Elizabeth A. Abel MD1
Mark Lebwohl MD2
1Clinical Professor of Dermatology, Stanford University School of Medicine
2Sol and Clara Kest Professor and Chairman, Department of Dermatology, Mount Sinai School of Medicine
Elizabeth A. Abel, M.D., has been an investigator, consultant, or speaker for Abbott Laboratories, Allergan, Inc., Amgen, Inc., Biogen, Inc., Centocor, Inc., Connetics Corp., Genentech, Inc., and 3M.
Mark Lebwohl, M.D., has been an investigator, consultant, or speaker for Abbott Laboratories, Allergan, Inc., Amgen, Inc., Biogen, Inc., Centocor, Inc., Connetics Corp., Fujisawa Healthcare, Inc., Galderma Laboratories, Genentech, Inc., Novartis AG., and Warner Chilcott.
Psoriasis is an immune-mediated inflammatory cutaneous disorder characterized by chronic, scaling, erythematous patches and plaques of skin. It can begin at any age and can vary in severity. Psoriasis can manifest itself in several different forms, including pustular and erythrodermic forms. In addition to involving the skin, psoriasis frequently involves the nails, and some patients may experience inflammation of the joints (psoriatic arthritis). Because of its highly visible nature, psoriasis can compromise both the personal and the working lives of its victims.
Breakthroughs in the treatment of psoriasis have led to a better understanding of its pathogenesis. This chapter reviews current knowledge of the genetics, pathogenesis, and treatment of psoriasis.
The estimated prevalence of psoriasis ranges from 0.5% to 4.6% worldwide. The reasons for the geographic variation in prevalence are unknown, but climate and genetics may play a role. Psoriasis is uncommon in blacks in tropical zones, but it is more often seen in blacks in temperate zones. It occurs commonly in Japanese persons but rarely in persons native to North and South America. In the United States, studies have variously reported that 4.5 million adults1 or 7 million adults and children2 have psoriasis.
Psoriasis can occur at any age, with some cases being reported at birth and others being reported in patients older than 100 years. In Farber and Nall's pioneer study of 5,600 patients, the average age of onset of psoriasis was 27.8 years; in 35% of patients, onset occurred before 20 years of age, and in 10%, onset occurred before 10 years of age.3 Psoriasis occurs with equal frequency in men and women, but in Farber and Nall's study, onset occurred later in men. In populations in which there is a high prevalence of psoriasis, onset tends to occur at an earlier age. In the Faroe Islands, for example, the prevalence is 3%, and the average age of onset is 12.5 years. The average age of onset is 23 years in the United States. In persons with earlier age of onset, psoriasis is more likely to be severe, with involvement of a large area of skin surface.
Psoriasis was once thought to be caused by an abnormality in epidermal cell kinetics; it is now thought that an abnormality in the immune system triggers epidermal proliferation. The role of activated lymphocytes in the development of psoriasis was first proved through investigations of DAB389 interleukin-2 (IL-2), a fusion protein consisting of molecules of IL-2 fused to diphtheria toxin. This fusion protein binds to high-affinity IL-2 receptors on activated T cells, destroying those cells. In a study of DAB389 IL-2 treatment in 10 patients, four patients showed dramatic clinical improvement and four others showed moderate improvement.4 Unfortunately, the side effects of DAB389 IL-2 have precluded its approval for the treatment of psoriasis.5
The skin of patients with lesional psoriasis has higher numbers of antigen-presenting cells that can activate T cells. For T cell activation to occur, antigen-presenting cells must deliver at least two signals to resting T cells. The first signal occurs when major histocompatibility complex (MHC) class II molecules of the antigen-presenting cells present antigens to the T cells. A second co stimulatory signal must be delivered through the interaction of ligands on the surface of the antigen-presenting cells with receptors on the surface of T cells. Examples of this process include the interaction of B7 molecules with CD28 on the surface of resting T cells and the interaction of lymphocyte function-associated antigen 3 (LFA-3) with CD2 or intercellular adhesion molecule-1 (ICAM-1) with LFA-1 on the surface of T cells.6,7Blockade of any of these steps results in clearing of psoriasis.8,9 Upon activation, T cells release Th1 (T helper type 1) cytokines, IL-2, and interferon gamma, which together induce proliferation of keratinocytes and further stimulation of T cells. Inflammatory cytokines such as tumor necrosis factor-α (TNF-α) are found in psoriatic skin lesions and joints, and treatment with TNF-α blockers results in clearing of psoriasis and of psoriatic arthritis.10
Several lines of evidence suggest that psoriasis has a genetic etiology. One third of persons affected have a positive family history. Studies have found a higher concordance rate in monozygotic twins than in dizygotic twins or siblings (70% versus 23%).11
Current evidence suggests genetic heterogeneity. Both autosomal dominant inheritance with incomplete penetrance and polygenic or multifactorial inheritance have been described. The most important psoriasis susceptibility gene appears to be PSORS1, which has been mapped to the region on chromosome 6p21 that codes for the MHC; seven other PSORS genes have been found on other chromosomes.12Psoriasis is also associated with a single-nucleotide polymorphism on chromosome 17q25 that impairs binding of a runt-related protein (RUNX1).13
The course and severity of psoriasis can be affected by a number of endogenous and exogenous factors, including stress, climate, concurrent infections, and medications.
Many patients believe that anxiety or psychological stress has an adverse effect on the course of their psoriasis. The etiologic significance of stress in psoriasis is difficult to evaluate, however, because of the subjective nature of the evidence used in many of the investigations into this question.14 In a prospective study, a multivariate statistical method revealed a positive correlation between severity of psoriasis symptoms and psychological stress related to adverse life events.15 Psoriasis itself can be a source of stress: the effects of psoriasis on physical and mental function have been compared with the effects of cancer, heart disease, diabetes, and depression.16
It has long been known that psoriasis improves when patients are exposed to sunny climates and to regions of lower latitude. In northern latitudes, exacerbation of psoriasis commonly occurs during the fall and winter.
