Psoriasis and psoriatic arthritis: clinical features and disease mechanisms
Introduction
Psoriasis is an immune-mediated, genetic papulosquamous skin disorder. Approximately 2.1% of the US population carries a diagnosis of psoriasis and 1% to 3% of the world is affected by the skin disorder. Psoriasis is a chronic illness that can severely affect patient's quality of life, with approximately 56 million hours of work lost by patients enduring this disorder. In addition, between 1.6 and 3.2 billions of dollars are spent per year on treatment.1 A substantial proportion of patients with psoriasis will develop a form of inflammatory arthritis known as psoriatic arthritis (PsA), which contributes significantly to the patient's disease burden with physical disability, pain, and further reduction in quality of life. The prevalence of PsA, a chronic inflammatory disease of the joints and connective tissue associated with psoriasis, is not well defined because of underrecognition and misdiagnosis. Estimates of its prevalence among patients with psoriasis range from 6% to 39%.2, 3, 4, 5
Psoriasis can clinically present at any age, although studies have noted a bimodal distribution of age of onset. A study by Henseler and Christophers in 1985 observed 2 clinical forms of psoriasis distinguished by age of onset, one with an early age and the other with a late age of onset. The early-onset subset was found to have unstable psoriasis with frequent relapses, as well as more extensive body involvement and more frequent nail involvement, whereas the later group displayed a more stable clinical course.6 A more recent study by Ferrandiz and colleagues in Spain observed that those with disease onset before 30 years of age was associated with a higher incidence of a positive family history, more severe disease, a higher incidence of guttate psoriasis and nail involvement, and greater psychosocial impact. Patients with a late onset of disease had less severe course, but more frequent palmoplantar pustulosis.7
Section snippets
Psoriasis: clinical features
Psoriasis can present in many ways, depending on disease activity, location, and severity. The lesions generally have several distinct characteristics. First, they are well demarcated, with distinct borders. Second, the lesions' surface has noncoherent, silvery scales. Third, beneath the scale, the skin has a glossy erythema. Lastly, an Auspitz sign, or the presence of small blood droplets after the mechanical removal of scale, is present.8 In addition to the Auspitz sign, the Koebner
Genetics of psoriasis
There is documented evidence for the genetic predisposition of psoriasis as evidenced by an increased incidence of psoriasis among relatives. Approximately a third of patients with psoriasis describe having some relatives with the disease.8, 9 The incidence of psoriasis has been documented in 117 monozygotic twins, with a concordance of 65%, whereas 30% concordance was noted in 112 dizygotic twins.10 Studies examining psoriasis in children with parents with the disease have also noted that a
Immunopathogenesis of Psoriasis
Before the mid-1980s, research into the etiology of psoriasis concentrated on abnormalities in keratinocyte differentiation and proliferation. This was due to the clinical and histologic appearance of the disease including thick, scaling plaques and epidermal hyperplasia, parakeratosis, and absence of a granular layer, respectively. Understanding of the pivotal role of T lymphocytes in psoriasis pathophysiology arose serendipitously from the observation of patients with psoriasis who had
T-cell activation
In the epidermis, antigen-presenting cells (APCs), such as Langerhans cells, capture and internalize antigen (either autoantigen or bacterial superantigen) and then proceed to a draining lymph node, where it can activate a naive T cell.14 Contact between the APC and T cell is created by intracellular adhesion molecule 1 (ICAM-1) and lymphocyte function–associated antigen (LFA) 3 on the APC and with LFA-1 and CD2 on T cells, respectively.15 Two signals, one between the interaction of major
Migration of T cells
Both memory T cells and effector T cells are released from the lymph nodes, where they circulate to preferentially migrate to the skin. Cell surface proteins such as common leukocyte antigen are responsible for slowing or tethering T cells in the vasculature. Common leukocyte antigen is an adhesion molecule that interacts with E selectin and P selectin on the vascular endothelium. Further interactions between LFA-1 on the T cell, and ICAM-1 and vascular cell adhesion molecule 1 on endothelial
