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Treatment of psoriasis

Last literature review version 17.3: September 2009  |  This topic last updated: October 16, 2009   (More)

INTRODUCTION — Psoriasis is a common chronic skin disorder typically characterized by erythematous papules and plaques with a silver scale, although other presentations occur. Most cases are not severe enough to affect general health and are treated in the outpatient setting. Rare life-threatening presentations can occur that require intensive inpatient management.

This topic reviews the treatment of psoriatic skin disease. The epidemiology, clinical manifestations, and diagnosis of psoriatic skin disease are discussed in detail separately, as are psoriatic arthritis and the management of psoriasis in pregnant women. (See "Epidemiology, pathophysiology, and diagnosis of psoriasis" and "Treatment of psoriatic arthritis" and "Pathogenesis of psoriatic arthritis" and "Clinical manifestations and diagnosis of psoriatic arthritis" and "Management of psoriasis in pregnant women".)

APPROACH

General — Numerous topical and systemic therapies are available for the treatment of psoriasis. Treatment modalities are chosen on the basis of disease severity, relevant comorbidities, patient preference (including cost and convenience), efficacy, and evaluation of individual patient response [1].

Because of the relatively poor compliance frequently seen with topical therapies, patient preference is a key aspect of decision making. Additionally, patients are typically started on safer therapies and then progress to more aggressive therapies if the response is inadequate. Clinicians need to carefully review the risk-benefit profiles of proposed therapies.

Psychosocial aspects — Psoriasis can be a frustrating disease for the patient and the provider. The clinician needs to be empathetic and spend adequate time with the patient. It may be helpful for the clinician to touch the patient when appropriate to communicate physically that the skin disorder is neither repulsive nor contagious.

Clinicians should lay out reasonable aims of treatment, making it clear to the patient that the primary goal of treatment is control of the disease rather than cure.

Educating the patient about psoriasis is important and referral to an organization such as the National Psoriasis Foundation (www.psoriasis.org) is often helpful.

Psoriasis may affect patients' perceptions of themselves and this can potentially initiate or exacerbate psychological disorders such as depression [2]. Patients with limited skin disease may still have significant psychosocial disability [3]. Some patients with psoriasis may benefit from counseling and/or treatment with psychoactive medications.

Choice of therapy — For most patients, the initial decision point around therapy will be between topical and systemic therapy. However, even patients on systemic therapy will likely continue to need some topical agents. Topical therapy may provide symptomatic relief, minimize required doses of systemic medications, and may even be psychologically cathartic for some patients.

For purposes of treatment planning, patients may be grouped into mild-to-moderate and moderate-to-severe disease categories. Limited, or mild-to-moderate, skin disease can often be managed with topical agents, while patients with moderate-to-severe disease may need systemic therapy. The location of the disease and the presence of psoriatic arthritis also affects the choice of therapy. Psoriasis of the hand, foot, or face can be debilitating functionally or socially and may deserve a more aggressive treatment approach. The treatment of psoriatic arthritis is discussed separately. (See "Treatment of psoriatic arthritis".)

Moderate-to-severe psoriasis is typically defined as involvement of more than 5 to 10 percent of the body surface area (the palm of one hand is approximately 1 percent of the body surface area) or involvement of the face, palm or sole, or disease that is otherwise disabling. Patients with more than 5 to 10 percent body surface area affected are generally candidates for systemic therapy, since application of topical agents to a large area is not usually practical or acceptable for most patients. Attempts to treat extensive disease with topical agents are often met with failure, can add cost, and lead to frustration in the patient-clinician relationship.

There is ample evidence of efficacy of the newer systemic therapies ("biologics"), however cost is a major consideration with these agents. Established therapies such as methotrexate and phototherapy continue to play a role in the management of moderate to severe plaque psoriasis. The management of patients with extensive or recalcitrant disease is a challenge even for experienced dermatologists.

Widespread pustular disease requires aggressive treatment, which may include hospitalization. The treatment of psoriatic arthritis is discussed separately. (See "Treatment of psoriatic arthritis".)

Mild-to-moderate disease — Limited plaque psoriasis responds well to topical corticosteroids and emollients. Alternatives include tar, topical retinoids (tazarotene), and calcipotriene (Dovonex). For facial or intertriginous areas, topical tacrolimus or pimecrolimus may be used as alternatives or as corticosteroid sparing agents, though improvement may not be as rapid. Localized phototherapy is another option for recalcitrant disease.

Combinations of potent topical corticosteroids (table 1A-B) and either calcipotriene, tazarotene, or UVB phototherapy are commonly prescribed by dermatologists. Calcipotriene in combination with Class I topical corticosteroids is highly effective for short-term control. Calcipotriene alone can then be used continuously and the combination with potent corticosteroids used intermittently (on weekends) for maintenance. A combination product containing calcipotriene and betamethasone dipropionate is available for this use. With proper adherence, drastic improvement with topical therapies may be seen in as little as one week, though several weeks may be required to demonstrate benefits.

Severe disease — Severe psoriasis requires phototherapy or systemic therapies such as retinoids, methotrexate, cyclosporine, or the biologic immune modifying agents such as alefacept, efalizumab, etanercept, or infliximab. Improvement will generally be seen within weeks. Patients with severe psoriasis generally require care by a dermatologist.

Intertriginous psoriasis — Intertriginous (inverse) psoriasis should be treated with class VI and VII low potency corticosteroids

(table 1A-B) due to an increased risk of corticosteroid-induced cutaneous atrophy in the intertriginous areas. Topical calcipotriene and the topical calcineurin inhibitors tacrolimus or pimecrolimus are additional first-line treatments [4]. These agents may be used alone or in combination with topical corticosteroids as corticosteroid sparing agents for long term maintenance therapy. Calcipotriene, tacrolimus, and pimecrolimus are more expensive options than topical corticosteroids. Some concerns have been raised about the safety of the calcineurin inhibitors. (See 'Calcineurin inhibitors' below.)

