From the AGA Journals

Immune modulators help anti-TNF agents battle Crohn’s disease, but not UC

View on the News

Timely findings on treatment optimization

Twenty years after the approval of the first anti–tumor necrosis factor (TNF) biologic agent for the treatment of inflammatory bowel disease (IBD), patients and providers are still learning how to optimize these medications. One optimization is the use of combination therapy (immunomodulator and anti-TNF). Immunomodulators are used independently for maintenance of remission of IBD, and they have been shown to reduce immunogenicity and improve efficacy when used in combination with an anti-TNF agent in prior short-term randomized controlled trials. However, use of combination therapy in the real-world is not universally practiced. Data are lacking on the risks and benefits of long-term use of these agents. Therefore, this article by Targownik et al. is very timely.

Dr. Millie Long

Patients with Crohn’s disease treated with combination therapy in this population-based cohort had improved efficacy including a significant decrease in treatment ineffectiveness, increased time to first hospitalization, and increased time to anti-TNF medication switch.

Importantly, a mixed group of patients who had previously been on azathioprine monotherapy and those newly starting this therapy at the time of anti-TNF initiation were included in this cohort (a group similar to what we see in real-world practice). Data on risk factors for disease complications, such as disease phenotype or severity, were not available. By contrast, none of the efficacy associations were improved in the smaller group of patients with ulcerative colitis on combination therapy.

As providers counsel patients on the benefits and risks of various IBD treatment choices, these data by Targownik et al. will inform decisions. Future research should incorporate additional means of biologic optimization, such as the use of therapeutic drug monitoring and/or risk factor–based selection of therapeutic agents, to better inform individualized treatment choices.

Millie D. Long MD, MPH, is an associate professor of medicine in the division of gastroenterology and hepatology; Inflammatory Bowel Diseases Center; vice chief for education; director, Gastroenterology and Hepatology Fellowship Program at the University of North Carolina at Chapel Hill. She has the following conflicts of interest: AbbVie, Takeda, Pfizer, UCB, Janssen, Salix, Prometheus, Target Pharmasolutions, and Valeant.



Adding an immune modulator (IM) to anti–tumor necrosis factor (anti-TNF) initiation therapy benefits patients with Crohn’s disease (CD) but not those with ulcerative colitis (UC), according to a recent retrospective look at more than 1,000 cases.

The study showed that patients with CD who started combination therapy instead of monotherapy had lower rates of treatment ineffectiveness, experienced longer delays until hospitalization, and less often needed to switch their anti-TNF agent, reported lead author Laura E. Targownik, MD, of the University of Manitoba, in Winnipeg, Canada, and colleagues.

“Current guidelines on the medical management of IBD strongly support the use of IMs and anti-TNFs in combination over anti-TNF monotherapy,” the investigators wrote in Clinical Gastroenterology and Hepatology. “However, there is a sparsity of real-world data demonstrating the incremental benefits of combination therapy.”

The investigators noted that the SONIC trial, conducted in 2010, showed that patients treated with combination therapy were more likely to achieve corticosteroid-free remission at weeks 26 and 50; this became the basis of evidence leading multiple clinical guidelines to recommend combination therapy for patients with CD.

The present study involved 852 patients with CD and 303 with UC who began treatment with an anti-TNF agent during 2001-2016. Data were drawn from the Manitoba Inflammatory Bowel Disease (IBD) Epidemiology database.

The main outcome of interest was treatment ineffectiveness, which was defined by any of the following four events: acute, IBD-related hospital admission for more than 48 hours; resective intestinal surgery; corticosteroid use at least 14 days after initiating anti-TNF therapy, or, if corticosteroids were used within 16 weeks of anti-TNF initiation, then subsequent corticosteroid use occurring at least 16 weeks after initiation; or switching to a different anti-TNF agent. The investigators also looked for differences in effectiveness between two agents from each class: anti-TNF agents infliximab and adalimumab, and immunomodulators methotrexate and azathioprine.

Results showed that patients with CD had higher rates of ineffectiveness-free survival when treated with combination therapy instead of monotherapy at 1 year (74.2% vs. 68.6%) and 2 years (64.0% vs. 54.5%). Using a Cox proportional hazards model, this translated to a 38% reduced risk of treatment ineffectiveness (adjusted hazard ratio, 0.62).

“This suggests that the findings of the SONIC trial may extend to real-world clinical practice, even in patients who had previous IM exposure,” the investigators noted.

Combination therapy was also significantly associated with longer time to first IBD-related hospitalization (HR, 0.53) and the need to switch anti-TNF agent (HR, 0.63). However, no such relationships were found for time to resective surgery or corticosteroid use. Although combination therapy had no impact on the rate of primary treatment ineffectiveness in multivariable logistic regression, those who received anti-TNF therapy for more than 90 days had delayed secondary treatment ineffectiveness and fewer IBD-related hospitalizations. Choice of agent from either class had no influence on effectiveness of combination therapy.

In contrast with the above findings, combination therapy in patients with UC was less promising, which aligns with previous studies.

“[W]e were not able to demonstrate a significant advantage to combination therapy in persons with UC,” the investigators wrote. “In addition, all published cohort studies to date have not been able to confirm a significant benefit to combination therapy in UC. ... In light of the lower quality of prior evidence, combined with the results from our study, the indication for combination therapy in UC would appear to be weaker.”

“Further analyses in larger cohorts may clarify whether there is a clinically relevant benefit of combination therapy in persons with UC,” the investigators concluded. “Because of the discrepancy between our findings and those of a meta-analysis of cohort studies previously published on this topic, confirmation of our results is required in future studies.”

The investigators disclosed no funding or conflicts of interest.

SOURCE: Targownik LE et al. Clin Gastroenterol Hepatol. 2018 Nov 15. doi: 10.1016/j.cgh.2018.11.003.

Next Article: