F
ROM THE ACADEMY
Guidelines of care for the management of
psoriasis and psoriatic arthritis
Section 1. Overview of psoriasis and guidelines of care
for the treatment of psoriasis with biologics
Wo rk Gr ou p: Al an Men ter, MD, C h ai r,
Alice Gottlieb, MD, PhD,
Steven R. Feldman, MD, PhD,
a
b
c
Abby S. Van Voorhees, MD,
Craig L. Leonardi, MD,
Kenneth B. Gordon, MD,
Mark Lebwohl, MD,
d
e
f
g
John Y. M. Koo, MD,
Craig A. Elmets, MD,
Neil J. Korman, MD, PhD,
Karl R. Beutner, MD, PhD,
h
i
j
k
and Reva Bhushan, PhD
l
Dallas, Texas; Boston, Massachusetts; Winston-Salem, North
Carolina; Philadelphia, Pennsylvania;
Saint Louis, Missouri; Chicago and Schaumburg, Illinois; New
York, New York; San Francisco
and Palo Alto, California; Birmingham, Alabama; and Cleveland,
Ohio
Psoriasis is a common, chronic, in ammatory, multisystem disease
with predominantly skin and joint
manifestations affecting approximately 2% of the population. In
this first of 5 sections of the guidelines of
care for psoriasis, we discuss the classification of psoriasis;
associated comorbidities including autoimmune
diseases, cardiovascular risk, psychiatric/psychologic issues,
and cancer risk; along with assessment tools
for skin disease and quality-of-life issues. Finally, we will
discuss the safety and efficacy of the biologic
treatments used to treat patients with psoriasis. ( J Am Acad
Dermatol 2008;58:826-50.)
DISCLAIMER
Abbreviations used:
Adherence to these guidelines will not ensure
AAD: American Academy of Dermatology
successful treatment in every situation. Furthermore,
BMI: body mass index
these guidelines do not purport to establish a legal
BSA: body surface area
CHF: congestive heart failure
standard of care and should not be deemed inclusive
CyA: cyclosporine
of all proper methods of care nor exclusive of other
FDA: Food and Drug Administration
methods of care reasonably directed to obtaining
IL: interleukin
LFA: lymphocyte function associated antigen
the same results. The ultimate judgment regarding
MS: multiple sclerosis
NB: narrowband
PASI: Psoriasis Area and Severity Index
PASI-75: 75% improvement in the Psoriasis Area
a
From the Baylor University Medical Center, Dallas
; Department of
and Severity Index score
Dermatology, Tufts-New England Medical Center, Tufts Univer-
PGA: Physicians Global Assessment
b
sity School of Medicine, Boston
; Department of Dermatology,
PUVA: psoralen plus ultraviolet A
c
Wake Forest University School of Medicine, Winston-Salem
;
QOL: quality of life
d
TB: tuberculosis
Department of Dermatology, University of Pennsylvania
; Saint
TNF: tumor necrosis factor
e
Louis University
; Division of Dermatology, Evanston North-
UV: ultraviolet
western Healthcare and Department of Dermatology, North-
f
western University, Fienberg School of Medicine, Chicago
;
Department of Dermatology, Mount Sinai School of Medicine,
New York
g
; Department ofDermatology, University ofCaliforniae
the propriety of any specific therapy must be
San Francisco
h
; Department of Dermatology, University of
made by the physician and the patient in light of
Alabama at Birmingham
i
; Murdough Family Center For Psori-
all the circumstances presented by the individual
asis, Department of Dermatology, University Hospitals Case
patient.
Medical Center, Cleveland
j
; Anacor Pharmaceuticals Inc, Palo
Alto
k
; and American Academy of Dermatology, Schaumburg.
l
Funding sources: None.
SCOPE
The authors conflict of interest/disclosure statements appear
at
These guidelines addres s the treatment of both
the end of the article.
Reprint requests: Reva Bhushan, PhD, 930 E Woodfield Rd,
adult and childhood psoriasis and psoriatic arthritis.
Schaumburg, IL 60173. E-mail:
[email protected].
This document will include the various treatments of
0190-9622/$34.00
psoriasis including topical modalities, ultraviolet
2008 by the American Academy of Dermatology, Inc.
(UV) light therapies, systemic agents, and the
doi:10.1016/j.jaad.2008.02.039
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Table I. Eight clinical questions used to structure the primary
issues in diagnosis and treatment of patients with
psoriasis
Gu ide lin e se ct ion Cli nic a l qu es tion s
Section 1
How is psoriasis classified?
d
What are the potential comorbidities of psoriasis?
d
What tools are used to measure quality of life in psoriasis and
how are these tools used in the treatment
d
of patients?
What are the safety and efficacy of biologic therapies used to
treat psoriasis?
d
Section 2
Discuss the classification, prognosis, assessment tools, and
systemic therapies used in the treatment of
d
patients with psoriatic arthritis.
Section 3
What are the safety and efficacy of topical therapies used to
treat psoriasis?
d
Section 4
What are the safety and efficacy of systemic therapies and
phototherapies used to treat psoriasis?
d
Section 5
Describe an overall approach to the treatment of patients with
psoriasis with an emphasis on decision-
d
making criteria that enable the clinician to individualize
therapy based on disease type, extent,
response to previous treatments, quality-of-life issues, and
comorbidities.
biologic therapies. In addition, quality of life (QOL)
Practice,andBMJ USA). This strategy was supported
parameters, the type of psoriasis, and the presence of
by a decision of the Clinical Guidelines Task Force in
comorbidities such as obesity and other associations
2005 with some minor modifications for a consistent
of the metabolic syndrome will be reviewed. This
approach to rating the strength of the evidence of
guideline will be subdivided into 5 separate docu-
scientific studies.
Evidence was graded using a 3-point
1
ments given the large breadth of material. The first
scale based on the quality of methodology as follows:
section will give an overview of classification, co-
I. Good-quality patient-oriented evidence.
morbidities, and assessment tools and cover the
II. Limited-quality patient-oriented evidence.
biologic treatments for psoriasis. The second section
III. Other evidence including cons ensus guidelines,
will cover treatments for psoriatic arthritis with an
opinion, or case studies.
emphasis on the biologics; the third section will
cover topical therapies; the fourth section will cover
Clinical recomme ndations were developed on the
UV light therapy and systemic nonbiologic therapies;
best available evidence tabled in the guideline.
and the fifth section will be an overall approach to
These are ranked as follows:
the treatment of patients with psoriasis with an
A. Recommendation based on consistent and good-
emphasis on decision-making criteria.
quality patient-oriented evidence.
It is important, however, for dermatologists to
B. Recommendation based on inconsistent or lim-
address psoriasis in its entire scope of manifestations.
ited-quality patient-oriented evidence.
This guideline will not cover the effectiveness of
C. Recommendation based on consensus, opinion,
treatments for the less common subtypes ofpsoriasis,
or case studies.
such as guttate, pustular, inverse, and erythrodermic.
Prior guidelines on psoriasis were also evalu-
ated.
This guideline has been developed in accor-
METHOD
2 , 3
dance with the American Academy of Dermatology
A work group of recognized psoriasis experts was
(AAD)/AAD Association Administrative Regulations
convened to determine the audience and scope of
for Evidence-based Clinical Practice Guidelines,
the guideline, and identify clinical questions to
which include the opportunity for review and com-
structure the primary issues in diagnosis and man-
ment by the entire AAD membership and final
agement (
Table I
). Work group members completed
review and approval by the AAD Board of Directors.
a disclosure of commercial support.
An evidence-based model was used and evidence
DEFINITION
was obtained using a search of the MEDLINE data-
base spanning the years 1990 through 2007. Only
Psoriasis vulgaris is a genetic, systemic, in amma-
English-language publications were reviewed.
tory, chronic disorder, which can be altered by envi-
The available evidence was evaluated using a uni-
ronmental factors. It may be associated with other
fied system called the Strength of Recommendation
in ammatory disorders such as psoriatic arthritis,
Taxonomy developed by editors of the US family
in ammatory bowel disease, and coronary artery
medicine and primary care journals (ie, American
disease. It is characterized by scaly, erythematous
Family Physician, Family Medicine, Journal of Family
patches, papules, and plaques that are often pruritic.
828 Menter et al
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INTRODUCTION
within plaques can occur when lesions are present
Psoriasis is a multisystem disease with predomi-
over joint lines or on the palms and soles. Psoriatic
plaques typically have a dry, thin, silvery-white or
nantly skin and joint manifestations affecting ap-
micaceous scale, often modified by regional ana-
proximately 2% of the population. Psoriatic arthritis
tomic differences, and tend to be symmetrically
is a member of the seronegative spondyloarthropa-
distributed over the body (
Fig 1
). Approximately
thies. Other conditions that may be associated with
80% of those affected with psoriasis have mild to
psoriasis, psoriatic arthritis, or both include autoim-
moderate disease, with 20% having moderate to
mune disease s such as in ammatory bowel disease,
components of the metabolic syndrome such as
severe psoriasis affecting more than 5% of the body
diabetes, cardiovascular disease, and lymphoma.
surface area (BSA) or affecting crucial body areas
As physicians who care for the large majority of
such as the hands, feet, face, or genitals.