Guttate psoriasis — Guttate psoriasis responds to UVB phototherapy (broadband or 311 nm), with or without medium potency topical corticosteroids. The underlying source of streptococcal infection should be treated if present.

Localized pustular psoriasis — Localized pustular psoriasis (palms and soles) is difficult to treat. Approaches include potent topical corticosteroids and topical bath PUVA. Systemic retinoids (acitretin) are particularly effective in the treatment of pustular psoriasis and we consider them first line therapy.

Nail psoriasis — Although nail involvement alone is uncommon, many patients with psoriasis have disease that involves the nails. (See "Epidemiology, pathophysiology, and diagnosis of psoriasis", section on 'Nail psoriasis'.)

Despite advances in the treatment of cutaneous disease, the treatment of psoriasis of the nails remains difficult. Psoriasis pathology resides in the nail matrix, nail bed, and hyponychium. Topical therapies are sometimes tried; however delivering topical treatment to these areas is difficult because of the physical barrier of the nail plate.

There is relatively little evidence to guide the choice of therapies for nail disease [5]. Physical maneuvers may be helpful for some patients. Patients can thin their nails by scraping them with a file or shaving them down with the edge of a glass slide. Thick toenails that are painful or interfering with footwear can be removed by a podiatrist.

If medical therapy is needed, we suggest starting with a Class I or II topical corticosteroid (table 1A-B), such as clobetasol 0.05 percent solution, combined with calcipotriene 0.005 percent solution dripped into the nail bed and hyponychium twice daily. If improvement in nail appearance occurs it can be expected to be slow, as 8 to 12 months are needed to generate a new, healthy nail.

For severe or recalcitrant nail disease, intralesional therapy with corticosteroids is a reasonable next option.

Systemic therapy and phototherapy may be more effective than topical therapy. A randomized trial of infliximab in patients with moderate to severe psoriasis (82 percent of whom had nail psoriasis) found marked improvements in nail pathology compared with baseline and with placebo [6].

Oral retinoids have also been utilized in the treatment of nail psoriasis with some success. A study of low-dose acitretin (0.2-0.3 mg/kg) given to 36 patients with isolated nail psoriasis for six months led to complete or almost complete clearance in 25 percent, moderate improvement in 25 percent, mild improvement in 33 percent, and no improvement in 11 percent. At a six month follow-up visit after the end of treatment, recurrence of nail psoriasis was noted. However, patients who improved with acitretin had less severe nail findings than at the start of treatment [7]. (See 'Retinoids' below.)

In choosing among treatments, serious consideration must be given to the risks of systemic therapy and phototherapy.

Erythrodermic psoriasis — Generalized pustular or erythrodermic psoriasis should be treated with potent topical corticosteroids, acitretin, methotrexate, or cyclosporine. Certain biologic agents with rapid onset, such as infliximab, may be appropriate [8]. These patients generally should be cared for by a dermatologist and may require hospitalization and/or combinations of treatments. Maintenance treatment is required.

Referral — Referral to a dermatologist should be considered in the following settings:

  • Confirmation of the diagnosis is needed.
  • The response to treatment is inadequate as measured by the physician, patient, or both.
  • There is significant impact on quality of life.
  • The primary care physician is not familiar with the treatment modality recommended such as PUVA, phototherapy, or immunosuppressive medications.
  • The patient has widespread severe disease.
  • In cases of psoriatic arthritis, referral and/or collaboration with a rheumatologist is indicated. (See "Treatment of psoriatic arthritis".)

TOPICAL THERAPIES — Patient adherence may be the largest barrier to treatment success with topical therapies; frequent patient follow-up (initially every week) may improve adherence.

Emollients — Hydration and emollients are valuable and inexpensive adjuncts to psoriasis treatment. Keeping psoriatic skin soft and moist minimizes the symptoms of itching and tenderness. Additionally, maintaining proper skin hydration can help prevent irritation and thus the potential for subsequent Koebnerization (development of new psoriatic lesions at sites of trauma).

The most effective are ointments such as petroleum jelly or thick creams, especially when applied immediately after a hydrating bath or shower.

Corticosteroids — Topical corticosteroids remain the mainstay of topical psoriasis treatment despite the development of newer agents. The mechanism of action of corticosteroids in psoriasis is not fully understood. Corticosteroids exert antiinflammatory, antiproliferative, and immunosuppressive actions by affecting gene transcription.

The inherent potency of a topical corticosteroid is frequently reported using a I to VII scale based on vasoconstrictive assays (table 1A-B). Although ointments are sometimes thought to be inherently more effective because of their occlusive properties, this is not uniformly correct. In practice, the efficacy/potency of a topical corticosteroid is dependent on many factors including skin type, plaque thickness, and, perhaps most importantly, compliance.

To minimize adverse effects and maximize compliance, the site of application needs to be considered in choosing the appropriately potent corticosteroid:

  • On the scalp or in the external ear canal, potent corticosteroids in a solution or foam vehicle (eg, fluocinonide 0.05 percent or clobetasol propionate 0.05 percent) are frequently indicated.
  • On the face and intertriginous areas, a low potency cream (eg, hydrocortisone 1 percent) will suffice.
  • For thick plaques on extensor surfaces, potent preparations (eg, betamethasone 0.05 percent or clobetasol propionate 0.05 percent) are often required.

The typical regimen consists of twice daily application of topical corticosteroids. Most patients will show a rapid decrease in inflammation with such therapy, but complete normalization of skin or lasting remission is unpredictable.

Topical corticosteroids generally can be continued as long as the patient has thick active lesions. Skin atrophy from topical corticosteroids usually is not a problem unless the medication is continuously applied after the skin has returned to normal thickness. Once clinical improvement occurs, the frequency of application should be reduced [9]. For patients in whom lesions recur quickly, topical corticosteroids can be applied intermittently (such as on weekends only) to maintain improvement. The addition of non-corticosteroid treatments can also facilitate the avoidance of long-term daily topical corticosteroids. (See 'Mild-to-moderate disease' above.)

