Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print 71 PSORIASIS Mark Pittlekow and Joseph Genebriera INTRODUCTION 1 Moderate to Severe Psoriasis 1000 Pregnancy and Psoriasis 1002 Psoriatic Arthritis 1002 Emerging Targets and Therapeutics 1004 ShK(L5) and PAP-1 1004 Apremilast (CC-10004) 1004 ABT-874 1004 MEDI-545 1004 Essential Fatty Acids (w-3) 1004 AL Psoriatic Nail Disease 986 Psoriatic Arthritis 986 THERAPEUTICS AND CLINICAL PHARMACOLOGY 986 Therapeutics by Class 986 Topical Treatments 986 Phototherapy 990 Oral Treatments 991 Biologics 995 Laser 998 Therapeutic Approaches 999 Mild Psoriasis 999 PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N INTRODUCTION 983 EPIDEMIOLOGY 983 PATHOPHYSIOLOGY 984 Disease Assessments 985 Clinical Types of Psoriasis 985 Plaque Psoriasis 985 Guttate Psoriasis 985 Flexural (Inverse) Psoriasis 986 Erythroderma 986 Localized and Generalized Pustular Psoriasis 986 Palmoplantar Pustulosis 986 Psoriasis is an inflammatory skin disorder with hyperproliferation and abnormal differentiation of the stratified epidermis that also affects the enthesium and joints in some patients. It commonly causes discrete, red, scaly plaques to appear on the skin, and thus is classified as a papulosquamous disorder (Fig. 71-1). The indurated and elevated plaques caused by psoriasis are due to enlargement and coalescence of papules with epidermal thickening and inflammation. Scale rapidly accumulates on the surface of these affected sites and typically appears silvery white with mica-like desquamation. Plaques most often occur on extensor regions of the skin, especially the elbows and knees, but can affect any areas including the scalp, skinfolds, and genital skin. The disorder is a chronic, recurring condition that affects approximately 2% to 3% of various genetically susceptible populations around the world and varies in severity from minor, localized lesions to complete body coverage, designated erythroderma. Fingernails and toenails are frequently affected (psoriatic nail dystrophy). Psoriasis can also cause inflammation of the joints and adjacent enthesial attachments and has the potential for articular destruction. This associated condition, psoriatic arthritis, affects up to 30% to 40% of the psoriatic population. Psoriasis became known as Willan’s lepra in the late 18th century when English dermatologists Drs. Robert Willan and Thomas Bateman differentiated it from other common skin diseases. They assigned names to the condition based on the appearance of lesions. Willan identified two categories: leprosa graecorum and psora leprosa. It was not until 1841 that the condition was finally given the New Latin name “psoriasis” by the Viennese dermatologist Ferdinand von Hebra, from the Greek psorian, “to have the itch.” In 1876 Balmanno Squire accidentally, but fortuitously, identified a treatment for psoriasis using Goa powder, a tree extract that contained anthralin (dithranol), which is still used to the present time in skindirected, topical therapies. In 1925, Dr. William Goeckerman, a dermatologist at Mayo Clinic, developed a highly effective, skin-directed treatment regimen that combined crude coal tar ointment with gradually increasing exposure to ultraviolet B (UVB) radiation from hot quartz, mercury vapor lamps. This therapeutic regimen still bears his name and remains one of the most effective topical treatments administered in courses for psoriasis. In the 1950s, Dr. John Ingram developed the “Ingram regimen,” combining UVB radiation and topically applied anthralin to the plagues. By the late 1950s, following the discovery of cortisone a decade earlier, topical corticosteroid formulations started to be developed and applied to affected lesions of psoriasis, sometimes with occlusive dressings to enhance penetration and effectiveness. Following the synthesis and development of aminopterin in the late 1940s and, subsequently, the folate acid antagonist methotrexate, these agents were administered in psoriasis patients to reverse epidermal hyperproliferation. Methotrexate was the first parenterally administered drug approved for use in psoriasis and remains a widely used systemic medication for treatment of the skin and joint manifestations of the disease. Over the past decade, however, the mechanism of action of methotrexate has come to be known to principally target and diminish the inflammatory, T-lymphocytic infiltrate within skin and, in turn, the hyperproliferation, abnormal scaling, and disrupted differentiation of the epidermis. In the 1980s, the oral agent cyclosporine, which attenuates T cell– specific immune responses, was observed to be effective in the treatment of psoriasis during chronic immune suppression of solid organ transplant recipients or rheumatoid arthritis patients who also had psoriasis. With this discovery and the findings that the epidermal and dermal lymphocytes were predominantly T cells, psoriasis was beginning to be recognized as a cell-mediated autoimmune disorder. In the past decade, extensive research and biotechnology efforts have been leveraged to develop biologic agents that act primarily on the immune system, target specific molecules that appear to be key in propagating the immunopathogenesis of psoriasis, and reestablish epidermal regulation of the abnormal hyperproliferation and differentiation of skin that typify various forms of psoriasis. EPIDEMIOLOGY The prevalence of psoriasis varies considerable among world populations and geography, especially latitude. It is essentially a disease of Caucasians (2% to 3%), being much less common in Asians (0.1%) and native Africans. In the United States, approximately 2% of the population is affected.1 High rates of psoriasis have been reported in people of the Faroe Islands, where one study found 2.8% of the population to be affected. Prevalence of psoriasis is low in certain ethnic groups such as the Japanese, and may be virtually absent in aboriginal 983 http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 983 9/18/2008 12:54:29 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print 984 Section 16 Dermatologic Therapeutics psoriasis, type I and II, distinguished by a bimodal age at onset. Type I begins at or before age 40 years; type II begins after the age of 40 years. Type I disease accounts for more than 75% of cases.4 Patients with early-onset, or type I, psoriasis tend to have more relatives affected and more severe disease than patients who have later-onset, type II psoriasis. In addition, strong associations have been reported with human leukocyte antigen (HLA)-Cw6 in patients with early onset, compared with later onset, of psoriasis. Recent genetic studies of psoriasis have identified several risk loci for the disease, but the strongest risk allele remains on chromosome 6, within the Cw6 locus. PATHOPHYSIOLOGY AL Psoriasis is characterized by hyperproliferation and abnormal differentiation of epidermal keratinocytes, lymphocyte infiltration consisting principally of T lymphocytes, and specific endothelial vascular changes within the dermal microvasculature, including limited neoangiogenesis, capillary dilation, and high endothelial venule formation, all this contributing to the visible redness (erythema) of psoriatic skin lesions. T lymphocytes, especially CD4+ cells in the dermis and T helper type 17 (Th17) and CD8+ cells within the epidermis, in conjunction with the characteristic cytokines and chemokines released by these cells and the epidermis and other resident cells appear to be the primary mediators of lesion development and persistence, although endothelial cells, neutrophils, and natural killer (NK) T cells also likely play modulating or exacerbating roles along with other inflammatory cell– specific cytokines and adhesion molecules/selectins/integrins, such as intracellular adhesion molecule-1 and integrin a1b1.5,6 Histologically, there is marked thickening (acanthosis) of the epidermis, due to increased proliferation of keratinocytes in the interfollicular epidermis. Epidermal rete pegs elongate and form long, thin downward projections into the dermis. Normal differentiation of stratified keratinocytes is extensively altered in psoriasis. Psoriatic plaques have surface scale, which is caused by aberrant terminal differentiation of keratinocytes (Fig. 71-2). Scaling and the consequent disruption of the protective epidermal barrier are caused by failure of psoriatic corneocytes (terminally differentiated keratinocytes) to form normally, develop tight junctions, synthesize and secrete the normal extracellular complement of lipids, and adhere efficiently to one another. In psoriatic lesions, the granular layer of the epidermis is reduced or absent, creating a stratum corneum with incompletely differentiated keratinocytes that retain a remnant of the cell nucleus (parakeratosis). Often, there are neutrophils in the stratum corneum and mononuclear cell infiltrates in the epidermis as well as specific PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N Practice: Dermatologic Therapeutics Australians2 and Indians from South America.3 Psoriasis affects the genders almost equally. Studies of monozygotic twins suggest a 70% chance of the twin developing psoriasis if the index twin has psoriasis. The concordance is much less, approximately 20%, for dizygotic twins. These findings were early evidence for both a genetic predisposition and environmental factors in the development of psoriasis. The course and progress of psoriasis is unpredictable. Psoriasis presents at any age and has been reported rarely at birth and, more commonly, in the advanced age population. The mean age of initial onset of psoriasis ranges from 15 to 20 years of age, with a second peak occurring at 55 to 60 years. Henseler and Christophers examined a series of 2147 patients and reported two clinical presentations of Demarcated plaque with white scale Neutrophils Epidermis Epidermal ridges elongated T. Lymphocytes Dermis Dilated capillaries Figure 71-1 • Psoriasis pathophysiology. Epidermis Lymph node LFA-1 CD11a Antigen Keratinocytes Antigen peptide APC APC ICAM-1 LFA-1 CD11a T-cell activation, proliferation, and cytokine production Transmigration lium othe End Dermis T-cell reactivation, keratinocyte proliferation, and cytokine production ICAM-1 T-cell 2 Adhesion Activated T-cell Rolling Blood flow Figure 71-2 • Dendritic-antigen presentation, T-cell activation and localization in skin. http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 984 9/18/2008 12:54:29 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print Chapter 71 Psoriasis of a potential RUNX binding site have been identified as loci affecting regulation of the immune synapse.17 Association of psoriasis with variant alleles of the lymphoid phosphatase PTPN22 have been reported. PTPN22 also regulates the immune synapse, and a R620W polymorphism is associated with at least four other autoimmune diseases. Associations with alleles encoding other components of the immune system, such as IL-12, IL-23 receptor, IL-19/20, IL-20/24, and IRF2 have also been described. Genetic variants within the epidermal differentiation complex (EDC) might also affect keratinocyte proliferation or differentiation and development of psoriasis.18 The challenge to validate psoriasis susceptibility loci also likely relates, in part, to heterogeneity among different populations. More sophisticated analyses, including genome-wide association studies and the HapMap project phase 2, will hopefully provide more definitive characterization. Though the genetic underpinnings of psoriasis are certain, the exact locations of the genes involved remain to be fully defined.19 Disease Assessments PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N AL Psoriasis is usually graded as mild (affecting less than 2% of the body surface area [BSA]), moderate (affecting 2% to 10% of BSA) or severe (>10% of BSA). Several scales exist for measuring the severity of psoriasis. The degree of severity is generally based on the following factors: the proportion of BSA affected; disease activity (redness, thickness, and scaling of plaques); response to previous therapies; and the impact of the disease on the individual. The Psoriasis Area and Severity Index (PASI) score remains the most accepted and widely used index in clinical trials. PASI combines the assessment of the severity of lesions and the area affected into a single score ranging from 0 (no disease) to 72 (maximal disease) based on clinical features such as erythema, scaling, and surface area affected. The major drawback is that the objective signs of erythema—scale and induration—are scored equally and assume linearity, but exceptions often occur in clinical practice. Percent improvement is routinely determined in clinical trials to assess efficacy of investigational agents. For example, PASI 75 designates 75% improvement in PASI score from baseline. The Physician Global Assessment (PGA) scale is the physician’s overall assessment of the severity of psoriasis. This is a 7-point scale with 0 being clear, 1 almost clear, 2 mild, 3 mild to moderate, 4 moderate, 5 moderate to severe, and 6 severe psoriasis. To more accurately capture both the PASI and the PGA, the lattice system-PGA (LS-PGA) has been recently developed. This is an 8-point scale (1 to 8) with 1 being clear and 8 very severe. It incorporates BSA (measured by palm surface) of seven “percent “ groupings as well as a matrix system to capture average plaque qualities (erythema, scale, and elevation). The Psoriasis Disability Index (PDI) is another quantitative measure aimed to standardize and accurately capture the overall quality of life in adult patients with psoriasis. Several other assessment instruments also are used in psoriasis, including the Dermatology Quality of Life Index (DLQI) and the SF-36. Practice: Dermatologic Therapeutics pathogenic leukocytes (T cells and dendritic cells [DCs]) within the dermis. Endothelial cells appear activated in psoriatic lesions, and specific subtypes of peripheral blood leukocytes enter into the lesional skin by transmigration through these activated vessels. It is increasingly being recognized that even normal skin contains a significant population and number of T lymphocytes7 as well as resident populations of DCs,8 suggesting that skin might be a potential site for the direct triggering of recall immune responses. The role of T lymphocytes in the pathogenesis of psoriasis can be summarized by three primary events: (i) the initial innate immune response(s), followed by specific sensitization and activation of T lymphocytes within skin; (ii) the transit, amplification, and migration of pathogenic T cells into skin sites where psoriasis will develop; and (iii) the pathogenic roles played by specific cytokines-chemokines released from T lymphocytes and cooperating cell types, including epidermal keratinocytes that provide the environment to sustain and propagate psoriasis. The initial signal is provided by binding of the T-cell receptor to peptide(s) presented by the major histocompatibility complex (MHC) on plasmacytoid DCs. This sensitization step characterizes the specificity of the immune response in psoriasis. The antigenpresenting cell (APC) is the plasmacytoid DC that is co-stimulated by specific peptides within the epidermis that serve as innate immune signals, specifically LL-37 among others, in the case of naive responses, although B cells and macrophages may also serve as APCs. The peptides presented to CD8+ T cells by MHC class I molecules are typically eight to nine amino acids in length; the peptides presented to CD4+ cells by MHC class II molecules are longer, as the ends of the binding cleft of the MHC class II molecule are more accessible. The second signal comes from co-stimulation, in which surface receptors on the APC are induced by a relatively small number of stimuli, usually products of pathogens but sometimes breakdown products of cells, such as necrotic bodies or heat-shock proteins. The only co-stimulatory receptor expressed constitutively by naive T cells is CD28, with co-stimulation for these cells by CD80 and CD86 on APCs. The activated T lymphocytes, via cell-cell interactions with vascular endothelial cells, migrate to inflamed skin.9,10 Once at the inflamed skin site, activated T lymphocytes encounter the potential initiating antigen, and release T helper type 1 (Th1) cytokines, which play a central role in the phenotypic expression of psoriasis. Both CD4+ and CD8+ T lymphocytes produce Th1 cytokines. Principal Th1 cytokines involved in the pathogenesis of psoriasis are interferon (IFN)–g, interleukin (IL)–2, and tumor necrosis factor (TNF)–a. Interleukin-2 stimulates T-lymphocyte replication, and IL-2 treatment is associated with psoriatic flares.11 Interferon-g may inhibit apoptosis of keratinocytes by stimulating expression of the antiapoptotic protein Bcl-x in these cells.12 Keratinocyte antiapoptotic signals may contribute to the overall hyperproliferative response and increase in epidermal cell mass of psoriatic lesions. TNF-a appears to promote psoriasis development by several mechanisms, including enhancing proliferation of keratinocytes and augmenting the production of proinflammatory cytokines from T lymphocytes and macrophages, as well as chemokines from macrophages and adhesion molecules on vascular endothelial cells.13,14 Th1 cytokines also induce the release of cytokines from other cells, producing a cascade of chemical messengers that, together, create the distinctive features of psoriatic lesions. Psoriasis is inherited as a complex trait; thus the genetic basis of psoriasis has been challenging to dissect, with evidence of multiple genetic loci. To date, between 15 and 20 chromosome regions have been proposed to harbor psoriasis risk alleles, but only a small number of genes have been identified.15,16 One locus consistently identified in studies of psoriasis is the class I region of the major histocompatibility locus antigen cluster (MHC). The exact identity of the psoriasis susceptibility 1 (PSORS1) locus remains controversial. Whether PSORS1 is a classical MHC allele or a regulatory variant within this region remains to be established. Other predisposing genes likely affect disease severity and onset, including those regulating the immune system and keratinocyte differentiation, barrier function, and innate immune responses. Common variants in the SLC9A3R1/NAT9 region and loss 985 Clinical Types of Psoriasis Plaque Psoriasis Chronic plaque psoriasis or vulgaris-type disease is the most common form of psoriasis. It is typically symmetric and bilateral. Plaques are well demarcated (Fig. 71-3) and typically exhibit Auspitz sign (punctate bleeding after the removal of the scale) as well as manifesting Köbner’s phenomenon (lesions induced by trauma). The most common distribution is the extensor surfaces (elbows and knees). The lower back, scalp, and nails are also frequently affected. Nail changes include onycholysis, pitting, oil spots, and nail dystrophy. Guttate Psoriasis The word “guttate” is derived from the Latin word gutta, meaning “drop.” This variant primarily occurs on the trunk and the proximal http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 985 9/18/2008 12:54:30 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print 986 Section 16 Dermatologic Therapeutics Palmoplantar Pustulosis Psoriatic Nail Disease AL Psoriatic nail dystrophy mainly occurs in patients suffering from psoriatic skin involvement. Fewer than 5% of patients solely manifest psoriasis of the nails. It is commonly seen in patients with psoriatic arthritis, especially when the arthritis affects the fingers and toes. Signs of nail psoriasis vary according to the part of the nail affected and the nature of the deformity. Oil drop sign, pitting, Beau’s lines (transverse lines in nails due to intermittent inflammation causing growth arrest lines), leukonychia (areas of white nail plate due to foci of parakeratosis within the body of the nail plate), subungueal hyperkeratosis, onycholysis, and nail plate crumbling are characteristic abnormalities of psoriatic nail disease. PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N Practice: Dermatologic Therapeutics Palmoplantar pustulosis affects the palms and soles and is associated with psoriasis in some individuals. It is characterized by groups of sterile pustules occurring in crops on one or both hands and/or feet. Pustulosis is associated with thickened, scaling, red skin that easily develops painful fissures. A considerably higher prevalence of smoking, in patients with palmoplantar pustulosis has been reported.20 Approximately 25% of cases are associated with classical psoriasis vulgaris, but palmoplantar pustulosis may also represent a distinct entity.21 This conclusion is derived from genetic studies showing no association with HLA-Cw6 or other markers on chromosome 6p- that are linked to chronic plaque and guttate psoriasis. The demographics of palmoplantar pustulosis are also different than classical plaque psoriasis, more commonly affecting women (9 : 1) and an older age group (onset 40 to 60 years), and having a strong association with smoking, either current or past, in up to 95% of subjects. Figure 71-3 • Psoriasis plaque. Psoriatic Arthritis extremities, but it may have a generalized distribution. Guttate psoriasis is characterized by small, droplike, 1- to 10-mm diameter, salmon pink papules, usually with a fine scale. This form is more common in individuals after a history of upper respiratory infection secondary to group A b-hemolytic streptococci and precedes the eruption by 2 to 3 weeks. In children, an acute episode of guttate psoriasis is usually selflimiting; in adults, guttate flares may complicate chronic plaque disease. Compared with control populations, a significant excess of HLA-Bw17 and increased prevalence of HLA-Cw6 have been found in patients with guttate psoriasis. Flexural (Inverse) Psoriasis Psoriasis affecting the flexures, particularly the inframammary, perineal, and axillary folds, is distinct morphologically from traditional plaques elsewhere on the trunk and limbs. Flexural lesions are devoid of scale and appear as red, shiny, well-demarcated plaques occasionally confused with candida, intertrigo, and dermatophyte infections. Erythroderma Erythroderma usually occurs in the setting of known worsening or unstable psoriasis but may uncommonly be the first presentation of psoriasis; it is characterized by total or near-total involvement of the skin by active psoriasis. It can be precipitated by infections, low calcium, withdrawal of oral corticosteroids, discontinuation of extensive topical corticosteroids, and certain medications, including lithium, antimalarials and IL-2. Complications may include dehydration, heart failure, infection, anemia (due to loss of iron, vitamin B12, and folate), hypothermia, protein loss, and malnutrion. Localized and Generalized Pustular Psoriasis This is an uncommon form of psoriasis, with the generalized form also known as von Zumbusch’s psoriasis. It is characterized by the development of erythema and pustules in flexural areas as well as their appearance within established plaques of psoriasis. The pustules rupture easily and may become secondarily infected. This condition can be fatal if the patient becomes dehydrated, or complications of infections ensue. Precipitants include withdrawal of systemic or potent topical corticosteroids and infections. Psoriatic arthritis is a type of inflammatory arthritis that affects up to 30% to 40% of people with psoriasis. It may have very mild symptoms, and more severe forms occur more commonly in patients harboring HLA-B27. Treatment of psoriatic arthritis is similar to that of rheumatoid arthritis. More than 80% of patients with psoriatic arthritis will have psoriatic nail lesions characterized by pitting of the nails or onycholysis. Psoriatic arthritis is categorized as a seronegative spondyloarthropathy. Psoriatic arthritis can develop at any age; however, on average, it tends to appear about a decade after the first signs of psoriasis. For the majority of individuals, onset is between the ages of 30 and 50 years, but it can rarely affect children. Men and women appear to be equally affected. In about one in seven cases, the arthritis symptoms occur before any skin involvement. It can also cause tendonitis, bursitis, and dactylitis. Psoriatic arthritis has been subdivided into five distinct groups. The symmetric type (50% of cases) affects joints bilaterally and may be mistaken for rheumatoid arthritis. The asymmetric type (35% of cases) usually involves fewer than three joints (pauciarticular). Arthritis mutilans (<5% of cases) is a severe, deforming, and destructive arthritis of small and large joints. The spondylitis type causes stiffness of the spine and/or neck but can also affect the hands and feet. The distal interphalangeal predominant type (5% of cases) is less frequent. In the very early stages of the disease, radiographs usually do not reveal signs of arthritis and often are not helpful in establishing the diagnosis. At later stages, radiographs may show changes that are characteristic of psoriatic arthritis not found with other types of arthritis, such as the “pencil-in-cup” phenomenon wherein the end of one bone is whittled and abuts an adjacent joint that forms the cup. THERAPEUTICS AND CLINICAL PHARMACOLOGY Therapeutics by Class Topical Treatments Topical Corticosteroids. Corticosteroids are a class of steroid hormones that are produced by the adrenal cortex. They are involved in a http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 986 9/18/2008 12:54:30 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print Chapter 71 Psoriasis 987 immune system. T cells are known to play a role in psoriasis, and it is thought that the binding of calcipotriol to the VDR modulates the T cells’ gene transcription of cell differentiation– and cell proliferation– related genes. Available as a cream, ointment, or scalp solution, calcipotriene is applied twice daily to plaque psoriasis on the body or scalp, but not the face. Improvement is usually detectable within 2 weeks. It is also available in combination with the synthetic glucocorticoid betamethasone under the trade name Dovobet. Calcipotriol has been shown in clinical trials to have an excellent safety profile. Reports of hypercalcemia are rare. However, less than 120 g should be used weekly. Other vitamin D analogues such as tacalcitol are also being used for psoriasis. Tazarotene. Tazarotene (Tazorac, Avage, Zorac) is a prescription topical retinoid formulated as a cream or gel. This medication is approved for treatment of psoriasis, acne, and sun-damaged skin (photodamage). It is commonly prepared in two concentrations: 0.05% and 0.1%. The retinoids are a class of chemical compounds that are related chemically to vitamin A. Retinoids are used in medicine primarily to regulate epithelial cell growth and gene expression. Tazarotene belongs to the third generation of retinoids. Tazarotene is a synthetic acetylenic retinoid that is hydrolyzed to its active form, tazarotenic acid. Unlike other retinoids, tazarotenic acid has selective affinity for the retinoic acid receptors. The exact molecular mechanism of action of topical tazarotene in the treatment of psoriasis has not been determined. Tazarotene appears to modulate the three main pathologic features of psoriasis: abnormal differen tiation of keratinocytes, increased keratinocyte proliferation, and inflammation.25 Monotherapy of once-daily topical tazarotene 0.05% or 0.1% cream or gel effectively controlled signs and symptoms of plaque psoriasis in adult patients in randomized, single- or double-blind studies of 12 weeks’ duration.26 In these trials, topical tazarotene was significantly more effective than vehicle in terms of global treatment success rates, reduction in plaque elevation, and reduction in scaling scores. The efficacy of tazarotene was maintained over a 12-week posttreatment period. The addition of some, but not all, mid- to high-potency topical corticosteroids to tazarotene 0.1% gel monotherapy significantly improved global success rates and reduction in plaque elevation, scaling, and erythema.26 The penetration across human skin and, consequently, systemic absortion are limited. Low plasma concentrations of tazarotene were detected in 1% to 3% of patients in 12-week, Phase III clinical trials of tazarotene 0.05% or 0.1% gel or cream monotherapy in patients with plaque psoriasis. Common side effects include dry skin, pruritus, redness, and, in some cases, extreme drying and cracking of skin. For most patients, these side effects are uncomfortable but mild and decrease markedly after the first 2 to 4 weeks of use. In clinical trials, 9% to 20% of tazarotene gel recipients discontinued treatment because of adverse effects. The addition of a corticosteroid to tazarotene monotherapy generally reduces the incidence of adverse effects. Tazarotene has also been shown to ameliorate the skin atrophy induced by a corticosteroid as it has been shown to increase epidermal thickness. Tars. Tar is a viscous black liquid derived from the destructive distillation of organic matter. Most tar is produced from coal as a by-product of coke production, but it can also be produced from petroleum, peat, or wood. In English and French convention, “tar” is a substance primarily derived from coal. It was formerly one of the products of gasworks. Tar made from coal or petroleum is considered toxic and carcinogenic because of its high benzene and aromatic hydrocarbon content. However, coal tar in low concentrations is used as a topical medicament. Coal and petroleum tar has a pungent odor. According to the International Agency for Research on Cancer, preparations that include more than 5% crude coal tar are Group 1 carcinogens. Despite this, the National Psoriasis Foundation claims coal tar is a valuable, safe, and inexpensive treatment option for millions of people with psoriasis and other scalp conditions. The U.S. Food and Drug Administration (FDA) agrees, and states that coal tar PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N Practice: Dermatologic Therapeutics wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior. Glucocorticoids such as cortisol control carbohydrate, fat, and protein metabolism and are anti-inflammatory by preventing phospholipid release, decreasing eosinophil action, and a number of other mechanisms. Mineralocorticoids such as aldosterone control electrolyte and water levels, mainly by promoting sodium retention in the kidney. The corticosteroids are synthesized from cholesterol within the adrenal cortex. Most steroidogenic reactions are catalyzed by enzymes of the cytochrome P-450 family. They are located within the mitochondria and require adrenodoxin as a cofactor (except 21-hydroxylase and 17a-hydroxylase). Aldosterone and corticosterone share the first part of their biosynthetic pathway. The last part is mediated either by aldosterone synthase or by 11b-hydroxylase. These enzymes are nearly identical (they share 11b-hydroxylation and 18-hydroxylation functions), but aldosterone synthase is also able to perform an 18oxidation. Moreover, aldosterone synthase is found within the zona glomerulosa at the outer edge of the adrenal cortex; 11b-hydroxylase is found in the zonae fasciculata and reticularis. Topical corticosteroids are absorbed at different rates and extent from different parts of the body. For example, a steroid having efficacy on the face may be ineffective on the palm. Extent of absorption from body areas includes • Forearm: 1% • Axilla: 4% • Face: 7% • Eyelids and genitals: 30% • Palm: 0.1% • Sole: 0.05% Despite their demonstrated effectiveness as treatment for psoriasis, topical corticosteroids are associated with various side effects that may limit their use. The risk of these side effects depends on the strength of the steroid, the duration of application, the site treated, and the nature of the skin problem. Local reactions usually occur when corticosteroids are used either with excessive frequency or duration or on particularly steroidsensitive areas such as the face and intertriginous areas; they include atrophy, striae, telangiectases, acneiform eruption, rosacea, and contact dermatitis.22 A potent steroid applied elsewhere on the body may cause side effects on the face. Systemic side effects, although uncommon, may occur when locally applied corticosteroids become absorbed through the skin and enter the general circulatory system. For example, if more than 50 g of clobetasol propionate (equivalent to 500 g of hydrocortisone) is used per week, sufficient steroid may be absorbed through the skin to result in adrenal gland suppression and/or eventually Cushing’s syndrome. The greatest risk of systemic side effects occurs when ultra-high-potency or high-potency agents (Table 71-1) are used over a wide surface area for a prolonged period. Infants and small children are at elevated risk with any corticosteroid potency because of their increased skin surface–to–body mass ratio. Systemic effects of most concern are suppression of the hypothalamic-pituitary-adrenal axis, growth retardation in children, cataract formation, and glaucoma development. Proper use of superpotent topical corticosteroids is imperative. They should be used cautiously in patients with a history of diabetes mellitus, hypertension, liver failure, glaucoma, or positive tuberculin test results.23 In addition to localized and systemic side effects, tachyphylaxis has been reported to occur after long-term treatment with topical corticosteroids,24 and this appears to be a major limiting factor in their use for psoriasis. Calcipotriene. Calcipotriene (Dovonex), or calcipotriol, is a sythetic derivative of calcitriol or vitamin D. The exact mechanism by which calcipotriene improves psoriasis is not well understood. Calcipotriene has been shown to have comparable affinity with calcitriol for the vitamin D receptor (VDR), while being less than 1% as active as calcitriol in regulating calcium metabolism. VDR belongs to the steroid/thyroid receptor superfamily, and is expressed by cells of many different tissues including the thyroid, bone, kidney, and T cells of the AL http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 987 9/18/2008 12:54:31 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print 988 Section 16 Dermatologic Therapeutics TABLE 71-1 TOPICAL CORTICOSTEROIDS Brand Name Generic Name CLASS 1—SUPERPOTENT (UP TO 600 TIMES AS POTENT AS HYDROCORTISONE) Clobex Lotion/Spray/Shampoo, 0.05% Cormax Cream/Solution, 0.05% Diprolene Gel/Ointment, 0.05% Olux Foam, 0.05% Psorcon Ointment, 0.05% Temovate Cream/Ointment/Solution, 0.05% Ultravate Cream/Ointment, 0.05% Vanos Cream, 0.1% Clobetasol propionate Clobetasol propionate Betamethasone dipropionate Clobetasol propionate Diflorasone diacetate Clobetasol propionate Halobetasol propionate Fluocinonide Amcinonide Betamethasone dipropionate Betamethasone dipropionate Mometasone furoate Diflorasone diacetate Halcinonide Fluocinonide Diflorasone diacetate Betamethasone dipropionate Diflorasone diacetate Betamethasone dipropionate and calcipotriene Desoximetasone Desoximetasone AL Cyclocort Ointment, 0.1% Diprolene Cream AF, 0.05% Diprosone Ointment, 0.05% Elocon Ointment, 0.1% Florone Ointment, 0.05% Halog Ointment/Cream, 0.1% Lidex Cream/Gel/Ointment, 0.05% Maxiflor Ointment, 0.05% Maxivate Ointment, 0.05% Psorcon Cream, 0.05% Taclonex Ointment, 0.064% Topicort Cream/Ointment, 0.25% Topicort Gel, 0.05% PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N Practice: Dermatologic Therapeutics CLASS 2—POTENT (50-100 TIMES AS POTENT AS HYDROCORTISONE) CLASS 3—UPPER MID-STRENGTH (2-25 TIMES AS POTENT AS HYDROCORTISONE) Aristocort A Ointment, 0.1% Cutivate Ointment, 0.05% Cyclocort Cream/Lotion, 0.1% Diprosone Cream, 0.05% Florone Cream, 0.05% Lidex-E Cream, 0.05% Luxiq Foam, 0.12% Maxiflor Cream, 0.05% Maxivate Cream/Lotion, 0.05% Topicort Cream, 0.05% Triamcinolone acetonide Fluticasone propionate Amcinonide Betamethasone dipropionate Diflorasone diacetate Fluocinonide Betamethasone valerate Diflorasone diacetate Betamethasone dipropionate Desoximetasone CLASS 4—MID-STRENGTH Aristocort Cream, 0.1% Cordran Ointment, 0.05% Elocon Cream, 0.1% Kenalog Cream/Ointment/Spray, 0.1% Synalar Ointment, 0.025% Uticort Gel, 0.025% Westcort Ointment, 0.2% Triamcinolone acetonide Flurandrenolide Mometasone furoate Triamcinolone acetonide Fluocinolone acetonide Betamethasone benzoate Hydrocortisone valerate CLASS 5—LOWER MID-STRENGTH Cordran Cream/Lotion/Tape, 0.05% Cutivate Cream, 0.05% DermAtop Cream, 0.1% DesOwen Ointment, 0.05% Diprosone Lotion, 0.05% Kenalog Lotion, 0.1% Locoid Cream, 0.1% Pandel Cream, 0.1% Synalar Cream, 0.025% Uticort Cream/Lotion, 0.025% Valisone Cream/Ointment, 0.1% Westcort Cream, 0.2% Flurandrenolide Fluticasone propionate Prednicarbate Desonide Betamethasone dipropionate Triamcinolone acetonide Hydrocortisone Hydrocortisone Fluocinolone acetonide Betamethasone benzoate Betamethasone valerate Hydrocortisone valerate CLASS 6—MILD Aclovate Cream/Ointment, 0.05% Derma-Smoothe/FS Oil, 0.01% DesOwen Cream, 0.05% Synalar Cream/Solution, 0.01% Tridesilon Cream, 0.05% Aclometasone dipropionate Fluocinolone acetonide Desonide Fluocinolone acetonide Desonide CLASS 7—LEAST POTENT Topicals with hydrocortisone, dexamethasone, methylprednisolone, and prednisolone Modified from National Psoriasis Foundation, 2006. http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 988 9/18/2008 12:54:31 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print Chapter 71 Psoriasis 989 ally increasing the strengths of dithranol formulations applied. Much of the irritation and staining from anthralin use can be prevented with the application of triethanolamine, a nonsteroidal chemical used for many years as a stabilizer in soaps and cosmetics. Psoriatec is an anthralin formulation designed to reduce the risk of staining and irritation. It is a 1% anthralin cream in which the active ingredient is surrounded