Even when taking medication, patients suffering from Crohn’s disease shoulder a heavy burden of symptoms and side effects which can drastically reduce their quality of life. In addition to the physically uncomfortable symptoms associated with Crohn’s, patients often experience self-consciousness, anxiety, and depression as they struggle to cope with the impact of the disease. Additionally, the medications patients take to control flare-ups or maintain remission can have a profound physiological and emotional consequences and, in many cases, set patients on a collision course with even more severe side effects after long periods of treatment.
For both patients and clinicians, it is critical to understand the nuances of the medications available and carefully consider the potential impact on both short and long-term well-being. Each class of medications has a different therapeutic niche, different side effects, and a different efficacy profile. Ultimately, finding the right medication may be a process of coming to terms with the side effects that patients can bear while controlling their symptoms as much as possible. However, it is also important to be aware of treatment options that go beyond conventional pharmaceuticals. For many, combining existing medications with advanced nutraceuticals may be the best way forward, allowing patients to experience enhanced symptom remission and preserve their long-term health without additional side effects.
Controlling inflammation is key to controlling Crohn’s symptoms, but over-the-counter solutions like NSAIDs are insufficient. Instead, patients with Crohn’s disease take two classes of specialized anti-inflammatory medications: the aminosalicylates and the corticosteroids. Both are considered first-line treatments, though their therapeutic niches differ; the aminosalicylates are intended for daily use to control background inflammation, whereas the corticosteroids are used when inflammation flares up and starts to spiral out of control. Between these two classes of medication, most patients with Crohn’s can experience a relatively normal quality of life. Nonetheless, there is substantial room for improvement with regard to these therapies.
While the aminosalicylates may provide some patients with durable remission, they are not curative. Furthermore, aminosalicylates may not be very effective within their role. A recently published literature review of 20 studies indicates that many of the clinical trials supporting the use of the aminosalicylates are methodologically flawed or fail to show that they are more effective than placebo with regard to preventing flare-ups. To identify the studies to be included in the review, researchers examined every academic journal article ever published pertaining to the efficacy of the aminosalicylates for mild to moderate Crohn’s disease. Across these studies, the review reports that after six weeks of treatment only 23% of aminosalicylate patients entered remission in comparison to 15% of patients taking a placebo. After 17 weeks of treatment, however, 45% of patients taking aminosalicylates experienced remission in comparison to 29% of patients taking a placebo. These results indicate that aminosalicylates take a long time to induce remission, and may not ever do so when used in isolation for a majority of patients.
Additionally, 33% of patients will experience persistent side effects of aminosalicylates regardless of whether their symptoms are driven into remission. Aminosalicylate-class anti-inflammatories such as mesalazine can cause immune suppression, rash, fever, hair loss, anemia, headache, nausea, and diarrhea. These side effects are typically of mild intensity and tend to resolve in the hours after the patient takes their dose. The gastrointestinal side effects of mesalazine are dose-dependent, whereas the majority of the others are inconsistent from patient to patient with regard to the dose. Critically, efficacy profile of mesalazine and other aminosalicylate remain stable and their side effects do not become more difficult to bear over time. Patients can thus take aminosalicylates as a maintenance therapy without worrying about detrimental long-term effects causing damage to their body. However, up to 22% of patients discontinue aminosalicylates as a result of the side effects and many others continue to struggle with side effects despite choosing to continue treatment.
Most patients with Crohn’s disease take aminosalicylates, but periods of remission maintained via daily aminosalicylates may be disrupted by severe flare-ups without warning, a risk which patients with incomplete remission face in higher proportions. After a flare-up of inflammation, corticosteroids are typically used in concert with aminosalicylates to restore remission. Medications in this class, such as prednisone, drastically reduce inflammation by triggering short-term genetic changes to the immune system.
Corticosteroid therapy is highly effective; an early clinical trial of 71 patients describes a 27% to 48% reduction in the Crohn’s Disease Activity Index (CDAI) after six weeks of treatment. However, corticosteroids exhibit a difficult side effect profile which grows in scope and severity with prolonged use. Nearly all patients experience asymptomatic high blood sugar, fluid retention, fatigue, dry mouth, indigestion, hunger, and other relatively minor short-term side effects when they take corticosteroids. A substantial subset of patients also experiences acute depression or anxiety, joint pain, confusion, severe acne, weakened executive functions, weight gain, blurry vision, thigh and bicep atrophy, hyperactivity, and headaches. Most patients will have at least one of these less-common symptoms during short-term corticosteroid use. Longer term, corticosteroids become very dangerous. Severe weight gain, mineral insufficiency, glaucoma, depression, type 2 diabetes, dementia, psychosis, immunosuppression, vomiting, and dying bone tissue start to become serious risks for patients who take corticosteroids for longer than 21 days.
While some patients have taken corticosteroids for several months without becoming debilitated by these side effects, other issues still preclude long-term use except in extraordinary circumstances. Significantly, corticosteroids very rapidly cause biological dependence; after as few as 7 days of taking corticosteroids, the body’s ability to produce anti-inflammatory molecules of its own begins to be downregulated as a result of disuse. Once this downregulation is complete—typically, after three weeks of taking corticosteroids—abrupt cessation of corticosteroids can result in life-threatening withdrawal symptoms which can include severe limb pain, vomiting, fainting, psychosis, and seizures. Because patients with Crohn’s may not experience sufficient reductions in inflammation after a short course of corticosteroids, they are at high risk of facing these withdrawal syndromes as they pursue longer-term treatment. Thus, patients and doctors alike opt to control flare-ups preventively as much as possible.
