Advertisement

New Frontiers in Psoriatic Disease Research, Part I: Genetics, Environmental Triggers, Immunology, Pathophysiology, and Precision Medicine

Open AccessPublished:July 22, 2021DOI:https://doi.org/10.1016/j.jid.2021.02.764
      Psoriasis is a chronic inflammatory condition characterized by systemic immune dysregulation. Over the past several years, advances in genetics, microbiology, immunology, and mouse models have revealed the complex interplay between the heritable and microenvironmental factors that drive the development of psoriatic inflammation. In the first of this two-part review series, the authors will discuss the newest insights into the pathogenesis of psoriatic disease and highlight how the evolution of these scientific fields has paved the way for a more personalized approach to psoriatic disease treatment.

      Abbreviations:

      CVD (cardiovascular disease), DC (dendritic cell), FMT (fecal microbiota transplantation), ILC (innate lymphoid cell), IMQ (imiquimod), KC (keratinocyte), KLK6 (kallikrein 6), MHC (major histocompatibility complex), PsA (psoriatic arthritis), PsO (psoriasis), PsV (psoriasis vulgaris), SCFA (short-chain fatty acid), SFA (saturated fatty acid), Th (T helper), TLR (toll-like receptor), Treg (regulatory T cell), WD (western diet)

      Introduction

      Psoriasis is a chronic, inflammatory disease affecting an estimated 3% of the United States population (
      • Rachakonda T.D.
      • Schupp C.W.
      • Armstrong A.W.
      Psoriasis prevalence among adults in the United States.
      ). In its skin manifestation, psoriasis (PsO) most commonly presents with plaques as PsO vulgaris (PsV) but also includes rarer subtypes such as guttate, pustular, erythrodermic, and inverse PsO. Approximately 30% of patients with PsO have psoriatic arthritis (PsA) (
      • Mease P.J.
      • Gladman D.D.
      • Papp K.A.
      • Khraishi M.M.
      • Thaçi D.
      • Behrens F.
      • et al.
      Prevalence of rheumatologist-diagnosed psoriatic arthritis in patients with psoriasis in European/North American dermatology clinics.
      ), which can manifest as synovitis, enthesitis, dactylitis, and spondylitis. Owing to the overlap between the skin manifestation of PsO, PsA, and other comorbidities associated with the systemic inflammation from this immune-mediated disease state, some researchers, providers, and patients as well as the National Institutes of Health consider these conditions to be part of a spectrum of psoriatic disease. It has only been in the last few decades that researchers have truly begun to unravel the pathogenesis of PsO and PsA. Since then, this research has evolved rapidly.
      Although the mechanism of PsO is now understood to involve IL-23/IL-17 signaling, there is increasing recognition that PsO is driven by a complex interplay between numerous other intrinsic and extrinsic factors. Recent innovations in next-generation sequencing and single-cell profiling coupled with increases in computing power have enabled a multiomics approach to understand the genetic landscape of PsO, tissue-specific immune microenvironments, and host‒microbiome interactions. These data provide a more nuanced understanding of PsO and PsA, revealing novel pathways and mechanisms that contribute to the development of PsA, particular psoriatic disease subtypes, and characteristic patterns of inflammation.
      In the first of this two-part review series, the authors highlight the latest developments in genetics, environmental triggers, and immunology of PsO and PsA, novel insights from mouse models, and how these new developments have enabled more personalized treatment for psoriatic disease.

