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Contributors

EDITORS HENRY W. LIM, MD

Chairman and Clarence S. Livingood Chair
JASHIN J. WU, MD Department of Dermatology
Los Angeles, CA, USA Henry Ford Hospital
Detroit, MI, USA
STEVEN R. FELDMAN, MD, PhD
Departments of Dermatology, Pathology, and
Public Health Sciences ELAINE J. LIN, MD
Wake Forest School of Medicine Department of Dermatology
Winston-Salem, NC, USA University of California—Davis
Sacramento, CA, USA
MARK G. LEBWOHL, MD
Professor and Chair
Kimberly and Eric J. Waldman Department LAUREN M. MADIGAN, MD
of Dermatology Department of Dermatology
Icahn School of Medicine at Mount Sinai Henry Ford Hospital
New York, NY, USA Detroit, MI, USA

AUTHORS CATHERINE NI, MD

David Geffen School of Medicine
JOHANN E. GUDJONSSON, MD, PhD University of California—Los Angeles
Frances and Kenneth Eisenberg Emerging Los Angeles, CA, USA
Scholar
Taubman Medical Research Institute
Assistant Professor JOHN K. NIA, MD
Department of Dermatology Clinical Dermatopharmacology Fellow
Director of Inpatient and Consultation Department of Dermatology
Dermatology Icahn School of Medicine at Mount Sinai
University of Michigan New York, NY, USA
Ann Arbor, MI, USA

PETER W. HASHIM, MD, MHS AMIT OM, BS

Clinical Dermatopharmacology Fellow Center for Dermatology Research
Department of Dermatology Department of Dermatology
Icahn School of Medicine at Mount Sinai Wake Forest School of Medicine
New York, NY, USA Winston-Salem, NC, USA

DANE HILL, MD
Center for Dermatology Research SANDRA PENA, BS
Department of Dermatology Center for Dermatology Research
Wake Forest School of Medicine Department of Dermatology
Winston-Salem, NC, USA Wake Forest School of Medicine
Winston-Salem, NC, USA

MICHAEL KELLY-SELL, MD
Department of Dermatology SHIVANI P. REDDY, BS
University of Michigan University of Illinois College of Medicine
Ann Arbor, MI, USA Chicago, IL, USA

vii
 VIDHI V. SHAH, BA ANJALI S. VEKARIA, MD
University of Missouri–Kansas City School of Resident
Medicine Department of Dermatology
Kansas City, MO, USA Icahn School of Medicine at Mount Sinai
New York, NY, USA

viii
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Therapy for Severe Psoriasis ISBN: 978-0-323-44797-3

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Therapy for
Severe Psoriasis

JASHIN J. WU, MD
Los Angeles, CA, USA

STEVEN R. FELDMAN, MD, PhD

Departments of Dermatology,
Pathology, and Public Health Sciences
Wake Forest School of Medicine
Winston-Salem, NC, USA

MARK G. LEBWOHL, MD
Department of Dermatology
Icahn School of Medicine at Mount Sinai
New York, NY, USA
Foreword

Our knowledge of the genetics and immuno-

pathogenesis of psoriasis has exploded over the
past two decades to the extent that psoriasis
now has to be considered a systemic disease for
a significant percentage of patients having other
organ involvement, including the joints. Thus,
more than 40 genes have been shown to be asso-
ciated with psoriasis. However, a much smaller
number of genes are associated with psoriatic
arthritis, throwing into doubt the actual specific
Alan Menter, MD association between psoriasis and psoriatic
arthritis. The severity of cutaneous inflammation
Psoriasis is a common, immune-medicated, ge- is frequently “mirrored” systemically in the
netic disorder affecting up to 2% of the world bloodstream with potential negative sequelae
population with significant interracial variation, for the heart, especially the coronary vasculature,
being far less common in Africa, Asia, and North as well as the liver, including steatohepatitis. In
America Indians than in Scandinavian countries, addition, psoriasis has been shown to be statisti-
Northern Europe, and the Americas. Men and cally associated with a relatively long list of other
women, boys and girls, are equally affected, comorbidities, including obesity; with the full
with the majority of patients developing their dis- spectrum of the metabolic syndrome, including
ease before the age of 40. obesity, hypertension, diabetes mellitus, and
Psoriasis shares much of its ancient history hypercholesterolemia; and with hypertriglyceri-
with leprosy, with Biblical references to leprosy demia. Other conditions, including sleep apnea,
likely representing actual psoriasis. Hippocrates chronic obstructive pulmonary disease, and renal
in fact described a series of skin disorders under disease, are also linked to psoriasis.
the heading “Lopoi,” Greek for epidermis, which Psoriasis likewise has a major effect on patients’
possibly included both psoriasis and leprosy. The quality of life with social and personal interactions
term “psoriasis” was derived from the Greek for frequently disrupted due to the visible nature of
epidermis, which possibly included both psoriasis the disabling condition, leading to depression, fa-
and leprosy. The term “psoriasis,” derived from tigue, and indeed a higher likelihood of suicidal
the Greek “psora” meaning “itch,” was first ideation, especially in younger patients.
used by Galen (133-200 AD). Sixteen centuries It is thus incumbent on all dermatologists with
later, Robert Willan (1757-1812) published the an interest in the fascinating disorder not only to
first true description of psoriasis in 1808. assess each and every psoriatic patient’s total skin
Psoriasis is not “one disease.” It has a vast surface, head to toe, at each consultation but also
array of clinical phenotypes with the classic “pla- to evaluate for comorbidities, including psoriatic
que” form being the commonest. It can vary joint disease and psychosocial issues. Collabora-
from a few discrete areas of activity, such as tion with colleagues in other specialties, including
the scalp, elbow, and knees, to generalized cuta- cardiology, endocrinology, hepatology, general
neous involvement with various forms, shapes, internal medicine, and family practice, is
and sizes of individual lesions. In addition, frequently indicated for the betterment of the
numerous other phenotypical manifestations health of the psoriatic population as a whole. In
can include guttate, erythrodermic, inverse, patients with less severe psoriasis, who account
and palmar-plantar forms, either individually or for approximately 75% of the psoriatic popula-
in association with the classic plaque-type dis- tion, topical agents are the treatment of choice
ease. Chapters in this book address multiple in the overwhelming majority. For the remaining
classes of therapy currently available for the 25% with moderate to severe psoriasis, the
treatment of psoriasis, together with investiga- wide array of systemic therapies, both oral and
tional new drugs and the advent of biosimilar injectable, offers the opportunity to maximize
agents. the benefits of treatment to our psoriasis ix
x Foreword

population, both short term and long term, while

also reducing the impact of the multiple comor-
bidities associated with the more severe forms
of psoriasis. Thus, the future for our psoriasis
population is exciting indeed.

Alan Menter, MD
Chair, Department of Dermatology
Clinical Professor of Dermatology
University of Texas Southwestern Medical School
Dallas, TX, USA
Preface

Jashin J. Wu, MD, Editor Steven R. Feldman, MD, PhD, Editor Mark G. Lebwohl, MD, Editor

The first edition of Therapy for Severe Psoriasis fills an insight into therapies in the pipeline that may
the need for an up-to-date resource for the rapidly be approved in the near future.
changing treatment arena for severe psoriasis. High- We hope that this textbook serves as both a
lights of this book are chapters devoted to newly reference book and a practical guide in treating
approved therapies such as apremilast, secukinu- patients with severe psoriasis. We look forward
mab, ixekizumab, and biosimilars. This is the golden to further advances in therapy for severe psoriasis
era for treating patients with severe psoriasis. As in the coming years, and we plan to update this
more and more medications are approved, each textbook with a second edition in a few years’ time.
wave seems to demonstrate higher efficacy with
minimal adverse events. It is hoped that this text-
book summarizes and guides the dermatologist in ACKNOWLEDGMENTS
learning and choosing among the myriad of options. The editors thank Russell Gabbedy, Colleen Viola, Louise
The lead authors of each chapter are world Cook, and others at Elsevier for their steady support over
leaders in their fields regarding their topics, and the 6-month period of writing, revising, and editing this
we thank them and their coauthors in textbook. The editors acknowledge the patients who
developing comprehensive but readable chap- allowed their photos to be used for educational pur-
ters. The opening chapter gives an updated poses like this and also for giving the authors inspiration
overview of psoriasis, including epidemiology, in developing strategies to treat their severe psoriasis.
pathogenesis, and clinical findings in each of the
subtypes of psoriasis. Each chapter devoted to Jashin J. Wu, MD
therapy has a concluding paragraph that frames
Steven R. Feldman, MD, PhD
the therapy in their own “expert” algorithm of
when to use the treatment. The final chapter gives Mark G. Lebwohl, MD

xi
CHAPTER 1
Overview of Psoriasis
Michael Kelly-Sell, MD, Johann E. Gudjonsson, MD, PhD

KEYWORDS
 Psoriasis  Plaque psoriasis  Clinical subtypes  Pustular psoriasis  Nail psoriasis
 Comorbidities

KEY POINTS
 Today, psoriasis is a global disease causing significant impairment in quality of life, disfiguring
morbidity, and increased mortality.
 Psoriasis affects men and women equally. Two-thirds of patients are thought to have mild disease,
and one-third of patients are thought to have more severe involvement.
 Psoriasis is found in practically all racial groups and is thought to affect approximately 2% of the
world’s population.
 Psoriasis may appear at any age, but it most commonly presents between the ages of 15 and 30.
 Over the last 20 years, many of the immunologic drivers of psoriasis have been uncovered, and this
research has been translated to the clinic with the development of increasingly powerful but
selective biologic drugs targeting these immune pathways.

Psoriasis was first described by the ancient Greeks, EPIDEMIOLOGY

Hippocrates and Galen, and grouped together Psoriasis affects male and female patients equally.
with leprosy. The term psoriasis was derived from Two-thirds of patients are thought to have mild
the Greek “psora” which means an, “itch, mange, disease, and one-third of patients are thought to
scab.” In the early nineteenth century, Robert have more severe involvement. Psoriasis is found
Wilan and Hebra refined the description of psoria- in practically all racial groups and is thought to
sis and distinguished it from leprosy. In 1879, affect approximately 2% of the world’s popula-
Koebner described the appearance of psoriatic le- tion. Although psoriasis is a global disease, there
sions at sites of injury, called the “Koebner phe- are some regional variations in prevalence, with
nomenon.” Today, psoriasis a global disease rates varying from 0.4% in Asians to 2.6% in the
affecting 125 million people across the world and United States and 2.9% in Denmark. In Africa,
causing significant impairment in quality of life, dis- there is a higher prevalence in East Africans as
figuring morbidity, and even mortality. In the late opposed to West Africans, which may help
twentieth century, basic science research demon- explain racial differences within the United States.
strated that psoriasis is an immune-mediated poly- Interestingly, a study of 26,000 South American
genic disorder that can be triggered by various Native Americans did not document a single
environmental triggers. Over the last 20 years, case of psoriasis.
many of the immunologic drivers of psoriasis
have been uncovered, and this research has been
translated to the clinic with the development of AGE OF ONSET
increasingly powerful but selective biologic drugs Psoriasis may appear at any age, but it most
targeting these immune pathways. This increased commonly presents between the ages of 15 and
understanding of the immunology of psoriasis 30. An earlier age of onset and family history
has led to remarkable improvements in the treat- have been associated with particular HLA class I
ment of psoriasis and makes it an exciting time to antigens, most notably HLA-Cw6. Based on this
care for patients with psoriasis. finding, Henseler and Christophers1 proposed

