Psoriasis: Update on Therapeutic Choices

AUTHORS:
Reagan B. Anderson, DO, MPH, MCS
Camp Pendleton Naval Hospital

John R. Holman, MD, MPH
Uniformed Services University of the Health Sciences

CITATION:
Anderson RB, Holman JR. Psoriasis: update on therapeutic choices. Consultant. 2007;47(5):461-

ABSTRACT:
Topical corticosteroids remain the mainstay of treatment, especially in patients with erythematous, acutely inflamed psoriatic plaques. The topical immunomodulators tacrolimus and pimecrolimus are used to treat psoriasis, although neither has FDA approval for this indication. Unlike corticosteroids, immunomodulators do not cause skin atrophy, irreversible striae, acne, or tachyphylaxis. Newer topical vehicles of delivery (eg, foam clobetasol propionate) and newer drug combinations (eg, once-daily calcipotriene/ betamethasone dipropionate ointment) may improve efficacy and reduce side effects. Reserve systemic therapy for patients with moderate to severe psoriasis. Until more long-term safety data become available, be cautious about prescribing biologic agents for patients at risk for infection (particularly tuberculosis) and malignancy. Key words: psoriasis, corticosteroids, phototherapy, biologic therapy

Key words: psoriasis, corticosteroids, phototherapy, biologic therapy

The prevalence of psoriasis ranges from 0.5% to 4.6% in the United States; the disease is more common among whites and those who live at higher altitudes.¹ Although psoriasis is rarely life-threatening, the disease has significant psychosocial ramifications.² Patients must bear the stigma of an often highly visible skin disease, and treatment can be time-consuming and expensive.³

In recent years, greater understanding of the pathophysiology of psoriasis has led to the development of new therapies. During the previous year, 25 potential psoriasis drugs have been in phase 1, 2, or 3 of clinical study and 4 new drugs were approved for treatment (2 for psoriasis and 2 for psoriatic arthritis).⁴New drug combinations are being studied to determine the minimal amount of medication needed to produce optimal results.

Here we focus on the novel therapeutic choices for the control of psoriasis and discuss their efficacy and side effects.

PATHOPHYSIOLOGY

A brief overview. Psoriasis is thought to be caused by multiple genetic defects that interact with each other and the environment to produce hyperproliferative keratinocytes in the basal layer of the epidermis. This hyperproliferative state is triggered by unknown antigens, which activate T cells located in regional lymph nodes. Memory T cells then migrate to areas of trauma where they secrete interferon-γ, interleukin-2, and tumor necrosis factor a (TNF-α) into the dermis and epidermis. These type 1 (T_h1) cytokines induce the formation of hyperproliferative and immature keratinocytes together with vascular changes that are characteristic of psoriasis.^1,5 T_h1 cytokines are also responsible for the migration of neutrophils to the site of inflammation, thus continuing the inflammatory cascade.^6,7

Precipitating factors. Cold weather is a common precipitant of psoriasis, whereas tropical climates usually help control the disease process. Stress is also an important trigger; many patients can link their first occurrence and subsequent outbreaks of psoriatic lesions to particularly stressful periods.⁸

DIAGNOSIS

TREATMENT

Treatment options consist of topical agents, phototherapy, and systemic agents. Online algorithms are available to help you decide which treatment is appropriate for your patient (Box).^10-12 For example, the Koo-Menter Psoriasis Instrument involves both the patient and physician in deciding whether systemic therapy or phototherapy is warranted.¹⁰

Topical agents. Salicylic acid, coal tar, and anthralin--used alone or in combination with other agents--still have a place in the treatment of psoriasis. Salicylic acid is a keratolytic treatment that promotes absorption of other topical preparations. Application of coal tar once daily followed by UV therapy (Goeckerman treatment) remains an effective modality. Adding topical corticosteroids to this treatment enhances efficacy. Anthralin is usually a rapid-acting and effective treatment for plaque psoriasis; however, its routine use is limited because it stains skin, clothing, and bedding.

