Inflammatory Bowel Disease: Crohn's Disease and its Pharmacological Therapies
This week, I would like to discuss a difficult disease for any adolescent or young adult to be diagnosed with and manage. Chron's disease is often diagnosed in a person's teenage years or early adulthood and is considered an autoimmune disease. It can be very debilitating with frequent hospitalizations and radical surgeries.
My purpose today is to educate a little bit on the disease and the nasty drugs that are required to manage it. If you or someone you know has it, I hope this is an easy synopsis for you to refer back to. If you knew nothing about it before reading this, then I hope I can raise some awareness for those who suffer from it on a daily basis.
The term "Inflammatory Bowel Disease (IBD)" actually refers to two different inflammatory bowel diseases: ulcerative colitis (UC) and Chron's Disease (CD) but we are going to focus on CD today although many of the treatments are very similar.
The true cause of CD still remains somewhat a mystery but both genetic and environmental components have been implicated in it's development. It does tend to happen more often in families with history of some form of IBD or another.
Chron's Disease can affect any section of the gastrointestinal tract from the esophagus to the rectum, but it most often affects the ileum or colon. It can also exhibit "skip patterns" where there will be an injured section followed by an untouched area that is followed by yet another injured section of bowel. The inflammation can also penetrate through the entirety of the bowel wall whereas UC typically does not injure as deeply through the membrane.
The typical presenting symptoms of a patient that has never been diagnosed with CD are generally: diarrhea (can be bloody or not), abdominal pain, weight loss, perianal lesions, and signs of malnutrition. These patients may also present with or have previously been diagnosed with other issues that seem non-related to the bowel such as arthritis, erythema nodosum, pyoderma gangrenosum, uveitis, episcleritis, and primary sclerosing cholangitis. Essentially, all of those long names refer to inflammatory processes of other parts of the body that may be related to what has triggered the Chron's disease.
Once it has been determined that the current presenting symptoms are indeed Chron's disease, it is very important to determine the appropriate treatment plan.
The main goals of treatment are:
- To suppress acute inflammation
- Improve patient symptoms and quality of life
- Avoid/minimize toxicities
- Prevent further complications
- Drug therapies should focus on inducing and maintaining remission for the long-term
The main drug classes for treatment include:
- Aminosalicylates
- Corticosteroids
- Immunomodulators
- Biologic Therapies (Anti-Tumor Necrosis Factor alpha)
**All drug classes and routes are chosen based on exactly where the Chron's disease is in each patient and its severity. Some information may vary on a case by case basis.
Aminosalicylates are on the most common agents used to fight CD and the main drug within the class that is utilized is sulfasalazine. The class also includes azulfidine, asacol, delzicol, pentasa, dipentum, colazal, lialda, and apriso. However the only two frequently used for CD are sulfasalazine and Colazal. These drugs work to deliver mesalamine (5-aminosalicylate) to the GI tract. It is activated in the colon by bacteria cleaving to the diazo bondand releasing the mesalamine. Sulfasalazine should not be used in patients with sulfa allergies and the common adverse effects are diarrhea, nausea, headache, and abdominal pain. The main difference between sulfasalazine and the newer drug Colazal is that Colazal actually does not contain the sulfa group and is safe for those with sulfa allergies. The objective of the mesalamine is to block the production of prostaglandins and leukotrienes, reducing inflammation in the area with the intent of inducing remission.
Corticosteroids are much stronger anti-inflammatories with much greater impact and even worse side effects. They are a double-edged sword in the management of Chron's Disease. They are extremely useful in flair ups and remissions because they work very quickly and effectively to reduce inflammation. They also can be used in patients that have not responded to aminosalicylates. Corticosteroids also can be used orally, parenterally, and topically to enhance the therapeutic response.
There are two types of corticosteroids: glucocorticoids and mineralocorticoids. Glucocorticoids work with glucocorticoid receptors all over the body while mineralocorticoid receptors are confined mostly to the kidneys, colon, salivary glands, and sweat glands. Corticosteroids all work towards the same effect of reducing inflammation and part of why their side effect list is so long is because they have systemic effects and are not very good at being specific. Steroid medications all work about the same, just in different dosage amounts.
