U 7 Biologics For The Primary Care Physician Review and Treatment of Psoriasis

Disease-a-Month 65 (2019) 51–90
Contents lists available at ScienceDirect
Disease-a-Month
journal homepage: www.elsevier.com/locate/disamonth
Biologics for the primary care physician:

Review and treatment of psoriasis
Eric D. Schadler, BS a,b,∗, Bernhard Ortel, MD a,b,
Stephanie L. Mehlis, MD a,b
a
University of Chicago Pritzker School of Medicine, Chicago, IL, United States
b
NorthShore University HealthSystem, Department of Medicine, Division of Dermatology, 9933 Woods Drive, Skokie,
IL, United States
a r t i c l e i n f o a b s t r a c t
Psoriasis is a chronic inflammatory disease that affects ap-

Keywords: proximately 7.5 million people in the United States. The dis-
Plaque psoriasis ease results in significant suffering, morbidity, and economic
Biologic
impact. Psoriasis is a multifaceted disease with a strong ge-
Clinical trials
netic component. Genetic data has revealed the presence of
particular risk alleles in patients with psoriasis. Triggers of
the disease have been elucidated and include factors such as
trauma, obesity, infection, stress, and medications. At its core,
psoriasis is a result of a dysfunctional immune response with
T-cells at the center of immunogenesis.
Clinically, psoriasis is characterized by discrete, erythematous
scaly plaques. These lesions are often found on extensor sur-
faces, especially the elbows and knees. Although extensor
surfaces are the prototypical destination of lesions, psoria-
sis may affect any area of the skin including the scalp, in-
tertriginous areas, nails, palms, and soles. Location of lesions
are important in assessing the impact on quality of life for
patients. Diagnosis of psoriasis can typically be made clin-
Abbreviations: AE, Adverse event; APL, Antigen presenting cell; BMI, Body mass index; BSA, Body surface area; CVD,
Cardiovascular disease; CZP, Certolizumab pegol; FDA, Food and Drug Administration; GWAS, Genome wide association
study; HLA, Human leukocyte antigen; HPA, Hypothalamic-pituitary-adrenal; IL, Interleukin; NF-κ B, Nuclear factor-kappa
beta; OR, odds ratio; PASI, Psoriasis area and severity index; PGA, Physician global assessment; PsA, Psoriatic arthritis;
PUVA, Psoralen and ultraviolet A; QOL, Quality of life; SAE, Serious adverse event; TLR, Toll-like receptor; TNF, Tumor
necrosis factor; UVR, Ultraviolet radiation.
∗
Corresponding author at: North Shore University Health System, 9933 Woods Drive, Skokie, IL 60637, United States.
E-mail address: eric.schadler@uchospitals.edu (E.D. Schadler).
https://doi.org/10.1016/j.disamonth.2018.06.001
0011-5029/© 2018 Elsevier Inc. All rights reserved.
52 E.D. Schadler et al. / Disease-a-Month 65 (2019) 51–90
ically based on characteristic history and physical examina-

tion findings. In rare cases, biopsy may be needed to rule out
other papulosquamous disease. Histologic findings of psoria-
sis can be non-specific and include marked epidermal hyper-
plasia, dilated vessels within the dermal papilla, and elon-
gated rete ridges. Importantly, psoriasis is a systemic dis-
ease and organ systems outside of the skin must be consid-
ered. Co-morbidities of psoriasis include psoriatic arthritis,
type 2 diabetes mellitus, cardiovascular disease, psychiatric
disease, inflammatory bowel disease, neoplasms, and ocular
disease.
Management of psoriasis depends on the severity of the dis-
ease. In mild to moderate cases, topical medications are the
cornerstone of treatment. Topical corticosteroids are the most
commonly used and have limited systemic effects due to the
localized application of medication. In moderate to severe
cases of psoriasis, topical medications are ineffective and not
feasible. Phototherapy and non-biologic systemic medications
have been useful treatments; however, phototherapy is time
consuming and non-biologic systemics have only modest re-
sponse rates. In the last decade, biologic medications have
become an important component of care for treating moder-
ate to severe psoriasis. These medications target various cy-
tokines responsible for psoriasis manifestations such as tu-
mor necrosis factor (TNF-α ), interleukin-12, interleukin-23,
and interleukin-17. In the past 15 years, numerous biologic
medications have been granted FDA approval, with the ma-
jority approved in the past several years. Some of the com-
monly used biologics include etanercept, adalimumab, inflix-
imab, ixekizumab, secukinumab, brodalumab, guselkumab,
ustekinumab, and tildrakizumab. Given the wealth of new
biologics, current treatment guidelines have rapidly become
outdated. This review provides summarized information of
landmark trials that led to the approval of these medications.
© 2018 Elsevier Inc. All rights reserved.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Triggering factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Sunlight. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Stress. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Alcohol and smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Endocrine factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Clinical classification and features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Psoriasis vulgaris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Guttate psoriasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
E.D. Schadler et al. / Disease-a-Month 65 (2019) 51–90 53
Pustular psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Erythrodermic psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Inverse psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Nail psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Immunopathogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Interleukin-17 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Interleukin-12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Interleukin-23. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Tumor necrosis factor-α . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Co-morbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Psoriatic arthritis (PsA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Metabolic syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Obesity & type 2 diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Psychological impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Inflammatory bowel disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Substance abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Ocular disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Clinical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Histological aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Medical management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
TNF-α inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
IL-12/IL-23 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
IL-17 inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Selective IL-23 inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Biologics in the pipeline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Management of patients on biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Topicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Phototherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Oral systemics (non-biologic) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Landmark clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Etanercept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Adalimumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Infliximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Certolizumab pegol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Ustekinumab. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Secukinumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Ixekizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Brodalumab. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Guselkumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Tildrakizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Financial disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Introduction
Psoriasis is a chronic inflammatory disease historically considered a condition of the skin.

Although one striking component of the condition are the characteristic scaly, erythematous
papules and plaques, psoriasis is a multifaceted systemic disease affecting patients internally,
externally, and psychosocially in various manners. According to the National Psoriasis Founda-
tion, approximately 7.5 million Americans have a diagnosis of psoriasis. Consequently, psoriasis
results in considerable amounts of patient suffering, morbidity, and economic impact each
year. This review will focus on the treatment of psoriasis using biologic therapy. The aim is to
familiarize physicians with the numerous biologic therapies that have been approved by the
FDA by highlighting the clinical trials that led to their approval. Before we get to this, however,
it is important for clinicians to have a thorough understanding of the disease. An initial review
of the epidemiology, genetics, disease triggers, clinical features, co-morbidities, and diagnosis
will be presented.
Epidemiology
Psoriasis is a global disease that affects approximately 2%–3% of the world’s population.1
Despite its worldwide reach, the prevalence differs significantly among different ethnicities and
geographic locations. In general, prevalence is increased at higher latitudes; East Asia tends to
have the lowest rates, whereas Northern Europe appears to be one the of highest.2
From a gender standpoint, psoriasis is a disease that affects men and women without dis-
cretion; however, in women the condition tends have its onset at an earlier age.3,4 Regardless,
psoriasis may present at any age and can be subclassified based on the age of onset. Type 1, or
early-onset psoriasis, occurs before the age of 40 and encompasses approximately 70% of cases.
Within this group, a peak onset between 16 and 22 years of age exists.5 Type 2, or late-onset
psoriasis, occurs after the age of 40 and has a peak seen at 57–60 years of age.5 Histologically,
these two classifications have no distinguishable characteristics; however, genetically there are
differences that will be discussed in the section on genetics.
Reports have indicated the incidence of psoriasis may be increasing. Between the 1970s and
20 0 0, one study found that the incidence nearly doubled.6 It is unclear if the disease incidence
has truly risen or if these reports instead demonstrate a dramatic shift in diagnosing patterns
and medical practice.
Genetics
Psoriasis is a complex disease with a multifactorial etiology. Ultimately, the interplay be-
tween genetics and trigging factor(s) result in manifestations of the disease.5 Multiple studies
have identified genetic loci, or psoriasis susceptibility regions, that are implicated in the disease.
Genetic linkage studies have identified 10 loci as potential psoriasis susceptibility regions
(Table 1).2 Although linkage studies are challenging to perform in complex diseases such as
psoriasis, these results provided a good starting place for future work.
Of the loci identified, PSORS1 is consistently replicated in studies and has been most thor-
oughly investigated. This region spans approximately 30 0,0 0 0 bases, contains 11 genes including
human leukocyte antigen (HLA)-B and HLA-C, and is thought to account for 35%–50% of the
hereditary nature of psoriasis.2 Nair et al. further explored this region using DNA sequencing.
They identified the HLA-Cw6 allele as the ultimate susceptibility risk allele located in the
PSORS1 region.7 As mentioned previously, the age of onset of psoriasis differs from a genetic
standpoint. Within early-onset psoriasis (type 1), over 90% of the time HLA-Cw6 was expressed;
in contrast, 50% of patients with late-onset psoriasis (type 2) and only 7% of the healthy
control population expressed the risk allele.4 With this in mind, type 1 psoriasis can be more
accurately associated with patients who have early-onset psoriasis, a positive family history,
and expression of the HLA-Cw6 allele whereas type 2 psoriasis includes patients with late-onset
psoriasis, a negative family history, and lack HLA-Cw6 expression.2
As laboratory techniques become more sophisticated, the ability to study the genetic basis
of psoriasis continue to improve. Genome-wide association studies (GWAS) are one example
Table 1
This table lists the 10 psoriasis susceptibility re-
gions identified using linkage studies. Of these,
PSORS1 has the most supporting results.
Loci Name Location
PSORS1 6p21.3
PSORS2 17q25
PSORS3 4q
PSORS4 1q21
PSORS5 3q21
PSORS6 19p13
PSORS7 1p
PSORS8 16q
PSORS9 4q31-34
PSORS10 18p11.23
Table 2
List of factors identified as triggers for the develop-
ment of psoriasis.
Triggering Factors
Trauma Sunlight (UV light)

