Psoriasis is a chronic autoimmune skin disease affecting approximately 6.7 million adults in the United States.1 Although its pathogenesis is not yet clear, risk factors and triggers provide insight into potential pathways by which psoriasis can occur. There is notable overlap between risk factors and triggers of psoriasis; perceived risk factors might, in fact, be triggers causing manifestation of disease in predisposed persons. In this review, we summarize the key factors contributing to onset and exacerbation of psoriasis. When learning to manage this chronic disease, it also may be helpful to educate patients about how these elements may affect the course of psoriasis.
The pathogenesis of psoriasis has a strong genetic component, with approximately 70% and 20% concordance rates in monozygotic and dizygotic twins, respectively.2 Moreover, studies have shown a positive family history in approximately 35% of patients.3,4 Family-based studies have found a 50% risk of developing psoriasis in patients with 2 affected parents.5 However, the genetics of psoriasis are complex and are attributed to many different genes. Thus far, genes involving antigen presentation, T-cell receptor development and polarization, and the nuclear factor κβ (NF-κβ) pathway have been identified.6
The most well-studied gene implicated in psoriasis is HLA-Cw6, which encodes a major histocompatibility complex class I allele supporting psoriasis as a T cell–mediated reaction to an autoantigen.6 Two potential antigens for HLA-Cw6 recently have been identified: LL-37, a cathelicidin-related antimicrobial peptide, and the A disintegrin and metalloproteinase with thrombospondin motifs-like protein 5 (ADAMTSL5), found on melanocytes and keratinocytes.7 The percentage of psoriasis patients with HLA-Cw6 ranges from 10.5% to 77.2%, with higher frequency in white individuals than in Asians.7
HLA-Cw6 manifests as specific features in psoriasis, including onset of disease before 21 years of age.8 It also is more strongly associated with guttate-type psoriasis, greater body surface area involvement, and higher incidence of Köbner phenomenon. Patients with positive HLA-Cw6 also reported worsening of psoriasis during and after throat infection.9
Caspase Recruitment Domain Family Member 14
Another gene mutation implicated in psoriasis pathogenesis is caspase recruitment domain family member 14, CARD14 (formerly PSORS2), a gene encoding a scaffolding protein important in the activation of NF-κβ.10,11 Missense CARD14 mutations cause upregulation of NF-κβ through formation of a complex with adapter protein B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1),12 which, in turn, causes increased transcription of cytokines IL-8, C-C motif chemokine ligand 20 (CCL-20), and IL-36 gamma in the keratinocyte.13 Mutations in CARD14 alone lead to psoriasiform skin in mice through amplified activation of the IL-23/IL-17 axis.14,15 Patients with a mutation in a CARD14 variant (p.Arg820Trp) have demonstrated better response to tumor necrosis factor (TNF) inhibitors.16
Further characterization of the genetic pathogenesis of psoriasis might lead to better targeted therapies, including the possibility of MALT1 inhibitors as a treatment option.12