Budesonide (Entocort) is one of the first-line corticosteroids most frequently employed for mild to moderate CD, especially when the main source of inflammation is in the ileum and ascending colon.
Oral prednisone, methylprednisolone, and hydrocortisone also may be prescribed in acute attacks. The greatest difference between the aforementioned steroids is that they get stronger and stronger. The strength of the steroid and its route are the two main differences between any two steroids, otherwise their mechanisms are the same.
Corticosteroids work by binding to specific intracellular cytoplasmic receptors in target tissues, blocking phospolipase A2 which allows the production of arachidonic acid which is a vital ingredient of inflammation mediator production. With that being blocked, there can be no inflammation in the targeted tissues. Topical steroids are also available in suppository and enema form with disease in a more distal location that can be reached better that way.
If the inflammation has progressed so severely that a fistulae has formed, corticosteroids are typically ineffective and not utilized.
The list of side effects, both with short term and long term use of corticosteroids is very lengthy and involved. It includes but is not limited to hypertension, poor glucose control, lipodystrophy, osteroporosis, immune suppression, cataract formation, and even psychiatric disturbances. These drugs really should not be used long term if it can be avoided.
Immunomodulators are used for their immunosuppresssive effects and are used as maintenance therapy in Chron's Disease as well as many other inflammatory diseases (such as Rheumatoid Arthritis) once the initial attack is controlled. They are typically added to the drug regimen after a patient has become either resistant to or entirely too dependent on corticosteroids because these drugs are not always very friendly either. The main ones utilized in CD are azathioprine, 6-Mercaptopurine (6-MP), and methotrexate. These three drugs also often end up utilized in combination therapy with the biologic therapy drugs we will talk about in a moment.
Oral azathioprine is the most frequently used of the three drugs and is typically started after the remission that is induced by short-term, high-dose corticosteroids. It is also the pro-drug form of 6-MP so you don't often see 6-MP prescribed very often, but rather azathioprine.
Azathioprine actually becomes incorporated into DNA by being converted into 6-thiouric acid, 6-methyl-MP and 6-thioguanine. One incorporated into the replicating DNA, azathioprine can block the construction of purine synthesis which keeps interleukin-2 from being produced, thereby reducing inflammation.
Methotrexate is a folate antagonist that is also used solely as a maintenance drug. It also has some DNA-inhibition effects where it blocks IL-1 and reduces neutrophil chemotaxis among other mechanisms of actions that inhibit other folate dependent enzymes which effects DNA synthesis at the site of inflammation.
All immunomodulators require close monitoring of toxicity, complete blood counts, liver transaminases, and chest x-rays. A baseline of each of those should be established previous to beginning therapy. An important side note about methotrexate is that it is indeed teratogenic so reliable contraceptive methods should be used in women of child-bearing age. These immunomodulator drugs are serious drugs with very serious immunosupression. Azathioprine and methotrexate are both used in the treatment of certain types of cancers as well, if that emphasizes it further for you. These are not drugs to mess around with.
Biologic therapies (or Tumor Necrosis Factor-Alpha Antagonists) are often used on conjunction with immunomodulators such as the combination of azathioprine and infliximab. These drugs can be used both to control acute CD and to maintain remission. All of these drugs specifically work to antagonize tumor necrosis factor-alpha and the main ones used are infliximab, adalimumab, certolizumab, and golimumab and are used to treat patients with moderate to severe CD. All of these medications have to be given parenterally and are very, very expensive. They also all can be used after fistulaes have formed, unlike the other drug categories. Antibodies have been shown to form against infliximab especially, rendering it ineffective over time.
Infliximab and Adalimumab are the two most common anti-TNFs used in the management of Chron's Disease while certolizumab and golimumab are used more often in Rheumatoid Arthritis and Psoriatic Arthritis.
Infliximab (Remicade) must be given over 1-2 hours via IV every 8 weeks and costs about $27,000/year. Remicade works by binding to the excess TNF-alpha floating around in the body of someone with Crohn's Disease. When it binds to TNF-alpha, it blocks TNF-alpha's pro-inflammatory actions which improves the symptoms of CD caused by inflammation. Because TNF-alpha is also important in basic immunity, this drug also can cause immunosuppression in patients receiving this therapy.
