- A new pathway: Researchers identify potential treatment target for Crohn’s disease
- Living With Crohn’s Disease
- A Cure for Crohn’s Disease — How Hopeful Should We Be?
- How Close Are We to a Cure for Crohn’s Disease?
- Crohn’s Disease Treatment Options
A new pathway: Researchers identify potential treatment target for Crohn’s disease
High magnification micrograph of Crohn’s disease. Biopsy of esophagus. H&E stain. Credit: Nephron/Wikipedia
There is no cure for the more than 1.6 million people in the United States living with Crohn’s disease (CD) and its symptoms, including abdominal pain, intestinal distress and severe weight-loss. CD is a form of inflammatory bowel disease (IBD) in which the body’s own immune system attacks the gastrointestinal tract, and treatment is focused on controlling the symptoms of the disease in its acute phase and managing it in remission. But recently, researchers at Case Western Reserve University School of Medicine identified a pathway in the immune system activated in CD and which holds promise for investigating new treatments.
Fabio Cominelli, MD, professor of medicine at the School of Medicine and chief of gastroenterology at University Hospitals Cleveland Medical Center, led a three-year study, published recently in Cellular and Molecular Gastroenterology and Hepatology, focusing on the chronic inflammation that occurs in genetically susceptible individuals with CD.
Using mouse models of CD, Cominelli and his team investigated the interaction between a class of proteins called tumor necrosis factor and receptors on the surface, called Fn14. Their goal was to see how the tumor necrosis factor (or TWEAK, for Tumor Necrosis Factor-like Weak Inducer of Apoptosis) and its cell receptor, Fn14, may play a dual role of both protecting the intestine from acute and chronic inflammation characteristic in CD, and how it might also trigger it.
Scientists have been studying the TWEAK/Fn14 interaction for at least two decades to understand its role in inflammation. Cominelli and his team, however, are the first to describe this signaling complex in CD.
“During early inflammation, TWEAK/Fn14 activates to heal tissue damage,” said Cominelli. “However, during later, chronic inflammation, increased and persistent levels of Fn14 may lead to pathologic inflammation and fibrosis.”
Today’s CD treatments, such as steroids and monoclonal antibodies, may work for a while, but often cease to be effective. They also may cause hypertension, infection and the risk of birth defects in pregnant women being treated for IBD. As CD patients endure a roller-coaster ride of flare-ups, repeated hospital stays, surgeries and treatments relieved by intervals of remission, the disease becomes dramatically life-changing and emotionally stressful.
To better understand the link between TWEAK/Fn14 and chronic inflammation, the team of researchers used mice bred to develop CD-like disease, and then genetically deleted the cell-surface receptor Fn14. The mice with genetically deleted Fn14 had less severe inflammation. Those with the Fn14 receptor had chronic intestinal inflammation and scarring.
To test whether their findings in mice could be meaningful to CD in humans, the research team then used molecular diagnostics to analyze resected intestinal tissues from patients with and without IBD. The results showed significant TWEAK/Fn14 overexpression in tissue from patients with CD. Cominelli believes that blocking Fn14 pharmacologically using novel drugs and antibodies may ameliorate the inflammation and fibrosis in CD.
The study has implications for cancer treatment as well. According to Cominelli, since chronic inflammation can lead to the initiation and growth of tumors in patients with IBD, those patients are exposed to a risk of developing colorectal cancer that is directly proportional to the extent and duration of their disease.
“This research establishes the rationale for investigating innovative therapies that can improve and save lives,” Cominelli said.
Study shows TWEAK-Fn14 is drug target for cancer More information: Luca Di Martino et al, TWEAK/Fn14 Is Overexpressed in Crohn’s Disease and Mediates Experimental Ileitis by Regulating Critical Innate and Adaptive Immune Pathways, Cellular and Molecular Gastroenterology and Hepatology (2019). DOI: 10.1016/j.jcmgh.2019.05.009 Provided by Case Western Reserve University Citation: A new pathway: Researchers identify potential treatment target for Crohn’s disease (2019, August 8) retrieved 2 February 2020 from https://medicalxpress.com/news/2019-08-pathway-potential-treatment-crohn-disease.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.
Living With Crohn’s Disease
Living With Crohn’s Disease Facts
What does Crohn’s disease look like? Picture of Crohn’s Disease
- If you have Crohn’s disease, you are already aware of the many challenges you face. If your disease was only recently diagnosed or you have a loved one with the disease, you may be struggling to understand what this disease will mean to you and your family. Here are some points that may help you understand Crohn’s disease, and tips to make a plan in living with this chronic illness.
- Crohn’s disease is a chronic illness. Crohn’s disease will be a part of you for the rest of your life. Adjusting to that alone is difficult for many people. It can be very hard to accept that you will be living not only with the effects of the disease, but also with the unpredictability of disease flare-ups, limitations of your activity, frequent doctor visits, uncomfortable medical tests, and medications and their side effects.
- Crohn’s disease is a potentially serious disease. Inflammation in the digestive tract can cause serious complications such as bleeding, holes in the intestinal wall (perforation), pockets of infection (abscesses), and abnormal connections between the digestive tract and other parts of the body (fistulas). Crohn’s disease also can cause inflammation and damage to other parts of the body, such as the joints, skin, eyes, mouth, liver, and bile ducts. You may need to spend time in the hospital if you have a severe flare-up or complication.
- Nothing you did or didn’t do caused you to have Crohn’s disease. There is no evidence that diet, stress, medications, or other lifestyle factors cause Crohn’s disease. The disease seems to be caused by some trigger in susceptible people. We don’t know what makes a person susceptible, but it is probably genetic. We also don’t know what causes the triggers. It may be infection with a specific bacteria or virus.
- There are many treatment options available to manage Crohn’s disease, although there currently is no cure for the disease. The critical part of treatment is reducing inflammation, which helps to relieve the symptoms, and decrease the risk of complications in most people. Several different types of medications including anti-inflammatory medications such as corticosteroids, immunosuppressants, biologic therapies, and antibiotics are available. If one drug doesn’t work, another probably will. Surgery is another treatment option if medications do not help.
- You are not alone. About 1 million people in the United States have Crohn’s disease. There are other people who understand exactly what you are going through and want to help. A number of groups exist to educate the public and policy makers, raise funds for research, and provide support and assistance to people affected with the disease.
A Cure for Crohn’s Disease — How Hopeful Should We Be?
Right now, Dr. Naser is working with a team of researchers at RedHill Biopharma to develop an oral antibiotic that specifically targets MAP in Crohn’s patients. The pill, called RHB-104, is currently undergoing an international phase 3 (large scale) clinical trial, with results to come in September 2018. This treatment, too, has curative potential — but further trials will be needed to confirm its lasting effects.
In a presentation to RedHill’s investors, David Graham, MD, the lead investigator on RedHill’s MAP study in the United States, said that if RHB-104 successfully heals intestinal lesions caused by Crohn’s, that would likely confirm the anti-MAP hypothesis to be true.
Others in the field, however, are not quite ready to endorse the MAP theory. Skeptics challenge the identification of MAP as the lone cause of Crohn’s. They argue that the illness is too complex to have just one culprit.
Benjamin Hall, MD, a gastroenterologist in Omaha (and also a Crohn’s patient), expressed some doubts.
“We’ve heard about these kind of silver bullets before,” Dr. Hall says. “And once the research is done, the numbers usually don’t bear them out. Crohn’s is multifactorial and complicated. I don’t think we’re going to see any one single cause of it .”
Aaron Castens, the executive director of the Crohn’s and Colitis Foundation of the Midwest, echoed Hall’s caution. It’s the Foundation’s official position that MAP “may play a role in the development of Crohn’s disease as one of many different microbes that might act as a trigger for an abnormal inflammatory response,” he says, “but until more convincing scientific proof emerges, it cannot be described as a primary or the sole cause of Crohn’s disease.”
