Treatment of Crohn’s disease: a balancing act
Crohn’s disease, an autoimmune disease that causes painful and often debilitating inflammation in the intestine and is incurable, is notoriously difficult to treat.
The diagnosis itself is not easy. Just ask Michael Weiss, a Crohn patient lawyer from Brooklyn who hasn’t been diagnosed for several years, faced with doubts and disbelief from doctors, friends, and even his psychiatrist. “I call it the diagnostic trip,” says Weiss. “It took me a long time to find a gastroenterologist who found out.”
A major stumbling block for diagnosis is that Morbuscror’s symptoms are abdominal pain, diarrhea, gastrointestinal bleeding and poor nutrient absorption – all symptoms that occur with many other diseases.
“[Crohn’s] first presentation can be so frequent and so subtle,” said Irfan Hisamuddin, MD, gastroenterologist at Christiana Care Health System in Wilmington, DE. “The disease can mimic other diseases, so it can take some time for patients to be diagnosed, or they can be misdiagnosed with irritable bowel syndrome for a while.”
The Crohn’s and Colitis Foundation of America estimates that approximately 780,000 Americans have Crohns. Most people are diagnosed between 10 and 35 years old, with about half of all cases diagnosed under 30 years old. However, another high point of diagnoses occurs around the age of 50, possibly because other diseases are more common at that age. Approximately half of all Crohn’s patients will have a gastrointestinal complication within 20 years of diagnosis that is likely to require surgery.
A search for treatment options
Once the diagnostic challenge is over, treatment comes – and Crohns is a notoriously difficult autoimmune disease to treat. For this reason, new opportunities and new treatment combinations are always being sought. The latest possible treatment includes a hydrogel that can potentially deliver medication directly to the areas of inflammation in the colon, researchers reported in a recent pre-clinical study. Although the gel has only been tested in human tissue samples and mice – given as an enema containing the anti-inflammatory corticosteroid dexamethasone – it reduced inflammation significantly more than the use of the dexamethasone itself. It will take further attempts before such a product targets the Could bring market, but the hydrogel is one of several encouraging research directions in the treatment of Crohn.
Another drug that is already approved for the treatment of psoriasis, called ustekinumab (Stelara, Centocor), appears to reduce Crohn’s disease by blocking 2 immune cell proteins, and studies with a new targeted drug called Mongersen also look promising. Participants with Crohn in a 2015 study reported in the New England Journal of Medicine who received Mongersen had significantly higher remission rates than those who received a placebo. Because Crohn’s disease is an autoimmune disease, the inflammation that causes symptoms occurs because the immune system attacks parts of the gastrointestinal tract. Mongersen, an oral medication, also blocks a certain protein, but the mechanism by which it works is not clear, says Kian Keyashian, MD, an assistant professor of medicine at Oregon Health and Science University in Portland.
Dr. Keyashian says Mongerson has looked good in smaller clinical trials so far, with minimal safety concerns. If larger studies show that it is effective and the Food and Drug Administration approves it, Mongersen would join other biologics, a class of drugs that manipulate the functioning of the immune system.
These developments have the potential to give gastroenterologists new opportunities to help those living with Crohn, but they won’t change the fact that the treatment of the disease is complex. The goal of treatment is threefold: reduce inflammation; ensure that a person receives adequate nutrition; and reduce symptoms, especially abdominal pain, diarrhea and rectal bleeding. In contrast to most other diseases, Crohn lacks a single standardized first-line therapy because the treatment plan depends so much on each individual.
“The choice of medical therapy depends on the location of the disease in the GI tract, the severity of the disease and the goal of treatment – whether it should induce remission or prevent relapse,” says Dr. Hisamuddin. Most of the time, he says, a combination of drugs is tried.
5 types of Crohn’s disease drugs
The different medications used to treat Crohn’s fall in 5 main categories. The 2 groups used for short-term treatment of acute symptoms are corticosteroids and antibiotics, also used to treat infections, such as abscesses, or other complications, such as fistula, when one part of the intestine is abnormally connected to another part. Neither of these types of drugs should be used long term because the side effects become unbearable. Prednisone, the most commonly used steroid, has a long list of side effects, including agitation, mood swings, fatigue, swelling, weakened bones, eye pressure, and infections, among others. The side effects of the steroid budesonide (Entocort, Uceris) tend to be milder. The two most common antibiotics are metronidazole (Flagyl) and ciprofloxacin (Cipro). Antibiotics can be a double-edged sword because they alter the gut’s bacterial makeup, possibly increase gastrointestinal symptoms, but their benefits for treating fistula outweigh these risks, says Dr. Keyashian.
Another group, anti-inflammatories called aminosalicylates, can be used to treat acute flare-ups as well as long-term maintenance to prevent future flare-ups. These include sulfasalazine (azulfidine) and mesalamine (Pentasa, Lialda, Apriso, Canasa, Asacol).
When steroids and / or anti-inflammatories have not adequately controlled a person’s symptoms, doctors usually move on prescribing immunomodulators that aim to control the disease by modifying or suppressing the immune system. These medications can be used to maintain the disease over the long term or to reduce a person’s steroid dose (and therefore side effects).
