IL-23 Versus IL-17 in the Pathogenesis of Psoriasis: There Is More to the Story Than IL-17A

August 2019 | Volume 18 | Issue 8 | Supplement Individual Articles | 202 | Copyright © August 2019

April W. Armstrong MD MPH,ª Charlotte Read MBBS BSc,ª Craig L. Leonardi MD,b Leon H. Kircik MDc

aDepartment of Dermatology, University of Southern California Keck School of Medicine, Los Angeles, CA bSaint Louis University School of Medicine, Saint Louis, MO; Central Dermatology Saint Louis, MO cIcahn School of Medicine at Mount Sinai, NY; Indiana Medical Center, Indianapolis, IN; Physicians Skin Care, PLLC; Skin Sciences, PLLC; DermResearch, PLLC, Louisville, KY

Currently, the only FDA-approved biologic therapy that can inhibit the effects of IL-17F is brodalumab, as discussed below. One molecule in late phase development that targets IL-17F is bimekizumab. Bimekizumab binds to both the IL-17A and F subunits, thereby blocking three of the five IL-17 isoforms (AA, FF, and AF) (Figure 2).72,73 It is unclear whether preliminary successes observed in psoriasis and psoriatic arthritis are secondary to effective inhibition of IL-17A or the combined effect of blocking IL-17A and IL-17F.71,72 Some studies suggest that combined blockade of IL-17A and IL-17F may be more effective at lowering inflammation than IL-17A alone.74,75

IL-17C in Psoriasis Pathogenesis and Therapies That Target IL-17C
IL-17C is the most abundant IL-17 cytokine in psoriatic skin lesions. 57 In psoriasis, the role of IL-17C is not well understood but it is believed to be crucial in the pathogenesis. The primary function of IL-17C is to promote inflammation through the induction of inflammatory cytokines, chemokines, and antimicrobial peptides.57,76,77 In vitro and in vivo studies suggest that IL-17C is upregulated in psoriasis skin inflammation and is involved in epidermal thickening.54,57,76,78 Preliminary studies also show that IL-17C may be involved in joint inflammation.79 Of note, IL-17C acts synergistically with TNF-α.57

IL-17C binds to IL-17RA and has a 23% homology with IL-17A.16 IL-17C also mediates further signaling by binding to a IL-17RA/ IL-17RE complex.80 IL-17C is expressed by many epithelial cells such as prostate and fetal kidney cells and keratinocytes rather than immune cells (Table 1).16 Brodalumab is a monoclonal antibody that binds to IL-17RA. IL- 17RA mediates the signaling for IL-17A, IL-17F, IL-17C, and IL-17E. Therefore, brodalumab blocks the function of all five IL-17 isoforms (AA, AF, FF, CC, and EE) by binding to IL-17RA (Figure 2).81 Importantly, brodalumab is the only therapeutic antibody that binds to all five IL-17 isoforms and that can bind to the IL-17C and E subunits. Data suggest that brodalumab also leads to a reduction in IL-23.82 Therefore, targeting IL-17RA by brodalumab appears to normalize the levels of IL-17 subtypes (IL-17A, IL-17F, IL-17C, and IL-17E) as well as IL-23. A recent network meta-analysis showed that brodalumab has superior efficacy compared to TNF-a inhibitors (adalimumab, etanercept, and infliximab), ustekinumab, and secukinumab.83–86 Although a direct comparison study has not been conducted, these findings suggest that targeting IL-17RA may be more efficacious than targeting IL-17A alone.83 Additionally, a comparison study showed that, compared to ustekinumab, almost twice as many patients treated with brodalumab achieved psoriasis area severity index (PASI)- 100; and in patients who had failed previous therapies, three times as many patients treated with brodalumab achieved PASI-100 (32.0% vs 11.3%).

Furthermore, recent studies have shown that patients who failed treatment with an IL-17A inhibitor (secukinumab and ixekizumab) or a IL-23/IL-23 inhibitor (ustekinumab), responded to brodalumab.86–89 Following failed treatment with secukinumab or ixekizumab, subsequent treatment with brodalumab, by week 16, led to PASI-75 in the majority of patients (67-69%), PASI-90 in 44% of patients, and PASI-100 in 28% of patients.87