- 7 Things to Know Before Stopping Ulcerative Colitis Medication
- Why Staying on Your Medication Is Important
- Tips for Sticking With Treatment
- True Stories: Living with Ulcerative Colitis
- Ulcerative Colitis Treatment Not Working? 8 Steps to Take Now
- 1. Learn about your options
- 2. Make sure you’re sticking to protocol
- 3. Watch for symptoms
- 4. Ask about adding another medication
- 5. Know when it’s time to switch drugs
- 6. Look at your diet
- 7. Consider whether it’s time for surgery
- 8. The bottom line
- Point–counterpoint: Are we overtreating patients with mild ulcerative colitis?
- Clinical vignette
- Maintenance 5-ASA therapy to prevent symptomatic relapse of disease
- Maintenance 5-ASA therapy to reduce colectomy rates
- Maintenance 5-ASA therapy to reduce colorectal cancer risk
- Conflict of interest
- Author notes
7 Things to Know Before Stopping Ulcerative Colitis Medication
- When people feel better, they may decide that they no longer need ulcerative colitis medication. “Some patients think that once their symptoms are gone, they can stop taking their meds,” Dr. Phanijphand says. “They believe they’re cured or that they may have been misdiagnosed and don’t need these meds.”
- People may not like side effects they experience from the drugs. Mesalamine can cause headaches, nausea, or fatigue at higher doses, for example. Biologics and immunomodulators suppress the immune system and make you more susceptible to infection.
- Ulcerative colitis medication can be expensive.
- They simply forget or find that taking medication is inconvenient.
Why Staying on Your Medication Is Important
None of these reasons justify stopping medication. In fact, here are some valid ones for staying on track:
You’ll stay in remission. The reason you are in remission is that you’re on a maintenance drug. Phanijphand says he can’t emphasize that point enough. Stop taking your medication and you increase your risk of a flare — and the longer you’re off the drug, the higher your risk of suffering a relapse, he says.
“Relapse usually results in patients being put on prednisone and other steroids to get them back into remission,” Phanijphand says. “But the objective is to avoid frequent steroid exposure.” Steroids come with many side effects, especially when used long term, such as weight gain, high blood pressure, increased appetite, mood instability, bone loss, cataracts, and difficulty sleeping. “One reason to avoid frequent flares is so you can avoid steroid exposure,” Phanijphand says.
Drugs can be less effective the second time around. If you have moderate or severe ulcerative colitis, you may be given biologics, drugs that target specific proteins that cause inflammation in the colon. “When people stop taking biologics, most of them will relapse over time,” Phanijphand says. Start again, and the biologic that had been working well for you may no longer be as effective as it was. “It’s less effective because your body may form antibodies to it,” he says. You may be able to switch to a different drug, but the options are limited.
You’ll lower your cancer risk. The longer you have ulcerative colitis, the greater your risk of developing colon cancer. Staying in remission with medication may reduce this risk.
Tips for Sticking With Treatment
Try these strategies to stay on your ulcerative colitis medication:
- Talk to your healthcare provider about better ways to manage side effects. Sometimes the dose can be lowered, or you can try another treatment option, Phanijphand says.
- Tell your doctor if you have signs of an infection, such as fever, flu-like symptoms, a cough, or exhaustion, so that you can be treated right away.
- Investigate financial assistance if out-of-pocket expenses are the problem. Drug manufacturers often provide free or low-cost medications to patients who qualify. Also, your state, county, or local government may be able to assist you.
- If forgetfulness is an issue, set an alarm or use an app on your smartphone to remind you when to take your meds.
“Your disease is likely to progress if you don’t take your medications,” Phanijphand says. That means that once you find a plan that works, you don’t want to mess with it.
The most serious adverse reactions seen in Asacol clinical trials or with other products that contain mesalamine or are metabolized to mesalamine are:
- Renal impairment, including renal failure
- Acute intolerance syndrome
- Hypersensitivity reactions
- Hepatic failure
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In total, Asacol tablets have been evaluated in 2,690 patients with ulcerative colitis in controlled and open-label trials. Adverse reactions presented in the following sections may occur regardless of length of therapy and similar reactions have been reported in short-and long-term studies and in the postmarketing setting.
Clinical studies supporting Asacol use for the treatment of mildly to moderately active ulcerative colitis included two 6-week, placebo-controlled, randomized, double-blind studies in adults with mildly to moderately active ulcerative colitis (Studies 1 and 2), and one 6-week, randomized, double-blind, study of 2 dose levels in children with mildly to moderately active ulcerative colitis. Clinical studies supporting the use of Asacol tablets in the maintenance of remission of ulcerative colitis included a 6-month, randomized, double-blind, placebo-controlled, multi-center study and four active-controlled maintenance trials comparing Asacol tablets with sulfasalazine. Asacol has been evaluated in 427 adults and 82 children with ulcerative colitis in these controlled studies.
Treatment of Mildly to Moderately Active Ulcerative Colitis in Adults
In two 6-week placebo-controlled clinical studies (Studies 1 and 2) involving 245 patients, 155 of whom were randomized to Asacol , 3.2 percent of the Asacol-treated patients discontinued therapy because of adverse reactions as compared to 2.2 percent of the placebo-treated patients. The average age of patients in Study 1 was 42 years and 48 percent of patients were male. The average age of patients in Study 2 was 42 years and 59 percent of patients were male. Adverse reactions leading to withdrawal from Asacol included (each in one patient): diarrhea and colitis flare; dizziness, nausea, joint pain, and headache; rash, lethargy and constipation; dry mouth, malaise, lower back discomfort, mild disorientation, mild indigestion and cramping; headache, nausea, aching, vomiting, muscle cramps, a stuffy head, plugged ears, and fever.
