The symptoms of ulcerative colitis (UC) are caused by inflammation of the large intestine, which is composed of the colon and the rectum. Most of the symptoms of UC are caused by inflammation of the rectum. The severity of your symptoms and additional factors help us choose the appropriate therapy for you. Patients having, for example, four or more bowel movements per day or other symptoms like fever or anemia are categorized as having moderately to severely active colitis. Because of your current symptoms, we believe your UC belongs to that category.

Your treatment will include a phase for induction of remission, in which our goal would be to suppress the inflammatory activity so you feel well, and a second phase for maintenance of remission in order to keep you well and to avoid future flares. Because UC is a chronic condition, it does require chronic therapy so that the condition stays under good control, and, ultimately, so we can avoid future complications and the rare risk of colorectal cancer.

For moderately active UC, the most common therapy is a class of drugs called “aminosalicylates.” Aminosalicylates are a family of non-immunosuppressive drugs that act locally on the bowel wall to reduce inflammation. The agents, of which there are many different ones, can induce and maintain remission in this type of UC and can be given in combination with other medications for more severely active UC. They can be administered both orally and rectally to increase their effectiveness. These medications are exceptionally safe, but 3 % of the population may be intolerant to them and actually have more diarrhea when they start them. In addition, there is a rare risk of kidney insufficiency which is monitored with periodic kidney function blood tests.

Most patients with moderately to severely active UC will require corticosteroids. Steroids are very effective and fast at inducing remission and are used mainly for their rapid effect. They are generally safe for short-term treatment, but we really work hard to limit your exposure to them due to an unfavorable long-term safety profile and taper down rapidly in case we do. The rectum and lower part of the colon can be treated with topical steroids given by foam or by enema. The most common side effects of short-term steroid use include sleep disturbances, weight gain, anxiety, acne, and mood changes. Steroids have no role in maintaining remission. A newer type of steroid called “budesonide MMX” (Uceris) works primarily topically on the colon and has fewer side effects than prednisone and may have some benefit for milder disease.

An additional class of immunosuppressant therapy, called thiopurines, has benefit in some UC patients. Thiopurine therapy includes azathioprine (Imuran or Azasan) and 6-mercaptopurine (Purinethol) and is used when patients needed steroids in order to get them off of them and keep them off. They are given orally, once daily, and their mechanism of action is not fully understood, although we know these drugs have suppressive effects on white blood cells that play a key role in inflammatory activity. Common but preventable side effects include suppression of blood counts, which is reversible when the drug is stopped and is monitored by periodic blood work. Some of the side effects depend on the individual’s ability to metabolize the drug. Fortunately, this can be tested with a simple blood test before treatment initiation. The rarer side effects include infections and minor increases in the rates of non-melanoma skin cancer and lymphoma. These risks can be decreased with flu and pneumonia vaccines and sun exposure protection measures combined with annual dermatologic screening. The risk of lymphoma is rare but slightly increased compared to the general population. It increases the longer a patient is on this medication and the older the patient is, but the risk goes away when the drug is discontinued.

Another class of therapy for moderately to severely active UC is the biological therapies known as anti-TNF therapies. Anti-TNF therapies are antibodies to an inflammatory mediator called TNF. Because these therapies are proteins, they must be administered intravenously or subcutaneously. Currently, there are three anti-TNFs approved for the treatment of UC in the USA including infliximab (Remicade), adalimumab (Humira), and golimumab (Simponi). These therapies are very effective for this type of UC and work even better when in combination with the thiopurine therapies. The side effects include rare risks of infection and, rarely, allergic reactions to the therapy that may also predict a loss of response. In order to protect our patients, we screen for tuberculosis and hepatitis B prior to treatment initiation and recommend influenza and pneumonia vaccines.

A recent addition to our therapeutic options is vedolizumab (Entyvio) which is also an intravenous biological therapy, but this drug works by inhibiting white blood cells, movement from the bloodstream to the gut. Because of this specific mechanism, vedolizumab is a more targeted approach to treating UC and has a very favorable safety profile, but does have a small risk of nasal and throat infections. Vedolizumab can be used to induce and to maintain remission.

There are occasions when more severe UC will require hospitalization, during which time intravenous treatment can be administered to induce remission. In a minority of the patients, surgical treatment may be required. The surgery for severe UC is removal of the entire colon and rectum. By removing the large intestine, UC is also removed from the body. Most patients have a new rectum made from small intestine, called a “J pouch.”

Moderately active UC is characterized by four or more bowel movements per day and minimal signs of toxicity, while patients with more than six bloody bowel movements and overt signs of toxicity (fever, tachycardia, anemia, or elevated ESR) are categorized as severely active UC [1].

