By Samantha Black, Ph.D.

October 8, 2019 -- Researchers in the UK seek to understand why commonly used medication fails to treat Chron's disease by identifying a new genetic marker. The research published in Gastroenterology on October 7, identified a genetic variation that decreases the efficiency of anti-tumor necrosis factor (anti-TNF) drugs.

Anti-TNF therapies are the most widely used biologic drug to treat immune-mediated diseases. Common anti-TNF drugs including infliximab (Remicade) and adalimumab (Humira) are used to treat patients with moderate to severe Crohn's disease and ulcerative colitis when other treatments have not worked. These monoclonal antibodies work through inhibition of tumor necrosis factor (TNF), part of the inflammatory response. TNF is implicated in a number of autoimmune and immune-mediated disorders such as rheumatoid arthritis, asthma, and inflammatory bowel disease. Infliximab has been approved for the treatment of Crohn's disease in the US since 1998 and in the UK since 2010. Likewise, adalimumab has been approved to treat Crohn's disease in the US since 2007 and in the UK since 2010.

Crohn's disease is an inflammatory bowel disease that causes inflammation of the gastrointestinal tract. Symptoms include urgent diarrhea, rectal bleeding, abdominal pain, profound fatigue, and weight loss. The causes of this debilitating disease are unknown, but experts believe that autoimmune reaction and genetics may play a key role in the condition. Inflammatory bowel disease affects over 500,000 people in the US and approximately 160,000 people in the UK. According to medical professionals, the disease is a hidden health crisis.

Researchers suggest that patients may lose response to medications over time due to immunogenicity, or development of an immune response to the drug. In these cases, the body recognizes the drug as a threat and produces antibodies against it and render the medication ineffective. The research time set out to identify patients at increased risk for development of anti-drug antibodies to facilitate the selection of personalized therapies and preventative strategies.

This study, titled the Personalized anti-TNF therapy in Chron's disease study (PANTS) examined the clinical data and genetics of 1,240 patients with Chron's disease undergoing anti-TNF treatment at 120 UK hospital. The research efforts were a collaboration between the University of Exeter, Royal Devon & Exeter NHS Foundation, and the Wellcome Sanger Institute. The researchers performed genome-wide association studies to identify variants associated with anti-drug antibodies. Immunogenicity was determined by drug-tolerant ELISA.

The team identified a genetic marker, HLA-DQA1*05, carried by approximated 40% of the cohort, significantly increased the rate of immunogenicity. This explains why some patients develop antibodies against the drugs and others do not. The authors of the study suggest that further testing is necessary to confirm that genetic testing prior to treatment can reduce the rate of treatment failure by allowing clinicians the ability to provide an effective therapy personalized for their patients.

PANTS study investigator Professor Tariq Ahmad, Head of the Inflammatory Bowel Disease and Pharmacogenetics Research Group at the University of Exeter, and consultant gastroenterologist at the Royal Devon and Exeter Hospital, U.K said: "We strongly believe that this type of research is essential to developing cost-effective, treatment strategies for patients with inflammatory bowel disease."

Helen Terry, Director of Research, Crohn's and Colitis UK said: "The future of Crohn's and Colitis treatment is personalized medicine, so the identification of a genetic marker that explains why anti-TNF drugs don't work for some people with Crohn's is highly significant. These results are extremely promising and further research could lead to individualized treatment and better outcomes for the people living with these debilitating conditions."


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