Ulcerative Colitis Blog

There are several notable side effects of the thiopurines [azathioprine (AZA)/ 6-mercaptopurine (6-MP)]. They can be classified as early or late onset.

The early reactions are allergic and affect about 5% of users. They include pancreatitis (inflammation of the pancreas), hepatitis (inflammation of the liver), fever, nausea, rash, and fatigue. Abrupt discontinuation of medication leads to complete resolution of symptoms.

Late onset, or dose dependent, reactions include decreased levels of white blood cells (leukopenia), red blood cells (anemia), and platelets (thrombocytopenia) due to suppression of the bone marrow and hepatitis. It is not clear if thiopurines increase the risk of lymphomas or other cancers. Several studies have produced conflicting results. Leukopenia causes an increased risk of infections and thrombocytopenia causes bruising and bleeding.

In order to minimize the risk of dose-dependent side effects, blood tests are performed regularly on patients using AZA/6-MP to evaluate bone marrow suppression and hepatitis. White blood cell count and liver enzymes are tested every 2-4 weeks during the first couple months of therapy and after dose increases, but once a steady dose is achieved testing is performed approximately every three months. If testing shows an abnormality then either the dosing is adjusted or the medicine is changed.

If the thiopurines are used appropriately and followed closely then they are very safe and effective medications for moderate to severe UC, but they cannot be safely taken without follow-up. Skipping blood tests can lead to life threatening complications.

What is severe ulcerative colitis?
The course of UC is variable among patients ranging from mild, limited colitis to severe, fulminant colitis. While the vast majority of UC patients are able to control their disease with currently available medications, approximately 15% will experience an attack of severe colitis requiring hospitalization and intensive therapy. Criteria that defines severe colitis includes the passage of > 6 bloody bowel movements per day, fever, accelerated heart rate, anemia (low blood count), elevated inflammatory markers in the blood, and electrolyte disturbances.

Patients manifesting symptoms of severe UC are typically admitted to the hospital for close monitoring and intravenous fluids and steroids. Examination of stool specimens for bacterial, viral, and parastitic organisms is performed in an attempt to identify potentially treatable causes of the disease flare. Careful attention to a patient’s vital signs, blood counts/chemistries, and abdominal exam is imperative. Potential serious complications of severe colitis may include toxic megacolon, gastrointestinal hemorrhage, perforation, and multi-organ system dysfunction requiring intensive care unit management.

Steroid treatment of severe ulcerative colitis
It is standard to initiate therapy with intravenous methylprednisolone at a dose of 40-60mg/day. Previous studies suggest that 75% of patients with severe colitis will respond to this form of treatment. Patients who respond to intravenous steroids will generally note an improvement in symptoms within 3-5 days. Failure of symptoms to improve within 7 days indicates steroid-refractory disease which may require alternative medical management or surgery.

Treatment options for steroid-refractory, severe ulcerative colitis
1) Cyclosporine - Cyclosporine is an immune suppressant administered intravenously at a dose of 2mg/kg/day. Response rates to cyclosporine range from 50-80%. As cyclosporine can be associated with serious side effects (hypertension, kidney failure, seizures, infection), drug administration must be carefully monitored and long-term use is not recommended. Patients who respond to intravenous cyclosporine in the hospital are subsequently placed on an oral formulation for a period of months, and then transitioned to azathioprine or 6-mercaptopurine.

2) Tacrolimus – Tacrolimus is an alternative therapy for steroid-refractory UC which has been administered both orally and intravenously in previous trials. Response rates to therapy are estimated to be about 50%. In one long-term follow-up study, 50% of patients with steroid-refractory colitis (UC and indeterminate colitis) still required surgery within 2 years.

3) Infliximab - Another alternative is infliximab, which is also a potent intravenous immune suppressant. Although there has been limited data regarding the use of infliximab in the setting of severe colitis, mounting evidence suggests it could be of at least short-term benefit. Infliximab is usually administered at a dose of 5mg/kg at 0, 2, and 6 weeks to induce remission. Current registry data regarding the safety of infliximab, indicates no greater mortality or infection risk with infliximab than other therapies. Whether infliximab can help stave off colectomy in the long-term is not known.

