Psoriasis epidermal proliferation

As described previously, one can induce dry, scaly skin, which shows features very similar to dermatitis such as atopic dermatitis and psoriasis. Use of this experimentally induced dry skin should enable the discovery of a new clinical methodology to cure or care for skin problems. Recently, several excellent in vitro skin models have been reported. Although they are also very useful models for the study of cutaneous metabolism, their function and microstructure are still different from those of intact skin. On the other hand, the mechanisms underlying abnormal desquamation, that is, scaling in the dry skin such as atopic dermatitis, are not completely known. Sato et al. reported55 the inhibition of protease in the SC induced scale without affecting epidermal mitosis. This result seems to be no direct relationship between skin surface appearance and epidermal proliferation. However, decline of SC barrier function induced epidermal hyperplasia, as described earlier.30 The loss of water content from SC also induced epidermal DNA synthesis.30 Further mechanistic studies on each of the dry skin features are required. 

Dithranol in combination with urea is widely used in psoriasis to improve the clinical efficacy, to minimize the dithranol concentration, to achieve the desired effect, to shorten the contact, to get a better hydration of the stratum corneum, and to decrease the proliferation rate of the keratinocytes. Gabard and Bieli showed an increased keratolytical effect of salicylic acid by adding 10% urea.54 Hagemann and Proksch55 showed in 10 patients with psoriasis under a 2-week treatment with a 10% urea ointment increased stratum corneum hydration, a small decrease in TEWL, a reduction in epidermal thickness (-29%), and a decreased epidermal proliferation (-51%). The altered expression of involucrin and cytokeratins as marker for epidermal proliferation was partially reversed.55... 

Different types of evidence exist for the clinical efficacy of 10% urea in the treatment of psoriasis (Table 19.1). Early clinical data from a clinical study on various types of hyperkeratosis showed no superior effects on from 10% urea cream compared to ordinary aqueous cream BP in the treatment of psoriasis.10 However, five psoriatic patients with chronic therapy-resistant lesions obtained soft and pliable skin after treatment with 10% urea, but no effect on erythema was observed.17 Psoriatic lesions on the extremities (at least 5 cm in diameter in size) also showed clinical improvement after two weeks of treatment with an ointment containing 10% urea (Basodexan S ointment) in a placebo-controlled study on ten patients.26 Higher values of skin capacitance (suggested to reflect skin hydration) were also noted on urea-treated areas. Increased hygroscopicity and water content were also obtained after treatment with 10% urea ointment in patients with psoriasis vulgaris.27 Moreover, urea treatment reduced epidermal proliferation, measured as an altered expression of involucrin and cytokeratins.26 Treatment of psoriasis vulgaris with 10% urea-formulations support clinical efficacy at evidence-level lb (cf. Figure 19.1). 

In the presence of UVA the psoralen interacts with DNA, forms thymine dimers, and inhibits DNA synthesis. Psoralen plus UVA (PUVA) treatment is used chiefly in severe psoriasis (a disease characterised by increased epidermal proliferation), and cutaneous T cell lymphoma. 

Voorhees et al. (V6) have recently reviewed the situation in psoriasis with regard to the formation of the histidine-rich protein. As has been stated previously, keratohyalin granules are absent from the intermediary layer in psoriasis, and these authors have demonstrated a lack of synthesis of the histidine-rich protein and a return toward normal with treatment and with the return of the keratohyalin granule. How the defect in formation of this protein is related to the increased epidermal proliferation is not known, but presumably on grounds of economy they should be related to one underlying abnormality. 

The mechanism of action of corticosteroids in psoriasis is not fully understood. Topical corticosteroids appear to inhibit phospholipase A, and to thus reduce levels of arachidonic acid, prostaglandins, and leukotrienes in skin. Moreover, steroid receptors have been identified in skin, with synthesis and mitosis of DNA in epidermal cells being inhibited by topical corticosteroids as demonstrated by decreased epidermal proliferation. ... 

Kuijpers, A.L., Van Pelt, J.P., Bergers, M., Boegheim, P.J., Den Bakker, J.E., Siegenthaler, G., Vande Kerkhof, P.C. and Schalkwijk, J. (1998) The effects of oral liarozole on epidermal proliferation and differentiation in severe plaque psoriasis are comparable with those of acitretin. The British Journal of Dermatology, 139, 380-389. 