5, 6
patients with psoriasis, dermatologists play an im-
portant role in identifying the morbidity of all aspects
Inverse
of psoriatic disease.
Inverse psoriasis is characterized by lesions in the
The major manifestation of psoriasis is chronic
skin folds. Becaus e of the moist nature of these areas,
in ammation of the skin. It is characterized by
the lesions tend to be erythematous plaques with
disfiguring, scaling, and erythematous plaques that
minimal scale. Common locations include the axil-
may be painful or often severely pruritic and may
lary, genital, perineal, intergluteal, and inframam-
cause significant QOL issues. Psoriasis is a chronic
mary areas. Flexural surfaces such as the antecubital
disease that waxes and wanes during a patients
fossae can exhibit similar lesions (
Fig 1
, B).
lifetime, is often modified by treatment initiation and
cessation and has few spontaneous remissions.
Erythrodermic
Erythrode rmic psoriasis can develop gradually
from chronic plaque disease or acutely with little
CLASSIFICATION OF PSORIASIS
preceding psoriasis. Generalized erythema covering
The phenotyping of psoriasis has traditionally
nearly the entire BSA with varying degrees of scaling
4
been based on historical morphologic descriptions.
is seen (
Fig 1
, E ). Altered thermoregulatory proper-
Although this phenotyping is very useful for classi-
ties of erythrodermic skin may lead to chills and
fication purposes, clinical findings in individual
hypothermia, and fluid loss may lead to dehydration.
patients frequently overlap in more than one
Fever and malaise are common.
category.
Pustular
Plaque
All forms of psoriasis may contain neutrophils in
Plaque psoriasis is the most common form, affect-
the stratum corneum. When the collections of neu-
ing approximately 80% to 90% of patients. The vast
trophils are large enough to be apparent clinically, it
majority of all high-quality and regulatory clinical
is termed pustular psoriasis. Pustular psoriasis may
trials in psoriasis have been conducted on patients
be generalized or localized. The acute generalized
with this form of psoriasis. Plaque psoriasis manifests
variety (termed the von Zumbusch variant) is an
as well-defined, sharply demarcated, erythematous
uncommon, severe form of psoriasis accompanied
plaques varying in size from 1 cm to several centi-
by fever and toxicity and consists of widespread
meters (
Figs 1 and 2
). These clinical findings are
pustules on an erythematous background (
Fig 1
, D,
mirrored histologically by psoriasiform epidermal
and
Fig 2
, C ). Cutaneous lesions characteristic of
hyperplasia, parakeratosis with intracorneal neutro-
psoriasis vulgaris may be present before, during, or
phils, hypogranulosis, spongiform pustules, an infil-
after an acute pustular episode. There is also a
trate of neutrophils and lymphocytes in the
localized pustular variant of psoriasis involving the
epidermis and dermis, along with an expanded
palms and soles, with or without evidence of class ic
dermal papillary vasculature. Patients may have
plaque-type disease.
involvement ranging from only a few plaques to
numerous lesions covering almost the entire body
Guttate
surface. The plaques are irregular, round to oval in
Guttate psoriasis is characterized by dew-drop-
shape, and most often located on the scalp, trunk,
like, 1- to 10-mm, salmon-pink papules, usually with
buttocks, and limbs, with a predilection for extensor
a fine scale. This variant of psorias is, common in
surfaces such as the elbows and knees. Smaller
individuals younger than 30 years, is found primarily
plaques or papules may coalesce into larger lesions,
on the trunk and the proximal extremities and occurs
especially on the legs and trunk. Painful fissuring
in less than 2% of patients with psoriasis. A history of
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Fig 1. Photographs of patients with psoriasis. A, Small plaque
psoriasis. B, Localized thick
plaque type psoriasis. C, Large plaque psoriasis. D,
Inflammatory localized psoriasis. E,
Erythrodermic psoriasis. F, Psoriasis and psoriatic
arthritis.
upper respiratory infection with group A beta-he-
(
Fig 3
). Up to 90% of patients with psoriatic arthritis
molytic streptococci often precedes guttate psoriasis,
may have nail changes. Psoriasis of the nails is a
especially in younger patients, by 2 to 3 weeks. This
significant therapeutic challenge.
sudden appearance of papular lesions may be either
the first manifestation of psoriasis in a previously
Psoriatic arthritis
unaffected individual or an acute exacerbation of
Psoriatic arthritis is an in ammatory arthropathy
long-standing plaque psoriasis (
Fig 2
, D).
associated with psoriasis that will be discussed at
length in Section 2 of the guidelines (
Fig 1
, F ).
Nail disease (psoriatic onychodystrophy)
Nail psoriasis can occur in all psoriasis subtypes.
COMORBIDITIES ASSOCIATED WITH
Fingernails are involved in approximately 50% of all
PSORIASIS
patients who are psoriatic and toenails in 35% of
patients. These changes include pitting, onycholysis,
Although psoriasis has been previously thought to
subungual hyperkeratosis, and the oil-drop sign
be a disease solely affecting primarily the skin and
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Fig 2. Photographs of patients with psoriasis. A, Thin plaque
type psoriasis. B, Inverse type
psoriasis. C, Pustular type psoriasis. D, Guttate type
psoriasis.
MEDICAL COMORBIDITIES
the joints, our understanding of the comorbidities
that may be associated with this disease has grown
Autoimmune diseases
significantly. Recent evidence has even suggested an
Some of the comorbidities associated with psori-
increased overall risk of mortality in patients with
asis have been attributed to shared or closely linked
severe psoriasis.
genetic susceptibility traits. For example, the
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Fig 3. Photographs of patients with nail psoriasis.
incidence of Crohns disease and ulcerative colitis is
play a role in the promotion of coronary heart
3.8 to 7.5 times greater in patients with psoriasis than
disease. Preliminary studies sugges t that therapy of
in the general population.
Although individual
both rheumatoid arthritis and psoriasis with metho-
8
susceptibility to all 3 of these diseases has been
trexate
and rheumatoid arthritis with tumor necro-
18
19
localized to a similar region of chromosome 16,
sis factor (TNF) inhibitors
can decrease the
multiple other genetic loci are found in each condi-
cardiovascular mortality.
9
tion.
Other studies suggest a possible link between
multiple sclerosis (MS) and psoriasis as psoriasis
Metabolic syndrome
occurs more commonly in families of patients with
The combination of obesity, impaired glucose
1 0
MS compared with control subjects.
Furthermore,
regulation, hypertriglyceridemia, reduced high-den-
in this study, families with more than one case of MS
sity lipoprotein, and hypertension is known as the
had the highest likelihood of having a family mem-
metabolic syndrome. Patients with the metabolic syn-
ber with psoriasis, supporting a genetic relationship
drome are at a significantly increased risk of develop-
between these two diseases.
10
ing cardiovascular morbidity and mortality. Although
the prevalence of metabolic syndrome is elevated in
most westernized countries, a recent study of hospi-
Cardiovascular disease
There is an increased risk of cardiovascular disease
talized patients demonstrates that the prevalence of
in patients with psoriasis. Several factors are believed
metabolic syndrome in hospitalized patients with
to contribute to the increased risk for cardiovascular
psoriasis is significantly elevated when compared
disease in these patients.
Patients with psoriasis are
with hospitalized patients who do not have psoriasis.
1 1
2 0
more frequently overweight, have an increased inci-
dence of diabetes, have an increased incidence of
Lymphoma, melanoma, and nonmelanoma
hypertension, and have an atherogenic lipoprotein
skin cancer
profile at the onset of psoriasis with significantly
The question of whether patients with psoriasis
higher very low-density lipoprotein cholesterol
are at greater risk of developing lymphoma than the
levels and high-density lipoprotein levels.
general population is an area of ongoing contro-
1 1 -1 6
Epidemiologic analysis of the United Kingdom
versy. One study of more than 2700 patients with
General Practice Database, which contains data on
psoriasis followed up for nearly 4 years showed an
more than 130,000 patients with psoriasis aged 20 to
almost 3-fold increased relative risk of developing
90 years, has determined that patients with psoriasis
any type of lymphoma compared with a control
2 1
have a higher than normal incidence of myocardial
group, after accounting for sex and age.
Although
11
infarction.
