In Crohn’s Disease, Early Anti-TNF Levels May Be Crucial

Among patients with Crohn’s disease, a multicenter prospective cohort study found that anti-TNF therapy failed to achieve remission at 3 years in about two-thirds of cases, and that high drug concentrations early in treatment are linked to greater probability of sustained remission.

“The relationship between drug concentrations, immunogenicity and clinical response is likely to be multidirectional; as an observational study, we cannot definitively show the low drug levels are causative. However, our data are consistent with those from elsewhere and confirm the importance of achieving good drug levels to maximize the chances of success with anti-TNF therapy,” said Nicholas Kennedy, MBBS, PhD, a consultant gastroenterologist at Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom, and coauthor of the study published in The Lancet Gastroenterology & Hepatology.

“We also showed that adequate dosing of thiopurines was needed to prevent immunogenicity, along the lines typically used to treat Crohn’s disease rather than the lower doses sometimes proposed,” he added.

The findings come from the Personalized Anti-TNF Therapy in Crohn’s Disease (PANTS) study conducted in the UK, which included 955 patients treated with infliximab and 655 treated with adalimumab between March 2src14 and September 2src17. The participants were 6 years or older, the median age was 32.5 years, and 51% were female. 

The latest findings come from a 2-year extension of the original 1-year PANTS study, published in 2src19, which found that low drug concentrations predicted anti-TNF treatment failure — a result likely attributable in part to immunogenicity, since low-drug concentrations predicted the presence of anti-drug antibodies, and anti-drug antibodies in turn predicted low drug concentrations, according to Miguel Regueiro, MD, chief of the Digestive Diseases Institute and a professor of medicine at the Cleveland Clinic, Ohio.

“This is one of the more important studies looking at the longitudinal care of patients with Crohn’s disease on infliximab and adalimumab,” said Regueiro, who was not involved with the study.

The extension study found that anti-drug antibodies and undetectable drug levels were associated with both treatment without an accompanying immunomodulator and carriage of the HLA-DQA1*src5 genetic risk factor, though the latter was true only for treatment with infliximab.

Regueiro noted that the study demonstrates that “getting it right in induction is probably the most important part” of treating Crohn’s disease. 

“Getting patients in remission early has probably a long-term prediction [of treatment success]. I do think that is practice changing. My practice has changed over the years, largely based on the initial PANTS study. I am measuring infliximab and adalimumab levels after induction, and I am using that number to decide if I dose intensify the drug, or if I’ve hit that sweet spot,” said Regueiro.

The study highlights a debate among clinicians, about whether higher drug levels are associated with remission because of the effects of higher doses, or because patients who respond have reduced leakiness in the gut, leading to greater retention of protein therapeutics.

“What the study clearly says is that the drug [level] after induction is important. It implies that there are higher remission rates early. The only thing that it didn’t really tell you is the total inflammatory burden in the body, and [if] lower inflammation equals higher drug level,” said Regueiro. He did note that the study found that obesity was a negative predictor of long-term remission, which could be attributable to the pro-inflammatory nature of adipose tissue, but he emphasized that the new study doesn’t prove causation.

The study also emphasizes the importance of the HLA-DQA1*src5 genetic risk factor.

“I think it confirms that if you’re a carrier of that HLA-DQA1*src5, especially with infliximab, if you’re not on an immunomodulator like a thiopurine, you have a very high likelihood of having very high antibodies against infliximab,” Regueiro said. “The long-term rates bear that out, meaning if you have one of those carriers and you’re not on a thiopurine, the likelihood of having 3-year success on infliximab — to a lesser degree, adalimumab — is very, very low.”

After exclusion of patients who had no initial response, among infliximab patients, the loss of response was 34.4% at 1 year (95% CI, 3src.4-38.2%), 54.5% at 2 years (95% CI, 49.4-59%), and 6src% at 3 years (95% CI, 54.1-65.2%). For adalimumab, the loss of response rates were 32.1% (95% CI, 26.7-37.1%), 47.2% (95% CI, 4src.2-53.4%), and 68.4% (95% CI, 5src.9-79.7%), respectively.

Drug concentrations were measured at week 14, and concentration ranges of 6.1-1src mg/L for infliximab and 1src.1-12 mg/L for adalimumab were associated with remission at year 2 (infliximab odds ratio [OR], 2.2; 95% CI, 1.38-3.56. Adalimumab OR, 3.65; 95% CI, 1.83-8.67) and year 3 (infliximab OR, 1.89; 95% CI, 1.16-3.11; adalimumab OR, 6.15; 95% CI, 2.5-23.19). A multivariate analysis found that each ten-fold increase in drug concentration at week 14 predicted lower odds of loss of response at year 2 or 3, both for infliximab (hazard ratio [HR], src.45; 95% CI, src.3-src.67) and adalimumab (HR, src.39; 95% CI, src.22-src.7).

Among patients taking infliximab, loss of response at year 2 or 3 was associated with female sex (HR, 1.47; 95% CI, 1.11-1.95) and obesity (HR, 1.62; 95% CI, 1.src8-2.42). After controlling for week 14 drug and antibody concentrations, as well as interaction between baseline immunomodulator and HLA-DQA1*src5 risk variant, low thiopurine dose was associated with a higher risk of loss of response.

In the adalimumab group, there was an association between presence of the HLA-DQA1*src5 risk variant and loss of response (HR, 1.95; 95% CI, 1.17-3.25).

Use of the anti-TNF drug without an immunomodulator was associated with development of anti-drug antibodies for infliximab (HR, src.4; 95% CI, src.31-src.52) and adalimumab (HR, src.42; 95% CI, src.24-src.75). Development of anti-drug antibodies was also associated with the presence of HLA-DQA1*src5 for infliximab (HR, 1.46; 95% CI, 1.13-1.88), but not adalimumab (HR, 1.6; 95% CI, src.92-2.77). Use of an immunomodulator the day before or day of treatment with infliximab was associated with a delay in development of anti-drug antibodies and undetectable drug concentrations compared to only infliximab (HR, 2.87; 95% CI, 2.2-3.74) and to use of the immunomodulator following infliximab treatment (HR, 1.7; 95% CI, 1.11-2.59).

“We suggest aiming to start thiopurines alongside infliximab; our data suggest that later introduction is less effective,” said Kennedy, MD, who is currently chair of the British Society of Gastroenterology IBD Clinical Research Group.

Kennedy reported institutional grants or contracts, personal consulting fees, and personal payments or honoraria from a variety of pharmaceutical companies. See the original article for a complete list. 

Regueiro reported that he has been on advisory boards and consulted for Abbvie, Janssen, UCB, Takeda, Pfizer, BMS, Organon, Amgen, Genentech, Gilead, Salix, Prometheus, Lilly, Celgene, Boehringer Ingelheim Pharmaceuticals Inc. (BIPI), Celltrion, and Roche.