Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

78. Psoriasis

Rebecca M. Law and Wayne P. Gulliver


KEY CONCEPTS1

 Images Patients with psoriasis have a lifelong illness that may be very visible and emotionally distressing. There is a strong need for empathy and a caring attitude in interactions with these patients.

 Images Psoriasis is a progressive T-lymphocyte–mediated systemic inflammatory disease that results from a complex interplay between multiple genetic factors and environmental influences. Genetic predisposition and precipitating “trigger”: factors play a role in the “march of psoriasis.” This march of innate and adaptive immune responses result in clinical expressions (e.g., keratinocyte proliferation) and is possibly responsible for psoriatic comorbidities.

 Images Diagnosis of psoriasis is usually based on recognition of the characteristic psoriatic lesion and not based on laboratory tests.

 Images Treatment goals for patients with psoriasis are to minimize signs such as plaques and scales, alleviate symptoms such as pruritus, reduce the frequency of flare-ups, ensure appropriate treatment of associated comorbid conditions such as psoriatic arthritis or clinical depression, and minimize treatment-related morbidity.

 Images Management of patients with psoriasis generally involves both nonpharmacologic and pharmacologic therapies.

 Images Nonpharmacologic alternatives such as stress reduction and the liberal use of moisturizers may be very beneficial and should always be considered and initiated when appropriate.

 Images Pharmacologic alternatives for psoriasis include topical agents, phototherapy, and systemic agents (both traditional agents and newer biologic response modifiers).

 Images Pharmacologic therapy is generally guided by the severity of disease, advancing from topical agents to phototherapy to systemic agents as needed.

 Images Rotational therapy (i.e., rotating systemic drug interventions) is a means to minimize drug-associated toxicities. However, continuous treatment has replaced rotational or sequential therapy and is now the standard of care for many dermatologists.

 Images Some biologic response modifiers (BRMs) have proven efficacy for psoriasis; however, there are differences among these agents, including mechanism of action, duration of remission, and adverse-effect profile. BRMS are often used for moderate-to-severe psoriasis and may be first-line therapy especially if comorbidities exist.


Psoriasis is a chronic disease that waxes and wanes. It is never cured, and it is now known to be associated with multiple comorbidities including heart disease, diabetes, and the metabolic syndrome. The signs and symptoms of psoriasis may subside totally (go into remission) and then flare up again (exacerbation). Triggers include stress, seasonal changes, and some drugs. Disease severity may vary from mild to disabling. Psoriasis imposes a burden of disease that extends beyond the physical dermatologic manifestations.

Images Patients with psoriasis have a lifelong illness that may be very visible and emotionally distressing. There is a strong need for empathy and a caring attitude in interactions with these patients. Thus, management of this condition is necessarily long-term and multifaceted, and management modalities may change according to the severity of illness at the time.

EPIDEMIOLOGY

Psoriasis is likely the most common immune-modulated inflammatory disease in North America and Europe, as it is thought to affect 17 million people, or approximately 2% of the population.2,3 Worldwide prevalences vary between 0.1% and 3%, with reasons for variation ranging from racial to geographic and environmental.3 Higher prevalences than 3% have been reported occasionally in Canada and the United States. Lower frequencies of between 0.4% and 0.7% are seen for people of African and Asian descent.4,5 Of interest is the fact that psoriasis is seldom seen in North and South American aboriginal Indians. It affects males and females equally.3,6 The majority of patients (approximately 75%) have onset before the age of 40 years,3 but psoriasis has been observed at birth and as late as the ninth decade of life.3 Many studies report two peak ages of onset: at 20 to 30 and 50 to 60 years of age.3,5

ETIOLOGY

Images Psoriasis is a T-lymphocyte–mediated systemic inflammatory disease that results from a complex interplay between multiple genetic factors and environmental influences. Genetic predisposition coupled with some precipitating factor triggers an abnormal immune response, resulting in the initial psoriatic skin lesions. This has more recently been called the “march of psoraisis”2 to reflect the innate and adaptive immune responses that are present. This march leads to expressions of psoriasis with keratinocyte proliferation being central to the clinical presentation of psoriasis. Subsequently, this march is possibly responsible for various comorbidities as a consequence of chronic inflammation.2 For example, there is an association between psoriasis and cardiovascular disease, which appears to be an ongoing, two-way interplay.2

Genetics

Dermatologists have recognized the familial tendencies of psoriasis for many years. Monozygotic twins have a concordance rate in the 80% range. Rates of family history in a psoriasis family range between 36% and 91%.69 A study using the founder population of Newfoundland and Labrador noted that more than 80% of the patients had a positive family history.

Genetic studies suggested at least seven loci are involved in psoriasis.3 In particular, PSORS1 appears to be a key gene locus determining susceptibility to psoriasis.2 In 2009, studies of the Newfoundland and Labrador population confirmed that major histocompatibility complex antigen HLA-Cw6 and tumor necrosis factor (TNF)-α as major psoriasis susceptibility genes, along with interleukin (IL)-23 loci that had previously been reported.3,10 The findings have been confirmed in multiple populations from North America, Europe, and China.11,12

Predisposing Factors and Precipitating Factors

Injury to the skin, infection, drugs, smoking, alcohol consumption, obesity, and psychogenic stress have been implicated in development of psoriasis. Examples of these precipitating factors include a horsefly bite causing skin trauma (known as the Koebner phenomenon),13 a viral or streptococcal infection, or the use of β-adrenergic blockers.14 Factors exacerbating preexisting psoriasis include drugs (e.g., lithium, nonsteroidal antiinflammatory drugs [NSAIDs], antimalarials, β-adrenergic blockers, and withdrawal of corticosteroids), and psoriatic patients commonly have exacerbations during times of stress.1,14Stressful situations occur for many patients, and it is thought that patients with a genetic predisposition to psoriasis and a precipitating event or trigger factor play a role.

PATHOPHYSIOLOGY

Psoriasis is a common chronic inflammatory disease that most likely involves both acquired and innate immunity. The interaction between dermal dendritic cells activated T cells of the TH-1, TH-17 lineage in concert with a multitude of cytokines and growth factors are responsible for the epidermal hyperplasia and dermal inflammation that is seen in the skin of patients with psoriasis. These inflammatory cells form lymphoid structures in psoriatic dermis, allowing the unimpeded inflammatory process to continue.15 When therapeutic intervention is initiated and positive the psoriatic phenotype is completely reversible without residual damage. This is in contrast to significant damage often seen in psoriatic arthritis that, if not treated early, is irreversible.

Comorbidities

It is now well documented that psoriasis patients have significant associated comorbidities.2 Psoriatic arthritis is one of the most common and well-known extracutaneous manifestations of disease. Other associated comorbidities include metabolic syndrome, other immune-mediated disorders such as Crohn’s disease, multiple sclerosis, and some psychological illnesses (anxiety, depression, and alcoholism).16Also, malignancies such as cutaneous T-cell lymphoma are associated with psoriasis, and melanoma and nonmelanoma skin cancer are associated with psoriasis treatments.

The National Psoriasis Foundation published a clinical consensus on psoriasis comorbidities with recommendations for screening and addressing issues such as cardiovascular risk, metabolic syndrome, and obesity.17 The importance of screening for comorbidities in psoriasis patients cannot be overemphasized: Nearly half of the psoriatic patients older than age 65 have at least three comorbidities, (with two-thirds of this patient population having two or more comorbidities).18 The presence of a specific comorbidity in a patient with psoriasis may influence the choice of pharmacotherapy.

Psoriatic arthritis (PsA) usually develops after the onset of psoriasis,3 typically 10 years later.16 However, 10% to 15% of patients report that the PsA appeared first.3 The prevalence of PsA in psoriatic patients is about 30% but varies by disease severity.16 In one U.S. study, the prevalences were 14% for patients with mild psoriasis, 18% for those with moderate psoriasis, and 56% for patients with severe psoriasis.19TNF-α and HLA-Cw6 are linked to both PsA and psoriasis.20 Although immunomodulating treatments for psoriasis (such as methotrexate or TNF-α inhibitors) are useful for PsA, NSAIDs effective for joint symptoms of PsA may exacerbate psoriasis.

