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IL-17 Responses Are the Dominant Inflammatory Signal Linking Inverse, Erythrodermic, and Chronic Plaque Psoriasis

Open ArchivePublished:July 20, 2016DOI:https://doi.org/10.1016/j.jid.2016.07.008

      Abbreviations:

      DEG (differentially expressed gene), FDR (false discovery rate)
      To the Editor
      Inverse and erythrodermic psoriasis are rare subtypes of psoriasis. Whereas the former is characterized by shiny erythematous nonscaly plaques in the body folds, the latter has widespread redness with fine scale, covering over 80% of the body surface area, and can be life threatening. Both are clinical subtypes of chronic plaque psoriasis and often coexist or evolve from plaque psoriasis (
      • Boyd A.S.
      • Menter A.
      Erythrodermic psoriasis. Precipitating factors, course, and prognosis in 50 patients.
      ,
      • Omland S.H.
      • Gniadecki R.
      Psoriasis inversa: A separate identity or a variant of psoriasis vulgaris?.
      ), but the pathogenic mechanisms involved are unknown, and current treatments are frequently unsatisfactory (
      • Rosenbach M.
      • Hsu S.
      • Korman N.J.
      • Lebwohl M.G.
      • Young M.
      • Bebo Jr., B.F.
      • et al.
      Treatment of erythrodermic psoriasis: from the medical board of the National Psoriasis Foundation.
      ).
      To assess the shared and unique processes between chronic plaque, inverse, and erythrodermic psoriasis, we analyzed archived formalin-fixed paraffin-embedded biopsy samples of clinically and histologically confirmed chronic plaque (n = 12), inverse (n = 40), and erythrodermic psoriasis cases (n = 30) and healthy control skin (n = 12) using Affymetrix ST 2.1 arrays (Affymetrix, Santa Clara, CA). Compared with healthy skin, psoriatic plaque lesions yielded 2,450 differentially expressed genes (DEGs) (false discovery rate, FDR, P < 0.05), inverse psoriasis lesions yielded 408 DEGs (FDR, P < 0.05), and erythrodermic psoriasis lesions yielded 447 DEGs (FDR, P < 0.05) (Figure 1a). In total, 294 genes were found to be shared among the three disease subtypes (FDR, P < 0.05). Although the overlap accounted for only 12% of the DEGs in chronic plaque psoriasis, it accounted for 66% and 72% of DEGs in erythrodermic and inverse psoriasis, respectively.
      Figure 1
      Figure 1Unique and shared canonical pathways between chronic plaque, inverse, and erythrodermic psoriasis. Venn diagram of the overlap between chronic plaque, inverse, and erythrodermic psoriasis and enriched canonical pathways. (a) The overlap group represented most differentially expressed genes in both the inverse and erythrodermic groups (>66%) but only about 12% of the differentially expressed genes in chronic plaque psoriasis. The dominant canonical pathway in the shared group was IL-17 responses. (b) Histologic confirmation of several genes shared between chronic plaque, inverse, and erythrodermic psoriasis (scale bar = 100 μm). ERYTH, erythrodermic psoriasis; Erythrod, erythrodermic psoriasis; INV, inverse psoriasis; KRT, keratin; PP, chronic plaque psoriasis.
      Disease processes specific to each psoriasis subtype were analyzed using Ingenuity Pathway Analysis (Qiagen, Redwood City, CA). Canonical processes unique to chronic plaque psoriasis included protein ubiquitination pathway (P = 2.10 × 10−22), oxidative phosphorylation (P = 3.81 × 10−13), glucocorticoid receptor signaling (P = 2.44 × 10−12), mitochondrial dysfunction (2.26 × 10−10), and mTOR signaling (P = 4.13 × 10−07). Genes unique to chronic plaque psoriasis included NFKBIZ (3.6-fold increase) and DDX58 (2.4-fold increase), genes recently implicated in the pathogenesis of psoriasis (
      • Johansen C.
      • Mose M.
      • Ommen P.
      • Bertelsen T.
      • Vinter H.
      • Hailfinger S.
      • et al.
      IkappaBzeta is a key driver in the development of psoriasis.
      ,
      • Tsoi L.C.
      • Spain S.L.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • Knight J.
      • et al.
      Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci.
