Positioning Therapies: What’s the Evidence?

Selecting the first therapy to administer to patients with inflammatory bowel disease (IBD) is particularly important because the first biologic works best, Monika Fischer, MD, said at the virtual regional meeting of Advances in Inflammatory Disease on April 30.

Dr Fischer, MD, is an associate professor of medicine and gastroenterologist at Indiana University School of Medicine in Indianapolis, Indiana.

She explained that there are 2 categories of issues to consider in positioning IBD therapy.

Treatment-related considerations include efficacy, safety, mechanism of action (MOA), immunogenicity/durability-persistence, time to response, mode of delivery, and issues of cost and insurance coverage.

Patient-related factors include disease activity, severity, and distribution; age, sex, race, ethnicity, and frailty; comorbidities; extraintestinal manifestations; and the patient’s response to previous drugs. In addition, patient preferences regarding efficacy, safety, and mode of delivery must be considered, and personal factors such as family planning and socioeconomic circumstances.

Predictors of response to therapy are also part of personalizing these decisions, Dr Fischer noted. “Biomarkers specific to underlying MOAs would be most helpful but currently are not available,” she said. Encouraging patients who smoke to stop smoking is important, because smokers have lower response to anti-tumor necrosis factor (TNFs) and among those who do respond, the duration of response is shorter.

Rapid drug clearance or absorption issues, such as body mass index, sex, C-reactive protein levels (CRP), albumin level, and any prior immunogenicity, must be considered, as well. Dr Fischer explained that clinical decision support tools are available to help predict endoscopic healing among patients with ulcerative colitis (UC) treated with infliximab; to predict

Corticosteroid-free remission among patients with UC treated with vedolizumab; and to identify patients with initial lack of response who benefited from shortened intervals for treatment. Among patients with Crohn disease (CD), clinical decision support tools can help to predict corticosteroid-free remission among patients treated with vedolizumab, she added.

Equally important is the ability to predict which patients are likely to experience adverse events with various IBD therapeutic agents, Dr Fischer stated. She explained that decreased activity in thiopurine S-methyltransferase (TPMT) enzymes are associated with thiopurine-induced leukopenia. In addition, nudix hydrolase (NUDT15) mutations are also linked to thiopurine-induced leukopenia. TPMT + NUDT15 mutations account for about 50% of leukopenias.

Dr Fischer further explained that the HLA-DQ A1*05 allele is associated with increased risk of development of antidrug antibodies (ADAs) among patients treated with biologics. A genome-wide association study of 1240 biologic naïve patients found that 92% of patients with 2 copies of the allele who were treated with infliximab had ADAs within 1 year; just 10% of patients with no copies of the allele who were being treated with adalimumab and an immunomodulator developed ADAs.

She added that the HLA-DQA1∗05 allele was not implicated in the development of ADAs among patients who did not achieve target drug concentrations during induction.

Dr Fischer set out some key guiding concepts for choosing IBD therapy:

• Match treatment with disease activity, severity, and risk for poor outcomes
  • Mild inflammatory CD can be monitored off therapy
  • Administer more intensive therapy for severe disease
  • Follow an intensive regimen for induction and then deintensify for maintenance
• Timing is important
  • Use a treat-to-target approach to meet short, intermediate, and long-term targets
  • Patients with a short disease duration may respond better
  • Introduce biologics rather than waiting for corticosteroid treatment to fail
• Safety
  • Choose an organ-specific drug whenever possible
  • Consider age- and gender-specific associated risks, comorbidities, and cardiovascular risk factors
• Mechanism of action
  • Choose a drug with shared therapeutic targets to cover coexisting immune-mediated inflammatory disease and/or EIMs
  • Consider any specific drug-related risks that are relevant to the patient

Dr Fischer spoke to the specific issues surrounding the treatment of CD and UC. Among patients with mild endoscopic activity, no symptoms, and a low risk of progression, she suggested that fecal calprotectin and C-reactive protein be monitored off therapy. Mild flares can be treated with budesonide at 8-week intervals and immunomodulators can be considered for maintenance. In the case of moderate CD, she suggested treatment with anti-TNFs, ustekinumab, or vedolizumab.

For severe or high-risk CD, such as perianal, fistulizing or proximal disease, Dr Fischer stated the first choice of therapy remains infliximab or another anti-TNF with or without an immunomodulator.

