Section 3 Anti-TNF Therapy

**Chapter 4**

**Abstract**

**1. Introduction**

**63**

Bowel Disease

*and Caio Almeida Perez*

Inhibitors of Tumoral Necrosis

Factor Alpha in Inflammatory

*Carlos Walter Sobrado, Natália Sousa Freitas Queiroz*

The treatment of inflammatory bowel disease (IBD) has undergone a major paradigm shift in the last two decades with the introduction of biological drugs. Tumoral necrosis factor (TNF) antagonists were the first monoclonal antibodies available for treatment of IBD. New emerging concepts as early initiation of treatment during the "opportunity window," and "treat to target" with a tight control strategy have contributed to optimum utilization of these drugs allowing better long-term outcomes for treated patients. This chapter aims to review all current pivotal data regarding efficacy and safety of infliximab, adalimumab, certolizumab pegol, and golimumab, as long as real life experience with these agents. Comparative efficacy among anti-TNF agents and the role of therapeutic drug monitoring in the management of IBD will also be discussed. Last, the authors present future perspectives with the drugs and position anti-TNF agents as viable therapeutic

**Keywords:** biologics, TNF inhibitors, therapy, Crohn's disease, ulcerative colitis

The treatment of inflammatory bowel disease (IBD) has remained a challenge for physicians involved in disease care because of its chronic nature and the impact on patient's quality of life. Traditionally, the pharmacological arsenal for the treat-

In the last two decades, there has been a major paradigm shift in the treatment of IBD, with the introduction of biological drugs (monoclonal antibodies) [4, 5]. Biological drugs were the only class of drugs that alter the natural course of the disease, reducing the risk of hospitalizations, and surgeries [6]. However, insights into the importance of early and optimized therapy have prompted interest in a 'treat to target' approach to achieve good disease control. This strategy involves treating to a pre-defined target that is associated with optimal long-term outcomes. Regular

ment of Crohn's Disease (CD) includes the aminosalicylates (sulfasalazine, mesalazine), immunosuppressants (e.g., azathioprine, 6-mercaptopurine, and methotrexate), corticosteroids (e.g., prednisone, hydrocortisone, methylprednisolone, and budesonide), and antibiotics. This therapeutic armamentarium, regarded as "conventional," does not seem to interfere with the natural history of the disease,

options in the current IBD therapeutic armamentarium.

while improving the symptoms of many patients [1–3].

#### **Chapter 4**

## Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease

*Carlos Walter Sobrado, Natália Sousa Freitas Queiroz and Caio Almeida Perez*

#### **Abstract**

The treatment of inflammatory bowel disease (IBD) has undergone a major paradigm shift in the last two decades with the introduction of biological drugs. Tumoral necrosis factor (TNF) antagonists were the first monoclonal antibodies available for treatment of IBD. New emerging concepts as early initiation of treatment during the "opportunity window," and "treat to target" with a tight control strategy have contributed to optimum utilization of these drugs allowing better long-term outcomes for treated patients. This chapter aims to review all current pivotal data regarding efficacy and safety of infliximab, adalimumab, certolizumab pegol, and golimumab, as long as real life experience with these agents. Comparative efficacy among anti-TNF agents and the role of therapeutic drug monitoring in the management of IBD will also be discussed. Last, the authors present future perspectives with the drugs and position anti-TNF agents as viable therapeutic options in the current IBD therapeutic armamentarium.

**Keywords:** biologics, TNF inhibitors, therapy, Crohn's disease, ulcerative colitis

#### **1. Introduction**

The treatment of inflammatory bowel disease (IBD) has remained a challenge for physicians involved in disease care because of its chronic nature and the impact on patient's quality of life. Traditionally, the pharmacological arsenal for the treatment of Crohn's Disease (CD) includes the aminosalicylates (sulfasalazine, mesalazine), immunosuppressants (e.g., azathioprine, 6-mercaptopurine, and methotrexate), corticosteroids (e.g., prednisone, hydrocortisone, methylprednisolone, and budesonide), and antibiotics. This therapeutic armamentarium, regarded as "conventional," does not seem to interfere with the natural history of the disease, while improving the symptoms of many patients [1–3].

In the last two decades, there has been a major paradigm shift in the treatment of IBD, with the introduction of biological drugs (monoclonal antibodies) [4, 5]. Biological drugs were the only class of drugs that alter the natural course of the disease, reducing the risk of hospitalizations, and surgeries [6]. However, insights into the importance of early and optimized therapy have prompted interest in a 'treat to target' approach to achieve good disease control. This strategy involves treating to a pre-defined target that is associated with optimal long-term outcomes. Regular

#### *Biological Therapy for Inflammatory Bowel Disease*

monitoring of objective measures of disease is required, and treatment is optimized based on these findings to ensure the target is achieved and maintained.

selecting therapeutic targets in inflammatory bowel disease (STRIDE), where 28 experts in IBD developed recommendations based on a systematic literature review and expert opinion proposing the strategy "treat to target" in IBD. In this publication, the recommended therapeutic targets were clinical remission defined by improvement in bowel movements and the resolution of the associated rectal bleeding for UC or abdominal pain for Crohn's disease. Furthermore, endoscopic remission with no ulcerations in CD and an endoscopic Mayo score 0-1 in UC should

*Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.90204*

The "treat to target" strategy defines the therapeutic goals that professionals should aim for, although it is important to emphasize which treatment strategy should be adopted in order to achieve the desired outcome. With that purpose, in 2017 the effect of tight control management on Crohn's disease (CALM) trial was published, a multicenter phase 3, randomized controlled trial designed to evaluate the safety and effectiveness of two treatment strategies in patients with CD scaling to biological therapy based on predefined criteria of treatment failure. The primary endpoint was the mucosal healing, defined by a CDEIS <4 score and the absence of deep ulcers at the end of 48 weeks, patients were randomized into two groups: the "tight control," where therapy was scaled based on clinical evaluation and biomarkers (fecal calprotectin and CRP), and the clinical management group, in which only the symptom assessment was considered. It was observed that a significantly higher proportion of patients in the "tight control" group reached the primary endpoint compared to the clinical management group, showing that the escalation of biological therapy guided by targets in patients with early CD is associated with better clinical and endoscopic outcomes when there is an association of clinical

The first group of biological medicines was composed by tumoral necrosis factor (TNF) antagonists, approved for use in Crohn's disease patients in 1998. The currently available anti-TNFs for treatment of CD are infliximab, adalimumab, and

The infliximab (IFX), a chimeric monoclonal IgG1 antibody, was the first biological used in CD. In 1997, Targan et al. published a randomized controlled trial demonstrating the superiority of the drug in inducing clinical remission in moderate to severe CD compared to placebo. Four groups were defined, involving 108 patients, to receive doses of 5, 10, 20 mg/kg, or placebo. The primary outcome was clinical response after 4 weeks, defined by a decrease of 70 points, or more in CDAI score after a single infusion. It was observed that 81% of patients receiving 5 mg/kg, 50% of those who received 10 mg/kg, and 64% receiving 20 mg/kg achieved the goal, compared to only 17% in the placebo group (*p* < 0.001). This was the first comparative, randomized, placebo-controlled trial involving IFX in the treatment of CD. It is a landmark in biological therapy because it has demonstrated superiority of this drug over placebo in a single infusion and guided the currently adopted dose of 5 mg/kg [14]. Subsequently, Present et al. published a longer lasting study with 18 weeks of follow-up involving patients with penetrating CD that had active fistulas. In addition of the initial dose at week 0, IFX was administered at weeks 2 and 6 in two groups with 5 or 10 mg/kg compared to the placebo group. The primary endpoint was the 50% reduction in the drainage of fistula, which occurred in 68, 56, and 26% in the groups 5, 10 mg/kg, and placebo, respectively, with

evaluation and biomarkers for decision-making [13].

certolizumab pegol (**Figure 1**).

**2. Infliximab (Remicade®)**

statistical significance [15].

**65**

be confirmed [11].

The natural course of inflammatory bowel disease is characterized by periods of remission and exacerbation and, over time, patients can develop irreversible damage such as stenosis and fistulas in Crohn's disease shortening and lead pipe appearance of colon in UC. However, it has been shown that early diagnosis with identification of severity predictors factors [7] and the early initiation of treatment with biological drugs during the "opportunity window," where symptoms are mainly derived from the diseases inflammatory activity in its initial phase, significantly reduces the rate of surgical complications, such as fistula stenosis in CD, as well as the need for colectomy in patients with UC who present severe acute colitis or chronic colitis refractory to corticoid, aminosalicylates, and immunosuppressive therapy [8–10].

The current IBD treatment goals include not only symptoms control, mainly but also sustained control of inflammation, through the mucosal healing and complication prevention (fistulae, abscesses, stenoses, dysmotility, and dysplasia), which may lead to hospitalization, surgery and substantial impact in quality of life [1, 11, 12]**.** In 2015, the International Organization for the Study of Inflammatory Bowel Diseases for the Study of Inflammatory Bowel Diseases (IOIBD) published the

#### **Figure 1.**

*TNF's mechanisms of action - In the pathophysiology of Crohn's disease,TNF is produced at high concentrations by a variety of cell types, presumably induced by endogenous or microbial stimuli. A cascade and network of cellular responses mediated by TNF are shown in the the diagram.*

#### *Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease DOI: http://dx.doi.org/10.5772/intechopen.90204*

selecting therapeutic targets in inflammatory bowel disease (STRIDE), where 28 experts in IBD developed recommendations based on a systematic literature review and expert opinion proposing the strategy "treat to target" in IBD. In this publication, the recommended therapeutic targets were clinical remission defined by improvement in bowel movements and the resolution of the associated rectal bleeding for UC or abdominal pain for Crohn's disease. Furthermore, endoscopic remission with no ulcerations in CD and an endoscopic Mayo score 0-1 in UC should be confirmed [11].

The "treat to target" strategy defines the therapeutic goals that professionals should aim for, although it is important to emphasize which treatment strategy should be adopted in order to achieve the desired outcome. With that purpose, in 2017 the effect of tight control management on Crohn's disease (CALM) trial was published, a multicenter phase 3, randomized controlled trial designed to evaluate the safety and effectiveness of two treatment strategies in patients with CD scaling to biological therapy based on predefined criteria of treatment failure. The primary endpoint was the mucosal healing, defined by a CDEIS <4 score and the absence of deep ulcers at the end of 48 weeks, patients were randomized into two groups: the "tight control," where therapy was scaled based on clinical evaluation and biomarkers (fecal calprotectin and CRP), and the clinical management group, in which only the symptom assessment was considered. It was observed that a significantly higher proportion of patients in the "tight control" group reached the primary endpoint compared to the clinical management group, showing that the escalation of biological therapy guided by targets in patients with early CD is associated with better clinical and endoscopic outcomes when there is an association of clinical evaluation and biomarkers for decision-making [13].

The first group of biological medicines was composed by tumoral necrosis factor (TNF) antagonists, approved for use in Crohn's disease patients in 1998. The currently available anti-TNFs for treatment of CD are infliximab, adalimumab, and certolizumab pegol (**Figure 1**).

#### **2. Infliximab (Remicade®)**

The infliximab (IFX), a chimeric monoclonal IgG1 antibody, was the first biological used in CD. In 1997, Targan et al. published a randomized controlled trial demonstrating the superiority of the drug in inducing clinical remission in moderate to severe CD compared to placebo. Four groups were defined, involving 108 patients, to receive doses of 5, 10, 20 mg/kg, or placebo. The primary outcome was clinical response after 4 weeks, defined by a decrease of 70 points, or more in CDAI score after a single infusion. It was observed that 81% of patients receiving 5 mg/kg, 50% of those who received 10 mg/kg, and 64% receiving 20 mg/kg achieved the goal, compared to only 17% in the placebo group (*p* < 0.001). This was the first comparative, randomized, placebo-controlled trial involving IFX in the treatment of CD. It is a landmark in biological therapy because it has demonstrated superiority of this drug over placebo in a single infusion and guided the currently adopted dose of 5 mg/kg [14]. Subsequently, Present et al. published a longer lasting study with 18 weeks of follow-up involving patients with penetrating CD that had active fistulas. In addition of the initial dose at week 0, IFX was administered at weeks 2 and 6 in two groups with 5 or 10 mg/kg compared to the placebo group. The primary endpoint was the 50% reduction in the drainage of fistula, which occurred in 68, 56, and 26% in the groups 5, 10 mg/kg, and placebo, respectively, with statistical significance [15].

monitoring of objective measures of disease is required, and treatment is optimized

The natural course of inflammatory bowel disease is characterized by periods of remission and exacerbation and, over time, patients can develop irreversible damage such as stenosis and fistulas in Crohn's disease shortening and lead pipe appearance of colon in UC. However, it has been shown that early diagnosis with identification of severity predictors factors [7] and the early initiation of treatment with biological drugs during the "opportunity window," where symptoms are mainly derived from the diseases inflammatory activity in its initial phase, significantly reduces the rate of

based on these findings to ensure the target is achieved and maintained.

*Biological Therapy for Inflammatory Bowel Disease*

surgical complications, such as fistula stenosis in CD, as well as the need for colectomy in patients with UC who present severe acute colitis or chronic colitis refractory to corticoid, aminosalicylates, and immunosuppressive therapy [8–10]. The current IBD treatment goals include not only symptoms control, mainly but also sustained control of inflammation, through the mucosal healing and complication prevention (fistulae, abscesses, stenoses, dysmotility, and dysplasia), which may lead to hospitalization, surgery and substantial impact in quality of life [1, 11, 12]**.** In 2015, the International Organization for the Study of Inflammatory Bowel Diseases for the Study of Inflammatory Bowel Diseases (IOIBD) published the

*TNF's mechanisms of action - In the pathophysiology of Crohn's disease,TNF is produced at high concentrations by a variety of cell types, presumably induced by endogenous or microbial stimuli. A cascade and network of*

*cellular responses mediated by TNF are shown in the the diagram.*

**Figure 1.**

**64**

With the efficacy of IFX in inducing clinical remission established, in order to evaluate its efficacy in maintain clinical response in CD, in 2002 the ACCENT I study was published, the most relevant publication related to IFX in CD; a multicenter study (US, Europe, and Israel), controlled trial involving 573 patients with moderate to severe Crohn's disease (CDAI between 220 and 400). All patients received a dose of IFX 5 mg/kg and were assessed after 2 weeks. Of these, 325 (58%) had clinical response (CDAI decrease of 70 points or more at baseline) and were randomized at week 2 into 03 groups: 5, 10 mg/kg, and placebo. Following treatment regimen suggested by Present et al., doses were administered at weeks 0, 2, and 6, and subsequently administered every 8 weeks. The primary endpoint was clinical remission (CDAI <150 points) maintained after 30 and 54 weeks of initiating therapy. It was observed that those who responded to induction dose had higher remission rate at weeks 30 and 54. The maintenance of clinical remission rates at 54 weeks were significantly higher in the groups that received IFX 5 and 10 mg/kg (28.3 and 38.4%, respectively) compared with placebo (13.6%), showing the effectiveness of maintenance therapy with IFX. No statistical significance was observed in the difference between 5 and 10 mg/kg groups. In addition, in the placebo group, there was no mucosal healing at week 10, whereas patients receiving IFX in doses of 5 and 10 mg/kg, healing was observed in 31% of cases [16]. Following this line of reasoning, ACCENT II was published in 2004, a phase III randomized, doubleblind, placebo-controlled study that included 306 patients with penetrating CD (enterocutaneous and perianal fistula), of which 282 were randomized at week 14 after the induction therapy (weeks 0, 2, and 6) for receiving infusions of 5 mg/kg or placebo every 8 weeks, aiming to evaluate the loss of IFX response in both groups after 54 weeks of treatment. It was observed that the time to loss of response was significantly higher in the IFX group over placebo (>40 weeks vs. 14, *p* < 0.001), and after 54 weeks, only 19% of the patients in the placebo group did not have fistulas in compared to 36% in the IFX group (*p* = 0.009) [17].

55 months follow-up, in which approximately 11% were primary nonresponders. Of the 547 remaining, 63.3% of patients had sustained clinical benefit. Treatment was discontinued in 31.7% of cases due to complete remission, 12.8% due to adverse events, and 21.6% due to loss of response to the drug. This study demonstrated that good results can be obtained with IFX treatment in

*Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.90204*

the real world, when the requirements of controlled studies are often not

center with a specific profile of patients. The most common infectious

complications were bacterial infection (intra-abdominal abscesses and pneumonia)

loss of response over time, with frequent need for dose escalation due to their immunogenicity. Then was raised the possibility of association of anti-TNF with immunosuppressive agents such as azathioprine (AZA) and 6-mercaptopurine, as synergists agents. In this context, the SONIC study was published in 2010 evaluating 508 patients with CD randomized to three different treatment strategies: IFX monotherapy, AZA monotherapy, or combination therapy with the two drugs. After 30 weeks of treatment, approximately 57% of patients treated with the combination therapy achieved corticosteroid free clinical remission (primary endpoint),

compared to 44.4% in IFX monotherapy group (*p* = 0.02) and 30% in AZA monotherapy group (*p* < 0.001 for combination therapy; *p* = 0.006 for IFX). The mucosal healing rate was also higher in the combination therapy and IFX monotherapy groups compared to isolated AZA (*p* < 0.001 and *p* = 0.02, respectively). The difference between the IFX monotherapy and combination therapy groups in this outcome was not statistically significant (*p* = 0.06) [21]. With a similar study design, the SUCCESS was published in 2014, analyzing 239 patients with moderate to severe UC who were randomized to treatment with the combination therapy (IFX + AZA), IFX monotherapy, or AZA alone. Steroid-free clinical remission at week 16 was achieved by 39.7% of patients treated with the combination therapy compared to 22.1% in the IFX group (*p* = 0.017) and 23.7% in the AZA group (*p* = 0.032). Similarly, the difference in mucosal healing was only statistically significant when the combination therapy was compared to AZA monotherapy

(62.8 and 36.8%, respectively, *p* = 0.001) [22].

Long-term studies have demonstrated that, despite its effectiveness, IFX shows

The data presented above have reassured that IFX, marketed for over 20 years,

are efficient and have a satisfactory safety profile, being considered as a first-line biological treatment of IBD, especially in the management of perianal Crohn's disease and severe acute colitis. Moreover, it plays an important

In order to evaluate the safety profile and long-term repercussions of IFX treatment based on real life clinical experience, Sandborn et al. published in 2012 a study involving 492 CD patients treated between 1998 and 2002 at the Mayo Clinic and followed until 2009. It was shown that approximately 80% of patients showed clinical response to induction therapy, of which 25% with partial and 75% with complete response, in agreement with previously reported data [16, 17]. Dose escalation or shortening of the interval between infusions occurred in approximately 57% of patients who received maintenance dose with a cumulative probability of a therapeutic adjustment of 19% in the first year, 57% in 5 years, and 74% in 10 years of follow-up, reflecting that there is a loss of response over time. Note that 10% of the 182 patients who received maintenance therapy, discontinued its use because of loss of response. The cumulative probability of adverse events was around 35% in the first year, increasing to 86% after 10 years of therapy. Approximately 5% of patients developed cancer, with a cumulative probability of 9.1% in 10 years, though it was unclear if this increased incidence of cancer was related to the CD itself, the use of IFX or because this study was performed at a reference

attained [19].

and viral [20].

**67**

In order to assess the IFX therapy effectiveness in induction and maintenance of clinical response in moderate to severe UC two phase III placebo-controlled studies were subsequently published: the ACT I and II. With a total of 364 patients involved in each study, they were randomized to receive placebo, 5 or 10 mg/kg at weeks 0, 2, and 6, followed by infusions every 8 weeks through weeks 46 (ACT I) and 22 (ACT II). The primary endpoint was to evaluate clinical response (defined as decrease of three points in Mayo score and, at least, one point in the sub-item for rectal bleeding) at week 8, having as secondary endpoints the clinical response or remission after corticosteroid withdrawal and mucosal healing at weeks 8, 30 in both studies, and at week 54 in ACT I. In this last study, only 37% of patients in placebo group had clinical response at week 8 versus 69% (*p* < 0.001) in the 5 mg/kg group and 62% (*p* < 0.002) in the 10 mg/kg group. In ACT II, 64% of patients receiving IFX 5 mg/kg and 69% of those who received 10 mg/kg had clinical response at week 8 compared to 29% of those receiving placebo (*p* < 0.001 for both comparisons). In both studies, clinical response was more frequently observed at week 30 among patients who received IFX (*p* < 0.002 for all comparisons). In ACT I, after 54 weeks, more patients receiving IFX 5 or 10 mg/kg (45 and 44%, respectively) showed clinical response compared to placebo (20%, *p*< 0.001) [18].

The pivotal studies mentioned consolidated IFX use as induction and maintenance therapy in CD and UC. However, in general, the clinical trials inclusion criteria are too restrictive, restricting the participation of most patients in daily clinical practice. One of the biggest real-life studies evaluating the effectiveness of treatment of CD with IFX was published in 2009 by Schnitzler et al. from Leuven group. Six hundred fourteen patients were evaluated with a median of

#### *Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease DOI: http://dx.doi.org/10.5772/intechopen.90204*

55 months follow-up, in which approximately 11% were primary nonresponders. Of the 547 remaining, 63.3% of patients had sustained clinical benefit. Treatment was discontinued in 31.7% of cases due to complete remission, 12.8% due to adverse events, and 21.6% due to loss of response to the drug. This study demonstrated that good results can be obtained with IFX treatment in the real world, when the requirements of controlled studies are often not attained [19].

In order to evaluate the safety profile and long-term repercussions of IFX treatment based on real life clinical experience, Sandborn et al. published in 2012 a study involving 492 CD patients treated between 1998 and 2002 at the Mayo Clinic and followed until 2009. It was shown that approximately 80% of patients showed clinical response to induction therapy, of which 25% with partial and 75% with complete response, in agreement with previously reported data [16, 17]. Dose escalation or shortening of the interval between infusions occurred in approximately 57% of patients who received maintenance dose with a cumulative probability of a therapeutic adjustment of 19% in the first year, 57% in 5 years, and 74% in 10 years of follow-up, reflecting that there is a loss of response over time. Note that 10% of the 182 patients who received maintenance therapy, discontinued its use because of loss of response. The cumulative probability of adverse events was around 35% in the first year, increasing to 86% after 10 years of therapy. Approximately 5% of patients developed cancer, with a cumulative probability of 9.1% in 10 years, though it was unclear if this increased incidence of cancer was related to the CD itself, the use of IFX or because this study was performed at a reference center with a specific profile of patients. The most common infectious complications were bacterial infection (intra-abdominal abscesses and pneumonia) and viral [20].

Long-term studies have demonstrated that, despite its effectiveness, IFX shows loss of response over time, with frequent need for dose escalation due to their immunogenicity. Then was raised the possibility of association of anti-TNF with immunosuppressive agents such as azathioprine (AZA) and 6-mercaptopurine, as synergists agents. In this context, the SONIC study was published in 2010 evaluating 508 patients with CD randomized to three different treatment strategies: IFX monotherapy, AZA monotherapy, or combination therapy with the two drugs. After 30 weeks of treatment, approximately 57% of patients treated with the combination therapy achieved corticosteroid free clinical remission (primary endpoint), compared to 44.4% in IFX monotherapy group (*p* = 0.02) and 30% in AZA monotherapy group (*p* < 0.001 for combination therapy; *p* = 0.006 for IFX). The mucosal healing rate was also higher in the combination therapy and IFX monotherapy groups compared to isolated AZA (*p* < 0.001 and *p* = 0.02, respectively). The difference between the IFX monotherapy and combination therapy groups in this outcome was not statistically significant (*p* = 0.06) [21]. With a similar study design, the SUCCESS was published in 2014, analyzing 239 patients with moderate to severe UC who were randomized to treatment with the combination therapy (IFX + AZA), IFX monotherapy, or AZA alone. Steroid-free clinical remission at week 16 was achieved by 39.7% of patients treated with the combination therapy compared to 22.1% in the IFX group (*p* = 0.017) and 23.7% in the AZA group (*p* = 0.032). Similarly, the difference in mucosal healing was only statistically significant when the combination therapy was compared to AZA monotherapy (62.8 and 36.8%, respectively, *p* = 0.001) [22].

The data presented above have reassured that IFX, marketed for over 20 years, are efficient and have a satisfactory safety profile, being considered as a first-line biological treatment of IBD, especially in the management of perianal Crohn's disease and severe acute colitis. Moreover, it plays an important

With the efficacy of IFX in inducing clinical remission established, in order to evaluate its efficacy in maintain clinical response in CD, in 2002 the ACCENT I study was published, the most relevant publication related to IFX in CD; a multicenter study (US, Europe, and Israel), controlled trial involving 573 patients with moderate to severe Crohn's disease (CDAI between 220 and 400). All patients received a dose of IFX 5 mg/kg and were assessed after 2 weeks. Of these, 325 (58%) had clinical response (CDAI decrease of 70 points or more at baseline) and were randomized at week 2 into 03 groups: 5, 10 mg/kg, and placebo. Following treatment regimen suggested by Present et al., doses were administered at weeks 0, 2, and 6, and subsequently administered every 8 weeks. The primary endpoint was clinical remission (CDAI <150 points) maintained after 30 and 54 weeks of initiating therapy. It was observed that those who responded to induction dose had higher remission rate at weeks 30 and 54. The maintenance of clinical remission rates at 54 weeks were significantly higher in the groups that received IFX 5 and 10 mg/kg (28.3 and 38.4%, respectively) compared with placebo (13.6%), showing the effectiveness of maintenance therapy with IFX. No statistical significance was observed in the difference between 5 and 10 mg/kg groups. In addition, in the placebo group, there was no mucosal healing at week 10, whereas patients receiving IFX in doses of 5 and 10 mg/kg, healing was observed in 31% of cases [16]. Following this line of reasoning, ACCENT II was published in 2004, a phase III randomized, doubleblind, placebo-controlled study that included 306 patients with penetrating CD (enterocutaneous and perianal fistula), of which 282 were randomized at week 14 after the induction therapy (weeks 0, 2, and 6) for receiving infusions of 5 mg/kg or placebo every 8 weeks, aiming to evaluate the loss of IFX response in both groups after 54 weeks of treatment. It was observed that the time to loss of response was significantly higher in the IFX group over placebo (>40 weeks vs. 14, *p* < 0.001), and after 54 weeks, only 19% of the patients in the placebo group did not have

*Biological Therapy for Inflammatory Bowel Disease*

fistulas in compared to 36% in the IFX group (*p* = 0.009) [17].

*p*< 0.001) [18].

**66**

In order to assess the IFX therapy effectiveness in induction and maintenance of clinical response in moderate to severe UC two phase III placebo-controlled studies were subsequently published: the ACT I and II. With a total of 364 patients involved in each study, they were randomized to receive placebo, 5 or 10 mg/kg at weeks 0, 2, and 6, followed by infusions every 8 weeks through weeks 46 (ACT I) and 22 (ACT II). The primary endpoint was to evaluate clinical response (defined as decrease of three points in Mayo score and, at least, one point in the sub-item for rectal bleeding) at week 8, having as secondary endpoints the clinical response or remission after corticosteroid withdrawal and mucosal healing at weeks 8, 30 in both studies, and at week 54 in ACT I. In this last study, only 37% of patients in placebo group had clinical response at week 8 versus 69% (*p* < 0.001) in the 5 mg/kg group and 62% (*p* < 0.002) in the 10 mg/kg group. In ACT II, 64% of patients receiving IFX 5 mg/kg and 69% of those who received 10 mg/kg had clinical response at week 8 compared to 29% of those receiving placebo (*p* < 0.001 for both comparisons). In both studies, clinical response was more frequently observed at week 30 among patients who received IFX (*p* < 0.002 for all

comparisons). In ACT I, after 54 weeks, more patients receiving IFX 5 or 10 mg/kg (45 and 44%, respectively) showed clinical response compared to placebo (20%,

The pivotal studies mentioned consolidated IFX use as induction and maintenance therapy in CD and UC. However, in general, the clinical trials inclusion criteria are too restrictive, restricting the participation of most patients in daily clinical practice. One of the biggest real-life studies evaluating the effectiveness of treatment of CD with IFX was published in 2009 by Schnitzler et al. from Leuven group. Six hundred fourteen patients were evaluated with a median of

role in the management of extra intestinal manifestations and the prevention of postoperative recurrence [23].

further published in 2006. Similarly to CLASSIC I, clinical remission was assessed at the end of 4 weeks after the randomization of 325 patients to receive induction therapy (160 and 80 mg at weeks 0 and 2) or placebo. It was observed that 21% of patients with ADA therapy reached the primary endpoint compared to only 7% in the placebo group (*p* < 0.001). This study has demonstrated that ADA is indeed

The therapy with ADA in UC was described later, when, in 2010, ULTRA 1 was published evaluating the drug efficacy in induction of clinical remission in patients naive for biological drugs. The study included 390 patients randomized into three groups to receive ADA in induction regimen with 160/80 mg at weeks 0 and 2, followed by 40 mg at weeks 4 and 6; 80/40 mg at weeks 0 and 2, followed by 40 mg every other week and the placebo group. At the end of 8 weeks, approximately 19% of patients in group 160/80 mg showed clinical remission compared with 9.2% of patients in the placebo group (*p* = 0.031), showing modest efficacy of this therapeutic regimen in UC patients who failed therapy with corticosteroids and/or immunosuppressant. The induction regimen with ADA 80/40 mg compared to

To analyze the efficiency in the induction of remission and also the maintenance of clinical response ULTRA 2 was sequentially published, studying 494 patients with UC who were initially stratified by prior use or not of anti-TNF alpha and randomized for induction therapy with ADA 160/80 mg at weeks 0 and 2 followed by ADA 40 mg every other week or placebo. The primary endpoint was clinical remission at weeks 8 and 52. Analyzing the group as a whole, there was no statistically significant difference at week 8, however, at week 52, 17.3% of patients with ADA achieved clinical remission superior to placebo group (8.5%, *p* = 0.004). The superiority was also observed at the end of 52 weeks (12.4 vs. 22%, respectively; *p* = 0.029). In the subgroup previously experienced with anti-TNF alpha, a statistically significant superiority was observed at the end of 52 weeks (10.2% in the ADA

Even though data in pivotal studies for ADA in UC are not as robust, Tursi et al. published in 2018 the results of a real-life study involving 102 UC patients demonstrating drug efficacy and safety more consistently. The primary outcome was the induction and maintenance of remission, defined by a Mayo score ≤ 2. At 3 months, 54.9% of patients achieved clinical remission and during an average follow-up of 18 months, 56.6% of the patients were in this same situation. Secondarily, clinical response and mucosal healing was achieved by 89.2 and 76.7% of the patients, respectively. Only three patients underwent colectomy (two because of primary therapeutic failure and one for secondary loss) and one patient discontinued treat-

In relation to real life experience in CD, Loftus et al. recently published the results of PYRAMID registry, evaluating the efficacy and safety of ADA in patients naive to biological therapy followed for 6 years. Taking into consideration the Physician's Global Assessment (PGA) and clinical remission (Harvey Bradshaw index <5), 2057 patients were analyzed with an improvement baseline PGA from 7.5 to 3.9 in the first year and 3.3 in the sixth year. The rate of patients in clinical remission increased from 29 to 68% and 75% after 1 and 6 years, respectively. As related to adverse events, 11.1% of patients had severe infections and the incidence

ADA has demonstrated superiority to placebo for induction and maintenance of remission in patients with CD and UC. Its subcutaneous administration seems to be a more convenient approach to patients who prefer to self-administer. It is also considered a first-line agent in the management of moderate to severe CD and UC patients refractory to conventional therapy with a satisfactory safety profile.

an alternative for patients with refractory CD or is intolerant to IFX [27].

*Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.90204*

placebo did not present statistical significance [28].

group vs. 3% in the placebo group, *p* = 0.039) [29].

ment due to leukopenia [30].

**69**

of malignancy was relatively low (1.9%) [31].

#### **3. Adalimumab (Humira®)**

Adalimumab, a fully humanized monoclonal antibody IgG1, was the second anti-TNF antibody released for treating IBD. The first paper published on the efficacy of ADA in induction of remission in CD was the CLASSIC I trial in 2006. Aiming the assessment of clinical response after 4 weeks of treatment (CDAI <150 points), 299 patients naïve to anti-TNF therapy were randomized to receive, respectively, at weeks 0 and 2, a dose of ADA 40/20, 80/40, 80/160 mg, or placebo. The results showed major clinical remission rate at a dose of 160/80 mg (36%) compared to placebo (12%, *p* < 0.001). Secondary endpoints were to evaluate the partial clinical improvement, defined by a decrease of 70 or 100 points in the CDAI. The first one was obtained with the three therapeutic regimens and the last only by the 160/80 mg dose, which has defined this regimen as the best option for ADA induction therapy [24].

In order to establish the efficacy of ADA in maintaining clinical response, CLASSIC II was subsequently published evaluating 55 patients from the CLASSIC I who were in clinical that were further randomized to three different treatment regimens: ADA 40 mg every other week, 40 mg weekly, or placebo until completing 56 weeks. In addition, 204 patients from CLASSIC I who were not in clinical remission were enrolled in an open label arm to use ADA 40 mg every other week. The primary endpoint was to evaluate the clinical remission (CDAI <150 points) among randomized patients and it was observed that 79% of patients receiving ADA every other week and 83% of those who received ADA weekly were in clinical remission against 44% in the placebo group (*p* < 0.05) Among the 204 patients assigned to treatment with ADA 40 mg every other week, 46% achieved clinical remission at the end of the 56 weeks. It is noteworthy that this is a study with a low randomized sample [25].

In order to emphasize the sustained efficacy of ADA in CD therapy, in 2007 Colombel et al. published the CHARM trial, a phase III study involving 854 patients who initially were subjected to induction with ADA, of which 499 (58%) had initial clinical response (CDAI decrease in ≥70 basal line) and were randomized to maintenance therapy with ADA 40 mg every other week, 40 mg weekly, or placebo with assess of clinical remission (CDAI <150) after 26 and 56 weeks of therapy. Analyzing the randomized groups, it was noted that clinical remission was significantly greater in the groups using ADA than to placebo at week 56, with 41% in the group receiving the drug weekly, 36% in the group receiving every other week, and 12% in the placebo group (*p* < 0.001). There was no statistically significance in the difference observed between the groups treated with ADA, confirming that the best initial regimen therapy with ADA is 40 mg every other week. It was noted that the superior results observed in CLASSIC II may be due to the fact that patients randomized in this study were in clinical remission, while in CHARM patients with a partial clinical response were included, giving a difference in population of the two studies, preventing direct comparison between them [26]. Analyzing the subgroup of patients who had been previous treated with IFX and discontinued therapy due to loss of response or intolerance it was also observed a higher remission rate compared to placebo, confirming that ADA therapy is a plausible alternative in this group of patients.

In order to properly evaluate the effectiveness of ADA as a rescue therapy in patients with CD who have intolerance or loss of response to IFX, GAIN study was

#### *Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease DOI: http://dx.doi.org/10.5772/intechopen.90204*

further published in 2006. Similarly to CLASSIC I, clinical remission was assessed at the end of 4 weeks after the randomization of 325 patients to receive induction therapy (160 and 80 mg at weeks 0 and 2) or placebo. It was observed that 21% of patients with ADA therapy reached the primary endpoint compared to only 7% in the placebo group (*p* < 0.001). This study has demonstrated that ADA is indeed an alternative for patients with refractory CD or is intolerant to IFX [27].

The therapy with ADA in UC was described later, when, in 2010, ULTRA 1 was published evaluating the drug efficacy in induction of clinical remission in patients naive for biological drugs. The study included 390 patients randomized into three groups to receive ADA in induction regimen with 160/80 mg at weeks 0 and 2, followed by 40 mg at weeks 4 and 6; 80/40 mg at weeks 0 and 2, followed by 40 mg every other week and the placebo group. At the end of 8 weeks, approximately 19% of patients in group 160/80 mg showed clinical remission compared with 9.2% of patients in the placebo group (*p* = 0.031), showing modest efficacy of this therapeutic regimen in UC patients who failed therapy with corticosteroids and/or immunosuppressant. The induction regimen with ADA 80/40 mg compared to placebo did not present statistical significance [28].

