IL-17 and Systemic Inflammation

Cytokines have an important role in the body by acting as the communicative channel to regulate cellular activity and immune responses. By binding to a target cell, these glycoproteins cause altered gene expression through various intracellular signaling cascades, leading to different effects by the different families of cytokines. Interleukins, one of the cytokine families, influence immune cell activity and carry proinflammatory and anti-inflammatory properties. In particular, IL-17 is now known to be critical in inflammatory responses.

“IL-17 is an inflammatory mediator that participates in a chain of events that ends up with inflammation in a variety of tissue targets such as the skin with psoriasis, the joints with psoriatic arthritis [PsA], and the gut with ulcerative colitis and Crohn disease, or inflammatory bowel diseases,” explained Craig Leonardi, MD.
Dr Leonardi is an associate clinical professor of dermatology at St. Louis University Medical School and in private practice at Central Dermatology in St Louis, MO. He is also a member of the National Psoriasis Foundation Medical Board.

“Either way, IL-17 has a role, and that role can be a little different depending on the disease. It can be accentuated for some diseases and suppressed for others.” He further noted that while there is a lot of learning left to do, this pathway is worth investigating.

IL-17 and Inflammation

“Early on, people referred to IL-17 as the master cytokine for inflammation,” said Dr Leonardi. “Personally, I thought that they had gone a little overboard with their enthusiasm, but I think that they were probably much more right than me.”

IL-17 colloquially refers to the isoform IL-17A, but the reference represents a family of isoforms IL-17A through IL-17F. These cytokines are mostly produced by T helper (T_H) 17 cells, though there has been evidence of production by CD8⁺ T cells, γδ T cells, natural killer T cells, mast cells, and neutrophils.^1,2 IL-17 causes the production and release of other proinflammatory cytokines, such as IL-6, IL-1β, and tumor necrosis factor, as well as antimicrobial peptides (eg, β-defensin and matrix metalloproteinase 9).¹ It also enhances antigen-presenting cell activity and stimulates chemokine synthesis by endothelial cells.³

There are 3 types of innate and adaptive immunity, each of which is defined by their type of cellular response. T_H17 cells are associated with type 3 immunity, which is thought to have an intrinsic immune response to extracellular bacteria and fungi.⁴ Psoriasis has been classically thought as a type 1 immunity disease, but the emerging research on this type 3 immune response in tissue inflammation shows overlap within psoriasis.^4,5 In particular, IL-17A, IL-17C, IL-17E, and IL-17F have all been found to have increased expression in psoriasis lesions.^6,7 Research shows that types 1 and 3 are believed to be related to immunity-mediated autoimmune diseases, which supports why psoriasis is now being considered to be an immune-mediated condition and not purely an autoimmune condition.⁴

IL-23, a cytokine of the IL-12 family, is an upstream regulator of inflammation in psoriasis.¹ In fact, IL-23 stimulates IL-17 production and expression via maintenance of T_H17 cells.^1,8 When it comes to treating psoriasis, antagonists for either interleukin have a positive effect on reducing psoriasis-related inflammation.

Dr Leonardi noted that IL-17 expression can cause different inflammatory responses. For example, IL-17 is one of several activators of nuclear factor κB, which triggers transcription of genes involved in PsA pathogenesis, thus demonstrating some involvement of IL-17 in entheseal and joint inflammation.⁹ However, in inflammatory bowel disease (IBD), IL-17 inhibition could be harmful by affecting tissue
homeostasis repair therefore impairing intestinal wall integrity.⁹

Further, IL-17 could be a link between psoriasis and the related common comorbidities of cardiovascular disease and metabolic disease, showing possible associations to atherosclerosis/acute myocardial infarction and insulin resistance/adipocyte dysfunction, respectively.^7,10 In addition, the liver, eye, and central nervous system all show evidence of IL-17-mediated inflammation,^5,10,11 though much more research is needed to better understand the role of IL-17 in these individual diseases.

IL-17-Targeted Biologics

There are several currently available biologics for psoriasis and PsA that inhibit the activity of IL-17: secukinumab, brodalumab, and ixekizumab. Of these, secukinumab and ixekizumab are monoclonal antibodies to IL-17A, whereas brodalumab targets the receptor of IL-17A (thus inhibiting IL-17A, IL-17E, and IL-17F).¹² Secukinumab and ixekizumab, but not brodalumab, are indicated to also treat PsA. The therapeutic pipeline also includes bimekizumab, notable for its inhibition of IL-17A as well as IL-17F; this biologic is still under review by the FDA for the treatment of psoriasis, and additional trials of PsA are underway.¹³

Dr Leonardi was an investigator for the clinical trials of many of these biologic agents. He noted that of the IL-17 current and emerging options, bimekizumab provides an interesting novel approach. “Blockade of IL-17A by itself has a profound effect on the inflammatory cascade. When you have a second molecule that you’re blocking, so the isoform IL-17F in addition to IL-17A, you get improved performance of whatever measurement you’re using, whether that is [Psoriasis Area and Severity Index (PASI)] or [Physician Global Assessments],” he explained.

