Loss of Anti-TNF Treatment Response Common in Crohn's Disease

Approximately two-thirds of patients with Crohn's disease who initially responded to tumor necrosis factor (TNF) inhibitors lost response by the third year of treatment, a population-based observational study showed.

Fully 60% treated with infliximab (Remicade) and 68% treated with adalimumab (Humira) lost treatment response by year 3, Nicholas Kennedy, MBBS, of the University of Exeter in England, and colleagues reported in Lancet Gastroenterology & Hepatology.

Higher concentrations of anti-TNF agents at the end of the induction period at week 14 were associated with lower risk for lost treatment response. For infliximab, each 10-fold increase in drug concentration reduced the risk by 55% (HR 0.45, 95% CI 0.30-0.67). For adalimumab, each 10-fold higher drug concentration reduced that risk by 61% (HR 0.39, 95% CI 0.22-0.70), the study found.

"Our observations support the current practice of dose intensification in the setting of low drug concentrations without immunogenicity," Kennedy and colleagues wrote. "For some patients who develop treatment failure despite adequate infliximab concentrations after dose intensification, our observations suggest targeting even higher drug concentrations to reach remission."

For patients treated with infliximab, loss of response was also associated with female sex (HR 1.47, 95% CI 1.11-1.95), obesity (HR 1.62, 95% CI 1.08-2.42), and thiopurine dose (HR 0.75, for each per-unit increase of thiopurine dosing, P=0.024). For patients treated with adalimumab, lost response was associated with the HLA-DQA1*05 risk variant (HR 1.95, 95% CI 1.17-3.25).

Using concomitant immunomodulatory agents during initial treatment was associated with reduced risk of immunogenicity to anti-TNF for both infliximab (HR 0.40, 95% CI 0.31-0.52) and adalimumab (HR 0.42, 95% CI 0.24-0.75).

The link between obesity and lost treatment response might be explained by a larger body surface area, enhanced proteolysis, and TNF stored in adipose tissue, while the association with gender might be explained by the higher rates of adverse events, non-adherence, and treatment discontinuation reported in female patients, Kennedy's group suggested.

Their Personalized Anti-TNF therapy in Crohn's disease (PANTS) study included 598 patients recruited at the time of first anti-TNF exposure from 120 National Health Service trusts across the U.K., making it one of the largest real-world cohorts of patients with Crohn's disease treated with anti-TNF drugs, Gareth Parkes, MBBS, of the Royal London Hospital, and Charlotte Hedin, PhD, of the Karolinska Institute in Stockholm, said in an editorial accompanying the study.

"The cohort is highly relevant to real-world clinical practice because it comprises a realistically diverse group of patients that includes pediatric cases," Parkes and Hedin wrote.

"These data provide clinicians with tools that they can apply to everyday practice for patients treated with intravenous infliximab in the long term," they said, "including pretreating patients with an immunomodulator, aiming for higher than previously reported drug concentrations by the end of induction, and, in patients who cannot tolerate an immunomodulator, considering alternative treatments in those who test positive for HLA-DQA1*05."

PANTS is a multicenter, prospective, observational cohort study evaluating infliximab and adalimumab in anti-TNF-naive patients ages 6 and older with active luminal Crohn's disease. At the end of the first year, participants still receiving study drug were invited to enroll in an extension study.

The researchers estimated rates of remission using a modified survival technique with permutation testing. They used multivariable regression and survival analyses to identify factors associated with loss of response and development of immunogenicity in patients who had initially responded to anti-TNF therapy.

Lost response was defined as new symptoms that warranted an escalation of therapy, resectional surgery, or exit from study due to treatment failure. This "pragmatic" definition was a limitation of the study, the authors noted. "We did not use endoscopic outcomes or obtain 6-TGN [6-thioguanine nucleotide] concentrations, which we acknowledge would have strengthened our data," they said.

Another limitation was that approximately one-third of patients who completed the first year of PANTS did not enter the extension phase, the researchers said. There were few differences between patients who continued and those who did not, but the slightly higher proportion of male patients who did not continue could have had a small effect on results, they explained.

Comment