Psoriasis is a chronic skin disease

Transcription

1 CLINICAL REVIEWS Pathophysiology and treatment of psoriasis BRYAN P. PETERS, FRED G. WEISSMAN, AND MARK A. GILL Psoriasis is a chronic skin disease that, although usually not lifethreatening, causes tremendous morbidity and has no cure. Although psoriasis has been ubiquitous throughout the ages, it was not until the end of the eighteenth century that it was first described as a separate skin disorder. 1 An estimated 7 million people in the United States are affected by psoriasis, 2 and each year 1.5 million of them seek a physician s treatment. 3 The estimated annual cost of psoriasis in the United States in 1993 was $1.6 billion to $3.2 billion. 4 Classic psoriasis is characterized by defects in the normal cycle of epidermal development that lead to epidermal hyperproliferation, altered maturation of the skin, inflammation, and vascular alterations. 5 These four characteristics are often observable as areas of dry, thickened, scaling, silvery white and reddened skin. 6 The psoriatic lesions may hurt, itch, and bleed. The extent of the disease can range from a few small plaques to generalized lesions. Psoriatic lesions may be located almost anywhere on the body. Psoriasis may be cyclical; some patients have signs of the disease and then go into remission for various periods. Others may never enter remission and always have active lesions. 7 Between 1% and 3% of the U.S. population is affected by some form of psoriasis. 8 The disease is seen in all ethnic groups but is most common in people of European ancestry. Asians and Africans seem to have a lower risk. The lowest risk is found in Abstract: The pathogenesis and treatment of psoriasis are reviewed. Psoriasis is characterized by defects in the normal cycle of epidermal development that lead to epidermal hyperproliferation, altered maturation of skin cells, and vascular changes and inflammation. The condition typically manifests as areas of thickened, flaky, silvery white and reddened skin that may hurt, itch, and bleed. Biochemical markers of psoriasis are changes in levels of keratins, keratinocyte transglutamase, migration inhibitory factor-related protein, skin-derived antileukoproteinase, involucrin, small protein rich protein 2, filaggrin, and cytokines. Types of psoriasis that may be clinically encountered include plaque psoriasis, guttate psoriasis, erythrodermic psoriasis, and pustular psoriasis. Psoriasis is believed to be genetically linked but can also be triggered by mechanical, ultraviolet, and chemical injury; various infections; prescription drug use; psychological stress; smoking; and other factors. Topical treatment of psoriasis is usually the first line of therapy. Topical treatments consist of emollients and keratolytic agents, anthralin, coal tar, corticosteroids, vitamin D 3 analogues, topical retinoids, and topical psoralens plus ultraviolet A (UVA) light. In patients who do not respond adequately to topical therapy, oral or injectable therapy, such as oral retinoids, methotrexate, cyclosporine, tacrolimus, and oral psoralens plus UVA light, may be warranted. Patients receiving systemic treatments should be carefully monitored for adverse effects and drugdrug interactions. Drug therapy is the mainstay of the treatment of psoriasis. The potential adverse effects and interactions necessitate vigilant monitoring. Index terms: Anthralin; Cholecalciferol derivatives; Coal tar; Cyclosporine; Emollients; Immunosuppressive agents; Keratolytic agents; Keratoplastic agents; Methotrexate; Methoxsalen; Pigmenting agents; Psoriasis; Radiation; Retinoids; Skin and mucous membrane preparations; Steroids, cortico-; Tacrolimus; Topical preparations Am J Health-Syst Pharm. 2000; 57: the indigenous peoples of the Americas. 4 Psoriasis is not age specific and occurs equally in men and women. This article reviews the pathogenesis and treatment of psoriasis. Pathogenesis The main function of the skin is BRYAN P. PETERS, PHARM.D., is Pharmacy Manager at a Rite Aid pharmacy in Los Angeles, CA; when this article was written he was a level 4 student, School of Pharmacy, University of Southern California (USC), Los Angeles. FRED G. WEISSMAN, PHARM.D., J.D., is Associate Professor of Clinical Pharmacy and Associate Dean, School of Pharmacy, USC. MARK A. GILL, PHARM.D., FASHP, FCCP, is Professor of Clinical Pharmacy, School of Pharmacy, USC. Address reprint requests to Dr. Gill at the School of Pharmacy, University of Southern California, 1985 Zonal Avenue, #208A, Los Angeles, CA This is article H01 in the ASHP Continuing Education System; it qualifies for 1.0 hour of continuing-education credit. See page 660 or for the learning objectives, test questions, and answer sheet. Copyright 2000, American Society of Health-System Pharmacists, Inc. All rights reserved /00/ $

2 Figure 1. Diagram of the epidermal layers of the skin. corneum granulosum spinosum basale Dermis Figure 2. Diagram of the epidermal features of psoriasis, including scaliness, hyperkeratosis, and neutrophil accumulation in the stratum corneum. corneum granulosum spinosum basale Dermis protection offered by an intact epidermal layer (Figure 1). The epidermis consists of five layers, which are, from deepest to most superficial, the stratum basale, the stratum spinosum, the stratum granulosum, the stratum lucidum, and the stratum corneum. Four types of cells compose these layers: keratinocytes (90% of the cells), melanocytes (8%), Langerhans cells, and tactile menisci (also known as Merkel cells). During the epidermal cell cycle, new cells formed in the stratum basale migrate toward the stratum corneum. As cells move toward the surface, they accumulate keratin and their organelles disappear. By the time the cells reach the stratum corneum, they have died and been completely filled with keratin. This smooth, keratinous external layer is what offers the skin its protection. The surface cells slough off (exfoliate) and are replaced by the underlying cells. The epidermal cell cycle normally takes about four weeks. Keratinocytes in the basal layer divide approximately once every two weeks. 4 In psoriatic skin, the epidermal cell cycle is accelerated. Cell division in the basal layer occurs every 1.5 days, 4 and the migration of keratinocytes to the stratum corneum occurs within just four days or so (Figure 2). Since the cells move to the surface so rapidly, they do not differentiate and mature properly. The stratum corneum is not fully keratinized, and epidermal cells build up abnormally and become scaly. The epidermis in psoratic lesions is three to five times thicker than normal. Blood vessels in the papillary layer of the dermis dilate in psoriasis, and inflammatory cells, such as neutrophils, infiltrate the epidermis. 4 Pathology Of the types of cells in the epidermis, it is not yet known which is the primary cause of psoriasis. However, keratinocyte activity is abnormal, and there is an infiltration of lymphocytes. Biochemical studies have recognized specific changes in the expression of many cellular markers in psoriasis. The markers of epidermal proliferation the keratins (K6, K10, K16, and K17), epidermal growth factor (EGF) receptor, and ornithine decarboxylase are usually increased in psoriasis. 9,10 Differentiation is associated with its own biochemical markers, including keratinocyte transglutamase, migration inhibitory factor-related protein, skin-derived antileukoproteinase, involucrin, and small protein rich protein 2. 9 Filaggrin, which is essential for the development of the stratum corneum, is decreased to below detectable levels. Also, there is a decrease in the differentiation-related keratins K1, K2, and K Keratinocytes also contain a variety of immunomodulating cytokines, such as interleukin-1 (IL-1), IL-6, IL-8, and tumor necrosis factor (TNF), that are expressed in different ways in psoriasis. 4 For example, expression of IL-8 and TNF is increased in psoriasis, yet administration of IL-10 may alleviate symptoms of psoriasis. Thus, there may be an imbalance of proinflammatory and inhibitory cytokines. 646

