NEW YORK – Using a single-cell transcriptomic sequencing-based approach, a team from the US and Korea was able to narrow in on a promising treatment for a difficult-to-treat case of drug-induced hypersensitivity syndrome.
"This study represents an in-depth study of a single patient with findings that need to be extended to a larger cohort of patients," senior author Keisuke (Chris) Nagao, a cutaneous leukocyte biology researcher at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and his colleagues wrote in their study, published online this week in Nature Medicine.
The researchers did single-cell RNA sequencing, single-cell T-cell receptor (TCR) sequencing, and other analyses on blood and skin samples from a 44-year-old man who developed refractory "drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms" (DiHS/DRESS) after receiving sulfamethoxazole and trimethoprim antibiotics.
His hypersensitivity to the drugs — marked by a severe rash and several systemic symptoms — were not sufficiently controlled with high doses of the corticosteroid prednisone, the team noted, and inflammatory features of the disease persisted after still other treatment attempts.
"Given the failure of conventional therapies and the lack of alternative therapeutic options in this DiHS/DRESS case, we hypothesized that scRNA-seq might provide a powerful personalized medicine approach to determine transcriptomic changes that not only deepen our insight into disease mechanisms, but also enable the identification of over-expressed genes or altered pathways that might be targeted via currently available monoclonal antibodies or small-molecule inhibitors."
Indeed, with single-cell sequence data for thousands of individual cells, the researchers detected apparent roles for the JAK-STAT signaling pathway in the patient's condition, along with an abundance of DNA stemming from the human herpesvirus 6b in his CD4+ central memory T immune cells. That prompted the patient's caregivers to incorporate a JAK-inhibiting drug called tofacitinib (Xeljanz from Pfizer) as well as antivirals in his treatment, which ultimately helped quell the condition.
"A successful intervention with tofacitinib in a refractory case of DiHS/DRESS was guided by the use of scRNA-seq, which demonstrated aberrant JAK-STAT activity," the authors explained. "While early events in the disease and the contribution of viruses remain to be elucidated, [lymphocyte transformation test] studies suggested that both JAK inhibition and antiviral agents are promising targets in drug-induced phases of DiHS/DRESS."
Nearly one-third of individuals with DiHS/DRESS are thought to be at risk of infection, autoimmune activity, and other serious symptoms, the team noted, but there have typically been relatively few avenues available for studying the roots of these complications. Based on their results in DiHS/DRESS, the researchers suggested that a similar strategy might help in unearthing treatment targets in other immune-related conditions as well.
"[T]he data suggest that single-cell omics-based approaches could be a powerful means for directing patient care in diseases with complex pathophysiology, including other inflammatory diseases and cancer," the authors concluded.