The role of diet in the prevention and treatment of Inflammatory Bowel Diseases.


Abstract

Inflammatory bowel diseases (IBD) – Crohn’s disease (CD) and ulcerative colitis (UC) – are chronic conditions characterised by relapsing inflammation of the gastrointestinal tract. They represent an increasing public health concern and an aetiological enigma due to unknown causal factors. The current knowledge on the pathogenesis of IBD is that genetically susceptible individuals develop intolerance to a dysregulated gut microflora (dysbiosis) and chronic inflammation develops as a result of environmental triggers. Among the environmental factors associated with IBD, diet plays an important role in modulating the gut microbiome, and, consequently, it could have a therapeutic impact on the disease course.

An overabundance of calories and some macronutrients typical of the Western dietetic pattern increase gut inflammation, whereas several micronutrients characteristic of the Mediterranean Diet have the potential to modulate gut inflammation, according to recent evidence. Immunonutrition has emerged as a new concept putting forward the role of vitamins such as vitamins A, C, E, and D, folic acid, beta carotene and trace elements such as zinc, selenium, manganese and iron. However, when assessed in clinical trials, specific micronutrients showed a limited benefit. Further research is required to evaluate the role of individual food compounds and complex nutritional interventions with the potential to decrease inflammation as a means of prevention and management of IBD.

The current dietary recommendations for disease prevention and management are scarce and non evidence-based. This review summarizes the current knowledge on the complex interaction between diet, microbiome and immune-modulation in IBD, with particular focus to the role of the Mediterranean Diet as a tool for prevention and treatment of the disease.

Are Carbs Bad for You? What Eating Carbs Actually Does to Your Body


Not all carbohydrates are created equal.
Sliced brown bread on a white background

Thinking about carbs probably conjures up images of anything and everything you’ve been programmed to avoid: pasta, cookies, cake, bread. These foods get a bad rap, so it’s no wonder that so many of us get the impression that carbs are bad for you. Nutritional advice in the past has trained us to almost fear them—and feel guilty for breaking down and indulging in their dense, bready goodness.

But what if we told you you’re thinking about this all wrong? (And not just because food guilt is a waste of time, as well as a harmful way to think about eating.) Yes, some types of carbohydrates don’t have much in the way of nutritional benefits: We’re looking at you, sugar. Sugar is a basic, broken-down carbohydrate, devoid of any nutrients. And as you’ve undoubtedly heard, eating too much added sugar is associated with a host of health problems. It’s reasonable to want to limit the amount of added sugar you consume on a regular basis, from a health perspective.

But complex carbohydrates, like those found in whole grain breads, grains like quinoa and farro, and yes, fruits, veggies, and dairy, are all part of a healthy diet. In fact, your body needs carbohydrates to complete its basic functions.Here’s what’s really happening inside your body when you eat carbs, and why they’re not the villains you’ve been taught to believe.

So, are carbs bad for you or good for you? Well, that’s really not the question you should be asking. Because when you look closely, not all carbs are created equal.

Carbs get a bad rap because we all think of the less-healthy ones—simple carbs like white bread, donuts, bagels, sugary cereal—which aren’t great for our health. But carbs come in two forms: simple and complex. “Simple carbohydrates are made up of short chains of carbon molecules that require little breakdown and go directly into the bloodstream [and cause a blood sugar spike],” Kim Larson, R.D., spokesperson for the Academy of Nutrition and Dietetics, tells SELF. Any simple carbohydrate, or just straight up sugar, really has no redeeming qualities, nutritionally speaking. Sugar is also associated with inflammation, which is connected to a slew of of problems, like heart disease and cancer. If you’re interested in the science around sugar and our bodies, you might want to check out Sugar Science, a (self-described) “authoritative source for the scientific evidence about sugar and its impact on health,” created by a team of health scientists from the University of California at San Francisco.

But about complex carbohydrates. These carbs have longer chains of carbon molecules, so it takes longer for your body to break them down. Which means the sugar isn’t dumped into our bloodstream such as what happens with simple carbs. “We experience a more steady-state infusion of sugar into our bloodstream that supplies longer lasting energy,” Larson says.

carbs_farro

 

Whatever type of carbohydrates you eat, your body works to break them down to their simplest form: glucose.

“The breakdown of carbohydrates starts in our mouth with salivary enzymes, then goes to the mechanical churning of the stomach using digestive enzymes, along with B vitamins (the helpers), and the journey ends when they are in their simplest form, glucose, which is then absorbed in the small intestine,” Larson explains. Glucose then travels to the liver to be distributed throughout the body. Your cells first use whatever glucose they need for energy, sending it to the muscles and tissues in your body. Some gets stored in the liver as a reserve tank, and any excess is stored as fat, both in the liver and in adipose tissue around your body. We know loading up on sugar is bad for our bodies, and can lead to chronic diseases like obesity and diabetes. Too much of any carbohydrate can do that, too, since it all ends up as glucose.