Hermon-Taylor is undeterred. “It’s true that Crohn’s disease is complex — but so was leprosy. All of these ailments are difficult to understand until we learn what causes them,” he says.
Answering the skepticism will require significant clinical results, which the professor and his organization, Crohn’s MAP Vaccine, are doggedly pursuing.
It has not been easy, because MAP is a uniquely resilient bug. Even pasteurization fails to kill it off completely, which is why people can contract it from drinking milk. It took 10 years for Herman-Taylor — and other scientists between London and Oxford University — to develop an effective vaccine against it, according to research published in PLoS One.
For all their efforts, the vaccine hasn’t attracted investment from drug makers. Instead, hopeful Crohn’s patients and their families donated the majority of the project’s expense, around £850,000 ($1.2 million).
Results for Hermon-Taylor’s vaccine trial will be announced in March of 2019. Until then, no one can say for certain whether he has succeeded.
“I’d like nothing better than to deliver good news to Crohn’s sufferers, but right now we don’t know if the vaccine can cure,” Hermon-Taylor said. “But from what we know about how the organism presents in humans, the odds are better than an even split, I’d say.”
For Crohn’s patients, those are the best odds they’ve heard of in a long time.
How Close Are We to a Cure for Crohn’s Disease?
Currently, there’s no known cure for Crohn’s disease. Treatment for the condition traditionally focuses on reducing symptoms. It also is sometimes effective at bringing a person’s Crohn’s disease into long-term remission.
Most of the time, Crohn’s is treated with medications. The first-line approach to reducing Crohn’s symptoms is to reduce inflammation in the bowel. In some cases, doctors will recommend surgery to help ease symptoms.
One or more of the following treatments are usually used:
- anti-inflammatory drugs
- immune system suppressors to reduce bowel inflammation
- antibiotics to help heal ulcers and fistulas, and to reduce the amount of harmful bacteria in the intestines
- fiber supplements
- pain relievers
- iron, calcium, and vitamin D supplements
- vitamin B-12 shots to help reduce risks of malnutrition
- nutritional therapy, such as a special diet plan or liquid diet to help reduce risk of malnutrition
- surgery to remove damaged parts of the digestive system for symptom relief
Corticosteroids, such as prednisone, have long been beneficial for people with Crohn’s disease. However, they are limited to short-term use when other treatments aren’t effective. This is because they can have many serious side effects on the entire body.
A 2012 review of studies suggests that more recently developed corticosteroids, such as budesonide and beclomethasone dipropionate, may be more effective at reducing symptoms, with fewer side effects.
Immune system suppressors
Common immune system suppressors that have been traditionally used to treat Crohn’s disease are azathioprine (Imuran) and mercaptopurine (Purinethol). But research has found that they can cause side effects, including increased risk of infection.
Another drug in this category is methotrexate, Typically, it’s used in addition to other medications. All of the immune system suppressor drugs require regular blood tests to monitor potential side effects.
Newer drugs, called biologics, are used in people with moderate to severe cases of Crohn’s disease. Depending on an individual’s overall health, not everyone may be a candidate for these medications.
TNF inhibitors work by blocking a protein that causes inflammation. Some examples include infliximab (Remicade), adalimumab (Humira), and certolizumab pegol (Cimzia). Researchers have also found that for some people, TNF inhibitors may become less effective over time.
Natalizumab (Tysabri) and vedolizumab (Entyvio)
These drugs are also used to treat people with moderate to severe Crohn’s disease who don’t respond well to other medications. They block inflammation in a different way than TNF inhibitors. Rather than blocking TNF, they block a substance called integrin.
They work by keeping inflammatory cells out of tissue. Natalizumab (Tysabri), however, carries a risk for a serious brain condition in certain people. It’s recommended that people get tested for a specific virus before using this medication in order to reduce this risk.
