only around 15 months (median= 12 months). This is due to the fact that vedolizumab is the newest of the biological drugs, which was launched at the end of 2014 in the UK.

6.3. Comparison with Literature

In the past, many trials were conducted to proof the safety and efficacy of infliximab, adalimumab and vedolizumab.

In the year 2002 the ACCENT I randomized trial was published. This trial deals with patients who suffer from CD and were on infliximab maintenance therapy. According to this trial, patients who responded to the induction regime at week 2 are more likely to be in remission at week 30 and 54 of maintenance treatment. After week 30, in group I 39% and in group II 45% responded to infliximab (group I- maintenance therapy with 5mg/kg, group II- maintenance therapy with 10mg/kg). [60] Almost 40% of all patients who started infliximab at Raigmore Hospital are in remission or respond to this drug and show the same result as the ACCENT I trial. The average duration before loss of response at the ACCENT I trial is situated at week 46. [60] Patients at Raigmore Hospital switched treatment after the average of 64 weeks. However, treatment was not only switched due to loss of response, but also because of several reasons like clinical decision or reaction. Nearly all patients who stayed 30 months on infliximab maintenance stopped their treatment because of remission.

According to the CLASSIC I trial, published in February 2006, the most common adverse events were reactions at the injection site. 26% of patients who received 40mg/20mg adalimumab, 24% patients with 80mg/40mg adalimumab and 38% with 160mg/80mg adalimumab experienced reactions like burning or pain at the injection site. 48

But only one percent of the 40mg/20mg and one percent of the 80mg/40mg had to discontinue treatment with adalimumab because of adverse events. [61] Whereas in this study, 14,8% switched treatment to vedolizumab because of different kind of reactions. Furthermore, about 37% had to switch from adalimumab due to clinical decision, which may include reactions, but were not identified as such. Three patients who stopped adalimumab and received no further biological treatment had to do this as a result of reactions.

The CHARM trial, published in 2007, deals with UC and CD patients on adalimumab maintenance therapy regarding their remission and response rate. Regarding to the CHARM trial 40% of patients on adalimumab maintenance with 40mg every two weeks were in remission at week 26 and 36% at week 56. The second group of patients received 40mg adalimumab weekly. 47% were in remission after week 26 and 41% after week 56. [62] About 31% of all patients who are or were on adalimumab maintenance therapy respond or are in remission at Raigmore Hospital. However, this study made no difference in how often or how much adalimumab was administered.

The GEMINI studies, conducted between 2008 and 2012, deal with safety and efficacy of vedolizumab for IBD patients. The GEMINI I study surveys patients who suffer from UC whereas GEMINI II relates to patients with CD. According to GEMINI I, 41,8% who received vedolizumab every eight weeks and 44,8% who received it every four weeks were in remission at week 52. [63] Whereas in GEMINI II, 39% of the patients who received vedolizumab every eight weeks and 36,4% of all who received it every four weeks were in remission at week 52. [64] In this study, no difference was made between UC and CD. The average duration of maintenance treatment until November 2017, for vedolizumab patients who primarily received infliximab and adalimumab, was 16 months (median= 12,5 months). The remission rate of vedolizumab for the third-line vedolizumab patients is 32,7% and for the second-line vedolizumab patients 19,23%.

49

The patients who switched directly from infliximab to vedolizumab show an average treatment duration of 8 months (median= 6 months) at the moment, so they are unlikely achieve the maintenance duration of 52 weeks.

Although there are lots of studies and trials, it is very difficult to find an exact statement of how long each of the biological drugs needs to work. Due to this fact, the patient information leaflets from The Crohn’s and Colitis UK charity were used to gather the needed information. The Crohn’s and Colitis UK website provides patient-friendly information about IBD and the different kind of treatments. They are also offering leaflets about the biological drugs infliximab, adalimumab and vedolizumab. According to the information provided, infliximab needs between two to six weeks, before the patient feels better. But there may also be an improvement after the first treatment. [65] So, the patient should response to the treatment at least after induction phase is completed. Adalimumab can work after a few days, but there can also pass three months before the biological starts to work. [66] Due to the fact that both, infliximab and adalimumab are TNF-α inhibitors, they need about the same time before the start to work, but as mentioned above, adalimumab is likely to take longer to develop its effect. [65][66] Vedolizumab is the newest biological drug. It needs between six and up to 14 weeks- for patients with CD, until it starts to work. [67]

6.4. Limitations

This study was the first retrospective evaluation at Raigmore Hospital of IBD patients on the biological drugs infliximab, adalimumab and vedolizumab. It provides valuable information about the number of patients who started their biological therapy with infliximab and their on-following treatment. It shows how many patients had to stop or switch their treatment to adalimumab and further on to vedolizumab. Furthermore, the study gives an overview of the reasons for stopping or switching therapy.

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However, this study is limited by a lack of data. Due to the fact that this study is retrospective, only existing data were surveyed. The data gathering was conducted very carefully but missing data cannot be replaced. Missing data would lead to an exclusion of patients to this study. To avoid the exclusion and further on decreasing the number of patients unnecessarily, the average of existing data was used to replace the missing ones. Due to this fact, generalisation of the findings should be made with prudence.

If there was a gap in data regarding the start or stop date of biological treatment, the average amount of months of all patients who stopped the treatment was used. Beside the missing start and stop date of the treatment, the missing data to examine the state of health for patients on maintenance therapy was a problem too. The same pattern, as above-mentioned, was used if there were missing FC levels and no HBI Score to define the response rate of patients. For patients on infliximab or vedolizumab maintenance the response rate can be defined by the HBI Score which is evaluated prior to the drug administration at the hospital. Patients who are on adalimumab maintenance, cannot be classified by their HBI Score, because it is self-administered at home. Furthermore, patients who are receiving their infliximab or vedolizumab infusion in community hospitals outside Raigmore Hospital, were never classified by the HBI Score. The second parameter, which was used to define the response rate on maintenance therapy was the FC value. If patients feel good, most of them would not send a stool sample as they think there is no need for it. However, often the FC level elevates before the patient feels a flair of symptoms or disease and no early intervention can be made. Also, often people have a flare of symptoms with FC levels in normal range or with increased FC level without feeling the active disease. In this study both parameters, FC and HBI Score, were used to define the response rate. For IBD treatment, it is very important to keep the inflammation under control, but due to the fact that UC and CD are not curable, the main goal is to make life of affected people easier.