      The genetics of PsO and PsA

      Genetic architecture of PsO

      Genetic susceptibility to PsV is polygenic, according to the sum of multiple genetic risk factors. To date, GWASs have identified over 63 genetic risk loci, which account for 28% of PsV heritability (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      ), whereas broader genome-wide heritability for PsV is estimated at 50% (
      • Li Q.
      • Chandran V.
      • Tsoi L.
      • O'Rielly D.
      • Nair R.P.
      • Gladman D.
      • et al.
      Quantifying Differences in heritability among psoriatic arthritis (PsA), cutaneous psoriasis (PsC) and psoriasis vulgaris (PsV).
      ). There is significant genetic concordance between ethnic groups, but 11 risk loci differ in Han Chinese and Caucasian populations (
      • Yin X.
      • Low H.Q.
      • Wang L.
      • Li Y.
      • Ellinghaus E.
      • Han J.
      • et al.
      Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility.
      ). GWASs have revealed valuable insights into disease pathogenesis (Table 1). Of particular importance are genes associated with antigen presentation, such as major histocompatibility complex (MHC) I: HLA-C∗06:02, HLA-C∗12:03, HLA-B∗57:01, HLA-B∗38:01, and HLA-A∗02:01. Coding mutations in ERAP1 and ERAP2, involved in peptide processing, have also been linked to PsV. Genetic risk loci have been identified in the NF-κB pathway, which mediates keratinocyte (KC) proliferation and differentiation, production of proinflammatory cytokines in T helper (Th)17 cells, clonal expansion of T cells, and Wnt signaling in osteoblasts (
      • Goldminz A.M.
      • Au S.C.
      • Kim N.
      • Gottlieb A.B.
      • Lizzul P.F.
      NF-κB: an essential transcription factor in psoriasis.
      ;
      • Ma B.
      • Hottiger M.O.
      Crosstalk between Wnt/β-catenin and NF-κB signaling pathway during inflammation.
      ;
      • Takao J.
      • Yudate T.
      • Das A.
      • Shikano S.
      • Bonkobara M.
      • Ariizumi K.
      • et al.
      Expression of NF-kappaB in epidermis and the relationship between NF-kappaB activation and inhibition of keratinocyte growth.
      ). These include genetic variants in TRAF3IP2, CARD14, TNFSF15, TNIP1, IKBKE, CHUK, REL, and NFKBIA and noncoding mutations in TNFAIP3. Other genetic risk loci, such as IFIH1, DDX58, KLF4, ZC3H12C, CARD14, and CARM1, are involved in IFN-I signaling and the innate immune response, whereas variants in IL23R, IL12B, IL23A, and TYK2 play a role in adaptive (IL-23/IL-17) immunity. PsV genes also include those involved in host defense and in the maintenance of the skin epithelial barrier, such as β-defensin gene DEFB and LCE3B/LCE3C.
      Table 1Major Identified Genetic Risk Loci for Psoriasis and Their Associated Pathways
      Type of VariantGene Loci
      Noncoding SNP
       IL-23/IL-17IL23R (
      • Gupta R.
      • Ahn R.
      • Lai K.
      • Mullins E.
      • Debbaneh M.
      • Dimon M.
      • et al.
      Landscape of long noncoding RNAs in psoriatic and healthy skin.
      ), IL23A (
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Stuart P.E.
      • Nair R.P.
      • Tsoi L.C.
      • Tejasvi T.
      • Das S.
      • Kang H.M.
      • et al.
      Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture.
      ), TYK2 (
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • Knight J.
      • Weale M.E.
      • et al.
      Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ,
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), IL12RB2 (
      • Gupta R.
      • Ahn R.
      • Lai K.
      • Mullins E.
      • Debbaneh M.
      • Dimon M.
      • et al.
      Landscape of long noncoding RNAs in psoriatic and healthy skin.
      ;
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      )
       NF-kBNFKBIA (
      • Stuart P.E.
      • Nair R.P.
      • Tsoi L.C.
      • Tejasvi T.
      • Das S.
      • Kang H.M.
      • et al.
      Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture.
      ), TNFAIP3 (
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Stuart P.E.
      • Nair R.P.
      • Tsoi L.C.
      • Tejasvi T.
      • Das S.
      • Kang H.M.
      • et al.
      Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture.
      ), CARD14 (
      • Gupta R.
      • Ahn R.
      • Lai K.
      • Mullins E.
      • Debbaneh M.
      • Dimon M.
      • et al.
      Landscape of long noncoding RNAs in psoriatic and healthy skin.
      ;
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), TRAF3IP2 (
      • Ellinghaus E.
      • Ellinghaus D.
      • Stuart P.E.
      • Nair R.P.
      • Debrus S.
      • Raelson J.V.
      • et al.
      Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2.
      ;
      • Stuart P.E.
      • Nair R.P.
      • Tsoi L.C.
      • Tejasvi T.
      • Das S.
      • Kang H.M.
      • et al.
      Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture.
      ), IKBKE (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      )
       Innate immuneIFIH1 (
      • Stuart P.E.
      • Nair R.P.
      • Tsoi L.C.
      • Tejasvi T.
      • Das S.
      • Kang H.M.
      • et al.
      Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture.
      ), TNIP1 (
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ), FUT2 (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      ), CHUK (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      ), KLRK1 (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      ), TRIM65 (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      ), DDX58 (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), GJB2 (
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • Zhang A.P.
      • Wang P.G.
      • Xu J.H.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      ), SERPINB8 (
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • Zhang A.P.
      • Wang P.G.
      • Xu J.H.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      ), NOS2 (
      • Stuart P.E.
      • Nair R.P.
      • Ellinghaus E.
      • Ding J.
      • Tejasvi T.
      • Gudjonsson J.E.
      • et al.
      Genome-wide association analysis identifies three psoriasis susceptibility loci.
      ), IL28RA (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), FBXL19 (
      • Stuart P.E.
      • Nair R.P.
      • Ellinghaus E.
      • Ding J.
      • Tejasvi T.
      • Gudjonsson J.E.
      • et al.
      Genome-wide association analysis identifies three psoriasis susceptibility loci.
      ), RNF114 (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      )
       Adaptive immuneERAP1 (
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • Zhang A.P.
      • Wang P.G.
      • Xu J.H.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      ), ERAP2 (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), MICA (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), TNFRSF9 (
      • Stuart P.E.
      • Nair R.P.
      • Tsoi L.C.
      • Tejasvi T.
      • Das S.
      • Kang H.M.
      • et al.
      Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture.
      ;
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), FASLG (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      ), PTPN2 (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      ), CFL1 (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      ), KLF4 (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), RUNX3 (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), IRF4 (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), SOCS1 (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), ETS1 (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), STAT gene STAT3 (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), IL-4 (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), IL-13 (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), IL-31 (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      )
       OtherIL28RA (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), PTEN (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      ), ZNF365 (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      ), UBAC2 (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      ), RP11 (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      ), FUBP1 (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      ), CAMK2G (
      • 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.
      ), MBD2 (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), ILF3 (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), ZC3H12C (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), ELMO1 (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), TAGAP (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), B3GNT2 (
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • Zhang A.P.
      • Wang P.G.
      • Xu J.H.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      ), CSMD1 (
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • Zhang A.P.
      • Wang P.G.
      • Xu J.H.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      ), PTTG1 (
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • Zhang A.P.
      • Wang P.G.
      • Xu J.H.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      ), ZNF816A (
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • Zhang A.P.
      • Wang P.G.
      • Xu J.H.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      ), ZNF365 (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      )
      Coding SNP
       IL-23/IL-17IL23R (
      • Tang H.
      • Jin X.
      • Li Y.
      • Jiang H.
      • Tang X.
      • Yang X.
      • et al.
      A large-scale screen for coding variants predisposing to psoriasis.
      ), TYK2 (
      • Dand N.
      • Mucha S.
      • Tsoi L.C.
      • Mahil S.K.
      • Stuart P.E.
      • Arnold A.
      • et al.
      Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.
      ), IL12B (
      • Zuo X.
      • Sun L.
      • Yin X.
      • Gao J.
      • Sheng Y.
      • Xu J.
      • et al.
      Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis.
      )
       NF-kBNFKBIA (
      • Zuo X.
      • Sun L.
      • Yin X.
      • Gao J.
      • Sheng Y.
      • Xu J.
      • et al.
      Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis.
      ), CARD14 (
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      ;
      • Mössner R.
      • Wilsmann-Theis D.
      • Oji V.
      • Gkogkolou P.
      • Löhr S.
      • Schulz P.
      • et al.
      The genetic basis for most patients with pustular skin disease remains elusive.
      ;
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ), TRAF3IP2 (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      )
       Innate immuneIFIH1 (
      • Dand N.
      • Mucha S.
      • Tsoi L.C.
      • Mahil S.K.
      • Stuart P.E.
      • Arnold A.
      • et al.
      Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.
      ), TNFSF15 (
      • Dand N.
      • Mucha S.
      • Tsoi L.C.
      • Mahil S.K.
      • Stuart P.E.
      • Arnold A.
      • et al.
      Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.
      ), TNIP1 (
      • Zuo X.
      • Sun L.
      • Yin X.
      • Gao J.
      • Sheng Y.
      • Xu J.
      • et al.
      Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis.
      ), FUT2 (
      • Tang H.
      • Jin X.
      • Li Y.
      • Jiang H.
      • Tang X.
      • Yang X.
      • et al.
      A large-scale screen for coding variants predisposing to psoriasis.
      ), IL36RN
      These genes are associated with pustular psoriasis.
      (
      • Marrakchi S.
      • Guigue P.
      • Renshaw B.R.
      • Puel A.
      • Pei X.Y.
      • Fraitag S.
      • et al.
      Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.
      ;
      • Onoufriadis A.
      • Simpson M.A.
      • Pink A.E.
      • Di Meglio P.
      • Smith C.H.
      • Pullabhatla V.
      • et al.
      Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.
      ;
      • Setta-Kaffetzi N.
      • Navarini A.A.
      • Patel V.M.
      • Pullabhatla V.
      • Pink A.E.
      • Choon S.E.
      • et al.
      Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes.
      ), AP1S3
      These genes are associated with pustular psoriasis.
      (
      • Setta-Kaffetzi N.
      • Simpson M.A.
      • Navarini A.A.
      • Patel V.M.
      • Lu H.C.
      • Allen M.H.
      • et al.
      AP1S3 mutations are associated with pustular psoriasis and impaired toll-like receptor 3 trafficking.
      ), SERPINA3
      These genes are associated with pustular psoriasis.
      (
      • Frey S.
      • Sticht H.
      • Wilsmann-Theis D.
      • Gerschütz A.
      • Wolf K.
      • Löhr S.
      • et al.
      Rare loss-of-function mutation in SERPINA3 in generalized pustular psoriasis.
      ), MPO
      These genes are associated with pustular psoriasis.
      (
      • Haskamp S.
      • Bruns H.
      • Hahn M.
      • Hoffmann M.
      • Gregor A.
      • Löhr S.
      • et al.
      Myeloperoxidase modulates inflammation in generalized pustular psoriasis and additional rare pustular skin diseases.
      ;
      • Vergnano M.
      • Mockenhaupt M.
      • Benzian-Olsson N.
      • Paulmann M.
      • Grys K.
      • Mahil S.K.
      • et al.
      Loss-of-function myeloperoxidase mutations are associated with increased neutrophil counts and pustular skin disease.
      ), GJB2 (
      • Tang H.
      • Jin X.
      • Li Y.
      • Jiang H.
      • Tang X.
      • Yang X.
      • et al.
      A large-scale screen for coding variants predisposing to psoriasis.
      )
       Adaptive immuneIL-13 (
      • Dand N.
      • Mucha S.
      • Tsoi L.C.
      • Mahil S.K.
      • Stuart P.E.
      • Arnold A.
      • et al.
      Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.
      ), ERAP1 (
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • Knight J.
      • Weale M.E.
      • et al.
      Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      )
       OtherLNPEP (
      • Cheng H.
      • Li Y.
      • Zuo X.B.
      • Tang H.Y.
      • Tang X.F.
      • Gao J.P.
      • et al.
      Identification of a missense variant in LNPEP that confers psoriasis risk.
      ), LCE3D (
      • Tang H.
      • Jin X.
      • Li Y.
      • Jiang H.
      • Tang X.
      • Yang X.
      • et al.
      A large-scale screen for coding variants predisposing to psoriasis.
      ;
      • Zuo X.
      • Sun L.
      • Yin X.
      • Gao J.
      • Sheng Y.
      • Xu J.
      • et al.
      Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis.
      ), LIPK (
      • Yang C.
      • Chen M.
      • Huang H.
      • Li X.
      • Qian D.
      • Hong X.
      • et al.
      Exome-wide rare loss-of-function variant enrichment study of 21,347 Han Chinese individuals identifies four susceptibility genes for psoriasis.
      ), PPP4R3B (
      • Yang C.
      • Chen M.
      • Huang H.
      • Li X.
      • Qian D.
      • Hong X.
      • et al.
      Exome-wide rare loss-of-function variant enrichment study of 21,347 Han Chinese individuals identifies four susceptibility genes for psoriasis.
      ), BBS7 (
      • Yang C.
      • Chen M.
      • Huang H.
      • Li X.
      • Qian D.
      • Hong X.
      • et al.
      Exome-wide rare loss-of-function variant enrichment study of 21,347 Han Chinese individuals identifies four susceptibility genes for psoriasis.
      ), GSTCD (
      • Yang C.
      • Chen M.
      • Huang H.
      • Li X.
      • Qian D.
      • Hong X.
      • et al.
      Exome-wide rare loss-of-function variant enrichment study of 21,347 Han Chinese individuals identifies four susceptibility genes for psoriasis.
      ), ZNF816A (
      • Tang H.
      • Jin X.
      • Li Y.
      • Jiang H.
      • Tang X.
      • Yang X.
      • et al.
      A large-scale screen for coding variants predisposing to psoriasis.
      )
      HLA alleleHLA-C∗06:02
      Associated with psoriasis vulgaris and guttate psoriasis.
      (
      • Feng B.J.
      • Sun L.D.
      • Soltani-Arabshahi R.
      • Bowcock A.M.
      • Nair R.P.
      • Stuart P.
      • et al.
      Multiple loci within the major histocompatibility complex confer risk of psoriasis.
      ;
      • Nair R.P.
      • Stuart P.E.
      • Nistor I.
      • Hiremagalore R.
      • Chia N.V.C.
      • Jenisch S.
      • et al.
      Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.
      ;
      • Okada Y.
      • Han B.
      • Tsoi L.C.
      • Stuart P.E.
      • Ellinghaus E.
      • Tejasvi T.
      • et al.
      Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes.
      ;
      • Tiilikainen A.
      • Lassus A.
      • Karvonen J.
      • Vartiainen P.
      • Julin M.
      Psoriasis and HLA-Cw6.
      ), HLA-C∗12:03 (
      • Okada Y.
      • Han B.
      • Tsoi L.C.
      • Stuart P.E.
      • Ellinghaus E.
      • Tejasvi T.
      • et al.
      Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes.
      ), HLA-B∗57:01 (
      • Chen H.
      • Hayashi G.
      • Lai O.Y.
      • Dilthey A.
      • Kuebler P.J.
      • Wong T.V.
      • et al.
      Psoriasis patients are enriched for genetic variants that protect against HIV-1 disease.
      ;
      • Feng B.J.
      • Sun L.D.
      • Soltani-Arabshahi R.
      • Bowcock A.M.
      • Nair R.P.
      • Stuart P.
      • et al.
      Multiple loci within the major histocompatibility complex confer risk of psoriasis.
      ), HLA-B∗40 (
      • Feng B.J.
      • Sun L.D.
      • Soltani-Arabshahi R.
      • Bowcock A.M.
      • Nair R.P.
      • Stuart P.
      • et al.
      Multiple loci within the major histocompatibility complex confer risk of psoriasis.
      ), HLA-B∗38:01 (
      • Chen H.
      • Hayashi G.
      • Lai O.Y.
      • Dilthey A.
      • Kuebler P.J.
      • Wong T.V.
      • et al.
      Psoriasis patients are enriched for genetic variants that protect against HIV-1 disease.
      ;
      • Okada Y.
      • Han B.
      • Tsoi L.C.
      • Stuart P.E.
      • Ellinghaus E.
      • Tejasvi T.
      • et al.
      Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes.
      ), HLA-B∗27:05 (
      • Chen H.
      • Hayashi G.
      • Lai O.Y.
      • Dilthey A.
      • Kuebler P.J.
      • Wong T.V.
      • et al.
      Psoriasis patients are enriched for genetic variants that protect against HIV-1 disease.
      ;
      • Okada Y.
      • Han B.
      • Tsoi L.C.
      • Stuart P.E.
      • Ellinghaus E.
      • Tejasvi T.
      • et al.
      Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes.
      ), HLA- B∗39:01 (
      • Chen H.
      • Hayashi G.
      • Lai O.Y.
      • Dilthey A.
      • Kuebler P.J.
      • Wong T.V.
      • et al.
      Psoriasis patients are enriched for genetic variants that protect against HIV-1 disease.
      ;
      • Okada Y.
      • Han B.
      • Tsoi L.C.
      • Stuart P.E.
      • Ellinghaus E.
      • Tejasvi T.
      • et al.
      Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes.
      ), HLA-B∗08:01 (
      • Chen H.
      • Hayashi G.
      • Lai O.Y.
      • Dilthey A.
      • Kuebler P.J.
      • Wong T.V.
      • et al.
      Psoriasis patients are enriched for genetic variants that protect against HIV-1 disease.
      ), HLA-B∗14:02 (
      • Chen H.
      • Hayashi G.
      • Lai O.Y.
      • Dilthey A.
      • Kuebler P.J.
      • Wong T.V.
      • et al.
      Psoriasis patients are enriched for genetic variants that protect against HIV-1 disease.
      ), HLA-B∗55:01 (
      • Chen H.
      • Hayashi G.
      • Lai O.Y.
      • Dilthey A.
      • Kuebler P.J.
      • Wong T.V.
      • et al.
      Psoriasis patients are enriched for genetic variants that protect against HIV-1 disease.
      ) HLA-A∗02:01 (
      • Chen H.
      • Hayashi G.
      • Lai O.Y.
      • Dilthey A.
      • Kuebler P.J.
      • Wong T.V.
      • et al.
      Psoriasis patients are enriched for genetic variants that protect against HIV-1 disease.
      ), HLA-DQα1 (
      • Okada Y.
      • Han B.
      • Tsoi L.C.
      • Stuart P.E.
      • Ellinghaus E.
      • Tejasvi T.
      • et al.
      Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes.
      )
      Copy number variationLCE3C/LCE3D (
      • de Cid R.
      • Riveira-Munoz E.
      • Zeeuwen P.L.
      • Robarge J.
      • Liao W.
      • Dannhauser E.N.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      ;
      • Li M.
      • Wu Y.
      • Chen G.
      • Yang Y.
      • Zhou D.
      • Zhang Z.
      • et al.
      Deletion of the late cornified envelope genes LCE3C and LCE3B is associated with psoriasis in a Chinese population.
      ), DEFB (
      • Hollox E.J.
      • Huffmeier U.
      • Zeeuwen P.L.
      • Palla R.
      • Lascorz J.
      • Rodijk-Olthuis D.
      • et al.
      Psoriasis is associated with increased beta-defensin genomic copy number.
      ;
      • Stuart P.E.
      • Nair R.P.
      • Tsoi L.C.
      • Tejasvi T.
      • Das S.
      • Kang H.M.
      • et al.
      Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture.
      )
      Small insertions/deletionsIFIH1 (
      • Zhen Q.
      • Yang Z.
      • Wang W.
      • Li B.
      • Bai M.
      • Wu J.
      • et al.
      Genetic study on small insertions and deletions in psoriasis reveals a role in complex human diseases.
      ), ERAP1 (
      • Zhen Q.
      • Yang Z.
      • Wang W.
      • Li B.
      • Bai M.
      • Wu J.
      • et al.
      Genetic study on small insertions and deletions in psoriasis reveals a role in complex human diseases.
      ), ERAP2 (
      • Zhen Q.
      • Yang Z.
      • Wang W.
      • Li B.
      • Bai M.
      • Wu J.
      • et al.
      Genetic study on small insertions and deletions in psoriasis reveals a role in complex human diseases.
      ), LNPEP (
      • Zhen Q.
      • Yang Z.
      • Wang W.
      • Li B.
      • Bai M.
      • Wu J.
      • et al.
      Genetic study on small insertions and deletions in psoriasis reveals a role in complex human diseases.
      ), UBLCP1 (
      • Zhen Q.
      • Yang Z.
      • Wang W.
      • Li B.
      • Bai M.
      • Wu J.
      • et al.
      Genetic study on small insertions and deletions in psoriasis reveals a role in complex human diseases.
      ), STAT3 (
      • Zhen Q.
      • Yang Z.
      • Wang W.
      • Li B.
      • Bai M.
      • Wu J.
      • et al.
      Genetic study on small insertions and deletions in psoriasis reveals a role in complex human diseases.
      ), GJB2 (
      • Zhen Q.
      • Yang Z.
      • Wang W.
      • Li B.
      • Bai M.
      • Wu J.
      • et al.
      Genetic study on small insertions and deletions in psoriasis reveals a role in complex human diseases.
      ), ZNF816A (
      • Zhen Q.
      • Yang Z.
      • Wang W.
      • Li B.
      • Bai M.
      • Wu J.
      • et al.
      Genetic study on small insertions and deletions in psoriasis reveals a role in complex human diseases.
      )
      Abbreviation: STAT, signal transducer and activator of transcription.
      1 These genes are associated with pustular psoriasis.
      2 Associated with psoriasis vulgaris and guttate psoriasis.