Even after correcting for the heart dis-
medications with a known risk of lymphoma had
ease risk factors of smoking, diabetes, obesity, hy-
only been used in 1.55% of patients in this study, they
pertension, and hyperlipidemia, the probability of
cannot be completely eliminated as a potential
myocardial infarction is higher in patients who are
confounding factor. In addition, the patients in this
psoriatic than in nonaffected individuals (the relative
study were all older than 65 years, and it is unknown
risk being particularly elevated in younger patients
whether these findings would hold true for a youn-
with more severe psoriasis). Patients with both
ger cohort. A more recent retrospective study of
rheumatoid arthritis and systemic lupus erythemato-
150,000 patients of all ages with psoriasis also dem-
sus also have an increased incidence of coronary
onstrates an increased risk of lymphoma, but sug-
heart disease,
suggesting that the chronic inflam-
gests that the relative risk for all lymphomas is lower
1 7
matory process found in all of these diseases may
at 1.34. In this study, there was a significantly
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increased risk of developing cutaneous T-cell lym-
may not reflect the degree of emotional impact of the
phoma (relative risk of 10.75), or Hodgkins lym-
disease, it is important that clinicians cons ider the
phoma (relative risk of 3.18) in patients with severe
psychosocial aspects of this illness.
psoriasis.
22
BEHAVIORS CONTRIBUTING TO MEDICAL
Although many
but not all
studies reveal that
2 3
2 4
AND PSYCHIATRIC COMORBIDITIES
the risk of melanoma and nonmelanoma skin cancer
in patients with psoriasis is equivalent to that of the
Smoking
general population, there are subpopulations in
In 2004, the prevalence of smoking among US
which there is an increased risk of skin cancer.
adults was 21%. Smoking increases the risk of
Caucasian individuals who have received more
hypertension, peripheral vascular disease, stroke,
than 250 psoralen plus UVA (PUVA) treatments
and myocardial infarction.
have a 14-fold higher risk of cutaneous squamous
An increased prevalence of smoking among pa-
cell carcinoma than patients who have received
tients with psoriasis has been observed in numerous
fewer treatments.
There is also evidence that
countries including Finland, Italy, the United
25 , 2 6
Caucasians with extensive PUVA exposure have an
Kingdom, Norway, China, and the United States.
3 5 -3 7
increased risk of melanoma, although this is not
Data from the Utah Psoriasis Initiative, which in-
universally accepted and has not been demonstrated
cluded more than 800 subjects, reveals that 37% of
2 7, 2 8
in the non-Caucasian population.
patients with psoriasis were smokers versus 13%
smokers in the general population. Among patients
PSYCHIATRIC/PSYCHOLOGIC
with psoriasis who smoke, 78% started smoking
COMORBIDITIES
before the onset of their psoriasis and 22% of patients
1 2
Depression/suicide
starting after onset.
Both the Italian studies and the
Psoriasis is associated with lack of self-esteem and
Nurses Health Study II clearly establish smoking as a
3 6 , 3 8
increased prevalence of mood disorders including
risk factor for incident psoriasis.
The increased
29
depression.
The prevalence of depression in pa-
prevalence of smoking in patients with psoriasis may
3 0
tients with psoriasis may be as high as 60%.
also contribute to an elevation in cardiovascular risk.
Depression may be severe enough that some pa-
tients will contemplate suicide. In one study of 217
Alcohol
patients with psoriasis, almost 10% reported a wish
The prevalence of psorias is is increased among
to be dead and 5% reported active suicidal idea-
patients who abuse alcohol.
However, conflicting
39
tion.
Treatments for psoriasis may affect depres-
evidence exists as to whether increased alcohol
31
sion. One study demonstrated that patients with
intake in patients with psoriasis is a factor in the
psoriasis treated with etanercept had a significant
pathogenesis or whether having a chronic disorder
decrease in their depression scores when compared
such as psoriasis leads to greater intake of alcohol.
with control subjects. However, clinically diagnosed
For example, one study of 144 patients with psoriasis
depression was an exclusionary criterion for entry
demons trated that alcohol consumption in the pre-
into this study.
Therefore, treatment of psoriasis
vious 12 months was linked to the onset of psorias is.
3 2
with etanercept lessened symptoms of depression in
This study suggests that psoriasis may lead to
patients without overt clinical depression.
sustained alcohol abuse and that alcohol intake
3 2
Increased rates of depression in patients with psori-
may perpetuate psoriasis.
In contrast, another
4 0
asis may be another factor leading to increased risk
study of 55 patients showed no association between
4 1
of cardiovascular disease. Although there is some
alcohol consumption and the onset of psoriasis.
suggestive evidence that treatment of depression
Support of increasing alcohol abuse as a postdiag-
with selective serotonin reuptake inhibitors may
nosis condition was found in a case-control study of
reduce cardiovascular events, conclusive evidence
60 twins discordant for psoriasis. In this study, no
3 3
is lacking.
difference in alcohol consumption between discor-
dant twins, either monozygotic or dizygotic, was
4 2
Psychologic and emotional burden of psoriasis
discovered.
In summary, alcohol consumption is
Psoriasis can have a substantial psychologic and
more prevalent in patients with psoriasis, and it may
emotional impact on an individual, which is not
also increase the severity of psoriasis.
always related to the extent of skin disease. There are
elevated rates of various psychopathologies among
Obesity
patients with psoriasis including poor self-esteem,
Obesity has become an epidemic within the
sexual dysfunction, anxiety, depression, and suicidal
United States. A body mass index (BMI) of more
ideation.
Because the clinical severity of psoriasis
than 30 is defined as obese with overweight being
34
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5 3
defined as a BMI between 25 and 30. In the United
severity of a specific skin disease such as psoriasis.
States, 65% of people older than 20 years are either
The Psoriasis QOL 12-item instrument discriminates
overweight or obese. Obesity has serious health
among patients with psoriasis and varying degrees
consequences including hypertension, vascular dis-
of disease severity and reliably captures clinical
ease, and type 2 diabetes mellitus. Psoriasis was first
changes from topical or systemic tre atments.
5 4 -5 6
associated with obesity in several large, European
Psoriasis clinical trial entry criteria have traditionally
epidemiologic studies. Studies from the United States
been based purely on the extent and character of the
also show an elevated BMI in patients with psoriasis.
skin lesions. However, clinical decision making must
These analyses of BMI compared subjects with and
incorporate the impact of the skin lesions on pa-
without psoriasis while controlling for age, sex, and
tients lives.
This involves assessing both the
57 , 5 8
race. Analysis of data from the Utah Psoriasis
burden of disease and the severity of the skin lesions.
Initiative revealed that patients with psoriasis had a
An instrument incorporating the Psoriasis QOL
significantly higher BMI than control subjects in the
12-item instrument with the physicians rating of
general Utah population.
The Nurses Health Study
severity by BSA measurement, the Koo-Menter
12
II, which contains prospective data from 78,626
Psoriasis Instrument, was designed to help physi-
women followed up during a 14-year period, indi-
cians perform a comprehensive and quantitative
cates that obesity and weight gain are strong risk
evaluation of patients with psoriasis including phys-
4 3
factors for the development of psoriasis in women.
ical severity, QOL impact, and arthritis issues, to help
In this study, multiple measures of obesity, including
the physician properly characterize all relevant as-
5 7
BMI, waist and hip circumference, waist-hip ratio,
pects of disease severity.
Another tool that attempts
and change in adiposity as assessed by weight gain
to capture several relevant aspects of psoriatic dis-
59
since the age of 18 years, were substantial risk factors
ease severity is the Salford index.
Treatments that
for the development of psoriasis. Multivariate anal-
are effective for psoriasis skin lesions also improve
60 - 66
ysis demonstrated that the relative risk of developing
patients QOL.
The specific characteristics of
psoriasis was highest in those with the highest BMIs.
psoriasis treatments may directly impact patients
In contrast, a low BMI (\21) was associated with a
QOL, requiring treatment to be tailored to the spe-
lower risk of psoriasis, further supporting these
cific patients situation and preferences.
The QOL
6 7
findings. Furthermore, the average weights of pa-
impact of psoriasis may be large even in patients with
tients with psoriasis in the large clinical trials of the
small areas of involvement.
For example, psori-
6, 6 8
biologic agents have been in the 90-to 95-kg range
asis of the palms and soles tends to have more impact
44 -4 7
(although these clinical trials all enrolled more men
than far more extensive involvement on the
than women) whereas the average body weight for
trunk.
Thus, patients with these types of psoriasis
6 9, 7 0
the US population from the NHANES database from
may be considered candidates for systemic
1999 to 2002 was 86 kg.
An association between
treatment.
4 8
58 , 7 1
psoriasis and elevated BMI appears to be yet another
PATHOGENESIS
factor that predisposes individuals with psoriasis to
cardiovascular disease.
Psoriasis is a complex genetic disease of dysregu-
4 9
lated in ammation, although the mechanism of in-
QOL
heritance has not been completely defined. To date,
Psoriasis causes psychosocial morbidity and dec-
at least 8 chromosomal loci have been identified for
rement in occupational function.
In a large study
which statistically significant evidence for linkage to
5 0 , 51
of more than 300 university-based patients with
psoriasis has been observed (these loci are known as
psoriasis, the physical and mental disability experi-
PSORS I-VIII). Detailed genetic mapping studies
enced by patients with psorias is was comparable or
demons trate that the HLA-Cw6 allele, also known
in excess of that found in patients with other chronic
as PSORS1, is the major susceptibility gene for
7 2
illnesses such as cancer, arthritis, hypertension, heart
psoriasis.