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Nevertheless, is one of these two parameters missing, interference regarding biological therapy is very difficult. Both, FC and HBI Score, are non-invasive marker to define response and are easy to measure. Regarding the reasons for switching or stopping biological therapy, the description “clinical decision” was used if primary reasons could not be investigated.

Last but not least, another limiting factor of this study is the bias of the student who conducted the research.

6.5. Ongoing Work

At the moment there are no other ongoing projects regarding IBD patients on biological therapy at Raigmore Hospital. This retrospective study was conducted to get a first idea how biological therapy is working due to efficacy at Raigmore Hospital. As a result of this study, many plans for future work were discussed and led to great ideas to improve IBD treatment.

6.6. Future Work

Many possible future projects were discussed in the final meeting of this study.

In 2018 the patent of the biological Humira© expires, a biosimilar will be launched around the end of 2018. Due to the potential cost-savings there are ideas of switching all Humira© patients to the biosimilar, as it has happened with almost all infliximab patients in the past. Therefore, all patients need to be informed and must agree the switch.

The majority of patients start with infliximab at the beginning of a biological therapy. There are hardly any data available for adalimumab or vedolizumab as first-line treatment. One future plan of the IBD team at Raigmore Hospital is to observe the efficacy of adalimumab and vedolizumab as first-line treatment. Moreover, there are intentions to conduct a clinical trial to observe the different response rate of vedolizumab as second- or third-line treatment.

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However, the funding for further investigations on the efficacy of first-line adalimumab and vedolizumab treatment and vedolizumab response is not resolved yet.

In addition, further research is needed regarding infliximab therapy. To optimize infliximab treatment and all other biological therapies, patients should be monitored more carefully. Future plans aim to observe every patient, especially after first and second infusion, to prevent treatment failures, as symptoms should improve after first or second dose. Furthermore, the importance of therapeutic drug monitoring needs to be evaluated and if necessary implemented in IBD treatment.

The main goal of future work is to improve biological therapy for IBD patients to increase response and in particular remission rate to give those patients the opportunity to live an almost normal life.

6.7. Recommendations

This retrospective study leads to many recommendations, shown in table 10, which concern hospital staff as well as patients. Most of them would be time consuming but they would simplify potential future research work and reduce different bias, which led to limitations of this study. The limitations of this study are listed in the section “6.4. Limitations” above.

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Table 10. Recommendations for Future Work

Recommendations Improve patient-data management The start and stop date of each treatment should be defined and collected, for instance, in an Excel sheet. This Excel sheet should also contain the well- defined reason for switching or stopping therapy. This sheet should always be up to date.

Improve patients’ compliance regarding Make patients aware how important it is stool samples to send in a stool sample regularly. Try to improve compliance during patient counselling. This regards adalimumab patients in particular.

Standardize pre-infusion examination Raigmore Hospital as well as other community hospitals in the Highlands, where biological drugs are administered, should investigate HBI Score before the drug is given.

To implement these recommendations a guideline regarding these issues would be a helpful tool.

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7. Conclusion

This retrospective study provides information about the treatment course of IBD patients on the biological medicines infliximab, adalimumab and vedolizumab. This study shows the different response and remission rates of these three biological drugs and the average duration of treatment before it had to be stopped or switched. The reasons for switching or stopping were also investigated. Infliximab and adalimumab, both TNF-α inhibitors, show, as expected, the same average of treatment duration. However, the different response rates of vedolizumab therapy, as second- or third-line therapy, was surprising and need further investigations. The response rates relating to infliximab and adalimumab were in the range of expectations. Although, adalimumab and vedolizumab show good response rates, infliximab should be still considered as first-line treatment in the future. Due to the fact that infliximab is faster acting than adalimumab and vedolizumab. Furthermore, the investigated data support the current working practices at Raigmore Hospital, because infliximab met the expected data the closest. After further investigations are made, vedolizumab may be considered as first- line treatment too.

As a result of this retrospective study recommendations were formulated. These recommendations support a potential future prospective study on IBD patients on biological therapy and are listed under the section “6.7. Recommendations”.

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References

[1] Roger Walkers, Clive Edwards: Clinical Pharmacy and Therapeutics, third Edition, 2003. Churchill Livingstone, 2003, p.163

[2] David S. Rampton, Fergus Shanahan: Fast Facts: Inflammatory Bowel Disease. Health Press, 2008, p.7

[3] Burisch J; Jess T; Martinato M; Lakatos PL; ECCO -EpiCom : The burden of inflammatory bowel disease in Europe. [Review], Journal of Crohn's & colitis., 2013 May, 7(4):322-37

[4] Kaplan GG; Ng SC.: Understanding and Preventing the Global Increase of Inflammatory Bowel Disease. [Review], Gastroenterology., 2017 Feb., 152(2):313-321.e2

[5] David S. Rampton, Fergus Shanahan: Fast Facts: Inflammatory Bowel Disease. Health Press, 2008, p.8-9

[6] Roger Walker, Clive Edwards: Clinical Pharmacy and Therapeutics, third Edition, Churchill Livingstone, 2003, p.163

[7] Carol Mattson Porth: Essentials of Pathophysiology third Edition, Wolters Kluwer Health| Lippincott Williams & Wilkins, 2011, p.712

[8] Richard J. Aspinall, Simon D. Taylor-Robinson: Mosby’s Color Atlas and Text of Gastroenterology and Liver Disease, Mosby, 2002, p.84

[9] Joseph D. Feuerstein MD, Adam S. Cheifetz MD: Crohn Disease: Epidemiology, Diagnosis, and Management, Mayo Clinic Proceedings, 2017-07-01, Volume 92, Issue 7, Pages 1088-1103, Copyright © 2017 Mayo Foundation for Medical Education and Research [10] Fernando Gomollón,* Axel Dignass,* Vito Annese, Herbert Tilg, Gert Van Assche, James O. Lindsay, Laurent Peyrin-Biroulet, Garret J. Cullen, Marco Daperno, Torsten Kucharzik, Florian Rieder, Sven Almer, Alessandro Armuzzi,

56

Marcus Harbord, Jost Langhorst, Miquel Sans, Yehuda Chowers, Gionata Fiorino, Pascal Juillerat, Gerassimos J. Mantzaris, Fernando Rizzello, Stephan Vavricka, Paolo Gionchetti, on behalf of ECCO: ECCO Guideline/Consensus Paper 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and Medical Management, Journal of Crohn's and Colitis, 2017, 3–25 doi:10.1093/ecco-jcc/jjw168 Advance Access publication September 22, 2016 ECCO Guideline/Consensus Paper