1
2 Therapy for Severe Psoriasis

that 2 different forms of psoriasis exist: type I pso- center with increasing parakeratosis, capillary
riasis, with onset before the age of 40; and type II elongation, and perivascular infiltration of various
psoriasis, with age of onset after the age of 40. types of immune cells. Mature psoriatic lesions
Both types of psoriasis respond similarly to contain elongated and uniform rete ridges with
treatment. thinning of the epidermis overlying the dermal
papillae. The tips of the rete ridges may become
Cause and Pathogenesis clubbed with dilated, tortuous capillaries in the
The root cause of psoriasis remains unknown. How- dermal papillae. There is typically confluent para-
ever, research is beginning to link the complex ge- keratosis and hyperkeratosis.5 More inflammatory
netic, biochemical, and immunologic abnormalities cells are present with CD41 T cells and dendritic
that underlie the disease. These changes can be cells in the upper dermis and CD81 T cells in the
seen in both psoriatic lesions and normal- epidermis. Neutrophils are commonly seen in pso-
appearing skin of psoriatic patients. riatic lesions and form characteristic collections in
There is strong evidence suggesting at least a the spinous layer (spongiform pustules of Kogoj)
partial genetic basis in psoriasis. Genome linkage and in the stratum corneum (Munro microab-
studies in the 1990s identified a locus termed pso- scesses). Eosinophils are not seen in psoriasis, un-
riasis susceptibility 1 (PSORS1) in the major histo- less the disease is drug induced.
compatibility complex (chromosome 6p21.3),
home of the HLA genes.2 Many HLA markers
have been associated with psoriasis, but HLA- T CELLS
Cw6 has constantly demonstrated the highest The role of T cells in psoriasis was first documented
relative risk for psoriasis in Caucasian popula- in the 1980s, and the last 30 years of scientific and
tions.3 HLA-Cw6 is also strongly associated with clinical research on psoriasis have further high-
early onset, guttate psoriasis, and psoriatic lighted their role in the pathophysiology of the dis-
arthritis. However, only about 10% of HLA-Cw6 ease. The latest biologic medications for psoriasis
carriers develop psoriasis and the PSORS1 may ac- target T-cell immune pathways, and their ability to
count for only one-third of the genetic liability to clear plaques underlines the importance of the
psoriasis.4 In recent years, additional genetic risk T-cell pathways these medications target.
variants have been identified for psoriasis, with In 1984, Dr Baker and colleagues6 were the
more than 60 genetic loci identified to date. These first to show a correlation between the eruption
findings confirm the polygenic nature of psoriasis of psoriatic skin lesions and the epidermal influx
and also its heterogeneity because most patients and activation of T cells. Subsequently, deletion
carry different combinations of these risk variants, of epidermal T cells was shown to predate resolu-
and this may influence clinical course of the dis- tion of psoriatic plaques in patients on photother-
ease as well as therapeutic responses. apy.7 In 1986, cyclosporine was shown to be
highly efficacious in treating psoriasis due to its
blockade of T-cell function.8 Ten years later in
DEVELOPMENT OF A LESION 1996, activated autologous T cells initiated psori-
Psoriasis is characterized clinically by red and scaly atic lesions when injected into uninvolved psori-
plaques sharply demarcated from normal skin. atic skin transplanted onto severe combined
Histologically, it is characterized by marked prolif- immunodeficient mice.9 This showed that T cells
eration of keratinocytes, altered epidermal differ- were sufficient to induce a psoriatic process.
entiation, and proliferation of endothelial cells More recently, using xenograft models where hu-
accompanied by an influx of a variety of inflamma- man skin is grafted onto immunodeficient mice,
tory cells. The development of a psoriatic lesion trafficking of T cells to the epidermis, particularly
is a complex and multicellular process that CD81 T cells, was shown to be critical for devel-
involves keratinocytes, T cells, dendritic cells, mac- opment of psoriatic plaques, highlighting the
rophages, mast cells, endothelial cells, and neutro- importance of these cells in psoriasis.
phils. Cytokines and growth factors initiate and Psoriatic lesions are typified by T helper 1 (Th1)
sustain inflammation in this process through path- polarized CD41 cells and T cytotoxic 1 (Tc1)
ways that involve cells of both the innate and the polarized CD81 T cells producing interferon
acquired immune systems. Initial pinhead-sized (IFN)-g, which is the dominant cytokine profile of
macular lesions show edema and mononuclear psoriatic lesions.10 IFN-g drives the production
cell infiltrates within the upper dermis. The over- of interleukin-12 (IL-12) and IL-23 by dendritic
lying epidermis becomes spongiotic, and there is cells. IL-23 supports and expands CD41 T cells,
a focal loss of the granular layer. As the plaque ma- and likely CD81 T cells, that produce IL-17 and/or
tures, the epidermis becomes thickened in the IL-22, whereas IL-12 promotes development of
 Chapter 1 Overview of Psoriasis 3

Th1 and Tc1 cells. The secretion of IL-17 and IL-22 enzymes. These changes lead to histopathologic
by these cell types likely maintains the chronic findings that can be identified on microscopic ex-
inflammation in psoriasis,11,12 but the exact role amination and have been termed “histochemical
of IFN-g in this process is still unclear. T cells parakeratosis.”
also contribute to the production of tumor necro-
sis factor-a (TNF-a), but TNF-a is a potent proin-
flammatory cytokine, the main role of which may CLINICAL FINDINGS
be to amplify the effect of other cytokines, History
including IFN-g and TNF-a. Biologic medications In approaching a patient with psoriasis, it is impor-
targeted at inhibiting these inflammatory media- tant for the clinician to obtain a thorough personal,
tors, including TNF-a, IL-12/IL-23, and IL-17, family, and social history because it often will influ-
have shown great efficacy in treating psoriasis, ence the choice of therapeutic agent. Relevant in-
underlining the important role this molecule plays formation includes the age of onset of psoriasis
in driving the disease. and whether psoriasis is present in any close rela-
tives, because both a younger age of onset and
a positive family history have been associated
MACROPHAGES AND DENDRITIC CELLS with more widespread and recurrent disease.18
Macrophages are important phagocytic cells that In addition, the prior course of disease and fre-
reside under the basement membrane, adjacent quency of relapses should be recorded, because
to proliferating keratinocytes, and are important there is significant variability in the clinical presen-
in the early development of psoriatic lesions. tation of disease and the disease may change from
They express Factor XIIIa and secrete the chemo- one clinical phenotype to another (Box 1.1). In
kine MCP-1 (CCL2).13 They are an important source some patients, the disease frequently relapses,
of TNF-a, inducible nitric oxide synthase, and and this has been associated with more severe dis-
IL-23.13,14 It has been shown in mouse models ease with rapidly enlarging lesions covering signif-
that the selective elimination of macrophages leads icant portions of the body surface.19 Other
to prompt improvement of psoriatic lesions.15 patients have more chronic, slowly developing le-
Dendritic cells have an important role in both sions with only occasional recurrences.
priming the adaptive immune response and The presence or absence of joint symptoms
inducing self-tolerance. Subtypes of dendritic should be recorded—such as painful, warm, or
cells, such as Langerhans cells, dermal dendritic swollen joints. Any of these complaints are con-
cells, and myeloid dendritic cells, help drive the cerning for psoriatic arthritis and prompt a more
Th1, Th17/Th22 polarization of psoriatic plaques. thorough evaluation. It is important to remember
In particular, myeloid dendritic cells help make that osteoarthritis is common and frequently co-
IL-12 and IL-23 cytokines that promote Th1 and exists with psoriasis.
Th17 differentiation and responses, respec-
tively.16 In a psoriatic plaque, myeloid dendritic
cells can be increased up to 30-fold as compared BOX 1.1
Clinical subtypes of psoriasis
with uninvolved skin and make up about 80% to
90% of the dendritic cells.17  Chronic plaque psoriasis (psoriasis vulgaris)
 Psoriasis geographica
NEUTROPHILS  Psoriasis gyrata
Although neutrophils are a common histopatho-  Annular
logic finding in the upper epidermis of psoriatic  Rupioid
lesions, they do not seem to a have a significant
role in lesional development in chronic plaque  Ostraceous
psoriasis, although they have a key role in pustular  Elephantine
variants of psoriasis.  Guttate psoriasis (eruptive psoriasis)
 Small plaque psoriasis
UNINVOLVED PSORIATIC SKIN  Flexural (Inverse) psoriasis
Normal-appearing skin of patients with psoriasis  Erythrodermic psoriasis
has been shown to have subclinical biochemical
changes that lead to subtle histologic findings.  Sebopsoriasis
Lipid biosynthesis is predominantly affected with  Napkin psoriasis
measurable changes in the levels, constitution of  Linear psoriasis
phospholipids, free a-amino acids, and hydrolytic
4 Therapy for Severe Psoriasis

Psoriasis is associated with several comorbid- response is still unclear. There is a broad differen-
ities, including increased incidence of myocardial tial diagnosis for psoriasis that physicians should
infarction, stroke, and death, particularly in pa- consider (Table 1.1), and treatment failures may
tients with moderate-to-severe psoriasis.20–23 prompt a reconsideration of the diagnosis.
Psoriasis has been shown to be an independent
risk factor for cardiovascular disease,24,25 and it
is important to screen patients for other cardio- CUTANEOUS LESIONS
vascular risk factors in their social and medical his- Psoriasis Vulgaris
tories, because modification of these can help Psoriasis vulgaris, or chronic plaque psoriasis, is the
offset their increased risk. Cardiovascular risk fac- most common clinical manifestation of psoriasis,
tors include smoking status, diet, and any previ- affecting approximately 90% of psoriasis patients.
ous diagnoses of hypertension, diabetes, Psoriasis vulgaris is characterized by well-
dyslipidemia, or obesity. demarcated, erythematous, raised plaques with
Treatment history should also be recorded. white micaceous scale. Lesions vary in size from
Although the ability to predict treatment re- pinpoint papules to large plaques and tend to be
sponses to a given agent are still very limited, pa- symmetrically distributed on the scalp, postauricu-
tients that have been on previous biologics and lar skin, elbows, gluteal cleft, and knees. These le-
failed generally respond less well to other biologic sions produce significant amounts of scale and
agents, even when these are in a different removing the scale produces pinpoint bleeding
class. The nature of this decreased therapeutic (the Auspitz sign), which is a sign of the dilated