To analyze the efficiency in the induction of remission and also the maintenance of clinical response ULTRA 2 was sequentially published, studying 494 patients with UC who were initially stratified by prior use or not of anti-TNF alpha and randomized for induction therapy with ADA 160/80 mg at weeks 0 and 2 followed by ADA 40 mg every other week or placebo. The primary endpoint was clinical remission at weeks 8 and 52. Analyzing the group as a whole, there was no statistically significant difference at week 8, however, at week 52, 17.3% of patients with ADA achieved clinical remission superior to placebo group (8.5%, *p* = 0.004). The superiority was also observed at the end of 52 weeks (12.4 vs. 22%, respectively; *p* = 0.029). In the subgroup previously experienced with anti-TNF alpha, a statistically significant superiority was observed at the end of 52 weeks (10.2% in the ADA group vs. 3% in the placebo group, *p* = 0.039) [29].

Even though data in pivotal studies for ADA in UC are not as robust, Tursi et al. published in 2018 the results of a real-life study involving 102 UC patients demonstrating drug efficacy and safety more consistently. The primary outcome was the induction and maintenance of remission, defined by a Mayo score ≤ 2. At 3 months, 54.9% of patients achieved clinical remission and during an average follow-up of 18 months, 56.6% of the patients were in this same situation. Secondarily, clinical response and mucosal healing was achieved by 89.2 and 76.7% of the patients, respectively. Only three patients underwent colectomy (two because of primary therapeutic failure and one for secondary loss) and one patient discontinued treatment due to leukopenia [30].

In relation to real life experience in CD, Loftus et al. recently published the results of PYRAMID registry, evaluating the efficacy and safety of ADA in patients naive to biological therapy followed for 6 years. Taking into consideration the Physician's Global Assessment (PGA) and clinical remission (Harvey Bradshaw index <5), 2057 patients were analyzed with an improvement baseline PGA from 7.5 to 3.9 in the first year and 3.3 in the sixth year. The rate of patients in clinical remission increased from 29 to 68% and 75% after 1 and 6 years, respectively. As related to adverse events, 11.1% of patients had severe infections and the incidence of malignancy was relatively low (1.9%) [31].

ADA has demonstrated superiority to placebo for induction and maintenance of remission in patients with CD and UC. Its subcutaneous administration seems to be a more convenient approach to patients who prefer to self-administer. It is also considered a first-line agent in the management of moderate to severe CD and UC patients refractory to conventional therapy with a satisfactory safety profile.

role in the management of extra intestinal manifestations and the prevention

Adalimumab, a fully humanized monoclonal antibody IgG1, was the second anti-TNF antibody released for treating IBD. The first paper published on the efficacy of ADA in induction of remission in CD was the CLASSIC I trial in 2006. Aiming the assessment of clinical response after 4 weeks of treatment (CDAI <150 points), 299 patients naïve to anti-TNF therapy were randomized to receive, respectively, at weeks 0 and 2, a dose of ADA 40/20, 80/40, 80/160 mg, or placebo. The results showed major clinical remission rate at a dose of 160/80 mg (36%) compared to placebo (12%, *p* < 0.001). Secondary endpoints were to evaluate the partial clinical improvement, defined by a decrease of 70 or 100 points in the CDAI. The first one was obtained with the three therapeutic regimens and the last only by the 160/80 mg dose, which has defined this regimen as the best option for ADA

In order to establish the efficacy of ADA in maintaining clinical response, CLASSIC II was subsequently published evaluating 55 patients from the CLASSIC I who were in clinical that were further randomized to three different treatment regimens: ADA 40 mg every other week, 40 mg weekly, or placebo until completing 56 weeks. In addition, 204 patients from CLASSIC I who were not in clinical remission were enrolled in an open label arm to use ADA 40 mg every other week. The primary endpoint was to evaluate the clinical remission (CDAI <150 points) among randomized patients and it was observed that 79% of patients receiving ADA every other week and 83% of those who received ADA weekly were in clinical remission against 44% in the placebo group (*p* < 0.05) Among the 204 patients assigned to treatment with ADA 40 mg every other week, 46% achieved clinical remission at the end of the 56 weeks. It is noteworthy that this is a study with a low

In order to emphasize the sustained efficacy of ADA in CD therapy, in 2007 Colombel et al. published the CHARM trial, a phase III study involving 854 patients who initially were subjected to induction with ADA, of which 499 (58%) had initial clinical response (CDAI decrease in ≥70 basal line) and were randomized to maintenance therapy with ADA 40 mg every other week, 40 mg weekly, or placebo with assess of clinical remission (CDAI <150) after 26 and 56 weeks of therapy. Analyzing the randomized groups, it was noted that clinical remission was significantly greater in the groups using ADA than to placebo at week 56, with 41% in the group receiving the drug weekly, 36% in the group receiving every other week, and 12% in

In order to properly evaluate the effectiveness of ADA as a rescue therapy in patients with CD who have intolerance or loss of response to IFX, GAIN study was

the placebo group (*p* < 0.001). There was no statistically significance in the difference observed between the groups treated with ADA, confirming that the best initial regimen therapy with ADA is 40 mg every other week. It was noted that the superior results observed in CLASSIC II may be due to the fact that patients randomized in this study were in clinical remission, while in CHARM patients with a partial clinical response were included, giving a difference in population of the two studies, preventing direct comparison between them [26]. Analyzing the subgroup of patients who had been previous treated with IFX and discontinued therapy due to loss of response or intolerance it was also observed a higher remission rate compared to placebo, confirming that ADA therapy is a plausible

of postoperative recurrence [23].

*Biological Therapy for Inflammatory Bowel Disease*

**3. Adalimumab (Humira®)**

induction therapy [24].

randomized sample [25].

alternative in this group of patients.

**68**

#### **4. Certolizumab pegol (Cimzia®)**

Certolizumab pegol (CZP), a pegylated humanized Fab fragment of IgG1 was also studied in CD. Although the initial induction trial did not demonstrate statistically significant difference in clinical remission after 6 weeks of treatment compared to placebo**,** PRECISE 2 study was further published assessing maintenance of clinical response in 213 patients that responded to induction phase with 400 mg at weeks 0, 2, and 6 and had values of CRP ≥ 10 mg/L (50% of 428 patients with a reduction in CDAI >100 points after induction phase). These patients were randomized into two groups to receive either 400 mg of CZP or placebo. At the end of 26 weeks of follow-up, 62% of patients treated with the drug maintained clinical response, showing superiority over placebo (34%, *p* < 0.001). Second, it was observed that this superiority was maintained even for patients with CRP < 10 mg/L after the induction phase [32]. Subsequently, analyzing CD patients treated with CZP and followed for 7 years, it was seen that it showed a comparable safety profile to the others anti-TNF drugs [33].

study combined the analysis of a phase 2 study (used to evaluate the appropriate dose of induction therapy) and phase 3, demonstrating the superiority of the drug over placebo. After determining the doses of 200/100 and 400/200 mg at the weeks 2 and 0 as the most appropriate induction regimen, 761 patients were randomized 1:1:1 to receive said regimens or placebo. At the end of 6 weeks, it was observed that the groups randomized to receive the golimumab 200/100 and 400/200 mg had better clinical response (51 and 54.9%, respectively) than placebo (30.3%; *p* < 0.0001 for both comparisons), with no statistically significant differences between the dosing schedules. Second, GOLI also demonstrated superiority to

Having 464 patients who responded to induction therapy with GOLI in previous studies (PURSUIT-SC and PURSUIT-IV), PURSUIT-M evaluated the efficacy of the drug in maintaining clinical response. Patients were randomized to receive 50, 100 mg, or placebo every 4 weeks and evaluated after 52 weeks of treatment at week 54. As a result, 47% of patients receiving 50 mg and 49.7% of those who received 100 mg had sustained clinical response, while 31.2% of those receiving placebo had the same result (*p* = 0.01 and *p* < 0.001, respectively). Second, it was observed that about 28% of the patients who had received 100 mg of golimumab were in clinical remission and 42.4% in endoscopic remission, reinforcing its superiority over placebo, in which 15.6% were in clinical remission (*p* = 0.004) and

Thus, GOLI is presented as another subcutaneous anti-TNF therapy option for ulcerative colitis. Due to its recent approval, more data on its long-term safety and

**Results Conclusion**

A single induction dose is superior to placebo to induce clinical response in patients with moderate to severe CD

Patients who initially responded to IFX are most commonly in remission at week 30 and 54, when a dose of IFX is maintained every 8

weeks

Placebo: 17% had clinical response IFX 5 mg/kg: 81% had clinical response IFX 10 mg/kg: 50% had clinical response IFX 20 mg/kg: 64% had clinical response

Placebo: 21% in remission at week 30; mean time to loss of response of 19 weeks IFX 5 mg/kg at weeks 2 and 6, followed by 5 mg/kg every 8 weeks: 39% in remission at week 30; mean time to loss of response of 38 weeks IFX 5 mg/kg at weeks 2 and 6, followed by 10 mg/kg every 8 weeks: 45% in remission at week 30; mean time to loss of response >54 weeks

placebo regarding clinical remission and mucosal healing [36].

*Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.90204*

26.4% achieved mucosal healing (*p* = 0.002) [37].

real life experience are needed (**Table 1**).

**Main studies Objective Primary end**

Assess the efficacy of IFX in inducing clinical response in patients with moderate to severe CD

ACCENT I Assess the benefit

of maintenance therapy with infliximab in patients with active CD who responded to a single initial infusion of infliximab

**Infliximab** *Cohort* de Targan et al.

**71**

**point**

dose

Reduction of CDAI ≥ 70 points after 4 weeks of single induction

Clinical remission at week 30 (CDAI < 150) and time to loss of clinical response by week 54

Since chronic inflammatory diseases usually have a higher incidence and prevalence in females, there is much discussion about what would be the best therapeutic strategy to be adopted during pregnancy, once treatment suspension may be associated with "flares" of the underlying disease with deleterious effects for both the mother and fetus, in addition to the fact that anti-TNF alpha present variables degrees of placental transfer that can influence the immune response of the newborn. Due to its molecular conformation devoid of the Fc region, which prevents recognition by the FcRn receptor and consequently the active placental transfer, certolizumab pegol was evaluated as a safe treatment option during pregnancy [34].

In 2017, a prospective pharmacokinetic study (CRIB study) was published evaluating 16 patients with at least 30 weeks pregnancy who were treated with CZP (three of them with CD) to assess the degree of placental transfer to the fetus via the dosage of the serum level of the drug in the newborn plasma. Patients were required to receive the last dose of CZP within a maximum of 35 days before delivery to be included. It was observed that even with maternal plasma levels within the therapeutic range of CZP, 13 of the 16 neonates had no detectable levels of CZP in plasma and one shows minimum levels (0.09% concentration in maternal plasma), which hardly had any clinical consequences [34]. In accordance with previous studies, it was shown that CZP presents minimal to no placental transfer even when used in the third trimester of pregnancy, unlike IFX, or ADA [35]. In the same year, CRADLE study analyzed breast milk from 17 mothers who were treated with the CZP (five of them with CD), showing that the drug concentration in breast milk is minimal, with a relative dose transferred to the newborn well below the 10% limit considered safe. Besides that, adverse events in patients exposed to CZP were consistent with the known safety profile and newborns had an adverse event profile that could be expected in an untreated population of similar age [36].

The CZP presents itself as another subcutaneously administered anti-TNF option for CD with a suitable safety profile, especially in women in the reproductive phase.

#### **5. Golimumab (Simponi®)**

Golimumab (GOLI), a fully humanized antibody anti-TNF alpha administered subcutaneously, has been described as effective in induction of clinical response and remission in ulcerative colitis in 2014, with the publication of PURSUIT-SC. This

#### *Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease DOI: http://dx.doi.org/10.5772/intechopen.90204*

study combined the analysis of a phase 2 study (used to evaluate the appropriate dose of induction therapy) and phase 3, demonstrating the superiority of the drug over placebo. After determining the doses of 200/100 and 400/200 mg at the weeks 2 and 0 as the most appropriate induction regimen, 761 patients were randomized 1:1:1 to receive said regimens or placebo. At the end of 6 weeks, it was observed that the groups randomized to receive the golimumab 200/100 and 400/200 mg had better clinical response (51 and 54.9%, respectively) than placebo (30.3%; *p* < 0.0001 for both comparisons), with no statistically significant differences between the dosing schedules. Second, GOLI also demonstrated superiority to placebo regarding clinical remission and mucosal healing [36].

Having 464 patients who responded to induction therapy with GOLI in previous studies (PURSUIT-SC and PURSUIT-IV), PURSUIT-M evaluated the efficacy of the drug in maintaining clinical response. Patients were randomized to receive 50, 100 mg, or placebo every 4 weeks and evaluated after 52 weeks of treatment at week 54. As a result, 47% of patients receiving 50 mg and 49.7% of those who received 100 mg had sustained clinical response, while 31.2% of those receiving placebo had the same result (*p* = 0.01 and *p* < 0.001, respectively). Second, it was observed that about 28% of the patients who had received 100 mg of golimumab were in clinical remission and 42.4% in endoscopic remission, reinforcing its superiority over placebo, in which 15.6% were in clinical remission (*p* = 0.004) and 26.4% achieved mucosal healing (*p* = 0.002) [37].

Thus, GOLI is presented as another subcutaneous anti-TNF therapy option for ulcerative colitis. Due to its recent approval, more data on its long-term safety and real life experience are needed (**Table 1**).


**4. Certolizumab pegol (Cimzia®)**

*Biological Therapy for Inflammatory Bowel Disease*

safety profile to the others anti-TNF drugs [33].

Certolizumab pegol (CZP), a pegylated humanized Fab fragment of IgG1 was also studied in CD. Although the initial induction trial did not demonstrate statistically significant difference in clinical remission after 6 weeks of treatment compared to placebo**,** PRECISE 2 study was further published assessing maintenance of clinical response in 213 patients that responded to induction phase with 400 mg at weeks 0, 2, and 6 and had values of CRP ≥ 10 mg/L (50% of 428 patients with a reduction in CDAI >100 points after induction phase). These patients were randomized into two groups to receive either 400 mg of CZP or placebo. At the end of 26 weeks of follow-up, 62% of patients treated with the drug maintained clinical response, showing superiority over placebo (34%, *p* < 0.001). Second, it was observed that this superiority was maintained even for patients with CRP < 10 mg/L after the induction phase [32]. Subsequently, analyzing CD patients treated with CZP and followed for 7 years, it was seen that it showed a comparable

Since chronic inflammatory diseases usually have a higher incidence and prevalence in females, there is much discussion about what would be the best therapeutic strategy to be adopted during pregnancy, once treatment suspension may be associated with "flares" of the underlying disease with deleterious effects for both the mother and fetus, in addition to the fact that anti-TNF alpha present variables degrees of placental transfer that can influence the immune response of the newborn. Due to its molecular conformation devoid of the Fc region, which prevents recognition by the FcRn receptor and consequently the active placental transfer, certolizumab pegol was evaluated as a safe treatment option during pregnancy [34]. In 2017, a prospective pharmacokinetic study (CRIB study) was published evaluating 16 patients with at least 30 weeks pregnancy who were treated with CZP (three of them with CD) to assess the degree of placental transfer to the fetus via the dosage of the serum level of the drug in the newborn plasma. Patients were required to receive the last dose of CZP within a maximum of 35 days before delivery to be included. It was observed that even with maternal plasma levels within the therapeutic range of CZP, 13 of the 16 neonates had no detectable levels of CZP in plasma and one shows minimum levels (0.09% concentration in maternal plasma), which hardly had any clinical consequences [34]. In accordance with previous studies, it was shown that CZP presents minimal to no placental transfer even when used in the third trimester of pregnancy, unlike IFX, or ADA [35]. In the same year, CRADLE study analyzed breast milk from 17 mothers who were treated with the CZP (five of them with CD), showing that the drug concentration in breast milk is minimal, with a relative dose transferred to the newborn well below the 10% limit considered safe. Besides that, adverse events in patients exposed to CZP were consistent with the known safety profile and newborns had an adverse event profile

that could be expected in an untreated population of similar age [36].

phase.

**70**

**5. Golimumab (Simponi®)**

The CZP presents itself as another subcutaneously administered anti-TNF option for CD with a suitable safety profile, especially in women in the reproductive

Golimumab (GOLI), a fully humanized antibody anti-TNF alpha administered subcutaneously, has been described as effective in induction of clinical response and remission in ulcerative colitis in 2014, with the publication of PURSUIT-SC. This


**Main studies Objective Primary end**

*DOI: http://dx.doi.org/10.5772/intechopen.90204*

assess the efficacy

monotherapy or combined therapy in patients with moderate to severe CD naïve for biological therapy

SONIC Comparatively

SUCCESS Comparatively

**Adalimumab**

CLASSIC I Assess ADA's

CLASSIC II Assess the

**73**

efficacy and safety of ADA in maintenance therapy in

efficacy in inducing clinical remission in patients with moderate to severe CD naive for biological therapy

evaluate the efficacy of IFX monotherapy, AZA

monotherapy, or combined therapy in patients with moderate to severe UC naïve for biological therapy

of IFX monotherapy, AZA

**point**

*Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease*

Clinical remission free of corticoid and, secondarily, mucosal healing at week 26

Clinical remission free of corticoid and secondarily mucosal healing at week 16

Clinical remission at week 4 after initial induction therapy

Maintenance of clinical remission at week 56 in the group of patients randomized after **Results Conclusion**

Patients with moderate to severe CD treated with IFX or IFX + AZA are more likely to achieve clinical remission free of corticosteroids than those treated with AZA alone

Patients naive for biological drugs with UC treated with combined therapy are more likely to achieve clinical remission than those treated with monotherapy drugs. Combined therapy is associated with better mucosal healing rates when compared to AZA monotherapy

The ADA was superior to placebo in clinical remission induction in patients naive for biological therapy with moderate to severe CD, with a dose of 160 mg at week 0 followed by 80 mg at week 2 as the recommended regimen

ADA was more effective than placebo in maintain remission after 56 follow-up

Clinical remission at

Clinical remission at

Placebo: 12% of the patients achieved remission

ADA 40/20 mg: 18% of the patients achieved remission 18% (p = 0.36) ADA 80/40 mg: 24% of the patients achieved remission (p = 0.06)

ADA 160/80 mg: 36% of the patients achieved remission (p = 0.001)

Placebo: 44% of the patients had clinical remission ADA 40 mg every other week: 79% of

week 16: • AZA: 23.7% • IFX: 22.1% • IFX + AZA: 39.7% Mucosal healing at week 16: • AZA: 36.8% • IFX: 54.6% • IFX + AZA: 62.8% Note: the difference in mucosal healing observed in IFX and IFX + AZA groups was not statistically significant

week 26: • AZA: 30% • IFX: 44.4% • IFX + AZA: 56.8% Mucosal healing at week 26: • AZA: 16.5% • IFX: 30.1% • IFX + AZA: 43.9% Note: the observed difference in mucosal healing between the IFX and IFX + AZA groups was not statistically significant


**Main studies Objective Primary end**

*Biological Therapy for Inflammatory Bowel Disease*

efficacy of IFX in induction and maintenance therapy in patients with moderate to severe UC

efficacy of maintenance treatment with IFX in the closure of fistulas in patients with CD having one or more fistulas who have responded to the induction therapy with IFX

ACCENT II Assess the

ACT I Assess the

ACT II Assess the

**72**

efficacy of IFX in induction and maintenance therapy in patients with moderate to severe UC

**point**

Time to loss of response during 54 weeks of follow-up among patients who had a response at week 14 and were randomized

Clinical response at week 8 and secondarily, clinical remission and mucosal healing at weeks 8, 30, and 54 (among other secondary end points)

Clinical response at week 8 and secondarily, clinical remission and mucosal healing at weeks 8 and 30 (within other secondary end points)

**Results Conclusion**

Patients with penetrating CD responding to induction therapy are more likely to have a sustained clinical response to maintenance therapy over a 54-week period

Patients with moderate to severe UC treated with IFX at weeks 0, 2, and 6, followed by maintenance every 8 weeks, more commonly have a clinical response at weeks 8, 30, and 54 than those who received placebo

Patients with moderate to severe UC treated with IFX at weeks 0, 2, and 6, followed by maintenance every 8 weeks, more commonly have a clinical response at weeks 8 and 30 than those receiving placebo

Placebo: mean time of 14 weeks to loss of response

IFX: mean time to loss of response of over 40

Clinical response at

Clinical response at

week 8: • Placebo: 29.3% • IFX 5 mg/kg: 64.5% • IFX 10 mg/kg: 69.2% Clinical remission at weeks 8 and 30: • Placebo: 5.7 and 10.6% • IFX 5 mg/kg: 33.9 and 25.6% • IFX 10 mg/kg: 27.5 and 35.8% Mucosal healing at weeks 8 and 30: • Placebo 30.9 and 30.1% • IFX 5 mg/kg: 60.3 and 46.3% • IFX 10 mg/kg: 61.7 and 56.7%

weeks

week 8: • Placebo: 37.2% • IFX 5 mg/kg: 69.4% • IFX 10 mg/kg: 61.5% Clinical remission at weeks 8, 30, and 54: • Placebo: 14.9, 15.7, and 16.5% • IFX 5 mg/kg: 38.8, 33.9, and 34.7% • IFX 10 mg/kg: 32, 36.9, and 34.4% Mucosal healing at weeks 8, 30, and 54: • Placebo: 33.9, 24.8, and 18.2% • IFX 5 mg/kg: 62, 50.4, 45.5% • IFX 10 mg/kg: 59%, 49.2, 46.7%


**6. Comparative efficacy among anti-TNF agents**

*Main studies with Anti-TNF in inflammatory bowel disease.*

**Main studies Objective Primary end**

response and clinical remission in patients with moderate to severe CD who have responded to induction therapy

*DOI: http://dx.doi.org/10.5772/intechopen.90204*

efficacy of golimumab in maintaining clinical response in patients with moderate to severe UC who responded to induction therapy

**Golimumab**

**Table 1.**

PURSUIT Assess the

**point**

*Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease*

Maintenance of clinical response at week 54

**Results Conclusion**

effective in maintaining clinical response than placebo

Golimumab maintenance therapy was more effective than placebo in maintaining clinical response after 54 weeks of follow-up

maintained clinical response

Placebo: 31.2% of the patients maintained clinical response Golimumab 50 mg: 47% of the patients maintained clinical response

Golimumabe 100 mg: 49.7% of the patients maintained clinical response

clinical trials, patient preference and safety profile [38].

other agents.

**75**

As stated above, the treatment of IBD with the advent of anti-TNF alpha and more recently, other classes of biological drugs (anti-integrin, anti-IL 12/23 etc.) has dramatically changed the natural history of the disease and the incidence of complications. However, no head to head studies directly compared the efficacy of different drugs. Lacking such data, the decision on which treatment regimen to be used is mainly based on reported clinical experience, proposed algorithms by

Although imperfect, indirect comparative analyses, such as network meta analyses are available evidence to assess efficacy of different drugs. In 2018, Singh et al., through a systematic review and network meta-analysis, compared the efficacy and safety of treatment with various biological drugs in CD in naive patients for biological therapy (first-line therapy) and in patients previously tested with some anti-TNF (second-line therapy). Comparing direct and indirect evidence from 18 randomized controlled trials (RCT's) involving patients with moderate to severe CD, it was observed that anti-TNF alpha, particularly IFX and ADA, were the options with strongest evidence in the induction of clinical remission and response as well as maintenance therapy. Ustekinumab and vedolizumab appear to have similar efficacy in the first-line therapy and were not higher when compared to IFX or ADA. The CZP at the standardized dose has been reported as inferior to the

As second-line therapy (non-RCT using IFX or CZP as a second biological drug

was identified), in the specific subgroup of patients who lost response or were intolerant to IFX, ADA seems to be superior compared to other agents. It is noteworthy that, for patients with primary nonresponse to IFX, the effectiveness of the ADA is uncertain, scenario in which ustekinumab seems to gain prominence. The

safety profile and the incidence of major adverse events were assessed in


**Table 1.**

**Main studies Objective Primary end**

*Biological Therapy for Inflammatory Bowel Disease*

patients with moderate to severe CD

effectiveness of ADA in clinical remission induction in patients with moderate to severe UC naive for biological therapy

efficacy and safety of ADA in maintenance therapy of patients with moderate to severe UC

efficacy and safety of ADA in maintenance therapy in patients with moderate to severe CD who responded to induction therapy

efficacy of ADA in inducing clinical remission in patients with moderate to severe CD who lost response or were intolerant to

ULTRA I Assess the

ULTRA II Assess the

CHARM Assess the

GAIN Assess the

IFX

efficacy and safety of CTZ in inducing and maintaining

PRECISE 2 Assess the

**Certolizumab pegol**

**74**

**point**

responding to induction therapy

Clinical remission at week 8 after initial induction therapy

Maintenance of clinical remission at week 8 and week 52 after induction therapy

Percentage of patients who responded to induction and achieved clinical remission at weeks 26 and 56

Clinical remission at week 4 after ADA induction therapy

Clinical response rates in patients with baseline CRP ≥10 mg/L at week

26

**Results Conclusion**

The 160/80 mg dose of ADA was effective and safe in inducing clinical remission in patients with moderate to severe UC who failed to corticoid or immunosuppressive

therapy

therapy

ADA was effective and safe in maintaining clinical remission in patients with moderate to severe UC who failed to corticoid or immunosuppressive

ADA maintenance therapy in patients with moderate to severe CD who responded to induction therapy was more effective than placebo in maintaining clinical remission after 56 weeks of follow-up

ADA was more effective than placebo in inducing clinical remission in patients who lost or were intolerant to

Among patients who responded to the initial induction dose, maintenance of CTZ was more

IFX

the patients maintained clinical remission ADA 40 mg weekly: 83% of the patients maintained clinical remission

Placebo: 9.2% of the patients achieved remission

ADA 80/40 mg: 10% of the patients achieved remission (p = 0.833) ADA 160/80 mg: 18.5% of the patients reached remission (p = 0.031)

Placebo: 9.3% at week 8 and 8.5% at week 52 ADA: 16.5% at week 8 and 17.3% at week 52

Placebo: 17% at week 26 and 12% at week 56 ADA 40 mg every other week: 40% at week 26 and 36% at

ADA 40 mg weekly: 47% at week 26 and 41% at week 56

Placebo: 7% achieved clinical remission at

ADA: 21% achieved clinical remission in

Placebo: 36% of patients maintained clinical response CTZ: 62% of patients

week 56

week 4

week 4

*Main studies with Anti-TNF in inflammatory bowel disease.*

#### **6. Comparative efficacy among anti-TNF agents**

As stated above, the treatment of IBD with the advent of anti-TNF alpha and more recently, other classes of biological drugs (anti-integrin, anti-IL 12/23 etc.) has dramatically changed the natural history of the disease and the incidence of complications. However, no head to head studies directly compared the efficacy of different drugs. Lacking such data, the decision on which treatment regimen to be used is mainly based on reported clinical experience, proposed algorithms by clinical trials, patient preference and safety profile [38].

Although imperfect, indirect comparative analyses, such as network meta analyses are available evidence to assess efficacy of different drugs. In 2018, Singh et al., through a systematic review and network meta-analysis, compared the efficacy and safety of treatment with various biological drugs in CD in naive patients for biological therapy (first-line therapy) and in patients previously tested with some anti-TNF (second-line therapy). Comparing direct and indirect evidence from 18 randomized controlled trials (RCT's) involving patients with moderate to severe CD, it was observed that anti-TNF alpha, particularly IFX and ADA, were the options with strongest evidence in the induction of clinical remission and response as well as maintenance therapy. Ustekinumab and vedolizumab appear to have similar efficacy in the first-line therapy and were not higher when compared to IFX or ADA. The CZP at the standardized dose has been reported as inferior to the other agents.

As second-line therapy (non-RCT using IFX or CZP as a second biological drug was identified), in the specific subgroup of patients who lost response or were intolerant to IFX, ADA seems to be superior compared to other agents. It is noteworthy that, for patients with primary nonresponse to IFX, the effectiveness of the ADA is uncertain, scenario in which ustekinumab seems to gain prominence. The safety profile and the incidence of major adverse events were assessed in

maintenance studies, not being seen clear superiority of one agent over the other, although the risk of adverse events appears to be low to IFX and ustekinumab. However, RCT's involved in the analysis were not powered to determine this difference, so this result should be evaluated with caution. Vedolizumab, a gutselective anti-integrin, has not been clearly associated with an increased risk of serious infections in RCT's analysis and longitudinal cohorts. It is noteworthy that the risk factors most associated with severe infections were concomitant use of corticosteroids, narcotics and severe disease activity [38].

**7. Safety of anti-TNF agents**

*DOI: http://dx.doi.org/10.5772/intechopen.90204*

thiopurines [45].

risk of cancer development [47].

therapy than either drug alone [51].

**77**

The use of TNF-alpha inhibitors and their combination with thiopurines has proved to be more effective in controlling severe forms of CD and UC compared to monotherapy [21, 22]. However the use of these drugs is associated to a higher risk

The analysis of a cohort study involving a large number of patients [43], showed a higher risk of serious and opportunistic infections in combination therapy than with the use of anti-TNF or thiopurines alone. Comparing anti-TNF and thiopurines in monotherapy, there was a higher incidence of serious infections and mycobacterial infections associated with anti-TNF, however, there is no difference in the incidence of opportunistic infections in general, since thiopurines were associated with higher chance of viral opportunistic infections and anti-TNF to bacterial infections. It is noteworthy that the results of a previous meta-analysis showed an increased incidence of opportunistic infections by bacteria and mycobacteria in patients treated with the combination therapy compared to monotherapy with anti-TNF, inferring that the use of thiopurines adds an extra risk for developing infections [44]. There was a higher incidence of viral opportunistic infections when combination therapy was compared to monotherapy with anti-TNF, but it did not differ when compared to monotherapy with the thiopurines, suggesting that the risk of this complication in the combination therapy is due to the use of

It should be considered that not only therapeutic option is linked with a higher risk of infectious complications, but also the patient's age, disease severity, and concomitant use of corticosteroids, all those associated with a worse outcome [46]. Classically, therapy with thiopurines is associated with an increased risk of

hepatosplenic lymphoma associated with EBV, cervical cancer associated with HPV, urinary tract cancer, and non-melanoma skin cancer, both as monotherapy and in combination therapy with an anti-TNF agent [42]. However, the association between malignancy and anti-TNF alpha use remains uncertain. In prior meta-analysis involving 21 placebo-controlled trials including more than 5000 patients with CD, treatment with anti-TNF was not associated with an increased

Through the analysis of the TREAT™ Registry database, a prospective cohort study that evaluated the outcomes of long-term treatment regimens in DC involving 6237 patients in with more than half used the IFX sometime in the follow-up, it was found that, in general, the incidence of cancers (benign or malignant) was similar between the group treated with IFX and with the other therapeutic options

[48]. In this study, age, disease duration and smoking were associated with increased risk of cancer. In a more recent meta-analysis including 44 RCT's and more than 14,000 patients, and the incidence of malignancy as a secondary outcome, it was not possible to conclude that the use of anti-TNF significantly affect the risk of cancer. However, the data were scarce and periods of exposure and follow-up were too short to allow conclusions [41]. The incidence of melanoma is described as higher in patients with IBD in general, however, some studies suggest a

possible association with the use of anti-TNF [49] while others do not [50].

Surprisingly, not only the use of thiopurines but also the use of anti-TNF

A recent French cohort gathered data from nearly 190,000 patients to assess risk of lymphoma in patients with IBD that used azathioprine and/or anti-TNF agents.

monotherapy was associated with a small but statistically significant increased risk of lymphoma among patients exposed. The risk was greater in the combination

malignancy in patients with IBD, particularly non-Hodgkin's lymphoma,

of adverse events, particularly infections and malignancies [41, 42].

*Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease*

The same group published a meta-analysis evaluating the therapy in UC, where, besides the efficacy of induction/maintenance of clinical remission and safety profile of the drug, mucosal healing was also assessed. Combining direct and indirect evidence of 14 RCT's including 4212 patients with moderate to severe disease, the group concluded that, as first-line therapy, all evaluated agents (IFX, ADA, golimumab, and vedolizumab tofacitinibe) were superior to placebo, with IFX and vedolizumab considered the most effective in the inducing of clinical remission and mucosal healing. In general, ADA was considered the least effective agent for both outcomes. Comparing IFX to ADA, data obtained favor IFX for induction of remission, however, as maintenance therapy, it appears to be no significant difference between the two drugs [39]. Superiority of IFX can be associated with pharmacokinetics and bioavailability of the drug since its dosage is variable according to the weight of the patient, unlike ADA with a fixed dose.

As second line therapy, tofacitinib (JAK-2 inhibitor) seems to be the best choice for induction of remission and mucosal healing. A direct meta-analysis further demonstrated that vedolizumab and ADA were not superior to placebo, conferring a low level of evidence to indicate these drugs as a therapeutic alternative in this scenario. Importantly however, the studies that assessed ADA included only patients who lost response or were intolerant to IFX as part of the patients treated with vedolizumab were not primary responders to IFX, which may be linked to a specific population with a more aggressive form of the disease, disadvantaging vedolizumab in this analysis. This information was not clear in studies with tofacitinib and no study using IFX or golimumab as a second biological drug was identified [39].

As a maintenance therapy, because of differences in the design of studies, RCT's involving IFX and ADA were considered separately from those involving golimumab, vedolizumab, and tofacitinib. As stated earlier, IFX and ADA appear to be equally effective in maintaining remission in naive treatment patients. The other drugs were also superior to placebo in patients who responded to induction therapy and did not seem to differ from each other. Regarding the safety profile, none of the options was significantly worse compared to placebo in the incidence of adverse events. Taking into account the incidence of serious infections, vedolizumab seems to be the safer drug, since there was no difference compared to placebo, while golimumab and tofacitinib were associated to higher risk of infection [39].

In an innovative way, the preliminary results of VARSITY, the first head to head trial in IBD were presented in a specific event. It is a phase 3b double-dummy, controlled and randomized trial, comparing ADA and vedolizumab in the treatment of moderate to severe UC. With a total of 769 patients who had failed conventional therapy (25% had been exposed to any anti-TNF), which were randomized into four groups to receive vedolizumab vs. placebo or adalimumab vs. placebo, clinical remission (primary endpoint), and mucosal healing were assessed after 52 weeks. It has been observed that patients treated with vedolizumab achieved clinical remission rates of 31.3% and mucosal healing of 39.7%, significantly better than patients treated with ADA (22.5% *p* = 0.0061 and 27.7% *p* = 0.0005, respectively), with no statistically significant difference in the incidence of infections and adverse events [40].

