Optimizing Existing Therapies in the Management of IBD: Dr Jessica Allegretti

The 3 pillars of inflammatory bowel disease (IBD) care are early intervention, a treat to target strategy, and tight control based on disease severity and prognostic factors, said Jessica Allegretti, MD, during her presentation at the Advances in Inflammatory Bowel Disease virtual meeting. 

Dr Allegretti is the medical director of the Crohn’s and Colitis Center and director of clinical research and the fecal microbiota transplant program at the Brigham and Women’s Hospital in Boston, Massachusetts. She also currently serves as an associate professor of medicine at the Harvard Medical School in Boston, Massachusetts.

“We must target disease burden, identify ideal markers to sustain deep remission, and achieve better long-term measures,” Dr Allegretti said during her presentation on optimizing existing therapies in the management of IBD.

She reviewed the objectives of IBD care by discussing the current goals, identifying high-risk factors for progressive disease, and finding the correct therapeutic drug for it. She also reviewed the pros and cons of monotherapy vs combination therapy and the use of a treat to target approach.

“Induce remission rapidly and maintain steroid-free remission,” Dr Allegretti stated with the understanding that normal bowel function and an improved quality of life are the ultimate goals of IBD care. "We are actively trying to overcome the challenges of the previous strategies," she said, which tended to be symptom-based or complication-based rather than focused on treating to a specific target to alter the natural history of the disease. In simple words, she said, prior strategies were more reactive than proactive.

Can one determine disease severity and prognosis to personalize treatment strategy? “Assessing disease severity at an early stage is essential for the development of an appropriate management plan,” Dr Allegretti explained.

Understanding the distinction between activity and severity is important in decision-making, she pointed out. Activity reflects the cross-sectional assessment of symptoms, signs, endoscopy, histology, and biomarkers at one point in time, while severity includes factors that provide a more complete picture of the overall burden of the disease.

The first pillar—early intervention—has demonstrated its value in controlling disease and preventing disease progression, thus protecting against irreversible damage and helping the patient to regain a normal quality of life. Moreover, rapid disease control “may effectively prevent disease progression and allow dose reduction or even withdrawal of treatment, reducing the risk of long-term adverse events and health care costs,” Dr Allegretti noted.

A study of health claims data in 2012 undertaken by David Rubin, MD, and colleagues, found early treatment to vastly improve patient response to biologic therapy in Crohn disease (CD). Data from more than 3,700 participants, all of whom received antitumor necrosis factor (TNF) therapy at some point, show that a top-down approach to anti-TNF therapy in CD is associated with reductions in loss of response and fewer surgeries than conventional stepwise management.

For patients with ulcerative colitis (UC), infliximab (69.4%) produced a better short-term response among patients than adalimumab (54.6%) or golimumab (51.8%) The remission rates were higher in the infliximab (38.8%) group than in the adalimumab (18.5%) or the golimumab group (18.7%) Mucosal healing, too, was significantly higher among patients taking infliximab (62.0%) vs those who took adalimumab (46.9%) or golimumab (43.2%).

“Identify patients at high risk and use advanced therapies early,” Dr Allegretti stressed.

She also talked about considering combination therapy with an anti-TNF and immunomodulator, such as azathioprine. In a study of 63 patients with early CD with no previous use of immunosuppressants or biologics, and no fistulas, 70.4% of the patients achieved mucosal healing after combination therapy. The numbers were much lower in the azathioprine monotherapy group (30.8%) and infliximab monotherapy group (43.5%) Similarly, clinical remission rates were significantly higher in the combination therapy group (64.7%) vs the azathioprine monotherapy (10.0%) or infliximab monotherapy (25.0%) groups.

However, she cautions against one approach for all and urges clinicians to consider risk factors before combining therapies and drugs. “It may not be right for everyone,” she warns.

In preventing adverse long-term outcomes in the treat-to-target approach, Dr Allegretti said, regular monitoring is a critically important step.

She referenced the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program, initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD), that examined potential treatment targets using an evidence-based expert consensus process. Among the 12 recommendations for UC and CD were patient-reported outcome remission, clinical remission, endoscopic remission, histological remission, biomarker remission, and composite endpoints.

A 2017 CALM study published in the Lancet proved the treat to target approach with adalimumab resulted in higher rates of endoscopic and biologic remission. The open-label phase 3 study, conducted in 22 countries at 74 hospitals and outpatient centers, evaluated 244 patients with active endoscopic CD. The patients were divided into 2 groups—tight control group and clinical management group—all separated based on smoking habits, weight, and disease duration.

In both groups, treatment was escalated in a stepwise manner, from no treatment to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to weekly adalimumab and daily azathioprine. 

A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (46% patients) than in the clinical management group (30% patients); 86% patients in the tight control group and 82% patients in the clinical management group reported treatment-emergent adverse events. There were no treatment-related deaths. The most common adverse events were nausea, nasopharyngitis, and headache in the tight control group, and worsening CD, arthralgia, and nasopharyngitis in the clinical management group.

“CALM shows that timely escalation with an anti-TNF therapy on the basis of clinical symptoms combined with biomarkers in patients with early CD results in better clinical and endoscopic outcomes than symptom-driven decisions alone,” Dr Allegretti summed up.

Speaking of the third pillar (tight control), she said, “Frequent monitoring is the key.”

Close monitoring in active phase of the disease is important to determine response to medication, stability, and to document mucosal healing. To detect relapse in the maintenance phase, Dr Allegretti noted, adherence to maintenance regimen and utilizing biomarker and laboratory assessment come into play. Some clinicians may also consider reactive therapeutic drug monitoring, particularly in patients with a secondary loss of response.

A 2016 retrospective single-center referral analysis of 101 patients with UC receiving scheduled induction therapy with infliximab at weeks 0, 2, and 6, who had an endoscopic evaluation at baseline and after induction therapy, revealed interesting correlation between infliximab levels and short-term mucosal healing, she said. More than half of the participants (53.4%) undergoing infliximab induction therapy with paired endoscopies achieved short-term mucosal healing.

Similarly, another observational study published in Clinical Gastroenterology and Hepatology found significant association between serum levels of anti-TNF agents and level of mucosal healing. “Serum levels of 6-10 μg/mL for infliximab and 8-12 μg/mL for adalimumab are required to achieve mucosal healing in 80%-90% of patients with IBD,” Dr Allegretti stated. This, she said, could be considered as a “therapeutic window.”

Dr Allegretti posed a final question: Is improving outcomes by treating beyond symptoms is even possible? It is very possible, she said, but requires the use of good clinical judgement. “Treating beyond symptoms will require a clear management plan influenced by disease severity at presentation, clinical and biological prognostic factors, achievement and maintenance of clinical and biological remission, and pharmacoeconomics,” she said.

In summary, Dr Allegretti stated, use early biologics with or without small molecules “among patients with moderate to severe symptoms and/or at high risk for disability,” and use reactive drug monitoring “if the patient has an incomplete response or loss of response.”

—Priyam Vora

Reference:
Allegretti J. Optimizing Existing Therapies in Patients with Inflammatory Bowel Disease. Presented at: Advances in Inflammatory Bowel Disease virtual meeting. April 20-21, 2023.