TABLE 1.1
Differential diagnosis of psoriasis
Psoriasis Vulgaris Guttate Erythrodermic Pustular
Common
 Discoid/nummular eczema  Pityriasis rosea  Drug-  Impetigo
 Cutaneous T-cell lymphoma  Pityriasis lichenoides induced  Superficial candidiasis
(CTCL) chronica erythroderma  Reactive arthritis
 Tinea corporis  Lichen planus  Eczema syndrome
 CTCL/Sézary  Superficial folliculitis
syndrome
 Pityriasis
rubra
pilaris
Consider
 Pityriasis rubra pilaris  Small plaque  Pemphigus foliaceus
 Seborrheic dermatitis parapsoriasis  Immunoglobulin A
 Subacute cutaneous lupus  Pityriasis lichenoides pemphigus
erythematosus et varioliformis acuta  Sneddon-Wilkinson
 Erythrkeratoderma (either (PLEVA) disease (subcorneal
erythrokeratoderma variabi-  Lichen planus pustular dermatosis)
lis and/or progressive sym-  Drug eruption  Migratory necrolytic
metric erythrokeratoderma)  Secondary syphilis erythema
 Hypertrophic lichen planus  Transient neonatal pus-
 Lichen simplex chronicus tular
 Contact dermatitis melanosis
 Chronic cutaneous lupus er-  Acropustulosis of infancy
ythematosus/discoid lupus  Acute generalized
erythematosus exanthematous
 Hailey-Hailey disease (more pustulosis
flexural)
 Intertrigo (flexures)
 Candida infection (flexures)
 Bowen disease/squamous
cell carcinoma in situ
 Extramammary Paget
disease
 Chapter 1 Overview of Psoriasis 5

capillaries below the epidermis and thinned supra- psoriatic papules across the upper trunk and
papillary plate. Disease presentation is impres- proximal extremities (Fig. 1.2). Guttate psoriasis
sively variable among patients, and the clinical typically presents in children, adolescents, and
findings can change quickly even within the same young adults. It is often preceded by a strepto-
patient. coccal throat infection, and less commonly, peri-
Psoriatic lesions can be induced by trauma, and anal strep infections, and more than half of
this is known as Koebnerization or the isomorphic patients will have molecular evidence of a recent
response. This phenomenon is more likely to occur streptococcal infection, such as an elevated anti-
when the disease is flaring and is an all-or-nothing streptolysin O, anti-DNase B, or streptozyme titer.
response (meaning if psoriasis appears at one site Despite this association, antibiotics are not helpful
of injury then it will appear at all sites of injury). The in the treatment of guttate psoriasis and do not
isomorphic response typically appears 7 to 14 days alter the course of the disease.28 One-third to
after injury, and the lifetime prevalence of the phe- one-half of patients who develop guttate psoriasis
nomenon is estimated to be 25% to 75%.26 The will later develop chronic plaque psoriasis. As
isomorphic response is not specific to psoriasis. mentioned above, guttate psoriasis shows the
Historically, psoriasis vulgaris has been subclas- strongest association with HLA-Cw6.29
sified by the shape and scale of the plaques.
Today, the terms have little significance clinically, Inverse Psoriasis (Flexural Psoriasis)
but they connect the modern disease to its long Inverse, or flexural, psoriasis is distinguished by
history. Psoriasis geographica describes plaques psoriatic lesions appearing in the major skin folds,
that resemble a land map. Psoriasis gyrata consists such as in the axillae, inguinal creases, intergluteal
of confluent, connected plaques with a circinate cleft, umbilicus, and inframammary folds. Lesions
appearance. Rupioid lesions present in the shape are erythematous and sharply demarcated, with a
of a cone or limpet. Ostraceous plaques have a cir- glossy appearance and little to no scale. The
cular, hyperkeratotic concave lesion resembling an lesion may contain a central fissure. The sharp
oyster shell. Elephantine psoriasis refers to large, demarcation and glossy appearance help distin-
thick, scaly plaques on the lower extremities. guish the lesions from other diseases of the skin
Annular lesions have partial central clearing, giving folds. Sweating is decreased in affected areas
a ring-shaped appearance, and are associated and localized fungal or bacterial infections may
with a good prognosis because the annular shape be a trigger.
suggests clearing (Fig. 1.1). Finally, a hypopig-
mented ring on the periphery of an individual pla- Erythrodermic Psoriasis
que, or Woronoff ring, may be seen after Erythrodermic psoriasis is the generalized form of
treatment with UV radiation or topical steroids. disease and affects all body sites: face, trunk, ex-
Woronoff rings are thought to be caused by inhibi- tremities, hands, and feet. Erythema is more
tion of prostaglandin synthesis and are associated prominent and the scaling is finer, more superfi-
with lesional clearing and a good prognosis.27 cial and diffuse, as compared with psoriasis vulga-
ris. Patients lose their autonomic control of body
Guttate Psoriasis temperature and may present with systemic
Derived from the Latin gutta, “a drop,” guttate symptoms. They lose excessive heat from gener-
psoriasis is distinguished by the eruption of small alized vasodilation and so may shiver to try to
compensate. In warm climates, there is a risk for
hyperthermia because patients do not sweat
from their psoriatic lesions.30 The generalized
vasodilatation also puts patients at risk for high-
output cardiac failure, impaired hepatic and renal
function, and lower extremity edema. Erythroder-
mic psoriasis is thought to have 2 general presen-
tations: first, as a chronic form that is thought to
be a slow progression of psoriasis vulgaris
(Fig. 1.3). A second form is distinguished by its
sudden onset and may be a generalized Koebner
reaction to treatments such as phototherapy or
anthralin. Finally, other generalized forms of pso-
Fig. 1.1 Annular plaque psoriasis. There are well- riasis may give an appearance of erythrodermic
defined erythematous plaques with thick micaceous psoriasis as they heal, such as generalized pustular
scale on the periphery. psoriasis.
6 Therapy for Severe Psoriasis

Fig. 1.2 Erythrodermic psoriasis associated with HIV. (A) Cutaneous disease often worsens as a patient’s CD4 count
drops. (B) Thick micaceous scale. (C) There was confluent erythema and scale on the hands. Note the prominent oil
spots below the fingernails and swelling of the left fifth PIP joint. (D) There is confluent scale on the feet with subtle
erythema. Note the left third toe dactylitis, also known as a “sausage digit,” a manifestation of psoriatic arthritis.

Pustular Psoriasis neutrophils on histopathologic examination

Clinically, pustular psoriasis is distinguished (Fig. 1.4). There are 4 main clinical categories
by the appearance of 2- to 3-mm sterile of pustular psoriasis: generalized pustular psori-
pustules that show infiltrated subcorneal asis (von Zumbusch type), annular pustular pso-
riasis, impetigo herpetiformis, and localized
forms (including pustulosis palmaris et plantaris
[PPP] and acrodermatitis continua of Hallopeau)
(Box 1.2). Finally, SAPHO syndrome (synovitis,
acne, pustulosis, hyperostosis, osteitis) is a ge-
netic syndrome that typically presents in chil-
dren and young adults, and palmoplantar
pustulosis is a main feature.

Generalized Pustular Psoriasis (von

Zumbusch)
Generalized pustular psoriasis (von Zumbusch) is
an acute variant of pustular psoriasis typified by
several days of fever preceding the sudden gener-
alized eruption of sterile pustules across the
body—face, trunk, extremities, nail beds, palms,
and soles. The attacks may occur in waves, and
the skin is painful. On examination, there is a
background of erythematous skin that initially
Fig. 1.3 Guttate psoriasis, involving the upper extrem- starts as patches but spreads to become
ities and torso. Clinically, the micaceous scale helps confluent, leading to erythroderma. With chronic
differentiate this disorder. disease, there may be atrophy of the fingertips.
 Chapter 1 Overview of Psoriasis 7

Fig. 1.4 Pustular psoriasis. The patient shown in (A) and (B) demonstrates flaccid subcorneal pustules on an
erythematous base. Note the pus accumulating in the dependent half of the pustules. The patient shown in (C)
and (D) had pustules form an annular or circinate pattern with an erythematous center. This may resemble erythema
annulare centrifugum or impetigo herpetiformis.

The cause of attacks is unknown but possible trig- successfully include methotrexate, cyclosporine,
gering factors include infections, irritating topical infliximab,33 and systemic corticosteroids.34
treatments (provoking a Koebner phenomenon), Loss-of-function mutations in the IL36RN gene,
and withdrawal of systemic corticosteroids. encoding IL-36 receptor antagonist (IL-36ra), have
Generalized pustular psoriasis may have been found in patients with generalized pustular
life-threatening complications, including hypocal- psoriasis. IL-36ra is an anti-inflammatory cytokine
cemia, acute respiratory distress syndrome, that inhibits signaling of proinflammatory IL-36
bacterial superinfection leading to sepsis, and proteins (a, b, and g).35
dehydration.31,32 The severity of the disease
makes rapid control important, and therefore, Annular Pustular Psoriasis and Impetigo
medications with a rapid onset of action should Herpetiformis
be chosen. Drugs that have been used Annular pustular psoriasis is a rare form of pustu-
lar psoriasis that presents with pustules on an
erythematous ring. It may initially resemble gyrate
BOX 1.2 erythemas, such as erythema annulare centrifu-
Clinical subtypes of pustular psoriasis gum. It can present during pregnancy, typically
in the early third trimester, and is called impetigo
 Generalized pustular psoriasis (von herpetiformis. There is significant risk for hypocal-
Zumbusch) cemia, and while the disease typically improves af-
 Annular pustular psoriasis ter delivery, it may recur during subsequent
 Impetigo herpetiformis pregnancies.31,36 There is often no personal or
family history of psoriasis.
 Localized pustular psoriasis
 Pustulosis palmaris et plantaris Localized Pustular Psoriasis Variants
 Acrodermatitis continua (of Hallopeau) There are 2 main forms of localized pustular pso-
 SAPHO (synovitis, acne, pustulosis, riasis: PPP and acrodermatitis continua (of Hallo-
hyperostosis, osteitis) peau). PPP is characterized by sterile pustules on
the palmoplantar surfaces with yellow-brown
8 Therapy for Severe Psoriasis

macules. There may be scaly, erythematous pla- BOX 1.3

ques. A minority of patients has psoriatic plaques Nail findings in psoriasis
elsewhere, and the pustules primarily remain on
the palmoplantar surfaces throughout the dis-  Nail matrix
ease. PPP is thought to affect femalemore than  Nail plate pits
male patients, with a ratio of approximately 3:1,  Onychorrhexis
and typically presents between the ages of 20 to
 Beau lines
60. In contrast to plaque psoriasis, PPP is not
associated with any HLA type. In epidemiologic  Nail plate thinning
surveys, PPP has been highly associated with  Erythema of the lunula
smoking, and cessation of smoking is the most  Nail bed
important measure to treat the disease.37 If a pa-
tient continues to smoke, PPP is highly resistant to  Oil drops or “salmon patch”
treatment.  Subungual hyperkeratosis
Acrodermatitis continua is a rare eruption of  Onycholysis
sterile pustules on the fingers or toes that slowly
 Splinter hemorrhages
extends proximally. Chronic disease leads to atro-
phy of the digit and destruction of the nail matrix.  Proximal and lateral nail folds
It is difficult to treat.  Cutaneous psoriasis

Napkin Psoriasis
Napkin psoriasis typically presents in the diaper arranged on the dorsal nail plate. Nail pitting is
(napkin) areas between the ages of 3 and 6 months caused by foci of parakeratosis at the proximal
with a red, confluent patch. Scattered small, red, nail matrix, which forms the dorsal nail plate,
papules with psoriatic white scale may appear a causing poor keratinization. Nail pitting is not
few days later on the rest of the body. It typically unique to psoriasis and can also be seen in alope-
responds readily to topical steroids and usually re- cia areata and other disorders. The nail pitting of
solves by 1 year of age. alopecia areata is typically thought to be more
linear than in psoriasis, although this is not always
Linear Psoriasis the case. Other findings of nail matrix disease
Linear psoriasis is a rare form of the disease that include leukonychia, a result of disease in the mid-
typically presents as a linear plaque on an extrem- portion of the nail matrix, and widespread disease
ity or dermatome of the trunk. There may be an leads to crumbling of the nail plate.
underlying nevus, such as an inflammatory linear Oil drops are translucent red-yellow discolor-
verrucous epidermal nevus (ILVEN). Separating ations on the nail bed, below the nail plate. They
linear psoriasis and ILVEN into distinct diseases are a result of psoriasiform hyperplasia, parakera-
is controversial.38 tosis, and microvascular changes of the nail bed
and trapping of neutrophils under the nail plate.39
Unlike nail pits, oil drops on the nail bed are a
RELATED PHYSICAL FINDINGS unique finding of psoriasis. Other nail bed findings
Nail Findings with psoriasis include splinter hemorrhages, from
Nail involvement is common in psoriasis and is capillary bleeding at thinned suprapapillary plates,
seen in up to 40% of psoriasis patients.18 It in- onycholysis, and subungual hyperkeratosis. These
creases with age, extent of disease, duration of findings are not as specific to psoriasis. Anonychia,
disease, and presence of psoriatic arthritis. Find- complete loss of nails, is common in acrodermati-
ings are classified as either evidence of nail matrix tis continua, but nail findings are not typically seen
or nail bed disease (Box 1.3). Nail matrix disease in other localized variants of pustular psoriasis.
leads to pitting, onychorrhexis, Beau lines, leuko- Nail changes are important to note clinically
nychia, and thinning of the nail plate. Nail bed dis- because they have been associated with increased
ease leads to findings of oil drops (or “salmon risk for psoriatic arthritis.
patches”), subungual hyperkeratosis, and splinter
hemorrhages. Fingernails are more often affected
than toenails, and nail involvement may cause PSORIATIC ARTHRITIS
pain and restrictions on activities of daily life. Psoriatic arthritis occurs in 5% to 30% of pa-
Nail pitting is one of the most common nail tients with cutaneous psoriasis, and its preva-
findings with psoriasis. Typically, there are single lence may be underestimated.40 Cutaneous
or multiple 0.5- to 2.0-mm pits irregularly disease typically precedes the joint disease by
 Chapter 1 Overview of Psoriasis 9