Adverse reactions in patients treated with Asacol occurring at a frequency of at least 2 percent and at a rate greater than placebo in 6-week, double-blind, placebo-controlled trials (Studies 1 and 2) are listed in Table 2 below.
Table 2: Adverse Reactions Reported in Two Pooled Six-Week, Placebo-Controlled Trials (Studies 1 and 2) Experienced by at Least 2 percent of Patients in the Asacol Group and at a Rate Greater than Placebo
|Adverse Reaction||% of Patients with Adverse Reactions|
(n = 152)
(n = 87)
Treatment of Mildly to Moderately Active Ulcerative Colitis in Pediatric Patients 5 to 17 Years Old
A randomized, double-blind, 6-week study of 2 dose levels of Asacol (Study 3) was conducted in 82 pediatric patients 5 to 17 years of age with mildly to moderately active ulcerative colitis. All patients were divided by body weight category (17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg) and randomly assigned to receive a low dose (1.2, 2.0, and 2.4 g/day for the respective body weight category) or a high dose (2.0, 3.6, and 4.8 g/day).
The high dose is not an approved dosage because it was not found to be more effective than the approved dose .
Duration of exposure to mesalamine among the 82 patients in the study ranged from 12 to 50 days (mean of 40 days in each dose group). The majority (88 percent) of patients in each group were treated for more than 5 weeks. Table 3 provides a summary of the specific reported adverse reactions (ARs).
Table 3: Adverse Reactions Reported in One Six-Week Trial (Study 3) Experienced by at Least 5% of Patients in the Low Dose Group or High Dose Group
|Adverse Reaction||% of Patients with Adverse Reactions|
|Low Dose = Asacol 1.2 – 2.4 g/day; High Dose = Asacol 2.0 – 4.8 g/day. Dosage was dependent on body weight. Adverse Reactions reported at the 1-week telephone follow-up visit are included.|
Twelve percent of the patients in the low dose group and 5 percent of the patients in the high dose group had serious adverse reactions (ARs). Ulcerative colitis was reported as a serious AR in one subject in each group. Other serious ARs consisted of sinusitis, abdominal pain, decreased body mass index, adenovirus infection, bloody diarrhea, sclerosing cholangitis, and pancreatitis in one subject each in the low dose group and anemia and syncope in one subject each in the high dose group.
Seven patients were withdrawn from the study because of ARs: 5 (12 percent) in the low dose group (ulcerative colitis, adenovirus infection, sclerosing cholangitis, pancreatitis) and 2 (5 percent) in the high dose group (increased amylase and increased lipase, upper abdominal pain).
In general, the nature and severity of reactions in the pediatric population was similar to those reported in adult populations of patients with ulcerative colitis.
Maintenance of Remission of Ulcerative Colitis in Adults
In a 6-month placebo-controlled maintenance trial involving 264 patients (Study 4) 177 of whom were randomized to Asacol, six (3.4 percent) of the patients using Asacol discontinued therapy because of adverse reactions, as compared to four (4.6 percent) of patients using placebo . The average age of patients in Study 4 was 42 years and 55 percent of patients were male. Adverse reactions leading to study withdrawal in patients using Asacol included (each in one patient): anxiety; headache; pruritus; decreased libido; rheumatoid arthritis; and stomatitis and asthenia.
In addition to reactions listed in Table 2, the following adverse reactions occurred in patients using Asacol at a frequency of 2 percent or greater in Study 4: abdominal enlargement, gastroenteritis, gastrointestinal hemorrhage, infection, joint disorder, migraine, nervousness, paresthesia, rectal disorder, rectal hemorrhage, stool abnormalities, tenesmus, urinary frequency, vasodilation, and vision abnormalities.
In 3342 patients in uncontrolled clinical studies, the following adverse reactions occurred at a frequency of 5 percent or greater and appeared to increase in frequency with increasing dose: asthenia, fever, flu syndrome, pain, abdominal pain, back pain, flatulence, gastrointestinal bleeding, arthralgia, and rhinitis.
In addition to the adverse reactions reported above in clinical trials involving Asacol, the adverse reactions listed below have been identified during post-approval use of Asacol and other mesalaminecontaining products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as a Whole: Neck pain, facial edema, edema, lupus-like syndrome, drug fever.
Cardiovascular: Pericarditis, myocarditis .
Gastrointestinal: Anorexia, pancreatitis, gastritis, increased appetite, cholecystitis, dry mouth, oral ulcers, perforated peptic ulcer bloody diarrhea.
Hematologic: Agranulocytosis aplastic anemia, thrombocytopenia, eosinophilia, leukopenia, anemia, lymphadenopathy.
Nervous: Depression, somnolence, emotional lability, hyperesthesia, vertigo, confusion, tremor, peripheral neuropathy, transverse myelitis, Guillain-Barré syndrome.
Renal: Renal failure, interstitial nephritis, minimal change nephropathy .
Respiratory/Pulmonary: Eosinophilic pneumonia, interstitial pneumonitis, asthma exacerbation, pleuritis.
Skin: Alopecia, psoriasis, pyoderma gangrenosus, dry skin, erythema nodosum, urticaria.
Special Senses: Eye pain, taste perversion, blurred vision, tinnitus.
Urogenital: Dysuria, urinary urgency, hematuria, epididymitis, menorrhagia, reversible oligospermia.
Laboratory Abnormalities: Elevated AST (SGOT) or ALT (SGPT), elevated alkaline phosphatase, elevated GGT, elevated LDH, elevated bilirubin, elevated serum creatinine and BUN.