Metabolic syndrome is a cluster of risk factors including abdominal obesity, atherogenic dyslipidemia, hypertension, insulin resistance or glucose intolerance, prothrombotic state, and proinflammatory state.17Patients with psoriasis are at increased risk of developing the metabolic syndrome.17 The syndrome is a strong predictor of cardiovascular diseases, stroke, and diabetes.17,21,22 Patients with this syndrome are three times as likely to have a myocardial infarction (MI) or stroke, twice as likely to die from the MI or stroke, and five times as likely to develop type 2 diabetes.17 A 2010 retrospective analysis of pooled data from three clinical trials (M02-528, CHAMPION, and REVEAL) showed that patients with psoriasis have a 28% and 12% increased 10-year risks of coronary heart disease (CHD) and stroke, respectively.22

Patients with psoriasis also have a decreased life expectancy and increased rates of mortality. Psoriasis is an independent risk factor for atherosclerosis, especially for younger patients with severe disease.17 A 2006 study found that a relative risk (RR) of death for a 30-year-old person with severe psoriasis was 3.10, after controlling for traditional cardiovascular risk factors (e.g., age, gender, hypertension, dyslipidemia, diabetes mellitus, smoking, body mass index [BMI], C-reactive protein [CRP], and family history of cardiovascular disease).17,23

Types of Psoriasis

Plaque psoriasis, also known as psoriasis vulgaris, is the most common type of psoriasis (Table 78–1) and is seen in about 90% of psoriasis patients. Plaque psoriasis presents as shown in the Clinical Presentation box.

TABLE 78-1 Phenotypic Classifications of Psoriasis

Images

DIAGNOSTIC CONSIDERATIONS

Images The diagnosis of psoriasis is a diagnosis based on recognition of the characteristic psoriatic lesion and not on laboratory tests. Diagnostic testing is rarely performed as a biopsy may be suggested but is not diagnostic of psoriasis.

Psoriasis is traditionally classified into mild, moderate, or severe disease. In 2011, a European consensus (19 countries) formalized the definition of disease severity and treatment goals and defined plaque psoriasis severity as two main categories: mild versus moderate-to-severe.24,25 Both classification systems are in use today. In clinical practice, assessment of the severity of disease includes both an objective evaluation of the extent and symptoms as well as a subjective evaluation of the impact of disease on the patient’s quality of life.26 Assessment typically includes measures of symptom and involvement such as body surface area (BSA), Psoriasis Area and Severity Index (PASI), or Physician’s Global Assessment (static PGA), as well as quality-of-life measures such as the Dermatology Life Quality Index (DLQI) or the Short Form (SF-36) Health Survey.26


CLINICAL PRESENTATION

Images

Classification of psoriasis as mild, moderate, or severe disease is generally based on BSA or PASI measurements (see Clinical Presentation box). Practically, to give a rough estimate of BSA involvement, palm size is approximately 1% BSA, head and neck involvement is approximately 10% BSA, both upper limbs approximately 20% BSA, trunk involvement (front and back) approximately 30% BSA, and both lower limbs approximately 40% BSA.

TREATMENT

Treatment of psoriasis is based on managing the underlying pathophysiology. Agents that modulate the abnormal immune response, such as corticosteroids and biologic response modifiers, are important treatment strategies for psoriasis. Topical therapies that affect cell turnover are also effective for psoriasis. In addition, nonpharmacologic therapies are effective adjuncts and should be considered for all patients with psoriasis. A treatment regimen should always be individualized, taking into consideration severity of disease, patient responses, and tolerability to various interventions. Furthermore, if comorbidities exist, they must be taken into treatment considerations and managed early. Optimal psoriasis care needs to maintain a focus on the patient’s overall health-related quality of life.

Desired Outcomes

Images Goals of treatment1:

    • Minimizing or eliminating the signs of psoriasis, such as plaques and scales

    • Alleviating pruritus and minimizing excoriations

    • Reducing the frequency of flare-ups

    • Ensuring appropriate treatment of associated comorbid conditions such as psoriatic arthritis, hypertension, dyslipidemia, diabetes, or clinical depression

    • Avoiding or minimizing adverse effects from treatments used (topical, phototherapy, and/or systemic)

    • Providing cost-effective therapy

    • Providing guidance or counseling as needed (e.g., stress-reduction techniques)

    • Maintaining or improving the patient’s quality of life

Evaluation of Therapeutic Outcomes

Successful management of psoriasis should include not only clearance of skin lesions, which may take weeks to months depending on the severity of disease, but also control of associated conditions such as itching, and, importantly, comorbidities, including dyslipidemia, hypertension, psoriatic arthritis, and clinical depression. The ultimate goal is to provide enough control of this chronic disease (and its comorbidities, if present) so that the patient’s quality of life is minimally affected.

The 2011 European consensus defined induction and maintenance phases and provided separate treatment goals for induction and maintenance.24,25 The induction phase is defined as the first 16 weeks of treatment for drugs with a rapid induction to remission (such as adalimumab or infliximab), extending the phase to 24 weeks of treatment for less rapidly effective drugs (such as methotrexate or etanercept).25To be considered successful therapy, a treatment regimen should result in a reduction of PASI greater than or equal to 75%, or PASI of 50% to 75% coupled with a DLQI less than 5.25 Otherwise, treatment modifications should be considered. Treatment goals should be assessed at 10 to 16 weeks and then every 8 weeks thereafter.25

General Approach to Treatment

Images Management of patients with psoriasis generally involves both nonpharmacologic and pharmacologic therapies. Nonpharmacologic therapies are important and should be used for all patients with psoriasis, regardless of the severity of disease. Pharmacologic therapies are always tailored to the individual patient with psoriasis and different treatment strategies would be used depending on psoriatic disease severity, presence or absence of comorbid illnesses, and any special considerations such as hepatic or renal dysfunction.

Nonpharmacologic Therapy

Images Nonpharmacologic alternatives may be very beneficial and should always be considered and initiated when appropriate.1 These include stress-reduction strategies, moisturizers, oatmeal baths, and skin protection using sunscreens.27

In particular, stress reduction has been shown to improve both the extent and severity of psoriasis and to include methods such as guided imagery and stress-management clinics. Liberal use of nonmedicated moisturizers, applied ad lib, helps to maintain skin moisture, reduces skin shedding, controls associated scaling, and may reduce pruritus. Oatmeal baths further reduce pruritus and with regular use may minimize the need for systemic antipruritic drugs.

Sunscreens, preferably with a sun protection factor (SPF) of 30 or more, should be regularly used because sunburns can trigger an exacerbation of psoriasis. Irritation to the skin should be minimized—harsh soaps or detergents should not be used. Cleansing should be done with tepid water and preferably with lipid-free and fragrance-free cleansers.1,27

For patients with comorbidities such as dyslipidemia, obesity, or cardiovascular disease, cessation of nicotine and alcohol consumption, diet control, and increasing physical activity are all important interventions.2

Pharmacologic Therapy

Images Pharmacologic alternatives for psoriasis are topical agents, phototherapy, and systemic agents, including biologic response modifiers.

Drug Treatments of First Choice

Images For limited or mild to moderately severe disease, topical treatments are the usual standard of care, with phototherapy and photochemotherapy used in moderate to severe cases. For patients presenting with extensive or moderate-to-severe disease, systemic therapies with or without the use of topical treatments are the usual standard of care. Newer systemic treatments such as biologic response modifiers (BRMs) may be the treatments of choice, especially for patients with comorbidities such as PsA or if traditional systemic treatments (such as methotrexate or cyclosporine) are contraindicated. Once the disease is under control, it would be important to step down to the least potent, least toxic agent(s) that maintain control. Images Sequential therapy and rotational therapy may minimize drug-associated toxicities; however, continuous treatment is now the standard of care for many dermatologists. Different treatment algorithms are used, depending on the severity of the plaque psoriasis (Figs. 78-1 and 78-2).1

Images

FIGURE 78-1 Treatment algorithm for mild-to-moderate psoriasis. (Reprinted from reference 1 with permission from the publisher.)

Images

FIGURE 78-2 Treatment algorithm for moderate-to-severe psoriasis. (Reprinted from reference 1 with permission from the publisher.

Published Guidelines or Treatment Protocols Treatment guidelines have recently been updated in both the United States and Canada.26,2835 All U.S. guidelines are endorsed by the American Academy of Dermatology or the National Psoriasis Foundation, and Canadian guidelines are endorsed by the Canadian Dermatology Association. In Europe, guidelines from the British Association of Dermatologists36and a European 19-country consensus have been published.24,25 These guidelines represent the current standards of care.

Topical Therapies

Approximately 80% of patients with psoriasis have mild-to-moderate disease,30 and the majority of these patients can be treated with topical therapies alone.30 Individualized approaches are essential because of the wide variation in patients’ presentations, their psychosocial health, and their personal opinions as to what would be acceptable treatment.26 Topical therapies include corticosteroids, vitamin D3 analogs, retinoids, anthralin, and coal tar. These are generally efficacious and safe for this patient population. Topical agents are also used as adjunctive therapy for patients with more extensive disease who are being treated concurrently with phototherapy or systemic agents.