about 10 to 12 years, but about 10% to 15% of Many patients with psoriasis manifest altered
patients with psoriatic arthritis present without lipid profiles with elevated levels of high-density li-
skin findings. Diagnosis is difficult to establish poproteins, altered cholesterol-triglyceride ratios
because there is no serologic marker, and the in very low-density lipoprotein particles, and
radiographic hallmark, erosive changes, may elevated plasma apolipoprotein-A1 concentra-
occur years after the initial periarticular inflam- tions.43 These alterations in lipids may contribute
mation. Classic findings include asymmetric to the increased cardiovascular risk for psoriasis
involvement of both the distal (DIP) and prox- patients. Other risk factors of cardiovascular dis-
imal (PIP) interphalangeal joints, seen in about ease should be considered and appropriate labo-
40% of patients.41 In contrast to rheumatoid ratory tests ordered, because patients with
arthritis, involvement of the metacarpophalan- psoriasis are predisposed to cardiovascular dis-
geal joints is rare. Prolonged disease in the PIP ease (see later discussion). General markers of sys-
and DIP of a single digit can lead to swelling temic inflammation, such as C-reactive protein and
(dactylitis) and the appearance of a “sausage” erythrocyte sedimentation rate, are elevated in a
digit. Enthesitis, or inflammation at the insertion minority of patients with chronic plaque psoriasis
site of tendons into bones, is also a common and may suggest the presence of psoriatic arthritis.
finding in psoriatic arthritis and is seen in
approximately 20% of patients with psoriatic
arthritis.42 Arthritis mutilans is the most severe COMPLICATIONS
form of psoriatic arthritis with extensive joint Psoriatic patients have increased morbidity and
damage and bone resorption and is seen in mortality from cardiovascular disease, which cor-
5% of patients.41 Early diagnosis of psoriatic relates with the severity and length of disease.44
arthritis alters the treatment approach for a Younger patients with psoriasis are at particular
patient, as the physician should consider sys- risk, because a large population-based cohort
temic or biologic medications to prevent life- study using the UK General Practice Research
changing morbidity from arthritic changes, Database found that 30-year-olds with severe
even when cutaneous disease is limited. psoriasis had a relative risk of myocardial infarc-
tion of 3.10 as compared with healthy controls.21
Other large epidemiology studies have shown
LABORATORY TESTS that patients with psoriasis are 2.9-fold more likely
Most patients can be diagnosed based on their to have a diagnosis of metabolic syndrome—
clinical history and features alone. However, histo- which is defined by having 3 of 5 risk factors for
pathologic examination can be helpful to estab- cardiovascular disease, including obesity, hyper-
lish the diagnosis in difficult cases. The typical triglyceridemia, low high-density lipoprotein, hy-
histopathologic features of chronic plaque psoria- pertension, or diabetes. Psoriasis patients had
sis and guttate psoriasis have been discussed pre- increased rates of hypertension (35.6% in psoriatic
viously (see “Development of Lesions”). patients vs 20.6% in controls), and hyperlipidemia
Pustular psoriasis is distinguished on histopa- (29% vs 17.1%).45 Psoriasis is thought to be an in-
thology by the presence of neutrophils migrating dependent risk factor for the development of
from dilated vessels and pooling in the upper metabolic syndrome because psoriasis patients
epidermis, within the upper Malpighian layer have increased odds of having hypertension
below the stratum corneum. In newer lesions, even after controlling for age, sex, smoking sta-
there may be mild acanthosis, whereas older le- tus, and other variables.46 There is an increased
sions have more typical psoriasiform hyperplasia. prevalence of rheumatoid arthritis (prevalence ra-
There are no serum markers that are specific tio [PR] 3.8), Crohn disease (PR 2.1), and ulcerative
for psoriasis and regularly used to establish a colitis (PR 2.0) in patients with psoriasis.45 There is
diagnosis. Laboratory workup is typically aimed an increased risk of both Hodgkin lymphoma and
at ruling out other disease processes in the differ- cutaneous T-cell lymphoma in psoriasis, particu-
ential diagnosis, such as checking an antinuclear larly in patients with severe disease.47
antibody to test for connective tissue disease. The psychological impact of psoriasis on
Nonetheless, it can be important to check serum patients is profound. Cutaneous disease leads
markers in patients with severe disease to assess to concerns about appearance, lowered self-
for systemic complications. Patients may have a esteem, social rejection, guilt, embarrassment,
decreased serum albumin, secondary to the nega- emptiness, sexual problems, and impairment of
tive nitrogen balance from the turnover of their professional ability (Fig. 1.5). These stressors
skin, or elevated uric acid, increasing their risk lead to higher rates of anxiety, depression, and sui-
for developing gouty arthritis. cidal ideation in psoriasis patients than in the
10 Therapy for Severe Psoriasis

Smoking also seems to play a role in the onset

of psoriasis. Neither characteristic affects treat-
ment strategies, although all patients should be
encouraged to quit and follow a healthy diet.
Quitting tobacco is particularly important for pa-
tients with palmoplantar pustulosis because to-
bacco use may drive the process and is
associated with recalcitrant disease.
Bacterial and viral infections have also been
associated with psoriasis flares or the onset of dis-
ease. There is a clear association between strepto-
coccal throat infection and guttate psoriasis, but
streptococcal infections may exacerbate chronic
plaque psoriasis, too.51,52 HIV infection can pre-
sent as a severe psoriasis exacerbation and, para-
doxically, a patient’s psoriasis may become more
severe as the immunodeficiency progresses.53
This helps to explain why treatment of a patient’s
underlying HIV with highly active antiretroviral
therapy improves the patient’s psoriasis.54
Finally, medications may help either induce dis-
ease or aggravate a patient’s psoriasis. Medica-
tions that have been reported to aggravate
psoriasis include lithium, b-blockers, TNF-a inhibi-
tors, antimalarials, nonsteroidal anti-inflammatory
drugs, type I and type II IFNs, imiquimod,
angiotensin-converting enzyme inhibitors, and
gemfibrozil. The mechanism and clinical presenta-
tion of drug-exacerbated psoriasis vary. For
example, lithium is thought to decrease levels of
inositol, an important component of the intracel-
lular second messenger system, altering calcium
homeostasis and keratinocyte differentiation.
b-Blockers decrease cellular AMP, an important
intracellular signaling protein, altering calcium ho-
meostasis, driving keratinocyte proliferation and
inhibiting keratinocyte differentiation.55 Counter-
intuitively, TNF-a inhibitors may cause a psoriasi-
form dermatitis in patients with rheumatoid
Fig. 1.5 Psoriatic alopecia and plaque psoriasis. (A) arthritis or inflammatory bowel disease.56 Most
Chronic inflammation and scale from psoriasis have patients reported developed palmoplantar pustu-
led to alopecia. This is typically a nonscarring alopecia losis, but about one-third developed chronic pla-
but the inflammation may be so severe that there is per-
que psoriasis.57 Psoriasis patients traveling to
manent destruction of hair follicles. (B) The same patient
countries where antimalarial prophylaxis is needed
demonstrated widespread erythematous plaques with
micaceous scale in a symmetric distribution. should be warned that their disease may flare and
plan accordingly.
general population.48 Pruritus and pain may exac-
erbate these psychosocial stressors. These issues
impact a large number of psoriatic patients with TREATMENT
one survey finding 79% of respondents reporting Psoriasis is an exciting field because the number of
their psoriasis caused a negative impact on their medications available for treating patients is broad
life.49 and growing quickly. Most, but not all, of these
agents are immunomodulatory medications.
Despite the high efficacy of these medications,
MODIFYING FACTORS older and more traditional therapies still have an
Obesity and smoking have both been associated important role as adjunctive treatment. This chap-
with more severe presentations of psoriasis.50 ter provides a general introduction to the major
 Chapter 1 Overview of Psoriasis 11

categories of treatment: topical therapies, photo- treatment available (Box 1.4). Topical treatments
therapy, oral medications, and biologic medica- are often inexpensive and efficacious and have an
tions (Table 1.2). This chapter covers topical excellent safety profile. Despite these benefits,
treatments at depth but leaves the other modal- 40% of patients report being noncompliant with
ities for the remainder of this book. their topical treatments because they feel these
In formulating a treatment regimen, the clini- treatments are time-consuming and cosmetically
cian must balance the patient’s goals with the unacceptable.58 Cosmetic considerations are
measurable severity of the disease, patient- particularly important, and physicians should pre-
specific factors (such as psoriatic arthritis, preg- scribe a medication as both a cream, to be used
nancy, or a history of malignancy), and limits set during the day, and a more potent ointment, to
by payors. There is no cure for psoriasis, and treat- be used at night. It is important to give a sufficient
ment can be frustrating, with many patients volume of medication for the patient to treat their
reporting their treatment regimens being ineffec- skin lesions appropriately, and 400 g of a topical
tive. With the advent of highly effective biologics agent is required to entirely cover an average
and the high level of treatment responses sized adult twice daily for 1 week.
achieved with these drugs, patient’s expectations
have grown. Therefore, these feelings are only
likely to grow. CORTICOSTEROIDS
As patients will use these medications for Topical corticosteroids are commonly first-line
years, safety is also a major concern and deserves therapy in mild-to-moderate psoriasis and on sen-
a frank discussion with patients. New treatments, sitive skin, such as the flexures and genitalia.
which can be highly efficacious, often have the These medications work by causing nuclear trans-
shortest safety record. Furthermore, although location of glucocorticoid receptors, leading to a
some treatments are safe for continuous use, wide variety of effects. Patients typically see
others have cumulative toxicity that limits their improvement with 2 to 4 weeks of daily treatment
use. Treatments may lose efficacy over time either and then can taper to a maintenance phase of
through a process called tachyphylaxis, which is applying the creams only 2 to 3 days per week.
mostly limited to topical treatments, through the Long-term daily use of topical corticosteroids
development of neutralizing antibodies to a may cause skin atrophy, telangiectasias, stretch
particular biologic agent, or possibly through marks, and adrenal suppression (from systemic
the changing nature of inflammatory responses absorption). With long-term use, these agents
in psoriatic skin, requiring the change or the addi- lose their efficacy, and patients should be
tion of other modalities. Physicians must individu- switched to an alternative formulation. Upon
alize a treatment regimen to the patient and, if discontinuation of a topical steroid, a patient’s
there is disease progression, progression of dis- disease may rebound.59 Topical corticosteroids
ease will likely have to use treatments in combina- are inexpensive, effective, and safe, when used
tion to achieve long-term control. appropriately; therefore, they should be a part
of every patient’s treatment plan.