Viral or bacterial infections, especially streptococcal pharyngitis or tonsillitis, may precipitate the onset or exacerbation of psoriasis.17Guttate psoriasis, in particular, is often attributed to a previous streptococcal infection. Attempts to reverse psoriasis by treatment with oral antibiotics have not proved effective in double-blind trials.18 Nevertheless, some investigators advocate antibiotic therapy for psoriasis.19
Infection with HIV has also been associated with psoriasis. In some patients with HIV infection, preexisting psoriasis becomes exacerbated; in other patients, psoriasis develops within a few years after HIV infection. Often, HIV-infected patients present with symptoms similar to those of Reiter syndrome.20
Numerous drugs can worsen psoriasis.21 Antimalarial agents such as chloroquine can cause exfoliative erythroderma or pustular psoriasis. Up to 31% of patients experience new onset or worsening of psoriasis as a result of antimalarial therapy. Lithium and beta blockers such as propranolol may precipitate the onset of psoriasis or cause exacerbations of psoriasis.22 Some nonsteroidal anti-inflammatory drugs (NSAIDs) also exacerbate psoriasis, although this effect is sufficiently minor to allow NSAIDs to be used in the treatment of psoriatic arthritis.23 Flares of pustular psoriasis may be precipitated by withdrawal from systemic corticosteroids or withdrawal from high-potency topical corticosteroids. Interferon therapy has been associated with development or exacerbation of psoriasis, presumably because of the Th1 effects of this therapy.24
Trauma to the clinically uninvolved skin of patients with psoriasis can cause a lesion to appear at the exact site of injury; this phenomenon is known as the Köbner response. Cuts, abrasions, injections, burns resulting from phototherapy, and other forms of trauma can elicit this reaction.
Smoking may be an exacerbating factor in psoriasis.25 Alcohol use has also been implicated in the exacerbation of psoriasis.26
Surveys have suggested that diet plays a role in the development of psoriasis, and attempts have been made to affect the clinical course of psoriasis through modification of diet.27 Double-blind studies, however, have failed to show that diet has either a beneficial or a detrimental effect on the severity of psoriasis.
The diagnosis of psoriasis is usually made on clinical grounds. If unusual features are present, biopsy of affected skin can be done to confirm the diagnosis.
Nearly 90% of patients with psoriasis have plaque type, a form that is characterized by sharply demarcated, erythematous, scaling plaques. The elbows [see Figure 1], knees, and scalp [see Figure 2] are the most commonly affected sites. The intergluteal cleft [see Figure 3], palms [see Figure 4], soles [see Figure 5], and genitals are also commonly affected, but psoriasis can involve any part of the body. Lesions frequently occur in a symmetrical pattern of distribution.
Figure 1. Plaque Psoriasis: Elbow Involvement
Involvement of the elbows is characteristic of plaque psoriasis.
Figure 2. Plaque Psoriasis: Scalp Involvement
The scalp is affected in the majority of patients with plaque psoriasis.
Figure 3. Plaque Psoriasis: Intergluteal Cleft Involvement
The intergluteal cleft is a common site of involvement in patients with plaque psoriasis.
Figure 4. Psoriasis of the Palms
Psoriasis of the palms is shown in this patient.
Figure 5. Psoriasis of the Soles
Sharply demarcated, erythematous, scaling plaques on the feet are apparent in this patient with psoriasis of the soles.
Many patients have only one or a few lesions that persist for years and that occasionally resolve after exposure to sunlight. Other patients can be covered with plaques that become confluent, affecting nearly 100% of the body surface area. Nail involvement is common, particularly in patients with severe disease.
The second most common form of psoriasis, guttate psoriasis, affects fewer than 10% of patients and is characterized by the development of small, scaling, erythematous papules on the trunk and the extremities [see Figure 6]. This form of psoriasis often follows streptococcal infection. Patients with plaque-type psoriasis can develop guttate psoriasis. Conversely, patients with guttate psoriasis frequently develop plaque-type psoriasis. Occasionally, guttate lesions enlarge and become confluent, resulting in the formation of plaques.
Figure 6. Guttate Psoriasis
Guttate psoriasis is characterized by small scaly papules and plaques.
Erythrodermic psoriasis is a severe form of psoriasis that often affects the entire cutaneous surface. Patients present with an exfoliative erythroderma in which the skin is very red and inflamed and is constantly scaling [see Figure 7]. Patients are acutely ill, their skin having lost all protective function. Loss of temperature control, loss of fluids and nutrients through the impaired skin, and susceptibility to infection make this a potentially life-threatening condition.
Figure 7. Erythrodermic Psoriasis
Erythrodermic psoriasis is characterized by generalized erythema and desquamation.
Erythrodermic psoriasis can develop de novo or evolve from typical plaque-type or guttate psoriasis. Erythrodermic psoriasis can occur after withdrawal of systemic corticosteroids, after phototherapy burns, as a result of antimalarial treatment, as a result of a drug-induced hypersensitivity reaction, or for no apparent reason. Cutaneous T cell lymphoma may also present as erythroderma and needs to be differentiated from erythrodermic psoriasis.
Pustular psoriasis, another severe form of the disease, can occur in patients with preexisting psoriasis or can arise de novo. Pustular psoriasis can be generalized (von Zumbusch type) or localized to the palms and soles [see Figure 8]. In either case, the condition is severe and debilitating. In generalized pustular psoriasis, the body is covered with sterile pustules. As with erythrodermic psoriasis, the protective functions of the skin are lost, and patients may succumb to infection or hypo volemia and electrolyte imbalance caused by loss of fluid through the skin. Although fever and leukocytosis are common features in pustular psoriasis, the possibility of infection should not be overlooked; patients with pustular psoriasis have died of staphylococcal sepsis.28
Figure 8. Pustular Psoriasis
Pustular psoriasis can be localized to the palms and soles or generalized.
As with erythrodermic psoriasis, pustular psoriasis is most commonly precipitated by withdrawal of systemic cortico steroids. However, it can also result from therapy with antimalarial drugs or lithium, and it can develop spontaneously.
Nail changes can be of immeasurable value when the diagnosis is in doubt [see Figure 9]. In one study, 55% of patients with psoriasis experienced such changes.29 The most common change consists of the appearance of tiny pits, as might be made with an ice pick, which often occur in groups. This characteristic pitting of the nails is highly specific for psoriasis, although a few isolated pits may be seen in healthy nails or as a result of past trauma. Yellowish discoloration is common in psoriatic toenails and may appear in fingernails as well. Onycholysis, or distal separation of the nail plate from its bed, frequently occurs.
