Inflammatory Bowel Disease: An Autoimmune Conundrum

Inflammatory Bowel Disease: An Autoimmune Conundrum
Assessing Traditional and Modern Treatment Paths, and How to Look Forward

by CT Heltzel

Introduction

In Western society, people’s immune systems are becoming increasingly unstable, and their guts more sensitive. A major contributor to this is the rising number of people in the world who suffer from Inflammatory Bowel Disease (IBD). An estimated 1-1.3 million people in the US live with IBD, with as many as 70,000 new cases every year. IBD refers to a group of several autoimmune conditions that affect the colon or entire gastrointestinal tract. The two major classifications of IBD are Crohn’s Disease (CD) and Ulcerative Colitis (UC). Physicians diagnose a comparatively small portion of IBD patients with various types of “indeterminate” colitis. Both CD and UC present similar symptoms resulting from an overactive immune response in the GI tract, and commonly require similar medications for treatment. However, significant differences exist between the conditions that both physicians and patients must take into account when deciding upon treatment. Expressed symptoms specific to UC and CD create a need for alterations and selectivity to the types of inflammation ameliorating drugs patients decide to use. Modern medical treatments of IBD vary widely in approach to relieving inflammatory symptoms. Many of these treatments successfully relieve patients of their symptoms, often to the point of total remission. Despite this, nearly 70% of CD patients and 35% of UC patients will require major surgery after diagnosis¹. Further, the medications required to treat IBD often cause dangerous side effects.

People with the condition are often on long term regimens of steroids and immunosuppressive biologics. In accordance with this, medical costs skyrocket and biologics have shot up to the top of the drug market. This is indicative of the impact autoimmunity is having on the US population. Millions of people pay extreme amounts to manage symptoms, but are never truly healthy. IBD is an emergent disease that is increasingly more threatening to population health in the US and other highly developed nations by forcing large groups of people to live immunocompromised and chronically ill. Fully understanding the current state of IBD research and treatments requires thorough investigation of several key subjects. Immune pathways and pathogenesis of the disease, modern treatments, and current research should be analyzed.

Pathobiology and Immunological Mechanisms

Among the many issues associated with IBD diagnosis and treatment is the lack of a primary source of known pathogenesis. Like many autoimmune conditions, IBD is described as a multifactorial disease, having several potential contributing actors and no easily recognized, common origin. These factors are broadly categorized as genetic predisposition, environmental triggers, and immune system disruption. Population studies demonstrate many common characteristics between people who have IBD, but they are not consistent as people may have one or a combination of many of these factors while maintaining similar or differentially severe pathogenicity as other patients. Examples of these factors include intestinal microbiome compositions, genetic mutations, lifestyle choices like smoking, or disease triggered after infection or injury.

Patients with active IBD show greater infiltration and activation of innate (e.g., macrophages) and adaptive (i.e., B and T cells) immune cells in the intestinal mucosa. The intestinal mucosa consists of the top epithelial layer of cells, or intestinal epithelial cells (IEC), in the gastrointestinal tract. Hyperactivity of immune cells causes heightened production and recruitment of more inflammatory agents in the mucosa. Proteins that signal immune cells to react in various ways, referred to as cytokines, represent the most relevant agents causing inflammatory proliferation. Specific cytokines of interest include tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ), and cytokines associated with the interleukin-23—T_h17 pathway². These cytokines and cytokine receptors associate with T-cells via secretion or expression on the cell membrane. IBD research and treatment focus primarily on modulation of CD4⁺ T-cells, or helper T-cells (T_h). Cytokine receptors can bind to various biological subunits and activate the differentiation of naïve (unactivated) CD4⁺ T-cells into several sub-types of helper T-cells. Differentiation into specific T_h cells depends n activation by respectively associated interleukins (IL), cytokines that foster growth and differentiation of T-cells. Dysregulation of CD4⁺ T-cell differentiation into T_h1, T_h2 and T_h17 holds a heavy implication in the pathogenesis of IBD³. Current research and treatment focuses heavily on the function of these immune cells as a potential route for therapeutic target discovery.

Modern medical treatments for IBD vary widely in mechanisms of action and biological targets. In essence, certain medications perform more effectively for ther CD or UC and for different severities and locations of disease symptoms. 5-Aminosalicylates (5-ASA), for example, provide greater symptom amelioration for UC since the medication mostly effects the colon. 5-ASA binds and activates the anti-inflammatory receptor Peroxisome proliferator-activated receptor-γ (PPARγ) in colon-based IECs⁴. Figure 1 highlights the differences between the diseases relevant to treatment.