In addition, a number of environmental
disease, diabetes, and depression as measured by the
factors play an important role in the pathogenesis of
5 2
SF-36 Health Survey Form.
QOL measures are an
psoriasis including drugs, skin trauma (Koebners
important adjunct to skin lesion assessments to
phenomenon), infection, and stress.
properly assess the full effect of an illness such as
Evidence suggesting that psorias is involves
psoriasis that is not life-threatening. Dermatology-
immunologic mechanisms includes the efficacy of
specific, but not psoriasis-specific, instruments such
immunosuppressive drugs such as methotrexate,
as the Dermatology Life Quality Index or SKINDEX
cyclosporine (CyA), immune-targeting biologic
are very useful to assess the QOL impact of psoriasis,
agents, immunotoxins (denileukin diftitox), and
but may have a limited correlation with the actual
TNF-blocking biologics in treating psoriasis, and
834 Menter et al
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exacerbation of psoriasis by certain cytokine thera-
with percent of BSAinvolvement are other commonly
pies such as interferons alfa, beta, and gamma;
used assessment tools for patients, particularly for
interleukin (IL)-2; granulocyte colony-stimulating
those with milder disease. After PASI, the PGA is the
factor; and bacterial superantigens such as strepto-
tool most often used to measure psoriasis severity.
coccal antigens. Resolution of psoriasis is associated
When using the PGA, the investigator assigns a single
with decreased lesional infiltration of T cells, dermal
estimate of the patients overall severity of disease;
dendritic cells, Langerhans cells, and neutrophils,
usually a 7-point scale from clear to severe is used.
and decreased expression of TNF-a-, interferon-Y-,
Efforts to improve quantitative psoriasis assessment
and IL-12/23-dependent genes . In addition, there are
continue, eg, the Lattice System-PGA, where 1% of
altered levels of chemokines and integrins affecting
BSA is approximately equal to the patients open
migration of T cells, dermal dendritic cells, macro-
handprint (from wrist to tips of fingers) with fingers
phages, and neutrophils into the plaques. Thus,
tucked together and the thumb tucked to the side.
7 4
psoriasis is an immune-mediated organ-specific
In clinical practice, the physician generally uses
(skin, and/or joints) in ammatory disease in which
subjective qualitative assessment of the severity of a
intralesional in ammation primes basal stem kerat-
patients psoriasis by combining objective assessment
inocytes to hyperproliferate and perpetuate the
of the BSA involvement, disease location, thickness,
disease process.
and symptoms, presence or absence of psoriatic
arthritis with the subjective assessment of the phys-
EVALUATION OF PSORIASIS TREATMENT
ical, financial, and emotional impact of the disease on
Assessment tools used to evaluate psoriasis
the patients life.
Most large double-blind, placebo-controlled clin-
ical trials of psoriasis treatments include patients with
GENERAL RECOMMENDATIONS FOR THE
chronic stable plaque psoriasis but exclude other less
TREATMENT OF PSORIASIS
common types of psoriasis including those involving
the palms and soles, scalp, and intertriginous areas.
(Points 1-6 will be discussed in detail in future
Similarly, erythrodermic and pustular psoriasis have
sections of the guidelines and point 7 will be
been excluded. These areas of involvement and
discussed in detail below [
Fig 4
].)
types of psoriasis should be considered in evaluating
1. Topical treatments are appropriate for patients
severity of disease because the impact of these types
who are candidates for localized therapy but may not
of psoriasis may be quite substantial.
be practical as monotherapy for most patients who
are candidates for systemic and/or phototherapy,
7 5
The Psoriasis Area and Severity Index
where traditional systemic treatments, including
The Psoriasis Area and Severity Index (PASI) is a
methotrexate, CyA, narrowband (NB) and broad-
measure of overall psoriasis severity and coverage
band UVB, PUVA, oral retinoids, and the newer
that assesses BSA and erythema, induration, and
biologic agents are prescribed.
scaling.
It is commonly used in clinical trials for
2. UVB is safe, effective, and cost-effective. NB
7 3
psoriasis treatments but is rarely used in clinical
UVB is more effective than broadband UVB. Up to 20
practice. Typically, the PASI score is calculated be-
to 25 NB UVB treatments, given 2 to 3 times a week,
fore, during, and after a treatment to determine how
are usually required for significant improvement.
well psoriasis responds to the treatment under test. A
Treatment can be offered in the office or at home;
decrease in the PASI score supports claims ofefficacy.
home UVB reduces the inconvenience of patients
The vast majority of clinical trials of biologics com-
having to travel a long distance for treatment. Other
pare the study drug with a placebo rather than other
forms of UV exposure, including sun exposure, may
effective treatments making it difficult to compare the
offer benefit in select patie nts.
efficacy of the various systemic and biologic treat-
3. PUVA therapy is very effective in the majority
ments for psoriasis. A 75% improvement in the PASI
of patients, with potential for long remissions.
score (PASI-75) is predominantly used to document
However, long-term PUVA treatment in Caucasians
the effectivenes s of individual therapies in clinical
is associated with an increased risk of squamous cell
trials of patients with extensive psoriasis. The PASI is
carcinoma and possibly malignant melanoma. PUVA
considered by the authors to be less sens itive in
induces photoaging and other skin changes includ-
patients with lower BSA involvement (\10%).
ing lentigines. Ingestion of psoralen may also pro-
duce nausea. Oral psoralen is contraindicate d in
Other measurement tools
pregnancy. NB-UVB therapy avoids some of the
Measures such as the Physicians Global
adverse side effects of PUVA, while being slightly less
Assessment (PGA) and target plaque scores, together
effective than PUVA.
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Fig 4. Decision tree. *Patients with nondeforming psoriatic
arthritis without any radiographic
changes, loss of range of motion, or interference with tasks of
daily living should not
automatically be treated with tumor necrosis factor (TNF )
inhibitors. It would be reasonable
totreat these patients with nonsteroidal anti-inflammatory agent
or to consult rheumatologist for
therapeutic options.
Patients withlimited skin disease shouldnot automatically be
treated with
y
systemic treatment if they do not improve, because treatment
with systemic therapy may carry
more risk than the disease itself. MTX, Methotrexate; PUVA;
psoralen plus ultraviolet (UV)-A.
4. Methotrexate, although effective in the majority
patients of childbearing potential. Mucocutaneous
of patients, has the potential for hepatotoxicity and is
side effects are frequent. Dyslipidemia may also
contraindicated in the following clinical scenarios:
ensue and require dose reduction or treatment with
pregnancy; individuals with renal impairment, he p-
lipid-lowering agents. Hepatotoxicity rarely arises
atitis, or cirrhosis; alcoholics; unre liable patients; and
during therapy. Acitretin is frequently used in com-
patients with leukemia or thrombocytopenia. In
bination therapy with UVB or PUVA.
addition, drug interactions are common. Methotrex-
7. Biologic agents are proteins that can be
ate is an immunosuppressive agent. In patients
extracted from animal tissue or produced by recom-
treated with methotrexate, drug interactions are
binant DNA technology and possess pharmacologic
common with resultant bone-marrow suppression a
activity. Five biologic agents are currently Food and
concern. Methotrexate may induce pneumonitis.
Drug Administration (FDA) approved for psorias is.
Methotrexate is a teratogen, an abortifacient, and
Their safety and efficacy are discussed in detail in the
decreases sperm count. Prior guidelines suggest a
following section.
liver biopsy after 1.5-g cumulative dose.
7 6
TREATMENT OF PSORIASIS WITH
5. CyA, another immunosuppressive medication,
BIOLOGICS
works rapidly and is effective in the majority of
patients. However, impaired renal function, hyper-
General recommendations for all patients who
tension, concerns about lymphoma, and a potential
will be treated with biologics including T-cell
increase in cutaneous malignancies are known ad-
inhibitors and TNF inhibitors
verse effects after long-term treatment with CyA. CyA
When planning to initiate treatment of a patient
is thus best used interventionally in short-term
with psoriasis with a biologic it is important to obtain
courses of 3 to 4 months. There are also numerous
an age appropriate history and physical examination
potential drug interactions with CyA. Guidelines
along with an updated medication list. In addition, it
exist for reducing the CyA dose in patients who
is also important to obtain a reliable set of baseline
develop hypertension or elevations in creatinine.
laboratory studies that will allow the clinician to
6. Acitretin is an effective systemic agent for the
detect and be aware of any underlying conditions or
treatment of psoriasis that is not immunosuppres-
risk factors. This is particularly important because
sive. Because it is teratogenic and should not be used
after patients have been initiated on a biologic
in women who are pregnant, breast-feeding, or may
treatment, they are likely to be treated with other
become pregnant within 3 years of discontinuing
biologics or systemic therapies and it may be useful
acitretin, its use is substantially limited in female
to have reliable baseline laboratory studies. A recent
836 Menter et al
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8 6
consensus statement from the Medical Board of the
therapy and transplantation.
Once immunosup-
National Psoriasis Foundation addresses the appro-
pressive therapy has begun, patients are advised to
priate monitoring of patients with psoriasis who are
avoid vaccination with live vaccines (including var-
being treated with biologics.