We need carbohydrates for our bodies to even function.

Carbohydrates are our bodies’ main source of energy. “Glucose is the form of sugar that our brains use,” explains Keri Glassman, R.D. We need a certain amount of it to fuel all of our metabolic processes “so we can have energy to do things like breathe, digest, run, work, think.” Literally, everything. Fat and protein have their jobs, too, but when it comes to getting that basic energy, carbs are key.

So, what about the whole weight-gain thing? “Certainly eating too much of anything (including protein and fat) will cause weight gain,” Larson explains. Just eating more calories than you burn in a day can lead to weight gain. The problem is that simple carbs and sugars won’t keep you full, so they’re really easy to overeat. If you eat healthy carbs, as part of a balanced diet that also includes protein and fat, your body will function the way it should.

carbs_cauliflower

 

Healthy, complex carbs are found in more foods than you think. And you should be eating them every day.

When someone says, “I’m cutting out carbs,” they usually mean they’re cutting out breads and pasta, Larson explains. Many of us forget that milk, whole grains, fruits, and vegetables are all carbohydrates, and also come with essential nutrients like fiber and protein. So when you’re eating cauliflower, peas, bananas, apples, broccoli—the list goes on—you’re indeed eating carbohydrates. And your body is happy about it.

Ditching all carbs isn’t a good move. Instead, eat the good kinds in moderation. “Over half of our daily calories should come from quality carbohydrates, like whole grains, dairy, fruits, and vegetables,” Larson notes. “We cannot support the brain if we are taking in less than 120 grams of carbohydrate per day, and a lack of glucose (like oxygen) to the brain can cause irreversible damage.” So certainly cut out those bad carbs, but you can (and should) eat the healthy ones every single day.

Here’s Why Your Poop Can Be So Freaking Weird on Your Period


You know what we’re talking about.
Poop-And-Periods

Most people are pretty open about the “joys” that come with having a period, like cramps, bloating, and sore boobs. But there’s one period side effect people really need to discuss more often, because maybe sharing the burden can at least make the load a little lighter: period poop.

Everyone’s situation is different, but it’s not uncommon for your regular poop habits to take a temporary vacation when you’re on your period, or be suddenly replaced with a whole lot of diarrhea, or both. “Many women do get bowel changes just before or during their period,” Kyle Staller, M.D., a gastroenterologist at Massachusetts General Hospital, tells SELF.

You’ve probably noticed this and dismissed it as just one of those body things, but there’s an actual biological cause you should know about.

“The reason that this happens is largely due to hormones,” says Dr. Staller. Pre-period constipation could be a result of an increase in the hormone progesterone, which starts to increase in the time between ovulation and when you get your period. Progesterone can cause food to move more slowly through your intestines, backing you up in the process.

So what about that diarrhea, though? Hormone-like substances called prostaglandins could be to blame for that. The cells that make up the lining of your uterus (known as endometrial cells), produce these prostaglandins, which get released as the lining of your uterus breaks down right before and during your period. If your body makes a lot of prostaglandins, they can make their way into the muscle that lines your bowels. There, they can cause your intestines to contract just like your uterus and push out fecal matter quickly, causing diarrhea in the process, Ashkan Farhadi, M.D., a gastroenterologist at MemorialCare Orange Coast Medical Center and director of MemorialCare Medical Group’s Digestive Disease Project in Fountain Valley, California, tells SELF. (Fun fact: These prostaglandins are also responsible for those painful cramps you might get every month.)

Of course, this can all vary in different people. But if you notice you experience constipation or diarrhea right around your period like clockwork, this may be why.

Having certain health conditions can also exacerbate period-related bowel changes.

If you struggle with a health condition like endometriosisCrohn’s diseaseirritable bowel syndrome, or ulcerative colitis, having your period can cause a flare-up of your symptoms. Ultimately, the symptoms you experience depend on your condition, Dr. Farhadi says.

For example, if you struggle with Crohn’s disease, which can often cause diarrhea, or IBS-D (a form of IBS that causes people to have diarrhea), your body’s release of prostaglandins during your period may cause you poop even more than usual. But if you suffer from IBS-C (IBS that causes people to have constipation), you may find yourself struggling even more to have a BM on your period as progesterone further slows your bowels’ activity. Since ulcerative colitis can lead to both diarrhea and constipation, you might experience an uptick in either during your period.

And unfortunately endometriosis can lead to pain during bowel movements around your period, Christine Greves, M.D., a board-certified ob/gyn at the Winnie Palmer Hospital for Women and Babies, tells SELF. Endometriosis is a disease where endometrial tissue that normally grows inside the uterus (or, as is up for debate, tissue similar to endometrial lining) grows outside of the uterus. This tissue can attach to your bowels and start trouble. “You then have bleeding around that area, and that can cause pain when you have a bowel movement,” Dr. Greves explains.

