MANAGING PSORIASIS
with TOPICAL GLUCOCORTICOIDS

Introduction
     Currently affecting some two percent of all Americans, psoriasis is diagnosed in an additional 150,000 victims each year in this country alone. Treatment of the disease, though complicated by the tremendous variation in both severity and symptomatic manifestations seen with psoriasis, continues to evolve along with theories of its pathogenesis. As evidence continues to accumulate, it is clear that both inflammatory and hyperproliferative aspects of the disease must both be addressed for successful treatment; and the chronic and recurrent nature of the disease demand maintenance therapy as well as acute management.

Pathophysiology - Current Views
     Psoriasis continues to defy definition, for though autoimmune theories persist, its hyperproliferative aspect departs from the norm in that category. Similarities remain obvious, and comorbidity of rheumatoid arthritis in ten percent of psoriasis victims points to definite autoimmune involvement.

Epidemiology -- Genetic Factors
     Voluminous genetic evidence tends to support autoimmune involvement, showing marked similarities with other autoimmune disorders. Autoimmune diseases are probably polygenic with no single gene being either necessary or sufficient for disease development; and comorbidity with multiple autoimmune diseases supports the assumption that the same genes may be involved in the different diseases.
     Occurring with greatest frequency in those of Northern European and Scandinavian ancestry, and least frequenly in Native Americans, psoriasis bears a strong association with certain HLA haplotypes; and familial history is demonstrable in about a third of all cases. A first-degree relative with psoriasis is seen in almost half of Type-I patients (early-onset - averaging age 16 for females and 22 for males). Monozygotic twins of psoriasis victims are affected 72% of the time.
     Susceptibility to Psoriasis Vulgaris (PV) is strongly associated with HLA Cw6 and Cw7, leading to the conclusion that etiological gene(s) may involve the HLA-C gene itself or a close neighbor.H Some 85% of Type-1 patients are positive for HLACw6, as are 15% of Type-2 patients; and A1, B13, B17, B27, B37, DR7 are also implicated by recent research. Research on Japanese psoriatic populations indicates that HLA-DQ is strongly associated with PV, so it or an adjacent gene may share responsibility for development of PV; while DQA1*0101, DQB1*0501, DRB1*0101, DRB1*0403 and DPB1*0402, all significantly less common in Japanese PV patients, may exert some genetic protective effect against developing PV. Most of the autoimmune diseases are associated with particular Class I (A, B, or C) or Class II (D) HLA antigens, but not both. Ankylosing spondylitis, Reiter's syndrome, and common psoriasis are linked to particular class I antigens and are more common in men, while other autoimmune diseases are associated with class II antigens and occur more frequently in women.

Inflammatory Findings
     Histologically, activated CD4+ T lymphocytes (high in both HLA-DR and IL-2R) can be observed in the dermis close to Langerhans cells known to act as antigen-presenting cells (ATCs). Since this observation can be made before symptoms arise, it is assumed that the interaction involves an abnormal reaction to some triggering antigen as an initial step in the disease process. The activated T cells migrate to the epidermis, where they activate epidermal keratinocytes and where a cycle of cytokine production and release begins the self-perpetuating inflammatory condition.

* Keratinocytic expression of both ICAM-1 and HLA-DR is a response to increased levels of IFN-gamma produced by activated T cells and tends to retain activated T cells within the area of the lesion.
* Keratinocytic expression of IL-6, IL-8, and TGF-alpha, also responses to elevated IFN-gama levels, stimulates keratinocytic mitosis and activation of neighboring keratinocytes to produce more ICAM-1, further enhancing retention of T cells in the area.
* Keratinocytic expression of IL-1 stimulates further ICAM-1 production.
* Keratinocytic expression of IL-8

Environmental Factors
     There seems little doubt, with the disease's relapsing nature, that environmental factors play a role in the disease process. Specific triggers have yet to be identified, and they indeed likely vary with the individual patient; but, as with other "true" autoimmune diseases, an association with Streptococcal infection is not uncommon. As many as 80% of guttate psoriasis cases show positive Streptococcal antibody titers. One theory suggests that Streptococcal antibodies may cross-react with components of keratinocytic components or products; and cytokeratins are a likely suspect, with their potent antigenic tendencies.
     Tumor necrosis factor (TNF) may also prove to play a role, produced by macrophages and other immune cells as a normal part of the inflammatory reaction in response to infection (and specifically stimulated by bacterial LPS endotoxin). With functions overlapping with several other cytokines, TNF-alpha is largely responsible for the septic shock, nausea, fever, lethargy, headache, and muscle aches characteristic of systemic infections. It is essential for destruction of tumor cells, but recent evidence has implicated TNF-alpha in the pathogenesis of erythema nodosum leprosum as well as manifestations of several autoimmune diseases. It is also suspected of contributing to the proliferation of HIV in infected individuals. Instead of subsiding normally, in these conditions TNF apparently persists to perpetuate the inflammatory response inappropriately, contributing to tissue injury.