#### **7. Safety of anti-TNF agents**

maintenance studies, not being seen clear superiority of one agent over the other, although the risk of adverse events appears to be low to IFX and ustekinumab. However, RCT's involved in the analysis were not powered to determine this difference, so this result should be evaluated with caution. Vedolizumab, a gutselective anti-integrin, has not been clearly associated with an increased risk of serious infections in RCT's analysis and longitudinal cohorts. It is noteworthy that the risk factors most associated with severe infections were concomitant use of

The same group published a meta-analysis evaluating the therapy in UC, where, besides the efficacy of induction/maintenance of clinical remission and safety profile of the drug, mucosal healing was also assessed. Combining direct and indirect evidence of 14 RCT's including 4212 patients with moderate to severe disease, the group concluded that, as first-line therapy, all evaluated agents (IFX, ADA, golimumab, and vedolizumab tofacitinibe) were superior to placebo, with IFX and vedolizumab considered the most effective in the inducing of clinical remission and mucosal healing. In general, ADA was considered the least effective agent for both outcomes. Comparing IFX to ADA, data obtained favor IFX for induction of remission, however, as maintenance therapy, it appears to be no significant difference between the two drugs [39]. Superiority of IFX can be associated with pharmacokinetics and bioavailability of the drug since its dosage is variable according to the

As second line therapy, tofacitinib (JAK-2 inhibitor) seems to be the best choice

As a maintenance therapy, because of differences in the design of studies, RCT's

golimumab, vedolizumab, and tofacitinib. As stated earlier, IFX and ADA appear to be equally effective in maintaining remission in naive treatment patients. The other drugs were also superior to placebo in patients who responded to induction therapy and did not seem to differ from each other. Regarding the safety profile, none of the options was significantly worse compared to placebo in the incidence of adverse events. Taking into account the incidence of serious infections, vedolizumab seems to be the safer drug, since there was no difference compared to placebo, while golimumab and tofacitinib were associated to higher risk of infection [39].

In an innovative way, the preliminary results of VARSITY, the first head to head

trial in IBD were presented in a specific event. It is a phase 3b double-dummy, controlled and randomized trial, comparing ADA and vedolizumab in the treatment of moderate to severe UC. With a total of 769 patients who had failed conventional therapy (25% had been exposed to any anti-TNF), which were randomized into four groups to receive vedolizumab vs. placebo or adalimumab vs. placebo, clinical remission (primary endpoint), and mucosal healing were assessed after 52 weeks. It has been observed that patients treated with vedolizumab achieved clinical remission rates of 31.3% and mucosal healing of 39.7%, significantly better than patients treated with ADA (22.5% *p* = 0.0061 and 27.7% *p* = 0.0005, respectively), with no statistically significant difference in the incidence of infections and adverse events [40].

involving IFX and ADA were considered separately from those involving

for induction of remission and mucosal healing. A direct meta-analysis further demonstrated that vedolizumab and ADA were not superior to placebo, conferring a low level of evidence to indicate these drugs as a therapeutic alternative in this scenario. Importantly however, the studies that assessed ADA included only patients who lost response or were intolerant to IFX as part of the patients treated with vedolizumab were not primary responders to IFX, which may be linked to a specific population with a more aggressive form of the disease, disadvantaging vedolizumab in this analysis. This information was not clear in studies with tofacitinib and no study using IFX or golimumab as a second biological drug

corticosteroids, narcotics and severe disease activity [38].

*Biological Therapy for Inflammatory Bowel Disease*

weight of the patient, unlike ADA with a fixed dose.

was identified [39].

**76**

The use of TNF-alpha inhibitors and their combination with thiopurines has proved to be more effective in controlling severe forms of CD and UC compared to monotherapy [21, 22]. However the use of these drugs is associated to a higher risk of adverse events, particularly infections and malignancies [41, 42].

The analysis of a cohort study involving a large number of patients [43], showed a higher risk of serious and opportunistic infections in combination therapy than with the use of anti-TNF or thiopurines alone. Comparing anti-TNF and thiopurines in monotherapy, there was a higher incidence of serious infections and mycobacterial infections associated with anti-TNF, however, there is no difference in the incidence of opportunistic infections in general, since thiopurines were associated with higher chance of viral opportunistic infections and anti-TNF to bacterial infections. It is noteworthy that the results of a previous meta-analysis showed an increased incidence of opportunistic infections by bacteria and mycobacteria in patients treated with the combination therapy compared to monotherapy with anti-TNF, inferring that the use of thiopurines adds an extra risk for developing infections [44]. There was a higher incidence of viral opportunistic infections when combination therapy was compared to monotherapy with anti-TNF, but it did not differ when compared to monotherapy with the thiopurines, suggesting that the risk of this complication in the combination therapy is due to the use of thiopurines [45].

It should be considered that not only therapeutic option is linked with a higher risk of infectious complications, but also the patient's age, disease severity, and concomitant use of corticosteroids, all those associated with a worse outcome [46].

Classically, therapy with thiopurines is associated with an increased risk of malignancy in patients with IBD, particularly non-Hodgkin's lymphoma, hepatosplenic lymphoma associated with EBV, cervical cancer associated with HPV, urinary tract cancer, and non-melanoma skin cancer, both as monotherapy and in combination therapy with an anti-TNF agent [42]. However, the association between malignancy and anti-TNF alpha use remains uncertain. In prior meta-analysis involving 21 placebo-controlled trials including more than 5000 patients with CD, treatment with anti-TNF was not associated with an increased risk of cancer development [47].

Through the analysis of the TREAT™ Registry database, a prospective cohort study that evaluated the outcomes of long-term treatment regimens in DC involving 6237 patients in with more than half used the IFX sometime in the follow-up, it was found that, in general, the incidence of cancers (benign or malignant) was similar between the group treated with IFX and with the other therapeutic options [48]. In this study, age, disease duration and smoking were associated with increased risk of cancer. In a more recent meta-analysis including 44 RCT's and more than 14,000 patients, and the incidence of malignancy as a secondary outcome, it was not possible to conclude that the use of anti-TNF significantly affect the risk of cancer. However, the data were scarce and periods of exposure and follow-up were too short to allow conclusions [41]. The incidence of melanoma is described as higher in patients with IBD in general, however, some studies suggest a possible association with the use of anti-TNF [49] while others do not [50].

A recent French cohort gathered data from nearly 190,000 patients to assess risk of lymphoma in patients with IBD that used azathioprine and/or anti-TNF agents. Surprisingly, not only the use of thiopurines but also the use of anti-TNF monotherapy was associated with a small but statistically significant increased risk of lymphoma among patients exposed. The risk was greater in the combination therapy than either drug alone [51].

Other adverse events associated with anti-TNF therapy are described and should also be remembered. Since there are reported the reactivation of tuberculosis and hepatitis B virus after initiation of therapy, the pretreatment screening, in order to guide the treatment of latent tuberculosis and prophylaxis with antiretroviral, is indicated [52, 53]. In those patients who are in triple immunosuppression, *Pneumocystis jirovecii* prophylaxis may be considered [54]. Infusion reactions (relatively frequent), angioedema, anaphylaxis, lupus-like syndrome, psoriasis induced by anti-TNF, eczematous lesions, demyelinating syndromes, and heart failure are also described [54].

#### **8. The role of therapeutic drug monitoring in the management of IBD with anti-TNF agents**

Although effective in the induction and maintenance of clinical remission and mucosal healing, the therapeutic fail of anti-TNF is not uncommon in IBD, occurring in patients which are considered as primary non-responders (10–40% approximately) or lose the response in the first year of treatment (24–46%), and those who have some adverse effect that lead to treatment interruption [24, 26]. An understanding of the factors involved in therapeutic failure, as the patient's profile, the presentation of the disease and the relationship between the concentration of the drug and its interaction with the anti-drug antibodies (ADAbs), are useful tools to guide the best strategy to be followed [55].

The concentration of drug in the site of action is directly linked to the magnitude of the expected pharmacological response and its monitoring in specific scenarios can assist in therapeutic decision. For example, the patient may experience an inadequate response due to the low concentration of the drug secondary to increased clearance, differing completely from one that has inadequate response with therapeutic trough levels, suggesting mechanistic failure. In the first situation, dose escalation can be effective, while the second would most benefit from exchange to a medication with a distinct mechanism of action (**Figure 2**) [56].

Based on these assumptions, in 2017, the American Gastroenterological Association has published a technical review on the role of therapeutic drug monitoring (TDM) as an auxiliary tool in decision-making regarding treatment of IBD. In the absence of adequate response, the dosage of the trough level of the drug has been suggested as a first step (reactive approach): if the serum levels of anti-TNF are within the therapeutic range, it is characterized the failure to the mechanism of action and class exchange is possibly the best option. However, if serum levels are below the appropriate, dosage of ADAbs can bring additional information: if they are high, it is likely that the clearance of the drug is being immune-mediated, and it is plausible the exchange of medication for a drug of the same class, besides the association with immunomodulator. If the ADAbs level is undetectable or low, it is likely that the clearance is increased due to mechanisms not immune-mediated, such as severe inflammatory burden leading to rapid use of anti-TNF and/or excessive loss in feces (indicated by hypoalbuminemia, CRP, and high fecal calprotectin), which would allow the optimization of the dosage instead of changing the biological agent. This strategy seems to be more effective than making decisions empirically, despite the low level of evidence further described [56]. In patients with the disease in remission, the dosage of the trough level and ADAbs as an auxiliary tool in decision-making (proactive proposal) is still uncertain, with few studies that corroborate its effectiveness, mainly regarding cost savings [57, 58].

Through regression logistic, it was identified that only low trough level in week 14 (IFX < 7 mg/L and ADA < 12 mg/L) was associated to the absence of primary response. Obesity, smoking, hypoalbuminemia, high levels of inflammatory markers, and the development of immunogenicity were associated with lower serum levels of the drug. It was also observed that low levels at week 14 were independently associated to non-clinical remission at week 54, and were associated with increased formation of ADAbs. The combination with immunomodulators (azathioprine or methotrexate) was associated with lower immunogenicity for both IFX and ADA, and in the group of patients with IFX, combination therapy was associated with higher clinical remission rate at week 54 compared to monotherapy with IFX, unlike ADA, which was not more effective in maintaining remission

*anti TNF's mechanisms of action are illustrated above. The inflammatory cascade triggered by TNFR is disrupted by anti TNF-mediated direct blockade, which prevents binding of sTNF and tmTNF to specific receptors. On the right are the results of tmTNF antagonization by the drug, which include cytotoxicity of the CDC (complement – dependent cytotoxicity) or ADCC (antibody-dependent cellular cytotoxicity), as well as reverse signaling via tmTNF. The pharmacokinetics-related are illustrated at the bottom of the image.*

*Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.90204*

The initiation of therapy with tumor necrosis factor inhibitors certainly was a milestone in the treatment of inflammatory bowel disease, drastically changing the natural course of the disease and offering better quality of life to treated patients.

when associated with immunomodulators [55].

**9. Final considerations**

**79**

**Figure 2.**

In order to examine predictors of therapeutic failure to anti-TNF, PANTS study has been recently published, a randomized clinical trial involving patients with luminal CD naive for biological therapy who started treatment with IFX or ADA.

*Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease DOI: http://dx.doi.org/10.5772/intechopen.90204*

#### **Figure 2.**

Other adverse events associated with anti-TNF therapy are described and should also be remembered. Since there are reported the reactivation of tuberculosis and hepatitis B virus after initiation of therapy, the pretreatment screening, in order to guide the treatment of latent tuberculosis and prophylaxis with antiretroviral, is indicated [52, 53]. In those patients who are in triple immunosuppression,

*Pneumocystis jirovecii* prophylaxis may be considered [54]. Infusion reactions (relatively frequent), angioedema, anaphylaxis, lupus-like syndrome, psoriasis induced by anti-TNF, eczematous lesions, demyelinating syndromes, and heart failure are

**8. The role of therapeutic drug monitoring in the management of IBD**

Although effective in the induction and maintenance of clinical remission and mucosal healing, the therapeutic fail of anti-TNF is not uncommon in IBD, occurring in patients which are considered as primary non-responders (10–40% approximately) or lose the response in the first year of treatment (24–46%), and those who have some adverse effect that lead to treatment interruption [24, 26]. An understanding of the factors involved in therapeutic failure, as the patient's profile, the presentation of the disease and the relationship between the concentration of the drug and its interaction with the anti-drug antibodies (ADAbs), are useful tools to

The concentration of drug in the site of action is directly linked to the magnitude of the expected pharmacological response and its monitoring in specific scenarios can assist in therapeutic decision. For example, the patient may experience an inadequate response due to the low concentration of the drug secondary to increased clearance, differing completely from one that has inadequate response with therapeutic trough levels, suggesting mechanistic failure. In the first situation,

Based on these assumptions, in 2017, the American Gastroenterological Association has published a technical review on the role of therapeutic drug monitoring (TDM) as an auxiliary tool in decision-making regarding treatment of IBD. In the absence of adequate response, the dosage of the trough level of the drug has been suggested as a first step (reactive approach): if the serum levels of anti-TNF are within the therapeutic range, it is characterized the failure to the mechanism of action and class exchange is possibly the best option. However, if serum levels are below the appropriate, dosage of ADAbs can bring additional information: if they are high, it is likely that the clearance of the drug is being immune-mediated, and it is plausible the exchange of medication for a drug of the same class, besides the association with immunomodulator. If the ADAbs level is undetectable or low, it is likely that the clearance is increased due to mechanisms not immune-mediated, such as severe inflammatory burden leading to rapid use of anti-TNF and/or excessive loss in feces (indicated by hypoalbuminemia, CRP, and high fecal calprotectin), which would allow the optimization of the dosage instead of changing the biological agent. This strategy seems to be more effective than making decisions empirically, despite the low level of evidence further described [56]. In patients with the disease in remission, the dosage of the trough level and ADAbs as an auxiliary tool in decision-making (proactive proposal) is still uncertain, with few studies that cor-

In order to examine predictors of therapeutic failure to anti-TNF, PANTS study has been recently published, a randomized clinical trial involving patients with luminal CD naive for biological therapy who started treatment with IFX or ADA.

dose escalation can be effective, while the second would most benefit from exchange to a medication with a distinct mechanism of action (**Figure 2**) [56].

roborate its effectiveness, mainly regarding cost savings [57, 58].

**78**

also described [54].

**with anti-TNF agents**

guide the best strategy to be followed [55].

*Biological Therapy for Inflammatory Bowel Disease*

*anti TNF's mechanisms of action are illustrated above. The inflammatory cascade triggered by TNFR is disrupted by anti TNF-mediated direct blockade, which prevents binding of sTNF and tmTNF to specific receptors. On the right are the results of tmTNF antagonization by the drug, which include cytotoxicity of the CDC (complement – dependent cytotoxicity) or ADCC (antibody-dependent cellular cytotoxicity), as well as reverse signaling via tmTNF. The pharmacokinetics-related are illustrated at the bottom of the image.*

Through regression logistic, it was identified that only low trough level in week 14 (IFX < 7 mg/L and ADA < 12 mg/L) was associated to the absence of primary response. Obesity, smoking, hypoalbuminemia, high levels of inflammatory markers, and the development of immunogenicity were associated with lower serum levels of the drug. It was also observed that low levels at week 14 were independently associated to non-clinical remission at week 54, and were associated with increased formation of ADAbs. The combination with immunomodulators (azathioprine or methotrexate) was associated with lower immunogenicity for both IFX and ADA, and in the group of patients with IFX, combination therapy was associated with higher clinical remission rate at week 54 compared to monotherapy with IFX, unlike ADA, which was not more effective in maintaining remission when associated with immunomodulators [55].

#### **9. Final considerations**

The initiation of therapy with tumor necrosis factor inhibitors certainly was a milestone in the treatment of inflammatory bowel disease, drastically changing the natural course of the disease and offering better quality of life to treated patients.

With an acceptable safety profile, anti-TNF agents are excellent therapeutic options in severe forms of the disease, with proven efficacy in both Crohn's disease and ulcerative colitis. The association with immunomodulators, particularly to infliximab is associated with better outcomes. A lack of head to head trials that compares the biological drugs limits the assessment of superiority among them to indirect comparisons, making it crucial that such evidence come to light. Therapeutic drug monitoring seems to be useful tools in decision-making and can increase the therapeutic success rates obtained. However, in the face of current evidence, it has not yet been consolidated as a cost effective strategy.

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244-250

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*Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease*

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[10] Allez M, Lemann M, Bonnet J, et al. Long term outcome of patients with active Crohn's disease exhibiting extensive and deep ulcerations at colonoscopy. American Journal of Gastroenterology. 2002;**97**:947-953

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[4] Ungar B, Kopylov U. Advances in the development of new biologics in

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[7] Beaugerie L, Seksik P, Nion-Larmurier I, Gendre JP, Cosnes J. Predictors of crohn's disease.

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[8] Sands BE, Arsenault JE, Rosen MJ, Alsahli M, Bailen L, Banks P, et al. Risk of early surgery for Crohn's disease: Implications for early treatment strategies. The American Journal of Gastroenterology. 2003;**98**:2712-2718

[9] Lakatos PL, Czegledi Z, Szamosi T, Banai J, David G, Zsigmond F, et al. Perianal disease, small bowel disease, smoking, prior steroid or early azathioprine/biological therapy are

inflammatory bowel disease.

[5] Löwenberg M, D'Haens G.

Future perspectives involving anti-TNF agents include the development of new molecules of this class. Currently, several new TNF-alpha inhibitors have been studied in patients with CD. The DLX 105 (esbat Tech) is an anti-TNF antibody that has been studied specifically in patients with fistulizing CD, trough a local injection in a phase II trial (ClinicalTrials.gov NCT01624376), but no results are available to date. Other two anti-TNF-alpha oral therapies, V565 (VHsquared) and OPRX-106 (Bio Protalix) are in the pipeline. The V565 is currently recruiting patients with moderate to severely active CD to a phase II study (NCT02976129) after favorable results in a phase Ib (NCT03010787). The OPRX-106 demonstrated efficacy in clinical improvement of biomarkers in a phase II study of patients with mild to moderate UC. It is worth to wait for these promising therapies, since the oral mode of administration may be more convenient for some patients [59, 60].

In the era of the new mechanisms of action, this critical analysis consolidates the anti-TNF agents as viable therapeutic options in the current IBD therapeutic armamentarium.

#### **Author details**

Carlos Walter Sobrado\*, Natália Sousa Freitas Queiroz and Caio Almeida Perez Department of Gastroenterology, University of São Paulo School of Medicine, Brazil

\*Address all correspondence to: cwsobrado@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease DOI: http://dx.doi.org/10.5772/intechopen.90204*

#### **References**

With an acceptable safety profile, anti-TNF agents are excellent therapeutic options in severe forms of the disease, with proven efficacy in both Crohn's disease and ulcerative colitis. The association with immunomodulators, particularly to infliximab is associated with better outcomes. A lack of head to head trials that compares the biological drugs limits the assessment of superiority among them to indirect comparisons, making it crucial that such evidence come to light. Therapeutic drug monitoring seems to be useful tools in decision-making and can increase the therapeutic success rates obtained. However, in the face of current evidence, it

Future perspectives involving anti-TNF agents include the development of new

In the era of the new mechanisms of action, this critical analysis consolidates the

molecules of this class. Currently, several new TNF-alpha inhibitors have been studied in patients with CD. The DLX 105 (esbat Tech) is an anti-TNF antibody that has been studied specifically in patients with fistulizing CD, trough a local injection in a phase II trial (ClinicalTrials.gov NCT01624376), but no results are available to date. Other two anti-TNF-alpha oral therapies, V565 (VHsquared) and OPRX-106 (Bio Protalix) are in the pipeline. The V565 is currently recruiting patients with moderate to severely active CD to a phase II study (NCT02976129) after favorable results in a phase Ib (NCT03010787). The OPRX-106 demonstrated efficacy in clinical improvement of biomarkers in a phase II study of patients with mild to moderate UC. It is worth to wait for these promising therapies, since the oral mode

of administration may be more convenient for some patients [59, 60].

armamentarium.

**Author details**

**80**

anti-TNF agents as viable therapeutic options in the current IBD therapeutic

Carlos Walter Sobrado\*, Natália Sousa Freitas Queiroz and Caio Almeida Perez Department of Gastroenterology, University of São Paulo School of Medicine, Brazil

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: cwsobrado@hotmail.com

provided the original work is properly cited.

has not yet been consolidated as a cost effective strategy.

*Biological Therapy for Inflammatory Bowel Disease*

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[13] Panaccione R, Colombel J-F, Hébuterne X, Bossuyt P, Robinson AM, Huang B, et al. Effect of tight control management on Crohn's disease (CALM): A multicentre, randomised, controlled phase 3 trial. The Lancet. 2017;**390**:2779-2789

[14] Targan SR, Hanauer SB, van Deventer SJH, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn's disease. The New England Journal of Medicine. 1997;**337**:1029-1035

[15] Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. The New England Journal of Medicine. 1999;**340**:1398-1405

[16] Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: The ACCENT I randomised trial. Lancet. 2002;**359**:1541-1549

[17] Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. The New England Journal of Medicine. 2004;**350**(9): 876-885

[18] Lichtenstein GR. Infliximab for induction and maintenance therapy for ulcerative colitis. Gastroenterology. 2008;**2006**:130-131

[19] Schnitzler F, Fidder H, Ferrante M, Noman M, Arijs I, Van Assche G, et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: Results from a single-centre cohort. Gut. 2009;**58**(4):492-500

[20] Seminerio JL, Loftus EV, Colombel JF, Thapa P, Sandborn WJ. Infliximab for Crohn's disease: The first 500 patients followed up through 2009. Digestive Diseases and Sciences. 2013; **58**(3):797-806

[21] Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. The New England Journal of Medicine. 2010;**362**(15): 1383-1395

[22] Panaccione R, Ghosh S, Middleton S, Márquez JR, Scott BB, Flint L, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014;**146**(2):392-400.e3

[23] De Cruz P, Kamm MA, Hamilton AL, Ritchie KJ, Krejany EO, Gorelik A, et al. Crohn's disease management after intestinal resection: A randomised trial. Lancet. 2015; **385**(9976):1406-1417

[24] Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, Macintosh D, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: The CLASSIC-I trial. Gastroenterology. 2006;**130**(2):323-333

[31] Loftus EV, D'Haens G, Reinisch W, Satsangi J, Panaccione R, Berg S, et al. Adalimumab long-term effectiveness in adalimumab-naive patients with Crohn's disease: Final data from PYRAMID registry. The American Journal of Gastroenterology. 2019;**112**:

*DOI: http://dx.doi.org/10.5772/intechopen.90204*

*Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease*

golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology.

[38] Singh S, Fumery M, Sandborn WJ, Murad MH. Systematic review and network meta-analysis: First- and second-line biologic therapies for moderate-severe Crohn's disease. Alimentary Pharmacology & Therapeutics. 2018;**48**(4):394-409

[39] Singh S, Fumery M, Sandborn WJ, Murad MH. Systematic review with network meta-analysis: First- and second-line pharmacotherapy for moderate-severe ulcerative colitis. Alimentary Pharmacology & Therapeutics. 2018;**47**(2):162-175

[40] Sands B, Peyrin-Biroulet L, Loftus EV Jr, et al. Vedolizumab shows superior efficacy versus adalimumab: Results of VARSITY: The first head-tohead study of biologic therapy for moderate-to-severe ulcerative colitis. In: Presented at Digestive Disease Week (DDW) San Diego, California (Oral Presentation—Sunday, May 19, 2019,

[41] Bonovas S, Fiorino G, Allocca M, Lytras T, Nikolopoulos GK, Peyrin-Biroulet L, et al. Biologic therapies and risk of infection and malignancy in patients with inflammatory bowel disease: A systematic review and network meta-analysis. Clinical

Gastroenterology and Hepatology. 2016;

[42] Beaugerie L, Itzkowitz SH. Cancers complicating inflammatory bowel

[43] Kirchgesner J, Lemaitre M, Carrat F, Zureik M, Carbonnel F, Dray-Spira R. Risk of serious and opportunistic infections associated with treatment of

Journal of Medicine. 2015;**372**(15):

17:16–17:30 PDT)

**14**(10):1385-1397.e10

1441-1452

disease. The New England

inflammatory bowel diseases.

2014;**146**(1):96-109.e1

[32] Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn's disease. The New England Journal of Medicine. 2007;**357**(3):239-250

[33] Sandborn WJ, Lee SD, Randall C,

Ambarkhane S, et al. Long-term safety and efficacy of certolizumab pegol in the treatment of Crohn's disease: 7-year results from the PRECiSE 3 study. Alimentary Pharmacology & Therapeutics. 2014;**40**(8):903-916

[34] Mariette X, Förger F, Abraham B, Flynn AD, Moltó A, Flipo RM, et al.

certolizumab pegol during pregnancy: Results from CRIB, a prospective, postmarketing, pharmacokinetic study. Annals of the Rheumatic Diseases. 2018;

Dubinsky M, et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clinical Gastroenterology and Hepatology. 2013;**11**:286-292

[36] Clowse ME, Förger F, Hwang C, Thorp J, Dolhain RJ, Van Tubergen A, et al. Minimal to no transfer of certolizumab pegol into breast milk: Results from CRADLE, a prospective,

pharmacokinetic study. Annals of the Rheumatic Diseases. 2017;**76**(11):

postmarketing, multicentre,

[37] Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al. Subcutaneous

1890-1896

**83**

Lack of placental transfer of

[35] Mahadevan U, Wolf DC,

**77**(2):228-233

Gutierrez A, Schwartz DA,

S363-S364

[25] Sandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lulcas M, MacIntosh DG, et al. Adalimumab for maintenance treatment of Crohn's disease: Results of the CLASSIC II trial. Gut. 2007;**56**(9):1232-1239

[26] Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: The CHARM Trial. Gastroenterology. 2007;**132**(1):52-65

[27] Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: A randomized trial. Annals of Internal Medicine. 2007;**146**: 829-838

[28] Reinisch W, Sandborn WJ, Hommes DW, D'Haens G, Hanauer S, Schreiber S, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: Results of a randomised controlled trial. Gut. 2011;**60**(6): 780-787

[29] Sandborn WJ, Van Assche G, Reinisch W, Colombel J, D'Haens G, Wolf DC, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;**142**(2):257-265.e3

[30] Tursi A, Elisei W, Faggiani R, Allegretta L, Della VN, Forti G, et al. Effectiveness and safety of adalimumab to treat outpatient ulcerative colitis: A real-life multicenter, observational study in primary inflammatory bowel disease centers. Medicine (Baltimore). 2018;**97**(34):e11897

*Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease DOI: http://dx.doi.org/10.5772/intechopen.90204*

[31] Loftus EV, D'Haens G, Reinisch W, Satsangi J, Panaccione R, Berg S, et al. Adalimumab long-term effectiveness in adalimumab-naive patients with Crohn's disease: Final data from PYRAMID registry. The American Journal of Gastroenterology. 2019;**112**: S363-S364

[17] Sands BE, Anderson FH,

Fedorak RN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. The New England Journal of Medicine. 2004;**350**(9):

876-885

2008;**2006**:130-131

Bernstein CN, Chey WY, Feagan BG,

*Biological Therapy for Inflammatory Bowel Disease*

necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: The CLASSIC-I trial. Gastroenterology.

[25] Sandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lulcas M, MacIntosh DG, et al. Adalimumab for maintenance treatment of Crohn's disease: Results of the CLASSIC II trial.

Gut. 2007;**56**(9):1232-1239

829-838

780-787

[26] Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: The CHARM Trial.

Gastroenterology. 2007;**132**(1):52-65

[28] Reinisch W, Sandborn WJ, Hommes DW, D'Haens G, Hanauer S, Schreiber S, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative

colitis: Results of a randomised controlled trial. Gut. 2011;**60**(6):

[29] Sandborn WJ, Van Assche G, Reinisch W, Colombel J, D'Haens G, Wolf DC, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology.

[30] Tursi A, Elisei W, Faggiani R, Allegretta L, Della VN, Forti G, et al. Effectiveness and safety of adalimumab to treat outpatient ulcerative colitis: A real-life multicenter, observational study in primary inflammatory bowel disease centers. Medicine (Baltimore).

2012;**142**(2):257-265.e3

2018;**97**(34):e11897

[27] Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: A randomized trial. Annals of Internal Medicine. 2007;**146**:

2006;**130**(2):323-333

[18] Lichtenstein GR. Infliximab for induction and maintenance therapy for ulcerative colitis. Gastroenterology.

[19] Schnitzler F, Fidder H, Ferrante M, Noman M, Arijs I, Van Assche G, et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: Results from a single-centre cohort. Gut. 2009;**58**(4):492-500

[20] Seminerio JL, Loftus EV,

[21] Colombel JF, Sandborn WJ,

[22] Panaccione R, Ghosh S,

2014;**146**(2):392-400.e3

**385**(9976):1406-1417

**82**

[23] De Cruz P, Kamm MA,

[24] Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, Macintosh D, et al. Human anti-tumor

Middleton S, Márquez JR, Scott BB, Flint L, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology.

Hamilton AL, Ritchie KJ, Krejany EO, Gorelik A, et al. Crohn's disease management after intestinal resection: A randomised trial. Lancet. 2015;

Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. The New England Journal of Medicine. 2010;**362**(15):

**58**(3):797-806

1383-1395

Colombel JF, Thapa P, Sandborn WJ. Infliximab for Crohn's disease: The first 500 patients followed up through 2009. Digestive Diseases and Sciences. 2013;

[32] Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn's disease. The New England Journal of Medicine. 2007;**357**(3):239-250

[33] Sandborn WJ, Lee SD, Randall C, Gutierrez A, Schwartz DA, Ambarkhane S, et al. Long-term safety and efficacy of certolizumab pegol in the treatment of Crohn's disease: 7-year results from the PRECiSE 3 study. Alimentary Pharmacology & Therapeutics. 2014;**40**(8):903-916

[34] Mariette X, Förger F, Abraham B, Flynn AD, Moltó A, Flipo RM, et al. Lack of placental transfer of certolizumab pegol during pregnancy: Results from CRIB, a prospective, postmarketing, pharmacokinetic study. Annals of the Rheumatic Diseases. 2018; **77**(2):228-233

[35] Mahadevan U, Wolf DC, Dubinsky M, et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clinical Gastroenterology and Hepatology. 2013;**11**:286-292

[36] Clowse ME, Förger F, Hwang C, Thorp J, Dolhain RJ, Van Tubergen A, et al. Minimal to no transfer of certolizumab pegol into breast milk: Results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study. Annals of the Rheumatic Diseases. 2017;**76**(11): 1890-1896

[37] Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al. Subcutaneous

golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;**146**(1):96-109.e1

[38] Singh S, Fumery M, Sandborn WJ, Murad MH. Systematic review and network meta-analysis: First- and second-line biologic therapies for moderate-severe Crohn's disease. Alimentary Pharmacology & Therapeutics. 2018;**48**(4):394-409

[39] Singh S, Fumery M, Sandborn WJ, Murad MH. Systematic review with network meta-analysis: First- and second-line pharmacotherapy for moderate-severe ulcerative colitis. Alimentary Pharmacology & Therapeutics. 2018;**47**(2):162-175

[40] Sands B, Peyrin-Biroulet L, Loftus EV Jr, et al. Vedolizumab shows superior efficacy versus adalimumab: Results of VARSITY: The first head-tohead study of biologic therapy for moderate-to-severe ulcerative colitis. In: Presented at Digestive Disease Week (DDW) San Diego, California (Oral Presentation—Sunday, May 19, 2019, 17:16–17:30 PDT)

[41] Bonovas S, Fiorino G, Allocca M, Lytras T, Nikolopoulos GK, Peyrin-Biroulet L, et al. Biologic therapies and risk of infection and malignancy in patients with inflammatory bowel disease: A systematic review and network meta-analysis. Clinical Gastroenterology and Hepatology. 2016; **14**(10):1385-1397.e10

[42] Beaugerie L, Itzkowitz SH. Cancers complicating inflammatory bowel disease. The New England Journal of Medicine. 2015;**372**(15): 1441-1452

[43] Kirchgesner J, Lemaitre M, Carrat F, Zureik M, Carbonnel F, Dray-Spira R. Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases.

Gastroenterology. 2018;**155**(2): 337-346.e10

[44] Rahier JF, Magro F, Abreu C, Armuzzi A, Ben-Horin S, Chowers Y, et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. Journal of Crohn's and Colitis. 2014;**8**(6):443-468

[45] Lorenzetti R, Zullo A, Ridola L, Diamanti AP, Laganà B, Gatta L, et al. Higher risk of tuberculosis reactivation when anti-TNF is combined with immunosuppressive agents: A systematic review of randomized controlled trials. Annals of Medicine. 2014;**46**(7):547-554

[46] Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Price S, et al. Serious infection and mortality in patients with crohn's disease: More than 5 years of follow-up in the TREAT registry. The American Journal of Gastroenterology. 2012; **107**(9):1409-1422

[47] Peyrin-Biroulet L, Deltenre P, de Suray N, Branche J, Sandborn WJ, Colombel JF. Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: Meta-analysis of placebo-controlled trials. Clinical Gastroenterology and Hepatology. 2008;**6**(6):644-653

[48] Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Langholff W, et al. Drug therapies and the risk of malignancy in crohn's disease: Results from the TREAT™ registry. The American Journal of Gastroenterology. 2014;**109**(2):212-223

[49] Long MD, Martin CF, Pipkin CA, Herfarth HH, Sandler RS, Kappelman MD. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. YGAST. 2012;**143**(2):390-399.e1 [50] Singh S, Nagpal SJS, Murad MH, Yadav S, Kane SV, Pardi DS, et al. Inflammatory bowel disease is associated with an increased risk of melanoma: A systematic review and meta-analysis. Clinical Gastroenterology and Hepatology. 2014;**12**(2):210-218

[57] Vande CN, Ferrante M, Van AG, Ballet V, Compernolle G, Van SK, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;1320-1329.

*DOI: http://dx.doi.org/10.5772/intechopen.90204*

*Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease*

[Epub 2015 Feb 24]

1343-1351.e1

2018;**154**(6):S-153

**85**

[58] D'Haens G, Vermeire S, Lambrecht G, Baert F, Bossuyt P, Pariente B, et al. Increasing infliximab dose based on symptoms, biomarkers, and serum drug concentrations does not increase clinical, endoscopic, and corticosteroid-free remission in patients with active luminal Crohn's disease. Gastroenterology. 2018;**154**(5):

[59] Almon E, Goldin E, Sbeit W, et al.

recombinant anti-TNF alpha fusion protein for the treatment of mild to moderate ulcerative colitis: Results of a phase 2A Clinical trials showing promissing results. Gastroenterology.

[60] Cohen BL, Sachar DB. Update on anti-tumor necrosis factor agents and others new drugs for inflammatory bowel disease. BMJ. 2017;**357**:J2505

A novel orally administered

[51] Lemaitre M et al. Association between use of tumor necrosis factor or thiopurines antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease. JAMA. 2017;**318**:1679-1686

[52] López-serrano P, Pérez-calle JL, Sánchez-tembleque MD. Hepatitis B and inflammatory bowel disease: Role of antiviral prophylaxis. 2013;**19**(9):1342- 1348

[53] Xie X, Li F, Chen J, Wang J. Risk of tuberculosis infection in anti-TNF-a biological therapy: From bench to bedside. Journal of Microbiology, Immunology, and Infection. 2013;**47**(4): 268-274. [Epub 2013 May 30]

[54] Quezada SM, McLean LP, Cross RK. Adverse events in IBD therapy: The 2018 update. Expert Review of Gastroenterology & Hepatology. 2018; **12**(12). DOI: 10.1080/17474124. 2018.1545574

[55] Kennedy NA, Heap GA, Green HD, Hamilton B, Bewshea C, Walker GJ, et al. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: A prospective, multicentre, cohort study. The Lancet Gastroenterology & Hepatology. 2019;**1253**(19):1-13

[56] Vande Casteele N, Herfarth H, Katz J, Falck-Ytter Y, Singh S. American Gastroenterological Association Institute Technical Review on the role of therapeutic drug monitoring in the management of inflammatory bowel diseases. Gastroenterology. 2017;**153**(3): 835-857.e6

*Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease DOI: http://dx.doi.org/10.5772/intechopen.90204*

[57] Vande CN, Ferrante M, Van AG, Ballet V, Compernolle G, Van SK, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;1320-1329. [Epub 2015 Feb 24]

Gastroenterology. 2018;**155**(2):

*Biological Therapy for Inflammatory Bowel Disease*

[50] Singh S, Nagpal SJS, Murad MH, Yadav S, Kane SV, Pardi DS, et al. Inflammatory bowel disease is associated with an increased risk of melanoma: A systematic review and meta-analysis. Clinical Gastroenterology and Hepatology. 2014;**12**(2):210-218

[51] Lemaitre M et al. Association between use of tumor necrosis factor or thiopurines antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease. JAMA. 2017;**318**:1679-1686

[52] López-serrano P, Pérez-calle JL, Sánchez-tembleque MD. Hepatitis B and inflammatory bowel disease: Role of antiviral prophylaxis. 2013;**19**(9):1342-

[53] Xie X, Li F, Chen J, Wang J. Risk of tuberculosis infection in anti-TNF-a biological therapy: From bench to bedside. Journal of Microbiology, Immunology, and Infection. 2013;**47**(4):

[54] Quezada SM, McLean LP, Cross RK. Adverse events in IBD therapy: The 2018 update. Expert Review of

Gastroenterology & Hepatology. 2018; **12**(12). DOI: 10.1080/17474124.