To determine the quantity of topical agents required, the fingertip unit37 can be used. One fingertip unit is approximately 500 mg,30,37 which is sufficient to cover one hand (front and back) or about 2% BSA.38The trunk (front and back) is about 30% BSA; to cover the entire trunk once, about 15 fingertip units, or 7500 mg (7.5 g), would be required.

In a 2012 systematic review of topical and phototherapies for psoriasis by dermatologists in France, nine recommendations based on evidence and expert opinion are offered. However, quality literature was limited, and the recommendations relating to optimal steroid use and optimal first-line treatment for psoriasis did not reach 80% consensus.37

Corticosteroids Topical corticosteroids have been the mainstay of therapy for the majority of patients with psoriasis for over half a century. They are generally well tolerated, although adverse effects can occur, including systemic ones on occasion. Table 78–2 provides a summary of topical corticosteroid formulations—including ointments, creams, gels, foams, lotions, sprays, shampoos, tape, and solutions30—and potencies.

TABLE 78-2 Topical Corticosteroid Potency Chart

Images

The choice of vehicle affects corticosteroid potency: Ointments, being the most occlusive, enhance drug penetration and provide the most potent formulations. However, patients may prefer a less greasy formulation, such as a cream or lotion for daytime use, although they may be willing to apply the more effective ointment-based corticosteroid during the night.30 Providing additional occlusion will increase drug penetration of a topical preparation, resulting in enhanced potency. For example, flurandrenolide cream and lotion are potency class 5, but flurandrenolide tape was found to have higher efficacy than diflorasone diacetate ointment (potency class 1).30,39,40

Despite their widespread use, there have been few large-scale, randomized placebo-controlled corticosteroid trials and even fewer head-to-head comparisons with other therapies. The most comprehensive review to date is the analysis of topical psoriasis therapies done in 2002 but recent studies aren’t included so this review was already somewhat out of date when published.26,41 This systematic review found that all topical corticosteroid treatments considered were efficacious and significantly better than placebo; and that the highest potency corticosteroids were the most efficacious, followed by vitamin D3analogs.26 The French group in 2012 found variable efficacy in their systematic review, noting that recommendations about topical steroid use should be mostly based on expert opinion, and that maintenance intermittent treatment may prolong remission.42

Corticosteroids have antiinflammatory, antiproliferative, immunosuppressive, and vasoconstrictive effects.30 These are mediated through a variety of mechanisms. Mechanisms of action include binding to intracellular corticosteroid receptors and regulation of gene transcription (in particular those which code for proinflammatory cytokines).30

Appropriate use of topical corticosteroids should include an assessment of disease severity and disease location as well as knowledge of the patient’s preference and age. Lower potency corticosteroids should be used for infants and for lesions on the face, intertriginous areas, and areas with thin skin. For other areas of the body in adults, mid- to high-potency agents are generally recommended as initial therapy.30The highest potency corticosteroids are generally reserved for patients with very thick plaques or recalcitrant disease, such as plaques on palms and soles. The use of potency class 1 corticosteroids should be limited to a duration of 2 to 4 weeks,30 recognizing that the risk of cutaneous and systemic side effects increases with continued use.

Cutaneous adverse effects include skin atrophy, acne, contact dermatitis, hypertrichosis, folliculitis, hypopigmentation, perioral dermatitis, striae, telangiectases, and traumatic purpura.26,30 Systemic adverse effects have been reported not only with superpotent corticosteroids but also with extended or widespread use of mid-potency agents.30 Systemic adverse effects include hypothalamic–pituitary–adrenal (HPA) axis suppression and less commonly Cushing’s syndrome, osteonecrosis of the femoral head, cataracts, and glaucoma.30

All topical corticosteroids are pregnancy category C.30

Tachyphylaxis can occur with prolonged use, although its clinical significance is difficult to verify.26 It is recommended that the frequency of use be gradually reduced once clinical response is seen, although there are no established tapering regimens.30 The French group recommended twice-weekly maintenance therapy.37 Other approaches include transitioning to weaker potency agents or combination with other nonsteroidal topical therapies.30Pulse dosing has also been used to minimize tachyphylaxis and adverse effects.43

Vitamin D3 Analogs Topical vitamin D3 analogs include calcipotriol (calcipotriene), calcitriol (the active metabolite of vitamin D), and tacalcitol. Only calcipotriol is currently available in the United States30and Canada.26 Other analogs currently under study include maxacalcitol and becocalcidiol.30 Their mechanisms of action include binding to vitamin D receptors, which results in inhibition of keratinocyte proliferation and enhancement of keratinocyte differentiation.26,30 They also inhibit T-lymphocyte activity.26

The efficacy of calcipotriol for patients with mild psoriasis is well established in randomized double-blind placebo-controlled trials. In head-to-head comparison studies with other topical agents, calcipotriol was found to be more effective than anthralin (dithranol)44 and comparable or slightly more effective than potency class 3 (upper mid-strength) topical corticosteroid ointments such as betamethasone valerate 0.1% ointment.26,45,46 In an analysis of topical psoriasis therapies done in 2002,41 calcipotriol was found to be as effective as all but the most potent topical corticosteroids.26 Combination therapy with a topical steroid is particularly effective47 and is discussed later in the chapter.

Vitamin D3 analogs are generally well tolerated and have a good safety profile in comparison with other topical therapies.47 Cutaneous adverse effects most commonly include a mild irritant contact dermatitis; others include burning, pruritus, edema, peeling, dryness, and erythema.26,30 These adverse effects may be mitigated with continued use.30 Systemic adverse effects, including hypercalcemia and parathyroid hormone suppression, are rare unless patients are using more than the recommended maximum of 5 mg calcipotriol (100 g of calcipotriol 50 mcg/g cream or ointment) per week26,30 or if there is underlying renal disease or impaired calcium metabolism.30 When applied sparingly over a BSA <30%, the risk of hypercalcemia is remote.37

Calcipotriol is pregnancy category C. It is inactivated by ultraviolet A (UVA) light thus it should be applied after rather than before UVA light exposure.30

Retinoids Tazarotene is a topical retinoid that acts through the following mechanisms: normalizing abnormal keratinocyte differentiation, diminishing keratinocyte hyperproliferation, and clearing the inflammatory infiltrate in the psoriatic plaque.26,30 It is effective in clearing psoriatic plaque lesions and achieving remission.

In a placebo-controlled trial of tazarotene 0.1% and 0.05% gels for patients with plaque psoriasis, tazarotene provided a 50% or greater improvement in 63% (0.1% gel) and 50% (0.05% gel) of patients, respectively, after 12 weeks of use.48 The therapeutic benefit appears to be maintained for 12 weeks after cessation of therapy.48 Later clinical trials with tazarotene 0.1% and 0.05% creams versus a placebo vehicle provided similar findings.49 The 2012 systematic review similarly found that about 50% of patients experienced a 50% or more improvement with no difference in formulations.37

Adverse effects of tazarotene include a high incidence of irritation at the site of application, a dose-dependent effect.26 This results in burning, itching, and erythema, which can occur in lesional and perilesional skin.30 Irritation may be reduced by using the cream formulation, lower concentration, alternate-day application, or short-contact (30 to 60 minutes) treatment.30 Ad lib use of moisturizers is also beneficial. Tazarotene is also potentially photosensitizing, due to thinning of the epidermis that can occur with continued use.30

Tazarotene is pregnancy category X and should not be used in women of childbearing age unless effective contraception is being used.

Anthralin Anthralin is not as commonly used as other topical therapies currently available for psoriasis; however, there are situations where its use is appropriate and efficacious. It has a direct antiproliferative effect on epidermal keratinocytes,1,14 normalizing keratinocyte differentiation.30 Although the exact mechanism of action is unknown, it may have a direct effect on mitochondria30,50 and reduce the mitotic activity. It also prevents T-lymphocyte activation.30 Small placebo-controlled studies demonstrated efficacy for anthralin used continuously or as very short contact (1 minute of treatment).30

Currently, short-contact anthralin therapy (SCAT) is usually the preferred regimen, where the anthralin ointment is applied only to the thick plaque lesions for 2 hours or less and then wiped off.1,30 Because lesions are generally well demarcated, zinc oxide ointment or a nonmedicated stiff paste should be applied to the surrounding normal skin to protect it from irritation and burning. Anthralin should be used with caution, if at all, on the face and intertriginous areas because of the risk of severe skin irritation.30

Concentrations for SCAT range from 1% to 4% or as tolerated; concentrations for continuous anthralin therapy vary from 0.05% to 0.4%. Aside from significant and often severe skin irritation, other adverse effects include folliculitis and allergic contact dermatitis, but these are uncommon.