This consensus state-
icella; mumps, measles, and rubella; oral typhoid;
77
ment points out that although there is no specific
yellow fever) and live-attenuated vaccines (including
guideline or single way of taking care of any patient,
intranasal influenza and the herpes zoster vac-
there are some tests that many dermatologists obtain
cine).
Package inserts for several of the biologics
8 7 , 8 8
in patients with psoriasis before commencing sys-
carry similar information. In patients with juvenile
temic therapies including biologics. These include a
rheumatoid arthritis and Crohns disease, vaccina-
chemistry screen with liver function tests, complete
tions are recommended before starting etanercept
8 9
blood cell count including platelet count, a hepatitis
and infliximab,
respectively. In patients with pso-
9 0
panel, and tuberculosis (TB) testing all obtained at
riasis who need vaccination, it is preferable to per-
baseline and with variable frequencies thereafter.
form these before initiating biologic therapy. Once
Although there are relatively minimal data on the use
patients have begun biologic therapies, physicians
of the biologics during pregnancy, 4 of the 5 agents
should consider the advantages and disadvantages of
are pregnancy category B, whereas efalizumab is
administering killed virus vaccines such as influenza.
pregnancy category C. All of the data for the bio-
Administration of live vaccines must be avoided in
logics are based on studies in adults aged 18 years
patients being treated with biologics under all
and older, with little data on the use of biologics for
circumstances.
psoriasis in children younger than 18 years, with the
BIOLOGICS THAT TARGET PATHOGENIC
exception of one study evaluating the safety and
T CELLS
efficacy of etanercept in this age group (see below
subsection on pediatric psoriasis within section on
Strength of recommendations for treatment of
etanercept). While being treated with biologics,
psoriasis using biologics that target pathogenic T
patients need to be periodically re-evaluated for
cells are shown in
Table II
.
the development of new symptoms including infec-
tion and malignancy. Treatment with biologics is
Alefacept: efficacy
contraindicated in patients with active, serious in-
Alefacept is a recombinant dimeric fusion protein
fections. If patients develop serious infections (usu-
that consists of the extracellular CD2-binding portion
ally defined as an infection that requires antibiotic
of lymphocyte function-associated antigen (LFA)-3
therapy) while being treated with a biologic agent, it
linked to the Fc portion ofhuman IgG1.
Alefacept
9 1- 93
is prudent to hold the biologic until the infection has
binds to CD2 on memory-effector T lymphocytes,
resolved.
thereby inhibiting the activation and reducing the
Because biologic therapies target the immune
number of these cells. The effects of alefacept in
system, it is important to use all approaches to
inducingin vitro apoptosis and selectively decreasing
prevent infection, including vaccinations. However,
circulating CD45RO cells suggest disease-remitting
it is also possible that biologic therapies may impair
properties of this agent.
Alefacept is approved for
91 , 9 4
the immunologic response to vaccinations. In one
the treatment of adult patients with moderate to
small study, efalizumab given before primary immu-
severe chronic plaque psorias is who are candidates
nization reduced the secondary immune response to
for systemic agents or phototherapy. Alefacept does
7 8
the immunizing agent.
In contrast, patients treated
not interfere with the primary and secondary
with alefacept had normal immune responses to
responses to a newly encountered antigen and
79
tetanus toxoid and to primary vaccination with a
acquired immune response to recall antigen.
In
7 9
neo-antigen.
Most studies evaluating the immune
the pivotal phase III trials of alefacept given intra-
response to vaccinations in patients treated with TNF
muscularly and dosed at 15 mg/wk, 21% of patients
blockers show adequate but attenuated immune
achieved at least PASI-75 at week 14, 2 weeks after
responses to pneumococcal or influenza vaccina-
cessation of the 12-week alefacept dosing period.
80 - 85
tion.
Patients treated with alefacept who achieve at least a
When developing recommendations for the use of
50% improvement in their PASI score also demon-
vaccinations in patients with psoriasis being treated
strate a statistically significant improvement in their
with biologics, it is reasonable to evaluate the stan-
Dermatology Life Quality Index compared with pla-
dard of care in organ transplantation where standard
6 1, 9 1 , 92 , 9 5 -1 0 0
cebo.
Although the primary end point for
vaccinations, including pneumococcal, hepatitis A
the alefacept studies was specified as 14 weeks, 2
and B, influenza, and tetanus-diphtheria are recom-
weeks after the 12-week course of therapy, the
mended before initiation of immunosuppressive
maximum response to alefacept generally occurred
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6 to 8 weeks after the last intramuscular shot ofthe 12-
Table II. The strength of recommendations for the
9 7 , 98 , 1 00
week course.
Although some patients do not
treatment of psoriasis using biologics that target
respond to this medication, patients who do respond
pathogenic T cells
to alefacept can achieve additional benefit from
S tr en gt h of
L e ve l of
successive 12-week treatment courses. A proportion
R e com me n da tion
r ec omm e nda ti on
ev id en ce Re f er en ce s
of patients who respond to alefacept by achieving
Alefacept A I 91-93, 95-100
PASI-75 or greater from baseline maintained a 50% or
Efalizumab A I 64, 103-105,
greater reduction in PASI for a median duration of 10
107-116
months.
9 1
Currently, there is no way to predict which pa-
tients will improve significantly with alefacept al-
responder patients eligible for maintenance therapy,
though investigation looking for predictive markers
which allowed for the concomitant use of UV pho-
is ongoing.
A baseline CD4 lymphocyte count
1 0 1
totherapy and topical corticosteroids, intent-to-treat
should be performed before treatment and according
analysis revealed that 44% to 50% of patients
to label repeated every other week.
Dosing of
1 02
achieved and maintained at least PASI-75 from 6
alefacept should be withheld whenever the CD4
months up to 36 months of ongoing efalizumab
count decreases below 250 cells/mL and dosing
therapy.
Efalizumab has also been shown to be
10 8 , 10 9
should be discontinued if the CD4 count remains
effective for hand and foot psoriasis in a phase IV,
10 2
below 250 cells/mL for 4 consecutive weeks.
randomized placebo-controlled trial.
11 6
Precautions
Alefacept therapy is not indicated for patients
Precautions
with a CD4 T-lymphocyte count below normal or in
Dose-related headache, fever, nausea, and vom-
those who are infected with HIV because of the
iting have been reported after initial dosing of
1 03 , 1 07 , 1 1 5
potential for acceleration of disease progression as a
efalizumab.
This may be minimized by the
result of CD4 T-lymphocyte count reduction in-
use of a lower, conditioning dose of 0.7 mg/kg of
duced by alefacept. Caution should be exercised in
efalizumab for the first weekly injection of efalizu-
patients who are at risk for or have a history of
mab. Some clinicians will premedicate patients with
malignancy or infection, espe cially clinically signif-
acetaminophen before the first few doses of efalizu-
icant infections. Alefacept is pregnancy category
mab but these symptoms typically resolve sponta-
B.
Recommendations for alefacept are listed in
neously after 3 weeks of treatment.
1 0 2
Table III
.
Efalizumab is not effective in treating psoriatic
arthritis
and psoriatic arthritis may develop or
11 7
Efalizumab: efficacy
recur in a small percentage of patients during
Efalizumab is a recombinant humanized mono-
efalizumab treatment of psoriasis. An advisory group
clonal IgG
antibody directed against the CD11a
report concludes that rebound on discontinuation of
1
subunit of LFA-1 that blocks LFA-1-mediated T-cell
efalizumab occurs in 14% of patients and particularly
adhesion. Blockade of LFA-1 interferes with T-lym-
in patients unresponsive to efalizumab treat-
phocyte activation, trafficking through blood vessels
ment.
Flares during therapy with efalizu-
11 1 , 1 12 , 1 1 8
into inflamed skin and T-lymphocyte reactiva-
mab, which may result in skin disease that is worse
tion.
Efalizumab is approved for the treatment
than at baseline, may occur in both responder and
10 3 -1 0 6
of adult patients with moderate to severe chronic
nonresponder patients. Treatment of these patients is
plaque psoriasis who are candidates for systemic
controversial; some physicians will add methotrex-
agents or phototherapy. Efalizumab is administered
ate or CyA and continue with efalizumab, whereas
subcutaneously by the patient. The recommended
others will immediately transition patients to another
dose is 0.7 mg/kg for the initiation dose followed by
systemic drug. Because of this risk, physicians
7 8
weekly 1-mg/kg doses thereafter.
The results of
should strongly consider transitioning to another
several phase III trials demonstrate that after 12
systemic agent when discontinuing efalizumab.
weeks of treatment with efalizumab, between 27%
Although the lymphocyte count increases in the
64 , 1 03 - 10 5 , 10 7 -1 1 5
and 39% of patients will have PASI-75.
blood and decreases in the skin in patients treated
After 24 weeks of continuous efalizumab therapy,
with efalizumab as a result of the drug decreasing
44% of patients achieved PASI-75. Efalizumab main-
migration of T cells out of the blood into the skin, this
tains, and in some patients continues to improve,
effect wears off rapidly. Because patients may rarely
efficacy during long-term therapy.
