Other Therapies

Introduction

In addition to aminosalicylates (5-ASAs), corticosteroids, immunomodulators, biologics and surgery, additional therapies may be used in the treatment of ulcerative colitis (UC), with or without the knowledge of the treating gastroenterologist and/or general practitioner. These therapies can be broadly categorized in two groups: other nonpharmacologic therapies available through medical supervision and non-conventional therapies which patients may readily initiate by themselves or through practitioners outside the medical community. Concerning the first group, this section will focus on fecal microbiota transplants (FMT), a procedure that has demonstrated tremendous efficacy in the treatment of recurrent Clostridiodes difficile infection, another gastrointestinal (GI) condition with dysbiosis as a feature.

Complementary and alternative medicines (CAMs), an assorted group of products and medical practices or disciplines that are not considered to be part of conventional medicine, comprise the other group of therapies. Complementary medicine is defined as the use of non-conventional therapies together with conventional medicine, whereas alternative medicine is where non-conventional therapies are used in lieu of conventional treatments. Example CAMs include herbal therapy, dietary supplementation, dietary practices, probiotics and prebiotics, Chinese medicine, acupuncture, moxibustion, massage therapy and others.

There are many reasons why patients may seek CAMs, including a desire for a holistic approach to supplement their conventional therapy, the perception that “natural” products can do no harm, a lack of response to or undesirable adverse reactions from conventional therapies and a desire to take control or their disease and symptoms to improve their quality of life. Although there is a plethora of CAMs available to patients, this section will focus on those most commonly used and those with the greatest promise as complementary medicines.

Fecal Microbiota Transplant

In recent years, the gut microbiota has gained increased recognition as an important factor in the pathogenesis of inflammatory bowel disease (IBD), where current models posit that inflammation is triggered by an inappropriate mucosal immunologic response to constituents of the gut microbiota in genetically predisposed individuals. Normally, the gut microbiota interacts with the immune system to modulate several aspects of physiology, including intestinal immune responses and resistance to pathogens. However, changes in the microbial composition of the gut have repeatedly been observed in IBD patients. This phenomenon, known as dysbiosis, is characterized by a substantial reduction in the presence of obligate anaerobes (e.g., members of the phyla Bacteroidetes and Firmicutes), with a corresponding increase in facultative anaerobes, such as Escherichia coli. This shift in bacterial composition is thought to be associated with elevated levels of inflammatory factor production, which is a key factor in the intestinal inflammation characteristic of IBD. As such, therapies aimed at restoring the healthy gut microbiota, such as FMT and probiotics, have been investigated in the treatment of IBD.

FMT is a procedure where fecal or stool material is collected from a healthy donor and placed into another patient’s gastrointestinal tract in an attempt to correct dysbiosis and improve disease symptoms. This procedure has demonstrated enormous success (>90% efficacy) in the treatment of recurrent Clostridioides difficile infection. Considering that an altered gut microbiota is observed in IBD patients, FMT has been viewed as a promising approach for this condition as well. The first reported application of FMT in UC was published in 1989, where the administration of fecal enemas resulted in both clinical and histologic remission. Since then, interest in FMT has grown rapidly. However, studies of FMT in UC have lacked uniformity in treatment protocols and route of administration, many lacked control groups and trial results have varied greatly, with many showing no benefit of FMT. A review and meta-analysis of nine studies that included 122 patients (79 with UC, 39 with Crohn’s disease (CD) and 4 with IBD unclassified) who underwent FMT reported a clinical remission rate of 45%, or 36.2% when only cohort studies were considered. Subgroup analysis found that among UC patients with only left-sided or extensive/pancolitis, the pooled estimate for clinical remission was 24.1% compared to 60.5% among CD patients.

