UC: Initial Treatments and Response Monitoring

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Not all that long ago, the only effective treatment for ulcerative colitis (UC) was colectomy, with its attendant risks and burdens on patients' daily lives. Now, most cases can be managed medically without a need for surgery ever.

Of course, the available medications and decision-making on which to use have evolved as new drugs, and better data about existing ones, have become available. The major gastroenterology societies have developed guidelines that are updated periodically to take account of these advancements. In this Medical Journeys installment, we address the currently accepted algorithms for determining initial treatment as well as procedures for monitoring response and deciding when to change a patient's regimen.

Points to Consider in Choosing Initial Therapy

The American Gastroenterological Association (AGA), in guidelines published in 2019, offered different advice depending on disease severity and extent. Thus, the first step in choosing therapy is to review the diagnostic findings related to symptom severity and lesion location.

The AGA guide for mild-moderate disease (the most common at diagnosis) defines it as follows:

• Four to six bowel movements per day

• Limited rectal bleeding

• No constitutional symptoms

• "Low overall inflammatory burden"

The AGA guidelines also define extensive disease, which has its own management recommendations, as inflammation "proximal to the splenic flexure." Left-sided disease is also considered a more severe presentation, and is defined as inflammation confined between the rectum and splenic flexure, or less than 50 cm from the anus.

Moderate-to-severe disease, according to the AGA's companion guideline, has the following features:

• More than six bowel movements per day

• Frequent or continuous rectal bleeding

• Mild (or greater) fever and high pulse rate

• Hemoglobin deficiency

• High erythrocyte sedimentation rate

• Colonic abnormalities visible on x-ray

• Abdominal tenderness or distention

This guideline also noted, "When reported, Mayo Clinic scores of 6–12 with an endoscopic subscore of 2 or 3 were considered moderate to severe disease." This scoring system was first used in a Mayo-conducted trial of a coated oral formulation of 5-aminosalicylic acid (5-ASA) reported in 1987.

Needless to say, the choice of therapy is ultimately up to the patient, and practice guidelines are just that -- treatment plans must be crafted for each individual patient. It's important to discuss the goals of therapy, and in particular to establish patients' tolerance for the side effects one might expect from particular drugs versus the degree of symptom control needed. There are choices to make between oral and rectal therapies, for which patient preferences may understandably vary.

In general, symptom remission is the overarching goal for initial therapy. As well, a guideline from the American College of Gastroenterology (ACG), also appearing in 2019, suggested mucosal healing as a therapeutic goal, "to increase the likelihood of sustained steroid-free remission and prevent hospitalizations and surgery."

Drug Options

For many inflammatory autoimmune conditions, corticosteroids are a common first choice. However, this is not the case in UC, except perhaps to relieve symptoms temporarily while a diagnosis is being finalized. The available guidelines do allow for rectal corticosteroids and oral budesonide (a steroid with limited systemic exposure) but they discourage standard oral steroids for UC unless needed to bring refractory disease under control, and never indefinitely. Systemic steroids should never be considered definitive long-term treatment for UC.

It is actually 5-ASA agents, which have been around since just after World War II, that form the backbone of initial therapy in UC. The following are recommended in the guidelines; they are formulated in different ways to deliver 5-ASA to the large bowel while preventing its destruction by digestive juices in the stomach and small intestine:

• Mesalamine (the agent used in the 1987 Mayo trial)

• Sulfasalazine

• Diazo-bonded 5-ASA agents including olsalazine and balsalazide

The AGA recommends doses of 2-4 g/day of oral mesalamine or diazo-bonded 5-ASAs; sulfasalazine comes with more side effects like nausea, which often limit the dose patients can tolerate. However, sulfasalazine may have other benefits such as treatment for peripheral arthritis so it still plays a role in UC management.

Mesalamine also comes in a rectal form, which may be added to oral treatment in patients with extensive or left-sided disease, both the AGA and ACG guidelines say. The ACG in particular recommends mesalamine enema over rectal steroids. Rectal mesalamine alone may be considered for patients whose endoscopic findings point to proctitis only, without more proximal involvement.

For patients who present with moderate-severe disease, the AGA recommends consideration of starting with biologic agents including tumor necrosis factor inhibitors, vedolizumab, or the interleukin 12/23 inhibitor ustekinumab. These agents and others are often used as step-up therapy for UC patients who do not achieve or maintain steroid-free remission, and thus will be addressed in a future Medical Journeys installment.

Also to be covered later in this series are less well-studied treatments such as probiotics, curcumin, and fecal transplant. These have shown promise in small studies but are far from standard-of-care in UC.

Response Monitoring

Not every therapy works for every patient, and thus it is necessary to follow up periodically after a treatment regimen is started. Patients should be asked about symptoms and lab tests (including those evaluating systemic inflammation, hemoglobin level, and fecal tests), and, most importantly, endoscopy needs to be repeated in order to determine if mucosal healing is taking place.

It is also important to check for adverse drug effects. The AGA guideline calls for periodic renal function tests in patients receiving mesalamine and diazo-bonded 5-ASA agents. Those on sulfasalazine need regular complete blood counts and liver function tests (and should take folic acid supplements, too). Patients on steroids for extended periods may need bone density evaluations. The most common side effect from mesalamine and diazo-bonded 5-ASAs is headache; both may also cause GI distress, but overall these drugs are tolerated easily by most patients.

The ACG recommends that the first clinical evaluation take place within 6 weeks of starting therapy. However, neither the ACG nor the AGA suggested specific intervals for follow-up checks; presumably that is up to the clinician's judgment based on initial disease characteristics and patient preferences and risk factors.

There is also a role for patients to self-monitor. A third guidance from the AGA, geared specifically to patients, suggests they watch for any of the following complications and report them promptly:

• Persistent or increased rectal bleeding

• New inflammation in other tissues

• Signs of megacolon -- i.e., dilation of the abdominal colon

Next up: Dietary and behavioral interventions

Read previous installments in this Medical Journeys series:

Part 1: UC: Understanding the Epidemiology and Pathophysiology

Part 2: UC: Symptoms, Exams, Diagnosis

Part 3: UC: How and Why Does It Arise?

Part 4: Case Study: Why Is This Teen's Ulcerative Colitis So Severe, So Resistant?