If your poop gets weird on your period, there are a few things you can do to cope.

The most important step is knowing what’s normal for you on your period and doing what you can to minimize any additional triggers. For instance, if you always get diarrhea during your period, and you know that coffee tends to make you poop more, it’s a good idea to cut back a little when you’re actually on your period, Dr. Farhadi says. You can also take Immodium on the first day of your period in anticipation of diarrhea, or carry it with you in case it strikes, he says. If you deal with constipation during your period, try upping your fiber and water intake in the middle of your cycle, when constipation-prompting progesterone levels start rising.

It can also help to pop some non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs, a common class of pain relievers, can block certain enzymes in your body from making prostaglandins. With fewer prostaglandins roaming around, you may get some relief from an achy belly and incessant pooping.

If you’re really having a hard time with poop issues on your period, talk to your doctor. They may be able to recommend next steps or refer you to a specialist who can. Your period is already annoying enough without spending forever on the toilet, either basically pooping water or straining hard to go in the first place.

Gastroenterologists Share 7 Things to Do When You Have Painful Gas


Pain is the cruel cherry on top.
Gas-Pains

Pretty much no one is happy to have gas (with the exception of the elementary school set, who of course finds it hilarious). Gas is a normal part of having a body, but it can also be straight-up painful sometimes.

Since you probably don’t feel comfortable calling out sick from work with gas or otherwise letting it disrupt your life, you likely want to get things sorted out ASAP. As it turns out, the key to fixing painful gas is knowing why it happens in the first place.

There are a few reasons gas can develop, and, well, it has to go somewhere.

Gas often happens as a normal part of your digestive process. Your stomach and small intestine don’t entirely break down certain carbohydrates you eat, so they end up getting to your large intestine intact, according to the National Institute of Diabetes and Digestive and Kidney Diseases. There, bacteria make gas as they process these undigested sugars, fibers, and starches. Certain foods, like dairy products and cruciferous vegetables such as Brussels sprouts, are more likely to cause gas than others, but everyone’s triggers are different.

You can also get gas if you swallow a lot of air. While it’s unlikely that you’re actually trying to suck down a bunch of oxygen, certain habits like regularly using a straw, drinking carbonated beverages, eating too quickly, and chewing gum can cause you to take in more air than normal. When this causes gas, it’s typically via burping, since the air comes back up before it can go all the way to your stomach.Beyond those causes, gas can happen if you have health conditions that affect your digestive system, like irritable bowel syndromeulcerative colitis, or Crohn’s disease, or bacterial overgrowth in the small intestine, according to the Mayo Clinic.

OK, but why does gas sometimes hurt so bad that you want to cry and check yourself into the ER?

Good question. Painful gas and other bothersome symptoms like bloating can happen if gas builds up in your system because you can’t expel it (like if you’re purposely holding it in), if you eat something that really doesn’t agree with you, or if you have an underlying condition that prevents gas from moving through your system normally. All of this can cause spasms and distension in your large intestine during the digestive process, which can be pretty painful, Jamile Wakim-Fleming, M.D., a gastroenterologist at the Cleveland Clinic, tells SELF.

Unfortunately, there isn’t one magic pill that will immediately get rid of any painful gas you may be experiencing. The drug simethicone, which is an anti-foaming agent present in medicines like Gas-X, is designed to reduce bloating and pain from gas and may help, but it’s not a guarantee, Kyle Staller, M.D., M.P.H., a gastroenterologist at Massachusetts General Hospital, tells SELF.

There are, however, a few tricks you can try to either make the gas go away or, at the very least, make you feel better.

1. Sip a glass of water slowly.

Drinking water does two things, says Dr. Wakim-Fleming: It can help move any gas-causing foods in your system through the digestive process, and it makes it harder for your intestines to contract in a way that gasses you up. See, your intestines contract to move food, and if they contract too strongly or for too long, that can lead to or exacerbate gas.

2. Try to stop swallowing so much air—seriously.

Downing some water can be counterproductive if you’re doing it in a way that will only lead to more gas. Until the pain abates, avoid habits that can lead to swallowing a ton of air, like taking big gulps of water at a time, using straws, drinking fizzy beverages, sucking your food down too quickly, talking a lot while eating, and chewing gum, Dr. Wakim-Fleming says.

3. Try getting up and walking around.

Exercise isn’t just great for your overall health—it can also help clear up painful gas and bloating. While a five-mile run probably isn’t first on your to-do list when you’re doubled over in pain, if you can manage a quick walk or other gentle movement, that can make a big difference.