3 Table 1. Types of Psoriasis 6 Type Plaque psoriasis a Guttate psoriasis Erythrodermic psoriasis Pustular psoriasis Nail psoriasis Psoriatic arthritis Scalp psoriasis b Inverse psoriasis a Synonym for psoriasis vulgaris or common psoriasis. b Occurs in half of patients with psoriasis. Characteristics Dry scaling patches Drop-like dots, occurs after streptococcal or viral infections Exfoliation of fine scales, widespread, often accompanied by severe itching and pain Pus-like blisters, noninfectious, fluid contains white blood cells Seen on toenails and fingernails, starts as numerous pits, at times progresses to yellowing, crumbly, and thickened nail; may slough Inflammation, swelling, and joint destruction Plaque-type lesion Smooth, inflamed lesions, mostly of flexural surfaces (e.g., the armpits) Figure 3. Plaque psoriasis on the elbows. The plaque on the right elbow is diffuse and single. Figure 4. Plaque psoriasis on the legs. The plaques are well described at the edges. There are several theories regarding how these chemical messengers are related. One theory is that injury in the form of physical, chemical, or ultraviolet damage to the epidermis activates keratinocytes to increase the release of cytokines. When the skin is traumatized, a psoriatic event may occur at the site of the trauma; this is referred to as Koebner s phenomenon. The cytokines that are released activate T lymphocytes. The activated T lymphocytes then produce more cytokines that may amplify inflammation and further increase T-cell and keratinocyte proliferation. A second immunologically based theory for trauma-induced psoriasis is that epidermal Langerhans cells interact with helper T lymphocytes, resulting in the release of cytokines that then activate keratinocytes. Yet another theory proposes that killer T lymphocytes inappropriately attack keratinocytes, triggering the effects seen in Koebner s phenomenon. 4 Probably none of these mechanisms is solely involved in psoriasis; several mechanisms may be operating concurrently in the same patient. Clinical types of psoriasis Several types of psoriatic lesions may occur; each differs slightly and responds differently to treatment (Table 1). The most common form is plaque psoriasis, occurring in about 90% of patients. In this type of psoriasis, lesions start as small papules that grow and unite to form plaques. 8 These lesions have the classic silvery white, scaly appearance (Figures 3 and 4). Guttate psoriasis is often preceded by streptococcal throat infections and is often seen in individuals in their teens. This type of psoriasis starts as papules that are initially pink and become scaly. The onset may be related to superantigen stimulation of the immune system resulting from the streptococcal infection. 5 Guttate psoriasis arises very rapidly but responds to treatment (especially ultraviolet therapies) better than psoriatic lesions that have a longer onset. 5,8 Erythrodermic psoriasis is a severe variant (Figure 5). Usually this type of psoriasis is widespread and is associated with massive protein losses, problems maintaining core body temperature, and excessive fluid loss. This type of psoriasis may arise on its own or from worsening of another form of psoriasis already present in the patient. Erythrodermic psoriasis usually needs to be treated aggressively; hospitalization is often required. The clinical course is often complicated by pustulosis, arthropathy, staphylococcal infections, and growth retardation. 8 Pustular psoriasis, another severe form, is characterized by superficial pustulation of the lesions. Lesions are frequently localized to the palms and soles (Figure 6) but may be generalized. Localized pustular psoriasis Figure 5. Erythrodermic psoriasis. has little systemic effect on the body, but the lesions can be hard to treat and recur frequently. Generalized pustular psoriasis is often associated with fever and malaise, and there may be fluid and electrolyte disturbances and infection. 5 This form of psoriasis has a high rate of relapse 647

4 and may lead to death. 8 Many patients with generalized pustular psoriasis are treated on an inpatient basis. Psoriasis patients often have two major extracutaneous manifestations, nail changes and psoriatic arthritis, in addition to their cutaneous abnormalities. Nail changes more frequently affecting the fingernails than the toenails 8 have been seen in up to 78% of psoriasis patients. There are four clinical changes seen in the nails: onycholysis, pitting, accumulation of subungual debris, and color alterations (Figure 7). These changes are similar to those in onychomycosis, from which nail psoriasis should be carefully differentiated. 5 The presence of pitting usually rules out a fungal infection. Psoriatic arthritis is seen in up to 20% of psoriasis patients and often affects the peripheral interphalangeal joints. 3 Patients with psoriatic arthritis do not have the elevated serum levels of rheumatoid factor seen in rheumatoid arthritis. Psoriatic arthritis is frequently seen in patients with nail and scalp psoriasis (Figures 810), although a few patients may have joint symptoms and no cutaneous changes. 8 It can be difficult to distinguish rheumatoid arthritis from psoriatic arthritis (the latter typically has a better prognosis, however). Factors associated with psoriasis Genetic factors. It is currently believed that psoriasis is a genetically linked disease and may be carried on more than one gene. About 30% of people affected with the disease have had psoriasis in their family. 7 If one parent has the disease, there is a 25% chance that his or her offspring will also get the disease; if both parents are carriers, the chance of passing psoriasis on to their children more than doubles. 11 Studies have suggested a pattern of autosomal dominant inheritance. The frequency of psoriasis is higher in monozygotic than dizygotic twins. 7 In many types of psoriatic patients, levels of human Figure 6. Pustular psoriasis on a foot. Figure 7. Nail psoriasis. Figure 8. Scalp psoriasis. leukocyte antigens (HLAs) are above normal, indicating a genetic predisposition favoring activation of psoriasis. 12 Not all persons with abnormal HLA presentation will become psoriatic in the future, but there is a notable increase in risk. Nongenetic factors. Along with genetic factors, there are many nongenetic factors that may trigger psoriasis. Mechanical, ultraviolet, or chemical injury of the skin can result in Koebner s phenomenon; the psoriatic lesions reflect the physical pattern of epidermal injury (Figures 11 Figure 9. Psoriatic lesion behind an ear fold. A patient may have scalp psoriasis only, without lesions on the torso. Figure 10. Moderate to severe whole-body psoriasis. Topical treatment of whole-body psoriasis is impractical and may be dangerous. and 12). 13 Various infections especially streptococcal infections, but also acute viral infections and HIV infection 4 can trigger lesions. Other nongenetic triggering factors are prescription drug use, psychological stress, endocrine and hormonal changes, obesity, alcohol, and smoking. 4,13,14 Medications that are implicated as psoriatic triggers are antimalarials, lithium, β-blockers, quinidine, systemic corticosteroids (upon withdrawal), and indomethacin. 14 Psoriasis patients must be monitored closely when taking these medications. Some topically applied medications that have an irritant effect 648

5 can induce Koebner s phenomenon. Treatment options A treatment algorithm for psoriasis is presented in Figure 13. Treatment options include emollients and keratolytic agents, anthralin, tars, topical corticosteroids, vitamin D 3 analogues, retinoids, methotrexate, cyclosporine, tacrolimus, and psoralens plus phototherapy. In general, topical treatment is begun first for mild to moderate psoriasis (Table 2). A more aggressive initial approach may be indicated for severe psoriasis. has an exfoliative action. Salicylic acid preparations need to be applied two or three times a day to produce keratolytic effects. Topical salicylic acid may enhance the absorption of other topically applied medications and may cause local irritation to the skin where these other topical preparations are applied. Figure 11. Koebner s phenomenon after surgical incision and suturing. When the area treated is large, there may be systemic adverse effects, including nausea, vomiting, tinnitus, and hyperventilation. 7 Anthralin Anthralin, or dithranol, has been used extensively for the topical treat- Figure 12. Koebner s phenomenon after a tissue injury sustained when the patient slid during a baseball game. Emollients and keratolytic agents Emollients and moisturizers are products that moisturize, lubricate, and soothe dry and flaky skin. 6 These products typically bath oils, soap substitutes, and skin creams work by producing an occlusive film that limits evaporation of water from the skin, allowing the stratum corneum to rehydrate itself. With increased hydration, the stratum corneum swells and assumes a more normalized flat contour, scaling is decreased, and the skin becomes more pliable. Emollients and moisturizers may also have antipyretic and vasoconstrictive properties. These products are often used for pretreatment of psoriatic plaques in preparation for other active topical treatments. Emollients and moisturizers can be applied all over the exterior surface of the body. To be effective, they need to be applied liberally; threetimes-daily application may be necessary to achieve a response. Two adverse effects seen with emollients and creams are contact dermatitis and folliculitis. 7 Keratolytic agents aid in the removal of scales and help reduce hyperkeratosis. The most common keratolytic agent is topical salicylic acid. It is presumed that salicylic acid exerts it keratolytic effects by decreasing corneocyte cohesion in the psoriatic horny layer. This effect primarily occurs at salicylic acid concentrations of less than 5%. At higher concentrations, salicylic acid Figure 13. Treatment algorithm for psoriasis. For the patient with mild to moderate psoriasis, treatment begins at step 1. If symptoms persist, second-line therapy is begun (step 2). Supplementary therapies can be used at any step. Management of progressive disease may require step 2 or 3 treatment. Climatotherapy involves the use of sunlight, commonly at solariums such as those at the Dead Sea in Israel. PUVA = psoralen plus ultraviolet A. Second-line therapy Supplementary therapies Coal tar Step 1 Anthralin Calcipotriene Tazarotene Topical corticosteroids Climatotherapy Moisturizers Keratolytics Step 2 PUVA PUVA step 1 agent Step 3 Acitretin Metotrexate Cyclosporine Intralesional injection of corticosteroids Rotational: months of each step 3 agent 649