      Genetics of PsA and PsO subtypes

      GWASs of PsA have found a significant overlap of PsA with PsV (
      • Bowes J.
      • Budu-Aggrey A.
      • Huffmeier U.
      • Uebe S.
      • Steel K.
      • Hebert H.L.
      • et al.
      Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis [published correction appears in Nat Commun 2015;6:7741].
      ;
      • Stuart P.E.
      • Nair R.P.
      • Tsoi L.C.
      • Tejasvi T.
      • Das S.
      • Kang H.M.
      • et al.
      Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture.
      ). Surprisingly, only a few genetic variants so far have been identified as being discrepant between PsA and PsV, one of the main ones being HLA-C∗06:02, which is a risk factor for PsV but protective for PsA, with other discrepant variants observed near IL23R, TNFAIP3, LCE3A, and TNFRSF9 (
      • Stuart P.E.
      • Nair R.P.
      • Tsoi L.C.
      • Tejasvi T.
      • Das S.
      • Kang H.M.
      • et al.
      Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture.
      ). This may indicate a more prominent role for environmental factors in the development of PsA. Notably, mice expressing three distinct targeted mutations of the ZF7 ubiquitin-binding motif of the TNFAIP3 gene were found to develop distal arthritis through IL-17‒mediated NF-κB activation (
      • Razani B.
      • Whang M.I.
      • Kim F.S.
      • Nakamura M.C.
      • Sun X.
      • Advincula R.
      • et al.
      Non-catalytic ubiquitin binding by A20 prevents psoriatic arthritis-like disease and inflammation.
      ). The genetic differences between PsO and PsA are also enriched in regulatory elements for lymphocytes, including CD8+ T cells (
      • Patrick M.T.
      • Stuart P.E.
      • Raja K.
      • Gudjonsson J.E.
      • Tejasvi T.
      • Yang J.
      • et al.
      Genetic signature to provide robust risk assessment of psoriatic arthritis development in psoriasis patients.
      ), which are present in the synovial fluid of patients with PsA and correlate with disease severity (
      • Menon B.
      • Gullick N.J.
      • Walter G.J.
      • Rajasekhar M.
      • Garrood T.
      • Evans H.G.
      • et al.
      Interleukin-17+CD8+ T cells are enriched in the joints of patients with psoriatic arthritis and correlate with disease activity and joint damage progression.
      ;
      • Steel K.J.A.
      • Srenathan U.
      • Ridley M.
      • Durham L.E.
      • Wu S.Y.
      • Ryan S.E.
      • et al.
      Polyfunctional, proinflammatory, tissue-resident memory phenotype and function of synovial interleukin-17A+CD8+ T cells in psoriatic arthritis.
      ). Interestingly, different HLA alleles have been found to be preferentially associated with PsA features such as synovitis, sacroiliitis, dactylitis, and enthesitis (
      • FitzGerald O.
      • Haroon M.
      • Giles J.T.
      • Winchester R.
      Concepts of pathogenesis in psoriatic arthritis: genotype determines clinical phenotype.
      ).
      Regarding PsO subtypes, HLA-C∗06:02 has been found to be highly associated with guttate PsO (
      • Gudjonsson J.E.
      • Karason A.
      • Runarsdottir E.H.
      • Antonsdottir A.A.
      • Hauksson V.B.
      • Jónsson H.H.
      • et al.
      Distinct clinical differences between HLA-Cw∗0602 positive and negative psoriasis patients--an analysis of 1019 HLA-C- and HLA-B-typed patients.
      ). Coding mutations in IL36RN, CARD14, AP1S3, SERPINA3, and MPO that affect IL-1 and IL-36 signaling have been associated with the clinical spectrum of pustular PsO (Supplementary Table S1). Psoriasis genetic variants overlap with Crohn’s disease (
      • Ellinghaus D.
      • Ellinghaus E.
      • Nair R.P.
      • Stuart P.E.
      • Esko T.
      • Metspalu A.
      • et al.
      Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci.
      ) and several cardiovascular disease (CVD) phenotypes (
      • Lu Y.
      • Chen H.
      • Nikamo P.
      • Qi Low H.
      • Helms C.
      • Seielstad M.
      • et al.
      Association of cardiovascular and metabolic disease genes with psoriasis.
      ) but share no common genetic features with atopic dermatitis (
      • Baurecht H.
      • Hotze M.
      • Brand S.
      • Büning C.
      • Cormican P.
      • Corvin A.
      • et al.
      Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms [published correction appears in Am J Hum Genet 2015;97:933].
      ).

      Recent discoveries in the genetics of PsO and PsA

      Sequencing data from a large Chinese cohort has revealed a potentially important, unexpected role for small genomic insertions and deletions in PsO susceptibility (
      • Zhen Q.
      • Yang Z.
      • Wang W.
      • Li B.
      • Bai M.
      • Wu J.
      • et al.
      Genetic study on small insertions and deletions in psoriasis reveals a role in complex human diseases.
      ). Because these variants are not adequately captured in GWAS, additional studies are warranted. Mendelian randomization (
      • Emdin C.A.
      • Khera A.V.
      • Kathiresan S.
      Mendelian randomization.
      ) has allowed researchers to show that obesity is not only associated with PsO but is a causal risk factor for PsO (
      • Budu-Aggrey A.
      • Brumpton B.
      • Tyrrell J.
      • Watkins S.
      • Modalsli E.H.
      • Celis-Morales C.
      • et al.
      Evidence of a causal relationship between body mass index and psoriasis: a Mendelian randomization study.
      ;
      • Ogawa K.
      • Stuart P.E.
      • Tsoi L.C.
      • Suzuki K.
      • Nair R.P.
      • Mochizuki H.
      • et al.
      A transethnic Mendelian randomization study identifies causality of obesity on risk of psoriasis.
      ). Future studies employing Mendelian randomization are likely to help define the directionality between PsO and its comorbidities. Finally, several studies have highlighted the potentially powerful role of psoriatic genetics in precision medicine. A meta-analysis showed that HLA-C∗06:02 is associated with favorable response to ustekinumab in patients with PsV (
      • van Vugt L.J.
      • van den Reek J.M.P.A.
      • Hannink G.
      • Coenen M.J.H.
      • dejong E.M.G.J.
      Association of HLA-C∗06:02 status with differential response to ustekinumab in patients with psoriasis: a systematic review and meta-analysis.
      ), whereas another study showed that lack of HLA-C∗06:02 is associated with better response to adalimumab (
      • Dand N.
      • Duckworth M.
      • Baudry D.
      • Russell A.
      • Curtis C.J.
      • Lee S.H.
      • et al.
      HLA-C∗06:02 genotype is a predictive biomarker of biologic treatment response in psoriasis.
      ). Using a machine learning approach involving ~200 genetic loci, researchers have developed a model to predict PsA with an area under the receiver operator curve of 0.82 (
      • Patrick M.T.
      • Stuart P.E.
      • Raja K.
      • Gudjonsson J.E.
      • Tejasvi T.
      • Yang J.
      • et al.
      Genetic signature to provide robust risk assessment of psoriatic arthritis development in psoriasis patients.
      ).

