71 PSORIASIS

Transcription

71 PSORIASIS

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
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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
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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
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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.
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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
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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.
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
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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
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Palmoplantar Pustulosis
Psoriatic Nail Disease
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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.
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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
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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
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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. 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
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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%
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
Betamethasone dipropionate
Diflorasone diacetate
Halobetasol propionate
Fluocinonide
Amcinonide
Mometasone furoate
Halcinonide
Fluocinonide
Betamethasone dipropionate and calcipotriene
Desoximetasone
Desoximetasone
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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%
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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
Fluocinonide
Betamethasone valerate
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%
Flurandrenolide
Mometasone furoate
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
Hydrocortisone
Hydrocortisone
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
Desonide
Desonide
CLASS 7—LEAST POTENT
Topicals with hydrocortisone, dexamethasone, methylprednisolone, and prednisolone
Modified from National Psoriasis Foundation, 2006.
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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
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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 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-
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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 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
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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
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Oral Treatments
Plasma membrane
CsA-cyclophillin
Calcineurin
NF-AT
Nuclear membrane
Interleukin-2
Stimulation of
immune response
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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 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
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
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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
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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.
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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-
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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 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
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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
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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-
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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.
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.
Ch071-X3291.indd 995
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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,
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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
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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
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Figure 71-8 • Mechanisms of action for different biologics.
Endothelial cell
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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
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999
Therapeutic Approaches
Mild Psoriasis
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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
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.
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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
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RePUVA
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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.
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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
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PUVA ± acitretin*
Moderate (2%–10% BSA) to
Severe (>10% BSA)
Biologics, MTX or CsA* ± acitretin†
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
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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
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.
Ch071-X3291.indd 1002
9/18/2008 12:54:36 PM
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.
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
Ch071-X3291.indd 1003
9/18/2008 12:54:36 PM
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
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.
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71 PSORIASIS

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