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Expert Critique
FROM THE ASCO Reading Room
There is a paucity of data on IBS-M, and primarily because of the variation in symptoms, diagnosing these patients is challenging. ICD-10 codes are yet to have an entry for IBS-M as well. Experts believe that because of the variation in stool consistency and frequency, it is difficult to determine study endpoints for these patients -- making studying this group of patients challenging. Obtaining a detailed, diary-based history of the patient’s bowel habits is key to making this diagnosis.
Management of IBS-M is challenging. Drugs used for IBS-C, like lubiprostone and linaclotide, can make symptoms of diarrhea worse, while drugs routinely used for IBS-D, like eluxadoline and elosetron, lead to worsening constipation. Some experts suggest a three-fold management approach to these patients: (1) Low FODMAP diet (fermentable, oligosaccharides, disaccharides, monosaccharides, and polyols); (2) peppermint oil-based products -- i.e. IBgard; and (3) rifaximin.
In summary, despite recent advances in the treatment of IBS, little is known about IBS-M. Future research in biomarkers, gut microbiota, and bacterial overgrowth theories is needed to aid with the diagnosis and management of patients with IBS-M.
Formerly known as IBS alternating, mixed-type IBS (IBS-M) remains poorly characterized, and clinical studies including IBS-M patients in their mix are few. Most gastroenterologists believe the characteristics of this subtype and the population it affects need better definition in biomarker studies and prospective trials.
According to , this heterogeneous condition is now defined as a pattern of hard or lumpy stools in more than 25% of bowel movements and loose or mushy stools in more than 25% according to Bristol Stool Form Scale 1-2 for constipation and scale 6-7 for diarrhea. A found that IBS-M patients' most bothersome symptoms resembled those of IBS with diarrhea (IBS-D) more than those of IBS with constipation (IBS-C), with the most common being irregular bowel habits, bloating, and abdominal pain.
In other experience the subtype seems to be closer to IBS-C: "It seems to affect slightly more women than men, but the difference is not as much as with IBS with constipation," said , of UCLA.
IBS-M symptoms can fluctuate rapidly, and the psychological burden on patients can be onerous, said assistant director of the Gastrointestinal Motility Program at Cedars-Sinai Medical Center in Los Angeles. Alternating bowel habits can happen on a daily basis: "One day you wake up, and this is your diarrhea day. You have six or seven bowel movements. Then the day after, constipation starts in with hard stools and straining."
Chang said she has seen patients who will have constipation for up to a week and then cycle back to a day or two of diarrhea or even normal bowel movements. "In those patients, clinicians will typically try to treat the constipation in an effort to minimize the chance of the day of diarrhea that follows it. The diarrhea seems almost like a self-purge."
Intervals between the two patterns can vary widely. "They can even happen within the same day," Rezaie said. "I have patients who say they have constipation early in the morning, and then by evening they have loose watery stools." Even within the same bowel movement, some patients may start with hard stool that has to be pushed and by the end it will be watery, he added.
In Rezaie's view, this subtype is harder on patients than either pure IBS-D or pure IBS-C. "A lot of these patients have classic IBS pain and urgency, as well significant abdominal distention and bloating that bother them more than the alternation itself."
Diagnosing this patient population is also problematic, he added. "There's no scale to put them on to say they have IBS-M. The ICD-10 Codes don't even have an entry for IBS-M." Alternating laxative and antidiarrheal medications can complicate the situation, and some IBS medications for diarrhea or constipation are not appropriate for this subtype. "The problem is, if you try an IBS-C medication like lubiprostone [Amitiza] or linaclotide [Linzess] on these patients, they get diarrhea. If you try IBS-D drugs like eluxadoline [Viberzi] or alosetron [Lotronex], they get very bad constipation."
Also giving his perspective, , of the Cleveland Clinic thinks IBS would be better considered not as one disease with subtypes, but as different diseases with constellations of symptoms and different etiologies. "We need to reevaluate the concept of grouping IBS patients. I think we should change the names based on cause. Instead of IBS-D or IBS-M, we should use names like bacterial overgrowth syndrome."
In the clinical setting, Rezaie's approach to managing his IBS-M patients is mainly three-fold: First, he recommends a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP), restricting poorly digested fermentable foods such as beans, broccoli, and cauliflower. "The low-FODMAP diet works pretty well but, clearly, dietary restriction can affect quality of life -- sometimes more than the symptoms themselves," Rezaie said.
Second, he favors the peppermint oil-derived product IBgard, a formulation that is time-released in the small intestine. In of the product to include IBS-M patients, those randomized to IBgard had improvement in symptoms over placebo. 'It is basically a 5-HT3 receptor antagonist and is very safe," Rezaie said.
Third, he said he uses rifaximin, a poorly absorbed antibiotic that targets the gut microbiome: "This is a good option in IBS-M, because the rate of constipation that results is very low – about half a percent." The two randomized reported in 2011 showed the antibiotic to be effective for symptoms of both IBS-D and IBS-M.
Rezaie also stressed the importance of getting a detailed, diary-based history of a patient's bowel habits.
As for the paucity of clinical studies specifically in IBS-M, Chang said the dilemma has been establishing outcome criteria for this poorly characterized subtype. "If you're going to determine that a patient is better off on a particular treatment, what symptoms are you going to use as endpoints? You can target pain, because all IBS patients have pain, but what can you say about stool frequency and consistency, because these go back and forth?"
Chang added that a substantial portion of IBS-M patients do not meet the Rome IV >25% thresholds for diarrhea and constipation when asked to keep stool diaries. "That's why the criteria were recently changed to use the 25% to apply only on days when patients have abnormal bowel movements, not on the days when bowel movements are normal," she explained.
Added Rezaie: "The problem is there are no set outcomes for the FDA to approve for a trial, and you can't run a trial without knowing what you're targeting."
According to Chang, a trial in IBS-M planned by Takeda Pharmaceuticals using the IBC-C drug lubiprostone ran into problems recruiting patients. "Clinicians have tended to kind of avoid this mixed subgroup. What we need to do now is use the new criteria to define this patient population and see if they have any traits or physiological parameters that are specific to them."
Rezaie agreed that a better classification of IBS-M patients is crucial: "Future research on biomarkers will be very important."
Shatnawei added, "We definitely need to dig deeper into the microbiome and bacterial overgrowth theories."
And if IBS-M isn't vague enough, there is always unsubtyped IBS, defined as insufficient abnormality of stool consistency to meet criteria for IBS-D, IBS-C, or IBS-M.