“Exercise helps exercise your intestines, too,” Dr. Wakim-Fleming says. Experts don’t know exactly why exercise helps move gas along, but something about physical activity helps to boost your intestines’ muscle activity, Ashkan Farhadi, M.D., a gastroenterologist at MemorialCare Orange Coast Medical Center and director of MemorialCare Medical Group’s Digestive Disease Project in Fountain Valley, Calif., tells SELF. (This is part of why exercise is recommended for constipation.)

4. Consider if dairy is actually the culprit.

If you’re currently in the fetal position dealing with gas pain, think back to how much cheese, milk, and ice cream you had recently—even if you don’t think you’re lactose intolerant. You can spend years having zero issues when you drink a venti latte in the A.M., followed by a grilled cheese sandwich at lunch…until you suddenly do. As most people age, they start making less lactase, an enzyme that breaks down lactose, the sugar in dairy products, Dr. Staller says. This is one cause of lactase deficiency and lactose intolerance. As your digestive system’s bacteria tries to break down lactose without enough lactase to do the job, you may experience annoying symptoms like more painful gas than usual.

“Many people in their 20s and 30s have symptoms and don’t suspect that it’s the dairy products,” Dr. Staller says. If you think dairy is behind your painful gas, try cutting it out for a few weeks (or at the very least, the rest of the day) and see where that gets you.

5. Have some peppermint oil or peppermint tea.

It’s not just for your breath—peppermint can act as a spasmolytic, meaning it may help stop your intestines from spasming too much (which is what increases gas), says Dr. Staller. While this mechanism has mainly been studied in regard to irritable bowel syndrome, the muscle contractions in that disorder are the same ones that can make gas feel so terrible, he says.

Doctors aren’t totally sure whether it’s better to take peppermint in a capsule form or via something more standard like a mint or peppermint tea, so feel free to try whatever you have handy (but be sure to follow the instructions if you’re ingesting peppermint oil as a pill).

6. Snuggle under a blanket with a heating pad on your abdomen.

It’s not a hard sell when you feel like crap, but cozying up under a blanket with a heating pad on your abdomen can actually help fight gas. Like peppermint, warmth can have an antispasmodic effect on your body and help your intestines to relax instead of contract too hard or too much, lessening that achy sensation that all too often comes along with gas, Dr. Wakim-Fleming says. And don’t worry that lying down means your gas is having to struggle against gravity to exit—it makes no difference either way, Dr. Farhadi says. (Though, as we said, getting up and walking around for a bit can also be helpful to do before or after you settle in with a heating pad.)

7. And lastly, commit to keeping your fiber intake in check.

Fiber is a key part of a healthy diet and digestive system. It bulks up your stool, which helps you stay regular instead of getting constipated. But on the flip side, having too much fiber can make you gassy as the bacteria in your colon works to break this tough nutrient down, Dr. Farhadi says.

If you find that you’re always in pain after you eat a salad with both broccoli and Brussels sprouts, it’s really best to avoid those foods (or whatever the fiber-heavy food may be) until you feel better—and to try to space out when you eat them in the future.

These tips should, at the very least, help make your painful gas feel a bit better. But if you’re struggling with incredibly painful gas and nothing is helping, call your doctor. They should be able to help you find the root of the issue—and how to stop it.

Real Food Diet Therapy Helps Children With Crohn’s Disease and Ulcerative Colitis


Digestive issues are running rampant and the modern diet is to blame. Crohn’s disease is one of the most debilitating of these conditions. Of the 1.4 million Americans dealing with IBD today, about 700,000 are suffering from Crohn’s. Crohn’s disease is a type of inflammatory bowel disease (IBD) that occurs when an abnormal immune system response leads to chronic inflammation anywhere in the GI or digestive tract — from the mouth to the anus.

A recent study in Science Daily offers a glimmer of hope to Crohn’s and ulcerative colitis sufferers. Researchers from Seattle Children’s Hospital successfully treated children who suffer from these conditions with dietary changes alone.

The dietary changes mandated by this study all fall in the category of common sense. No sugar except for honey, no pasteurized dairy products, no processed foods and no grains. Instead, the children in the study were allowed to consume only nutritional and nourishing whole foods.

That this approach was successful should come as no surprise. The sugar-laden modern diet is to blame for the myriad health problems that plague the western world. Life expectancy is plunging in the US and obesity is on the rise. Poor nutritional choices play an outsized role in these negative health trends.

It can be daunting to navigate the vast amount of dietary information and misinformation that is available online. It is for this reason that I created a convenient and informative nutrition plan. The first step to a healthier diet is to jettison all processed foods from your diet. The convenience and perceived value they provide is entirely illusory. Instead, consume exclusively nourishing whole foods and plenty of healthy fats. Taking control of your health is a transformational journey that starts with a healthy diet.

