BackgroundInterleukin-23 is thought to be critical to the pathogenesis of psoriasis. We compared risankizumab (BI 655066), a humanized IgG1 monoclonal antibody that inhibits interleukin-23 by specifically targeting the p19 subunit and thus prevents interleukin-23 signaling, and ustekinumab, an interleukin-12 and interleukin-23 inhibitor, in patients with moderate-to-severe plaque psoriasis. MethodsWe randomly assigned a total of 166 patients to receive subcutaneous injections of risankizumab (a single 18-mg dose at week 0 or 90-mg or 180-mg doses at weeks 0, 4, and 16) or ustekinumab (45 or 90 mg, according to body weight, at weeks 0, 4, and 16). The primary end point was a 90% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12. ResultsAt week 12, the percentage of patients with a 90% or greater reduction in the PASI score was 77% (64 of 83 patients) for risankizumab (90-mg and 180-mg groups, pooled), as compared with 40% (16 of 40 patients) for ustekinumab...

Risankizumab versus Ustekinumab for Moderate-to-Severe Plaque Psoriasis.

https://www.cell.com/trends/immunology/pdf/S1471-4906(14)00126-4.pdf

Long non-coding RNAs in the regulation of the immune response.

Cytokines in psoriasis

IL-1F6, IL-1F8, and IL-1F9 and the IL-1R6(RP2) receptor antagonist IL-1F5 constitute a novel IL-1 signaling system that is poorly characterized in skin. To further characterize these cytokines in healthy and inflamed skin, we studied their expression in healthy control, uninvolved psoriasis, and psoriasis plaque skin using quantitative RT-PCR and immunohistochemistry. Expression of IL-1F5, -1F6, -1F8, and -1F9 were increased 2 to 3 orders of magnitude in psoriasis plaque versus uninvolved psoriasis skin, which was supported immunohistologically. Moreover, treatment of psoriasis with etanercept led to significantly decreased IL-1F5, -1F6, -1F8, and -1F9 mRNAs, concomitant with clinical improvement. Similarly increased expression of IL-1F5, -1F6, -1F8, and -1F9 was seen in the involved skin of two mouse models of psoriasis. Suggestive of their importance in inflamed epithelia, IL-1α and TNF-α induced IL-1F5, -1F6, -1F8, and -1F9 transcript expression by normal human keratinocytes. Microarray analysis revealed that these cytokines induce the expression of antimicrobial peptides and matrix metalloproteinases by reconstituted human epidermis. In particular, IL-1F8 increased mRNA expression of human β-defensin (HBD)-2, HBD-3, and CAMP and protein secretion of HBD-2 and HBD-3. Collectively, our data suggest important roles for these novel cytokines in inflammatory skin diseases and identify these peptides as potential targets for antipsoriatic therapies.

IL-1F5, -F6, -F8, and -F9: A Novel IL-1 Family Signaling System That Is Active in Psoriasis and Promotes Keratinocyte Antimicrobial Peptide Expression

Atopic Dermatitis Is an IL-13–Dominant Disease with Greater Molecular Heterogeneity Compared to Psoriasis

Transcriptome analysis of psoriasis in a large case-control sample: RNA-seq provides insights into disease mechanisms.

https://www.jidonline.org/article/S0022-202X(15)34890-9/pdf

Evidence for altered Wnt signaling in psoriatic skin.

https://dash.harvard.edu/bitstream/handle/1/11877119/3570705.pdf?sequence=1

Alteration of the EphA2/Ephrin-A signaling axis in psoriatic epidermis.

The IL12B gene encodes the common p40 subunit of IL-12 and IL-23, cytokines with key roles in Th1 and Th17 biology, respectively, and genetic variation in this region significantly influences risk of psoriasis. Here, we demonstrate that a psoriasis-associated risk haplotype at the IL12B locus leads to increased expression of IL12B by monocytes and correlated with increased serum levels of IL-12, IFN-γ and the IFN-γ induced chemokine, CXCL10. In contrast, serum IL-23 levels were decreased in risk carriers when compared with non-carriers. We further demonstrate that IL-12 is increased in psoriatic skin and that risk carriers manifest a skewing of the inflammatory network toward stronger IFN-γ responses. Taken together, our data demonstrate that the risk variant in IL12B associates with its increased expression and predisposes to stronger Th1 polarization through deviation of the local inflammatory environment toward increased IL-12/IFN-γ at the expense of IL-23/IL-17 responses.

James J. Kochkodan

Papers

Transcriptome analysis of psoriasis in a large case-control sample: RNA-seq provides insights into disease mechanisms.

Evidence for altered Wnt signaling in psoriatic skin.

Alteration of the EphA2/Ephrin-A signaling axis in psoriatic epidermis.

Susceptibility-associated genetic variation at IL12B enhances Th1 polarization in psoriasis