Immunodermatology: Part 2: Practical Immunology

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.


Immunodermatology: Part 1

Andrew Blauvelt, MD, MBA

Immunodermatology is an important content area for dermatologists to consider when managing patients with psoriasis. The genetics of psoriasis has been an exciting and complex area of research over the last few years, especially in terms of how genetics relate to the immunology of psoriasis. A recent paper highlighted how psoriasis genetics and pathogenesis are much more complicated than was formerly believed. Previously, there were 26 identified genetic susceptibility loci associated with psoriasis risk, and now there have been an additional 15 loci identified. Dr. Blauvelt, when discussing psoriasis with his patients, describes it as a complex polygenic disease; yet, according to Dr. Blauvelt, up to 60% of psoriasis patients will have no other family members with the disease. According to the paper, investigators are “just scratching the surface” and these 41 genetic signals account for approximately 22 percent of estimated psoriasis heritability and further genetic studies, including fine-mapping studies and searches for uncommon susceptibility variants, are in order (Tsoi LC, et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012;44(12):1341-1348).

It is also important to consider the overlap between psoriasis genes and susceptibility genes identified for other autoimmune diseases, such as Crohn’s disease, ulcerative colitis, celiac disease, ankylosing spondylitis, rheumatoid arthritis, systemic lupus, multiple sclerosis, and types 1 and 2 diabetes. All of these diseases are polygenic (numerous genes are contributing to the susceptibility), which is a common theme of many common diseases. Of particular interest is the fact that 11 out of 41 susceptibility genes overlap between psoriasis and Crohn’s disease; in fact, six of the 11 genes are related to the IL-23/Th17 cell signaling pathway, suggesting that Crohn’s disease may respond to IL-23/Th17 blockade.

Psoriasis genes fall into five major functional categories and are either related to the innate or acquired immune system. These categories include genes linked with IL-23/Th17 cell activation (acquired); antigen presentation (acquired); type 1 interferon induction (innate); NF-kB signaling (innate); and skin barrier function (innate). Genes that are psoriasis-specific, i.e., no other disease associations, are mostly associated with innate immunity.

Examples
IL-36

The genetic basis for generalized pustular psoriasis has been identified. Mutations occur in the gene that encodes for the IL-36 receptor antagonist. This is an example of classic Mendelian inheritance, in that patients who have mutations in this gene develop disease; if they do not have defects, then they do not have the disease. Therapeutically, there is no IL-36 antagonist drug yet, however, this may be developed in the future for patients with generalized pustular psoriasis. IL-36 normally stimulates keratinocytes to produce IL- 8, which is a major neutrophil chemotactic factor. IL-36 will drive neutrophils into the skin, and patients who have this defect in their IL-36 antagonist will have uncontrolled levels of IL-36, leading to elevations in other more downstream pro-inflammatory cytokines (TNF, IL-8, IL-6, IL-1).

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CARD14

CARD14 is another example of Mendelian inheritance, being that patients who have critical mutations in this gene develop chronic plaque psoriasis. On chromosome 17, a mutation in Card14 (G to A) at position 349 was seen in certain familial cases of psoriasis. CARD14 mutation is involved in the innate immune system. Dysfunction in this gene leads to increased NF-kB activity; this, in turn, leads to increased pro-inflammatory cytokine production by keratinocytes.

Numerous other CARD14 variations are associated with non-familial cases of psoriasis as well. These variations however, are not Mendelian. The genetic variations translate into increased NF-kB activity in keratinocytes and increased risk to develop psoriasis.

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IL23R

Dr. Blauvelt notes that this gene is very clinically relevant as it relates to the mechanism of action of ustekinumab. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. If patients don’t have fully functional IL-23 receptor, then IL-23 does not function well as a stimulator of Th17 cells; thus, this gene defect protects against psoriasis development. This is a genetic “hit” to the system, whereas ustekinumab would be a pharmacologic “hit” to the system.

Other genes associated with the IL-23/Th17 pathway include the p19 subunit and the p40 subunit of IL-23 itself.

Summary
There is a tremendous amount of new information regarding genes and psoriasis. Psoriasis pathogenesis represents a complex interplay between innate (how the skin initially reacts) and acquired immunity (mostly related to the IL-23/Th17 pathway). There is certainly a lot more detailed research to come in this area. Regarding translating this information to the bedside, the hope is that genetic profiling will help clinicians predict severity and course of disease as well as to help determine the response to specific therapeutic agents.