What’s New in the Management of Crohn Disease

The goals of therapy in Crohn disease (CD) and ulcerative colitis have gone beyond remission of clinical symptoms to include mucosal healing and monitoring of fecal biomarkers, Millie Long, MD, stated at the virtual Advances in Inflammatory Bowel Disease (AIBD) regional meeting on August 22.

Dr Long is vice chief for education and associate professor of medicine at the Inflammatory Bowel Disease Center at the University of North Carolina at Chapel Hill.

She explained that while older definitions of disease severity were based on symptoms only as measured by the Crohn Disease Activity Index (CDAI) and other indices, defining CD severity today includes endoscopic assessment of ulcerations and the use of the simple endoscopic score for Crohn disease (SES-CD). The SES-CD scores 5 segments—the left colon, transverse colon, right colon, ileum, and rectum—according to the disease activity. The total score is the sum of the scores of each segment. “A score greater than 6 on the SES-CD indicates moderate to severe disease,” Dr Long stated.

Further, the assessment of disease severity also includes consideration of prognostic factors. Poor prognostic factors such as young age at diagnosis, extensive bowel involvement, perianal or severe rectal disease, and penetrating/stenosing at diagnosis, are considered risk factors for aggressive disease. “The greater the number of poor prognostic factors, the worse the prognosis,” she explained.

Gaining a clear understanding of the severity of disease and of a patient’s prognosis is particularly important when making treatment decisions, Dr Long said. “Only 20% to 30% of patients [with CD] have an indolent disease course. Up to 80% of patients will require hospitalization at some points, and the 10-year risk of needing surgery ranges from 40% to 55%.”

One change in the approach to CD treatment is optimization of medical therapy, including the use of treat-to-target and biomarkers to make therapy more precise. “There is a specific role for fecal calprotectin at diagnosis to differentiate inflammatory bowel disease (IBD) from irritable bowel syndrome,” Dr Long explained.

That surgery risk may be decreasing, dropping to approximately 30%, Dr Long said. “We do see increasing rates of elective surgeries and fewer emergent surgeries,” suggesting that medical management of moderate to severe CD is having a positive impact.

The advent of anticytokine therapies such as tumor necrosis factor (TNF) inhibitors and interleukin (IL) 12/23 inhibitors is the primary driver of such changes, Dr Long said. The first TNF inhibitor, infliximab, was approved for CD in 1998 and for ulcerative colitis in 2005. There are now 4 commercially available anti-TNFs for IBD and biosimilars are now available for infliximab and adalimumab, she noted.

Dr Long reviewed research conducted on the induction of remission and maintenance therapy for CD with infliximab, adalimumab, and certolizumab pegol, noting that CDAI 70 and CDAI 100 responses with these biologic agents show significant percentages of patients achieving and maintaining remission. Infliximab, she stated, has generally shown the greatest efficacy in treatment of CD, particularly when administered in combination therapy with azathioprine. “Higher infliximab doses may be beneficial for perianal fistulizing disease with target levels of more than 10 ug/kg being associated with better response,” she pointed out.

Biosimilars for infliximab have shown similar efficacy and no difference in safety, Dr Long said.
“They are here to stay.”

Adverse events, including immunogenicity, infections, and the reactivation of herpes zoster, latent tuberculosis, and hepatitis B virus, are concerns. Other, more-severe adverse events, including lymphoma and other malignancies, are rare but must be considered when choosing therapy.

One of the newest therapeutics approved for use in treating CD is ustenkinumab, Dr Long said. This novel biologic IL-12/23 inhibitor has demonstrated the highest efficacy in TNF-naïve patients. In the UNITI trial, Dr Long explained, patients without previous exposure to TNF inhibitors achieved 57.9% response to ustekinumab vs 37.7% of patients with TNF exposure. At week 8, 40.2% of TNF-naïve patients achieved remission vs 20.9% of patients exposed to TNF inhibitors. “This is a theme you’ll see over and over again,” she explained. Once a patient has been exposed to a TNF inhibitor they are more likely to have lower response to other anti-TNFs. Further, in the IM-UNITI trial, Dr Long said, the rate of antibody formation was just 2% at week 44.

Ustekinumab dose escalation is also associated with recapture of response in patients who show only partial response or secondary loss of response to therapy. In a study of adult patients with CD who showed loss of response or partial response, intravenous reinduction with ustekinumab yielded complete remission in 28.6% and clinical remission in 53.8%. Dr Long noted that she has found ustekinumab IV reinduction can be used to “recapture” response in patients who have shown loss of response.

Data from PSOLAR (the psoriasis safety registry) shows no increased association between ustekinumab with malignancy, major cardiovascular events, serious infections, or mortality, Dr Long added. “It’s a pretty safe drug; I have been very impressed.”

The increasing emphasis on a treat-to-target approach has proved a major development in the care of patients with CD, Dr Long said, enabling not only therapeutic drug monitoring but also the “tight control” of medical therapy. On the Crohn Disease Endoscopic Index of Severity (CDEIS) in the CALM trial, 45.9% of patients achieved a CDEIS score of less than 4 with no deep ulcerations, compared with 30.3% of patients undergoing standard clinical management. Across outcomes, “we did see benefits associated with this tight control paradigm.” She stated that she has moved to this treat-to-target approach in her own practice and fecal biomarkers have a role, particularly in indicating when a patient should receive an endoscopy to determine disease recurrence.

Noting that gastroenterologists now have “multiple anticytokine choices for moderate to severe CD,” Dr Long advised her colleagues to select therapeutics “based on specifics of disease, such as perianal disease, of each patients and weigh the relationship between efficacy, speed of onset, and safety in the setting of individual comorbidities, to ensure the best outcome for your patients.”

—Rebecca Mashaw

Reference:

Long MD. What’s new in the management of Crohn disease: anticytokine therapy. Talk presented at: Advances in Inflammatory Bowel Disease 2020 regional meeting; August 22, 2020; virtual.