Anthralin is pregnancy category C. People who handle the dry anthralin powder should avoid skin contact (e.g., by wearing gloves while compounding).1

Coal Tar Coal tar was one of the earliest agents used to treat psoriasis. It is keratolytic and may have antiproliferative and antiinflammatory effects.1 Coal tar formulations include crude coal tar and tar distillates (liquor carbonis detergens) in ointments, creams, and shampoos. Because of limited efficacy coupled with patient acceptance and compliance issues, coal tar preparations are less commonly used today, especially in North American and European37countries.

A 2007 comparative study in Thailand reported that betamethasone valerate was significantly more effective than coal tar.26,51 Although coal tar may have similar efficacy as calcipotriol, it has a slower onset of action.26 In addition, coal tar has an unpleasant odor and will stain clothing; thus, it may be cosmetically unappealing to patients.

Adverse effects include folliculitis, acne, local irritation, and phototoxicity.26 It is carcinogenic in animals, but for humans no convincing data have emerged regarding carcinogenicity with topical use.30

Coal tar concentrations as used in psoriasis treatments (0.5% to 5%) are considered safe by the FDA.33 However, occupational exposure to coal tar, especially in very high concentrations such as coal tar used in industrial paving,33 was reported to increase the risk of lung cancer, scrotal cancer, and skin cancer.30,33 The risk of teratogenicity when used in pregnancy is likely to be small, if it exists.30

Salicylic Acid Salicylic acid has keratolytic properties and has been used in various formulations including shampoos or bath oils for patients with scalp psoriasis. In combination with topical corticosteroids, it enhances steroid penetration thus increasing efficacy. It should not be used in combination with ultraviolet B (UVB) light phototherapy because of a filtering effect that may reduce efficacy. Systemic absorption and toxicity can occur, especially when applied to more than 20% BSA or when used for patients with renal impairment.

Avoid the use of salicylic acid in children. However, it may be used for limited and localized plaque psoriasis in pregnancy.30

Calcineurin Inhibitors Topical calcineurin inhibitors such as pimecrolimus 1% cream (Elidel) are used for the treatment of inflammatory skin diseases such as atopic dermatitis.5254 Pimecrolimus was found to be effective for plaque psoriasis when used under occlusion53 and also effective for patients with moderate to severe inverse psoriasis (intertriginous areas are affected).54 Because this cream is less irritating than calcipotriol and also avoids steroid adverse effects such as skin atrophy, it may be a useful alternative for patients with lesions in intertriginous areas.

Phototherapies and Photochemotherapy

Phototherapy has been used for treating psoriasis for years and is still an important treatment modality today. It has been known for centuries that some skin diseases improve with sun exposure, and clinical studies with phototherapies have been reported since the late 19th century.28 Phototherapy consists of using nonionizing electromagnetic radiation, either UVA or UVB, as light therapy to treat psoriatic lesions.55

UVB is given alone as either broadband or narrowband UVB (NB-UVB), currently with NB-UVB being the preferred method. Broadband UVB is also given as photochemotherapy with topical agents such as crude coal tar (Goeckerman regimen)55 or anthralin (Ingram regimen) for enhanced efficacy.28

UVA is generally given with a photosensitizer, such as an oral psoralens, to enhance efficacy—this regimen is known as PUVA (photochemotherapy with oral methoxypsoralen and ultraviolet A light).55

With respect to comparative efficacy, NB-UVB is more efficacious than broadband UVB, but may be slightly less effective than PUVA.28,56 PUVA is very effective in the majority of patients, with the potential for long remissions.28 A meta-analysis showed that more patients are still clear at 6 months with PUVA versus with NB-UVB.56 However, because of greater availability of UVB treatment centers, more evidence available now of the efficacy of UVB treatments for psoriasis (in particular, NB-UVB), and especially the increasing concerns about PUVA toxicities (including skin cancers), phototherapy for psoriasis currently uses UVB or NB-UVB where available. Failure of NB-UVB may justify PUVA therapy.55

UVB interferes with protein and nucleic acid synthesis, leading to decreased proliferation of epidermal keratinocytes.28 UVA has similar effects on epidermal keratinocytes. However, because of deeper penetration into the dermis, it also has effects on dermal dendritic cells, fibroblasts, endothelial cells, mast cells, and skin-infiltrating inflammatory cells including granulocytes and T lymphocytes.28

Adverse effects of phototherapy include erythema, pruritus, xerosis, hyperpigmentation, and blistering, especially with higher dosages. It should be used with caution for patients with photosensitivity concerns, and drug interactions include photosensitizing medications such as tetracyclines. Patients must be provided with eye protection during UVB, NB-UVB, or PUVA treatments, and for 24 hours55 or the remainder of the day28 after PUVA treatments. In addition, patients receiving PUVA therapy may experience gastrointestinal symptoms such as nausea or vomiting, which may be minimized by taking the oral psoralens with food or milk.28 For patients also receiving oral retinoids plus PUVA (RE-PUVA), the UVA dose should be reduced by one-third.28

Long-term PUVA use can lead to photoaging and the development of PUVA lentigines. Psoralens bind to proteins in the lens of the eye; thus, there is a potential for increased cataract formation. Furthermore, although UVB has a theoretical risk of photocarcinogenesis, the risk is significantly higher with PUVA and is dose related.28,55 A meta-analysis reported a 14-fold increase in the incidence of squamous cell carcinoma (SCC) in patients receiving high-dose PUVA when compared with low-dose PUVA, with SCC of the male genitalia particularly elevated.28,57 PUVA may also increase the risk of basal cell carcinoma and possibly melanoma,28 which may occur 15 years after the first treatment.55

Systemic Therapies

Systemic therapies are the mainstay of treatment for patients with moderate-to-severe psoriasis, with topical therapies remaining as useful adjuncts. However, as discussed below under combination therapies, topical calcipotriol and betamethasone dipropionate ointment may provide sufficient disease control for some patients.26,58 Conversely, a subset of patients with limited disease may have debilitating symptoms, and the use of systemic therapies would be warranted.29 Systemic therapies include the following traditional agents acitretin, cyclosporine, methotrexate, mycophenolate mofetil (MMF), and hydroxyurea; as well as the newer BRMs, specifically adalimumab, alefacept, etanercept, infliximab, and ustekinumab.

Acitretin In the 1980s, etretinate became the first oral retinoid, or vitamin A acid derivative, available for the treatment of psoriasis. It has since been replaced by acitretin, its active metabolite.

Retinoids may be less effective than methotrexate or cyclosporine when used as monotherapy. Currently, acitretin is more commonly used in combination with topical calcipotriol or phototherapy.26,29 Its efficacy appears to be dose dependent,29 but low-dose acitretin (25 mg/day) is safer and better tolerated than higher-dose (50 mg/day) therapy.26

Common adverse effects of acitretin include hypertriglyceridemia and mucocutaneous adverse effects such as dryness of the eyes, nasal and oral mucosa, chapped lips, cheilitis, epistaxis, xerosis, brittle nails, and burning or sticky skin.26,29 Less commonly, “retinoid dermatitis” may occur. Periungual pyogenic granulomas are sometimes seen after long-term use of acitretin.29 Rarely, skeletal abnormalities—such as disseminated idiopathic skeletal hyperostosis (DISH) syndrome—may occur.26

All retinoids are teratogenic and are pregnancy category X, including topical retinoids. Acitretin should not be used for women of childbearing age unless they are able and willing to use effective birth control not only for the duration of acitretin therapy but also for 3 years after discontinuing the agent.26,29 Men receiving acitretin should not donate blood for a similar time period.

Ethanol should be avoided during therapy and for 2 months after drug discontinuation because it causes the transesterification of acitretin to etretinate, which has a much longer elimination half-life.