Crohn’s Disease and Ulcerative Colitis: Find Out Their Similarities and Differences


Some people interchange Crohn’s disease and ulcerative colitis (UC) because there are certain similarities between these two ailments. They are two different types of inflammatory bowel disease (IBD)1 — this is the umbrella term for these conditions (Other lesser-known types of IBD include collagenous colitis and lymphocytic colitis).

ulcerative colitis

Story at-a-glance

  • Some people interchange Crohn’s disease and ulcerative colitis (UC) because there are certain similarities between these two ailments
  • Crohn’s disease and ulcerative colitis both occur in teenagers and young adults. They affect women and men equally, and their symptoms are very similar

Crohn’s disease and ulcerative colitis both occur in teenagers and young adults. They affect women and men equally, and their symptoms are very similar.

What’s more, their definitive causes have not yet been determined, although genes, environmental exposure, and poor immune response are both seen as contributing factors to both of these diseases.

However, what sets these two apart is the area (or areas) they affect. While they both cause chronic inflammation in the gastrointestinal (GI) tract, ulcerative colitis is limited to the rectum and colon, or the large intestine.

It begins in the rectum or sigmoid colon, and spreads up through the colon as the disease progresses. The inflammation and irritation mostly affect only the innermost layer of the intestine lining.2

On the other hand, Crohn’s disease can manifest generally on any area throughout the GI, from the mouth to the anus. It may also appear in patches. Some areas may be affected, while some sections can be inflammation-free.3 However, it occurs in all the layers of the bowel walls (unlike UC, which only affects the innermost layer).

As a result of the deep ulcers and tissue swelling, the bowel walls affected by Crohn’s disease become thicker, with a cobblestoned appearance.

In ulcerative colitis, the bowel walls remain thin, but lose their vascular pattern (meaning the blood vessels are not visible), and there are no patches of healthy tissue that can be seen in the affected areas.

Another telltale sign of Crohn’s disease is the presence of granulomas, which are inflamed cells that are lumped together to form a lesion. Since granulomas are present in Crohn’s disease, but not in ulcerative colitis, the presence of these can help your physician reach a definite diagnosis.

Crohn’s disease may also lead to complications like strictures, fistulas, and fissures, which are less frequent in UC cases. Both Crohn’s disease and UC are chronic conditions, meaning they may have periods of being symptom-free (remission), but with occasional flare-ups. Their symptoms are generally the same: cramping, persistent diarrhea, and abdominal pain.4

However, Crohn’s disease patients usually feel the pain in their lower right abdomen, while UC patients experience it in the lower left abdomen. Most UC patients also have some bloody discharge with their stool, while this occurs much less commonly in people with Crohn’s disease.

Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.


BACKGROUND: Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial.

OBJECTIVES: To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis.

SEARCH METHODS: The MEDLINE, EMBASE and Cochrane Library databases were searched from inception to 30 July 2015. Both full randomized controlled trials and associated abstracts were included.

SELECTION CRITERIA: Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (e.g. mesalazine) were included.

DATA COLLECTION AND ANALYSIS: Two authors independently extracted data using standard forms. Disagreements were solved by consensus including a third author. Study quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to maintain clinical or endoscopic remission. Secondary outcomes included adverse events and withdrawal due to adverse events. Analyses were performed separately by type of control (placebo, or active comparator). Pooled risk ratios were calculated based on the fixed-effect model unless heterogeneity was shown. The GRADE approach was used to assess the overall quality of evidence for pooled outcomes.

MAIN RESULTS: Seven studies including 302 patients with ulcerative colitis were included in the review. The risk of bias was high in three of the studies due to lack of blinding. Azathioprine was shown to be significantly superior to placebo for maintenance of remission. Fourty-four per cent (51/115) of azathioprine patients failed to maintain remission compared to 65% (76/117) of placebo patients (4 studies, 232 patients; RR 0.68, 95% CI 0.54 to 0.86). A GRADE analysis rated the overall quality of the evidence for this outcome as low due to risk of bias and imprecision (sparse data). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity and thus were not pooled. Fifty per cent (7/14) of 6-mercaptopurine patients failed to maintain remission compared to 100% (8/8) of mesalazine patients (1 study, 22 patients; RR 0.53, 95% CI 0.31 to 0.90). Fifty-eight per cent (7/12) of azathioprine patients failed to maintain remission compared to 38% (5/13) of sulfasalazine patients (1 study, 25 patients; RR 1.52, 95% CI 0.66 to 3.50). One small study found that 6-mercaptopurine was superior to methotrexate for maintenance of remission. In the study, 50% (7/14) of 6-mercaptopurine patients and 92% (11/12) of methotrexate patients failed to maintain remission (1 study, 26 patients; RR 0.55, 95% CI 0.31 to 0.95). One very small study compared azathioprine with cyclosporin and found that there was no significant difference between patients failing remission on azathioprine (50%, 4/8) or cyclosporin (62.5%, 5/8) (1 study, 16 patients, RR 0.80 95% CI 0.33 to 1.92). When placebo-controlled studies were pooled with aminosalicylate-comparator studies to assess adverse events, there was no statistically significant difference between azathioprine and control in the incidence of adverse events. Nine per cent (11/127) of azathioprine patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 to 8.01). Patients receiving azathioprine were at significantly increased risk of withdrawing due to adverse events. Eight per cent (8/101) of azathioprine patients withdrew due to adverse events compared to 0% (0/98) of control patients (5 studies, 199 patients; RR 5.43, 95% CI 1.02 to 28.75). Adverse events related to study medication included acute pancreatitis (3 cases, plus 1 case on cyclosporin) and significant bone marrow suppression (5 cases). Deaths, opportunistic infection or neoplasia were not reported.

