Genome study may explain why Crohn’s drugs are ineffective for some patients
In the largest observational study of its kind, researchers have identified a genetic mutation prevalent in approximately 40% of the population that may explain why common anti-inflammatory drugs are ineffective for Crohn's disease patients.
Anti-TNF-α biologics are common treatments for patients with Crohn’s disease, however, they are ineffective in a large proportion of these patients. Now, the results of the largest ever study investigating why this may be identifies a genetic mutation that may lead to more personalized treatments for this disease.
Infliximab and adalimumab are biologic drugs that antagonize the effects of TNF-α – a pro-inflammatory cytokine. These drugs are commonly prescribed to patients with severe Crohn’s disease and ulcerative colitis who are resistant to first-line treatments.
Anti-TNF-α drugs, first introduced to the drug market in the 1990s, currently rank in the top five drugs on which NHS spending is greatest.
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However, previous data highlights that many patients prescribed infliximab and adalimumab frequently develop resistance and fail to derive clinical benefit from them. This is largely due to patient’s immunogenicity against anti-TNF-α drugs; the complex drugs are recognized as foreign and patients generate antibodies against them. These antibodies both increase drug clearance from the body and reduce the effectiveness of the drugs.
In the largest study of its kind, researchers from the University of Exeter , Royal Devon & Exeter NHS Foundation Trust (both Exeter, Devon and Cornwall, UK) and the Wellcome Sanger Institute (London, UK) have analyzed the clinical and genetic data of 1240 Crohn’s disease patients, across 120 UK hospitals, receiving anti-TNF-α therapy.
The results, published in Gastroenterology, reveal that 40% of patients carry a genetic mutation that alters their HLA proteins and doubles their risks of developing antibodies against infliximab and adalimumab.
Contributing study investigator 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, commented: “We strongly believe that this type of research is essential to developing cost effective, treatment strategies for patients with inflammatory bowel disease.”
The study researchers conclude that further investigation is now required to determine how pre-treatment genetic testing may improve the prescription of the most effective treatments for patients with the debilitating disease.
Sazonovs A, Kennedy NA, Moutsianas L et al. HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn’s disease. Gastroenterology. doi: 10.1053/j.gastro.2019.09.041 (Epub ahead of print) (2019);
TNF-α is a pro-inflammatory cytokine released by cells of the immune system during acute inflammation that innitiates a diverse range of signaling cascades in responsive cells, eventually leading to cell necrosis. Inappropriate TNF-α production can be associated with chronic inflammation.
Crohn's disease is an inflammatory bowel condition resulting from inflammation of the digestive tract. Symptoms of the active disease can include abdominal pain, fatigue, fever, reduced appetite and weight loss, blood in one's stool and mouth sores, amongst others.