More recently, randomized placebo-controlled studies evaluated the efficacy of FMT in IBD. In one such study, 75 patients with UC were randomized to receive either FMT or placebo via enema once weekly for 6 weeks. FMT resulted in a higher rate of remission compared to placebo at 7 weeks (24% vs 5%). The stool from patients who received FMT had greater microbial diversity compared to baseline and to patients who received placebo (P=0.02). Interestingly, three of four patients with UC for less than 1 year entered remission, compared to six of 34 patients with UC for longer than 1 year, suggesting that the efficacy of FMT is higher early in the disease course. In another randomized controlled study, 50 patients with mild to severe UC were randomized to receive FMT or autologous fecal microbiota (control) via nasoduodenal delivery at weeks 0 and 3. The study found no significant difference in clinical or endoscopic remission between treatment groups (30.4% vs 20%; P=0.51). However, in patients who did respond to FMT, their microbiota was similar to that of their healthy donors at week 12. A 2023 Cochrane review of 12 studies (with a total of 550 participants) concluded that FMT may increase the proportion of patients who achieve clinical and endoscopic remission of UC; however, the evidence was not conclusive, and was particularly uncertain regarding maintenance of remission, the risk of serious adverse events and quality of life improvements.

In 2019, the Food and Drug Administration (FDA) warned health care providers (HCPs) and patients of the potential risk for serious or life-threatening infections with the use of FMT, due to the possibility of transmitting multi-drug resistant organisms (MDRO) to recipients. Two incidents were reported, one of which was fatal, where immunocompromised adults who received investigational FMT developed invasive infections due to Extended-Spectrum Beta-Lactamases (ESBL)-producing E. coli. Both recipients in question received donor stool from the same individual, who was not tested for ESBL-producing gram-negative organisms. Due to these incidents, the FDA has determined that protections are needed for any investigational use of FMT, including the exclusion of donors found to be at high risk of colonization with MDRO and the introduction of MDRO testing of all donor stools. Current guidelines from the American College of Gastroenterology and American Gastroenterological Association do not recommend the use of FMT for routine treatment of UC at this time.

Recently, FMT in the form of a rectally-administered live fecal microbiota suspension (RBX2660; brand name Rebyota) has gained regulatory FDA approval for the prevention of recurrent Clostridioides difficile. It is approved for the prevention of recurrence of Clostridioides difficile infection (CDI) in individuals 18 years of age and older following antibiotic treatment for recurrent CDI. Approval was granted on the basis of the PUNCH CD3 trial, a randomized, double-blind, placebo-controlled, phase 3 study, which applied a hierarchical Bayesian model to also integrate data from an earlier phase 2b trial. Patients were eligible for recruitment if they had ≥1 CDI recurrence and completed ≥1 round of antibiotic therapy or had ≥2 episodes of severe CDI that required hospitalization in the past year. A total of 289 eligible patients were randomized (2:1) to receive either RBX2660 (n = 193) or a placebo (n = 96). In the RBX2660 group, 70.6% of patients achieved the primary endpoint (absence of CDI-related diarrhea at 8 weeks), compared to 57.5% in the placebo group, demonstrating the superiority of RBX2660 in the prevention of CDI recurrence (posterior probability of superiority 0.991, compared to a pre-defined threshold of 0.975). Although adverse events (AEs) were numerically more common in the RBX2660 group (55.6%) than in the placebo group (44.8%), this was mostly driven by AEs of mild severity. The majority of AEs were mild or moderate in severity and occurred during the first two weeks of the trial, with gastrointestinal disorders being the only AEs to occur in 5% or more of patients.

In summary, the results from FMT trials in patients with IBD are conflicting. These trials reinforce that IBD is not purely a microbiota-driven process, but far more complex. Since most studies have involved few patients and have been inconsistent in design, additional randomized placebo-controlled studies are merited to clarify the potential role of FMT in UC.

Complementary and Alternative Medicine

Although many CAMs are ancient, they have only recently gained traction in Western societies, specifically North America and Europe. Increased CAM usage has been observed particularly among patients with chronic disease, such as IBD, with an estimated prevalence in IBD patients ranging between 21% and 61%. Predictors of CAM use include dissatisfaction with conventional medicine or their patient-doctor relationship; psychiatric comorbidities; AEs from conventional therapies; use of CAM among friends or family; long disease duration; female sex; corticosteroid use; vegetarianism; and high education, socioeconomic and economic status.