[55] Kennedy NA, Heap GA, Green HD, Hamilton B, Bewshea C, Walker GJ, et al. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: A prospective, multicentre, cohort study. The Lancet Gastroenterology & Hepatology. 2019;**1253**(19):1-13

[56] Vande Casteele N, Herfarth H, Katz J, Falck-Ytter Y, Singh S. American

Institute Technical Review on the role of therapeutic drug monitoring in the management of inflammatory bowel diseases. Gastroenterology. 2017;**153**(3):

Gastroenterological Association

268-274. [Epub 2013 May 30]

2018.1545574

835-857.e6

1348

[44] Rahier JF, Magro F, Abreu C, Armuzzi A, Ben-Horin S, Chowers Y, et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. Journal of Crohn's and Colitis.

[45] Lorenzetti R, Zullo A, Ridola L, Diamanti AP, Laganà B, Gatta L, et al. Higher risk of tuberculosis reactivation when anti-TNF is combined with immunosuppressive agents: A systematic review of randomized controlled trials. Annals of Medicine.

[46] Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Price S, et al. Serious infection and mortality in patients with crohn's disease: More than 5 years of follow-up in the TREAT registry. The American Journal of Gastroenterology. 2012;

[47] Peyrin-Biroulet L, Deltenre P, de Suray N, Branche J, Sandborn WJ, Colombel JF. Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: Meta-analysis of placebo-controlled trials. Clinical Gastroenterology and Hepatology.

[48] Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Langholff W, et al. Drug therapies and the risk of malignancy in crohn's disease: Results from the TREAT™ registry. The American Journal of Gastroenterology.

[49] Long MD, Martin CF, Pipkin CA,

Kappelman MD. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. YGAST. 2012;**143**(2):390-399.e1

337-346.e10

2014;**8**(6):443-468

2014;**46**(7):547-554

**107**(9):1409-1422

2008;**6**(6):644-653

2014;**109**(2):212-223

**84**

Herfarth HH, Sandler RS,

[58] D'Haens G, Vermeire S, Lambrecht G, Baert F, Bossuyt P, Pariente B, et al. Increasing infliximab dose based on symptoms, biomarkers, and serum drug concentrations does not increase clinical, endoscopic, and corticosteroid-free remission in patients with active luminal Crohn's disease. Gastroenterology. 2018;**154**(5): 1343-1351.e1

[59] Almon E, Goldin E, Sbeit W, et al. A novel orally administered recombinant anti-TNF alpha fusion protein for the treatment of mild to moderate ulcerative colitis: Results of a phase 2A Clinical trials showing promissing results. Gastroenterology. 2018;**154**(6):S-153

[60] Cohen BL, Sachar DB. Update on anti-tumor necrosis factor agents and others new drugs for inflammatory bowel disease. BMJ. 2017;**357**:J2505

**87**

**Chapter 5**

**Abstract**

of Crohn

*Dolores Ortiz-Masià*

bowel disease, stem cells

**1. Introduction**

Biological Therapy in the

in the prevention of complications of Crohn's disease.

Prevention of Complications

In recent years, the advent of biological agents has revolutionized the treatment of inflammatory bowel disease (IBD). TNF is a cytokine with a very important role in the pathogenesis of Crohn's disease (CD), so it is a therapeutic target to highlight. The efficacy and safety of the anti-TNF, IFX and ADA is widely established, becoming two of the therapeutic pillars of CD. Today the experience with other more recent antibodies and stem cells therapy is more limited. Various limitations such as lack of studies, heterogeneity in inclusion criteria, and achievement of objectives make it difficult to establish which treatment is more appropriate in each case and even the superiority between drugs and/or cellular therapy. This chapter will compare the different currently available therapies with special interest in new therapies and their relationship

**Keywords:** Crohn's disease, fibrosis, inflammation, biological therapy, inflammatory

Acute inflammatory processes affecting the intestine are relatively frequent and self-limiting, such that the intestinal mucosa is able to regenerate and regain homeostasis in a matter of days. However, chronic inflammation can cause irreversible structural changes and severe complications in the gastrointestinal tract [1]. The term inflammatory bowel disease (IBD) is used to refer generically to chronic inflammatory diseases, with recurrent course and unknown origin that affect the gastrointestinal tract and are distinguished mainly on the basis of histological findings. Basically in this group we find Crohn's disease (CD) and ulcerative colitis (UC), processes that have their peak incidence in young people and that constitute the most relevant pathologies within this classification. These pathologies are identified and diagnosed thanks to clinical, endoscopic, and histological characteristics, although on certain occasions it is not possible to distinguish which form of IBD is present, being classified as indeterminate colitis. Microscopic colitis is a term designated for a group of colitis in which we find microscopic but not macroscopic alterations when endoscopy or surgery is performed. Unlike the previous ones, this process mainly affects elderly people and includes collagenous colitis and lymphocytic colitis. Despite having similar epidemiological, clinical, and

#### **Chapter 5**

## Biological Therapy in the Prevention of Complications of Crohn

*Dolores Ortiz-Masià*

#### **Abstract**

In recent years, the advent of biological agents has revolutionized the treatment of inflammatory bowel disease (IBD). TNF is a cytokine with a very important role in the pathogenesis of Crohn's disease (CD), so it is a therapeutic target to highlight. The efficacy and safety of the anti-TNF, IFX and ADA is widely established, becoming two of the therapeutic pillars of CD. Today the experience with other more recent antibodies and stem cells therapy is more limited. Various limitations such as lack of studies, heterogeneity in inclusion criteria, and achievement of objectives make it difficult to establish which treatment is more appropriate in each case and even the superiority between drugs and/or cellular therapy. This chapter will compare the different currently available therapies with special interest in new therapies and their relationship in the prevention of complications of Crohn's disease.

**Keywords:** Crohn's disease, fibrosis, inflammation, biological therapy, inflammatory bowel disease, stem cells

#### **1. Introduction**

Acute inflammatory processes affecting the intestine are relatively frequent and self-limiting, such that the intestinal mucosa is able to regenerate and regain homeostasis in a matter of days. However, chronic inflammation can cause irreversible structural changes and severe complications in the gastrointestinal tract [1].

The term inflammatory bowel disease (IBD) is used to refer generically to chronic inflammatory diseases, with recurrent course and unknown origin that affect the gastrointestinal tract and are distinguished mainly on the basis of histological findings. Basically in this group we find Crohn's disease (CD) and ulcerative colitis (UC), processes that have their peak incidence in young people and that constitute the most relevant pathologies within this classification. These pathologies are identified and diagnosed thanks to clinical, endoscopic, and histological characteristics, although on certain occasions it is not possible to distinguish which form of IBD is present, being classified as indeterminate colitis. Microscopic colitis is a term designated for a group of colitis in which we find microscopic but not macroscopic alterations when endoscopy or surgery is performed. Unlike the previous ones, this process mainly affects elderly people and includes collagenous colitis and lymphocytic colitis. Despite having similar epidemiological, clinical, and even therapeutic characteristics, there are a series of peculiarities that help to define the existing process [2]. CD is characterized by the existence of transmural inflammation, cryptic abscesses, and the formation of granulomas, being able to affect any part of the intestine and may reappear after surgical resection of the affected segment [3]. UC, on the other hand, is typically associated with inflammation and ulceration limited to the mucosa and submucosa, only of the colon and rectum. In this way, and unlike CD, UC has a definitive treatment of the pathology in proctocolectomy. The main differential characteristics between CD and UC are shown in **Table 1**. The incidence of both diseases is increasing in the last decades and in the case of CD at younger ages [4].

Current CD therapies are solely targeting inflammation by administration of immunosuppressive therapies, corticosteroids, or biologicals. While these therapies in some—but not all—cases lead to symptomatic disease remission, recurrent flares interspaced with periods of remission will still result in cumulative gut wall remodeling. The evolution towards organ failure and surgical resection occurs in 70% of cases, with a subsequent need of second surgery in up to 30% of cases [5]. The postsurgical recurrence can occur very early, even a few weeks after surgical


**89**

**Table 2.**

*Biological Therapy in the Prevention of Complications of Crohn*

cellular therapy in fistulizing and luminal disease.

their influence on the prevention of complications.

increasingly diagnosed at earlier ages [4].

resection, because the drugs currently available for the prevention of postsurgical recurrence have limited efficacy; up to 50% of cases return to CD activity despite preventive treatment, which may lead to further surgery with consequent loss of bowel function which may eventually lead to the development of short bowel syndrome as an irreversible complication in some patients. Therefore, management of CD patients undergoing bowel resection should be oriented towards prevention, early detection, and, in the worst case, treatment of postsurgical

Given the great evolution experienced in IBD therapy, there is a need to compare the effectiveness of different treatments in the achievement of objectives as well as a clear definition of the objectives. The symptoms, although an indicator of quality of life, have a very poor correlation with the severity of inflammation. On the other hand, endoscopic activity, serological markers, and fecal calprotectin have greater correlation with the future need for surgery and occurrence of complications.

Among the objectives of the therapeutics of IBD, we highlight the induction of remission, the reduction of hospitalizations and surgeries, and the effectiveness of

CD is a chronic, recurrent inflammatory disease that belongs to the spectrum of IBD. It predominantly affects the gastrointestinal tract, being able to find lesions in any part of it, from the mouth to the anus. In it we also find important extraintestinal manifestations and association with other autoimmune diseases [7]. CD is an entity whose incidence increases as the development of society advances, being very

The maximum incidence is observed between the second and fourth decade of life, and a second peak is observed between the seventh and ninth, although it is

Although several factors have been described that may be related to the develop-

Environmental factors Non-breastfeeding, improved hygiene conditions, sedentary lifestyles, western

diet and fast food, tobacco, contraceptives, environmental pollution

Increase in potentially pathogenic flora: *Mycobacterium avium paratuberculosis*,

Deregulation in the immune system that initiates, mediates, and perpetuates inflammation. Rapid recruitment and inappropriate accumulation of

ment of CD, the exact causes of this process remain unknown (see **Table 2**).

Genetics Seventy-one susceptibility locus for CD have been identified on 17

Microbiota Reduction of commensal microbiota: *Bacteroidetes* and *Firmicutes*

*Campylobacter*, *Salmonella*, and *E. coli*

leukocytes in the affected intestinal wall

chromosomes

prevalent in developed countries and rare in less developed countries.

The general objective of this chapter is to address this gap in literature by reviewing bibliography comparing the different biological therapies available and

*DOI: http://dx.doi.org/10.5772/intechopen.90557*

recurrence [6].

**2. Crohn's disease**

**2.1 Etiopathogenesis**

Alteration of the immune system

*Etiopathogenesis of CD.*

*The table shows the main causes of CD.*

**Table 1.**

*Differential characteristics between CD and UC.*

*Biological Therapy in the Prevention of Complications of Crohn DOI: http://dx.doi.org/10.5772/intechopen.90557*

resection, because the drugs currently available for the prevention of postsurgical recurrence have limited efficacy; up to 50% of cases return to CD activity despite preventive treatment, which may lead to further surgery with consequent loss of bowel function which may eventually lead to the development of short bowel syndrome as an irreversible complication in some patients. Therefore, management of CD patients undergoing bowel resection should be oriented towards prevention, early detection, and, in the worst case, treatment of postsurgical recurrence [6].

Given the great evolution experienced in IBD therapy, there is a need to compare the effectiveness of different treatments in the achievement of objectives as well as a clear definition of the objectives. The symptoms, although an indicator of quality of life, have a very poor correlation with the severity of inflammation. On the other hand, endoscopic activity, serological markers, and fecal calprotectin have greater correlation with the future need for surgery and occurrence of complications.

Among the objectives of the therapeutics of IBD, we highlight the induction of remission, the reduction of hospitalizations and surgeries, and the effectiveness of cellular therapy in fistulizing and luminal disease.

The general objective of this chapter is to address this gap in literature by reviewing bibliography comparing the different biological therapies available and their influence on the prevention of complications.

#### **2. Crohn's disease**

*Biological Therapy for Inflammatory Bowel Disease*

case of CD at younger ages [4].

**Macroscopic**

**Microscopic**

**Clinics**

even therapeutic characteristics, there are a series of peculiarities that help to define the existing process [2]. CD is characterized by the existence of transmural inflammation, cryptic abscesses, and the formation of granulomas, being able to affect any part of the intestine and may reappear after surgical resection of the affected segment [3]. UC, on the other hand, is typically associated with inflammation and ulceration limited to the mucosa and submucosa, only of the colon and rectum. In this way, and unlike CD, UC has a definitive treatment of the pathology in proctocolectomy. The main differential characteristics between CD and UC are shown in **Table 1**. The incidence of both diseases is increasing in the last decades and in the

Current CD therapies are solely targeting inflammation by administration of immunosuppressive therapies, corticosteroids, or biologicals. While these therapies in some—but not all—cases lead to symptomatic disease remission, recurrent flares interspaced with periods of remission will still result in cumulative gut wall remodeling. The evolution towards organ failure and surgical resection occurs in 70% of cases, with a subsequent need of second surgery in up to 30% of cases [5]. The postsurgical recurrence can occur very early, even a few weeks after surgical

**Characteristics Crohn's disease Ulcerative colitis**

Distribution Sautéed lesions Diffuse lesions

Inflammation Transmural Limited to *mucosa* Pseudopolyps Moderate Important Ulcers Depths Superficial Lymphoid reaction Important Moderate Fibrosis Important Mild or absent Serositis Important Mild or absent

Intestinal region Ileum ± colon Colon

Stenosis Yes No Wall appearance Thick Thin

Granulomas Yes No Fistulas Yes No

Small bowel involvement Frequent Rare Perianal fistula Yes No Malabsorption of fats and vitamins Yes No Malignant potential Affecting the colon Yes Relapses after surgery Frequent No Toxic megacolon No Yes pANCA + ++ ASCA ++ + *The table shows the main macroscopic, microscopic, and clinical characteristics between CD and UC.*

Rectal involvement Frequent Almost always

**88**

**Table 1.**

*Differential characteristics between CD and UC.*

CD is a chronic, recurrent inflammatory disease that belongs to the spectrum of IBD. It predominantly affects the gastrointestinal tract, being able to find lesions in any part of it, from the mouth to the anus. In it we also find important extraintestinal manifestations and association with other autoimmune diseases [7]. CD is an entity whose incidence increases as the development of society advances, being very prevalent in developed countries and rare in less developed countries.

The maximum incidence is observed between the second and fourth decade of life, and a second peak is observed between the seventh and ninth, although it is increasingly diagnosed at earlier ages [4].

#### **2.1 Etiopathogenesis**

Although several factors have been described that may be related to the development of CD, the exact causes of this process remain unknown (see **Table 2**).


Several studies [8, 9] have found different genetic alterations that increase susceptibility to this disease along with certain environmental triggers, resulting in an altered immune response, both innate and adaptive, and epithelial bowel dysfunction. An alteration in the commensal microbiota has also been described, with a decrease in the potentially beneficial flora and an increase in that which is potentially pathogenic [8]. Genetic alterations, the immune system, microbiota, environmental factors, and their combined effects occupy a large number of pages in the scientific literature, and their description surpasses the objectives of this study.

#### **2.2 Symptoms, diagnosis, and classification**

CD is a heterogeneous entity comprising different phenotypes, so the symptoms are and change with the course of the disease. It usually has an insidious onset, the most common symptom being chronic diarrhea (80% of patients), followed by abdominal pain (70%), primarily in the right iliac fossa.

Other symptoms are weight loss (50%), malnutrition, fatigue, malaise, and the presence of rectorrhagia (more common in UC). Perianal disease (4–10% debut with it), nausea, vomiting, asthenia, anorexia, fever, and night sweats may also occur.

Diagnosis is currently established by combining clinical presentation and laboratory findings (such as anemia, elevation of globular sedimentation velocity and serum C-reactive protein, elevation of calprotectin and/or lactoferrin in stool, endoscopic appearance, histology, and radiological and/or biochemical findings). Serological and genetic tests are not recommended as routine diagnostic methods. However, despite advances in diagnostic methods, in the first year, up to 5% of cases with the diagnosis of CD has to be changed to UC or indeterminate colitis [10].

Once the diagnosis of CD is established, it is necessary to categorize patients based on the Montreal classification [11] and investigate the possible existence of extraintestinal manifestations and other autoimmune diseases (see **Table 3**). This stratification of patients makes it easier for them to receive the best follow-up and treatment in an individualized manner as well as to identify early possible complications [12]. However, it is important to bear in mind that the patient's stratification is not stable. It has been seen that 19% of patients progress to more aggressive forms of the disease 90 days after being staged and up to 51% of patients did so 20 years after the initial diagnosis [12]. These patients progressed developing complications that were not present at the time of diagnosis.


**91**

*Biological Therapy in the Prevention of Complications of Crohn*

88% of the cases, being very frequent the surgical reintervention.

Complications depend on the clinical course and control of the disease. Some may appear in any phenotype, such as massive hemorrhage, toxic megacolon, and neoplasia of the colon (the IBD favors the presence of multiple tumors with a higher degree of malignancy), while other complications are encompassed in different phenotypes of the disease. Thus, in the obstructive fibro-stenotic pattern, we find stenosis, intestinal obstruction, and perianal disease; and in the penetrating,

Most complications require a surgical approach; in fact, 70–80% of patients with CD will need some surgery throughout their lives. Even so, there are recurrences in

There are currently multiple drugs available for the treatment of IBD; however, there are no predictive response factors that allow us to select the most appropriate drug for a patient at any given time. In general, the choice of treatment is made on an individual basis according to the activity, location, and phenotype of the

The objectives include symptomatic control, remission of the outbreak and maintenance of long-term remission, as well as endoscopic healing, as there is no

• *Aminosalicylates*: indicated as maintenance treatment in mild to moderate CD. They include those molecules with aminosalicylic acid or 5-ASA in their molecular structure (also known as mesalazine in Europe and mesalamine in the USA). They have been shown to reduce the incidence of relapses (28 versus 55% with placebo) and have a higher percentage of remissions versus placebo (43 versus 18%, respectively). However, the efficacy in postoperative patients is greater. In general, they are well tolerated, and adverse effects such as

gastrointestinal disorders, headache, arthralgias, and cutaneous eruptions may appear. The nephrotoxicity and hematological toxicity are the more serious,

• *Glucocorticoids*: indicated for the induction of remission in an outbreak. They intervene on the vascular [decreasing permeability] and cellular [inhibiting tissue migration and phagocytosis of macrophages] phases. Prednisone is usually used at a dose of 40–60 mg/day orally or intravenously in severe outbreaks (with remission rates of 66–73%). Budesonide has shown similar efficacy to prednisone for mild to moderate ileocolonic CD (55% remissions). In addition, its topical action confers fewer adverse effects. However, they have not shown efficacy as a therapy for maintenance. In addition, this would be inadvisable given the risk of dependence and adverse effects: fluid retention, stretch marks, redistribution of body fat, subcapsular cataracts, myopathy, osteonecrosis, emotional disturbances, withdrawal symptoms, etc., many of which are

• *Antibiotics*: have no role in the treatment of CD, except metronidazole in

• *Thiopurines*: azathioprine (AZA) and 6-mercaptopurine (6MP). They are used in the management of corticosteroid-dependent CD, in the prevention of postsurgical recurrence, and in combination with biologics. The efficacy is appreciated from 3 to 4 weeks both as maintenance therapy and in perianal

*DOI: http://dx.doi.org/10.5772/intechopen.90557*

curative treatment. The drugs used are:

but infrequent, effects [13, 14].

related to the duration of treatment [15, 16].

perianal disease.

fistulas and abscesses.

**2.3 Treatment**

affectation.

**Table 3.** *CD Montreal classification [11].*

#### *Biological Therapy in the Prevention of Complications of Crohn DOI: http://dx.doi.org/10.5772/intechopen.90557*

Complications depend on the clinical course and control of the disease. Some may appear in any phenotype, such as massive hemorrhage, toxic megacolon, and neoplasia of the colon (the IBD favors the presence of multiple tumors with a higher degree of malignancy), while other complications are encompassed in different phenotypes of the disease. Thus, in the obstructive fibro-stenotic pattern, we find stenosis, intestinal obstruction, and perianal disease; and in the penetrating, fistulas and abscesses.

Most complications require a surgical approach; in fact, 70–80% of patients with CD will need some surgery throughout their lives. Even so, there are recurrences in 88% of the cases, being very frequent the surgical reintervention.

#### **2.3 Treatment**

*Biological Therapy for Inflammatory Bowel Disease*

**2.2 Symptoms, diagnosis, and classification**

that were not present at the time of diagnosis.

A2:17–40 years A3:>40 years

L2:colonic L3:ileocolon

L4:upper gastrointestinal tract

Behavior B1:without stricture formation, non-penetrating B2:stenosant B3:penetrating P:perianal disease

Age at diagnosis A1:<16 years

Location L1:terminal ileum

abdominal pain (70%), primarily in the right iliac fossa.

Several studies [8, 9] have found different genetic alterations that increase susceptibility to this disease along with certain environmental triggers, resulting in an altered immune response, both innate and adaptive, and epithelial bowel dysfunction. An alteration in the commensal microbiota has also been described, with a decrease in the potentially beneficial flora and an increase in that which is potentially pathogenic [8]. Genetic alterations, the immune system, microbiota, environmental factors, and their combined effects occupy a large number of pages in the scientific literature, and their description surpasses the objectives of this study.

CD is a heterogeneous entity comprising different phenotypes, so the symptoms are and change with the course of the disease. It usually has an insidious onset, the most common symptom being chronic diarrhea (80% of patients), followed by

Other symptoms are weight loss (50%), malnutrition, fatigue, malaise, and the presence of rectorrhagia (more common in UC). Perianal disease (4–10% debut with it), nausea, vomiting, asthenia, anorexia, fever, and night sweats may also occur. Diagnosis is currently established by combining clinical presentation and laboratory findings (such as anemia, elevation of globular sedimentation velocity and serum C-reactive protein, elevation of calprotectin and/or lactoferrin in stool, endoscopic appearance, histology, and radiological and/or biochemical findings). Serological and genetic tests are not recommended as routine diagnostic methods. However, despite advances in diagnostic methods, in the first year, up to 5% of cases with the diagnosis of CD has to be changed to UC or indeterminate colitis [10]. Once the diagnosis of CD is established, it is necessary to categorize patients based on the Montreal classification [11] and investigate the possible existence of extraintestinal manifestations and other autoimmune diseases (see **Table 3**). This stratification of patients makes it easier for them to receive the best follow-up and treatment in an individualized manner as well as to identify early possible complications [12]. However, it is important to bear in mind that the patient's stratification is not stable. It has been seen that 19% of patients progress to more aggressive forms of the disease 90 days after being staged and up to 51% of patients did so 20 years after the initial diagnosis [12]. These patients progressed developing complications

**90**

**Table 3.**

*CD Montreal classification [11].*

There are currently multiple drugs available for the treatment of IBD; however, there are no predictive response factors that allow us to select the most appropriate drug for a patient at any given time. In general, the choice of treatment is made on an individual basis according to the activity, location, and phenotype of the affectation.

The objectives include symptomatic control, remission of the outbreak and maintenance of long-term remission, as well as endoscopic healing, as there is no curative treatment. The drugs used are:


disease. They present a great interindividual variability, due to the genetic polymorphisms of TPMT (thiopurine methyltransferase), an enzyme that activates them. In general they are well tolerated, being hepatotoxicity, myelotoxicity and pancreatitis acute, the adverse effects to highlight, able to justify abandonment of the treatment. Other effects are nausea, fever, skin rash, hepatitis, and the development of lymphomas.


#### **3. Biological therapy in CD**

Biologic therapy was introduced as a treatment for CD 20 years ago, revolutionizing the handling of it. So far, infliximab (IFX), adalimumab (ADA), vedolizumab (VDZ), and ustekinumab have been approved in Europe for this purpose. In general they have a good safety profile, although the experience is limited in new drugs.

They have been shown to be effective in decreasing intestinal damage from inflammation, surgeries, and admissions, improving the quality of life of patients. Its benefits, specially their early administracion as well as their favorable safety profile, have meant that they are being used more and more frequently.

It should be noted that before starting treatment with biological therapy, it is necessary to rule out an active infection (mainly tuberculosis or hepatitis B). In addition, the appearance of hypersensitivity reactions, cutaneous reactions, cytopenias, heart failure, and autoimmune hepatitis forces to rule them out and assess a possible interruption of treatment. Its paradoxical inflammatory reactions have been described with psoriasis and dermatitis, which can affect even 10% of patients. Treatment with biologics contraindicates attenuated vaccines.

Its potential adverse effects make it necessary to stratify the patients, so that only those with severe or complicated illness receive early intensive therapy. Although there is no established definition of serious or complicated disease, greater complications are seen in patients who start the disease young (<40 years), perianal disease and/or ileocolic localization, with need to administer corticosteroids in the treatment of the first outbreak, in these cases. When two or more factors are present, it is indicated to start the treatment of the first outbreak with immunomodulators or biologicals. Various studies support that, although the monoclonal

**93**

*Biological Therapy in the Prevention of Complications of Crohn*

therapy, especially as a therapy of the maintenance.

of infections, infections, etc.) and its high cost.

for latent infections [20].

(AZA, 6-MP, or methotrexate).

specific monitoring is not required.

**3.2 Anti-integrin α4β7**

antibodies are more expensive than other treatments, the decrease in the number of hospitalizations and surgeries contributes to increase the cost/benefit ration of the

Anti-TNFs are so far the most effective agents in the treatment of moderateto-severe luminal disease (induction of remission and maintenance) and Crohn's fistulizer, and they are the first-line treatment in complex perianal disease. In Europe, IFX and ADA are approved in EC and CU and golimumab in CU. The results obtained have raised treatment expectations, with healing of the mucosa being the main objective, associated with a lower rate of hospitalizations and surgery and with a higher percentage of long-term remission. Difficulty in selecting patients that are going to benefit from these treatments lies in safety problems (risk

Anti-TNFs have demonstrated a good safety profile, the main drawback being the risk of infections, such as tuberculosis, pneumocystis, and nocardiosis. More than half of infections occur in the first 6 months of treatment and in guidelines combined with immunosuppressants. All of these risks justify the recommendation to update the vaccination schedule before starting treatment, as well as screening

The increased risk of cancer is controversial in the literature. A meta-analysis that included 12 cohort studies concluded that although the risk of melanoma is increased by 37% in patients with IBD, treatment with anti-TNF did not influence it [21].

Less frequently, they have also been associated with optic neuritis, seizures, and demyelinating disorders, including multiple sclerosis and exacerbation of heart failure symptoms grade III/IV. Adverse effects make it necessary to discontinue

Another aspect to mention is the lack of effect (30%) and the loss of therapeutic efficacy, which occurs in 23–26% of patients in the first 12 months of treatment. The causes are varied: in some patients there is a pharmacodynamic failure, when the main pathway of inflammation is not dependent on TNF. Others do not get a good pharmacokinetics, when the concentrations in plasma are insufficient, due to

There is evidence that good plasma levels of anti-TNF are associated with greater clinical efficacy, so monitoring of antibody levels has become a tool to optimize the treatment. They appear more frequently in patients treated sporadically than those treated every 8 weeks. In these situations, it is possible to add immunosuppressants

Until 2015, anti-TNFs were the only biologicals approved for the treatment of IBD in Europe. This year anti-integrin α4β7 antibodies were incorporated: vedolizumab (VDZ) and ustekinumab. In general, they present an acceptable safety profile, as no case of leukoencephalopathy has been recorded to be progressive multifocal, its most fearsome adverse effect. As for the rest of the adverse effects,

Vedolizumab is a recombinant humanized IgG1 AcM that specifically blocks the integrin α4β7 by joining MadCAM-1. It has recently been approved for EC and moderate-to-severe CU that have failed conventional treatment but also as a first-line drug. It is administered via IV, for which it has demonstrated efficacy in inducing remission and maintaining disease, the maintenance in postoperatives

treatment in 20.6% of patients with IFX and 14.4% with ADA [22–25].

increased clearance or appearance of anti-drug antibodies.

*DOI: http://dx.doi.org/10.5772/intechopen.90557*

**3.1 Anti-TNF**

antibodies are more expensive than other treatments, the decrease in the number of hospitalizations and surgeries contributes to increase the cost/benefit ration of the therapy, especially as a therapy of the maintenance.

#### **3.1 Anti-TNF**

*Biological Therapy for Inflammatory Bowel Disease*

pregnancy and lactation [17].

will discuss with more depth below.

**3. Biological therapy in CD**

hepatitis, and the development of lymphomas.

disease. They present a great interindividual variability, due to the genetic polymorphisms of TPMT (thiopurine methyltransferase), an enzyme that activates them. In general they are well tolerated, being hepatotoxicity, myelotoxicity and pancreatitis acute, the adverse effects to highlight, able to justify abandonment of the treatment. Other effects are nausea, fever, skin rash,

• *Methotrexate*: inhibitor of dihydrofolate reductase (folic acid antagonist). It is effective in maintenance of remission (65 versus 39% with placebo), with an evaluation necessary of hepatic enzymes. Hypersensitivity pneumonitis is a very rare but very serious adverse effect. Supplementation with folic acid reduces adverse effects. It is a teratogenic drug, so it is contraindicated during

• *Calcineurinics*: cyclosporine (CyA) and tacrolimus. Its usefulness is limited, although tacrolimus seems useful in perianal EC. CyA has a series of cases that

• *Monoclonal antibodies*: include the anti-TNF and anti-integrin α4β7, which we

Biologic therapy was introduced as a treatment for CD 20 years ago, revolutionizing the handling of it. So far, infliximab (IFX), adalimumab (ADA), vedolizumab (VDZ), and ustekinumab have been approved in Europe for this purpose. In general they have a good safety profile, although the experience is limited in new drugs. They have been shown to be effective in decreasing intestinal damage from inflammation, surgeries, and admissions, improving the quality of life of patients. Its benefits, specially their early administracion as well as their favorable safety

profile, have meant that they are being used more and more frequently.

patients. Treatment with biologics contraindicates attenuated vaccines.

It should be noted that before starting treatment with biological therapy, it is necessary to rule out an active infection (mainly tuberculosis or hepatitis B). In addition, the appearance of hypersensitivity reactions, cutaneous reactions, cytopenias, heart failure, and autoimmune hepatitis forces to rule them out and assess a possible interruption of treatment. Its paradoxical inflammatory reactions have been described with psoriasis and dermatitis, which can affect even 10% of

Its potential adverse effects make it necessary to stratify the patients, so that only those with severe or complicated illness receive early intensive therapy. Although there is no established definition of serious or complicated disease, greater complications are seen in patients who start the disease young (<40 years), perianal disease and/or ileocolic localization, with need to administer corticosteroids in the treatment of the first outbreak, in these cases. When two or more factors are present, it is indicated to start the treatment of the first outbreak with immunomodulators or biologicals. Various studies support that, although the monoclonal

support it in luminal and perianal EC, but the evidence is not robust.

• *Hematopoietic stem cell transplantation (HSCT)*: might be useful in some treatment-resistant cases. Mesenchymal stem cells (MSCs) have regenerative and immunomodulatory properties which lead to reduction of inflammation and healing of affected intestinal tissue in CD. Meta-analysis studies show that 23–40.5% of patients achieved remission after systemic infusion of MSCs [18, 19].

**92**

Anti-TNFs are so far the most effective agents in the treatment of moderateto-severe luminal disease (induction of remission and maintenance) and Crohn's fistulizer, and they are the first-line treatment in complex perianal disease. In Europe, IFX and ADA are approved in EC and CU and golimumab in CU. The results obtained have raised treatment expectations, with healing of the mucosa being the main objective, associated with a lower rate of hospitalizations and surgery and with a higher percentage of long-term remission. Difficulty in selecting patients that are going to benefit from these treatments lies in safety problems (risk of infections, infections, etc.) and its high cost.

Anti-TNFs have demonstrated a good safety profile, the main drawback being the risk of infections, such as tuberculosis, pneumocystis, and nocardiosis. More than half of infections occur in the first 6 months of treatment and in guidelines combined with immunosuppressants. All of these risks justify the recommendation to update the vaccination schedule before starting treatment, as well as screening for latent infections [20].

The increased risk of cancer is controversial in the literature. A meta-analysis that included 12 cohort studies concluded that although the risk of melanoma is increased by 37% in patients with IBD, treatment with anti-TNF did not influence it [21].

Less frequently, they have also been associated with optic neuritis, seizures, and demyelinating disorders, including multiple sclerosis and exacerbation of heart failure symptoms grade III/IV. Adverse effects make it necessary to discontinue treatment in 20.6% of patients with IFX and 14.4% with ADA [22–25].

Another aspect to mention is the lack of effect (30%) and the loss of therapeutic efficacy, which occurs in 23–26% of patients in the first 12 months of treatment. The causes are varied: in some patients there is a pharmacodynamic failure, when the main pathway of inflammation is not dependent on TNF. Others do not get a good pharmacokinetics, when the concentrations in plasma are insufficient, due to increased clearance or appearance of anti-drug antibodies.

There is evidence that good plasma levels of anti-TNF are associated with greater clinical efficacy, so monitoring of antibody levels has become a tool to optimize the treatment. They appear more frequently in patients treated sporadically than those treated every 8 weeks. In these situations, it is possible to add immunosuppressants (AZA, 6-MP, or methotrexate).

### **3.2 Anti-integrin α4β7**

Until 2015, anti-TNFs were the only biologicals approved for the treatment of IBD in Europe. This year anti-integrin α4β7 antibodies were incorporated: vedolizumab (VDZ) and ustekinumab. In general, they present an acceptable safety profile, as no case of leukoencephalopathy has been recorded to be progressive multifocal, its most fearsome adverse effect. As for the rest of the adverse effects, specific monitoring is not required.

Vedolizumab is a recombinant humanized IgG1 AcM that specifically blocks the integrin α4β7 by joining MadCAM-1. It has recently been approved for EC and moderate-to-severe CU that have failed conventional treatment but also as a first-line drug. It is administered via IV, for which it has demonstrated efficacy in inducing remission and maintaining disease, the maintenance in postoperatives

being its main indication. It has been postulated that its answer is slower because it does not block the pre-existing inflammation; it simply avoids recruiting more inflammatory cells. In addition, transmural involvement of CD may explain its action to be slower than CU.

The induction dose is 300 mg IV in weeks 0, 2, and 6, followed by 300 mg every 8 weeks as maintenance. A long-term loss of response has been noted, although usually in patients who have already failed other biologics. VDZ is a well-tolerated drug with a good security profile in IBD. The risk of infections increases but no cases of progressive multifocal leukoencephalopathy (PML), and the frequency of transfusion reactions is lower than that of the 5%. The development of anti-VZD antibodies occurred in less than 4% of patients, being a cause of therapeutic failure [26].

Natalizumab is a humanized IgG4 against the subunit α4, so it blocks both the integrin α4β7 and integrin α4β1; it therefore, has a non-specific action. It has shown promising results as maintenance therapy but has not been approved by its association with cases of progressive multifocal leukoencephalopathy. It is approved for CD in the USA under very severe conditions (concomitance with multiple sclerosis).

