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Chief of Pediatric Gastroenterology and Nutrition
Co-Director, Susan and Leonard Feinstein IBD Clinical Center
Icahn School of Medicine
Mount Sinai, New York
Marla Dubinsky, MD, has disclosed that she has received consulting fees from AbbVie, Arena, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Lilly, Pfizer, Prometheus, Takeda, and UCB; funds for research support from AbbVie, Janssen, Pfizer, and Prometheus; has ownership interest and intellectual property rights in Trellus Health; and has received other financial or material support from Takeda.
Dr. Burrill B. Crohn Professor of Medicine
Chief of the Dr. Henry D. Janowitz Division of Gastroenterology
Mount Sinai Hospital
Chief, Division of Gastroenterology
Mount Sinai Health System
Director, Digestive Disease Institute
Icahn School of Medicine at Mount Sinai
New York, New York
Bruce E. Sands, MD, MS, AGAF, has disclosed that he has received consulting fees from 4D Pharma, AbbVie, Abivax, Alimentiv, Allergan, Amgen, Arena, AstraZeneca, Bacainn, Boehringer-Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Calibr, Capella, Celgene, Celltrion, ClostraBio, Enthera, F. Hoffmann-La Roche, Ferring, Galapagos, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Immunic, Index, Innovation, Ironwood, Janssen, Kaleido, Kallyope, Lilly, MiroBio, Morphic, Oppilan, OSE, Otsuka, Palatin, Pfizer, Progenity, Prometheus, Protagonist, Q32 Bio, Redhill, Rheos, Salix, Seres, Shire, Sienna, Sun Pharma, Surrozen, Takeda, Target PharmaSolutions, Teva, Thelium, Theravance, TLL Pharma, USWM Enterprises, Ventyx, Viela Bio, Vivante, and Vivelix; has received funds for research support from Janssen, Pfizer, Takeda, and Theravance; and has ownership interest in Ventyx and Vivante.
Recent data have raised interest in the contribution of the HLA-DQA1*05 allele to treatment outcomes with anti–tumor necrosis factor (TNF) therapy in patients with inflammatory bowel disease (IBD). But should you screen every patient for this allele? Here’s our take.
An Intriguing Finding From the PANTS Study
The Personalizing Anti-TNF Therapy in Crohn’s Disease (PANTS) study sought to identify risk factors for developing antidrug antibodies (ADAs) in patients with IBD receiving anti-TNF therapy. In this prospective, observational cohort study, 1240 biologic-naive patients initiating therapy with infliximab or adalimumab were followed for 1 year, and a genome-wide significant association was identified between the HLA-DQA1*05 allele and the development of ADAs. By Week 54, patients carrying this haplotype were more likely to develop ADAs and less likely to have persistent serum drug concentrations. This was especially true among patients receiving anti-TNF monotherapy; adding an immunomodulator lowered this risk but did not negate the risk of ADA development.
Focusing on patients who received infliximab monotherapy, a striking 92% of HLA-DQA1*05 carriers had detectable ADAs by 1 year vs 60% of noncarriers. Among patients who received infliximab combined with an immunomodulator, 64% of HLA-DQA1*05 carriers developed ADAs at 1 year vs 36% of noncarriers. This pattern was consistent in the adalimumab group, albeit with lower overall rates of ADAs.
The carrier rate for HLA-DQA1*05 was 39% in this study population, which was based in the United Kingdom. Based on PANTS, it is tempting to conclude that we should test every patient with IBD for the presence of HLA-DQA1*05 given the relatively high frequency of the allele. However, an important detail of this study was that patients received standard of care dosing, meaning there were no protocol-defined dose adjustments to optimize therapy based on drug concentrations. Selection of anti-TNF agent, dosing, and immunomodulator use was at the discretion of the treating physician.
So, how much of the immunogenicity observed was driven by HLA-DQA1*05 vs a lack of proactive therapeutic drug monitoring (TDM) and dose optimization?
HLA-DQA1*05 or TDM?
In response to the findings in PANTS, we performed a post hoc analysis of the Precision-IFX cohort, in which 186 patients with IBD started infliximab therapy using early dashboard-guided dosing at induction. The dashboard platform assists investigators in achieving target drug concentrations by allowing them to input patient-specific characteristics—including weight, albumin, inflammatory markers, and ADA and infliximab concentrations—and receive a recommendation for infliximab dose and interval to achieve a prespecified therapeutic trough concentration.
The frequency of HLA-DQA1*05 carriage was 46% in our cohort, in which >80% of patients were White. However, in contrast with the PANTS data, after 1 year of therapy we found no association between HLA-DQA1*05 carriage and ADA development. Instead, we identified a significant difference in the rate of ADA formation in patients who did not achieve target infliximab trough concentrations by the third infusion vs those who did. That is, ADA development was more common in patients who did not achieve therapeutic drug concentrations at the third infusion. This was true even among patients who received infliximab monotherapy. Of importance, in this early proactively optimized cohort, the overall rates of ADA formation were low (12%).
So, what is the take-home message about HLA-DQA1*05? Should we screen every patient with IBD for this allele before initiating anti-TNF therapy? Probably not. Instead, we should emphasize proactive TDM early in induction to ensure that a patient’s maintenance dosing regimen is optimized to maintain a therapeutic drug concentration of 7-10 µg/mL. Combination therapy may help reduce the risk of ADA in carriers. There also are some patients for whom the clinical significance of loss of response to anti-TNF therapy is high and for whom combination therapy may be warranted. However, without proactive dose optimization, ADA risk remains high.
Have you considered screening for HLA-DQA1*05 in patients with IBD who are initiating anti-TNF therapy? Answer the polling question and join the discussion by posting a comment.