      Environmental triggers of PsO and PsA

      The increased risk of PsV with smoking (
      • Armstrong A.W.
      • Harskamp C.T.
      • Dhillon J.S.
      • Armstrong E.J.
      Psoriasis and smoking: a systematic review and meta-analysis.
      ) may be modulated by interactions with genetic factors such as HLA-C∗06:02 and CYP1A1 (
      • Jin Y.
      • Yang S.
      • Zhang F.
      • Kong Y.
      • Xiao F.
      • Hou Y.
      • et al.
      Combined effects of HLA-Cw6 and cigarette smoking in psoriasis vulgaris: a hospital-based case-control study in China.
      ;
      • Krämer U.
      • Esser C.
      Cigarette smoking, metabolic gene polymorphism, and psoriasis.
      ). Although smoking is associated with a higher risk of PsA in the general population, among patients with PsO, there is either a decreased incidence of PsA or no significant relationship (
      • Pezzolo E.
      • Naldi L.
      The relationship between smoking, psoriasis and psoriatic arthritis.
      ). Unlike smoking, the effects of alcohol consumption on PsO incidence are unclear (
      • Brenaut E.
      • Horreau C.
      • Pouplard C.
      • Barnetche T.
      • Paul C.
      • Richard M.A.
      • et al.
      Alcohol consumption and psoriasis: a systematic literature review.
      ;
      • Dai Y.X.
      • Wang S.C.
      • Chou Y.J.
      • Chang Y.T.
      • Chen T.J.
      • Li C.P.
      • et al.
      Smoking, but not alcohol, is associated with risk of psoriasis in a Taiwanese population-based cohort study.
      ).
      Medications such as β-blockers, lithium, antimalarials, imiquimod (IMQ), nonsteroidal anti-inflammatory drugs, IFN-α, and terbinafine have been linked to induction and exacerbation of PsO (
      • Balak D.M.
      • Hajdarbegovic E.
      Drug-induced psoriasis: clinical perspectives.
      ;
      • Kim G.K.
      • Del Rosso J.Q.
      Drug-provoked psoriasis: is it drug induced or drug aggravated?: understanding pathophysiology and clinical relevance.
      ). More recently, paradoxical PsO induced by TNF-α inhibitors (
      • Mazloom S.E.
      • Yan D.
      • Hu J.Z.
      • Ya J.
      • Husni M.E.
      • Warren C.B.
      • et al.
      TNF-α Inhibitor-Induced psoriasis: a decade of experience at the Cleveland Clinic.
      ) has been shown to be associated with increased production of IFN-I by plasmacytoid dendritic cells (DCs) in a T-cell‒independent fashion (
      • Conrad C.
      • Di Domizio J.
      • Mylonas A.
      • Belkhodja C.
      • Demaria O.
      • Navarini A.A.
      • et al.
      TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis.
      ).
      Obesity and diet are modifiable risk factors for PsO. Patients with psoriasis have a higher prevalence and incidence of obesity (
      • Armstrong A.W.
      • Harskamp C.T.
      • Armstrong E.J.
      The association between psoriasis and obesity: a systematic review and meta-analysis of observational studies.
      ). Animal studies have shown that mice with diet-induced obesity have more severe psoriasiform dermatitis, suggesting that the chronic inflammatory state caused by adipokines in excessive fat tissue could be a pathogenic link between obesity and PsO (
      • Kanemaru K.
      • Matsuyuki A.
      • Nakamura Y.
      • Fukami K.
      Obesity exacerbates imiquimod-induced psoriasis-like epidermal hyperplasia and interleukin-17 and interleukin-22 production in mice.
      ). A meta-analysis showed that weight loss through dietary intervention in individuals who are obese improves pre-existing PsO and prevents de novo PsO (
      • Mahil S.K.
      • McSweeney S.M.
      • Kloczko E.
      • McGowan B.
      • Barker J.N.
      • Smith C.H.
      Does weight loss reduce the severity and incidence of psoriasis or psoriatic arthritis? A Critically Appraised Topic.
      ).
      However, more recent studies suggest that mechanisms other than obesity may mediate the impact of diet on PsO. For example, an increase of saturated fatty acids (SFAs) in healthy, lean mice alone was sufficient to induce an exacerbation of psoriasiform inflammation, and reduction of nutritional SFAs diminished the psoriatic phenotype in mice without obesity (
      • Herbert D.
      • Franz S.
      • Popkova Y.
      • Anderegg U.
      • Schiller J.
      • Schwede K.
      • et al.
      High-fat diet exacerbates early psoriatic skin inflammation independent of obesity: saturated fatty acids as key players.
      ). Another study showed that exposure to a high-sugar and moderate-fat western diet (WD), even in the absence of obesity, was enough to induce skin inflammation in mice in as little as 4 weeks through the recruitment of IL-17A‒producing γδ-type T cells (
      • Shi Z.
      • Wu X.
      • Yu S.
      • Huynh M.
      • Jena P.K.
      • Nguyen M.
      • et al.
      Short-term exposure to a Western diet induces psoriasiform dermatitis by promoting accumulation of il-17a-producing γδ T cells.
      ). Interestingly, WD-induced skin inflammation was blocked by systemic antibiotic treatment, suggesting a critical role of gut dysbiosis in diet-induced inflammation. Further studies are warranted to determine whether specific diets, in the absence of weight reduction, would bring meaningful clinical improvement in PsO and PsA.
      Biomechanical stress is another major microenvironmental factor in psoriatic inflammation (
      • Belasco J.
      • Wei N.
      Psoriatic arthritis: what is happening at the joint?.
      ). For example, animal models show that hind limb unloading reduced Achilles tendon inflammation (
      • Jacques P.
      • Lambrecht S.
      • Verheugen E.
      • Pauwels E.
      • Kollias G.
      • Armaka M.
      • et al.
      Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells.
      ). Furthermore, mechanical stress induced the expression of IL-17A by entheseal T cells at anatomic locations commonly affected by arthritis in mice (
      • Reinhardt A.
      • Yevsa T.
      • Worbs T.
      • Lienenklaus S.
      • Sandrock I.
      • Oberdörfer L.
      • et al.
      Interleukin-23-dependent γ/δ T cells produce interleukin-17 and accumulate in the enthesis, aortic valve, and ciliary body in mice.
      ). Local biomechanical stress is also thought to promote the differentiation of murine osteoclasts in the joint (
      • Gracey E.
      • Burssens A.
      • Cambré I.
      • Schett G.
      • Lories R.
      • McInnes I.B.
      • et al.
      Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis.
      ). This is supported by a recent study showing that erosive disease in mice is confined to mechanosensitive regions and driven by mesenchymal cells that recruit monocytes by CXCL1 and CCL2 before differentiation into mature osteoclasts (
      • Cambré I.
      • Gaublomme D.
      • Burssens A.
      • Jacques P.
      • Schryvers N.
      • Demuynck A.
      • et al.
      Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis.
      ). The pathogenic importance of exogenous mechanical loading suggests that rather than inherent genetic predisposition, dynamic interplay between the immune system and microenvironmental factors plays a major role in the development of PsA.
      Various infections have been known to trigger or worsen PsO. HIV has been linked to a higher prevalence of PsO (
      • Ceccarelli M.
      • Venanzi Rullo E.
      • Vaccaro M.
      • Facciolà A.
      • d’Aleo F.
      • Paolucci I.A.
      • et al.
      HIV-associated psoriasis: epidemiology, pathogenesis, and management.
      ), worsening of pre-existing PsO, the eruptive onset of de novo PsO (
      • Duvic M.
      • Johnson T.M.
      • Rapini R.P.
      • Freese T.
      • Brewton G.
      • Rios A.
      Acquired immunodeficiency syndrome-associated psoriasis and Reiter's syndrome.
      ), and more recalcitrant disease (
      • Menon K.
      • Van Voorhees A.S.
      • Bebo Jr., B.F.
      • Gladman D.D.
      • Hsu S.
      • Kalb R.E.
      • et al.
      Psoriasis in patients with HIV infection: from the medical board of the National Psoriasis Foundation.
      ), which may be due to an increased CD8+-to-CD4+ T-cell ratio, HIV viral protein superantigens (
      • Ceccarelli M.
      • Venanzi Rullo E.
      • Vaccaro M.
      • Facciolà A.
      • d’Aleo F.
      • Paolucci I.A.
      • et al.
      HIV-associated psoriasis: epidemiology, pathogenesis, and management.
      ), and a shared genetic architecture of the MHC I region (
      • Chen H.
      • Hayashi G.
      • Lai O.Y.
      • Dilthey A.
      • Kuebler P.J.
      • Wong T.V.
      • et al.
      Psoriasis patients are enriched for genetic variants that protect against HIV-1 disease.
      ). Preceding streptococcal pharyngitis (
      • Telfer N.R.
      • Chalmers R.J.
      • Whale K.
      • Colman G.
      The role of streptococcal infection in the initiation of guttate psoriasis.
      ), possibly through similarities between streptococcal antigens and KC proteins, may induce cross reactivity in streptococcal specific T cells leading to the activation of PsO (
      • Prinz J.C.
      Psoriasis vulgaris--a sterile antibacterial skin reaction mediated by cross-reactive T cells? An immunological view of the pathophysiology of psoriasis.
      ). Periodontitis has also been associated with PsO, with patients with PsO demonstrating more gingival inflammation, alveolar bone loss, and missing teeth (
      • Qiao P.
      • Shi Q.
      • Zhang R.
      • E L
      • Wang P.
      • Wang J.
      • et al.
      Psoriasis patients suffer from worse periodontal status-a meta-analysis.
      ) and showing a significant reduction in PsO severity after nonsurgical periodontitis treatment (
      • Ucan Yarkac F.
      • Ogrum A.
      • Gokturk O.
      Effects of non-surgical periodontal therapy on inflammatory markers of psoriasis: a randomized controlled trial.
      ).
      Emerging research now suggests that the interactions between the skin and gut microbiome and the host immune system may play a key pathogenic role in the development of PsO and PsA (Supplementary Table S1). Bacteria play crucial roles in host IL-17–mediated mucosal barrier immunity, Th17 cell development, and RORγt+ regulatory T cells (Tregs) immune homeostasis (
      • Zheng D.
      • Liwinski T.
      • Elinav E.
      Interaction between microbiota and immunity in health and disease.
      ). PsV skin is enriched in proinflammatory Streptococcus and Staphylococcus, although not all studies observed this enrichment. Both Streptococcus aureus and Staphylococcus aureus elicit a strong Th17-type response in skin T effector cells, resulting in the induction of IL-17A, IL-17F, and IL-22 cytokines in murine models (
      • Okada K.
      • Matsushima Y.
      • Mizutani K.
      • Yamanaka K.
      The role of gut microbiome in psoriasis: oral administration of Staphylococcus aureus and Streptococcus danieliae exacerbates skin inflammation of imiquimod-induced psoriasis-like dermatitis.
      ). Interestingly, murine models of PsA and PsV do not develop inflammatory disease when treated with antibiotics or raised in a germ-free environment (
      • Rath H.C.
      • Herfarth H.H.
      • Ikeda J.S.
      • Grenther W.B.
      • Hamm Jr., T.E.
      • Balish E.
      • et al.
      Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats.
      ;
      • Zákostelská Z.
      • Málková J.
      • Klimešová K.
      • Rossmann P.
      • Hornová M.
      • Novosádová I.
      • et al.
      Intestinal microbiota promotes psoriasis-like skin inflammation by enhancing Th17 response.
      ). In addition to increased proinflammatory bacteria, there is a reduction in immunomodulatory Propionibacterium, a major producer of propionate (
      • Yan D.
      • Issa N.
      • Afifi L.
      • Jeon C.
      • Chang H.W.
      • Liao W.
      The role of the skin and gut microbiome in psoriatic disease.
      ), a short-chain fatty acid (SCFA) that promotes Treg homeostasis (
      • Smith P.M.
      • Howitt M.R.
      • Panikov N.
      • Michaud M.
      • Gallini C.A.
      • Bohlooly-Y M
      • et al.
      The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.
      ).
      Similarly, the gut microbiome in PsV has demonstrated a decrease in Bacteroides and Faecalibacterium prausnitzii, a gut commensal that produces the immunomodulatory SCFA, butyrate (
      • Furusawa Y.
      • Obata Y.
      • Fukuda S.
      • Endo T.A.
      • Nakato G.
      • Takahashi D.
      • et al.
      Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.
      ). The only study of the gut microbiome in PsA showed decreases in Akkermansia, Ruminococcus, and Pseudobutyrivibrio, which were associated with decreased levels of immunomodulatory medium-chain fatty acids (
      • Scher J.U.
      • Ubeda C.
      • Artacho A.
      • Attur M.
      • Isaac S.
      • Reddy S.M.
      • et al.
      Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease.
      ).
      In addition to its role in disease pathogenesis, the microbiome may also be a modulator of therapeutic response. Gut bacteria are not only involved in drug metabolism but also indirectly influence drug efficacy through effects on host gene expression and interactions between drugs and bacterial metabolites (
      • Scher J.U.
      • Nayak R.R.
      • Ubeda C.
      • Turnbaugh P.J.
      • Abramson S.B.
      Pharmacomicrobiomics in inflammatory arthritis: gut microbiome as modulator of therapeutic response.
      ). For example, patients with PsV and PsA who responded to secukinumab had a higher abundance of intestinal Citrobacter, Staphylococcus, and Hafnia/Obesumbacterium (
      • Yeh N.L.
      • Hsu C.Y.
      • Tsai T.F.
      • Chiu H.Y.
      Gut microbiome in psoriasis is perturbed differently during secukinumab and ustekinumab therapy and associated with response to treatment.
      ). However, there was no difference in the gut microbiome between responders and nonresponders to ustekinumab (
      • Yeh N.L.
      • Hsu C.Y.
      • Tsai T.F.
      • Chiu H.Y.
      Gut microbiome in psoriasis is perturbed differently during secukinumab and ustekinumab therapy and associated with response to treatment.
      ).
      Not surprisingly, the microbiome is now a prime target for novel therapeutics. Already, clinical trials are investigating the efficacy of probiotic supplements for the treatment of PsO. One double-blinded, placebo-controlled clinical trial did not find any significant clinical improvement in PsV with a probiotic containing Lactobacillus (
      • Kaur M.
      • Conde J.
      • Willard J.D.
      • Taylor S.
      • Camacho F.
      • Fleischer A.B.
      • et al.
      A randomized, double-blind clinical trial of a probiotic nutritional intervention in the treatment of mild to moderate non-scalp psoriasis.
      ). However, a different study found that patients with PsV who received an oral probiotic cocktail were more likely to achieve PASI-75 at 12 weeks (
      • Navarro-López V.
      • Martínez-Andrés A.
      • Ramírez-Boscá A.
      • Ruzafa-Costas B.
      • Núñez-Delegido E.
      • Carrión-Gutiérrez M.A.
      • et al.
      Efficacy and safety of oral administration of a mixture of probiotic strains in patients with psoriasis: a randomized controlled clinical trial.
      ). Oral supplements of Bifidobacterium infantis have also been found to reduce serum levels of TNF-α and CRP in patients with PsV (
      • Groeger D.
      • O’Mahony L.
      • Murphy E.F.
      • Bourke J.F.
      • Dinan T.G.
      • Kiely B.
      • et al.
      Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut.
      ). Intriguingly, a recent case report described a patient who developed sustained remission of her PsA after undergoing fecal microbiota transplantation (FMT) for a Clostridium difficile infection (
      • Selvanderan S.P.
      • Goldblatt F.
      • Nguyen N.Q.
      • Costello S.P.
      Faecal microbiota transplantation for Clostridium difficile infection resulting in a decrease in psoriatic arthritis disease activity.
      ). The therapeutic efficacy of FMT in patients with PsA is now under investigation through a double-blind, randomized, placebo-controlled trial (
      • Kragsnaes M.S.
      • Kjeldsen J.
      • Horn H.C.
      • Munk H.L.
      • Pedersen F.M.
      • Holt H.M.
      • et al.
      Efficacy and safety of faecal microbiota transplantation in patients with psoriatic arthritis: protocol for a 6-month, double-blind, randomised, placebo-controlled trial.
      ).