#### **3.3 IL-12 and/or IL-23 inhibitors**

IL-12 and IL-23 have been shown to be key cytokines in the adaptive immunity, which is found in IBD and intervenes in its chronification. Both ILs have in common the subunit p40, whose blocking inhibits the intracellular signaling cascade. The Crohn's immune response is influenced by resident lymphocytes and those recruited into the lymphoid organs. Antibodies from this group, such as the ustekinumab, prevent the binding of soluble IL-12 and IL-23 to their specific receptors, although they do not intervene on cytokines that are already attached to their membrane receptor. The blockage of IL-12 prevents the activation of Th1 lymphocytes, and IL-23 prevents the production of IFNγ, TNFα, IL-1β, and IL-6.

#### **3.4 Sphingosine receptor modulators**

Sphingosine-1 is a phospholipid that binds to specific receptors (S1P1–5) expressed in lymphocytes, dendritic cells, cardiomyocytes, and endothelial cells, regulating multiple cellular activities such as growth and survival, vascular integrity, and lymphocytic migration.

Sphingosine modulators behave like agonists producing functional antagonism, sequestering lymphocytes in peripheral lymphoid organs, and reinforcing the endothelial barrier (which makes intestinal migration difficult) [27].

#### **3.5 JAK kinase inhibitors**

Protein kinases are enzymes capable of modifying other proteins or enzymes, altering their function depending on the target. Certain polymorphisms of the same ones have been related with greater susceptibility to IBD. The signaling of this group of drugs is very complex, but it is a promising research in the field of IBD therapy (currently in phase 3 for both UC and CD).

In its mechanism of action, B lymphocytes and T effectors decrease without affecting the T regulators.

#### **3.6 Biological therapy in the induction of remission**

We speak of partial or total remission to refer to the reduction or disappearance of symptoms and signs of disease.

**95**

*Biological Therapy in the Prevention of Complications of Crohn*

The effectiveness of biological therapy in the induction of remission is indisputable. However, the percentages vary considerably between different molecules. At

The study PRECISE 1 investigated the effects of CTZ at week 6 and shows remission rates of 37% with CTZ and 31.4% for VDZ [30]. Clearly higher percentages are

Considering luminal disease, remission rates have been described as 63.8 and 54.1% for IFX and ADA, respectively, and remission in cortico-dependent patients as 76.3 and 44.7% for IFX and ADA at 12 months. Combination with immunosuppressants led to higher remission rates in patients with IFX (81 versus 52%), but not

In general, IFX is given to patients with a more severe phenotype of the disease, as it is believed to have faster action and more clinical experience. However, the results were similar in patients who received IFX and ADA, without finding significant differences in Crohn naïve patients except in the safety profile (adverse effects were more frequent with IFX than with ADA, 36.1 versus 15.5%, respectively), including transfusion reactions, skin rashes, arthralgias, and hypersensitivity [31]. This information is contradicted by other studies, such as the meta-analysis of Singh and collaborators, whose results support the superiority of IFX over the rest of the biologics for induction of clinical remission in naïve anti-TNF patients [32].

The effectiveness of biological therapy in the prevention of hospitalizations and

The anti-TNF therapy reduces significantly the hospitalizations and surgeries in patients with CD. No differences were observed between IFX and ADA, with a reduction of 46% (36–60%) of the hospitalizations and 13–42% of surgery with IFX. The onset of treatment may also be relevant in modifying the natural history of the disease. In this line, it has noted that early use of biological therapy (less than 2 years after diagnosis) improves the course of the disease. However, no significant reduction in the number of surgeries has been found in hospitalizations with

Human stem cell therapy for the treatment of CD is still in its infancy, and

Preliminary studies have shown that allogeneic HSCT may restore, at a genetic level, the immune system [35, 36], and autologous HSCT could remove atypical clones by immunoablation and replacement with not committed stem cells (SCs), allowing for the de novo generation of an altered T-cell repertoire [37]. Some studies describe that autologous and allogeneic HSCT produce a long-term treatmentfree disease regression in some patients with CD [19]. Nevertheless, the Autologous

patients treated with VDZ or AZA in similar follow-up periods [33].

whether SCT is associated with improved outcomes is unclear.

surgeries has not yet been clearly demonstrated. We know from previous studies that in the prebiological era, approximately 50% of patients required surgery 10 years after diagnosis, with a risk of recurrence of 50% at 10 years, and 80% of patients required surgery at some point in their lives. Recent studies indicate that surgery rates since the introduction of biologics (2001–2008) are lower than those of 1988. In addition, a very relevant characteristic of biologics is their high cost, and it is here that the reduction of the overall cost through the prevention of complica-

week 4, remission rates reach 75% with IFX [28] and 59% with ADA [29].

**3.7 Impact of biological therapy in the prevention of complications of** 

*DOI: http://dx.doi.org/10.5772/intechopen.90557*

noticeable with IFX and ADA.

in ADA [31].

**Crohn's disease**

tions becomes especially important [33, 34].

**4. Hematopoietic stem cell transplantation**

*Biological Therapy in the Prevention of Complications of Crohn DOI: http://dx.doi.org/10.5772/intechopen.90557*

*Biological Therapy for Inflammatory Bowel Disease*

action to be slower than CU.

**3.3 IL-12 and/or IL-23 inhibitors**

**3.4 Sphingosine receptor modulators**

rity, and lymphocytic migration.

**3.5 JAK kinase inhibitors**

affecting the T regulators.

of symptoms and signs of disease.

being its main indication. It has been postulated that its answer is slower because it does not block the pre-existing inflammation; it simply avoids recruiting more inflammatory cells. In addition, transmural involvement of CD may explain its

The induction dose is 300 mg IV in weeks 0, 2, and 6, followed by 300 mg every 8 weeks as maintenance. A long-term loss of response has been noted, although usually in patients who have already failed other biologics. VDZ is a well-tolerated drug with a good security profile in IBD. The risk of infections increases but no cases of progressive multifocal leukoencephalopathy (PML), and the frequency of transfusion reactions is lower than that of the 5%. The development of anti-VZD antibodies occurred in less than 4% of patients, being a cause of therapeutic failure [26].

Natalizumab is a humanized IgG4 against the subunit α4, so it blocks both the integrin α4β7 and integrin α4β1; it therefore, has a non-specific action. It has shown promising results as maintenance therapy but has not been approved by its association with cases of progressive multifocal leukoencephalopathy. It is approved for CD in the USA under very severe conditions (concomitance with multiple sclerosis).

IL-12 and IL-23 have been shown to be key cytokines in the adaptive immunity, which is found in IBD and intervenes in its chronification. Both ILs have in common the subunit p40, whose blocking inhibits the intracellular signaling cascade. The Crohn's immune response is influenced by resident lymphocytes and those recruited into the lymphoid organs. Antibodies from this group, such as the ustekinumab, prevent the binding of soluble IL-12 and IL-23 to their specific receptors, although they do not intervene on cytokines that are already attached to their membrane receptor. The blockage of IL-12 prevents the activation of Th1 lymphocytes, and

Sphingosine-1 is a phospholipid that binds to specific receptors (S1P1–5) expressed in lymphocytes, dendritic cells, cardiomyocytes, and endothelial cells, regulating multiple cellular activities such as growth and survival, vascular integ-

sequestering lymphocytes in peripheral lymphoid organs, and reinforcing the

endothelial barrier (which makes intestinal migration difficult) [27].

therapy (currently in phase 3 for both UC and CD).

**3.6 Biological therapy in the induction of remission**

Sphingosine modulators behave like agonists producing functional antagonism,

Protein kinases are enzymes capable of modifying other proteins or enzymes, altering their function depending on the target. Certain polymorphisms of the same ones have been related with greater susceptibility to IBD. The signaling of this group of drugs is very complex, but it is a promising research in the field of IBD

In its mechanism of action, B lymphocytes and T effectors decrease without

We speak of partial or total remission to refer to the reduction or disappearance

IL-23 prevents the production of IFNγ, TNFα, IL-1β, and IL-6.

**94**

The effectiveness of biological therapy in the induction of remission is indisputable. However, the percentages vary considerably between different molecules. At week 4, remission rates reach 75% with IFX [28] and 59% with ADA [29].

The study PRECISE 1 investigated the effects of CTZ at week 6 and shows remission rates of 37% with CTZ and 31.4% for VDZ [30]. Clearly higher percentages are noticeable with IFX and ADA.

Considering luminal disease, remission rates have been described as 63.8 and 54.1% for IFX and ADA, respectively, and remission in cortico-dependent patients as 76.3 and 44.7% for IFX and ADA at 12 months. Combination with immunosuppressants led to higher remission rates in patients with IFX (81 versus 52%), but not in ADA [31].

In general, IFX is given to patients with a more severe phenotype of the disease, as it is believed to have faster action and more clinical experience. However, the results were similar in patients who received IFX and ADA, without finding significant differences in Crohn naïve patients except in the safety profile (adverse effects were more frequent with IFX than with ADA, 36.1 versus 15.5%, respectively), including transfusion reactions, skin rashes, arthralgias, and hypersensitivity [31]. This information is contradicted by other studies, such as the meta-analysis of Singh and collaborators, whose results support the superiority of IFX over the rest of the biologics for induction of clinical remission in naïve anti-TNF patients [32].

#### **3.7 Impact of biological therapy in the prevention of complications of Crohn's disease**

The effectiveness of biological therapy in the prevention of hospitalizations and surgeries has not yet been clearly demonstrated. We know from previous studies that in the prebiological era, approximately 50% of patients required surgery 10 years after diagnosis, with a risk of recurrence of 50% at 10 years, and 80% of patients required surgery at some point in their lives. Recent studies indicate that surgery rates since the introduction of biologics (2001–2008) are lower than those of 1988. In addition, a very relevant characteristic of biologics is their high cost, and it is here that the reduction of the overall cost through the prevention of complications becomes especially important [33, 34].

The anti-TNF therapy reduces significantly the hospitalizations and surgeries in patients with CD. No differences were observed between IFX and ADA, with a reduction of 46% (36–60%) of the hospitalizations and 13–42% of surgery with IFX. The onset of treatment may also be relevant in modifying the natural history of the disease. In this line, it has noted that early use of biological therapy (less than 2 years after diagnosis) improves the course of the disease. However, no significant reduction in the number of surgeries has been found in hospitalizations with patients treated with VDZ or AZA in similar follow-up periods [33].

#### **4. Hematopoietic stem cell transplantation**

Human stem cell therapy for the treatment of CD is still in its infancy, and whether SCT is associated with improved outcomes is unclear.

Preliminary studies have shown that allogeneic HSCT may restore, at a genetic level, the immune system [35, 36], and autologous HSCT could remove atypical clones by immunoablation and replacement with not committed stem cells (SCs), allowing for the de novo generation of an altered T-cell repertoire [37]. Some studies describe that autologous and allogeneic HSCT produce a long-term treatmentfree disease regression in some patients with CD [19]. Nevertheless, the Autologous Stem Cell Transplantation International Crohn's Disease Trial [38] did not validate a statistically significant improvement in continued disease remission at 1 year of autologous HSCT compared with orthodox therapy, suggesting that further studies are needed in order to know the feasibility of using HSCT in patients with refractory CD [19].

#### **4.1 Luminal disease**

The number of patients requiring surgical resection for the stenosing and uncontrolled inflammatory complications of CD has not declined significantly, despite advances in biological therapy. Moreover, following a surgical resection, many patients will require a second operation. Currently, the use of systemically infused mesenchymal stem cell to reduce the altered inflammatory response and to repair impaired tissue has a promising future for avoiding surgery and its potentially serious complications. Conversely, since biological therapies are not always useful in some patients, the development of all-purpose anti-inflammatory therapies for patients with inflammatory luminal disease is still needed.

In luminal disease, the mechanism of the intravenous transplantation of MSCs is not understood yet. Animal studies and graft-versus-host disease treated by bone marrow MSC studies suggest, on the one hand, that the MSCs are able to transmigrate from the circulation into the inflamed tissues as a response to cytokine stimulus; on the other hand, MSC can release anti-inflammatory cytokines, which can modify the phenotype of macrophages towards repairing phenotype and can mediate the activation and proliferation of regulatory T and B cells.

One study that demonstrated the safety and viability of MSC in luminal disease was evaluated in nine patients with refractory CD, where the patients received two infusions of autologous bone marrow-derived MSC (days 0 and 7). At 6 weeks, endoscopic improvement was reported in two patients and clinical improvement in three, while three patients required surgery due to worsening disease [39]. In the same line, similar results were also seen in 15 CD patients with moderate-to-severe active disease who were refractory to anti-TNFα therapy [40]. In that study, at 6 weeks, a clinical response was observed in 80% of patients, clinical remission in 53% of patients, and endoscopic improvement in 47% of patients [40].

Evidence that MSC therapy contributes to neoplastic development is currently lacking. However, this view is based on a systematic review in which not all patients were assessed by repeated endoscopy during the 10-year follow-up, so the presence of dysplastic lesions cannot be excluded [19]. New and better studies are needed to test the safety of MSC therapy in luminal disease.

#### **4.2 Fistulizing disease**

Fistulae commonly complicate CD. There has been more research on the efficacy of MSC therapy in perianal fistulizing CD than on luminal CD. In all cases, the reduction of fistula frequency and the improved rate of complete fistula closure are the most important therapeutic goals. Administration of the therapeutic agent is performed locally under general anesthesia during perianal surgery. In the intervention, the surgeon initially scans the fistula tracts to remove setons and residual inflamed tissues. Once the internal opening is sealed with absorbing suture, the submucosa surrounding the internal orifices of fistulas and parallel to the lumen of tracts receives an injection of MSCs. The difference between results depends on different parameters like used dosage, origin and type of MSCs, therapeutic schedules, definition of end points, and therapeutic efficacy.

**97**

*Biological Therapy in the Prevention of Complications of Crohn*

tive in combination with immunosuppressants.

The safety and therapeutic potential of MSCs in treating perianal CD was first demonstrated in 2005 when autologous adipose-derived MSC was injected into nine perianal fistulae from four patients. After 8 weeks, complete healing was observed in six fistulae [41]. Fistula tract healing has been observed in 71% of patients treated with MSC and fibrin glue as compared to 16% of patients treated with fibrin glue alone. In patients receiving MSCs, closure was observed in 46% of patients after a single treatment and in a further 25% after a second rescue treatment [42, 43]. The currently available largest randomized, double-blind placebo-controlled study summarizes the clinical data of fistulizing CD patients which show that a greater proportion of patients in the treated group than the placebo group achieved the combined remission at week 24 in the intent-to-treat population (53 of 103

• The evidence places IFX over the rest of the biologics in the induction of remission in patients with naïve CD. It has shown higher remission percentages in numerous quality studies and in direct meta-analysis comparisons. While this information is contradicted by other articles, IFX seems to be more effective and faster acting, so it is the preferred biological therapy in patients with severe disease. In addition, it is the only one that has proven to be more effec-

• The biological treatments are the only ones that have shown effectiveness in the reduction of hospitalizations and surgeries. A number of studies have highlighted the superiority of IFX over other biologicals, as well as the equivalence

• Clinical trials demonstrated that MSC transplantation has an outstanding, durable efficacy with low fistula recurrence in biological therapy-refractory fistulizing CD; however, further clinical trials are required to confirm its

*DOI: http://dx.doi.org/10.5772/intechopen.90557*

(51%) vs. 36 of 101 (34%)) [44].

between ADA and CTZ.

effectiveness in luminal CD.

The author declares no conflict of interest.

**Conflict of interest**

**5. Conclusions**

*Biological Therapy in the Prevention of Complications of Crohn DOI: http://dx.doi.org/10.5772/intechopen.90557*

The safety and therapeutic potential of MSCs in treating perianal CD was first demonstrated in 2005 when autologous adipose-derived MSC was injected into nine perianal fistulae from four patients. After 8 weeks, complete healing was observed in six fistulae [41]. Fistula tract healing has been observed in 71% of patients treated with MSC and fibrin glue as compared to 16% of patients treated with fibrin glue alone. In patients receiving MSCs, closure was observed in 46% of patients after a single treatment and in a further 25% after a second rescue treatment [42, 43].

The currently available largest randomized, double-blind placebo-controlled study summarizes the clinical data of fistulizing CD patients which show that a greater proportion of patients in the treated group than the placebo group achieved the combined remission at week 24 in the intent-to-treat population (53 of 103 (51%) vs. 36 of 101 (34%)) [44].

#### **5. Conclusions**

*Biological Therapy for Inflammatory Bowel Disease*

tory CD [19].

**4.1 Luminal disease**

Stem Cell Transplantation International Crohn's Disease Trial [38] did not validate a statistically significant improvement in continued disease remission at 1 year of autologous HSCT compared with orthodox therapy, suggesting that further studies are needed in order to know the feasibility of using HSCT in patients with refrac-

The number of patients requiring surgical resection for the stenosing and uncontrolled inflammatory complications of CD has not declined significantly, despite advances in biological therapy. Moreover, following a surgical resection, many patients will require a second operation. Currently, the use of systemically infused mesenchymal stem cell to reduce the altered inflammatory response and to repair impaired tissue has a promising future for avoiding surgery and its potentially serious complications. Conversely, since biological therapies are not always useful in some patients, the development of all-purpose anti-inflammatory thera-

In luminal disease, the mechanism of the intravenous transplantation of MSCs is not understood yet. Animal studies and graft-versus-host disease treated by bone marrow MSC studies suggest, on the one hand, that the MSCs are able to transmigrate from the circulation into the inflamed tissues as a response to cytokine stimulus; on the other hand, MSC can release anti-inflammatory cytokines, which can modify the phenotype of macrophages towards repairing phenotype and can

One study that demonstrated the safety and viability of MSC in luminal disease was evaluated in nine patients with refractory CD, where the patients received two infusions of autologous bone marrow-derived MSC (days 0 and 7). At 6 weeks, endoscopic improvement was reported in two patients and clinical improvement in three, while three patients required surgery due to worsening disease [39]. In the same line, similar results were also seen in 15 CD patients with moderate-to-severe active disease who were refractory to anti-TNFα therapy [40]. In that study, at 6 weeks, a clinical response was observed in 80% of patients, clinical remission in

Evidence that MSC therapy contributes to neoplastic development is currently lacking. However, this view is based on a systematic review in which not all patients were assessed by repeated endoscopy during the 10-year follow-up, so the presence of dysplastic lesions cannot be excluded [19]. New and better studies are needed to

Fistulae commonly complicate CD. There has been more research on the efficacy of MSC therapy in perianal fistulizing CD than on luminal CD. In all cases, the reduction of fistula frequency and the improved rate of complete fistula closure are the most important therapeutic goals. Administration of the therapeutic agent is performed locally under general anesthesia during perianal surgery. In the intervention, the surgeon initially scans the fistula tracts to remove setons and residual inflamed tissues. Once the internal opening is sealed with absorbing suture, the submucosa surrounding the internal orifices of fistulas and parallel to the lumen of tracts receives an injection of MSCs. The difference between results depends on different parameters like used dosage, origin and type of MSCs, therapeutic schedules, definition of end points, and

pies for patients with inflammatory luminal disease is still needed.

mediate the activation and proliferation of regulatory T and B cells.

53% of patients, and endoscopic improvement in 47% of patients [40].

test the safety of MSC therapy in luminal disease.

**4.2 Fistulizing disease**

therapeutic efficacy.

**96**


#### **Conflict of interest**

The author declares no conflict of interest.

*Biological Therapy for Inflammatory Bowel Disease*

### **Author details**

Dolores Ortiz-Masià Facultad de Medicina y Odontología, Medicine Department, Universitat de València, Valencia, Spain

\*Address all correspondence to: m.dolores.ortiz@uv.es

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**99**

*Biological Therapy in the Prevention of Complications of Crohn*

Pathogenesis of Crohn's disease: Bug

Barrett JC, Wang K, Radford-Smith GL, Ahmad T, et al. Genome-wide metaanalysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature Genetics. 2010;**42**:1118-

[10] Stange EF, Travis SP, Vermeire S, Beglinger C, Kupcinkas L, Geboes K, et al. European evidence based consensus on the diagnosis and management of Crohn's disease: Definitions and diagnosis. Gut. 2006;**55**(Suppl 1):1. DOI:

[11] Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Canadian Journal of Gastroenterology and Hepatology. 2005;**19**(Suppl A):5- 36A. DOI: 10.1155/2005/269076

[12] Thia KT, Sandborn WJ, Harmsen WS,

Zinsmeister AR, Loftus EV. Risk factors associated with progression to intestinal complications of Crohn's disease in a population-based cohort. Gastroenterology. 2010;**139**:1147-1155. DOI: 10.1053/j.gastro.2010.06.070

[13] Singleton JW, Hanauer SB, Gitnick GL, Peppercorn MA, Robinson MG, Wruble LD, et al. Mesalamine capsules for the treatment of active Crohn's disease: Results of a 16-week trial. Gastroenterology. 1993;**104**:1293-1301. DOI: 0016-

[14] Prantera C, Pallone F, Brunetti G, Cottone M, Miglioli M, The Italian IBD

5085[93]90337-C [pii]

or no bug. World Journal of Gastrointestinal Pathophysiology. 2015;**6**:1-12. DOI: 10.4291/wjgp.v6.i1.1

[9] Franke A, McGovern DP,

1125. DOI: 10.1038/ng.717

55/suppl\_1/i1 [pii]

*DOI: http://dx.doi.org/10.5772/intechopen.90557*

[1] Rieder F, Brenmoehl J, Leeb S, Scholmerich J, Rogler G. Wound healing and fibrosis in intestinal disease. Gut. 2007;**56**:130-139. DOI: 56/1/130 [pii]

[2] Langner C, Aust D, Ensari A, Villanacci V, Becheanu G, Miehlke S, et al. Histology of microscopic colitisreview with a practical approach for pathologists. Histopathology. 2015;**66**:613-626. DOI: 10.1111/his.12592

[3] Peyrin-Biroulet L, Loftus EV,

history of adult Crohn's disease in population-based cohorts. The American Journal of Gastroenterology. 2010;**105**:289-297. DOI: 10.1038/

[4] Burisch J, Jess T, Martinato M, Lakatos PL, ECCO-EpiCom. The burden

of inflammatory bowel disease in Europe. Journal of Crohn's and Colitis. 2013;**7**:322-337. DOI: 10.1016/j.

[5] Cosnes J, Bourrier A, Nion-Larmurier I, Sokol H, Beaugerie L, Seksik P. Factors affecting outcomes in Crohn's disease over 15 years. Gut. 2012;**61**:1140-1145. DOI: 10.1136/

[6] Domenech E, Lopez-Sanroman A, Nos P, Vera M, Chaparro M, Esteve M, et al. Recommendations of the Spanish Working Group on Crohn's disease and Ulcerative colitis [GETECCU] on the monitoring, prevention and treatment of post-operative recurrence in Crohn's disease. Journal of Gastroenterology and Hepatology. 2017;**40**:472-483. DOI:

S0210-5705[17]30126-7 [pii]

[8] Bosca-Watts MM, Tosca J,

[7] Baumgart DC, Sandborn WJ. Crohn's disease. Lancet. 2012;**380**:1590-1605. DOI: 10.1016/S0140-6736[12]60026-9

Anton R, Mora M, Minguez M, Mora F.

Colombel JF, Sandborn WJ. The natural

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crohns.2013.01.010

gutjnl-2011-301971

*Biological Therapy in the Prevention of Complications of Crohn DOI: http://dx.doi.org/10.5772/intechopen.90557*

#### **References**

*Biological Therapy for Inflammatory Bowel Disease*

**98**

**Author details**

Dolores Ortiz-Masià

València, Valencia, Spain

Facultad de Medicina y Odontología, Medicine Department, Universitat de

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: m.dolores.ortiz@uv.es

provided the original work is properly cited.

[1] Rieder F, Brenmoehl J, Leeb S, Scholmerich J, Rogler G. Wound healing and fibrosis in intestinal disease. Gut. 2007;**56**:130-139. DOI: 56/1/130 [pii]

[2] Langner C, Aust D, Ensari A, Villanacci V, Becheanu G, Miehlke S, et al. Histology of microscopic colitisreview with a practical approach for pathologists. Histopathology. 2015;**66**:613-626. DOI: 10.1111/his.12592

[3] Peyrin-Biroulet L, Loftus EV, Colombel JF, Sandborn WJ. The natural history of adult Crohn's disease in population-based cohorts. The American Journal of Gastroenterology. 2010;**105**:289-297. DOI: 10.1038/ ajg.2009.579

[4] Burisch J, Jess T, Martinato M, Lakatos PL, ECCO-EpiCom. The burden of inflammatory bowel disease in Europe. Journal of Crohn's and Colitis. 2013;**7**:322-337. DOI: 10.1016/j. crohns.2013.01.010

[5] Cosnes J, Bourrier A, Nion-Larmurier I, Sokol H, Beaugerie L, Seksik P. Factors affecting outcomes in Crohn's disease over 15 years. Gut. 2012;**61**:1140-1145. DOI: 10.1136/ gutjnl-2011-301971

[6] Domenech E, Lopez-Sanroman A, Nos P, Vera M, Chaparro M, Esteve M, et al. Recommendations of the Spanish Working Group on Crohn's disease and Ulcerative colitis [GETECCU] on the monitoring, prevention and treatment of post-operative recurrence in Crohn's disease. Journal of Gastroenterology and Hepatology. 2017;**40**:472-483. DOI: S0210-5705[17]30126-7 [pii]

[7] Baumgart DC, Sandborn WJ. Crohn's disease. Lancet. 2012;**380**:1590-1605. DOI: 10.1016/S0140-6736[12]60026-9

[8] Bosca-Watts MM, Tosca J, Anton R, Mora M, Minguez M, Mora F. Pathogenesis of Crohn's disease: Bug or no bug. World Journal of Gastrointestinal Pathophysiology. 2015;**6**:1-12. DOI: 10.4291/wjgp.v6.i1.1

[9] Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, et al. Genome-wide metaanalysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature Genetics. 2010;**42**:1118- 1125. DOI: 10.1038/ng.717

[10] Stange EF, Travis SP, Vermeire S, Beglinger C, Kupcinkas L, Geboes K, et al. European evidence based consensus on the diagnosis and management of Crohn's disease: Definitions and diagnosis. Gut. 2006;**55**(Suppl 1):1. DOI: 55/suppl\_1/i1 [pii]

[11] Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Canadian Journal of Gastroenterology and Hepatology. 2005;**19**(Suppl A):5- 36A. DOI: 10.1155/2005/269076

[12] Thia KT, Sandborn WJ, Harmsen WS, Zinsmeister AR, Loftus EV. Risk factors associated with progression to intestinal complications of Crohn's disease in a population-based cohort. Gastroenterology. 2010;**139**:1147-1155. DOI: 10.1053/j.gastro.2010.06.070

[13] Singleton JW, Hanauer SB, Gitnick GL, Peppercorn MA, Robinson MG, Wruble LD, et al. Mesalamine capsules for the treatment of active Crohn's disease: Results of a 16-week trial. Gastroenterology. 1993;**104**:1293-1301. DOI: 0016- 5085[93]90337-C [pii]

[14] Prantera C, Pallone F, Brunetti G, Cottone M, Miglioli M, The Italian IBD Study Group. Oral 5-aminosalicylic acid [Asacol] in the maintenance treatment of Crohn's disease. Gastroenterology. 1992;**103**:363-368. DOI: 0016- 5085[92]90822-G [pii]

[15] Rutgeerts P, Lofberg R, Malchow H, Lamers C, Olaison G, Jewell D, et al. A comparison of budesonide with prednisolone for active Crohn's disease. The New England Journal of Medicine. 1994;**331**:842-845. DOI: 10.1056/ NEJM199409293311304

[16] Malchow H, Ewe K, Brandes JW, Goebell H, Ehms H, Sommer H, et al. European Cooperative Crohn's Disease Study [ECCDS]: Results of drug treatment. Gastroenterology. 1984;**86**:249-266. DOI: S001650858400024X [pii]

[17] Patel V, Wang Y, MacDonald JK, McDonald JW, Chande N. Methotrexate for maintenance of remission in Crohn's disease. Cochrane Database of Systematic Reviews. 2014;**8**:CD006884. DOI: 10.1002/ 14651858.CD006884.pub3

[18] Dave M, Mehta K, Luther J, Baruah A, Dietz AB, Faubion WA. Mesenchymal stem cell therapy for inflammatory bowel disease: A systematic review and metaanalysis. Inflammatory Bowel Diseases. 2015;**21**:2696-2707. DOI: 10.1097/ MIB.0000000000000543

[19] Qiu Y, Li MY, Feng T, Feng R, Mao R, Chen BL, et al. Systematic review with meta-analysis: The efficacy and safety of stem cell therapy for Crohn's disease. Stem Cell Research and Therapy. 2017;**8**:13-1x. DOI: 10.1186/ s13287-017-0570-x

[20] Baddley JW, Winthrop KL, Chen L, Liu L, Grijalva CG, Delzell E, et al. Non-viral opportunistic infections in new users of tumour necrosis factor inhibitor therapy: Results of the SAfety assessment of

biologic ThERapy [SABER] study. Annals of the Rheumatic Diseases. 2014;**73**:1942-1948. DOI: 10.1136/ annrheumdis-2013-203407

[21] Chaparro M, Ramas M, Benitez JM, Lopez-Garcia A, Juan A, Guardiola J, et al. Extracolonic cancer in inflammatory bowel disease: Data from the GETECCU Eneida registry. The American Journal of Gastroenterology. 2017;**112**:1135-1143. DOI: 10.1038/ ajg.2017.96

[22] Kopylov U, Vutcovici M, Kezouh A, Seidman E, Bitton A, Afif W. Risk of lymphoma, colorectal and skin cancer in patients with IBD treated with immunomodulators and biologics: A Quebec Claims Database Study. Inflammatory Bowel Disease. 2015;**21**:1847-1853. DOI: 10.1097/ MIB.0000000000000457

[23] Long MD, Martin CF, Pipkin CA, Herfarth HH, Sandler RS, Kappelman MD. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology. 2012;**143**:39-399.e1. DOI: 10.1053/j. gastro.2012.05.004

[24] McKenna MR, Stobaugh DJ, Deepak P. Melanoma and nonmelanoma skin cancer in inflammatory bowel disease patients following tumor necrosis factor-alpha inhibitor monotherapy and in combination with thiopurines: Analysis of the Food and Drug Administration adverse event reporting system. Journal of Gastrointestinal and Liver Diseases. 2014;**23**:267-271. DOI: 10.15403/ jgld.2014.1121.233.mrmk

[25] Singh S, Nagpal SJ, Murad MH, Yadav S, Kane SV, Pardi DS, et al. Inflammatory bowel disease is associated with an increased risk of melanoma: A systematic review and meta-analysis. Clinical Gastroenterology and Hepatology.

**101**

*Biological Therapy in the Prevention of Complications of Crohn*

network meta-analysis: Efficacy of induction therapy with a second biological agent in anti-TNF-

experienced Crohn's disease patients. Gastroenterology Research and Practice. 2018;**2018**:6317057. DOI:

[33] Mao EJ, Hazlewood GS, Kaplan GG, Peyrin-Biroulet L, Ananthakrishnan AN.

10.1155/2018/6317057

10.1111/apt.13847

jjv190

[34] Annese V, Duricova D, Gower-Rousseau C, Jess T,

[35] Engelhardt KR, Shah N, Faizura-Yeop I, Kocacik Uygun DF, Frede N, Muise AM, et al. Clinical outcome in IL-10- and IL-10 receptordeficient patients with or without hematopoietic stem cell transplantation. The Journal of Allergy and Clinical Immunology. 2013;**131**:825-830. DOI:

10.1016/j.jaci.2012.09.025

5085[98]70525-6 [pii]

[37] Muraro PA, Douek DC, Packer A, Chung K, Guenaga FJ, Cassiani-Ingoni R, et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. Journal of Experimental

[36] Lopez-Cubero SO, Sullivan KM, McDonald GB. Course of Crohn's disease after allogeneic marrow transplantation. Gastroenterology. 1998;**114**:433-440. DOI: S0016-

Langholz E. Impact of new treatments on hospitalisation, surgery, infection, and mortality in IBD: A focus paper by the epidemiology committee of ECCO. Journal of Crohn's and Colitis. 2016;**10**:216-225. DOI: 10.1093/ecco-jcc/

Systematic review with metaanalysis: Comparative efficacy of immunosuppressants and biologics for reducing hospitalisation and surgery in Crohn's disease and Ulcerative colitis. Alimentary Pharmacology and Therapeutics. 2017;**45**:3-13. DOI:

*DOI: http://dx.doi.org/10.5772/intechopen.90557*

2014;**12**:210-218. DOI: 10.1016/j.

[26] Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. The New England Journal of Medicine. 2013;**369**:711-721. DOI:

10.1056/NEJMoa1215739

4914[17]30021-7 [pii]

[27] Nielsen OH, Li Y, Johansson-Lindbom B, Coskun M. Sphingosine-1-phosphate signaling in inflammatory bowel disease. Trends in Molecular Medicine. 2017;**23**:362-374. DOI: S1471-

[28] Lemann M, Mary JY, Duclos B, Veyrac M, Dupas JL, Delchier JC, et al. Infliximab plus azathioprine for steroiddependent Crohn's disease patients: A randomized placebo-controlled trial. Gastroenterology. 2006;**130**:1054-1061. DOI: S0016-5085[06]00276-9 [pii]

[29] Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, et al. Human anti-tumor necrosis factor monoclonal antibody [adalimumab] in Crohn's disease: The CLASSIC-I trial. Gastroenterology. 2006;**130**:32-33; quiz 591. DOI: S0016-

[30] Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, et al. Certolizumab pegol for the treatment of Crohn's disease. The New England Journal of Medicine. 2007;**357**:228-238. DOI: 357/3/228 [pii]

[31] Benmassaoud A, Al-Taweel T, Sasson MS, Moza D, Strohl M, Kopylov U, et al. Comparative effectiveness of infliximab versus Adalimumab in patients with biologicnaive Crohn's disease. Digestive Diseases and Sciences. 2018;**63**:1302-1310. DOI:

10.1007/s10620-017-4874-6

[32] Pagnini C, Siakavellas SI, Bamias G. Systematic review with

5085[05]02315-2 [pii]

cgh.2013.04.033

*Biological Therapy in the Prevention of Complications of Crohn DOI: http://dx.doi.org/10.5772/intechopen.90557*

2014;**12**:210-218. DOI: 10.1016/j. cgh.2013.04.033

*Biological Therapy for Inflammatory Bowel Disease*

Study Group. Oral 5-aminosalicylic acid [Asacol] in the maintenance treatment of Crohn's disease. Gastroenterology.

biologic ThERapy [SABER] study. Annals of the Rheumatic Diseases. 2014;**73**:1942-1948. DOI: 10.1136/ annrheumdis-2013-203407

Benitez JM, Lopez-Garcia A, Juan A, Guardiola J, et al. Extracolonic cancer in inflammatory bowel disease: Data from the GETECCU Eneida registry. The American Journal of Gastroenterology. 2017;**112**:1135-1143. DOI: 10.1038/

[22] Kopylov U, Vutcovici M, Kezouh A, Seidman E, Bitton A, Afif W. Risk of lymphoma, colorectal and skin cancer in patients with IBD treated with immunomodulators and

biologics: A Quebec Claims Database Study. Inflammatory Bowel Disease. 2015;**21**:1847-1853. DOI: 10.1097/ MIB.0000000000000457

[23] Long MD, Martin CF, Pipkin CA,

Kappelman MD. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology. 2012;**143**:39-399.e1. DOI: 10.1053/j.

