Ulcerative Colitis Blog

Prevalence of UC
IBD is a prevalent condition in the United States, affecting approximately 1 million people. It is believed to be almost twice as common in Northern Europe, with a prevalence of 2 million people. With regard to the spectrum of disease, UC appears to occur more frequently than Crohn's. Estimates suggest that the prevalence of UC among individuals in the US is 100-200 cases per 100,000 people.

Whether the incidence and prevalence of IBD is increasing has been an active area of research. Prior to 1940, UC was more common than Crohn's disease in the US. After 1940, an increase in the incidence of Crohn's disease was noted. Between 1940 and 1990, a rise in the US prevalence of both disorders was described. Since the early 1990's, reports suggest that the incidence of UC and Crohn's has plateaued and there may be a decrease in disease prevalence in some areas of the US. There have been discrepancies among studies, however, depending on location, age of population, and methodologies.

Age Distribution of UC
While IBD can be diagnosed at any age, two peaks of disease onset are most commonly seen: 1) between 15-30 years and 2) around age 50 years. Approximately 25% of patients with IBD develop disease during childhood and adolescence. Recent studies have suggested that among young children with IBD (<5years), the incidence of UC is greater than Crohn's. Over time, there is a reversal of this trend with a higher incidence of Crohn's disease in adolescence than UC.

Gender Distribution of UC
UC affects males and females at equivalent rates.

Geographic Distribution of UC
The highest prevalence of IBD is seen in so-called "developed" and "Westernized" regions of the world such as the US and Northern Europe. There have been several reports, however, of increasing incidence in Asia. One interesting trend that has been observed is an apparent north-south disease gradient. Investigators have described higher incidence rates in northern latitudes which decrease across southern latitudes. The rationale for this is not well understood but may be related to pathogens residing in these latitudes or population genetics.

Racial/Ethnic Distribution of UC
IBD is most common in the Caucasian population with a higher predilection among those of Jewish descent. Within the US, increasing disease incidence has been noted among African Americans and Hispanics. Whether this change in disease pattern is due to environment or improvements in diagnosis and access to care remains speculative.

Once a new diagnosis of UC is made there are several available treatment options ranging from no treatment at all to various medical therapies to surgical resection of the colon.

The mainstay of medical treatment for mild to moderate UC is the 5-aminosalicylic acid (5ASA) class of medications, including sulfasalazine, mesalamine and balsalazide. While all of these medications have similar efficacy, sulfasalazine has a higher rate of dose dependent side effects including nausea, vomiting, and headache. Sulfasalazine and balsalazide are only available in pill form for oral delivery, while mesalamine is available in pill form, as well as suppository and enema formulations. Side effects of mesalamine include diarrhea and rare kidney toxicity.

The 5ASA’s are anti-inflammatory drugs that block several important immune response pathways. They seem to work both locally, by direct effects on the intestinal cells, and systemically, once absorbed in to the circulation. While chemically similar to acetylsalicylic acid (aspirin), 5ASA has different effects on the gastrointestinal tract and immune system. Most notably, aspirin exacerbates UC in some cases.

Several clinical trials have shown that there is a dose dependent effect of the 5ASA’s. A high dose is more effective at inducing remission, while a lower dose is effective at maintaining remission. Distal UC, affecting the left colon (descending, sigmoid, or rectum) may be treated with 5ASA in suppository or enema formulations. Enemas reach the entire left colon, but suppositories only treat the rectum. These rectal formulations may be effective on their own, but response is even better when paired with oral 5ASA therapy.

The potential role of 5ASA as a chemopreventive (see posting 8/23) against colon cancer in UC makes its long term use a compelling, though unproven, consideration.

The inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are chronic, relapsing disorders characterized by periods of quiescence and recurrent inflammation. The overall goal of treatment is to halt the inflammatory process and keep it at bay long-term. Treatment for UC consists of medication therapy and, in some patients, surgery if the disease proves to be refractory to medical management. Because UC affects people differently, a variety of factors are taken into consideration when creating an individual treatment plan for each patient. The following provides a brief overview of the key aspects physicians consider when choosing therapies.

