IBD Treatment Landscape

[00:30]

Hello, I’m Kimberly Kearns, and welcome to IBDIQ, part of The IBD Project by Takeda, where we’re coming together to help enhance expertise in IBD care—right from the start.

Welcome to this presentation where we will review the treatment landscape for IBD, tracing its historical evolution. We will discuss the importance of tailoring treatment to a patient's disease severity.^1,2 And then we will take a closer look at aminosalicylates, corticosteroids, and immunomodulators which are considered conventional IBD treatments - exploring potential safety considerations associated with each treatment class and how they factor into a treat-to-target approach in IBD management.^3-5

[01:13]

IBD is a chronic and progressive disease of the intestinal tract, which includes ulcerative colitis (or UC) and Crohn’s disease (or CD).⁶ IBD can lead to serious complications, such as bowel damage, the need for hospitalization and surgery, as well as disability and decreased quality of life.

As with any disease, our goal as clinicians is to effectively identify and appropriately manage a patient’s IBD. Fortunately, today we have many more tools in our toolbox than we did back in the early 1900s.⁷

At the beginning of the 20th century, patients with IBD were subject to bed rest and colon irrigation as treatment.⁷ For decades after, patients still didn’t have pharmaceutical options to address their clinical needs.

[02:05]

Some of the first disease-specific therapeutic agents of the 20th century included aminosalicylates (also known as 5-aminosalicylic acid or 5-ASAs).⁸

In the 1950s, corticosteroids became a treatment option for IBD.⁹ In 1955, a breakthrough study by Truelove and Witts demonstrated that after 6 weeks, approximately 40% of corticosteroid-treated patients with UC achieved remission versus nearly 16% on placebo. But science is always exploring what is next - and so innovation continued and in the 1960s, immunomodulators came onto the scene.¹⁰

Thanks to advances in molecular biology and our understanding of the immunologic pathway in IBD, the treatment landscape has expanded considerably since the 1990s.^7,11

[03:04]

Advancements began initially with anti-tumor necrosis factor, or anti-TNF monoclonal antibodies, followed by anti-integrins, interleukin inhibitors, Janus kinase (or JAK) inhibitors, biosimilars, and sphingosine-1-phosphate, or S1P receptor modulators.^7,11,12 And as history has shown, innovation is likely to continue in the treatment landscape, which will likely result in more therapeutic options for patients and clinicians. The options available continue to evolve rapidly.¹¹

With so many options, it can be challenging to determine the most appropriate treatment to pursue following diagnosis, as well as over the course of the patient's experience with the disease. Assessing the severity of disease is the first step toward determining what is right for the patient.^1,2

[03:59]

Although various tools are available to assess UC disease activity, such as the commonly used Truelove and Witts' criteria from 1955, the American College of Gastroenterology (or ACG) has proposed a UC activity index that takes into account laboratory and endoscopy-based values along with patient-reported outcomes to assist in defining mild, moderate, and severe disease.¹

The proposed ACG guidelines UC Activity Index shown here includes many of these measures of disease.¹ For patients with UC, disease severity is indicated by the daily number of stools, the presence of blood in the stools, and bowel urgency. Patients with mild UC tend to have fewer than 4 stools a day, which may progress to moderate-to-severe disease when there are more than 6 stools a day.

[04:57]

If disease progresses, the symptoms worsen with greater frequency in bloody stools and urgency of toilet use.¹ 

Lab values vary according to disease severity. Hemoglobin levels in mild disease tend to be in the normal range, compared to levels that are less than 75% of normal levels in moderate-to-severe disease.¹

With mild UC, erythrocyte sedimentation rate (or ESR) is below 30, and greater than 30 is associated with more severe disease.¹

It should also be noted that, unsurprisingly, patients with mild disease have lower endoscopy scores than those with moderate-to-severe disease.¹ 

[05:40]

According to ACG guidelines, for patients diagnosed with Crohn’s, disease severity is generally dictated by the impact of disease on the patient.²

Patients with mild Crohn’s can be described as ambulatory with normal eating and drinking capabilities.² So, mild disease is not likely to cause significant weight loss or complications such as abdominal mass, obstruction, fever, and dehydration.

Of course, when the symptoms are more prominent, the disease is more severe. Importantly, it needs to be said that patients with CD who are not responsive to therapy may experience disease progression, with more severe disease categorized by significant weight loss, intra-abdominal abscess, or obstructions, that can possibly lead to hospitalization.^2,13

[06:32]

Similarly, patients with UC who experience disease progression may exhibit persistent symptoms, leading to prolonged disease activity and an increased risk of complications. This includes potential for frequent flares, hospitalization, development of extraintestinal manifestations (EIMs), development of colon cancer, and the need for surgical intervention.¹³

Now, back to that toolbox. What are the options for conventional treatment for IBD?