[24] McKenna MR, Stobaugh DJ, Deepak P. Melanoma and non-

jgld.2014.1121.233.mrmk

[25] Singh S, Nagpal SJ, Murad MH, Yadav S, Kane SV, Pardi DS, et al. Inflammatory bowel disease is associated with an increased risk of melanoma: A systematic review and meta-analysis. Clinical Gastroenterology and Hepatology.

melanoma skin cancer in inflammatory bowel disease patients following tumor necrosis factor-alpha inhibitor monotherapy and in combination with thiopurines: Analysis of the Food and Drug Administration adverse event reporting system. Journal of Gastrointestinal and Liver Diseases. 2014;**23**:267-271. DOI: 10.15403/

Herfarth HH, Sandler RS,

gastro.2012.05.004

[21] Chaparro M, Ramas M,

ajg.2017.96

[15] Rutgeerts P, Lofberg R, Malchow H, Lamers C, Olaison G, Jewell D, et al. A comparison of budesonide with prednisolone for active Crohn's disease. The New England Journal of Medicine. 1994;**331**:842-845. DOI: 10.1056/

[16] Malchow H, Ewe K, Brandes JW, Goebell H, Ehms H, Sommer H, et al. European Cooperative Crohn's Disease Study [ECCDS]: Results of drug treatment. Gastroenterology.

[17] Patel V, Wang Y, MacDonald JK, McDonald JW, Chande N. Methotrexate

for maintenance of remission in Crohn's disease. Cochrane Database of Systematic Reviews. 2014;**8**:CD006884. DOI: 10.1002/

14651858.CD006884.pub3

Luther J, Baruah A, Dietz AB, Faubion WA. Mesenchymal stem cell therapy for inflammatory bowel disease: A systematic review and metaanalysis. Inflammatory Bowel Diseases. 2015;**21**:2696-2707. DOI: 10.1097/ MIB.0000000000000543

[19] Qiu Y, Li MY, Feng T, Feng R, Mao R, Chen BL, et al. Systematic review with meta-analysis: The efficacy and safety of stem cell therapy for Crohn's disease. Stem Cell Research and Therapy. 2017;**8**:13-1x. DOI: 10.1186/

[20] Baddley JW, Winthrop KL, Chen L, Liu L, Grijalva CG, Delzell E, et al. Non-viral opportunistic infections in new users of tumour necrosis factor inhibitor therapy: Results of the SAfety assessment of

[18] Dave M, Mehta K,

s13287-017-0570-x

1992;**103**:363-368. DOI: 0016- 5085[92]90822-G [pii]

NEJM199409293311304

1984;**86**:249-266. DOI: S001650858400024X [pii]

**100**

[26] Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. The New England Journal of Medicine. 2013;**369**:711-721. DOI: 10.1056/NEJMoa1215739

[27] Nielsen OH, Li Y, Johansson-Lindbom B, Coskun M. Sphingosine-1-phosphate signaling in inflammatory bowel disease. Trends in Molecular Medicine. 2017;**23**:362-374. DOI: S1471- 4914[17]30021-7 [pii]

[28] Lemann M, Mary JY, Duclos B, Veyrac M, Dupas JL, Delchier JC, et al. Infliximab plus azathioprine for steroiddependent Crohn's disease patients: A randomized placebo-controlled trial. Gastroenterology. 2006;**130**:1054-1061. DOI: S0016-5085[06]00276-9 [pii]

[29] Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, et al. Human anti-tumor necrosis factor monoclonal antibody [adalimumab] in Crohn's disease: The CLASSIC-I trial. Gastroenterology. 2006;**130**:32-33; quiz 591. DOI: S0016- 5085[05]02315-2 [pii]

[30] Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, et al. Certolizumab pegol for the treatment of Crohn's disease. The New England Journal of Medicine. 2007;**357**:228-238. DOI: 357/3/228 [pii]

[31] Benmassaoud A, Al-Taweel T, Sasson MS, Moza D, Strohl M, Kopylov U, et al. Comparative effectiveness of infliximab versus Adalimumab in patients with biologicnaive Crohn's disease. Digestive Diseases and Sciences. 2018;**63**:1302-1310. DOI: 10.1007/s10620-017-4874-6

[32] Pagnini C, Siakavellas SI, Bamias G. Systematic review with network meta-analysis: Efficacy of induction therapy with a second biological agent in anti-TNFexperienced Crohn's disease patients. Gastroenterology Research and Practice. 2018;**2018**:6317057. DOI: 10.1155/2018/6317057

[33] Mao EJ, Hazlewood GS, Kaplan GG, Peyrin-Biroulet L, Ananthakrishnan AN. Systematic review with metaanalysis: Comparative efficacy of immunosuppressants and biologics for reducing hospitalisation and surgery in Crohn's disease and Ulcerative colitis. Alimentary Pharmacology and Therapeutics. 2017;**45**:3-13. DOI: 10.1111/apt.13847

[34] Annese V, Duricova D, Gower-Rousseau C, Jess T, Langholz E. Impact of new treatments on hospitalisation, surgery, infection, and mortality in IBD: A focus paper by the epidemiology committee of ECCO. Journal of Crohn's and Colitis. 2016;**10**:216-225. DOI: 10.1093/ecco-jcc/ jjv190

[35] Engelhardt KR, Shah N, Faizura-Yeop I, Kocacik Uygun DF, Frede N, Muise AM, et al. Clinical outcome in IL-10- and IL-10 receptordeficient patients with or without hematopoietic stem cell transplantation. The Journal of Allergy and Clinical Immunology. 2013;**131**:825-830. DOI: 10.1016/j.jaci.2012.09.025

[36] Lopez-Cubero SO, Sullivan KM, McDonald GB. Course of Crohn's disease after allogeneic marrow transplantation. Gastroenterology. 1998;**114**:433-440. DOI: S0016- 5085[98]70525-6 [pii]

[37] Muraro PA, Douek DC, Packer A, Chung K, Guenaga FJ, Cassiani-Ingoni R, et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. Journal of Experimental

Medicine. 2005;**201**:805-816. DOI: jem.20041679 [pii]

[38] Hawkey CJ, Allez M, Clark MM, Labopin M, Lindsay JO, Ricart E, et al. Autologous hematopoetic stem cell transplantation for refractory Crohn disease: A randomized clinical trial. JAMA. 2015;**314**:2524-2534. DOI: 10.1001/jama.2015.16700

[39] Duijvestein M, Vos AC, Roelofs H, Wildenberg ME, Wendrich BB, Verspaget HW, et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: Results of a phase I study. Gut. 2010;**59**:1662-1669. DOI: 10.1136/ gut.2010.215152

[40] Forbes GM, Sturm MJ, Leong RW, Sparrow MP, Segarajasingam D, Cummins AG, et al. A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn's disease refractory to biologic therapy. Clinical Gastroenterology and Hepatology. 2014;**12**:64-71. DOI: 10.1016/j. cgh.2013.06.021

[41] Garcia-Olmo D, Garcia-Arranz M, Herreros D, Pascual I, Peiro C, Rodriguez-Montes JA. A phase I clinical trial of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation. Diseases of the Colon and Rectum. 2005;**48**:1416-1423. DOI: 10.1007/s10350-005-0052-6

[42] Ibraheim H, Giacomini C, Kassam Z, Dazzi F, Powell N. Advances in mesenchymal stromal cell therapy in the management of Crohn's disease. Expert Review of Gastroenterology and Hepatology. 2018;**12**:141-153. DOI: 10.1080/17474124.2018.1393332

[43] Garcia-Olmo D, Herreros D, Pascual I, Pascual JA, Del-Valle E, Zorrilla J, et al. Expanded adiposederived stem cells for the treatment of complex perianal fistula: A phase II

clinical trial. Diseases of the Colon and Rectum. 2009;**52**:79-86. DOI: 10.1007/ DCR.0b013e3181973487

**Chapter 6**

**Abstract**

Is Necessary

Biological Therapy for

*Maria de Lourdes Setsuko Ayrizono,*

proceed when surgery is necessary in these patients.

infectious diseases, vaccines

these drugs is also provided.

**1. Introduction**

**103**

Inflammatory Bowel Diseases:

Screening Prior to Initiating and

How to Proceed When Surgery

*Priscilla de Sene Portel Oliveira and João José Fagundes*

Biological therapy has revolutionized the management of inflammatory bowel disease (IBD) in the last 30 years. However, these drugs have side effects and adverse events. Before starting this therapy, it is necessary to screen for specific infectious diseases and monitoring protocols. Screening for human immunodeficiency virus, hepatitis C, hepatitis B, and *Mycobacterium tuberculosis* infections must be included. In addition, vaccination should be checked and updated if necessary. Despite the advent of biological therapy, a significant number of patients with IBD will need surgery in their lifetime due to either clinical intractability or disease complications. Many of them will be on biological therapy, and there is a considerable controversy about adverse effects of biologics on surgical outcomes. In this chapter, we will approach the screening required to start this therapy and how to

**Keywords:** inflammatory bowel disease, surgery, biologic agents, complications,

Biological therapy brought a better control of inflammatory bowel diseases (IBD). However, its use requires specific care before the beginning and during the treatment. Some essential points in its management have raised discussions.

when surgery is required. A brief review of what is necessary before the use of

We address the needs before starting the biological therapy and how to proceed

The management of other immunosuppressive agents such as corticosteroids, azathioprine, 6-mercaptopurine, and methotrexate is not covered in this chapter.

[44] Panes J, Garcia-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, et al. Expanded allogeneic adipose-derived mesenchymal stem cells [Cx601] for complex perianal fistulas in Crohn's disease: A phase 3 randomised, double-blind controlled trial. Lancet. 2016;**388**:1281-1290. DOI: 10.1016/ S0140-6736[16]31203-X

#### **Chapter 6**

*Biological Therapy for Inflammatory Bowel Disease*

clinical trial. Diseases of the Colon and Rectum. 2009;**52**:79-86. DOI: 10.1007/

[44] Panes J, Garcia-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, et al. Expanded allogeneic adipose-derived mesenchymal stem cells [Cx601] for complex perianal fistulas in Crohn's disease: A phase 3 randomised, double-blind controlled trial. Lancet. 2016;**388**:1281-1290. DOI: 10.1016/

DCR.0b013e3181973487

S0140-6736[16]31203-X

Medicine. 2005;**201**:805-816. DOI:

[38] Hawkey CJ, Allez M, Clark MM, Labopin M, Lindsay JO, Ricart E, et al. Autologous hematopoetic stem cell transplantation for refractory Crohn disease: A randomized clinical trial. JAMA. 2015;**314**:2524-2534. DOI:

jem.20041679 [pii]

10.1001/jama.2015.16700

[39] Duijvestein M, Vos AC, Roelofs H, Wildenberg ME, Wendrich BB, Verspaget HW, et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease:

Results of a phase I study. Gut. 2010;**59**:1662-1669. DOI: 10.1136/

[40] Forbes GM, Sturm MJ, Leong RW, Sparrow MP, Segarajasingam D, Cummins AG, et al. A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn's disease refractory to biologic therapy. Clinical Gastroenterology and Hepatology. 2014;**12**:64-71. DOI: 10.1016/j.

[41] Garcia-Olmo D, Garcia-Arranz M,

Rodriguez-Montes JA. A phase I clinical trial of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation. Diseases of the Colon and Rectum. 2005;**48**:1416-1423. DOI:

Kassam Z, Dazzi F, Powell N. Advances in mesenchymal stromal cell therapy in the management of Crohn's disease. Expert Review of Gastroenterology and Hepatology. 2018;**12**:141-153. DOI:

Herreros D, Pascual I, Peiro C,

10.1007/s10350-005-0052-6

[42] Ibraheim H, Giacomini C,

10.1080/17474124.2018.1393332

[43] Garcia-Olmo D, Herreros D, Pascual I, Pascual JA, Del-Valle E, Zorrilla J, et al. Expanded adiposederived stem cells for the treatment of complex perianal fistula: A phase II

gut.2010.215152

cgh.2013.06.021

**102**

## Biological Therapy for Inflammatory Bowel Diseases: Screening Prior to Initiating and How to Proceed When Surgery Is Necessary

*Maria de Lourdes Setsuko Ayrizono, Priscilla de Sene Portel Oliveira and João José Fagundes*

#### **Abstract**

Biological therapy has revolutionized the management of inflammatory bowel disease (IBD) in the last 30 years. However, these drugs have side effects and adverse events. Before starting this therapy, it is necessary to screen for specific infectious diseases and monitoring protocols. Screening for human immunodeficiency virus, hepatitis C, hepatitis B, and *Mycobacterium tuberculosis* infections must be included. In addition, vaccination should be checked and updated if necessary. Despite the advent of biological therapy, a significant number of patients with IBD will need surgery in their lifetime due to either clinical intractability or disease complications. Many of them will be on biological therapy, and there is a considerable controversy about adverse effects of biologics on surgical outcomes. In this chapter, we will approach the screening required to start this therapy and how to proceed when surgery is necessary in these patients.

**Keywords:** inflammatory bowel disease, surgery, biologic agents, complications, infectious diseases, vaccines

#### **1. Introduction**

Biological therapy brought a better control of inflammatory bowel diseases (IBD). However, its use requires specific care before the beginning and during the treatment. Some essential points in its management have raised discussions.

We address the needs before starting the biological therapy and how to proceed when surgery is required. A brief review of what is necessary before the use of these drugs is also provided.

The management of other immunosuppressive agents such as corticosteroids, azathioprine, 6-mercaptopurine, and methotrexate is not covered in this chapter.

### **2. Pre-exposure biological therapy evaluations**

The general recommendations include screening patients for risk factors of infection [1]:

recommendations. Complete therapeutic regimen for latent tuberculosis must be initiated if identified after the screening examination and the biological therapy should be delayed [4, 5]. This full latent tuberculosis investigation can be modified or even indicated only if some exposure is suspected depending on where the patient lives. In this case, regional guidelines for prophylaxis must be followed. Only 22 countries worldwide represent 80% of the world's incidence. Therefore,

*Biological Therapy for Inflammatory Bowel Diseases: Screening Prior to Initiating and How…*

If results of IGRA test or PPD are negative, they should be repeated, but there is

Despite the variations in relation to screening for latent tuberculosis, when an alteration in the PPD test (≥5 mm) is found, the prophylaxis with isoniazid or appropriated antituberculous therapy must be initiated and maintained for 6 months. After at least 4 weeks with the use of the medication, we can initiate

It is worth noting that the patient's entire history of vaccination must be checked. If they did not receive the vaccines, they must be updated. Attention should be given, also to the recommended waiting period between each vaccine and

ing vaccines before starting the treatment with biological therapy [4–7, 9]:

• Zoster vaccine—for immunocompetent individuals over 60 years old

• Pneumococcal (PPSV 23 and PCV13 vaccines)—every 3–5 years

• Meningococcal—for certain at-risk individuals (college students living in residential housing, military recruits, and immunosuppressed patients like

It is important to emphasize that immunosuppressed patients do not respond properly to immunization. In addition, patients receiving biological therapy cannot be vaccinated with live attenuated virus (varicella zoster, yellow fever, measles,

A brief algorithm for preparing the patient for biological therapy is outlined in

or if past vaccination history is uncertain

• Tetanus and diphtheria toxoid—every 10 years

• Human papilloma virus—according to national guidelines

• Influenza virus—annual vaccination for all patients

asplenia, HIV, and complement deficiency)

• Hepatitis A—in endemic areas

mumps, and rubella) [9].

**Figure 1**.

**105**

In addition to the hepatitis B vaccine, the patient should also receive the follow-

• Varicella zoster virus (VZV)—if lacking clear history of chickenpox, shingles

local variations in the tuberculosis screening are accepted [4–6, 8].

no consensus as to how long [5].

*DOI: http://dx.doi.org/10.5772/intechopen.90001*

biological therapy [6].

the initiation of therapy.

**3. Vaccination**


Patients receiving treatment with therapeutic monoclonal antibodies (specifically the tumor-necrosis-factor alpha inhibitors) are considered immunodeficient [2]. Therefore, before the onset of biological therapy, we should screen for some diseases, and the patients should be properly immunized [3–5].

Screening for human immunodeficiency virus infection (HIV), hepatitis C (HVC), hepatitis B (HVB), and *Mycobacterium tuberculosis* infection for all patients must be performed prior to starting biological therapy [1, 4–6].

Because of the risk and the severity of infections, which are increased in HIV-infected patients receiving biological therapy, they should be closely monitored. Biological therapy is not contraindicated in HIV-infected patients [4].

Screening of HVC in some European countries is not recommended because of its low prevalence and the fact that patients with HVC can be treated with biological therapy [5]. However, immunomodulators may influence active chronic HVC infection and may worsen liver function when concomitant infection with hepatitis B (concomitant HVB and HVC infection is common in some regions of the world) [4].

Every patient with hepatitis B negative tested (HBsAg, anti-HAbs, and anti-HBcAb negatives) should be vaccinated before starting biological therapy. One to two months after the last dose of vaccine, patients should have their serological response evaluated. If infection is present by testing before vaccination, other specific tests should be performed, and the patient should be evaluated by a specialist for the need of treatment. The importance of care in relation to HVB infection consists in the fact that reactivation of HBV is a well-described complication of immunosuppression [4, 5, 7].

One infectious agents which should get more attention before the beginning of the biological therapy is *Mycobacterium tuberculosis*, because the reactivation of latent tuberculosis is increased and more severe in patients who follow this therapy. Proper latent tuberculosis search is performed by an assessment of an exposure history, skin test (PPD-tuberculosis skin test), interferon gamma release assay (IGRA), and chest X-ray, according to local prevalence and national

*Biological Therapy for Inflammatory Bowel Diseases: Screening Prior to Initiating and How… DOI: http://dx.doi.org/10.5772/intechopen.90001*

recommendations. Complete therapeutic regimen for latent tuberculosis must be initiated if identified after the screening examination and the biological therapy should be delayed [4, 5]. This full latent tuberculosis investigation can be modified or even indicated only if some exposure is suspected depending on where the patient lives. In this case, regional guidelines for prophylaxis must be followed. Only 22 countries worldwide represent 80% of the world's incidence. Therefore, local variations in the tuberculosis screening are accepted [4–6, 8].

If results of IGRA test or PPD are negative, they should be repeated, but there is no consensus as to how long [5].

Despite the variations in relation to screening for latent tuberculosis, when an alteration in the PPD test (≥5 mm) is found, the prophylaxis with isoniazid or appropriated antituberculous therapy must be initiated and maintained for 6 months. After at least 4 weeks with the use of the medication, we can initiate biological therapy [6].

#### **3. Vaccination**

**2. Pre-exposure biological therapy evaluations**

*Biological Therapy for Inflammatory Bowel Disease*

• History of travel to areas of endemic diseases

diseases, and the patients should be properly immunized [3–5].

must be performed prior to starting biological therapy [1, 4–6].

HIV-infected patients receiving biological therapy, they should be

• High-risk sexual activity, drug abuse

• Exposure to tuberculosis

• Blood transfusion

infection [1]:

• Age

patients [4].

the world) [4].

**104**

of immunosuppression [4, 5, 7].

• Occupation

diabetes mellitus)

The general recommendations include screening patients for risk factors of

• Comorbidities (e.g., transplant history, malignancy, renal or liver failure,

Patients receiving treatment with therapeutic monoclonal antibodies (specifically the tumor-necrosis-factor alpha inhibitors) are considered immunodeficient [2]. Therefore, before the onset of biological therapy, we should screen for some

Screening for human immunodeficiency virus infection (HIV), hepatitis C (HVC), hepatitis B (HVB), and *Mycobacterium tuberculosis* infection for all patients

Because of the risk and the severity of infections, which are increased in

Screening of HVC in some European countries is not recommended because of its low prevalence and the fact that patients with HVC can be treated with biological therapy [5]. However, immunomodulators may influence active chronic HVC infection and may worsen liver function when concomitant infection with hepatitis B (concomitant HVB and HVC infection is common in some regions of

Every patient with hepatitis B negative tested (HBsAg, anti-HAbs, and anti-HBcAb negatives) should be vaccinated before starting biological therapy. One to two months after the last dose of vaccine, patients should have their serological response evaluated. If infection is present by testing before vaccination, other specific tests should be performed, and the patient should be evaluated by a specialist for the need of treatment. The importance of care in relation to HVB infection consists in the fact that reactivation of HBV is a well-described complication

One infectious agents which should get more attention before the beginning of the biological therapy is *Mycobacterium tuberculosis*, because the reactivation of latent tuberculosis is increased and more severe in patients who follow this therapy. Proper latent tuberculosis search is performed by an assessment of an exposure history, skin test (PPD-tuberculosis skin test), interferon gamma release

assay (IGRA), and chest X-ray, according to local prevalence and national

closely monitored. Biological therapy is not contraindicated in HIV-infected

It is worth noting that the patient's entire history of vaccination must be checked. If they did not receive the vaccines, they must be updated. Attention should be given, also to the recommended waiting period between each vaccine and the initiation of therapy.

In addition to the hepatitis B vaccine, the patient should also receive the following vaccines before starting the treatment with biological therapy [4–7, 9]:


It is important to emphasize that immunosuppressed patients do not respond properly to immunization. In addition, patients receiving biological therapy cannot be vaccinated with live attenuated virus (varicella zoster, yellow fever, measles, mumps, and rubella) [9].

A brief algorithm for preparing the patient for biological therapy is outlined in **Figure 1**.

These inconsistent results may be due to single institution experience, different

Most studies use a 3-month cutoff to include patients in the anti-TNF group, but the serum level of the drug should also be taken into account [22]. Lau et al. [23] observed in their study that 53% of the IBD patients using preoperative anti-TNF had no detectable drug level at the time of surgery and it was more frequent in the

Regarding ulcerative colitis, the results are also conflicting with some studies showing increase in postoperative complications [24], while others show no associ-

Lightner et al. [26], in a retrospective multicenter cohort study, observed that IBD patients (Crohn's disease and ulcerative colitis) treated with vedolizumab had increased risk of postoperative surgical site infection and mucocutaneous separation of the diverting stoma as compared with anti-TNF-treated patients. They studied 146 patients who received vedolizumab 12 weeks before abdominal surgery and 289 patients who received anti-TNF therapy. However, two systematic reviews and meta-analysis [27, 28] did not find increased risks of postoperative complications with the use of vedolizumab when compared to either preoperative anti-TNF therapy or no biological therapy. Studies regarding the use of ustekinumab comparing with anti-TNF therapy also demonstrated no increase in the risk of postoperative

The occurrence of infectious and noninfectious complications after surgery in patients with IBD depends on several factors besides biological therapy. Among them one can mention the concomitance of the use of other medications, especially corticosteroids; the very severity of the disease; anemia, marked malnutrition in these patients, and smoking which greatly influence the occurrence of these complications [31]. Literature dates are conflicting, and in most studies, the patients and disease are heterogeneous. In addition, the time of exposure to the biological, the

*Biological therapy and surgery. Source: Adapted from Lightner AL. Perioperative management of biologic and immunosuppressive medications in patients with Crohn's disease. Dis Colon Rectum 2018;61:428-31.*

ation in preoperative anti-TNF therapy and increased risk of infectious and

duration of biological therapy, different periods between the last biologic dose and surgery, and concomitance with use of immunosuppressive agents and besides, may be a reflection of the severity of the disease and not the biological itself [16, 18,

*Biological Therapy for Inflammatory Bowel Diseases: Screening Prior to Initiating and How…*

21, 22].

ulcerative colitis group.

complications [29, 30].

**Figure 2.**

**107**

noninfectious complications after surgery [25].

*DOI: http://dx.doi.org/10.5772/intechopen.90001*

**Figure 1.** *Algorithm for preparing the patient for biological therapy.*

#### **4. Biological therapy and surgery**

When the screening and prophylaxis prior to initiating biological therapy involve numerous details regarding each disease that should be treated or prevented, the issue regarding biological therapy use and performing surgery can be come even more complex. This complexity is due to the difficult analysis of patients since the groups submitted to surgery are extremely heterogeneous.

Despite the increasing number of available biological agents available, many patients will require operation due to intractability or complications of IBD. In a systematic review and meta-analysis of population-based studies, Frolkis et al. [10] showed that the risk of intestinal surgery among patients with IBD has decrease over the past six decades. They concluded that the risk of surgery in Crohn's disease after 1, 5, and 10 years of diagnosis was 16.3, 33.3, and 46.6%, respectively, and in ulcerative colitis was 4.9, 11.6, and 15.6%, respectively.

In this way, many IBD patients will be on biological therapy when surgery is indicated. Literature data are conflicted with regard to the preoperative management of biological therapy in IBD surgery. Several large single-center studies and systematic reviews have found an increased risk of infectious complications with the use of anti-TNF preoperatively [11–14], whereas others have not [15–20].

#### *Biological Therapy for Inflammatory Bowel Diseases: Screening Prior to Initiating and How… DOI: http://dx.doi.org/10.5772/intechopen.90001*

These inconsistent results may be due to single institution experience, different duration of biological therapy, different periods between the last biologic dose and surgery, and concomitance with use of immunosuppressive agents and besides, may be a reflection of the severity of the disease and not the biological itself [16, 18, 21, 22].

Most studies use a 3-month cutoff to include patients in the anti-TNF group, but the serum level of the drug should also be taken into account [22]. Lau et al. [23] observed in their study that 53% of the IBD patients using preoperative anti-TNF had no detectable drug level at the time of surgery and it was more frequent in the ulcerative colitis group.

Regarding ulcerative colitis, the results are also conflicting with some studies showing increase in postoperative complications [24], while others show no association in preoperative anti-TNF therapy and increased risk of infectious and noninfectious complications after surgery [25].

Lightner et al. [26], in a retrospective multicenter cohort study, observed that IBD patients (Crohn's disease and ulcerative colitis) treated with vedolizumab had increased risk of postoperative surgical site infection and mucocutaneous separation of the diverting stoma as compared with anti-TNF-treated patients. They studied 146 patients who received vedolizumab 12 weeks before abdominal surgery and 289 patients who received anti-TNF therapy. However, two systematic reviews and meta-analysis [27, 28] did not find increased risks of postoperative complications with the use of vedolizumab when compared to either preoperative anti-TNF therapy or no biological therapy. Studies regarding the use of ustekinumab comparing with anti-TNF therapy also demonstrated no increase in the risk of postoperative complications [29, 30].

The occurrence of infectious and noninfectious complications after surgery in patients with IBD depends on several factors besides biological therapy. Among them one can mention the concomitance of the use of other medications, especially corticosteroids; the very severity of the disease; anemia, marked malnutrition in these patients, and smoking which greatly influence the occurrence of these complications [31]. Literature dates are conflicting, and in most studies, the patients and disease are heterogeneous. In addition, the time of exposure to the biological, the

#### **Figure 2.**

*Biological therapy and surgery. Source: Adapted from Lightner AL. Perioperative management of biologic and immunosuppressive medications in patients with Crohn's disease. Dis Colon Rectum 2018;61:428-31.*

**4. Biological therapy and surgery**

*Algorithm for preparing the patient for biological therapy.*

*Biological Therapy for Inflammatory Bowel Disease*

**Figure 1.**

**106**

When the screening and prophylaxis prior to initiating biological therapy involve numerous details regarding each disease that should be treated or

since the groups submitted to surgery are extremely heterogeneous.

ulcerative colitis was 4.9, 11.6, and 15.6%, respectively.

prevented, the issue regarding biological therapy use and performing surgery can be come even more complex. This complexity is due to the difficult analysis of patients

Despite the increasing number of available biological agents available, many patients will require operation due to intractability or complications of IBD. In a systematic review and meta-analysis of population-based studies, Frolkis et al. [10] showed that the risk of intestinal surgery among patients with IBD has decrease over the past six decades. They concluded that the risk of surgery in Crohn's disease after 1, 5, and 10 years of diagnosis was 16.3, 33.3, and 46.6%, respectively, and in

In this way, many IBD patients will be on biological therapy when surgery is indicated. Literature data are conflicted with regard to the preoperative management of biological therapy in IBD surgery. Several large single-center studies and systematic reviews have found an increased risk of infectious complications with the use of anti-TNF preoperatively [11–14], whereas others have not [15–20].

interval between the last dose and the surgery, the serum level of the medication, and drug pharmacokinetic should be considered.

**References**

[1] Ponzo MG, Hong CH. A dermatologist's guide to infection screening prior to initiating immunosuppressive therapy. Skin Therapy Letter. 2017;**22**(1):8-11

[2] Available at: https://www.cdc.gov/ mmwr/previent/mmwrhtml/rr5515a1htm

*DOI: http://dx.doi.org/10.5772/intechopen.90001*

Gastroenterology & Hepatology. 2019;

[10] Frolkis AD, Aykeman J, Negron ME, deBruyn J, Jette N, Fiest KM, et al. Risk of surgery for IBD has decreased over time: A systematic review and metaanalysis of population-based studies. The American Journal of Gastroenterology.

[11] Brouquet A, Maggiori L, Zerbib P, Lefevre JH, Renost Q, Germain A, et al. Anti-TNF therapy is associated with an

morbidity after surgery for ileocolonic Crohn disease: Results of a prospective nationwide cohort. Annals of Surgery.

[12] Ahmed Ali U, Martin ST, Rao AD, Kiran RP. Impact of preoperative immunosuppressive agents on postoperative outcomes in Crohn's disease. Diseases of the Colon and Rectum. 2014;**57**(5):663-674

[13] Chang MI, Cohen BL, Greenstein AJ. A review of the impact of biologics on surgical complications in Crohn's disease. Inflammatory Bowel Diseases. 2015;

[14] Scarpa M, Martinato M, Bertib E, Da Roit A, Pozza A, Ruffolo C, et al. Intestinal surgery for Crohn's disease: Role of preoperative therapy in postoperative outcome. Digestive

[15] Marchal L, R'Haens G, Van Assche G, Vermeire S, Noman M, Ferrante M, et al. The risk of postoperative complications associated whit infliximab therapy for Crohn's disease: A controlled cohort study. Alimentary Pharmacology & Therapeutics. 2004;**19**:749-754

[16] Waterman M, Xu W, Dinani A, Steinhart AH, Croitoru K, et al.

increased risk of postoperative

**13**(3):229-239

*Biological Therapy for Inflammatory Bowel Diseases: Screening Prior to Initiating and How…*

2014;**109**:1739-1748

2018;**267**:221-228

**21**(6):1472-1477

Surgery. 2015;**32**:243-250

[3] Maaser C, Sturm A, Vavricka SR, Kucharzik T, Fiorino G, Annese V, et al. ECCO-ESGAR guideline for assessment

monitoring of know IBD, detection of complications. Journal of Crohn's and

opportunistic infections in inflammatory bowel disease. Journal of Crohn's and

[5] Nordgaard-Lanssen I, Dahlerup JF,

[6] Kane S. Preparing the patient for immunosuppressive therapy. Current Gastroenterology Reports. 2010;**12**:

[7] Carrera E, Manzaro R, Garrido E. Efficacy of the vaccination in inflammatory bowel diseases. World Journal of Gastroenterology. 2013;**19**(9):

[8] Organization WH. Global Tuberculosis Central 2017. Geneva: World Health Organization; 2017

[9] Zullow S, Farraye F. Updates on vaccinating the inflammatory bowel disease patient. Expert Review of

in IBD part 1: Initial diagnosis,

Colitis. 2019;**13**(2):144-64K

consensus on the prevention, diagnosis and management of

Colitis. 2014;**8**(6):443-468

Belard E, Gerstof J, Kjeldsen J, Kragballe K, et al. Guidelines for information prior to initiating anti-TNF-alpha treatment. Danish Medical

Journal. 2012;**59**(7):C4480

502-506

1349-1353

**109**

[4] Rahier JF, Magro F, Abreu C, Armuzz A, Ben-Horis S, Chowees Y, et al. Second European evidence-based

For patients who are receiving biological therapy and will undergo abdominal surgery, we should consider [32] the following:


### **Author details**

Maria de Lourdes Setsuko Ayrizono<sup>1</sup> \*, Priscilla de Sene Portel Oliveira<sup>2</sup> and João José Fagundes<sup>1</sup>

1 Surgery Department, Colorectal Surgery Unit, School of Medical Sciences, University of Campinas, São Paulo, Brazil

2 School of Medical Sciences, University of Campinas, São Paulo, Brazil

\*Address all correspondence to: luayrizono@terra.com.br

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Biological Therapy for Inflammatory Bowel Diseases: Screening Prior to Initiating and How… DOI: http://dx.doi.org/10.5772/intechopen.90001*

#### **References**

interval between the last dose and the surgery, the serum level of the medication,

• Discontinue the medication 4 weeks before operation for anti-TNF-α and

• For urgent situation, there is no need to delay the operation. The increased risks of infectious complications do not outweigh the risk of delaying surgery.

malnourished patients (serum albumin <3 g/L, body weight loss >10%) and/or

\*, Priscilla de Sene Portel Oliveira<sup>2</sup>

• The medication should be reintroduced after 4 weeks, if necessary.

• Consider derivative ileostomy in emergency surgery and severely

1 Surgery Department, Colorectal Surgery Unit, School of Medical Sciences,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 School of Medical Sciences, University of Campinas, São Paulo, Brazil

\*Address all correspondence to: luayrizono@terra.com.br

For patients who are receiving biological therapy and will undergo abdominal

and drug pharmacokinetic should be considered.

*Biological Therapy for Inflammatory Bowel Disease*

surgery, we should consider [32] the following:

ustekinumab and 4–8 weeks before for vedolizumab.

concomitant use of corticosteroids (**Figure 2**).

**Author details**

**108**

and João José Fagundes<sup>1</sup>

Maria de Lourdes Setsuko Ayrizono<sup>1</sup>

University of Campinas, São Paulo, Brazil

provided the original work is properly cited.

[1] Ponzo MG, Hong CH. A dermatologist's guide to infection screening prior to initiating immunosuppressive therapy. Skin Therapy Letter. 2017;**22**(1):8-11

[2] Available at: https://www.cdc.gov/ mmwr/previent/mmwrhtml/rr5515a1htm

[3] Maaser C, Sturm A, Vavricka SR, Kucharzik T, Fiorino G, Annese V, et al. ECCO-ESGAR guideline for assessment in IBD part 1: Initial diagnosis, monitoring of know IBD, detection of complications. Journal of Crohn's and Colitis. 2019;**13**(2):144-64K

[4] Rahier JF, Magro F, Abreu C, Armuzz A, Ben-Horis S, Chowees Y, et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. Journal of Crohn's and Colitis. 2014;**8**(6):443-468

[5] Nordgaard-Lanssen I, Dahlerup JF, Belard E, Gerstof J, Kjeldsen J, Kragballe K, et al. Guidelines for information prior to initiating anti-TNF-alpha treatment. Danish Medical Journal. 2012;**59**(7):C4480

[6] Kane S. Preparing the patient for immunosuppressive therapy. Current Gastroenterology Reports. 2010;**12**: 502-506

[7] Carrera E, Manzaro R, Garrido E. Efficacy of the vaccination in inflammatory bowel diseases. World Journal of Gastroenterology. 2013;**19**(9): 1349-1353

[8] Organization WH. Global Tuberculosis Central 2017. Geneva: World Health Organization; 2017

[9] Zullow S, Farraye F. Updates on vaccinating the inflammatory bowel disease patient. Expert Review of

Gastroenterology & Hepatology. 2019; **13**(3):229-239

[10] Frolkis AD, Aykeman J, Negron ME, deBruyn J, Jette N, Fiest KM, et al. Risk of surgery for IBD has decreased over time: A systematic review and metaanalysis of population-based studies. The American Journal of Gastroenterology. 2014;**109**:1739-1748

[11] Brouquet A, Maggiori L, Zerbib P, Lefevre JH, Renost Q, Germain A, et al. Anti-TNF therapy is associated with an increased risk of postoperative morbidity after surgery for ileocolonic Crohn disease: Results of a prospective nationwide cohort. Annals of Surgery. 2018;**267**:221-228

[12] Ahmed Ali U, Martin ST, Rao AD, Kiran RP. Impact of preoperative immunosuppressive agents on postoperative outcomes in Crohn's disease. Diseases of the Colon and Rectum. 2014;**57**(5):663-674

[13] Chang MI, Cohen BL, Greenstein AJ. A review of the impact of biologics on surgical complications in Crohn's disease. Inflammatory Bowel Diseases. 2015; **21**(6):1472-1477

[14] Scarpa M, Martinato M, Bertib E, Da Roit A, Pozza A, Ruffolo C, et al. Intestinal surgery for Crohn's disease: Role of preoperative therapy in postoperative outcome. Digestive Surgery. 2015;**32**:243-250

[15] Marchal L, R'Haens G, Van Assche G, Vermeire S, Noman M, Ferrante M, et al. The risk of postoperative complications associated whit infliximab therapy for Crohn's disease: A controlled cohort study. Alimentary Pharmacology & Therapeutics. 2004;**19**:749-754

[16] Waterman M, Xu W, Dinani A, Steinhart AH, Croitoru K, et al.