      ). Overlapping canonical processes between plaque and inverse psoriasis included epithelial adherens junction signaling (P = 2.52 × 10−4) and unfolded protein responses (P = 1.19 × 10−3), whereas the overlap between plaque and erythrodermic psoriasis included remodeling of epithelial adherence junction (P = 6.8 × 10−04) and phagosome maturation (P = 7.0 × 10−04). The numbers of genes unique to inverse and erythrodermic psoriasis were too small for analyses of enriched biologic processes (see Supplementary Materials online). Genes shared among all three clinical presentations included S100A7 (32-fold increase in plaque psoriasis, 8.7-fold increase in inverse psoriasis, and 6-fold increase in erythrodermic psoriasis), KRT16 (15-, 5- and 4.8-fold increases, respectively), IL36G (10-, 3.7- and 3.9-fold increases, respectively), and human β-defensin 2 (hBD2/DEFB4) (10-, 4.5-, 3.5-fold increases, respectively). These were confirmed by immunohistochemistry (Figure 1b).
      The most enriched canonical pathway from the group of genes shared among plaque, inverse, and erythrodermic psoriasis included IL-17a signaling (P = 3.24 × 10−09), followed by p38 mitogen-activated protein kinase signaling (P = 5.8 × 10−05) and communication between innate and adaptive immune cells (P = 5.35 × 10−04). The key biologic nodes in the shared gene set included keratinocyte differentiation, regulation of endopeptidase activity, response to external biotic stimulus, viral genome replication, and response to cytokines (Figure 2a). We next screened the overlapping gene set to determine if such genes were disproportionately induced by cytokine treatments applied to cultured keratinocytes using cytokine-response analyses previously described by our group (
      • Swindell W.R.
      • Johnston A.
      • Voorhees J.J.
      • Elder J.T.
      • Gudjonsson J.E.
      Dissecting the psoriasis transcriptome: inflammatory- and cytokine-driven gene expression in lesions from 163 patients.
      ,
      • Swindell W.R.
      • Johnston A.
      • Xing X.
      • Voorhees J.J.
      • Elder J.T.
      • Gudjonsson J.E.
      Modulation of epidermal transcription circuits in psoriasis: new links between inflammation and hyperproliferation.
      ). Consistent with the Ingenuity pathway analysis results, the overlapping gene set among the three transcriptomes was most strongly enriched with respect to genes induced by IL-17a in cultured keratinocytes, with strong enrichment also observed with respect to genes induced by IL-17a plus tumor necrosis factor and tumor necrosis factor (Figure 2b). Quantitative real-time reverse transcriptase–PCR confirmed elevated mRNA expression of IL-17a in all three clinical presentations, with the highest expression in chronic plaque psoriasis and the lowest in inverse psoriasis (Figure 2c). IL-17a mRNA expression was about 10-fold higher in plaque compared with inverse psoriasis (P < 0.01). The reason for this difference is not clear and will need to be addressed in future studies. Similarly, IL36G mRNA expression was elevated in all three but was highest in plaque psoriasis. In contrast, IL36RN, the receptor antagonist for the IL-36 family of cytokines, had the highest expression in erythrodermic psoriasis (P < 0.01). Interestingly, IFNG and IL22 mRNA expression was highest in erythrodermic psoriasis than in plaque and inverse psoriasis (about 5-fold higher compared with both plaque and inverse psoriasis, P < 0.05), whereas, in stark contrast, expression of IL26 mRNA, a cytokine recently implicated in the pathogenesis of psoriasis (
      • Meller S.
      • Di Domizio J.
      • Voo K.S.
      • Friedrich H.C.
      • Chamilos G.
      • Ganguly D.
      • et al.
      T(H)17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26.
      ), was higher in both erythrodermic and inverse psoriasis than in plaque psoriasis (i.e., erythrodermic vs. plaque psoriasis was 6-fold higher, P < 0.01) (Figure 2c).
      Figure 2