      The immunology of PsO and PsA

      Data from GWAS and other preclinical studies suggest that although certain immunopathogenic mechanisms may be shared, there are likely also tissue-specific microenvironmental factors that contribute to the phenotypic heterogeneity of PsO and PsA. The IL-23/IL-17 axis is common to the pathogenesis of both cutaneous PsO, PsA, and enthesitis (
      • Iwakura Y.
      • Ishigame H.
      The IL-23/IL-17 axis in inflammation.
      ;
      • Sherlock J.P.
      • Joyce-Shaikh B.
      • Turner S.P.
      • Chao C.C.
      • Sathe M.
      • Grein J.
      • et al.
      IL-23 induces spondyloarthropathy by acting on ROR-γ+ CD3+CD4-CD8- entheseal resident T cells.
      ). Binding of IL-23 to the heterodimeric IL-23R/IL-12Rβ1 receptor activates Tyk2- and Jak2-dependent signal transducer and activator of transcription 3 signaling, which promotes the expansion of Th17 and Tc17 cells that secrete IL-17A, IL-17F, and TNF (
      • Hile G.
      • Kahlenberg J.M.
      • Gudjonsson J.E.
      Recent genetic advances in innate immunity of psoriatic arthritis.
      ). Components of innate immunity also facilitate the inflammatory cascade in cutaneous PsO and PsA in which plasmacytoid and conventional DCs are activated in the skin (
      • Nestle F.O.
      • Conrad C.
      • Tun-Kyi A.
      • Homey B.
      • Gombert M.
      • Boyman O.
      • et al.
      Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production.
      ) and synovial fluid (
      • Penkava F.
      • Velasco-Herrera M.D.C.
      • Young M.D.
      • Yager N.
      • Nwosu L.N.
      • Pratt A.G.
      • et al.
      Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis.
      ), respectively, and produce inflammatory cytokines, including IL-23, to facilitate the priming and proliferation of Th17 and Tc17 cells. Antimicrobial peptides, most notably cathelicidin (LL37), bind to self-DNA and stimulate plasmacytoid DCs through toll-like receptor (TLR) 9 or serve as autoantigen presented to T cells by HLA-C∗06:02. IL-17A can also be produced by group 3 innate lymphoid cells (ILCs) that are abundant in PsV and PsA (
      • Polese B.
      • Zhang H.
      • Thurairajah B.
      • King I.L.
      Innate lymphocytes in psoriasis.
      ;
      • Soare A.
      • Weber S.
      • Maul L.
      • Rauber S.
      • Gheorghiu A.M.
      • Luber M.
      • et al.
      Cutting edge: homeostasis of innate lymphoid cells is imbalanced in psoriatic arthritis.
      ).
      In addition to heightened proinflammatory signaling, PsO involves the suppression of anti-inflammatory pathways. Both PsO and PsA demonstrate decreased numbers of CD73+ Tregs (
      • Han L.
      • Sugiyama H.
      • Zhang Q.
      • Yan K.
      • Fang X.
      • McCormick T.S.
      • et al.
      Phenotypical analysis of ectoenzymes CD39/CD73 and adenosine receptor 2A in CD4+ CD25high Foxp3+ regulatory T-cells in psoriasis.
      ), expansion of dysfunctional RORγt+ Tregs with Th17 potential (
      • Liu Y.
      • Jarjour W.
      • Olsen N.
      • Zheng S.G.
      Traitor or warrior-Treg cells sneaking into the lesions of psoriatic arthritis.
      ;
      • Scher J.U.
      • Ogdie A.
      • Merola J.F.
      • Ritchlin C.
      Preventing psoriatic arthritis: focusing on patients with psoriasis at increased risk of transition.
      ), and decreased levels of the anti-inflammatory cytokine IL-38 (
      • Mercurio L.
      • Morelli M.
      • Scarponi C.
      • Eisenmesser E.Z.
      • Doti N.
      • Pagnanelli G.
      • et al.
      IL-38 has an anti-inflammatory action in psoriasis and its expression correlates with disease severity and therapeutic response to anti-IL-17A treatment.
      ) and reduction in ILC2s (
      • Soare A.
      • Weber S.
      • Maul L.
      • Rauber S.
      • Gheorghiu A.M.
      • Luber M.
      • et al.
      Cutting edge: homeostasis of innate lymphoid cells is imbalanced in psoriatic arthritis.
      ).
      Differences in tissue-specific cues result in the activation of unique pathogenic pathways in the skin and synovium. In the skin, IL-17 and IL-22 stimulate KC hyperplasia as well as CXCL8-dependent neutrophil recruitment and microabscess formation (
      • Liang Y.
      • Sarkar M.K.
      • Tsoi L.C.
      • Gudjonsson J.E.
      Psoriasis: a mixed autoimmune and autoinflammatory disease.
      ). In the joints, local inflammatory cytokines and GFs promote osteoclast‒osteoblast decoupling and RANKL-mediated destructive bone remodeling in PsA (
      • Paine A.
      • Ritchlin C.
      Altered bone remodeling in psoriatic disease: new insights and future directions.
      ). Chronic psoriatic inflammation also upregulates Wnt signaling (RUNX1, FUT8, and CTNNAL1) (
      • Patrick M.T.
      • Stuart P.E.
      • Raja K.
      • Chi S.
      • He Z.
      • Voorhees J.J.
      • et al.
      Integrative approach to reveal cell type specificity and gene candidates for psoriatic arthritis outside the MHC.
      ) in the osteoblasts of patients with PsA. A recent study utilizing an in vitro cell culture system to mimic the local inflammatory microenvironment of bone-forming sites validated the link between Wnt signaling and inflammation, establishing that constitutive low-intensity stimulation with TNF induces persistent expression of Wnt proteins, causing increased bone formation through NF-κB signaling (
      • Li X.
      • Wang J.
      • Zhan Z.
      • Li S.
      • Zheng Z.
      • Wang T.
      • et al.
      Inflammation intensity-dependent expression of osteoinductive Wnt proteins is critical for ectopic new bone formation in ankylosing spondylitis.
      ). Furthermore, binding of osteoclast-derived RANK to osteoblastic RANKL leads to the activation of RUNX2, which mediates bone remodeling and bone formation in Rankl-mutant mice (
      • Ikebuchi Y.
      • Aoki S.
      • Honma M.
      • Hayashi M.
      • Sugamori Y.
      • Khan M.
      • et al.
      Coupling of bone resorption and formation by RANKL reverse signalling.
      ).
      Locally presented antigens are another element of the immune microenvironment that may play a key role in psoriatic inflammation. In PsV, a large proportion of cutaneous CD8+ T cells is oligoclonal, with the oligoclonality usually confined to lesional skin. To date, putative autoantigens in PsO include LL-37, ADAMTSL5 (
      • Fuentes-Duculan J.
      • Bonifacio K.M.
      • Hawkes J.E.
      • Kunjravia N.
      • Cueto I.
      • Li X.
      • et al.
      Autoantigens ADAMTSL5 and LL37 are significantly upregulated in active psoriasis and localized with keratinocytes, dendritic cells and other leukocytes.
      ;
      • Yuan Y.
      • Qiu J.
      • Lin Z.T.
      • Li W.
      • Haley C.
      • Mui U.N.
      • et al.
      Identification of novel autoantibodies associated with psoriatic arthritis.
      ); keratin gene, K17, (
      • Yunusbaeva M.
      • Valiev R.
      • Bilalov F.
      • Sultanova Z.
      • Sharipova L.
      • Yunusbayev B.
      Psoriasis patients demonstrate HLA-Cw∗06:02 allele dosage-dependent T cell proliferation when treated with hair follicle-derived keratin 17 protein.
      ); and neolipids generated by PLA2G4D (
      • Cheung K.L.
      • Jarrett R.
      • Subramaniam S.
      • Salimi M.
      • Gutowska-Owsiak D.
      • Chen Y.L.
      • et al.
      Psoriatic T cells recognize neolipid antigens generated by mast cell phospholipase delivered by exosomes and presented by CD1a.
      ).