Read the entire FDA prescribing information for Asacol (Mesalamine Delayed-Release Tablets)
True Stories: Living with Ulcerative Colitis
Ulcerative colitis (UC) affects about 900,000 people in the United States. In any single year, about 20 percent of these people have moderate disease activity and 1 to 2 percent have severe disease activity, according to the Crohn’s and Colitis Foundation of America.
It’s an unpredictable disease. Symptoms tend to come and go, and sometimes they progress over time. Some patients go for years without symptoms, while others experience frequent flare-ups. Symptoms vary depending on the extent of the inflammation, as well. Because of this, it’s important for people with UC to keep track of how it affects them on an ongoing basis.
Here are the stories of four people’s experiences with UC.
When were you diagnosed?
How do you manage your symptoms?
My first treatment was with suppositories, which I found extremely uncomfortable, hard to put in, and hard to hold. For the next year and a half or so I was treated with rounds of prednisone and mesalamine (Asacol). This was awful. I had terrible ups and downs with prednisone, and every time I started to feel better I would feel sick again. I finally switched doctors to Dr. Picha Moolsintong in St. Louis, who actually listened to me and treated my case and not just my disease. I am still on azathioprine and escitalopram (Lexapro), which have been working very well.
What other treatments have worked for you?
I also tried a series of homeopathic treatments, including a gluten-free, starch-free diet. None of that really worked for me except meditation and yoga. UC can be stress-related, diet-related, or both, and my case is very stress-related. Nonetheless, maintaining a healthy diet is also important. If I eat processed food, pasta, beef, or pork, I pay for it.
It’s important with any autoimmune disease to exercise regularly, but I would argue it’s even more so for digestive diseases. If I don’t keep my metabolism high and my heart rate up, I find it hard to muster up the energy to do anything.
What advice would you give to other people with UC?
Try not to be embarrassed or stressed by your symptoms. When I first got sick, I tried to hide all of my symptoms from my friends and family, which just caused more confusion, anxiety, and pain. Also, don’t lose hope. There are so many treatments. Finding your individual balance of treatment options is key, and patience and good doctors will get you there.
How long ago were you diagnosed?
I was originally with UC at 18. Then I was diagnosed with Crohn’s disease about five years ago.
How difficult has it been to live with UC?
The major impact has been social. When I was younger, I was extremely ashamed of the disease. I’m very social but at that time, and even to this day, I would avoid large crowds or social situations because of my UC. Now that I’m older and have undergone surgery, I still have to be careful about crowded spots. I choose not to do group things at times simply because of the side effects of the surgery. Also, back when I had UC, the prednisone dosage would affect me physically and mentally.
Any food, medication, or lifestyle recommendations?
Stay active! It was the only thing that would halfway control my flare-ups. Beyond that, choice of diet is the next most important thing to me. Stay away from fried foods and excessive cheese.
Now I try to stay close to a Paleo diet, which seems to help me out. Especially for younger patients, I’d say don’t be ashamed, you can still lead an active life. I’ve run triathlons, and now I’m an active CrossFitter. It’s not the end of the world.
What treatments have you had?
I was on prednisone for years before having ileoanal anastomosis surgery, or J-pouch. Now I’m on certolizumab pegol(Cimzia), which keeps my Crohn’s in check.
How long ago were you diagnosed?
I was diagnosed with UC in 1998, immediately after the birth of my twins, my third and fourth children. I went from an extremely active lifestyle to being practically unable to leave my house.
What medications have you taken?
My GI doctor immediately put me on medications, which were ineffective, so he eventually prescribed prednisone, which only masked the symptoms. The next doctor got me off the prednisone but put me on 6-MP (mercaptopurine). The side effects were horrible, especially the effect on my white blood cell count. He also gave me a terrible and downhill prognosis for the rest of my life. I was very depressed and worried that I would not be able to raise my four children.
What helped you?
I did a lot of research, and with help I changed my diet and eventually was able to wean myself off of all the meds. I am now gluten-free and eat a primarily plant-based diet, although I do eat some organic poultry and wild fish. I have been symptom- and drug-free for several years. In addition to the dietary changes, getting adequate rest and exercise are important, as well as keeping stress under control. I went back to school to learn nutrition so I could help others.
When were you diagnosed?
I was diagnosed about 18 years ago, and at times it has been very challenging. The difficulty comes when the colitis is active and interferes with daily living. Even the simplest tasks become a production. Making sure there is a bathroom available is always at the forefront of my mind.
How do you deal with your UC?
I am on a maintenance dose of medication, but I am not immune to occasional flare-ups. I have simply learned to “deal.” I follow a very strict food plan, which has helped me tremendously. However, I do eat things that many people with UC say they cannot eat, such as nuts and olives. I try to eliminate stress as much as possible and to get enough sleep each day, which is impossible sometimes in our crazy 21st-century world!
Do you have advice for other people with UC?
My biggest piece of advice is this: Count your blessings! No matter how bleak things look or feel at times, I can always find something for which to be grateful. This keeps both my mind and body healthy.
Ulcerative Colitis Treatment Not Working? 8 Steps to Take Now
With ulcerative colitis (UC), you’ll have periods when you experience symptoms, called flare-ups. Then you’ll have symptom-free periods called remissions.
Treatments don’t cure UC. But getting on the right medication should make your flares shorter and less frequent.
Sometimes, a treatment you try won’t be the right one for you, or the treatment you’re currently on may stop working. If your medication doesn’t manage your flares, here are eight steps you can take to start feeling better again.
