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PSORIASIS
Mark Pittlekow and Joseph Genebriera
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
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
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
INTRODUCTION
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 approxi-mately 2% to 3% of various genetically susceptible populations around the world and varies in severity from minor, localized lesions to com-plete 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 condi-tion, 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 skin-directed, 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 adminis-tered 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 dimin-ish 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 treat-ment 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 begin-ning 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 epi-dermal regulation of the abnormal hyperproliferation and differentia-tion of skin that typify various forms of psoriasis.
EPIDEMIOLOGY
The prevalence of psoriasis varies considerable among world popula-tions 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 popu-lation to be affected. Prevalence of psoriasis is low in certain ethnic groups such as the Japanese, and may be virtually absent in aboriginal 1
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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
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 pso-riasis have identified several risk loci for the disease, but the strongest risk allele remains on chromosome 6, within the Cw6 locus.
PATHOPHYSIOLOGY
Psoriasis is characterized by hyperproliferation and abnormal differ-entiation of epidermal keratinocytes, lymphocyte infiltration consist-ing principally of T lymphocytes, and specific endothelial vascular changes within the dermal microvasculature, including limited neo-angiogenesis, 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 mod-ulating 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 epi-dermis, due to increased proliferation of keratinocytes in the interfol-licular 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 dif-ferentiation 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 dif-ferentiated 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
FIGURE 71-1 • Psoriasis pathophysiology.
Dilated capillaries Neutrophils Epidermis
Demarcated plaque with white scale
Epidermal ridges elongated Dermis T. Lymphocytes Lymph node T-cell activation, proliferation, and cytokine production LFA-1 CD11a ICAM-1 LFA-1 CD11a ICAM-1 APC Antigen peptide APC Antigen Keratinocytes T-cell reactivation, keratinocyte proliferation, and cytokine production Trans-migration Adhesion Rolling Activated T-cell Epidermis Dermis Endothelium Blood flow T-cell FIGURE 71-2 • Dendritic-antigen
presentation, T-cell activation and localization in skin. 2
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pathogenic leukocytes (T cells and dendritic cells [DCs]) within the dermis. Endothelial cells appear activated in psoriatic lesions, and spe-cific 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 popula-tion and number of T lymphocytes7 as well as resident populations of DCs,8 suggesting that skin might be a potential site for the direct trig-gering 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 lym-phocytes 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 charac-terizes the specificity of the immune response in psoriasis. The antigen-presenting 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 pep-tides 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 prod-ucts of pathogens but sometimes breakdown prodprod-ucts of cells, such as necrotic bodies or heat-shock proteins. The only co-stimulatory recep-tor expressed constitutively by naive T cells is CD28, with co-stimula-tion 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 antiapop-totic 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 macro-phages and adhesion molecules on vascular endothelial cells.13,14 Th1 cytokines also induce the release of cytokines from other cells, produc-ing a cascade of chemical messengers that, together, create the distinc-tive 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 sus-ceptibility 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
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
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 pso-riasis. 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.
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 (punc-tate 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
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extremities, but it may have a generalized distribution. Guttate psoria-sis 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 self-limiting; 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, peri-neal, 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, antima-larials and IL-2. Complications may include dehydration, heart failure, infection, anemia (due to loss of iron, vitamin B12, and folate), hypo-thermia, 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 develop-ment of erythema and pustules in flexural areas as well as their appear-ance 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.
Palmoplantar Pustulosis
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 Approx-imately 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 palmoplan-tar 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.
Psoriatic Nail Disease
Psoriatic nail dystrophy mainly occurs in patients suffering from pso-riatic 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 parakerato-sis within the body of the nail plate), subungueal hyperkeratoparakerato-sis, ony-cholysis, and nail plate crumbling are characteristic abnormalities of psoriatic nail disease.
Psoriatic Arthritis
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 rheuma-toid 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). Arthri-tis 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 char-acteristic 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 hor-mones that are produced by the adrenal cortex. They are involved in a
FIGURE 71-3 • Psoriasis plaque.
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wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior. Glucocorti-coids such as cortisol control carbohydrate, fat, and protein metabo-lism 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 mitochon-dria 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 func-tions), but aldosterone synthase is also able to perform an 18- oxidation. 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 steroid- sensitive 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 hydrocorti-sone) 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 cortico-steroids,24 and this appears to be a major limiting factor in their use for psoriasis.