Psoriasis is a chronic, inflammatory and hyperprolifera-tive disease of the skin, scalp, nails, and joints, affecting 1 to 2% of the U.S. population. It is found worldwide its frequency varies from 0 to 3% among different ethnic groups. Most of its variable clinical presentations eventuate into erythematous, scaly plaques with or without nail disease and arthritis. Susceptibility to psoriasis is umnistakably heritable, but the phenotype is controlled by multiple genes as well as enviromnental factors. Trauma, stress, and infections are important determinants of disease onset and severity. At the cellular level, psoriasis is characterized by markedly increased epidermal proliferation and incomplete differentiation elongation, dilatation, and leakiness of the superficial plexus of dermal capillaries and a mixed inflammatory and immune cell infiltrate of the epidermis and papillary dermis. A multitude of plausible pathomechanisms... 

It may at first appear paradoxical that diseases such as psoriasis and lamellar ichthyosis, which are characterized by a hyperproliferative epidermis, can benefit from dmgs such as the retinoids, which can stimulate epidermal proliferation under certain experimental conditions. However, when tested in patients with psoriasis, etretinate led to decreased ornithine decarboxylase activity, decreased levels of urinary and cutaneous polyamines, and decreased epidermal DNA synthesis (Kaplan et al., 1983). 

Decreased epidermal proliferation is considered to be the main mechanism of action of PUVA in the treatment of psoriasis. Once excited by UVA, psoralens can react with molecular oxygen, producing reactive oxygen species that cause mitochondrial dysfunction and lead to apoptosis of skin Langerhans cells, keratinocytes, and lymphocytes [134]. PUVA further decreases epidermal cell proliferation by noncompetitively binding to epidermal growth factor receptors and directly altering the cell surface membrane. 

In mouse models of skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), there is a close association between elevated XO activity in the epidermis and hyperplasia (Pence and Reiners, 1987). This association is also seen in psoriasis patients (Eisen and Seegmiller, 1961 Zimmer and Demis, 1966 Kizaki et al., 1977). In the study by Kizaki etal. (1977), the epidermis was increased about five-fold in comparison to normal. It is not known whether XO-derived ROS have any role in psoriatic epidermal hyperproliferation but low levels of hydrogen peroxide added to the culture medium are well known to induce skin fibroblast proliferation in vitro, an eflfect that is greatest at low passage numbers (Murrell et al., 1990). The generation of... 

Calcipotriol is a vitamin D3 derivative which is used as a topical agent in the treatment of psoriasis. Although not completely elucidated its mechanism of action seems to be based on inhibition of the proliferation and stimulation of the differentiation of epidermal keratinocytes. Adverse effects include irritation of the skin but also urticarial reactions. Calcipotriol has 100 fold less vitamin D activity as its active vitamin D3 metabolite calcitriol. However, calcipotriol in overdose can cause symptoms of hypercalcemia. 

The stratum corneum consists of denucleated corneocytes filled with cross-linked proteins, while the intercellular space is occupied by lipids synthesized prior to and during cornification [24], Formation of this barrier relies on the cornification of epidermal keratinocytes, which undergo growth arrest, terminal differentiation, and an epidermal-specific cell death, referred to as planned cell death [25], Abnormalities in any of these programmed events may lead to epidermal disorders such as psoriasis, atopic dermatitis, and cancer. Flowever, biological events that enable basal cells (stem cells) to proliferate, differentiate, and commit planned cell death are still poorly understood [10]. The keratinocyte differentiation process can be stimulated by prodifferentiation agents such as extracellular calcium and 1,25-dihydroxy cholecalciferol (referred to as vitamin D3 hereafter) [23], Aberrant or absent differentiation can be found in other skin disorders such as atopic keratosis, seborrheic keratosis, and rosacea. 

Although the physiological function of IL-20 has not been identified, three lines of evidence support a role for IL-20 and its receptor in inflammatory skin diseases such as psoriasis. For example, overexpression of IL-20 in transgenic mice results in neonatal lethality with skin abnormalities similar to those observed in human psoriatic skin (Bll). These include several hallmark characteristics of this multigenic diseases such as increased proliferation of keratinocytes in the basal and the suprabasal layers of the epidermis, aberrant epidermal differentiation, and infiltration of immune cells into the skin (R3). Recombinant IL-20 protein... 