As mentioned, there are three drug classes in conventional treatment that patients may receive: aminosalicylates, corticosteroids, and immunomodulators.³ I am going to explain how each class works and evaluate their general utility in the management of UC and Crohn's.

[07:25]

I am also going to discuss some of the risk factors that come with each of these treatment classes.³ Knowing what adverse events, or AEs, to expect with IBD therapeutics is essential for the optimal treatment of patients.¹⁴ Please note, this overview is intended to be used in combination with your clinical assessment and latest guidelines to facilitate decisions regarding disease management plans.

Let's take a closer look at 5-ASAs. They work by blocking production of prostaglandins and leukotrienes, which affect the inflammatory cascade.³

The ACG guidelines endorse the use of 5-ASA for certain patients with UC and Crohn’s.^1,2 The choice of specific 5-ASA formulation and dosing regimen can be tailored to individual patient factors and disease severity.¹

[08:22]

AEs in this class can include nausea, dyspepsia, and headache. More serious AEs may include hemolytic anemia, agranulocytosis, and rarely, hepatitis, pneumonitis, myocarditis, and acute interstitial nephritis.³

Additionally, with certain formulations of aminosalicylates, oligospermia and infertility may occur, which can be reversed with treatment withdrawal.¹⁶

Based on its mechanism of action and safety profile, it may be appropriate for patients on aminosalicylates to consider taking folate supplements and undergo liver testing, complete blood count, and periodic renal function tests.³ Regarding renal function, it should be stated that although nephrotoxicity is a rare drug complication associated with aminosalicylates therapy, end-stage kidney failure is a prominent concern, therefore monitoring kidney function is critical.^17,18

[09:25]

The next class, corticosteroids, act as anti-inflammatories by inhibiting the production of proinflammatory cytokines like interleukin (IL)-1β and TNFα, while also reducing the production of immunomodulatory cytokines.⁹ Corticosteroids are available in several formulations and different methods of administration depending on the clinical setting.^1,2

Now, let’s discuss the guideline for the administration of corticosteroids in patients with IBD.

The ACG guidelines recommend the use of corticosteroids for inducing remission in certain patients with UC who fail to respond or are intolerant to 5-ASA therapy, based on disease severity and presentation.¹ In certain patients with Crohn’s, the ACG guidelines recommend the use of corticosteroids for induction of symptomatic remission. The ACG guidelines suggest primarily using corticosteroids for treating flares in Crohn’s.² Since corticosteroids may not consistently achieve mucosal healing, they can be used as bridge therapy for symptom control until other agents become effective.

[10:45]

Corticosteroids may offer patients short-term symptomatic relief.² However, the ACG guidelines recommend against systemic corticosteroids for maintenance of remission due to lack of efficacy in patients with UC and inability to achieve endoscopic healing in patients with Crohn’s.^1,2 The British Society of Gastroenterology guidelines provide additional context around steroid use.¹⁶ Use of corticosteroids may lead to dependency in patients (which is characterized by an inability to taper off this class within three months without recurrence of symptoms).¹⁸ There are potential side effects and possible complications with corticosteroid use.^1,19

[11:31]

AEs associated with short-term use of high doses of corticosteroids include hyperglycemia, hypertension, insomnia, hyperactivity, acute psychotic episodes, weight gain, cataracts, peptic ulcer disease, and osteoporosis.³  Long-term use is not recommended by ACG guidelines, and patients with prolonged exposure to corticosteroids may be subject to serious AEs such as bone loss and increased rate of infection.^1,2,18

Patients should be monitored throughout treatment to help identify and manage potential risks associated with corticosteroid use. Monitoring may involve assessing vitamin D and calcium levels, as well as hepatic function, especially in patients with chronic liver disease.³ Additionally, monitoring for signs of corticosteroid-related adverse effects such as osteoporosis, hypertension, and hyperglycemia is crucial.²

[12:33]

Immunomodulators modify the activity of the immune system, in turn, decreasing the inflammatory response.²⁰

Immunomodulators can play a role in maintenance therapy.^1,2 Importantly, immunomodulators can potentially reduce the need for prolonged corticosteroid use. Consequently, they are commonly used to sustain remission following induction therapy with corticosteroids.²¹

According to the UC and CD ACG guidelines, once remission has been induced, immunomodulators are recommended for maintenance therapy, taking into account disease severity and presentation.^1,2