Calcipotriene. Calcipotriene (Dovonex), or calcipotriol, is a syth-etic derivative of calcitriol or vitamin D. The exact mechanism by which calcipotriene improves psoriasis is not well understood. Calci-potriene 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
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 betametha-sone 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 (pho-todamage). 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 molecu-lar 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 mil-lions of people with psoriasis and other scalp conditions. The U.S. Food and Drug Administration (FDA) agrees, and states that coal tar
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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% Clobetasol propionate
Cormax Cream/Solution, 0.05% Clobetasol propionate
Diprolene Gel/Ointment, 0.05% Betamethasone dipropionate
Olux Foam, 0.05% Clobetasol propionate
Psorcon Ointment, 0.05% Diflorasone diacetate
Temovate Cream/Ointment/Solution, 0.05% Clobetasol propionate
Ultravate Cream/Ointment, 0.05% Halobetasol propionate
Vanos Cream, 0.1% Fluocinonide
CLASS 2—POTENT (50-100 TIMES AS POTENT AS HYDROCORTISONE)
Cyclocort Ointment, 0.1% Amcinonide
Diprolene Cream AF, 0.05% Betamethasone dipropionate
Diprosone Ointment, 0.05% Betamethasone dipropionate
Elocon Ointment, 0.1% Mometasone furoate
Florone Ointment, 0.05% Diflorasone diacetate
Halog Ointment/Cream, 0.1% Halcinonide
Lidex Cream/Gel/Ointment, 0.05% Fluocinonide
Maxiflor Ointment, 0.05% Diflorasone diacetate
Maxivate Ointment, 0.05% Betamethasone dipropionate
Psorcon Cream, 0.05% Diflorasone diacetate
Taclonex Ointment, 0.064% Betamethasone dipropionate and calcipotriene
Topicort Cream/Ointment, 0.25% Desoximetasone
Topicort Gel, 0.05% Desoximetasone
CLASS 3—UPPER MID-STRENGTH (2-25 TIMES AS POTENT AS HYDROCORTISONE)
Aristocort A Ointment, 0.1% Triamcinolone acetonide
Cutivate Ointment, 0.05% Fluticasone propionate
Cyclocort Cream/Lotion, 0.1% Amcinonide
Diprosone Cream, 0.05% Betamethasone dipropionate
Florone Cream, 0.05% Diflorasone diacetate
Lidex-E Cream, 0.05% Fluocinonide
Luxiq Foam, 0.12% Betamethasone valerate
Maxiflor Cream, 0.05% Diflorasone diacetate
Maxivate Cream/Lotion, 0.05% Betamethasone dipropionate
Topicort Cream, 0.05% Desoximetasone
CLASS 4—MID-STRENGTH
Aristocort Cream, 0.1% Triamcinolone acetonide
Cordran Ointment, 0.05% Flurandrenolide
Elocon Cream, 0.1% Mometasone furoate
Kenalog Cream/Ointment/Spray, 0.1% Triamcinolone acetonide
Synalar Ointment, 0.025% Fluocinolone acetonide
Uticort Gel, 0.025% Betamethasone benzoate
Westcort Ointment, 0.2% Hydrocortisone valerate
CLASS 5—LOWER MID-STRENGTH
Cordran Cream/Lotion/Tape, 0.05% Flurandrenolide
Cutivate Cream, 0.05% Fluticasone propionate
DermAtop Cream, 0.1% Prednicarbate
DesOwen Ointment, 0.05% Desonide
Diprosone Lotion, 0.05% Betamethasone dipropionate
Kenalog Lotion, 0.1% Triamcinolone acetonide
Locoid Cream, 0.1% Hydrocortisone
Pandel Cream, 0.1% Hydrocortisone
Synalar Cream, 0.025% Fluocinolone acetonide
Uticort Cream/Lotion, 0.025% Betamethasone benzoate
Valisone Cream/Ointment, 0.1% Betamethasone valerate
Westcort Cream, 0.2% Hydrocortisone valerate
CLASS 6—MILD
Aclovate Cream/Ointment, 0.05% Aclometasone dipropionate
Derma-Smoothe/FS Oil, 0.01% Fluocinolone acetonide
DesOwen Cream, 0.05% Desonide
Synalar Cream/Solution, 0.01% Fluocinolone acetonide
Tridesilon Cream, 0.05% Desonide
CLASS 7—LEAST POTENT
Topicals with hydrocortisone, dexamethasone, methylprednisolone, and prednisolone
Modified from National Psoriasis Foundation, 2006.