Cyclosporine Cyclosporine is a systemic calcineurin inhibitor. The original formulation, marketed as Sandimmune, was first approved as a posttransplant immunosuppressant to prevent organ rejection. The more bioavailable microemulsion formulation, Neoral, was approved by the FDA in 1997 for the treatment of psoriasis and rheumatoid arthritis.32

Cyclosporine is efficacious for both inducing remission and maintenance therapy for patients with moderate to severe plaque psoriasis. It is also effective in treating pustular, erythrodermic, and nail psoriasis.32

In comparative randomized controlled trials (RCTs), cyclosporine was significantly more effective than etretinate59 and similar or slightly better in efficacy than methotrexate.26,32,60 After inducing remission, maintenance therapy using low doses (1.25 mg/kg/day to 3.0 mg/kg/day) may prevent relapse.32 The dose should always be titrated to the lowest effective dose for maintenance. In one placebo-controlled study, the relapse rate was 42% for patients on 3.0 mg/kg/day versus 84% for patients on placebo.61

For patients discontinuing cyclosporine, a gradual taper of 1 mg/kg/day each week may prolong the time before relapse, as compared with abrupt discontinuation.29,32 Abrupt discontinuation resulted in a dramatic rebound of psoriasis in a few cases.26 Because more than half of patients discontinuing cyclosporine will relapse within 4 months, patients should be provided with appropriate alternative treatments shortly before or after discontinuing cyclosporine therapy.32

Adverse effects of cyclosporine include cumulative renal toxicity, hypertension, and hypertriglyceridemia. The latter two are particularly significant for patients with prior elevation of diastolic blood pressure or triglycerides.26Hypertriglyceridemia can occur in up to 15% of patients with psoriasis who are treated with cyclosporine, although this effect is generally reversible upon cessation of therapy.29

The risk of SCC and other nonmelanoma skin cancers increases with duration of treatment26 and with prior PUVA treatments.29 Thus, although continuous therapy for up to 2 years may be efficacious,32 it should be used only in a subset of patients26 in whom renal function is monitored with annual determinations of glomerular filtration rate (GFR) and monthly measurements of blood pressure and creatinine clearance, with more frequent measurements during the initial 6 weeks of treatment.26

Baseline blood pressure, serum creatinine, serum urea nitrogen, triglycerides, complete blood count, uric acid, potassium, and magnesium should be obtained before initiating therapy, every 2 weeks for the first 12 weeks of therapy, and monitored monthly thereafter during therapy.26,32 Age-appropriate malignancy screens should also be done, and patients should be seen for dental examinations at least yearly because of the risk of gingival hyperplasia.32

The 2009 Canadian Guidelines recommended that cyclosporine be normally reserved for intermittent use in periods up to 12 weeks for most patients with psoriasis,26 although other recommendations are for periods of 1 year or up to 2 years.32 Risk of toxicity increases with treatment duration.

As a cytochrome P450 isoenzyme 3A4 (CYP3A4) substrate, cyclosporine has significant drug interactions. Serum concentration monitoring is not routinely needed for patients with psoriasis because doses used are lower than in transplant recipients, although monitoring may be advisable for patients taking interacting drugs.

Drugs that can increase cyclosporine concentrations include calcium channel blockers (verapamil, diltiazem, and nicardipine), amiodarone, thiazide diuretics, macrolide antibiotics, allopurinol, oral contraceptives, ezetimibe, selective serotonin reuptake inhibitors (fluoxetine, sertraline), fluoroquinolones (ciprofloxacin, norfloxacin), antifungals (ketoconazole, itraconazole, fluconazole, voriconazole), and cimetidine.32 Grapefruit juice will also increase cyclosporine concentrations.

Drugs that can reduce cyclosporine concentrations include anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, valproic acid), efavirenz, and St. John’s wort.32

Conversely, cyclosporine may also affect the drug levels of some drugs. Concurrent use of potentially interacting drugs should be avoided when possible.

Methotrexate For decades, methotrexate has been the mainstay of systemic therapy for patients with moderate-to-severe psoriasis. It has direct antiinflammatory benefits due to its effects on T-cell gene expression and also has cytostatic effects.26 It is more efficacious than acitretin and similar or slightly less efficacious than cyclosporine.26,34

Although it also has a significant adverse effects profile, methotrexate is generally considered a safer alternative than cyclosporine unless there are preexisting contraindications such as liver disease. In some head-to-head clinical studies more patients dropped out of the cyclosporine treatment arms due to adverse effects.29,34 While BRMs are undoubtedly more efficacious, they are much more costly, and some insurance companies require an inadequate response or intolerance to methotrexate (the gold standard) as a prerequisite for approving their use.34 In a recent placebo-controlled comparative study with adalimumab (CHAMPION), the efficacy of methotrexate was 36% versus 80% for adalimumab and 19% for placebo.62 Adalimumab also provided a more rapid response; however, the duration of remission is unclear. In another recent randomized phase 3 trial (RESTORE), the efficacy of methotrexate was 42% versus 78% for infliximab.63

Initial doses of 7.5 to 15 mg/week may be increased to 20 to 25 mg/week if the response is inadequate at 8 to 12 weeks, with appropriate adverse effect monitoring. Methotrexate can be used continuously for years or decades with sustained benefits.26 Methotrexate inhibits folate biosynthesis; and the use of folate supplementation during prolonged methotrexate therapy as seen in dermatology remains controversial (see Clinical Controversy box).


Clinical Controversy…

Folate Supplementation for Methotrexate Therapy

Although some experts recommend folate supplementation for all patients receiving methotrexate for psoriasis, others add folate only when patient issues occur, such as gastrointestinal adverse effects or early bone marrow toxicity (as manifested by an increased mean corpuscular volume) that can be caused by megaloblastic anemia.29,34 Lack of folate supplementation has also been listed as a risk factor for hepatotoxicity from methotrexate use.34One small placebo-controlled study suggested that folate supplementation may result in a slight decrease in efficacy of treatment,116 but the study methodology has been questioned.29,34

The most significant adverse effect is cumulative liver toxicity; and total lifetime dose of methotrexate must be monitored. Traditionally, patients received a pretreatment liver biopsy and subsequent biopsies when a cumulative dose of 1.5 g is reached. Currently, it is recognized that pretreatment liver biopsies may not be practical or appropriate in all cases26,34 and that baseline liver biopsies only be considered for patients with a history of significant liver disease.34 It has also been recommended that a baseline liver biopsy be delayed for 2 to 6 months so that medication efficacy and tolerability can first be established34(i.e., intention to continue with methotrexate use). Risk factors for hepatotoxicity from methotrexate include the following: a history of or current alcohol consumption, persistent abnormal liver chemistry studies, history of liver disease including chronic hepatitis B or C, family history of inheritable liver disease, history of significant exposure to hepatotoxic drugs or chemicals, diabetes mellitus, obesity, and hyperlipidemia.29,34 For patients without preexisting risk factors for hepatotoxicity, it is recognized that they would likely have a low risk of fibrosis and would not require a baseline liver biopsy; furthermore, consideration can be made to continue methotrexate treatment for these patients without biopsies at all, to perform a liver biopsy after 3.5 to 4.0 g total cumulative dose, or to switch therapy to an alternate drug at that point.29,34

Other adverse effects include significant nausea, pulmonary toxicity, pancytopenia, acute myelosuppression, megaloblastic anemia, and a small but significant increase in lymphoma.26 Although rare, pancytopenia can occur anytime with the use of low-dose weekly methotrexate and even after single doses of methotrexate.29 Methotrexate is an abortifacient and is teratogenic (pregnancy category X) and should not be used in pregnancy. After methotrexate therapy is discontinued, it is recommended that men continue an effective birth control for 3 months (since one cycle of spermatogenesis is 74 days), and women should be on effective birth control for at least one ovulatory cycle.26,29

Significant drug interactions include serum albumin binding interactions with salicylates, phenytoin, sulfonamides/trimethoprim, ciprofloxacin, and thiazide diuretics, potentially increasing toxicity. Drugs that can reduce methotrexate renal elimination (such as acidic drugs, including salicylates or vitamin C) will also increase serum methotrexate levels and hence increase toxicity. In addition, drugs with hepatotoxic potential may pose an additive risk with methotrexate use.29

Systemic Therapy with Biologic Response Modifiers

Images Some BRMs have proven efficacy for psoriasis; however, there are differences among these agents, including mechanism of action, duration of remission, and adverse-effect profile. In general, because of their immunomodulatory effects, there is an increased risk of infection with most of these agents. The use of live or live-attenuated vaccines during therapy is generally contraindicated. Currently, BRMs are often considered for patients with moderate to severe psoriasis when other systemic agents are inadequate or relatively contraindicated. BRMs are sometimes recommended for first-line therapy, alongside conventional systemic agents, for patients with moderate to severe psoriasis; however, in practice, drug access due to cost considerations may be a limiting factor. BRMs may be appropriate as first-line therapy if comorbidities exist. For example, BRMs such as infliximab or adalimumab would be an appropriate treatment option for patients with both plaque psoriasis and active PsA. BRMs currently available for treatment of psoriasis include adalimumab, alefacept, etanercept, infliximab, and ustekinumab.64,65

