The gastrointestinal (GI) tract is a remarkable organ: it resides on the inside of our bodies, but is regularly in contact with the outside world by virtue of what we ingest. It is quite incredible that the immune cells of the GI tract are not activated more regularly by the many foreign products it encounters every day. Only when the GI tract encounters an intruder that risks causing disease do the immune cells of the GI tract spring into action.
That is, of course, under normal circumstances. In people with Crohn’s disease, the normally tolerant immune cells of the GI tract are activated without provocation, and this activation leads to chronic or relapsing — but ultimately uncontrolled — inflammation.
Crohn’s disease: A primer
First described by Dr. Burrill B. Crohn and colleagues in 1932, Crohn’s disease is a complex inflammatory disorder that results from the misguided activity of the immune system. It can involve any part of the GI tract from the mouth to the anus, but most commonly involves the end of the small intestine.
Depending on the precise location of GI inflammation, Crohn’s disease may cause any number of symptoms including abdominal pain, diarrhea, weight loss, fever, and sometimes blood in the stool.
Treatment options for Crohn’s disease have evolved dramatically since Dr. Crohn and colleagues first described the condition, but the basic principle has remained the same: reduce the uncontrolled inflammation. Early approaches to treatment involved nonspecific anti-inflammatory medications such as corticosteroids, which have many potentially serious side effects outside the intestines.
Today, a number of newer therapies exist that act more specifically on the immune system to target inflammatory pathways known to be active in Crohn’s disease. These newer drugs, termed biologics, are antibodies that block proteins involved in specific inflammatory pathways relevant to Crohn’s disease. Since we don’t fully understand which pathways are involved in which patients, however, choosing a medication for a given patient is as much an art as it is a science.
Evidence grows for early, aggressive treatment of Crohn’s disease
Early approaches to treatment of Crohn’s disease followed a step-up algorithm in which the newer medications would only be used if the patient did not benefit from established therapies. This sequential approach — termed step therapy — has more recently been called into question, as studies have repeatedly shown that the newer drugs for Crohn’s disease are more effective than the old standards, and have preferable side effect profiles. Research also indicates that early, aggressive intervention and treatment, targeting not just symptoms but objective evidence of inflammation (as assessed through blood work, stool tests, imaging, and endoscopy), lead to better health and quality of life, at least in the short term.
Researchers recently published a study in the journal Gastroenterology on the longer-term benefits of treating Crohn’s patients to reduce both symptoms and inflammation. Specifically, they analyzed follow-up data from patients enrolled in the CALM study — a multicenter trial that compared two approaches to the treatment of early, moderate to severe Crohn’s disease. In the first approach, the decision to escalate therapy was based on symptoms alone; in the other approach, the decision was based on both symptoms and objective evidence of inflammation (found in blood work or a stool test, for example). This second approach is called tight control. A patient under tight control might feel well, but therapy would be escalated if there was objective evidence of inflammation. The primary end point of the original CALM study was healing the inflamed lining of the intestines, and the data showed that the tight control approach to treatment was more effective at reaching this goal.
The Gastroenterology study took the results of the original CALM study one step further. The researchers looked at how the patients who achieved healing of their intestinal lining are doing several years later. To this end, the researchers looked at the rates of various adverse outcomes (including the need for surgery and hospitalization for Crohn’s disease) in the CALM study patients since the trial ended.
They found that patients who were both feeling well and had demonstrated healing of the intestinal lining (called deep remission) had a significantly decreased risk of Crohn’s disease progression. Healing of the intestinal lining without feeling well, and feeling well without healing of the intestinal lining, were also associated with a lower risk of disease progression when compared to patients with active symptoms and inflammation, but to a lesser extent.
Study findings may not generalize to many Crohn’s disease patients
The recent study lends strength to a growing body of evidence in support of a treatment approach that emphasizes early intervention aimed at healing the lining of the intestines and resolving symptoms. Can we generalize the findings to most patients with Crohn’s disease? Not necessarily.
Enrolled patients had never been treated with a newer biologic drug, or with a drug called an immunomodulator that affects the way the immune system functions, before enrolling in the CALM study. Immunomodulators have been used to treat inflammatory bowel disease (IBD) since the 1960s, and they are often one of the first drug classes used for treatment of IBD. As a result, these study results may not generalize to the many people who have had a Crohn’s diagnosis for long enough to have already been treated with an immunomodulator.
Furthermore, those who received escalation of therapy were treated with increasingly optimized doses of a single biologic, adalimumab (Humira). It remains to be seen whether we would see the same results in patients already exposed to a biologic or with the use of another biologic.
Doctor-patient collaboration is critical for successful Crohn’s treatment
In my practice, I regularly encourage using highly effective therapies early to pursue tight control. For some, the decision to follow this approach is easy. For others, the idea of escalating therapy, perhaps in the absence of symptoms, and to target something they may not feel, is more difficult to be convinced of. Concerns about side effects and the need for frequent monitoring are paramount among the roadblocks.
Collaborating with my patients so that they can make medical decisions that are in line with their values but still informed by evidence is critical for success, as is a commitment to regularly revisit and rethink the approach over time.
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