Jessica Allegretti, MD, on Optimizing Existing Therapies in IBD

When designing a treatment plan for patients with ulcerative colitis (UC), clinicians should risk-stratify patients based on clinical, endoscopic, and biologic factors, and set goals using shared decision making with the patient, Jessica Allegretti, MD, said at the Advances in Inflammatory Bowel Diseases (AIBD) regional meeting.

Dr Allegretti is the medical director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

She stressed that the many new therapies available for the treatment of UC present gastroenterologists with more choices than ever before, but also require that several factors when selecting and positioning these medications. Dr Allegretti noted that onset of action varies by therapeutic class, and the efficacy of therapies can differ among patients who have been exposed to tumor necrosis factor inhibitors (TNFis) compared to those who are TNF-naïve. Patient preferences must also be weighed and discussed.

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 fulminant UC, characterized by 10 or more stools per day, continuous bleeding, abdominal pain, and the potential for mortality.

Control of UC symptoms is no longer the exclusive focus of IBD treatment, Dr Allegretti explained. Prognostic factors —such as being diagnosed at age 40 or younger, the presence of more extensive colitis, a Mayo Endoscopic Subscore of 3 and a UC Endoscopic Index of Severity (UCEIS) of 7 which indicates more severe disease, elevated C-reactive protein (CRP), low serum albumin, and hospitalization for colitis—are given more attention today.

“Symptoms alone poorly correlate with actual inflammation in UC,” she pointed out. With the understanding that endoscopic and mucosal inflammation may still be present among patients who are in clinical remission, there has been a transition to applying objective measures of control, including improved quality of life, decreased risk of hospitalization, fewer surgeries, and achieving minimal to no disability. “The treatment paradigm today moves toward deep remission,” she stated.

With all these changes in available therapies and approaches to care, however, complications still occur, Dr Allegretti noted. This calls for the optimization of therapies to reach predefined goals, which should include biologic as well as symptomatic targets. Once treatment goals are achieved, patients must continue to be monitored for possible recurrence. “We need to utilize our increased therapeutic armamentarium to induce and maintain remission” among patients with UC, she said.

Dr Allegretti reviewed the STRIDE 2 consensus of treatment targets beginning with symptomatic response, continuing to remission of symptoms and normalization of CRP; decrease in fecal calprotectin and normalized growth in pediatric patients; and ultimately to endoscopic healing, normalized quality of life, and the absence of disability. Clinicians should also consider histologic and mucosal healing among patients with UC as possible but informal targets, she added.

A retrospective analysis illustrated that treat-to-target is feasible for UC, showing substantially greater mucosal and histologic healing among patients who were monitored and whose therapy was adjusted to work toward the target of mucosal healing, Dr Allegretti observed.

Such monitoring is important during both active and quiescent phases of UC, Dr Allegretti emphasized. Checks of CRP, hemoglobin, fecal calprotectin, and lactoferrin, in addition to follow-up endoscopy, are essential parts of the monitoring process. “Timelines will depend on disease activity, but even patients in remission should undergo regular monitoring,” she stated.

Dr Allegretti reviewed the new therapies that have been introduced in recent years for UC. Among them are ozanimod, a sphingosine-1-phosphate (S1P) receptor modulator, which prevents lymphocyte mobilization to inflammatory sites. “It really traps lymphocytes inside the lymph nodes,” Dr Allegretti stated. Data from trials show positive trends across 52 weeks. Its efficacy is affected by patient exposure to antitumor necrosis factor (TNF), as with many other therapies. Safety adverse events have included bradycardia, elevated liver enzymes, macular edema, and serious infections.

Tofacitinib, an oral small molecule Janus kinase (JAK) inhibitor approved in 2018, showed efficacy in the OCTAVE trials for induction and maintenance of UC, with rates of remission ranging from 16.5% to 40.6%. Symptomatic improvement measured by rectal bleeding may be seen as early as day 3, with improvement in Mayo scores often occurring at day 7, making this a fast-acting agent.

Upadacitinib, a JAK inhibitor engineered for increased selectivity to JAK1 approved in 2022, showed significant improvement among patients with UC in the U-ACCOMPLISH and U-ACHIEVE trial, achieving deltas of greater than 30% in comparison to placebo and up to 52% to 64% clinical response even in patients exposed to biologic therapies. This therapy also acts very quickly, Dr Allegretti pointed out, yielding improvement in stool frequency and rectal bleeding within a few days in many cases.

Both JAK inhibitors are restricted by the US Food and Drug Administration for 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.

Dr Allegretti observed that 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. “We really are looking at high-risk patients in this study,” she noted.

Patients with UC should receive herpes zoster vaccine, along with complete blood count, liver function tests, and lipid panels before beginning therapy, Dr Allegretti said.

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. It proved highly effective in both induction and maintenance in trials, with patients achieving clinical response rates up to 71% at week 44 and clinical remission rates of up to 65% also at week 44.

Important considerations in choosing and positioning therapies, Dr Allegretti explained, include an agent’s rapidity of onset, durability, and pharmacokinetics, and whether to use combination or monotherapy. The overall safety and risks of infection, malignancy, and any specific concerns must be factored into the choice of therapy. Patient-specific factors that should be considered include age, comorbidities, and preferences; lifestyle factors; history of malignancy; severity of disease; age at diagnosis; extraintestinal manifestations; and prior treatment failures and successes.

For induction of remission among bio-naïve patients, infliximab and vedolizumab are top choices, Dr Allegretti stated. Among patients who have been exposed to TNFis, tofacitinib or ustekinumab should be considered and may perform better than vedolizumab in induction; for maintenance of remission, there is no difference among these therapies. Vedolizumab and ustekinumab are the lowest-risk options for patients with risks of adverse events and when infection prevention is a priority, which were compared in the VARSITY study in the first head-to-head trial of biologics in UC. Vedolizumab bested adalimumab by moderate levels.

“It’s a great time to be a clinician and a patient in this space,” thanks to the multiple new therapies available,” she concluded.

—Rebecca Mashaw

Allegretti, J. Update on the management of ulcerative colitis. Presented at: Advances in Inflammatory Bowel Diseases regional meeting. May 19, 2023. Boston.