TOPICAL THERAPIES
Most patients with psoriasis are treated initially VITAMIN D3 AND ANALOGUES
with topical treatments, and these medications The topical vitamin D preparations that are
can be used safely with nearly every other commercially available for the treatment of skin

TABLE 1.2
Treatments for psoriasis
Topical Phototherapy Systemic Biologics
 Corticosteroids  Narrowband UVB  Cyclosporine TNF-a inhibitors
 Vitamin D analogues (310–331 NM)  Methotrexate  Etanercept
 Tazarotene  Broadband UVB  Acitretin  Humira
 Salicylic acid  PUVA  Fumaric acid esters  Infliximab
 Calcineurin inhibitors (for  Excimer laser (308 NM) (available in Germany IL-12/IL-23
inverse psoriasis) but not the US or UK) inhibitor
 Apremilast  Ustekinumab
IL-17 inhibitor
 Secukinumab
 Ixekizumab
12 Therapy for Severe Psoriasis

BOX 1.4 TOPICAL CALCINEURIN INHIBITORS

Topical therapies Tacrolimus and pimecrolimus are topical calci-
neurin inhibitors, blocking both T-lymphocyte
 Topical steroids function and IL-2 production. In clinical trials,
 Vitamin D analogues neither agent proved efficacious for chronic pla-
 Tazarotene que psoriasis. However, there is evidence that
tacrolimus is effective for the treatment of inverse
 Calcineurin inhibitors
psoriasis.62,63 Clinically, these agents are limited
 Tacrolimus by their main side effect, which is a burning sensa-
 Pimecrolimus tion at the application site. The US Food and Drug
 Dithranol Administration has placed a “black-box warning”
on these medications after anecdotal reports of
 Coal tar
malignancy were published. The American Acad-
 Salicylic acid emy of Dermatology and the American Academy
of Allergy, Asthma, and Immunology have pro-
tested these warnings. Furthermore, large after-
marketing surveillance databases of the topical
disease include calcipotriene (or calcipotriol), cal- formulations have not detected any increased
citriol, tacalcitol, and maxacalcitol (tacalcitol and risk of lymphoma or cutaneous malignancies.64
maxacalcitol are not currently available in the
United States). Topical calcipotriene is commonly
thought of as being about as potent as a mild SALICYLIC ACID
topical steroid. These medications are more effec- Salicylic acid is a topical keratolytic that lowers the
tive if applied twice daily rather than once daily pH of the stratum corneum and reduces keratino-
and do not lose their efficacy with long-term cyte adhesion. This helps to soften plaques and
use.60 Irritation to the skin is a common side ef- reduce their scale, which enhances the penetra-
fect, so patients should be instructed not to apply tion of other therapies. Like tazarotene, it is often
vitamin D preparations to sensitive skin. There are best used in combination with a topical cortico-
almost no systemic side effects when these med- steroid. Unlike tazarotene, salicylic acid decreases
ications are used appropriately. However, hyper- the efficacy of UVB phototherapy.59 Systemic ab-
calcemia can occur if a patient applies more sorption can occur if applied to more than 20% of
than 100 g per week of calcipotriene or 200 g the body surface area, particularly in patients with
per week of calcitriol. Treatment with calcipo- renal or hepatic dysfunction. There are no
triene can complement the use of potent topical placebo-controlled studies using salicylic acid as
corticosteroids, with patients applying topical cal- monotherapy.
cipotriene 5 times per week when they taper their
topical steroid to 2 times per week, minimizing
the risk for steroid-induced atrophy. BLAND EMOLLIENTS
Patients should be encouraged to apply bland
emollients regularly between medical treatments.
TAZAROTENE Emollients can limit dryness, scale, and pruritus.
Tazarotene is a third-generation retinoid available They should be applied immediately after bathing
in 0.05% and 0.1% gels and a cream formulation. or showering for maximum effect. They can also be
It is used primarily to reduce plaque thickness and applied over a thin layer of a topical medication to
scaling. It is not as effective for plaque erythema. improve hydration of the skin. By smoothing the
The drug’s specific molecular targets are un- skin and preventing epidermal scatter, emollients
known, but it is thought to act by binding to reti- may increase the efficacy of phototherapy.
noic acid receptors. Local irritation is a significant
side effect and is dose related. Therefore, this
medication is best used in combination with PHOTOTHERAPY
topical corticosteroids or phototherapy. By Goeckerman first started using artificial light sour-
decreasing thickness and causing irritation, tazar- ces to treat psoriasis in the 1920s—using a combi-
otene lowers the minimal erythema dose for both nation of topical crude coal tar and subsequent
UVB and UVA. Therefore, if tazarotene is started UV irradiation. In the 1970s, photochemotherapy
in the middle of a phototherapy course, it is rec- with psoralen and UVA light (PUVA) was devel-
ommended that the UV dose be reduced by at oped, but has now been mostly discontinued
least one-third.61 given increased incidence of skin cancer,
 Chapter 1 Overview of Psoriasis 13

BOX 1.6
Biologic therapies
 TNF-a inhibitors
 Etanercept
 Adalimumab
 Infliximab
 IL-12/IL-23 p40 subunit inhibitor
 Ustekinumab
 IL-17 inhibitor
 Secukinumab
Fig. 1.6 Lentigines from ultraviolet treatment of psori-
asis. Chronic damage from the ultraviolet treatment of  Ixekizumab
these psoriatic patches has led to the formation of len-
tigines bilaterally. There is also epidermal atrophy,
likely from chronic use of topical steroids. A closer that they have an excellent safety profile. This is
view of the lentigines and epidermal atrophy (inset). an exciting time for the treatment of psoriasis
with multiple classes of biologics available:
particularly squamous cell carcinoma (Fig. 1.6).65 TNF-a inhibitors, anti-p40 (IL-12/IL-23 antago-
In the 1980s, narrow band UVB (311–313 nm) nists), IL-17 inhibitors, and the promise of new
was developed and shown to be efficacious. Since anti-p19 inhibitors (selective for IL-23) on the hori-
that time, phototherapy has proven to be a safe, zon. These medications are changing the treat-
effective treatment for psoriasis that does not ment of patients with psoriasis and improving
cause immunosuppression. clinical outcomes.

ORAL AGENTS REFERENCES

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by newer biologic agents, but they remain effec- studies of psoriasis susceptibility loci: a review.
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loci revealed by a two stage genome-wide search
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Since 1998, with the release of etanercept, there 5. Cox AJ, Watson W. Histological variations in le-
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Oral therapies Immunol 1985;61(3):526–34.
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Cyclosporine improves psoriasis in a double-blind
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 Apremilast immunocytes induces psoriasis. J Clin Invest 1996;
98(8):1878–87.
14 Therapy for Severe Psoriasis

10. Uyemura K, Yamamura M, Fivenson DF, et al. The severe psoriasis and severe atopic dermatitis. Am
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tion of epidermal hyperplasia by TNF inhibition is enon: review of the literature. J Eur Acad Dermatol
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Med 2007;204(13):3183–94. 27. van de Kerkhof PC. The Woronoff zone surrounding
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represent a distinct human T cell subset involved 167–8.
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Invest 2009;119(12):3573–85. A systematic review of treatments for guttate psori-
13. Fuentes-Duculan J, Suarez-Farinas M, Zaba LC, asis. Br J Dermatol 2001;145(6):891–4.
et al. A subpopulation of CD163-positive macro- 29. Mallon E, Bunce M, Savoie H, et al. HLA-C and gut-
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14. Wang H, Peters T, Kess D, et al. Activated macro- Br J Dermatol 1969;81(2):119–24.
phages are essential in a murine model for T cell- 31. Zelickson BD, Muller SA. Generalized pustular pso-
mediated chronic psoriasiform skin inflammation. riasis. A review of 63 cases. Arch Dermatol 1991;
J Clin Invest 2006;116(8):2105–14. 127(9):1339–45.
15. Stratis A, Pasparakis M, Rupec RA, et al. Patho- 32. Abou-Samra T, Constantin JM, Amarger S, et al.
genic role for skin macrophages in a mouse Generalized pustular psoriasis complicated by
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skin inflammation. J Clin Invest 2006;116(8): 2004;150(2):353–6.
2094–104. 33. Varma R, Cantrell W, Elmets C, et al. Infliximab for
16. Zaba LC, Fuentes-Duculan J, Eungdamrong NJ, the treatment of severe pustular psoriasis: 6 years
et al. Psoriasis is characterized by accumulation of later. J Eur Acad Dermatol Venereol 2008;22(10):
immunostimulatory and Th1/Th17 cell-polarizing 1253–4.
myeloid dendritic cells. J Invest Dermatol 2009; 34. Umezawa Y, Ozawa A, Kawasima T, et al. Therapeu-
129(1):79–88. tic guidelines for the treatment of generalized pus-
17. Zaba LC, Krueger JG, Lowes MA. Resident and “in- tular psoriasis (GPP) based on a proposed
flammatory” dendritic cells in human skin. J Invest classification of disease severity. Arch Dermatol
Dermatol 2009;129(2):302–8. Res 2003;295(Suppl 1):S43–54.
18. Gudjonsson JE, Karason A, Runarsdottir EH, et al. 35. Marrakchi S, Guigue P, Renshaw BR, et al. Inter-
Distinct clinical differences between HLA-Cw*0602 leukin-36-receptor antagonist deficiency and
positive and negative psoriasis patients–an analysis generalized pustular psoriasis. N Engl J Med 2011;
of 1019 HLA-C- and HLA-B-typed patients. J Invest 365(7):620–8.
Dermatol 2006;126(4):740–5. 36. Oumeish OY, Parish JL. Impetigo herpetiformis.
19. Christophers E. Psoriasis–epidemiology and clinical Clin Dermatol 2006;24(2):101–4.
spectrum. Clin Exp Dermatol 2001;26(4):314–20. 37. Michaelsson G, Gustafsson K, Hagforsen E. The
20. Wu JJ, Choi YM, Bebchuk JD. Risk of myocardial psoriasis variant palmoplantar pustulosis can be
infarction in psoriasis patients: a retrospective improved after cessation of smoking. J Am Acad
cohort study. J Dermatolog Treat 2015;26(3):230–4. Dermatol 2006;54(4):737–8.
21. Gelfand JM, Neimann AL, Shin DB, et al. Risk of 38. Happle R. Linear psoriasis and ILVEN: is lumping or
myocardial infarction in patients with psoriasis. splitting appropriate? Dermatology 2006;212(2):
JAMA 2006;296(14):1735–41. 101–2.
22. Gelfand JM, Troxel AB, Lewis JD, et al. The risk of 39. Kvedar JC, Baden HP. Nail changes in cutaneous
mortality in patients with psoriasis: results from a disease. Semin Dermatol 1991;10(1):65–70.
population-based study. Arch Dermatol 2007; 40. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J
143(12):1493–9. Med 2009;361(5):496–509.
23. Gelfand JM, Dommasch ED, Shin DB, et al. The risk 41. Reich K, Kruger K, Mossner R, et al. Epidemiology
of stroke in patients with psoriasis. J Invest Derma- and clinical pattern of psoriatic arthritis in Germany:
tol 2009;129(10):2411–8. a prospective interdisciplinary epidemiological
24. Hjuler KF, Bottcher M, Vestergaard C, et al. study of 1511 patients with plaque-type psoriasis.
Increased prevalence of coronary artery disease in Br J Dermatol 2009;160(5):1040–7.
 Chapter 1 Overview of Psoriasis 15