Adalimumab (or Humira, the drug you see in all of those commercials) can be given via a subcutaneous injection that you can do at home every 2 weeks. It also is the better deal at $20,000/year, you can save an average of $7,000 each year. Humira works in the same way as Remicade, blocking TNF-alpha throughout the body. However, it has one more additional anti-inflammatory factor that gives it a slight edge above Remicade. It doesn't just bind to free TNF-alpha but it also can augment TNF-alpha that is already membrane-bound giving it a stronger anti-inflammatory effect.
These drugs carry various serious side effects with the greatest one being the potential for severe immunosuppression and it is important to get baseline labs and images prior to beginning therapy to ensure the patient doesn't already have a serious illness such as tuberculosis.
If you or a loved one have recently been diagnosed with Chron's Disease, it is very important to tell your doctor of any other medications you are prescribed and even those that you take frequently but not daily. When many of the aforementioned drugs are taken in conjunction with other drugs such as narcotics and anticholinergics, it can cause a life threatening problem called toxic megacolon. It is a direct reaction to the combination of these strong medications and decreased bowel motility and is a medical emergency.
In summary, this is what the progression of the drugs are:
- Acute phase and then to induce remission: corticosteroids
- Management of mild to moderate CD: aminosalycylates
- Management of moderate to severe CD: Immunomodulators and biologic therapies (anti-TNFalphas)
My purpose today is to educate a little bit on the disease and the nasty drugs that are required to manage it. If you or someone you know has it, I hope this is an easy synopsis for you to refer back to. If you knew nothing about it before reading this, then I hope I can raise some awareness for those who suffer from it on a daily basis.
The term "Inflammatory Bowel Disease (IBD)" actually refers to two different inflammatory bowel diseases: ulcerative colitis (UC) and Chron's Disease (CD) but we are going to focus on CD today although many of the treatments are very similar.
The true cause of CD still remains somewhat a mystery but both genetic and environmental components have been implicated in it's development. It does tend to happen more often in families with history of some form of IBD or another.
Chron's Disease can affect any section of the gastrointestinal tract from the esophagus to the rectum, but it most often affects the ileum or colon. It can also exhibit "skip patterns" where there will be an injured section followed by an untouched area that is followed by yet another injured section of bowel. The inflammation can also penetrate through the entirety of the bowel wall whereas UC typically does not injure as deeply through the membrane.
The typical presenting symptoms of a patient that has never been diagnosed with CD are generally: diarrhea (can be bloody or not), abdominal pain, weight loss, perianal lesions, and signs of malnutrition. These patients may also present with or have previously been diagnosed with other issues that seem non-related to the bowel such as arthritis, erythema nodosum, pyoderma gangrenosum, uveitis, episcleritis, and primary sclerosing cholangitis. Essentially, all of those long names refer to inflammatory processes of other parts of the body that may be related to what has triggered the Chron's disease.
Once it has been determined that the current presenting symptoms are indeed Chron's disease, it is very important to determine the appropriate treatment plan.
The main goals of treatment are:
- To suppress acute inflammation
- Improve patient symptoms and quality of life
- Avoid/minimize toxicities
- Prevent further complications
- Drug therapies should focus on inducing and maintaining remission for the long-term
The main drug classes for treatment include:
- Aminosalicylates
- Corticosteroids
- Immunomodulators
- Biologic Therapies (Anti-Tumor Necrosis Factor alpha)
**All drug classes and routes are chosen based on exactly where the Chron's disease is in each patient and its severity. Some information may vary on a case by case basis.
Aminosalicylates are on the most common agents used to fight CD and the main drug within the class that is utilized is sulfasalazine. The class also includes azulfidine, asacol, delzicol, pentasa, dipentum, colazal, lialda, and apriso. However the only two frequently used for CD are sulfasalazine and Colazal. These drugs work to deliver mesalamine (5-aminosalicylate) to the GI tract. It is activated in the colon by bacteria cleaving to the diazo bondand releasing the mesalamine. Sulfasalazine should not be used in patients with sulfa allergies and the common adverse effects are diarrhea, nausea, headache, and abdominal pain. The main difference between sulfasalazine and the newer drug Colazal is that Colazal actually does not contain the sulfa group and is safe for those with sulfa allergies. The objective of the mesalamine is to block the production of prostaglandins and leukotrienes, reducing inflammation in the area with the intent of inducing remission.