The main types of drugs used to reduce IBD symptoms in current treatments fall under a few specific categories. From least to most extreme, physicians and researchers commonly group treatments as 5-aminosalicylates (5-ASA), corticosteroids, immunomodulators, or biologics. Physicians regularly prescribe all of these medications, sometimes in a combination treatment including more than one. However, physicians must balance medication effectiveness with harmful side effects. The balance between the two fuels a controversial argument in the scientific community: which treatment path best leads to long-term remission with the lowest potential for negative side-effects? The treatment paths in question for IBD generally fall under two schemes known as “Step-up” and “Top-down”⁵.

The former represents the traditional approach in which treatment uses weaker medications followed by harsher medication in accordance with increasing symptom severity. Top-down involves first utilizing the most powerful immunosuppressive drugs, such as biologics and immunomodulators, to eliminate symptoms quickly. Subsequently, physicians treat with weaker medicines as the patient moves towards remission⁶. The top-down approach becomes increasingly popular as more patients see positive results from use of biologics. However, many physicians and scientists are not supportive of such an approach, seeing the dangers of immune system suppression as an unethical first-line of defense. The most common immunosuppressive biologics commercially available include anti-TNFα antibodies, such as infliximab (Remicade^®) or adalimumab (Humira^®). These antibodies locate and bind to the TNFα cytokine and inhibit its activity⁷. This approach provides effective amelioration of IBD symptoms since TNFα is greatly overexpressed. However, lowering function of this cytokine lowers overall immune function and T-cell development which can be unhealthy and leads to potential infections.

Biological Target and Drug Efficacy

The uncertainty towards a superior therapeutic treatment method within the scientific community suggests significant room for innovation in the realm of IBD medications. Deciding on what constitutes a high efficacy biological target forms the first major hurdle in the research process. Measurability of the target in question can make pursuing research either plausible or unlikely very early on. Time and expenses limit the necessary devices and techniques at a laboratory’s disposal to measure a potential target, as well as the feasibility of measuring it based on biological and chemical characteristics. Beyond financial and experimental obstacles, the most important criteria relate to biological function. Specificity of a target to the disease process probably counts as a main feature of significance towards efficacy. Preferably, the target is unique to the condition’s mode of action and has a potent effect on symptoms without unwanted inhibition of other physiological processes. A target proximal to symptom initiation holds a similar importance to specificity. Proximity refers to closeness to disease related symptom initiation. Affecting the target hopefully does not affect other, possibly unrelated, processes prior to symptom initiation in the inflammatory cascade. Another scenario for good proximity involves prevention of symptoms, rather than clearing the aftermath. For the purposes of IBD treatment, a target that has high systemic expression instead of local expression to one part of the GI tract can be of great interest to researchers. Some targets fail to be useful, as they do not have great presence in all possible areas of inflammation.

The types of compounds composing drugs used to treat inflammation are also relevant to the quality of a treatment. The difference between a small molecule and large molecule drug can make a great difference in the comfort of a patient. Currently, anti-TNF-α biologics represent the most potent drugs on the market. These antibody-based medications are large molecules and patients apply them via injection/infusion. Small molecule drugs commonly utilize oral delivery, a preferable method for most patients. For the sake of easy application to the patient, a small molecule with potent effects on inflammation makes for a desirable compound to research. Most importantly, a drug should have low toxicity. Additional short or long-term side effects from therapy essentially defeat the purpose of researching a new IBD drug. The negative side effects researchers observe in preclinical trials root out potential drugs early on.

Current IBD Treatments

As described previously, physicians prescribe several types of medications to treat IBD. Each classification differs greatly in biochemical mechanism and there are many drugs on the market within these classifications for physicians to utilize. A patient with severe IBD symptoms commonly begins treatment with corticosteroids. A typical beginning of treatment shared by many IBD patients involves use of the drug Prednisone. Corticosteroids such as Prednisone bind to glucocorticoid receptors and proceed to downregulate gene transcription for various inflammatory agents⁸. This corticosteroid has uses in many conditions outside IBD and thus has the negative attribute of many side effects unrelated to inflammatory relief. Physicians avoid use of prednisone and other steroids as a long-term solution. Once patients achieve short-term symptom relief by use of steroids, physicians attempt design a new treatment regimen for long-term stability.

