Andrew Blauvelt, MD, MBA
Practical immunology is important for dermatologists to understand as it relates to a wide variety of pipeline drugs currently under investigation. In Dr Blauvelt’s view, there are three major cell types involved in psoriasis pathogenesis: 1) dendritic cells (upstream/initiating immune responses); 2) T cells (making pro-inflammatory cytokines); and 3) keratinocytes. Targeting IL-23, which is made by dendritic cells, leads to reductions in Th17 cells, since IL-23 is the major survival and growth factor for this type of T cell. Thus, ustekinumab is an indirect T-cell targeting agent. The main cytokine that is being made by the Th17 cells is IL-17A, which leads to activation and growth of keratinocytes. IL-17A is now considered the main effector cytokine of psoriasis. So, by targeting IL-17, downstream function of keratinocytes can be normalized.
A recent study looked at patients on either etanercept or ixekizumab (an anti IL-17A antibody currently under investigation for the treatment of psoriasis). Within two weeks of initiation of therapy, ixekizumab led to the down-modulation of psoriasis-related gene expression to a much greater extent when compared to etanercept. Of the 959 genes up-regulated with psoriasis, 559 were turned off within two weeks of ixekizumab therapy versus 84 with etanercept therapy. This proof-of-concept translational study supports the idea that IL-17A is a key cytokine involved in the pathogenesis of psoriasis.
Pipeline products that specifically block IL-23
These products are unlike ustekinumab in that they do not block IL-12.
MK-3222, an anti-p19 monoclonal antibody (mAb), from Merck
Phase 3 studies underway
CNTO1959, an anti-p19 mAb, from Janssen
Phase 2 studies completed
AMG139, an anti-p19 mAb, from Amgen
Phase 1 studies completed
Pipeline products that block IL-17A function
Secukinumab, a fully human anti-IL-17A mAb, from Novartis
In Phase 3 studies, phase 2 studies published in 2012 (Br J Dermatol)
Ixekizumab, a humanized anti-IL-17A mAb, from Lilly
In Phase 3 studies, phase 2 studies published in 2012 (N Engl J Med)
Brodalumab, a fully human anti-IL-17RA receptor mAb, from Amgen
In Phase 3, phase 2 studies published in 2012 (N Engl J Med)
According to Dr. Blauvelt, all three of the IL-17 blockers look incredibly good from published results and the safety signals, thus far, also look good. If Phase 3 studies confirm these initial results, clinicians will soon have a variety of new promising agents to treat psoriasis patients.
Acquired T-cell Immunity
Regarding the normal function of Th17 cells, individuals who have impaired Th17 responses develop chronic mucocutaneous infections, especially with Candida albicans and Staphylococcus aureus (e.g., Job’s syndrome); these patients also do not develop psoriasis. Normal Th17 responses lead to healing of acute infections with these organisms and no psoriasis (e.g., healthy individuals). Exaggerated Th17 responses lead to healing of acute infections, but eventual development of psoriasis. Of importance, the IL-23/Th17 pathway seems to be less important to systemic immunity when compared to skin and mucosal immunity.
Interestingly, there is also emerging literature regarding the role of IL-17A in the pathogenesis of atherosclerosis. This may mean that targeting of IL-17A may not only treat psoriasis, but also improve atherosclerosis. This, in turn, may decrease the risk of cardiovascular disease associated with psoriasis.
Looking into the Future
As dermatologists, it is important to consider whether drugs that inhibit IL-23 or IL-17 cause or worsen skin or mucosal infections, such as those caused by S. aureus and Candida. Based upon the normal function of this immune pathway, it is unlikely that these drugs will cause or worsen systemic infections. Lastly, it remains to be determined whether they will impact systemic anti-inflammatory activity, including atherosclerosis. Obviously, this latter point will be very important when choosing the proper therapy for patients with moderate-to-severe psoriasis.