1. Phase of Disease
Based upon the relapsing and remitting nature of IBD, disease activity and treatment is divided into 2 phases: Induction of Remission and Maintenance of Remission.

1) Induction of remission: When a person has signs or symptoms of active disease (either at diagnosis or during relapse), potent medications are used to decrease inflammation as quickly as possible and induce remission. As an analogy, you can liken the inflammation of IBD to a bonfire and the medications used to induce remission are akin to buckets of water being dumped over the flames to stamp out the fire. Examples of medications commonly used to induce remission are steroids, infliximab, and cyclosporine.

2) Maintenance of remission: As UC is a chronic disease, medications are required to maintain remission of disease once an acute flare has been controlled. These may be the same medications used to induce remission, or others which are selected due to lower toxicity long-term. Examples of medications used for maintenance of remission are: 5-ASA drugs (sulfasalazine, mesalamine), azathioprine, 6-mercaptopurine, and infliximab.

2. Extent and Severity of Disease

1) Extent of disease: UC universally involves the rectum and may extend to involve part or the entire colon. If only a limited portion is involved at the end of the colon/rectum the disease is termed “proctosigmoiditis”; if the disease progresses and affects the entire colon it is called “pancolitis”. The extent of disease guides the choice of medication in that disease limited to the very bottom of the rectum may be effectively treated with enema preparations, as opposed to more extensive disease which requires the use of oral medicines.

2) Severity of disease: The severity of UC varies among individuals and can change over the course of a person’s disease. Typically, disease severity is categorized as mild, moderate, or severe. The severity of disease may alter the choice of medications used to treat UC as more severe disease is treated with medications of greater potency.

3. History of Disease
Choice of medication may also be affected by the duration of disease and number of relapses/flares a patient has experienced. Medications used on initial presentation of disease may be changed later in the course depending on the number and intensity of relapses.

4. Other Considerations
Outside of specific disease characteristics, other considerations for choice of medical therapy may be impacted by patient drug allergies, tolerability, and cost.

The use of a class of steroids known as “corticosteroids,” is common for the induction of disease remission in IBD. This form of steroid is different from the anabolic type of steroids which receive media attention regarding use among athletes. Corticosteroids have a variety of anti-inflammatory effects which make them useful in the short-term to aid in achieving control of disease. Corticosteroids are produced in topical, oral, and intravenous formulations which can be administered depending on the severity and locations of a patient's disease.

Topical Corticosteroids
UC which is limited to the very bottom portion of the rectum is called ulcerative proctitis or proctosigmoiditis. Patients with mild-moderate forms of ulcerative proctitis limited to the rectum or distal portion of the colon may be candidates for topical corticosteroid therapy. Topical corticosteroids come in enema solution and foam preparations. During periods of active disease, enemas are typically administered at night. Patients should be instructed to use the washroom prior using enema preparations in an attempt to empty the rectum. Ideally, enemas should be retained on the rectum as long as possible (hours to overnight). Many patients note that the foam preparations are easier to retain due to the consistency of the medication. As disease activity subsides, the enemas can be spaced out and tapered. The corticosteroids applied topically are systemically absorbed to some degree, and can result in side effects similar to those of oral steroids. For this reason, they are not recommended for long-term use and topical 5-ASA preparations may supplant them.

Systemic Corticosteroids
For disease that involves more extensive portions of the colon (beyond the left side of the colon) or is of greater severity, oral and/or intravenous corticosteroids may aid in inducing remission of disease. Oral prednisone is commonly prescribed at diagnosis and during flares of disease to quickly abolish the cycle of inflammation. At maximum doses (typically 40mg daily), patients responsive to corticosteroids will note abrupt improvement in symptoms over a period of days to weeks. Once a patient feels well again (1-2 formed bowel movements per day, no blood, no urgency, no nighttime symptoms), the steroids can be gradually tapered. In instances where the colitis is severe, patients may fail to respond to oral steroids. For these forms of severe, acute disease, hospitalization with intravenous corticosteroids is recommended. The vast majority of patients receiving intravenous therapy will note an improvement in symptoms within 5-7 days; a transition is then made to oral steroids with eventual taper.