Despite its widespread use, up to 75% of patients with IBD fail to discuss CAM usage with their physicians. If patients do discuss their CAM use, physicians often have limited knowledge regarding these treatments and may quickly dismiss them as having no benefit to the patient, an attitude that can embarrass the patient, strain the physician-patient relationship and cause the patient to hide their CAM use going forward. Being aware of CAM use in IBD patients is important, since certain oral CAMs may have drug-drug interactions, organ-specific toxicities, or be associated with adverse events (AEs). Additionally, CAM use is associated with worse compliance with conventional therapies. As such, physicians should aim to improve their knowledge of CAMs so that they may engage in informed discussions with patients who are interested in or already use CAMs. Although there is insufficient evidence to recommend most CAMs, physicians should strive to approach these conversations with sensitivity.

Due to the growing interest and use of CAMs, there is a need for official recommendations regarding their use in conjunction with conventional medicine. Unfortunately, one major issue is the lack of well-designed, randomized, controlled trials studying their safety and efficacy. As such, data on their use is limited and comes mostly from survey studies, case reports and case series. Consistency across studies, methodologic quality and absence of control conditions also plague much of the available literature. However, controlled randomized trials do exist and will be discussed in the sections below, when available.

Probiotics

Probiotics are formulated in various forms, including single or multiple strains of bacteria and/or yeast. Despite being poorly regulated, probiotics are among the most popular CAM therapies. Similar to FMT, they are proposed to restore healthy gut microbiota and thus have anti-inflammatory effects. In IBD patients, VSL#3, a high-concentration preparation of eight live bacterial strains, is the most well-studied probiotic. Studies suggest that VSL#3 can prevent recurrent pouchitis, a complication of IPAA that can occur in over 50% of patients following surgery. One randomized controlled trial randomized 40 patients to either VSL#3 (900 billion bacteria daily) or placebo following IPAA and found that fewer patients receiving probiotics developed their first episode of pouchitis over a 12-month period (10% vs 40%; P<0.05).

Probiotics may also be effective at inducing and maintaining remission in mild to moderate UC. In a randomized clinical trial of 147 patients receiving either VSL#3 (900 billion bacteria/day) or placebo, significantly more patients receiving probiotics achieved a 50% improvement in the Ulcerative Colitis Disease Activity Index at week 6 compared to placebo (32.5% vs 10.0%; P=0.001). At week 12, 42.9% of probiotic-treated and 15.7% of placebo-treated patients achieved remission (P=0.001). Moreover, a meta-analysis found when VSL#3 is added to conventional therapy at a dose of 3.6 × 10 colony-forming units/day, it is safe and more effective than conventional therapy alone in achieving remission in patients with mild to moderate UC. In a randomized clinical trial of VSL#3 as add-on to 5-ASA in the maintenance of remission in pediatric patients with mild to moderate UC, fewer patients treated with probiotic relapsed within 1 year of follow-up (21.4% vs 73.3%). Another small trial of 36 patients found that 85% of patients taking 6 g VSL#3 daily maintained remission after 12 months of follow-up, compared to 6% of patients on placebo.

In summary, although VSL#3, has demonstrated promise in certain areas of management, additional randomized clinical trials will be required to determine its optimal usage.

Another intensely studied microorganism with probiotic properties is E. coli strain Nissle 1917, abbreviated as EcN. For over 100 years, this strain has been used as the active pharmaceutical ingredient in MUTAFLOR, a licensed medical product distributed in several countries, including Germany, Canada, Australia and others. This strain of E. coli obtained its name after its discoverer, Dr. Alfred Nissle, isolated it from the feces of a German soldier in 1917, during World War I. This solider had been deployed to a region which was heavily contaminated by Shigella; however, unlike his fellow comrades, he did not develop any diarrhea or intestinal disease. Suspecting a component of the soldier’s intestinal flora protected him from developing GI symptoms, he obtained a stool sample and successfully isolated a strain of E. coli with strong antagonistic activity against pathogenic enterobacteria. This antagonistic activity of EcN has more recently been shown to be partly due to the production of antimicrobial peptides and the ability to produce a range of siderophores, which are high-affinity iron-chelating compounds.