AUTHORS’ CONCLUSIONS: Azathioprine therapy appears to be more effective than placebo for maintenance of remission in ulcerative colitis. Azathioprine or 6-mercaptopurine may be effective as maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine. This review updates the existing review of azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis which was published in the Cochrane Library

Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.


BACKGROUND: Oral 5-aminosalicylic (5-ASA) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. Previously, it was found that 5-ASA drugs were more effective than placebo but had a statistically significant therapeutic inferiority relative to SASP. This updated review includes more recent studies and evaluates the effectiveness, dose-responsiveness, and safety of 5-ASA preparations used for maintenance of remission in quiescent ulcerative colitis.

OBJECTIVES: The primary objectives were to assess the efficacy, dose-responsiveness and safety of oral 5-ASA compared to placebo, SASP, or 5-ASA comparators for maintenance of remission in quiescent ulcerative colitis. A secondary objective was to compare the efficacy and safety of once daily dosing of oral 5-ASA with conventional (two or three times daily) dosing regimens.

SEARCH METHODS: A literature search for relevant studies (inception to 9 July 2015) was performed using MEDLINE, EMBASE and the Cochrane Library. Review articles and conference proceedings were also searched to identify additional studies.

SELECTION CRITERIA: Studies were accepted for analysis if they were randomized controlled trials with a minimum treatment duration of six months. Studies of oral 5-ASA therapy for treatment of patients with quiescent ulcerative colitis compared with placebo, SASP or other 5-ASA formulations were considered for inclusion. Studies that compared once daily 5-ASA treatment with conventional dosing of 5-ASA and 5-ASA dose ranging studies were also considered for inclusion.

DATA COLLECTION AND ANALYSIS: The primary outcome was the failure to maintain clinical or endoscopic remission. Secondary outcomes included adherence, adverse events, withdrawals due to adverse events, and withdrawals or exclusions after entry. Trials were separated into five comparison groups: 5-ASA versus placebo, 5-ASA versus sulfasalazine, once daily dosing versus conventional dosing, 5-ASA versus comparator 5-ASA formulation, and 5-ASA dose-ranging. Placebo-controlled trials were subgrouped by dosage. Once daily versus conventional dosing studies were subgrouped by formulation. 5-ASA-controlled trials were subgrouped by common 5-ASA comparators (e.g. Asacol and Salofalk). Dose-ranging studies were subgrouped by 5-ASA formulation. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention-to-treat basis.