      Mouse models of PsO and PsA

      Preclinical mouse models are a valuable tool for investigating the pathogenic role of pathways, genes, or transcripts identified in genetic analyses and other studies. These approaches model one or more components of human PsO, but none to date replicate the disease in its full complexity. Mouse models of PsO can be broadly classified as spontaneous, xenotransplants, induced/acute, and genetically engineered (reviewed in
      • Gudjonsson J.E.
      • Johnston A.
      • Dyson M.
      • Valdimarsson H.
      • Elder J.T.
      Mouse models of psoriasis.
      and
      • Schön M.P.
      • Manzke V.
      • Erpenbeck L.
      Animal models of psoriasis-highlights and drawbacks.
      ). The first models of PsO involved spontaneous gene mutations in Scd, Sharpin, or Ttc resulting in a flakey skin phenotype (
      • Gates A.H.
      • Karasek M.
      Hereditary absence of sebaceous glands in the mouse.
      ;
      • HogenEsch H.
      • Gijbels M.J.
      • Offerman E.
      • van Hooft J.
      • van Bekkum D.W.
      • Zurcher C.
      A spontaneous mutation characterized by chronic proliferative dermatitis in C57BL mice.
      ;
      • Sundberg J.P.
      • Boggess D.
      • Shultz L.D.
      • Beamer W.G.
      The Flaky Skin (fsn) mutation chromosome?.
      ). However, the use of these models was limited because they lacked T-cell infiltration.
      Other early approaches used grafts of uninvolved skin from patients with PsO onto immunodeficient mice (athymic nude, AGR), which triggered a conversion into a psoriatic plaque (
      • Boyman O.
      • Hefti H.P.
      • Conrad C.
      • Nickoloff B.J.
      • Suter M.
      • Nestle F.O.
      Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha.
      ;
      • Fraki J.E.
      • Briggaman R.A.
      • Lazarus G.S.
      Uninvolved skin from psoriatic patients develops signs of involved psoriatic skin after being grafted onto nude mice.
      ;
      • Krueger G.G.
      • Chambers D.A.
      • Shelby J.
      Involved and uninvolved skin from psoriatic subjects: are they equally diseased? Assessment by skin transplanted to congenitally athymic (nude) mice.
      ). Xenografts and ex vivo PsO skin explants (
      • Billi A.C.
      • Ludwig J.E.
      • Fritz Y.
      • Rozic R.
      • Swindell W.R.
      • Tsoi L.C.
      • et al.
      KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease.
      ;
      • Ward N.L.
      • Bhagathavula N.
      • Johnston A.
      • Dawes S.M.
      • Fu W.
      • Lambert S.
      • et al.
      Erlotinib-induced skin inflammation is IL-1 mediated in KC-Tie2 mice and human skin organ culture.
      ) are the most translatable approach for studying treatment efficacy and the role of skin-resident versus that of circulating immune cells. However, developing them is challenging, as they require full-thickness patient skin, and some of them require autologous activated T cells (
      • Nickoloff B.J.
      • Wrone-Smith T.
      Injection of pre-psoriatic skin with CD4+ T cells induces psoriasis.
      ).
      The most widely used model involves topical application of IMQ, a TLR7 agonist. Since 2009 (
      • van der Fits L.
      • Mourits S.
      • Voerman J.S.
      • Kant M.
      • Boon L.
      • Laman J.D.
      • et al.
      Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.
      ), over 600 publications have used this approach and interpreted their findings, often incorrectly, as critical for PsO pathogenesis (
      • Hawkes J.E.
      • Gudjonsson J.E.
      • Ward N.L.
      The snowballing literature on imiquimod-induced skin inflammation in mice: a critical appraisal.
      ). However, nonlesional skin from patients with PsV treated with IMQ has different transcriptomic signatures from those of lesional skin, suggesting that IMQ models recapitulate only limited aspects of PsO (
      • Vinter H.
      • Iversen L.
      • Steiniche T.
      • Kragballe K.
      • Johansen C.
      Aldara®-induced skin inflammation: studies of patients with psoriasis.
      ).
      Investigators have also studied the effects of cytokines through intradermal injections of IL-17C (
      • Ramirez-Carrozzi V.
      • Sambandam A.
      • Luis E.
      • Lin Z.
      • Jeet S.
      • Lesch J.
      • et al.
      IL-17C regulates the innate immune function of epithelial cells in an autocrine manner.
      ), IL-17A (
      • Vasseur P.
      • Serres L.
      • Jégou J.F.
      • Pohin M.
      • Delwail A.
      • Petit-Paris I.
      • et al.
      High-fat diet-induced IL-17A exacerbates psoriasiform dermatitis in a mouse model of steatohepatitis.
      ), IL-36 (
      • Foster A.M.
      • Baliwag J.
      • Chen C.S.
      • Guzman A.M.
      • Stoll S.W.
      • Gudjonsson J.E.
      • et al.
      IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin.
      ), IL-21 (
      • Caruso R.
      • Botti E.
      • Sarra M.
      • Esposito M.
      • Stolfi C.
      • Diluvio L.
      • et al.
      Involvement of interleukin-21 in the epidermal hyperplasia of psoriasis.
      ), and IL-23 (
      • Chan J.R.
      • Blumenschein W.
      • Murphy E.
      • Diveu C.
      • Wiekowski M.
      • Abbondanzo S.
      • et al.
      IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis.
      ), either alone or in combination (
      • Guilloteau K.
      • Paris I.
      • Pedretti N.
      • Boniface K.
      • Juchaux F.
      • Huguier V.
      • et al.
      Skin inflammation induced by the synergistic action of IL-17A, IL-22, oncostatin M, IL-1{alpha}, and TNF-{alpha} recapitulates some features of psoriasis.
      ). These models reproduce some features of PsO and provide insight into the pathogenic role of individual cytokines and their synergistic effects. However, the need for repeated injections limits their utility for long-term study. The development of novel DNA minicircles allowing for sustained transgenic expression of IL-23 (
      • Sherlock J.P.
      • Joyce-Shaikh B.
      • Turner S.P.
      • Chao C.C.
      • Sathe M.
      • Grein J.
      • et al.
      IL-23 induces spondyloarthropathy by acting on ROR-γ+ CD3+CD4-CD8- entheseal resident T cells.
      ) reproduces chronic psoriasiform skin inflammation, enthesitis, arthritis, and vascular inflammation in mice, providing an innovative model for studying psoriatic comorbidities.
      Recently, advances in genetic engineering have led to the development of transgenic and knockout animal models, which have provided novel insights into PsO. For example, the CD18 hypomorphic model (CD18hypo PL/J background; CD18[Itgb2tm1Bay]) helped to define the role of skin-infiltrating T cells (
      • Bullard D.C.
      • Scharffetter-Kochanek K.
      • McArthur M.J.
      • Chosay J.G.
      • McBride M.E.
      • Montgomery C.A.
      • et al.
      A polygenic mouse model of psoriasiform skin disease in CD18-deficient mice.
      ) and TNF-α‒producing macrophages (
      • Wang H.
      • Peters T.
      • Sindrilaru A.
      • Scharffetter-Kochanek K.
      Key role of macrophages in the pathogenesis of CD18 hypomorphic murine model of psoriasis.
      ).
      The growing interest in KCs and their derived factors resulted in an influx of KC-specific transgenic models: VEGF-A (
      • Kunstfeld R.
      • Hirakawa S.
      • Hong Y.K.
      • Schacht V.
      • Lange-Asschenfeldt B.
      • Velasco P.
      • et al.
      Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia.
      ;
      • Xia Y.P.
      • Li B.
      • Hylton D.
      • Detmar M.
      • Yancopoulos G.D.
      • Rudge J.S.
      Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis.
      ), TGF-β1 (
      • Li A.G.
      • Wang D.
      • Feng X.H.
      • Wang X.J.
      Latent TGFbeta1 overexpression in keratinocytes results in a severe psoriasis-like skin disorder.
      ), IL-17C (
      • Johnston A.
      • Fritz Y.
      • Dawes S.M.
      • Diaconu D.
      • Al-Attar P.M.
      • Guzman A.M.
      • et al.
      Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation.
      ), ectopic Tie2 (
      • Wolfram J.A.
      • Diaconu D.
      • Hatala D.A.
      • Rastegar J.
      • Knutsen D.A.
      • Lowther A.
      • et al.
      Keratinocyte but not endothelial cell-specific overexpression of Tie2 leads to the development of psoriasis.
      ), and IL-17A (
      • Karbach S.
      • Croxford A.L.
      • Oelze M.
      • Schüler R.
      • Minwegen D.
      • Wegner J.
      • et al.
      Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease.
      ), all resulted in flakey skin phenotypes. The Tie2, IL-17A, and IL-17C models also developed CVD, including vascular inflammation (
      • Karbach S.
      • Croxford A.L.
      • Oelze M.
      • Schüler R.
      • Minwegen D.
      • Wegner J.
      • et al.
      Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease.
      ;
      • Schüler R.
      • Brand A.
      • Klebow S.
      • Wild J.
      • Veras F.P.
      • Ullmann E.
      • et al.
      Antagonization of IL-17A attenuates skin inflammation and vascular dysfunction in mouse models of psoriasis.
      ;
      • Wang H.
      • Peters T.
      • Sindrilaru A.
      • Scharffetter-Kochanek K.
      Key role of macrophages in the pathogenesis of CD18 hypomorphic murine model of psoriasis.
      ) and thrombosis (
      • Golden J.B.
      • Groft S.G.
      • Squeri M.V.
      • Debanne S.M.
      • Ward N.L.
      • McCormick T.S.
      • et al.
      Chronic psoriatic skin inflammation leads to increased monocyte adhesion and aggregation.
      ;
      • Wang Y.
      • Golden J.B.
      • Fritz Y.
      • Zhang X.
      • Diaconu D.
      • Camhi M.I.
      • et al.
      Interleukin 6 regulates psoriasiform inflammation-associated thrombosis.
      ), which are also seen in patients with PsO (
      • Gelfand J.M.
      • Neimann A.L.
      • Shin D.B.
      • Wang X.
      • Margolis D.J.
      • Troxel A.B.
      Risk of myocardial infarction in patients with psoriasis.
      ). These models will be helpful in identifying the cellular mechanisms underlying CVD comorbidities.
      The newest murine model of PsO overexpresses a serine protease called kallikrein 6 (KLK6). Klk6 mice (Klk6+) develop severe psoriasiform dermatitis and arthritis that are Klk6- and PAR1- (F2R) dependent (
      • Billi A.C.
      • Ludwig J.E.
      • Fritz Y.
      • Rozic R.
      • Swindell W.R.
      • Tsoi L.C.
      • et al.
      KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease.
      ). Other models develop PsA-like disease, including KC overexpression of constitutively active Stat3c (
      • Yamamoto M.
      • Nakajima K.
      • Takaishi M.
      • Kitaba S.
      • Magata Y.
      • Kataoka S.
      • et al.
      Psoriatic inflammation facilitates the onset of arthritis in a mouse model.
      ), Rac1 (
      • Winge M.C.G.
      • Marinkovich M.P.
      Epidermal activation of the small GTPase Rac1 in psoriasis pathogenesis.
      ), and Il17a (
      • Croxford A.L.
      • Karbach S.
      • Kurschus F.C.
      • Wörtge S.
      • Nikolaev A.
      • Yogev N.
      • et al.
      IL-6 regulates neutrophil microabscess formation in IL-17A-driven psoriasiform lesions.
      ) and KC deletion of JunB/c-Jun (
      • Uluçkan Ö.
      • Jimenez M.
      • Karbach S.
      • Jeschke A.
      • Graña O.
      • Keller J.
      • et al.
      Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts.
      ;
      • Zenz R.
      • Eferl R.
      • Kenner L.
      • Florin L.
      • Hummerich L.
      • Mehic D.
      • et al.
      Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins.
      ). These models demonstrate how epidermal factors can cause arthritis.