Side Effects
While corticosteroids have a variety of useful anti-inflammatory properties, the duration of their use is limited by toxicities which are time and dose dependent. As such, corticosteroids are indicated for a limited time (weeks to 3 months) to obtain disease control and then should be safely tapered; their use for maintenance of disease remission is not recommended. Many side effects are dose-dependent and reversible with the exception of osteoporosis, osteonecrosis, and cataracts which are irreversible.

1) High blood pressure - Corticosteroids cause sodium (salt) and water retention which results in swelling and can elevate blood pressure.

2) High blood glucose - Hyperglycemia (a high blood sugar) can occur with steroids. Signs and symptoms of high blood glucose include excessive thirst and urination as well as fatigue. Careful monitoring of blood glucose levels is necessary for diabetics with IBD who require steroid treatment. Other patients exhibiting signs and symptoms of hyperglycemia should have a blood glucose checked.

3) Low potassium levels - Low blood potassium levels can be associated with corticosteroid use and are manifested by musculoskeletal cramps, weakness, nausea, and vomiting

4) Osteoporosis - Long-term corticosteroid use (>3 months) impairs calcium metabolism and can weaken bone mineralization. Patient’s receiving corticosteroids for > 3 months should have a bone density scan performed to assess for changes in bone mineralization.

5) Osteonecrosis - Osteonecrosis is a form of irreversible bone injury resulting from loss of blood flow to bony tissue. It most commonly affects the hip, shoulder joints, leg and foot joints.

6)Cataracts - Cataracts are associated with long-term corticosteroids use. Patient’s utilizing recurrent courses of steroids should have routine eye exams.

7) Fluid retention - As noted above, corticosteroids result in salt and water retention which makes patient’s swell. Many people will note fullness in the cheeks as well as fluid around the ankles.

8) Skin changes - Corticosteroids may thin skin or result in striae, the technical name for stretch marks.

9) Increased appetite - Many patients note a dramatic increase in their appetite after starting steroids.

10) Irritability/Insomnia - High doses of corticosteroids often make people feel jittery or hyperactive. Sleep disturbances may be noted.

If mesalamine type medications fail to induce and maintain a remission of UC then other medications are required. Corticosteroids, such as prednisone, are able to induce remission, but are not appropriate for long-term maintenance of remission due to significant side effects such as osteoporosis, weight gain, acne, elevated sugars, exacerbation of psychiatric illness, and insomnia.

In this case, use of the thiopurine drugs azathioprine (AZA) and 6-mercaptopurine (6-MP), is appropriate. Azathioprine is a pro-drug which the body immediately breaks down to 6-MP. Azathioprine is 50% 6-MP by weight, so the dose of azathioprine is twice 6-MP, but the two drugs are otherwise identical.

The mechanism of action is not fully understood, but AZA/6-MP are thought to block DNA synthesis and decrease the number and function of white blood cells. They can take one to three months to take effect, so they are not practical for induction of remission, but are effective at maintaining remission.

Your doctor may test you for thiopurine methyltransferase (TPMT) before starting AZA/6-MP. TPMT is one of the enzymes that metabolizes 6-MP. There are three levels of TPMT enzyme function: normal; intermediate; and low. These are based upon whether a person has two normal genes, one normal gene, or no normal genes for the enzyme, respectively. Patients with intermediate or low functioning TPMT have a higher risk of developing bone marrow suppression resulting in low white blood cell count and an increased risk of infection. They require lower doses of medication and closer monitoring of laboratory tests for side effects.