Obesity Stress
Infections Alcohol and smoking
Medications Endocrine factors
that have allowed for in depth analysis of the disease. Multiple studies have taken this chal-
lenge head on and identified an additional 41 genetic loci associated with psoriasis.2 Not only
did these studies identify genetic locations of interest, they also confirmed Nair et al. groups
findings regarding the HLA-C locus. Lastly, these studies revealed an association between pso-
riasis and other genes involved in inflammatory signaling. Some of these genes include nuclear
factor (NF)-kB, tumor necrosis factor (TNF) and interleukin (IL)−23/TH17 pathways.2 Not sur-
prisingly, many of the loci found as a result of GWAS have been reported in other autoimmune
conditions.
Microarray analysis of skin biopsy specimens is another technique that has improved our
knowledge of psoriasis. Using this technique, over 1300 genes were found to be differently
expressed when comparing psoriatic skin to healthy skin.4 These analyses confirmed the role
of multiple key pathways in psoriasis pathogenesis that will be discussed in greater detail
later.
From a hereditary standpoint, a positive family history is present in 35% to 90% of patients
diagnosed with the disease.4 One study found a 41% risk of a child developing psoriasis if both
parents were affected.8 This risk decreased to 14% if only one parent was affected, and 6% if
a sibling carried the diagnosis. Using a large Danish twin registry, Lønnberg et al. found the
concordance for psoriasis was greater in both monozygotic and dizygotic twins compared to the
general population.9 In the authors population, a monozygotic twin had an eightfold increase
and dizygotic twin a fourfold increase risk compared to the general population when their
co-twin had psoriasis.
Triggering factors
The genetic component of psoriasis serves as a “primer” in disease development. Triggering

factors serve as the ignition of this primer resulting in the clinical manifestations. Table 2 shows
a list of some of the known triggering factors of psoriasis.
Trauma
Heinrich Koebner recognized in 1872 that patients with psoriasis developed skin lesions in
unaffected areas following trauma. This principle is today known as the Koebner phenomenon,
and helps explain the characteristic distribution of lesions on extensor surfaces of the elbows,
knees, and sacral regions. Within these areas the skin experiences continuous friction and
microtrauma resulting in epidermal damage. This disruption of the epidermis induces an
inflammatory response, which in turn leads to the development of psoriatic lesions.10
Obesity
The psoriatic population tends to be obese. Currently, there are two viewpoints regarding the
link between obesity and psoriasis. On one hand, obesity has been shown to be a direct conse-
quence of the disease course. Alternatively, other studies have shown patients with obesity are
at additional risk of developing psoriasis and obesity serves as a trigger. Each of these stances
have their own supporting data. More likely, these two thoughts are not mutually exclusive and
both true. The Nurses’ Health Study (NHS) has evaluated obesity as a potential triggering factor.
They followed a cohort of 67,300 women and over a 12-year period and found a significant
association between increasing body mass index (BMI) and risk of psoriasis.11 Compared to
women with a BMI less than 25, the relative risk of developing psoriasis was greater in women
with BMI ranges of 25.0–29.9 [RR: 1.21 (95% CI, 1.03–1.43)], 30.0 to 34.9 [RR: 1.63 (95% CI,
1.33–2.00)], and 35.0 or greater [RR: 2.03 (95% CI, 1.58–2.61)].11 In addition to overall weight
influencing psoriasis onset, changes in weight also have been shown to predispose patients
to psoriasis. Setty et al. identified a graded association between weight changes and risk
of psoriasis.12 After controlling for other variables, patients who gained 35 pounds or more
between age 18 and weight updated every 2 years experienced a relative risk incidence of 1.88
(95% CI, 1.44–2.46) compared to patients who maintained their weight within 5 lbs.
Infections
Infections have been implicated in the pathogenesis of numerous diseases by triggering

a cascade of internal changes. In psoriasis, various infections have been shown to have an
inducing and/or an exacerbating effect on the disease. Streptococcal infections in particular
have demonstrated a strong relationship to the sudden development of generalized guttate
psoriasis.13 One theory regarding the mechanism of this association involves bacterial T-cell
activating toxins that induce expression of cutaneous lymphocyte antigen (CLA), a skin homing
receptor.14 This antigen draws the inflammation to the skin resulting in psoriatic lesions in ge-
netically predisposed individuals. Other infections that may result in triggering psoriasis include
Staphylococcus aureus, Malassezia species, Candida, and viruses, such as human papillomavirus
and human immunodeficiency virus.15
Medications
An array of medications can induce psoriasis in patients with susceptibility to the disease.
Medications can also aggravate existing disease. Table 3 shows a list of drug that have been
implicated either as a class or from individual case reports.10,15 For brevity, not all drugs
have been included; however, key medications to be aware of include β -blockers, lithium,
non-steroidal anti-inflammatory drugs (NSAIDs), and antimalarial agents. For further interest
regarding the proposed mechanisms of action and studies support please refer to the literature.
Table 3
Short list of drugs or classes that have been implicated in psoriasis.
Beta-blockers∗
Lithium
NSAIDs
Hydroxychloroquine
Cytokines (α - and β -interferon)
Antibiotics (penicillin, amoxicillin, ampicillin, doxycycline)
Psychiatric drugs (fluoxetine, olanzapine)
Carbamazepine
∗
Most commonly encountered drug resulting in exacerbation
Sunlight
Ultraviolet radiation (UVR) can be used as a therapeutic agent for psoriasis; however, in
some individuals, UVR can paradoxically exacerbate the disease.10,16 Two patterns have been
established. About half of patients with sensitivity to UVR experience a polymorphous light
eruption (a hypersensitivity reaction to UVR that does not have any similarity to psoriasis
clinically), which later develops into psoriatic lesions. The other half develop psoriatic lesions
without the preceding non-psoriatic eruption. Generally, UVR is beneficial for most patients
with psoriasis and likely contributes to the decreased disease prevalence near the equator.
Stress
If you speak to a patient who suffers from psoriasis, chances are high they will attribute
flares of their disease to periods of additional stress. One study by Verhoeven et al. determined
that cognitive and behavior patterns of worrying and scratching were independently related
to more severe psoriasis conditions 4 weeks later (as measured by the psoriasis area and
severity index and pruritus scales).17 The mechanism of this is currently debated, but strong
evidence has supported alterations in the hypothalamic-pituitary-adrenal (HPA) axis responsible
for regulation of stress hormones, and sympathoadrenal system responsible for producing
catecholamines.18,19 Stress has also been established as a common trigger associated with initial
presentations of psoriasis patients.20
Alcohol and smoking
Several studies have identified smoking habits and alcohol consumption as two environ-
mental factors that play a role in the development and worsening of psoriasis. One study
performed in Italy found that the odds ratios (OR) of having psoriasis was higher in patients
who were previous or current smokers.21 As the number of cigarettes smoked per day increased
so too did the OR’s of developing psoriasis. Additionally, examination of ex-smokers revealed
a decrease in risk with increasing time since quitting. Excessive alcohol consumption has also
been associated with onset of psoriasis and severity of disease. Patients who drink more heavily
are more likely to have more severe and extensive disease, as well as higher degrees of systemic
inflammation.22
Endocrine factors
The importance of the endocrine system on psoriasis has been briefly illustrated in the role
of the HPA axis as a mediator of the stress trigger. Additionally, some hormones have been
found to affect psoriasis directly. These include androgens, prolactin, and thyroid hormone. As
mentioned in the epidemiology section of this review, the age of onset for psoriasis has peaks
near puberty and menopause – times when hormones are in flux. Considering the skin’s ability
to respond to hormonal signals, and its role as a neuroendocrine organ, it should come as no
surprise that psoriasis can be closely tied to endocrine factors.
Pregnancy is one example of a period the endocrine system changes. During pregnancy
there are dramatic shifts in levels of estrogen, progesterone, and cortisol. Also, a variety of
immunologic changes occur during this process. Although a majority of pregnancy patients
do well during pregnancy, they may experience new-onset, improvement, or worsening of
psoriasis.23 In the immediate post-partum period psoriasis tends to exacerbate.
Definitions
In clinical practice, standardized definitions for psoriasis are challenging due to the spectrum
of presentation and the subjective impact of the disease on the individual. For example. is a
treatment considered successful if all skin manifestations on a patient resolve, yet they continue
to have debilitating joint involvement? Despite this ambiguity, it is important from a clinical
trials standpoint to have reproducible definitions that can serve unifying and comparative
purposes. Below are some common definitions used in the psoriasis literature that may have
clinical or research importance.
A. Active disease – A patient who is afflicted with one or more features of psoriasis has active
disease.
B. Severity of disease – Severity is often signified based on body surface area (BSA) in-
volvement and intensity of plaque characteristics including erythema, induration, and
scale. Practically speaking, these markers are meaningless in defining mild, moder-
ate, and severe disease without also considering the individual impacts on qual-
ity of life (QOL). Often these areas are intrinsically linked, but not always. Below
are proposed definitions using QOL-based definitions for mild, moderate, and severe
disase.24
1. Mild disease – Disease that does not alter quality of life, has impacts that can be min-
imized by the patient, and may not require treatment. If treatment is required, the
appropriate therapeutic classes have no serious risks. Generally, mild disease covers
less than 5% BSA.
2. Moderate disease – Disease that affects quality of life and can be improved with treat-
ment. Therapeutic options have minimal side effect risks. Generally, moderate disease
involves between 2 and 20% BSA.
3. Severe disease – Disease that affects quality of life and requires therapeutics that
present higher risks to patients. These patients are willing to accept more severe med-
ication side effects and risk to improve their condition. Generally, severe disease cov-
ers more than 10% BSA. Severe disease may be deemed a result of disease location
(face, feet, hands, etc.), symptoms (sleep loss, pruritus, bleeding, etc.), or presence of
an arthritic component.
C. Response – In clinical practice, response is subjective and is defined as a decrease in the
extent, severity, or an improved quality of life. An adequate clinical response is deter-
mined by physician assessment of disease and discussions with the patient to assess their
satisfaction with their disease state.
D. Remission – Complete clearing of psoriasis.25 For majority of patients and treatments, this
is an unrealistic goal.
E. Treatment success – the Medical Advisory Board defines this as a 50% improvement from
the baseline psoriasis area and severity index score (defined below).
F. Relapse – In patients who previously achieved treatment success, but then falls below the
50% improvement mark.25
G. Rebound – This is a sudden or drastic change in severity and or character of psoriasis that
is worse than prior to treatment.25 A disease rebound may occur following withdrawal of
a treatment.
H. Duration of therapeutic effect – The time between stopping a therapy and experiencing a
50% reduction in prior response.25
I. Psoriasis area and severity index (PASI) – Used in clinical trials to quantitively evaluate the
severity of psoriasis. The score accounts for the degree of erythema, induration, and scale
by rating each from 0 to 4 with 0 being “absent” and 4 being “very severe”. Investigators
determine this score separately for 4 different body areas: head (including face, scalp,
and neck), upper extremities, trunk, and lower extremities (includes genital region and
buttocks). In addition to evaluating these plaque characteristics, the extent of involvement
is determined for each body region and assigned a score from 0 to 6. After each value is
assigned a simple equation is used to calculate a PASI score. Raw scores range from 0 to
72 with 72 representing the most severe disease possible and 0 being completely clear.
1. PASI 75, 90, and 100 – These represent 75%, 90%, and 100% reductions – usually by
treatment – in PASI score when compared to the patient’s baseline.
J. Physician global assessment (PGA) – another assessment used in clinical trials to assign
a gestalt score representing severity of disease. The assessment accounts for the same
plaque components as the PASI (erythema, induration, and scale), but does not include
the extent of disease. There are 5-point and 6-point scales that can be used. Because the
PGA does not account for extent, a patient could theoretically have a miniscule plaque
with extraordinary erythema, induration, and scale resulting in a maximum PGA score,
but a PASI calculation that would be near 0.
K. Serious adverse event (SAE) – used in clinical trials and defined as any medical event that
results in death, requires or prolongs a hospitalization, results in significant disability, or
is a congenital abnormality.
Clinical classification and features
Psoriasis exists in a variety of clinical and anatomic phenotypes including plaque, guttate,
pustular, erythrodermic, palmoplantar, inverse, and nail psoriasis. Plaque psoriasis, or psoriasis
vulgaris, accounts for an overwhelming majority of cases (∼90%).26 A large proportion of
research aimed at psoriasis has focused on the plaque form of the disease.
Psoriasis vulgaris
Psoriasis vulgaris, more commonly referred to as plaque psoriasis, is characterized by erythe-