      Precision medicine

      Although major advances in the treatment of PsO have been made over the last few decades, many patients are treatment refractory, especially those with PsA (
      • Ritchlin C.
      • Scher J.U.
      Strategies to improve outcomes in psoriatic arthritis.
      ), and achieving long-term remission remains a significant challenge. Precision medicine can be used to address these gaps in care by tailoring treatment on the basis of individual patient characteristics.
      Clinical features, serologic factors, and omics datasets can help us classify patients into subpopulations on the basis of their likelihood to respond to a specific therapy or their probability of developing systemic comorbidities (
      • van Vugt L.J.
      • van den Reek J.M.P.A.
      • Coenen M.J.H.
      • dejong E.M.G.J.
      A systematic review of pharmacogenetic studies on the response to biologics in patients with psoriasis.
      ). For example, patients with nail and scalp involvement have a higher likelihood of developing PsA (
      • Scher J.U.
      • Ogdie A.
      • Merola J.F.
      • Ritchlin C.
      Preventing psoriatic arthritis: focusing on patients with psoriasis at increased risk of transition.
      ;
      • Wilson F.C.
      • Icen M.
      • Crowson C.S.
      • McEvoy M.T.
      • Gabriel S.E.
      • Kremers H.M.
      Incidence and clinical predictors of psoriatic arthritis in patients with psoriasis: a population-based study.
      ). Factors such as therapeutic levels and neutralizing antidrug antibody levels can also help to guide clinicians when assessing the initial response and sustained efficacy of a drug (
      • Loeff F.C.
      • Tsakok T.
      • Dijk L.
      • Hart M.H.
      • Duckworth M.
      • Baudry D.
      • et al.
      Clinical impact of antibodies against ustekinumab in psoriasis: an observational, cross-sectional, multicenter study.
      ;
      • Pan S.
      • Tsakok T.
      • Dand N.
      • Lonsdale D.O.
      • Loeff F.C.
      • Bloem K.
      • et al.
      Using real-world data to guide ustekinumab dosing strategies for psoriasis: a prospective pharmacokinetic-pharmacodynamic study.
      ;
      • Tsakok T.
      • Wilson N.
      • Dand N.
      • Loeff F.C.
      • Bloem K.
      • Baudry D.
      • et al.
      Association of serum ustekinumab levels with clinical response in psoriasis.
      ). However, in the near future, clinicians will be able to utilize more sophisticated approaches that integrate clinical phenotypic data with predictive or diagnostic classifiers constructed from omic datasets, such as for the transcriptome (
      • Le S.T.
      • Merleev A.A.
      • Luxardi G.
      • Shimoda M.
      • Adamopoulos I.E.
      • Tsoi L.C.
      • et al.
      2D visualization of the psoriasis transcriptome fails to support the existence of dual-secreting IL-17A/IL-22 Th17 T cells.
      ;
      • Li B.
      • Tsoi L.C.
      • Swindell W.R.
      • Gudjonsson J.E.
      • Tejasvi T.
      • Johnston A.
      • et al.
      Transcriptome analysis of psoriasis in a large case-control sample: RNA-seq provides insights into disease mechanisms.
      ;
      • Merleev A.A.
      • Marusina A.I.
      • Ma C.
      • Elder J.T.
      • Tsoi L.C.
      • Raychaudhuri S.P.
      • et al.
      Meta-analysis of RNA sequencing datasets reveals an association between TRAJ23, psoriasis, and IL-17A.
      ;
      • Tsoi L.C.
      • Rodriguez E.
      • Degenhardt F.
      • Baurecht H.
      • Wehkamp U.
      • Volks N.
      • et al.
      Atopic dermatitis is an IL-13-dominant disease with greater molecular heterogeneity compared with psoriasis.
      ), genome (Supplementary Table S1), microbiome (Supplementary Table S1), lipidome (
      • Sorokin A.V.
      • Domenichiello A.F.
      • Dey A.K.
      • Yuan Z.X.
      • Goyal A.
      • Rose S.M.
      • et al.
      Bioactive lipid mediator profiles in human psoriasis skin and blood.
      ;
      • Zeng C.
      • Wen B.
      • Hou G.
      • Lei L.
      • Mei Z.
      • Jia X.
      • et al.
      Lipidomics profiling reveals the role of glycerophospholipid metabolism in psoriasis.
      ), glycome (
      • Li Q.
      • Kailemia M.J.
      • Merleev A.A.
      • Xu G.
      • Serie D.
      • Danan L.M.
      • et al.
      Site-specific glycosylation quantitation of 50 serum glycoproteins enhanced by predictive Glycopeptidomics for improved disease biomarker discovery.
      ;
      • Maverakis E.
      • Kim K.
      • Shimoda M.
      • Gershwin M.E.
      • Patel F.
      • Wilken R.
      • et al.
      Glycans in the immune system and the altered glycan theory of autoimmunity: a critical review.
      ;
      • Park D.D.
      • Xu G.
      • Wong M.
      • Phoomak C.
      • Liu M.
      • Haigh N.E.
      • et al.
      Membrane glycomics reveal heterogeneity and quantitative distribution of cell surface sialylation.
      ), proteome (
      • Broome A.M.
      • Ryan D.
      • Eckert R.L.
      S100 protein subcellular localization during epidermal differentiation and psoriasis.
      ;
      • Carlén L.M.
      • Sánchez F.
      • Bergman A.C.
      • Becker S.
      • Hirschberg D.
      • Franzén B.
      • et al.
      Proteome analysis of skin distinguishes acute guttate from chronic plaque psoriasis.
      ), and metabolome (
      • Alonso A.
      • Julià A.
      • Vinaixa M.
      • Domènech E.
      • Fernández-Nebro A.
      • Cañete J.D.
      • et al.
      Urine metabolome profiling of immune-mediated inflammatory diseases.
      ;
      • Kamleh M.A.
      • Snowden S.G.
      • Grapov D.
      • Blackburn G.J.
      • Watson D.G.
      • Xu N.
      • et al.
      LC-MS metabolomics of psoriasis patients reveals disease severity-dependent increases in circulating amino acids that are ameliorated by anti-TNFalpha treatment.
      ;
      • Zeng C.
      • Wen B.
      • Hou G.
      • Lei L.
      • Mei Z.
      • Jia X.
      • et al.
      Lipidomics profiling reveals the role of glycerophospholipid metabolism in psoriasis.
      ). Recent technologies such as single-cell RNA sequencing have begun to identify novel cell subsets in the skin and synovium (
      • Cheng J.B.
      • Sedgewick A.J.
      • Finnegan A.I.
      • Harirchian P.
      • Lee J.
      • Kwon S.
      • et al.
      Transcriptional programming of normal and inflamed human epidermis at single-cell resolution.
      ;
      • Croft A.P.
      • Campos J.
      • Jansen K.
      • Turner J.D.
      • Marshall J.
      • Attar M.
      • et al.
      Distinct fibroblast subsets drive inflammation and damage in arthritis.
      ;
      • Liu J.
      • Chang H.W.
      • Huang Z.M.
      • Nakamura M.
      • Sekhon S.
      • Ahn R.
      • et al.
      Single-cell RNA sequencing of psoriatic skin identifies pathogenic Tc17 cell subsets and reveals distinctions between CD8+ T cells in autoimmunity and cancer [e-pub ahead of print].
      ;
      • Orange D.E.
      • Agius P.
      • DiCarlo E.F.
      • Robine N.
      • Geiger H.
      • Szymonifka J.
      • et al.
      Identification of three rheumatoid arthritis disease subtypes by machine learning integration of synovial histologic features and RNA sequencing data.
      ;
      • Stephenson W.
      • Donlin L.T.
      • Butler A.
      • Rozo C.
      • Bracken B.
      • Rashidfarrokhi A.
      • et al.
      Single-cell RNA-seq of rheumatoid arthritis synovial tissue using low-cost microfluidic instrumentation.
      ). Already, some promising biomarkers and predictive models are starting to emerge (Supplementary Table S2).
      Further advancements in omic datasets will give rise to more precise clinically relevant PsO models in the future. Complementing these technologies are the advances driven by big data analysis and machine learning, which has been applied to improve the diagnostic accuracy of tissue pathology (
      • Correa da Rosa J.
      • Kim J.
      • Tian S.
      • Tomalin L.E.
      • Krueger J.G.
      • Suárez-Fariñas M.
      Shrinking the psoriasis assessment gap: early gene-expression profiling accurately predicts response to long-term treatment.
      ;
      • Emam S.
      • Du A.X.
      • Surmanowicz P.
      • Thomsen S.F.
      • Greiner R.
      • Gniadecki R.
      Predicting the long-term outcomes of biologics in patients with psoriasis using machine learning.
      ;
      • Foulkes A.C.
      • Watson D.S.
      • Carr D.F.
      • Kenny J.G.
      • Slidel T.
      • Parslew R.
      • et al.
      A framework for multi-omic prediction of treatment response to biologic therapy for psoriasis.
      ;
      • Orange D.E.
      • Agius P.
      • DiCarlo E.F.
      • Robine N.
      • Geiger H.
      • Szymonifka J.
      • et al.
      Identification of three rheumatoid arthritis disease subtypes by machine learning integration of synovial histologic features and RNA sequencing data.
      ;
      • Tomalin L.E.
      • Kim J.
      • Correa da Rosa J.
      • Lee J.
      • Fitz L.J.
      • Berstein G.
      • et al.
      Early quantification of systemic inflammatory proteins predicts long-term treatment response to tofacitinib and etanercept.
      ;
      • Zhang F.
      • Wei K.
      • Slowikowski K.
      • Fonseka C.Y.
      • Rao D.A.
      • Kelly S.
      • et al.
      Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry.
      ). The last critical element is to improve the high throughput capture of multimodal clinical data from the electronic medical record, a major requirement in the development of precision medicine (
      • Haendel M.A.
      • Chute C.G.
      • Robinson P.N.
      Classification, ontology, and precision medicine.
      ).

