Millie Long, MD, Reviews the Management of Ulcerative Colitis

Decisions about how to position and sequence the multiplicity of new therapies for the treatment of ulcerative colitis (UC) should be patient-centric and informed by shared decision making between the physician and the patient, Millie Long, MD, stressed in her presentation at the Advances in Inflammatory Bowel Diseases regional meeting.

Dr Long is professor of medicine, vice chief of education, and director of the fellowship program in the Division of Gastroenterology and Hepatology at the University of North Carolina at Chapel Hill.

“The onset of action varies by class,” she said. The efficacy of these new therapies can differ depending on whether the patient has or has not been exposed to tumor necrosis factor inhibitors (TNFis), so their previous treatments must be taken into consideration when considering the switch to a different agent.

Dr Long explained that the severity of UC was previously gauged primarily according to symptoms, ranging from mild cases with a few loose stools and mild abdominal pain, to moderate disease with greater abdominal pain, more bloody stools, and anemia, to severe UC marked by fever, anemia and more than 6 bloody stools daily. Fulminant UC was characterized by more than 10 stools daily, continuous bleeding, abdominal pain, distension, and was potentially fatal.

Today, however, prognostic factors are given greater attention, she said. “The greater the number of poor prognostic factors, the worse the prognosis as measured by likelihood of colectomy.” These prognostic factors include age 40 or younger at diagnosis, more extensive colitis, more severe endoscopic disease with a Mayo Endoscopic Subscore of 3 and a UC Endoscopic Index of Severity (UCEIS) of 7, elevated C-reactive protein (CRP), low serum albumin, and hospitalization for colitis.

“Our goals have shifted beyond control of symptoms alone in UC,” Dr Long stated, with the understanding that endoscopic and mucosal inflammation may still be present among patients who are in clinical remission. There has been “a movement to objective measures of control and a chronic care model of IBD.”

With a greater understanding of UC and better therapies, she asked, “why are complications still occurring? We need to optimize therapies to reach predefined goals, which should include biologic as well as symptomatic targets. We have to actively monitor disease once those goals are reached. And we need to utilize our increased therapeutic armamentarium to induce and maintain remission” among patients with UC.

Dr Long reviewed the STRIDE 2 consensus of treatment targets beginning with symptomatic response and going through to remission of symptoms, normalization of CRP, decrease in fecal calprotectin and normalized growth in pediatric patients, to endoscopic healing, normalized quality of life, and the absence of disability.

“Real-world treat to target is possible in UC,” she stated, reviewing a retrospective analysis that showed substantially greater mucosal and histologic healing among patients with UC who were monitored and whose therapy was adjusted to work toward the target of mucosal healing.

“Disease monitoring is key during active and quiescent phases of UC,,” Dr Long emphasized, and should include checks of CRP, hemoglobin, fecal calprotectin, and lactoferrin, in addition to follow-up endoscopy.

Among numerous new UC therapies that have been introduced over the past 5 years is ozanimod, Dr Long explained. This sphingosine-1-phosphate (S1P) receptor modulator prevents lymphocyte mobilization to inflammatory sites. In studies of patients with prior exposure to TNFis, clinical response rates to ozanimod ranged from 36.9% at week 10 to 55.3% at week 52. Among TNFi-naïve patients, response rates at week 52 were 62.3%.

Adverse events have been associated with S1P receptor modulation, she noted, including bradycardia, some serious or opportunistic infections, macular edema, and elevated liver enzymes.

Another new entry into the UC therapy lineup is tofacitinib, an oral small molecule Janus kinase (JAK) inhibitor approved in 2018. Its efficacy in UC was demonstrated in the phase 3 OCTAVE 1 and OCTAVE 2 induction trials and the OCTAVE Sustain maintenance trial. Clinical remission rates in the induction trials ranged from 16.6% to 18.5% compared to placebo rates of 3.6% and 8.2%. The maintenance trial showed remission rates of 34.3% at the 5mg dose and 40.6% at 10mg.

The adverse events noted in these trials included herpes zoster, lipid abnormalities, serum creatinine kinase increases, nasopharyngitis, and venous thromboembolism (VTE). However, Dr Long noted, these trials among patients with UC revealed that VTE and pulmonary embolism (PE) occurred more often among placebo-treated patients, and those who developed DVT or PE had risk factors for those conditions.