In a 3-year,
develop thrombocytopenia or hemolytic anemia
1 0 4 , 11 0
open-label, nonrandomized trial of efalizumab
during treatment with efalizumab and pancytopenia
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Table III. Recommendations for alefacept
Indication: moderate to severe psoriasis
d
Dosing: 15 mg every wk given as an intramuscular injection for
12 wk, with a 12-wk follow-up nontreatment period
d
Short-term results:
d
21% of patients achieved a PASI-75 at wk 14
Long-term results:
d
Associated with long remissions in a subset of responders
Prior response to alefacept is a likely marker of future
treatment response; thus, patients responding to the first course
of
therapy may be treated long-term with repeated 12-wk courses of
alefacepteat a minimum of 24-wk intervals
Toxicity: excellent safety profile in clinical trials
d
Baseline monitoring: CD4 count
d
Ongoing monitoring: biweekly CD4 count required; hold dose for
counts \250
d
Pregnancy category: B
d
Contraindications: HIV infection
d
PASI-75, 75% Improvement in the Psoriasis Area and Severity
Index score.
Table IV. Recommendations for efalizumab
Indication: moderate to severe psoriasis
d
Dosing: 0.7 mg/kg first dose followed by 1.0 mg/kg/wk
subcutaneously
d
Short-term response: 27% of patients achieve a PASI-75 at 3
mo
d
Long-term response: 44%-50% of patients achieved and maintained
a PASI-75 response in a 3-y open-label study that only
d
enrolled responders
Toxicities:
d
Flu-like symptoms frequently occur initially and generally
disappear after the third wk of treatment
Thrombocytopenia, hemolytic anemia, pancytopenia, and peripheral
demyelination have all been reported
Other issues:
d
Small percentage of patients may develop rebound or flare
Do not discontinue treatment abruptly unless essential
Not effective in psoriatic arthritis; flares and new-onset
psoriatic arthritis have been reported in a subset of patients
Baseline monitoring: CBC
d
Ongoing monitoring:
d
CBCs monthly for the first 3 mo and at periodic intervals
thereafter
LFT and a periodic history and physical examination are
recommended while on treatment
Pregnancy category: C
d
CBC, Complete blood cell count; LFT, liver function test;
PASI-75, 75% improvement in the Psoriasis Area and Severity Index
score.
Table V. The strength of recommendations for the
have also been reported.
Caution should be
1 20
treatment of psoriasis using tumor necrosis factor
exercised in patients who are at risk for or have a
inhibitors
history of malignancy or infection, especially clini-
cally significant infections. Efalizumab may decrease
St ren g th of
L ev e l o f
the immune response to other biologically inactive
R e com me n da tion
re com me n dat ion
e v ide n ce R e fe re nc es
vaccines. Efalizumab is pregnancy category C.
Rec-
78
Adalimumab A I 46, 47,
ommendations for efalizumab are listed in
Table IV
.
121, 122
Etanercept A I 32, 44,
TNF INHIBITORS FOR THE TREATMENT
123-129
OF PSORIASIS
Infliximab A I 45, 130-136
The potential importance of TNF-a in the patho-
physiology of psoriasis is underscored by the obser-
vation that there are elevated levels of TNF-a in both
1 1 9
has also been reported,
it is recommended that
the affected skin and serum of patients with psorias is.
all patients treated with efalizumab have a complete
These elevated levels have a significant correlation
blood cell count including a platelet count every
with psoriasis severity as measured by the PASI score.
month for the first 3 months and every 3 months
Furthermore, after successful treatment of psorias is,
afterward. Rare cases of peripheral demyelination
TNF-a levels are reduced to normal levels.
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Table VI. General recommendations for TNF inhibitors
Anti-TNF agents are contraindicated in patients with active,
serious infections
d
Tuberculosis testing (PPD) should be performed on all patients
who will be treated with TNF inhibitors as there are reports
d
of tuberculosis reactivation in patients treated with this class
of drug
17 7
Do not use with live vaccines; biologically inactive or
recombinant vaccines may be considered, although the immune
d
response of these vaccines could be compromised
Because there is an association between anti-TNF therapy and
demyelinating diseases (ie, MS), TNF inhibitors should not
d
be used in patients with MS or other demyelinating diseases;
first-degree relatives of patients with MS have an increased
risk of developing MS, with a sibling relative risk of between
18 and 36, evidence strongly suggesting that TNF inhibitors
should not be used in first-degree relatives of patients with
MS
Because there have been reports of new onset and worsening of
CHF in patients treated with TNF inhibitors, caution
d
should be used when considering TNF inhibitor use in patients
with CHF; it is recommended that patients with New York
Heart Association class III or IV CHF avoid all use of TNF
inhibitors and patients with class I or II CHF undergo
echocardiogram testing; if the ejection fraction of these
patients is \50%, then TNF inhibitor treatment should
potentially
be avoided
177
Hepatitis B reactivation after treatment with TNF inhibitors has
been reported; in the appropriate clinical setting, patients
d
should be screened for hepatitis B infection
CHF, Congestive heart failure; MS, multiple sclerosis; PPD,
purified protein derivation; TNF, tumor necrosis factor.
EFFICACY OF THE TNF INHIBITORS IN
occur when adalimumab is discontinued, however,
PSORIASIS
clearance is better maintained with continuous use
The strength of recommendations for the treat-
and there is loss of efficacy after restart of adalimu-
47
ment of psorias is using TNF inhibitors are shown in
mab.
Recommendations for adalimumab are listed
Table V
. The general recommendations for TNF
in
Table VII
.
inhibitors are listed in
Table VI
. The efficacy of the
3 TNF inhibitors in the treatment of psoriasis will be
Etanercept: efficacy
reviewed in alphabetic order.
Etanercept is a recombinant human TNF-a recep-
tor (p75) protein fused with the Fc portion of IgG1
Adalimumab: efficacy
that binds to soluble and membrane-bound TNF-
Adalimumab is the first fully human anti-TNF-a-
a.
Etanercept has demonstrated efficacy in the
4 4 , 12 3
monoclonal antibody. It binds specifically to soluble
treatment of several inflammatory diseases and is
and membrane-bound TNF-f and blocks TNF-f
currently approved for treatment of moderate to
interactions with the p55 and p75 cell surface TNF
severe plaque psoriasis, psoriatic arthritis, rheuma-
receptors.
Adalimumab is currently approved for
toid arthritis, juvenile rheumatoid arthritis, and an-
46
psoriasis, juvenile rheumatoid arthritis, ankylosing
kylosing spondylitis. The dosing of etanercept differs
spondylitis, psoriatic arthritis, adult rheumatoid ar-
in psoriasis than for its other indications. The ap-
thritis, and Crohns disease. Adalimumab dosing for
proved regimen is 50 mg given subcutaneously twice
psoriasis is 80 mg given subcutaneously the first
weekly for the first 12 weeks followed by 50 mg
week, followed by 40 mg subcutaneously given the
weekly thereafter. Dosing is continuous.
The effi-
8 9
next week and then every 2 weeks thereafter.
cacy of etanercept has been demonstrated in many
1 2 1 ,1 2 2
In the phase III studies of adalimumab, 1212
clinical trials.
At week 12 there was an
3 2 ,4 4 , 1 24 -1 2 6
patients were randomized to receive adalimumab
improvement from baseline of PASI-75 or more in
(given as 80 mg at week 1, 40 mg at week 2, and then
34% of the etanercept group receiving 25 mg twice
40 mg every other week) or placebo for the first 15
weekly and 49% of the etanercept group receiving 50
weeks. At week 16, 71% of patients treated with
mg twice weekly, as compared with 4% of the
adalimumab and 7% treated with placebo achieved
patients in the placebo group (P \ .001 for both
60 , 1 2 3, 1 2 7, 1 2 8
at least PASI-75. During weeks 33 to 52, the percent-
comparisons with the placebo group).
age of patients rerandomized to placebo who lost
The clinical responses continued to improve with
adequate response (defined as 50% improvement in
longe r treatment. At week 24, there was at least PASI-
the PASI score and at least a 6-point increase in PASI
75 in 44% of those in the 25 mg twice weekly group,
1 27
score from week 33) was 28% compared with 5% of
and 59% in the 50 mg twice weekly group.
Some
patients treated continuously with adalimumab.
patients will show a loss of clinical response after 12
4 7
Adalimumab is used continuously, at a dosage of
weeks when the weekly dose is reduced from 50 mg
40 mg every other week. Rebound does not typically
twice weekly to 50 mg once weekly.
