—  SHORT COURSE  —

INFLAMMATORY DISORDERS OF THE SKIN AND SUBCUTIS:
A PRACTICAL AND ANALYTICAL APPROACH



CASE #3: PSORIASIS

Cynthia M. Magro, M.D., A.Neil Crowson, M.D., and Martin C. Mihm Jr., M.D.




Introduction
Psoriasis is an idiopathic hyperproliferative state of the epidermis which produces a chronic inflammatory skin disorder which affects one to two percent of the population can be broadly categorized into specific subtypes, namely; 1) psoriasis vulgaris, 2) generalized pustular psoriasis, 3) localized pustular psoriasis, 4) psoriasis associated with a erythroderma, 5) psoriasis associated hypersensitivity reactions, and 6) psoriasis associated with HIV infection.

Clinical
The lesions are pink to red papules and plaques which typically involve the scalp, sacral region and the extensor surfaces of the extremities and are covered with fine silvery scales which bleed when scraped, to yield the Auspitz sign. When the flexural aspects of the extremities, intertriginous areas, and genitilia are involved, the term inverse psoriasis is applied. Oral lesions refered to as geographic stomatitis/mucositis can be seen in some patients. Psoriatic arthritis, classically observed in psoriasis vulgaris, may also be seen in other variants. It afflicts the interphalangeal joints, although a symmetrical large joint arthritis indistinguishable from rheumatoid arthritis may also be seen. Regarding generalized pustular psoriasis, there are three forms; 1) acute generalized pustular psoriasis of von Zumbusch , 2) generalized pustular psoriasis of pregnancy (impetigo heptaformis), and 3) infantile or juvenile pustular psoriasis. The lesions clinically comprise sterile pustules on an erythematous scaly base accompanied by severe constitutional symptoms.

Localized pustular psoriasis, classically presents as pustules confined to the palms and soles, the term pustolosis palmaris et plantaris has been used. In psoriasis associated with HIV infection, extensive erythroderma is the rule. Palmo-plantar involvement, inverse psoriasis and psoriatic arthritis are more frequent in patients who develop psoriasis in the setting of HIV infection.

Histopathology
In psoriasis vulgaris, there is a distinctive pattern of epidermal hyperplasia characterized by regularly elongated rete with variable rete fusion.


Psoriasis
Psoriasis

There is diminution of the granular cell layer with areas of complete granular cell layer absence. The stratum corneum is markedly thickened with both parakeratosis, orthohyperkeratosis, and plasma admixed with neutrophils. There may be architectural disarray and dysmaturation of the epidermis and suparbasilar mitoses are frequent. Striking alterations of the dermal papillae capillaries are observed; capillaries appear increased in number and are dilated, lying in intimate apposition to the cytoplasmic membranes of the basilar keratinocytes. Attenuation of the suprapapillary plates is frequent. Inflammation is a ubiquitous feature of the psoriatic plaque. The infiltrate is located both within the superficial dermis and in the epidermis. The superficial dermal infiltrate is of maximum intensity within the dermal papillae and is composed almost exclusively of lymphocytes with a minor neutrophilic population. There is exocytosis of inflammatory cells into the epidermis, localized mainly to the suprapapillary plates. The initial infiltrating cell is a lymphocyte, followed by an influx of neutrophils into the epidermis and stratum corneum. Permeation of widened keratinocytic spaces of the more superficial layers of the epidermis by neutrophils is referred to as spongiform pustulation of Kogoj. Intracorneal and subcorneal micro-abscesses referred to as Munro micro-abscesses may be seen. Incipient lesions of psoriasis may show minimal epidermal hyperplasia. In the eruptive form of psoriasis vulgaris that follows b-hemolytic streptococcal infection, the epidermal hyperplasia is typically minimal and a lymphocyte-dominant infiltrate with only few neutrophils may be observed. Probably the most useful and distinctive diagnostic feature of psoriasis is the psoriatic capillary, the morphologic hallmarks of which include the dilated capillary lying in direct apposition to basal layer keratinocytes of the epidermis.

Pathogenesis
Epidermal cell replication is markedly accelerated in active lesions of psoriasis. Keratinocyte differentiation is also altered. Normally the suprabasilar epidermis expresses keratins K1-K10. In psoriatic skin, keratins K1-K10 are replaced by the so-called hyperproliferative keratins, keratins K6 and K16. In addition, involucrin, a major precursor protein of the cornified cell envelope normally found in only in the very upper layers of the epidermis, is expressed prematurely in the lower superbasilar portion of the epidermis.

There is an integral role for a T-lymphocyte mediated response in psoriasis. Oligoclonal expansion of specific CD8+ve lymphocyte subsets, namely, those expressing V b 13.1 and V b 3 genes, has been demonstrated. Psoriasis appears to be an example of Th1-mediated autoimmune disease, with Th cells mediating the accumulation of the aforementioned CD8+ve oligoclones. As well, Th-lymphocytes produce various cytokines including TNFa, a cytokine which may be involved in the formation of Munro microabscesses. In addition, interferon also plays a role in the propagation of the psoriatic plaque; being over-expressed by keratinocytes in psoriatic lesional skin. It has been hypothesized that decreased reponsiveness of keratinocytes to IFNg may contribute to the hyperproliferation and altered differentiation of epidermal cells in psoriasis. This protein has chemotatic as well as mitogenic properties. Interferon g also induces the expression of intercellular adhesion molecules in keratinocytes and endothelial cells and mediates the adhesion and trafficking of lymphocytes into the epidermis by binding to its ligand LFA-1. Among other cytokines produced by the Th1 lymphocyte is IL8, which is a potent neutrophilic chemoattractant. As psoriasis can follow streptococcal infection, a pathogenetic role for superantigens has been postulated; superantigens induce a mitogenic response in large sub-populations of T-lymphocytes. Recent evidence has suggested that there is a potential "psoriasis gene" located on chromosome 17Q. Attention has also been focused on chromosome 1Q21. Genes clustered in this region are responsible for epidermal proliferation. Psoriasis has also been associated with HLA-CW6, B13 and B17.