Immunomodulators are methotrexate (Trexall, Rheumatrex), azathioprine (Azasan, Imuran), 6-mercaptopurine or 6-MP (Purinethol), cyclosporin A (Sandimmun, Neoral) and tacrolimus (Prograf). Azathioprine and 6-MP, both oral medications, can take 3 to 6 months to take full effect, while methotrexate, a weekly injection, and cyclosporin, which is oral, work faster. Tacrolimus is a topical medication used for fistula in the perineal area.
The last group includes the latest type of Crohn’s disease drugs, biologics, targeted immunomodulators that work on very specific immune cells by targeting individual proteins that cause inflammation or by moving white blood cells to specific areas. Both can address acute symptoms, but patients often take them over the long term. The 2 groups of currently approved biologics include TNF inhibitors (which suppress tumor necrosis factor) and anti-integrins, which prevent white blood cells from entering the intestine. TNF inhibitors include the IV drug Infliximab (Remicade) and the injectable drugs Adalimumab (Humira) and Certolizumab (Cimzia). Antiintegrins include natalizumab (Tysabri) and vedolizumab (Entyvio).
While each of these classes of medicines has its place in the treatment of Crohn, each also involves risks and side effects. Azathioprine, 6-MP, and the TNF inhibitors have been shown to increase the risk of non-Hodgkin’s lymphoma, for example, but the additional cases pay about 2 to 7 more per 10,000 people a year, says Dr. Keyashian. Antiintegrins are tolerated fairly well, he said, but a person can develop antibodies in response to one of the biologicals over time, making them ineffective. “It definitely takes expertise to optimize these drugs and keep them working for as long as possible,” he says.
Steroids present the highest rate of complications, especially in relation to infections. “Any doctor who puts a patient on steroids must have a good exit strategy,” says Dr. Keyashian. “They’re fine in the short term, but the patients shouldn’t be on them for more than a month or a month or a month.”
Crohn’s management as a journey
Dealing with Crohn involves paying close attention to side effects and sometimes medications no longer work optimally. Michael Weiss experienced a rare delayed anaphylactic reaction to infliximab shortly after it broke out in the late 1990s and had to stop using 6-MP and adalimumab. The former caused obstacles, and the latter was contraindicated for a rare lung disease he had.
That’s why doctors usually have to do several tests before choosing a course of treatment with newly diagnosed patients, says Dr. Keyashian. For example, TNF inhibitors can reactivate previous infections of tuberculosis or chronic hepatitis B. Before prescribing immunomodulators, doctors need to test the enzyme that is responsible for the metabolism of the medication to determine the safety and dosage of the drug for a particular patient.
David Dimmick, a 37-year-old from West Norriton, PA, was lucky enough to get his diagnosis shortly after he was 9 thanks to an excellent GI specialist. Luckily, however, there were few treatments for Crohn in the 1980s, so Dimmick took sulfasalazine and then prednisone in one dose or another for at least 2 years.
“It definitely had an impact on my quality of life,” said Dimmick. “I had to fight just to go outside to play with the neighborhood kids.” He suggests that people with Crohn’s try budesonide before prednisone because the latter side effects become so intense at higher doses: water weight gain, extreme photosensitivity and mood swings, as well as long-term deterioration in bone density and connective tissues such as tendons and ligaments.
Dimmick’s current drug cocktail includes methotrexate, budesonide, and vedolizumab, as well as folic acid, B12, iron, calcium, and vitamin D supplements, since methotrexate can cause folate deficiency and leg cramps.
Methotrexate can also cause liver abnormalities if the person who binges it on alcohol notices Dr. Keyashian, and women who become pregnant could also use effective contraception while taking the medication because it is a medication used to induce abortions. (It’s also not FDA approved for Crohn.)
While swapping medications from a treatment regimen to find the right balance of reduced symptoms without too many side effects, those who live with Crohn can also make some lifestyle choices to improve their quality of life.
3 things make Crohn’s disease worse, says Dr. Keyashian: second-hand smoking or smoke radiation; Using NSAIDs such as ibuprofen or naproxen that can cause ulcers; and certain antibiotics that can flare up. There is not much evidence to support the use of supplements or probiotics for Crohn.
After 20 years of smoking and unsuccessful attempts at the nicotine replacement patch and chewing gum, Dimmick finally stopped by replacing traditional cigarettes with e-cigarettes. The transition to vaping has eliminated his chronic cough and allowed him to do more cardiovascular exercises. He also avoids raw fruits and vegetables, seeds and nuts, the foods he has learned cause the worst flare-ups of his illness.
Keeping a food diary for several weeks is one of the suggestions Weiss makes for Crohn. “People with Crohn’s disease eat the same food every day because they eat the foods they know they won’t have a problem with,” he said.
The other advice Weiss gives to others with Crohn’s disease focuses on their attitudes. He remembers telling his girlfriend that he feared that his illness would hurt their relationship. “Your Crohn’s disease will never affect our relationship,” she said to him, “but how you deal with it will.” He said it was the best advice he had ever received. “People will want to help you if you try to help yourself,” he said. “But if you indulge in it, you won’t have many friends.”