by a protective layer of lipids. These layers melt at body temperature, releasing the anthralin only on the skin where it is applied, not on clothes, bedding, or bathroom fixtures. The Ingram regimen combines anthralin paste and UVB exposure. Anthralin is applied to lesions as a thick paste. Once the anthralin is removed, the patient is then exposed to UVB and may also take coal tar baths. Generally, a patient using the Ingram regimen in the hospital or a day treatment program will require 3 weeks of therapy, with clearing in an average of 20 days. Salicylic Acid. Salicylic acid is the chemical compound with the formula C6H4(OH)CO2H, where the OH group is adjacent to the carboxyl group. It is also known as 2-hydroxybenzoic acid. Salicylic acid belongs to a group of medicines known as keratolytics. Salicylic acid works by softening keratin, a protein that forms the major part of the outer skin structure. This helps to loosen dry, scaly skin, making it easier to remove. When salicylic acid is used in combination with other medicines, it desquamates the upper layer of skin, allowing the additional medicines to penetrate more effectively. Salicylic acid is available over the counter in concentrations up to 3%; concentrations greater than 3% are only available by prescription. Salicylic acid preparations are usually well tolerated. Mild stinging may occur, especially on broken skin and when higher concentrations are used. Salicylic acid can irritate or burn healthy skin, so it is important to keep the medicine confined to the affected area(s). Tacrolimus. Tacrolimus (Prograf, Protopic) and Pimecrolimus (Elidel) is an immunosuppressive drug whose main use is after allogenic organ transplant to reduce the activity of the patient’s immune system and so the risk of organ rejection. It is a 23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. It is also used in a topical preparation in the treatment of severe atopic dermatitis, vitiligo and other skin conditions. Topically, it suppresses inflammation similar to steroids, and is equally as effective as a mid-potency steroid. An important advantage of tacrolimus is that, unlike steroids, it does not cause skin atrophy or other steroid related side-effects. It has been approved for the treatment of atopic dermatitis, however it can be used topically to treat mild psoriasis in pediatric patients and/or treat areas where a topical steroid is not recommended. Long-term efficacy and safety of topical tacrolimus solely or in combination in the treatment of psoriasis must be evaluated. It can be used 0.3% ointment daily or 0.1% ointment twice per day. Similarly, pimecrolimus (Elidel) can be used as the 1% formulation twice per day. Tacrolimus is chemically known as a macrolide. It reduces peptidylprolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin, thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription.28 Although this activity is similar to cyclosporine, studies have shown that the incidence of acute rejection is reduced by tacrolimus versus cyclosporine. Pimecrolimus is an ascomycin macrolactam derivative. It has been shown in vitro that pimecrolimus binds to macrophilin-12 and inhibits calcineurin. Thus pimecrolimus inhibits T-cell activation by inhibiting the synthesis and release of cytokines from T-cells. Pimecrolimus also prevents the release of inflammatory cytokines and mediators from mast cells. Topical pimecrolimus is also used in mild psoriasis in areas where other topical treatments are contraindicated, even though it has been approved for atopic dermatitis. Tacrolimus and pimecrolimus have been suspected of carrying a cancer risk, though the matter is still a subject of controversy. The FDA issued a health warning in March 2005 for the topical formulations of PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N Practice: Dermatologic Therapeutics concentrations between 0.5% and 5% are safe and effective for psoriasis and that no scientific evidence suggests that the coal tar in the concentrations used in nonprescription treatments is overtly carcinogenic. Exactly how coal tar exerts its activity in these conditions is not completely understood. It appears to have antimicrobial, antipruritic, and keratoplastic (normalizes epidermal growth and reduce scaling) effects. Most patients tolerate coal tar preparations well. Coal tar may initially cause mild burning or skin irritation. When used on the scalp, it may temporarily discolor bleached, tinted, light blond, or grey hair. Coal tar also stains skin and clothing. Skin staining fades after the treatment has been stopped. Coal tar may cause photosensitivity (ultraviolet A [UVA] range), hence the need to stay out of direct sunlight when using these preparations. Goeckerman Regimen. The Goeckerman regimen was described by Dr. Goeckerman in 1925 at the Mayo Clinic. Once- or twice-daily skin applications of crude coal tar for at least 4 hr/day are performed, followed by vegetable oil removal before the patient is exposed to total body UVB radiation. This is followed by a cleansing bath or shower to remove the residual tar and scales. The regimen can be supplemented with steroid medications and keratolytics, particularly in the early stages of treatment. In a modification of the Goeckerman regimen, anthralin is used instead of coal tar (this is called the Ingram regimen). Compared with the original Goeckerman method, the modern, modified Goeckerman therapy in use in the 21st century shows significantly enhanced efficacy through improvements in technology (e.g., narrowband UVB [NB-UVB]) and the possibility of adding other relatively safe therapeutic options for more resistant cases to enhance efficacy without compromising the basic safety profile. Studies have demonstrated attainment of PASI 75 within 3 to 4 weeks of intensive treatment.27 The Goeckerman regimen is one of the most effective treatments for psoriasis. It is regarded as messy, inconvenient, and time consuming compared to most newer therapies, and, thus, has limited utility in modern psoriasis treatment, even in day care programs that formerly offered this treatment option to many patients. Anthralin. Anthralin or dithranol (Dithrocream, Micanol, Psorlin) is a hydroxyanthrone (anthracene derivative) medicine applied to the skin of people with psoriasis. It is available as creams, ointment, or pastes in 0.1 to 2% stengths. This substance has been used to treat psoriasis for more than 100 years. Several mechanisms of action have been identified. Dithranol accumulates in mitochondria, where it interferes with the supply of energy to the cell, probably by the oxidation of dithranol releasing free radicals. This impedes DNA replication and so slows the excessive cell division that occurs in psoriatic plaques. Dithranol has also been shown to cause apoptosis and cell death of lymphocytes with significantly greater sensitivity than keratinocytes, effectively eliminating these pathogenic immune-inflammatory cells from lesional skin. In addition, dithranol may act by reducing the elevated levels of cyclic GMP that occurs in psoriasis. More dithranol penetrates into impaired skin in 30 minutes than into intact skin over 16 hours. For this reason, weaker 0.1% to 0.5% preparations are applied overnight, but stronger 1% to 2% products are applied for between 30 minutes and 1 hour (short-contact anthralin therapy) depending upon the formulation. Short-contact therapy is designed for patients with localized areas of psoriasis. Anthralin is left on the involved skin for a short period of time, ranging from 10 minutes to an hour. Patients may be instructed to gradually increase the amount of contact time as their skin becomes accustomed to the medication. Dithranol has a slower onset of action in controlling psoriasis, typically several weeks, compared to glucocorticoid steroids, but has far less potential for rebound reactions on withdrawal or tachyphylaxis. It cannot be used on the face or genitalia. It temporarily stains the skin a yellowish brown and permanently stains clothing fabrics. It may cause a local burning sensation and irritation; this can be minimized by careful attention to the details of treatment application and gradu- AL http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 989 9/18/2008 12:54:31 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print Section 16 Dermatologic Therapeutics these drugs, based on animal models and a small number of patients. Until further human studies yield more conclusive results, the FDA recommends that users be advised of the potential risks. The European FK506 Multi-Center Psoriasis Study Group randomized 50 patients with recalcitrant plaque-type psoriasis to receive either oral tacrolimus or placebo in a double-blind, prospective study.29 The initial dose of tacrolimus was 0.05 mg/kg per day and increased gradually to 1.5 mg/kg per day at week 6 to improve efficacy. At 9 weeks, tacrolimus-treated patients experienced greater reductions in PASI compared to placebo. The group determined that oral tacrolimus was an effective treatment for recalcitrant plaque-type psoriasis, and that most side-effects were mild to moderate in severity. Light therapy or phototherapy consists of exposure to specific wavelengths of light using lasers, light-emitting diodes, fluorescent lamps, dichroic lamps, or very bright, full-spectrum light (radiation) for a prescribed amount of time. Ultraviolet (UV) radiation (light) is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than soft xrays. UVA, long-wave, or black light has a wavelength of 400 to 320 nm. UVB or medium-wave radiation has a wavelength of 320 to 280 nm, and ultraviolet C (UVC), short-wave, or germicidal radiation has a wavelength of less than 280 nm. The sun emits UV radiation in the UVA, UVB, and UVC band ranges, but because of absorption in the atmosphere’s ozone layer, 99% of the ultraviolet radiation that reaches the Earth’s surface is UVA. The primary advantageous biologic effect of UVB exposure for humans is that it induces the production of vitamin D in the skin. UVA, UVB, and UVC each have several target chromogens in skin. UV has the potential to damage proteins, including collagen fibers, and thereby accelerate aging of the skin. In general, UVA is the least harmful, but can contribute to the aging of skin, DNA damage, and possibly skin cancer. UVB radiation can cause skin cancer. The radiation alters DNA molecules in skin cells, causing covalent bonds to form between adjacent thymine bases, producing thymidine dimers. Thymidine dimers do not base pair normally, which can cause distortion of the DNA helix, stalled replication, gaps, and mis-incorporation. These lead to mutations, which can result in cancer development. Phototherapy, especially UVB light therapy and photochemotherapy, remains an essential treatment option for patients with moderate to severe psoriasis. Natural sunlight for the treatment of psoriasis has been used for centuries. A mainstay of therapy for psoriasis during the midportion of the 20th century was the use of UVB produced by an artificial light source. The current mainstay for office-based UV light therapy is fluorescent lamp sources, which produce a wide range of UV radiation emissions. UVB sources contain higher energy, lower frequency UV radiation and carry a greater potential for erythemogenic responses and sunburning reactions. UVB treatment can be administered to adults and children, and is effective in treating psoriasis for at least two thirds of patients who meet these criteria: thinner plaques, moderate to severe disease (involving >2% of the skin), and/or responsive to natural sunlight. The most efficient approach is first to determine the minimal erythema dose (MED), which is a biologic response (pink-red appearance) of the skin to that particular UVB radiation source or unit. The MED is determined and phototherapy is initiated at 70% to 75% MED, increasing steadily (as much as 50% MED) at each visit. A patient generally will receive treatments three to five times per week. It takes an average of 30 treatments to reach maximum improvement of psoriasis lesions. NB-UVB refers to a specific wavelength of UV radiation, 311 to 312 nm. Compared with broadband UVB (BB-UVB), exposure times are shorter but of higher intensity. The course of treatment is typically shorter, and efficacy of NB-UVB is typically greater. Longer periods of remission also have been shown for NB-UVB. The long-term safety of NB- versus BB-UVB phototherapy is uncertain. “Selective” BB-UVB lamps, which have little emission less than 290 nm, are also available but have not been adequately compared to NB-UVB lamps. Dosing of PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N Practice: Dermatologic Therapeutics Phototherapy NB-UVB has been compared by a half-body treatment study with either 70% or 35% MED. A total of 55% of patients in the 70% MED group and 27% in the 35% MED group achieved PASI 75 or greater at 3 weeks.30 A randomized comparison of NB-UVB and selective BB-UVB in 100 patients with psoriasis has been performed. Side effects, including the development of erythema during phototherapy, were similar for the two lamp types. Risk estimates based on the human photocarcinogenesis action spectrum predict that NB-UVB lamps will be 50% more carcinogenic for equal erythemal doses than selective BB-UVB lamps. As these two lamp types appear to be of similar efficacy, phototherapy using a selective BB-UVB source may be a safer option than use of NB-UVB.31 Combination Photochemotherapy UVA (Psoralen + UVA). PUVA photochemotherapy has been in routine clinical use since the 1970s. Psoralen is applied topically or taken orally to sensitize the skin, followed by UVA exposure. Longterm use has been associated with higher rates of skin cancer. Psoralens are photosensitizing agents found in plants. 8-Methoxypsoralen is used in the United States, and, in Europe, 5-methoxypsoralen is also used as it has fewer gastrointestinal (GI) side effects. Therapeutic benefits of psoralens have been known since ancient Egypt but have only been available in chemically synthesized forms since the 1970s. Psoralens are taken systemically or can be applied directly to the skin. The psoralens are photosensitizing and allow a much lower dose of UVA to achieve a biologic response. When they are combined with exposure to UVA in PUVA, they are highly effective at clearing psoriasis. The full mechanism(s) of action of the psoralen molecule and UVA in the treatment of psoriasis have not been entirely clear but likely involve targeting the pathogenic T cells within psoriatic lesions. The psoralen molecule intercalates between DNA base pairs but also has effects on the cell membrane. There is no biochemical interaction between the psoralen molecule and DNA itself without activation or absorption of photons of UV radiation as a photodynamic effect. A photochemical reaction results with the psoralen molecule and a pyrimidine base, and DNA cross-links occur. Formation of the cyclobutane ring requires an additional photochemical reaction. In addition to its therapeutic effects, DNA alterations likely account for the increased development of squamous cell and basal cell carcinomas with repetitive therapy over years. A second mechanism of action of PUVA therapy on inflammatory skin disorders is oxygen-dependent photochemical reactions. This type of reaction causes membrane and cell damage and may be central to the observable effects of UV light on the skin. APCs and T lymphocytes are more susceptible to these oxygen-dependent reactions than keratinocytes, and the underlying mechanism of action of PUVA photochemotherapy appears to be inhibition of immunocyte activation and immune recruitment of additional T cells into the skin.32 The duration of remission following clearing with PUVA is more durable than with UVB therapy. However, with new treatment alternatives and the increased risk of squamous cell carcinoma (SCC), especially in fair-skinned individuals with greater than 250 treatments over time, PUVA has diminished popularity. PUVA is considered for moderate to severe cases of psoriasis in adults. Stable plaque psoriasis, guttate psoriasis, and psoriasis of the palms and soles are especially responsive to PUVA treatments. PUVA is not normally recommended for children or teenagers. However, it can be used by young people to avoid unwanted side effects of other treatments or if other treatments have not been successful. Choosing the proper dose for PUVA is similar to the procedure followed with UVB. A starting dose is typically selected based on the patient’s skin type. Often, however, a small area of the patient’s skin is exposed to UVA after ingestion of psoralen. The dose of UVA that produces uniform redness 48 to 72 hours later, called the minimum phototoxic dose, becomes the starting dose for treatment. One of the most common side effects of psoralen is nausea. The primary long-term risk of PUVA treatment is a higher risk of skin cancer, particularly SCC as well as basal cell carcinoma. Some AL 990 http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 990 9/18/2008 12:54:31 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print Chapter 71 Psoriasis Oral Treatments Plasma membrane CsA-cyclophillin Calcineurin NF-AT Nuclear membrane Interleukin-2 Stimulation of immune response PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N studies have shown that oral retinoid use during PUVA treatment decreases the risk of developing SCCs.33 There is a potential for PUVA to induce cataracts if the eyes are not protected. Psoralen remains in the eye lens for a period of time following ingestion of the drug. To date, no increase in cataracts has been noted in patients using proper eye protection. Other Combinations. Combination photochemotherapy for treatment of psoriasis has gained popularity over the past several decades as more therapeutic agents become clinically available. Topical steroids are still the most common treatment for mild plaque-type psoriasis and can be used safely in combination with phototherapy. When superpotent topical corticosteroids are used, a regimen of using the initial treatment for induction followed by tapering and discontinuation of topical steroids should be used. Calcipotriene can also be used with phototherapy. However, it should be applied after phototherapy as UV will inactivate the compound. Topical retinoids also should be used a few hours after phototherapy. Another effective combination therapy with UV radiation is use of systemic retinoids.34 The treatment rationale for combining retinoids with UV light is to reduce the total energy delivered to the skin and enhance the therapeutic regimen by decreasing the total number of treatments needed. Retinoids also have antitumorigenic activities and suppress carcinogenic progression. The approach of this treatment is to initiate therapy with the retinoid for at least 7 to 14 days to establish the retinoid effect on the skin and its modification on the psoriatic plaques. The effect of the retinoids is to decrease the thickness of the plaques and the scaling, allowing the UV therapy to be more effective. Retinoids also increase susceptibility to erythema from UVB and enhance the phototoxic effects from PUVA. Nowadays acitretin is the most widely used retinoid in combination with phototherapy. Other systemic treatments can be used in combination with phototherapy. Methotrexate and cyclosporine have both been used. Cyclosporine and phototherapy should be used cautiously because, in combination with PUVA, cyclosporine further increases the risk of SCC development.35 Calcipotriol-PUVA has shown to be more effective than PUVA alone. A randomized, multicenter, vehicle-controlled, double-blind, 12-week comparative study examined 120 patients with psoriasis covering 20% to 50% of BSA. The study consisted of a washout phase followed by a 10-week treatment phase. PUVA therapy three times weekly was added within 1 week after randomization. At baseline, the mean PASI scores were 17.5 and 19.2 in the calcipotriol and vehicle (placebo) groups, respectively. At the end of treatment, the mean PASI scores were 2.65 and 7.03, respectively. A reduction in PASI score greater than 90% was observed in 69% of the patients in the calcipotriol-treated group and in 36.4% of the patients in the vehicle group.36 Practice: Dermatologic Therapeutics Figure 71-4 • Mechanism of action of cyclosporine. Methotrexate. Methotrexate (Folex, Mexate, Amethopterin, Rheumatrex, Trexall) was the first systemic therapy for patients with moderate to severe psoriasis and remains one of the most prescribed systemic agents. Methotrexate replaced the more powerful and toxic antifolate aminopterin, and the two should not be confused with each other. Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR), an enzyme that is part of the folate synthesis metabolic pathway. The affinity of methotrexate for DHFR is about 1000-fold that of folate for DHFR. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate. Folic acid is required for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins (Fig. 71-4). Methotrexate acts specifically during DNA and RNA synthesis and, thus, is cytotoxic during the S phase of the cell cycle. It therefore has a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells as well as GI and oral mucosa) and, thus, inhibits the growth and proliferation of these noncancerous cells as well as causing the side effects noted later. Lower doses of methotrexate have been shown to be very effective for the management of rheumatoid arthritis and psoriasis. In these cases, inhibition of DHFR is not thought to be the main mechanism. Rather, there is inhibition of enzymes involved in purine metabolism like amidophosphoribosyltransferase, leading to accumulation of adenosine, or the inhibition of T-cell activation and suppression of intracellular adhesion molecule expression by T cells.37 Mean oral bioavailability is 33% (range 13% to 76%), and there is no clear benefit to subdividing an oral dose. Mean intramuscular bioavailability is 76%. Methotrexate is metabolized by intestinal bacteria to the inactive metabolite 4-amino-4-deoxy-N-methylpteroic acid, which accounts for less than 5% loss of the oral dose. Factors that decrease absorption include food, oral nonabsorbable antibiotics (e.g., vancomycin, neomycin, and bacitracin), and more rapid transit through the GI tract (e.g., with diarrhea), while slower transit time in the GI tract (e.g., with constipation) will increase absorption. Possible side effects include anemia, neutropenia, increased risk of bruising, nausea and vomiting, dermatitis and diarrhea with blood in the stools, headache and alopecia. A small percentage of patients develop hepatitis, and there is an increased risk of pulmonary fibrosis. If sores appear in the mouth, the dose may be too high. The higher doses of methotrexate often used in cancer chemotherapy can cause toxic effects to the rapidly dividing cells of bone marrow and GI mucosa. The resulting myelosuppression and mucositis are often prevented (termed methotrexate “rescue”) by using folinic acid supplements (not to be confused with folic acid). Methotrexate is a highly teratogenic drug and is categorized in Pregnancy Category X by the FDA. Women must not take the drug during pregnancy, if there is a risk of becoming pregnant, or if they are breastfeeding. Men who are trying to get their partner pregnant must also not take the drug. To safely engage in any of these activities (after discontinuing the drug), women must wait until the end of a full ovulation cycle and men must wait 3 months. The main risk of long-term methotrexate treatment is the potential for liver damage. A small percentage of patients (0.5%) will develop reversible liver scarring. This is a risk after a cumulative dose of 1.5 g. How long it takes to reach 1.5 g depends on the patient’s dose, treatment schedule and rest periods from the drug. When a patient reaches a cumulative dose of 1 to 1.5 g, liver biopsy to test for liver damage is often recommended. If significant liver damage is observed, methotrexate is usually discontinued. Anti-inflammatory medications should be avoided while the patient is receiving methotrexate. These drugs elevate the effects of methotrexate to potentially harmful levels. Vaccines should be avoided due to the immunosuppressive action of methotrexate, and ethanol consumption should be strictly avoided to reduce the risk of liver complications. Methotrexate is indicated for use in adults with severe psoriasis. Methotrexate is often prescribed for severe plaque psoriasis, ery AL CsA NF-ATp 991 http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 991 9/18/2008 12:54:32 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print 992 Section 16 Dermatologic Therapeutics Antigen Presenting Cell corticosteroids Antigen Costimulation B7 Anti CD3 CTLA4lg Anti CD40L Anti CD25 IL-2 T Cell Receptors IL-15 and others CD28 Target of Rapamycin corticosteroids sirolimus Mycophenolate mofetil AL cyclosporine tacrolimus MAP kinases IMPDH Nuclear factor of AP-1 activated T Cells PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N Practice: Dermatologic Therapeutics CD40L calcineurin G1 S azathioprine IL-2 and others T Cell M Cell cycle G2 Figure 71-5 • Mechanism of action of different biologics and systemic treatments. throdermic psoriasis, and acute pustular psoriasis. The drug can also be used to treat psoriatic arthritis. Methotrexate is sometimes used on a rotational basis with other treatments such as PUVA, acitretin, or cyclosporine in order to decrease treatment duration side effects or improve results. It is usually taken once per week, either orally or by injection. In psoriasis, the weekly dose is often divided into three doses given at 12-hour intervals each week. There is evidence that this dosing schedule increases efficacy. In psoriasis, the recommended starting dose schedule is weekly single oral, intramuscular, or intravenous administration of 10 to 25 mg/wk until an adequate response is achieved. The divided oral dose schedule is 2.5 to 5 mg at 12-hour intervals for three doses. Dosages in each schedule may be gradually adjusted to achieve optimal clinical response, and the minimum effective dose should be sought for long-term control of skin disease; however, 30 mg/wk should not ordinarily be exceeded. Folic acid supplementation 1 mg/day is recommended because it mitigates the GI effects of methotrexate (nausea, diarrhea, elevated liver enzymes) without altering its efficacy. It also prevents megaloblastic anemia due to folic acid deficiency. A randomized, controlled trial comparing methotrexate and cyclosporine was conducted with an average dose of cyclosporine 4.5 mg/kg per day and methotrexate 22.5 mg/wk for 16 weeks, with a 36-week follow up. By week 16, PASI 75 was achieved by 60% of the metho trexate group and 71% of cyclosporine group.38 Cyclosporine. Cyclosporine (Sandimmune, Cicloral, Gengraf, Neoral) is an immunosuppressant drug widely used in postallogeneic organ and bone marrow transplantation to reduce the activity of the patient’s immune system and the risk of organ rejection. Cyclosporin A, the main form of the drug, is a cyclic peptide of 11 amino acids produced by the fungus Tolypocladium inflatum Gams, initially isolated from a Norwegian soil sample. Cyclosporine is thought to bind to the cytosolic protein cyclophilin of immunocompetent lymphocytes, especially T lymphocytes (Fig. 715). This complex of cyclosporine and cyclophilin inhibits calcineurin, which activates transcription of IL-2. It also inhibits lymphokine production and interleukin release and, therefore, leads to a reduced func- tion of effector T cells. It does not affect cytostatic activity. It has also an effect on mitochondria. Cyclosporin A also prevents mitochondrial PT pore opening, thus inhibiting release of cytochrome c, a potent apoptotic stimulation factor. However, this is not the primary mode of action in clinical use. An alternate form of the drug, cyclosporin G, has been found to be much less nephrotoxic than the standard cyclosporin A. Cyclosporin G differs from cyclosporin A in the amino acid 2 position, where an L-nor-valine replaces the a-aminobutyric acid. Cyclosporine side effects include gum hyperplasia, convulsions, peptic ulcers, pancreatitis, fever, vomiting, diarrhea, confusion, breathing difficulties, numbness and tingling, pruritus, high blood pressure, potassium retention and possibly hyperkalemia, nephrotoxicity, hepatotoxicity, and obviously an increased vulnerability to opportunistic fungal and viral infections. Cyclosporine interacts with a wide variety of other drugs and other substances, including grapefruit juice, although there have been studies using grapefruit juice to increase the blood level of cyclosporine. Extended use of cyclosporine by transplantation patients is well established. However, long-term use as a treatment for psoriasis is more limited. Therefore, use of the drug is not currently recommended by the FDA for longer than 1 year. A risk of long-term cyclosporine treatment is kidney damage/toxicity. In some cases, the damage to the kidneys can be irreversible. People taking cyclosporine have an increased risk of developing skin malignancies, particularly if they have a history of nonmelanoma skin cancers. Oral Retinoids. Retinoids have a structure similar to vitamin A and regulate normal growth and differentiation of skin cells. Acitretin acts by inhibiting the excessive cell growth and aberrant keratinization seen in psoriasis. It reduces acanthosis of the epidermis as well as plaque formation and scaling. Acitretin is the only oral retinoid approved by the FDA specifically for treating psoriasis. Isotretinoin is sometimes used as an alternative. Isotretinoin is cleared from the body much faster than acitretin, often making it a safer choice for young women of childbearing potential. However, both have the potential for severe birth defects if a woman becomes pregnant and drug remains in the system. Side effects of oral retinoids are extensive, and physicians prescribing this medication should recognize its potentially serious consequences. http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 992 9/18/2008 12:54:33 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print Chapter 71 Psoriasis 993 treatments may potentially minimize toxicity by using lower doses of each of the two agents. Women must avoid becoming pregnant for at least 3 years after discontinuing acitretin. In comparison, etretinate was not recommended at all for women who planned to become pregnant. Clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and ethanol. Because the longer elimination halflife of etretinate would increase the duration of teratogenic potential for female patients, ethanol must not be ingested by female patients either during treatment with acitretin or for 2 months after cessation of therapy. This allows for elimination of acitretin, thus removing the substrate for transesterification to etretinate. Acitretin may also be prescribed in rotation with other systemic medications, such as cyclosporine or methotrexate. Soriatane is most effective for treating psoriasis when it is used with phototherapy rather than by itself. Combination therapy can speed clearing and help reduce the amount of phototherapy needed to clear symptoms, thereby reducing risks and side effects. Isotretinoin. Isotretinoin (13-cis-retinoic acid) is used primarily to treat cystic nodular acne. Isotretinoin (Accutane, Amnesteem, Claravis, Sotret) comes in dosages of 5, 10, 20 and 40 mg. Isotretinoin dosing is dependent on weight and the severity of the condition. Generally it is prescribed at a dose of 0.5 to 2 mg/kg per day (most often 1 to 1.25 mg/ kg per day) and tapered to a dose that maintains control of disease with minimum side effects. Hydroxyurea (Hydrea). Hydroxyurea is an oral anticancer medication that, in the 1960s, was found to be effective for psoriasis. It is an antineoplastic drug used primarily in hematologic malignancies. It is also used as an antiretroviral agent. Its mechanism of action is believed to be based on its inhibition of the enzyme ribonucleotide reductase by scavenging tyrosyl free radicals as they are involved in the reduction of nucleotide diphosphates. Hydroxyurea is a second-line modality for the treatment of psoriasis. It is usually reserved for cases in which other second-line agents have failed or are contraindicated. The dose used has generally been 0.5 to 1.5 g daily, give orally either as a single dose or divided into two doses (morning and evening). Hydroxyurea avoids the hepatotoxicity associated with methotrexate and the nephrotoxicity associated with cyclosporine, and can often be useful when other drugs are contraindicated, although it should be avoided, if possible, when renal function is markedly impaired. Reported side effects are drowsiness, nausea and vomiting, diarrhea, constipation, mucositis, anorexia, stomatitis, bone marrow toxicity (which may take 7 to 21 days to recover after the drug has been discontinued), alopecia, skin changes, and abnormal liver enzymes, creatinine, and blood urea nitrogen. The main concern regarding toxicity of hydroxyurea has been over myelosuppression, which may manifest as megaloblastic anemia, thrombocytopenia, or leukopenia. These side effects may develop after several months of treatment. They have generally been reversible after discontinuation of the drug. Due to its effect on the bone marrow, regular monitoring of the complete blood count is vital, as well as close monitoring for possible infections. In addition, renal function, uric acid and electrolytes, and liver enzymes are commonly checked. Hydroxyurea is a cytotoxic drug with potential for teratogenic effects and is best avoided in women of childbearing age. There is reported experience with severe psoriasis using a combination of hydroxyurea (500 mg daily) with methotrexate (12.5 to 15 mg weekly).39 An adequate response was obtained in the vast majority of patients, and hydroxyurea appeared to reduce the quantity of methotrexate required. Successful treatment of recalcitrant psoriasis with a combination of infliximab and hydroxyurea has been reported. The combination was used to treat psoriasis that proved resistant to conventional therapy, including vitamin D analogues, topical steroids, dithranol, crude coal tar, NB-UVB, bath PUVA, and acitretin. Hydroxyurea 1 g daily combined with infliximab infusions repeated at 3month intervals led to satisfactory control of psoriasis and psoriatic arthritis.40 Mycophenolate Mofetil. Introduced in the 1970s as a treatment for psoriasis, mycophenolic acid has since been reformulated as mycophe- PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N Practice: Dermatologic Therapeutics Patients should be evaluated frequently for adverse effects and to ensure compliance with therapy. Side effects include Common: dryness of skin, lips, and mucous membranes; cheilitis, itch, skin fragility, skin peeling, rash, flushing, photosensitivity; nosebleeds; dry eyes, eye irritation, conjunctivitis, reduced tolerance to contact lenses; hyperlipidemia, raised liver enzymes; headaches; hair thinning; myalgia and/or arthralgia Infrequent: raised blood glucose level, increased erythrocyte sedimentation rate, fatigue and/or mood changes Rare: impaired night vision, cataracts, optic neuritis, menstrual disturbances, inflammatory bowel disease, pancreatitis, hepatitis, corneal opacities, papilloedema, idiopathic intracranial hypertension, skeletal hyperostosis, extraosseous calcification, moderate memory loss The following adverse effects have been reported to persist, even after discontinuing therapy: alopecia (hair loss), arthralgias, decreased night vision, degenerative disk disease, keloids, bone disease, and depression (in some cases). Patients receiving oral retinoid therapy are not permitted to donate blood during and for at least 1 month after discontinuation of therapy. Several studies have suggested a possible link between oral retinoids and clinical depression. However, no conclusive evidence has been produced. Oral retinoids can cause birth defects in the developing fetus, including defects of the central nervous system, skull, eyes, and cardiovascular system. It is important that women of childbearing age are not pregnant and do not become pregnant while taking this medication. Women must sign consent forms and take a pregnancy test prior to initiation of retinoids. Women must use two separate effective forms of birth control at the same time for 1 month before treatment begins, during the entire course of treatment, and for 1 full month after stopping the drug. In the United States, the process of ensuring that pregnancy is avoided has been mandated by the U.S. government via the iPLEDGE program. iPLEDGE is a computer-based risk management program designed to further the public health goal to eliminate fetal exposure to isotretinoin through a special restricted distribution program approved by the FDA. The program strives to ensure that • No female patient starts isotretinoin therapy if pregnant • No female patient on isotretinoin therapy becomes pregnant Since March 2006, the dispensing of isotretinoin in the United States has been controlled by an FDA-mandated website called iPLEDGE. Dermatologists are required to register their patients before prescribing, and pharmacists are required to check the web site before dispensing the drug. The concurrent use of oral retinoids with tetracycline antibiotics or vitamin A supplementation is not recommended. Concurrent use of oral retinoids with tetracycline significantly increases the risk of idiopathic intracranial hypertension. Concurrent intake of vitamin A supplementation increases the risk of vitamin A toxicity. Acitretin. Acitretin (Soriatane) is a second-generation retinoid. It is a metabolite of etretinate, which was marketed prior to the introduction of acitretin. Etretinate was discontinued because it had a narrow therapeutic index as well as a long elimination half-life of 120 days, making dosing difficult. In contrast, acitretin’s half-life is approximately 2 days. The mechanism of action of acitretin likely involves targeting specific retinoid receptors in the skin to normalize the abnormal growth cycle of psoriatic skin cells. It is taken orally and typically used for psoriasis. It is usually taken at a dose of 0.25 to 1 mg/kg of body weight per day. Acitretin is particularly effective for pustular psoriasis, erythrodermic psoriasis, and psoriasis affecting hands and feet. It is not effective for psoriatic arthritis. Acitretin is a convenient once-a-day oral medication that is available in 10- and 25-mg capsules approved for both the initial and maintenance treatment of severe psoriasis (BSA > 10%) in adults. It can be considered one of the treatments of choice for pustular and erythrodermic psoriasis. However, the efficacy of acitretin as a monotherapy for plaque psoriasis is less, although it is often used in combination therapy with other systemic psoriasis therapies, especially UVB or PUVA phototherapy, to increase efficacy. Such combination AL http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 993 9/18/2008 12:54:33 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print 994 Section 16 Dermatologic Therapeutics Keratinocyte Medicines that bind to cytokines and block them ABX-IL8 Adalimumab Fontalizumab HuMax-IL15 Infliximab Ustekinumab Receptor-blocking medicines Medicines that prevent direct cell-to-cell contact Alefacept Efalizumab HuMax-CD4 Siplizumab Alefacept Efalizumab? SYNTHETIC PATHWAY Medicines that interfere with DNA and gene expression Cyclosporin Tacrolimus ISIS 104838 CYTOKINES IMPLICATED In Psoriasis TNFα IFNγ IL-2 IL-8 IL-11 IL-12 IL-13 IL-15 IL-22 IL-23 Cell responding to cytokine Accessory immune cell CK AL Cytokine producing cell CK in receptor PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N Practice: Dermatologic Therapeutics IL-15 Medicines blocking the synthetic pathways in lymphocytes Soluble TNF-α receptor Etanercept VX-148 RCX 1777 DGR 796 Mycophenolate mofetil Figure 71-6 • Mechanism of action for different biologics and systemic treatments for psoriasis. nolate mofetil. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolate is derived from the fungus Penicillium stoloniferum. Mycophenolate mofetil is metabolized in the liver to the active moiety mycophenolic acid. It inhibits inosine monophosphate dehydrogenase, the enzyme that controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes. Mycophenolate mofetil (CellCept, Myfortic) is an immunosuppressant drug used to prevent rejection in organ transplantation, as well as in the treatment of several inflammatory or autoimmune skin diseases. It can be used in combination with cyclosporine, and some doctors use it when tapering patients off of cyclosporine. Its relative lack of hepatonephrotoxicity and seemingly low risk of carcinogenicity offer important therapeutic advantages. Doses range from 1 to 1.5 g twice daily for the treatment of psoriasis and most other skin diseases (typically up to a maximum dose of 3 g daily). As psoriasis begins to improve, the dose can be decreased to 1 g daily in divided doses. Common adverse drug reactions (≥1% of patients) associated with mycophenolate therapy include diarrhea, nausea, vomiting, infections, leukopenia, and/or anemia. Mycophenolate sodium is also commonly associated with fatigue, headache, and/or cough. Intravenous administration of mycophenolate mofetil is also commonly associated with thrombophlebitis and thrombosis. Infrequent adverse effects (0.1% to 1% of patients) include esophagitis, gastritis, GI tract hemorrhage, and/or invasive cytomegalovirus infection. A sequential study comparing the efficacy and toxicity of mycophenolate mofetil and cyclosporine in the treatment of moderate to severe chronic plaque psoriasis showed cyclosporine being more effective, fast, and predictable in its effect than mycophenolate mofetil to control moderate to severe chronic plaque psoriasis41 (Fig. 71-6). Both drugs were well tolerated in short courses of treatment. Patients were treated with oral mycophenolate mofetil (30 mg/kg per day) over a period of 16 weeks. Following a variable washout period and after a new outbreak of the disease, oral cyclosporine was introduced at a dose of 4 mg/kg per day. Sulfasalazine. Sulfasalazine is a sulfa drug, a derivative of mesalazine (5-aminosalicylic acid [5-ASA]), used primarily as an anti-inflammatory agent in the treatment of inflammatory bowel disease as well as for rheumatoid arthritis. Sulfasalazine, and its metabolite 5-ASA, are poorly absorbed. Its main mode of action is therefore believed to be within the intestine. It is significantly less effective than methotrexate. However, sulfasalazine tends to have less serious systemic side effects. Sulfasalazine (Azulfidine) is a second-line treatment for psoriatic arthritis. Sulfasalazine can be used in the treatment of moderate to severe psoriasis in patients whose disease severity does not justify use of methotrexate, etretinate, or PUVA, but whose disease is too wide- http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 994 9/18/2008 12:54:33 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print 995 Chapter 71 Psoriasis PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N AL rate. They were first introduced in the late 1950s by the German chemist Schweckendiek. Dimethylfumarate, the main ingredient of the marketed mixture, is the active compound. Currently, FAE (Fumaderm) is only available for use in Europe and is undergoing clinical trials in the United States. Although the mode of action of FAEs in the treatment of psoriasis is not fully understood, they seem to shift a Th1-type cytokine response to a T helper type 2 (Th2)-type pattern whereby IL-10 inhibits Th1 cytokines IL-2, IL-12, and IFN-g, and act by inhibiting translocation of nuclear factor-kB (NF-kB) and inhibiting proliferation of keratinocytes. It has been demonstrated that the nuclear translocation of the activated transcription factor NF-kB is inhibited in human endothelial cells and fibroblasts activated with TNF-a. The NF-kB pathway plays a major role in regulating inflammatory cytokine production as well as in cell differentiation and apoptosis. The influence of FAEs on the expression of nuclear transcription factors in T cells has not yet been investigated.43 Patients tolerating the therapy can expect a 75% reduction in PASI in 4 months. FAEs are being used in combination with second-line drugs such as cyclosporine, methotrexate, and hydroxyurea for additional benefit or to facilitate dose reduction of the second-line agent. However, all studies of the mixture of esters have a high dropout rate due to GI complaints of diarrhea and stomach pain and complaints of flushing, which is worse at the onset of therapy and can occur in up to 60% of patients. Headaches may be associated with sudden flushing. The frequency of flushing is greatest at the onset of therapy and decreases with prolonged treatment time. Laboratory monitoring is required monthly particularly for lymphopenia, transient eosinophilia, and lymphocytopenia. Liver enzymes are frequently raised and reverse on stopping therapy, and there is an increase in triglycerides, cholesterol, potassium, and serum creatinine; however, there is no evidence of significant nephrotoxicity as seen with cyclosporine. It is important to emphasise the difference between fumaric acid and FAEs. Fumaric acid formulations are available as health supplements and often marketed as a natural alternative medicine to treat psoriasis. They are, in fact, poorly absorbed and basically excreted via the urine without having any therapeutic effect. Practice: Dermatologic Therapeutics spread for safe and practical use of topical corticosteroids.42 Response to therapy with sulfasalazine is low compared to methotrexate or cyclosporine; typically only 30% to 40% of patients respond. The most common side effect is nausea, but often this can be controlled by a reduction in dose. Sometimes other medications may be needed. Occasionally mouth ulcers, a sore mouth, or loose bowel movements may occur. Certain patients may develop a headache or slight dizziness, but adjusting the dosage may bring things under control. Drug eruptions can develop that may be pruritic, but usually resolve quite quickly once the drug is stopped. Sulfasalazine can in rare cases cause a drop in the numbers of white blood cells, which are needed to fight infection. If the blood count is monitored closely, it is unusual for this to be serious. Sulfasalazine can cause thrombocytopenia, but it is rare for this to actually cause problems. Easy bruising, nosebleeds, or bleeding gums are infrequent side effects. The other potential problem is that sulfasalazine can cause a type of hepatitis. This is most commonly minor and does not cause symptoms. Most often, liver function tests may become slightly elevated, but these soon return to normal if the treatment is stopped. Sulfasalazine may cause a decrease in the sperm count, which may result in temporary infertility. This reverses when the drug is stopped. Temporary infertility may also occur in women. Mercaptopurine and Azathioprine. Mercaptopurine (6mercaptopurine; Purinethol) is an immunosuppressive drug used to treat leukemia. It is also used for pediatric non-Hodgkin’s lymphoma, polycythemia vera, psoriatic arthritis, and inflammatory bowel disease. Azathioprine (Azasan, Imuran) is a prodrug that is converted in the body to the active metabolites 6-mercaptopurine and 6-thioinosinic acid. Azathioprine acts to inhibit purine synthesis necessary for proliferation of cells, especially leukocytes and lymphocytes. Some of the adverse effects of taking mercaptopurine include diarrhea, nausea, vomiting, loss of appetite, abdominal pain, weakness, skin rash, darkening of the skin, and hair loss. Serious adverse effects include mouth sores, fever, sore throat, easy bruising or bleeding, petechiae (pinpoint red spots on the skin), yellowing of eyes or skin, dark urine, and painful or difficult urination. Unlikely but serious side effects include black or tarry stools, bloody stools, and bloody urine. Mercaptopurine causes myelosuppression, suppressing the production of white blood cells. Weekly blood counts are recommended for patients on mercaptopurine. Caution should be taken when it is used in conjunction with purine analogues such as allopurinol. Patients who exhibit myelosuppression or bone marrow toxicity should be tested for thiopurine methyltransferase (TPMT) enzyme deficiency. Patients with TPMT deficiency are much more likely to develop dangerous myelosuppression. In such patients, it may be possible to continue using mercaptopurine, but at a lower dose. Screening of the TPMT blood level, therefore, is often performed prior to starting mercaptopurine or azathioprine. This drug is traditionally not recommended during pregnancy, but this issue has been debated, and current evidence indicates that pregnant women on mercaptopurine show no increase in fetal abnormalities. However, women receiving mercaptopurine during the first trimester of pregnancy have an increased incidence of abortion. Azathioprine can be used as a second-line agent to treat severe psoriasis and/or psoriatic arthritis if other treatment options have failed. It is usually given at a dosage of 2 to 4 mg/kg per day, with an upper limit of 300 mg/day. Azathioprine is listed as a human carcinogen in the 11th Report on Carcinogens of the U.S. Department of Health and Human Services. The risks involved seem to be related both to the duration and dosage used. People who have previously been treated with an alkylating agent may have an excessive risk of cancers if treated with azathioprine. It is used mostly in patients requiring transplantation. Those patients with increased risk of malignancies, especially nonmelanoma skin cancers, may have further increased risk with azathioprine. Fumaric Acid Esters. Fumaric acid esters (FAEs) are marketed in some European countries and constitute a mixture of dimethylfumarate, calcium, magnesium, and zinc salts of monoethyl hydrogen fuma- Biologics Biologics include a wide range of medicinal products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins (Fig. 71-7). Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living components such Metalloproteinase induction M-, GM-CSF induction Interleukin-1, 6 induction Vascular adhesion molecule induction Acute phase response Tumor necrosis factor α Weight loss Fever Macrophage activation Figure 71-7 • TNF-a actions. http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 995 9/18/2008 12:54:34 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print Section 16 Dermatologic Therapeutics multiple sclerosis, and new onset or exacerbation of seizure disorders. A variable percentage of patients receiving infliximab developed low- to higher titer antibodies with potential importance for the clinical efficiency of the drug. Neutralizing antibodies may affect the activity and doses required for achieving and maintaining clinical responses. Many fewer reports of antibodies have been reported for etanercept and the other biologics. Long-term immune effects have begun to be investigated in more detail, especially for infliximab, Rarely, development of a lupus-like syndrome and other autoimmune disorders have been reported for anti-TNF agents. Treatment should be discontinued if symptoms of lupus-like syndrome develop. It may be desirable to monitor liver function studies in patients at high risk to develop liver toxicity. Postmarketing reports revealed asymptomatic increases in transaminases, fatty liver degeneration, decompensation of preexisting liver cirrhosis, and acute treatmentrelated liver failure. It is not known if some or all of these manifestations are attributable to alefacept therapy, but it is recommended to discontinue therapy as soon as any sign of liver toxicity develops. Etanercept. Etanercept (Enbrel) is a recombinant human soluble TNF-a receptor fusion protein. It is a large molecule, with a molecular weight of 150 kDa, that binds to TNF-a and decreases its activity in disorders involving excess inflammation in humans and other animals, including autoimmune diseases such as ankylosing spondylitis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and, potentially, a variety of other disorders mediated by excess TNF-a. This therapeutic potential is based on the fact that TNFa is one of the “master regulators” of the inflammatory response in many organ systems. Etanercept is a dimeric molecule, and this dimeric structure is necessary for its proper therapeutic activity. It is made from the combination of two naturally occurring soluble human 75-kDa TNF receptors linked to an Fc portion of immunoglobulin G (IgG)1. The effect is an artificially engineered dimeric fusion protein. Etanercept mimics the inhibitory effects of naturally occurring soluble TNF receptors, the difference being that etanercept, because it is a fusion protein rather than a simple TNF receptor, has a greatly extended half-life in the bloodstream, and therefore a more profound and long-lasting biologic effect than a naturally occurring soluble TNF receptor. Enbrel is marketed as a lyophylized powder in 25-mg vials that must be reconstituted with a diluent and then injected subcutaneously, typically by the patient at home. (It cannot be administered orally, because the digestive system would destroy the drug.) Because patients with arthritis found the reconstitution procedure difficult, Enbrel was made available as prefilled 50-mg/ml syringes in late 2004, and a singleuse 50-mg autoinjector “pen” was brought to market in mid-2006. the FDA-approved dose is 25 mg twice weekly or 50 mg once weekly. Enbrel is an approved treatment for rheumatoid arthritis, polyarticular-course juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and chronic moderate to severe plaque psoriasis. It has shown to be effective in about 50% of psoriatic arthritis patients who used it. Clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through 6 months of therapy. Enbrel is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. One of the major side effects was injection site reaction. A multicenter 24-week study with 583 patients with stable plaque psoriasis involving at least 10% of BSA has been reported. During the first 12 weeks of the study, patients were randomly assigned to receive by subcutaneous injection etanercept twice weekly (BIW) at a dose of 50 mg or 25 mg, or placebo BIW in a double-blind fashion. During the second 12 weeks, all patients received etanercept 25 mg BIW. At week 12, a PASI 75 was achieved by 49% of patients in the etanercept 50 mg BIW group, 34% in the 25 mg BIW group, and 3% in the placebo group. At week 24 (after 12 weeks of open-label 25 mg etanercept BIW), a PASI 75 was achieved by 54% of patients whose dose was reduced from 50 mg BIW to 25 mg BIW, by 45% of patients in the continuous 25 mg BIW group, and by 28% in the group that received AL as cells and tissues. Biologics are isolated from a variety of natural sources—human, animal, and microorganism—and may be produced by biotechnological methods and other advanced technologies. The current biologics manufactured by recombinant DNA technology, and approved or available for use in the treatment of psoriasis, are adalimumab, alefacept, efalizumab, etanercept, and infliximab. Infliximab and adalimumab are in the subclass of “anti-TNF antibodies,” and are capable of neutralizing all forms (extracellular, transmembrane, and receptor-bound) of TNF-a. Etanercept, a third TNF antagonist, is in a different subclass (receptor-construct fusion protein), and, because of its modified form, cannot neutralize receptor-bound TNFa. Additionally, the anti-TNF antibodies infliximab and adalimumab have the capability of lysing cells involved in the inflammatory process, whereas etanercept apparently lacks this capability. Although the clinical significance of these differences have not been firmly established, they may account for the differential actions of these drugs in both efficacy and side effects. Various common side effects such as pharyngitis, cough, dizziness, nausea, pruritus, myalgias, chills, and reactions at injection sites were observed quite frequently. Urticaria and angioedema were also observed. If an anaphylactic reaction should occur, symptomatic treatment should be initiated at once. Since these biologics share many side effects and cautions in their use, common or general observations regarding these agents are reviewed and summarized together here. In clinical studies, 0.9% of patients experienced significant infections compared to 0.2% in the placebo group. Among the infections were more serious events such as sepsis, pneumonia, abscesses, wound infections, and toxic shock syndrome. Many of these infections occurred in patients predisposed to infections because of concomitant immunosuppressive therapy in addition to their underlying disease. Caution should be taken in patients with a history of recurrent infection or with underlying conditions that may predispose patients to infections, or patients who have resided in regions where tuberculosis and histoplasmosis are endemic. Serious infections were seen in studies with concurrent use of anakinra and another TNF-blocking agent; therefore, the combination of biologics and anakinra is not recommended. Patients currently undergoing immunosuppressive therapy should not receive biologics in order to avoid the risks of excessive immunosuppression. The efficacy of concomitant application of live vaccines has not been fully examined yet. However, the effect of tetanus toxoid was well preserved in selected clinical trials where tested. CD4+ cell counts should be obtained before initiation of therapy and during the course of therapy in intervals of 2 weeks for alefacept. Most common in clinical trials was a significant and dose-related reduction of CD4+ and CD8+ counts, again for alefacept versus the other biologics. Consequences of lymphopenia may be infections and/or treatment-related malignancies. Most malignancies observed in patients receiving these biologics were nonmelanoma and melanoma skin cancers, other solid tumors, and lymphomas. The malignancies other than lymphoma and nonmelanoma skin cancer were similar in type and number to what would be expected in the general population. Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF-blocking agents. Use of TNF blockers may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases have been fatal. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF-blocker therapy. There appears to be relatively more safety of the TNF blockers in patients with concurrent hepatitis C and psoriasis. They may worsen the clinical course of human immunodeficiency virus (HIV) infections. All these biologics are therefore contraindicated in patients with HIV infections. Worsening congestive heart failure (CHF) has been observed with TNF-blocking agents, and new-onset CHF has been reported with TNF-blocking agents. TNF-blocking agents have also been associated in rare cases with new onset or exacerbation of demyelinating disease (some cases presenting with mental status changes and some associated with permanent disability), transverse myelitis, optic neuritis, PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N Practice: Dermatologic Therapeutics 996 http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 996 9/18/2008 12:54:34 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print Chapter 71 Psoriasis Natural killer cell Fcγ III Receptor Alefacept 997 Tumor necrosis factor Etanercept Infliximab Adalimumab Ustekinumab CD-2 CD-2 T cell LFA-1 LFA-3 Alefacept Antigen-presenting cell Efalizumab ICAM-1 rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and Crohn’s disease, and data have been submitted to the FDA for expanding the label to include the treatment of plaque psoriasis. Humira is marketed in both preloaded 0.8-ml syringes and also in preloaded pen devices, both injected subcutaneously, typically by the patient at home. It cannot be administered orally, as the digestive system destroys the protein. The most frequent adverse effects versus placebo from rheumatoid arthritis placebo-controlled studies were injection site reactions (20% vs. 14%), upper respiratory infection (17% vs. 13%), injection site pain (12% vs. 12%), headache (12% vs. 8%), rash (12% vs. 6%), and sinusitis (11% vs. 9%). Discontin uations due to adverse events were 7% for Humira versus 4% for placebo. A clinical trial of 147 patients with moderate to severe psoriasis received adalimumab 80 mg at week 0, followed by 40 mg every other week; or 80 mg at weeks 0 and 1, followed by 40 mg/wk; or placebo. The number of patients achieving PASI 75 at week 12 was 53%, 80%, and 4%, respectively. The responses were maintained for 60 weeks.46 Alefacept. Alefacept is a genetically engineered immunosuppressive drug that seems to inhibit the activation of CD2+, CD4+, and CD8+ T cells, which stimulate hyperproliferation of keratinocytes resulting in the typical psoriatic symptoms. It is a fusion protein composed of the external domain of LFA-3 and a human IgG1 Fc region. It eliminates pathogenic T cells by binding to NK cells; it also blocks T-cell activation. Alefacept (Amevive) is the first biologic approved by the FDA for the treatment of moderate to severe chronic plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. The standard dosing regimen is the weekly application of either 7.5 mg intravenously or 15 mg intramuscularly for a course of 12 weeks. The drug was approved based upon studies involving 1869 patients with plaques covering at least 10% of BSA. Either 7.5 mg intravenously or 15 mg intramuscularly once a week was administered. The long-term results (reduction of at least 75% in pretreatment PASI scores) were 14% and 21%, respectively. Additional improvements ensuing after completion of the 12-week treatment phase or after completion of a second alefacept treatment were also seen. Often the remissions were maintained for 7 to 12 months after end of treatment. Commonly observed side effects with Amevive include sore throat, dizziness, cough, nausea, itching, muscle aches, chills, injection site reactions, and accidental injury. Alefacept has been assigned to Pregnancy Category B in the United States and to Category C in Australia. It is not known if the drug is excreted into human milk. Either the drug or breast-feeding should be terminated, taking into account the importance of treatment to the mother. An international, randomized, double-blind, placebo-controlled, parallel-group trial with 507 patients with chronic plaque psoriasis PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N placebo followed by etanercept 25 mg BIW. Etanercept was well tolerated throughout the study.44 Infliximab. Infliximab is known as a chimeric monoclonal antibody. Infliximab neutralizes the biologic activity of TNF-a by binding with high affinity to the soluble and transmembrane forms of TNF-a and inhibits or prevents the effective binding of TNF-a with its receptors. Infliximab has high specificity for TNF-a, and does not neutralize TNF-b (also called lymphotoxin a), a related but less inflammatory cytokine that utilizes the same receptors as TNF-a. Biologic activities that are attributed to TNF-a (Fig. 71-8) include induction of proinflammatory cytokines such as IL-1 and IL-6, enhancement of leukocyte movement or migration from the blood vessels into the tissues by increasing the permeability of endothelial layer of blood vessels, and increasing the release of adhesion molecules. Infliximab prevents disease in transgenic mice (a special type of mice that are biologically engineered to produce a human form of TNF-a and that are used to test the results of these drugs that might be expected in humans). These experimental mice develop arthritis as a result of their production of human TNF-a, and, when administered after disease onset, infliximab allows eroded joints to heal. Infliximab (Remicade) has been approved by the FDA for the treatment of psoriasis, pediatric and adult Crohn’s disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. Remicade is administered by intravenous infusion at infusion centers established within a clinic or hospital. (It cannot be administered orally, because the digestive system would destroy the drug.) It is administered typically every 6 to 8 weeks, with an initial start-up period requiring smaller time frames between infusions. In psoriasis and psoriatic arthritis, the dose is typically initiated at 5 mg/kg. A Phase III multicenter, double-blind trial was conducted in which 378 patients with moderate to severe plaque psoriasis were allocated in a 4 : 1 ratio to receive infusions of either infliximab 5 mg/kg or placebo at weeks 0, 2, and 6, then every 8 weeks to week 46. At week 24, placebo-treated patients crossed over to infliximab treatment. At week 10, 80% of patients treated with infliximab achieved PASI 75 and 57% achieved at least PASI 90, compared with 3% and 1% in the placebo group, respectively. At week 50, 61% achieved PASI 75 and 45% achieved PASI 90 in the infliximab group. Infliximab was generally well tolerated in most patients.45 Adalimumab. Adalimumab (Humira) is the third TNF antagonist (after infliximab and etanercept) to be approved in the United States. Adalimumab was constructed from a fully human monoclonal antibody, while infliximab is a mouse-human chimeric antibody and etanercept is a TNF receptor–IgG fusion protein. Like infliximab and etanercept, adalimumab binds to TNF-a, preventing it from activating TNF receptors. TNF-a inactivation has proven to be important in down-regulating the inflammatory reactions associated with autoimmune diseases. Adalimumab has been approved for the treatment of AL Figure 71-8 • Mechanisms of action for different biologics. Practice: Dermatologic Therapeutics Endothelial cell http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 997 9/18/2008 12:54:34 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print Section 16 Dermatologic Therapeutics also received an additional dose at week 16 if they did not achieve an excellent or complete response (75% clearing) as measured by the standard Physician’s Global Assessment (PGA). Subjects in the placebo group also received 100 mg of CNTO 1275 at week 20. At week 12, more than 75% improvement in PASI score was achieved by 52%, 59%, 67%, and 81% of subjects treated with 50 mg, 100 mg, for weekly 50-mg injections, or four weekly 100-mg injections of CNTO 1275, respectively. This compared to 2% of placebo subjects, the researchers reported. There was also at least a 90% improvement in PASI score, or virtual clearing of disease, in 23%, 30%, 44%, and 52% of subjects in the respective CNTO 1275 groups, versus 2% of placebo. Only 87 patients were re-treated with CNTO 1275 at week 16. No uncommon adverse events were reported during treatment in any of the CNTO 1275 groups. Laser Excimer Laser. An excimer laser is a form of UV chemical laser that is commonly used in eye surgery and semiconductor manufacturing. The excimer laser delivers high-energy monochromatic UVB at 308 nm. An excimer laser typically uses a combination of an inert gas (argon, krypton, or xenon) and a reactive gas (fluorine or chlorine). Under the appropriate conditions of electrical stimulation, a pseudomolecule called a dimer is created, which can only exist in an energized state and can give rise to laser light in the UV range. The UV light from an excimer laser is well absorbed by biologic matter and organic compounds. Rather than burning or cutting material, the excimer laser adds enough energy to disrupt the molecular bonds of the surface tissue, which effectively disintegrates into the air in a tightly controlled manner through ablation rather than burning. Thus excimer lasers have the useful property of being able to remove exceptionally fine layers of surface material or interact with and target cells within tissues with almost no heating or change to the remainder of the material, which is left intact. Pulsed Dye Laser. A dye laser is a laser that uses an organic dye as the lasing medium, usually as a liquid solution. Compared to gases and most solid-state lasing media, a dye can usually be used for a much wider range of wavelengths. The wide bandwidth makes dyes particularly suitable for tunable lasers and pulsed lasers. Moreover, one dye can be replaced by another in order to generate different wavelengths with the same laser, although this usually requires replacing other optical components in the laser as well. Taibjee et al. conducted a prospective trial comparing excimer and pulsed dye lasers in the treatment of psoriasis.49 Twenty-two adult patients with a mean PASI of 7.1 were recruited. Fifteen patients completed the full treatment, of which 13 were followed up to 1 year. Two selected plaques were treated, one with an excimer laser twice weekly and the other with V Beam pulsed dye laser (PDL), following pretreatment with salicylic acid, every 4 weeks. Two additional plaques, treated with salicylic acid alone or untreated, served as controls. The mean improvement in PASI was 4.7 with excimer laser and 2.7 with PDL. PASI improvement was significantly greater in excimer laser than PDL or both control plaques. Thirteen patients responded best with excimer laser, two patients best with PDL, and in seven patients there was no difference between the two lasers. Nine patients (41%) cleared with excimer laser, after a mean 8.7 weeks (median 10 weeks) of treatment. Seven of these nine patients were followed up to 1 year; four remained clear, two relapsed at 1 month, and one relapsed at 6 months. Six patients (27%) cleared with PDL, after a mean 3.3 (median 4) treatments. All six patients were followed up to 1 year; four remained clear, one relapsed at 4 months, and one relapsed at 9 months. Despite common side effects including blistering and hyperpigmentation, patient satisfaction was high.49 PDL requires fewer treatments and has fewer side effects; in addition, it might be useful in excimer laser–resistant cases as some of these patients did not respond to the excimer laser but did respond to the PDL. The two systems target different parts of the psoriasis pathway, with the PDL targeting the abnormal microvasculature of psoriatic plaques versus the excimer laser, which targets the immuneinflammatory cells within the lesions. AL was conducted. Placebo, 10 mg of alefacept, or 15 mg of alefacept was administered once weekly for 12 weeks, followed by 12 weeks of observation. Throughout the study, a greater percentage of patients in the 15-mg group than in the placebo group achieved a significant reduction in PASI. Of patients in the 15-mg group who achieved at least 75% PASI reduction 2 weeks after the last dose, 71% maintained at least 50% improvement in PASI throughout the 12-week follow-up.47 Efalizumab. Efalizumab is a recombinant humanized monoclonal antibody that binds to CD11a of LFA-1 and acts as an immunosuppressant. It blocks T-cell activation and reactivation, also blocking Tcell trafficking into dermis and epidermis. It is the only biologic that is a targeted, reversible T-cell modulator. It does not bind TNF or induce T-cell apoptosis. Efalizumab (Raptiva) is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. The recommended dose of Raptiva is 1 mg/kg by subcutaneous injection once weekly, following an initial conditioning dose of 0.7 mg/kg. The maximum dose should not exceed a total of 200 mg. In Raptiva clinical trials, there were no signals for demyelinating disorders or for new-onset or exacerbated CHF, no pancytopenia or aplastic anemia was observed, and there was a low incidence of granulomatous infections such as tuberculosis, histoplasmosis, or Listeria. Reports of immune-mediated hemolytic anemia, some serious, diagnosed 4 to 6 months after the start of Raptiva treatment have been received. Raptiva should be discontinued if hemolytic anemia occurs. The most common adverse reactions associated with Raptiva were a symptom complex that included headache, chills, fever, nausea, and myalgia within 48 hours following the first two injections. These events were largely mild to moderate when a conditioning dose of 0.7 mg/kg was given, and by the third dose acute adverse affects were no different than placebo. Less than 1% of patients discontinued Raptiva treatment because of these adverse events. Worsening of psoriasis can occur during or after treatment with Raptiva. During clinical studies, 19 of 2589 Raptiva-treated patients (0.7%) had serious worsening of psoriasis during treatment (n = 5, 0.2%) or after discontinuation of Raptiva (n = 14, 0.5%). Some patients required hospitalization (n = 17, 0.7%). Infrequent new-onset or recurrent severe arthritis events, including psoriatic arthritis events, have been reported in clinical trials and postmarketing. Infrequent cases (0.3%) of immune-mediated thrombocytopenia were observed during clinical trials, and reports of severe thrombocytopenia have been received postmarketing; therefore, platelet monitoring is recommended. A multinational, randomized, double-blind, placebo-controlled, parallel-group trial was designed to evaluate the safety and efficacy of subcutaneous efalizumab 1.0 mg/kg once weekly for 12 weeks compared with placebo. Patients with moderate to severe plaque psoriasis were randomized in a 2 : 1 ratio to receive efalizumab or placebo. A total of 793 patients were enrolled (529 received efalizumab and 264 placebo), including 526 high-need patients (342 received efalizumab and 184 placebo). At week 12, PASI 75 rates were 29.5% for efalizumab compared with 2.7% for placebo among high-need patients and 31.4% for efalizumab compared with 4.2% for placebo in the full study population.48 CNTO 1275. CNTO 1275 (Ustekinumab) is an antagonist to interleukins 12 and 23, two key cytokines known to be involved in type 1 immune responses. The Biologics License Application (BLA) for ustekinumab (CNTO 1275) has been accepted for review by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with chronic moderate to severe plaque psoriasis. The study performed by Centocor was a 52-week, double-blind and placebo-controlled trial. The investigators enrolled 320 patients and randomized them to placebo or one of four doses of CNTO 1275 administered subcutaneously: one injection of 50 mg; one injection of 100 mg; four weekly injections of 50 mg; four weekly 100-mg injections. Each of the five groups had 64 subjects. CNTO 1275 subjects PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N Practice: Dermatologic Therapeutics 998 http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 998 9/18/2008 12:54:34 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print 999 Chapter 71 Psoriasis Therapeutic Approaches Mild Psoriasis PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N AL Most patients with psoriasis have skin lesions limited to localized areas such as the elbows or knees, affecting less than 2% of BSA. For these patients, topical therapy may remain part of their therapeutic regimen increasing toxicity Systemic biologics cyclosporine methotrexate Photo retinoids PUVA Practice: Dermatologic Therapeutics There can be substantial variation between individuals in the effectiveness of specific psoriasis treatments. Because of this, dermatologists often resort to an empirical or trial-and-error approach to finding the most appropriate treatment for their patients with psoriasis. The decision to employ a particular treatment is based on the type of psoriasis and its location, extent, and severity. The patient’s age, gender, quality of life, comorbidities, and attitude toward risks associated with the treatment are also taken into consideration, as well as availability of the therapy at specific sites and accessibility of the patient to return for ongoing therapies. Medications with the least potential for adverse