matous papules that coalesce into well-defined plaques (Figs. 1 and 2). Plaques may have steep,
“drop-off” edges or be relatively smooth. Silvery white scale is characteristic of the disease. The
removal of scale may result in pinpoint bleeding known as Auspitz sign. This is a consequence
of increased vascularity within the papillary dermis. Lesions tend to be located on extensor
surfaces with elbows and knees symmetrically involved in many cases.
Guttate psoriasis
Guttate psoriasis is an acute, often generalized onset of numerous, smaller sized lesions that
favor the trunk and extremities. The papules are monomorphic, and appear as droplets (“gutta”
is Latin for drop).26 Guttate psoriasis has been strongly associated with upper respiratory, specif-
ically streptococcal infections making this phenotype common in children and adolescents, in
whom these infections are more prevalent. Fortunately, guttate psoriasis tends to be self-limited;
Fig. 1. Discrete plaques with thick silvery scale characteristic of plaque psoriasis.
however, some patients will go on to develop chronic plaque psoriasis. In one small study, 38.9%
(n = 14) of patients with an episode of guttate psoriasis progressed to chronic plaque psoriasis.27
Pustular psoriasis
As the name implies, pustular psoriasis is characterized by numerous pustules overlying an

erythematous base.26 Interestingly, pustules are sterile and not a result of an infectious source.28
Pustular psoriasis may appear in a localized distribution or be generalized. Palmoplantar pustu-
lar psoriasis is one form of localized disease. Unfortunately, the condition is notoriously difficult
to treat and causes significant impacts on the QOL of patients due to the location. Physicians
unfamiliar with this clinical variety may be concerned about superinfection in such patients,
however, due to cutaneous overexpression in defensins, superinfection almost never happens
in psoriatic skin.29 Pustular psoriasis is sometimes induced by sudden withdrawal of treatment,
specifically, if a patient has been erroneously managed with systemic corticosteroids.
Erythrodermic psoriasis
Erythrodermic psoriasis can be a result of an escalation of preexisting psoriasis, discontinu-

ation of therapy, a drug-reaction, or a systemic infection.26 It is characterized by a generalized,
confluent erythema with fine scale over 90% of the patient’s body. Erythrodermic psoriasis is an
emergency and typically requires impatient management for close monitoring.
Inverse psoriasis
Inverse psoriasis differs from psoriasis vulgaris in that locations affected are often in folds
such as the inframammary, axillary, perineal, intergluteal, and inguinocrural regions. Plaques
Fig. 2. Psoriasis plaques may be associated with significant erythema.
tend to be erythematous and indurated, but have much less scale due to moisture in these
locations.26
Nail psoriasis
Nail psoriasis may occur in isolation; however, more commonly it is a feature in patients
with psoriasis present elsewhere. Studies have revealed that approximately 50% of psoriasis
patients have nail involvement. This finding can be an important tool in suspecting psoriatic
arthritis.30 In one study, patients with nail dystrophy were three times more likely to develop
psoriatic arthritis than those without.31 In a different study of 69 patients with psoriatic arthri-
tis, 83% of patients had characteristic nail disease.32 The results of nail psoriasis can be apparent
Fig. 3. Nail changes that may occur in patients with psoriasis including nail crumbling, oil spots, and subtle pitting.
within the nail matrix or nail bed. Involvement of the matrix is established by clinical features
of nail pitting, leukonychia, red spots in the lunula, and superficial crumbling. Nail bed involve-
ment is characterized by onycholysis, oil-drop or salmon spots, hyperkeratosis, and splinter
hemorrhages.30 Fig. 3 illustrates some of these changes that may be seen in patients with nail
psoriasis.
Immunopathogenesis
The pathogenesis of psoriasis has switched from being a disease related to a dysfunctional
skin barrier toward one with much greater complexity. Put simply, studies have supported an
altered immune system as a primary cause for psoriasis. At its core, psoriasis is a T-cell medi-
ated disease with an elaborate interplay between immune cells from the innate and adaptive
immune system. Therapies targeting these key players have proven to be effective therapeutics.
Initial pathogenesis may start with activation of the innate immune system, specifically
dendritic cell activation. Dendritic cells are antigen presenting cells (APC) that serve as a bridge
between innate and adaptive immunity.33 Within psoriatic plaques, myeloid dermal dendritic
cells appear in increased quantity implicating them in the disease process.34 Multiple studies
by Gilliet, Lande, et al. have exhibited this process of dendritic cell activation.35,36 Their studies
suggest keratinocytes respond to a triggering factor by producing LL37, an antimicrobial peptide,
which can complex with self-DNA and RNA. Normally, dendritic cells refrain from inappropri-
ately recognizing self-DNA by two mechanisms: fast degradation of DNA by nucleases, and the
location of toll-like receptors (TLR) within endosomes. Self-DNA does not enter cells sponta-
neously and therefore does not get recognized by APC’s. However, LL37-DNA and LL37-RNA
complexes can enter dendritic cells, and stimulate TLR-9 and TLR-7 respectively. This results in
activation of dendritic cells to self-antigens.
After activation of the innate immune system, the adaptive immunity becomes involved.
Activated dendritic cells result in the production of numerous cytokines including IL-12 and
IL-23.37 These interleukins will be described in more detail later. Briefly, IL-23 binds to the
IL-23 receptor (IL-23R) and promotes T-cells of the Th17 class to expand. On the other hand,
IL-12 acts on T-cells to induce the Th1 class of T-cells to expand.
The Th17 class is at the center of psoriasis immunopathogenesis. These cells produce a
number of inflammatory cytokines including IL-17A, IL-17F, IL-22, IL-26, IL-6, IL-21, TNF-α , and
interferon-γ .37 The IL-17 cytokine is currently a leading target for research and therapeutics
along with IL-23. Receptors to IL-17 can be found primarily on keratinocytes.38 Stimulation of
these receptors create a host of responses, one of which is a proliferative response. More details
on this important cytokine will be described in the section below.
This loop of dendritic cell activation, increased T-cell expression, cytokine release, and
keratinocyte proliferation results in the well-demarcated plaques seen in psoriasis. Products
produced by keratinocytes at the end of this process act back on dendritic cells to cause a
self-amplifying loop and perpetual inflammation.38
In the following paragraphs we will describe the pathogenetic roles of specific molecules.
Interleukin-17
IL-17 is a proinflammatory, homodimeric glycoprotein discovered in 1993.39 Six homogenous

cytokines have since been discovered; together they exist as a family and are labeled IL-17A
through IL-17F. Genes for IL-17A and IL-17F are closely situated on chromosome 6 and expressed
simultaneously; the two cytokines share approximately 50% of their protein structure.40 The
related structure and expression of these two cytokines implies they are most likely also related
in their function. IL-17A has been found to be the most potent of the family inducing a psoriasis
phenotype; however, IL-17F may also be involved.
The Th17 helper T-cell is the primary source of IL-17. Traditionally, helper T-cells were
categorized as either a Th1 or Th2 class. Discovery of IL-17A led to the discovery that a unique
type of helper T-cell class was responsible for its production. Using murine models, the Th17
cell class was determined to develop from naïve T-cells when in the presence of TGF-β and
IL-6.41 Importantly, activated dendritic cells can produce all the necessary signals to initiate this
maturation process to mature Th17 cells.39
IL-17 has been implicated in numerous processes including allergy, autoimmune disease,
host defense and malignancy. From binding to the IL-17 receptor to eliciting the downstream
effects, the signaling pathway of IL-17 continues to be uncovered. Current research has sup-
ported two different pathways exist after IL-17 binding: one dependent on a ACT1 adaptor
protein, and the other independent of the adaptor.39 ACT1 is able to interact with tumor
necrosis factor receptor-associated factor 6 (TRAF6) which subsequently activates nuclear
factor (NF)-κ B. This pathway plays a key role in inflammation through its ability to induce
the transcription of inflammatory genes.41 In addition to interacting with TRAF6, ACT1 also
activates p38 mitogen-activated protein kinases which are critical for stabilization of cytokine
and chemokine mRNA.39 The independent pathway acts through Janus kinase (JAK) to alter gene
transcription.
Functionally, IL-17 results in transcription of genes responsible for chemotaxis, inflamma-
tion, antimicrobial peptide formation, and production of tissue remodeling substances.39 Key
chemokine genes that are upregulated include CXCL-1, CXCL-2, CXCL-5, CXCL-8 (IL-8), and
CXCL-10, all resulting in attraction of neutrophils.39,42 Proinflammatory cytokines produced
include IL-6, TNF-α , and IL-1β . The expression of IL-6 – the same cytokine with a role in
Th17 cell maturation – sets up a positive feedback loop.39 Neutrophilic expansion results from
increased expression of granulocyte colony stimulating factor (G-CSF). With the production of
tissue remodeling substances, IL-17 has a key role in psoriatic arthritis by promoting osteolysis
and production of cytokines that result in bone erosion.39
Interleukin-12
In 1989 the heterodimeric glycoprotein IL-12 was discovered. The cytokine is one of four
members in the IL-12 family.43 IL-12 is composed of a p35 subunit and a p40 subunit. Notably,
IL-12 and IL-23 share the p40 subunit allowing for a common therapeutic target.
The key cells expressing IL-12 are activated myeloid dendritic cells. Once the cytokine is re-
leased, it acts on a heteromeric receptor composed of IL-12Rβ 1 and IL-12Rβ 2. These receptors
are expressed on T-cells, natural killer cells, and dendritic cells.43 Binding of IL-12 to the receptor
results in TYK2/JAK2/STAT signal transduction, and activation of the STAT4 transcription factor.43
The downstream effect of IL-12 binding is the differentiation of naïve T-cells to class 1 helper
T-cells. These Th1 cells are responsible for the release of numerous inflammatory cytokines
including interferon-γ (IFN-γ ), IL-2, and TNF.44 Additionally, Th1 cells are responsible for syn-
thesis of chemokines that perpetuate the inflammatory response by recruiting additional cells.45
Interleukin-23
IL-23 is a pro-inflammatory heterodimeric glycoprotein discovered in 20 0 0.46 The cytokine

