Elsevier

Immunology Letters

Volume 114, Issue 2, 15 December 2007, Pages 59-65
Immunology Letters

Review
Immune regulation in psoriasis and psoriatic arthritis—Recent developments

https://doi.org/10.1016/j.imlet.2007.08.009Get rights and content

Abstract

Psoriasis and psoriatic arthritis (PsA) are common diseases associated with considerable morbidity and disability. Their pathophysiology comprises a dysfunctional stromal–immune cell and cytokine network leading to inflammation of skin, entheses and joints. Recent advances in understanding of disease pathogenesis have led to the introduction of novel therapeutics providing the ultimate proof of concept in defining the role of these targets in the pathogenetic response. The pro-inflammatory cytokines TNF, IL-12/IL-23 and a variety of co-stimulator molecules have all been identified as critical factors in disease progression. In this short review we summarise key recent developments in understanding of the role of cytokines, T cells, B cells in psoriatic disease pathogenesis. We also describe the pathways that are believed to link such inflammatory pathways to articular matrix dysregulation.

Introduction

Psoriasis is an autoimmune, chronic inflammatory disease targeting primarily the skin and nails. It is characterized by hyperplasia of the epidermis (acanthosis), infiltration of leukocytes of dermis and epidermis as well as dilatation and proliferation of blood vessels. As a common skin disease it appears in different clinical variants. Most frequently, psoriasis vulgaris presents with scaly red plaques on predilectionary areas, e.g. on scalp, the back, dorsal skin of the elbows and ventral skin of knees. Other clinical variants may present, e.g. guttate psoriasis, palmar pustular psoriasis however that speak to considerable variation in the phenotype of the disease. This considerable clinical heterogeneity in the cutaneous presentation of the disorder indicates that a variety of pathogenetic events may be ongoing and need not be common or consistent across each clinical presentation.

Approximately 6–20% of patients with psoriasis develop a chronic inflammatory arthritis or enthesitis. Thus psoriatic arthritis (PsA) affects approximately 0.05% of the general population presenting as peripheral arthritis, axial disease or a combination of both. In comparison to rheumatoid arthritis (RA), peripheral PsA evolves with a distinct joint pattern, typically asymmetric and potentially involving the distal inter-phalangeal joints. Dactylitis with enthesitis involving the complete digit is a characteristic feature which is also quite distinct from RA. Interestingly, in PsA, articular damage assessed by radiographic erosion occurs less commonly than in RA with characteristic radiological features of periostitis and resorption, often seen at distal areas at the sites of entheseal insertion. Thus far, no immunological or molecular mechanisms have been identified that distinguish between the distinct patterns of psoriasis and their typical predilection domains; furthermore, the cause of arthritis in distinct joints and tendons and their particular radiological features are not clearly understood. Finally, the pathways that distinguish inflammatory arthritis in psoriasis from those of other inflammatory arthropathies such as RA are poorly defined.

The clinical therapeutic response to the above presentations has previously involved the use of immune modulatory agents used both systemically and topically as required to modulate disease activity. Such approaches have not been based on firm pathogenesis understanding but rather on an empirical approach to immune modulation exemplified for example in the use of methotrexate, Vitamin D analogues and cyclosporine. A major breakthrough in treatment of a variety of inflammatory diseases has been the advent of inhibitors of the proinflammatory cytokine tumour necrosis factor (TNF) α. TNF antagonists including antibodies (Infliximab, Adalimumab) or soluble receptor constructs (Etanercept) are successfully and now widely employed in clinical autoimmune diseases as RA, PsA and psoriasis. Similarly co-stimulatory blockade is finding a place in therapy in psoriasis and more recently RA. Together these clinical studies have lent new momentum to understanding the critical immune pathologic events in psoriasis and PsA as therein may lie novel therapeutic opportunities as the age of biologic therapeutics progresses. This short review considers recent insights into the network of cytokines and the underlying inflammatory cells in psoriasis and PsA, with particular emphasis on their potential in clinical intervention studies in due course.

Section snippets

Keratinocytes: a critical role in lesion development and perpetuation?

For many years there has been debate as to whether the onset of psoriasis is due to a fundamental disorder of tissue cells or their regulation in the skin or of the immune system a priori. Recently, Wagner and colleagues generated a murine model with psoriasis-like skin disease with concomitant arthritis by deleting epidermal Jun proteins (JunB and c-Jun) normally expressed by keratinocytes. These deletions lead to upregulation of the chemotactic proteins S100A8 and S100A9 associated with

Cytokine networks in psoriatic inflammation

In autoimmune inflammation, an interactive network between cells and cytokines supports the initiation and perpetuation of disease. Breaking this vicious circle of inflammation has proven successful in psoriasis and PsA for some cytokines particularly TNF. Thus far however, although many cytokines have proven of interest, relatively few have reached such a firm evidence base founded in clinical trials. Similarly in RA, TNF, IL-1 and recently IL-6 have been used as therapeutic targets with some

The Th1-Th2-Th17 axis in disease pathogenesis

T cells are considered to be of fundamental importance in a variety of immune disorders—psoriasis is no exception. CD4+ and CD8+ T cell subsets of memory phenotype are present in the psoriatic skin lesion and are present in large numbers in the PsA synovium. A proportion of these cells express activation markers including CD69 and CD40L suggesting a local effector role. Studies examining clonality, usually employing TCR immunospectrotyping analyses, suggest that local antigen recognition may

B cells: a role in psoriasis or PsA?

B cells have been strongly implicated in RA by virtue of the autoantibody profile, synovial antigen presenting function and local cytokine release. Several studies show the presence of competent germinal centres in synovium [46], [47], [48]—these ectopic lymphoid neogenesis formations are organized by T and B cells, associated with high endothelial venules (HEV) and result from ectopic expression of homing chemokines. In RA, rituximab, a B cell depleting chimeric anti-CD20 antibody, shows

New insights to tissue damage

The articular damage associated with PsA is increasingly recognised as an important facet of the disease spectrum. Untreated chronic PsA leads to narrowing of the joint space, erosions and subsequently to loss of function. PsA offers distinct challenges in understanding bone remodelling since, unlike RA, there is evidence not only of destruction but also of apparently attempted healing in the form of neo-ossification evident on plain radiographic analyses. The cytokine environment and their

Conclusions

The foregoing discussion provides new insights to the critical cytokines, adaptive cellular pathways and downstream regulatory matrix protein dependent pathways that in turn sustain the pathogenesis of psoriasis and PsA. However, many questions arise. Do different patterns of skin involvement represent distinct pathogenesis and therefore the need for discrete therapeutic pathways? Is the arthropathy a continuum with the skin disease or does it represent a separate condition occurring on a

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