[11] Roger Walker, Clive Edwards: Clinical Pharmacy and Therapeutics, third Edition. Churchill Livingstone, 2003, p.166

[12] Carol Mattson Porth: Essentials of Pathophysiology third Edition. Wolters Kluwer Health| Lippincott Williams & Wilkins, 2011, p.713

[13] Fernando Magro,a,† Paolo Gionchetti,b,† Rami Eliakim,c,# Sandro Ardizzone,d Alessandro Armuzzi,e Manuel Barreiro-de Acosta,f Johan Burisch,g Krisztina B. Gecse,h Ailsa L. Hart,i Pieter Hindryckx,j Cord Langner,k Jimmy K. Limdi,l Gianluca Pellino,m Edyta Zagórowicz,n Tim Raine,o Marcus Harbord,p# Florian Rieder;q for the European Crohn’s and Colitis Organisation [ECCO]: Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra- intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders; Journal of Crohn's and Colitis, 2017, 649–670 doi:10.1093/ecco-jcc/jjx008 Advance Access publication February 2, 2017 ECCO Guideline/Consensus Paper

[14] M. K. Chourasia, S. K. Jain: Pharmaceutical approaches to colon targeted drug delivery systems. Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour University, Sagar, India. Received 18 July 2002, Revised 16 January 2003, Accepted 3 February 2003.] https://sites.ualberta.ca/~csps/JPPS6(1)/S.Chourasia/colon.htm (23.10.2017) [15] David S. Rampton, Fergus Shanahan: Fast Facts: Inflammatory Bowel Disease, Health Press, 2008, p.56-61

57

[16] Peter M. Irving, Corey A. Siegel, David S. Rampton, Fergus Shanahan: Clinical Dilemmas in Inflammatory Bowel Disease New Challenges Second Edition. Wiley-Blackwell, 2011, p.65-76

[17] Louise Langmead, Peter Irving: thefacts, Inflammatory Bowel Disease. Oxford University Press, 2008, p.69-70

[18] David S. Rampton, Fergus Shanahan: Fast Facts: Inflammatory Bowel Disease, Health Press, 2008, p.53-56

[19] Peter M. Irving, Corey A. Siegel, David S. Rampton, Fergus Shanahan: Clinical Dilemmas in Inflammatory Bowel Disease New Challenges Second Edition. Wiley-Blackwell, 2011, p.79-82

[20] David S. Rampton, Fergus Shanahan: Fast Facts: Inflammatory Bowel Disease, Health Press, 2008, p.55

[21] David S. Rampton, Fergus Shanahan: Fast Facts: Inflammatory Bowel Disease, Health Press, 2008, p.63-65

[22] Louise Langmead, Peter Irving: thefacts, Inflammatory Bowel Disease. Oxford University Press, 2008, p.71

[23] Peter M. Irving, Corey A. Siegel, David S. Rampton, Fergus Shanahan: Clinical Dilemmas in Inflammatory Bowel Disease New Challenges Second Edition. Wiley-Blackwell, 2011, p.85-88

[24] Jaimin Amin, MD,* Brian Huang, MD,† Jessica Yoon, MD,† and David Q. Shih, MD, PhD†: Update 2014: Advances to Optimize 6-Mercaptopurine and Azathioprine to Reduce Toxicity and Improve Efficacy in the Management of IBD. Inflamm Bowel Dis Volume 21, Number 2, February 2015, p.445-452

58

[25] David S. Rampton, Fergus Shanahan: Fast Facts: Inflammatory Bowel Disease, Health Press, 2008, p.67

[26] Louise Langmead, Peter Irving: thefacts, Inflammatory Bowel Disease. Oxford University Press, 2008, p.72-73

[27] Peter M. Irving, Corey A. Siegel, David S. Rampton, Fergus Shanahan: Clinical Dilemmas in Inflammatory Bowel Disease New Challenges Second Edition. Wiley-Blackwell, 2011, p.102-105

[28] Hans H. Herfarth: Methotrexate for Inflammatory Bowel Diseases – New Developments. ivision of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, C hapel Hill, N.C., USA. Dig Dis 2016; 34: p.140–146

[29] Thibaut Vaysse, Franck Carbonnel : Methotrexate in IBD: The Return of the Prodigal Son. Journal of Crohn's and Colitis, Volume 9, Issue 4, 1 April 2015, Pages 303–304,

[30] David S. Rampton, Fergus Shanahan: Fast Facts: Inflammatory Bowel Disease, Health Press, 2008, p.66

[31] Louise Langmead, Peter Irving: thefacts, Inflammatory Bowel Disease. Oxford University Press, 2008, p.75

[32] Aurelien Amiot, Laurent Peyrin-Biroulet: Current, new and future biological agents on the horizon for the treatment of inflammatory bowel diseases. Therap Adv Gastroenterol. 2015 Mar; 8(2): 66–82. [33] Gaspare Solina, Stefano Mandalà, Camillo La Barbera, Vincenzo Mandalà: Current management of intestinal bowel disease: the role of surgery. Updates in Surgery, March 2016, Volume 68, Issue 1, p. 13–23

[34] Quinton M. Hatch, Rubina Ratnaparkhi, Alison Althans, Michael Keating, Ruel

59

Neupane, Madhuri Nishtala, Eric K. Johnson, Scott R. Steele: Is Modern Medical Management Changing Ultimate Patient Outcomes in Inflammatory Bowel Disease? J Gastrointest Surg, Received: 18 May 2016/Accepted: 7 September 2016/Published online: 15 September 2016, 20:1867–1873,

[35] Louise Langmead, Peter Irving: thefacts, Inflammatory Bowel Disease. Oxford University Press, 2008, p.79

[36] Blonski,Wojciech; Buchner,Anna M.; Lichtenstein,Gary R.: Inflammatory bowel disease therapy: current state-of-the-art. Current Opinion in Gastroenterology 2011, 27:346–357

[37] Keith S Sultan, Joshua C Berkowitz, Sundas Khan: Combination therapy for inflammatory bowel disease. World J Gastrointest Pharmacol Ther. 2017 May 6; 8(2): 103– 113.