New Insights into the Pathophysiology of Psoriasis
Interactions between infiltrating T cells and keratinocytes via the secretion of the TH1 cytokines interleukin (IL) 2 and interferon gamma (INF-gamma), the keratinocyte growth factor transforming growth factor alpha (TGF-alpha) and the cytokines IL-6 and IL-8 are thought to be the predominant mechanisms inducing skin lesions in psoriatic patients. Flow cytometric immunophenotyping of lymphocyte cultures derived from psoriatic plaques reveals a CD4+ alpha beta receptor positive T lymphocyte population which manifests a Th1 cytokine dominant milieu. The main Th1 cytokines are tumor necrosis factor beta, interleukin 2, and interferon gamma while the main Th2cytokines are interleukin 4 and interleukin 10. In psoriatic synovium, a Th1 dominant milieu along with the monokines tumor necrosis factor alpha and interleukin 1 beta are at levels higher than the cytokine concentrations seen in the rheumatoid synovium. Further support of a dominant Th1 cytokine milieu in the pathogenesis of psoriasis are the beneficial effects of dimethyl and monomethyl fumaric acid on psoriatic skin lesions. This agent has been shown to alter the cytokine milieu from a dominant Th1 profile to a TH2 dominant profile as revealed by reduced levels of interferon gamma and interleukin 2 to a Th2 dominant profile revealed by high levels of interleukin 10. In addition it suppresses the epidermal derived transforming growth factor alpha within cultured keratinocytes. The presence of tissue eosinophilila in fumaric acid treated psoriatic plaques, the classic light microscopic hallmark of a Th2 mediated immune response, provides a practical light microscopic correlation of this altered cytokine profile. In one study monomethylfumaric acid greatly enhanced IL-4 and IL-5 production without affecting IFN-gamma. When peripheral blood mononuclear cells were challenged with Mycobacterium tuberculosis, an agent which typically induces Th1 recall responses with strong IFN-gamma secretion, monomethylfumaric acid again appeared to induce high levels of IL-4 and IL-5 secretion while IFN-gamma production was unaffected. There may be a critical role for IL12 in maintaining the Th1 response. IL12 is a heterodimer cytokine which is important in the propagation of a Th1 immune response; this cytokine is significantly elevated within the skin of psoriatic plaques compared to controls.

As psoriasis can follow streptococcal infection, a pathogenetic role for superantigens has been postulated; superantigens induce a mitogenic response in large sub-populations of T-lymphocytes. Recent studies have confirmed that psoriasis is likely an autoimmune disorder whereby the antigenic target is streptococcal peptide which share homology with epidermal keratin. Recent papers have been published which support this construct. Two studies showed that peripheral blood mononuclear cells in patients with psoriasis responded with a Th1 dominant response to streptococcal M peptides which had sequence homology with epidermal keratin. A similar response was not observed when peptides without sequence homology to epidermal keratin were used. This excessive Th1 response was not seen in patients who had atopic eczema or were healthy controls.The response was blunted during UVB treatment. An immunoperoxidase technique was used to look for autoantibodies in autologous sera in skin sections obtained from lesions or from healthy areas of psoriatic patients, before and after immunoadsorption with a Streptooccus pyogenes extract. The skin biopsies were also analyzed with a pool of sera from mice immunized with the streptococcal extract. The investigators found that all psoriatic patients had autoantibodies to antigens present in keratinocytes prior to immunoadsorption with a Streptococcus pyogenes extract whereas healthy subjects did not. Immunoadsorption of autologous sera removed the reactivity to antigens in skin lesions in all cases.

Further support of a role of the superantigens in the propagation of the psoriatic plaque was recently demonstrated when staphylococcal enterotoxin B (SEB)-stimulated peripheral blood mononuclear cells from psoriatic patients injected repeatedly under the grafted full-thickness involved psoriatic skin onto severe combined immunodeficient (SCID) mice resulted in the persistence of a psoriasiform epidermis whereas those mice with a single injection or injections of unstimulated peripheral blood mononuclear cells could not maintain a hyperplastic epidermis. E-selectin expression interleukin-1 beta (IL-1 beta) and and interferon gamma were only detected in those mice receiving continuous injections of stimulated peripheral blood mononuclear cells.

Psoriasis lesions are associated with increased numbers of cutaneous nerves. The pathogenetic basis of this finding is unclear as is its significance regarding the pathogenesis of psoriasis. In psoriatic tissue the number of keratinocytes per square millimeter of epidermis positive for nerve growth factor has been demonstrated in non-lesional psoriatic skin rleative to normal skin and lichen planus. Nerve growth factor is mitogenic to keratinocytes, activates T-lymphocytes and can induce migration of inflammatory cellular infiltrates, histological features characteristic of psoriasis.

Some observers consider pustulosis palmoplantaris a localized form of pustular psoriasis. However a recent study closely assessed the light microscopic appearance of these lesions, suggesting that it is a distinct clinical pathological entity. Clinically there is a definite association with autoimmune thyroid disease and smoking and gluten sensitive enteropathy. At a light microscopic level, inflammation preferentially involves the acrosyringium and as well the infiltrate may contain eosinophils in addition to large numbers of mast cells.

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