6 Table 2. Topical Treatments for Psoriasis 7 Agent or Class Emollients Salicylic acid Coal tar Anthralin Calcipotriol Corticosteroids Psoralen Tazarotene Aquaderm (C & M Pharmacal), Cetaphil (Galderma), Curel (Bausch & Lomb), Keri Lotion (Westwood Squibb), Lubriderm Lotion (Warner Lambert), and others Various gels and lotions Balnetar (Westwood Squibb), Denorex (Whitehall Robins), Estar (Westwood Squibb), Neutrogena T/Gel (Neutrogena), Polytar (Stiefel), Zetar (Dermik), and others (available as lotions and shampoos) Dritho Creme (Dermik) Dovonex cream and ointment (Westwood Squibb) See Table 3 Commercial Product(s) Oxsoralen lotion (ICN) Tazorac gel (Allergan) Strength (%) NA a Various and 0.1 Application Regimen Three or four times daily Two or three times daily At bedtime; allow to remain on until morning At bedtime; allow to remain on until morning. Short-contact therapy can also be effective Once or twice daily; not more than 100 g of vehicle base per week. May use for up to 8 wk Two to four times daily for maintenance. May use occlusive wrap at night Apply to area 20 min before UVA b irradiation Once or twice daily for up to 12 wk Adverse Effects Folliculitis, contact dermatitis Skin irritation, salicylism Staining potential, skin irritation, photosensitivity Staining potential, skin irritation, inflammation Skin irritation, hypercalcemia risk Local tissue atrophy, fine hair growth, hypopigmentation, contact dermatitis, adrenal suppression Photosensitivity, exaggerated sunburn Pruritus, burning, erythema a NA = not applicable. b UVA = ultraviolet A light. ment of psoriasis. 15 Anthralin is a derivative of chrysarobin, which is from the Brazilian tree Andira araroba and has been used in India and Brazil since the mid-1800s. 7,16 Anthralin is very effective and is considered one of the safest treatment options, with no systemic adverse effects. 10,16,17 Still, patient acceptance is limited by the product s staining of the skin and clothing. The mechanism of action of anthralin is not completely understood. Clinically, anthralin slows cellular proliferation, decreases inflammation, and increases cellular differentiation in psoriasis. 15,16 Often during treatment, patients may see an increase in irritation and inflammation of nonpsoriatic skin. 7 Studies have revealed changes in several markers of psoriasis before and after treatment. Transforming growth factor-α (a keratinocyte growth factor) and its receptor EGF are down-regulated by anthralin treatment, reducing cellular proliferation. These factors are overexpressed in psoriatic cells and are associated with the hyperproliferative activity of keratinocytes. Other chemical messengers abnormally elevated in psoriasis that affect proliferation are the keratins K6, K16, and K17. Anthralin treatment has been shown to lower the concentrations of these keratins. Also, the keratins responsible for differentiation K1, K2, and K10 are elevated after anthralin treatment; this is associated with an increase in cellular differentiation. 10 There is a restoration of filaggrin levels, which, with keratin K10, is essential in restoring the normal horny layer of the skin. 10,15 Decreases in T-lymphocyte transformation and activation and in chemotaxis of white blood cells are also seen. 10 Proposed mechanisms for these effects include decreased glucose 6-phosphatase activity, reduced mitochondrial respiration, changes in protein kinase C activity, and oxygen free-radical formation causing DNA strand breaks, cell membrane damage, and fragmentation of proteins. 7,15-17 Anthralin is applied topically to the skin at an initial concentration of %. The application is best done nightly at bedtime. In the morning, the medication should be rinsed off and the skin coated with an emollient. The dosage may be increased after five days of treatment. There is little improvement in efficacy at concentrations above 5%. 16 Adverse effects of therapy are inflammation and irritation of nonpsoriatic skin and staining of the skin and clothing; these effects have led some patients to discontinue the therapy. 7 If adverse effects are troublesome, the duration of application of anthralin may be reduced. When applied at a 0.1% concentration over a 5- to 20- minute period and at a 1% concentration over 5 minutes, anthralin still had desirable antipsoriatic activity and minimal adverse effects. 16 In a clinical trial comparing anthralin and topical calcipotriol (a vitamin D 3 analogue), anthralin was not as effective as the other agent in clearing 650

7 lesions. 18 In addition, calcipotriol was judged superior in improving quality of life. Tars Tars have been used in the treatment of psoriasis (and other skin disorders) for hundreds of years, but little is known about their mechanism of action. Tars are obtained from organic materials, principally shale, wood, and coal, by heating them in the absence of oxygen. 19 Shale tar has no benefit in psoriasis. Wood tar has some benefit, but it also irritates the skin. For most dermatologic conditions, coal tar is the tar of choice. Coal tar is made from crude coal. When coal is heated in the absence of oxygen, it turns into a vapor. Upon cooling, this vapor condenses to a viscous liquid, or tar. 19 The tar consists of a variety of organic compounds, including phenols, heterocyclic oxygens, hydrocarbons, sulfurs, and nitrogens. The many organic compounds found in coal tar make it very difficult to determine which compound is responsible for the effects seen in psoriasis. Coal tar decreases epidermal cell mitosis and scale development, reduces the amount of sebum produced by sebaceous glands, and has anti-inflammatory effects. 11,19 Coal tar can be made into various topical preparations by suspension in such vehicles as soft yellow paraffin and white petrolatum. For acute outbreaks of psoriasis, a zinc paste can be used that hastens the absorption of the tar. 19 Available liquid or semiliquid preparations are lotions, gels, and shampoos. A 5% coal tar concentration has been found to be the most effective. Coal tar is especially beneficial in psoriasis when there is severe itching. It can be very useful in guttate psoriasis, but coal tar is not recommended as a first-line treatment in erythrodermic or pustular psoriasis because it may cause extensive irritation leading to Koebner s phenomenon. 19 Monotherapy with coal tar may be beneficial in patients with mild to moderate psoriasis. Tar preparations are also used in conjunction with other treatments to obtain synergistic effects. Skin irritation is a common adverse effect. Because of this, coal tar should not be applied over too large an area; it should be used in patients whose lesions are well separated and not too big. 11 Coal tar-induced irritation can cause an acneiform eruption or folliculitis. Contact dermatitis may also result, especially if the patient was previously exposed to tar compounds. 19 Some people may have a phototoxic response. Sunlight alters various organic compounds in the tar that are absorbed into the skin, and these altered compounds exacerbate sunburn. The exposed skin burns and may sting, develops wheals, and becomes erythematous. In animal studies, tar has been shown to have some carcinogenic and teratogenic effects. However, in humans there is little data showing that medicated tar preparations are carcinogenic or teratogenic. The major problem with coal tar is patient acceptance. Tar preparations are usually greasy, messy, and smelly, and they can stain clothing. Some commercially available products are formulated to have more cosmetic appeal, but there is still some odor and staining potential. Corticosteroids Topical corticosteroids are the most extensively used medications for psoriasis in the United States. 2 They reduce inflammation, itching, and scaling of lesions. Topically applied corticosteroid formulations are generally nonirritating and have high patient acceptability. Oral corticosteroids were first used in 1949 to treat rheumatoid arthritis. The first topical corticosteroid, hydrocortisone acetate, was introduced in 1953; since then a vast number of topical corticosteroids have been developed that are based on the original 17-carbon corticosteroid molecule. 20 Corticosteroids enter cells and bind to glucocorticoid receptors. This complex then enters the nucleus and binds to a region on the DNA molecule. Once bound, the complex is able to stimulate or inhibit the transcription of genes downstream from the binding location. The anti-inflammatory effect seen is a decrease in vascular permeability that leads to a decrease in dermal edema and leukocyte penetration into the skin. Topical corticosteroids also have antiproliferative and immunosuppressive effects. The potency of a topical corticosteroid is standardized according to the decrease in vasoconstriction that it causes. Potency classifications range from mild to high (Table 3). Topical preparations are formulated into ointments, creams, lotions, and gels. The application of each corticosteroid formulation is dependent on the type of psoriatic lesion present and the properties of the vehicle. Lesions that are dry, hyperkeratotic, and scaly are best treated with an ointment. Ointments allow the stratum corneum to rehydrate itself. Since ointments are inherently oily and greasy, they are best used on areas with little hair because of the difficulty in cleaning. Cream formulations are well accepted for use on all areas, especially those involved in movement, and are useful for infected lesions. Lotions and gels are very easily applied and rapidly disappear into the skin; they tend to be less viscous than ointments and creams and are generally used for scalp psoriasis. Corticosteroids are applied directly to psoriatic lesions. In some patients this may be all that is needed to make a lesion subside. However, many lesions will recur after discontinuation of the treatment. The goal of therapy with corticosteroid preparations, therefore, is to increase the time of remission. Plaque psoriasis can be managed with a high-potency topical corticosteroid. The corticosteroid should be applied twice daily until the lesions are under control. The corticosteroid 651