[38] MedicineNet, Inc. ©1996-2018: Medical Definition of Remission. https://www.medicinenet.com/script/main/art.asp?articlekey=5296 Cited 27.10.2017, last accessed 13.03.2018

[39] Floor Bennebroek Evertsz’, Msc; Ce ´line C. M. Q. Hoeks, Msc; Pythia T. Nieuwkerk, PhD; Pieter C. F. Stokkers, PhD; Cyriel Y. Ponsioen, MD, PhD; Claudi L. H. Bockting, PhD; Robbert Sanderman, PhD; Mirjam A. G. Sprangers, PhD: Development of the Patient Harvey Bradshaw Index and a Comparison With a Clinician-based Harvey Bradshaw Index Assessment of Crohn’s Disease Activity. J Clin Gastroenterol Volume 47, Number 10, November/December 20; p.850-856

[40] D'Angelo F., Felley C., Frossard J.L.: Calprotectin in Daily Practice: Where Do We Stand in 2017? Digestion 2017;95: p.293–301

[41] Anjan Dhar: Faecal calprotectin—ready for prime time?. Frontline Gastroenterol. 2015 Jan; 6(1): p.11–13.

60

[42] James Turvill, Lisa Rook, Maxine Rawle, Gerry Robins, Simon Smale, Prashant Kant, Anne Phillip: Validation of a care pathway for the use of faecal calprotectin in monitoring patients with Crohn’s diseas. Turvill J, et al. Frontline Gastroenterology 2017;8:183–188. doi:10.1136/flgastro-2016-100780

[43] Prepared jointly by the European Medicines Agency and the European Commission: Biosimilars in the EU, Information guide for healthcare professionals. © European Medicines Agency, 2017, p.5 http://www.ema.europa.eu/docs/en_GB/document_library/Leaflet/2017/05/WC500226 648.pdf Cited 24.10.2017, last accessed 13.03.2018

[44] World Health Organization: Guidelines on evaluation of monoclonal antibodies as similar biotherapeutic products (SBPs). © World Health Organization 2016, 1 Mar 2016. http://www.who.int/biologicals/mAb_1st_draft_KG_IK_1_March_2016_clean.pdf Cited 24.10.2017, last accessed 13.03.2018

[45] Committee for medicinal products for human use (CHMP): Guideline on development, production, characterisation and specification for monoclonal antibodies and related products. © European Medicines Agency, 2016, 21 July 2016. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/08 /WC500211640.pdf Cited 24.10.2017, last accessed 13.03.2018

[46] H. Matthew Cohn, MD,* Maneesh Dave, MD, MPH,*,† and Edward V. Loftus, Jr, MD‡: Understanding the Cautions and Contraindications of Immunomodulator and Biologic Therapies for Use in Inflammatory Bowel Disease. Inflamm Bowel Dis Volume 23, Number 8, August 2017, p.1301-1315

[47] ValentinaPecoraro, ElenaDe Santis, AlessandraMelegari, TommasoTrenti: The impact of immunogenicity of TNFα inhibitors in autoimmune inflammatory disease. A systematic

61 review and meta-analysis. Autoimmunity Reviews Volume 16, Issue 6, June 2017, p.564- 575

[48] Fabien B Vincent, Eric F Morand, Kim Murphy, Fabienne Mackay, Xavier Mariette, Christian Marcelli: Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective. Annals of the Rheumatic Diseases 2013;72:165-178.

[49] PaulRutgeerts, Gertvan Assche, SéverineVermeire: Optimizing anti-TNF treatment in inflammatory bowel disease. Gastroenterology Volume 126, Issue 6, May 2004, p.1593- 1610

[50] NielsVande Casteele, MarcFerrante, GertVan Assche, VeraBallet, GrietCompernolle, KristelVan Steen, StevenSimoens, PaulRutgeerts, AnnGils, SéverineVermeire: Trough Concentrations of Infliximab Guide Dosing for Patients With Inflammatory Bowel Disease. Gastroenterology Volume 148, Issue 7, June 2015, p.1320-1329

[51] Janssen Biologics B.V.: Remicade 100mg powder for concentrate for solution for infusion. (last revision of the text 09.11.2017) http://www.medicines.org.uk/emc/medicine/3236 Cited 23.11.2017, last accessed 13.03.2018

[52] Y. Mazor, U. Koplov, D. Ben Hur, R. Almog, M. Waterman, S. Ben-Horin, Y. Chowers: Evaluating Adalimumab drug and antibody levels as predictors of clinical and laboratory response in Crohn’s disease patient. Journal of Crohn's and Colitis, Volume 7, Issue Supplement_1, 1 February 2013, P. 217

[53] AbbVie Ltd: Humira 40 mg solution for injection in pre-filled syringe. (last revision of the text 08.12.2017) http://www.medicines.org.uk/emc/medicine/31860 (last accessed: 13.03.2018) Cited 23.11.2017, last accessed 13.03.2018

62

[54] Daniel R van Langenberg: New choices, new challenges: Anti-TNF versus anti-integrin molecule therapy in IBD. Journal of Gastroenterology and Hepatology, Volume 31, Issue S1 June 2016, p.10–11

[55] IvanaBravatà, MariangelaAllocca, GionataFiorino, SilvioDanese: Integrins and adhesion molecules as targets to treat inflammatory bowel disease. Current Opinion in Pharmacology Volume 25, December 2015, p.67-71

[56] Takeda Pharma A/S: Entyvio 300 mg powder for concentrate for solution for infusion (last revision of the text 09.02.2018) http://www.medicines.org.uk/emc/medicine/28980 Cited 23.11.2017, last accessed 13.03.2018

[57] European Medicines Agency's (EMA) website: Biosimilar medicines. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/general/general_conte nt_001832.jsp&mid=WC0b01ac0580bb8fda Cited 26.10.2017, last accessed 13.03.2018

[58] Healhcare Improvement Scotland: Biosimilar Medicines: A National Prescribing Framework. NHS Scotland, 19 May 2015. http://www.healthcareimprovementscotland.org/our_work/technologies_and_medicines /programme_resources/biosimilar_medicines_framework.aspx (26.10.2017) Cited 26.10.2017, last accessed 13.03.2018

[59] Scaldaferri F, D‘Ambrosio D, Holleran G, Poscia A, Petito V, Lopetuso L, et al. (2017) Body mass index influences infliximab post-infusion levels and correlates with prospective loss of response to the drug in a cohort of inflammatory bowel disease patients under maintenance therapy with Infliximab. PLoS ONE12(10): e0186575. https://doi.org/10.1371/journal.pone.0186575

[60] Dr. Stephen B Hanauer, MD, Brian G Feagan, MD, Gary R Lichtenstein, MD, Lloyd F

63

Mayer, MD, S Schreiber, MD, Jean Frederic Colombel, MD, Daniel Rachmilewitz, MD, Douglas C Wolf, MD, Allan Olson, MD, Weihang Bao, PhD, Paul Rutgeerts, MD, the ACCENT I Study Group: Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial; The Lancet, Volume 359, No. 9317, p1541–1549, 4 May 2002.

