Patients with DRESS/DIHS hypersensitivity reactions and active HHV-6 often develop autoimmune diseases such as type 1 diabetes and autoimmune thyroiditis. Investigators at National Taiwan University Hospital believe that IP-10 is key to this process.
Led by professor Chia-Yu Chu of the National Taiwan University Hospital, the group determined that elevated interferon-γ-induced protein-10 (IP-10) is strongly associated with both HHV-6 reactivation and autoimmune sequelae in patients with drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DIHS). This builds on their earlier 2015 study that noted IP-10 was the only cytokine/chemokine found to be significantly higher in DRESS patients with HHV-6 reactivation (Chen 2015).
To elucidate the relationship between HHV-6, IP-10, and long-term sequelae from DRESS, Yang et al performed a prospective study measuring IP-10 in HHV-6 positive and negative DRESS patients, as well as those with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). The mechanism behind of SJS is understood to be the release of granulysin from drug-specific cytotoxic CD8 T cells, natural killer cells and natural killer-like T cells, but the mechanism behind DRESS/DIHS has been a mystery.
They studied 52 patients with DRESS and 35 patients with SJS/TEN. While 40% of the DRESS patients had HHV-6 reactivation, only 2.5% of those with SJS/TEN were positive. IP-10 levels were significantly higher in DRESS patients with long term sequelae and the IP-10 levels declined more slowly in the HHV-6 reactivation group. The incidence of autoimmune sequelae among DRESS patients was 14.3%. An additional 8% developed serious long-term skin problems. A cutoff level of 2440.86 for IP-10 could be considered useful to predict long term sequelae with 85.7% sensitivity and 66.7% specificity. There was also a positive correlation between log-transformed IP-10 levels and DRESS scores (p=0.06). IP-10 levels did not predict long-term sequelae following SJS/TEN.
Other studies have shown that serum level of TNF-alpha or thymus and activation regulated chemokine (TARC) can be used as a marker for HHV-6 reactivation in DRESS (Uno 2014, Ogawa 2014).
IP-10 plays an important role in recruiting cytotoxic T lymphocytes into target tissues (Liu 2011), and it is increased in many autoimmune diseases (Antonelli 2014). It is also a biomarker for Kawasaki disease (Ko 2015) and acute respiratory infections (Hayney 2017).
The Taiwanese group suggests that a monoclonal antibody directed against IP-10 may be useful for the prevention of long-term sequelae in DRESS patients. They note that although a phase IIb trial of an IP-10 monoclonal antibody eldelumab proved ineffective for ulcerative colitis, it was found to be reasonably safe.
Read the full paper: Yang 2020