Figure 9. Nail Involvement
Involvement of the nails is common in psoriasis.
Other changes include subungual hyperkeratosis—an accumulation of keratinous debris under the nail—as well as transverse and longitudinal ridging. These findings, however, are much less specific because they also occur secondary to dermatitis, fungal infection, vascular insufficiency, and other conditions. Occasionally, a patient shows typical psoriatic nail changes without any other cutaneous signs at initial examination; all such patients are probably psoriatic and may eventually manifest psoriatic lesions.
Psoriatic arthritis has been estimated to occur in 7% to 42% of patients with psoriasis.30 Joint inflammation in psoriatic arthritis is chronic, with occasional remissions.31 There are five classic subtypes. The most common presentation is an oligoarthritis in which one or a few joints are affected. This form accounts for approximately 70% of cases of psoriatic arthritis. Skin lesions of psoriasis usually precede articular disease by 5 to 10 years, but joint inflammation develops before skin lesions in some patients. If a diagnosis of psoriatic arthritis is suspected, the physician should carefully examine the scalp, nails, intergluteal cleft, external ear canal, and genital region for psoriasis lesions.
The second most common type of psoriatic arthritis is virtually identical to rheumatoid arthritis. This form is characterized by symmetrical involvement of the joints with ulnar deviation and typical deformities, such as swan-neck deformity and boutonnière deformity. The only distinguishing features are the presence of psoriasis and the absence of circulating rheumatoid factor.
Arthritis mutilans is a rare, severely destructive form of psoriatic arthritis in which the interphalangeal joints of the hands and feet are destroyed, resulting in deformed digits. Ankylosing spondylitis accounts for 5% of cases of psoriatic arthritis. As in other forms of ankylosing spondylitis, the genetic marker HLA-B27 is usually present.
Distal interphalangeal joint involvement is the most characteristic form of psoriatic arthritis. It is usually associated with nail involvement.
The classic microscopic features of a psoriatic plaque include the following:
The differential diagnosis of psoriasis includes other scaling dermatoses [see 2:II Papulosquamous Disorders]. Such dermatoses include the following:
More treatments are available for psoriasis than perhaps for any other dermatologic disease. New topical therapies, new systemic therapies, and new forms of phototherapy have been introduced, and additional treatments are in development. Biologic therapies that target specific molecules are likely to change the treatment of psoriasis in the future. Topical therapy will continue to be used by most patients, however.
The 1990s saw the development of many new therapies for psoriasis.32 Topical therapy is the mainstay of treatment for most patients, particularly those with mild disease. Topical cortico steroids are the most commonly prescribed class of medication, but they are now often used together with topical calcipotriene, a vitamin D3 analogue, or topical tazarotene, a retinoid; both calcipotriene and tazarotene have approval by the Food and Drug Administration for the treatment of psoriasis.33 Tar and salicylic acid are available by prescription and as over-the-counter products. Use of anthralin has declined as effective nonsteroidal agents have become available.
Emollients are an important part of any topical regimen for psoriasis. Application of petrolatum alone may be sufficient therapy for some patients. More elegant creams and lotions are helpful but are somewhat less effective than greasy ointments. Tar and salicylic acid shampoos are valuable in the treatment of patients with scalp involvement. These preparations are available without prescription.
Topical corticosteroids are indicated for limited plaques of psoriasis. Because of their ease of use and their wide availability, topical corticosteroids are the most commonly prescribed medication for treatment of psoriasis. They have anti-inflammatory, antiproliferative, and antipruritic effects. Corticosteroids are more potent when they are applied under occlusion, which increases their percutaneous penetration. Unfortunately, occlusion also increases side effects.
Topical steroids have been ranked in seven categories in decreasing order of potency, with potency determined by a vasoconstriction assay [see Table 1]. Superpotent corticosteroids are in group I, and weak over-the-counter topical corticosteroids are in group VII.34
Table 1 Ranking of Topical Steroids for Psoriasis in Order of High to Low Potency
The most commonly encountered side effects of topical corticosteroids are local cutaneous reactions. Development of cutaneous atrophy, telangiectasia, and irreversible striae are the most common side effects. Perioral dermatitis, which is characterized by erythematous papules and pustules on the face, is caused by chronic use of topical corticosteroids. Tachyphylaxis, with habituation to topical corticosteroids and loss of response to them, is noted by most patients. Flare or rebound of psoriasis upon sudden withdrawal of topical corticosteroids can occur. Finally, suppression of the hypothalamic-pituitary-adrenal axis can occur, especially with use of superpotent topical corticosteroids, the widespread application of corticosteroids, occlusion, or chronic use. Because of concern over side effects, the package inserts for some superpotent corticosteroids suggest that use be limited to 2 weeks' duration. A number of regimens have been developed in which, after the initial weeks of continuous treatment with superpotent topical corticosteroids, psoriasis plaques are subsequently treated only on weekends.35
Vitamin D Analogues
The first topical vitamin D analogue to receive FDA approval for use in the United States, calcipotriene has rapidly gained acceptance, despite the fact that it is not as effective as superpotent topical corticosteroids. Calcipotriene is available in ointment and cream form and as a solution. The primary reason for its success is its freedom from any corticosteroid side effects—namely, cutaneous atrophy, telangiectasia, striae, or suppression of the hypothalamic-pituitary-adrenal axis. Calcipotriene is comparable in efficacy to a group II corticosteroid. It is applied twice daily.