Preoperative biological therapy and short-term outcomes of abdominal surgery in patients with inflammatory bowel disease. Gut. 2013; **62**:387-394

[17] Asfshar SE, Nikfar S, Rezaire A, Abdollahi M. A systematic review and meta-analysis of the effects of infliximab on the rate of colectomy and postoperative complications in patients with inflammatory bowel disease. Archives of Medical Science. 2011;**7**(6): 1000-1012

[18] Bafford AC, Powers S, Ha C, Kruse D, Gorfine SR, Chessin DB. Immunosuppressive therapy does not increase operative morbidity in patients with Crohn's disease. Journal of Clinical Gastroenterology. 2013;**47**:491-495

[19] Yang Z, Wu Q, Wang F, Wu K, Fan D. Meta-analysis: Effect of preoperative infliximab use on early postoperative complications in patients with ulcerative colitis undergoing abdominal surgery. Alimentary Pharmacology & Therapeutics. 2012; **36**(10):922-928

[20] Rosenfeld G, Qian H, Bressler B. The risk of postoperative complication following preoperative infliximab therapy for Crohn's disease in patients undergoing abdominal surgery: A systematic review and meta-analysis. Journal of Crohn's & Colitis. 2013;**7**(11): 868-877

[21] McKenna NP, Habermann EB, Glasgow AE, Dozois EJ, Ligthner AL. Intra-abdominal sepsis after ileocolic resection in Crohn's disease: The role of combination immunosuppression. Diseases of the Colon and Rectum. 2018; **61**(12):1393-1402

[22] Zaghivan K, McGovern D, Fleshner P. Should biologic agents be stopped before surgery for inflammatory bowel disease? Expert

Review of Gastroenterology & Hepatology. 2015;**9**(3):269-272

[23] Lau C, Dubinski M, Melmed G, Vasiliauskas S, Berel D, McGovern D, et al. The impact of preoperative serum anti-TNFα therapy levels on early postoperative outcomes in inflammatory bowel disease surgery. Annals of Surgery. 2015;**261**(3):487-496 postoperative complications in inflammatory bowel disease.

Postoperative outcomes in ustekinumab-treated patients

Colitis. 2018;**12**(4):402-407

[30] Shim HH, Ma C, Kotze PG,

et al. Preoperative ustekinumab treatment is not associated with increased postoperative complications in Crohn's disease: A Canadian multi-Centre observational cohort study. Journal of the Canadian Association of Gastroenterology. 2018;**1**(3):115-123

[31] Hansen TM, Targownik LE, Karimuddin A, Leung Y. Management of biological therapy before elective inflammatory bowel disease surgeries. Inflammatory Bowel Diseases. 2019;**25** (10):1613-1320. DOI: 10.1093/ibd/

[32] Lightner AL. Perioperative management of biologic and immunosuppressive medications in patients with Crohn's disease. Diseases of the Colon and Rectum. 2018;**61**:

izz002

428-431

**111**

**24**(11):2327-2328

Inflammatory Bowel Diseases. 2018;

[29] Lightner AL, McKenna NP, Tse CS, Hyman N, Smith R, Ovsepyan G, et al.

*DOI: http://dx.doi.org/10.5772/intechopen.90001*

*Biological Therapy for Inflammatory Bowel Diseases: Screening Prior to Initiating and How…*

undergoing abdominal operations for Crohn's disease. Journal of Crohn's &

Seow CH, Al-Farhan H, Al-Darmaki AK,

[24] Kulaylat AS, Kulaylat AN, Schaefer EW, Tinsley A, Williams E, Koltun W, et al. Association of preoperative anti-tumor necrosis factor therapy with adverse postoperative outcomes in patients undergoing abdominal surgery for ulcerative colitis. JAMA Surgery. 2017;**152**(8):e171538

[25] Zitan E, Milgron R, Ma GW, Wong-Chong N, O'Connor B, Mc Leod RS, et al. Preoperative anti-tumor necrosis factor therapy in patients with ulcerative colitis is not associated with an increased risk of infectious and noninfectious complications after ileal pouch-anal anastomosis. Inflammatory Bowel Diseases. 2016;**22**(10):2442-2447

[26] Lightner AL, Mathis KL, Tse CS, Pemberton JH, Shen B, Kochlar G, et al. Postoperative outcomes in vedolizumab-treated patients undergoing major abdominal operations for inflammatory bowel disease: Retrospective multicenter cohort study. Inflammatory Bowel Diseases. 2018; **24**(4):871-876

[27] Law CCY, Narula A, Ligthner AL, McKenna NP, Colombel JF, Narula N. Systematic review and meta-analysis: Preoperative vedolizumab treatment and postoperative complications in patients with inflammatory bowel disease. Journal of Crohn's & Colitis. 2018;**12**(5):538-545

[28] Yung DE, Horesh N, Lightner AL, Bem-Horin S, Eliakim R, Koulaozidis A, et al. Systematic review and metaanalysis: Vedolizumab and

*Biological Therapy for Inflammatory Bowel Diseases: Screening Prior to Initiating and How… DOI: http://dx.doi.org/10.5772/intechopen.90001*

postoperative complications in inflammatory bowel disease. Inflammatory Bowel Diseases. 2018; **24**(11):2327-2328

Preoperative biological therapy and short-term outcomes of abdominal surgery in patients with inflammatory bowel disease. Gut. 2013;

*Biological Therapy for Inflammatory Bowel Disease*

Review of Gastroenterology & Hepatology. 2015;**9**(3):269-272

[23] Lau C, Dubinski M, Melmed G, Vasiliauskas S, Berel D, McGovern D, et al. The impact of preoperative serum anti-TNFα therapy levels on early postoperative outcomes in

inflammatory bowel disease surgery. Annals of Surgery. 2015;**261**(3):487-496

preoperative anti-tumor necrosis factor therapy with adverse postoperative outcomes in patients undergoing abdominal surgery for ulcerative colitis. JAMA Surgery. 2017;**152**(8):e171538

[25] Zitan E, Milgron R, Ma GW, Wong-Chong N, O'Connor B, Mc Leod RS, et al. Preoperative anti-tumor necrosis

ulcerative colitis is not associated with an increased risk of infectious and noninfectious complications after ileal pouch-anal anastomosis. Inflammatory Bowel Diseases. 2016;**22**(10):2442-2447

[26] Lightner AL, Mathis KL, Tse CS, Pemberton JH, Shen B, Kochlar G, et al.

undergoing major abdominal operations

Retrospective multicenter cohort study. Inflammatory Bowel Diseases. 2018;

[27] Law CCY, Narula A, Ligthner AL, McKenna NP, Colombel JF, Narula N. Systematic review and meta-analysis: Preoperative vedolizumab treatment and postoperative complications in patients with inflammatory bowel disease. Journal of Crohn's & Colitis.

[28] Yung DE, Horesh N, Lightner AL, Bem-Horin S, Eliakim R, Koulaozidis A, et al. Systematic review and meta-

Postoperative outcomes in vedolizumab-treated patients

**24**(4):871-876

2018;**12**(5):538-545

analysis: Vedolizumab and

for inflammatory bowel disease:

factor therapy in patients with

[24] Kulaylat AS, Kulaylat AN, Schaefer EW, Tinsley A, Williams E, Koltun W, et al. Association of

[17] Asfshar SE, Nikfar S, Rezaire A, Abdollahi M. A systematic review and

infliximab on the rate of colectomy and postoperative complications in patients with inflammatory bowel disease. Archives of Medical Science. 2011;**7**(6):

meta-analysis of the effects of

[18] Bafford AC, Powers S, Ha C, Kruse D, Gorfine SR, Chessin DB. Immunosuppressive therapy does not increase operative morbidity in patients with Crohn's disease. Journal of Clinical Gastroenterology. 2013;**47**:491-495

[19] Yang Z, Wu Q, Wang F, Wu K, Fan D. Meta-analysis: Effect of preoperative infliximab use on early postoperative complications in patients with ulcerative colitis undergoing abdominal surgery. Alimentary Pharmacology & Therapeutics. 2012;

[20] Rosenfeld G, Qian H, Bressler B. The risk of postoperative complication following preoperative infliximab therapy for Crohn's disease in patients undergoing abdominal surgery: A systematic review and meta-analysis. Journal of Crohn's & Colitis. 2013;**7**(11):

[21] McKenna NP, Habermann EB, Glasgow AE, Dozois EJ, Ligthner AL. Intra-abdominal sepsis after ileocolic resection in Crohn's disease: The role of combination immunosuppression. Diseases of the Colon and Rectum. 2018;

[22] Zaghivan K, McGovern D, Fleshner P. Should biologic agents be

inflammatory bowel disease? Expert

stopped before surgery for

**62**:387-394

1000-1012

**36**(10):922-928

868-877

**110**

**61**(12):1393-1402

[29] Lightner AL, McKenna NP, Tse CS, Hyman N, Smith R, Ovsepyan G, et al. Postoperative outcomes in ustekinumab-treated patients undergoing abdominal operations for Crohn's disease. Journal of Crohn's & Colitis. 2018;**12**(4):402-407

[30] Shim HH, Ma C, Kotze PG, Seow CH, Al-Farhan H, Al-Darmaki AK, et al. Preoperative ustekinumab treatment is not associated with increased postoperative complications in Crohn's disease: A Canadian multi-Centre observational cohort study. Journal of the Canadian Association of Gastroenterology. 2018;**1**(3):115-123

[31] Hansen TM, Targownik LE, Karimuddin A, Leung Y. Management of biological therapy before elective inflammatory bowel disease surgeries. Inflammatory Bowel Diseases. 2019;**25** (10):1613-1320. DOI: 10.1093/ibd/ izz002

[32] Lightner AL. Perioperative management of biologic and immunosuppressive medications in patients with Crohn's disease. Diseases of the Colon and Rectum. 2018;**61**: 428-431

**113**

Section 4

Anti-Integrin, Anti-p40

Subunit and JAK Inhibitor

Therapies

### Section 4

## Anti-Integrin, Anti-p40 Subunit and JAK Inhibitor Therapies

**115**

**1. Introduction**

factors [2].

**Chapter 7**

**Abstract**

Treatment

Anti-Integrins, Anti-Interleukin

12/23p40, and JAK Inhibitors for

the Inflammatory Bowel Disease

*Karine Mariane Steigleder, Fernando Lopes Ponte Neto,* 

Inflammatory bowel diseases (IBD) present a broad inflammatory cascade that is sometimes difficult to control. Patients with ulcerative colitis (UC) and Crohn's disease (CD) are exposed to intense and harmful effects that compromise their quality of life. There is a constant need for new classes of drugs that act on different fronts of inflammation control. Initially, biologics revolutionized inflammatory bowel disease treatment. Anti-tumor necrosis factor (anti-TNF) agents and infliximab, followed by adalimumab and certolizumab pegol, have been proven to induce clinical and endoscopic remission. However, some patients are primary nonresponders, and a significant proportion of initial responders lose response throughout the treatment. The emergence of new therapies, such as anti-integrins, anti-interleukins, and inhibitors of Janus kinase (JAK), can become an alternative option for patients with previous therapeutic failures, besides offering greater safety than other biological therapies up to now. Among anti-integrins, vedolizumab is the drug with proven efficacy in both induction and maintenance of remission and has local and selective action in the intestine. Ustekinumab represents the group of anti-interleukins, acting to control interleukin-12 (IL12) and interleukin-23 (IL23). JAK inhibitors (tofacitinib) act on intracellular inflammatory

*Cristiane Kibune Nagasako and Raquel Franco Leal*

mediators and have the advantage of being orally administered.

America, Asia, and Africa, making it a rising global disease [3].

**Keywords:** ulcerative colitis, Crohn's disease, vedolizumab, ustekinumab, tofacitinib

Crohn's disease (CD) and ulcerative colitis (UC) are the main inflammatory bowel diseases (IBD) [1]. Inappropriate inflammatory response is multifactorial and involves environmental, genetic, immune-mediated, and gut microbial

IBDs were previously more prevalent in North America, Europe, and Oceania, but since 1990 the incidence rate is stable or decreasing in those areas. In contrast, increasing incidence was observed in developing regions, such as Latin and South

#### **Chapter 7**

## Anti-Integrins, Anti-Interleukin 12/23p40, and JAK Inhibitors for the Inflammatory Bowel Disease Treatment

*Karine Mariane Steigleder, Fernando Lopes Ponte Neto, Cristiane Kibune Nagasako and Raquel Franco Leal*

#### **Abstract**

Inflammatory bowel diseases (IBD) present a broad inflammatory cascade that is sometimes difficult to control. Patients with ulcerative colitis (UC) and Crohn's disease (CD) are exposed to intense and harmful effects that compromise their quality of life. There is a constant need for new classes of drugs that act on different fronts of inflammation control. Initially, biologics revolutionized inflammatory bowel disease treatment. Anti-tumor necrosis factor (anti-TNF) agents and infliximab, followed by adalimumab and certolizumab pegol, have been proven to induce clinical and endoscopic remission. However, some patients are primary nonresponders, and a significant proportion of initial responders lose response throughout the treatment. The emergence of new therapies, such as anti-integrins, anti-interleukins, and inhibitors of Janus kinase (JAK), can become an alternative option for patients with previous therapeutic failures, besides offering greater safety than other biological therapies up to now. Among anti-integrins, vedolizumab is the drug with proven efficacy in both induction and maintenance of remission and has local and selective action in the intestine. Ustekinumab represents the group of anti-interleukins, acting to control interleukin-12 (IL12) and interleukin-23 (IL23). JAK inhibitors (tofacitinib) act on intracellular inflammatory mediators and have the advantage of being orally administered.

**Keywords:** ulcerative colitis, Crohn's disease, vedolizumab, ustekinumab, tofacitinib

#### **1. Introduction**

Crohn's disease (CD) and ulcerative colitis (UC) are the main inflammatory bowel diseases (IBD) [1]. Inappropriate inflammatory response is multifactorial and involves environmental, genetic, immune-mediated, and gut microbial factors [2].

IBDs were previously more prevalent in North America, Europe, and Oceania, but since 1990 the incidence rate is stable or decreasing in those areas. In contrast, increasing incidence was observed in developing regions, such as Latin and South America, Asia, and Africa, making it a rising global disease [3].

For years, the therapeutic management of IBD has been restricted to local action medications with mild anti-inflammatory power, such as amino salicylates and corticosteroids. Adverse effects of prolonged use of corticosteroids include infections, diabetes, osteoporosis, cataracts, metabolic syndrome, and esthetic changes that further raise morbidity and mortality [4].

Immunomodulators initially used in rheumatologic conditions have also been applied in IBD treatment. Thiopurines (azathioprine and 6-mercaptopurines) and methotrexate were widely used against both UC and CD, but these medications alone failed to induce and maintain clinical and endoscopic remission in a significant percentage of cases. Failure to control the disease increases the risk of complications, like strictures, abscesses, fistulas, and the need for surgical approaches. Additionally, worse quality of life and an increase in clinical complications like anemia and malnutrition [5] may occur.

The therapeutic revolution of IBDs began with biological therapy containing anti-tumor necrosis factor (anti-TNF) agents such as infliximab, which was widely used in the management of rheumatologic, dermatological, and inflammatory bowel diseases. Subsequently, other drugs of the same class emerged, such as adalimumab, a fully human monoclonal antibody, and certolizumab, which does not have the Fc portion, making it less immunogenic [5].

Anti-TNF treatment (alone or in combination with immunomodulators) can induce clinical and endoscopic remission. However, only 10–30% will have a primary no-response, and over 50% will, after an initial response, have a secondary loss [6].

New classes of immunobiological therapies are available to treat patients with loss of response to anti-TNF treatment, since the response to a second anti-TNF is low [4, 5]. Integrins and interleukins are the main targets of the available drugs to treat IBD. They act on receptors of cells involved in the inflammatory process and on proinflammatory cytokines, respectively. Furthermore, the intracellular inhibition of kinases by JAK inhibitors acts on intracellular inflammatory mediators. Each of these action pathways will be detailed in this chapter.

#### **2. Anti-integrins and anti-interleukin 12/23p40**

#### **2.1 Anti-integrins**

Integrins are cell surface glycoprotein receptors that play a role in leukocyte adhesion, signaling, proliferation, and migration [7]. Migration of circulating leucocytes from blood to intestinal tissue is a key step for intestinal inflammation. α4β7 integrin expressed on the surface of the leukocyte binds to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on endothelial cells. Anti-integrin blocks the action of integrins, inhibiting leukocyte trafficking from the systemic circulation to the gastrointestinal endothelial cells [8].

Natalizumab is a chimeric recombinant human IgG4 antibody that blocks the α4 subunits in α4β7 and α4β1 integrins on leukocytes, inhibits binding to vascular cell adhesion molecule 1 (VCAM-1), and decreases inflammatory cells in affected gastrointestinal tissue, contributing to induction and maintenance of remission in CD [9]. Natalizumab also blocks lymphocyte infiltration in the central nervous system and is also approved for multiple sclerosis treatment [10]. However, association with progressive multifocal leukoencephalopathy (PML), a rare disabling and potentially fatal neurological syndrome caused by reactivation of the John Cunningham virus (JCV), has limited its use in treating CD patients [11].

**117**

*Anti-Integrins, Anti-Interleukin 12/23p40, and JAK Inhibitors for the Inflammatory Bowel…*

studies failed to demonstrate an advantage when compared to placebo [13].

Etrolizumab is a humanized IgG1 monoclonal antibody against the β7 subunit of the α4β7 and αEβ7 integrins that blocks binding to MAdCAM-1 and E-cadherin, respectively [12]. Still under study, it is not part of the IBD therapeutic arsenal, and

Vedolizumab is an anti-integrin currently used to treat IBD. It is a humanized monoclonal antibody composed of two light chains of kappa subclass and two heavy chains linked by two disulfide bridges, which form an immunoglobulin that targets α4β7 integrin, selectively blocking gut lymphocyte trafficking [14]. Its inhibitory effect on T-lymphocyte recruitment is reversible with its suspension. Renal elimination occurs after drug degradation into peptides and amino acids in the liver. The drug half-life was estimated at 25.5 days, being the potential predictors of poor response to therapy: albumin <3.2 g/dl and

The currently recommended dosage is 300 mg vedolizumab with intravenous administration at weeks 0, 2, and 6 and then every 8 weeks. The interval can be shortened to every 4 weeks when the patient's response is not satisfactory [15]. Studies showed no difference in serious adverse events resulting in death, life-threatening conditions, hospitalization, or disability, comparing vedolizumab and placebo [14]. However, possible adverse events can occur such as nasopharyngitis, headache, arthralgia, and other less uncommon events. Among the contraindications, we can highlight the presence of active infections, such as tuberculosis, sepsis, cytomegalovirus, listerioses, and opportunistic infections

There are no controlled studies of vedolizumab during pregnancy and breastfeeding, and current data are based on observational cases. FDA classified this drug as category B, being safe for use in pregnancy. During breastfeeding, caution is required because it is not known if the medication is transferred to the newborn [4]. In 2013, the randomized, double-blind, placebo-controlled phase 3, GEMINI I study showed the efficacy of vedolizumab in induction and maintenance of remission in patients with UC. For induction, a 300 mg-day intravenous dose repeated at 15 days was used. For maintenance, both groups received the medication after 4 or 8 weeks; therapeutic serum levels were obtained with 95% saturation of the α4β7 receptor and proven clinical remission for 52 weeks. The intestinal selectivity of vedolizumab gives the drug greater safety, especially in countries with a marked presence of mycobacteria. No cases of PML were documented during the GEMINI I

Also, in 2013, the GEMINI II placebo-controlled, randomized, double-blind, phase 3 study evaluated induction and maintenance remission in patients with moderately to severely active CD for 4 years in 39 countries. The study analyzed patients aged 18–80 years, diagnosed for at least 3 years, with active CD. Compared to placebo, patients treated with vedolizumab had better response in both induction and remission maintenance at week 52. The rates were discrete and may be justified by patient selection bias, since a significant part of the group had severe disease,

Of the 1434 patients who used vedolizumab for 52 weeks evaluated in the GEMINI I and GEMINI II studies, 56 (4%) had anti-drug antibodies, of which only 9 (0.6%) had persistent positivity after two or more consecutive dosages. Immunogenicity increases with exposure time reaching 10% at week 66. However, it is believed that the presence of antibodies in low to moderate-titer does not affect drug response, as therapeutic failure occurred in only nine patients and elevated

In 2014, Sands et al. (GEMINI III) evaluated the response of vedolizumab in patients with previous anti-TNF treatment. The study showed an advantage of

difficult to control and refractory to anti-TNF treatment [18].

antibody levels were maintained for a prolonged period [15].

*DOI: http://dx.doi.org/10.5772/intechopen.90536*

weight > 120 kg [15].

such as PML [16, 17].

study [14].

*Anti-Integrins, Anti-Interleukin 12/23p40, and JAK Inhibitors for the Inflammatory Bowel… DOI: http://dx.doi.org/10.5772/intechopen.90536*

Etrolizumab is a humanized IgG1 monoclonal antibody against the β7 subunit of the α4β7 and αEβ7 integrins that blocks binding to MAdCAM-1 and E-cadherin, respectively [12]. Still under study, it is not part of the IBD therapeutic arsenal, and studies failed to demonstrate an advantage when compared to placebo [13].

Vedolizumab is an anti-integrin currently used to treat IBD. It is a humanized monoclonal antibody composed of two light chains of kappa subclass and two heavy chains linked by two disulfide bridges, which form an immunoglobulin that targets α4β7 integrin, selectively blocking gut lymphocyte trafficking [14]. Its inhibitory effect on T-lymphocyte recruitment is reversible with its suspension. Renal elimination occurs after drug degradation into peptides and amino acids in the liver. The drug half-life was estimated at 25.5 days, being the potential predictors of poor response to therapy: albumin <3.2 g/dl and weight > 120 kg [15].

The currently recommended dosage is 300 mg vedolizumab with intravenous administration at weeks 0, 2, and 6 and then every 8 weeks. The interval can be shortened to every 4 weeks when the patient's response is not satisfactory [15].

Studies showed no difference in serious adverse events resulting in death, life-threatening conditions, hospitalization, or disability, comparing vedolizumab and placebo [14]. However, possible adverse events can occur such as nasopharyngitis, headache, arthralgia, and other less uncommon events. Among the contraindications, we can highlight the presence of active infections, such as tuberculosis, sepsis, cytomegalovirus, listerioses, and opportunistic infections such as PML [16, 17].

There are no controlled studies of vedolizumab during pregnancy and breastfeeding, and current data are based on observational cases. FDA classified this drug as category B, being safe for use in pregnancy. During breastfeeding, caution is required because it is not known if the medication is transferred to the newborn [4].

In 2013, the randomized, double-blind, placebo-controlled phase 3, GEMINI I study showed the efficacy of vedolizumab in induction and maintenance of remission in patients with UC. For induction, a 300 mg-day intravenous dose repeated at 15 days was used. For maintenance, both groups received the medication after 4 or 8 weeks; therapeutic serum levels were obtained with 95% saturation of the α4β7 receptor and proven clinical remission for 52 weeks. The intestinal selectivity of vedolizumab gives the drug greater safety, especially in countries with a marked presence of mycobacteria. No cases of PML were documented during the GEMINI I study [14].

Also, in 2013, the GEMINI II placebo-controlled, randomized, double-blind, phase 3 study evaluated induction and maintenance remission in patients with moderately to severely active CD for 4 years in 39 countries. The study analyzed patients aged 18–80 years, diagnosed for at least 3 years, with active CD. Compared to placebo, patients treated with vedolizumab had better response in both induction and remission maintenance at week 52. The rates were discrete and may be justified by patient selection bias, since a significant part of the group had severe disease, difficult to control and refractory to anti-TNF treatment [18].

Of the 1434 patients who used vedolizumab for 52 weeks evaluated in the GEMINI I and GEMINI II studies, 56 (4%) had anti-drug antibodies, of which only 9 (0.6%) had persistent positivity after two or more consecutive dosages. Immunogenicity increases with exposure time reaching 10% at week 66. However, it is believed that the presence of antibodies in low to moderate-titer does not affect drug response, as therapeutic failure occurred in only nine patients and elevated antibody levels were maintained for a prolonged period [15].

In 2014, Sands et al. (GEMINI III) evaluated the response of vedolizumab in patients with previous anti-TNF treatment. The study showed an advantage of

*Biological Therapy for Inflammatory Bowel Disease*

that further raise morbidity and mortality [4].

anemia and malnutrition [5] may occur.

not have the Fc portion, making it less immunogenic [5].

of these action pathways will be detailed in this chapter.

**2. Anti-integrins and anti-interleukin 12/23p40**

circulation to the gastrointestinal endothelial cells [8].

For years, the therapeutic management of IBD has been restricted to local action

Immunomodulators initially used in rheumatologic conditions have also been applied in IBD treatment. Thiopurines (azathioprine and 6-mercaptopurines) and methotrexate were widely used against both UC and CD, but these medications alone failed to induce and maintain clinical and endoscopic remission in a significant percentage of cases. Failure to control the disease increases the risk of complications, like strictures, abscesses, fistulas, and the need for surgical approaches. Additionally, worse quality of life and an increase in clinical complications like

The therapeutic revolution of IBDs began with biological therapy containing anti-tumor necrosis factor (anti-TNF) agents such as infliximab, which was widely used in the management of rheumatologic, dermatological, and inflammatory bowel diseases. Subsequently, other drugs of the same class emerged, such as adalimumab, a fully human monoclonal antibody, and certolizumab, which does

Anti-TNF treatment (alone or in combination with immunomodulators) can induce clinical and endoscopic remission. However, only 10–30% will have a primary no-response, and over 50% will, after an initial response, have a secondary

New classes of immunobiological therapies are available to treat patients with loss of response to anti-TNF treatment, since the response to a second anti-TNF is low [4, 5]. Integrins and interleukins are the main targets of the available drugs to treat IBD. They act on receptors of cells involved in the inflammatory process and on proinflammatory cytokines, respectively. Furthermore, the intracellular inhibition of kinases by JAK inhibitors acts on intracellular inflammatory mediators. Each

Integrins are cell surface glycoprotein receptors that play a role in leukocyte adhesion, signaling, proliferation, and migration [7]. Migration of circulating leucocytes from blood to intestinal tissue is a key step for intestinal inflammation. α4β7 integrin expressed on the surface of the leukocyte binds to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on endothelial cells. Anti-integrin blocks the action of integrins, inhibiting leukocyte trafficking from the systemic

Natalizumab is a chimeric recombinant human IgG4 antibody that blocks the α4 subunits in α4β7 and α4β1 integrins on leukocytes, inhibits binding to vascular cell adhesion molecule 1 (VCAM-1), and decreases inflammatory cells in affected gastrointestinal tissue, contributing to induction and maintenance of remission in CD [9]. Natalizumab also blocks lymphocyte infiltration in the central nervous system and is also approved for multiple sclerosis treatment [10]. However, association with progressive multifocal leukoencephalopathy (PML), a rare disabling and potentially fatal neurological syndrome caused by reactivation of the John Cunningham virus (JCV), has limited its use in treating

medications with mild anti-inflammatory power, such as amino salicylates and corticosteroids. Adverse effects of prolonged use of corticosteroids include infections, diabetes, osteoporosis, cataracts, metabolic syndrome, and esthetic changes

**116**

CD patients [11].

loss [6].

**2.1 Anti-integrins**

anti-integrin when compared to placebo only after 10 weeks, concluding that in patients who fail anti-TNF treatment, longer time is required to achieve clinical remission with vedolizumab [16].

The VARSITY study presented in 2019 was the first study that compared two biological drugs (vedolizumab and adalimumab). The randomized, double-blind phase 3 study evaluated clinical and endoscopic response at week 52 in patients with moderate-to-severe active UC treated with standard drug doses. Vedolizumab was more effective in inducing clinical remission and mucosal healing. There was no statistically significant difference between the drugs when the outcome evaluated was steroid-free remission. Both drugs were safe and well tolerated for treatment of moderate-to-severe UC [19].

No studies compared the efficacy of different biological agents in patients with CD.

#### **2.2 Anti-interleukin 12/23p40**

IBD presents a large infiltration of leukocytes, especially T lymphocytes. When activated, these cells produce a high concentration of cytokines that have an important role in the inflammatory process of the disease [20]. However, there seems to be a distinction in the profile of cytokines produced in CD and UC. While in CD there is a predominant synthesis of type 1 helper T-cell (Th1) cytokines, such as interferon-γ (IFN-γ) and TNF-α; in UC, Th2 cytokines, such as interleukin-5 and interleukin-13, are more relevant [20, 21].

CD mucosa has an increased production of interleukin-12 (IL-12), a proinflammatory cytokine that induces IFN-γ production and promotes Th1 cell differentiation [22, 23]. IL-12 is a heterodimeric cytokine produced by macrophages, monocytes, and dendritic cells, with two covalently linked subunits: p40 and p35 [23].

The IL-12p40 subunit can be combined with another cytokine, derived of IL-6 subfamily structures, the p19 protein, to form the p19p40 complex, also nowed like interleukin-23 cytokine (IL-23) [24]. The natural function of IL-23 is to coordinate inflammatory responses within peripheral tissues. However, unregulated expression of IL-23 may promote detrimental immune pathology at these sites [25]. In IBD, IL-23 may play the role of initiating and perpetuating innate T cell-mediated intestinal inflammation [26], thus leaving the place to IL-12/IFN-γ/T-cell pathway in the late phase [20].

A systematic review published by MacDonald et al. evaluated the use of ustekinumab (CNTO 1275) and briakinumab (ABT-874), monoclonal antibodies that target the standard p40 subunit of the cytokines IL-12 and IL-23 (IL-12/23p40), in patients with CD [27]. In this review two studies that compared briakinumab to placebo and four studies that compared ustekinumab to placebo were analyzed.

In 2004, Mannon et al. investigated two different doses of briakinumab. This was a multisite, randomized, double-blind, placebo-controlled study where 79 CD patients received 1 or 3 mg of anti-IL-12p40 monoclonal antibody subcutaneous injections versus placebo. The results showed that the use of anti-IL-12p40 might induce clinical responses and remissions in patients with active CD, with responses in 75% of CD patients compared with 25% in the placebo group. These results were associated with decreases in Th1-mediated inflammatory cytokines (IFN-γ and TNF-α) at the site of disease. There were no significant differences in the rate of adverse effects between placebo and anti-IL-12, except a higher rate of local reactions at injection sites in the former group [28].

The other study testing the use of briakinumab was published in 2015 and evaluated the efficacy and safety of this drug [29]. This was a phase 2b, multicenter,

**119**

maintenance phase [31].

optimal dose of ustekinumab is 6 mg/kg [27].

*Anti-Integrins, Anti-Interleukin 12/23p40, and JAK Inhibitors for the Inflammatory Bowel…*

double-blind, parallel group study, conducted with 246 patients with moderateto-severe CD stratified by prior TNF-α antagonist use and response to anti-TNF-α therapy, who were randomly given placebo and 200, 400, or 700 mg briakinumab over the period of 0, 4, and 8 weeks. On week 12, patients who got clinical response in the placebo or 400-mg induction groups proceeded to the maintenance phase with the same protocol. Those who responded clinically with 700 mg were randomized to receive placebo and 200 or 700 mg briakinumab at weeks 12, 16, and 20 during the maintenance phase. Patients in remission stopped receiving the study drug at week 24. During the induction and maintenance phase of this study, briakinumab was well tolerated and had a safety profile similar to placebo. However, the authors pointed out that infusion reactions were observed in a higher percentage of patients treated with briakinumab than placebo during the induction phase (up to week 12). After week 12, adverse events and severe reactions occurred at a higher rate, mainly due to the increase in serious infusion reactions. The sponsor stopped the study during the open-label phase due to poor induction of remission results. These investigations did not find severe side effects comparing briakinumab and placebo. However, there were common reactions to the site of injection and some secondary infections produced by briakinumab therapy. Due to these results, the

Sandborn et al. conducted a phase IIa study of ustekinumab comparing clinical effects to placebo [30]. They made a double-blind, crossover design with 104 patients with moderate-to-severe CD, including both TNF-α antagonist naive patients and those who had previously failed one or more of these agents. These patients were divided into four groups: two groups received subcutaneous treatment doses, of which one group received placebo at weeks 0–3 and then 90 mg ustekinumab at weeks 8–11, while the other group received 90 mg ustekinumab at weeks 0–3 and then placebo at weeks 8–11. The other two groups followed the same weekly protocol, but the pathway was intravenous, and the dose was 4.5 mg/kg ustekinumab. Furthermore, a sub study like open-label trial evaluated the effects of four weekly subcutaneous injections of 90 mg or one intravenous infusion of 4.5 mg/kg ustekinumab in 27 patients who were primary or secondary nonresponders to infliximab, but it was not placebo-controlled. They showed that ustekinumab induced a clinical response in CD patients, who were previously

In 2012, Sandborn et al. published another study that evaluated ustekinumab therapy in patients with moderate-to-severe CD which was resistant to anti-TNF-α. This was a double-blind, placebo-controlled phase 2b trial with 526 patients who were randomized to receive intravenous ustekinumab (1, 3, or 6 mg/kg) or placebo at week 0. After 6 weeks, the clinical response was measured, and 145 patients who responded to ustekinumab were randomized to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16 in the maintenance phase. Patients who used ustekinumab as an induction therapy had a higher response than the placebo group but did not differ in remission. These patients, during the maintenance phase with ustekinumab administration, had a significant increase in response and remission rates when compared to placebo. It is noteworthy that some serious infections occurred during the study, which affected 7 patients (6 receiving ustekinumab) in the induction phase and 11 (4 receiving ustekinumab) in the

According to MacDonald et al., strong evidence indicates that ustekinumab is efficient for remission induction and that it improves symptoms in patients with moderate-to-severe CD. Moderate- to high-quality evidence implies that the

*DOI: http://dx.doi.org/10.5772/intechopen.90536*

production of briakinumab was interrupted [27].

treated infliximab, with the best effect in weeks 4–6 [30].

#### *Anti-Integrins, Anti-Interleukin 12/23p40, and JAK Inhibitors for the Inflammatory Bowel… DOI: http://dx.doi.org/10.5772/intechopen.90536*

double-blind, parallel group study, conducted with 246 patients with moderateto-severe CD stratified by prior TNF-α antagonist use and response to anti-TNF-α therapy, who were randomly given placebo and 200, 400, or 700 mg briakinumab over the period of 0, 4, and 8 weeks. On week 12, patients who got clinical response in the placebo or 400-mg induction groups proceeded to the maintenance phase with the same protocol. Those who responded clinically with 700 mg were randomized to receive placebo and 200 or 700 mg briakinumab at weeks 12, 16, and 20 during the maintenance phase. Patients in remission stopped receiving the study drug at week 24. During the induction and maintenance phase of this study, briakinumab was well tolerated and had a safety profile similar to placebo. However, the authors pointed out that infusion reactions were observed in a higher percentage of patients treated with briakinumab than placebo during the induction phase (up to week 12). After week 12, adverse events and severe reactions occurred at a higher rate, mainly due to the increase in serious infusion reactions. The sponsor stopped the study during the open-label phase due to poor induction of remission results.