A test can be performed to measure the level of AZA/6-MP metabolites in the blood stream. Levels of 6-TG and 6-MMP are predictive of symptom response and toxicity and can be used to help guide dosing.

Next week I will review the adverse effects of AZA/6-MP, which needlessly frighten many patients.

In response to my last blog on steroid use in UC, a comment was posted regarding options for patients who experience recurrent symptoms while reducing steroid doses.

As a brief overview, patients with UC on steroid therapy fall into 1 of 3 categories:
1) Steroid responsive - Approximately 50-55% of UC patients enter into prolonged disease remission with steroids and are able to transition to stable maintenance therapies.
2) Steroid dependent - This group encompasses about 25-30% of patients who experience remission of disease with high steroid doses, but then have recurrent symptoms as the steroids are titrated to lower doses or within 6 months of finishing the first steroid course.
3) Steroid refractory - A smaller proportion of patients (15-25%) have severe colitis that fails to respond to the highest acceptable dosages of oral steroids.

The comment posted raises the question about alternative therapies for patients who have developed steroid dependent UC. A few notes on this topic:

5-ASA Medications (ie; mesalamine, balsalazide)
Based on current scientific literature, the use of oral 5-ASA medications, either alone or in combination with other therapies, has not been shown to have a significant beneficial effect in steroid-dependent UC. There is little data regarding the use of topical 5-ASA medications (enema/suppository) in limited rectal disease for steroid-dependent UC.

As such, if a patient experiences rectal bleeding from a limited segment of disease in the rectum while tapering steroids, a trial of topical therapy could be considered. This would not be of value for patients with more extensive disease.

Thiopurines (ie; azathioprine, 6-mercaptopurine)
Thiopurines are commonly used in steroid-dependent UC in an effort to maintain remission as steroids are tapered. Since they have shown success as steroid-sparing agents, their use has gained wide acceptance in clinical practice. In order to be effective, however, they should be administered at optimal doses of 2-3mg/kg body weight for azathioprine and 1-1.5mg/kg body weight for 6-mercaptopurine. In patients who have persistent symptoms despite a routine dosage of medication, levels of the drug can be measured in the blood to see if it is being metabolized effectively. If the levels are low, the medication dose may need to be increased to fully treat the inflammation.

Methotrexate
Current guidelines do not advocate the use of methotrexate in steroid-dependent UC; however, this is mostly based upon the fact that there is a paucity of well-designed studies investigating this drug in steroid-dependent UC. There is limited evidence that higher doses of oral methotrexate or the injectable formulation may benefit a subset of steroid-dependent UC patients who are intolerant of or fail treatment with thiopurines. The use of this medication may warrant further study for this indication.

Infliximab
Infliximab received FDA approval for the treatment of moderate-severe active UC in the last year or so. At least one study specifically examining its utility in steroid-dependent patients has suggested it is potentially beneficial. Infliximab is typically administered as a dose of 5mg/kg at 0, 2, and 6 weeks, then once every 8 weeks. In patients who have an inadequate or waning response, the dose of the medication can be increased to 10mg/kg and/or the dosing interval can be shortened to every 4-6 weeks. The efficacy of adalimumab in UC is under investigation.

Experimental therapies
Some medical centers offer experimental therapies for patients who are failing the currently accepted medical regimens. Before exploring such therapies, patients and physicians should have a thorough discussion about the state of the patient's overall health status, realistic expectations for the future, and risks vs. benefits.

Surgery
The goal of any treatment is to restore a patient's physical health and wellbeing. For patients who have exhausted all possible medications, surgery may be the only tenable option to give a patient his or her quality of life back. While the prospect of surgery is understandably daunting and procedures are not without the possibility of complications, surgical management eliminates the future risk of colon cancer and has the potential to restore quality of life. Any UC patient considering surgery should discuss with his/her doctor referral to a colorectal surgeon who is specifically experienced in the surgical management of IBD patients. More on issues surrounding surgery will be discussed in future blogs.