consists of a p19 subunit combined with a p40 subunit. It was initially thought to be IL-12 be-
cause of a similar p40 subunit, but with its unique p19 unit it is now considered part of the IL-12
family.43 Studies have found elevated mRNA levels coding for these subunits in lesional skin
from psoriasis patients when compared to healthy controls.47 Interestingly, mRNA expression in
non-lesional skin from patients with psoriasis was also elevated when compared to controls.
Multiple cells within the body express IL-23. These include activated myeloid dendritic
cells, macrophages, monocytes, epithelial cells, and endothelial cells.37,46 Once expressed, IL-23
binds to a heteromeric receptor complex to continue the signal pathway. These IL-23 receptor
complexes are formed from an IL-23R subunit and an IL-12Rβ 1 subunit.37 The first of these
subunits is unique to the IL-23 receptor complex, whereas the second, IL-12Rβ 1 subunit, is also
found in the IL-12 receptor complex as previously mentioned. After IL-23 binds to the receptor
complex, these subunits require intracellular proteins for continued signaling. In this case, the
Janus Kinase family become involved in signal transduction. Unlike IL-12Rβ 1, which is associ-
ated with TYK2, the IL-23R subunit is associated with JAK2. After a series of phosphorylation
events, signal transducer and activator of transcription (STAT) becomes active and translocates
into the nucleus. STAT3 is the primary transcription factor involved in the IL-23 pathway.37
Expression of IL-23 results in numerous downstream effects related to the development of
psoriasis. First and arguably most important, IL-23 is critically involved with Th17 cells. Al-
though IL-23 does not induce the transition from naïve to mature Th17 cells, the cytokine plays
a key role in the expansion and survival of these cells.41 (Also see above section on IL-17). Next,
IL-23 alters the expression of TNF-α by stimulating macrophages. One study in mice found
that injecting mice with IL-23 resulted in epidermal thickening and features of psoriasis.47
Concomitant injection of an anti-TNF antibody eliminated this finding; notably, administering an
anti-IL-17 antibody along with IL-23 did not negate the epidermal thickening.47 This indicates
the epidermal thickening may be the result of a TNF-dependent process. Lastly, IL-23 has been
found to directly affect keratinocytes by increasing keratin 16 (K16) gene expression. which is
associated with epidermal hyperplasia.47,48
Tumor necrosis factor-α
TNF-α is a pro-inflammatory cytokine secreted primarily by macrophages and activated

T-cells.49 In its active form, TNF-α exists as a trimer before binding to receptors.
Two high-affinity receptors bind TNF-α : TNF receptor 1 (TNFR1) and TNF receptor 2
(TNFR2).50 One difference between these two transmembrane receptors is the location of
expression. TNFR1 is expressed throughout most tissues, whereas TNFR2 is expressed primarily
in immune cells.50 TNF-α is notorious for its role in inflammation. Activation of TNFR1 is
the primary driver of this. Formation of the TNF-α /TNFR1 complex results in downstream
signaling and ultimately the release of NF-κ B through a complex interaction of proteins and
degradation pathways.50 Free NF-κ B translocates into the nucleus and regulates gene expression
of inflammatory cytokines.
TNF-α has been referred to as the “master regulator” in regard to its role in the cytokine
production cascade. In the presence of interferon-γ , TNF-α results in activation of macrophages.
Not only does TNF-α initiate inflammation, but it also perpetuates it by stimulating the release
of interferon-β ; this produces a synergistic effect by expressing additional genes that code for
inflammation.50
TNF-α has an array of other roles, affecting atherosclerosis and osteolysis. These are
particularly important for the psoriasis population who experience increased cardiovascular
mortality and suffer from bone diseases such as psoriatic arthritis. Its role in atherosclerosis is
thought to occur by modulating and inhibiting scavenger-receptor mediated accumulation of
lipoproteins by macrophages.51 In regards to osteolysis, TNF-α induces osteoclast differentiation,
promotes bone resorption via inducing RANKL secretion, and increases the number of circulating
osteoclast precursors.50,52 , 53
Co-morbidities
Several significant co-morbidities exist in the psoriasis population. Physicians must remain
vigilant when managing these patients to treat the entire disease, and not focus solely on skin
manifestations. Table 4 lists some of the known co-morbidities associated with psoriasis.
Psoriatic arthritis (PsA)
Psoriatic arthritis is a seronegative spondyloarthropathy occurring in patients with psoriasis,