42. Radtke MA, Reich K, Blome C, et al. Prevalence and 54. Vittorio Luigi De Socio G, Simonetti S, Stagni G.
clinical features of psoriatic arthritis and joint com- Clinical improvement of psoriasis in an AIDS patient
plaints in 2009 patients with psoriasis: results of a effectively treated with combination antiretroviral
German national survey. J Eur Acad Dermatol Vene- therapy. Scand J Infect Dis 2006;38(1):74–5.
reol 2009;23(6):683–91. 55. O’Brien M, Koo J. The mechanism of lithium and
43. Mallbris L, Granath F, Hamsten A, et al. Psoriasis is beta-blocking agents in inducing and exacerbating
associated with lipid abnormalities at the onset psoriasis. J Drugs Dermatol 2006;5(5):426–32.
of skin disease. J Am Acad Dermatol 2006;54(4): 56. Famenini S, Wu JJ. Infliximab-induced psoriasis in
614–21. treatment of Crohn’s disease-associated ankylosing
44. Mallbris L, Akre O, Granath F, et al. Increased risk spondylitis: case report and review of 142 cases.
for cardiovascular mortality in psoriasis inpatients J Drugs Dermatol 2013;12(8):939–43.
but not in outpatients. Eur J Epidemiol 2004;19(3): 57. Ko JM, Gottlieb AB, Kerbleski JF. Induction and
225–30. exacerbation of psoriasis with TNF-blockade ther-
45. Augustin M, Reich K, Glaeske G, et al. Co-morbidity apy: a review and analysis of 127 cases.
and age-related prevalence of psoriasis: analysis of J Dermatolog Treat 2009;20(2):100–8.
health insurance data in Germany. Acta Derm Vene- 58. Richards HL, Fortune DG, O’Sullivan TM, et al. Pa-
reol 2010;90(2):147–51. tients with psoriasis and their compliance with
46. Cohen AD, Weitzman D, Dreiher J. Psoriasis and hy- medication. J Am Acad Dermatol 1999;41(4):581–3.
pertension: a case-control study. Acta Derm Vene- 59. Menter A, Korman NJ, Elmets CA, et al. Guidelines
reol 2010;90(1):23–6. of care for the management of psoriasis and psori-
47. Gelfand JM, Shin DB, Neimann AL, et al. The risk of atic arthritis. Section 3. Guidelines of care for the
lymphoma in patients with psoriasis. J Invest Der- management and treatment of psoriasis with
matol 2006;126(10):2194–201. topical therapies. J Am Acad Dermatol 2009;60(4):
48. Gupta MA, Gupta AK, Watteel GN. Early onset (< 643–59.
40 years age) psoriasis is comorbid with greater psy- 60. Ramsay CA. Management of psoriasis with calcipo-
chopathology than late onset psoriasis: a study of triol used as monotherapy. J Am Acad Dermatol
137 patients. Acta Derm Venereol 1996;76(6):464–6. 1997;37(3 Pt 2):S53–4.
49. Krueger G, Koo J, Lebwohl M, et al. The impact of 61. Hecker D, Worsley J, Yueh G, et al. Interactions be-
psoriasis on quality of life: results of a 1998 National tween tazarotene and ultraviolet light. J Am Acad
Psoriasis Foundation patient-membership survey. Dermatol 1999;41(6):927–30.
Arch Dermatol 2001;137(3):280–4. 62. Zonneveld IM, Rubins A, Jablonska S, et al. Topical
50. Herron MD, Hinckley M, Hoffman MS, et al. Impact tacrolimus is not effective in chronic plaque psori-
of obesity and smoking on psoriasis presentation asis. A pilot study. Arch Dermatol 1998;134(9):
and management. Arch Dermatol 2005;141(12): 1101–2.
1527–34. 63. Gribetz C, Ling M, Lebwohl M, et al. Pimecrolimus
51. Telfer NR, Chalmers RJ, Whale K, et al. The role of cream 1% in the treatment of intertriginous psoria-
streptococcal infection in the initiation of guttate sis: a double-blind, randomized study. J Am Acad
psoriasis. Arch Dermatol 1992;128(1):39–42. Dermatol 2004;51(5):731–8.
52. Gudjonsson JE, Thorarinsson AM, Sigurgeirsson B, 64. Margolis DJ, Abuabara K, Hoffstad OJ, et al.
et al. Streptococcal throat infections and exacerba- Association between malignancy and topical use
tion of chronic plaque psoriasis: a prospective of pimecrolimus. JAMA Dermatol 2015;151(6):
study. Br J Dermatol 2003;149(3):530–4. 594–9.
53. Obuch ML, Maurer TA, Becker B, et al. Psoriasis and 65. Chuang TY, Heinrich LA, Schultz MD, et al. PUVA
human immunodeficiency virus infection. J Am and skin cancer. A historical cohort study on 492 pa-
Acad Dermatol 1992;27(5 Pt 1):667–73. tients. J Am Acad Dermatol 1992;26(2 Pt 1):173–7.
CHAPTER 2
Ultraviolet B Phototherapy
Sandra Pena, BS, Dane Hill, MD, Steven R. Feldman, MD, PhD

KEYWORDS
 Phototherapy  Narrowband UV-B  UV therapy  Psoriasis  Excimer laser

KEY POINTS
 Phototherapy with UV light can be used in the treatment of several cutaneous disorders.
 Phototherapy is an efficacious treatment option in the management of psoriasis and should be a
first therapy considered in patients with moderate-to-severe plaque psoriasis.
 Narrowband UV-B is used as the first-line phototherapy treatment option for moderate-to-severe
psoriasis due to its clinical efficacy and mild side-effect profile.
 Targeted UV-B therapy phototherapy and employment of excimer lasers are excellent options for
patients with more limited disease, although there are now reports of use for extensive disease.

INTRODUCTION lamps. However, in 1978, Wiskemann introduced

Definition broadband UV-B radiation in a closed chamber
Phototherapy refers to the use of nonionizing ra- to treat psoriasis, which mitigated this drawback.8
diation, from the UV range, in the treatment of Despite these advances, broadband UV-B radia-
skin disorders (Table 2.1).1 It represents an effica- tion was less efficacious than psoralens followed
cious, cost-effective, and generally nonimmuno- by UV-A radiation, also known as PUVA therapy,
suppressive staple in the management of and as a result, did not gain widespread popu-
psoriasis.2 larity.5 It was not until the late 1970s when Parrish
and Jaenicke determined the action spectrum of
History psoriasis with a peak response at 313 nm that
The use of sunlight in the treatment of cutaneous gave impetus to narrowband (NB) UV-B as a new
diseases can be traced back to ancient times. Ev- phototherapeutic modality.9 In 1988, both Van
idence dating thousands of years demonstrates Weelden and colleagues10 and Green and col-
the use of plant extracts, including those from leagues11 demonstrated the superior clinical effi-
the Ammi majus plant (psoralens), followed by cacy of NB UV-B and subsequently marked the
sun exposure to treat vitiligo in Egypt and India.3 decline of broadband-UV-B (BB-UV-B) use for
However, it was not until the late nineteenth cen- psoriasis.
tury that heralded major advances in the develop-
ment and use of phototherapy.4 In 1901, Niels Types
Ryberg Finsen published the results of the treat- This chapter provides an overview of UVB photo-
ment of lupus vulgaris with a carbon arc lamp, therapy in the management of psoriasis.
which marked a breakthrough in the treatment
of skin diseases. For this, Finsen received a Nobel Broadband ultraviolet B (290–320 nm)
Prize in medicine, the first and only one ever Broadband (BB) UV-B phototherapy was initially
awarded in the field of dermatology.5 described in the Goeckerman regimen in 1925.
Shortly after in 1925, William Goeckerman For many decades, BB-UV-B remained an option
combined the use of UV radiation with coal tar in in the psoriasis treatment arsenal despite being
the treatment of psoriasis.6 The Goeckerman less efficacious than other treatment modalities.
regimen as it came to be known would remain a Presently, however, BB-UV-B has largely been
mainstay in phototherapy treatment of psoriasis replaced by NB-UV-B radiation, which has
for several decades.7 A major shortcoming of the demonstrated superior efficacy in clearing psori-
Goeckerman regimen was the low output of the atic lesions.12
17
18 Therapy for Severe Psoriasis

TABLE 2.1 it can also be used for severe psoriasis of the

Ultraviolet radiation spectrum palms/soles or even for extensive disease.
UV Spectrum (10–400 nm)
Abbreviation Wavelength (nm) TANNING BEDS
The use of commercial tanning beds may be a
UV-A 320–400
viable alternative for patients in which in-office
UV-B 290–320 and home phototherapy are either unaccessible
UV-C 200–290 or impractical. Although evidence to support the
routine use of tanning beds may be sparse,
approximately 36% to 52% of patients have
Narrowband ultraviolet B (311–313 nm) used tanning beds in the treatment of their psori-
First defined in 1976, NB-UV-B has taken the asis.20,21 However, given the increased risk of skin
place of BB-UV-B in the treatment and manage- cancer and full-body UV exposure, tanning bed
ment of psoriasis.9 NB-UV-B has gained popu- use remains controversial, and not all dermatolo-
larity over PUVA in the treatment of psoriasis for gists agree that they should be used.
several reasons. First, NB-UV-B had similar effi-
cacy rates compared with PUVA.12 Therefore,
NB-UV-B is generally favored over PUVA due to INDICATIONS
greater ease of use for the patient. Another factor Indications for UV-B radiation include psoriasis,
is the increased risk of squamous cell cancer (SCC) atopic dermatitis, vitiligo, and mycosis fungoides,
associated with PUVA treatments. The risk of SCC among several others (Table 2.2).22
increases as the number of PUVA treatments in-
creases.13 NB-UV-B phototherapy has not been
shown to incur any increased risk of skin cancer.14 MECHANISM OF ACTION
Last, NB-UV-B is safe to use in children and preg- The epidermal layer of human skin, composed pri-
nant patients and lacks psoralen-related side ef- marily of keratinocytes, absorbs most UV radia-
fects, which ultimately makes it more favorable tion, with only the longer wavelengths having
as an initial phototherapy modality.15 the ability to penetrate the dermis. It was thought
that UV-B’s antiproliferative properties were a

TARGETED PHOTOTHERAPY
Targeted phototherapy is a method of photother-
apy in which only affected areas of skin are treated. TABLE 2.2
Various devices can be used to deliver focused Ultraviolet B phototherapy indications
UV-B radiation on skin lesions while sparing unin-
Common Less Common
volved skin. These devices include high fluence
devices, like the excimer laser and flash lamp, Psoriasis Acquired perforating
and lower output devices, like UV-B light-emitting Vitiligo dermatosis
Atopic dermatitis Chronic urticaria
diodes.16 Introduced in 1997, the 308-nm excimer
Mycosis fungoides Cutaneous graft-
laser contains an unstable mixture of xenon and Pruritus (associated versus-host disease
chloride, which form “excited dimmers.” It is the with renal disease, Polymorphous light
dissociation of these dimers that produces the polycythemia vera) eruption
monochromatic wavelength, which is transmitted Cutaneous
via a fiber-optic cable to the lesion.17 The excimer mastocytosis
laser allows for targeted therapy that spares unin- Granuloma annulare
volved skin, especially in areas that are otherwise Lichen planus
difficult to treat, like the scalp, hands, and feet.17 Lichen simplex
In addition, it can generate high fluencies of chronicus
Lymphomatoid
UV-B, resulting in faster clearing and fewer expo-
papulosis
sures.18 Although the excimer laser is not suitable Parapsoriasis
for large body surface areas because the treat- Pityriasis lichenoides
ment may be considerably resource intensive Pityriasis rosea
and lengthy, the availability of more powerful UV Pityriasis rubra pilaris
emitting devices (and aggressive treatment proto- Seborrheic dermatitis
col) is extending the range of area that can be From Walker D, Jacobe H. Phototherapy in the age of bi-
treated.7,19 Although targeted treatment has ologics. Semin Cutan Med Surg 2011;30(4):196; with
generally been used for mild, localized psoriasis, permission.
Another random document with
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 CHAP. XIII.