Calcipotriene has been used very successfully in combination with several other medications. It is most effective when used in combination with a superpotent topical corticosteroid. A regimen of calcipotriene ointment and halobetasol propionate ointment, each applied once daily, has been found to be more effective than monotherapy with either calcipotriene twice daily or halobetasol propionate twice daily.36 Up to 90% of patients achieve marked improvement within 2 weeks of combination therapy with once-daily calcipotriene and once-daily halobetasol propionate ointment. For long-term maintenance of remission, a regimen has been developed in which halobetasol propionate is applied only on weekends and calcipotriene is applied on weekdays.37 Using this regimen, 76% of patients achieved marked improvement for at least 6 months; this level of improvement was achieved in only 40% of patients receiving halobetasol propionate ointment on weekends only. Calcipotriene has also been shown to improve the response to ultraviolet B light (UVB)38 and to psoralen plus ultraviolet A light (PUVA).39
Caution must be used when combining calcipotriene ointment with other medications, because it is easily inactivated. Salicylic acid, for example, completely inactivates calcipotriene on contact. Several other topical medications, including topical corticosteroids, can inactivate calcipotriene. In contrast, halobetasol propionate ointment is compatible with calcipotriene even when one medication is applied on top of the other.40 UVA has been shown to inactivate calcipotriene,41 so calcipotriene should be applied after PUVA therapy, not before. Use of calcipotriene should be limited to a maximum of 120 g a week because of isolated reports of hypercalcemia.42
A combination product containing calcipotriene and betamethasone dipropionate is now available in Europe and Canada. It appears to be more effective than the individual medications applied separately.43
Other vitamin D analogues
Several new vitamin D analogues are under investigation in the United States or are in use elsewhere. Tacalcitol and maxacalcitol are promising medications for the treatment of psoriasis. The only common side effect is irritation, which occurs in up to 20% of patients, most often on the face and in intertriginous areas. Topical calcitriol has FDA approval for the treatment of psoriasis in several countries around the world44; it may be less irritating than calcipotriene in intertriginous sites.
Tazarotene is a retinoid that has been developed for the treatment of psoriasis. It is available in 0.05% and 0.1% gels and in cream formulations. Tazarotene is comparable in efficacy to a group II corticosteroid cream. Patients receiving tazarotene 0.1% gel experience longer periods of remission after discontinuance of therapy than patients receiving corticosteroids.
Tazarotene has several advantages over the corticosteroids. First, it is not associated with cutaneous atrophy, telangiectasia, or the development of striae. In fact, tazarotene, like other retinoids, may actually prevent corticosteroid atrophy. Tazarotene has been shown to enhance the efficacy of UVB phototherapy.45 It does, however, increase the ability of ultraviolet light to induce erythema.46 Doses of UVB and UVA should therefore be reduced in patients who are also receiving tazarotene.
The main side effect of tazarotene is local irritation, which has caused many patients to discontinue its use. The combination of tazarotene and a topical corticosteroid reduces irritation and enhances the efficacy of both agents.
Tar has been used since the 19th century to treat psoriasis. Crude coal tar, a complex mixture of thousands of hydrocarbon compounds, affects psoriatic epidermal cells through enzyme inhibition and antimitotic action.47 Crude coal tar is messy to apply, has a strong odor, and stains skin and clothing. It is applied in conjunction with UVB phototherapy in the Goeckerman regimen [see Phototherapy, below]. More refined tar preparations, which are cosmetically acceptable, are available by prescription and over the counter in the form of gels, creams, bath oils, shampoos, and solutions (liquor carbonis detergens). Tar is often used in combination therapies and as maintenance therapy after psoriasis plaques have resolved.
Anthralin (dithranol) has been used to treat psoriasis since 1916.48 It is an extremely effective topical agent for psoriasis, probably because it inhibits enzyme metabolism and reduces epidermal mitotic turnover.48
Because of the staining and irritation associated with the use of anthralin, this agent is usually prescribed for patients who do not respond to other topical therapies.
Formulations and regimens
A modified Ingram regimen combines the daily application of anthralin in a stiff paste with tar baths and with exposure to ultraviolet light. This therapy involves application of progressively higher concentrations of anthralin for 6 to 8 hours at a time; it was introduced in the United States for hospitalized psoriatic patients44 and for ambulatory patients in a psoriasis day care center.49
Modified anthralin formulations have been used to minimize the staining from anthralin, to decrease irritation, and to promote home use of the medication. Short-contact therapy consists of the application of anthralin to localized plaques for 30 minutes to 2 hours, after which time the anthralin must be thoroughly removed to minimize irritation of the surrounding skin.50 Anthralin in a cream base, which can be removed by washing with water, is suitable for home use; it is available in 1% and 0.5% concentrations, for application to localized lesions on the skin and the scalp.
A formulation of 1% anthralin cream, composed of microencapsulated lipid crystals that release anthralin for absorption at skin temperature, is available. When used as short-contact therapy, this preparation carries a low risk of staining and irritation.51
Anthralin is most effective therapeutically when it is compounded in the form of a hard paste containing paraffin; this form is most commonly used in ambulatory psoriasis treatment centers. Anthralin ointment is less effective than anthralin paste, and anthralin cream is even less effective. With regard to patient compliance, this order is reversed. The end point of treatment is resolution of plaques to a macular state; this is usually associated with residual postinflammatory hyperpigmentation and temporary staining from anthralin. Resolution of symptoms usually occurs within 2 to 3 weeks after a modified Ingram regimen; remissions last for weeks to months.
Staining of skin, clothing, and the home is common with anthralin, as is irritation at the site of application.
Ultraviolet radiation has a beneficial effect on psoriasis. Sun bathing for 2 to 4 weeks lessens the morbidity associated with the disorder, and climatotherapy at the Dead Sea is an effective alternative therapy for psoriasis for those who can travel to that part of the world. Because of its unique geographic location, 300 m below sea level, patients are exposed to naturally filtered ultraviolet light, which results in significant improvement or complete resolution of symptoms in 83% of patients over several weeks.52 The sunlight at the Dead Sea ac counts for most of the response, with little additional improve ment resulting from bathing in the Dead Sea. Not surprisingly, patients treated at the Dead Sea have higher rates of nonmelanoma skin cancer.53
Phototherapy with UVB is an important therapeutic option for patients with extensive psoriasis. UVB irradiation can be used alone, but it has traditionally been combined with topical application of tar. Daily in-hospital application of crude coal tar and exposure to ultraviolet light (the Goeckerman regimen) can lead to a resolution of symptoms in widespread psoriasis within 3 or 4 weeks and can effect remissions that last for weeks to months.
In a reevaluation of the Goeckerman regimen, application of a 1% tar preparation was found to be as effective as a 6% preparation. Furthermore, application of the tar preparation for 2 hours before irradiation was equivalent to longer periods of application.54Contraindications to the use of the Goeckerman regimen include the presence of severely excoriated or inflamed psoriasis, erythrodermic and pustular forms of the disease, folliculitis, and a history of photosensitivity.