[61] Stephen B.Hanauer, William J.Sandborn, PaulRutgeerts, Richard N.Fedorak, MilanLukas, DonaldMacIntosh, RemoPanaccione, DouglasWolf, PaulPollack: Human Anti– Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in Crohn’s Disease: the CLASSIC-I Trial. Gastroenterology Volume 130, Issue 2, February 2006, Pages 323-333.

[62] Jean–Frédéric Colombel, William J. Sandborn, Paul Rutgeerts, Robert Enns, Stephen B. Hanauer, Remo Panaccione, Stefan Schreiber, Dan Byczkowski, Ju Li, Jeffrey D. Kent, Paul F. Pollack: Adalimumab for Maintenance of Clinical Response and Remission in Patients With Crohn’s Disease: The CHARM Trial. Gastroenterology Volume 132, Issue 1, January 2007, Pages 52-65.

[63] Brian G. Feagan, M.D., Paul Rutgeerts, M.D., Ph.D., Bruce E. Sands, M.D., Stephen Hanauer, M.D., Jean-Frédéric Colombel, M.D., William J. Sandborn, M.D., Gert Van Assche, M.D., Ph.D., Jeffrey Axler, M.D., Hyo-Jong Kim, M.D., Ph.D., Silvio Danese, M.D., Ph.D., Irving Fox, M.D., Catherine Milch, M.D., Serap Sankoh, Ph.D., Tim Wyant, Ph.D., Jing Xu, Ph.D., and Asit Parikh, M.D., Ph.D., for the GEMINI 1 Study Group: Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med 2013; 369:699-710August 22, 2013DOI: 10.1056/NEJMoa1215734.

[64] William J. Sandborn, M.D., Brian G. Feagan, M.D., Paul Rutgeerts, M.D., Ph.D., Stephen Hanauer, M.D., Jean-Frédéric Colombel, M.D., Bruce E. Sands, M.D., Milan Lukas, M.D., Ph.D., Richard N. Fedorak, M.D., Scott Lee, M.D., Brian Bressler, M.D., Irving Fox, M.D., Maria Rosario, Ph.D., Serap Sankoh, Ph.D., Jing Xu, Ph.D., Kristin Stephens, B.A., Catherine Milch, M.D., and Asit Parikh, M.D., Ph.D., for the GEMINI 2 Study Group: Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med 2013; 369:711- 721August 22, 2013DOI: 10.1056/NEJMoa1215739.

64

[65] © Crohn’s and Colitis UK 2016 Infliximab Edition 7 Last review: July 2016 Contact details updated: October 2017 https://www.crohnsandcolitis.org.uk/about-inflammatory-bowel- disease/publications/infliximab Cited 12.12.2017, last accessed 13.03.2018

[66] © Crohn’s and Colitis UK 2015 Adalimumab Edition 4 Last Review October 2015 Next full review planned – 2018 https://www.crohnsandcolitis.org.uk/about-inflammatory-bowel- disease/publications/adalimumab Cited 12.12.2017, last accessed 13.03.2018

[67] © Crohn’s and Colitis UK 2017 Vedolizumab Edition 1 Last review - July 2017 Next planned review - 2020 https://www.crohnsandcolitis.org.uk/about-inflammatory-bowel- disease/publications/vedolizumab Cited 12.12.2017, last accessed 13.03.2018

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List of Abbreviations

This list gives an overview of the abbreviations, used in this thesis:

Letter Abbreviation A AS Ankylosing spondylitis ASA Aminosaicylate AZA Azathioprine C CD Crohn’s Disease D DNA Deoxyribonucleic acid E ECCO European Crohn’s and Colitis Organisation EMA European Medicine Agency eMC electronic Medicines Compendium EU European Union F FC Faecal calprotectin G g Gram H HBI Harvey-Bradshaw Index I IBD Inflammatory Bowel Disease IgG1 Immunoglobulin G1 IL Interleukin M MAdCAM-1 Mucosal addressin cell adhesion molecule 1 ml Millilitre MTX Methotrexate N NF-kB Nuclear factor kappa B NHS National Health Service P PsA Psoriatic arthritis R RA Rheumatoid arthritis RNA Ribonucleic acid

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S SCI Store Scottish Care Information SPS Sulfasalazine sTNFα Soluble TNFα T tmTNFα Transmembrane TNFα TNF-α Tumour necrosis factor alpha TPMT Thiopurine methyltransferase U UC Ulcerative Colitis W WHO World Health Organization 6-MMP 6-methylmercaptopurine 6-MP 6-Mercaptopurine 6-TGN 6-thioguanine nucleotide

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List of Figures

Figure 1. 5-ASA Release in the Colon; (i) Sulfasalazine, (ii) 5-ASA, (iii) Sulfapyridine [14] .... 8 Figure 2. Step-Up Treatment [36] ...... 13 Figure 3. Examples Biological Medicines EU [43] ...... 17 Figure 4. Infliximab Patients ...... 34 Figure 5. Reason for Stopping Infliximab Treatment (%) ...... 35 Figure 6. Infliximab Maintenance (%) ...... 35 Figure 7. Reason for Switching from Infliximab to Adalimumab (%) ...... 36 Figure 8. Adalimumab Patients ...... 37 Figure 9. Reason for Stopping Infliximab Treatment (%) ...... 38 Figure 10. Maintenance Adalimumab (%) ...... 38 Figure 11. Reason for Switching from Adalimumab to Vedolizumab (%) ...... 39 Figure 12. Vedolizumab Third-Line Patients...... 40 Figure 13. Reason for Stopping Treatment on Third-Line Vedolizumab (%) ...... 41 Figure 14. Maintenance Third-Line Vedolizumab (%) ...... 41 Figure 15. Vedolizumab Second-Line Patients ...... 42 Figure 16. Reason for Switching from Infliximab to Vedolizumab (%) ...... 43 Figure 17. Reason for Stopping Treatment on Second-Line Vedolizumab (%) ...... 43 Figure 18. Maintenance Second-Line Vedolizumab (%) ...... 44 Figure 19. Response/ Remission Rate of all Patients (%) ...... 46 Figure 20. Median Duration of Biological Therapy in Months ...... 47