Physicians commonly prescribe 5-ASA as a next step after steroids, or possibly before if symptoms start out mild. This progression falls in line with the top-down treatment path. As stated earlier, 5-ASA acts as a ligand, binding to PPARγ and activating its anti-inflammatory effects in IECs. 5-ASA drugs commonly prescribed by physicians include Asacol and Pentasa. These drugs act locally in the gut, which make them very effective for UC and mild-moderate cases of CD. The local predominance allows for minimal systemic side effects, leaving the most common ones related to digestive organs. Such side effects could include diarrhea, flatulence, or cramping. Despite minimal side effects, the inability of 5-ASA to cause potent anti-inflammatory effects outside colonic IECs makes these drugs ineffective in severe cases of CD. A preemptive colonoscopy allows physicians to find areas of inflammation local to the colon. Observing severe inflammation outside the colon may cause a physician to bypass 5-ASA treatment.

Chemical immunomodulators cause potent immunosuppressant effects to reduce inflammation, often in relief of or in conjunction with 5-ASA usage. Thiopurines such as mercaptopurine (6-MP) and azathioprine (AZA) act as small molecule immunomodulators that suppress the immune system much like biologics. They are used for more moderate IBD symptoms and have less potent effects⁹. 6-MP functions as a competitive antagonist of GTP, binding to a small GTPase protein, Rac1. Binding to Rac1 suppresses activation of the protein in gut CD4+ T-cells, and causes cell apoptosis¹⁰. This reduction of CD4+ T-cell activity creates significant anti-inflammatory effects throughout the GI tract. However, thiopurines have many faults outside of immunosuppression that make them ineffective as a final treatment for many patients. Not all sever cases of IBD appear to associate with Rac1 based T-cell proliferation, often causing patients to use biologics as a powerful alternative.

Physicians prescribe biologics such as Remicade (infliximab), Humira (adalimumab), and Cimzia (certolizumab) in cases of severe CD, often when all other medications fail to relieve symptoms. All the biologic medicines above consist of monoclonal antibodies that work as TNFα antagonists. The antibodies bind TNFα and inhibit its ability to signal, lowering development and recruitment of various inflammatory agents. With the FDA approval of Humira as a CD medication in 2007 and for UC in 2012, biologics will continue to rise to the top of the IBD drug market¹¹. Negative side effects such as risk of infections due to high immunosuppression and the possibility of increased lymphoma occurrence (uncommon in short term use) present significant issues with anti-TNFα biologics¹². Despite this, the usual high remission rates using these medications often outweigh any negatives for IBD patients. Non-TNF based biologics such as ustekinumab (Stelara) and vedolizumab (Entyvio) have hit the market in recent years, as well, and provide potential alternatives in the realm of powerful large molecule drugs. Stelara binds to the p-40 subunit shared by the IL-12 and IL-23 cytokines. This keeps p-40 from binding to these cytokines, making it unable to send a signal for T-cells to differentiate into inflammation promoting T_h17 cells¹³. Entyvio blocks lymphocyte trafficking and adhesion in the gut through its recognition and blocking of the α4-β7 integrin glycoprotein on B and T-cells¹⁴. This does not appear to cause systemic immune suppression in the rest of the body, making the drug a potential safe alternative to anti-TNFα antibodies. Still, immunosuppression in general is an unhealthy practice, leaving significant room for innovation in future IBD treatments.

Because of the aforementioned success of biologics in diminishing the symptoms of people with IBD, as well as millions of others suffering from autoimmunity, these drugs are more and more likely to be prescribed and have risen to top grossing positions in the pharmaceutical market¹⁵. With this comes the implication that millions of people are also being critically immunocompromised over significant periods of time, causing dysregulation of the body’s innate bio-molecular mechanisms. Such blanket treatments could be viewed as unethical on that large of a scale without looking forward to new methods. But what could be done to better regulate this system of treatment? How can we better meet patient’s needs? One answer is using precision medicine as a path towards pinpointing disease pathogenesis on a person by person basis. The concept of precision medicine utilizes multiple avenues of modern clinical research tools to personalize the treatment path for patients. This method seeks to combine pharmaceuticals, nutraceuticals, bioinformatics/genomics, and microbiology to understand and approach the driving force behind a patient’s condition¹⁶. IBD is one of the most practical areas to start using precision medicine because of its multifactorial nature. Computational models of the intestinal immune response can be developed that use patient data on microbiome and immune cells and molecules as a baseline and are calibrated to an individual using their specific bacteria, mutations and disease pathology as input parameters. The outputs of such a model would inform clinicians on the best types and amounts of therapy needed to return someone to a healthy immunological baseline. In order to do this, however, massive epidemiological studies must continue to be conducted on willing patients through public health initiatives that involve numerous practitioners, hospitals, and testing sites. Using the collected data, researchers will be more capable of creating refined and accurate models of disease that can be turned into a reliable clinical tool¹⁷.  This data will also be critical in determining what initiatives must be put forward to focus on preventive measures. Big epidemiological data can lead to pathological origin trails that may inform what needs to be regulated or removed from typical human consumption. It is likely this will involve limitations on regulations on human exposures to antibiotics, food pesticides, preservatives, and other chemicals that we come into contact with on a daily basis that could be brought to light via connections made in the computational model of disease. If bioinformatics continues to progress as quickly as computational systems typically do in modern times, there may yet be hope for a world unburdened by chronic inflammatory bowel disease in the near future.