Topical immunomodulators. Tacrolimus and pimecrolimus have found a niche in the treatment of psoriasis, even though neither has FDA approval for such use.¹³ These agents block the nuclear factor of activated T cells and inhibit the inflammatory cascade of psoriasis. Unlike corticosteroids, the immunomodulators do not cause skin atrophy, irreversible striae, acne, or tachyphylaxis (corticosteroid tolerance that requires higher potency for therapeutic efficacy).¹⁴

Neither tacrolimus nor pimecrolimusshould be applied to virus- or bacteria-infected skin.¹⁵ These medications are not associated with high systemic concentrations or with statistically significant increases in opportunistic infections.^16-18 However, in 2006, the FDA mandated a black-box warning for these agents because of a possible cancer risk.¹⁹ More long-term studies are needed to determine whether this association is statistically significant. Currently, the FDA recommends these drugs for use as second-line treatments.

Tacrolimus (0.1%) ointment is used off-label for the treatment of facial and intertriginous psoriasis.¹⁸ Skin burning, erythema, and pruritus are the most common adverse effects; they decrease as treatment continues.²⁰ Tachyphylaxis from tacrolimus has not occurred in the treatment of atopic dermatitis, and researchers postulate that it will not occur in the treatment of psoriasis.²¹ The cost is about $80 for a 30-g tube.²²

Pimecrolimus (1%) cream, with or without occlusion, is used off-label for the treatment of intertriginous inverse psoriasis.^17,23,24 The adverse effects of pimecrolimus are the same as those of tacrolimus; however, they are less severe and usually do not cause discontinuation of therapy. The cost is about $67 for a 30-g tube.²⁵ Oral pimecrolimus is currently under evaluation by the FDA as an indication for psoriasis.²⁶

Corticosteroids. These agents are the backbone of psoriatic treatment, especially when the plaques are erythematous and acutely inflamed. Table 1 lists the currently available corticosteroids. Newer vehicles for topical corticosteroid delivery, such as foams, sprays, and shampoos, may offer improved efficacy and fewer side effects.

Betamethasone valerate and clobetasol propionate are now available in thermolabile, low-residue foam preparations, which appear to improve patient compliance and perceived quality of life.²⁷ In patients with scalp and nonscalp psoriasis, the foam preparations were well-tolerated and an increased response to treatment was noted. Hypothalamic-pituitary-adrenal (HPA) axis suppression was similar to that observed with the nonfoam preparations.

The side effects of foam preparations are similar to those of nonfoam formulations; they include local burning, stinging, and itching. Systemic reactions are uncommon. However, as little as 14 g/wk of clobetasol propionate has been shown to significantly reduce plasma cortisol levels.²⁸ Thus, be careful to avoid HPA axis suppression when prescribing these new corticosteroid vehicles. The foam formulations are generally not recommended for use under occlusion, on large body surface areas, in children, or with continuous unmonitored application.²⁹

Foam betamethasone valerate has been approved for scalp psoriasis; nonscalp indications are not yet FDA-approved. A foam preparation of clobetasol propionate has been approved for short-term treatment (less than 2 weeks) of mild to moderate psoriasis in scalp and nonscalp regions, excluding the face and skin folds.³⁰ Estimated cost for a 100-g tube of foam clobetasol propionate is $243³¹; estimated cost for a 100-g can of betamethasone valerate is $123.³²

A clobetasol propionate spray appears to result in good clinical outcomes and is easy to use. Clobetasol propionate shampoos are more effective than other vehicles in delivering corticosteroids to the scalp.³³

Combination topical therapy. Emphasis on combination, rotational, and sequential therapies has increased because of the numerous mechanisms of action, vehicles of delivery, and side effects of psoriasis medications.³⁴ When various medications with different mechanisms of action are combined, the therapeutic risk/benefit ratio can potentially be greatly reduced. One study suggests that the addition of another class of medication to corticosteroid therapy can reduce the corticosteroid dose required and thereby decrease the risk of side effects (such as tachyphylaxis, atrophy, and telangiectasia).³⁵

