Ulcerative Colitis: Second-Line Treatments

"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.

Fortunately, most patients with ulcerative colitis (UC) respond well to initial therapy with standard medications such as mesalamine and others in the so-called 5-ASA (aminosalicylic acid) class. But some patients may find these drugs not effective enough, and there may come a time when those who do respond see symptoms recur to the point where a change in therapy should be considered.

What are the options?

As with patients newly diagnosed, the first step should be to conduct a thorough evaluation via endoscopy and blood and other diagnostic tests. It's possible the initial diagnosis was wrong or missed important features that could contribute to the lack of response. Or the patient may have developed something altogether new, such as bowel cancer or infection, or pathology further up the digestive tract that causes diarrhea and pain. These must be ruled out before determining the best course of action.

Let's say you've done this and it's clear that, despite initial treatment, UC pathology has returned and/or worsened. If 5-ASA drugs as initially prescribed aren't working, it's time to look at other approaches.

Second-Line Management With Conventional Immunomodulators

Increasing the dosage or changing the route of administration for the initially prescribed agent may be considered. Blood testing may reveal that drug concentrations are too low to be effective, in which case dose escalation can be a reasonable option.

Switching to a different 5-ASA agent is an obvious potential choice. Diazo-bonded 5-ASA drugs such as olsalazine or balsalazide may be substituted for mesalamine, for example, as can sulfasalazine, although at the cost of increased risk for side effects such as nausea.

Recommendations from the Swiss Society of Gastroenterology call for combination therapy in most patients who appear unresponsive to 5-ASA monotherapy. Choices for add-ons include corticosteroids, thiopurine agents such as azathioprine, and more directly immunosuppressant medications like cyclosporine or tacrolimus. All of these do come with increased risks for side effects, however, some of which (such as infections) can be serious.

Biologic and Targeted Agents

If symptoms have progressed to a point where the disease is considered moderate to severe, or if drug switching or combinations fail to bring adequate relief -- or if patients cannot be weaned from systemic steroid therapy without symptoms recurring (a.k.a. steroid dependency) -- the most commonly recommended options are drugs that block specific immune pathways. These include:

• Tumor necrosis factor (TNF) inhibitors

• Janus-associated kinase (JAK) inhibitors

• Anti-adhesion molecule (e.g., vedolizumab)

• Interleukin-12/23 inhibitor (e.g., ustekinumab)

• Sphingosine-1 phosphate (S1P) receptor agonist (e.g., ozanimod)

JAK inhibitors, including tofacitinib (Xeljanz) and upadacitinib (Rinvoq) and S1P agonists, are oral medications, while the others require periodic injections or infusions. TNF inhibitors are the longest established, having been marketed since the 1990s, and thus have the longest longitudinal data on safety.

Some TNF inhibitors, including infliximab (originator Remicade) and adalimumab (originator Humira) are now also available as so-called biosimilars, which may cost somewhat less. Although most data have shown no major rates of adverse events with switching from an originator to a biosimilar, data are lacking on patients who undergo multiple switches.

While biologics and JAK inhibitors are generally safer than immunosuppressants and long-term systemic corticosteroids, they come with a range of adverse effects. These include injection-site reactions and increased risks for certain infections such as sepsis and tuberculosis (their labels include a boxed warning about them).

As well, JAK inhibitors have been linked with serious infections and a higher risk for cardiovascular events compared with TNF inhibitors, also highlighted in a boxed warning. The FDA has recommended this class of drug only for patients for whom TNF blockers have failed, and the two drug types should not be combined.

One last point may go without saying, but we will reiterate it here: decision-making about medications should be shared with the patient. This is an opportunity to review patients' goals for therapy, which may have changed now that they have more experience with the disease and have a clearer understanding of what they may realistically expect. Their tolerance for side effects may have decreased (e.g., if they had difficulty with first-line therapy), or conversely, they may be more willing to accept risks in exchange for better symptom control. These discussions will inform your recommendations for revised therapy.

Next up: Case Study

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?

Part 5: UC: Initial Treatments and Response Monitoring

Part 6: UC: Dietary and Lifestyle Interventions