reactions are preferentially employed. If the treatment goal is not achieved, then therapies with greater potential toxicity may be used. Medications with significant toxicity are reserved for severe, unresponsive psoriasis. This is called the psoriasis treatment ladder (Fig. 71-9). In the first step, medicated ointments or creams are applied to the skin (Table 71-2). If topical treatment fails to achieve the desired goal, then the next step would be to expose the skin to UV radiation. The third step involves the use of medications that are administered orally or by injection (Table 71-3). An alternative algorithmic approach to psoriasis therapy has been developed by the National Psoriasis Foundation, in conjunction with a panel of dermatology experts. Rather than designing a more linear decision tree or “ladder” approach, therapeutic decisions and initiation of treatment are determined by the extent of psoriasis as well as disease severity based on specific patient criteria (Fig. 71-10). Topical therapeutics are initially employed, and therapeutics are advanced to the next levels of phototherapy or systemics, including biologics, based on these patient characteristics and relative toxicities of agents. This has been a widely adopted algorithmic approach and continues to undergo revisions and updating as newer agents become available and more clinical experience and safety data on newer agents are reported and assimilated. UVB Topical corticosteriods calcipotriene anthralin coal tar Figure 71-9 • Psoriasis treatment ladder. increasing effectiveness TABLE 71-2 TOPICAL TREATMENTS SIDE EFFECTS Drug Most Common Side Effects Other Side Effects Topical corticosteroids Atrophy, striae, telangiectases, acneiform eruption, rosacea, contact dermatitis, infections. Very rare and only with prolonged use of superpotent corticosteroids, suppression of the HPA axis, growth retardation in children, cataract formation, and glaucoma development Calcipotriene Burning, itching, skin irritation. Hyperpigmentation, hypercalcemia, folliculitis Tazarotene Dry skin, pruritus, redness and in some cases extreme drying and cracking of skin. Tars Mild burning or skin irritation. When used on the scalp, it may temporarily discolor bleached, tinted, or light blond or gray hair. Stains skin and clothing. Anthralin It temporarily stains the skin a yellowy-brown and permanently stains clothing fabrics. Burning sensation and irritation. Salicyclic acid Mild stinging and burning. Potential skin carcinogenicity Solicylism (systemic absortion) HPA, hypothalamic-pituitary-adrenal. http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 999 9/18/2008 12:54:35 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print 1000 Section 16 Dermatologic Therapeutics Drug Most Common Side Effects Other Side Effects Adalimumab Increased risk of tuberculosis reactivation, injection site reaction. Lymphoma, CHF, demyelinating process, lupuslike syndrome, opportunistic infections Efalizumab Rebound effect and flare-up during therapy. Hemolytic anemia, decreased platelets, arthritis Infliximab Increased risk of tuberculosis reactivation, injection site reaction. Lymphoma, CHF, demyelinating process, lupuslike syndrome, opportunistic infections Etanercept Injection site reaction. CHF, demyelinating process, lupus-like syndrome, bone marrow suppresssion, opportunistic infections Alefacept Injection site reaction, CD4+ count to <250 cells/ml. Liver inflammation NB-UVB, 311 nm Phototoxicity. Phototoxicity, photoaging. Cutaneous carcinogenesis Phototoxicity, photoaging. Cutaneous carcinogenesis (less risk than with PUVA alone) Goeckerman regimen Skin irritation, folliculitis, phototoxicity. Acitretin Teratogenicity, liver inflammation, hyperlipidemia, mucous membrane side effects. Osteoporosis, pseudotumor cerebri Methotrexate Teratogenicity, bone marrow suppression, cirrhosis, alopecia, fatigue, GU symptoms. Lymphoma Nephrotoxicity, high blood pressure; increased uric acid, potassium, and magnesium. Paresthesias Drowsiness, nausea and vomiting, diarrhea, constipation, mucositis, anorexia, stomatitis, alopecia, skin changes; abnormal liver enzymes, creatinine, and blood urea nitrogen. Myelosuppression (megaloblastic anemia, thrombocytopenia, or leukopenia) Diarrhea, nausea, vomiting, infections, leukopenia, anemia, fatigue, headache, cough. IV administration can cause thrombophlebitis and thrombosis. Esophagitis, gastritis, gastrointestinal tract hemorrhage, invasive cytomegalovirus infection Nausea, diarrhea, mouth ulcers, headache or slight dizziness, skin rash, bruising. Decreased platelets, liver inflammation, infertility Diarrhea, nausea, vomiting, loss of appetite, abdominal pain, weakness, skin rash, darkening of the skin, alopecia. Myelosuppression Increased liver enzymes, triglycerides, cholesterol, potassium, and serum creatinine. Lymphopenia, transient eosinophilia Skin reactions up to life-threatening forms (StevensJohnson syndrome and toxic epidermal necrolysis), heart problems, alopecia. Hepatitis, liver cirrhosis, myelosuppression, myeloid/lymphatic malignancies, solid cancers, interstitial lung disease, infections Cyclosporine Hydroxyurea Mycophenolate mofetil Sulfasalazine Mercaptopurine Fumaric acid esters Leflunomide AL PUVA RePUVA PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N Practice: Dermatologic Therapeutics TABLE 71-3 systemic TREATMENTS AND PHOTOTHERAPY SIDE EFFECTS CHF, congestive heart failure; GU, genitourinary; IV, intravenous; NB-UVB, narrow-band ultraviolet B; PUVA, psoralen plus ultraviolet A; RePUVA, retinoid plus psoralen plus ultraviolet A. whether or not they require additional treatments for psoriatic arthritis. Patients receiving systemic therapies and/or phototherapy may also require the use of topical treatments.50 Topical therapies may be used in combination, rotational, or sequential treatment strategies for patients with more severe disease. Topical corticosteroids continue to be the cornerstone of mild to moderate psoriasis treatment, despite the introduction of newer nonsteroidal drugs. Topical corticosteroids are effective and provide superior results compared with vitamin D derivatives such as calcipotriene.51 The age of the patient, disease severity, type, and extent of surface area involvement must be considered when deciding which topical corticosteroid to prescribe and in what vehicle. Low-potency corticosteroids are typically used on the face, groin, and axillary areas and areas with thin skin, and in infants.52 In other areas and in adult patients, initial therapy usually involves mid-potency agents, with higher potency corticosteroids used on thick chronic plaques resistant to lower potency agents. Topical corticosteroids are best used to treat psoriasis affecting less than 20% of total BSA.53 There are other topical treatments that can be used depending on the severity of psoriasis, age of the patient, and area affected. Tazarotene is also very effective and can be combined or alternated with topical corticosteroids for higher efficacy. Angelo et al. compared the efficacy of once-daily tazarotene 0.1% cream and clobetasol propionate 0.05% in psoriatic plaques during 12 weeks of treatment.54 Patients with bilaterally symmetric lesions were enrolled in this doubleblind, randomized, controlled study. Clobetasol cream was better than tazarotene cream in reducing the erythema and scaling, and tazarotene was better in reducing the induration. Treatment success rate was 100% with clobetasol and 88% with tazarotene at the end of week 12, with clobetasol achieving 100% success at the end of week 6. Moderate to Severe Psoriasis Moderate (2% to 10% BSA) to severe (>10% BSA) psoriasis patients initially undergo topical treatment in the mildest cases and topical treatment plus phototherapy in cases with higher percentage of BSA affected (Table 71-4). If topical treatments plus phototherapy fail, acitretin can be added to the regimen. If the BSA is greater or the previous treatment fails, the Goeckerman regimen or PUVA plus acitretin is a common treatment of choice. In more severe cases or when previous treatments fail, methotrexate or cyclosporine alone can be started, depending on the comorbidities of the patient; if this treatment fails, a combination with acitretin or biologics can be used. Methotrexate and cyclosporine can also be used in combination with topicals and/or phototherapy. http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 1000 9/18/2008 12:54:35 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print Chapter 71 Psoriasis Treatment Algorithm UVB phototherapy or UVB + adjunct topical tx* ± acitretin (especially if plaque is thick) If patient lives too far away for phototherapy, can go directly to systemic tx 1001 Mild (<2% BSA) Topical tx* If topical tx fails, follow therapy for mild to moderate AL PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N PUVA ± acitretin* Moderate (2%–10% BSA) to Severe (>10% BSA) Biologics, MTX or CsA* ± acitretin† Practice: Dermatologic Therapeutics Goeckerman* Maintenance tx* (sequential or rotational) ± acitretin • Once stable, transition to maintenance tx • If resistant, initiate combination tx Combination therapy* using Systemic + topical tx or Systemic + phototherapy or Systemic + topical + phototherapy 3 *Topical therapy may be added to any regimen. † No currently available biologic tx is approved or available for psoriasis at the time of writing. (Etanercept is approved for psoriatic arthritis.) These algorithms may be updated as more data become available. † Preliminary data suggest that tumor necrosis factor (TNF) inhibitors may be safe and highly effective treatments for plaque psoriasis. Although these and other biologics are not yet approved for psoriasis, they may be considered for patients with severe, resistant disease. BSA = body surface area, tx = therapy, MTX = methotrexate, CsA = cyclosporine A. Figure 71-10 • Psoriatic treatment algorithm. (From National Psoriasis Foundation. Psoriasis: Treatment Options and Patient Management. City: National Psoriasis Foundation, 2002.) Once the treatment has achieved a clearance or improvement of the BSA affected, the patient can initiate a maintenance therapy that can be either rotational or sequential. Rotational therapy minimizes the risk of cumulative toxicity by switching from one therapy to another before the initial agent or more toxic agent can create adverse effects. Sequential therapy is a sequence of specific therapies to maximize the rate of initial improvement, minimize long-term adverse effects, and improve clearance. This therapy entails three phases: a clearing phase using a rapidly acting therapy; a transitional phase once the patient improves, to taper the initial therapy; and a maintenance phase. A recent review of treatments, with the percentage of PASI 75 reduction at approximately 12 weeks, showed the following outcomes: Goeckerman regimen and retinoids plus PUVA (RePUVA), 100%; calcipotriene plus PUVA, 87%; cyclosporine, 78.2% to 80.3%; infliximab, 80%; adalimumab 40 mg every other week, 53%, and 40 mg/week, 80%; PUVA, 63%; methotrexate, 60%; NB-UVB, 55%; acitretin 52%; etanercept 50 mg twice weekly, 49%, and 25 mg twice weekly, 34%; efalizumab, 31.4%; and alefacept, 21% (Fig. 71-11). Psoriatic treatments with safer profiles compared with other agents include bath PUVA, the Goeckerman regimen, and RePUVA. Based on the literature review of efficacy and safety of biologics and prebiologic treatment options for moderate to severe psoriasis, the risk : benefit ratio seems most favorable for the Goeckerman regimen and RePUVA, followed by either etanercept or adalimumab.55 There are other considerations besides the PASI 75. The treatment should be individualized depending on the severity, the areas affected, the age of the patient, and other comorbidities. Infliximab is noted to have the highest PASI 75 among biologics; however, its efficacy decreases over time, in part due to the formation of anti-infliximab antibodies. Efalizumab has shown to have a “rebound” effect in 13.8% of patients. Adalimumab, unlike etanercept, is not expected to need a decrease in dosage after 3 months of therapy, which will give adalimumab better long-term efficacy. Cyclosporine is one of the most effective traditional systemic drugs. The traditional dosage of less than 5 mg/kg per day seems to have an acceptable side effect profile. Cyclosporine is not recommended for long-term use; however, it is highly effective in achieving fast clearing in psoriasis. Methotrexate was the first systemic therapy for patients http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 1001 9/18/2008 12:54:36 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print 1002 Section 16 Dermatologic Therapeutics TABLE 71-4 TREATMENT OF PSORIASIS Severity Treatment Maintenance Therapy MILD PSORIASIS (<2% BSA) Localized Topical Corticosteroids (high potency) + Tazarotene or Calcipotriene Scalp Tar or Ketoconazole shampoo ↓ High-potency Corticosteroid solution or foam ± Calcipotriene solution Topical Corticosteroids (low/medium potency) and/or Tazarotene or Calcipotriene AL Sequential: CsA or MTX ↓ Acitretin ↓ Topicals Phototherapy Rotational: Rotation of different systemic and/or phototherapy treatments to avoid toxicity PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N High-potency Topical Corticosteroids + Tazarotene or Calcipotriene ↓ UVB + Topicals ± Acitretin ↓ Goeckerman regimen ↓ PUVA + Acitretin ↓ MTX, CsA, Biologics ± Acitretin ↓ Combination therapy: • Systemic + Topicals • Systemic + Phototherapy • Systemic + Topicals + Phototherapy BSA, body surface area; CsA, cyclosporin A; MTX, methotrexate; PUVA, psoralen plus ultraviolet A; UVB, ultraviolet B. 100% 100% 80% Pregnancy and Psoriasis Topical corticosteroids and topical calcipotriene as well as topical anthralin and topical tacrolimus appear to be safe choices for control of localized psoriasis in pregnancy. UVB is the safest treatment for extensive psoriasis during pregnancy, particularly when topical application of other agents is not practical. Short-term use of cyclosporine during pregnancy is probably the safest option for management of severe psoriasis that has not responded to topical or UVB treatment.56 UV A PU G VA oe ck er m an ab with moderate to severe psoriasis and is one of the most frequently prescribed treatments nowadays. The treatment of moderate to severe psoriasis in healthy children younger than 18 years old would consist of an initial treatment of UVB; if the treatment with light is not enough, tar, calcipotriene, or tazarotene can be added in combination. If this treatment fails, the Goeckerman regimen can be chosen. PUVA can be considered only in selected cases, and a low-dose retinoid (consider isotretinoin in females) can be added to the treatment. If all these treatments fail or the case is severe, a systemic treatment can be initiated. DP im flix In or in e VA sp clo Cy te xa tre ho et M PU VB ab -U um im al Ad NB in et pt itr Ac ce an (B rs te Es er -1 2) ab G m ep izu ac al ef Ef Al ic Ac id ar Fu m Et 21% 71% 60% 63% 52% 53% 55% 42% 45% 29% 87% re 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% t Practice: Dermatologic Therapeutics MODERATE TO SEVERE (BSA > 2%) Figure 71-11 • PASI 75 of different treatments for moderate to severe psoriasis. Alefacept: 14 weeks, 15 mg/wk.47 Efalizumab: 12 weeks, 1 mg/ wk.48 Fumaric acid esters (BG-12): 12 weeks, 720 mg three times daily.65 Etanercept: 12 weeks, 25 mg twice per week.45 Acitretin: 12 weeks, 0.54 mg/kg per day.66 Adalimumab: 12 weeks, 40 mg every other week.44 NB-UVB: 3 weeks.28 Methotrexate: 16 weeks, 20.6 mg/wk.36 PUVA: 34 days.67 Cyclosporine: 16 weeks, 4.5 mg/kg per day.36 Infliximab: 10 weeks, 5 mg/kg at weeks 0, 2, and 6.46 Calcipotriol-PUVA: 12 weeks.34 RePUVA: 20 mg/day retinoid + PUVA three times per week.68 Goeckerman regimen: 12 weeks, 5 days per week.27 Psoriatic Arthritis The treatments used in psoriatic arthritis are directed at reducing and controlling inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac and naproxen are usually the first-line medication. Other treatment options for this disease include joint injections with corticosteroids; however, this is only practical if just a few joints are affected. If acceptable control is not achieved using NSAIDs or joint injections, then second-line treatments with immunosuppressants such as methotrexate are added to the treatment regimen. An advantage of immunosuppressive treatment is that it also treats the psoriasis in addition to the arthropathy. Some NSAIDs, when taken in high doses or over long periods of time, carry a risk of causing stomach problems, including ulcers and GI bleeding. The risk depends on the strength of the NSAID and how long it is taken. The NSAIDs known as cyclooxygenase-2 (COX-2) inhibitors have proven to be less problematic for the stomach than other NSAIDs. The COX-2 inhibitor Celebrex has been approved for treating the symptoms of rheumatoid arthritis and osteoarthritis. http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 1002 9/18/2008 12:54:36 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print Chapter 71 Psoriasis 80% 71% 70% 60% 54% 59% 59% 50% 39% 40% 30% 23% 20% 10% Figure 71-12 • American College of Rheumatology core criteria (ACR20) of different treatments of psoriatic arthritis. PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N Antimalarial treatment, commonly used with success in rheumatoid arthritis, has sometimes been used to treat psoriatic arthritis. Steroid medications taken orally are not generally recommended for long-term treatment of psoriatic arthritis, although in some circumstances they may be needed for relief of acute, severe joint inflammation and swelling. Cyclosporine is an immunosuppressive drug that is FDA approved for treating psoriasis, and it may produce improvement in psoriatic arthritis. Sulfasalazine is sometimes used for psoriatic arthritis. Approximately one-third of psoriatic arthritis patients respond rapidly to this treatment (usually within 4 to 8 weeks). Biologics. The FDA approved the use of etanercept for patients with moderate to severe psoriatic arthritis in January 2002. Adalimumab was approved by the FDA in October 2005, and infliximab was approved in May 2005. The primary efficacy end point to evaluate the efficacy of treatment was the percentage of patients who met the American College of Rheumatology (ACR) core criteria (ACR20) (Fig. 71-12), 20% improvement in tender and swollen joint counts and 20% improvement in at least three of the following five ACR core set measures: pain, patient global assessment, physician global assessment, self-assessed physical disability, and acute-phase reactant. Etanercept plus methotrexate combination therapy is generally superior to either monotherapy in reducing disease activity and structural joint damage, as well as improving health-related quality of life. Etanercept monotherapy is superior to placebo and at least as effective as methotrexate monotherapy in reducing disease activity and