Currently, a number of RCTs describe short-term efficacy of various BRMs for psoriasis but few long-term studies are available. A recent 3-year open-label extension of a 1-year adalimumab phase 3 trial (REVEAL) has demonstrated sustained response with continuous use in initial PASI 75 responders, as discussed below.66 More clinical evidence has enabled the development of guidelines in an attempt to optimize BRM therapies for psoriasis.25,65The current European consensus recommends either adalimumab or infliximab with etanercept as a suggested alternative, but these guidelines are incomplete as other BRMs such as ustekinumab have not been included.25

Tumor Necrosis Factor-α Inhibitors Dysregulation of TNF-α production has been associated with various inflammatory conditions, including rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, PsA, and psoriasis.6668 Elevated TNF-α levels are seen in both the affected skin and serum of patients with psoriasis; and these elevated levels have a significant correlation with psoriasis severity.31 The biologic agents etanercept, adalimumab, and infliximab are TNF-α inhibitors. They offer the prospect of more rapid disease control than is commonly seen with the other BRMs.26 After successful control of psoriasis, TNF-α levels are reduced to normal.41

There are safety concerns common to TNF-α inhibitors, mainly from observations made through their use in rheumatoid arthritis and inflammatory bowel disease and more recently psoriasis.6668 One concern is an increased risk of infections, most commonly upper respiratory tract infections, and less commonly serious infections including sepsis, new-onset or reactivation tuberculosis, and opportunistic infections such as histoplasmosis, cryptococcosis, aspergillosis, candidiasis, and pneumocystis.26,31,6668 There have been reports of serious pulmonary and disseminated histoplasmosis, coccidioidomycosis, and blastomycosis infections,69,70 sometimes with fatal outcomes when these infections were not consistently recognized and promptly treated in the patients taking TNF-α inhibitors.69

A second concern is the development or worsening of autoimmune diseases such as peripheral and central demyelinating disorders including multiple sclerosis and drug-induced lupus-like syndromes.26,31,70A third concern is the potential increased risk of malignancies such as lymphoma,26,31,70 melanoma, and nonmelanoma skin cancer.31 A fourth concern is the potential for other cutaneous adverse effects including vasculitis, granulomatous reactions, cutaneous infections, psoriasiform eruptions, and infusion or injection site reactions.67 Flares of pustular psoriasis have been reported primarily for patients undergoing treatment for nondermatologic conditions such as rheumatoid arthritis.26 There is also a concern about chronic heart failure (CHF), although this has now become controversial because of conflicting studies demonstrating both worsening and improvement.31

The current recommendation from the American Academy of Dermatology is that TNF-α inhibitors be avoided in patients with severe CHF (New York Heart Association class III or IV), and those with milder CHF should have their TNF-α inhibitors withdrawn at the onset of new symptoms or worsening of preexisting CHF.31

Although the above are safety concerns common to etanercept, adalimumab, and infliximab, their safety profiles are not identical. For example, the risk for tuberculosis (TB) is lowest with etanercept and highest with infliximab.26 They are pregnancy category B and safe to use in pregnancy.31

Adalimumab is a human monoclonal antibody that provides rapid and efficacious control of psoriasis.31 Clinical trials in patients with moderate-to-severe psoriasis have shown dramatic results. A 2006 12-week RCT with open-label extension to 52 weeks showed significant improvement within 1 week of therapy, with complete or nearly complete clearance in some patients, and clinical benefits were maintained for at least 1 year with continuous therapy for most patients.26,71

A 2008 52-week RCT (REVEAL) with an initial 16-week double-blind placebo-controlled (DBPC; period A) phase followed by a 17-week open-label phase (period B) followed by a 19-week DBPC phase (period C) showed a 71% PASI 75 response for adalimumab treated patients versus 7% for placebo-treated patients at week 16. All patients received open-label adalimumab from weeks 17 through 32. At week 33, patients achieving PASI 75 were rerandomized to adalimumab or placebo; patients achieving PASI 50 but <75 were continued on open-label adalimumab; and therapy for patients with PASI <50 was discontinued. At week 52, 5% of patients rerandomized to adalimumab lost adequate response versus 28% of patients rerandomized to placebo. Adalimumab was continued at 40 mg every other week. The study showed that adalimumab can produce rapid and dramatic results which can be sustained on continued use, in patients with moderate-to-severe psoriasis.72

Additional 3-year open-label extension study for patients in REVEAL showed that in patients with sustained initial PASI 75 responses, adalimumab efficacy was maintained for more than 3 years of continuous therapy and maintenance was best at PASI 100. Some patients with PASI <75 in REVEAL also achieved long-term PASI 75 responses.66

For comparative studies, as discussed in the methotrexate section, a head-to-head study showed that adalimumab was significantly more efficacious than methotrexate.62

Adalimumab is given as 80 mg subcutaneously in the first week, then 40 mg the following week, and thereafter 40 mg every other week continuously.26,31 More frequent dosing has been explored.26

Adverse effects in adalimumab clinical trials including the 3-year extension were similar to those already described for this class of BRMs (i.e., tuberculosis and other opportunistic infections such as candidiasis, congestive heart failure, malignancies including nonmelanoma skin cancer that may be related to psoriasis, and allergic reactions).66,71,72

Etanercept was one of the earliest BRMs available on the market for use in inflammatory diseases. It has demonstrated efficacy for rheumatoid arthritis. It was approved for use in PsA in the United States in June 2002 and approved in 2004 for use in moderate to severe psoriasis.70 It is also approved for treatment of juvenile rheumatoid arthritis and ankylosing spondylitis. Thus, as opposed to some of the other BRMs approved for psoriasis, etanercept has been extensively used in rheumatology both for adults and children.

The dosing of etanercept in psoriasis differs from its other indications, reflective of the dosing regimens found to be effective for psoriasis in clinical trials. Etanercept is used continuously, given as 50 mg subcutaneously twice weekly for the first 12 weeks, followed by 25 mg twice weekly26 or 50 mg once weekly.31,70 Significant improvement was seen in about 50% of patients in clinical trials by week 12 and more than 50% of participants by week 24; with continuing therapy, weaker responders continued to improve for up to 1 year.26,29,73 Continuing therapy using 50 mg twice weekly regimens are being explored and may provide greater benefit.26 Etanercept was efficacious in children and adolescents (aged 4 to 17 years) with plaque psoriasis dosed at 0.8 mg/kg (maximum 50 mg) once weekly.74

Infliximab also received approval for rheumatologic diseases before psoriasis and was on the market before adalimumab. Infliximab may be more efficacious than etanercept. A 2011 open-label study showed that psoriatic patients with an inadequate response to etanercept had rapid and sustained improvement when switched to infliximab.75 Unlike etanercept or adalimumab, infliximab is a chimeric antibody with both murine and human components; thus, antibodies to the drug can develop, resulting in infusion reactions.31 Regular therapy rather than intermittent dosing on an as-needed basis may minimize this occurrence.31 The standard dosing regimen is three IV infusions of 5 mg/kg given over a 6-week induction period, followed by regular infusions every 8 weeks.31

Clinical response is seen rapidly. In a randomized controlled phase III trial, 80% of patients responded by week 10 (after 3 doses of infliximab); however, the response dropped to about 50% by week 50.76,77Rare reports of serious adverse events, including fatal cases of hepatosplenic T-cell lymphomas, have been associated with infliximab use.28 Other rare instances of cholecystitis and autoimmune hepatitis, which may be a class effect for TNF-αinhibitors, have also been reported.26

Alefacept Alefacept was the first BRM to receive approval for the treatment of psoriasis, in January 2003 in the United States and in October 2004 in Canada. Over the years, it has accumulated an extensive and reassuring safety record, with no evidence of increased incidence of infections, cancers, or any other serious adverse events beyond background levels. The exception is that CD4 T lymphocytes can be depleted, and CD4 cell counts must be monitored. CD4 cell counts must be monitored, since those T lymphocytes can be depleted.26,78

In comparison with other BRMs, alefacept monotherapy provides only limited control of psoriasis, and as discussed later, it is often explored in combination regimens to enhance response.26 However, even with monotherapy, long periods of near complete remission can be seen occasionally.26

Dosing is intended to be intermittent. Alefacept is given for a 12-week course, then repeated only when the loss of control becomes unacceptable (up to two more courses per year).26 Maximal response was generally seen by 6 to 8 weeks in responders, and currently there is no measure to predict which patients will respond.31

Ustekinumab Ustekinumab is an IL-12/23 monoclonal antibody approved for the treatment of psoriasis in adults 18 years or older with moderate-to-severe plaque psoriasis.67 It selectively targets IL-12 and IL-23, two cytokines that play a role in the pathogenesis of psoriasis.