These investigations did not find severe side effects comparing briakinumab and placebo. However, there were common reactions to the site of injection and some secondary infections produced by briakinumab therapy. Due to these results, the production of briakinumab was interrupted [27].

Sandborn et al. conducted a phase IIa study of ustekinumab comparing clinical effects to placebo [30]. They made a double-blind, crossover design with 104 patients with moderate-to-severe CD, including both TNF-α antagonist naive patients and those who had previously failed one or more of these agents. These patients were divided into four groups: two groups received subcutaneous treatment doses, of which one group received placebo at weeks 0–3 and then 90 mg ustekinumab at weeks 8–11, while the other group received 90 mg ustekinumab at weeks 0–3 and then placebo at weeks 8–11. The other two groups followed the same weekly protocol, but the pathway was intravenous, and the dose was 4.5 mg/kg ustekinumab. Furthermore, a sub study like open-label trial evaluated the effects of four weekly subcutaneous injections of 90 mg or one intravenous infusion of 4.5 mg/kg ustekinumab in 27 patients who were primary or secondary nonresponders to infliximab, but it was not placebo-controlled. They showed that ustekinumab induced a clinical response in CD patients, who were previously treated infliximab, with the best effect in weeks 4–6 [30].

In 2012, Sandborn et al. published another study that evaluated ustekinumab therapy in patients with moderate-to-severe CD which was resistant to anti-TNF-α. This was a double-blind, placebo-controlled phase 2b trial with 526 patients who were randomized to receive intravenous ustekinumab (1, 3, or 6 mg/kg) or placebo at week 0. After 6 weeks, the clinical response was measured, and 145 patients who responded to ustekinumab were randomized to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16 in the maintenance phase. Patients who used ustekinumab as an induction therapy had a higher response than the placebo group but did not differ in remission. These patients, during the maintenance phase with ustekinumab administration, had a significant increase in response and remission rates when compared to placebo. It is noteworthy that some serious infections occurred during the study, which affected 7 patients (6 receiving ustekinumab) in the induction phase and 11 (4 receiving ustekinumab) in the maintenance phase [31].

According to MacDonald et al., strong evidence indicates that ustekinumab is efficient for remission induction and that it improves symptoms in patients with moderate-to-severe CD. Moderate- to high-quality evidence implies that the optimal dose of ustekinumab is 6 mg/kg [27].

*Biological Therapy for Inflammatory Bowel Disease*

remission with vedolizumab [16].

moderate-to-severe UC [19].

**2.2 Anti-interleukin 12/23p40**

and p35 [23].

were analyzed.

interleukin-13, are more relevant [20, 21].

tions at injection sites in the former group [28].

anti-integrin when compared to placebo only after 10 weeks, concluding that in patients who fail anti-TNF treatment, longer time is required to achieve clinical

The VARSITY study presented in 2019 was the first study that compared two biological drugs (vedolizumab and adalimumab). The randomized, double-blind phase 3 study evaluated clinical and endoscopic response at week 52 in patients with moderate-to-severe active UC treated with standard drug doses. Vedolizumab was more effective in inducing clinical remission and mucosal healing. There was no statistically significant difference between the drugs when the outcome evaluated was steroid-free remission. Both drugs were safe and well tolerated for treatment of

No studies compared the efficacy of different biological agents in patients with CD.

IBD presents a large infiltration of leukocytes, especially T lymphocytes. When activated, these cells produce a high concentration of cytokines that have an important role in the inflammatory process of the disease [20]. However, there seems to be a distinction in the profile of cytokines produced in CD and UC. While in CD there is a predominant synthesis of type 1 helper T-cell (Th1) cytokines, such as interferon-γ (IFN-γ) and TNF-α; in UC, Th2 cytokines, such as interleukin-5 and

CD mucosa has an increased production of interleukin-12 (IL-12), a proinflammatory cytokine that induces IFN-γ production and promotes Th1 cell differentiation [22, 23]. IL-12 is a heterodimeric cytokine produced by macrophages, monocytes, and dendritic cells, with two covalently linked subunits: p40

The IL-12p40 subunit can be combined with another cytokine, derived of IL-6 subfamily structures, the p19 protein, to form the p19p40 complex, also nowed like interleukin-23 cytokine (IL-23) [24]. The natural function of IL-23 is to coordinate inflammatory responses within peripheral tissues. However, unregulated expression of IL-23 may promote detrimental immune pathology at these sites [25]. In IBD, IL-23 may play the role of initiating and perpetuating innate T cell-mediated intestinal inflammation [26], thus leaving the place to IL-12/IFN-γ/T-cell pathway in the late phase [20]. A systematic review published by MacDonald et al. evaluated the use of ustekinumab (CNTO 1275) and briakinumab (ABT-874), monoclonal antibodies that target the standard p40 subunit of the cytokines IL-12 and IL-23 (IL-12/23p40), in patients with CD [27]. In this review two studies that compared briakinumab to placebo and four studies that compared ustekinumab to placebo

In 2004, Mannon et al. investigated two different doses of briakinumab. This was a multisite, randomized, double-blind, placebo-controlled study where 79 CD patients received 1 or 3 mg of anti-IL-12p40 monoclonal antibody subcutaneous injections versus placebo. The results showed that the use of anti-IL-12p40 might induce clinical responses and remissions in patients with active CD, with responses in 75% of CD patients compared with 25% in the placebo group. These results were associated with decreases in Th1-mediated inflammatory cytokines (IFN-γ and TNF-α) at the site of disease. There were no significant differences in the rate of adverse effects between placebo and anti-IL-12, except a higher rate of local reac-

The other study testing the use of briakinumab was published in 2015 and evaluated the efficacy and safety of this drug [29]. This was a phase 2b, multicenter,

**118**

In addition to the improvement in patients' clinical condition and symptomatology, positive responses were also observed in histological examinations of patients who used maintenance therapy with ustekinumab every 8 weeks [32]. When analyzing histological data from participants in phase 3 induction and maintenance studies, significant histological improvement was observed in patients receiving ustekinumab compared to placebo [32].

Indeed, in 2016, with phase III UNITI trial program's positive results [33], the US Food and Drug Administration (FDA) approved ustekinumab for the treatment of moderate-to-severe CD [34]. Although there is no increased risk of serious adverse events, further studies are needed to assess the long-term benefit of their use in patients with CD [27].

Recently a study was published evaluating the use of ustekinumab to treat patients with moderate-to-severe active UC who do not respond well or were unable to tolerate conventional treatment or biological therapies [35]. It was a randomized, double-blind, placebo-controlled phase 3 study. Patients receiving a single intravenous ustekinumab dose of 130 mg or 6 mg/kg body weight (320 and 322 patients respectively) achieved clinical remission, endoscopic healing, clinical response, and mucosal healing at week 8, significantly better than placebo. It has been shown to be effective not only for the treatment of CD but also for the induction and maintenance of remission in patients with moderate-to-severe UC [35].

Serious infections were the most common side effects in the ustekinumab studies [27]. The therapeutic target of this drug is the p40 subunit, and it is not selective for IL-12 or IL-23. IL-12 is known to mediate protective systemic antimicrobial immunity, so this immune suppression may be responsible for these secondary opportunistic infections [23].

Studies support the specific blockade of IL-23, for its blockade may be as effective as the blockade of both cytokines but may result in fewer infectious problems [26]. A recently published review study evaluated the use of two drugs as a specific antagonist of the p19 subunit [34]. Risankizumab and brazikumab are the first anti-IL23p19 whose results were positive in randomized placebo-controlled phase II study to induction and maintenance therapy for moderate-to-severe CD patients. This review showed that both adverse events and serious adverse events did not differ between the treated groups and placebo. These results were observed in phase II studies with risankizumab and brazikumab, to treat not only IBD but also psoriasis. Based on symptomatic, endoscopic, and positive biomarker results, as well as treatment safety and efficacy during phase II trials, phase III studies are ongoing. These studies will help answer questions about the optimal dosage of drugs and their action at other levels of CD involvement [34].

#### **3. JAK inhibitors**

Despite advances in the therapeutic arsenal of IBDs, significant numbers of patients do not achieve mucosal healing. Janus kinase (JAK) inhibitors already used in oncological, rheumatological, and dermatological disease treatment are being studied as a new therapeutic resource against IBDs.

Many cytokines involved in IBD act on the JAK/signal transducer and activator of transcription (STAT) cell signaling pathway, generating cellular responses through gene expression [36]. By binding to specific membrane receptors, cytokines activate JAK, which catalyzes the phosphorylation of the complex enabling STAT binding [37]. After phosphorylation, STATs dimerize, leave the receptor, and go to the cell nucleus to activate the transcription of the target gene [38].

**121**

placebo [45].

*Anti-Integrins, Anti-Interleukin 12/23p40, and JAK Inhibitors for the Inflammatory Bowel…*

Some JAKs, like JAK1, JAK2, and JAK3, play an important role in the growth, differentiation, and survival of immune system cells in general. Unlike the others, JAK3 is present in hematopoietic cells, acting mediated signaling pathways by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 [38]. According to Lovato et al., patients with CD have an overactivation of STAT3 and STAT4 in intestinal T cells [39]. Therefore, despite the importance in diverse cellular activities, changes in the JAK/STAT signaling path-

JAK inhibitors have been developed and are under clinical investigation to assess

their ability to attenuate the inflammation process in UC [40]. Tofacitinib (CP-690,550), a first-class JAK360 inhibitor, works by inhibiting JAK1/JAK3 and has a lower side effect on JAK2 and TYK2 [41]. This JAK inhibitor was tested in clinical trials to verify its potential treatment for some immune system disorders, including

To test the efficacy of tofacitinib in UC, a double-blind, placebo-controlled, phase 2 trial study was conducted [40]. Patients with moderately to severely active UC (n = 194) randomly received placebo or tofacitinib at a dose of 0.5, 3, 10, or 15 mg twice daily for 8 weeks. Significant clinical remission (Mayo score ≤ 2, with no subscore >1) at 8 weeks occurred in patients who received 10 mg (48%, p < 0.001) and 15 mg (41%, p < 0.001), compared with 10% in placebo group. Endoscopic remission at 8 weeks occurred in patients receiving 10 mg (30%, p < 0.001) and 15 mg (27%, p < 0.001), compared with 2% in placebo group.

OCTAVE Induction 1 and 2 were phase 3, randomized, double-blind, placebocontrolled studies in patients with moderately to severely active UC [43]. Patients randomly received tofacitinib (10 mg twice daily) or placebo for 8 weeks. In the OCTAVE Induction 1 (n = 598 patients), remission occurred in 18.5% of the patients in tofacitinib group and in 8.2% in placebo group (p = 0.007). In OCTAVE Induction 2 (n = 541 patients), remission occurred in 16.6 versus 3.6%, respectively (p < 0.001). According to the results, tofacitinib use showed remission induction after 8 weeks of use in patients with moderate-to-severe UC compared with

In OCTAVE sustain study, the rate of maintenance of clinical remission was evaluated. The patients with clinical response to induction therapy in OCTAVE Induction 1 and 2 were followed for 52 weeks. The patients were randomized into three groups (placebo, 10 mg and 5 mg, 2 times daily). The clinical remission at 52 weeks occurred in 34.3% (n = 68/ 198) of patients taking 5 mg; 40.6% (n = 80/197) with 10 mg; and 11.1% (n = 22/198) in the placebo group. The mucosal healing rate at 52 weeks was 37.4% (n = 74/198) in patients on 5 mg; 45.7% (n = 90/197) in those who used 10 mg; and 13.1% in the placebo group

In patients with CD, initial studies with JAK inhibitors have shown unsatisfactory results in inducing clinical and endoscopic remission of the disease. In a, multicenter, randomized, double-blind, placebo-controlled phase 2 study, patients with severe CD (CDAI between 220 and 450) were randomized to receive placebo or 1 mg, 5 mg, and 15 mg tofacitinib, twice daily for 4 weeks. Clinical response and remission were similar between both groups. However, this outcome could be

Another multicenter phase IIb, randomized, double-blind, placebo-controlled

study evaluated patients with moderate-to-severe CD. Patients were assigned randomly to receive placebo or tofacitinib 5 or 10 mg twice daily for 8 and 26 weeks. The rates of clinical response (decrease in CDAI ≥100 from baseline) and clinical remission (CDAI <150) at week 8 and 26 were not significantly different from the

associated with a selection bias in the control group [44].

*DOI: http://dx.doi.org/10.5772/intechopen.90536*

CD and UC [42].

placebo [43].

(26/198) [43].

ways have been related to various immune disorders [38].

#### *Anti-Integrins, Anti-Interleukin 12/23p40, and JAK Inhibitors for the Inflammatory Bowel… DOI: http://dx.doi.org/10.5772/intechopen.90536*

Some JAKs, like JAK1, JAK2, and JAK3, play an important role in the growth, differentiation, and survival of immune system cells in general. Unlike the others, JAK3 is present in hematopoietic cells, acting mediated signaling pathways by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 [38]. According to Lovato et al., patients with CD have an overactivation of STAT3 and STAT4 in intestinal T cells [39]. Therefore, despite the importance in diverse cellular activities, changes in the JAK/STAT signaling pathways have been related to various immune disorders [38].

JAK inhibitors have been developed and are under clinical investigation to assess their ability to attenuate the inflammation process in UC [40]. Tofacitinib (CP-690,550), a first-class JAK360 inhibitor, works by inhibiting JAK1/JAK3 and has a lower side effect on JAK2 and TYK2 [41]. This JAK inhibitor was tested in clinical trials to verify its potential treatment for some immune system disorders, including CD and UC [42].

To test the efficacy of tofacitinib in UC, a double-blind, placebo-controlled, phase 2 trial study was conducted [40]. Patients with moderately to severely active UC (n = 194) randomly received placebo or tofacitinib at a dose of 0.5, 3, 10, or 15 mg twice daily for 8 weeks. Significant clinical remission (Mayo score ≤ 2, with no subscore >1) at 8 weeks occurred in patients who received 10 mg (48%, p < 0.001) and 15 mg (41%, p < 0.001), compared with 10% in placebo group. Endoscopic remission at 8 weeks occurred in patients receiving 10 mg (30%, p < 0.001) and 15 mg (27%, p < 0.001), compared with 2% in placebo group.

OCTAVE Induction 1 and 2 were phase 3, randomized, double-blind, placebocontrolled studies in patients with moderately to severely active UC [43]. Patients randomly received tofacitinib (10 mg twice daily) or placebo for 8 weeks. In the OCTAVE Induction 1 (n = 598 patients), remission occurred in 18.5% of the patients in tofacitinib group and in 8.2% in placebo group (p = 0.007). In OCTAVE Induction 2 (n = 541 patients), remission occurred in 16.6 versus 3.6%, respectively (p < 0.001). According to the results, tofacitinib use showed remission induction after 8 weeks of use in patients with moderate-to-severe UC compared with placebo [43].

In OCTAVE sustain study, the rate of maintenance of clinical remission was evaluated. The patients with clinical response to induction therapy in OCTAVE Induction 1 and 2 were followed for 52 weeks. The patients were randomized into three groups (placebo, 10 mg and 5 mg, 2 times daily). The clinical remission at 52 weeks occurred in 34.3% (n = 68/ 198) of patients taking 5 mg; 40.6% (n = 80/197) with 10 mg; and 11.1% (n = 22/198) in the placebo group. The mucosal healing rate at 52 weeks was 37.4% (n = 74/198) in patients on 5 mg; 45.7% (n = 90/197) in those who used 10 mg; and 13.1% in the placebo group (26/198) [43].

In patients with CD, initial studies with JAK inhibitors have shown unsatisfactory results in inducing clinical and endoscopic remission of the disease. In a, multicenter, randomized, double-blind, placebo-controlled phase 2 study, patients with severe CD (CDAI between 220 and 450) were randomized to receive placebo or 1 mg, 5 mg, and 15 mg tofacitinib, twice daily for 4 weeks. Clinical response and remission were similar between both groups. However, this outcome could be associated with a selection bias in the control group [44].

Another multicenter phase IIb, randomized, double-blind, placebo-controlled study evaluated patients with moderate-to-severe CD. Patients were assigned randomly to receive placebo or tofacitinib 5 or 10 mg twice daily for 8 and 26 weeks. The rates of clinical response (decrease in CDAI ≥100 from baseline) and clinical remission (CDAI <150) at week 8 and 26 were not significantly different from the placebo [45].

*Biological Therapy for Inflammatory Bowel Disease*

ustekinumab compared to placebo [32].

patients with CD [27].

opportunistic infections [23].

**3. JAK inhibitors**

In addition to the improvement in patients' clinical condition and symptomatology, positive responses were also observed in histological examinations of patients who used maintenance therapy with ustekinumab every 8 weeks [32]. When analyzing histological data from participants in phase 3 induction and maintenance studies, significant histological improvement was observed in patients receiving

Indeed, in 2016, with phase III UNITI trial program's positive results [33], the US Food and Drug Administration (FDA) approved ustekinumab for the treatment of moderate-to-severe CD [34]. Although there is no increased risk of serious adverse events, further studies are needed to assess the long-term benefit of their use in

Recently a study was published evaluating the use of ustekinumab to treat patients with moderate-to-severe active UC who do not respond well or were unable to tolerate conventional treatment or biological therapies [35]. It was a randomized, double-blind, placebo-controlled phase 3 study. Patients receiving a single intravenous ustekinumab dose of 130 mg or 6 mg/kg body weight (320 and 322 patients respectively) achieved clinical remission, endoscopic healing, clinical response, and mucosal healing at week 8, significantly better than placebo. It has been shown to be effective not only for the treatment of CD but also for the induction and mainte-

Serious infections were the most common side effects in the ustekinumab studies [27]. The therapeutic target of this drug is the p40 subunit, and it is not selective for IL-12 or IL-23. IL-12 is known to mediate protective systemic antimicrobial immunity, so this immune suppression may be responsible for these secondary

Studies support the specific blockade of IL-23, for its blockade may be as effective as the blockade of both cytokines but may result in fewer infectious problems [26]. A recently published review study evaluated the use of two drugs as a specific antagonist of the p19 subunit [34]. Risankizumab and brazikumab are the first anti-IL23p19 whose results were positive in randomized placebo-controlled phase II study to induction and maintenance therapy for moderate-to-severe CD patients. This review showed that both adverse events and serious adverse events did not differ between the treated groups and placebo. These results were observed in phase II studies with risankizumab and brazikumab, to treat not only IBD but also psoriasis. Based on symptomatic, endoscopic, and positive biomarker results, as well as treatment safety and efficacy during phase II trials, phase III studies are ongoing. These studies will help answer questions about the optimal dosage of drugs and their action at other levels of CD involvement [34].

Despite advances in the therapeutic arsenal of IBDs, significant numbers of patients do not achieve mucosal healing. Janus kinase (JAK) inhibitors already used in oncological, rheumatological, and dermatological disease treatment are being

Many cytokines involved in IBD act on the JAK/signal transducer and activator of transcription (STAT) cell signaling pathway, generating cellular responses through gene expression [36]. By binding to specific membrane receptors, cytokines activate JAK, which catalyzes the phosphorylation of the complex enabling STAT binding [37]. After phosphorylation, STATs dimerize, leave the receptor, and

go to the cell nucleus to activate the transcription of the target gene [38].

studied as a new therapeutic resource against IBDs.

nance of remission in patients with moderate-to-severe UC [35].

**120**

In 2018, tofacitinib was the first JAK inhibitor to be approved by the US FDA and the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) to treat moderate-to-severe active UC. According to EMA it should be used in patients who have tried conventional therapy or biological agents and failed or did not progress positively.

There is another small molecule, still in the testing phase, which selectively acts on important specific pathways in UC and CD, thus limiting some of the side effects such as bacterial and viral infections [41].

Indeed, tofacitinib therapy in rheumatoid arthritis showed an increased risk of infection, including herpes zoster [46]. Herpes zoster infection, among others, was also observed in the OCTAVE study comparing the use of 10 mg tofacitinib with placebo [43]. Vaccination against herpes zoster is indicated 3–4 weeks before starting tofacitinib treatment as a preventive strategy [47].

The other most common adverse effects of using JAK inhibitors are influenza, rhinopharyngitis, arthralgia, and headache. Studies in patients with rheumatologic diseases and psoriasis have not shown increased cardiovascular risk in patients treated with tofacitinib [43], although there may be an increase in HDL and LDL cholesterol serum levels [40].

In a cohort analysis, including OCTAVE I and II and Sustain, with UC patients exposed to tofacitinib, 25 cases of pregnancy occurred, but no definitive conclusions about maternal and fetal risks, due to methodological limitations (absence of control group, retrospective study, and small number of cases) [48]. Further studies are needed to assess medication safety in pregnant women. It is not currently approved for pregnant and breastfeeding women [47, 48]. In addition, information provided by the manufacturer itself showed preclinical trials with rabbits and rats that showed a risk of fetal malformations with the use of tofacitinib but at doses 10 times higher than recommended for humans [Pfizer Inc. Xeljanz prescribes information, http://labeling.pfizer.com/ShowLabeling.aspx?id=959 (2014, accessed July 13, 2019)] [47].

Vermeire et al. evaluated the efficacy of filgotinib, a kind of selective JAK1 inhibitor [49]. This search was a randomized, double-blinded, placebo-controlled phase II FITZROY study, with CD patients with moderate-to-severe activity. The patients received 200 mg filgotinib once daily or placebo for 10 weeks. As a result, the number of patients who received the drug and went into remission was much larger than that of those who received placebo after 10 weeks of treatment. This study showed the first evidence for potential clinical efficacy and safety of a selective JAK1 inhibitor for the treatment of active CD [49]. Filgotinib might represent a new oral treatment to induce remission in patients with CD, but a phase III study will still be necessary [42]. According to Soendergaard et al., a combined phase IIb/III randomized, placebo-controlled study with filgotinib for the treatment of moderate-to-severe UC (the SELECTION1 study) is ongoing.

#### **4. Conclusion**

Inflammatory bowel diseases have very complex pathophysiological mechanisms, which makes treatment difficult. Advances in research presented here show new possibilities for alternative treatments, some already approved by the FDA (ustekinumab and tofacitinib) and others still under investigation.

The study of these alternative biological therapies is very important to help treat severe CD and UC patients with previous therapeutic failures, who no longer respond to or have not adapted to conventional treatments.

**123**

**Author details**

and Raquel Franco Leal\*

*Anti-Integrins, Anti-Interleukin 12/23p40, and JAK Inhibitors for the Inflammatory Bowel…*

Karine Mariane Steigleder, Fernando Lopes Ponte Neto, Cristiane Kibune Nagasako

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

University of Campinas – UNICAMP, Campinas, Brazil

provided the original work is properly cited.

\*Address all correspondence to: rafranco.unicamp@gmail.com

*DOI: http://dx.doi.org/10.5772/intechopen.90536*

The authors declare no conflict of interest.

**Conflict of interest**

*Anti-Integrins, Anti-Interleukin 12/23p40, and JAK Inhibitors for the Inflammatory Bowel… DOI: http://dx.doi.org/10.5772/intechopen.90536*

### **Conflict of interest**

*Biological Therapy for Inflammatory Bowel Disease*

such as bacterial and viral infections [41].

starting tofacitinib treatment as a preventive strategy [47].

or did not progress positively.

cholesterol serum levels [40].

13, 2019)] [47].

is ongoing.

**4. Conclusion**

In 2018, tofacitinib was the first JAK inhibitor to be approved by the US FDA and the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) to treat moderate-to-severe active UC. According to EMA it should be used in patients who have tried conventional therapy or biological agents and failed

There is another small molecule, still in the testing phase, which selectively acts on important specific pathways in UC and CD, thus limiting some of the side effects

Indeed, tofacitinib therapy in rheumatoid arthritis showed an increased risk of infection, including herpes zoster [46]. Herpes zoster infection, among others, was also observed in the OCTAVE study comparing the use of 10 mg tofacitinib with placebo [43]. Vaccination against herpes zoster is indicated 3–4 weeks before

The other most common adverse effects of using JAK inhibitors are influenza, rhinopharyngitis, arthralgia, and headache. Studies in patients with rheumatologic diseases and psoriasis have not shown increased cardiovascular risk in patients treated with tofacitinib [43], although there may be an increase in HDL and LDL

In a cohort analysis, including OCTAVE I and II and Sustain, with UC patients exposed to tofacitinib, 25 cases of pregnancy occurred, but no definitive conclusions about maternal and fetal risks, due to methodological limitations (absence of control group, retrospective study, and small number of cases) [48]. Further studies are needed to assess medication safety in pregnant women. It is not currently approved for pregnant and breastfeeding women [47, 48]. In addition, information provided by the manufacturer itself showed preclinical trials with rabbits and rats that showed a risk of fetal malformations with the use of tofacitinib but at doses 10 times higher than recommended for humans [Pfizer Inc. Xeljanz prescribes information, http://labeling.pfizer.com/ShowLabeling.aspx?id=959 (2014, accessed July

Vermeire et al. evaluated the efficacy of filgotinib, a kind of selective JAK1 inhibitor [49]. This search was a randomized, double-blinded, placebo-controlled phase II FITZROY study, with CD patients with moderate-to-severe activity. The patients received 200 mg filgotinib once daily or placebo for 10 weeks. As a result, the number of patients who received the drug and went into remission was much larger than that of those who received placebo after 10 weeks of treatment. This study showed the first evidence for potential clinical efficacy and safety of a selective JAK1 inhibitor for the treatment of active CD [49]. Filgotinib might represent a new oral treatment to induce remission in patients with CD, but a phase III study will still be necessary [42]. According to Soendergaard et al., a combined phase IIb/III randomized, placebo-controlled study with filgotinib for the treatment of moderate-to-severe UC (the SELECTION1 study)

Inflammatory bowel diseases have very complex pathophysiological mechanisms, which makes treatment difficult. Advances in research presented here show new possibilities for alternative treatments, some already approved by the FDA

The study of these alternative biological therapies is very important to help treat severe CD and UC patients with previous therapeutic failures, who no longer

(ustekinumab and tofacitinib) and others still under investigation.

respond to or have not adapted to conventional treatments.

**122**

The authors declare no conflict of interest.

#### **Author details**

Karine Mariane Steigleder, Fernando Lopes Ponte Neto, Cristiane Kibune Nagasako and Raquel Franco Leal\* University of Campinas – UNICAMP, Campinas, Brazil

\*Address all correspondence to: rafranco.unicamp@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[20] Peluso I, Pallone F, Monteleone G. Interleukin-12 and Th1 immune

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[14] Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel J-F, Sandborn WJ, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. The New England Journal of Medicine. 2013;**369**(8):699-710. DOI: 10.1056/NEJMoa1215734

[15] Rosario M, Dirks NL, Milch C, Parikh A, Bargfrede M, Wyant T, et al. A review of the clinical pharmacokinetics, pharmacodynamics, and immunogenicity of vedolizumab. Clinical Pharmacokinetics. 2017;**56**(11):1287-1301. DOI: 10.1007/ s40262-017-0546-0

[16] Sands BE, Feagan BG, Rutgeerts P, Colombel JF, Sandborn WJ, Sy R, et al. Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology. 2014;**147**(3):618-627. e3. DOI: 10.1053/j.gastro.2014.05.008

[17] Poulakos M, Machin JD, Pauly J, Grace Y. Vedolizumab: A new opponent in the battle against Crohns disease and ulcerative colitis. Journal of Pharmacy Practice. 2016;**29**(5):503-515. DOI: 10.1177/0897190015579610

[18] Balzola F, Cullen G, Ho GT, Russell R. Vedolizumab as induction and maintenance therapy for Crohn's disease: Commentary. Inflammatory bowel disease monitor. Remedica Medical Education and Publishing. 2014;**14**:55-56

[19] Schreiber S, Peyrin-Biroulet L, LoftusJr EV, Danese S, Colombel JF, Abhyankar B, et al. VARSITY OP34: A double-blind, double-dummy, randomized, controlled trial of vedolizumab versus adalimumab in patients with active ulcerative colitis. Gastroenterology & Hepatology. 2019;**15**(5 Suppl 2):1-24

[20] Peluso I, Pallone F, Monteleone G. Interleukin-12 and Th1 immune

response in Crohn's disease: Pathogenetic relevance and therapeutic implication. World Journal of Gastroenterology. 2006;**12**(35):5606- 5610. DOI: 10.3748/wjg.v12.i35.5606

[21] Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology. 2005;**129**:550-564. DOI: 10.1016/j. gastro.2005.05.002

[22] Monteleone G, Biancone L, Marasco R, Morrone G, Marasco O, Luzza F, et al. Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology. 1997;**112**:1169-1178. DOI: 10.1016/ s0016-5085(97)70128-8

[23] Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Reviews. Immunology. 2003;**3**(2):133-146. DOI: 10.1038/nri1001

[24] Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;**13**:715-725. DOI: 10.1016/S1074-7613(00)00070-4

[25] Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, et al. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. The Journal of Experimental Medicine. 2006;**203**(11):2473-2483. DOI: 10.1084/ jem.20061099

[26] Neurath MF. IL-23: A master regulator in Crohn disease. Nature Medicine. 2007;**13**:26-28. DOI: 10.1038/ nm0107-26

[27] MacDonald JK, Nguyen TM, Khanna R, Timmer A. Anti-IL-12/23p40

**124**

*Biological Therapy for Inflammatory Bowel Disease*

[1] Allez M, Karmiris K, Louis E, Van Assche G, Ben-Horin S, Klein A, et al. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: Definitions, frequency and pharmacological aspects. Journal of Crohn's & Colitis. 2010;**4**(4):355-366. DOI: 10.1016/j.crohns.2010.04.004

International Journal of Molecular Sciences. 2017;**18**:2020. DOI: 10.3390/

[8] Park SC, Jeen YT. Anti-integrin therapy for inflammatory bowel disease. World Journal of Gastroenterology. 2018;**24**(17):1868-1880. DOI: 10.3748/

[9] Sakuraba A, Keyashian K, Correia C, Melek J, Cohen RD, Hanauer SB, et al. Natalizumab in Crohn's disease:

inflammatory bowel disease center. Inflammatory Bowel Diseases. 2013;**19**(3):621-626. DOI: 10.1097/

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10.1056/NEJMoa1602773

10.1016/j.bpg.2019.02.006

[35] Sands BE, Sandborn WJ, Panaccione R, O'Brien C,

as induction and maintenance therapy for ulcerative colitis. The New England Journal of Medicine.

2019;**381**(13):1201-1214

Zhang H, Johanns J, et al. Ustekinumab

[36] Coskun M, Salem M, Pedersen J, Nielsen OH. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease.

Pharmacological Research. 2013;**76**:1-8.

[37] Aaronson DS, Horvath CM. A road map for those who don't know JAK-STAT. Science. 2002;**296**(5573):1653- 1655. DOI: 10.1126/science.1071545

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[38] Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nature Reviews. Immunology. 2003;**3**(11):900-911. DOI: 10.1038/

[39] Lovato P, Brender C, Agnholt J, Kelsen J, Kaltoft K, Svejgaard A, et al. Constitutive STAT3 activation in intestinal T cells from patients with Crohn's disease. The Journal of Biological Chemistry. 2003;**278**:16777- 16781. DOI: 10.1074/jbc.M207999200

[40] Sandborn WJ, Ghosh S, Panes J, Vranic I, Su C, Rousell S, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. The New England Journal of Medicine. 2012;**367**(7):616-624. DOI: 10.1056/

nri1226

NEJMoa1112168

[28] Mannon PJ, Fuss IJ, Mayer L, Elson CO, Sandborn WJ, Present D, et al. Anti-IL-12 Crohn's disease study group. Anti-interleukin-12 antibody for active Crohn's disease. The New England Journal of Medicine. 2004;**351**(20):2069-2079. DOI: 10.1056/

[29] Panaccione R, Sandborn WJ, Gordon GL, Lee SD, Safdi A, Sedghi S, et al. Briakinumab for treatment of Crohn's disease: Results of a randomized trial. Inflammatory Bowel Diseases. 2015;**21**(6):1329-1340. DOI: 10.1097/

MIB.0000000000000366

[30] Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S, et al. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology. 2008;**135**:1130-1141. DOI: 10.1053/j.gastro.2008.07.014

[31] Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Guzzo C, et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. The New England Journal of Medicine. 2012;**367**(16):1519- 1528. DOI: 10.1056/NEJMoa1203572

[32] Li K, Friedman JR, Chan D, Pollack P, Yang F, Jacobstein D, Brodmerkel C, Gasink C, Feagan BG, Sandborn WJ, Rutgeerts P, De

Hertogh G. Effects of ustekinumab on histologic disease activity in patients with Crohn's disease. Gastroenterology. 2019;**157**: pii: S0016-5085(19)41079-2. DOI: 10.1053/j.gastro.2019.06.037

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NEJMoa033402

**126**

[42] Soendergaard C, Bergenheim FH, Bjerrum JT, Nielsen OH. Targeting JAK-STAT signal transduction in IBD. Pharmacology & Therapeutics. 2018;**192**:100-111. DOI: 10.1016/j. pharmthera.2018.07.003

[43] Sandborn WJ, Su C, Sands BE, D'Haens GR, Vermeire S, Schreiber S, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. The New England Journal of Medicine. 2018;**376**:1723-1736. DOI: 10.1056/NEJMoa1606910

[44] Sandborn WJ, Ghosh S, Panes J, Vranic I, Wang W, Niezychowski W, et al. A phase 2 study of Tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn's disease. Clinical Gastroenterology and Hepatology. 2014;**12**(9):1485-1493. DOI: 10.1016/j. cgh.2014.01.029

[45] Panés J, Sandborn WJ, Schreiber S, Sands BE, Vermeire S, D'Haens G, et al. Tofacitinib for induction and maintenance therapy of Crohn's disease: Results of two phase IIb randomised placebo-controlled trials. Gut. 2017;**66**(6):1049-1059. DOI: 10.1136/ gutjnl-2016-312735

[46] Yamanaka H, Tanaka Y, Takeuchi T, Sugiyama N, Yuasa H, Toyoizumi S, et al. Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: An open-label, long-term extension study. Arthritis Research & Therapy. 2018;**18**:34. DOI: 10.1186/ s13075-016-0932-2

[47] Amico FD, Parigi TL, Fiorino G, Peyrin-biroulet L, Danese S. Tofacitinib in the treatment of ulcerative colitis:

Efficacy and safety from clinical trials to real-world experience. Therapeutic Advances in Gastroenterology. 2019;**12**:1-10. DOI: 10.1177/1756284819848631

[48] Mahadevan U, Dubinsky MC, Su C, Lawendy N, Jones TV, Marren A, et al. Outcomes of pregnancies with maternal/paternal exposure in the Tofacitinib safety databases for ulcerative colitis. Inflammatory Bowel Diseases. 2018;**24**(12):2494-2500. DOI: 10.1093/ibd/izy160

[49] Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, Roblin X, et al. Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): Results from a phase 2, double-blind, randomised, placebo-controlled trial. The Lancet. 2017;**389**(10066):266-275. DOI: 10.1016/ S0140-6736(16)32537-5

### *Edited by Raquel Franco Leal and Tristan Torriani*

The treatment of inflammatory bowel disease (IBD) has posed a major challenge since its appearance. Biomedical researchers, physicians, gastroenterologists, and surgeons have struggled to improve the quality of life of their patients and have sought, above all else, to keep the disease under remission for as long as possible. Blockers for tumoral necrosis factor alpha (TNF-α) were the first biological drugs to be discovered and for this reason they played a crucial role in the subsequent evolution of IBD treatment. The aim of this book is to provide an overview of such drugs and the latest developments in IBD immunopathology. Our contributors discuss the main indications, efficacy, and possible side effects of the different types of drugs available today for IBD treatment.

Published in London, UK © 2020 IntechOpen © Christoph Burgstedt / iStock

Biological Therapy for Inflammatory Bowel Disease

Biological Therapy for

Inflammatory Bowel Disease

*Edited by Raquel Franco Leal and Tristan Torriani*