List of Tables

Table 1. Types of Ulcerative Colitis [13] ...... 6 Table 2. Classification Disease Activity [13] ...... 6 Table 3. Montreal Classification [13] ...... 7 Table 4. Corticosteroids- Mechanism of Action [20] ...... 9 Table 5. FC-Level Classification [40][42] ...... 15 Table 6. Characteristics Infliximab Adalimumab [47] ...... 19 Table 7. Definition Disease Activity ...... 29

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Table 8. Infliximab Patients Total ...... 33 Table 9. Biological Patients Total ...... 46 Table 10. Recommendations for Future Work ...... 54

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Appendix

A. HBI Score

Clinician-based Harvey Bradshaw Index (HBI) and Patient-based HBI

Symptoms refer to the previous week.

Variable Description Scoring HBI Scoring P-HBI (0-10)

1 General well-being (0-4) 0 = very well (score ≥7) 1 = slightly below par (score = 6) 2 = poor (score = 5) 3 = very poor (score = 4) 4 = terrible (score < 4)

2 Abdominal pain (0-3) 0 = none (score = 0) 1 = mild (score = 1-3) 2 = moderate (score = 4-7) 3 = severe (score = 8-10)

3 Abdominal mass (0-3) 0 = none 1 = dubious 2 = definite 3 = definite and tender

4 Number of liquid stools * n (1 per occurrence)

5 Extra intestinal manifestations 1 per item:

Arthralgia Yes = 1 No = 0

Uveitis Yes = 1 No = 0

Erythema nodosum Yes = 1 No = 0

Pyoderma gangrenosum Yes = 1 No = 0

Aphthous ulcer Yes = 1 No = 0

Anal fissure Yes = 1 No = 0

New fistula Yes = 1 No = 0

Abscess Yes = 1 No = 0

* In case of a stoma or pouch please score deviation in comparison to its normal state. [39]

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B. Patients total

NAME SEX DIAG. TREAT. DUR. TREAT. DUR. TREAT. DUR. TREAT. HBI FC µg/g Patient 1 2 CD Infl. - 1,6 65 Patient 2 1 CD Infl. 101 Vedo. - 2 141 Patient 3 1 UC Infl. - 1,6 < 30 Patient 4 2 CD Infl. - 0 388 Patient 5 1 CD Infl. 31 Ada. - - 1322 Patient 6 1 CD Infl. 32 stopped - < 30 Patient 7 1 CD Infl. 26,9 stopped - 206 Patient 8 1 CD Infl. - 0 675 Patient 9 1 CD Infl. 29,6 stopped - 879 Patient 10 1 UC Infl. 6 Vedo. - 2,4 1110 Patient 11 2 UC Infl. 19 Ada. - - - Patient 12 2 UC Infl. 2 Ada. 7 stopped - 76 Patient 13 2 CD Infl. 7 Ada. - Goli. - - - Patient 14 1 UC Infl. - 0 - Patient 15 1 CD Infl. - 0 49 Patient 16 2 UC Infl. - 0 < 30 Patient 17 2 CD Infl. - 1,6 349 Patient 18 2 CD Infl. 25 stopped - 215 Patient 19 2 CD Infl. 1 Ada. 22 stopped - - Patient 20 2 CD Infl. 5 Ada. - - - Patient 21 1 UC Infl. - 0 398 Patient 22 1 UC Infl. - 0 < 30 Patient 23 1 CD Infl. 12 Ada. 23 stopped - -

71

Patient 24 1 UC Infl. - Goli. - - 77 Patient 25 1 CD Infl. 7 Vedo. - 2,4 - Patient 26 1 CD Infl. 9 Ada. - - - Patient 27 2 CD Infl. - 2 739 Patient 28 2 CD Infl. - 6 48 Patient 29 1 UC Infl. - 1,6 > 1800 Patient 30 2 CD Infl. - 1,6 60 Patient 31 1 UC Infl. 9 stopped - - Patient 32 1 UC Infl. 26 stopped - 94 Patient 33 1 UC Infl. 6 Vedo. - 2,4 > 1800 Patient 34 1 CD Infl. - 0 128 Patient 35 1 UC Infl. - Goli. - Vedo. - - 86 Patient 36 2 CD Infl. 25 stopped - 35 Patient 37 2 CD Infl. 14 Ada. - - 926 Patient 38 2 CD Infl. 16,1 Ada. - - - Patient 39 2 CD Infl. 28 Ada. - - - Patient 40 2 CD Infl. 12 stopped - 235 Patient 41 2 CD Infl. 21 stopped - 204 Patient 42 2 CD Infl. 16,1 Ada. - - - Patient 43 1 CD Infl. - 1,6 377 Patient 44 2 CD Infl. 16,1 Ada. - - 203 Patient 45 1 CD Infl. - 0 < 30 Patient 46 1 CD Infl. 29,6 stopped - < 30 Patient 47 1 CD Infl. - 1 - Patient 48 1 CD Infl. 12 stopped - < 30 Patient 49 1 UC Infl. 52 stopped - 80 Patient 50 1 CD Infl. 16,1 Ada. - - -

72

Patient 51 1 UC Infl. 16,1 Ada. 4 Vedo. - 0 69 Patient 52 1 UC Infl. - 0 225 Patient 53 1 CD Infl. 17 stopped - - Patient 54 1 CD Infl. - 1,6 < 30 Patient 55 1 UC Infl. 3 Vedo. 6 stopped - - Patient 56 1 CD Infl. 5 Ada. - - - Patient 57 1 UC Infl. - 1,6 55 Patient 58 1 UC Infl. 2 Vedo. 5 stopped - 112 Patient 59 2 CD Infl. 16,1 Ada. 17,4 Vedo. - 2 162 Patient 60 1 CD Infl. - 1,6 138 Patient 61 1 UC Infl. 20 Vedo. - 2,4 71 Patient 62 1 CD Infl. - 1 977 Patient 63 2 CD Infl. 16,1 Ada. 29 stopped - - Patient 64 2 CD Infl. - 1,6 < 30 Patient 65 2 CD Infl. 7 Ada. 31 Vedo. 31 Ustek. 4 - Patient 66 1 CD Infl. - 0 247 Patient 67 1 CD Infl. 4 Ada. - - 1496 Patient 68 2 CD Infl. 16,1 Ada. 17,4 Vedo. - 0 - Patient 69 2 UC Infl. 13 Ada. - - < 30 Patient 70 2 IBD-U Infl. 16,1 Ada. 2 Vedo. - 4 < 30 Patient 71 1 CD Infl. - 3 82 Patient 72 1 UC Infl. - 0 39 Patient 73 1 UC Infl. 41 Vedo. - 2,4 95 Patient 74 1 UC Infl. 32 stopped - 59 Patient 75 2 CD Infl. - 1,6 452 Patient 76 2 CD Infl. 75 stopped - 70 Patient 77 2 CD Infl. - 8 < 30