8 strength should be tapered and the dosage interval increased to find the lowest corticosteroid strength and longest dosage interval that are still effective. Topical corticosteroids are not innocuous. Patients may experience skin atrophy within 314 days of the initial application of a corticosteroid; other adverse effects are an increase in fine hair growth, hypopigmentation, allergic contact dermatitis, and systemic absorption leading to adrenal suppression. The adverse effects of corticosteroids depend on their potency. To reduce the risk of systemic absorption, corticosteroid preparations should be used sparingly. Upon withdrawal of high-potency corticosteroids, a patient may have a flare-up. Tapering a corticosteroid will help minimize flare-ups. Vitamin D 3 analogues The utility of vitamin D for psoriasis was discovered accidentally in the mid-1980s. 21 A physician was treating a woman with osteoporosis with vitamin D. She also had severe, resistant psoriasis. The vitamin D supplementation led to clearing of her psoriatic lesions. Vitamin D 3, or cholecalciferol, was first isolated from cod liver oil in It is also made in the skin through a reaction involving 7-dehydrocholesterol and ultraviolet light. Cholecalciferol is metabolized to its physiologically active form, calcitriol, by hydroxylation in the liver and then the kidneys. The vitamin D 3 receptor was first discovered in intestinal epithelial, bone, and kidney cells. However, it is now known that vitamin D 3 receptors are also found in epidermal keratinocytes, dermal fibroblasts, T and B lymphocytes, monocytes, and macrophages. 22,23 Calcitriol has three important properties of potential use in the treatment of psoriasis: It increases cellular differentiation, it inhibits cellular proliferation, and it has immune-modulating activity. At physiological concentration, calcitriol decreases proliferation and increases the morphological and biochemical differentiation of cultured keratinocytes. The mechanism of action is not completely understood, but the effects may be related to an increase in the concentration of intracellular calcium. 21 Calcitriol increases levels of protein kinase C, which has been associated with keratinization of epidermal cells. 23 The immune system is modu- Table 3. Relative Potencies of Topical Corticosteroids a Level of Potency Rank Corticosteroid Ultra-high High Mild to high Mild Low to mild Low Halobetasol propionate Clobetasol propionate Betamethasone dipropionate Diflorasone diacetate Halcinonide Amcinonide Betamethasone dipropionate Mometasone furoate Diflorasone diacetate Fluocinonide Desoximetasone Halcinonide Triamcinolone acetonide Betamethasone dipropionate Fluocinonide Hydrocortisone valerate Triamcinolone acetonide Flurandrenolide Mometasone furoate Fluocinolone acetonide Hydrocortisone valerate Triamcinolone acetonide Flurandrenolide Betamethasone dipropionate Hydrocortisone butyrate Fluocolone acetonide Alclometasone dipropionate Betamethasone valerate Fluocinolone acetonide Hydrocortisone, dexamethasone, prednisolone, methylprednisolone a Adapted from reference 2, with permission from Janetti Publications, Inc., East Holly Avenue, Box 56, Pitman, NJ Commercial Products Ultravate cream and ointment 0.05% (Westwood Squibb) Temovate cream and ointment 0.05% (Glaxo Wellcome) Diprolene ointment 0.05% (Schering-Plough) Psorcon ointment 0.05% (Dermik) Halog cream 0.1% (Westwood Squibb) Cyclocort ointment 0.1% (ESI Lederle) Diprolene AF cream 0.05% (Schering-Plough), Diprosone ointment 0.05% (Schering-Plough) Elocon ointment 0.1% (Schering-Plough) Florone ointment 0.05% (Dermik) Lidex cream, gel, and ointment 0.05% (Roche) Topicort cream and ointment 0.25% and gel 0.05% (Hoechst Marion Roussel) Halog ointment, cream, and solution 0.1% (Westwood Squibb) Aristocort A ointment 0.1% (Fujisawa) Diprosone cream 0.05% (Schering-Plough) Lidex-E cream 0.05% (Roche) Westcort ointment 0.2% (Westwood Squibb) Kenalog cream and ointment 0.1% (Westwood Squibb) Cordran ointment 0.05% (Eli Lilly) Elocon cream 0.1% (Schering-Plough) Synalar ointment 0.025% (Roche) Westcort cream 0.2% (Westwood Squibb) Kenalog lotion 0.1% (Westwood Squibb) Cordran cream 0.05% (Eli Lilly) Diprosone lotion 0.05% (Schering-Plough) Locoid cream 0.1% (Ferndale) Synalar cream 0.025% (Roche) Aclovate cream and ointment 0.05% (Glaxo Wellcome) Valisone lotion 0.05% (Schering-Plough) Synalar solution and cream 0.01% (Roche) Various topical products containing corticosteroids 652

