Psoriasis is a common, chronic inflammatory skin disease most often appearing in the form of well-demarcated, scaly plaques. These lesions highlight the fundamental processes underlying its pathogenesis, namely, inflammation and epidermal hyperproliferation. Both phenomena are considered consequences of an intimate interplay between the innate and the adaptive immune system. This concept is supported by results of genetic studies, pointing toward the signaling pathways of nuclear factor-κB, interferon-γ, and interleukin (IL)-23 as well as antigen presentation as central axes of the psoriatic inflammation. Efficacy of biologics targeting tumor necrosis factor-α, IL-23, or IL-17 provides further evidence in favor of this model.
Key points
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Psoriasis is characterized by the parallel appearance of epidermal hyperproliferation, inflammation, and angioneogenesis.
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Psoriasis is driven by an intimate interplay between the innate and the adaptive immune systems.
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The central axes of psoriatic inflammation comprise the nuclear factor-κB, interferon-γ, and interleukin (IL)-23 signaling pathways as well as antigen presentation.
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Biologic therapies targeting tumor necrosis factor-α, IL-23, or IL-17 are highly effective, underlining the clinical importance of these inflammatory mediators.
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Recent genetic and clinical observations allow differentiation of generalized pustular psoriasis as a distinct entity.
Introduction
Given the prevalence of around 2% in most populations studied so far, psoriasis is a common disease. In its most typical type, the disease manifests as well-demarcated, red, scaly plaques about the size of a palm. These lesions highlight already clinically the 2 pillars of its pathogenesis, namely epidermal hyperproliferation (scaling) and inflammation (infiltrated, red lesions; Fig. 1 ). Genetic analyses, particularly genome-wide association studies, identified key players in these processes, namely cells as well as mediators. Proof for their relevance in patients arises from the successful use of biologic drugs targeting these crucial components, resulting in unparalleled efficacy in relief of the signs and symptoms of psoriasis.
Noteworthy, pustular forms of psoriasis also exist. These forms do not respond to many of the drugs proven effective in chronic plaque-type psoriasis. Recent genetic studies suggest that at least generalized pustular psoriasis should be viewed as a distinct entity distinct from what formerly was regarded as “psoriasis.”
This review provides an overview of the etiology of psoriasis, followed by a more in-depth discussion of pathogenesis, the need to differentiate between “psoriasis” and “generalized pustular psoriasis,” and a discussion of the concept of “psoriatic disease” extending beyond the level of the skin.
Introduction
Given the prevalence of around 2% in most populations studied so far, psoriasis is a common disease. In its most typical type, the disease manifests as well-demarcated, red, scaly plaques about the size of a palm. These lesions highlight already clinically the 2 pillars of its pathogenesis, namely epidermal hyperproliferation (scaling) and inflammation (infiltrated, red lesions; Fig. 1 ). Genetic analyses, particularly genome-wide association studies, identified key players in these processes, namely cells as well as mediators. Proof for their relevance in patients arises from the successful use of biologic drugs targeting these crucial components, resulting in unparalleled efficacy in relief of the signs and symptoms of psoriasis.
Noteworthy, pustular forms of psoriasis also exist. These forms do not respond to many of the drugs proven effective in chronic plaque-type psoriasis. Recent genetic studies suggest that at least generalized pustular psoriasis should be viewed as a distinct entity distinct from what formerly was regarded as “psoriasis.”
This review provides an overview of the etiology of psoriasis, followed by a more in-depth discussion of pathogenesis, the need to differentiate between “psoriasis” and “generalized pustular psoriasis,” and a discussion of the concept of “psoriatic disease” extending beyond the level of the skin.
Etiology
Psoriasis is a multifactorial disease with extrinsic as well as intrinsic factors playing major roles, as evidenced by the so-called Koebner phenomenon: nonspecific—extrinsic—triggers induce the manifestation of typical psoriatic lesions locally in the skin of patients, intrinsically “set” to develop such lesions. In addition, numerous triggers for a general aggravation have been described. Among the factors known to induce or worsen psoriasis, are:
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Mild localized trauma, such as scratching, piercings, tattoos, sunburns, chemical irritants (“classical” Koebner phenomenon)
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Drugs, including β-blockers, lithium, antimalarials, and nonsteroidal antiinflammatory drugs
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HIV infection
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Streptococcal pharyngitis.