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Patient 78 1 UC Infl. 13 Ada. - - 165 Patient 79 1 CD Infl. 16,1 Ada. 22 Vedo. - 2,1 172 Patient 80 1 CD Infl. 24 Ada. - - 42 Patient 81 1 CD Infl. - 0 < 30 Patient 82 1 UC Infl. 5 Ada. - - 224 Patient 83 1 UC Infl. - 0 149 Patient 84 2 CD Infl. 1 Ada. - - - Patient 85 2 UC Infl. 8 Vedo. - 1 304 Patient 86 1 UC Infl. - 0 > 1800 Patient 87 1 CD Infl. 29,6 stopped - 169 Patient 88 1 CD Infl. - 0 < 30 Patient 89 1 UC Infl. - 0 152 Patient 90 2 CD Infl. 48 stopped - 1090 Patient 91 2 CD Infl. 16,1 Ada. - - - Patient 92 2 CD Infl. 16,1 Ada. - - - Patient 93 2 UC Infl. 4 Ada. - - 258 Patient 94 2 CD Infl. 33 Ada. 8 Vedo. - 2 > 1800 Patient 95 1 CD Infl. 9 stopped - 57 Patient 96 1 CD Infl. - 0 785 Patient 97 1 CD Infl. 29,6 stopped - 54 Patient 98 1 CD Infl. - 0 760 Patient 99 1 UC Infl. - 3 455 Patient 100 1 CD Infl. - 0 83 Patient 101 1 CD Infl. - 0 92 Patient 102 1 CD Infl. 24 Ada. - - 61 Patient 103 1 UC Infl. 10 Ada. 54 Vedo. - 3 468 Patient 104 2 CD Infl. - 7 < 30

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Patient 105 1 UC Infl. 1 Vedo. - 0 < 30 Patient 106 2 CD Infl. 9 Ada. 30 stopped - - Patient 107 2 CD Infl. - 0 67 Patient 108 2 UC Infl. 9 stopped - 618 Patient 109 2 CD Infl. 29,6 stopped - 147 Patient 110 2 CD Infl. 29,6 stopped - 181 Patient 111 2 CD Infl. - 7 55 Patient 112 2 CD Infl. 10 Ada. 1 stopped - - Patient 113 1 CD Infl. - 0 62 Patient 114 1 CD Infl. - 2 426 Patient 115 1 CD Infl. - 0 430 Patient 116 1 CD Infl. 50 Ada. - - 393 Patient 117 1 CD Infl. 14 Ada. 7 Vedo. - 0 316 Patient 118 2 CD Infl. 16,1 Ada. 19 Vedo. 19 stopped - - Patient 119 2 CD Infl. - 1,6 - Patient 120 2 UC Infl. - 1,6 > 1800 Patient 121 2 CD Infl. 76 Vedo. - 2,4 658 Patient 122 2 UC Infl. - 1,6 > 1800 Patient 123 2 CD Infl. 16,1 Ada. - - - Patient 124 2 UC Infl. - 3 < 30 Patient 125 2 CD Infl. 16,1 Ada. 17,4 Vedo. - 2,1 - Patient 126 2 CD Infl. 16,1 Ada. - - - Patient 127 2 UC Infl. 13 Ada. 8 Vedo. - 0 874 Patient 128 2 CD Infl. - 3 < 30 Patient 129 2 CD Infl. 16,1 Ada. - - - Patient 130 1 UC Infl. - 0 61 Patient 131 1 UC Infl. 53 Ada. - - 396

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Patient 132 1 CD Infl. 59 Ada. - - 34 Patient 133 1 UC Infl. - 1,6 < 30 Patient 134 1 CD Infl. - 0 < 30 Patient 135 2 CD Infl. 8 Ada. - Ustek. - - Patient 136 2 CD Infl. - 10 82 Patient 137 1 CD Infl. - 0 35 Patient 138 1 UC Infl. - 0 32 Patient 139 2 CD Infl. 16,1 Ada. - - < 30 Patient 140 1 CD Infl. 72,4 Vedo. - - > 1800 Patient 141 2 CD Infl. 1 Ada. 3 Vedo. - 1 - Patient 142 2 CD Infl. - 6 < 30 Patient 143 2 UC Infl. 1 Vedo. 1 stopped - 201 Patient 144 2 UC Infl. - 1,6 < 30 Patient 145 2 CD Infl. 22 + 9 Ada. - - 201 Patient 146 1 UC Infl. 10 Ada. 17,4 Vedo. - 0 - Patient 147 2 CD Infl. 16,1 Ada. - - - Patient 148 2 UC Infl. 16 Vedo. - 6 51 Patient 149 2 CD Infl. 16,1 Ada. 17,4 Vedo. 16 stopped 4 224 Patient 150 2 CD Infl. - 0 168 Patient 151 1 UC Infl. 33 stopped - < 30 Patient 152 1 CD Infl. - 4 252 Patient 153 2 UC Infl. 26 Ada. 4 Vedo. - 0 - Patient 154 1 CD Infl. 37 stopped - 1308 Patient 155 1 UC Infl. - 0 299 Patient 156 1 CD Infl. - 2 188 Patient 157 2 CD Infl. - 0 323 Patient 158 2 CD Infl. - 0 < 30