Immunosuppressants may be used to prevent flare-ups by patients who do not respond to or cannot tolerate aminosalicylate drugs. These medications, such as azathioprine, are used on a continuous and long-term basis, though patients taking the immunosuppressants may still need the help of a corticosteroid to suppress a flare-up. When flare-ups occur, however, the immunosuppressants tend to make them less severe, potentially minimizing reliance on corticosteroids. Indeed, in a systematic review published in 2016, immunosuppressants help 64% of patients with Crohn’s disease reduce their usage of corticosteroids. The review also found that across 13 clinical trials, 36% of patients avoided corticosteroid use entirely when using immunosuppressants in lieu of aminosalicylates. Only 10% of patients taking immunosuppressants discontinued them on the basis of side effects, which include severe allergic reactions, nausea, low white blood cell count, and pancreatitis. However, immunosuppressants were no better than the aminosalicylates at helping patients maintain remission over a 12-month period.
Importantly, immunosuppressants are confirmed carcinogens which are known to cause lymphoma in patients with inflammatory bowel diseases, which makes their use a calculated risk. Patients who are of especially high risk for cancer are thus often advised to avoid immunosuppressants even if they might be therapeutically beneficial to maintain Crohn’s remission. Likewise, patients with weakened immune systems face a dangerously high chance of infection when they take these medications. But patients who can benefit from immunosuppression yet who are unwilling to accept the risks can still do so thanks to innovations in using the body’s natural immunosuppressants for the purposes of controlling inflammation.
In light of the serious drawbacks associated with immunosuppressant drugs, researchers have turned to the body’s set of regulatory chemicals to find an effective immunomodulator which won’t harm patients. Butyric acid is one such chemical and has been identified as uniquely promising to reduce the inflammation associated with Crohn’s. Butyric acid is a critical short-chain fatty acid produced by the gastrointestinal tract for the purposes of reducing the activity of the white blood cells. When the white blood cells of the gastrointestinal tract encounter a molecule of butyric acid, they downregulate their production of proinflammatory molecules, leading to fewer symptoms of Crohn’s disease. Patients with Crohn’s disease tend to have lower than normal quantities of butyric acid in their guts, which may be a contributing factor to their high levels of chronic inflammation as well as their inability to control inflammation before it flares up. Butyric acid therapy can thus help to achieve and maintain remission. Importantly, butyric acid can work in conjunction with the aminosalicylates to provide the reduction in inflammation which Crohn’s disease patients need without the carcinogenicity of standard immunosuppressants or the long-term side effects of the corticosteroids.
An in vitro study from 2012 describes the mechanism of butyric acid, indicating that it prevents the immune cells of the colon from proliferating during periods of immune activation. Immune activation typically prompts populations of colon-dwelling immune cells to grow by as much as 900%, causing a similarly explosive increase in the secretion of inflammatory molecules. When treated with butyric acid, however, researchers documented that the population of immune cells from patients with Crohn’s disease shrunk by 60% even in the face of immune activation. This means that pre-treatment with butyric acid could lower baseline levels of inflammation in addition to preventing runaway inflammation that would trigger a flare-up of the disease.
There is also evidence that suggests butyric acid may be useful in the rescue of patients during a flare-up as well thanks to this immunosuppressive effect. A 2005 pilot study found that 69% of patients with remission-resistant and moderate-intensity Crohn’s disease responded to butyric acid therapy in conjunction with standard aminosalicylate treatment, allowing 53% of the subset which responded to achieve remission. Over the course of 8 weeks of daily treatment with butyric acid, these patients experienced their Crohn’s disease activity index drop from 252 to 140. Clinicians consider any activity index beneath 150 to be indicative of remission, meaning that butyric acid made the difference between a moderately distressing symptom load and asymptomatic disease. Significantly, the butyric acid treatment was well-tolerated and only 7.6% of the study’s cohort dropped out. Researchers were unable to find any evidence of side effects which might have caused these patients to drop out of the study, though subsequent patient reports indicate that transient nausea or headaches may occur in a minority of patients.
While butyric acid was not historically used as a treatment for Crohn’s disease, new formulations, such as those pioneered by Tesseract Medical Research, have enabled its therapeutic use. Older formulations of butyric acid have lacked bioavailability and failed to localize the chemical in the gut, meaning that patients couldn’t experience its benefits in the location where they were needed the most. In contrast, these new formulations are designed to promote optimal absorption, allowing butyric acid therapy to start reducing inflammation within half an hour and provide relief for as long as eight hours. Importantly, butyric acid’s metabolic profile in Crohn’s disease is not significantly different than in healthy people, and butyric acid doesn’t interfere with the mechanism of action of aminosalicylates or corticosteroids. This means that it could be used in conjunction with these other classes of medicines to provide more robust maintenance of remission or faster rescue from a flare-up.
The Future Of Crohn’s Disease Therapy
While nutraceutical therapies like butyric acid can be a critical factor for patients with Crohn’s disease, multimodal therapy will typically remain necessary for the foreseeable future. However, patients may be able to reduce the dosage of their other medications and experience fewer side effects with the addition of butyric acid to their therapeutic repertoire. Given the high tolerability of butyric acid and suitability for long-term use, some patients may find that their mild Crohn’s symptoms can be treated by it in isolation.
Additionally, butyric acid is not the only promising nutraceutical for those who want to enhance management of Crohn’s. Other molecules derived from the human body, like glutathione, as well as curcumin have also been linked to reducing inflammation in people with inflammatory bowel diseases, and it may be possible to combine nutraceutical therapies for greater symptom relief. While research is ongoing, patients seeking to reduce the burden of their other Crohn’s disease therapies can include innovative, natural therapies in their treatment today.
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