Hyperproliferatory Factors
     The inflammatory component of psoriasis and the very classification of the disease are complicated by the changes observed in epidermal keratinocytes. The epidermis increases in thickness (acanthosis), with downgrowth of elongated epidermal ridges, abnormal keratinization with extensive overlying parakeratotic scale, absence of granular layer, and accumulation of both antibodies and activated complement in the stratum corneum. The keratinocytes, which produce their own sets of cytokines to assist Langerhans cells in their antigen-presenting role and perpetuate the inflammatory processes, undergo a dramatic increase in mitotic rate - ten times that of normal keratinocytes. The stratum granulosum becomes thin or absent; dermal papillae elongate and contain dilated capillaries that lie close to the parakeratotic scale with the thinning of overlying epidermis. The epidermis contains focal areas of edema (spongiosis); and retention of neutrophils within the stratum corneum produce the characteristic Munro's microabscesses. While turnover of normal keratinocytes is one month, psoriatic keratinocytes turnover in as little as three days. The processes in keratin differentiation are thus truncated to produce reductions in high-molecular-weight keratin polypeptides, filaggrin and involucrin. Platelet-activating factor (PAF), abnormally high levels of which are observed in a number of epidermal inflammatory states, stimulates keratinocytic production of mRNA and protein for the inducible isozyme of cyclooxygenase (COX-2) as well as IL-6 and IL-8.L
     It is hypothesized that genetic abnormalities in one or both of these cell types may be significant factors in the etiology, for lesional Langerhans cells more closely resemble nodal Langerhans cells in their ability to activate naïve T lymphocytes as do nodal Langerhans cells.

Topical Corticosteroids In Treatment
     Though it is seldom appropriate to utilize topical corticosteroids as a sole treatment, they can provide an invaluable adjunct to other therapeutic modalities via mechanisms uniquely suited for effective treatment of psoriasis. Topical preparations, though absorbed systemically, exert most of their effects locally at the site of application. They are diffused across cell membranes to act as ligands to cytoplasmic receptors, producing a triad of effects advantageous in psoriasis:
* They counter the vascular dilation and permeability characteristic of inflammatory reactions, retarding the migration of immune cells and macromolecules and thus impeding the inflammatory process, reducing pruritis, edema, and erythema.
* They suppress release, production, and activity of histamine, prostaglandins, kinins, the complement system, and liposomal enzymes, countering the inflammatory process by a second avenue. It is hypothesized that these reactions are pursuant to induction of lipocortins, which are phospholipase A2 inhibitory proteins.
* They inhibit DNA synthesis to slow the runaway mitosis of psoriatic keratinocytes.

      The relative potencies of these adrenocorticosteroid derivatives and their tendencies to produce mineralocorticoid effects can be augmented by hydroxylation, methylation, fluorination, or esterification of the essential 4-ring steroid structure; and relative potency is measured by degree of localized vasoconstriction or blanching produced by application. (See table) Extent of absorption depends upon:

* Lipophilicity of the individual agent,
* Vehicle, Duration of exposure,
* Surface area to which the agent is applied, and
* Condition of the skin to which it is applied.

     The choice of vehicle for topical corticosteroid therapy is important not only as a function of penetration-related efficacy and systemic absorption/toxicity, but for a number of other reasons as well. Ointments, typically formulated with combinations of petrolatum, paraffin, waxes, mineral oil, or propylene glycol, act as their own occlusive barrier to prevent evaporation and maximize hydration of the stratum corneum. Their lipophilic nature enhances both tissue penetration and systemic absorption, so they are the obvious choice when maximum penetration is required or on thick, dry, scaly lesions.
     Creams, with their water content that may approach 50%, fail to provide any occlusive barrier; so they do not enhance penetration. They are generally the first choice on oozing or blistered lesions where hydration is not necessary. They may also be more appropriate for intertriginous areas where minimizing systemic absorption is a serious concern, since tissue penetration and systemic absorption from creams is much less than with ointments. Easier to apply than ointments, creams are more comfortable and convenient for the patient, especially when treating hair-covered skin. They also create fewer laundry problems than ointments. Gels and lotions contain even greater percentages of water than creams and may be better options (along with solutions, and aerosols) for hairy areas.
     Penetration and systemic absorption are generally enhanced by improving the hydration of treated skin and by elevated skin temperature. While penetration through palmar and plantar surfaces, calluses, and crusty areas is diminished, penetration through thinner stratum corneum (face and scrotum, intertriginous areas, and denuded areas) can be greatly enhanced. Addition of urea to vehicle formulations can also enhance hydration and thus penetration, and vehicle formulations designed specifically to enhance penetration of an active ingredient can be very effective.