Two large randomized placebo-controlled trials (PHOENIX 1 and PHOENIX 2) demonstrated clinical efficacy of ustekinumab, with approximately 70% of patients achieving 75% skin clearance after two doses and maintaining the response for 1 year with continued treatment.7981 The improvements were dramatic. The impact of ustekinumab on patients’ health-related quality of life (QOL) in PHOENIX 2 was also evaluated.82 Patients showed a significant improvement not only in skin-related QOL, but also in symptoms of anxiety and depression (as assessed by the Hospital Anxiety and Depression Scale).82 The subset of patients with PsA in PHOENIX 1 and PHOENIX 2 also showed significant improvement in QOL, anxiety, and depression.83

Weight-based dosing rather than fixed-dose was found to be clinically significant for efficacy in PHOENIX 1 and PHOENIX 2—heavier patients required a higher dose.84 Serum ustekinumab concentrations were also affected by weight.84 Dosing is 45 mg for patients weighing 100 kg (220 lb) or less, and 90 mg for those of higher weights. Ustekinumab is administered subcutaneously at weeks 0 and 4, then every 12 weeks as maintenance therapy.

Cumulative 3-year safety data from PHOENIX 1 and 2, and a third RCT (ACCEPT) have also been published.85,86 Common adverse effects include upper respiratory infections, headache, fatigue, pruritus, back pain, injection site reactions, and arthralgia, with the most common events being headache and nasopharyngitis.85 Ustekinumab does not appear to exacerbate atopic diseases.85 Serious adverse effects include those seen with other BRMs, including serious tubercular, fungal, viral infections, and cancers. No evidence of a dose-response to infection rates was seen.86 Serious infections and malignancy rates did not increase with long-term ustekinumab treatment up to 3 years.85,86In addition, a reversible posterior leukoencephalopathy syndrome (RPLS) has been reported.67

Combination Therapies

Combination therapies may be beneficial in the management of plaque psoriasis: generally to either enhance efficacy or minimize toxicity. As shown in Figures 78–1 and 78-2, combinations can include two topical agents, a topical agents plus phototherapy, a systemic agent plus topical therapy, a systemic agent plus phototherapy, two systemic agents used in rotation, or a systemic agent and a BRM. Rotational therapy is not commonly used in practice, and the use of a BRM added to a systemic agent is still under investigation.

The combination of a topical corticosteroid and a topical vitamin D3 analog is particularly useful. This was shown in several studies to be efficacious and safe, with less skin irritation than monotherapy with either agent, and the combination product containing calcipotriol and betamethasone dipropionate ointment has demonstrated efficacy in RCTs for patients with relatively severe psoriasis.26,30 The combination may also be steroid sparing.30

The combination of retinoids with phototherapy has also been shown to increase efficacy. Because retinoids may be photosensitizing and increase the risk of burning after ultraviolet (UV) light exposure, doses of phototherapy should be reduced to minimize adverse effects. A RCT with tazarotene and broadband UVB not only showed significant enhancement of UVB efficacy but also reduced the number of UVB treatment sessions needed for response.28,30,87 The combination of acitretin and broadband UVB reduced the number of needed treatments, compared with UVB alone.26,88 Acitretin with NB-UVB (RE-UVB) was highly effective for patients with difficult-to-control psoriasis.30,89 The combination of acitretin and PUVA (RE-PUVA) also showed greater efficacy than monotherapy with either agent.28,90 RE-PUVA can be used to achieve clearance with up to a twofold reduction in total UV exposure.26 Phototherapy has also been used with other topical agents, such as UVB with coal tar (Goeckerman regimen)55 to increase treatment response, because coal tar is also photosensitizing.

BRMs used in combination with other therapies are being explored. Some beneficial combinations have been found. Alefacept and NB-UVB in combination significantly reduced the number of UVB treatments needed with clearance seen in 43% of patients within 12 weeks.26,91 Infliximab given concurrently with immunosuppressive agents such as methotrexate or azathioprine may result in a lower incidence of infusion reactions to infliximab.31

Alternative Drug Treatments

Mycophenolate Mofetil (MMF) is a systemic agent occasionally used for patients with resistant cases of moderate-to-severe psoriasis.26 This is currently not an approved indication in either Canada or the United States.

A few reports and small studies are available describing the efficacy of MMF when used as monotherapy or adjuvant therapy.92 In addition, one small study evaluated the switch for eight patients with severe psoriasis from cyclosporine to MMF after a washout period of 2 to 4 weeks. On cyclosporine, seven of these patients had deteriorating renal function and hypertension, and one experienced loss of efficacy.93After the switch to MMF, there was significant loss of psoriasis control in five of the eight patients but also significant improvement in renal function for six patients.92,93

Conversely, another small study evaluated the sequential use of MMF followed by cyclosporine in eight patients with moderate-to-severe psoriasis.94 There was significant improvement with MMF in all patients, and all patients further improved when switched to cyclosporine.94

MMF has some uncommon but significant adverse effects, including increased incidence of opportunistic infections such as cytomegalovirus, cryptococcosis, candidiasis, and Pneumocystis jirovecii.92 Cases of progressive multifocal leukoencephalopathy have also been reported.92 There may be an associated risk of malignancy.95

Hydroxyurea Hydroxyurea is an antimetabolite usually used for cancer treatments, but it has also been used in the systemic treatment of psoriasis for more than 30 years.26,29 It is still occasionally tried for patients with recalcitrant severe psoriasis, although BRMs may be a better option for these patients.

Hydroxyurea has been compared with methotrexate for patients with moderate-to-severe psoriasis.96 Weekly regimens showed greater efficacy for methotrexate with a faster clearance rate, although hydroxyurea was also efficacious. The authors concluded that weekly doses of hydroxyurea may be an alternative to methotrexate for patients experiencing intolerable methotrexate side effects or have reached the recommended cumulative dose.96

Adverse effects of hydroxyurea include significant bone marrow suppression, lesional erythema, localized tenderness, and reversible hyperpigmentation.26,96

Complementary and Alternative Medicines The use of complementary and alternative medicine (CAM) among patients with psoriasis is common, with a prevalence of 43% to 69% in various studies.97 Most of these patients use herbs, special diets, or dietary supplements in conjunction with their usual antipsoriatic medications and not as replacements. Most patients do not discuss CAM use with their physicians.97

A 2009 systematic review of RCTs found that, although there is a large body of literature on CAM use in psoriasis, the quality of most studies was relatively low.97 CAM agents and interventions with documented clinical efficacy in psoriasis include Mahonia aquifolium, fish oil, climatotherapy (Dead Sea salts), and stress reduction techniques.

Mahonia aquafolium (Oregon grape, Mountain grape, or barberry but not European barberry) is an evergreen native to southern British Columbia, western Oregon, and northern Idaho. The rhizome and root contain berberine as the primary active constituent. Berberine is an alkaloid that inhibits keratinocyte growth and reduces keratinocyte proliferation, and it also has antibacterial and antifungal activities. In at least two clinical trials Mahonia aquifoliumwas efficacious in reducing disease severity: In one randomized placebo-controlled study a Mahonia aquifolium 10% preparation applied topically twice daily resulted in a significant improvement in the PASI score and the Quality of Life Index (QLI), compared with placebo.98 Adverse effects in clinical trials included rash, burning sensation, redness, and itching.