MAIN RESULTS: Forty-one studies (8928 patients) were included. The majority of included studies were rated as low risk of bias. Ten studies were rated at high risk of bias. Seven of these studies were single-blind and three studies were open-label. However, two open-label studies and four of the single-blind studies utilized investigator performed endoscopy as an endpoint, which may protect against bias. 5-ASA was significantly superior to placebo for maintenance of clinical or endoscopic remission. Forty-one per cent of 5-ASA patients relapsed compared to 58% of placebo patients (7 studies, 1298 patients; RR 0.69, 95% CI 0.62 to 0.77). There was a trend towards greater efficacy with higher doses of 5-ASA with a statistically significant benefit for the 1 to 1.9 g/day (RR 0.65; 95% CI 0.56 to 0.76) and the > 2 g/day subgroups (RR 0.73, 95% CI 0.60 to 0.89). SASP was significantly superior to 5-ASA for maintenance of remission. Forty-eight per cent of 5-ASA patients relapsed compared to 43% of SASP patients (12 studies, 1655 patients; RR 1.14, 95% CI 1.03 to 1.27). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome for the placebo and SASP-controlled studies was high. No statistically significant differences in efficacy or adherence were found between once daily and conventionally dosed 5-ASA. Twenty-nine per cent of once daily patients relapsed over 12 months compared to 31% of conventionally dosed patients (8 studies, 3127 patients; RR 0.91, 95% CI 0.82 to 1.01). Eleven per cent of patients in the once daily group failed to adhere to their medication regimen compared to 9% of patients in the conventional dosing group (6 studies, 1462 patients; RR 1.22, 95% CI 0.91 to 1.64). There does not appear to be any difference in efficacy among the various 5-ASA formulations. Forty-four per cent of patients in the 5-ASA group relapsed compared to 41% of patients in the 5-ASA comparator group (6 studies, 707 patients; RR 1.08, 95% CI 0.91 to 1.28). A pooled analysis of two studies showed no statistically significant difference in efficacy between Balsalazide 6 g and 3 g/day. Twenty-three per cent of patients in the 6 g/day group relapsed compared to 33% of patients in the 3 g/day group (216 patients; RR 0.76; 95% CI 0.45 to 2.79). One study found Balsalazide 4 g to be superior to 2 g/day. Thirty-seven per cent of patients in the 4 g/day Balsalazide group relapsed compared to 55% of patients in the 2 g/day group (133 patients; RR 0.66; 95% CI 0.45 to 0.97). One study found a statistically significant difference between Salofalk granules 3 g and 1.5 g/day. Twenty-five per cent of patients in the Salofalk 3 g/day group relapsed compared to 39% of patients in the 1.5 g/day group (429 patients; RR 0.65; 95% CI 0.49 to 0.86). Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache, dyspepsia, and nasopharyngitis. There were no statistically significant differences in the incidence of adverse events between 5-ASA and placebo, 5-ASA and SASP, once daily and conventionally dosed 5-ASA, 5-ASA and comparator 5-ASA formulations and 5-ASA dose ranging studies. The trials that compared 5-ASA and SASP may have been biased in favour of SASP because most trials enrolled patients known to be tolerant to SASP which may have minimized SASP-related adverse events.

AUTHORS’ CONCLUSIONS: 5-ASA was superior to placebo for maintenance therapy in ulcerative colitis. However, 5-ASA had a statistically significant therapeutic inferiority relative to SASP. Oral 5-ASA administered once daily is as effective and safe as conventional dosing for maintenance of remission in quiescent ulcerative colitis. There does not appear to be any difference in efficacy or safety between the various formulations of 5-ASA. Patients with extensive ulcerative colitis or with frequent relapses may benefit from a higher dose of maintenance therapy. High dose therapy appears to be as safe as low dose and is not associated with a higher incidence of adverse events.

New Drug Class in the Works for Ulcerative Colitis


Ozanimod, a novel sphingosine 1-phosphate receptor modulator, is safe and effective in the treatment of patients with moderate to severe ulcerative colitis, according to results from the phase 2 TOUCHSTONE study.

“Ozanimod 1 mg induced clinical remission at week 8, the primary end point, and met all three secondary end points,” said William Sandborn, MD, from the University of California, San Diego.

“And the favorable benefit–risk profile supports the planned phase 3 trial and the phase 2 study in Crohn’s disease,” he reported here at Digestive Disease Week 2015.
The drug, an oral S1P receptor of subtypes 1 and 5, is also being evaluated in relapsing multiple sclerosis, Dr Sandborn explained. However, ozanimod has a more favorable safety profile than the SP1 receptor modulator fingolimod, which has been used on more than 100,000 multiple sclerosis patients.

The international 8-week induction trial involved 197 patients with moderate to severe ulcerative colitis, defined as a Mayo score of 6 to 12 and an endoscopy subscore of at least 2. For responders, there was a continuing maintenance period.

Patients were randomized to ozanimod 0.5 mg, ozanimod 1.0 mg, or placebo.

The primary end point was remission at week 8, defined as a Mayo score of 2 or lower and no subscore greater than 1.

The secondary end point of response was defined as a reduction in Mayo score of at least 3 and at least 30%, and a decrease in the rectal bleeding score of at least 1 or a rectal bleeding score of 1 or lower. The other secondary end points were mucosal improvement, defined as an endoscopy subscore of 1 or lower, and change in Mayo score.

The induction portion of the study was completed by 95% of patients.

“A dose–response relationship was observed for all primary and key secondary efficacy end points,” Dr Sandborn reported.

The differences between high-dose ozanimod and placebo were significant for clinical response (P = .0207), clinical remission (P = .0482), mucosal improvement (P = .0023), and improvement in Mayo score (P = .0035).

The differences between low-dose ozanimod and placebo were significant for mucosal improvement (P = .0348).

Table 1. TOUCHSTONE Study Outcomes

Outcome Ozanimod 1.0 mg Ozanimod 0.5 mg Placebo
Clinical remission at week 8, % 16.4 13.8 6.2
Clinical response at week 8, % 56.7 53.8 36.9
Mucosal improvement at week 8, % 34.3 27.7 12.3
Improvement in Mayo Score from baseline, points 3.3 2.6 1.9

Safety assessments included electrocardiogram, Holter monitoring, pulmonary function testing, optical coherence tomography, and adverse events.