Some studies are evaluating whether topical medications that are combined in the same tube can produce a synergistic effect with fewer side effects. The combination of calcipotriene, a vitamin D₃ analog, with betamethasone dipropionate was found to improve clinical outcomes with an earlier onset of action in patients with psoriasis vulgaris.³⁶ The FDA has approved this combination as the first once-daily topical ointment for the treatment of plaque psoriasis in adults.³⁷ Similarly, tazarotene 0.1% gel combined with a mid- to high-potency topical corticosteroid decreased disease severity as well as adverse events.³⁸

Phototherapy. UV radiation is one of the oldest treatments of psoriasis. Narrowband UV-B is more effective than broadband UV-B. Because narrowband UV-B does not require administration of an erythemogenic dose to achieve results, there is less tissue damage and a decreased risk of the Koebner phenomenon. Psoralen-UV-A is a highly effective treatment of moderate to severe psoriasis. Although efficacious, these phototherapeutic modalities are associated with UV radiation-related adverse reactions, such as cutaneous neoplasms, premature aging, and other skin diseases. Theoretically, the use of combination therapy could decrease exposure and minimize adverse effects.

The safety and efficacy profile of phototherapy in combination with other modalities, specifically the biologic agents, is being studied.³⁹ In addition, the concomitant use of methotrexate( or a systemic retinoid with phototherapy has been shown to decrease the amount of UV radiation needed for improved therapeutic effects.^40,41

Systemic agents. These are usually reserved for patients with moderate to severe psoriasis (Figure 2).⁴² Oral retinoids remain part of the armamentarium; acitretin(, in particular, is very effective when given concomitantly with photochemotherapy. Cyclosporine and methotrexate are also effective in treating moderate to severe psoriasis; however, like the oral retinoids, they have significant side-effect profiles that can limit their use.

Biologic immunomodulators cause potentially fewer side effects than other systemic psoriasis treatments while providing the same degree of efficacy. The key features of the immunomodulatorsare highlighted in Table 2. Treatment with the biologic agents is expensive (between $10,000 and $25,000 per year).⁴³

Alefacept, efalizumab, and etanercept have been approved for use in patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy.⁴⁴Infliximab was recently approved for the treatment of severe chronic plaque psoriasis. Until more long-term data on the safety of the biologic agents become available, be cautious when prescribing these drugs for patients at risk for infection (particularly tuberculosis) and malignancy.⁴⁵

Alefacept inhibits T-cell activation and proliferation. It reduces symptoms and the severity of lesions during and after treatment. One course of alefacept is given via intramuscular or intravenous route once a week for 12 weeks.⁴³ Studies show a 75% or more reduction in psoriasis area and severity in 21% of actively treated patients after treatment, compared with 5% of patients given placebo.⁴⁶ Because CD4⁺ levels fall during treatment, a complete blood cell (CBC) count and CD4⁺ count need to be monitored weekly. No opportunistic infections have been reported with alefacept use, even when CD4⁺ concentrations fall below 250/µL, the level at which treatment is discontinued.¹⁶

Side effects--most commonly chills--have been minor, have not caused discontinuation of therapy, and are transient.^47,48 Patients can undergo another 12-week cycle when the benefits from the initial cycle begin to decrease, typically after 3 to 10 months.⁴⁸ Limited data are available on the safety and efficacy of multiple treatment cycles.

Efalizumab, like alefacept, inhibits T-cell activation, migration to affected skin, and adherence to keratinocytes. This drug is given subcutaneously once a week for 12 weeks; increased efficacy has been observed with continued use.⁴⁹ Studies show a 75% or more reduction in psoriasis area and severity in 28% of patients after treatment, compared with 5% of patients given placebo.⁴⁶