The risks of cutaneous and systemic side effects associated with chronic topical corticosteroid use are increased with high potency formulations. Current data support limiting the continuous application of Class I topical corticosteroids to two to four weeks; thus, close clinician supervision should be employed if longer treatment durations are required (table 1A-B) [9]. Data are less clear regarding treatment durations for less potent topical corticosteroids. Side effects of topical corticosteroids, including the potential for suppression of the hypothalamic axis, are discussed separately. (See "Pharmacologic use of glucocorticoids" and "General principles of dermatologic therapy and topical corticosteroid use".)

The cost of topical corticosteroids varies widely. The price of a 60 gram tube of a potent corticosteroid brand name product can be as high as $80. There are now generic preparations in each potency class that have reduced the cost somewhat. Examples of available generics include, in order of increasing potency, hydrocortisone 1 percent, triamcinolone 0.1 percent, fluocinonide 0.05 percent, and betamethasone dipropionate 0.05 percent.

Different formulations have been developed in an effort to enhance the delivery of topical corticosteroids. Betamethasone valerate in a foam was found to have superior efficacy for scalp psoriasis and was preferred by patients when compared with betamethasone valerate lotion [10]. The foam becomes a liquid on contact with skin and is also well tolerated by patients with trunk and extremity psoriasis [11]. A clobetasol propionate spray is also available; like foams, sprays are easy to apply to large areas [12]. The main advantage of these newer preparations is likely greater patient acceptance, which may translate into greater adherence; the main disadvantage is cost.

Topical vitamin D analogs — Topical vitamin D analogs for the treatment of psoriasis include calcipotriene (calcipotriol), calcitriol, and tacalcitol. Although topical vitamin D analogs are effective as monotherapy for some patients, a systematic review found that combination therapy with a topical corticosteroid is more effective than either treatment alone [13].

Until 2009, calcipotriene was the only topical vitamin D analog available in the United States. Calcipotriene is obtainable as a cream and solution (Dovonex®), or as a combination ointment with betamethasone dipropionate (Taclonex®). Topical calcitriol ointment has been prescribed in Europe for years, and is now available in the United States (Vectical™). When compared with calcipotriene, calcitriol appears to induce less irritation in sensitive areas of the skin (eg, skin folds) [14].

Calcipotriene — Calcipotriene (calcipotriol) is an established therapy in psoriasis. The precise mechanism is not clear, but a major effect is the hypoproliferative effect on keratinocytes [15]. An immune modulating effect has been postulated for calcipotriene, but has not been shown to be significant in psoriasis to date [16]. Comparison studies with potent topical corticosteroids have been favorable [17].

In a systematic review of randomized controlled trials, calcipotriene was at least as effective as potent topical corticosteroids, calcitriol, short contact dithranol, tacalcitol, coal tar and combined coal tar 5 percent, allantoin 2 percent, and hydrocortisone 0.5 percent [18]. Only potent topical corticosteroids appeared to have comparable efficacy at eight weeks. Skin irritation is the main adverse event associated with calcipotriene.

Combined use of calcipotriene and superpotent corticosteroids has demonstrated increased clinical response and tolerance in clinical trials compared to either agent used alone [19-21]. One regimen employed daily use of both calcipotriene ointment and halobetasol ointment for two weeks, followed by weekend use of the halobetasol ointment and weekday use of calcipotriene [19]. This regimen produced six-month remission maintenance in 76 percent compared with 40 percent with weekend halobetasol alone. A similar regimen with calcipotriene ointment and clobetasol propionate foam also appears to be effective [22].

In addition, a randomized trial found that a preparation that combines calcipotriene with betamethasone dipropionate (0.064 percent) was effective with once daily usage, and more effective than once daily therapy with either betamethasone or calcipotriene [23]; this combination preparation (Taclonex®) typically costs more than $400 for a 60 g tube. Patients who use topical corticosteroids in combination with calcipotriene must be monitored for adverse effects as with corticosteroid monotherapy. (See 'Corticosteroids' above.)

Thus, topical calcipotriene may be used as an alternative or adjunct to topical corticosteroid therapy. It is applied twice daily when used as monotherapy. No controlled trials guide how best to use topical corticosteroids in conjunction with calcipotriene. Once daily use of each may be adequate. Acidic products can inactivate topical calcipotriene, and some topical corticosteroids may be acidic. A reasonable approach to combination therapy is to have patients apply topical calcipotriene and topical corticosteroids each once daily at different times of day.

Other than skin irritation, side effects of topical calcipotriene are usually minimal; the risk of hypercalcemia is low. However, topical calcipotriene is more expensive than most potent corticosteroids (approximately $300 in the United States for 100 grams).

Calcitriol — The mechanism of action of calcitriol is thought to be similar to that of calcipotriene and involves the drug's ability to inhibit keratinocyte proliferation and stimulate keratinocyte differentiation [24]. In addition, it has been demonstrated that calcitriol inhibits T cell proliferation and other inflammatory mediators [24]. In two randomized trials with a total of 839 patients with mild to moderate plaque psoriasis, calcitriol 3 mcg/g ointment was more effective than vehicle [25]. At the end of the study periods (up to eight weeks), 39.6 and 32.7 percent of the calcitriol groups versus 21.2 and 12 percent of the vehicle groups exhibited at least marked global improvement.

In a systematic review, calcipotriene and calcitriol were equally effective [13]. However, on sensitive areas of the skin, calcitriol appears to be less irritating than calcipotriene. An intraindividual randomized trial of 75 patients compared treatment with calcitriol 3 mcg/g ointment to calcipotriene 50 mcg/g ointment for mild to moderate psoriasis on facial, hairline, retroauricular, and flexural areas [14]. Perilesional erythema, perilesional edema, and stinging or burning sensations were significantly lower in the areas treated with calcitriol. A 52-week open-label study of the safety of calcitriol ointment did not reveal an adverse effect on calcium homeostasis [26].

Calcitriol ointment is expensive; the cost of a 100 gram tube is approximately $400. The drug is applied twice daily.