Newer regimens, which are more convenient and aesthetically acceptable, combine UVB with emollients. The emollient or vehicle decreases reflectance of the psoriatic scale, thereby increasing light transmission. According to a report by Lowe and colleagues, results with emollients are equivalent to those with tar, when used in regimens that utilize UVB in doses sufficient to cause erythema (erythemogenic); however, tar may have an additive effect when combined with a less aggressive regimen of suberythemogenic UVB.55
In a comparison study, outpatient UVB phototherapy was administered three times weekly, along with the application of either a tar oil or an emollient twice a day. This approach led to clearing of psoriatic lesions in 78% of patients [see Figures 10a and 10b]. No difference in response was observed between the tar oil and the emollient.56 Although the Lowe study had shown an additive effect for tar combined with UVB irradiation when patients were evaluated after 3 to 4 weeks (before their lesions had cleared),57 this comparison study showed no such advantage in patients who were evaluated at the time of lesion clearing. Remission lasted longer in patients who received maintenance UVB phototherapy twice weekly for 1 to 2 months and then once weekly for up to 4 months than in patients who stopped receiving UVB phototherapy after the initial clearing.
Figure 10a. Psoriasis in a Child Before Phototherapy
Psoriasis in a child before phototherapy.
Figure 10b. Psoriasis in a Child After Phototherapy
Psoriasis in a child after phototherapy.
Narrow-band UVB, which comprises wavelengths of approximately 311 nm (as opposed to the 295 to 320 nm range of broad-band UVB), is a newer approach that is more effective than broad-band UVB.58 Like other forms of phototherapy, narrow-band UVB works through local effects; therefore, covered areas, such as the scalp, do not respond.59
Photochemotherapy with PUVA is indicated for patients with extensive, disabling psoriasis that has failed to respond to conventional forms of therapy, including conventional or narrow-band UVB phototherapy. PUVA therapy entails the administration of the photosensitizing drug methoxsalen (8-methoxypsoralen)—in an oral dose or by soaking in a tub containing methoxsalen or applying topical methoxsalen—followed by exposure of the patient to high-intensity longwave ultraviolet light in a walk-in irradiation chamber. The initial UVA dose (in joules/cm2) is based on the patient's skin type and calculated in accordance with established protocols.60
Although its therapeutic effect is local, PUVA is a systemic treatment in which photoactivated methoxsalen binds to epidermal DNA, forming monofunctional and bifunctional adducts. It has been postulated that the resulting interference with epidermal mitosis is one of the mechanisms of action of PUVA therapy for psoriasis, although effects on immune function in the skin play an important role.
The efficacy of oral PUVA therapy has been established by several multicenter clinical trials.61 A course of PUVA therapy administered two or three times weekly resulted in significant clearing of psoriasis lesions in approximately 90% of patients within a mean of 25 total treatments. After the initial course, a tapering maintenance regimen is instituted, and PUVA therapy is eventually discontinued. In most patients, psoriasis recurs months to years after PUVA is discontinued, indicating that this therapy is palliative rather than curative.
Acute side effects caused by phototoxicity, such as erythema and blistering, are dose related and can therefore be controlled. Pruritus, usually associated with dryness of the skin, is fairly common and can be alleviated by the use of emollients and oral antihistamines. Nausea may follow ingestion of methoxsalen. Of greater concern are the potential long-term side effects, particularly carcinogenicity. Although the FDA has approved the use of PUVA to treat psoriasis, patients must be closely monitored for long-term side effects. A multicenter study of more than 1,300 PUVA-treated patients in the United States who were evaluated after 1 to 3 years of follow-up revealed a significant increase in the number of squamous cell carcinomas (SCCs) in those patients with a history of exposure to ionizing radiation or a history of skin cancer.62 A higher-than-expected ratio of SCCs to basal cell epitheliomas and an excess of SCCs in areas of the body that were not exposed to the sun were significant findings of the study. A 5.7-year follow-up study of the original cohort group revealed a dose-dependent increase in the risk of SCC.63 There was only a slight increase in the risk of basal cell carcinoma in these patients. The risk of SCC was almost 13-fold higher in patients who had received high cumulative doses of PUVA than in patients who received low-dose therapy.
A follow-up study of the surviving members of that cohort, at least 15 years after original treatment, again assessed the risk of skin cancers. Of great concern was a small but statistically significant increase in the incidence of malignant melanoma.64 Because that increase did not become apparent until after a period of at least 15 years, there is great concern that high rates of melanoma will occur in patients who began PUVA therapy years ago. Fortunately, this has not happened thus far.
Studies in animals suggest that PUVA may have ocular side effects. Methoxsalen has been detected in the lenses of rats after they have ingested the drug; subsequent exposure to UVA enhances such ultraviolet-induced changes as cataracts.65 The risk of ocular toxicity and possible retinal damage is of particular concern in young persons, whose lenses transmit more UVA than the more opaque lenses of older persons, and in aphakic persons, in whom lenses are absent.66 The use of UVA-opaque goggles during PUVA treatment sessions is extremely important. Glasses that block UVA must be worn from the time that methoxsalen is administered throughout the rest of the day. Some investigators advise protection of the eyes the day after therapy. Thus far, studies of patients treated with PUVA have not revealed an increase in the incidence of cataracts.
Short-term use of the antimetabolite methotrexate can be an extremely effective treatment for psoriasis. Methotrexate is indicated for patients who do not respond adequately to phototherapy and for patients with psoriatic arthritis.
The source of methotrexate's efficacy against psoriasis was once thought to be its antimitotic effect on proliferating keratinocytes. However, tissue culture studies have suggested that activated lymphoid cells in the lymph nodes, blood, and skin are a likely target of methotrexate; proliferating macrophages and T cells are 100 times more sensitive to methotrexate than are proliferating epithelial cells.67 These findings may be relevant to the mechanism of action of methotrexate in other immunologically based disorders, including psoriatic arthritis, rheumatoid arthritis, and Crohn disease.