9 lated by calcitriol s action on T and B lymphocytes, neutrophils, and macrophages. Calcitriol inhibits many of the interleukins, γ-interferon, and granulocyte colony-stimulating factor. The result is a decrease in T-cell proliferation, promotion of suppressor T- cell activity, inhibition of cytotoxic and natural killer T cells, a decrease in neutrophil migration into the skin, and an increase in macrophage activity. The major adverse effects of calcitriol are hypercalcemia and hypercalciuria, 22 which can lead to calcification of soft tissues, including the blood vessels and heart. 23 The main risk of mild calcitriol intoxication is renal stone development. The adverse effects of calcitriol outweigh its benefits and render it unsuitable for use in long-term treatment of psoriasis. This prompted research to develop vitamin D 3 analogues that would retain the antipsoriatic effects of calcitriol but not adversely affect calcium homeostasis and metabolism. Calcipotriol is a vitamin D 3 analogue first synthesized in It has activity comparable to that of calcitriol with respect to cellular proliferation and differentiation; there is no appreciable immune-modulating activity, however. 23 Calcipotriol is times less potent in its effect on calcium homeostasis than calcitriol and is thus less likely to produce hypercalcemia. 22 Calcipotriol may reduce scaling and the thickness of the psoriatic plaque, but the erythema may still occur. 24 A topical corticosteroid alternating with calcipotriol is attractive in this situation to reduce the redness. Calcipotriol is available as a 50-µg/g ointment or cream and as a 50-µg/mL solution for use on the scalp. The recommended maximum weekly cumulative dose is 5 mg. This equates to 100 g of ointment or cream base or 100 ml of solution. Calcipotriol may be applied once or twice daily. 24,25 A therapeutic response is usually noticed after the second week of treatment, with the maximum effect occurring between weeks 6 and Regular application for extended periods is the norm. If the by allowing the protein to bind to other proteins. 26 Induction of gene expression is mediated by RARretinoid complex binding to retinoic acid-responsive elements in the promoter region of certain genes. Inhibition, or down-regulation, of gene expression occurs when the RARretinoid complex antagonizes activator protein 1 transcription factor. 9 These effects on gene transcription cause a change in the expression of a wide variety of chemical messengers inside and outside the cell. Studies of chemical changes in cells have provided evidence of how the retinoid effects are mediated. 9 The normalization of keratinocyte differentiation is noted by changes in differentiation markers within psoriatic cells. The markers that seem to be decreased during treatment are keratinocyte transglutamase, migration inhibitory factor-related protein, skin-derived antileukoproteinase, involucrin, small protein rich protein 2, K6, and K16. An increase in expression of filaggrin was noted. Proliferation markers also are modulated with retinoids. Changes that are seen are a decrease in the expression of EGF receptor, activator protein 1 transcription factor, and ornithine decarboxylase. These factors are related to keratinocyte proliferation. Also, there is a reduction in the inflammatory markers IL-6 and intercellular adhesion molecule-1, and there is a decrease in the number of dermal cells positive for HLA-DR. Topical retinoids. Tazarotene is a topically applied, third-generation retinoid in a water-based emollient gel. It has FDA-approved labeling for use in patients with plaque psoriasis and severe facial psoriasis. Tazarotene s pharmacologic mechanism of action is exerted by its selective binding to retinoid acid receptor subtypes β and γ. This selectivity may be responsible for limiting the undesirable adverse effects seen with other retinoids. 27 Tazarotene s clinical effects in psoriasis are a normalization of abnormal keratinocyte differentiation, a reduction in keratinocyte proliferation, and a repatient uses calcipotriol only intermittently, the lesions often flare up and require more aggressive treatment. Regular use may then be in a sense prophylactic against exacerbations. The most common adverse effect is skin irritation; calcipotriol should not be used on the face or on flexural areas (e.g., the armpits). 23 Some patients may notice a peripheral ring of scaling around treated lesions; patients should be told that this may be a sign that the lesions are starting to improve or clear. A few cases of hypercalcemia have been reported, but these occurred when inappropriately large dosages were used or when the medication was excessively absorbed because of the nature of the lesions. The clinician should investigate how the patient is applying the product and ensure that no more than 100 g is used in a week. Calcipotriol should not be used where there is a high tendency for systemic absorption, such as in severe erythrodermic or pustular psoriasis. Calcipotriol is contraindicated in pregnancy and lactation, and its use in children has not yet been assessed. 22,23 Retinoids Retinoids are biological derivatives of vitamin A. Vitamin A was found many years ago to be effective for phrynoderma, a vitamin A deficiencyrelated follicular hyperkeratosis. However, vitamin A was found to have a low therapeutic index. Research was started in the late 1960s to find a derivative with a lower toxicity profile. 26 Retinoids exert their biological effect after binding to retinoid receptors in the cytoplasm or nucleus. There are two main types of receptors that bind retinoids: retinoic acid receptors (RARs) and retinoid X receptors. Each of these can be further classified into α, β, and γ subtypes. Retinoid receptors in skin cells comprise approximately 90% RAR-γ, and 10% RAR-α receptors. 9 It is presumed that the binding of the retinoid to these receptors causes transcriptional activation or inhibition by changing the conformation of the receptor proteins or 653

10 duction in inflammation. 9 In patients with psoriatic lesions covering less than 20% of the body in areas on the trunk, limbs, elbows, and knees, tazarotene reduced the severity of the lesions over a 12-week course involving a once-daily application of 0.1% and 0.05% gel formulations. 28 Posttreatment results were also seen: Twelve weeks after the end of treatment, the lesions were less severe than at baseline; this was true for both strengths of tazarotene. Similar results were obtained in another study of 0.1% and 0.05% tazarotene gel used once or twice daily. 29 The twice-daily applications of 0.05% tazarotene gel had the highest success rate, followed by twice-daily 0.1%, once-daily 0.1%, and once-daily 0.05% gel applications. There was also posttreatment activity. The most common adverse effects were pruritus, burning, and erythema; their severity and frequency were greatest among patients receiving the 0.1% gel. 28,29 Tazarotene gel should be used sparingly; a pea-sized amount is sufficient for a lesion the size of the palm. The gel should be thoroughly rubbed into the lesion, leaving no residue. None of the gel should be smeared onto the normal surrounding skin. Any gel that gets onto normal skin should be washed off with water. As with retinoid use for acne, tazarotene may cause a retinoid erythema. The clinician should advise the patient to anticipate this and not to assume the psoriasis is getting worse (actually, the healing process is beginning). If the reaction is unacceptable, the gel can be applied every other day. Scratching the reddened skin may cause Koebner s phenomenon. To prevent itching, a topical corticosteroid may be applied. Oral retinoids. The oral retinoids used in psoriasis etretinate and acitretin are considered second-generation retinoids. Acitretin is the active metabolite of etretinate. Etretinate was withdrawn from the U.S. market in March 1998 and replaced by acitretin because the parent compound was toxic and had a long half-life. The use of oral retinoids is limited to treatment of severe forms of psoriasis. Oral retinoids tend to be most effective for pustular and erythrodermic psoriasis and are significantly less effective as monotherapies for chronic plaque psoriasis. 30 Acitretin is administered twice daily for all types of psoriasis. The initial dosage for pustular psoriasis is mg/kg/day. 26 This type of psoriasis responds rapidly to treatment normally in 210 days. 30 The maintenance dosage is mg/kg/day. The initial dosage of acitretin for erythrodermic psoriasis is mg/kg/ day. Symptoms usually start to resolve in two to four weeks. 30 The maintenance dosage is the same as for pustular psoriasis. For chronic plaque psoriasis, adjuvant topical therapies are often used in combination with acitretin. In such regimens for plaque psoriasis, the initial dosage of acitretin is mg/kg/day. After clearing of lesions, the maintenance dosage is mg/kg/day for three to six months. 26 Emollients or topical corticosteroids may help maintain remission during the maintenance period. Acitretin should be avoided in patients with severe diseases of the liver and kidneys and in patients with a history of alcohol abuse. Alcohol ingestion has been shown to alter the metabolism of acitretin and may lead to measurable blood levels of etretinate for up to two years. Because of the teratogenic risk, retinoids are contraindicated in pregnancy. Women should use effective contraception one month before treatment begins and for up to two years after it ends. 30 During treatment with acitretin, patients should be monitored for changes in concentrations of serum lipids, liver enzymes, and serum creatinine. 26 Adverse effects seen with oral retinoid use are peeling and drying skin, diffuse alopecia, nail changes, and sticky or clammy skin. There may also be muscle pain and calcification of ligaments. 30 Therefore, use of this medication should be limited to severe psoriasis. Of the oral treatments used for psoriasis, acitretin induces and maintains remission least often. 31 Yet, when the patient s immune system is impaired, such as in AIDS-related psoriasis, acitretin may be particularly useful. 32 Methotrexate Methotrexate is indicated for use in the treatment of moderate to severe psoriasis when there has been no response to topical treatment. 33 Methotrexate is a folic acid analogue and antagonist. 34 Folic acid antagonists were first noted to be effective in the treatment of psoriasis in 1951 with the use of aminopterin. In 1971, methotrexate received FDA-approved labeling for use in the treatment of severe psoriasis. 35 Methotrexate binds to dihydrofolate reductase with an affinity about 100,000 times greater than that of folic acid. 34 This inhibition leads to a reduction in the synthesis of tetrahydrofolate, which in turn inhibits pyrimidine synthesis. Pyrimidine is essential to the formation of DNA base pairs, so there is a resultant decrease in DNA replication. Methotrexate can also inhibit RNA and protein synthesis. 35 The complete mechanism of action in psoriasis is only partially understood, but it is thought that methotrexate affects epidermal cells and various immunesystem cell lines. 35 Division in proliferating epidermal cells is halted, and blood mononuclear cells (precursors of mature lymphocytes) are reduced in number. Methotrexate is not a first-line treatment; it should be reserved for patients who are unresponsive to topical treatment modalities, retinoids, and phototherapy and who have severe psoriatic erythroderma, psoriatic arthritis, acute pustular psoriasis, localized pustular psoriasis, or plaque psoriasis involving more than 20% of the body surface. 35 Also, this treatment should be limited to patients who are having problems emotionally, physically, or economically with other treatment options. Methotrexate is contraindicated in patients with renal or 654