Subverting, therefore, in this manner the common absurd

opinions concerning sacrifices, we shall introduce in their place true
conceptions about them; omitting the particular discussion of each
species of sacrifice, which the peculiar and distinct consideration of
sacrifices requires, because this pertains to another inquiry, and
because, at the same time, every one who is intelligent may be able to
accomplish this from what has been already said, and from one thing
may extend his reasoning power to many, and may easily know what
is omitted from what has been discussed. And I, indeed, think that
these things have been sufficiently explained, both in other respects
and because the explanation pays attention in a becoming manner to
the purity of the Gods. Because, however, it may perhaps appear to
others to be incredible, and not sufficiently manifest, and the
veracity of it may be suspected, as not exciting the discursive energy
of reason, I wish to consider these things a little more fully; and, if
possible, to add arguments more evident than those which have been
adduced.
 CHAP. XIV.

We shall begin, however, the elucidation of this subject in the best

possible manner, if we demonstrate that the sacred law of sacrifices
is connected with the order of the Gods. In the first place, therefore,
we say, that of the Gods some are material, but others immaterial.
And the material, indeed, are those that comprehend matter in
themselves, and adorn it; but the immaterial are those that are
perfectly exempt from, and transcend, matter. But, according to the
sacrific art, it is requisite to begin sacred operations from the
material Gods for the ascent to the immaterial Gods will not
otherwise be effected. The material Gods, therefore, have a certain
communion with matter, so far as they preside over it. Hence they
have dominion over things which happen about matter, such as the
division, percussion, repercussion, mutation, generation, and
corruption of all material bodies. He, therefore, who wishes to
worship these theurgically, in a manner adapted to them, and to the
dominion which they are allotted, should, as they are material,
employ a material mode of worship. For thus we shall be wholly led
to a familiarity with them, and worship them in an allied and
appropriate manner. Dead bodies, therefore, and things deprived of
life, the slaying of animals, and the consumption of victims, and, in
short, the mutation of the matter which is offered, pertain to these
Gods, not by themselves, but on account of the matter over which
they preside. For though they are in the most eminent degree
separate from it, yet at the same time they are present with it. And
though they comprehend matter in an immaterial power, yet they are
coexistent with it. Things that are governed, also, are not foreign
from their governors; and things which are subservient as
instruments, are not unadapted to those that use them. Hence, it is
foreign to the immaterial Gods, to offer matter to them through
sacrifices, but this is most adapted to all the material Gods.
 CHAP. XV.

Let us then, in the next place, direct our attention to that which
accords with what has been before said, and with our twofold
condition of being. For there is a time when we become wholly soul,
are out of the body, and sublimely revolve on high, in conjunction
with all the immaterial Gods. And there is also a time when we are
bound in the testaceous body, are detained by matter, and are of a
corporeal-formed nature. Again, therefore, there will be a twofold
mode of worship. For one mode, indeed, will be simple, incorporeal,
and pure from all generation, and this mode pertains to undefiled
souls. But the other is filled with bodies, and every thing of a material
nature, and is adapted to souls which are neither pure nor liberated
from all generation. We must admit, therefore, that there are twofold
species of sacrifices; one kind, indeed, pertaining to men who are
entirely purified, which, as Heraclitus says, rarely happens to one
man, or to a certain easily to be numbered few of mankind; but the
other kind, being material and corporeal-formed, and consisting in
mutation, is adapted to souls that are still detained by the body.
Hence, to cities and people not yet liberated from genesiurgic fate
and the impeding communion of bodies, if such a mode of sacrifice
as this latter is not permitted, they will wander both from immaterial
and material good. For they will not be able to receive the former,
and to the latter they will not offer what is appropriate. At the same
time, likewise, every one in sacrificing performs the sacrifice with
reference to what he is, and not with reference to what he is not. It is
not proper, therefore, that the sacrifice should transcend the proper
measure of him by whom it is offered. The same thing will also be
said by me concerning the connexion which appropriately coadapts
the men who worship and the powers that are worshiped. For this
connexion requires that a mode of worship should be chosen adapted
to itself; viz. an immaterial connexion, a mode of worship
immaterially mingled, and purely conjoining by pure incorporeal
powers, incorporeal natures to themselves; but a corporeal-formed
connexion, a corporeal-formed mode which depends on bodies, and
is mingled with the essences that preside over bodies.
 CHAP. XVI.

Farther still, therefore, we must not disdain to add what follows;

that we frequently perform something to the Gods who are the
inspective guardians of body, and to good dæmons, for the sake of
the necessary use of the body; as, for instance, when [by sacrifices]
we purify it from ancient stains, or liberate it from diseases, and fill it
with health, or remove from it heaviness and torpor, or procure for it
any other good. In this case, therefore, we evidently must not busy
ourselves with the body in an intellectual and incorporeal manner.
For the body is not adapted to participate of modes of this kind; but,
obtaining things which are allied to itself, it is meliorated and
purified by bodies. The rites of sacrifices, therefore, will necessarily,
for a purpose of this kind, be corporeal-formed; partly cutting off
what is superfluous in us; partly supplying us with that of which we
are in want; and partly leading into symmetry and order such things
in us as are immoderately disturbed. We also frequently engage in
sacred operations, entreating superior beings to grant us such things
as are adapted to the wants of human life. And these are such as
preserve the body in health, or pertain to those things which we
procure for the sake of the body.
 CHAP. XVII.

What, therefore, shall we derive from the Gods who are entirely
exempt from all human generation, with respect to sterility, or
abundance or any thing else pertaining to [the mortal] life? Nothing
whatever. For it is not the province of those who are liberated from
all things to meddle with gifts of this kind. But if some one should
say that the perfectly immaterial comprehend in themselves the
material Gods, and that through this they also contain in themselves
their gifts according to one first cause; such a one will also say, that
in consequence of this an abundance of divine gifts descend from the
immaterial Gods. It must not, however, be granted to any one to say
that the immaterial Gods bestow these gifts by proximately
interfering with the actions of human life. For such an
administration of our affairs is partible, is accomplished with a
certain conversion [to the subjects of its care], is not entirely
separate from bodies, and is incapable of receiving a pure and
undefiled domination. Will not, therefore, that mode of sacrifice in
works of this kind be most appropriate which is mingled with bodies,
and adheres to generation; and not that which is entirely immaterial
and incorporeal? For the pure mode of sacrifice is perfectly
transcendent and incommensurate [with our concerns]. But the
mode which employs bodies, and the powers that subsist through
bodies, is in the most eminent degree allied to human affairs. It is
also capable of producing a certain prosperous condition of things,
and of imparting symmetry and temperament to the mortal race.
 CHAP. XVIII.

According to another division, therefore, the numerous herd [or

the great mass] of men is arranged under nature, is governed by
physical powers, looks downward to the works of nature, gives
completion to the administration of Fate, and to things pertaining to
Fate, because it belongs to the order of it, and always employs
practical reasoning about such particulars alone as subsist according
to nature. But there are a certain few who, by employing a certain
supernatural power of intellect, are removed indeed from nature, but
are conducted to a separate and unmingled intellect; and these, at
the same time, become superior to physical powers. Others again,
who are the media between these, tend to things which subsist
between nature and a pure intellect. And of these, some indeed
equally follow both nature and an immaculate intellect; others
embrace a life which is mingled from both; and others are liberated
from things subordinate, and betake themselves to such as are more
excellent.
This division, therefore, being made, that which follows will most
manifestly take place. For those who are governed by the nature of
the universe, who lived conformably to this, and employ the powers
of nature, these should embrace a mode of worship adapted to
nature, and to the bodies that are moved by nature, and should
choose for this purpose appropriate places, air, matter, the powers of
matter, bodies, and the habits of bodies, qualities, and proper
motions, the mutations of things in generation, and other things
connected with these, both in other parts of piety and in that part of
it which pertains to sacrifice. But those who live conformably to
intellect alone, and to the life of intellect, and are liberated from the
bonds of nature, these should exercise in all the parts of theurgy the
intellectual and incorporeal mode of worship. And those who are the
media between these, should labour differently in the paths of piety,
conformably to the differences of this middle condition of life, either
by embracing both modes of piety, or separating themselves from
one of the modes [and adhering to the other], or receiving both these
modes as the foundation of things of a more honourable nature. For
without these they never can arrive at things supereminent. Or, in
some other way, they should thus, in a becoming manner, labour in
the paths of sanctity.
 CHAP. XIX.

On this subject, however, there is also the following division. Of

divine essences and powers some have [a genesiurgic] soul and
nature subject and ministrant to their fabrications, whenever they
wish to use them. But others are entirely separate from soul and
nature, I mean from a divine, and not only from a mundane and
genesiurgic soul and nature.[110] And others are the media[111] between
these, and afford to the extremes a communion with each other,
either according to an exuberant participation of greater good, or
according to an unimpeded reception of less good, or according to a
concord which binds together both the extremes. When, therefore,
we worship the Gods who reign over soul and nature, it is not foreign
to these to offer to them physical powers, and bodies which are
governed by nature. For all the works of nature are subservient to
them, and contribute to their government. But when we undertake to
honour those Gods who are essentially uniform, then it is requisite to
venerate them with liberated honours. Hence, intellectual gifts are
adapted to these, and things which pertain to an incorporeal life,
together with the fruits of virtue and wisdom, and whatever perfect
and total goods of the soul there may be. Moreover, to the Gods who
subsist as media, and who are the leaders of goods of a middle
nature, sometimes twofold gifts will be adapted, and sometimes such
as have a communication with both these; or such as are separated
from inferiors, and pertain to more elevated natures; or, in short,
such as in one of the modes give completion to the medium.
 CHAP. XX.

Being impelled, therefore, from another principle, viz. from the

world and the mundane Gods, from the arrangement of the four
elements in the world, and the association of the elements according
to [appropriate] measures, and also from the orderly circulation of
bodies about centres, we shall have an easy ascent to the truth of the
piety respecting sacrifices. For if we are in the world, are contained
as parts in the universe, are primarily produced by it, and perfected
by the total powers that are in it, and if we consist of its elements,
and receive from it a certain portion of life and nature; if this be the
case, it is not proper to pass beyond the world and the mundane
orders. We must admit, therefore, that in each part of the world
there is this visible body, and that there are also incorporeal powers,
which are divided about bodies. Hence the law of religion distributes
similars to similars, and thus extends from on high, through wholes,
as far as to the last of things; assigning, indeed, incorporeals to
incorporeals, but bodies to bodies, and this commensurately to the
nature of each. If, however, some theurgist should participate of the
supermundane Gods, which is the rarest of all things, he, indeed, in
the worship of the Gods will transcend both bodies and matter; being
united to the Gods by a supermundane power. But that which
happens to one person with difficulty and late, and at the end of the
sacerdotal office, ought not to be promulgated as common to all
men; nor ought it to be made a thing common to those who are
commencing theurgic operations, nor to those who have made a
middle proficiency in it. For these, after a manner, pay a corporeal-
formed attention to sanctity.
 CHAP. XXI.