Methotrexate is best given in a single weekly oral dose of up to 30 mg or in three divided doses at 12-hour intervals during a 24-hour period (e.g., at 8:00 A.M., at 8:00 P.M., and again at 8:00 A.M.).
Hepatoxicity and liver biopsy
The use of liver biopsy has been advocated for monitoring patients with psoriasis who are receiving methotrexate. This recommendation is controversial, however; critics point out that liver biopsies are not routinely performed in patients with rheumatoid arthritis who are undergoing treatment with methotrexate.68 Nevertheless, a review of the literature clearly shows that patients with psoriasis who are treated with methotrexate are more likely to develop hepatic fibrosis, possibly because of their underlying disease or because of the concomitant treatments they are given.
Current guidelines call for the use of liver biopsy in patients with psoriasis who have received a cumulative dose of 1 to 1.5 g of methotrexate and who do not have a history of liver disease or alcoholism. Biopsy should be performed early in the course of treatment in patients with a history of hepatitis C, alcoholism, or other liver disease. Other risk factors for hepatotoxicity are obesity, diabetes, and abnormalities on liver function testing.
Pathologic liver changes caused by methotrexate therapy have been graded as follows: grade I, normal liver histology or mild fatty infiltration; grade II, moderate to severe fatty infiltration with portal tract inflammation and necrosis; grade IIIA, mild fibrosis; grade IIIB, moderate to severe fibrosis; and grade IV, cirrhosis. Methotrexate should be discontinued in patients with grade IIIB or IV pathologic liver changes. The importance of strict adherence to current guidelines for the administration of methotrexate is emphasized by the occurrence of methotrexate-induced cirrhosis necessitating liver transplantation in three patients with long-term psoriasis who did not undergo serial liver biopsies.69
Other side effects
In addition to hepatotoxicity, other side effects of methotrexate therapy include bone marrow suppression, nausea, diarrhea, and stomatitis. Methotrexate is teratogenic and can cause reversible oligospermia. Pneumonitis can occur early in the course of treatment if methotrexate is administered in oncologic doses. Evaluation by tests of liver function, renal function, and blood elements must be made before and throughout the course of methotrexate therapy.
Certain drugs increase the toxicity of methotrexate by reducing renal tubular secretion; these drugs include salicylates, sulfonamides, probenecid, and penicillins. Other drugs increase toxicity by displacing methotrexate from its binding sites on plasma proteins; these drugs include salicylates, probenecid, barbiturates, and phenytoin. Many of the NSAIDs and trimethoprim-sulfamethoxazole enhance methotrexate toxicity.68 Cases of pancytopenia after low-dose methotrexate therapy underscore the hazards of using this drug in patients with renal insufficiency or in patients who are concomitantly receiving drugs that increase methotrexate toxicity.70
Contraindications to treatment with methotrexate and indications for stopping treatment should be heeded. Constant medical supervision is necessary, and therapy must be stopped at once if toxicity develops.
Indications and dosage
Acitretin, an oral retinoid, has FDA approval for the treatment of plaque psoriasis. It is highly effective in the treatment of pustular psoriasis and can be very effective as monotherapy for erythrodermic psoriasis. For plaque-type and guttate psoriasis, however, acitretin is most useful in combination with other treatments, particularly UVB and PUVA phototherapy.71,72 Acitretin is initiated 1 to 2 weeks before UVB or PUVA therapy is started. With combination treatment, symptoms resolve much more quickly. Doses of only 10 to 25 mg daily are effective, thus minimizing retinoid side effects.71,72 When used as monotherapy, acitretin is prescribed in doses of 25 mg daily, which can be increased to 50 mg a day or higher.
Acitretin side effects are dose related and are common with doses above 25 mg daily. Hair loss, cheilitis, desquamation of the palms and soles, sun sensitivity, and periungual pyogenic granulomas are among the mucocutaneous side effects. Hyperlipidemia is common but is easily controlled with lipid-lowering agents. Elevations in liver enzyme levels can occur, and enzyme levels must be monitored. Serial liver biopsies have not demonstrated hepatic fibrosis in patients treated with oral retinoids.73
Acitretin poses a significant risk of teratogenicity. Characteristic retinoid birth defects occur in a high proportion of fetuses exposed to even small amounts of the drug in utero. Acitretin is eliminated from the body much more quickly than its prodrug etretinate. In the presence of alcohol, however, acitretin is converted back to etretinate,74 raising concerns that women of childbearing age who take acitretin and who later become pregnant would then be at risk for exposing their fetus to acitretin's teratogenic effects. The FDA therefore requires that acitretin not be given to women planning a pregnancy within 3 years.
Long-term side effects of oral retinoids include calcification of ligaments and tendons and osteoporosis.75,76 The long-term safety of etretinate, acitretin's prodrug, was examined in a 5-year prospective study of 956 patients with psoriasis. The investigators concluded that with appropriate patient selection and monitoring, there was no substantially increased risk of side effects related to cardiovascular disease, cancer, diabetes, cataracts, and inflammatory bowel disease. Although joint symptoms improved in some patients, more patients had joint problems associated with etretinate. Etretinate also caused short-term changes in liver enzyme levels in some patients and, in rare cases, caused acute hepatitis. The long-term risk of liver disease and cirrhosis with etretinate, however, was less than that associated with comparable periods of methotrexate.77
Cyclosporine in a microemulsion formulation was approved by the FDA for the treatment of psoriasis after extensive worldwide experience. In dosages of 2.5 to 5 mg/kg/day, cyclosporine is highly effective for psoriasis. Even at such doses, however, it may be associated with significant side effects, which have limited its use in patients with severe or refractory disease.
Indications and dosage
Cyclosporine is indicated for patients in whom phototherapy or methotrexate therapy has failed. The microemulsion formulation of cyclosporine is better absorbed than earlier formulations. It is available in gel capsules of 25 and 100 mg and is most commonly taken in divided doses twice daily. At dosages of 5 mg/kg/day, a response is usually seen within 4 weeks, and some patients respond as quickly as 1 week. It should be noted that in the United States, the package insert for cyclosporine recommends an upper dosage limit of 4 mg/kg/day, although worldwide experience regarding the efficacy and safety of this drug has established an upper limit of 5 mg/kg/day.78 In the United States, the maximum FDA-approved duration of treatment of cyclosporine is 1 year.