11 liver problems; pregnant patients; lactating mothers; individuals who are trying to conceive; patients with severe anemia, leukopenia, or thrombocytopenia; alcoholics; and patients with active infectious diseases in whom a compromise in immune function could result in worsening of the disease. 33 Dosing of methotrexate has changed considerably in the many years of its use in psoriasis. At first, the drug was given aggressively then tapered. Clinicians now prefer to begin methotrexate at a low dosage and then adjust the dosage upward to achieve the desired response. In an ideal 70-kg patient with normal renal function, the initial dosage can be 2.55 mg orally taken at 12-hour intervals for a total of three doses each week. Thereafter, on a weekly basis, the total weekly dose can be increased in 2.5-mg increments if blood counts and liver function test results permit this. The dosage should be adjusted upward until symptoms respond. Usually, the maximum weekly dose is 30 mg. Methotrexate may also be given intramuscularly or subcutaneously. Injections are often administered once weekly; the maximum dosage is usually 50 mg/wk, but some patients will require up to 75 mg/wk. 33 Adverse effects of methotrexate include headaches, chills, fever, fatigue, abdominal pain, nausea, vomiting, and dizziness. Patients may also complain of pruritus, alopecia, urticaria, ecchymosis, and phototoxic responses, such as sunburn. A rare adverse effect associated with low-dose methotrexate is osteopathy. Methotrexate-induced osteopathy is indicated by bone pain, radiologic findings of osteoporosis, and stress fractures localized to the distal tibias. 36 Blood counts should be performed routinely in methotrexate recipients to check for anemia, leukopenia, and thrombocytopenia. Also, methotrexate may lead to pulmonary fibrosis, so yearly chest x-rays are recommended. 33,35 Folic acid has been used to limit the toxicity of methotrexate. It is particularly useful in reducing the abdominal pain, which can be debilitating. Folic acid may also decrease the effects of methotrexate on white and red blood cells. Doses of about 1 mg can be given daily except on those days when methotrexate is administered. American College of Rheumatology guidelines for monitoring methotrexate therapy to prevent liver damage are presented in Figure 14. Traditional guidelines suggested that cumulative dose was predictive of hepatotoxicity. 33 Clinicians would calculate the cumulative dose and, if it exceeded 1.5 g, perform a liver biopsy whether liver function test results were normal or not. Prospectively evaluated risk factors have been correlated with biopsy results in juvenile patients with arthritis. 37 The useful predictors of liver damage are increases in liver enzymes and obesity but not the cumulative dose of methotrexate. Liver biopsy is a potentially life-threatening invasive procedure and should be used conservatively. Cyclosporine There is increasing interest in using cyclosporine to treat psoriasis because of outstanding improvements seen with it and because of this agent s immunomodulating properties. As with some other medications, the usefulness of cyclosporine for psoriasis was found serendipitously when it was used to treat another condition. Cyclosporine works by forming a complex with cyclophilin, an isomerase found in nearly all mammalian cells. Until bound to cyclophilin, cyclosporine is inactive. This complex exerts immunosuppressive effects by inhibiting calcineurin, an enzyme essential in the transduction of calciumdependent signals from T-cell receptors to cytokine promoters. Since the cytokine promoters are inhibited, transcription and processing of cytokines in the T cells are inhibited. Cytokines responsible for T-cell growth, such as IL-2 and IL-4, are thus inhibited, decreasing T-cell growth and migration. The cytokines that are secreted are important in the functions of keratinocytes, antigen-presenting cells, and polymorphonuclear cells. Oral cyclosporine has been shown to be effective in the treatment of psoriatic lesions resistant to other thera- Figure 14. American College of Rheumatology algorithm for managing methotrexate (MTX)-induced liver damage. LFTs = liver function tests, CBC = complete blood count, HBV = hepatitis B virus, HCV = hepatitis C virus, d/c = discontinue. Adapted from Kremer JM, Alarcon GS, Lightfoot RWJ et al. Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. Arthritis Rheum. 1994; 37: LFTs, CBC, renal function tests albumin, bilirubin, hepatitis serology Normal laboratory results Initiate MTX Monitor LFT results, albumin every 48 weeks Prior to starting MTX Ethanol abuse, chronic HBV or HCV infection, known elevated LFT results Persistent elevation of LFTs and decrease in albumin to below normal Persistent elevation of LFT results and decrease in albumin to below normal Liver biopsy Normal results Normal results Liver biopsy Fibrosis or cirrhosis Continue MTX Fibrosis or cirrhosis d/c MTX d/c MTX 655