      Conclusion

      The latest developments in psoriatic research suggest that a multitude of interconnected factors is responsible for the heterogeneous presentation of psoriatic disease (Figure 1). Numerous genetic variants and the interactions occurring in the microenvironment between immune cells, KCs, osteoclasts, and the microbiome determine the development of psoriatic disease, disease severity, therapeutic response, and the development of comorbidities such as inflammatory arthritis and cardiometabolic conditions. These advances have not only revealed novel therapeutic targets but also provide data to optimize treatment for the individual patient. The next frontier lies in harnessing this information in the clinical setting to deliver more timely, effective, and personalized care.
      Figure thumbnail gr1
      Figure 1The multifactorial pathogenesis of psoriatic disease. The development of psoriasis and psoriatic arthritis is influenced by a combination of genetic risk loci (red), many of which are involved in the regulation of IL-23 receptor signaling and the NF-kB pathway, imbalances in Treg/T17 immunity (blue), as well as changes in the gut and cutaneous microbiome (yellow). Heather McDonald, BioSerendipity, LLC (Elkridge, MD) assisted with the illustration. KLK6, kallikrein 6; MCFA, medium-chain fatty acid; SCFA, short-chain fatty acid; STAT, signal transducer and activator of transcription; Th, T helper; Treg, regulatory T cell.
      Illustration assistance provided by Heather McDonald, BioSerendipity, LLC, Elkridge, MD.

      ORCIDs

      Conflict of Interest

      JEG has received grant support from AbbVie, Almirall, Bristol-Myers Squibb/Celgene Novartis, Eli Lilly, and Kyowa-Kirin and served as an advisor to Almirall, Novartis, Eli Lilly, and AnaptysBio. JUS has consulted for AbbVie, Janssen, Novartis, Sanofi, Eli Lilly, UCB, Amgen, and Pfizer and received research grant support from Pfizer and Amgen. WL has received research grant support from AbbVie, Amgen, Janssen Pharmaceuticals, Novartis, Pfizer, Regeneron, and TRex Bio. SB is an employee of the National Psoriasis Foundation. The remaining authors state no conflict of interest.

      Acknowledgments

      The authors would like to thank Jerry Bagel, Jackie Domire, Joel Gelfand, George Gondo, Alice Gottlieb, Samantha Koons, and Gil Yosipovitch for the review of the manuscript. DY is supported by a grant from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. JEG is supported by P30-AR075043 and R01-AR060802. OP is supported by T32 AR007197. JUS is supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institute of Health (NIH) (R01AR074500), the Snyder Family Foundation, the Riley Family Foundation, and the National Psoriasis Foundation. NLW is supported by the following awards from the NIH: R01-AR073196, P50-AR070590, and R01-AR069071. CR is supported by a grant from the NIH (R01 AR0609000). WL is supported by grants from the NIH U01-AI119125 and the National Psoriasis Foundation.

      Author Contributions

      Conceptualization: WL, JEG, SB; Data Curation: DY, JEG, SL, EM, OP, CR, JUS, RS, NLW, SB, WL; Writing - Original Draft Preparation: DY, JEG, SL, EM, OP, CR, JUS, RS, NLW, SB, WL; Writing - Review and Editing: DY, SB, JEG, WL

      Supplementary Material

      Supplementary Table S1Differences in the Skin and Gut Microbiome Composition in Patients with PsV, Patients with PsA, and Healthy Controls
      Cutaneous Microbiome (PsV vs. Healthy Controls)
      StudyPropionibacteriumStaphylococcusStreptococcus
      • Alekseyenko A.V.
      • Perez-Perez G.I.
      • De Souza A.
      • Strober B.
      • Gao Z.
      • Bihan M.
      • et al.
      Community differentiation of the cutaneous microbiota in psoriasis.
      NS
      Nonsignificantly different between PsV or PsA and healthy controls.
      • Chang H.W.
      • Yan D.
      • Singh R.
      • Liu J.
      • Lu X.
      • Ucmak D.
      • et al.
      Alteration of the cutaneous microbiome in psoriasis and potential role in Th17 polarization.
      NS
      • Drago L.
      • De Grandi R.
      • Altomare G.
      • Pigatto P.
      • Rossi O.
      • Toscano M.
      Skin microbiota of first cousins affected by psoriasis and atopic dermatitis.
      S. aureus
      • Fahlén A.
      • Engstrand L.
      • Baker B.S.
      • Powles A.
      • Fry L.
      Comparison of bacterial microbiota in skin biopsies from normal and psoriatic skin.
      ↓ (trend)
      This study reported a significant increase in the Streptococcus-to-Propionibacterium ratio between PsV skin and healthy controls but did not report the significance of the difference in Streptococcus abundance on its own.
      • Fyhrquist N.
      • Muirhead G.
      • Prast-Nielsen S.
      • Jeanmougin M.
      • Olah P.
      • Skoog T.
      • et al.
      Microbe-host interplay in atopic dermatitis and psoriasis.
      NSNS
      • Gao Z.
      • Tseng C.H.
      • Strober B.E.
      • Pei Z.
      • Blaser M.J.
      Substantial alterations of the cutaneous bacterial biota in psoriatic lesions.
      NS
      • Langan E.A.
      • Künstner A.
      • Miodovnik M.
      • Zillikens D.
      • Thaçi D.
      • Baines J.F.
      • et al.
      Combined culture and metagenomic analyses reveal significant shifts in the composition of the cutaneous microbiome in psoriasis.
      NS
      • Quan C.
      • Chen X.Y.
      • Li X.
      • Xue F.
      • Chen L.H.
      • Liu N.
      • et al.
      Psoriatic lesions are characterized by higher bacterial load and imbalance between Cutibacterium and Corynebacterium.
      NSNS
      • Tett A.
      • Pasolli E.
      • Farina S.
      • Truong D.T.
      • Asnicar F.
      • Zolfo M.
      • et al.
      Unexplored diversity and strain-level structure of the skin microbiome associated with psoriasis.
      Tett et al. (2017) compared the cutaneous microbiome composition in lesional PsV skin with that of the uninvolved skin, not that of healthy controls.
      NSNS
      Gut Microbiome (PsV vs. Healthy controls)
      StudyAkkermansiaRuminococcusBacteroidesFaecalibacterium prausnitzii
      • Chen Y.J.
      • Ho H.J.
      • Tseng C.H.
      • Lai Z.L.
      • Shieh J.J.
      • Wu C.Y.
      Intestinal microbiota profiling and predicted metabolic dysregulation in psoriasis patients.
      NSNS
      • Codoñer F.M.
      • Ramírez-Bosca A.
      • Climent E.
      • Carrión-Gutierrez M.
      • Guerrero M.
      • Pérez-Orquín J.M.
      • et al.
      Gut microbial composition in patients with psoriasis.
      • Eppinga H.
      • Sperna Weiland C.J.
      • Thio H.B.
      • van der Woude C.J.
      • Nijsten T.E.
      • Peppelenbosch M.P.
      • et al.
      Similar depletion of protective Faecalibacterium prausnitzii in psoriasis and inflammatory bowel disease, but not in hidradenitis suppurativa.
      NSNSNS
      • Hidalgo-Cantabrana C.
      • Gómez J.
      • Delgado S.
      • Requena-López S.
      • Queiro-Silva R.
      • Margolles A.
      • et al.
      Gut microbiota dysbiosis in a cohort of patients with psoriasis.
      NSNS
      • Shapiro J.
      • Cohen N.A.
      • Shalev V.
      • Uzan A.
      • Koren O.
      • Maharshak N.
      Psoriatic patients have a distinct structural and functional fecal microbiota compared with controls.
      NSNS
      • Tan L.
      • Zhao S.
      • Zhu W.
      • Wu L.
      • Li J.
      • Shen M.
      • et al.
      The Akkermansia muciniphila is a gut microbiota signature in psoriasis.
      NSNS
      Gut Microbiome (PsA vs. Healthy Controls)
      StudyAkkermansiaRuminococcusBacteroidesFaecalibacterium prausnitzii
      • Scher J.U.
      • Ubeda C.
      • Artacho A.
      • Attur M.
      • Isaac S.
      • Reddy S.M.
      • et al.
      Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease.
      NSNS
      Abbreviations: NS, not significant; PsA, psoriatic arthritis; PsV, psoriasis vulgaris.
      1 Nonsignificantly different between PsV or PsA and healthy controls.
      2 This study reported a significant increase in the Streptococcus-to-Propionibacterium ratio between PsV skin and healthy controls but did not report the significance of the difference in Streptococcus abundance on its own.
      3
      • Tett A.
      • Pasolli E.
      • Farina S.
      • Truong D.T.
      • Asnicar F.
      • Zolfo M.
      • et al.
      Unexplored diversity and strain-level structure of the skin microbiome associated with psoriasis.
      compared the cutaneous microbiome composition in lesional PsV skin with that of the uninvolved skin, not that of healthy controls.
      Supplementary Table S2Biomarkers of Psoriatic Disease that Were Found to be Associated with the Development of PsA, Disease Severity, and Therapeutic Response in Larger Patient Cohorts and Consortium Studies
      BiomarkerAssociationReferences
      Genetic markersA set of 200 genetic markers were able to predict the development of PsAwith an area under the curve of 0.82% and 100% specificity