<b>Background</b>: Ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin-17A, has shown superiority to ustekinumab (UST) and etanercept in skin clearance from randomized clinical trials in patients with moderate-to-severe psoriasis.
As in anti-IL-17 or anti-IL-23 antibody treatment, the dual action of phototherapy on skin and the immune system is likely responsible for sustained resolution of lesions in diseases such as psoriasis.
Importantly, in an in vivo mouse model, EFLA 945 attenuates imiquimod (IMQ)-induced psoriasis-related pro-inflammatory responses in topical psoriatic skin, including caspase-1 activation, IL-1β maturation, and IL-17 production, and decreases the severity of psoriasis.
The dominance of the interleukin (IL)-23/IL-17 axis is a significant breakthrough in the understanding of the pathogenesis of psoriasis, and treatment targeting IL-23 and IL-17 has successfully benefited patients with the disease.
With this aim, we used Secukinumab, a potent human anti-IL17A monoclonal antibody which has been approved for the treatment of some IL-17A related inflammatory diseases, notably Psoriasis.
Topically-applied L-SNAs targeting the gene encoding the mouse IL-17A receptor (Il17ra) reversed the development of psoriasis clinically, histologically, and transcriptionally in imiquimod-treated psoriasis-like mouse skin.
Since the connection of dysregulated IL-17 and psoriasis pathogenesis turned out to be particularly evident, a number of monoclonal antibodies targeting IL-17 pathways have been approved and are used as first line treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis, and further agents are currently in clinical development.
The signaling elicited by the cytokine interleukin-17A (IL-17) is important for antimicrobial defense responses, whereas excessive IL-17 production leads to autoimmune diseases such as psoriasis and multiple sclerosis.
Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has demonstrated efficacy and safety in patients with moderate-to-severe psoriasis.
A comprehensive review of the literature and analysis of the most outstanding evidence have provided the basis for discussing the most relevant data related to IL-17A blocking agents for the treatment of different disorders, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, cardiovascular disorders, non alcoholic fatty liver disease, multiple sclerosis, inflammatory bowel disease, uveitis, hematological and solid cancer.
Our study showed a significant association between IL-17rs4819554 SNP and psoriasis risk, evidenced by higher G allele and AG genotype frequencies in psoriatic patients when compared to controls (allelic: OR 2.283, 95% CI 1.321-3.946, p = 0.003, and genotype: OR 3.026, 95% CI 1.356-6.752, p = 0.007).
Administration of anti-IL-17A monoclonal antibody improved hyperglycemia in patients with psoriasis and imiquimod-treated mice with psoriasiform features.
Spleen weight and the levels of cytokines, including IL-22, IL-23, and IL-17, decreased after the treatment, indicating the high therapeutic potential of this formulation for psoriasis.
IL-17A has been identified as key regulatory molecule in several autoimmune and chronic inflammatory diseases followed by the successful use of anti-IL-17 therapy, e.g. in ankylosing spondylitis and psoriasis.
Importantly, we report that IL-17-induced targets of A20 show similar aberrant epidermal layer-specific transcriptional upregulation in keratinocytes from diseases as diverse as psoriasis, atopic dermatitis, and erythrokeratodermia variabilis, suggesting a contributory role for epidermal inflammation in a broad spectrum of rashes.
This data-driven approach developed predictive models able to accurately predict the 12-week clinical endpoint for psoriasis following tofacitinib (auROC=78%), or etanercept (auROC=71%) treatment in a validation dataset, revealing a robust predictive protein signature including well-established psoriasis markers such as IL-17A & IL-17C, highlighting potential for biologically meaningful and clinically useful response predictions using blood protein data.