Research from 2016 suggests that vedolizumab works similarly to natalizumab, but so far it does not have the same risk of brain disease. Vedonlizumab seems to work more specifically on the intestinal tract rather than the whole body.
Ustekinumab (Stelara) is the most recent biologic approved to treat Crohn’s. It’s used in the same way as other biologics, and 2016 research suggests that it may be helpful in treating Crohn’s disease when other medications don’t work.
This drug works by blocking certain pathways of inflammation. However, in rare instances it can also affect the brain.
Crohn’s Disease Treatment Options
A combination of treatment options can help you stay in control of your disease and help you to lead a full and rewarding life. Remember that there is no standard treatment that will work for all patients. Each patient’s situation is different and treatment must be followed for each circumstance.
Treatment for Crohn’s and other IBD varieties can include the use of medication, alterations in diet and nutrition, and sometimes surgical procedures to repair or remove affected portions of your GI tract.
Medication treating Crohn’s disease is designed to suppress your immune system’s abnormal inflammatory response that is causing your symptoms. Suppressing inflammation not only offers relief from common symptoms like fever, diarrhea, and pain, it also allows your intestinal tissues to heal.
In addition to controlling and suppressing symptoms (inducing remission), medication can also be used to decrease the frequency of symptom flare ups (maintaining remission). With proper treatment over time, periods of remission can be extended and periods of symptom flare ups can be reduced. Several types of medication are being used to treat Crohn’s disease today.
In some circumstances, a health care provider may recommend adding an additional therapy that will work in combination with the initial therapy to increase its effectiveness. For example, combination therapy could include the addition of a biologic to an immunomodulator. As with all therapy, there are risks and benefits of combination therapy. Combining therapies can increase the effectiveness of IBD treatment, but there may also be an increased risk of additional side effects and toxicity. Your health care provider will identify the treatment option that is most effective for your individual health care needs.
Diet & Nutrition
While Crohn’s disease may not be the result of bad reactions to specific foods, paying special attention to your diet may help reduce symptoms, replace lost nutrients, and promote healing.
For people diagnosed with Crohn’s disease, it is essential to maintain good nutrition because Crohn’s often reduces your appetite while increasing your body’s energy needs. Additionally, common Crohn’s symptoms like diarrhea can reduce your body’s ability to absorb protein, fat, carbohydrates, as well as water, vitamins, and minerals.
Many people who experience Crohn’s disease flare ups find that soft, bland foods cause less discomfort than spicy or high-fiber foods. While your diet can remain flexible and should include a variety of foods from all food groups, your doctor will likely recommend restricting your intake of dairy if you are found to be lactose-intolerant. Watch this webcast to learn more about nutrition in inflammatory bowel diseases.
Even with proper medication and diet, as many as two-thirds to three-quarters of people with Crohn’s disease will require surgery at some point during their lives. While surgery does not cure Crohn’s disease, it can conserve portions of your GI tract and return you to the best possible quality of life.
Surgery becomes necessary when medications can no longer control symptoms, or if you develop a fistula, fissure, or intestinal obstruction. Surgery often involves removal of the diseased segment of bowel (resection), the two ends of healthy bowel are then joined together (anastomosis). While these procedures may cause your symptoms to disappear for many years, Crohn’s frequently recurs later in life.
Key things to know about Surgery:
- About 70% of people with Crohn’s disease eventually require surgery.
- Different types of procedures may be performed depending on the reason, severity of illness, and location of the disease.
- Approximately 30% of patients who have surgery for Crohn’s disease experience recurrence of their symptoms within three years and up to 60% will have recurrence within ten years.
Making Informed Decisions
If you’re confused about all the medications and therapies out there, you are not alone! IBD is extremely complex, and it is important to review the risks and benefits of all treatment options with your doctor. Learn more about available tools and resources that can help you make informed decisions about your care.