12 pies. Studies have shown that cyclosporine 35 mg/kg/day results in remission in approximately 90% of treated patients within 710 weeks. 38,39 Remission is defined as a 75% reduction from baseline in the area of psoriatic involvement. In almost all patients, relapse occurred two to four months after the end of treatment. These episodes were successfully managed by reintroducing cyclosporine therapy. 38 Three oral formulations of cyclosporine are commercially available: an oil-in-water emulsion (Sandimmune oral solution and capsules, Novartis) and two microemulsions (Neoral oral solution and capsules, Novartis, and SangCya oral solution, SangStat). The problem with the oilin-water emulsion is that its bioavailability is variable and changes with the gut contents. The microemulsion formulations allow cyclosporine to be delivered with much more consistent bioavailability, so more precise pharmacokinetic predictions can be made. In one study, the oil-in-water formulation and a microemulsion were administered to patients at mg/kg/day. 40 Both treatment groups improved, but patients given the microemulsion formulation did so sooner and required less of the drug to obtain therapeutic benefit. The current recommendation is to use the lowest possible dosage of cyclosporine that will maintain efficacy without causing excessive toxicity. To maintain safety, a dosage of 3 mg per kilogram of ideal body weight per day should be used. If there is no improvement after one month of use, the daily dose may be increased by 1 mg/kg. The dosage of cyclosporine should never exceed 5 mg/kg/ day. After remission, which takes 7 10 weeks, the dosage can be gradually adjusted downward by 0.5 mg/kg every two weeks. 38,39,41 During remission, patients may use topical agents, such as coal tar, anthralin, corticosteroids, emollients, keratolytics, vitamin D 3 analogues, and retinoids, to control plaque formation. 39 Common adverse effects associated with the use of cyclosporine in clinical trials include paresthesia, musculoskeletal pains, flu-like symptoms, headache, abdominal pain, nausea, and upper-respiratory-tract infections. 39,42 Blood pressure increased by up to 13 mm Hg (systolic) and 5 mm Hg (diastolic). 42 Cyclosporine may be nephrotoxic. 39,40,42 All preparations of cyclosporine are associated with the same frequency of adverse effects. 40 Tacrolimus Tacrolimus is a macrolide antibiotic that was first isolated in 1984 from the soil fungus Streptomycin tsukubaensis. This drug is very similar to cyclosporine but has times as much immunosuppressive activity. Tacrolimus interferes with IL-2 and IL-8 production. IL-2 is a T-cell growth factor, and IL-8 is thought to play a role in the chemotaxis of neutrophils toward psoriatic lesions. 43 Good results were seen in a study that compared oral tacrolimus with placebo in patients with treatmentresistant plaque psoriasis. 43 After nine weeks of treatment, the tacrolimus group had an 83% decrease in the area of psoriatic involvement, versus a 47% decrease in the placebo group. The initial tacrolimus dosage was 0.05 mg/kg/day. After three weeks, this dosage showed no significant improvement over placebo and was increased to 0.1 mg/kg/day. This increased dosage was associated with improvement over placebo and may be the minimum effective dosage. At the end of the sixth week, the dosage was increased again to 0.15 mg/kg/ day. Further changes in the dosage were made if there was no clinical improvement and the patient was able to tolerate the drug. The main adverse effects of tacrolimus were diarrhea, abdominal pain, nausea, paresthesia, tremor, hypertension, and palpitations. 43 Other adverse effects that may occur are nephrotoxicity and changes in liver enzyme concentrations. Phototherapy Phototherapy has been used to treat various skin disorders for over 100 years and is a key treatment for moderate to severe psoriasis. Ultraviolet A (UVA) and ultraviolet B (UVB) are the two types of ultraviolet light that have been used in the treatment of dermatologic problems. 44 In 1981 it was discovered that 313 nm is the most effective wavelength of ultraviolet light for psoriasis. 45 The light source for ultraviolet light treatments is commercially available cabinets in which UVA light is produced by metal halide or fluorescent bulbs. Many units are designed to irradiate the entire body during therapy and consist of large stand-up cubicles or beds. Panel units have a panel that directs light at one side of the body at a time. Smaller units are designed for use on limited areas, such as the hands and feet. Photochemotherapy is the combination of ultraviolet light and drugs. One of the most common photochemotherapeutic regimens for psoriasis is psoralen plus ultraviolet A (PUVA). Psoralen is a skin sensitizer. 44 Either of these two treatments alone is ineffective. 46 PUVA has been beneficial in psoriasis because of the treatment s antiproliferative, anti-inflammatory, and immunosuppressive effects. 44 PUVA currently has two proposed mechanisms of action. According to the first theory, psoralen is photoactivated within the skin by UVA and is then intercalated into DNA, causing cross-links to form between the pyrimidine bases. 47,48 These cross-links are thought to inhibit epidermal cell hyperproliferation by inhibiting replication of DNA. 48 In the second theory, the effects observed with PUVA are related to free-radical formation within the epidermal cells. 47 Free radicals can damage the cell membrane, cytoplasmic contents, and the nucleus. The damage prevents the cell from undergoing normal physiological processes necessary for growth and interferes with the production of various pro- 656

13 teins and chemical messengers. Clinically, PUVA has been associated with a 73% decrease in the proliferation of keratinocytes in psoriatic skin. 47 Studies have revealed that epidermal and dermal T lymphocytes, as well as CD4 lymphocytes, CD8 lymphocytes, and IL-2 receptors, were suppressed during PUVA treatment. There was also a decrease in HLA-DR expression; expression of HLA-DR is related to the amount of keratinocyte growth and proliferation. The enhanced chemotaxis of monocytes and neutrophils toward lesions was normalized during PUVA treatment, leading to a decrease in polymorphonuclear cells within the lesion. It is thought that remissions seen with PUVA are also related to a direct cytotoxic effect on T lymphocytes within psoriatic lesions. Oral PUVA therapy. Currently, methoxsalen is the only psoralen available for use in the United States. It is taken orally two hours before UVA irradiation. 48 The amount of UVA radiation applied is variable and depends on the patient s skin type. The initial dosage of UVA ranges from 1.5 to 7 J/cm 2 for 2.5 to 11 minutes; generally, darker or tanned individuals require higher dosages. 47 The phototoxicity of PUVA is related to the quantity of psoralen in the skin and the amount of UVA applied. Patients who accumulate a higher concentration of psoralen will require less UVA. Phototoxic reactions to UVA peak at 4872 hours, so it is necessary to wait at least that long before administering the next treatment. Phototoxicity generally manifests itself as erythema, blistering, and edema. After the initial treatment, PUVA should be administered two to four times per week. Since repeated exposure to UVA can cause tanning, the UVA dosage may need to be gradually increased to maintain efficacy. Typically, about 20 sessions are needed before lesions clear. 48 Common adverse effects of oral psoralens are constipation, diarrhea, nausea, vomiting, pruritus, and delayed-onset erythema. 44 Nausea and pruritus have been observed in approximately 15% of patients. 49 Some investigators have also noted a transient rise in serum transaminase levels. 48 Oral psoralens can be distributed throughout the body and into the eyes. For six hours after treatment has stopped, patients should shield their eyes and skin from exposure to sunlight. 47 PUVA has been in use for 20 years. Adverse effects that may be associated with long-term PUVA are premature cutaneous aging, cataracts, and skin cancers, including melanoma. 49 One study suggested that there is a significant increase in skin cancers in patients who have received 100 or more sessions of PUVA and a cumulative dose of UVA of 250 J/cm 2 or more. 50 Another study found an increased risk of squamous-cell carcinoma. 51 Rahman et al. 52 reported an increased risk of melanoma after 15 years in individuals who had more than 250 sessions of PUVA. The patients with melanoma had not had any PUVA treatments within the preceding five years. Patients who have had PUVA should be monitored on a long-term basis for early signs of melanoma. Topical PUVA therapy. Topical psoralens are also beneficial for psoriasis. The psoralen is applied in a cream, lotion, ointment, or waterbath vehicle. 45 The advantage of topical psoralens is fewer adverse effects, such as gastrointestinal problems 53 and cataract formation (since the drug does not penetrate the eyes). 47 Cream-based formulations of methoxsalen have good effects in clinical situations in which it may be difficult to obtain high absorption through the skin, such as when the lesions are in the palmar or plantar regions. A cream formulation of methoxsalen is a more potent therapy than bath treatment because of the higher concentration of the psoralen in the cream vehicle. In a study in patients with palmar psoriasis, PUVA with bath application of methoxsalen only improved the lesions; the cream was able to clear them. 54 Also, with the cream treatment, the quantity of UVA could be reduced; this was not the case with the bath. Cream formulations of methoxsalen are most beneficial in patients with plaques confined to certain areas of the body, however. Attempts to use this agent for widespread lesions may result in inconsistent results because the cream may not be applied evenly. Also, there may be a risk of systemic toxicity. 44 For extensive disease, PUVA with bathing is an effective alternative. 53,55 The patient soaks in an aqueous solution of psoralen for 1520 minutes. The skin is then dried with a towel, and low-dose UVA is given immediately in an amount that will produce minimal erythema. Not only does this approach lack many adverse effects seen with oral administration of psoralens, the efficacy of the drug may be improved. This is indicated by a decrease in the amount and duration of UVA exposure necessary to obtain results similar to those of oral psoralens. 44 Treatment approaches Table 4 reviews the systemic medications for psoriasis that have been reviewed in this article. These medications can be used as monotherapy in some cases (Table 5); in others, they may be used in various combinations (Table 6). The variety of drugs available for managing psoriasis gives the practitioner the flexibility to tailor the treatment to the needs of the patient and the clinical response. When using combination therapy, it is important to use drugs with different mechanisms of action. This will allow targeting of two or more pathways of inhibition within the cells and may cause a synergistic effect. Drawbacks of combination therapy include the increased risk of adverse effects, especially when the medications have immunosuppressive activities. Psoriasis treatment will differ from patient to patient. In general, the treatments with the least severe adverse effects (primarily, topical therapies) should be tried initially. If topical medications fail, systemic therapies may be warranted. These therapies will be 657

