Optimization of Treatment for IBD

A treat-to-target strategy that focuses on mucosal healing can significantly improve outcomes in patients with IBD, David A. Schwartz, MD, FACG, AGAF, said in his presentation on optimizing IBD treatment at the September 12 virtual Advances in Inflammatory Bowel Diseases regional meeting.

Dr Schwartz is the director of the McClain Family Directorship in Gastroenterology and of the Inflammatory Bowel Disease Center at Vanderbilt University Medical Center in Brentwood, Tennessee.

He began his presentation with the case study of a 28-year-old man with a 3-year history of ulcerative colitis. Despite treatment with infliximab 5 mg/kg every 8 weeks, 2.5 mg/kg per day of azathioprine, and 4.8 grams of mesalamine for more than 1 year, the patient continued to have abdominal pain, diarrhea with urgency 10 to 12 times per day, and a 10-lb weight loss. A nonsmoker with no history of surgery, the patient showed no evidence of ileal disease on colonoscopy but had colonic thickening. His c-reactive protein (CRP) level was 20 and platelet count of 600.

Dr Schwartz posed the question, “How would you approach this patient? Double the infliximab dose? Switch to another anti-TNF? Switch to another mechanism of action? Send the patient to surgery? Punt?” He suggested, “After you rule out other causes, such as infection, check drug levels to help guide the most efficient and effective way to achieve remission.”

Reactive drug monitoring of thiopurines will show whether the patient has the appropriate level of 6-thioguanine nucleotide levels (6-TGN). Dr Schwartz noted that patients with 6-TGN levels above a threshold of 230 to 260 had 3-fold odds of being in remission compared with those with lower levels; a meta-analysis showed that 62% of patients over the threshold achieved remission, compared with 36% of those below the threshold.

If monitoring reveals therapeutic levels of 6-TGN, and levels of 6-MPP are normal or high, the patient may be thiopurine-refractory; the dose should be changed or the patient should be switched to another therapy, Dr Schwartz said. If both levels are low, the patient is either underdosed or noncompliant, requiring education on compliance and/or increase in the dose. If both are high, the thiopurine is being overdosed. If 6-TGN is low but 6-MP is high, the patient is likely a 6-MMP shunter. “Change therapy or add allopurinol and reduce thiopurine dose to 25%,” he said.

Dr Schwartz pointed out the clinical utility of monitoring infliximab and human antichimeric antibody (HACA) levels among patients being treated with this biologic. He noted that 92% of patients with detectable HACA levels who were switched to another anti-TNF achieved complete or partial remission, compared with just 17% of those who remained on infliximab. Of those with subtherapeutic concentrations of HACAs, 86% achieved partial or complete remission while continuing with infliximab, compared with 40% of those who switched to another anti-TNF agent.

He explained that among patients who are not responding to therapy or have loss of response, anti-TNF doses should be increased for those with low drug levels and low antibodies. For patients with no or low antibody levels and adequate drug levels, if there is active inflammation, a switch to an agent in a different class is indicated. Without inflammation, Dr Schwartz suggested, “look for non-IBD causes” to explain the lack of response. If a patient shows high antibody levels and low drug levels, he recommended a switch to a different TNF inhibitor.

A variety of factors can affect how quickly or slowly a patient clears a biologic, he explained. The presence of antidrug antibodies decreases the serum drug concentration and results in a 3-fold increase in clearance. Use of an immunomodulator reduces the formation of antidrug antibodies, increases drug concentration, and slows drug clearance to improve clinical outcomes.  A high baseline anti-TNF may decrease serum drug concentrations, Dr Schwartz remarked, while a high baseline CRP protein level accelerates clearance. Body size and sex also may affect drug clearance, along with albumin levels.

Certain genetic factors increase the risk of developing antidrug antibodies, he explained. Patients with the human leukocyte antigen (HLA) DQA1*05 show significantly higher levels of antidrug antibody development than those without this marker. 

Dr Schwartz reported one study found a lower incidence of complications in both Crohn disease and ulcerative colitis when proactive drug monitoring was utilized. A second retrospective study found much less treatment failure among patients with IBD who were treated with adalimumab on a proactive drug monitoring regimen than among those receiving standard of care. 

With the introduction and widespread use of biologic agents, he noted, mucosal healing has emerged as increasingly important in treatment of IBD. Patients who achieve mucosal healings experience fewer hospitalizations, less surgery, lower relapse rates after medical therapy withdrawal, a better quality of life, and lower rates of colorectal cancer.

To help achieve mucosal healing, Dr Schwartz proposed an algorithm for treatment beginning with a baseline assessment of disease activity via endoscopy with a paired surrogate marker. Based on the severity of the disease and prognostic indicators, a choice of therapy is made. After 3 to 6 months of therapy, the patient is reassessed for documentation of mucosal healing. If healing has occurred, the patient should be clinically followed and assessed for disease stability within 6 to 12 months. If the mucosa does not show evidence of healing, the patient and physician should discuss other treatment options. If the patient is willing to follow the recommended course of treatment, then the therapy is adjusted with continued assessment.

In the case of the patient Dr Schwartz introduced earlier, he noted that the trough level of infliximab was undetectable, but the patient had no antidrug antibodies. He reinduced the patient with 10 mg/kg of infliximab, achieving a post reinduction trough level of 11. The patient was in remission at week 8. The patient at 6 months continued to feel well and showed some mild disease activity on colonoscopy. His infliximab trough level was 5; Dr Schwartz increased his dose and shortened the interval between treatments to attempt to achieve mucosal healing.

"We definitely want to treat to the target of mucosal healing to achieve the best possible outcome," he said. "This is a key therapeutic aim and can change the natural course of the disease. This is a very important treatment endpoint for IBD." He noted that patients who achieve mucosal healing have "dramatically reduced" rates of colectomy.

Optimizing therapy for patients with IBD requires continued monitoring of therapies, he concluded. Metabolite levels must be checked for patients treated with thiopurines, while those treated with biologics must be monitored for drug and antibody levels. Reactive therapeutic drug monitoring should be done in cases of no response or loss of response to therapy, while proactive monitoring should be part of routine clinical care to optimize outcomes.

--Rebecca Mashaw

Reference:

Schwartz, DA. Optimization of treatment in patients with IBD.  Talk presented at: Advances in Inflammatory Bowel Disease 2020 regional meeting; September 12, 2020; virtual.