      Figure 2Overlapping and unique biologic and cytokine responses in chronic plaque, inverse, and erythrodermic psoriasis. (a) On the basis of biologic process analyses by Cytoscape and ClueGO (www.cytoscape.org), the shared genes between chronic plaque, inverse, and erythrodermic psoriasis belonged to five major groups, including keratinocyte differentiation and response to cytokine. (b) From gene-set enrichment analyses, IL-17a signatures were observed to dominate the shared gene set, along with IL-17a + tumor necrosis factor and tumor necrosis factor responses. (c) Quantitative real-time reverse transcriptase–PCR of chronic plaque (n = 12), inverse (n = 40), and erythrodermic psoriasis (n = 30) showed differences in the mRNA expression of key cytokines among the three clinical presentations. Data shown with standard error of the mean, two-tailed t test. P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001. Eryth, erythrodermic psoriasis; Inv, inverse psoriasis; NN, normal skin; PP, chronic plaque psoriasis; OSM, oncostatin M; TGF, transforming growth factor; TNF, tumor necrosis factor.
      These results show that IL-17a is the major shared pathway for chronic plaque, inverse, and erythrodermic psoriasis. This is consistent with recently published case series showing six out of eight erythrodermic patients achieving complete clearance with anti–IL-17 treatment (
      • Saeki H.
      • Nakagawa H.
      • Ishii T.
      • Morisaki Y.
      • Aoki T.
      • Berclaz P.Y.
      • et al.
      Efficacy and safety of open-label ixekizumab treatment in Japanese patients with moderate-to-severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis.
      ), but to our knowledge, similar data on flexural psoriasis does not yet exist. In addition, our data show pronounced differences in the expression of several key proinflammatory cytokines between each clinical subtype, suggesting that although IL-17 may provide a common inflammatory pathway, other inflammatory signals may modify the clinical presentation and contribute to the unique manifestations of each subtype. This includes the nonpustular presentation of erythrodermic psoriasis and its higher risk of septicemia (
      • Green M.S.
      • Prystowsky J.H.
      • Cohen S.R.
      • Cohen J.I.
      • Lebwohl M.G.
      Infectious complications of erythrodermic psoriasis.
      ), particularly from skin pathogens including Staphylococcus aureus (
      • Prystowsky J.H.
      • Cohen P.R.
      Pustular and erythrodermic psoriasis.
      ), although the extent of skin involvement is likely to be a contributing factor as well. Similarly, the clinical appearance of inverse psoriasis, with its decreased scale and thinner, shinier plaques, may therefore be less due to its localization in the moist, warm milieu of flexural body sites (
      • Omland S.H.
      • Gniadecki R.
      Psoriasis inversa: A separate identity or a variant of psoriasis vulgaris?.
      ) but more due to differences in the composition of the inflammatory network in skin and variation in growth factors such as epiregulin, heparin-binding epidermal growth factor, amphiregulin, and vascular endothelial growth factor, which in our study were found to be increased in chronic plaque but not in erythrodermic or inverse psoriasis (data not shown).
      In summary, the findings presented here provide information that may change the existing therapeutic approach to treating patients with inverse and erythrodermic psoriasis, such as the use of anti–IL-17 treatments. This provides direction for the design of future clinical trials, which will be needed to validate our conclusions. Furthermore, to our knowledge, our data provide previously unreported insights into how variations in the cytokine network in psoriatic skin may shape different clinical manifestations of psoriasis.

      ORCID

      Conflict of Interest

      JEG has received research support from Amgen, AbbVie, and Novartis.

      Acknowledgments

      The work was in part supported by a research grant from Novartis; the University of Michigan Babcock Endowment Fund (AJ, JJV, JEG); National Institutes of Health awards K08-AR060802 and R01-AR069071 (JEG), K01-AR064765 (AJ), and K08-AR063668 (JMK); the A. Alfred Taubman Medical Research Institute Kenneth and Frances Eisenberg Emerging Scholar Award (JEG); and Doris Duke Charitable Foundation Grant #2013106 (JEG).

      Supplementary Material

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