4) Visilizumab – A recent study reported encouraging results pertaining to the use of a new drug, visilizumab, in the treatment of steroid-refractory ulcerative colitis. Thirty-two patients with severe ulcerative colitis unresponsive to intravenous steroids were treated with visilizumab at doses of 10-15mcg/kg. After one month, 84% demonstrated a clinical response and 40-45% achieved disease remission. Forty-five percent did not require surgery or other salvage therapies within one year of receiving the medication. Further studies regarding the use of vislizumab are ongoing.

5) Surgery
Of the 15% of UC patients who develop severe colitis, 30% will ultimately require colectomy. The timing of surgery is dependent on the severity of the patient’s colitis, age, co-morbid medical conditions, response to medical therapy, and presence of complications of colitis noted above. Discussion regarding surgery in UC will be presented in future blogs.

In response to a recent blog, Lee wrote in with a question about how to approach a family member or friend about a possible diagnosis of UC. While there are certainly individual differences based upon the dynamics of each relationship, some things we have found helpful in these situations are:

1) Express that the reason you are broaching the topic is primarily out of your care and concern for the individual. For example, starting off by saying "I've noticed that you haven't really been feeling very well lately and I'm genuinely concerned about you." Some people find having a digestive illness embarrassing and difficult to talk about. Discussing symptoms of bloody diarrhea and gas is not as easy as talking about a backache or twisted knee. Others, who have been healthy for most of their lives, try to deny the symptoms for some time in the hope they will go away. Yet, the disruption to a person's quality of life and emotional health from gastrointestinal problems can be substantial. By bringing up the topic, you are demonstrating an openness and understanding.

2) Provide appropriate support. In Lee's situation, it sounds as if she is concerned a family member is exhibiting symptoms of UC and should seek medical attention. It may be helpful to mention to the individual that you happened to come across some information about a condition that seems to fit his symptoms, and would be happy to share it with him to see what his thoughts are. Providing a resource for the person you are concerned about may help him acknowledge and start understanding that perhaps something could be wrong.

3) Encourage the person to discuss these issues with a health care professional. Symptoms of UC (bloody diarrhea, constipation, abdominal pain, gas, bloating) can also be seen in irritable bowel syndrome, infectious diarrhea, proctitis secondary to sexually transmitted diseases, celiac disease, food allergy, and other forms of colitis. As such, it is important that the individual has an appropriate evaluation to determine the source of symptoms.

In a majority of cases, UC can be managed medically, but there are certain situations when surgery is indicated. Historically, 30-40% of all UC patients eventually underwent removal of the colon, or colectomy.

The following are reasons for colectomy:

1) Medically refractory disease - Flares are either frequent or continuous despite maximal medical therapy.

2) Corticosteroid dependence - When continous steroids are required to prevent flares.

3) Inability to tolerate medical therapy - If the medications cause side effects that are not tolerable or allergic reactions.

4) Dysplasia (pre-cancer) or cancer - Although not all dysplasia requires surgery, some do and all cancer does.

5) Prophylaxis against cancer - For those who do not want to take the chance of getting cancer and do not want to undergo frequent colonoscopy to look for dysplasia an cancer

6) Avoid chronic medical therapy - For those who do not want to take chronic medication.

As the peak incidence of IBD is among young men and women between the ages of 20 and 40, questions regarding family planning often arise. One of the greatest concerns often voiced by patients is whether having UC will affect their reproductive capability. Several studies have looked at this topic and have determined that the diagnosis of UC unto itself does not alter fertility for men or women. There are, however, disease related issues that may affect reproduction:

1) Active disease - The presence of active disease has been shown to diminish fertility among women with Crohn's disease, likely due to inflammation and scarring of the ovaries and fallopian tubes from adjacent bowel. While studies have not borne out the same results in UC, it seems reasonable to recommend family planning during a period of quiescent disease.

2) Medications - Among the wide array of medications used to treat UC, none have been shown to affect female fertility. For men with UC, however, there is well documented evidence of diminished sperm counts and motility while taking sulfasalazine. This effect is reversible; sperm counts and motility usually return to normal within 3 months of stopping the medication. As such, it recommended that men attempting to conceive stop sulfasalazine or replace it with a 5-ASA medication.

3) Surgery - Women who undergo colectomy with an ileal-pouch anal anastomosis for UC prior to reproduction, may experience difficulty becoming pregnant. It is believed that manipulation in the pelvis required for creation of a pouch can disrupt the ovaries and fallopian tubes, making conception more challenging.