The climate in general and exposure to natural sun light in particular are discussed as additional extrinsic factors with clinically important impacts on disease activity. Some researchers suggest the ultraviolet index is of interest based on the known effects of weather patterns on cutaneous psoriasis and psoriatic arthritis, which both worsen during winter and improve during summer. Others reported a weak link between latitude and psoriasis prevalence, suggesting that other factors, or combinations of factors may also be important.
One factor of central importance is genetics. The importance of genetic factors is highlighted by the following observations:
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Population studies indicate a greater incidence of psoriasis among first- and second-degree relatives of patients than among the general population.
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Concordance rates between monozygotic twins are up to 3 times higher than among dizygotic twins.
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Patients with an early disease onset exhibit a more severe course and a positive family history, whereas patients with late-onset disease tend to experience a less severe presentation and course and often exhibit a negative family history.
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Although commonly in the order of 2%, the prevalence of psoriasis does differ among different ethnic groups. Ethnicities basically free of psoriasis comprise American Samoa and the Mapuche in Chile.
Psoriasis susceptibility loci
These studies point toward genetics as an important component in the etiology of psoriasis in general. Indeed, the first chromosomal locus associated with the risk of psoriasis was found on chromosome 6p several decades ago. Since then, most genome-wide linkage analyses have reproduced this association and suggested HLA-Cw6 to be the susceptibility allele within what is now called the psoriasis susceptibility locus 1 (PSORS1). To date, PSORS1 is still by far the most strongly associated locus with psoriasis, thought to account for around 50% of the heritability of the disease. Meanwhile, around 40 additional loci have been found to be associated with psoriasis ( Table 1 ). Many of the potentially corresponding genes point toward a central role of both the innate as well as the adaptive immune system. The importance of T cells in general and T helper (Th)17 lymphocytes in particular is underlined by variants in the genes encoding the interleukin (IL)-23 receptor and IL-12 as indicators of psoriasis risk.
| Gene | Protein Function | Pathway | Comment |
|---|---|---|---|
| TNFA1P3 | Inhibitor of TNF-α– induced NF-κB signaling | NF-κB signaling | TNF-α inhibitors are clinically effective in treating psoriasis |
| TNIP1 | Inhibitor of TNF-α–induced NF-κB signaling | NF-κB signaling | TNF-α inhibitors are clinically effective in treating psoriasis |
| IL28RA | IL-29 receptor subunit | IFN signaling | –– |
| IL12B | Shared subunit of IL-12 and IL-23 | IL-23 signaling | –– |
| IL23R | IL-23 receptor subunit | IL-23 signaling | –– |
| IL23A | IL-23 subunit | IL-23 signaling | Ustekinumab (inhibiting IL-12 and IL-23) and specific anti–IL-23 antibodies are clinically effective in treating psoriasis |
| PSORS1 (HLA-C) | HLA class I antigen | Antigen presentation | –– |
| ERAP1 | Peptidase processing HLA class I ligands | Antigen presentation | –– |
Pathogenesis
Psoriasis is currently widely regarded as an immune-mediated disease. As discussed, genome-wide association studies identified predominantly immune-related genes to be linked to psoriasis. Psoriatic plaques are thus considered to originate from dysregulated interactions of innate and adaptive components of the immune system with resident cells of the skin ( Fig. 2 ).
Cross-Talk Between Innate and Adaptive Immunity
The cross-talk between the innate and the adaptive immune system through cytokines such as tumor necrosis factor (TNF)-α, interferon-γ, and IL-1 is a hot spot of current research in the field. At the cellular level, dendritic cells and T cells are regarded as key effector cells, with important and complex interactive feedback loops with antigen-presenting cells, neutrophilic granulocytes, keratinocytes, vascular endothelial cells, and the cutaneous nervous system. A potential initiating event, triggering the inflammatory cascade and resulting in psoriatic plaque formation, might be the stimulation of dermal plasmacytoid dendritic cells by DNA complexed with LL-37 (cathelicidin), an antimicrobial peptide produced by keratinocytes. Among the cytokines produced by activated dendritic cells are TNF-α and IL-23. The former exerts pleiotropic effects on a wide array of cells from different lineages. Among the proinflammatory activities of TNF-α is the induction of several secondary mediators as well as adhesion molecules, all of which are implicated in the psoriatic disease process.