Corticosteroids are much stronger anti-inflammatories with much greater impact and even worse side effects. They are a double-edged sword in the management of Chron's Disease. They are extremely useful in flair ups and remissions because they work very quickly and effectively to reduce inflammation. They also can be used in patients that have not responded to aminosalicylates. Corticosteroids also can be used orally, parenterally, and topically to enhance the therapeutic response.
There are two types of corticosteroids: glucocorticoids and mineralocorticoids. Glucocorticoids work with glucocorticoid receptors all over the body while mineralocorticoid receptors are confined mostly to the kidneys, colon, salivary glands, and sweat glands. Corticosteroids all work towards the same effect of reducing inflammation and part of why their side effect list is so long is because they have systemic effects and are not very good at being specific. Steroid medications all work about the same, just in different dosage amounts.
Budesonide (Entocort) is one of the first-line corticosteroids most frequently employed for mild to moderate CD, especially when the main source of inflammation is in the ileum and ascending colon.
Oral prednisone, methylprednisolone, and hydrocortisone also may be prescribed in acute attacks. The greatest difference between the aforementioned steroids is that they get stronger and stronger. The strength of the steroid and its route are the two main differences between any two steroids, otherwise their mechanisms are the same.
Corticosteroids work by binding to specific intracellular cytoplasmic receptors in target tissues, blocking phospolipase A2 which allows the production of arachidonic acid which is a vital ingredient of inflammation mediator production. With that being blocked, there can be no inflammation in the targeted tissues. Topical steroids are also available in suppository and enema form with disease in a more distal location that can be reached better that way.
If the inflammation has progressed so severely that a fistulae has formed, corticosteroids are typically ineffective and not utilized.
The list of side effects, both with short term and long term use of corticosteroids is very lengthy and involved. It includes but is not limited to hypertension, poor glucose control, lipodystrophy, osteroporosis, immune suppression, cataract formation, and even psychiatric disturbances. These drugs really should not be used long term if it can be avoided.
Immunomodulators are used for their immunosuppresssive effects and are used as maintenance therapy in Chron's Disease as well as many other inflammatory diseases (such as Rheumatoid Arthritis) once the initial attack is controlled. They are typically added to the drug regimen after a patient has become either resistant to or entirely too dependent on corticosteroids because these drugs are not always very friendly either. The main ones utilized in CD are azathioprine, 6-Mercaptopurine (6-MP), and methotrexate. These three drugs also often end up utilized in combination therapy with the biologic therapy drugs we will talk about in a moment.
Oral azathioprine is the most frequently used of the three drugs and is typically started after the remission that is induced by short-term, high-dose corticosteroids. It is also the pro-drug form of 6-MP so you don't often see 6-MP prescribed very often, but rather azathioprine.
Azathioprine actually becomes incorporated into DNA by being converted into 6-thiouric acid, 6-methyl-MP and 6-thioguanine. One incorporated into the replicating DNA, azathioprine can block the construction of purine synthesis which keeps interleukin-2 from being produced, thereby reducing inflammation.
Methotrexate is a folate antagonist that is also used solely as a maintenance drug. It also has some DNA-inhibition effects where it blocks IL-1 and reduces neutrophil chemotaxis among other mechanisms of actions that inhibit other folate dependent enzymes which effects DNA synthesis at the site of inflammation.
All immunomodulators require close monitoring of toxicity, complete blood counts, liver transaminases, and chest x-rays. A baseline of each of those should be established previous to beginning therapy. An important side note about methotrexate is that it is indeed teratogenic so reliable contraceptive methods should be used in women of child-bearing age. These immunomodulator drugs are serious drugs with very serious immunosupression. Azathioprine and methotrexate are both used in the treatment of certain types of cancers as well, if that emphasizes it further for you. These are not drugs to mess around with.
