Jami Kinnucan, MD, on Dosing Optimization Strategies

Before initiating or transitioning therapy for any patient with inflammatory bowel disease (IBD), “you must have a monitoring strategy in place, know your target and plan to reassess frequently,” Jami Kinnucan, MD, told attendees at the Advances in Inflammatory Bowel Disease regional meeting in Boston on June 11.

Dr Kinnucan is a senior associate consultant in the Section of Gastroenterology and Hepatology at the Mayo Clinic in Jacksonville, Florida.

“If a patient has been on therapy X and through disease monitoring but still has inflammatory burden, then when is there room for optimization and when is it time to move on?” she asked. Following a step-by-step approach can help answer that question.

Step 1 is determining if the patient really has active inflammation causing symptoms, Dr Kinnucan explained. “Don’t make the mistake of treating noninflammatory symptoms with escalating inflammatory therapy or changing therapy.” Using objective markers to monitor inflammatory burden, such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fecal calprotectin can clarify this issue, along with imaging via magnetic resonance enterography (MRE), computed tomography enterography (CTE), and intestinal ultrasound (IUS). "The gold standard remains colonoscopy and endoscopy."

Step 2 requires understanding a patient’s risk for severe disease. In the subclinical inflammatory stage, "we're almost there" and the ideal place of optimizing treatment. Dr Kinnucan explained that with ulcerative colitis (UC), patients with mild endoscopic disease and a limited extent of disease are at low risk of progression to severe disease. However, patients of older age, with extensive disease, deep ulcerations, steroid dependence, a history of hospitalization, high levels of CRP and ESR, and who have or have had Clostridioides difficile or cytomegalovirus are at significantly higher risk of progression.

In the case of Crohn disease (CD), patients over the age of 30 at diagnosis with limited anatomic involvement, no perianal or rectal disease, no stricturing or penetrating phenotype, superficial ulcerations, and no prior surgery are considered lower risk, she said. Patients who were 30 or younger at diagnosis, who have extensive anatomic involvement, perianal disease, a stricturing or penetrating pattern, deep ulceration, and prior surgical resection, are at higher risk of severe disease.

Step 3 is to determine the target of a treat to target strategy, Dr Kinnucan said, including short-term targets such a clinical response and remission; intermediate targets, such as CRP and fecal calprotectin normalization; and the long-term target of endoscopic healing. There are also adjuvant targets such as histologic healing. "You have to realize individualize this to the patient."

Step 4 is therapy selection and optimization, she continued. “Choose your optimal therapy early and first!” She warned against the common mistakes of not giving therapy enough time to achieve targets and of failing to escalate dosage when indicated. Reviewing the “toolbox” for immune-mediated treatment for IBD and the response rates for various therapies ranging from mesalamine to JAK inhibitors and more, Dr Kinnucan noted that IBD medications can take more than 4 weeks to yield a clinical response, 6-12 weeks to achieve clinical remission and normalization of CRP, as much as 12 weeks to demonstrate a decrease in fecal calprotectin, and 4 to 6 months or more to achieve endoscopic healing. "We have an incredible tool box now, with more selective JAK inhibitors and biologics and more therapies coming."

“Time is an important consideration,” she emphasized. “Make sure you have given the therapy enough time at optimized dose to see therapeutic benefit.” These decisions can be complex and should be based on real-world data as well as clinical trial data. Treatment experienced patients actually may need more time to respond than the treatment-naive patient.

Step 5 is to monitor patients demonstrating loss of response. “Remember, nonadherence to nonbiologic and biologic therapies is common, and a common cause of loss of response,” especially among patients who self-administer therapies, Dr Kinnucan stated. “Some reports show adherence at only near 50%!” Patients most at risk of nonadherence are women, smokers, patients with anxiety, those taking multiple therapies, and patients with a longer duration of disease since initiation.

A monitoring strategy requires reassessment over time. Patients with active disease should be reassessed every 3 to 6 months until the target is reached while patients with inactive disease should be reassessed at least annually.

Another, different type of treatment optimization is the de-escalation of therapy, Dr Kinnucan pointed out. With oral mesalamine, a patient showing endoscopic improvement may have the dose safely reduced from 4.8 g to 2.4 g for maintenance, she said. If a biologic therapy is initiated, discontinuing a 5-ASA is appropriate. Among patients on thiopurine monotherapy, discontinuation led to severe disease relapse among 23% of patients with CD and 12% of patients with UC, she noted.  

For patients taking a combination of anti-TNF and immunomodulator, “shared decision-making about the why?” of withdrawing one agent is essential, Dr Kinnucan said. Patients in deep remission with CD show no increased risk of relapse at years 1 and 2 after the withdrawal of the immunomodulator, she said. In the STORI study, however, withdrawing the infliximab caused a 50% rate of relapse at 1 year. In the SPARE trial, discontinuation of infliximab but not of the immunomodular was also associated with high relapse rates, but most patients were able to recapture remission after resuming therapy.

Dr Kinnucan noted that the future holds promise for more clinical prediction tools, therapeutic biomarkers, advances in therapeutic drug monitoring, and complementary treatments, as well as therapies that offer new routes and new mechanisms.

“Optimization of therapy can be individualized to the patient’s disease, risk for progression, and preferences,” she said. “Remember to give therapies time to work and to monitor carefully to ensure the disease is not being undertreated, and not all symptoms mean active inflammatory burden.”

 —Rebecca Mashaw

Reference:

Kinnucan, J. When is it time to give up: dosing optimization strategies. Presented at: Advances in Inflammatory Bowel Disease regional meeting. June 11, 2022; Boston.