Cyclosporine is associated with a number of side effects that are easily managed; other side effects are of greater concern. Hypertrichosis, tremors, paresthesias, head ache, gingival hyperplasia, joint pain, and fatigue can occur. Elevations in serum lipid levels and minor elevations in liver enzyme levels are also common. Hypomagnesemia may require magnesium supplementation. The most serious common side effects are hypertension and nephrotoxicity. Hypertension can be managed by lowering the dose or by instituting treatment with calcium channel blockers such as amlodipine besylate. There is some evidence that in normotensive patients receiving cyclosporine, amlodipine therapy may prevent some of the nephrotoxicity that has been associated with this potent psoriasis treatment.79
Renal interstitial fibrosis and renal tubular atrophy are common in patients on long-term therapy with cyclosporine.80,81 Consequently, serum creatinine levels must be monitored on a regular basis. If the serum creatinine level rises more than 30% above baseline (or more than 25%, according to the United States package insert), the dosage may have to be reduced.78
Organ transplant patients taking cyclosporine, as well as other immunosuppressive drugs, to prevent rejection have experienced an increase in lymphoproliferative diseases and skin cancers.82,83 It is hoped that the lower doses and intermittent usage of cyclosporine in psoriasis patients will not be associated with an increase in malignancies, but caution must be exercised. In one study, no increase in lymphoproliferative disorders was found in rheumatoid arthritis patients who were treated with cyclosporine for a short period (median, 1.6 years), compared with a parallel group of rheumatoid patients who were not treated with cyclosporine.84 Nevertheless, caution must be used with this powerful new psoriasis treatment.
Although tacrolimus does not have FDA approval for use in psoriasis, it is a potent immunosuppressive agent that may be substituted for cyclosporine in patients who cannot tolerate the hypertrichosis associated with this agent. Tacrolimus has proved to be effective in the treatment of psoriasis. In a double-blind trial, 50 patients with severe recalcitrant psoriasis were given either oral tacrolimus or placebo.85In the tacrolimus group, starting dosages were 0.5 mg/kg/day, and the dosages could be increased to 0.10 mg/kg at week 3 or 6 if patient response was judged to be insufficient. After 9 weeks of treatment, patients receiving tacrolimus had an 84% reduction in Psoriasis Area and Severity Index (PASI) scores.
As with cyclosporine, there are concerns about hypertension, nephrotoxicity, and immunosuppressive effects with tacrolimus. This drug is not associated with hypertrichosis or gingival hyperplasia. Tacrolimus has not been studied as extensively as cyclosporine for the treatment of psoriasis, and further investigations are warranted for this very effective antipsoriatic agent.
Hydroxyurea may be considered for the treatment of psoriasis in patients with hepatic disease, because hepatotoxicity is uncommon with this agent.86 Response is slower and less complete than with methotrexate, however, and resistance to hydroxyurea may develop more frequently. Hydroxyurea is administered orally at a dosage of 1 to 2 g/day. Careful monitoring of blood counts is necessary during therapy.
Sulfasalazine does not have FDA approval for the treatment of psoriasis but is highly effective in selected patients. It is typically given in dosages of 3 to 4 g daily. In one study, over 25% of patients given sulfasalazine stopped the treatment because of side effects (cutaneous eruptions or nausea). In clinical practice, results have been less promising than in studies.87
Combinations of various psoriasis treatments have proved to be superior in efficacy to monotherapy. Acitretin is routinely used with UVB and PUVA, a combination that allows the use of smaller doses and minimizes toxicities of both retinoid therapy and phototherapy.71,72 The combination of methotrexate and acitretin has been used successfully despite some concern that both drugs are hepatotoxic.88 Careful monitoring of liver enzyme levels is essential. Methotrexate and cyclosporine can be used together, and their concurrent administration in small doses can result in greater efficacy and less toxicity than that which can be achieved with higher doses of either agent used alone.89Methotrexate has also been used very successfully in combination with UVB90 and PUVA,91 although there is some concern that methotrexate may potentiate the carcinogenic effect of PUVA.92 Because cyclosporine has been associated with skin cancers, it is not routinely used in combination with PUVA. It can be used in combination with retinoids and mycophenolate mofetil.
Other Systemic Therapies
Mycophenolate mofetil, a drug that has FDA approval for the prevention of organ transplant rejection, is highly effective for some patients with psoriasis.93 Mycophenolate mofetil is the prodrug of mycophenolic acid, a medication that was tested for psoriasis in the 1970s.94Although mycophenolic acid was found to be highly effective in the treatment of psoriasis, the manufacturers did not pursue FDA approval for that indication because of its side effects, which included gastrointestinal toxicity and an immunosuppressive effect that resulted in herpes zoster infections in more than 10% of treated patients.
6-Thioguanine is another anticancer chemotherapeutic agent that is highly effective for psoriasis. Unfortunately, it has been associated with bone marrow suppression in approximately 50% of patients.95 Bone marrow toxicity from 6-thioguanine can be reduced by administering the drug two to three times a week rather than daily.96
The ability to create molecules that target specific steps in the pathogenesis of psoriasis has led to the development of biologic agents that can treat psoriasis without the nephrotoxicity associated with cyclosporine and without the bone marrow and liver toxicities associated with methotrexate. Biologic agents are immunosuppressive, and their long-term toxicity is not known. As with other immunosuppressive agents, there is concern about the potential to predispose patients to infections or malignancies. Several biologic agents have FDA approval for use in psoriasis—namely, alefacept, efalizumab, and etanercept. Others have been approved for use in other diseases but are undergoing clinical trials for use in psoriasis—namely, adalimumab and infliximab. Still other agents, such as onercept, a TNF-α blocking agent, and anti-IL-12, are at earlier stages of development.