and very rarely in patients without. Compared to the general United States population, rates
of PsA in psoriasis populations are enormous – 6% to 42% in the psoriasis population versus
0.1%–0.24% in the general population.55,56 PsA can occur in both young and old patients. There
is a peak onset occurring around 40–50 years of age.57 Those who develop PsA have signs of
active cutaneous psoriasis around 70% time. Despite this visible marker to raise suspicion, a
large portion of patients with psoriasis have active PsA which remains undiagnosed. One obser-
vational study in Germany included 1,511 patients. Of this population, 20.6% were determined
to have PsA and a staggering 85% of them were newly diagnosed.58
Clinically patients may present with axial disorders, peripheral joint inflammation, enthesitis,
tenosynovitis, or dactylitis also known as a “sausage digit”. Within this cohort, PsA causes a
significant impact on quality of life. In one study, 77% of patients responded that PsA is a
“problem” or “large problem” in everyday life.56
The pathogenesis of PsA is thought to be autoimmune and places CD8+ T-cells at the
center of disease.59 Like psoriasis, PsA involves the presence of susceptibility genes placing an
individual at risk. Not surprisingly, these genes include HLA-Cw6 – the same allele that places
individuals at risk for psoriasis. In patients with this risk allele, features of musculoskeletal dis-
eases tend to occur much later after the initial skin manifestations of psoriasis.59 Other alleles
include HLA-B27 and HLA-B39. In individuals with these risk alleles the onset of PsA is more
likely to occur concomitantly with skin manifestations.59 Studies have shown the prevalence of
PsA increases significantly with increasing body surface area involvement of psoriatic lesions.56
Following a trigger the body reacts with an immune response resulting in an inflammatory
infiltrate of the synovium and entheses. High cytokine levels of TNF-α , IL-1, IL-6, IL-8, IL-10, and
matrix metalloproteinases can be found in the synovium.55 Long-term joint destruction occurs
as a result of ongoing inflammation.
Table 4
Co-morbidities frequently occurring in psoriasis population.
Co-morbidity Screening recommendations?54 , ∗
Psoriatic arthritis (PsA) Screen patients for early signs of PsA using the CASPAR criteria. Utilize
rheumatologist for diagnosis and treatment if needed.
Metabolic syndrome Screening overlaps with other co-morbidity screening.
Cardiovascular disease The American Heart Association guidelines indicates the following in
patients without risk factors:
• Blood pressure evaluated at least every 2 years with
target < 120/80 mmHg
• BMI measured at least every 2 years; target < 25 Kg/m2
• Waist circumference measured at least every 2 years; target for
men < 40 inches, women < 35 inches
• Pulse evaluated at least every 2 years
• Fasting lipid panel measured at least every 5 years (or 2 if risk
factors)
• Fasting blood sugar measured at least every 5 years (or 2 if risk
factors)
With knowledge that psoriasis increases risk we recommend blood
pressure, vitals, and weight at each clinic visit. Additionally,
laboratory data tends to be available more frequently due to
monitoring of prescribed medications.
Obesity Routine clinical practices should detect obesity, we recommend
recording weights at each visit.
Type 2 Diabetes mellitus Screening overlaps with other co-morbidity screening.
Psychological impact (depression, Screen using one of numerous screening tests or asking about
anxiety, suicide) symptoms. At minimum we recommend exploring questions of
mood and behavior at each visit.
Inflammatory bowel disease No established screening guidelines; physicians should be aware of the
association to recognize signs and symptoms.
Substance abuse Ask appropriate history questions at each visit.
Neoplasms Practice with an increase vigilance for signs and symptoms. Patients on
immunosuppressive or PUVA therapy should undergo an annual full
skin exam. Continue age appropriate screenings per the American
Cancer Society recommendations.
Ocular disorders No established screening guidelines; be aware of the association to
recognize signs and symptoms.
∗
Recommendations taken from the National Psoriasis Foundation Clinical Consensus
Table 5
CASPAR criteria for classifying patients with PsA.60
CASPAR criteria are met in patients with inflammatory articular disease and at least 3 points from the
following categories:
1. Evidence of current psoriasis, history of psoriasis, or family history (1st or 2nd degree relative) of
psoriasis. Patients with a current history gain 2 points; other categories are 1 point each.
2. Evidence of psoriatic nail changes
3. Negative rheumatoid factor test
4. Current or history of dactylitis
5. Radiographic features of bone formation near joint margins on x-ray. Excludes osteophyte formation.
Early diagnosis of PsA is critical to prevent permanent joint damage and improve patient
quality of life. Diagnosis requires dermatologist and primary care physicians to be active in their
search for early signs of disease. Unfortunately, no serologic tests exist for diagnosis. CASPAR
(ClASsification criteria for Psoriatic ARthritis) is a highly specific (98.7%) tool used to define
patients with PsA (Table 5).60 It is important to keep in mind these criteria were garnered from
patients with well-established disease and may be of limited use in the early course of disease.
Other screening questionnaires available are the psoriatic arthritis screen and evaluation
(PASE), Toronto psoriatic arthritis screen (ToPAS), and the psoriatic and arthritic questionnaire
(PAQ).61–63 During appointments, detailed joint examinations should be performed. Additionally,
radiographic imaging can be a helpful aid. Findings of joint erosion, joint space narrowing, bony
proliferation, osteolysis (“pencil-in-cup” deformity), ankylosis, spur formation, and spondylitis
are classic findings. Erosive changes at the DIP joints are sensitive and specific for PsA.55 Lastly,
appropriate utilization of experts in rheumatology should be utilized by dermatologists and
primary care physicians who need additional assistance in screening, diagnosing, or managing
this complex population.
Metabolic syndrome
Metabolic syndrome is a cluster of abnormalities that are associated with the development
of cardiovascular disease and type 2 diabetes mellitus. The clinical diagnosis of metabolic syn-
drome requires patients to meet criteria laid out by the National Cholesterol Education Program
Adult Treatment Panel III. These include: 1. Elevated waist circumference defined as ≥ 102 cm
in men or ≥ 88 cm in women; 2. Elevated triglycerides ≥ 150 mg/dL or on treatment for hyper-
triglyceridemia; 3. Reduced HDL-C defined as < 40 mg/dL in men or < 50 mg/dL in women; 4.
Elevated blood pressure (bp) defined as systolic bp ≥ 130 mmHg or diastolic bp ≥ 85 mmHg or
on an antihypertensive medication for history of hypertension; and 5. Elevated fasting glu-
cose ≥ 100 mg/dL or on treatment for hyperglycemia.64 If patients meet three of these criteria,
a diagnosis of metabolic syndrome is made. Shockingly, approximately 35% of all US adults and
50% of adults over 60 years of age meet the criteria for this syndrome.65
In a large meta-analysis including nearly 1.5 million patients from 20 different countries,
patients with psoriasis were over twice as likely to meet metabolic syndrome criteria compared
to the general population66 The underlying pathogenesis of this association relies on the
Th1 and Th17 response that drives psoriasis. The inflammatory “stew” of cytokines released
from these cells affect numerous components of the body. TNF has been shown to induce
insulin-signaling defects, reduce production of adiponectin (important for regulating glucose
and fatty acids), stimulate the expression of adhesion molecules on endothelial cells, and have a
role in hypertension.67 IL-6 has been linked to insulin resistance and may alter the function of
hepatocytes to result in increased acute phase proteins such as C-reactive protein.67 Lastly, there
is a shared genetic component that may associate psoriasis and metabolic syndrome. PSOR2,
PSOR3, and PSOR4 are known susceptibility loci for the development of psoriasis and also asso-
ciated with susceptibility to developing metabolic syndrome, type 2 diabetes, and cardiovascular
disease.68
Treatment of metabolic syndrome should focus on the patient specific areas of concern.
For each of the criteria, weight loss and lifestyle modification is typically first implemented
change for patients to make. Weight loss goals should be a 7% to 10% decrease from base-
line over a period of 6 to 12 months.64 Lifestyle modifications such as physical activity and
dieting are important components of management. Physical activity for more than 30 minutes
a day has been shown to improve metabolic and atherosclerotic cardiovascular disease risk.
Diets can improve cholesterol, triglycerides, and promotes weight loss. Ultimately, medications
may be necessary for improving individual criteria that do not respond adequately to these
measures.
Cardiovascular disease
It should be no surprise after learning the prevalence of metabolic syndrome in the psoriasis
population that these patients are also at increased risk for cardiovascular disease (CVD). One
large meta-analysis concluded patients with psoriasis experience a 24% increased relative risk
of CVD; this risk was found to exist independent of smoking status, obesity, and hyperlipi-
demia.69,70 Not only are these patients at increased risk to experience CVD, they also experience
a poorer CVD-related prognosis compared to the general population.71 Clearly, careful attention
must be afforded to these patients to minimize these risks.
The link between psoriasis and CVD has a foundation in metabolic syndrome. Ultimately,
this overlap has been thought to be due the body’s state of chronic inflammation secondary to
T-cell activation. Chronic inflammation has been known to be a factor in CVD pathogenesis and
cytokines that mediate psoriasis overlap significantly with CVD mediators. Armstrong et al. have
described the role of Th1 and Th17 cells in this overlap.72 IL-12-activated Th1 cells release TNF-
α , leading to endothelial dysfunction and T-cell homing to sites of atherosclerosis. Simultane-
ously, IL-17 released from Th17 cells can interact with receptors on vascular smooth muscle and
endothelial cells creating a pro-inflammatory feedback loop secondary to a variety of cytokines,
chemokines, and adhesion molecules. This cascade results in atherosclerotic plaque instability.
Together, these two pathways result in an increased amount of unstable atherosclerosis.
Appropriate therapies aimed at managing any risk factors should be provided accordingly.
Patient education is crucial for adherence to management and modification of their risk. As al-
ways, lifestyle modification should be the primary step in reducing the morbidity and mortality
from CVD. Importantly, primary care physicians are paramount in the assistance in screening
and managing this at-risk population.
Obesity & type 2 diabetes mellitus
Many of these comorbidities overlap; obesity, type 2 diabetes, and cardiovascular disease are
each closely related and each serve as a component to the overarching metabolic syndrome.
Hence, it is logical a patient with one of these co-morbidities is likely to have others.
Obesity in psoriasis is complex and as mentioned may be an initiator and a byproduct of the
disease. Since the link was first identified, large clinical trials have helped to substantiate the
connection. One Italian study including over 10,0 0 0 psoriasis patients found the average BMI to
be 30.6 Kg/m2 .73 Cohen et al. concluded that obesity and type 2 diabetes mellitus were nearly
twice as common in the psoriasis population they studied.73
The pathogenesis of these two conditions is discussed in the section on metabolic syn-
drome. In short, inflammation results in mediators that alter insulin secretion, resistance, and
adiponectin production which alter the body’s ability to control blood sugar and fat.
Management of these co-morbidities is important from a general health standpoint, but may
also result in better overall control of psoriasis.74 Additionally, the co-morbidities have impor-
tant implications on treatment. Studies have found the effectiveness of different therapeutics
are negatively affected by an increased BMI. This is particularly true for the medications that
are not weight based.75
Psychological impact
In the beginning of this review, psoriasis was introduced as a disease affecting patients
internally, externally, and psychosocially. Thus far, the internal and external somatic conse-
quences of psoriasis have been made apparent. Equally important are the psychological and
social consequences of the disease. Patients with psoriasis are more likely to experience social
or professional stigmatization, have lower self-esteem, and impaired sense of self-worth.76
Rates of depression, anxiety, and suicidality are increased in the psoriasis population.77–79
A study including nearly 5,0 0 0 participants with various dermatologic conditions found that
clinical depression was present in 10.1% (4.3% in the controls), clinical anxiety in 17.2% (11.1%
in controls), and suicidal ideation in 12.7% (8.3% in controls).77 Unfortunately, patients with
psoriasis (n = 626) exceeded each of these averages. Individual analysis revealed 13.8% (n = 84)
experienced depression, 22.7% (n = 139) anxiety, and 17.3% (n = 106) suicidality.77 One study
set out to determine the main determinants of these psychological conditions in patients with
psoriasis.76 Their results were revealing. Depression was found to be significantly related to a
patient’s subjective assessment of disease severity and having a negative emotional attitude
toward their body. Controlling for the negative body-image reduced the correlation between
depression and disease severity indicating the three components are closely intertwined.
Regarding anxiety, particularly social anxiety, experiences of stigmatization and belief that
self-worth is tied to appearance were strongly predictive.
Fortunately, it appears that treating psoriasis can improve the psychosocial symptoms that
are associated with the disease.80–82 Continued studies to observe the effects of new thera-
peutics on depression and psychological factors are important, as some have been reported to
increase the risk of suicide. Physicians should constantly aim to understand the psychological
impact of psoriasis on a patient to patient basis and attempt to mitigate these risks accordingly.
Inflammatory bowel disease
Crohn’s disease and ulcerative colitis cause significant morbidity and mortality. Depending
on the severity of psoriasis, the 10-year incidence of Crohn’s disease in patients with psoriasis
was 2–5 per 10 0 0 patients.83 This same study found the incidence of ulcerative colitis in
these patients was 7–10 per 10 0 0 patients. In comparison, the annual incidence of these two
conditions in the general population according to the Crohn’s & Colitis Foundation are 0.11 and
0.12 per 10 0 0 patients, respectively.
Similar to psoriasis, a dysfunctional immune system is the foundation on which Crohn’s
disease and ulcerative colitis occurs. These diseases also have a strong genetic component. In
fact, studies have shown Crohn’s disease and psoriasis share 7 different susceptibility loci.84 In
addition to this genetic overlap, the cytokines that drive the diseases are also quite similar. In
particular IL-23, IL-12, IL-17 and TNF-α are the main mediators that are shared.
There are no guidelines or recommendations to actively screen patients with psoriasis for
inflammatory bowel disease. Such process could be costly and inefficient. Instead, physicians
should be vigilant for signs and symptoms of these conditions and refer to gastroenterologist
accordingly.
Substance abuse
Patients with psoriasis have high rates of excessive alcohol consumption and tobacco
use.22,85 , 86 One study in the UK identified approximately 1 in 5 psoriasis patients had problems
with alcohol using the CAGE questionnaire.22 Of these patients, 13% thought they had a current
drinking problem and 18% admitted to having a past drinking problem. In Norway, daily
cigarette usage was found to be greater in psoriasis patients (48%) compared to those without
the disease (36%).86 Psoriasis patients were also less likely to have never smoked compared to
the general population. The use of these substances creates many health issues for an already
unhealthy population. Additionally, physicians must be careful with therapeutics in psoriasis
patients with substance abuse issues. This is particularly true with medications known to have
hepatotoxicity such as methotrexate. Questions about self-medicating behaviors with alcohol
and tobacco use should discussed with patients. Physicians with stronger patient relationships
are more likely to be successful in navigating this topic. Education and patient counseling are
a cornerstone of treatment with escalation of certain therapies. Currently, studies to determine
the use of other recreational or illicit drugs are not readily available in the literature.
Neoplasms
Given that psoriasis is a disease associated with a dysregulated immune system, there has
been concern regarding the risk of malignancy in these patients. Specifically, cancers such as
lymphoma have been identified as worrisome. The largest available study included over 90 0,0 0 0
patients (153,197 diagnosed with psoriasis) and demonstrated patients with psoriasis were at
increased risk of lymphoma.87 The strongest association was found in Hodgkin’s lymphoma and
cutaneous T-cell lymphoma. Another cancer found at increased frequency in psoriasis patients
is squamous cell carcinoma (SCC) of the skin.88 Psoriasis sub-populations treated with psoralen
and ultraviolet A (PUVA), coal-tar, or cyclosporine are at even higher risk of SCC.54 Studying the
rates of solid malignancies is difficult, and numerous factors must be controlled to get an accu-
rate picture. For example, the increased smoking rates, alcohol consumption, and treatment with
potentially carcinogenic therapies like phototherapy make this a hard association to ascertain.
There are no established guidelines in screening patients with psoriasis for malignancy.
Table 4 describes the general recommendations provided by the National Psoriasis Foundation
Clinical Consensus.
Ocular disorders
Ophthalmic complications of psoriasis may occur at numerous anatomic locations including

the eyelids, conjunctiva, cornea, uvea, and lens. Few studies have assessed the prevalence of
these complications in psoriatic patients; however, reports have stated approximately 10% of
psoriasis cases experience an ophthalmic complication.89 Uveitis specifically appears to have
one of the strongest associations. When occurring, the inflammation tends to be anterior,
bilateral, and chronic.89
The etiology of this association is currently unknown. Results of a study by Okamoto et al.
suggested patients with psoriasis exhibit a damaged blood-aqueous barrier even in the absence
of a history of ocular disease.90 This may account for the added susceptibility.
Authors have suggested annual or biannual examination in patients with severe psoriasis
to screen for ocular disorders.91 At follow-up visits dermatologist or primary care physicians
should ask a thorough ocular review of systems and screen for common ophthalmic disorders
including dry eyes, blepharitis, conjunctivitis, and uveitis.
Diagnosis
Clinical aspects
The diagnosis of psoriasis is made clinically using history and physical examination findings.
Patients will often present with new onset lesion(s) that won’t go away. Lesions are character-
istically well-demarcated, erythematous papules and plaques with palpable edges and overlying
scale. Symptomatically, these patients may complain of pruritus, irritation, burning, sensitivity,
pain, bleeding, or any combination of above.92 Itching is by far the most common with one
study reporting the symptom in 63.8% of cases; other symptoms reported were irritation
(59.7%), burning (46.1%), sensitivity (39%), pain (26%), and bleeding (25.4%).92 Additionally,
about 1 in 4 patients may complain of water bothering their skin. The physical examination of
the entire integument (including the scalp, intertriginous, and anogenital regions), and the nails,
should include a joint exam in search of any additional evidence of disease.
When the stereotypical lesions are absent, psoriasis can be more challenging to diagnose.
The broad differential diagnosis of other papulosquamous disorders should routinely be applied
and can aid in the diagnosis of these more difficult cases. These include dermatologic conditions
such as atopic dermatitis, seborrheic dermatitis, nummular dermatitis, tinea corporis, lichen
planus, mycosis fungoides, pityriasis rubra pilaris, and pityriasis rosea. Scrapings for potassium
hydroxide preparation assist in ruling out fungal infections. Time course along with the presence
of a herald patch will support pityriasis rosea over psoriasis. In atypical cases of psoriasis, a
biopsy may be necessary to confirm the diagnosis.
Equally important to obtaining the diagnosis, are the steps that follow. Significant patient
education regarding the disease course, co-morbidities, treatment options, and implications
of the diagnosis should occur. One study found patients with psoriasis often lack important
information of their disease resulting in poorer adherence to treatments.93 A survey by Brown