Tar — The use of tar is a time-honored modality for treating psoriasis, although newer (and less messy) treatment options have reduced its popularity. The precise mechanism of action of tar is not known; it has an apparent antiproliferative effect.

Tar can be helpful as an adjunct to topical corticosteroids. There are no commercially available corticosteroid/tar combinations. Tar products are available without a prescription in the form of shampoos, creams, lotions, ointments, and oils. Newer products include a solution (Psorent™) and a foam (Scytera™). Some patients may prefer the less messy new formulations.

Tar can also be compounded into creams and ointments. A commonly used compound is 2 or 3 percent crude coal tar in triamcinolone cream 0.1 percent applied twice daily to individual plaques. An alternative is 4 to 10 percent LCD (liquor carbonis detergens, a tar distillate) in triamcinolone cream or ointment, used similarly. A preparation of 1 percent tar in a fatty-acid based lotion (Exorex) may be superior to conventional 5 percent tar products [27] and appears to have efficacy similar to that of calcipotriene [28].

Topical tar preparations, including shampoos, creams, and other preparations, can be used once daily. Patients should be warned that tar products have the potential to stain hair, skin, and clothing. It may help to use them at night and wear inexpensive night clothes (eg, old pajamas) as they tend to be messy. For shampoos, the emphasis should be on making sure the product reaches the scalp. Tar shampoo should be left in place for 5 to 10 minutes before rinsing it out.

Tazarotene — Tazarotene is a topical retinoid that was found to be safe and effective in two randomized, vehicle-controlled trials that included 1303 patients with psoriasis [29]. The 0.1 percent cream was somewhat more effective than 0.05 percent cream, but with a slightly higher rate of local side effects. Another study found that once daily administration of tazarotene gel, 0.05 or 0.1 percent, compared favorably with the twice daily administration of topical fluocinonide 0.05 percent [30]. Absorption of tazarotene was minimal over the 12-week course of the study, suggesting that systemic toxicity is unlikely during long-term therapy. A small uncontrolled study of short contact tazarotene found that a 20 minute application followed by washing appeared to be less irritating than traditional use, and seemed to have similar efficacy [31].

Calcineurin inhibitors — Topical tacrolimus 0.1 percent and pimecrolimus 1 percent are effective in the treatment of psoriasis [32-35]. Facial and intertriginous areas may be suited to these treatments, which can allow patients to avoid chronic topical corticosteroid use:

  • An eight-week randomized trial in 167 patients ages 16 and older found that twice daily treatment to intertriginous and facial lesions with tacrolimus 0.1 percent ointment resulted in more patients achieving clearance of lesions or excellent improvement compared with placebo (65 versus 32 percent) [36].
  • An eight-week randomized trial in 57 adults with moderate to severe inverse psoriasis found that twice daily treatment with pimecrolimus 1 percent cream resulted in more patients clearing or almost clearing lesions compared with placebo (71 versus 21 percent) [37].

Topical tacrolimus and pimecrolimus are generally well-tolerated when used to treat facial and intertriginous psoriasis [36,37]. However, corticosteroid therapy may be more effective, at least compared to pimecrolimus. This was suggested in a four-week randomized trial in 80 patients with intertriginous psoriasis that compared various therapies applied once daily [38]. Betamethasone valerate 0.1 percent was more effective than pimecrolimus 1 percent.

In 2005, the US Food and Drug Administration (FDA) issued an alert about a possible link between topical tacrolimus and pimecrolimus and cases of lymphoma and skin cancer in children and adults [39], and in 2006 placed a "black box" warning on the prescribing information for these medications [40]. No definite causal relationship has been established; however, the FDA recommended that these agents only be used as second line agents for atopic dermatitis. If these drugs are used for the treatment of psoriasis, it would be reasonable to follow the additional safety recommendations made by the FDA for their use in atopic dermatitis. (See "Treatment of atopic dermatitis (eczema)", section on 'Topical calcineurin inhibitors'.)

ULTRAVIOLET LIGHT — Ultraviolet (UV) irradiation has long been recognized as beneficial for the control of psoriatic skin lesions. As an example, patients often notice improvement in skin lesions during the summer months. UV radiation may act via antiproliferative effects (slowing keratinization) and anti-inflammatory effects (inducing apoptosis of pathogenic T-cells in psoriatic plaques). In choosing UV therapy, consideration must be given to the potential for UV radiation to accelerate photodamage and increase the risk of cutaneous malignancy.

Phototherapy and photochemotherapy require the supervision of a dermatologist trained in these treatment modalities. Despite high efficacy and safety, the use of office-based phototherapy has declined in the United States because of administrative issues [41].

Modalities — Therapeutic doses of ultraviolet light can be administered in several ways:

  • Phototherapy refers to treatment with ultraviolet B (UVB) radiation (290 to 320 nm). This treatment is used in patients with extensive disease, alone or in combination with topical tar. The mechanism of action of UVB is likely through its immunomodulatory effects [42]. Patients receive near-erythema-inducing doses of UVB at least three times weekly until remission is achieved, after which a maintenance regimen is usually recommended to prolong the remission.
  • Narrow band UVB (311 nm) is an alternative to standard (broadband- 290 to 320 nm) UVB in the treatment of psoriasis. Suberythemogenic doses of narrow band UVB are more effective than broadband UVB in clearing plaque psoriasis [43]. Apoptosis of T cells is also more common with 311 nm than with broadband UVB. However, the higher cost of narrow band UVB bulbs compared with broadband bulbs currently limits its availability.
  • Photochemotherapy (PUVA) involves treatment with either oral or bath psoralen followed by ultraviolet A (UVA) radiation (320 to 400 nm) under strict medical supervision. UVA penetrates deeper into the dermis than UVB and does not have the latter's potential for burning the skin. A number of possible mechanisms have been postulated to explain PUVA's effects (figure 1) [44]. With oral PUVA, patients ingest the photosensitizing drug, 8-methoxypsoralen, followed within two hours by exposure to UVA; this sequence is performed three times weekly in increasing doses until remission, then twice or once weekly as a maintenance dose. With bath PUVA, the psoralen capsules are dissolved in water, and affected skin (hands, feet, or total body) is soaked for 15 to 30 minutes prior to UVA exposure. Some patients take psoralen prior to coming into the office/clinic for PUVA and increased photosensitivity is typically present starting one hour after an oral dose and resolves after eight hours. Pre and post treatment photoprotection (eg, hat, sunscreen, sun protective goggles) are critical in preventing serious burn injury to the skin and eyes from being outside.