Adverse event profiles were comparable in the three groups, with approximately 31% of patients experiencing a treatment-emergent adverse event in each group.

Table 2. Adverse Events

Adverse Event Ozanimod 1.0 mg, % Ozanimod 0.5 mg, % Placebo, %
Worsening of ulcerative colitis 1.5 3.1 4.6
Anemia or decreased hemoglobin level 0.0 4.6 6.2
Serious treatment-emergent event 1.5 1.5 6.2

Three patients receiving ozanimod experienced transient elevations in alanine aminotransferase. There were no significant cardiac, ophthalmologic, or infectious findings.
During a plenary lecture, Maria Abreu, MD, from the University of Miami Health System, expressed optimism about the use of SP1 receptor modulators in ulcerative colitis.

SP1 receptor modulators sequester T-cells, “so they can’t get out of the gut,” she explained. “Ozanimod basically interferes with the ability of the cells to recognize their way back out of the lymph node.”

“Presumably this is a new and improved version of molecules that have been used effectively in multiple sclerosis,” she added.

“This is a new class of drug that might work differently from current drugs for inflammatory bowel disease,” said Charles Bernstein, MD, from the University of Manitoba in Winnipeg, Canada.

“They’ve been successful in multiple sclerosis, and both IBD and MS are T-cell-mediated diseases,” he told Medscape Medical News. “There’s a lot of enthusiasm, therefore, that this may be a class of drug that will be very beneficial. Also, the safety data in TOUCHSTONE look very good.

“We are looking forward to seeing more about this drug,” he said.

New Clinical Trial Data: Scripps Research Institute MS Drug Candidate Also Shows Promise for Ulcerative Colitis


Positive new clinical data were released today on a drug candidate for ulcerative colitis that was first discovered and synthesized at The Scripps Research Institute (TSRI).

According to results released today from a Phase 2 study of 199 patients with active, moderate to severe disease, the drug candidate RPC1063 has potential to significantly improve the treatment paradigm for ulcerative colitis patients. The latest results show that, after eight weeks of treatment with a 1 mg dose of RPC1063, 16.4 percent of patents were in clinical remission, as compared to 6.2 percent of patients on placebo.

“We are delighted that RPC1063 is showing promise for ulcerative colitis patients in addition to its already significant efficacy and safety data in multiple sclerosis,” said TSRI Professor Hugh Rosen, who together with Professor Ed Roberts led the team that discovered RPC-1063. “Research carried out at TSRI since 2002 has led to the discovery of fundamental mechanisms that can be modulated for potential treatments of a variety of autoimmune diseases including ulcerative colitis and multiple sclerosis, and the unique multidisciplinary environment in chemistry and biology at TSRI allowed this progression to clinical trials.”

The clinical trial, sponsored by Receptos, Inc., the San Diego biotechnology company now developing the drug, also showed that RPC1063 was generally well tolerated.

Ulcerative colitis is a chronic condition that involves inflammation and sores in the inner lining of the digestive tract. Ulcerative colitis is an inflammatory bowel disease, which, along with Crohn’s disease, affects more than one million people nationwide, according to the U.S. Centers for Disease Control and Prevention. Some people have mild disease, while others are affected with life-threatening complications.

While existing medications for ulcerative colitis do help some patients, 23 to 45 percent of ulcerative colitis sufferers progress and eventually require surgical removal of all or part of the colon, according to the Crohn’s and Colitis Foundation of America.

The drug candidate RPC1063 was derived from a screening “hit” from the National Institutes of Health molecular library at Scripps Florida’s Molecular Screening Center, using assay technology from the Rosen lab in La Jolla. The Roberts and Rosen labs then developed significant medicinal chemistry to turn that hit into a validated lead, and then ultimately a drug candidate.

TSRI then licensed the compound to Receptos, which is developing RPC1063 for approval by the U.S. Food and Drug Administration.

The latest results come from Receptos’s multi-national, multi-center, double-blind, randomized, placebo-controlled study investigating the effect of two active doses of RPC1063 versus placebo for the treatment of moderately to severely active ulcerative colitis. For more information on the results, see the press release from Receptos athttp://ir.receptos.com/releasedetail.cfm?ReleaseID=878411

In light of the current positive results, Receptos plans to initiate a Phase 3 trial of RPC1063 for ulcerative colitis, as well as a Phase 2 study of the drug candidate for Crohn’s disease.

The mechanism of RPC1063 (Sphingosine 1-Phosphate Receptor modulation) may also be significant in the treatment of other autoimmune diseases. Receptos is also currently evaluating the drug candidate in a Phase 3 study for the treatment of multiple sclerosis.

 

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