et al. aimed to identify areas where psoriasis patients wanted more knowledge about. Most
common answers were the triggers of disease (75%), treatment options with mechanisms of
actions (55%), and side effects of treatment options (53%).94
Histological aspects
The histology of psoriatic lesions differ depending on the age of the lesion. Murphy and
Grant-Kels describe the histologic components of psoriasis.95 In the earliest stages, findings
may be minimal and consist primarily of dermal change with a sparse perivascular lymphocytic
infiltrate of T-cells. With time, subepidermal blood vessels become more prevalent, tortuous,
and dilated. Their location within the dermal papilla may result clinically in the pinpoint
bleeding after removal of scale (Ausptiz sign). Dermal edema, spongiosis, and exocytosis of
neutrophils and lymphocytes may be seen.
It isn’t until the early plaque stage develops that epidermal hyperplasia begins to become
obvious. Mounds of parakeratosis – abnormally retained nuclei in the stratum corneum indicat-
ing abnormal keratinocyte maturation – are seen, with underlying loss of the granular layer.96
Additionally, the dermal infiltrate becomes more substantial and composed of lymphocytes,
histiocytes, neutrophils, and red blood cells.
A mature psoriatic lesion will have the following characteristics: marked epidermal hyperpla-
sia, elongated rete ridges with bulbous enlargement, significant dilation and tortuosity of blood
vessels in the dermal papilla, and epidermal thinning above the dermal papillae. Often, marked
hyperkeratosis is present, accounting for the scale that is visible clinically. In approximately
75% of cases, Munro’s micro-abscesses – collections of neutrophils in the epidermis – can be
identified.
Differences between psoriatic and normal epidermal cells have been found, leading to some
of the histologic findings described above. Compared to the 311-hour cell cycle of normal
epidermal keratinocytes, those in psoriatic epidermis exhibit a dramatically shortened cell cycle
of only 36 hours.97 The cited study also found the proliferative cell population was doubled
in skin affected by psoriasis. Taken together, a 28-fold greater production of cells compared to
normal skin explains the increased epidermal mass in the psoriatic plaque.97
Medical management
Physicians have a multitude of treatment options to choose from in treating patients with
psoriasis. These treatments include numerous topicals, non-biologic systemic medications,
biologics, and phototherapy. A variety of factors should be considered when choosing which
medication is best for a patient. This includes consideration of disease severity, co-morbidities,
insurance coverage, and safety. Often a physician’s perception of “best choice” may differ from
the patient’s depending on which of these factors are most heavily weighed. A study performed
by Alcusky et al. examined patients with moderate or severe psoriasis to determine which
variables dermatologists and their patients considered when choosing a biologic medication
option.98 Physicians rated safety, low likelihood of adverse advents, and overall perception of
efficacy as most important. They were concerned with objective measures such as reduction in
affected body surface area and maintenance of response over time. Physicians considered drug
mechanism of action and ability to tailor the dosing least important. Conversely, patients had
greater concern regarding the subjective symptoms associated with lesions and improvement in
quality of life. They also were concerned with the degree of erythema, scaling, and induration,
out-of-pocket costs, and safety of the medication. Clearly, physicians must avoid the pitfall of
choosing medications based solely on a medical expertise perspective, but also need to consider
patient preferences. This will help ensure a common goal with improved patient satisfaction
and adherence to treatment.
Severity of disease is the critical determination when choosing an appropriate therapeutic.

Using a topical medication as the core treatment modality in a patient with extensive body
surface area involvement would be inappropriate. Alternatively, the risk and cost involved in
systemic medications outweigh their use in patients with small, localized lesions that could be
easily managed with a topical drug. Choosing an appropriate modality is paramount to effective
and efficient care of patients with psoriasis. In general, for mild to moderate disease topical
treatments should be used. Patients with moderate to severe psoriasis may require control with
systemic medications or phototherapy.
The primary goal of this section is to introduce the numerous biologic treatments available
to patients with moderate or severe plaque psoriasis. Very briefly, we will mention topical,
phototherapy, and non-biologic systemic therapeutics.
Biologics
Biologics are complex glycoproteins produced with or from a living organism.99 Their ability
to target and influence highly specific targets of the immune system have resulted in their rapid
development as a standard component of medical care. Biologics encompass a variety of classes
including monoclonal antibodies, cytokines, fusion proteins, RNA, antisense oligonucleotides,
and kinase inhibitors.100 Each class uses unique mechanisms to achieve their theraputic goal.
Classes most commonly used in psoriasis include monoclonal antibodies and fusion proteins.
Monoclonal antibodies are created using a single B-lymphocyte clone that binds a specific
antigenic epitope.100 Thus, the antibody produced is very specific to the targeted antigen. Using
a different lymphocyte clone in this process will result in the formation of a unique antibody
with different specificity. Targets of these monoclonal antibodies are numerous and may include
cell surface receptors or ligands. By binding surface receptors, antibodies prohibit the binding
of native ligands to their receptor thus blocking the downstream signaling that would normally
occur. Blockage of an entire receptor prevents all ligands from binding that receptor. Alterna-
tively, targeting the ligands directly accomplishes the same goal but in a different, more direct
manner. For therapeutic purposes antibodies must be stable and have strong binding properties
to be efficient. The immunogenicity of non-human antibodies will elicit a host response – which
was an expected limitation to the use of early monoclonal antibodies. Techniques to humanize
antibodies (which reduces their immunogenicity) have improved these issues and resulted in
efficacious, although costly, therapeutics.
Fusion proteins are created using genetic engineering to combine two unique proteins
together. These often consists of a peptide chain fused with a Fc region of human IgG. Usually,
this class of biologic acts as a competitive inhibitor and thus prevent ligand binding to its
receptor (e.g. etanercept) or as direct ligand of a receptor and thus blocking proinflammatory
cell interactions (e.g. alefacept).100
The biologics used in psoriasis vary in class and target. As a result, each molecule behaves
differently, and produces a different downstream result. Although clinicians often group differ-
ent biologic classes together according to their target (e.g. TNF-inhibitors), each theraputic may
function uniquely.
Table 6 shows an overview some of newer biologic drugs, their mechanism of action, and
different reported psoriasis area and severity index (PASI) scores that will be discussed in more
detail in the “Landmark clinical trials” section.
TNF-α inhibitors
Etanercept (Enbrel®, Amgen). Etanercept is a TNF-receptor fusion protein, and thus acts by com-
petitively inhibiting the binding of TNF-α to TNF receptors 1 and 2. Etanercept was approved for
the treatment of psoriatic arthritis in 2002. It wasn’t until May of 2004 the drug was also FDA
approved for the treatment of plaque psoriasis in adults. More recently, approval was granted
for use in children age 4–17 with chronic plaque psoriasis making it the first biologic treatment
approved for this population. Important considerations for the physician prior to prescribing
Table 6
Current list of FDA approved biologics used in adult plaque psoriasis.
Drug Name Dose Place of Action Specific Action PASI 75 PASI 90 PASI 100
Etanercept 50 mg injections twice a week for three Ligand Receptor fusion protein Leonardi et al. Leonardi et al. Not reported
months; maintenance injections of that binds TNF-α Week 12: 49% Week 12: 22%
E.D. Schadler et al. / Disease-a-Month 65 (2019) 51–90

50 mg weekly. Papp et al. Papp et al.
Week 12: 49% Week 12: 21%
Adalimumab 80 mg loading dose; 40 mg injections Ligand Binds TNF-α REVEAL REVEAL REVEAL
every other week. Week 16: 71% Week 16: 37% Week 16: 14%
Infliximab 5 mg/kg IV induction at weeks 0, 2, Ligand Binds TNF-α EXPRESS 1 EXPRESS 1 Not reported
and 6 then every 8 weeks Week 10: 80% Week 10: 57%
Week 50: 61% Week 50: 45%
EXPRESS 2 EXPRESS 2
Week 10: 75.5% Week 50: 34.3%
Week 50: 54.5%
Certolizumab 400 mg every other week Ligand Binds TNF- α CIMPASI-1 CIMPASI-1 CIMPASI-1
Pegol Week 16: 76% Week 16: 44% Week 16: 13%
Week 48: 87% Week 48: 60% Week 48: 24%
CIMPASI-2 CIMPASI-2 CIMPASI-2
Week 16: 83% Week 16: 55% Week 16: 19%
Week 48: 81% Week 48: 62% Week 48: 38%
Ustekinumab Patients ≤ 100 kg: 45 mg doses at Ligand Binds the p40 subunit PHOENIX-1 PHOENIX-1 PHOENIX-1
weeks 0, 4, and 12, followed by of IL-12 and IL-23 Week 12: 45 mg: 67.1% Week 12: 45 mg: 41.6% Week 12: 45 mg: 12.5%
injections every 12 weeks 90 mg: 66.4% 90 mg: 36.7% 90 mg: 10.9%
Patients > 100 kg: same as above but PHOENIX-2 PHOENIX-2 PHOENIX-2
with 90 mg dose Week 12: 45 mg: 66.7% Week 12: 45 mg: 42.3% Week 12: 45 mg: 18.1%
90 mg: 75.7% 90 mg: 50.9% 90 mg: 18.2%
(continued on next page)
73
74
Table 6 (continued)
Drug Name Dose Place of Action Specific Action PASI 75 PASI 90 PASI 100
Secukinumab 300 mg weekly for 4 weeks, then Ligand Binds IL-17A ERASURE ERASURE ERASURE
300 mg monthly beginning at week 8 Week 12: 81.6% Week 12: 59.2% Week 12: 28.6%
FIXTURE Week 52: 60.0% Week 52: 39.2%
Week 12: 77.1% FIXTURE FIXTURE
Week 12: 54.2% Week 12: 24.1%
E.D. Schadler et al. / Disease-a-Month 65 (2019) 51–90