The safety protocol for using tofacitinib in the treatment of UC calls for week 0 complete blood count (CBC), liver function tests (LFTs) and lipid panel, and discussion of vaccination for herpes zoster. CBC and LFT should be repeated at weeks 2 and 4, and again at week 8 along with a repeat lipid panel.

Unlike tofacitinib, which a is a pan-JAK inhibitor, upadacitinib is an oral small molecule engineered for increased selectivity to JAK1, Dr Long said. As with tofacitinib, the US Food and Drug Administration requires that a patient fail to respond, lose response, or show intolerance to TNFis before they can be treated with either JAK inhibitor. Upadacitinib was approved in 2022 for moderate to severe UC.

In the U-ACCOMPLISH and U-ACHIEVE clinical trials, which included patients who had shown an inadequate response to biologics, upadacitinib showed clinical remission rates at week 8 of 33.5% at 45mg. In the maintenance trial of responders 42.0% achieved clinical remission at 15mg, compared to 52% of those who received 30 mg doses.

A subgroup analysis of patients with inadequate or loss of response to biologics, 67.0% showed clinical response at week 2, and 82.0% achieved clinical response at week 8 in the U-ACHIEVE trial. In the U-ACCOMPLISH trial 64.0% had clinical response at week 2, 80.0% showed clinical response at week 8, and 38% achieved clinical remission at week 8.

There were no DVTs or PEs seen in the induction studies. The most common adverse events were acne, lymphopenia, herpes zoster, opportunistic infections, and creatinine phosphokinase elevation.

Both JAK inhibitors are restricted by the FDA to use among patients who have not responded to TNFis due to the black box warning required on this class of drugs following a

randomized, noninferiority safety study evaluating the long-term risk of major adverse coronary events (MACE) and malignancy in patients with rheumatoid arthritis. However, Dr Long pointed out, the patients in the RA study were over 50 years of age and had at least 1 cardiovascular risk factor, unlike most patients with UC, who trend younger.

Ustekinumab, a monoclonal antibody against the p40 subunit of IL-12 and IL-23, was approved in 2019 for the treatment of adults with moderately to severely active UC, Dr Long continued. In its induction trial, ustekinumab achieved the unique endpoint of histo-endoscopic mucosal healing in 20.3% of patients who received a 130 mg dose and 18.4% of patients dosed as 6mg/kg.

At week 44 of the extension study 38.4% of those who received 90 mg of ustekinumab every 12 weeks achieved clinical remission, compared to 43.8% of those who received the same dose every 8 weeks.

Overall malignancies were infrequently reported, with rates generally similar between treatment groups, Dr Long stated, noting that this is considered one of the safest drugs available for the treatment of UC.

In what she described as the “therapy choice puzzle in UC,” Dr Long explained that the main pieces are the drug, considering its indication, rapidity of onset, durability, pharmacokinetics and whether to use a combination or monotherapy, along with its overall safety and risks of infection, malignancy, and any specific concerns. The patient piece of the puzzle must take into account age, comorbidities, and preferences; lifestyle factors; history of malignancy; severity of disease; age at diagnosis; extraintestinal manifestations; and prior treatment failures and successes.

In positioning UC therapies, Dr Long said, for induction of remission among bio-naïve patients, infliximab and vedolizumab are top choices. For patients who have been exposed to TNFis, tofacitinib or ustekinumab should be considered and may perform better than vedolizumab; for maintenance of remission, there is no difference among these therapies. When the risk of adverse events or infection is a priority, vedolizumab and ustekinumab are the lowest-risk options.

In summary, Dr Long stated, when choosing among the many therapies for UC, “Risk-stratify your UC patients with clinical, endoscopic, and biologic factors; define treatment goals using shared decision making and include both symptom-based and biologic goals; consider efficacy differences when selecting therapies for patients who have been exposed to TNFis and for those who are TNFi-naïve; and remember that these decisions should all be patient-centric.”

—Rebecca Mashaw

Long, M. Update on the management of ulcerative colitis. Presented at: Advances in Inflammatory Bowel Diseases regional meeting; March 31. Baltimore, Maryland.