The Interleuikn-23/T Helper 17 Axis
Several years ago, the IL-23/Th17 pathway entered the center stage of scientific attention. Although psoriasis was considered a Th1 cell–mediated disease, it is now clear that a subset of T lymphocytes expressing IL-17 (hence named Th17 cells) and distinct from the “classical” Th1 cells plays a predominant role in the pathogenesis of psoriasis and other inflammatory disorders. IL-23, produced by myeloid cells, is a major expansion and survival factor for these T cells. Differentiation into Th17 cells occurs primarily on memory T cells, because naïve T cells lack expression of the IL-23 receptor. Th17 cells are themselves a source of multiple proinflammatory cytokines, such as IL-17A, IL-17F, and IL-22, resulting among others in keratinocyte proliferation as a hallmark of psoriasis. Although CD4 + Th17 cells were initially believed to be the principal source of IL-17, evidence is accumulating that other cell types such as epidermal CD8 + T cells, neutrophils, innate lymphocytes, and macrophages substantially contribute in this regard.
Impact on Resident Cells of the Skin
TNF-α and IL-23 exert pleiotropic effects, multiplied by mediators derived from cells responding to activation by these 2 cytokines, and resulting in complex dysregulation of virtually all cutaneous cell types. Keratinocytes are a prominent target, responding with hyperproliferation and cytokine production as well as secretion of antimicrobial peptides. These latter molecules act as chemoattractants for infiltrating immune cells, establishing a positive feedback loop between cells of the immune system and resident epithelial cells in psoriasis.
Beside inflammation and epidermal hyperproliferation, angio(neo)genesis is the third key process in psoriatic pathogenesis. The function of vascular endothelial cells is altered substantially by the inflammatory milieu, because the latter leads to induction and activation of various proangiogenic factors. Furthermore, regulatory T cells influence the vascular endothelial growth factor–related angiogenic microenvironment and contribute to epidermal hyperplasia. Another important feature is the induction of adhesion molecules on endothelial cells, which facilitate the recruitment of circulating leukocytes into psoriatic skin. The direct effects of the inflammatory milieu on endothelial (dys)function are discussed separately elsewhere in this article.
Additional feedback loops with other cutaneous cell types, such as nerve fibers, which presumably contribute to the psoriatic pathophysiology. Indeed, a recent study showed that nocicoceptors in murine psoriasiform lesions induced by imiquimod can induce activation of IL-23 expressing cutaneous dendritic cells underscoring the interplay between nerve activation and inflammation in the skin.
Clinical Observations
The importance of these findings is underlined by the striking efficacy of innovative therapies targeting key components of the respective pathways. Conventional systemic antipsoriatic drugs such as methotrexate or fumaric acid esters exhibit rather generic modes of action, yielding acceptable therapeutic responses within around 3 to 4 months in about one-half of patients treated. Biologics blocking TNF-α or IL-23 are considerably more effective in most patients. And a novel generation of biologics targeting IL-17A or the IL-17 receptor seem to exhibit an even faster mode of onset along with striking efficacy. Preliminary results in early studies of the p19 Ab also demonstrated very high efficacy, further highlighting the pivotal importance of this pathway. In addition, antiangiogenic therapeutic approaches are explored with some success.
Related posts:
The Epidemiology of Psoriatic Arthritis
Clinical Features and Diagnostic Considerations in Psoriatic Arthritis
Natural History, Prognosis, and Socioeconomic Aspects of Psoriatic Arthritis
Outcome Measures in Psoriatic Arthritis
Biologic Therapy for Psoriatic Arthritis
Novel Treatment Concepts in Psoriatic Arthritis
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