Pretreatment emollients have long been thought to improve results with UVB. However, while thin oils do not impede UV penetration, emollient creams can actually inhibit the penetration of the UV and should not be applied before treatment [45]. Gentle removal of plaques by bathing does help prior to UV exposure.

Home phototherapy — An alternative to office-based phototherapy is the use of a home ultraviolet B (UVB) phototherapy unit prescribed by the treating clinician. This option may be preferred by patients who are not in close proximity to an office-based phototherapy center, whose schedules do not permit frequent office visits, or for whom the costs of in-office treatment exceed those of a home phototherapy unit. Home units cost about $3000, but may prove cost-effective in the long term, particularly when compared to biologic therapies. Insurance coverage of these units varies.

For some dermatologists, uncertainty regarding the safety of home units has led to a reluctance to prescribe them. Some have expressed concern for the potential for improper or excessive usage of these devices [46]. In contrast, a randomized trial of 196 subjects found that narrowband UVB administered via home units was as safe and effective as office-based treatments [46]. Home phototherapy units that are equipped with electronic controls that allow only a prescribed number of treatments are available and may help to mitigate clinician concerns.

Excimer laser — Another development in ultraviolet therapy for psoriasis involves use of a high energy 308 nm excimer laser. The laser allows treatment of only involved skin; thus, considerably higher doses of UVB can be administered to psoriatic plaques at a given treatment compared with traditional phototherapy. Uncontrolled trials suggest that laser therapy results in faster responses than conventional phototherapy [47,48]. As an example, one study of excimer laser therapy involved 124 patients with stable mild to moderate plaque psoriasis, of whom 80 completed the entire protocol [47]. Treatments were scheduled twice weekly. After 10 or fewer treatments, 84 and 50 percent of patients achieved the outcomes of 75 percent or better and 90 percent or better clearing of plaques, respectively. This number of treatments was far fewer than that typically required of phototherapy (25 or more). Side effects of laser therapy included erythema and blistering; these were generally well tolerated, and no patient discontinued therapy because of adverse effects.

Like 311 nm UVB, the excimer laser represents a therapeutic advance toward specific wavelength therapies for psoriasis. While both the excimer laser and narrow band UVB are approved for use in psoriasis, inconsistencies in third party coverage for these treatments limit their current utilization.

Cancer risk — A concern with PUVA is an increased risk of nonmelanoma skin cancer and melanoma. Ongoing monitoring is indicated in patients who have received prolonged courses of PUVA. In general, phototherapy is contraindicated in patients with a history of melanoma or extensive nonmelanoma skin cancer. (See "Epidemiology and clinical features of cutaneous squamous cell carcinoma" and "Epidemiology and clinical features of basal cell carcinoma" and "Risk factors for the development of melanoma".)

Folate deficiency — Folate deficiency has been associated with health disorders such as neural tube defects in fetuses of affected pregnant women, anemia, and hyperhomocysteinemia (a risk factor for cardiovascular disease). In an in vitro study, exposure of plasma to UVA led to a 30 to 50 percent decrease in the serum folate level within 60 minutes [49]. However, folate deficiency secondary to UVA exposure has not been proven to occur in vivo. In a small randomized trial of healthy subjects, no difference in serum folate levels was identified between subjects irradiated with UVA for six sessions and untreated subjects [50]. In addition, an observational study of 35 psoriasis patients found that narrow band UVB had no effect on serum folate levels after 18 treatment sessions [51].

Saltwater baths — As discussed above, exposure to natural sunlight has been observed to improve psoriasis. Bathing in sea water in combination with sun exposure (climatotherapy) has also been used as a therapy for psoriasis, as has the use of salt water baths with artificial UV exposure (balneophototherapy).

A large, open, randomized trial found that treatment with UVB after a saltwater bath had greater efficacy than UVB after a tap-water bath, and similar efficacy to bath PUVA [52]. Although the raters of disease severity were intended to be blinded, treatment assignment was known to the raters in nearly 60 percent of cases. Additionally, less than half the patients were considered to have met the study's prespecified criteria for having been eligible and treated per protocol. In per-protocol analyses, no difference was found between saltwater and tap-water baths, and bath PUVA was superior to UVB after a saltwater bath.

Additional studies are required to demonstrate that combining saltwater baths with phototherapy is superior to tap-water baths plus phototherapy or to phototherapy alone.

SYSTEMIC THERAPIES

Methotrexate — The folic acid antagonist methotrexate has been used successfully in the treatment of psoriasis for over 30 years. It is also effective for the treatment of psoriatic arthritis and psoriatic nail disease. Initial thoughts on the mechanism of action centered around the antiproliferative effects of methotrexate on DNA synthesis in epidermal cells; more recent evidence supports the concept that it is the immunosuppressive effects of methotrexate on activated T-cells that controls psoriasis [53]. The efficacy of methotrexate appears similar to that of cyclosporine [54]. However, long-term therapy is more commonly performed with methotrexate; cyclosporine is generally used only for limited courses of treatment. (See 'Systemic calcineurin inhibitors' below.)

Methotrexate appears to be less effective than at least some of the immunomodulatory drugs (see 'Immunomodulatory drugs' below. In one trial, 271 patients with moderate to severe plaque psoriasis were randomized to receive methotrexate, adalimumab, or placebo [55]. After 16 weeks, the proportion of patients achieving a 75 percent improvement in symptoms with methotrexate was more than that with placebo but less than with adalimumab (36, 19, and 80 percent respectively).

