Research in recent years has provided evidence that two types of T cells—Th1 and Th17—are involved in the pathogenesis of psoriasis. Whereas clonal proliferation of Th1 cells induce the production of TNF and Interferon Gamma, Th17 cells produce, in addition to TNF and interferon gamma, what is known as IL-17, a pro-inflammatory cytokine, as well as IL-22, which directly enhances the proliferation of epidermal proliferation. Secondary to the clonal activation of Th17 cells, IL-17 activates keratinocytes, neutrophils, antigen-presenting cells, as well as cross talks with Th1 and Th2 TREG cells. IL-17 is also directly activated by stress to the innate immune cells, inducing the recruitment of neutrophils. As compared to non-lesional psoriatic skin, IL-17 is increased 30-fold in psoriatic skin. IL-17 binds to IL-17 receptors in order to mediate its effect. It also induces endothelial cell migration, angiogenesis, keratinocyte proliferation, neutrophil recruitment, and antimicrobial peptides.
There are several agents currently in the pipeline addressing the IL-17 pathway. And while it is difficult to foresee what (if any) impact they will have on psoriasis treatment in years to come, it is worth examining how each of these agents has fared in trials thus far.
AMG 827: Brodalumab (Amgen). Brodalumab is a human monoclonal antibody against IL-17 receptor A (IL-17RA) that blocks the biologic activity of IL-17. In a Phase II trial, patients receiving 210mg sq every other week garnered PASI 75, 90, and 100 response rates of 82, 75, and 62, repectively, at week 12.1 Out of 40 patients, one serious adverse event was recorded. Eight percent of patients experienced injections site reactions, as compared to three percent in the placebo group, and 10 percent had pain in extremities, versus none in the placebo group.
Secukinumab (Novartis). Secukinumab is a monoclonal antibody to IL-17. In a trial, patients received three sq injections of 150mg at weeks zero, one, and two. In total, 81.5 percent of patients achieved PASI 75, as compared to 9.1 percent of the placebo group. Additionally, 14 weeks after the last administration, 56 percent of patients maintained results. There were no serious adverse events in the 150mg x 3 group, and there were two in the placebo group. There was an increase in nasopharnynigits, URI, as well as fatigue in patients receiving secukinumab.
Ixekizumab (Eli Lilly). Ixekizumab is a monoclonal antibody to IL-17. In a 12-week study, 142 patients received 150mg sq treatment at weeks zero, two, four, eight, and 12, with some patients achieving PASI 75 as early as two weeks.2 At 12 weeks, 82 percent of patients achieved PASI 75, as compared to eight percent of controls. In addition, 71 percent of patients achieved PASI 90. A total of 71 percent of patients had a PGA score of zero or one and 40 percent achieved PASI 100.
The most common adverse events were nasopharyngitis, upper respiratory infections, injection site reactions, and headache. Importantly, no serious adverse events were reported.
Inflammation in psoriasis histologically shows activated T cells. And while Th1 has been considered a key pathway, evidence increasingly suggests that Th17 plays a significant role, as well. Highly upregulated in lesional versus non-lesional psoriatic skin, IL-17 requires an IL-17 receptor for signaling, which each of the three investigational agents examined in this article offer. It is worth noting, however, that over-activation of IL-17 is associated with epidermal inflammation, keratinocyte proliferation, and epidermal thickening in the self-perpetuating cycle of psoriasis. Nevertheless, as the immunologic basis of psoriasis is increasingly elucidated, more inhibitors of specific interleukins are being compromised.
The efficacy of the IL-17 inhibitors looks very promising, but much more safety data is necessary before we can say that this new generation of medications is the new gold standard. After all, briakinamab's efficacy was excellent, but major adverse cardiovascular events resulted in discontinuation of clinical trials. We must proceed cautiously with IL-17 inhibitors.
Dr. Bagel has served as consultant, researcher, or speaker for Amgen, LEO, Abbott, Janssen, Galderma, and GlaxoSmithKline.
Jerry Bagel, MD, FAAD, is director of the Psoriasis Treatment Center of Central New Jersey.
- Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012; 366(13):1181-9.
- Leonardi C, Matheson R, Zacariae C, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012; 366(13):1190-9.