Ixekizumab 160 mg initial loading dose; 80 mg Ligand Binds IL-17A UNCOVER-1 UNCOVER-1 UNCOVER-1
every 2 weeks for 3 months; 80 mg Week 12: 82.6% Week 12: 64.6% Week 12: 33.6%
monthly UNCOVER-2 UNCOVER-2 UNCOVER-2
Week 12: 77.5% Week 12: 59.7% Week 12: 30.8%
UNCOVER-3 UNCOVER-3 UNCOVER-3
Week 60: 83% Week 60: 73% Week 60: 55%
Brodalumab 210 mg weekly for 3 weeks, then Receptor Binds IL-17 Receptor A AMAGINE-1 AMAGINE-1 AMAGINE-1
210 mg every 2 weeks (IL-17RA) Week 12: 83.3% Week 12: 70.3% Week 12: 41.9%%
AMAGINE-2 AMAGINE-2 AMAGINE-2
Week 12: 86.3% Week 12: 70% Week 12: 44.4%
Week 52: 80% Week 52: 75% Week 52: 56%
AMAGINE-3 AMAGINE-3 AMAGINE-3
Week 12: 85.1% Week 12: 69% Week 12: 36.7%
Week 52: 80% Week 52: 73% Week 52: 53%
Guselkumab 100 mg at weeks 0 and 4 followed by Ligand Binds the p19 subunit VOYAGE-1 VOYAGE-1 VOYAGE-1
every 8-week injections of IL-23 Week 16: 91.2% Week 16: 73.3% Week 16: 37.4%
Week 48: 87.8% Week 48: 76.3% Week 48: 47.4%
VOYAGE-2 VOYAGE-2 VOYAGE-2
Week 16: 86.5% Week 16: 70.0% Week 16: 34.1%
Tildrakizumab 100 mg at weeks 0 and 4, followed by Ligand Binds the p19 subunit reSURFACE1 reSURFACE1 reSURFACE1
injections every 12 weeks of IL-23 Week 12: 100 mg: 64% Week 12: 100 mg: 35% Week 12: 100 mg: 42%
200 mg: 62% 200 mg: 35% 200 mg: 14%
ReSURFACE 2 ReSURFACE 2 ReSURFACE 2
Week 12: 100 mg: 61% Week 12: 100 mg: 39% Week 12: 100 mg: 12%
200 mg: 66% 200 mg: 37% 200 mg: 12%
etanercept include a patient assessment for history of malignancy and risk of infection. A black
box warning for etanercept regarding the risks of serious infections and malignancy was added
to the label based on data from trials. Additionally some reports have implicated TNF-inhibitors
in new-onset or worsening of heart failure.101 As a result physicians should be cautious of using
this medication in the heart failure population. The recommended dosing for etanercept con-
sists of 50 mg injections twice a week for three months followed by maintenance injections of
50 mg weekly. Studies also found that starting doses of 25 mg or 50 mg weekly for the first three
months were efficacious.
Adalimumab (Humira®, AbbVie). Adalimumab is a monoclonal antibody against TNF-α . It func-

tions by binding the host TNF ligand thereby preventing interaction with TNF receptors. In Jan-
uary of 2008, adalimumab was approved for the treatment of adults with moderate to severe
plaque psoriasis based on results of the REVEAL study.102 Previously the medication was ap-
proved for use in psoriatic arthritis. As of 2017, adalimumab gained approval for use in finger-
nail psoriasis. This makes it the first biologic with data on this difficult to treat indication. As
with other TNF inhibitors physicians should be aware of the risk of malignancy, infection, and
new-onset or worsening of heart failure. A black box warning has also been added to this med-
ication regarding the increased risk of serious infection and malignancy. Recommend dosing for
the drug is an initial loading dose of 80 mg followed by 40 mg injections every other week.
Infliximab (Remicade®, Janssen Pharmaceutica). Infliximab is a monoclonal anti-TNF-α antibody

that works in the same manner as adalimumab. It was approved for the treatment of psoriatic
arthritis in 2005 and later in 2006 gained approval for chronic plaque psoriasis. This approval
came as a result of two phase-3 trials, EXPRESS 1 and EXPRESS 2.103,104 As with other TNF-
inhibitors, the same black box warning regarding risk of infection and malignancy is added to
the label. Infliximab is administered as an infusion rather than injection. Recommended dos-
ing of infliximab begins with a 5 mg/kg IV induction at weeks 0, 2, and 6 followed by 5 mg/kg
maintenance infusions every 8 weeks.
Certolizumab Pegol (Cimzia®, UCB). Certolizumab pegol is a PEGylated TNF-α antibody fragment
approved for use in Crohn’s disease, rheumatoid arthritis, psoriatic arthritis, and ankylosing
spondylitis. The PEG moiety extends lifetime of the molecule in circulation. In May of 2018, the
drug received FDA approval for the treatment of moderate to severe plaque psoriasis in adults.
Unlike other biologics, certolizumab pegol has been found not to be transferred through breast-
milk and has minimal to no placental transfer.105,106 As a result, this medication may become
a targeted therapy in the treatment of pregnant and nursing women with psoriasis requiring
systemic medication. Current dosing approved for plaque psoriasis is 400 mg (2 injections of
200 mg each) every other week. In patients less than 90 kg, physicians can consider lower the
dosage to involve an induction period of 400 mg initially and at week 2 and 4, followed by
200 mg maintenance injections every other week.
IL -12/IL -23 inhibitors

Ustekinumab (Stelara®; Janssen Pharmacetuica). Ustekinumab is a dual inhibitor that targets IL-23
and IL-12. It is an antibody that binds the p40 subunit which is shared between IL-23 and IL-
12. Binding of this subunit prevents each interleukin from interacting with the receptor. Ustek-
inumab was FDA approved for treatment of adults with psoriasis in September of 2009. The
drug was also granted approval for the treatment of psoriatic arthritis based off the results
of the PSUMMIT trials, and more recently, was approved for use in adolescents aged 12 and
older with plaque psoriasis.107–109 Dosing of ustekinumab is weight based. Patients less than
or equal to 100 kg should receive 45 mg at weeks 0, 4, and every 12 weeks subsequently; pa-
tients greater than 100 kg should be up-titrated to receive 90 mg injections during the same
time period. Three phase-3 trials were performed to demonstrate the efficacy of ustekinumab in
psoriasis (PHOENIX-1, PHOENIX-2, and ACCEPT).110–112
IL-17 inhibitors
Secukinumab (Cosentyz®, Novartis). Secukinumab is a humanized, IgG monoclonal antibody that
targets IL-17A. The FDA approved this drug in January of 2015 making it the first anti-IL-17
antibody on the market for the treatment of psoriasis in adults. In addition, the drug is approved
for use in psoriatic arthritis and severe scalp psoriasis.113–115 , Secukinumab should be avoided in
patients with inflammatory bowel disease as should the other IL-17 inhibitors. Recommended
dosing of the medication involves an induction phase of 300 mg dose once weekly for 4 weeks,
followed by a maintenance phase of 300 mg monthly beginning at week 8.
Ixekizumab (Taltz®, Eli Lilly and Company). Ixekizumab is a humanized monoclonal antibody
specifically targeting IL-17A ligand. Binding to IL-17A prevents the interaction of this cytokine
with its receptor. Ixekizumab was approved for the treatment of adults with plaque psoriasis in
March of 2016. Efficacy was demonstrated by three phase-3 trials (UNCOVER-1,2, and 3).116,117
Later in 2017 the drug was also approved for psoriatic arthritis based on results of the SPIRIT
trials.118,119 IL-17 is involved in regulation of the gastrointestinal tract. As a result, caution must
be used in patients with concomitant inflammatory bowel disease. Recommended dosing for
this medication include a 160mg-loading dose, an induction phase of 80 mg every 2 weeks for 3
months, and a maintenance phase of 80 mg monthly.
Brodalumab (Siliq®; Valeant Pharmaceuticals). Brodalumab is a monoclonal antibody directed

against IL-17 receptor A. The IL-17 receptor exists as dimer complex of which receptor A is a
common subunit. Binding of this subunit interferes with the ability for IL-17 to complex with the
receptor. It was granted FDA approval in February of 2017 for use in adults with chronic plaque
psoriasis based on three phase-3 trials.120,121 Physicians prescribing this medication should take
care to identify any prior or current suicidal behaviors. A black box warning for brodalumab for
increased risk of suicidal ideation or behavior has been added to labels. Current dosing recom-
mendation is 210 mg once weekly for 3 weeks followed by 210 mg every 2 weeks.
Selective IL-23 inhibitors

Guselkumab (Tremfya®; Janssen Pharmaceutica). Guselkumab is a monoclonal antibody that func-
tions by binding the p19 subunit of IL-23. This allows for selective targeting of IL-23. It is the
first selective IL-23 inhibitor on the market and was granted FDA approval in July 2017 for use
in adults. Recommended dosing of the medication is 100 mg at weeks 0, 4, followed by dosing
every 8 weeks.
Tildrakizumab (Ilumya®, Sun Pharmaceutical Industries Ltd.). Tildrakizumab is an IgG humanized

antibody targeting the p19 subunit of IL-23. As a result, tildrakizumab is selective for IL-23 in-
hibition alone. The drug received approval by the FDA for treatment of adults with moderate to
severe plaque psoriasis in March of 2018. Dosing for tildrakizumab is every 12 weeks following
induction injections at week 0 and 4. This 12-week dosing schedule makes tildrakizumab and
ustekinumab particularly beneficial for patients with adherence issues. Two phase-3 randomized
controlled trials were used to demonstrate efficacy of tildrakizumab in psoriasis (reSURFACE 1
and reSURFACE 2).122
Biologics in the pipeline