Biologic therapies (or Tumor Necrosis Factor-Alpha Antagonists) are often used on conjunction with immunomodulators such as the combination of azathioprine and infliximab. These drugs can be used both to control acute CD and to maintain remission. All of these drugs specifically work to antagonize tumor necrosis factor-alpha and the main ones used are infliximab, adalimumab, certolizumab, and golimumab and are used to treat patients with moderate to severe CD. All of these medications have to be given parenterally and are very, very expensive. They also all can be used after fistulaes have formed, unlike the other drug categories. Antibodies have been shown to form against infliximab especially, rendering it ineffective over time.
Infliximab and Adalimumab are the two most common anti-TNFs used in the management of Chron's Disease while certolizumab and golimumab are used more often in Rheumatoid Arthritis and Psoriatic Arthritis.
Infliximab (Remicade) must be given over 1-2 hours via IV every 8 weeks and costs about $27,000/year. Remicade works by binding to the excess TNF-alpha floating around in the body of someone with Crohn's Disease. When it binds to TNF-alpha, it blocks TNF-alpha's pro-inflammatory actions which improves the symptoms of CD caused by inflammation. Because TNF-alpha is also important in basic immunity, this drug also can cause immunosuppression in patients receiving this therapy.
Adalimumab (or Humira, the drug you see in all of those commercials) can be given via a subcutaneous injection that you can do at home every 2 weeks. It also is the better deal at $20,000/year, you can save an average of $7,000 each year. Humira works in the same way as Remicade, blocking TNF-alpha throughout the body. However, it has one more additional anti-inflammatory factor that gives it a slight edge above Remicade. It doesn't just bind to free TNF-alpha but it also can augment TNF-alpha that is already membrane-bound giving it a stronger anti-inflammatory effect.
These drugs carry various serious side effects with the greatest one being the potential for severe immunosuppression and it is important to get baseline labs and images prior to beginning therapy to ensure the patient doesn't already have a serious illness such as tuberculosis.
If you or a loved one have recently been diagnosed with Chron's Disease, it is very important to tell your doctor of any other medications you are prescribed and even those that you take frequently but not daily. When many of the aforementioned drugs are taken in conjunction with other drugs such as narcotics and anticholinergics, it can cause a life threatening problem called toxic megacolon. It is a direct reaction to the combination of these strong medications and decreased bowel motility and is a medical emergency.
In summary, this is what the progression of the drugs are:
- Acute phase and then to induce remission: corticosteroids
- Management of mild to moderate CD: aminosalycylates
- Management of moderate to severe CD: Immunomodulators and biologic therapies (anti-TNFalphas)
References:
Greenfield,
S.M., Punchard, N.A., Teare, J.P, &Thompson, R.P (2014). Review Article: The
mode of action of the aminosalicylates in inflammatory bowel disease. Alimentary Pharmacology & Therapeutics 7(4):
369-383.
How
Does Remicade Work? Remicade Influximab. Janssen
Biotech, Inc: 2017.
Prince,
J. (2015). Comparison of Available Anti-TNFa Inhibitors. Product Monographs: Humira & Remicade. URL: http://mpap.vch.ca/wp-content/uploads/sites/16/2014/08/Comparison-of-Anti-TNFs.pdf
Maltzman,
J. & Koretzky, G. (2013). Azathioprine: Old Drug, New Actions. Journal of Clinical Investigation 111(8):
1122-1124. doi:10.1172/JCI200318384
Ramamoorthy,
S. & Cidlowski, J.A. (2016). Corticosteroids: Mechanisms of Action in Health
and Disease. Rheumatic Disease Clinics of
North America 42(1): 15-31. Doi:10.1016/j.rdc.2015.08.002
Rampton,
D. S (2016). Methotrexate in Crohn’s Disease. BMJ Journals: GUT, 48(6):790-791. doi: http://dx.doi.org/10.1136/gut.48.6.790
Sutton,
S.S (2012). Naplex Review Guide. New
York: McGraw-Hill.
Whalen.
K. (2015). Lippincott Illustrated Reviews: Pharmacology, 6th ed.
Philadelphia: Wolters-Kluwer.
Nice job, Korey. This is helpful.
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