Immunosuppressants associated with severe reactions in people with a common genetic profile | News Center

Meanwhile, Mellin’s human leukocyte antigen (HLA) extracted profiles from the genetic data of 20 lung disease patients and found that more than half shared the same genetic signature. HLAs are the proteins on cell surfaces that differentiate “self” from “non-self” tissues.

Evidence points to drug reaction

“I picked up the phone and called Jill Hollenbach, an immunogeneticist at UCSF, and she said, ‘This is remarkable,'” Mellins said. Hollenbach believed the results suggested a serious drug reaction rather than a genetically linked trait of Still’s disease.

The researchers realized that patients with lung problems met the criteria for drug response with eosinophilia and systemic symptoms, or DRESS, a form of severe, delayed drug response. Although the features of DRESS, which are easily missed with Still’s disease, began shortly after the drug was started, it took an average of 14 months on the drugs before patients’ severe lung disease became visible.

The researchers compared 66 patients with Still’s disease who had DRESS with 65 patients who did well on the drugs. Among other problems, three-quarters of patients with DRESS, with or without lung disease, had liver enzyme levels, indicating severe liver dysfunction, and 64% developed a cytokine storm.

The reactions were not always recognized by the patients’ doctors. Patients who were taken off and kept off the drugs did well. Tragically, nine out of 33 patients who continued to take the drug died after their reactions began.

“This [drug reaction] is a very, very complicated signal, and it’s hard for clinicians to realize that stopping the medication is what you do, especially if there is organ involvement, such as lung or liver dysfunction, ”Saper said.

The higher-risk genetic signature is found in 20% of the population as a whole and in 80% of the patients in the study who had DRESS. Blood samples for HLA markers are available in clinical laboratories. As the genetic test did not predict everyone who responded, this study indicates that physicians should monitor DRESS responses to IL-1 and IL-6 inhibitors.

COVID-19 concern

Two of the immunosuppressive drugs, tocilizumab and anakinra, have recently been used in patients experiencing cytokine storms due to severe COVID-19.

This worries the research team because the risky HLA markers are quite common. A recent scientific report on 24 very ill COVID-19 patients treated with tocilizumab noted that six patients died. Stanford researchers suggest caution when using this drug for COVID-19.

“There are all these clues in COVID patients, but it requires more investigation,” Saper said.

Meanwhile, the researchers hope the results will promptly prompt HLA testing of Stills patients.

“An imperative we have is, ‘The right drug, for the right person, at the right time,'” Saper said. “In Still’s disease, these drugs are just right for most people. But we have been able to identify a simple genetic test that could tell if this is not the right drug for you.”

The paper’s other Stanford authors are research assistant Gonzalo Montero-Martin, PhD; Serena Tan, MD, assistant professor of pathology; postdoctoral researchers Vamsee Mallajosyula, PhD, Debopam Ghosh, PhD, and Jianpeng Xu, PhD; Lu Tian, ​​PhD, Professor of Biomedical Computer Science; and Marcelo Fernandez-Vina, PhD, Professor of Pathology.

Tian and Mellins are members of the Stanford Maternal and Child Health Research Institute, Mellins is a member of the Interdisciplinary Program in Immunology and the Wu Tsai Neurosciences Institute at Stanford, and Tian is a member of the Stanford Cardiovascular Institute.

Among the contributors are other researchers from UCSF and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, as well as researchers from UC-San Diego, Emory University School of Medicine and Children’s Healthcare in Atlanta, University of Pittsburgh, University of Washington, National Human Genome Research Institute , University of Pennsylvania, Pennsylvania State University College of Medicine, Yale University Medical School and University of Hong Kong, also contributed to this research.

The research was funded by the Lucile Packard Foundation for Children’s Health, Stanford Maternal and Child Health Research Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases (Grant Z01-AR041198), National Human Genome Research Institute (Grant Z01-HG200370), Gordon and Marilyn Macklin Foundation, RK Mellon Institute for Pediatric Research and Marcus Foundation Inc.

Some of the authors received personal fees, grants, or both from Novartis, which manufactures canakinumab.


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