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Patient 159 1 UC Infl. - 0 < 30 Patient 160 1 UC Infl. 98 stopped - < 30 Patient 161 2 CD Infl. 16,1 Ada. 16,1 stopped - - Patient 162 1 UC Infl. 13 stopped - 152 Patient 163 1 UC Infl. - 9 1065 Patient 164 1 CD Infl. 16,1 Ada. 84 Vedo. - 6 877 Patient 165 2 CD Infl. 20 Ada. 7 Vedo. - 2,1 - Patient 166 2 UC Infl. 20 Vedo. - 3 39 Patient 167 2 UC Infl. 7 Ada. - - 477 Patient 168 1 CD Infl. 16,1 Ada. - - - Patient 169 1 UC Infl. - 0 748 Patient 170 1 CD Infl. 63 stopped - < 30 Patient 171 1 CD Infl. - 3 67 Patient 172 2 CD Infl. 16,1 Ada. 17,4 Vedo. - 14 34 Patient 173 2 CD Infl. 62 Ada. 2 Vedo. 2 Ustek. - 367 Patient 174 1 CD Infl. 16,1 Ada. 17,4 Vedo. - 0 66 Patient 175 2 CD Infl. 58 stopped - 43 Patient 176 2 CD Infl. - 1,6 371 Patient 177 2 CD Infl. - 0 130 Patient 178 1 CD Infl. 16,1 Ada. - - - Patient 179 1 UC Infl. 20,8 Vedo. - 0 < 30 Patient 180 2 CD Infl. 14 Ada. - - 299 Patient 181 2 CD Infl. 12 + 17 Ada. - - < 30 Patient 182 2 CD Infl. 5 Vedo. 11 stopped - > 1800 Patient 183 2 CD Infl. 34 stopped - 958 Patient 184 1 UC Infl. 1 Vedo. - 2,4 - Patient 185 1 CD Infl. - 4 777

77

Patient 186 2 CD Infl. - 4 46 Patient 187 1 CD Infl. 11 Vedo. - 2,4 - Patient 188 1 CD Infl. 3 Vedo. - 8 609 Patient 189 1 Pouchitis Infl. - 5 - Patient 190 1 CD Infl. - 0 < 30 Patient 191 1 UC Infl. - 0 - Patient 192 1 CD Infl. - 7 - Patient 193 1 UC Infl. 16,1 Ada. - - - Patient 194 1 CD Infl. - 7 43 Patient 195 1 UC Infl. 2 Vedo. 3 Infl. - 4 - Patient 196 1 CD Infl. 16,1 Ada. 16,1 stopped - - Patient 197 2 CD Infl. 16,1 Ada. 6 Vedo. - 3 118 Patient 198 2 CD Infl. 16,1 Ada. 39 Vedo. - 0 128 Patient 199 1 CD Infl. 31 Ada. - - 87 Patient 200 2 CD Infl. 1 Ada. 3 Vedo. - 2,1 71 Patient 201 1 UC Infl. 49 stopped - < 30 Patient 202 1 UC Infl. - 1,6 - Patient 203 2 CD Infl. 7 stopped - 1087 Patient 204 2 UC Infl. 17 stopped - 50 Patient 205 2 CD Infl. 62 Vedo. - 2 374 Patient 206 1 UC Infl. - 0 - Patient 207 1 CD Infl. 16,1 Ada. 5 Vedo. 5 stopped - > 1800 Patient 208 1 UC Infl. - - > 1800 Patient 209 2 CD Infl. 20 Ada. - - 507 Patient 210 1 UC Infl. 23 Vedo. - 0 653 Patient 211 2 UC Infl. - 0 35 Patient 212 2 CD Infl. - 0 676

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Patient 213 1 CD Infl. - 0 86 Patient 214 1 UC Infl. 12 stopped - < 30 Patient 215 1 UC Infl. 1 Vedo. 7 stopped - < 30 Patient 216 1 CD Infl. - 1,6 333 Patient 217 1 CD Infl. - 1,6 < 30 Patient 218 1 UC Infl. 7 Vedo. 22 stopped - 1430 Patient 219 1 CD Infl. 14 Ada. - - 63 Patient 220 2 CD Infl. 16,1 Ada. 17,4 Vedo. - 0 169 Patient 221 2 CD Infl. 3 Ada. 1 stopped - - Patient 222 2 CD Infl. 18 stopped - 218 Patient 223 2 CD Infl. 14 Ada. 16,1 stopped - - Patient 224 2 CD Infl. 29,6 stopped - 71 Patient 225 2 CD Infl. - 0 < 30 Patient 226 1 CD Infl. - 2 36 Patient 227 2 CD Infl. 7 stopped - 38 Patient 228 2 UC Infl. - 1 60 Patient 229 1 UC Infl. - 1 217 Patient 230 2 CD Infl. 8 stopped 1 193 Patient 231 2 CD Infl. - 1 147 Patient 232 2 CD Infl. 2 Ada. 23 Vedo. 23 Ustek. - 1288

TREAT treatment (biological) DUR duration (months) HBI Harvey-Bradshaw index FC feacal calprotection SEX 1 male SEX 2 female

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TOTAL UC CD OTHER M F Infl. Patients 232 75 155 2 125 107 still on Infl. 90 31 58 1 58 32 stopped Infl. 37 11 26 - 20 17 switched Ada. 78 14 61 1 27 49 still on Ada. 37 8 29 - 16 21 stopped Ada. 10 1 9 - 2 8 switched Vedo. 27 5 21 1 9 18 still on Vedo 21 5 15 1 8 13 stopped Vedo 6 - 6 - 1 5 Infl.-Vedo 25 17 8 - 18 7 still on Vedo 18 11 7 - 13 5 stopped Vedo 7 6 1 - 5 2 Infl.-Goli. 2 exclude Infl.-Ada.-Goli. 1 exclude Infl.-Ada.-Ustek. 1 exclude % M 53,88 F 46,12 Other = Pouchitis, IBD-U Ada………………Adalimumab Goli…………...Golimumab Infl………………..Infliximab Ustek…………….Ustekinumab Vedo……………..Vedolizumab

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C. Reason for Switching primary non response n=14 17,95%

secondary non response n=28 switched Infliximab- 35,90% Adalimumab n=78 reaction n=20 25,64%

clinical decision n=16 20,51%

primary non response n=8 29,63%

secondary non response n=5 switched Adalimumab- 18,52% Vedolizumab n=27 reaction n=4 14,81%

clinical decision

n=10

37,04%

primary non response n=5 20%

secondary non response n=9 switched Infliximab- 36% Vedolizumab n=25 reaction n=1 4%

clinical decision n=10 40%

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