Treating Crohn’s Disease: A Balancing Act

Crohn’s disease, an autoimmune disorder that causes painful and often debilitating inflammation in the intestines, and which is incurable, is notoriously difficult to treat.

Classified as an inflammatory bowel disease (IBD) along with ulcerative colitis, diagnosis of Crohn’s itself isn’t straightforward. Just ask Michael Weiss, a Crohn’s patient advocate from Brooklyn who went undiagnosed for several years, during which he faced doubt and disbelief from doctors, friends and even his psychiatrist. “I call it the diagnosis journey,” Weiss says. “It took me a long time to find a gastroenterologist who figured it out.”

A major stumbling block to diagnosis is that Crohn’s symptoms include abdominal pain, diarrhea, gastrointestinal bleeding and poor absorption of nutrients — all symptoms that occur with many other illnesses.

“The initial presentation [of Crohn’s] can be so common and so subtle,” says Irfan Hisamuddin, MD, a gastroenterologist with Christiana Care Health System in Wilmington, Delaware. “The disease can mimic other diseases, so there could be some period of time before patients are diagnosed, or they may be misdiagnosed with irritable bowel syndrome for a while.”

The Crohn’s and Colitis Foundation estimates that about 780,000 Americans have Crohn’s. Most individuals are diagnosed between ages 15 and 35, with about half of all cases diagnosed under 30. However, another peak of diagnoses occurs between ages 55 and 70, possibly because other diseases also become more prevalent at this age. About 70% of all Crohn’s patients will have a complication in their gastrointestinal tract requiring surgery, and about 60% of those will have a recurrence of symptoms within 10 years of surgery.

A Search for Treatment Options

Once the diagnosis challenge is overcome, next comes treatment — and Crohn’s is a notoriously difficult autoimmune disease to treat. For that reason, the search is always on for fresh possibilities and new combinations of treatments. 

A possible new treatment involves a hydrogel which can potentially deliver drugs directly to the areas of inflammation on the colon, reported researchers in a  preclinical trial. The gel was tested in human tissue samples and in mice, administered as an enema containing the anti-inflammatory corticosteroid dexamethasone. It reduced inflammation significantly more than using the dexamethasone by itself. In a 2020 study published in the journal Theranostics, researchers used hydrogel injections to administer a stem cell treatment to mice with bowel disease. The experimental treatment reduced the inflammatory response and improved the disease.  Hydrogel is one of several encouraging research directions in the treatment of Crohn’s.

A new drug in the pipeline, labeled AZD4205, shows potential for zeroing in on the GI tract in rodent studies. Based on early trials in mice and a phase I study in 66 human volunteers where the drug was well tolerated with no serious adverse effects, researchers say the drug shows promise for Crohn’s disease. A phase II study in people with moderate to severe Crohn’s is planned. 

An experimental biologic called etrolizumab is in phase III clinical trials involving more than 1,100 people with Crohn’s disease. Researchers hope to determine whether the drug can induce and maintain remission of moderate to severe Crohn’s. In studies of etrolizumab for ulcerative colitis the drug did not meet its endpoints of disease remission. But trials of the drug for Crohn’s are ongoing.

A number of other innovative drugs are under study for possible use in Crohn’s disease. These developments have the potential to give gastroenterologists new options in helping those living with Crohn’s, but they will not change the fact that treating the condition is complex. The goal of treatment is threefold: decrease inflammation; ensure a person receives adequate nutrition; and reduce the symptoms, particularly abdominal pain, diarrhea and rectal bleeding. Unlike most other conditions, though, Crohn’s lacks a single standardized first-line therapy because the treatment plan depends so much on each individual.

Because Crohn’s is an autoimmune disease, the inflammation that causes symptoms occurs because the immune system attacks parts of the gastrointestinal tract. “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 to induce remission or to prevent relapse,” says Dr. Hisamuddin. Most often, he says, a combination of drugs will be tried.

5 Types of Crohn’s Drugs

The different medications used to treat Crohn’s fall into five major categories. The two 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 becomes abnormally connected to another part. Neither of these drug types should be used long-term because the side effects become intolerable. 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. Commonly used antibiotics include metronidazole (Flagyl) and ciprofloxacin (Cipro). Antibiotics can be a double-edged sword because they alter the bacterial composition of the gut, possibly increasing gastrointestinal symptoms, but their benefits for treating fistula outweigh those risks, says gastroenterologist Kian Keyashian, MD, clinical associate professor of medicine at Stanford University.

Another group, anti-inflammatories called aminosalicylates, are approved for ulcerative colitis but can be used both to treat acute flare-ups and as longer-term maintenance to prevent future flare-ups in Crohn’s. These include sulfasalazine (Azulfidine) and mesalamine (Pentasa, Lialda, Apriso, Delzicol, Asacol). Mesalamine can also be delivered by a suppository, called Canasa, or in an enema formulation called Rowasa. Other aminosalicylates include olsalazine (Dipentum) and balsalazide (Colazal).

If steroids and/or anti-inflammatories have not adequately controlled a person’s symptoms, doctors usually move on to prescribing immunomodulators, which aim to control the disease by modifying or suppressing the immune system. These drugs can be used for long-term maintenance of the disease or to reduce a person’s steroid dose (and therefore side effects).

Immunomodulators include methotrexate (Otrexup, Rasuvo), azathioprine (Azasan, Imuran), 6-mercaptopurine, or 6-MP (Purinethol), cyclosporine (Sandimmune, Neoral) and tacrolimus (Prograf). Azathioprine and 6-MP, both oral medications, can take three to six months before taking full effect, while methotrexate injection, and cyclosporine, which is oral, work more quickly. A topical version of tacrolimus is used for fistula in the perineal area.

