Immunosuppressants linked to severe reactions in people with common genetic profile – Stanford Medical Center Report

Meanwhile, Mellins extracted human leucocyte antigen (HLA) 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 distinguish self from nonself tissues.

I picked up the phone and called Jill Hollenbach, an immunogeneticist at UCSF, and she said, This is remarkable, Mellins said. Hollenbach thought that the results indicated a severe drug reaction rather than a genetically linked feature of Stills disease.

The researchers realized that patients with the lung problems met criteria for drug reaction with eosinophilia and systemic symptoms, or DRESS, a type of severe, delayed medication reaction. Although features of DRESS, easily missed with Stills disease, began soon after the drug was started, on average it took 14 months on the drugs for patients severe lung disease to become apparent.

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

The reactions were not always recognized by the patients physicians. Patients who were taken off and kept off the drugs did well. Tragically, of 33 patients who kept taking the medications after their reactions began, nine died.

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

The genetic signature that confers higher risk is found in 20% of the population at large and in 80% of patients in the study who had DRESS. Blood testing for HLA markers is available in clinical labs. Since the gene test did not predict all who reacted, this study indicates that physicians should watch carefully for DRESS reactions to inhibitors of IL-1 and IL-6.

Two of the immune-blocking medications, 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. The Stanford researchers suggest caution in using this drug for COVID-19.

Theres all this circumstantial evidence in COVID patients, but it requires more investigation, Saper said.

Meanwhile, the researchers hope the findings will quickly prompt HLA testing of Stills patients.

One imperative we have is, The right drug, for the right person, at the right time, Saper said. In Stills disease, for most people these drugs are exactly right. But weve been able to identify a simple genetic test that could tell if this is not the right drug for you.

The papers other Stanford authors are research associate Gonzalo Montero-Martin, PhD; Serena Tan, MD, assistant professor of pathology; postdoctoral scholars Vamsee Mallajosyula, PhD, Debopam Ghosh, PhD, and Jianpeng Xu, PhD; Lu Tian, PhD, professor of biomedical data 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 areother scientists from UCSF and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, as well as scientists from UC-San Diego, Emory University School of Medicine and Childrens Healthcare of Atlanta, the University of Pittsburgh, the University of Washington, the National Human Genome Research Institute, the University of Pennsylvania, Pennsylvania State University College of Medicine, Yale University Medical School and the University of Hong Kong, also contributed to this research.

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

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

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Immunosuppressants linked to severe reactions in people with common genetic profile - Stanford Medical Center Report