Since the pathogenesis of UC involves the interaction between genetic and immune factors as well as the gut microbiota, EcN has been of great interest as a treatment for IBD, in particular UC. In fact, EcN is the only probiotic recommended in the European Crohn’s and Colitis Organization’s guidelines as an effective alternative to mesalazine for the maintenance of remission in UC patients. Three major double-blind, randomized controlled trials (RCTs) have compared EcN to mesalazine in the prevention of relapse in UC patients. The largest of these trials was published in 2004 and enrolled 327 patients, with 162 receiving EcN and 165 receiving mesalazine. Over 12 months, 36.4% of EcN-treated patients relapsed compared to 33.9% in the mesalazine group, meeting the statistical criteria for equivalence of the two treatments. In addition, no difference in quality of life or tolerance were found and no unexpected drug reactions occurred. MUTAFLOR is not currently available in the US, but future studies that establish its safety and efficacy may change that.

Curcumin (Tumeric)

Curcumin, widely used in Indian medicine, demonstrates anti-inflammatory and anti-oxidative properties in human gut epithelial cell lines and reduces histologic features of inflammation in mice models. In a randomized controlled trial, curcumin was investigated in inducing remission in patients with active mild to moderate UC who had failed 5-ASA therapy. In this trial, 50 patients were randomized to receive continued maintenance mesalamine with either curcumin (3 g/day) or placebo. At 4 weeks, 53.8% of patients receiving curcumin achieved clinical remission compared to 0% in the control group (P=0.01) and 38% achieved endoscopic remission (partial Mayo score ≤1) compared to 0% in the control group (P=0.043).

In another randomized controlled trial, 89 patients with quiescent UC were randomized to receive either curcumin 1 g twice daily or placebo in addition to sulfasalazine or a 5-ASA for 6 months. During these 6 months, patients who received placebo experienced a higher rate of relapse (20.5%) compared to those treated with curcumin (4.65%). However, during a 6-month follow-up period, relapse rates became similar between groups. Given these results and the good safety profile of curcumin, this CAM shows promise as a complementary therapy in active or quiescent UC. It should be noted that these trials used very pure (~95%) curcumin; retail brands may not be sufficiently pure to be effective.

A recent meta analysis evaluated six randomized controlled clinical trials comprising a total of 349 patients. Eligible trials suggested that adjuvant curcumin (in addition to mesalamine therapy at baseline) treatment in UC was effective in inducing clinical remission (odds ratio [OR] = 5.18, 95% confidence interval [CI]: 1.84-14.56, P = 0.002), endoscopic remission (OR = 5.69, 95% CI: 1.28-25.27, P = 0.02) and endoscopic improvement (OR = 17.05, 95% CI: 1.30-233.00, P = 0.03), but not in clinical improvement (OR = 4.79, 95% CI: 1.02-22.43, P = 0.05). The authors concluded that curcumin, as an adjuvant treatment of mesalamine, was proved to be effective and safe in UC.

Traditional Chinese Medicine

Traditional Chinese medicine (TCM) involves the application of various herbal agents and is one of the oldest and most developed branches of CAM. In the treatment of UC, two agents have been of particular interest: Andrographis paniculate and Indigo naturalis. In a randomized clinical trial of patients with active mild to moderate UC, extracts from Andrographis paniculate were found to produce similar rates of clinical remission, response and endoscopic remission as 5-ASAs at 8 weeks. In another randomized controlled trial, a different extract of Andrographis paniculate was found to be superior to placebo at inducing clinical response. Adverse events were similar between treatment groups, with the most common being abdominal pain, diarrhea and headache.

The safety and efficacy of Indigo naturalis were assessed in an 8-week randomized clinical trial enrolling 86 patients with active UC refractory to conventional treatments. Compared to placebo, patients randomized to daily Indigo naturalis had significantly higher rate of clinical response, remission and mucosal healing. Adverse events included diarrhea, abdominal pain, nausea, vomiting and headaches. In addition, mild liver dysfunction was observed in 10 patients. The trial was terminated early due to a report of a patient outside the trial developing pulmonary arterial hypertension after 6 months of Indigo naturalis use. These results demonstrate that natural compounds may not be harmless, as can often be assumed by patients and highlights the general need for well-designed clinical trials in the assessment of CAMs.

Acupuncture, Massage Therapy and Moxibustion

Some of the most commonly used CAMs by IBD patients include massage, acupuncture and moxibustion. However, since acupuncture and moxibustion are relatively new practices in western society, many physicians are unaware of what these therapies involve.

