What is daclizumab telling us about MS? I think a lot. #ClinicSpeak #ResearchSpeak #MSBlog #MSResearch
"I have been presenting and discussing the data below ever since it was presented at the ACTRIMS-ECTRIMS meeting in Boston two years ago. It describes the different cutaneous adverse events that pwMS may develop on Daclizumab. Most of the skin reactions are mild and self-limiting and are not a major concern. However, there are few hypersensitivity reactions that can be severe and need treatment with steroids. In short some of these skin reactions are autoimmune. In addition, there are other autoimmune events that occur with daclizumab including autoimmune hepatitis. Isn't interesting that daclizumab another highly effective DMT for MS has secondary autoimmunity as a complication? What is even more interesting is that the autoimmune diseases seen with daclizumab differ to those seen post-alemtuzumab. The alemtuzumab ones are all antibody mediated and the daclizumab ones cell mediated. Wow. If I was a hardcore immunologist I would be studying pwMS starting these therapies to get a better understanding about what triggers and drive autoimmunity."
"What we do know is that daclizumab is an IL-2 modulator and by blocking the high-affinity IL2 receptor on T-reg and activated T-cells it allows IL-2 to signal via its intermediate affinity receptor. The latter is expressed on NK or natural killer cells and as a result they expand. The effectiveness of daclizumab has been linked to expansion of the NK cell pool. These cells are part of the innate immune system and are responsible for fighting viral infections amongst other things. We suspect the autoimmunity may arise because of the reduction in T-reg cells that are responsible for keeping autoimmune T-cells under control. What is very interesting is that daclizumab does not have a major effect on B cell numbers of function. It is therefore an outlier in the high efficacy family of DMTs. This is why daclizumab is such an interesting drug. If we can work out how NK cells are doing their job in daclizumab-treated patients we will have a clearer idea about what is causing and driving MS."
OBJECTIVE: To analyze the spectrum and mechanisms of cutaneous adverse events (AEs) in patients with multiple sclerosis treated with daclizumab high-yield process (DAC-HYP).
METHODS: A total of 31 participants in an institutional review board-approved open-label phase I study of DAC-HYP (NCT01143441) were prospectively evaluated over 42 months for development of cutaneous AEs. Participants provided written informed consent. Fifteen participants were naive to anti-CD25 therapy (cohort B), while 16 had received daclizumab (Zenapax; Hoffmann-La Roche) IV for 4-9 years (mean 5.8 years) prior to enrollment (cohort A). Immunohistochemistry was performed on pretreatment and posttreatment skin biopsies of normal-appearing skin (cohort B only) and on lesional biopsies in participants presenting with rash (both cohorts).
RESULTS: Cutaneous AEs occurred in 77% of patients, the majority presenting with patches of eczema requiring no treatment. Moderate to severe rash developed in 6 participants (19%) and required discontinuation of DAC-HYP in 4 (13%). More severe rashes presented psoriasiform phenotype, but lesional biopsies lacked features of either psoriasis or drug hypersensitivity eruptions. Instead, irrespective of clinical severity, lesional biopsies showed nonspecific features of eczematous dermatitis, but with prominent CD56+ lymphocytic infiltrates. Pretreatment and posttreatment biopsies of normal-appearing skin demonstrated no histopathologic changes.
CONCLUSIONS: Observed cutaneous AEs are likely related to the immunomodulatory effects DAC-HYP exerts on innate lymphoid cells, including natural killer cells. Vigilance and timely management of skin reactions may prevent treatment discontinuation in participants with severe rash.