Methotrexate is usually administered in an intermittent low-dose regimen such as once weekly. Similar regimens are currently in use in patients with rheumatoid arthritis. Administration can be oral, intravenous, intramuscular, or subcutaneous; the usual dose range is between 7.5 mg and 25 mg per week. (See "Use of methotrexate in the treatment of rheumatoid arthritis".)

Folic acid, 1 mg daily, protects against some of the common side effects seen with low-dose methotrexate such as stomatitis [56]. Folate does not appear to protect against pulmonary toxicity, and it is uncertain whether it protects against hepatic toxicity; monitoring for bone marrow suppression and hepatotoxicity are necessary during therapy. Concurrent use of other medications that interfere with folic acid metabolism, such as sulfa antibiotics, can increase the toxicity of methotrexate. (See "Major side effects of low-dose methotrexate".)

For patients with one or more risk factors for hepatotoxicity, use of a different systemic drug should be considered. (See 'Hepatotoxicity and liver biopsy' below.)

Hepatotoxicity and liver biopsy — In the past, the American Academy of Dermatology (AAD) recommended that all patients with psoriasis undergo liver biopsy to evaluate for hepatotoxicity after every 1 to 1.5 g of cumulative methotrexate [57]. In 2009, the AAD and the National Psoriasis Foundation updated this recommendation with monitoring guidelines that are dependent upon the presence or absence of risk factors for hepatotoxicity [58,59].

Risk factors for hepatotoxicity from methotrexate include [58]:

  • History of more than moderate alcohol consumption
  • Persistent abnormal liver chemistry studies
  • History of liver disease, such as chronic hepatitis B or C
  • Family history of inherited liver disease (eg, hemochromatosis)
  • Diabetes mellitus
  • Obesity
  • History of significant exposure to hepatotoxic drugs (other than methotrexate) or chemicals
  • Absence of folate supplementation during methotrexate therapy
  • Hyperlipidemia

Patients without risk factors for hepatotoxicity should have liver chemistries drawn every one to three months. If five out of nine serum AST levels are elevated over the course of 12 months, or if the serum albumin level is decreased in the context of normal nutritional status and well-controlled psoriasis, a liver biopsy should be performed.

Liver biopsy should also be considered after a cumulative dose of 3.5 to 4 g of methotrexate has been administered. Once patients have reached this dose, options include proceeding with a liver biopsy, continuing to monitor without a liver biopsy, or discontinuing methotrexate therapy.

In patients with risk factors for hepatotoxicity in whom the decision is made to proceed with methotrexate, a liver biopsy should be performed at or near the beginning of therapy. Since a fair number of patients will discontinue therapy within the first two to six months, it is reasonable to perform the biopsy after this time period. For patients who continue methotrexate, liver biopsies should be performed after every 1 to 1.5 g of cumulative methotrexate.

Retinoids — Systemic retinoids (derivatives of vitamin A) are indicated in patients with severe psoriasis, including pustular and erythrodermic forms, and in patients with HIV-associated psoriasis. The retinoid of choice in psoriasis is acitretin (Soriatane®). In a pilot study, 6 of 11 patients with psoriasis and HIV infection achieved good to excellent results with acitretin therapy, with four achieving complete clearing of their skin disease [60]. The usual dose range of acitretin is 25 mg every other day to 50 mg daily.

Acitretin has become a valuable modality when used in combination with UVB or PUVA therapy. Used in this way, patients have higher response rates with better tolerance and less UV exposure [61,62].

Monitoring for hypertriglyceridemia and hepatotoxicity are required with retinoid therapy. Common side effects include cheilitis and alopecia. Acitretin is teratogenic; it is only indicated in men and in women of nonreproductive potential. Pregnancy is contraindicated for three years after discontinuing the drug [63].

Systemic calcineurin inhibitors — The T-cell suppressor cyclosporine is effective in patients with severe psoriasis [64]. Usual doses are in the range of 3 to 5 mg/kg per day orally. Improvement is generally observed within four weeks.

The efficacy of cyclosporine and methotrexate for psoriasis is similar. A randomized trial in 88 patients with moderate to severe chronic plaque psoriasis found that after 16 weeks, psoriasis severity scores decreased by 1.3 more points (95% CI -0.2-2.8) among patients treated with cyclosporine than among patients treated with methotrexate [54]. Of note, although the authors concluded that there were no significant differences in efficacy between the treatments, the study appears to have been designed to exclude a difference of two or more points in the severity scores, and while it did not find a difference this large, such a difference is not excluded by these results. (See "Proof, p-values, and hypothesis testing".)

Twelve patients in the methotrexate group discontinued treatment because of elevations in liver enzymes; however, patients were not treated with folate, which may be helpful in preventing liver toxicity. One patient in the cyclosporine group discontinued treatment because of an elevated bilirubin concentration. (See "Major side effects of low-dose methotrexate".)

Close monitoring is required since renal toxicity and hypertension are common and often limit the long-term use of cyclosporine in patients with psoriasis. (See "Cyclosporine and tacrolimus nephrotoxicity".)

An investigational oral calcineurin inhibitor, ISA247, has also shown efficacy in randomized trials in patients with moderate to severe plaque psoriasis, and may have less nephrotoxicity than cyclosporine [65].

Other immunosuppressive agents — Other immunosuppressive agents are sometimes used in selected cases of severe psoriasis [64]. These drugs include hydroxyurea and azathioprine, both of which have a place in the treatment of psoriasis when other systemic modalities cannot be used, and tacrolimus, which is similar to cyclosporine and requires larger studies before it can be considered an accepted alternative. Daclizumab, which is used for prevention of renal transplant rejection, and the cancer chemotherapeutic drug paclitaxel are also under investigation for use in severe psoriasis [66,67].

Immunomodulatory drugs — Immunomodulatory agents ("biologics") are becoming important treatment alternatives for moderate to severe plaque type psoriasis [68-70]. Treatment decisions around biologics are complex, and even patients who have failed treatment with one or more biologic agents may still experience benefit from a different immunologic agent [71].