I think, therefore, that all who are lovers of the contemplation of

theurgic truth will acknowledge this, that the piety which pertains to
divine natures ought not to be exercised towards them partially or
imperfectly. Hence, since prior to the appearance of the Gods, all
such powers as are presubjacent to them are moved, and when the
Gods are about to descend to the earth, precede them as in a solemn
procession;[112] he who does not distribute to all these powers that
which is adapted to them, and does not honour each in an
appropriate manner, will depart imperfect, and destitute of the
participation of the Gods. But he who propitiates all of them, and
offers to each acceptable gifts, and such as are to the utmost of his
power adapted to them, will always remain secure and
irreprehensible, giving completion in a proper manner to the perfect
and entire receptacle of the divine choir. Since this, therefore, is the
case, whether is it necessary that the mode of sanctity should be
simple, and consist of a certain few things, or that it should be
multiform and all-harmonic, and mingled, as I may say, from every
thing contained in the world? If, indeed, the power which is invoked,
and is excited in the performance of sacred rites, was simple, the
mode of sacrifice should necessarily be simple. But if the multitude
of powers which are excited when the Gods descend and are moved,
is not to be comprehended by any one, except theurgists alone, who
accurately know this through experience in sacred operations; if this
be the case, they alone are capable of knowing what the perfection is
of the sacrific art; and they also know that the omission, though of a
few things, subverts the whole work of religion; just as in harmony,
from the bursting of one chord, the whole becomes dissonant and
incommensurate.[113] As, therefore, in the visible descents of the
Gods, a manifest injury is sustained by those who leave some one of
the more excellent genera unhonoured,[114] thus also in the invisible
appearances of the Gods in sacrifices, it is not proper to honour one
of them, and not honour another, but it is entirely requisite to
honour each of them according to the order which he is allotted. But
he who leaves some one of them unhonoured, confounds the whole
work of piety, and divulses the one and whole orderly distribution of
it; not, in so doing, as some one may think, imperfectly receiving the
Gods, but entirely subverting all the ceremonies of religion.
 CHAP. XXII.

What then [it may be said], does not the summit of the sacrific art
recur to the most principal one of the whole multitude of Gods, and
at one and the same time worship the many essences and principles
that are [rooted and concentred] in it? Entirely so, but this happens
at the latest period, and to a very few, and we must be satisfied if it
takes place when the sun of life is setting. Our present discussion,
however, does not ordain laws for a man of this kind; for he is
superior to all law;[115] but it promulgates a law such as that of which
we are now speaking, to those who are in want of a certain divine
legislation.[116] It says, therefore, that as the world has one
coarrangement from many orders, thus also it is necessary that the
consummation of sacrifices, being never failing and entire, should be
conjoined to the whole order of more excellent natures. If, however,
the world is multiform, and all perfect, and is united from many
orders, it is also necessary that sacred operations should imitate its
omniform variety through the whole of the powers which they
employ. Hence, in a similar manner, since the things which surround
us are all-various, it is not fit that we should be connected with the
divine causes that preside over them, from a certain part which they
contain. Nor is it proper that we should ascend imperfectly to the
primordial causes of them.
 CHAP. XXIII.

The various mode, therefore, of sanctity in sacred operations

partly purifies and partly perfects some one of the things that are in
us or about us. And some things, indeed, it restores to symmetry and
order; but others it liberates from mortal-formed error. But it
renders all things familiar and friendly to all the natures that are
superior to us. Moreover, when divine causes, and human
preparations which are assimilated to them conspire in one and the
same, then the perfection of sacred operations imparts all the perfect
and great benefits of sacrifice. It will not be amiss, also, to add such
particulars as the following, in order to the accurate comprehension
of these things. An exuberance of power is always present with the
highest causes, and at the same time that this power transcends all
things, it is equally present with all with unimpeded energy. Hence,
conformably to this, the first illuminate the last of things, and
immaterial are present with material natures immaterially. Nor
should it be considered by any one as wonderful, if we say that there
is a certain pure and divine matter.[117] For matter being generated by
the father and demiurgus of wholes, receives a perfection adapted to
itself, in order to its becoming the receptacle of the Gods. At the
same time nothing prevents more excellent beings from being able to
impart their light to subordinate natures. Neither, therefore, is
matter separated from the participation of better causes; so that such
matter as is perfect, pure, and boniform, is not unadapted to the
reception of the Gods. For, since it is requisite that terrestrial natures
should by no means be destitute of divine communion, the earth also
receives a certain divine portion from it, sufficient for the
participation of the Gods. The theurgic art, therefore, perceiving this
to be the case, and thus having discovered in common, appropriate
receptacles, conformably to the peculiarity of each of the Gods, it
frequently connects together stones, herbs, animals, aromatics, and
other sacred, perfect, and deiform substances of the like kind; and
afterwards, from all these, it produces an entire and pure receptacle.
For it is not proper to despise all matter, but that alone which is
foreign from the Gods. But that matter is to be chosen which is
adapted to them, as being able to accord with the edifices of the
Gods, the dedication of statues, and the sacred operations of
sacrifices. For no otherwise can a participation of superior beings be
obtained by places in the earth, or by men that dwell in it, unless a
foundation of this kind is first established. It is also requisite to be
persuaded by arcane assertions, that a certain matter is imparted
by the Gods, through blessed visions. This matter, therefore, is
doubtless connascent with those by whom it is imparted. Hence,
does it not follow that the sacrifice of a matter of this kind excites the
Gods to present themselves to the view, immediately calls forth the
participation of them, receives them when they accede, and perfectly
unfolds them into light?
 CHAP. XXIV.

The same things also may be learned from the distribution of the
Gods according to places; and from this, and the partible dominion
over each particular thing, it may be seen how many allotments,
greater or less, superior beings are assigned according to their
different orders. For it is evident, that to the Gods who preside over
certain places, the things produced by them are most appropriately
offered in sacrifice; and that what pertains to the governed is most
adapted to be sacrificed to the governors. For always to makers their
own works are particularly grateful; and to those who primarily
produce certain things, such things are primarily acceptable.
Whether, therefore, certain animals, or plants, or any other
productions of the earth, are governed by superior beings, at one and
the same time, they participate of their inspective care, and impart to
us an indivisible communion with the Gods. Some things, therefore,
of this kind, if they are carefully preserved, increase the familiarity of
those that retain them with the Gods; and these are such as by
remaining entire, preserve the communion between Gods and men.
Of this kind are some of the animals in Egypt, and man, who is
everywhere sacred. But some things, when consecrated, produce a
more manifest familiarity; and these are such as by an analysis into
the principle of the first elements, effect an alliance more sacredly
adapted to superior causes. For the more perfect this alliance is, the
more perfect always is the good which is imparted by it.
 CHAP. XXV.

If, therefore, these things were human customs alone, and derived
their authority through our legal institutions, it might be said that
the worship of the Gods was the invention of our conceptions. Now,
however, divinity is the leader of it, who is thus invoked by sacrifices,
and who is surrounded by a numerous multitude of Gods and angels.
Under him, likewise, a certain common presiding power, is allotted
dominion according to each nation of the earth. And a peculiar
presiding power is allotted to each temple. Of the sacrifices, also,
which are performed to the Gods, the inspective guardian is a God;
but an angel, of those which are performed to angels; and a dæmon,
of such as are performed to dæmons. After the same manner, also, in
other sacred operations, the presiding power is allotted dominion
over each, in a way allied to his proper genus. When, therefore, we
offer sacrifices to the Gods, accompanied by the presiding Gods, who
give completion to sacred operations, then at the same time, it is
necessary in sacrifices to venerate the sacred law of divine sanctity;
and at the same time, also, we ought to be confident, as sacrificing
under the Gods who are the rulers of such works. We ought, likewise,
to be very cautious, lest we should offer any gift unworthy of, or
foreign from, the Gods. And, as the last admonition, we should in a
manner entirely perfect, pay attention to all that surrounds us, and
to the Gods, angels, and dæmons that are distributed according to
genera in the universe. And to all these, in a similar manner, an
acceptable sacrifice should be offered; for thus alone sanctity can be
preserved in a way worthy of the Gods who preside over it.
 CHAP. XXVI.

Since, however, prayers are not the smallest [but on the contrary a
very great] part of sacrifices, especially give completion to them, and
through these the whole operation of them is corroborated and
effected; and since, besides this, they afford a common utility to
religion, and produce an indissoluble and sacred communion with
the Gods, it will not be improper to discuss a few particulars
concerning prayer. For this is of itself a thing worthy to be known,
and renders more perfect the science concerning the Gods. I say,
therefore, that the first species of prayer is collective; and that it is
also the leader of contact with, and a knowledge of, divinity. The
second species is the bond of concordant communion, calling forth,
prior to the energy of speech, the gifts imparted by the Gods, and
perfecting the whole of our operations prior to our intellectual
conceptions. And the third and most perfect species of prayer is the
seal of ineffable union with the divinities, in whom it establishes all
the power and authority of prayer; and thus causes the soul to repose
in the Gods, as in a never failing port. But from these three terms, in
which all the divine measures are contained, suppliant adoration not
only conciliates to us the friendship of the Gods, but supernally
extends to us three fruits, being as it were three Hesperian apples of
gold.[118] The first of these pertains to illumination; the second, to a
communion of operation; but through the energy of the third, we
receive a perfect plenitude of divine fire. And sometimes, indeed,
supplication precedes; like a precursor preparing the way before the
sacrifice appears. But some times it intercedes as a mediator; and
sometimes accomplishes the end of sacrificing. No operation,
however, in sacred concerns, can succeed without the intervention of
prayer. Lastly, the continual exercise of prayer nourishes the vigour
of our intellect, and renders the receptacles of the soul far more
capacious for the communications of the Gods. It likewise is the
divine key, which opens to men the penetralia of the Gods;
accustoms us to the splendid rivers of supernal light; in a short time
perfects our inmost recesses, and disposes them for the ineffable
embrace and contact of the Gods; and does not desist till it raises us
to the summit of all. It also gradually and silently draws upward the
manners of our soul, by divesting them of every thing foreign to a
divine nature, and clothes us with the perfections of the Gods.
Besides this, it produces an indissoluble communion and friendship
with divinity, nourishes a divine love, and inflames the divine part of
the soul. Whatever is of an opposing and contrary nature in the soul,
it expiates and purifies; expels whatever is prone to generation, and
retains any thing of the dregs of mortality in its etherial and splendid
spirit; perfects a good hope and faith concerning the reception of
divine light; and, in one word, renders those by whom it is employed
the familiars and domestics of the Gods. If such, then, are the
advantages of prayer, and such its connexion with sacrifice, does it
not appear from hence that the end of sacrifice is a conjunction with
the Demiurgus of the world? And the benefit of prayer is of the same
extent with the good which is conferred by the demiurgic causes on
the race of mortals. Again, from hence the anagogic, perfective, and
replenishing power of prayer appears; likewise how it becomes
efficacious and unific; and how it possesses a common bond
imparted by the Gods. And, in the third and last place, it may easily
be conceived from hence how prayer and sacrifice mutually
corroborate and confer on each other a sacred and perfect power in
divine concerns.
Hence, since it appears that there is a perfect conspiration and
cooperation of the sacerdotal discipline with itself, and that the parts
of it are more connascent than those of any animal, being entirely
conjoined through one connexion; this being the case, it is not by any
means proper to neglect this concord, nor to admit some of its parts
and reject others; but it is fit that all of them should be exercised in a
similar manner, and that those should be perfected through all of
them who wish to be genuinely conjoined to the Gods. These things
therefore, cannot subsist otherwise.
 SECTION VI.

CHAP. I.

It is now, however, time for me to pass on to the next doubt which

you propose, viz. “Why it is requisite that the inspector [who
presides over sacred rites] ought not to touch a dead body, though
most sacred operations are performed through dead bodies?”
Again, therefore, that we may dissolve this doubt, we shall direct our
attention to this apparent opposition; for there is not in reality any,
but these things alone seem to subsist contrarily. For if the laws of
sacred rites ordered that the same dead bodies should not be touched
and should be touched, this would be a thing contrary to itself. But if
they order that some dead bodies should be abstained from as
impure, but that others which are consecrated should be touched,
this is not attended with any contrariety. Farther still, it is not lawful
to touch human bodies when the soul has left them, since a certain
vestige, image, or representation of divine life is extinguished in the
body by death. But it is no longer unholy to touch other dead bodies,
because they did not [when living] participate of a more divine life.
To other Gods, therefore, who are pure from matter, our not
touching dead bodies is adapted; but to those Gods who preside over
animals, and are proximately connected with them, invocation
through animals is properly made. According to this, therefore, no
contrariety takes place.