1. Learn about your options
UC medications bring down inflammation and allow your colon to heal. Knowing which ones are available and who they work best for can help you have a more informed discussion with your doctor.
Drugs that treat UC include:
These medications help control inflammation in people with mild to moderate UC. They may be the first drugs you receive. You can take them by mouth, or as an enema or suppository.
Steroid drugs (corticosteroids)
These medications help control more severe symptoms. You should only use them for short periods because they can cause side effects like weight gain and weakened bones. Steroid medications are available as a pill, foam, or suppository. The oral form is more potent, but it causes more side effects than topical forms.
These medications are for people who don’t get better on aminosalicylates. They reduce the immune system response to prevent damage to the colon.
These medications block an immune system protein that contributes to inflammation. You get them through an IV or injection that you give yourself. Biologics are for people with a moderate to severe disease that hasn’t improved with other treatments.
These medications can be used in adults with moderate to severe UC. If you haven’t experienced relief with aminosalicylates, steroid drugs, immunosuppressants, or biologics, you may want to talk to your doctor about this type of medication.
2. Make sure you’re sticking to protocol
Treating ulcerative colitis is a long-term commitment. Even if you feel well, skipping doses or stopping your medication could cause your symptoms to come back.
When you get a new prescription, make sure you know exactly how and when to take your medication. Ask your doctor what to do if you accidentally miss a dose.
If you develop side effects from the drugs you’re on, make an appointment with your doctor to discuss switching to another drug. Don’t stop taking medication on your own.
3. Watch for symptoms
A sudden return of symptoms like belly pain, diarrhea, and bloody stools can be an obvious sign that you’ve entered a flare-up and may need to adjust your treatment. But sometimes the symptoms are subtler.
Keep track of any changes in the way you feel, no matter how small they are. Let your doctor know if:
- you have more bowel movements than usual
- your bowel movements change in amount or texture
- you notice blood in your stool
- you feel tired or have less energy
- you have less of an appetite or you’ve lost weight
- you have other symptoms, like joint pain or mouth sores
Writing down your symptoms in a diary can help you explain them to your doctor.
4. Ask about adding another medication
Sometimes one drug isn’t enough to tackle severe UC symptoms. Your doctor might give you a second drug to help you get more control over your disease. For example, you might need to take both a biologic and an immunosuppressant drug.
Taking more than one medication can increase the odds of treatment success. But it can also increase your chances of experiencing side effects. Your doctor will help you balance the benefits and risks of the medications you take.
5. Know when it’s time to switch drugs
If you begin to have more frequent flare-ups, it may be time to talk to your doctor about switching to a new medication. You might start by changing to a different version of the same drug, like going from an aminosalicylate enema to a pill.
If your symptoms get worse, it’s time to consider switching to a stronger medication. Your doctor might prescribe an immunosuppressant or biologic, or steroids for a short period.
6. Look at your diet
Medication isn’t the only way to control your symptoms. Changing your diet could help, too.
Certain foods and drinks can aggravate UC symptoms. You might want to avoid or limit these foods if they bother you:
- milk and other dairy products
- coffee, tea, sodas, and other caffeinated drinks and foods
- fruit and fruit juices
- fried foods
- high-fat foods
- high-fiber foods, including whole-grain bread
- cruciferous vegetables like cabbage and broccoli
- beans and other legumes
- steak, burgers, and other red meats
- artificial colors and sweeteners
Keeping a food diary can help you pinpoint which foods worsen your symptoms.
7. Consider whether it’s time for surgery
Most people with UC can manage their disease with medication alone. But about one-quarter may need surgery because they’re not getting better or they have complications.
You may feel hesitant about undergoing surgery. But the upside of removing the colon and rectum is that you’ll be “cured” and essentially freed from most symptoms. However, since UC affects the immune system, symptoms that extend beyond the digestive system, such as joint pain or skin conditions, may recur after surgery.
Treating UC can take some trial and error. Symptoms come and go, and the disease is more severe in some people than in others.
Schedule regular visits with your doctor to stay on top of your disease. In between visits, keep track of your symptoms and note what seems to trigger them.
The more you know about your disease and the closer you stick with your treatment, the greater your odds of controlling ulcerative colitis.
Before taking mesalamine,
- tell your doctor and pharmacist if you are allergic to mesalamine, balsalazide (Colazal, Giazo); olsalazine (Dipentum); salicylate pain relievers such as aspirin, choline magnesium trisalicylate, diflunisal, magnesium salicylate (Doan’s, others); sulfasalazine (Azulfidine), any other medications, or any of the ingredients found in mesalamine. Ask your pharmacist for a list of the ingredients.
- tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antacids such as aluminum hydroxide and magnesium hydroxide (Maalox), calcium carbonate (Tums), or calcium carbonate and magnesium (Rolaids); aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn); azathioprine (Azasan, Imuran); or mercaptopurine (Purinethol). Your doctor may need to change the doses of your medications or monitor you more carefully for side effects.
- tell your doctor if you have or have ever had myocarditis (swelling of the heart muscle), pericarditis (swelling of the sac around the heart), or liver or kidney disease. If you will be taking the delayed-release tablets or capsules, tell your doctor if you have or have ever had a gastrointestinal obstruction (a blockage in your stomach or intestine).
- tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking mesalamine, call your doctor.
- you should know that mesalamine may cause a serious reaction. Many of the symptoms of this reaction are similar to the symptoms of ulcerative colitis, so it may be difficult to tell if you are experiencing a reaction to the medication or a flare (episode of symptoms) of your disease. Call your doctor if you experience some or all of the following symptoms: stomach pain or cramping, bloody diarrhea, fever, headache, weakness, or rash.