Autoimmune conditions like IBD remain difficult to control because of the high complexity of human immunity. Diagnosis rates for the condition grow yearly, and more individual must learn to manage crippling intestinal damage or depleted immune systems. Current medicines provide effectiveness relief for many patients, but have the potential to be much safer. For this reason, it is important that research on new therapeutic targets and treatment paths for IBD treatment continue to develop.

1. Maggiori, L.; Panis, Y., Surgical management of IBD–from an open to a laparoscopic approach. Nature reviews. Gastroenterology & hepatology 2013, 10 (5), 297-306.
2. Abraham, C.; Cho, J. H., Inflammatory Bowel Disease. New England Journal of Medicine 2009, 361 (21), 2066-2078.
3. Abraham, C.; Medzhitov, R., Interactions Between the Host Innate Immune System and Microbes in Inflammatory Bowel Disease. Gastroenterology 2011, 140 (6), 1729-1737.
4. Iacucci, M.; de Silva, S.; Ghosh, S., Mesalazine in inflammatory bowel disease: a trendy topic once again? Canadian journal of gastroenterology = Journal canadien de gastroenterologie 2010, 24 (2), 127-33.
5. Hanauer, S. B., Positioning biologic agents in the treatment of Crohn’s disease. Inflammatory bowel diseases 2009, 15 (10), 1570-82.
6. Blonski, W.; Buchner, A. M.; Lichtenstein, G. R., Inflammatory bowel disease therapy: current state-of-the-art. Curr. Opin. Gastroenterol. 2011, 27 (4), 346-357.
7. Pollack, P. F.; Hoffman, R. S.; Renz, C., Uses and compositions for treatment of Crohn’s desease. Google Patents: 2013.
8. Emilie, D.; Etienne, S., [Glucocorticoids: mode of action and pharmacokinetics]. La Revue du praticien 1990, 40 (6), 511-7.
9. Goracinova, K.; Glavas-Dodov, M.; Simonoska-Crcarevska, M.; Geskovski, N. In Drug targeting in IBD treatment-existing and new approaches, InTech: 2012; pp 301-332.
10. Neurath, M., Thiopurines in IBD: What Is Their Mechanism of Action? Gastroenterology & hepatology 2010, 6 (7), 435.
11. FDA FDA approves Humira to treat ulcerative colitis. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm321650.htm.
12. Williams, C. J. M.; Peyrin-Biroulet, L.; Ford, A. C., Systematic review with meta-analysis: malignancies with anti-tumour necrosis factor-alpha therapy in inflammatory bowel disease. Aliment. Pharmacol. Ther. 2014, 39 (5), 447-458.
13. Frleta, M.; Siebert, S.; McInnes, I. B., The Interleukin-17 Pathway in Psoriasis and Psoriatic Arthritis: Disease Pathogenesis and Possibilities of Treatment. Curr. Rheumatol. Rep. 2014, 16 (4), 8.
14. Ghosh, N.; Chaki, R.; Mandal, S. C., Inhibition of Selective Adhesion Molecules in Treatment of Inflammatory Bowel Disease. Int. Rev. Immunol. 2012, 31 (5), 410-427.
15. FDA FDA approves Humira to treat ulcerative colitis. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm321650.htm.
16. NIH, All of Us Research Program. https://www.nih.gov/research-training/allofus-research-program
17. MIEP, Computational Models. http://modelingimmunity.org/computational-models