840 Menter et al
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Table VII. Recommendations for adalimumab
Indications: moderate to severe psoriatic arthritis, moderate to
severe psoriasis, adult and juvenile rheumatoid arthritis (as
d
young as age 4 y), ankylosing spondylitis, and Crohns
disease
Dosing for psoriasis: 80 mg the first wk, 40 mg the second wk,
followed by 40 mg every other wk given subcutaneously
d
Short-term results: 80% of patients achieve PASI-75 at 12 wk
d
Long-term results: 68% of patients achieve PASI-75 at 60 wk
d
Small percentage of patients lose efficacy with continued
use
d
Toxicities:
d
Moderately painful injection site reactions are noted
Rare reports of serious infections (ie, tuberculosis and
opportunistic infections) and malignancies
There are rare reports of drug-induced, reversible side effects
including lupus without renal or CNS complications,
cytopenia, MS, and exacerbation of and new onset of CHF
Baseline monitoring:
d
PPD is required
LFT, CBC, and hepatitis profile
Ongoing monitoring:
d
Periodic history and physical examination are recommended while
on treatment
Consider a yearly PPD, and periodic CBC and LFT
Pregnancy category B
d
CBC, Complete blood cell count; CHF, congestive heart failure;
CNS, central nervous system; LFT, liver function test; MS, multiple
sclerosis;
PASI-75, 75% improvement in the Psoriasis Area and Severity
Index score; PPD, purified protein derivation.
Table VIII. Recommendations for etanercept
Indications: moderate to severe psoriasis, moderate to severe
psoriatic arthritis, adult and juvenile rheumatoid arthritis
(as
d
young as 4 y), and ankylosing spondylitis
Dosing: 50 mg twice/wk given subcutaneously for 3 mo followed by
50 mg once/wk
d
Short-term results: 49% of patients given 50 mg twice/wk
achieved a PASI-75 at 12 wk; 34% of patients given 25 mg
d
twice/wk achieved a PASI-75 at 12 wk
Step-down results: 54% of patients whose dose was decreased from
50 mg twice/wk to 25 mg twice/wk achieved a PASI-
d
75 at 24 wk; 45% of patients whose dose remained at 25 mg
twice/wk achieved a PASI-75 at 24 wk
Toxicities:
d
Mildly pruritic injection site reactions may occur
Rare cases of serious infections (ie, tuberculosis) and
malignancies
There are also rare cases of drug-induced, reversible side
effects including lupus without renal or CNS complications,
cytopenia, MS, and exacerbation and new onset of CHF
Baseline monitoring:
d
PPD is required
LFT and CBC
Ongoing monitoring
d
Periodic history and physical examination are recommended while
on treatment
Consider yearly PPD, and periodic CBC and LFT
d
Pregnancy category B
d
Contraindications: sepsis
d
CBC, Complete blood cell count; CHF, congestive heart failure;
CNS, central nervous system; LFT, liver function test; MS, multiple
sclerosis;
PASI-75, 75% improvement in the Psoriasis Area and Severity
Index score; PPD, purified protein derivation.
In rheumatoid and psoriatic arthritis, TNF inhib-
antibodies. Recommendations for etanercept are
itors including etanercept are often used in combi-
listed in
Table VIII
.
nation with methotrexate. In psoriasis, all clinical
studies have been performed with etanercept as
Pediatric psoriasis
monotherapy. Rebound does not typically occur
In a study ofetanercept treatment for children and
1 2 3, 1 2 6 , 12 8
when etanercept is discontinued.
An im-
adolescents (ages 4-17 years) with plaque psoriasis
portant issue to consider with etanercept, as with
who were dosed once weekly with 0.8 mg/kg of
other TNF inhibitors, is the potential loss of efficacy
etanercept (up to a maximum of 50 mg), 57% of
over time, possibly related to the development of
patients receiving etanercept achieved PASI-75 as
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Table IX. Recommendations for infliximab
Indications: severe psoriasis, moderate to severe psoriatic
arthritis, adult rheumatoid arthritis, ankylosing spondylitis,
d
ulcerative colitis, and Crohns disease
Dosing: 5 mg/kg dose infusion schedule at wk 0, 2, and 6 and
then every 6-8 wk; dose and interval of infusions may be
d
adjusted as needed
Short-term response: 80% of patients achieved a PASI-75 at wk
10, 50% PASI improvement noted by wk 2
d
Long-term response: 61% of patients achieved a PASI-75 at wk
50
d
Toxicities:
d
Infusion reactions and serum sickness can occuremore commonly in
patients who have developed antibodies
The incidence of infusion reactions may be reduced by concurrent
administration of methotrexate
Rare cases of serious infections (ie, tuberculosis) and
malignancies including hepatosplenic T-cell lymphoma (in
children);
there are rare reports of drug-induced, reversible side effects
including lupus without renal or CNS complications,
cytopenia, MS, and exacerbation of and new onset of CHF
Baseline monitoring:
d
PPD is required
LFT, CBC, and hepatitis profile
Ongoing monitoring:
d
Periodic history and physical examination are recommended while
on treatment
Consider a yearly PPD, and periodic CBC and LFT
Pregnancy category B:
d
Contraindications: infliximab at doses [ 5 mg/kg should not be
given to patients with New York Heart Association
d
functional class III or IV CHF
CBC, Complete blood cell count; CHF, congestive heart failure;
CNS, central nervous system; LFT, liver function test; MS, multiple
sclerosis;
PASI-75, 75% improvement in the Psoriasis Area and Severity
Index score; PPD, purified protein derivation.
compared with 11% of those receiving placebo
maintaining clinical efficacy over time.
In the
4 5
(P \ .001).
pivotal phase III trial of infliximab, although 80% of
1 2 9
patients achieved PASI-75 at week 10, by week 50,
61% of patients treated with infliximab (5 mg/kg at 8-
In iximab: efficacy
week intervals) maintained PASI-75.
A 91%
45 , 1 36
In iximab is a chimeric antibody constructed
improvement in the Dermatology Life Quality
from murine and human DNA sequences comprising
Index occurred after 10 weeks of therapy with
a mouse variable region and human IgG1-
a constant
infliximab.
Recommendations for infliximab are
1 32
region. In iximab binds to both the soluble and the
listed in
Table IX
.
transmembrane TNF-a molecules, thereby neutral-
izing the effects of TNF-a.
1 3 0
GENERAL SAFETY ISSUES OF THE TNF
In iximab is approved for the treatment of pso-
INHIBITORS
riasis and psoriatic arthritis, adult rheumatoid arthri-
tis, ankylosing spondylitis, Crohns disease in adults
The TNF inhibitors have been available for more
and children, and ulcerative colitis. In iximab is
than 10 years, predominantly for in ammatory
administered intravenously at a dose of 5 mg/kg over
bowe l disease and rheumatoid arthritis with more
2 to 3 hours at weeks 0, 2, and 6 and then every 8
than 1.5 million patients being dosed with the 3
weeks for psoriasis and psoriatic arthritis.
Patients
agents. In recent years, the indications for use of TNF
9 0
are less likely to develop antibodies against inflix-
inhibitors have expanded to their use in psoriasis and
imab (or human antichimeric antibodies) if they are
psoriatic arthritis among other diseases. The follow-
continuously treated with infliximab rather than on
ing discussion about the safety of the TNF inhibitors
an as-needed basis and clinical responses are better
is derived in large part from observations made from
maintained with continuous compared with inter-
their use in rheumatoid arthritis and in ammatory
4 5, 1 3 1 -1 3 5
mittent therapy.
Approximately 80% of pa-
bowe l disease (
Table VI
). Patients with both rheu-
tients achieve PASI-75 at week 10 (after 3 doses of
matoid arthritis and inflammatory bowel disease are
infliximab). Infliximab is remarkable for the rapidity
often treated with the combination of TNF inhibitors
of clinical response. Loss of efficacy over time
and an immunosuppressive agent (methotrexate or
may also occur with infliximab therapy. Some
azathioprine), whereas patients with psoriasis are
dermatologists prescribe low-dose methotrexate
most often treated with the TNF inhibitors as mono-
concurrently with the goal of decreasing the forma-
therapy. It, therefore, seems possible that extrapola-
tion of antibodies against infliximab and, hence,
tions regarding the safety of TNF inhibitors derived
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from this combination therapy data may overesti-
methotrexate with lamivudine can stabilize hepatitis
1 44
mate the potential risk of these agents when used as
B viral disease activity.
Given the lack of prospec-
monotherapy in psoriasis. In addition, as discussed,
tive randomized controlled trials using TNF-a antag-
patients with psoriasis may have distinctive comor-
onists in patients with hepatitis B infection, screening
bidities that distinguish them from patients with
patients for hepatitis B before treatment with anti-
either rheumatoid arthritis or Crohns disease.
TNF therapy should be cons idered in the appropriate
clinical setting. There is an FDA warning suggesting
Infections: bacterial, viral, and mycobacterial
that patients who have concurrent hepatitis B infec-
All of the TNF inhibitors carry the potential for an
tion should not be treated with any of the TNF
increased risk ofinfection with upper respiratory tract
inhibitors.
90
infections being the most common. Serious infections
TNF-a plays an important role in the host re-
are uncommon, with patients with underlying
sponse against TB.