- if you have phenylketonuria (PKU, an inherited condition in which a special diet must be followed to prevent mental retardation), you should know that the extended release capsules contains aspartame that forms phenylalanine.
Point–counterpoint: Are we overtreating patients with mild ulcerative colitis?
A 26 year-old man with a history of mild, left-sided ulcerative colitis presents to your clinic for a routine follow-up appointment. He initially presented approximately 5 years ago with intermittent rectal bleeding and diarrhea, which led to a diagnostic colonoscopy. His symptoms resolved in 1–2 weeks with a combination of oral and rectal mesalamine, and you have seen him annually since that time. At today’s visit, he readily admits that he fails to take his medication on a regular basis, opting instead to use oral mesalamine as needed in response to symptoms. He estimates that he uses the medication for several weeks at a time, once or twice a year. Currently, he is having 1–2 formed bowel movements a day, with no blood and no nocturnal symptoms. His laboratory studies, including inflammatory markers and complete blood count, are normal. Upon questioning, you learn that he sees little benefit in taking a daily medication. His symptoms flare infrequently and improve quickly with initiation of mesalamine. He asks you if continuous, long-term mesalamine use confers any advantage or disadvantage over intermittent use based on symptoms, as he is currently doing.
Over the last several decades, we have seen a dramatic increase in the number and variety of medications available for the treatment of inflammatory bowel disease (IBD). This increase in therapeutic options is the result of concerted and coordinated efforts by dedicated researchers, patient advocacy groups, and the pharmaceutical industry. As a result, patients with IBD now have more options for treatment than ever before. But like most chronic diseases, IBD has a wide spectrum of disease severity. For conceptual simplicity, we can dichotomize this spectrum according to whether the natural history of the disease is favorable or unfavorable. In individuals with severe disease, where the natural history is unfavorable (e.g., ulcerative pancolitis that is refractory to corticosteroids), aggressive systemic immunomodulatory treatment is often needed. High-quality care in these patients should ideally lead to resolution of symptoms, a prolonged remission, and avoidance of long-term disease complications. On the other hand, in individuals with established quiescent or mild disease, which has a favorable prognosis even without therapy, the benefits of long-term maintenance treatment are less certain. Though it is difficult to precisely estimate the prevalence of mild disease with a favorable prognosis, these patients are common in clinical practice. Current guidelines recommend that these patients be treated with continuous 5-ASA therapy, with the goal of preventing disease flares and potentially reducing long-term complications.1,2 But complications such as colectomy or colorectal cancer (CRC) are exceedingly uncommon in this population, and (as detailed below) available data have failed to show a clear benefit from continuous 5-ASA maintenance therapy. In this piece, we will examine the pros and cons of long-term, continuous 5-ASA use in patients with established mild UC. Because the benefits of such therapy are likely to be small, and our ability to precisely quantify these benefits is limited, we propose a more shared, informed, and individualized approach to decision-making in these patients that explicitly acknowledges these uncertainties.
Maintenance 5-ASA therapy to prevent symptomatic relapse of disease
Point: Maintenance 5-ASA therapy prevents disease flares in patients with established mild UC
UC is characterized by a wide spectrum of disease severity, with episodes of relapse and remission. Occurrence of relapse is unpredictable, and the likelihood is high. Across all degrees of UC severity, relapse rates without maintenance therapy are between 38% and 76%.3 Of those achieving remission with 5-ASA agents, a prospective study demonstrated that patients who were subsequently non-adherent had an approximately 5-fold greater risk of relapse, with an absolute risk reduction of approximately 40% for patients who were adherent with therapy.4 Admittedly, the vast majority of these patients will have resolution of symptoms with re-initiation of 5-ASA therapy. However, some non-adherent patients may also be risking escalation of disease severity. In a retrospective study, patients who had been in remission on 5-ASA therapy for at least 6 months were twice as likely to require high-dose oral or parenteral steroids when later becoming non-adherent.5
Counterpoint: Many patients perceive little clinical benefit from maintenance 5-ASA therapy
There is little doubt that 5-ASA therapy is effective for induction and maintenance of clinical remission in mild UC. In patients who are responsive to 5-ASAs, however, the primary question is whether disease flares are frequent enough and severe enough to warrant continuous, daily medication use, particularly if such therapy is also effective when used on an as-needed basis. Though it is difficult to directly address this question, studies of 5-ASA adherence and cost–utility suggest that many patients have already decided for themselves that the answer is “no”. For instance, studies examining adherence to 5-ASA medications among patients with mild UC have demonstrated that many patients (up to 60%) often fail to take their medications as prescribed.6,7 Though the reasons for non-adherence are multifactorial, a substantial proportion of non-adherent patients believe that the benefits are limited, and that these limited benefits are outweighed by the harms of inconvenient dosing regimens, large numbers of pills, and cost.4,8 The high placebo response rates reported in clinical trials (up to 77%) further support the notion that 5-ASA therapy is of limited benefit for disease maintenance in some patients with established mild disease.9,10 Finally, it is important to note that the burden of daily medication use can have an important negative effect on a patient’s quality of life.11–13 A simulation model that weighed the disutility (burden) of continuous 5-ASA therapy against the frequency and severity of disease flares provided quantitative evidence for this phenomenon, with mild UC patients achieving a similar quality of life, on average, with or without 5-ASA maintenance.14
Maintenance 5-ASA therapy to reduce colectomy rates
Point: Maintenance of remission with 5-ASA agents is likely to reduce the rate of colectomy in mild UC
Colectomy rates in UC range from 9% to 25% within 10 years following diagnosis,15 with the vast majority (approximately 90%) performed to address unremitting disease activity.16 Though the use of 5-ASA agents has not been shown to reduce colectomy rates, these agents have been shown to lead to variable degrees of mucosal healing.17 Achieving mucosal healing has been associated with lower rates of colectomy in both retrospective and prospective studies,18,19 though it should be noted that evaluating and treating for mucosal healing are not without risk and cost. Taking these data into account, it is reasonable to treat patients to potentially modify their disease course and prevent colectomy, especially when we consider the favorable safety profile of 5-ASA agents.