Alefacept is a fusion protein consisting of LFA-3 fused to the Fc portion of human IgG1. The LFA-3 portion of the molecule attaches to its naturally occurring receptor, CD2, on the surface of a resting T cell, thereby blocking T cell activation. The Fc portion of the molecule attaches to Fc receptors on natural killer cells and macrophages, resulting in apoptosis of the bound T cell.97
Alefacept originally received FDA approval as intravenous and intramuscular formulations, but it is now available only in the intramuscular form. Alefacept is administered weekly for 12 weeks in a dose of 15 mg. In one study, by 14 weeks after the start of therapy, 21% of patients achieved PASI 75 (75% reduction in disease from baseline) and 42% of patients achieved PASI 50 (50% reduction in disease from baseline). Improvement typically progresses after the completion of treatment, with maximal disease reduction 8 weeks after a second course of therapy; in one study, 33% of patients achieved PASI 75 and 57% achieved PASI 50 by this point.98 The most striking benefit of alefacept therapy is the long duration of remission achieved in a subgroup of patients. In patients who achieved PASI 75, the median time to recurrence of psoriasis (as defined by maintenance of PASI 50) was 7 months after a single 12-week course of therapy and more than a year after two courses of therapy.99
Drawbacks of alefacept therapy include the high cost of the drug and the need for weekly CD4+ T cell counts because the drug tends to reduce the number of these cells. The onset of action of alefacept is slow, with many patients achieving maximal response weeks after completing the 12-week course. Moreover, only a proportion of patients achieve a satisfactory response.
Efalizumab is a humanized monoclonal antibody directed against the CD11a portion of LFA-1. Efalizumab blocks the interaction between LFA-1 and ICAM-1, an interaction that is responsible for T cell activation and trafficking of T cells into inflamed skin. After a conditioning dose of 0.7 mg/kg the first week, patients self-administer subcutaneous injections of efalizumab at a dose of 1 mg/kg weekly. In double-blind, placebo-controlled trials, 22% to 39% of patients treated with weekly efalizumab for 12 weeks achieved PASI 75,100,101,102 and nearly 60% of patients achieved PASI 50. With longer therapy, higher proportions of patients achieve greater degrees of improvement. Like the other biologic agents, efalizumab does not cause the nephrotoxicity associated with cyclosporine or the bone marrow or liver toxicity associated with methotrexate. The drug is fairly expensive, however, and flulike symptoms may develop after the first or second injection; a serious concern is the development of psoriasis rebound (defined as a worsening of psoriasis over baseline), which occurs in up to 15% of patients. To avoid psoriasis rebound, efalizumab should not be stopped abruptly but, rather, slowly converted to alternative therapies.
Etanercept is a recombinant fusion protein that includes the p75 TNF receptor that binds to TNF-α, blocking its interaction with cell surface receptors. Etanercept originally received FDA approval for a dosage of 25 mg administered subcutaneously by the patient at home twice weekly for the treatment of psoriatic arthritis. Subsequently, etanercept received approval for the treatment of psoriasis at a dosage of 50 mg administered subcutaneously twice weekly for 3 months and then once weekly. In a double-blind, placebo-controlled, four-arm trial comparing placebo with three dosage regimens, analysis after 12 weeks of treatment showed that PASI 75 was achieved in 14% of patients who received 25 mg once a week, in 34% who received 25 mg twice a week, and in 49% who received 50 mg twice a week. Response rates were even higher at 24 weeks of therapy.103
The drawbacks of etanercept include its cost and the need to self-inject the medication on a long-term basis. Injection-site reactions, although common, are almost always minor and seldom require any treatment other than temporarily using a different site for injections. There is evidence that TNF-α blockers can cause an exacerbation of multiple sclerosis, so the drug should be avoided in patients with a personal or family history of demyelinating disease. Some controversy exists as to whether TNF-α blockers exacerbate chronic heart failure, and there is concern that the immunosuppressive effects of TNF-α blockers may contribute to an increase in the development of lymphoproliferative diseases.104 Antinuclear antibodies also develop in etanercept-treated patients, but they are of questionable physiologic significance.
Infliximab is a chimeric monoclonal antibody directed against TNF-α. In the short term (12 weeks), it is the most effective treatment for psoriasis, but it does not yet have FDA approval for this indication. It is administered by slow intravenous infusion at baseline, at weeks 2 and 6, and then every 8 weeks thereafter. In a double-blind, placebo-controlled trial evaluating patients at week 10, after only three infusions, 82% of patients achieved PASI 75.105 Moreover, 55% of patients maintained PASI 50 or higher during 6 months of follow-up.
Like the other TNF-α blockers, infliximab is associated with worsening of chronic heart failure, multiple sclerosis, and lymphoproliferative diseases. In addition, infusion reactions develop in a significant proportion of patients; these appear to be related to the development of human antichimeric antibodies. Although infusion reactions are mild in the majority of patients, they can be severe, resulting in chest pain and hypotension. Pretreating patients with antibiotics is beneficial. TNF-α blocking plays a significant role in the control of mycobacterial infection, and an increase in reactivation of latent tuberculosis has been observed in patients treated with infliximab. Consequently, patients should undergo tuberculosis testing before starting on this medication.106
Adalimumab is a fully human monoclonal antibody against TNF-α. It has FDA approval for the treatment of rheumatoid arthritis and has been successfully tested for psoriasis.107 Like the other biologics, adalimumab is not toxic to kidneys, liver, or bone marrow; however, also like the other biologic agents, it is quite expensive. The same concerns about heart failure, multiple sclerosis, and lymphoproliferative diseases that exist with etanercept and infliximab are also described in adalimumab's package insert. In a three-arm, placebo-controlled trial, PASI 75 was achieved by 53% of patients who received adalimumab every other week and by 80% of patients who received it weekly. An even greater number of patients achieved PASI 50. Adalimumab, 40 mg, is given by subcutaneous injection.
Psoriasis is usually lifelong, but the severity of the disease may vary, with periodic exacerbations and relative remissions in some patients. Although pustular psoriasis and erythrodermic psoriasis can be life-threatening, even stable plaque psoriasis can have a negative impact on overall health, possibly because of comorbid conditions such as psoriatic arthritis or obesity or because of complications of therapy.
Severe exacerbation of psoriasis taxes the ingenuity of even the most skilled clinician. Fortunately, because of the wide range of psoriasis therapies now available, clinicians are able to successfully treat almost all patients with psoriasis. The goal of therapy must be to minimize toxicity while achieving satisfactory improvement both in physical signs and symptoms and in patients' quality of life.
Editors: Dale, David C.; Federman, Daniel D.