At least some of the immunomodulatory drugs appear to be more efficacious than some older systemic therapies. As an example, adalimumab appears to be significantly more effective than methotrexate (see 'Methotrexate' above.

Most of these agents are expensive, as is the laboratory monitoring for side effects that may be required. Cost-effectiveness may be a consideration in choosing to use a biologic agent and in picking among the available agents [72].

There is a concern that all TNF-alpha inhibitors have the potential to activate latent infections such as tuberculosis and increased rates of infection have been seen in patients with rheumatoid arthritis treated with etanercept, infliximab, and adalimumab. TNF-alpha inhibitors have also been associated with an increased risk of malignancies, including lymphoma and leukemia, and the development of new-onset psoriasis [73]. (See "Tumor necrosis factor-alpha inhibitors: Risk of bacterial, viral, and fungal infections" and "Tumor necrosis factor-alpha inhibitors and mycobacterial infections" and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy" and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

Alefacept — The recombinant protein alefacept (Amevive) has benefit in the treatment of psoriasis. It binds to CD2 on memory effector T lymphocytes, inhibiting their activation in psoriatic plaques. Randomized, double-blind phase II and phase III studies in patients with chronic plaque psoriasis have found that alefacept is associated with lesion improvement compared with placebo, and some patients have a sustained clinical response after cessation of therapy [74,75].

Alefacept is approved by the US Food and Drug Administration (FDA) for treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy. It is administered weekly for 12 weeks as a 15 mg intramuscular (IM) injection.

Additional 12-week courses of treatment can be considered if a minimum of 12 weeks has passed since the last treatment and the CD4 count has returned to normal; data on treatment beyond two cycles are limited [76]. Since responses may be delayed, we suggest administering two full courses of therapy to adequately assess efficacy. Preliminary data also raise the possibility that courses of therapy longer than 12 weeks may provide some additional benefit [77].

CD4 cell counts should be checked every week or every other week while on therapy, and the dose should not be administered if the count is less than 250/µL; alefacept should be discontinued if the CD4 count remains below 250/µL for one month. It is contraindicated in patients infected with HIV because of theoretical concerns related to the effects of alefacept on CD4 cell counts [78].

Efalizumab — Multicenter randomized, controlled trials have shown effectiveness of efalizumab (Raptiva), a humanized monoclonal antibody to CD11A, in the treatment of psoriasis [79-81].

However, in 2009, the FDA issued a public health advisory based upon reports of the development of progressive multifocal leukoencephalopathy (PML) in patients taking Raptiva [82]. Three confirmed cases (two fatal), and one possible case (fatal) of PML were reported. All patients had taken Raptiva continuously for more than three years. Due to the increased risk of PML, efalizumab was withdrawn from the United States market on June 8, 2009 [83]. Production of efalizumab has also been suspended in international markets.

Discontinuation of efalizumab can lead to an acute and sometimes severe worsening of psoriasis within several weeks after stopping treatment, a risk that is highest in patients who are nonresponders to efalizumab therapy [84]. All patients should be followed closely after cessation of the drug. Because of the increased risk of rebound flares, an alternative treatment should be started immediately in nonresponders [84,85].

Patients who have responded well to efalizumab therapy can be followed clinically after treatment cessation and may not require immediate introduction of an alternative therapy [84,85]. However, the decision of whether to rapidly initiate another treatment should be made on a case by case basis, considering factors such as disease severity and stability [86].

Etanercept — The TNF-alpha inhibitor etanercept (Enbrel) is of benefit in psoriasis [87,88]. It is approved by the FDA for psoriatic arthritis and for adults with chronic moderate to severe plaque psoriasis. A randomized trial of etanercept in 652 adult patients with active but stable plaque psoriasis involving at least 10 percent of the body surface area found three doses of subcutaneous etanercept (25 mg weekly, 25 mg twice weekly, 50 mg twice weekly) significantly superior to placebo [88]. After 12 weeks, there was at least a 75 percent improvement in a psoriasis severity index in 14, 34, 49, and 4 percent, respectively. After 24 weeks, such an improvement was seen in 25, 44, and 59 percent, respectively (no patients received placebo for more than 12 weeks). Etanercept was well tolerated with adverse events and infections occurring at similar rates in all four groups.

A 12 week randomized trial found similar benefits with subcutaneous etanercept 50 mg twice weekly, and also found that, compared with placebo, patients receiving etanercept had significant improvements in measures of fatigue and depression [89]. Another randomized trial demonstrated efficacy in children and adolescents with moderate to severe plaque psoriasis [90]. The long-term safety of etanercept for psoriasis is supported by a 96-week study of etanercept 50 mg twice weekly [91].

Infliximab — The TNF-alpha inhibitor infliximab (Remicade) is of benefit in patients with moderate to severe plaque psoriasis and appears to generally be well-tolerated [92-95].

As an example, a multicenter randomized trial in 249 patients with severe plaque psoriasis found that compared with placebo, more patients treated with infliximab 3 mg/kg or 5 mg/kg (given intravenously at weeks zero, two, and six) achieved at least a 75 percent improvement at week 10 (6 percent versus 72 and 88 percent, respectively) [94]. The duration of response appeared to be longer with the higher dose. More patients treated with infliximab had serious adverse events (12 versus 0), including four cases that the authors felt were reasonably related to treatment: squamous cell carcinoma, cholecystitis, diverticulitis, and pyelonephritis with sepsis.

Maintenance therapy also appears to be effective. A randomized trial using the dosing schedule above with infliximab 5 mg/kg through six weeks, but then adding maintenance dosing of infliximab 5 mg/kg every eight weeks through 46 weeks found that 61 percent of patients had at least a 75 percent improvement at week 50 [95]. Infliximab was generally well tolerated.

Adalimumab — Adalimumab (Humira), a humanized monoclonal antibody with activity against TNF-alpha, was originally used for patients with rheumatoid arthritis and is also effective for psoriatic arthritis. (See "Treatment of psoriatic arthritis".) Adalimumab is approved by the FDA for treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy.