• Massage therapy: involves applying pressure on joints and muscles while the patient is in the prone or supine position on a specially designed massage table.
• Acupuncture: Involves placing fine needles into the skin at precise locations called acupoints. Several variations exist, sometimes used in conjunction with small electrical currents or heat.
• Moxibustion: Involves burning dried mugwort cones placed at specific points on the body, depending on the ailment being treated. Mugworts (genus Artemisia), including the common mugwort (Artemisia vulgaris) and Japanese mugwort (Artemisia princeps), are flowering plants in the daisy family, related to ragweed. Mugworts are used to flavor food and as herbal medicine in many different foods, including German Christmas goose, Korean clam soup, and kusa mochi (a Japanese dessert). In moxibustion, the burning cones warm the underlying skin and are removed before the skin burns. An alternative method is to hold a burning mugwort stick near the skin, warming it. Different herbs may be used in conjunction with mugwort.
• Massage therapy is commonly used to treat exercise-related injuries, but many studies have reported benefits in a variety of other conditions, including anxiety, depression and pain. In IBD, Swedish and Canadian studies reported than 20% and 30% of CAM-using patients, respectively, used massage therapy. However, clinical trials evaluating the efficacy of massage therapy are lacking, in both patients with IBD and in general, in part due to difficulty around developing an appropriate control treatment. Similarly, few studies with high enough methodologic quality exist for moxibustion or acupuncture in the treatment of IBD, as there is also debate regarding appropriate controls.

While these therapies may be beneficial alone or in combination with conventional therapies, further data are necessary before more formal recommendations can be made on their use in the management of UC.

Exercise

Patients are often interested in learning about modifiable factors, such as exercise, that can impact the course or severity of their disease. In healthy individuals, exercise is associated with several benefits, including improvements to physical, psychological and cognitive health indicators. For example, exercise decreases all-cause mortality independent of BMI and has beneficial effects on bone mineral density, functional capacity and muscle mass. Exercise also has demonstrated benefits in gastrointestinal disease, with mild to moderate intensity exercise being linked to a decrease in constipation, diverticular disease and cholelithiasis. Moderate exercise is also associated with an average risk reduction of 20% to 25% for colorectal cancer.

Considering many IBD patients have low bone mineral density, due to medications such as corticosteroids, nutritional deficiencies, and the disease itself and are at greater risk for risk for developing colorectal dysplasia, exercise has distinct benefits for the IBD patient. However, barriers to exercise in IBD patients do exist. For instance, with ongoing symptoms, patients may be resistant to exercise in public areas or in areas outside the home without readily accessible bathrooms. Symptom exacerbation is yet another concern. In a survey of 900 patients with CD or UC, 23% reported that exercise worsened their IBD symptoms, with 41% of these patients reporting fatigue, 12% reporting increased frequency, and 17% reporting increased abdominal pain. However, most of the patients (72%) reported that exercise improved their symptoms. Thus, moderate-intensity exercise may have beneficial effects on both disease course and quality of life in IBD patients with non-severe disease. Additional studies are required to guide specific recommendations regarding the types, intensity and frequency of exercises that would be of greatest benefit to IBD patients.

Vitamin D

Vitamin D deficiency has been shown to be more frequent among patients with IBD compared with the general population. Although it is unclear whether vitamin D deficiency is a causative factors in the pathogenesis of IBD, its deficiency is linked to increased disease activity, more frequent relapses, poorer quality of life and impaired response to biologicals compared to patients with normal or elevated levels of the biologically active form of vitamin D, 1,25(OH)2D. The benefits of vitamin D extend beyond its classical effects on bone mineralization: since it is a negative modulator of proinflammatory cascades, vitamin D deficiency may increase the risk of flaring IBD, leading to intestinal epithelial barrier defects, an exacerbated immune response and intestinal barrier deterioration. A meta-analysis of 18 RCTs involving 908 IBD patients found that treatment with vitamin D reduced relapse rates more significantly than placebo, but there were no significant differences between the low-dose and high-dose vitamin D treatment. Altogether, the available evidence suggests vitamin D supplementation could be recommended as part of the treatment regimen for IBD, at least as an adjunctive treatment. However, additional RCTs are required to solidify its treatment benefits.