Lymphocytosis and thrombocytopenia are transient, uncommon, and usually benign side effects of treatment.⁵⁰ Baseline and then monthly CBC counts need to be performed.⁵¹ Headaches, nonspecific infections, fevers, chills, nausea, and pain are the most common adverse effects.⁵² No statistically significant increase in infections, cumulative toxicity, or end-organ damage has been documented.⁴⁹ After treatment is discontinued, monitor patients closely for psoriatic flaring.⁵³ Until more conclusive evidence is available, avoid administration of live or live-attenuated viruses in patients taking efalizumab because of the potential for immune suppression.⁴⁵

Etanercept inhibits TNF-α and thus decreases the release of chemokines and adhesion molecules from keratinocyte and vascular endothelial cells.⁵⁴ Etanercept is given subcutaneously twice a week for 12 weeks and then once a week thereafter.⁵⁵ Studies show 75% or more reduction in psoriasis area and severity in 30% of treated patients compared with 2% of patients given placebo.⁴⁶

Several deaths have been reported with use of etanercept; these usually occurred in patients who were also taking other immunomodulators, such as methotrexate.⁵⁶ Demyelinating diseases have been associated with etanercept. Patients with multiple sclerosis should not be given the drug, and treatment should be discontinued if neurological symptoms develop.⁵⁷

No routine monitoring is required.⁵¹ Etanercept is generally well tolerated; among the biologic agents, it has had the most data collected about its adverse effects. Etanercept has a number of generic side effects that are associated with all biologic agents; these usually cease after the first month of therapy. The most common side effect, local inflammation around the injection site, can usually be treated with topical corticosteroids, compresses, and oral antihistamines (if necessary).⁵⁸

Infliximab is another inhibitor of TNF-α. It has been approved for use in psoriatic arthritis and chronic severe plaque psoriasis.⁵⁹ Infliximab is given intravenously at intervals of 0, 2, and 6 weeks and then every 8 weeks thereafter, as tolerated.⁵⁹

Infliximab appears to have a higher rate of opportunistic infections, especially tuberculosis and histoplasmosis.^44,60,61 Like etanercept, infliximab is also linked to demyelinating disease and potentially to decreased efficacy of vaccinations. Currently, purified protein derivative (tuberculin) tests before and during treatment are recommended.⁴⁴

The most common side effect with infliximab is an infusion reaction, which tends not to be serious and has not caused discontinuation of therapy.⁴⁴ Although the clinical significance of antibody formation to infliximab is unknown, its incidence is higher with intermittent use than with regular maintenance dosing schedules.⁶²

Adalimumab is a TNF-&alpha inhibitor that has been approved for the treatment of psoriatic arthritis; it is currently undergoing trials for its effectiveness in treating psoriasis. If approved for this indication, the agent will be administered as a subcutaneous injection every other week.

QUALITY OF LIFE

Psoriasis can significantly reduce a patient's quality of life and impair social development and interaction and emotional health.^2,8 Despite the significant advances in the understanding and management of psoriasis, a cure cannot be offered and many patients are unsatisfied with the currently available treatments.⁶³

Lifestyle modification. The role of stress as an exacerbating factor of psoriasis is well documented.⁶⁴ The effect of stress reduction, limitation of alcohol consumption, and smoking cessation on psoriatic disease has not been well studied; however, preliminary evidence suggests that these behavior modifications can be effective.^65-67

Resources for patients. As with any disease, consider all aspects of the patient's life to ensure that treatment involves the whole person, not just the disease process. Encourage your patients to take advantage of available support groups, online chat rooms, and other Internet resources for persons with psoriasis. The National Psoriasis Foundation (available at: http://www.psoriasis.org) is an excellent resource. The Web site provides information for both patients and physicians on currently available prescription medications, new over-the-counter formulations, and patient testimonials.

Dr Anderson is a dive medical officer with the First Reconnaissance Battalion stationed at the Marine Corps Base, Camp Pendleton, Calif. He completed his family medicine internship at Camp Pendleton Naval Hospital. Dr Holman is adjunct professor of medicine at the Uniformed Services University of the Health Sciences in Bethesda, Md. He is also program director of the family medicine residency at Camp Pendleton Naval Hospital and a captain in the United States Navy.