The primary treatment goal is to rapidly induce remission, followed by developing a plan for steroid-free maintenance. In general, the choice of maintenance agent is determined by the agent required for induction. A more strict aim, currently emerging, is achieving endoscopic remission (mucosal healing) which has been associated with decreased need for corticosteroids, lower hospitalization rates, sustained clinical remission, decreased colectomy rates, and cancer risk [2–5].

Aminosalicylates are preferred as initial treatment of mildly to moderately active UC for their convenient dosing and favorable safety profile. Sulfasalazine, in a daily dose of 4–6 g, is an effective, low-cost treatment for induction and maintenance of remission, but carries a higher incidence of side effects. Mesalamine, olsalazine, and balsalazide have been shown to be as effective in inducing and maintaining remission in moderate UC [6, 7]. This effect may be more pronounced at a dose of 4.8 g per day and with concomitant topical rectal therapy in the form of either suppository or enema [8, 9]. Intolerance to sulfasalazine is common, but is rarely seen with mesalamine.

Many patients with moderately active UC and patients with severely active UC will require immune-based therapeutic strategies. Thiopurines may be effective as maintenance therapy in patients who failed aminosalicylates or are steroid dependent, but because of their slower onset of action, they are not practical for induction of remission and therefore usually require concomitant administration of steroids or anti-TNFs. The use of thiopurines in the management of UC is not based on high-quality evidence; it remains unclear if they should be given with aminosalicylates or as monotherapy [10, 11].

Thiopurines are metabolized by the enzyme thiopurine methyltransferase (TPMT) to 6-thioguanine (6-TGn) and 6-methylmercaptopurine (6MMP). 6-MMP is associated with elevated liver enzymes [12]. 6-TGn is associated with relapse-free remission, but also with bone marrow suppression in patients with low TPMT activity and high 6-TGn levels [13, 14]. In patients wtih normal TPMT activity, dosing is weight based with a target dose of 2–3 mg/kg for azathioprine and 1–1.5 mg/kg for 6MP.

It is currently considered a quality measure to assess TPMT activity prior to initiation of treatment with a thiopurine [15]. Absence of enzyme activity (0.3 % of the population) precludes treatment with thiopurines. Patients with intermediate enzyme activity (11 %) should be started on a low dose (25–50 mg) and increased gradually (25–50 mg/week), while patients with normal enzyme activity treatment can be initiated at the target dose [16]. Patients should be monitored for bone marrow suppression and liver enzyme elevations, and although not standard of care, we recommend thiopurine metabolite measurement for drug optimization [17]. Liver enzyme elevation and bone marrow suppression are reversible dose-dependent side effects, while allergic reactions such as fever, rash, arthralgia, and myalgia usually require trial of a different thiopurine. There is still a 50 % risk of cross-reaction. Pancreatitis is class-related side effect and precludes further treatment with thiopurines [18]. Thiopurines also carry the risk for increased rate of nonmelanoma skin cancers, overall infections and serious infections, and lymphoma [19–21].

Anti-TNF therapy is an effective therapeutic option for patients with moderately to severely active UC, patients with steroid-dependent or refractory disease, and patients refractory or intolerant to aminosalicylates or thiopurines. Infliximab, adalimumab, and golimumab are approved in the USA for inducing and maintaining remission in UC [22–26]. Concomitant therapy of anti-TNFs and thiopurines leads to higher rates of remission induction, maintained remission, and mucosal healing [23]. Concomitant therapy also results in decreased immunogenicity (anti-drug antibodies) and higher drug trough levels [23, 27, 28]. This was shown for infliximab/adalimumab and thiopurines in UC; however, recent evidence supports the use of methotrexate, which may be preferred in patients that have higher risk of lymphoma (males younger than 30 or older than 50) [28]. We also generalize the current knowledge to utilize golimumab in combination therapy.

Secondary loss of response to anti-TNF therapy is well described. When it occurs, it is recommended to assess for infection and to consider the possibility of increased clearance due to anti-drug antibodies [29]. Infliximab and adalimumab have commercially available assays for their serum levels and anti-drug antibodies. In a patient who previously responded to anti-TNF therapy and has now developed anti-drug antibodies and undetectable drug levels, switching to another anti-TNF within the same drug class makes sense [30–34]. There has been a movement in the field to monitor for subclinical disease activity in order clinical relapse and colonic dysplasia; details regarding appropriate interventions and monitoring strategies have not been formulized [35]. However, there is considerable interest in utilizing fecal calprotectin for noninvasive monitoring of disease activity [36].

Vedolizumab, an α₄β₇ integrin inhibitor, is effective for inducing and maintaining remission in anti-TNF naïve and experienced patients with moderately to severely active UC [37]. Current data suggest an excellent safety profile, low immunogenicity, and high rates of sustained response.