14 Table 4. Systemic Treatments for Psoriasis 7 Drug Methoxsalen Methotrexate Acitretin Cyclosporine Tacrolimus a UVA = ultraviolet A light. b LFT = liver function test. Commercial Product Oxsoralen Ultra (ICN) Various Soriatane (Roche) Sandimmune (Novartis) Neoral (Novartis) SangCya (SangStat) Prograf (Fujisawa) Strength and Dosage Form 10-mg capsules 2.5-mg tablets 10- and 25-mg capsules 25-, 50-, and 100-mg capsules; 100-mg/mL oral solution; 50-mg/ ml ampuls 25- and 100-mg capsules, 100-mg/mL oral solution 100-mg/mL oral solution 1- and 5-mg capsules, 5- mg/ml ampuls Dosage Regimen 0.6 mg/kg 2 hr before exposure to UVA a 2.55 mg every 12 hr for 3 doses, once a week; adjust dosage according to response Varies with psoriasis type; initially, mg/kg/day taken in 2 divided doses Initially 3 mg/kg/day; increase daily dose by 1 mg/kg if no response within 1 mo; maximum dosage, 5 mg/kg/day 0.15 mg/kg twice daily; adjust dosage according to patient s tolerance for adverse reactions Adverse Events GI upset, pruritus, delayed erythema Headache, chills, dizziness, nausea, vomiting, phototoxicity, bone marrow depression Dry mouth and skin, alopecia, muscle pains, changes in LFT b results Nephrotoxicity, myalgia, GI upset, hypertension, flu-like symptoms, tremor, changes in LFT results Nephrotoxicity, GI upset, hypertension, tremor, changes in LFT results Table 5. Relative Utility of Monotherapies for Psoriasis a Therapy Calcipotriol Topical corticosteroids Anthralin Coal tar PUVA c Methotrexate Acitretin Cyclosporine Time until Clearance of Lesions (wk) Varies Clearance of Lesions / Varies Effectiveness b Maintenance of Clearance a Adapted from Van de Kerkhof PC, Combinations and comparisons, Clin Dermatol. 1997; 15:831-4, with permission from Elsevier Science. b = excellent, = moderate, = poor, = not recommended. c PUVA = psoralen plus ultraviolet A. based on the type of psoriasis and the responses to the previous therapies. Future therapies Other antimetabolites besides methotrexate have been studied for use in psoriasis. Oral thioguanine has been found to be helpful in patients who did not respond satisfactorily to conventional treatment. 56 Thioguanine improved symptoms in 71% of patients; however, it is more likely than methotrexate to cause bone marrow suppression. Another approach under study is the use of immunomodulation to block the T-cell stimulation seen in psoriasis. A compound, CTLA4Ig (BMS ), has been developed that is a soluble chimeric protein capable of binding to antigen-presenting cells. 28 This binding prevents the stimulation of T cells. In Phase I studies of stable plaque psoriasis, CTLA4Ig reduced the number of T cells in the dermis while reducing epidermal thickness and proliferation. Clinical improvement in the psoriasis was noted. Future studies will decide the role for immunomodulators in psoriasis. Conclusion Drug therapy is the mainstay of the treatment of psoriasis. The extensive adverse effects associated with the drugs used to treat psoriasis and the potential for these drugs to interact with other drugs necessitate vigilant monitoring of patients. References 1. Schmidt JE. Medical discoveries, who and when. Springfield, IL: Thomas; 1959: McClelland PB. New treatment options for psoriasis. Dermatol Nurs. 1997; 9: National Psoriasis Foundation. Psoriasis statistics. (accessed 1999 Feb 22). 4. Ortonne JP. Aetiology and pathogenesis of psoriasis. Br J Dermatol. 1996; 135(suppl 49): Stern RS. Psoriasis. Lancet. 1997; 350: Van Onselen J. Psoriasis in general practice. Nurs Stand. 1998; 12: Han N, Nowakowski P, West D. Common skin disorders: acne and psoriasis. In: DiPiro J, Talbert RL, Yee GC et al., eds. Pharmacotherapy: a pathophysiologic approach. Stamford, CT: Appleton & Lange; 1999: De Jong EM. The course of psoriasis. Clin Dermatol. 1997; 15: Duvic M, Nagpal S, Asano AT et al. Molecular mechanisms of tazarotene action in psoriasis. J Am Acad Dermatol. 1997; 37(2, part 3):S

15 Table 6. Relative Utility of Combination Therapies for Psoriasis a,b Therapy Acitretin Cyclosporine Methotrexate PUVA Coal tar Anthralin Topical corticosteroids Calcipotriol / Topical Corticosteroids... Anthralin /... Coal Tar a Adapted from Van de Kerkhof PC, Combinations and comparisons, Clin Dermatol. 1997; 15:831-4, with permission from Elsevier Science. b = combination is strongly recommended, = combination is recommended, = combination is contraindicated, PUVA = psoralen plus ultraviolet A.... / PUVA b... Methotrexate... Cyclosporine Mahrle G, Bonnekoh B, Wevers A et al. Anthralin: how does it act and are there more favourable derivatives? Acta Derm Venereol. 1994; 74(suppl 186): Bardolph E, Ashton R. Psoriasis: a review of present and future management. Nurs Stand. 1998; 12: Van Steensel M, Steijlen P. Genetics of psoriasis. Clin Dermatol. 1997; 15: Tagami H. Triggering factors. Clin Dermatol. 1997; 15: National Psoriasis Foundation. Be aware of medications that may cause psoriasis to flare. (accessed 1999 Feb 22). 15. Van der Vleuten C, de Jong EM, Van de Kerkhof P. Epidermal differentiation characteristics of the psoriatic plaque during short contact treatment with dithranol cream. Clin Exp Dermatol. 1996; 21: Mahrle G. Dithranol. Clin Dermatol. 1997; 15: Muller K. Antipsoriatic and proinflammatory action of anthralin. Biochem Pharmacol. 1997; 53: Wall AR, Poyner TF, Menday AP. A comparison of treatment with dithranol and calcipotriol on the clinical severity and quality of life in patients with psoriasis. Br J Dermatol. 1998; 139: Arnold WP. Tar. Clin Dermatol. 1997; 15: Hughes J, Rustin M. Corticosteroids. Clin Dermatol. 1997; 15: Rationale for the use of vitamin D3 analogues in psoriasis. Br J Clin Pract Suppl. 1996; 83: Fogh K, Kragballe K. Vitamin D3 analogues. Clin Dermatol. 1997; 15: Stewart DG, Lewis HM. Vitamin D analogues and psoriasis. J Clin Pharm Ther. 1996; 21: Ramsay CA. Management of psoriasis with calcipotriol used as monotherapy. J Am Acad Dermatol. 1997; 37:S Pariser DM, Pariser RJ, Breneman D et al. Calcipotriene ointment applied once a day for psoriasis: a double-blind, multicenter, placebo-controlled study. Arch Dermatol. 1996; 132:1527. Letter. 26. Gollnick HP, Dummler U. Retinoids. Clin Dermatol. 1997; 15: Chandraratna RA. Tazarotene first of a new generation of receptor-selective retinoids. Br J Dermatol. 1996; 135: Weinstein G, Krueger G, Lowe NJ et al. Tazarotene gel, a new retinoid, for topical therapy of psoriasis: vehicle-controlled study of safety, efficacy and duration of therapeutic effect. J Am Acad Dermatol. 1997; 37: Krueger G, Drake LA, Elias PM et al. The safety and efficacy of tazarotene gel, a topical acetylenic retinoid, in the treatment of psoriasis. Arch Dermatol. 1998; 134: Gollnick HP. Oral retinoids efficacy and toxicity in psoriasis. Br J Dermatol. 1996; 135(suppl 49): Spuls PI, Bossuyt PM, van Everdingen JJ et al. 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