Elsevier

The Lancet

Volume 370, Issue 9583, 21–27 July 2007, Pages 263-271
The Lancet

Series
Pathogenesis and clinical features of psoriasis

https://doi.org/10.1016/S0140-6736(07)61128-3Get rights and content

Summary

Psoriasis, a papulosquamous skin disease, was originally thought of as a disorder primarily of epidermal keratinocytes, but is now recognised as one of the commonest immune-mediated disorders. Tumour necrosis factor α, dendritic cells, and T-cells all contribute substantially to its pathogenesis. In early-onset psoriasis (beginning before age 40 years), carriage of HLA-Cw6 and environmental triggers, such as β-haemolytic streptococcal infections, are major determinants of disease expression. Moreover, at least nine chromosomal psoriasis susceptibility loci have been identified. Several clinical phenotypes of psoriasis are recognised, with chronic plaque (psoriasis vulgaris) accounting for 90% of cases. Comorbidities of psoriasis are attracting interest, and include impairment of quality of life and associated depressive illness, cardiovascular disease, and a seronegative arthritis known as psoriatic arthritis. A more complete understanding of underlying pathomechanisms is leading to new treatments, which will be discussed in the second part of this Series.

Introduction

“I think it also necessary…to express the scaly psora by a distinctive appellation; for this purpose, the term psoriasis…” So wrote Robert Willan in his treatise On Cutaneous Diseases,1 published in 1808. Willan, a British dermatologist, is credited with the first accurate description of psoriasis and thereby helping to distinguish the disorder from leprosy. Psoriasis, one of the few skin diseases common and distinctive enough to be recognised by medical students (and most doctors) remains something of an enigma. Relatively little attention has been paid to identifying clinical phenotypes of psoriasis, or understanding the natural history and prognosis of the disease. In the past quarter century, substantial advances have been made in our understanding of the genetics and pathomechanisms of psoriasis. Debate continues as to whether psoriasis is an autoimmune disorder. Belatedly, researchers and clinicians have started to recognise and document the substantial impairment to quality of life caused by psoriasis, resulting in recognition that the disease leads to marked loss of productivity2 in those it afflicts. In this review, we will detail and put into clinical context recent advances in the understanding of psoriasis.

Section snippets

Clinical features

The commonest type of psoriasis, accounting for 90% of all cases, is psoriasis vulgaris, in which papulosquamous plaques are well-delineated from surrounding normal skin. The plaques are red or salmon pink in colour, covered by white or silvery scales (figure 1), and may be thick, thin, large or small. They are most active at the edge: rapidly progressing lesions may be annular, with normal skin in the centre. Plaques are usually distributed symmetrically, and occur most commonly on the

Epidemiology

Accurate figures for the prevalence of psoriasis are difficult to obtain because of an absence of validated diagnostic criteria. Moreover, rates vary greatly between people of different ethnic backgrounds: psoriasis is most common in white people, but is estimated to affect only 0·3% of the general population in China,3 and is very rare or absent in some isolated populations. Latitude also seems to affect prevalence, probably because of the beneficial effect of sunlight on the disease.13

Comorbidity

Awareness is increasing that psoriasis as a disease is more than skin deep and that it is associated with systemic disorders,16 including Crohn's disease, diabetes mellitus (notably type 2),17 metabolic syndrome,18 depression,19 and cancer. It is unclear whether cancers, particularly lymphoma20 and skin cancer,21 are related to psoriasis or to its treatment. For example, the risk of developing non-melanoma skin cancer is increased by the excessive use of photochemotherapy—and can be compounded

Histological features

Psoriasis has three principal histological features: epidermal hyperplasia; dilated, prominent blood vessels in the dermis; and an inflammatory infiltrate of leucocytes, predominantly into the dermis (figure 6). Histology of uninvolved, clinically symptomless areas of skin is normal.

The hyperplastic epidermal changes are associated with an underexpression of markers of keratinocyte differentiation, including keratins K1 and K10; loss of the granular cell layer; parakeratosis (retention of

The immune response in psoriasis

Until the early 1980s, psoriasis was believed to be a disease primarily of epidermal keratinocyte proliferation, and the cutaneous inflammatory infiltrate to be a secondary event.32 However, strong evidence now exists that the cell-mediated adaptive immune response is crucial in psoriasis. The leucocyte infiltrate in psoriasis consists predominantly of CD4-positive and CD8-positive T-cells (figure 7), and may precede epidermal hyperplasia.33 Some adhesion molecules which promote leucocyte

Genetic contributions to psoriasis

Population studies show that the incidence of psoriasis vulgaris is greater in first and second degree relatives of patients than in the general population.52 About 30% of individuals with psoriasis vulgaris have an affected first degree relative.53 If both parents and a sibling are affected, a further child has a 50% chance of developing psoriasis vulgaris; if the sibling is affected but not the parents, the risk drops to 8%.53 The risk of psoriasis vulgaris is two to three times greater in

Potential contribution of genetic studies to treatment

Without definitive identification of a major susceptibility gene for psoriasis, prediction of how genetic discovery might inform disease pathogenesis is difficult at present. Nevertheless, several recent genetic observations show how pathogenic models can integrate perturbations in the epidermal barrier and inflammation. For example, in mice, disruption in keratinocyte signalling, either by abrogation of activation protein 1 (AP1) pathways66 or by upregulation of signal transduction and

Animal models

Psoriasis vulgaris is unique to human beings. However, transgenic knockout/deletion animal models of psoriasis have been proposed as surrogates for the disease. Epidermal overexpression of VEGF in mice produces a phenotype of chronic inflammation, psoriasiform hyperplasia, and vascular proliferation reminiscent of psoriasis.74 Mice that are transgenic for epidermal keratinocyte expression of STAT367 have a psoriasiform appearance. A recently described mouse model in which epidermal expression

Psychosocial aspects

Psoriasis is rarely life-threatening; however, it is life-ruining for the majority of patients. Dennis Potter80 and John Updike81 have written eloquently and movingly about the despair and social isolation that accompany psoriasis. Although Willan1 separated psoriasis from leprosy, the stigma of psoriasis persists. These difficulties manifest as significant impairment of quality of life82 and profound psychosocial disability.83 Studies have shown reliably that psoriasis produces a decrease in

Conclusion

The past 20 years, and in particular the past 5 years, have witnessed great advances in our knowledge of the pathogenesis of psoriasis, courtesy of genetic and immunological techniques. It is now accepted that psoriasis is a chronic, immune-mediated inflammatory disease that can act as a paradigm for other diseases of this genre. These basic science observations have catalysed the development of targeted biological treatments that will revolutionise the management of psoriasis. There are still

Search strategy and selection criteria

We identified publications relating to psoriasis pathogenesis and psoriasis in general by searching Medline, Ovid, and the Cochrane Library databases with the term “psoriasis” alone or in combination with the terms “pathogenesis”, “genetics”, “psychosocial”, “history”, “immunology”, “comorbidity”, “angiogenesis”, “prevalence”, “epidemiology”, “innate immunity”, “adaptive immunity”, “keratinocyte”, “animal models”, and “phenotype”. We preferentially selected the most recent papers and

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