Reactivation of TB has been
1 45 , 1 4 6
predisposing medical conditions being more at risk.
associated with TNF inhibitors and patients under-
Rare opportunistic infections, including histoplasmo-
going anti-TNF therapy are at higher risk for devel-
sis, listeriosis, coccidioidomycosis, cryptococcosis,
oping TB. In addition to several case reports of TB
aspergillosis, candidiasis, and pneumocystis,
reactivation in patients on anti-TNF therapy, registry
1 37 -1 3 9
have been reported more often in patients treated
data from patients with rheumatoid arthritis and
with anti-TNF antibodies such as infliximab or
postmarketing reports to the FDA have identified
adalimumab than in those treated with fusion protein
numerous cases of TB reactivation associated with all
receptor drugs such as etanercept. However, many
3 TNF inhibitors. Importantly, there is an increased
of these patients were also treated with other immu-
incidence of extrapulmonary or disseminated cases
nosuppressive agents, such as methotrexate, sys-
of TB occurring in patients on anti-TNF therapy.
temic corticosteroids, or both. Despite the rarity
Although there is an increased risk of reactivation of
and sometime subtlety of clinical presentation of
TB with etanercept treatment compared to the gen-
these types of potentially serious infections, careful
eral population, it is likely to be less frequent than
with infliximab or adalimumab treatment.
The
14 7
monitoring and early evaluation is critical. In the
FDA recommends TB screening with a purified
event of an infection requiring antibiotic therapy, the
protein derivation for adalimumab, etanercept, and
TNF inhibitor should be withheld and in the event of
infliximab. Furthermore, the Centers for Disease
more serious infections or opportunistic infections,
the TNF inhibitor should be discontinued. Treatment
Control and Prevention also recommends TB screen-
with TNF inhibitors should be avoided if possible
ing with a purified protein derivation for all patients
in patients with chronic, serious, or recurring
being treated with TNF inhibitors.
Patients at
14 8
infections.
increased risk for TB, eg, institutional workers and
1 4 0
There are elevated levels of TNF-a in patients with
frequent travelers abroad, must be carefully
hepatitis C compared with control subjects suggest-
screened at appropriate intervals.
ing that TNF-a may be involved in the pathogenesis
of hepatocyte destruction in chronic hepatitis C
Neurologic disease
infection.
There is one prospective study and
Both peripheral and central demyelinating disor-
1 4 1
one small randomized, double-blind, placebo-con-
ders, including MS, have been reported to not only
trolled study suggesting that anti-TNF therapy may
to develop but also to worsen in patients taking
be safe to use in chronic hepatitis C infection.
TNF-a antagonists.
These medications
1 4 2, 1 4 3
8 9, 1 4 9 -1 52
However, these data are preliminary, and one must
should be avoided in the setting of a personal history
exercise great caution when considering anti-TNF
of demyelinating conditions. First-degree relatives of
therapy in patients with concomitant chronic hepa-
patients with MS have an increased risk of MS, with a
titis C infection. Consultation with liver specialists as
sibling relative risk of between 18 and 36, evidence
indicated may be appropriate when considering the
strongly suggesting that TNF inhibitors should not
use of anti-TNF therapy in this setting. Interval
be used in first-degree relatives of patients with
1 53 , 1 54
monitoring of serum aminotransferases and hepatitis
MS.
Although some patients symptoms of
C viral load are also recommended in this setting.
demyelinating disease have abated despite contin-
TNF-a promotes viral clearance in hepatitis B
ued TNF inhibition, other reports demonstrate that
infection in animals; this is different from its role in
patients who develop neurologic symptoms sugges-
hepatitis C where it is thought to promote chronic
tive of MS after treatment with a TNF inhibitor resolve
liver injury. Treatment with in iximab 6 methotrex-
after the TNF inhibitor is stopped.
Onset of new
1 5 0
ate can reactivate chronic hepatitis B viral infection,
neurologic symptoms in a patient on TNF-a inhibi-
yet concurrent treatment with in iximab 6
tors that suggest the development of a demyelinating
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13 6
disorder should be promptly evaluated by a neurol-
aminotransferase.
After 24 weeks of treatment
ogist while the TNF inhibitor is withheld.
with infliximab, 6% and 2% of patients in the
infliximab group had markedly abnormal increases
in alanine aminotransferase and aspartate amino-
Heart disease
The issue of prescribing TNF-a blockers in pa-
transferase, respectively (defined as [150 U/L and
tients with congestive heart failure (CHF) is some-
100% increase from baseline), compared with none
what controversial. Several studies have evaluated
in the placebo group.
In 2004, the FDA issued a
13 6
the use of etanercept and in iximab in CHF. The
warning that hepatic disease, including severe he-
etanercept studies were either terminated early as a
patic failure, might complicate infliximab therapy.
1 6 2
result of lack of efficacy
or showed no benefit on
These cases included patients who were also taking
1 55
CHF morbidity or mortality
whereas one inflix-
multiple concomitant drugs some of which were
15 6
imab study revealed an increased mortality caused
known to be hepatotoxic. No similar reports of
by CHF in the highest dose group (10 mg/kg). There
hepatotoxicity caused by etanercept or adalimumab
is, however, preliminary evidence that TNF-a block-
have been published. Risks associated with viral
ade could be of benefit to the failing heart as one
hepatitis are discussed above.
report found the incidence of CHF in patients with
rheumatoid arthritis on either infliximab or etaner-
Lymphoma
cept to be significantly lower than in those not on
The potential risk of lymphoma induction by the
1 5 7
TNF inhibitors.
TNF inhibitors is a much-debated issue. As discussed
Moreover, another study demonstrated a dose-
previous ly, patients with psoriasis may have an
dependent improvement in both left ventricular
increased risk of lymphoma (particularly Hodgkins
21 , 2 2
function and CHF in patients being treated with
lymphoma and cutaneous T-cell lymphoma).
1 58
etanercept.
We recommend that TNF inhibitors be
While a consensus panel of experts reviewing the
avoided in patients with severe CHF (New York
clinical trial evidence concluded that the overall risk
Heart Association class III or IV) and those with
of malignancies including lymphoma was not in-
milder CHF should have their TNF inhibitors with-
creased over baseline levels in patients with rheu-
drawn at the onset of new symptoms or worsening of
1 4 9
matoid arthritis being treated with TNF inhibitors,
pre-existing CHF.
clinical trials are underpowered to evaluate the risk
of rare events such as cancer.
However, there have
1 6 3
Drug-induced lupus-like syndromes
been numerous anecdotal cases of lymphomas
The development of or an increase in the levels of
reported in patients being treated with TNF inhibi-
circulating antinuclear antibodies may occur in pa-
tors, and many of these have resolved after discon-
tients taking any of the 3 anti-TNF agents. Although
tinuation of the drug.
Therefore, one should
1 64
there hav e been several reported cases of patients
carefully consider the decision to use TNF antagonist
who developed signs and symptoms of systemic
in patients with a history of malignancy, particularly
lupus erythematosus while receiving anti-TNF ther-
lymphoma.
apy,
this condition may be reversible on cessation
15 9
of the drug. To date, there have been only anecdotal
Melanoma and nonmelanoma skin cancer
reports of full-blown systemic lupus erythematosus
The potential risk of melanoma, cutaneous T-cell
including renal or central nervous system involve-
lymphoma, and nonmelanoma skin cancer in pa-
ment induced by anti-TNF therapy. There are, like-
tients treated with the TNF inhibitors has been raised
wise, case reports in which treatment with
by several case reports.
1 6 5- 1 69
etanercept was associated with disappearance of
A large observational study of patients with rheu-
1 6 0, 1 6 1
subacute cutaneous lupus erythematosus.
matoid arthritis demonstrated an increased risk for
Although clinicians treating patients with anti-TNF
the development ofnonmelanoma skin cancer (odds
agents need to be aware of this entity, it is not
ratio 1.5, 95% confidence interval 1.2-1.8) and a trend
necessary to evaluate patients for antinuclear anti-
toward increased risk of melanoma (odds ratio 2.3,
bodies or to conduct other serologic tests before or
95% confidence interval 0.9-5.4) in patients treated
during anti-TNF therapy unless clinical symptoms
with biologic agents (largely the 3 TNF inhibitors).
warrant.
Importantly, this large study also demonstrated no
1 7 0
increased risk of any other types of solid cancers.
Hepatic disease
These findings contrast with the results of a
In the phase III trial of in iximab, patients
meta-analysis of rheumatoid arthritis studies examin-
treated with monotherapy in iximab had elevated
ing patients treated with adalimumab and infliximab,
levels of aspartate aminotransferase and alanine
which revealed an increased risk of solid cancers.
1 7 1
844 Menter et al
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Hematologic disease
intervals are likely to have a lowered incidence of
Aplastic anemia, isolated leukopenia, and throm-
infusion reactions.
bocytopenia have been reported in individual pa-
Rare postmarketing cases of hepatosplenic T-cell
tients treated with TNF antagonists.
These
lymphoma have been reported in adolescent and
1 7 2 , 17 3
appear to be isolated cases but it is prudent to
young adult patients with Crohns d