Counterpoint: Maintenance of remission with 5-ASA agents is unlikely to substantially reduce the rate of colectomy in mild UC
Many providers fear that patients who discontinue therapy will develop a disease flare that does not respond to medical therapy, ultimately requiring colectomy. Outcome data on long-term colectomy rates in patients with established mild UC are limited, but we would expect that absolute rate of colectomy in these patients to be low (meaning that the absolute benefit of therapy is also low). The strongest observational data on this topic comes from a European cohort that examined outcomes over 10 years after diagnosis among 5-ASA users and non-users. Indeed, this study found that 5-ASA medications had no significant effect on colectomy rates in patients with UC.20
Maintenance 5-ASA therapy to reduce colorectal cancer risk
Point: 5-ASA maintenance therapy may reduce the rate of colorectal cancer in UC patients
Colorectal cancer (CRC) is one of the most feared outcomes in patients with long-standing UC. Historically, large population based studies have estimated that the lifetime incidence of CRC is up to 5 times greater in UC patients than in unaffected populations.21–23 Mechanistically, there is strong evidence that chronic inflammation leads to the development of colonic dysplasia and, ultimately, CRC.24,25 Fortunately, the incidence of CRC appears to be dropping in the UC population with the advent of modern medical therapy and endoscopic surveillance.26 Though some have questioned the chemopreventive properties of 5-ASA agents in UC,27,28 it is reasonable to use these agents in light of their relative safety and tolerability, particularly when weighed against the consequences of a new cancer diagnosis.
Counterpoint: 5-ASA maintenance therapy does not reduce the rate of colorectal cancer in UC patients
Prior studies demonstrated that chronic colonic inflammation is associated with the development of colonic dysplasia, a precursor of CRC. But population-based outcome data have failed to support the role of chronic inflammation as an important risk factor for CRC in UC.29,30 Other studies, including a recent meta-analysis, have called into question the chemopreventive effects of 5-ASA agents.31–33 Thus, the theoretical benefits of chemoprevention for CRC in UC are not borne out by the sum of available outcome data.
5-ASA agents have long been the mainstay of treatment in patients with mild UC. Though these agents are less potent than other available therapies for UC, they have a favorable side-effect profile, leading to their widespread use. The potential benefits of 5-ASA agents include: (1) symptom control,34,35 and associated improvements in quality of life and health care utilization; (2) reduction in colectomy rates; and, (3) reduction in CRC incidence. However, the absolute benefit of any intervention is dependent on the baseline risk of the condition. In individuals with mild UC, a prevalent patient population with a favorable long-term prognosis, the absolute risk of CRC and colectomy is low. Therefore, the long-term benefits of therapy are small at best and deserve to be weighted against the potential clinical and economic harms.
We propose that the decision of whether or not to treat patients with established mild UC is more complex than the treatment decision in individuals who have more severe disease (in whom the benefits clearly outweigh the harms). Braddock et al. have defined complex decisions as those in which the effect on the patient is extensive, the medical consensus is controversial, and the outcomes are uncertain.36 In mild UC treated with 5-ASA therapy, the patient is asked to take daily medication, often at significant cost, for a small benefit. There is reasonable consensus that daily use of 5-ASA agents can reduce the risk of flares. However, there is also evidence that on-demand use of 5-ASA may be an effective strategy, decreasing the marginal benefits of daily medication use.36 Arguments that daily 5-ASA use may be effective in reducing the risk of more feared UC outcomes such as colectomy and CRC risk are largely theoretical and are not consistently supported by existing (though limited) data. While there is substantial uncertainty about the exact magnitude of the benefit of 5-ASA therapy, the sum of available evidence suggests that the overall benefit is likely to be small.
On the other hand, there is a small but real potential for harm (renal injury, and in some instances, end-stage renal disease),37–39 and there is a daily burden and cost to taking medication. It is clear that for many patients, daily medication use is viewed as being of relatively little benefit, as patients who achieve remission in the short-term often fail to adhere to their medication in the long-term. While this non-adherence is certainly multifactorial, there is reasonable evidence that some patients perceive little benefit to continuous medication use in a low-risk setting.
Based on the evidence outlined above, we believe that patients warrant a shared, informed approach to decision-making about chronic therapy for mild UC.40 Current guidelines suggest a relatively one-size fits all approach — namely that nearly all patients with mild UC take daily 5-ASA medications. Instead, a shared approach to decision-making considers both potential benefits and potential clinical and economic harms on a case-by-case basis, allowing doctor and patient to make the best decision for a given individual.
One widely endorsed approach to complex decision-making is the use of decision aids, interventions that help individuals explicitly consider the pros and cons of treatment in order to improve informed decision-making. High-quality decision aids educate patients on the decision context and present tailored risk and benefit information in various ways. They also help patients more explicitly weigh the factors that are important in making an informed decision. Decision aids have been used in a variety of healthcare contexts, including treatment for IBD.41 Studies of decision aids for IBD have shown that they are effective in educating patients and, in some instances may influence decision-making behavior.42,43 However, prior work on decision aids in IBD has focused primarily on high-risk patients who have an unfavorable prognosis and are making a choice between treatment strategies with varying degrees of toxicity. We believe that such an approach is also needed in patients with established, mild UC, a prevalent population in whom the benefits of long-term 5-ASA therapy are small or uncertain.