There are a few things to remember when prescribing IL-17 targeted for patients with psoriasis. First, while screening patients with psoriasis for PsA at every visit is recommended,¹⁴ this information can also be helpful in determining whether an IL-17 inhibitor is an appropriate choice for biologic treatment. Similarly, patients should be screened for IBD, because there may be some instances when this biologic class should be avoided in patients positive for history of or active IBD.¹⁵ Dermatologists should also caution use of IL-17-targeted biologics in patients with preexisting immunosuppression-related conditions.¹⁵ Infection, particularly candidiasis, can be a concern, and Armstrong et al¹⁶ recommend regularly screening for these infections.

Once prescribed and initiated, dermatologists should evaluate treatment response after 12 weeks of continuous therapy.

“In real estate, its location, location, location, and in psoriasis, it’s PASI, PASI, PASI. What we are seeing now with these newer biologics is a terrific skin response with a dramatic clearing of the skin and maintenance of that clearing effect. These are all great things for our patients,” added Dr Leonardi.

References

1. Girolomoni G, Strohal R, Puig L, et al. The role of IL-23 and the IL-23/TH17 immune axis in the pathogenesis and treatment of psoriasis. J Eur Acad Dermatol Venereol. 2017;31(10):1616-1626. doi:10.1111/jdv.14433

2. Blauvelt A, Chiricozzi A. The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis. Clin Rev Allergy Immunol. 2018;55(3):379-390. doi:10.1007/s12016-018-8702-3

3. Justiz Vaillant AA, Qurie A. Interluekin. In: StatPearls. StatPearls Publishing; 2021. Accessed November 26, 2021. https://www.ncbi.nlm.nih.gov/books/NBK499840/

4. Annunziato F, Romagnani C, Romagnani S. The 3 major types of innate and adaptive cell-mediated effector immunity. J Allergy Clin Immunol. 2015;135(3):626-635. doi:10.1016/j.jaci.2014.11.001

5. Novelli L, Lubrano E, Venerito V, et al. Extra-articular manifestations and comorbidities in psoriatic disease: a journey into the immunologic crosstalk. Front Med (Lausanne). 2021;8:737079. doi:10.3389/fmed.2021.737079

6. Martin DA, Towne JE, Kricorian G, et al. The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings. J Invest Dermatol. 2013;133(1):17-26. doi:10.1038/jid.2012.194

7. von Stebut E, Boehncke WH, Ghoreshi K, et al. IL-17A in psoriasis and beyond: cardiovascular and metabolic implications. Front Immunol. 2019;10:3096. doi:10.3389/fimmu.2019.03096

8. Tang C, Chen S, Qian H, Huang W. Interleukin-23: as a drug target for autoimmune inflammatory diseases. Immunology. 2012;135(2):112-124. doi:10.1111/j.1365-2567.2011.03522.x

9. Wang EA, Suzuki E, Maverakis E, Adamopoulos IE. Targeting IL-17 in psoriatic arthritis. Eur J Rheumatol. 2017;4(4):272-277. doi:10.5152/eurjrheum.2017.17037

10. Miossec P. Local and systemic effects of IL-17 in joint inflammation: a historical perspective from discovery to targeting. Cell Mol Immunol. 2021;18:860-865. doi:10.1038/s41423-021-00644-5

11. Milovanovic J, Arsenijevic A, Stojanovic B, et al. Interleukin-17 in chronic inflammatory neurological disease. Front Immunol. 2020;11:947. doi:10.3389/fimmu.2020.00947

12. Ly K, Smith MP, Thibodeaux Q, Reddy V, Liao W, Bhutani T. Anti IL-17 in psoriasis. Exp Rev Clin Immunol. 2019;15(11):1185-1194. doi:10.1080/1744666X.2020.1679625

13. Update on U.S. FDA review of Biologics License Application (BLA) for bimekizumab. Press release. UCB; October 16, 2021. Accessed November 26, 2021. https://www.ucb.com/stories-media/Press-Releases/article/Update-on-U-S-FDA-Review-of-Biologics-License-Application-BLA-for-bimekizumab

14. Elmets CA, Leonardi CL, Davis DMR, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and attention to comorbidities. J Am Acad Dermatol. 2019;80(4):1073-1113. doi:10.1016/j.jaad.2018.11.058

15. Menter A, Strober BE, Kaplan DH, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. J Am Acad Dermatol. 2019;80(4):1029-1072. doi:10.1016/j.jaad.2018.11.057

16. Armstrong AW, Bukhalo M, Blauvelt A. A clinician’s guide to the diagnosis and treatment of candidiasis in patients with psoriasis. Am J Clin Dermatol. 2016;17:329-336. doi:10.1007/s40257-016-0206-4