Fish oil contains two important long-chain polyunsaturated fatty acids—eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are omega-3 fatty acids. They act as substrates competing with arachidonic acid for cyclooxygenase and lipoxygenase, thus reducing the production of proinflammatory molecules in psoriatic plaques.97 Several randomized placebo-controlled and/or comparative trials for patients with psoriasis have demonstrated efficacy of fish oils. One study comparing EPA plus etretinate to etretinate monotherapy found significantly greater efficacy with the combination of EPA plus etretinate.99

Climatotherapy refers to the practice of traveling to the Dead Sea and sunbathing and/or bathing in the sea—the beneficial effects are likely from the high salinity of the sea and UV rays.97 Several studies have demonstrated efficacy, including two studies using saline spa baths. One study used highly concentrated (25% to 27%) saline spa baths plus UVB compared with UVB alone, and the other used low concentrated (4.5% to 12%) saline spa bath plus UVB again compared with UVB alone. In both studies the clinical response was significantly better with the saline spa bath plus UVB combination.97,100,101

Stress-reduction techniques have inconsistently shown some benefit. One randomized study demonstrated that both meditation or meditation and imagery were efficacious as adjunctive treatments for patients with scalp psoriasis.102 A second randomized study for patients with psoriasis receiving either UVB or PUVA therapy showed that the addition of a mindfulness-based stress-reduction audiotape played during light treatments reduced response times for patients receiving UVB but not PUVA therapy.103 This confirmed the belief that psychological stress plays a role in psoriasis. More recently, in a case-control study of risk factors during the year before the onset of psoriasis, stressful life events were found to be significant.104,105

Personalized Pharmacotherapy

Despite the availability of good quality evidence and clinical practice guidelines, patients with psoriasis are still often undertreated or inappropriately managed.25 A 2007 study in the U.S. involving 1,657 patients from National Psoriasis Foundation surveys found that 40% of patients with psoriasis were receiving no current treatment; of those, 27% had psoriasis involving >10% body surface area.106 In addition, those receiving care may be undertreated.106Early access to care and adherence may also be issues.

Patient-specific therapies that take into consideration comorbid illnesses, adherence, and pharmacoeconomic issues in addition to the patient’s psoriatic manifestations and responses to treatments are important, and will ultimately improve the quality of care. Treatment goals need to be defined for both short-term and long-term management time frames.25 Without optimizing patient care, the concern is that patients with poorly managed psoriasis may follow a “diminished” life course compared with the course they might have taken if they did not have psoriasis, as the disease has significant psychological, social, and economic impacts in addition to its physical manifestations.107

To this end, a current focus is defining frameworks107 and specific treatment goals25 for implementation of practice guidelines, as described earlier in this chapter. The reader is encouraged to review the noted references for further information.

Special Populations

Psoriasis in Children Pediatric psoriasis is more often attributable to direct precipitating factors such as skin trauma, infections, drugs, or stress.26,108 Compared with adults, plaque lesions in children are often smaller, thinner, and less scaly, which can make diagnosis more difficult. Face and flexures are more commonly involved than for adults. Psoriatic diaper rash can occur up to age 2. PsA is rare.26

Topical treatment is the standard of care for children with psoriasis, with topical corticosteroids often the treatment of first choice.26 Other useful pharmacologic therapies include calcipotriol and anthralin; calcipotriol with or without topical corticosteroids has also been recommended as treatment of first choice109 because it produces minimal adverse effects.26 Since children’s skin is thinner and better hydrated than that of adults, they are at higher risk of drug absorption leading to systemic adverse effects. The lowest potency corticosteroid that provides control should be used, and it should be tapered as the lesions improve. If long-term calcipotriol is used, monitoring of ionized calcium is recommended because of the risk of hypercalcemia.26

Systemic therapies are reserved for children with severe and recalcitrant psoriasis.26,109 Methotrexate can provide near to complete clearance109 and has been safely used to control severe childhood psoriatic episodes and then withdrawn as lesions improve.26 Regular monitoring for liver and blood toxicity is required.26 The BRM etanercept was studied in a randomized placebo-controlled trial of 211 children and adolescents (4 to 17 years) with moderate-to-severe plaque psoriasis. It significantly reduced disease severity; however, four serious adverse events occurred (ovarian cyst requiring removal, gastroenteritis, gastroenteritis-associated dehydration, and left basilar pneumonia).110 Etanercept has been studied in children with polyarticular juvenile rheumatoid arthritis without new safety concerns emerging.26

Phototherapy should be used with caution, especially for younger children, because of long-term carcinogenic risks and phototoxicities. For older children and adolescents with severe, extensive, or treatment-resistant disease, UVB may be a treatment option.26

Psoriasis in Pregnancy Hormonal changes in pregnancy can improve symptoms for patients with plaque psoriasis. In one study, 55% of patients showed improvements during pregnancy.26,111 For patients with more than 10% BSA involvement who reported improvement, lesions decreased by more than 80% during pregnancy.111 This appeared to correlate with high estrogen but not progesterone levels.111 Thus, some pregnant women may require minimal treatment for their psoriasis.

Some antipsoriatic drugs have significant teratogenic risks, placing them in pregnancy category X. Thus, women of childbearing potential must use effective birth control during therapy, and may need to continue effective contraception after discontinuing therapy for a period of time, as discussed in detail throughout this chapter. In addition, drugs listed as pregnancy category C may carry known teratogenic risks in animal studies or have limited available data for use in pregnancy.

UVB has been considered the safest treatment for extensive psoriasis during pregnancy. It is recommended for patients with widespread disease not controlled by topical agents. One problem with this therapy is an increased potential for reactivation of herpes simplex, which may be transmitted to the infant at delivery.26

For more detailed information about antipsoriatic drugs in pregnancy, a systematic, drug-by-drug review of case reports and case-control studies is available.112 The 2009 Canadian Guidelines for the Management of Plaque Psoriasis provides a drug-by-drug summary of recommendations for topical agents, phototherapy, and systemic agents in pregnancy.26

Psoriasis in the Elderly Age-related changes in organ function/drug clearance and greater drug sensitivity increase the risk of adverse drug events for elderly patients with psoriasis.

Methotrexate is hepatotoxic and should be used with caution in the elderly. Cyclosporine has nephrotoxic potential and may also increase blood pressure. Both drugs have significant drug interactions, and polypharmacy, common in older patients, make management of interactions challenging.

In addition, older patients may have preexisting comorbidities, such as hyperlipidemia and metabolic syndrome, and this may further limit drug use. Adalimumab appears equally efficacious in older patients (older than 65) who may have higher incidences of hypertension, hyperlipidemia, depression, obesity, and diabetes.113 Adverse effects profiles were similar between subgroups (various weights and comorbidities) with no significant differences in serious adverse events.113 Topical psoriasis treatments are often prescribed for elderly patients as first-line therapy26; however, even with topicals, adverse effects—including systemic ones—can occur with greater frequency in these patients.26

Psoriasis in Patients with a History of Solid Tumors As discussed throughout this chapter, many antipsoriatic therapies carry significant cancer risks. PUVA, systemic therapies such as cyclosporine, and some BRMs are associated with increased risks of oncologic disorders.

A systematic review of the risk of malignancy associated with therapies for moderate to severe psoriasis confirmed the following95: PUVA is associated with an increased risk of cutaneous SCC and malignant melanoma; UVB is a much safer therapeutic modality than PUVA; cyclosporine increases risks of lymphoma, internal malignancies, and skin cancers; methotrexate may be associated with increased melanoma and Epstein–Barr virus–associated lymphomas; MMF may be associated with lymphoproliferative disorders; and the malignancy risk may be increased for biologic agents, especially the TNF-αinhibitors.95

The 2009 Canadian guidelines recommend that TNF-α inhibitors be used with caution for patients with a history of malignancy or existing malignancies, and the T-cell modulator alefacept is contraindicated for these patients.26

Pharmacoeconomic Considerations

Images The wide gap in costs of agents for psoriasis makes economics and availability of insurance or other coverage important considerations in formulating a therapeutic plan.

Currently, the expensive BRMs are often considered for patients with moderate-to-severe psoriasis when less expensive systemic agents are inadequate or relatively contraindicated. BRMs have also been recommended as first-line therapy, alongside conventional systemic agents, for patients with moderate-to-severe psoriasis; however, in practice, drug access secondary to cost considerations can limit use. These agents may be needed early, though, for some patients with comorbidities.

A recent pharmacoeconomic analysis of BRMs in the treatment of psoriasis suggests that the cost-to-benefit ratio for BRMs may be favorable.68 There are also cost differences among the BRMs. Of the TNF-α inhibitors, etanercept is the least costly, followed by adalimumab than infliximab.114 However, etanercept is less efficacious. Adalimumab (at doses of 40 mg every other week) is significantly less costly than ustekinumab, with similar efficacies, in patients with suboptimal response to etanercept.115

CONCLUSIONS

Psoriasis is a lifelong illness with no known cure. Significant comorbidities may coexist. Treatment should be patient-specific, with consideration given to disease severity, patient risk factors, age, and comorbidities. Newer treatment modalities, including numerous BRMs, are now parts of the armamentarium available in the management of this disease.

ABBREVIATIONS

Images

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