Though a more informed approach to decision-making is needed in this patient population, we must also contend with gaps in our understanding of established mild UC. For instance, we have limited data on the absolute long-term prognosis in terms of colectomy and CRC. We also have no direct data to support or refute the notion that disease activity may accelerate in these patients if untreated, requiring more aggressive therapies. Finally, we have insufficient quantitative data on the optimal balance between the benefits and risks of 5-ASA therapy. Prior work in this area has largely ignored the renal risks of long-term 5-ASA therapy, a clinical harm that could have important consequences.37–39 Of course, the uncertainty that currently exists in the literature on this topic does not preclude efforts to develop decision aids to more systematically inform patients about the potential benefits, harms, and uncertainty associated with use of these medications.
You explain to your patient that continuous, long-term mesalamine use has several potential benefits, but the supporting data are limited. For symptom control, studies suggest that, on average, remission is more likely in patients who use mesalamine regularly. On the other hand, there is less data to suggest that treating on demand is less efficacious. Furthermore, the data on long-term benefits in terms of colectomy rate and CRC risk are also controversial. The risks of the medication are small, but renal toxicity is possible. It is important that renal function be monitored periodically to assess for the interval development of renal injury. Finally, if cost is an issue, lower cost alternatives (such as sulfasalazine or balsalazide) could be considered. The patient appreciates your honesty and time in explaining these issues. He decides to begin taking mesalamine more regularly, primarily due to concern for CRC. He tells you that his friend, who also suffered from UC, recently developed CRC unexpectedly.
Conflict of interest
1 Kornbluth A. Sachar D.B. Practice Parameters Committee of the American College of Gastroenterology, ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee Am J Gastroenterol 105 3 2010 501–523 2 Mowat C. Cole A. Windsor A. Ahmad T. Arnott I. Driscoll R. et al. Guidelines for the management of inflammatory bowel disease in adults Gut 60 5 2011 571–607 3 Su C. Lewis J.D. Goldberg B. Brensinger C. Lichtenstein G.R. A meta-analysis of the placebo rates of remission and response in clinical trials of active ulcerative colitis Gastroenterology 132 2 2007 516–526 4 Kane S. Huo D. Aikens J. Hanauer S. Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis Am J Med 114 1 2003 39–43 5 Khan N. Abbas A.M. Bazzano L.A. Koleva Y.N. Krousel-Wood M. Long-term oral mesalazine adherence and the risk of disease flare in ulcerative colitis: nationwide 10-year retrospective cohort from the Veterans Affairs Healthcare System Aliment Pharmacol Ther 36 8 2012 755–764 6 Shale M.J. Riley S.A. Studies of compliance with delayed-release mesalazine therapy in patients with inflammatory bowel disease Aliment Pharmacol Ther 18 2 2003 191–198 7 Kane S.V. Cohen R.D. Aikens J.E. Hanauer S.B. Prevalence of nonadherence with maintenance mesalamine in quiescent ulcerative colitis Am J Gastroenterol 96 10 2001 2929–2933 8 Levy R.L. Feld A.D. Increasing patient adherence to gastroenterology treatment and prevention regimens Am J Gastroenterol 94 7 1999 1733–1742 9 Feagan B.G. Macdonald J.K. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis Cochrane Database Syst Rev 10 2012 CD000544 10 Bebb J.R. Scott B.B. How effective are the usual treatments for ulcerative colitis? Aliment Pharmacol Ther 20 2 2004 143–149 11 Matza L.S. Boye K.S. Yurgin N. Brewster-Jordan J. Mannix S. Shorr J.M. et al. Utilities and disutilities for type 2 diabetes treatment-related attributes Qual Life Res 16 7 2007 1251–1265 12 Vijan S. Hayward R.A. Ronis D.L. Hofer T.P. Brief report: the burden of diabetes therapy: implications for the design of effective patient-centered treatment regimens J Gen Intern Med 20 5 2005 479–482 13 Hayward R.A. Krumholz H.M. Zulman D.M. Timbie J.W. Vijan S. Optimizing statin treatment for primary prevention of coronary artery disease Ann Intern Med 152 2 2010 69–77 14 Saini S.D. Waljee A.K. Higgins P.D. Cost utility of inflammation-targeted therapy for patients with ulcerative colitis Clin Gastroenterol Hepatol 10 10 2012 1143–1151 15 Langholz E. Munkholm P. Davidsen M. Binder V. Course of ulcerative colitis: analysis of changes in disease activity over years Gastroenterology 107 1 1994 3–11 16 Waljee A.K. Higgins P.D. Waljee J.F. Tujios S.R. Saxena A. Brown L.K. et al. Perceived and actual quality of life with ulcerative colitis: a comparison of medically and surgically treated patients Am J Gastroenterol 106 4 2011 794–799 17 Romkens T.E. Kampschreur M.T. Drenth J.P. van Oijen M.G. de Jong D.J. High mucosal healing rates in 5-ASA-treated ulcerative colitis patients: results of a meta-analysis of clinical trials Inflamm Bowel Dis 18 11 2012 2190–2198 18 Froslie K.F. Jahnsen J. Moum B.A. Vatn M.H. IBSEN