Psoriasis research: IL-17, comorbidities take center stage

Andrew Blauvelt, MD, MBAKey psoriasis studies from the past year underscore the importance of interleukin (IL)-17 as a therapeutic target, and the impact of biologic drugs in addressing comorbidities.

In the latter area, says Andrew Blauvelt, M.D., M.B.A., who spoke at MauiDerm 2016, dermatologists who do not discuss biologic drugs with patients who have moderate-to-severe psoriasis and cardiovascular comorbidities likely do these patients a disservice. He is president and investigator at the Oregon Medical Research Center.

Many studies regarding the association between cardiovascular disease and psoriasis continue to be published, he says. "In perhaps the most important of these papers, Gelfand and Mehta showed that aortic inflammation (as measured by fluorine-18-deoxyglucose/FDG PET/CT scanning), a harbinger of atherosclerosis, was directly correlated with the degree of psoriasis severity (as measured by the psoriasis area and severity index/PASI).¹ That is, the more severe the psoriasis, the more severe the degree of large artery inflammation." These same investigators are performing important follow-up studies to determine whether biologic therapies that clear the skin would decrease aortic inflammation, says Dr. Blauvelt.

"The bottom line is that all dermatologists should now be discussing moderate-to-severe psoriasis as a risk factor for cardiovascular disease, as well discussing the possibility that clearing the skin may improve cardiovascular disease. Furthermore, emerging data now suggest that dermatologists who continue to not incorporate biologics into their treatment regimens for moderate-to-severe psoriasis are likely undertreating many of their patients, with adverse consequences that extend far beyond the skin."² Specifically, he says, various studies have shown associations between psoriasis and psoriatic arthritis (PSA), major adverse cardiovascular events (MACE) and metabolic syndrome, as well as psychosocial consequences and diminished quality of life and life expectancy.

Undertreatment of psoriasis persists, Dr. Blauvelt says, because many physicians still have misperceptions about biologics. Despite mounting evidence to the contrary, he says, many dermatologists still believe that psoriasis is a trivial or cosmetic matter, and that biologic drugs carry more risks than conventional systemic treatments for psoriasis. "In contrast to biologics that target inflammatory cytokines in skin," he and his co-authors write, "conventional systemic agents generally act via nonspecific mechanisms, likely increasing off-target systemic side effects."²

Granted, says Dr. Blauvelt, biologics remain expensive, and prescribing them can be burdensome due to the need for pretreatment screenings and insurance-related paperwork. Although the initial visit for using a biologic drug takes about 20 minutes longer than average, he says, based on his experience, subsequent visits are markedly shorter and simpler. Because patients express higher satisfaction with biologic treatments than conventional systemic agents, he explains, their treatment regimens generally require minimal adjustment.

Regarding the pathogenesis of psoriasis, says Dr. Blauvelt, findings from three basic immunology studies over the past year further strengthen the importance of IL-17A as a key mediator of psoriasis pathogenesis:

• Certain genes associated with higher IL-17A production have been linked with more severe forms of psoriasis.³ Researchers compared genotype data from 696 patients with mild psoriasis versus that of 715 patients with severe disease requiring systemic therapy. After controlling for gender and age at disease onset, they found that HLA-C*06 combined with single nucleotide polymorphisms (SNPs) in IL-23A, IL-23R, IL-12B, nuclear factor kappa B subunit 1 (NFKB1) or TNIP1 correlated strongly with severe disease.

• Transgenic mice engineered to produce continual low levels of IL-17A in skin eventually developed psoriasis-like disease as adults, a process that was quickened with skin trauma (i.e., the Koebner phenomenon).⁴

• Long-lived IL-17-producing cells in the dermis were found to be responsible for psoriasis recurrences in the same skin areas.⁵ Specifically, researchers found in a genetically engineered mouse model that IL-17A/F-producing Vγ4(+) Vδ4(+) T cells populate and persist in the dermis long after initial stimulation with imiquimod. Experienced Vγ4(+) Vδ4(+) cells show enhanced effector functions and mediate an exacerbated secondary inflammatory response. "In addition to identifying a unique feature of γδ T cells during inflammation," these authors write, "our results have direct relevance to the human disease, as this quasi-innate memory provides a mechanistic insight into relapses and chronification of psoriasis."

Newer biologic therapies, including secukinumab and ixekizumab, directly target IL-17A, and thus strike at the heart of psoriasis, Dr. Blauvelt says. "Interestingly, retinoic acid-related orphan nuclear receptor gamma T (RORγt), an intracellular transcription factor directly involved in IL-17A production, is now being targeted via oral small-molecule drugs in early phase clinical trials."⁶

Investigators also are exploring new ways of targeting pro-inflammatory mediators like IL-17A, he says. Examples include use of implantable genetically-engineered cells that produce anti-inflammatory cytokines when they sense excessive pro-inflammatory cytokines within surrounding tissue.⁷ Dr. Blauvelt says, "This therapeutic approach for psoriasis would be analogous to implantable continuous monitors that release insulin when they sense glucose levels to be too high in diabetics. Although such an advance is many years from being utilized in real-life clinical settings, the idea of making delivery of anti-psoriatic medications seamless, and only when needed, could prove to be a major breakthrough in the future." 

Disclosures: Dr. Blauvelt has been a scientific advisor and clinical study investigator for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Dermira, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron and Sandoz.

References

1. Naik HB, Natarajan B, Stansky E, et al. Severity of psoriasis associates with aortic vascular inflammation detected by FDG PET/CT and neutrophil activation in a prospective observational study. Arterioscler Thromb Vasc Biol. 2015;35(12):2667-76.

2. Blauvelt A, Armstrong AW, Krueger GG. Essential truths for the care and management of moderate-to-severe psoriasis. J Drugs Dermatol 2015;14:805-812.

3. Nikamo P, Lysell J, Ståhle M. Association with genetic variants in the IL-23 and NF-κB pathways discriminates between mild and severe psoriasis skin disease.J Invest Dermatol. 2015;135(8):1969-76.

4. Wohn C, Brand A, van Ettinger K, et al. Gradual development of psoriatic skin lesions by constitutive low-level expression of IL-17A. Cell Immunol. 2015;pii:S0008-8749(15)30040-X. doi: 10.1016/j.cellimm.2015.11.006.

5. Hartwig T, Pantelyushin S, Croxford AL, Kulig P, Becher B. Dermal IL-17-producing γδ T cells establish long-lived memory in the skin. Eur J Immunol. 2015;45(11):3022-33.

6.  Banerjee D, Zhao L, Wu L, et al. Small molecule mediated inhibition of RORγ-dependent gene expression and autoimmune disease pathology in vivo.Immunology. 2016;147(4):399-413.

7. Schukur L, Geering B, Charpin-El Hamri G, Fussenegger M. Implantable synthetic cytokine converter cells with AND-gate logic treat experimental psoriasis. Sci Transl Med. 2015;7(318):318ra201.