improving health-related quality of life in patients with early or refractory disease.57 In patients with psoriatic arthritis, etanercept 25 mg twice weekly significantly reduced disease activity and improved skin lesions in two double-blind, placebo-controlled, 12- to 24-week trials. In the 24-week study, ACR20 response rates (50% vs. 13%), psoriatic arthritis response rates (70% vs. 23%), and the median improvement in skin lesions (33% vs. 0%) were significantly greater in etanercept than in placebo recipients. Furthermore, etanercept has been shown to inhibit radiographic progression in those patients with early disease.58 Genovese et al. conducted a double-blind, randomized, multicenter study in which patients were treated for 12 weeks with subcutaneous injections of adalimumab 40 mg every other week or placebo.59 Secondary efficacy measures included the modified Psoriatic Arthritis Response Criteria (PsARC) and assessments of disability, psoriatic lesions, and quality of life. A total of 100 patients received a study drug (51 adalimumab, 49 placebo). At week 12, an ACR20 response was achieved by 39% of adalimumab patients versus 16% of placebo patients and a PsARC response was achieved by 51% with adalimumab versus 24% with placebo. No serious infections occurred during adalimumab therapy. Practice: Dermatologic Therapeutics M et ho tre xa te Ad (1 al 4 im we um ek Al ef ab s) ac ( 1 ep 2 t+ we M ek TX s) (2 4 we In ek flix s) im ab Et an (1 er ye Et ce an ar pt ) er (1 ce 2 pt we + ek M TX s) (1 2 we ek s) 0% 1003 Kavanaugh et al. conducted a double-blind, placebo-controlled, Phase III study of 200 patients with active psoriatic arthritis who were randomized to receive infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, and every 8 weeks thereafter through 1 year. Through 1 year of treatment, 58.9% and 61.4% of patients in the randomized infliximab and placebo/infliximab groups, respectively, achieved ACR20; corresponding figures for PASI 75 were 50.0% and 60.3%. At week 54, major clinical response was achieved by 12.1% of patients in the infliximab group.60 To evaluate the efficacy of alefacept in combination with methotrexate (MTX) a randomized, double-blind, placebo-controlled trial was performed by Mease et al.61 Alefacept (15 mg) or placebo was administered intramuscularly once weekly for 12 weeks in combination with MTX, followed by 12 weeks of observation during which only MTX treatment was continued. A total of 185 patients were randomly assigned to receive alefacept plus MTX or placebo plus MTX. At week 24, 54% of patients in the alefacept plus MTX group achieved an ACR20 response, compared with 23% of patients in the placebo plus MTX group. Mean reductions in tender and swollen joint counts in patients receiving alefacept plus MTX were -8.0 and -6.3, respectively. A 50% reduction from the baseline PASI at week 14 was achieved by 53% of patients receiving alefacept plus MTX compared with 17% of those receiving placebo plus MTX. Most adverse events were mild to moderate in severity. Disease-Modifying Antirheumatic Drugs. Disease-modifying antirheumatic drugs (DMARDs) may relieve more severe symptoms and attempt to slow or stop joint and tissue damage and progression of psoriatic arthritis. Leflunomide (Arava) is a pyrimidine synthesis inhibitor belonging to the DMARD class of drugs. It is an immunomodulatory drug inhibiting dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis). Antiproliferative and antiinflammatory activity has been shown. An oral loading dose of 100 mg is followed by a once-daily administration of 10 to 20 mg as determined. The onset of clinical improvement can be expected after 4 to 6 weeks of continued therapy. Aspirin or other NSAIDs and/or low-dose corticosteroids may be continued during treatment with leflunomide. The combined use of leflunomide with antimalarials, intramuscular or oral gold, D penicillamine, azathioprine, or methotrexate has not been adequately studied and is therefore contraindicated. The concomitant use of methotrexate may lead to severe or even fatal liver or hematotoxicity. Important contraindications are preexisting pregnancy, or women of childbearing potential not using reliable contraceptive methods. Finally, women should not become pregnant before 2 years after termination of therapy have elapsed or should undergo a rapid washout procedure. Men wishing to father a child should discontinue leflunomide after consultation with their prescribing physician and also undergo the washout procedure. Due to its potent immunosuppression, leflunomide has the potential to promote myeloid/lymphatic malignancies or solid cancers. In rheumatoid arthritis patients, a several-fold increase of lymphoma is already present in those patients not treated with any DMARD. The most serious side effect is symptomatic liver damage ranging from jaundice to hepatitis, which can be fulminant, severe liver necrosis, and liver cirrhosis. Fatalities have occurred. Abnormal liver function studies may or may not preceede the outbreak of clinical disease. The total incidence of severe liver damage is estimated to be as high as 0.5%, according to an internal report of the FDA. Also very important is a relatively high incidence of myelosuppression with leukopenia, and/or hypoplastic anemia, and/or thrombocytopenia. Infections, sometimes as severe as development of active tuberculosis, pneumonia (including Pneumocystis jiroveci pneumonia), and severe viral or mycotic infections, possibly leading to sepsis, death, or permanent damage, have been seen. Anemia or bleeding episodes may also lead to serious complications. Interstitial lung disease may occasionally be noticed and is recognized by progressive dyspnea and typical radiographic findings. This disease may or may not be reversible upon treatment, and may lead to permanent disability or death. Other adverse effects are skin AL http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 1003 9/18/2008 12:54:36 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print 1004 Section 16 Dermatologic Therapeutics reactions ranging up to life-threatening forms (Stevens-Johnson syndrome and toxic epidermal necrolysis), heart problems, and alopecia (17%). If severe side effects are encountered, leflunomide can be readily removed from the body with oral cholestyramine or activated charcoal to slow or reverse the noted side effects. Elevated type-1 interferon messenger RNA levels have been found in preclinical models of psoriasis, and inhibition of type 1 interferon in these models has been shown to block the development of psoriasis mediated by plasmacytoid dendritic cells. Preclinical study results have also demonstrated that IFN-a–induced genes and proteins are overexpressed in the skin in animal models of psoriasis. Emerging Targets and Therapeutics Essential Fatty Acids (w-3) Apremilast (CC-10004) CC-10004 is a novel, orally available small molecule with antiinflammatory activities that inhibits the production of multiple proinflammatory mediators, including phosphodiesterase-4, TNF-a, IL-2, IFN-g, leukotrienes, and nitric oxide synthase. CC-10004 (Apremilast) is the lead investigational drug in this class of anti-inflammatory compounds, and is being studied in Phase II clinical trials by Celgene Corporation for the treatment of psoriasis and other chronic inflammatory diseases. ABT-874 AL ShK(L5) is a synthetic version of a component of sea anemone venom. PAP-1 is derived from a shrub, the common rue. Both compounds act to block channels that allow potassium ions to flow into or out of cells. These ion channels appear to play an important role in regulating the activity of cells in the immune system and are especially abundant on a type of immune cell implicated in diseases such as multiple sclerosis and psoriasis. In effector memory T cells, Kv1.3 potassium channel traffic moves to the immunologic synapse during antigen presentation, where it colocalizes with Kvb2, SAP97, ZIP, p56(lck), and CD4. Although Kv1.3 inhibitors [ShK(L5) amide (SL5) and PAP1] do not prevent immunologic synapse formation, they suppress Ca2+ signaling, cytokine production, and proliferation of autoantigen-specific T cells at pharmacologically relevant concentrations while sparing other classes of T cells.62 Psoriasis is uncommonly seen in Africans, probably partly due to genetic factors. However, the dietary habits of Africans may provide another explanation. Maize, the staple diet in most parts of Africa, is high in linoleic acid but low in other polyunsaturated fatty acids and riboflavin. Linoleic acid is a precursor of prostaglandin E2, and its high intake, especially in the absence of other polyunsaturated fatty acids and riboflavin, results in high tissue production of prostaglandin E2.63 The w-3 fatty acids are a family of polyunsaturated fatty acids that have in common a carbon-carbon double bond in the w-3 position. Important w-3 fatty acids in nutrition are a-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). The human body cannot synthesize w-3 fatty acids de novo, but can synthesize all the other necessary w-3 fatty acids from the simpler w-3 fatty acid a-linolenic acid. Therefore, a-linolenic acid is an essential nutrient that must be obtained from food, and the other w-3 fatty acids that can be either synthesized from it within the body or obtained from food are sometimes also referred to as essential nutrients. Mayser et al. conducted a double-blind, randomized, parallel group study performed in eight European centers.64 Eighty-three patients hospitalized for chronic plaque-type psoriasis were randomly selected to receive daily infusions with either a w-3 fatty acid–based lipid emulsion (Omegavenous; 200 ml/day with 4.2 g of both EPA and DHA; 43 patients) or a conventional w-6 lipid emulsion (Lipovenous; EPA + DHA < 0.1 g/100 ml; 40 patients). The total PASI score decreased by 11.2 ± 9.8 in the w-3 group and by 7.5 ± 8.8 in the w-6 group. In addition, the w-3 group was superior to the w-6 group with respect to change in severity of psoriasis per body area, change in overall erythema, overall scaling, and overall infiltration, as well as change in overall assessment by the investigator and self-assessment by the patient. Thirty-seven percent of patients receiving the w-3 emulsion and 23% of those receiving the w-6 emulsion had a decrease in total PASI of at least 50% between admission and last value. No major side effects were observed. PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N Practice: Dermatologic Therapeutics ShK(L5) and PAP-1 Abbott Laboratories reported significant results in Phase II testing for its experimental biologic currently known as ABT-874. ABT-874 is a fully human monoclonal antibody designed to target and neutralize IL-12 and IL-23, two proteins associated with inflammation in psoriasis and other autoimmune disorders. It reduced psoriasis symptoms significantly in the majority of patients treated. One hundred eighty patients with moderate to severe psoriasis were enrolled in a 12-week, double-blind, placebo-controlled study. Patients were randomized evenly to six treatment groups: a single, subcutaneous 200-mg injection of ABT-874 at week zero; 100 mg every other week for 12 weeks; 200 mg weekly for 4 weeks; 200 mg every other week for 12 weeks; 200 mg weekly for 12 weeks; or placebo. The primary end point was the proportion of patients achieving 75% improvement in the degree and severity of skin lesions after 12 weeks, as measured by the PASI. At 12 weeks, 90% of patients achieved 75% improvement in psoriasis signs and symptoms in four of the five dosing groups receiving ABT-874, versus 3% of patients receiving placebo. Also, more than half of patients achieved 90% improvement, in the same four of five ABT-874 dosing groups, versus 0% of those receiving placebo. ABT-874 represents a novel approach to treating psoriasis, targeting a part of the inflammatory response that is not addressed by any therapy available today. The most common adverse events observed were injection site reactions, nasopharyngitis, upper respiratory infections, and headache. MEDI-545 MedImmune has initiated a Phase I trial with its monoclonal antibody targeting IFN-a, known as MEDI-545, in patients with psoriasis. The psoriasis treatment trial marks a second clinical study underway with MEDI-545, which is also being evaluated in an ongoing Phase I trial in patients with systemic lupus erythematosus. REFERENCES 1. Lomholt G. Prevalence of skin disease in a population: a census study from the Faroe Islands. Dan Med Bull 1964;11:1-7. 2. Green AC. Australian Aborigines and psoriasis. Australas J Dermatol 1984;25:18-24. 3. Convit J. Investigation of the incidence of psoriasis amongst Latin-American Indians. In Proceedings of 13th Congress on Dermatology. Amsterdam: Excerpta Medica, 1962, p 196. 4. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. 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Apoptosis in proliferating, senescent, and immortalized keratinocytes. J Biol Chem 1999;274:23358-23367. 13. Victor FC, Gottlieb AB. TNF-alpha and apoptosis: implications for the pathogenesis and treatment of psoriasis. J Drugs Dermatol 2002;1:264-275. 14. Goffe B, Cather JC. Etanercept: an overview. J Am Acad Dermatol 2003;49:S105S111. 15. Bowcock AM, Krueger JG. Getting under the skin: the immunogenetics of psoriasis. Nature Rev Immunol 2005;5:699-711. 16. Liu Y, Krueger JG, Bowcock AM. Psoriasis: genetic associations and immune system changes. Genes Immun 2007;8:1-12. http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 1004 9/18/2008 12:54:37 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print Chapter 71 Psoriasis 1005 45. Reich K, Nestle FO, Papp K, et al, for the EXPRESS study investigators. 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A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nature Genet 2003;35:349-356. 18. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature 2007;445:866-873. 19. Langley RG, Krueger GG, Griffiths CE. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis 2005;64(Suppl 2):ii18-ii23; discussion ii24-ii5. 20. O’Doherty CJ, MacIntyre C. Palmoplantar pustulosis and smoking. Br Med J (Clin Res Ed) 1985;289:861-864. 21. Asumalahti K, Ameen M, Suomela S, et al. Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis. J Invest Dermatol 2003;120:627-632. 22. Callis KP, Krueger GG. Topical agents in the treatment of moderate-to-severe psoriasis. In Weinstein GD, Gottlieb AB (eds): Therapy of Moderate-to-Severe Psoriasis, 2nd ed. New York: Marcel Dekker, 2003, pp 29-51. 23. Trozak DJ. Topical corticosteroid therapy in psoriasis vulgaris. Cutis 1990;46:341350. 24. Du Vivier A, Stoughton RB. Tachyphylaxis to the action of topically applied corticosteroids. Arch Dermatol 1975;111:581-583. 25. Foster RH, Brogden RN, Benfield P. Tazarotene. Drugs 1998;55:705-711. 26. Dando TM, Wellington K. Topical tazarotene: a review of its use in the treatment of plaque psoriasis. Am J Clin Dermatol 2005;6:255-272. 27. Lee E, Koo J. Modern modified “ultra” Goeckerman therapy: a PASI assessment of a very effective therapy for psoriasis resistant to both prebiologic and biologic therapies. J Dermatolog Treat 2005;16:102-107. 28. Liu J, Farmer J, Lane W, et al. Calcineurin is a common target of cyclophilincyclosporin A and FKBP-FK506 complexes. Cell 1991;66:807-815. 29. The European FK506 Multicentre Psoriasis Study Group. Systemic tacrolimus (FK506) for the treatment of psoriasis in a double-blind, placebo-controlled study Arch Dermatol 1996;132:419-423. 30. Hofer A, Fink-Puches R, Kerl H, Wolf P. Comparison of phototherapy with near vs. far erythemogenic doses of narrow-band ultraviolet B in patients with psoriasis. Br J Dermatol 1998;138:96-100. 31. Kirke SM, Lowder S, Lloyd JJ, et al. A randomized comparison of selective broadband UVB and narrowband UVB in the treatment of psoriasis. J Invest Dermatol 2007;127:1641-1646. 32. Coven TR, Walters IB, Cardinael I, Krueger JG. PUVA-induced lymphocyte apoptosis: mechanism of action in psoriasis. Photodermatol Photoimmunol Photomed 1999;15:22-27. 33. Nijsten TE, Stern RS. Oral retinoid use reduces cutaneous squamous cell carcinoma risk in patients with psoriasis treated with psoralen-UVA: a nested cohort study. J Am Acad Dermatol 2003;49:644-650. 34. Lebwohl M, Drake L, Menter A, et al. Consensus conference: acitretin in combination with UVB or PUVA in the treatment of psoriasis. J Am Acad Dermatol 2001;45:544553. 35. Zanolli M. Phototherapy arsenal in the treatment of psoriasis. Dermatol Clin 2004;397406. 36. Torras H, Aliaga A, López-Estebaranz JL, et al. A combination therapy of calcipotriol cream and PUVA reduces the UVA dose and improves the response of psoriasis vulgaris. J Dermatolog Treat 2004;15:98-103. 37. Johnston A, Gudjonsson JE, Sigmundsdottir H, et al. The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin Immunol 2005;14:154-163. 38. Heydendael VM, Spuls PI, Opmeer BC, et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med 2003;349:658-665. 39. Sauer GC. Combined methotrexate and hydroxyurea therapy for psoriasis. Arch Dermatol 1973;107:369-370. 40. Gach JE, Berth-Jones J. Successful treatment of recalcitrant psoriasis with a combination of infliximab and hydroxyurea. J Dermatolog Treat 2003;14:226-228. 41. Pedraz J, Daudén E, Delgado-Jiménez Y, et al. Sequential study on the treatment of moderate-to-severe chronic plaque psoriasis with mycophenolate mofetil and cyclosporin. J Eur Acad Dermatol Venereol 2006;20:702-706. 42. Gupta AK, Ellis CN, Siegel MT, et al. Sulfasalazine improves psoriasis: a double-blind analysis. Arch Dermatol 1990;126:487-493. 43. Gerdes S, Shakery K, Mrowietz U. Dimethylfumarate inhibits nuclear binding of nuclear factor kappaB but not of nuclear factor of activated T cells and CCAAT/ enhancer binding protein beta in activated human T cells. Br J Dermatol 2007;156:838842. 44. Papp KA, Tyring S, Lahfa M, et al, for the Etanercept Psoriasis Study Group. A global Phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol 2005;152:1304-1312. AL http://www.us.elsevierhealth.com/product.jsp?isbn=9781416032915 Ch071-X3291.indd 1005 9/18/2008 12:54:37 PM Pharmacology and Therapeutics - Principles to Practice, Expert Consult - Online and Print Author query form Dear Author: During the preparation of your manuscript for publication, the questions listed below have arisen. Please attend to these matters and return this form with your proof. Many thanks for your assistance. Query References Query Remarks AU: Per book style, all figures and tables are cited in the text. Please check inserted citations for appropriateness of location. Note: Some figures and tables may have been renumbered for citation purposes. 2. AU: References have been cited out of order beyond ref. 4, and have been renumbered. Original reference 14 was not cited; please cite, using 00a format to avoid renumbering. 3. AU: Please provide location for foundation. PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N AL 1. 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