Group Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort Gastroenterology 133 2 2007 412–422 19 Ardizzone S. Cassinotti A. Duca P. Mazzali C. Penati C. Manes G. et al. Mucosal healing predicts late outcomes after the first course of corticosteroids for newly diagnosed ulcerative colitis Clin Gastroenterol Hepatol 9 6 2011 483–489 20 Hoie O. Wolters F.L. Riis L. Bernklev T. Aamodt G. Clofent J. et al. Low colectomy rates in ulcerative colitis in an unselected European cohort followed for 10 years Gastroenterology 132 2 2007 507–515 21 Bernstein C.N. Blanchard J.F. Kliewer E. Wajda A. Cancer risk in patients with inflammatory bowel disease: a population-based study Cancer 91 4 2001 854–862 22 Karlén P. Löfberg R. Broström O. Leijonmarck C.E. Hellers G. Persson P.G. Increased risk of cancer in ulcerative colitis: a population-based cohort study Am J Gastroenterol 94 4 1999 1047–1052 23 Herrinton L.J. Liu L. Levin T.R. Allison J.E. Lewis J.D. Velayos F. Incidence and mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease from 1998 to 2010 Gastroenterology 143 2 2012 382–389 24 Rutter M. Saunders B. Wilkinson K. Rumbles S. Schofield G. Kamm M. et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis Gastroenterology 126 2 2004 451–459 25 Gupta R.B. Harpaz N. Itzkowitz S. Hossain S. Matula S. Kornbluth A. et al. Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study Gastroenterology 133 4 2007 1099–1105 26 Jess T. Simonsen J. Jørgensen K.T. Pedersen B.V. Nielsen N.M. Frisch M. Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years Gastroenterology 143 2 2012 375–381 27 Velayos F.S. Terdiman J.P. Walsh J.M. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and meta-analysis of observational studies Am J Gastroenterol 100 6 2005 1345–1353 28 Ullman T. Croog V. Harpaz N. Hossain S. Kornbluth A. Bodian C. et al. Progression to colorectal neoplasia in ulcerative colitis: effect of mesalamine Clin Gastroenterol Hepatol 6 11 2008 1225–1230 29 Bergeron V. Vienne A. Sokol H. Seksik P. Nion-Larmurier I. Ruskone-Fourmestraux A. et al. Risk factors for neoplasia in inflammatory bowel disease patients with pancolitis Am J Gastroenterol 105 11 2010 2405–2411 30 Winther K.V. Jess T. Langholz E. Munkholm P. Binder V. Long-term risk of cancer in ulcerative colitis: a population-based cohort from Copenhagen County Clin Gastroenterol Hepatol 2 12 2004 1088–1095 31 Bernstein C.N. Nugent Z. Blanchard J.F. 5-Aminosalicylate is not chemoprophylactic for colorectal cancer in IBD: a population based study Am J Gastroenterol 106 4 2011 731–736 32 Terdiman J.P. Steinbuch M. Blumentals W.A. Ullman T.A. Rubin D.T. 5-Aminosalicylic acid therapy and the risk of colorectal cancer among patients with inflammatory bowel disease Inflamm Bowel Dis 13 4 2007 367–371 33 Nguyen G.C. Gulamhusein A. Bernstein C.N. 5-Aminosalicylic acid is not protective against colorectal cancer in inflammatory bowel disease: a meta-analysis of non-referral populations Am J Gastroenterol 107 9 2012 1298–1304 34 Robinson M. Hanauer S. Hoop R. Zbrozek A. Wilkinson C. Mesalamine capsules enhance the quality of life for patients with ulcerative colitis Aliment Pharmacol Ther 8 1 1994 27–34 35 Pruitt R. Hanson J. Safdi M. Wruble L. Hardi R. Johanson J. et al. Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild-to-moderate ulcerative colitis Am J Gastroenterol 97 12 2002 3078–3086 36 Braddock C.H.III Edwards K.A. Hasenberg N.M. Laidley T.L. Levinson W. Informed decision making in outpatient practice: time to get back to basics JAMA 282 24 1999 2313–2320 37 Gisbert J.P. Gonzalez-Lama Y. Mate J. 5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review Inflamm Bowel Dis 13 5 2007 629–638 38 Corrigan G. Stevens P.E. Review article: interstitial nephritis associated with the use of mesalazine in inflammatory bowel disease Aliment Pharmacol Ther 14 1 2000 1–6 39 Van Staa T.P. Travis S. Leufkens H.G. Logan R.F. 5-Aminosalicylic acids and the risk of renal disease: a large British epidemiologic study Gastroenterology 126 7 2004 1733–1739 40 Charles C. Gafni A. Whelan T. Shared decision-making in the medical encounter: what does it mean? (or it takes at least two to tango) Soc Sci Med 44 5 1997 681–692 41 Siegel C.A. Marden S.N. Siegel L.S. Development of the first Crohn’s disease decision aid: helping patients make informed, preference-based decisions for their treatment Gastroenterology 140 2011 S769 42 Siegel C.A. Siegel L.S. Hyams J.S. Kugathasan S. Markowitz J. Rosh J.R. et al. Real-time tool to display the predicted disease course and treatment response for children with Crohn’s disease Inflamm Bowel Dis 17 1 2011 30–38 43 Siegel C.A. Marden S.N. Crohn’s disease patients report their definitions of “rare” adverse event, remission and the importance of mucosal healing: a quantitative and qualitative study of what patients really think Gastroenterology 140 2011 S:141
☆ Grant support: Dr. Saini’s and Dr. Waljee’s research is funded by a VA HSR&D CDA-2 Career Development Award. Dr. Stidham’s research is funded through the Crohn’s and Colitis Foundation of America Career Development Award. © 2013 European Crohn’s and Colitis Organisation