When utilizing immunomodulators, commonly reported AEs may include nausea, vomiting, malaise, pancreatitis, high fever, hepatotoxicity, lymphoma, nonmelanoma skin cancers, myelosuppression, pulmonary toxicity, nephrotoxicity and asymptomatic liver test abnormalities.³

[13:40]

Thiopurine methyltransferase (or TPMT) testing is used to assess TPMT enzymatic activity.¹⁶ Prior to initiating certain immunomodulators, TPMT testing should be completed to identify patients at risk for complications and to help guide dosing.^22,23 TPMT testing can identify patients at a higher risk for thiopurine-induced leukopenia.²³

For adult IBD patients starting certain immunomodulators, the American Gastroenterological Association (or AGA) suggests routine TPMT testing to guide dosing and laboratory monitoring including complete blood count, regardless of TPMT results.²⁴

[14:33]

For patients initiating immunomodulators, it is recommended that all patients have routine lab tests inclusive of a complete blood count, urea and electrolytes, and liver function tests.^3,16

In addition, considering the increased risk of nonmelanoma skin cancer in patients with IBD being treated with certain immunomodulators, patients should be advised to regularly use sunscreen during sun exposure and have annual skin exams by their healthcare provider.²⁵

Consistent with the ACG guidelines, when prescribing certain immunomodulators to women of childbearing age with Crohn’s, highly effective contraception should be utilized.² Additionally, men taking certain immunomodulators for Crohn’s should receive counseling to avoid conceiving while taking the immunomodulator and for three months after cessation, due to concerns about potential impacts on spermatogenesis and teratogenicity.

[15:39]

At this point, we've provided an overview of safety considerations and monitoring of conventional IBD treatments. Now, let’s explore the nature of IBD. Both Crohn’s and UC are chronic diseases that can lead to complications if not properly managed.^1,2,26

Now, let’s start with Crohn’s. Even when patients on treatment feel well, they may have underlying inflammation, illustrated by the teal line in the graph shown here.^27-28 Studies have demonstrated that this persistent underlying inflammation places patients with Crohn’s at risk for disease-related complications represented by the blue line on the graph.^26-28

[16:23]

And among patients with UC, there is a limited body of evidence that demonstrated that uncontrolled disease activity is associated with impaired gastrointestinal functioning and structural damage.²⁹ Further research – including prospective, randomized clinical trials – is needed to determine if early therapeutic intervention in UC can modify the course of disease.

Careful monitoring can help healthcare providers know if their patients with IBD are improving and determine if the current treatment may need to be changed or further optimized.⁴

Now, let's shift our focus to the International Organization for the Study of IBD (or IOIBD) Selecting Therapeutic Targets in Inflammatory Bowel Disease (or STRIDE-II) recommendations, which focuses on attempts to modify disease progression and include a treat-to-target algorithm for clinical practice.^4,5

[17:23]

Within the treat-to-target framework, the overarching goal is to achieve long-term treatment targets, not just the intermediate targets.⁵ This can be done by conducting regular disease activity assessments to ensure appropriate therapy choices until long-term targets are achieved. Monitoring can allow the optimization of existing treatment or switching to a different one.

Treatment targets for a treat-to-target approach can be further categorized based on the length of treatment, some of which are included here.^4,5

Treatment targets for the intermediate term encompass achieving clinical remission and returning inflammatory biomarkers (CRP and fecal calprotectin) to normal levels for IBD.⁵

[18:14]

Long-term targets involve achieving endoscopic healing, restoring health-related quality of life to normal levels, and reduction in disability.⁵

Taking into account patients' clinical and historical characteristics, adjustments to the treatment plan can be made regularly if the treatment target is not achieved. Patient involvement in treatment decisions and planning is also a crucial component of a treat-to-target strategy.⁵

In summary, IBD is a chronic, progressive disease that can lead to serious complications, and therefore requires effective management.⁶

[18:56]

The IBD treatment landscape has evolved significantly with advances in molecular biology and our understanding of immunologic pathway in IBD, offering multiple options tailored to disease severity and presentation.^7,9-11,30

Conventional treatments for IBD include three drug classes, aminosalicylates, corticosteroids, and immunomodulators. Each of these classes has specific safety and monitoring needs that should be considered when personalizing therapy.^2,3,17

A treat-to-target approach involving frequent disease activity monitoring and treatment optimization to achieve long-term targets can be used for the management of IBD.⁵

[19:44]

Thank you for your interest and spending some time with IBDIQ today to help adapt to the evolving care needs of all patients with IBD.