Pullmann, H., K.J. Lennartz, and G.K. Steigleder, The effect of salicylic acid on epidermal cell proliferation kinetics in psoriasis. Autoradiographic in vitro-investigations (author s transl). Arch. Dermatol. Forsch, 1975,251 271-5. 

In psoriasis there is increased (x 10) epidermal undifferentiated cell proliferation and inflammation of the epidermis and dermis. The consequence of increased numbers of horn cells containing abnormal keratin is that no normal stratum comeum is formed. Drugs are used to... 

Caldpotriene. Calcipotriene. (la.3j3.SZ7 .22 .245l-24-cyclopropyl-9.IO-secochola-.5.7.IO(l9).22-teuaene-l,3. 24-triul. calciputriol (Dovonex). is a. synthetic vitamin D< analogue indicated for topical application in the treatment of moderate plaque psoriasis. It has the same affinity for the vitamin D receptor as calcitriol. but its effect on calcium metabolism is 100 to 200 times less. Calcipotriene inhibits epidermal cell proliferation and enhances cell differentia-... 

In addition, 5-FU and methotrexate are used to treat certain forms of breast cancer, and methotrexate is the drug of choice for the treatment of choriocarcinoma in women. It is also effective in the treatment of psoriasis, a disease in which there is an over-proliferation of epidermal cells in the skin. Finally, it is worth recalling that azidothymidine (AZT) was first synthesised in 1964 as a potential anti-metabolite for cancer chemotherapy, but proved to be ineffective in this role. Its subsequent efficacy as an inhibitor of viral reverse transcriptase in the treatment of HIV infections has assured its place in the history of the 20th century. 

Tazarotene (Tazorac) is a third-generation retinoid approved for the treatment of psoriasis and acne vulgaris. This retinoid binds to aU three RARs. In mice, tazarotene blocks ornithine decarboxylase activity, which is associated with cell proliferation and hyperplasia. In cell culmre, it suppresses markers of epidermal inflammation and inhibits comification of the keratinocyte. 

The ability to bind to DNA has been used to provide an effective treatment for the stubborn and disfiguring skin disease, psoriasis, a disorder characterized by the proliferation of epidermal cells. Oral doses of xanthotoxin (19) followed by controlled exposure to ultraviolet irradiation have shown remarkable success in controlling this problem. Angular furanocoumarins do not bind to DNA in the same manner and have little effect (Beier and Nigg, 1992 Brown, 1986 Ivie, 1987 Ivie et al., 1987). 

Vitamin A deficiency is characterized by squamous metaplasia of a variety of epithelia with increased cell proliferation and hyperkeratosis. These changes are also features of some benign dermatoses, for example, psoriasis. Once beneficial effects of oral vitamin A were observed, its use spread to the treatment of other diseases of the epidermis and epidermal appendages, including acne, psoriasis, and basal cell carcinoma. Since the hypervitaminosis A syndrome (see Chapter 13) interfered with long-term therapy with vitamin A, the need arose for synthetic derivatives that could be at least as efficacious as vitamin A and yet be less toxic. The use of isotretinoin and etretinate, as described above, represents the first development of this concept in clinical practice. 

There are five reported cases of infants who have multiple defects " Unilateral ectromelia, and central nervous system anomalies and a skin disorder similar to that described above in patients with generalized skin involvement, limited to one side of the body. There is also a family history of psoriasis. The unique feature in these cases is that all abnormalities are unilateral (Figure 13.9). The kinetics of epidermal cell proliferation in the psoriasis-like skin are similar to... 

Psoriasis is another chronic and autoimmune skin disorder characterized by raised, scaly, and reddened patches (or plaques), which result from hyperproliferation of the epidermis and inflammation of both epidermal and dermal layers [126]. This disease is also characterized by periods of remissirMi and relapse. Psoriasis is mediated by activated T cells [127] and activated dendritic cells located in psoriatic plaques. These cells release proinflammatory cytokines, including both TNF-a and IFN-y, that increase blood vessel synthesis, vasodilatation, and keratinocyte proliferation [128]. 

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