Effects of T cells and the role of cytokines
Activated T cells generally produce 2 types of cytokines, type 1 and type 2. Type 1 T cells produce inflammatory cytokines such as interleukin-2 (IL-2), interferon γ, and TNF-α. Type 2 T cells produce IL-5, IL-4, and IL-10. These cells have a regulatory role with respect to type 1 T cells because high concentrations of type 2 cytokines suppress the differentiation of T cells into type 1 cells.18, 19 The differentiation of T cells into type 1 cells is directed by IL-12 released from activated
Psoriatic arthritis: clinical features
Psoriatic arthritis typically presents with characteristic features of joint inflammation, including swelling, erythema, and warmth. It often presents initially in one or a few joints in an asymmetric pattern and then gradually involves more joints over time, ultimately manifesting in a polyarticular fashion that tends to be more symmetric. At this stage, joint damage and deformity are present in most patients. In 75% to 85% of patients, the arthritis follows the development of psoriasis, on
Genetics of PsA
Epidemiologic and genetic association studies demonstrate a strong genetic contribution to PsA. Psoriatic arthritis is second only to AS in the strength of genetic contribution to its development among the rheumatic diseases.29
A genetic link with the short arm of chromosome 6 (6p) has been demonstrated showing associations with HLA-B13, HLA-B17, HLA-B27, HLA-B38, HLA-B39, HLA-Cw6, HLA-DRB1*07.30, 31 There are modest associations of PsA with non-HLA alleles within the MHC region (TNF-α promoter
Pathophysiology of PsA
There is a great deal of similarity in the cellular and cytokine patterns in the skin, as described above, and joints of patients with PsA. Synovial immunohistopathology is now well characterized and has been recently reviewed.24, 32, 33, 34 Synovial tissue hypertrophies due to cellular infiltrate with T cells, macrophages, dendritic cells, monocytes, fibroblasts, neutrophils, and B cells. There is significantly increased expression of various cytokines such as TNF-α, IL-1, IL-6, and others,
Treatment of psoriasis and PsA
The different treatment options for psoriasis are vast and vary a great deal in terms of modality, mechanism of action, toxicity, and efficacy. Which therapy is best for a patient depends a great deal on the severity of the disease, disease location, accessibility to treatment (as for phototherapy), and patient preference. For milder disease, there are topical therapies in the form of topical corticosteroids, vitamin D3 analogs, retinoids, tar, salicylic acid, calcineurin inhibitors (not Food
Alefacept
Memory effector T cells are a predominant cell type in the psoriatic plaque. Alefacept is a fusion protein consisting of the first extracellular domain of LFA-3 fused to the hinge CH2 and CH3 sequences of human immunoglobulin G1.44 It binds to CD2 on T cells, and leads to the inhibition of T cell co-stimulation and a reversible reduction of memory effector T cells.44 Clinical trials have demonstrated the efficacy and safety of alefacept for adults with chronic moderate to severe plaque
Cytokine antagonism
Based on highly successful effects in RA, for which they are approved, 3 anti-TNF agents (etanercept, infliximab, and adalimumab) have been tested and approved for PsA. Currently, etanercept, a recombinant human TNF-α receptor fusion protein, is also approved for the treatment of moderate to severe plaque psoriasis without arthritis. It antagonizes the effects of endogenous TNF by competitively inhibiting its interaction with the cell surface.43 A phase 3 placebo-controlled study examining
Conclusions
The past decade has seen significant strides in our understanding of the pathophysiology of psoriasis and PsA, as well as increased awareness on the part of physicians, patients, and the general public about these diseases and their impact. There are similar processes accounting for the pathophysiology of the skin lesions, arthritis, and enthesitis. Both the skin and joints have a significant impact on function and quality of life for the patient and significant adverse impact on their families
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