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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 sun-light 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, fol-lowed 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 sig-nificantly 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 accu-mulates in mitochondria, where it interferes with the supply of energy to the cell, probably by the oxidation of dithranol releasing free radi-cals. 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 signifi-cantly 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 anthra-lin 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, typ-ically 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-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 hospi-tal 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 car-boxyl 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 addi-tional 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 impor-tant 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 sup-presses 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 dermati-tis, 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 com-bination 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 peptidyl-prolyl 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 its calcineurin. Thus pimecrolimus inhibits T-cell activation by inhib-iting 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
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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 random-ized 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 grad-ually 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.
Phototherapy
Light therapy or phototherapy consists of exposure to specific wave-lengths 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 x-rays. 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 photochemother-apy, 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 fre-quency UV radiation and carry a greater potential for erythemogenic responses and sunburning reactions. UVB treatment can be adminis-tered 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 respon-sive to natural sunlight.
The most efficient approach is first to determine the minimal ery-thema dose (MED), which is a biologic response (pink-red appear-ance) 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
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 photocarcino-genesis 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. Long-term 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 cyclobu-tane 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 kerati-nocytes, and the underlying mechanism of action of PUVA photoche-motherapy 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 alterna-tives 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
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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
treat-ment 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 discontinua-tion 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 reti-noid for at least 7 to 14 days to establish the retireti-noid effect on the skin and its modification on the psoriatic plaques. The effect of the reti-noids 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 photo-therapy. Methotrexate and cyclosporine have both been used. Cyclo-sporine 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
Oral Treatments
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 ade-nosine, or the inhibition of T-cell activation and suppression of intra-cellular 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 bio-availability 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 Preg-nancy 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 breast-feeding. 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, treat-ment 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, metho-trexate is usually discontinued.
Anti-inflammatory medications should be avoided while the patient is receiving methotrexate. These drugs elevate the effects of methotrex-ate 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-CsA Plasma membrane CsA-cyclophillin Calcineurin NF-ATp NF-AT Nuclear membrane Stimulation of immune response Interleukin-2
FIGURE 71-4 • Mechanism of action of cyclosporine.
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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 megaloblas-tic anemia due to folic acid deficiency.
A randomized, controlled trial comparing methotrexate and cyclo-sporine was conducted with an average dose of cyclocyclo-sporine 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 iso-lated from a Norwegian soil sample.
Cyclosporine is thought to bind to the cytosolic protein cyclophilin of immunocompetent lymphocytes, especially T lymphocytes (Fig. 71-5). This complex of cyclosporine and cyclophilin inhibits calcineurin, which activates transcription of IL-2. It also inhibits lymphokine pro-duction 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 posi-tion, where an L-nor-valine replaces the a-aminobutyric acid.
Cyclosporine side effects include gum hyperplasia, convulsions, peptic ulcers, pancreatitis, fever, vomiting, diarrhea, confusion, breath-ing difficulties, numbness and tbreath-inglbreath-ing, pruritus, high blood pressure, potassium retention and possibly hyperkalemia, nephrotoxicity, hepa-totoxicity, 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 childbear-ing 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.
Cell cycle Antigen Presenting Cell
corticosteroids Antigen Costimulation B7 Anti CD25 Anti CD40L Anti CD3 CTLA4lg CD28 CD40L MAP kinases AP-1 cyclosporine tacrolimus calcineurin T Cell Receptors Nuclear factor of activated T Cells IL-2 and others
T Cell G1 G2 S M azathioprine IMPDH Target of Rapamycin sirolimus Mycophenolate mofetil IL-15 and others IL-2 corticosteroids
FIGURE 71-5 • Mechanism of action of different biologics and systemic treatments.
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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 toler-ance to contact lenses; hyperlipidemia, raised liver enzymes; head-aches; 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 dis-turbances, inflammatory bowel disease, pancreatitis, hepatitis, corneal opacities, papilloedema, idiopathic intracranial hyperten-sion, 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 con-clusive evidence has been produced.
Oral retinoids can cause birth defects in the developing fetus, includ-ing defects of the central nervous system, skull, eyes, and cardiovascu-lar 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 man-agement program designed to further the public health goal to elimi-nate 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 prescrib-ing, and pharmacists are required to check the web site before dispens-ing 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 idio-pathic 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 introduc-tion of acitretin. Etretinate was discontinued because it had a narrow therapeutic index