The final group includes the newest type of Crohn’s drugs, biologics, targeted immunomodulators that act on very specific immune cells by going after individual proteins that cause inflammation or by moving white blood cells to specific areas. Either of these can address acute symptoms, but patients also frequently take them long-term. 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 may take up to eight weeks to have an effect. They include the IV drug infliximab (Remicade) and the injectable drugs adalimumab (Humira) and certolizumab (Cimzia). Anti-integrins include natalizumab (Tysabri) and vedolizumab (Entyvio). In addition to TNF inhibitors and anti-integrins, the monoclonal antibody known as ustekinumab (Stelara) is approved to treat Crohn’s. Also approved for psoriasis, it appears to reduce Crohn’s inflammation by blocking two immune cell proteins. 

While each of these medication classes has its place in treatment of Crohn’s, each also involves risks and side effects. Azathioprine and 6-MP have been shown to increase the risk of non-Hodgkin’s lymphoma, for example, but the additional cases number about 4 per 10,000 people per year, says Dr. Keyashian. Combining TNF inhibitors with another immunomodulator boosts the risk of lymphoma. Anti-integrins are tolerated fairly well, he says, but a person can develop antibodies in response to any of the biologics over time, which renders them ineffective. “It definitely takes expertise to optimize these drugs and keep them working as long as possible,” he says.

Steroids present a high rate of complications, especially in terms of infections. “Any doctor who puts a patient on steroids needs to have a good exit strategy,” says Dr. Keyashian. “For the short-term, they’re fine, but patients should not be on them more than a month or month and a half.”

Crohn’s Management as a Journey

Dealing with Crohn’s involves watching closely for side effects and times medication stops working optimally. Michael Weiss experienced a rare delayed anaphylactic reaction to infliximab shortly after it came out in the late 1990s, and he had to stop using 6-MP and adalimumab. The former was causing obstructions, and the latter was contraindicated for a rare lung condition he had.

That’s why doctors must usually run several tests before deciding on a treatment course with newly diagnosed patients, says Dr. Keyashian. TNF-inhibitors, for example, can reactivate prior infections of tuberculosis or chronic hepatitis B. Before prescribing immunomodulators, doctors must test for the enzyme partly responsible for metabolizing the drugs to determine the safety and dosage of the drug for a particular patient.

David Dimmick, a 42-year-old from West Norriton, Pennsylvania, was fortunate to receive his diagnosis shortly after turning 9, thanks to an excellent GI specialist. Less fortunately, however, few treatment options existed for Crohn’s in the 1980s, so Dimmick took sulfasalazine and then prednisone at some dosage or another for at least two years.

“That definitely had an impact on my quality of life,” Dimmick said. “I had to battle just to go outside to play with the neighborhood kids.” He suggests that people with Crohn’s try budesonide before prednisone because the latter’s side effects become so intense at higher doses: water-weight gain, extreme photosensitivity and mood swings, as well as longer term deterioration to bone density and connective tissues such as tendons and ligaments.

Dimmick’s current drug cocktail includes methotrexate, budesonide and vedolizumab, along with iron, calcium, vitamin D, folic acid and B12 supplements, since methotrexate can cause folate deficiency and leg cramping.

Methotrexate can also cause liver abnormalities if the person taking it binges on alcohol, notes Dr. Keyashian, and women who might become pregnant must also use effective contraception while taking the drug, because it’s a medication used to induce abortions. (It’s also not FDA-approved for Crohn’s.)

Lifestyle Changes

While swapping in and out drugs from a treatment regime to strike the right balance of reduced symptoms without too many side effects, those living with Crohn’s can also make some lifestyle choices to improve their quality of life.

Three things make Crohn’s disease worse, says Dr. Keyashian: smoking or secondhand smoke exposure; use of NSAIDs such as ibuprofen or naproxen, which can cause ulcers; and certain antibiotics, which can trigger flare-ups of the disease. 

Although Crohn’s disease is not triggered by any particular foods, dietary changes may help curb symptoms and reduce flares. One area of research focuses on imbalances in the intestinal microbiome, or the balance of bacteria in the gut. Researchers at the University of Massachusetts Medical School have developed an anti-inflammatory diet that aims to restore the balance between helpful and harmful bacteria in people with IBD, with the goal of disease remission. The main components of the diet include increasing probiotic and prebiotic foods, avoiding pro-inflammatory carbohydrates, and maintaining good nutrition with foods rich in nutrients eaten in a form your body can handle, even mixing them in a blender if necessary. 

Some people find herbal products helpful when included in their treatment plan. There is research showing evidence that Chinese herbal medicines may help, but the studies are small and lack adequate follow up. So until larger trials confirm the usefulness and safety of herbal supplements for Crohn’s disease, experts are reluctant to recommend them.

Dimmick avoids raw fruits and vegetables, seeds and nuts, the foods he has learned cause the worst flare-ups of his disease. Keeping a food diary for several weeks is one of the suggestions Weiss makes to those with Crohn’s. “People with Crohn’s disease end up eating the same food every day because they eat the foods they know they won’t have a problem with,” he says.

The other advice Weiss gives to others with Crohn’s disease focuses on their attitude. He recalls telling his girlfriend that he worried his disease would hurt their relationship. “Your Crohn’s disease will never affect our relationship,” she told him, “but how you handle it will.” He says it was the best advice he ever received. “People will want to help you if you’re trying to help yourself,” he says. “But if you wallow in it, you won’t have a lot of friends.”