Gastroenterologists have consistently called for more head-to-head trials of therapies to better inform decisions on treatment choice and positioning. Dr Fischer reported that a network meta-analysis of 18 randomized controlled clinical trials among biologic-naïve patients with CD showed that infliximab and adalimumab ranked highest for inducing clinical remission and endoscopic improvement. Among patients with moderate CD, especially when disease is limited to the colon, both vedolizumab and ustekinumab were efficacious and safe first-line options. Ustekinumab had the lowest risk of serious adverse events and infections.

She also reviewed the SEAVUE study, a head-to-head trial of ustekinumab vs adalimumab for biologic-naïve moderate-to-severe (CD), which showed no significant difference in clinical remission or endoscopic remission among patients at week 52. However, ustekinumab had a rate of just 1.0% for injection site reactions, compared to 10.3% for adalimumab,

Dr Fischer noted that several head-to-head trials are now ongoing or are soon to begin that will provide more guidance on selection of therapies for CD.

She explained that ileocolonic resection can be considered as first-line therapy for CD. The LIRIC trial—a multicenter randomized controlled trial that compared the outcomes of surgery vs infliximab in 143 adult patients with inflammatory and immunomodulator refractory ileocecal Crohn’s disease—found no difference in measures of quality of life at 12 months.

A retrospective follow-up of LIRIC that followed 94% of patients from the original trial for a median 5 years found virtually equivalent duration of treatment between the resection group (33 months) and the infliximab group (34 months.) There were no subsequent resections among patients in the surgery group and 42% required no treatment.

Dietary therapy offers another approach to treatment for patients with CD. Dr Fischer noted that exclusive enteral nutrition (EEN) over a period of 8-12 weeks has shown efficacy in inducing remission in CD, with remission rates of 73% to 95% among pediatric patients.

Because EEN presents major issues with adherence, especially among adults, a combination of partial enteral nutrition (PEN) and the CD exclusion diet (CDED) was tested in an open label study of 40 adults with mild to moderate CD who were biologic naïve. Dr Fischer reported that

68% of patients on CDED plus PEN and 57% on CDED alone achieved clinical remission at week 6. At week 24, 80% were in clinical remission and 35% were in endoscopic remission.

Among patients with mild UC, pharmacological therapy typically consists of oral and/or topical

mesalamine, Dr Fischer stated. For patients with moderate UC, vedolizumab and ustekinumab have proven effective and may be the best first-line options given safety their safety profile, she said; other therapeutic options include infliximab, ozanimod, tofacitinib, and upadacitinib.

Infliximab with or without an immunomodulator is the top choice for patients with severe UC, she said, adding that early monitoring of drug concentration is essential to achieve the best outcome. There is no benefit from continuing mesalamine once treated with a biologic begins, Dr Fischer added.

Cases of acute severe UC (ASUC) generally require treatment with therapeutic agents that can achieve a rapid response, including infliximab and cyclosporine. Dr Fischer said there is an emerging role for tofacitinib and for the combination of vedolizumab with cyclosporine. Again, no benefit is seen for starting or continuing mesalamine.

Patients with ASUC may require surgery, specifically colectomy with the creation of an ileal pouch, Dr Fischer said.

The VARSITY trial showed that vedolizumab was superior to adalimumab in achieving clinical remission and mucosal healing at week 52 among patients with moderate to severe UC. Vedolizumab has also shown superior treatment persistence in UC in comparison to infliximab or adalimumab, Dr Fischer noted. Immunomodulator cotherapy did not significantly increase the persistence of vedolizumab.

A network meta-analysis of therapies for moderate to severe UC reviewed 23 randomized controlled clinical trials to assess safety and efficacy as induction therapy among 10,061 patients. Upadacitinib was significantly superior to all other agents for induction of clinical remission but ranked highest for adverse events, Dr Fischer said. Ozanimod also had a high ranked for serious adverse events, while vedolizumab ranked highest for safety.

The comparative safety of IBD therapy should be viewed in conjunction with efficacy, Dr Fischer said. “A specific agent may be safer in isolation, but if it has lower efficacy compared to another intervention, patients may fail to achieve remission. Uncontrolled disease and ongoing inflammation will lead to an overall higher risk of adverse events,” ranging from the need for corticosteroid therapy to infection, hospitalization, malnutrition, and colorectal cancer.

—Rebecca Mashaw

Reference:
Fischer, M. Positioning therapies: What’s the evidence? Presented at: Advances in Inflammatory Bowel Disease regional meeting. April 30, 2022. Virtual.