A randomized trial in 147 patients with moderate to severe plaque psoriasis compared adalimumab by subcutaneous injection 40 mg every other week, 40 mg weekly, and placebo [96]. After 12 weeks, more patients treated with adalimumab every other week or weekly achieved at least a 75 percent improvement (53 and 80 percent, respectively), versus 4 percent with placebo. In an open label extension of the study, improvements were sustained for 60 weeks.

A randomized trial in 490 patients with moderate to severe psoriasis who had achieved a 75 percent improvement after 32 weeks of adalimumab found that continuing adalimumab resulted in a higher percentage of patients maintaining their response at 52 weeks (95 versus 72 percent) [97].

Therapy wth adalimumab was superior to methotrexate in a randomized trial involving 271 patients with moderate to severe psoriasis [55]. (See 'Methotrexate' above.)

Ustekinumab — Ustekinumab is a human monoclonal antibody that targets IL-12 and IL-23. In September 2009, ustekinumab was approved by the US Food and Drug Administration for the treatment of adult patients with moderate to severe psoriasis who are candidates for phototherapy or systemic therapy.

A phase 2 randomized trial suggested that ustekinumab is highly effective in the treatment of moderate to severe plaque psoriasis [98], and three phase 3 trials have confirmed these results [99,100]:

  • A randomized trial in 766 patients with moderate to severe plaque psoriasis found that more patients treated with ustekinumab 45 mg or 90 mg achieved at least a 75 percent improvement at week 12 than those treated with placebo (67 and 66 versus 3 percent) [99]. Ustekinumab was administered monthly by subcutaneous injection for the first two doses and then every 12 weeks. Responders who were kept on therapy generally maintained improvements in psoriasis out to at least 76 weeks. Serious adverse events were seen at similar rates in the ustekinumab and placebo arms.
  • A second similarly designed trial in 1230 patients with moderate to severe plaque psoriasis also found that more patients treated with ustekinumab 45 mg or 90 mg achieved at least a 75 percent improvement at week 12 than those treated with placebo (67 and 76 versus 4 percent) [100]. Patients who achieved a partial response at week 28 were randomly assigned to continue every 12 week dosing or escalate to every 8 week dosing. More frequent dosing did not enhance response rates at one year in patients receiving 45 mg, but did enhance 75 percent improvement rates in those receiving 90 mg (69 versus 33 percent with continued 12 week dosing). Serious adverse events were again seen at similar rates in the ustekinumab and placebo arms.

Future therapies — Interleukins play a pivotal role in the pathogenesis of psoriasis and have become targets for drug development. In addition to ustekinumab, another monoclonal antibody targeting IL-12/23 appeared highly effective in a phase 2 randomized trial in patients with moderate to severe plaque psoriasis [101]. An earlier phase 2 trial in 10 patients with psoriasis found some evidence that treatment with IL-10 was of benefit [102]. IL-19, 20, and 24 are in the IL-10 family and have been proposed as potential therapeutic targets.

Although some studies have suggested that thiazolidinediones had efficacy in psoriasis, perhaps through effects on IL-2 [103-105], large randomized trials of rosiglitazone failed to show benefits [106]. Other potential therapies include various small molecules targeted at interrupting cellular signaling; such signaling is critical to propagation of the inflammatory response. Fumaric acid esters (fumarates) have been used to treat psoriasis in Northern Europe [107], and additional trials of fumarates are being performed.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Psoriasis".) We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

The National Psoriasis Foundation is a nonprofit organization that provides useful information to patients with psoriasis and their physicians. Membership includes access to a newsletter that provides information on current areas of research and new treatments.

  National Psoriasis Foundation

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SUMMARY AND RECOMMENDATIONS — Numerous topical and systemic therapies are available for the treatment of psoriasis. Treatment modalities are chosen on the basis of disease severity, relevant comorbidities, patient preference (including cost and convenience), efficacy, and evaluation of individual patient response. (See 'Approach' above.)

  • We suggest that patients with mild-to-moderate plaque psoriasis be initially treated with topical corticosteroids and emollients (Grade 2B). (See 'Mild-to-moderate disease' above.)

Alternatives include tar, topical retinoids (tazarotene), and topical vitamin D. For facial or intertriginous areas, topical tacrolimus or pimecrolimus may be used as alternatives or as corticosteroid sparing agents. Improvement can be anticipated within one or two months. Combination regimens may be required, including localized phototherapy. Patient adherence may be the largest barrier to treatment success with topical therapies; frequent patient follow-up (initially every week) may improve compliance. (See 'Topical therapies' above and 'Ultraviolet light' above.)

  • We suggest that most patients with moderate-to-severe plaque psoriasis be initially treated with phototherapy if possible (Grade 2B). (See 'Severe disease' above.)

The topical therapies discussed above are generally also required as adjuvant therapy and for symptomatic relief. (See 'Topical therapies' above.) In patients with a history of melanoma or extensive nonmelanoma skin cancer, or in patients with moderate-to-severe disease who also have psoriatic arthritis, we suggest treatment with a systemic agent (Grade 2B).

Financial considerations or time constraints may also make systemic therapy preferable to phototherapy for some patients. Systemic agents include retinoids, methotrexate, cyclosporine, and biologic immune modifying agents such as alefacept, efalizumab, adalimumab, etanercept, infliximab, and ustekinumab. Treatment of psoriatic arthritis is discussed in detail separately. (See "Treatment of psoriatic arthritis".)

Improvement should be observed within weeks. Such patients will generally require care by a dermatologist. (See 'Severe disease' above.)

For patients receiving methotrexate for the management of psoriasis, the decision to perform a liver biopsy should be individualized based upon a patient's risk factors, liver chemistry results, and cumulative methotrexate dose, in accord with updated guidelines from the American Academy of Dermatology (AAD). (See 'Hepatotoxicity and liver biopsy' above.)

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