Impact of Adalimumab Treatment on Interleukin-17 and Interleukin-17 Receptor Expression in Skin and Synovium of Psoriatic Arthritis Patients with Mild Psoriasis

Abstract

Interleukin (IL)-17 and tumor necrosis factor-alpha (TNF)-α are key players in psoriatic arthritis (PsA) pathogenesis. While both cytokines can be therapeutically targeted with beneficial clinical outcome, it is unclear whether inhibiting one cytokine will affect the other at sites of inflammation. If both act independently, this might provide a rationale for dual or combined inhibition of both cytokines. Here, we evaluated the effect of TNF blockade in PsA patients on IL-17 levels in both skin and synovial tissue biopsies. PsA patients with mild psoriatic skin lesions were randomized to receive either adalimumab or placebo for four weeks. Synovial and skin biopsies were obtained at weeks zero and four. Skin from healthy donors (HDs) was used for comparison. Expression of IL-17A, IL-17F, IL-17RA and IL-17RC was assessed by immunohistochemistry and analyzed with digital image analysis. We found relatively low levels of IL-17 and its receptors in the skin of PsA patients compared to HD, and only IL-17F in the dermis of lesional psoriatic skin was significantly higher compared to HD skin (p = 0.0002). Histologically IL-17A, IL-17F, IL-17RA and IL-17RC in skin and synovial tissue were not downregulated by adalimumab treatment. Thus, in this cohort of PsA patients with mild psoriasis, TNF blockade did not affect the protein levels of IL-17 cytokines and its receptors in skin and synovium, despite reduced cellular inflammation and improved clinical outcome for joint involvement.

Keywords: adalimumab; immunohistochemistry; immunopathogenesis; interleukin-17; psoriatic arthritis; skin; synovium.

Figure 1

Expression of IL-17A was lower in the epidermis and dermis of nonlesional psoriatic skin compared to healthy donor skin. (A) Representative immunohistochemical staining of baseline IL-17A expression (arrows) in skin from HD and PsA patients. Original magnification 200 ×. (B) Quantification of IL-17A (Kruskal-Wallis test, epidermis p = 0.07, dermis p = 0.07) and expression in HD, PsA L skin and PsA NL skin. Results are shown as median IOD/mm² and IQR of epidermis and dermis of HD and PsA patients. Per subject the median expression level of 18 high-power fields is used for analysis. E, epi-dermis; D, dermis; IL, interleukin; HD, healthy donor; PsA, psoriatic arthritis; L; lesional, NL; nonlesional, IOD; integrated optical density, IQR; interquartile range.

Figure 2

Expression of IL-17F was higher in the dermis of lesional psoriatic skin compared to healthy donor skin. (A) Representative immunohistochemical staining of baseline IL-17F expression (arrows) in skin from HD and PsA patients. Original magnification 200 ×. (B) Quantification of IL-17F (Kruskal-Wallis test, epidermis p = 0.17, dermis p = 0.0002) expression in HD, PsA L skin and PsA NL skin. Results are shown as median IOD/mm² and IQR of epidermis and dermis of HD and PsA patients. Per subject the median expression level of 18 high-power fields is used for analysis. p values given in the graphs are cal-culated from a post Dunn’s test. E, epidermis; D, dermis; IL, interleukin; HD, healthy donor; PsA, psoriatic arthritis; L; lesional, NL; nonlesional, IOD; integrated optical density, IQR; interquartile range.

Figure 3

Expression of IL-17RA was lower in the epidermis of the nonlesional psoriatic skin compared to healthy donor skin. (A) Representative immunohistochemical staining of baseline IL-17RA expression (arrows) in skin from HD and PsA patients. Original magnification 200 ×. (B) Quantification of IL-17RA (Kruskal-Wallis test, epidermis p = 0.03, dermis p = 0.007) expression in HD, PsA L skin and PsA NL skin. Results are shown as median IOD/mm² and IQR of epidermis and dermis of HD and PsA patients. Per subject the median expression level of 18 high-power fields is used for analysis. p values given in the graphs are calculated from a post Dunn’s test. E, epidermis; D, dermis, IL, interleukin; HD, healthy donor; PsA, psoriatic arthritis; L; lesional, NL; nonlesional, IOD; integrated optical density, IQR; interquartile range.

Figure 4

Expression of IL-17RC in psoriatic skin was higher in the dermis of nonlesional psoriatic skin compared to healthy donor skin. (A) Representative immunohistochemical staining of baseline IL-17RC expression (arrows) in skin from HD and PsA patients. Original magnification 200 ×. (B) Quantification of IL-17RC (Kruskal-Wallis test, epidermis p = 0.13, dermis p = 0.03) expression in HD, PsA L skin and PsA NL skin. Results are shown as median IOD/mm² and IQR of epidermis and dermis of HD and PsA patients. Per subject the median expression level of 18 high-power fields is used for analysis. p values given in the graphs are calculated from a post Dunn’s test. E, epidermis; D, dermis, IL, interleukin; HD, healthy donor; PsA, psoriatic arthritis; L; lesional, NL; nonlesional, IOD; integrated optical density, IQR; interquartile range.

Figure 5

Representation of expression of IL-17A, IL-17F, IL-17RA and IL-17RC in psoriatic skin of one PsA patient before and after adalimumab treatment. Expression was not altered after 4 weeks of adalimumab. Representative immunohistochemical staining of IL-17A (A), IL-17F (B), IL-17RA (C) and IL-17RC (D) expression in skin of one PsA patient before (baseline) and after treatment with adalimumab. Original magnification 200 ×. E; epidermis, D; dermis, IL, interleukin; PsA, psoriatic arthritis.

Figure 6

Representation of expression of IL-17A, IL-17F, IL-17RA and IL-17RC (arrows) in synovial tissue of one PsA patient before and after adalimumab treatment. Expression was not altered after 4 weeks of adalimumab. Representative immunohistochemical staining of IL-17A, IL-17F, IL-17RA and IL-17RC expression in synovial tissue of one PsA patient before (baseline) and after treatment with adalimumab. Original magnification 200 ×. IL, interleukin; PsA, psoriatic arthritis.