Several new biologics are currently under study and shown promising preliminary data. Many
of these drugs share similar mechanisms of actions as described above. Others have novel mech-
anisms of action and it will be intriguing to see their final results. A couple of these many drugs
currently in phase three trials include bimekizumab and risankizumab.
Bimekizumab is currently starting phase 3 trials and had promising phase 2b results. The
drug is an IL-17 inhibitor, but is unique to any other IL-17 antibody on the market. Unlike cur-
rent IL-17 inhibitors that only bind IL-17A, bimekizumab inhibits both IL-17A and IL-17F. Al-
though IL-17F is a much less potent inflammatory agent than IL-17A, studies on bimekizumab
have demonstrated increased efficacy and rapid onset of action with this dual inhibition. The 12
week phase 2 study, BE ABLE evaluated multiple doses of bimekizumab (64 mg, 160 mg, 160 mg
with a 320 mg loading dose, 320 mg, and 480 mg every 4 weeks) versus placebo.123 The efficacy
increased in a dose-dependent manner from placebo to 320 mg of drug. In the 320 mg group
PASI 75/90/100 scores were achieved by 93/79/56% at week 12. Rates were also high in the
160 mg group who received a 320 mg loading dose (85/75/60). Onset of action was rapid – after
just one injection all groups displayed meaningful improvement compared to placebo.
Risankizumab, is another inhibitor of the p19 subunit of IL-23. It has demonstrated safety
and efficacy in multiple phase 3 trials that are yet to be published. In a phase 2 head-to-head
comparison with ustekinumab, risankizumab demonstrated superiority in treating moderate to
severe plaque psoriasis.124 166 subjects were randomized to receive 180 mg of risankizumab as
a one-time injection, 90 mg or 180 mg of risankizumab at weeks 0, 4, and 16, or ustekinumab
using the standard weight based dosing. With 90 mg of risankizumab injections, PASI 75/90/100
was achieved by 98/73/41% at week 12. In the 180 mg group, the percent of subjects achiev-
ing a PASI 75/90/100 were 88/81/48%. Only 72/40/18% of the ustekinumab patients achieved
PASI 75/90/100 respectively. Onset of action was rapid with decreased PASI scores by week 2.
Risankizumab thus also improved quality of life for patients. Analysis of patients with psori-
atic arthritis revealed 69% of subjects randomized to the 90 mg dosage, and 83% on the 180 mg
dosage had a greater than 50% reduction in pain by week 24.
Unlike the biologics mentioned thus far that interact with one of the cytokines implicated
in disease, new drugs with differing mechanisms of action are under also investigation. Nei-
hulizumab is an antibody with a unique mechanism of action. It acts to induce apoptosis of late-
stage activated T-cells. By preferentially eliminating the population of T-cells that are pathogenic
for psoriasis but maintaining the host immature T-cells a theoretical reduced risk of malignancy
and infections has been proposed and supported by early proof-of-concept studies. Tregaliumab,
as suggested in the name, acts to activate regulatory T-cells. It accomplishes this as an anti-CD4
antibody that binds and subsequently activates T-cells. Until studies in psoriasis are performed
it is unclear if this drug will become one of many therapeutics for the disease.
Management of patients on biologics

Management of this patient population will depend on a physician’s frequency of prescrib-
ing these powerful medications. We recommend basic blood work including complete metabolic
panel and complete blood counts be obtained initially every 3 months to examine for any ab-
normalities. Once patients have been on a stable dose, blood work can be spaced out to every 6
months or more depending on physician comfort. Yearly tuberculosis screening should be per-
formed. This is for both patient safety and a requirement for majority of insurances. During
our clinic visits blood pressure, pulse, and weight measurements are recorded at each follow-up
visit for monitoring. Questions regarding mood and signs of anhedonia are routine to screen for
any red flags of depression or potential suicidality. A complete review of systems with focus on
questions pertaining to prolonged infections, palpable lymph nodes, fatigue, unexpected weight
loss, joint pain, and abdominal pain should be discussed. Complete skin examination should be
performed to detect skin cancers and track improvement or worsening of their psoriasis. Care
should be taken to check all folds, as psoriasis is commonly found in unchecked clefts. Given
the reported risks of lymphoma, lymph node examination should be performed at each visit in
these patients. Signs of edema should be checked in patients on TNF-inhibitors to evaluate for
signs of new or worsening heart failure.
Topicals
Topical medications are the mainstay of treatment for patients with mild to moderate
psoriasis. These medications are also often used concomitantly with systemic drugs in patients
with more extensive disease. Practically speaking, patients with psoriasis will at some point use
a topical medication. Benefits include reduced side effect profiles, lower costs, and delivery of
medication in an effective and non-invasive manner. This last part is unique to dermatology.
Despite, their widespread use, there are disadvantages of topicals to consider. Their strength
is less than that of systemic medication, they absorb slowly lending them vulnerable to removal,
and adherence to the use of topicals is challenging for patients. One review found that in short-
term studies only 50% to 60% of applications are performed by patients.93 Topical medications
can be time consuming to apply or associated with unpleasant sensations such as a greasy
residue or foul odor leading to poor adherence. Unfortunately, asking patients about their use
is not a great for evaluating their adherence as patients tended to overestimate their usage of
topical medications.125 Improving adherence can be done with improving patient education,
stronger doctor-patient relationships, and discussions of treatment goals/expectations.
Topicals indicated for use in patients with psoriasis include topical corticosteroids, vitamin
D analogues, retinoids, calcineurin inhibitors, and – mostly historical – anthralin and tar.
Corticosteroids are far and above the most common and are available in multiple different
potency formulations, allowing choices tailored for each patient based on location and severity
of lesions. Combination formulations are also available for use including corticosteroid/vitamin
D analogues, corticosteroid/retinoid, and corticosteroid/salicylic acid combinations.
The vehicle of the topical is a critical component to consider. Topicals may be formulated
as ointment, cream, lotion, gel, foam, or a variety of other forms. As the vehicle becomes more
occlusive, penetration of the active drug increases. Physicians should be sure to discuss the ve-
hicle options with patients – remember, adherence is key for successful treatment with topical
medications. If someone avoids applying their ointment because of the greasy characteristic the
therapy will ultimately fail.
Phototherapy
Phototherapy involves the use of ultraviolet radiation (UVR) as a treatment modality. UVR
wavelengths range from 100 to 400 nm with the therapeutically relevant range from 290 nm
and up. Its use in psoriasis tends to be most beneficial in patients with extensive disease
making treatment with topicals infeasible. Phototherapy can be delivered as ultraviolet B (UVB),
ultraviolet A plus psoralen (PUVA), ultraviolet A1 (UVA1), and excimer laser, a monochromatic
UVB source at 308 nm.126 Today, PUVA is rarely used due to an increased skin cancer risk
associated with excessive use. Instead, UVB is the primary phototherapy modality used in
psoriasis patients. Narrowband UVB (NB-UVB, mostly delivering 311 nm radiation) is currently
the most prevalent phototherapeutic modality, as its spectrum is most effective among UVB
sources in treating psoriasis.
Phototherapy works most likely based on altered cytokine expression, apoptosis of lympho-
cytes, and by promoting cutaneous immunosuppression.127 Approximately 40%–80% of patients
treated with UVB therapy achieve a 75% reduction in their PASI.126 Unfortunately, phototherapy
is a time intensive treatment requiring 2–3 times weekly clinic visits during the clearance phase
of several weeks. This time commitment and the distance from a phototherapy center may be
barriers for patients to access phototherapy. Those planning for treatment with phototherapy
should be directed to a dermatologist with expertise in the area to ensure treatment safety.
Oral systemics (non-biologic)
Systemic medications outside the realm of biologics can be used in the treatment of mod-
erate to severe psoriasis. Because their side effects are potentially much greater than topical
medications, systemic drugs are reserved for patients not achieving adequate control with
topicals. Common oral systemics include apremilast, methotrexate, cyclosporine, and acitretin.
Apremilast is an orally administered phosphodiesterase 4 (PDE4) inhibitor taken twice daily.
By inhibiting the breakdown of cyclic adenosine monophosphate (cAMP) via PDE4 inhibition,
apremilast results in decreased production of inflammatory cytokines. Clinical trials of this
medication showed improvement in plaque, nail, scalp, and palmoplantar psoriasis. In general,
it is considered to have a modest effect size and indirect comparisons to biologics have shown
reduced treatment effects.128 In a phase three study of this medication, 33.1% of subjects
achieved a PASI 75 at week 16.129
Methotrexate is a cheap, relatively effective therapy for psoriasis that has been used for
decades. It works in the treatment of psoriasis due to its anti-inflammatory, anti-proliferative,
and immunosuppressive actions.130 Methotrexate is a dihydrofolate reductase inhibitor resulting
in reduced synthesis of purines and pyrimidines necessary for DNA synthesis. Downstream,
this decreases hyperplasia of the epithelium and induces apoptosis of T-cells.131 Data from a
comparator study found that 41.9% (n = 90) of subjects randomized to methotrexate achieved a
PASI 75 score at week 16.132 The main limitation of this drug is the liver toxicity that occurs
with long-term use.
Cyclosporine is an immunosuppressive that works by inhibition of calcineurin. A result of
this inhibition is a decreased production of IL-2. Like methotrexate, cyclosporine has also been
used for decades in patients with psoriasis. Cyclosporine has a rapid onset of action; however,
care must be taken with the drug concerning hypertension and nephrotoxicity, and therefore
cyclosporine is not a good choice for long-term management of psoriasis.
Lastly, acitretin is an oral systemic used in psoriasis patients. This is a vitamin-A-derived
retinoid that has only modest effects on psoriasis. Because of this, the therapeutic is often
used as a combination therapy rather than monotherapy. Acitretin functions as a treatment in
psoriasis by interfering with epidermal cell growth and differentiation.133
Landmark clinical trials
The approval of biologic medications is challenging and expensive. Trials working with med-
ications for psoriasis aim to demonstrate a theraputic effect by a decrease in PASI score with
treatment. The components of the PASI and PGA assessments can be found in the “definitions”
section of this paper. Fig. 4 below shows an example of a PASI worksheet. As a reminder, a
higher PASI score correlates with more severe disease. Rather than focus on the individual
score alone, the improvement in PASI score is the most important variable to evaluate the
success of a medication. This clinical scoring has remained relatively consistent and reports
of 75, 90, and 100% improvements in PASI scores are now the standard for reporting. The
subsequent presentation of trials is not to encourage the use of one drug over another. Instead,
it is intended to be a common source of previously reported information, remembering every
patient can respond differently to each of these medications. For ease of reading, PASI scores
have been rounded to the nearest whole number.
Etanercept
Leonardi et al. reported findings from a large (n = 672), 24-week, randomized control trial.134
Four treatment groups were defined – a low dose (25 mg weekly), medium dose (25 mg twice
weekly), high dose (50 mg twice weekly), and placebo group. At week 12, the percent of subjects
achieving a PASI 75/90 in the placebo cohort was 4/1%. In the low dose group these percentages
increased to 14/3%, respectively. Within the medium dose group 34/12% achieved these PASI
scores. Lastly, the high dose group experienced the greatest success with 49/22% achieving a
PASI 75/90. At the week 24 endpoint, PASI 75/90 in the low dose: 25/6%, medium does: 44/20%,
and high dose: 59/30% were increased compared to week 12.
A second study reported by Papp et al. randomized 583 subjects to receive placebo, etan-
ercept 25 mg twice a week, or etanercept 50 mg twice a week for 12 weeks.135 After this time
point all subjects received 25 mg of etanercept twice a week for an additional 12 weeks. As
expected, treatment groups significantly outperformed placebo. The PASI 75/90 scores for the
25 mg twice weekly versus 50 mg twice weekly were as follows: 34/11% vs 49/21%, respectively.
Following week 12, researchers wanted to identify if subjects initially on 50 mg twice weekly
Fig. 4. The PASI score is calculated by summing the severity scores for each region and multiplying them by their
corresponding area and involvement scores. Each region score is then summed to give an overall PASI score. Of note, the
buttock is included within the lower extremities.
would experience a sustained response following a dose reduction to 25 mg twice weekly.

A total of 179 subjects underwent this dosage change. Of the 51% who had achieved a PASI
75 at week 12, 23% of them lost it by week 24 while on the reduced dosage. Of the 49%
who did not achieve a PASI 75 at week 12, only 32% went on to achieve this endpoint at
week 24.
These trials demonstrated etanercept as a well-tolerated biologic with similar rates of adverse
events (AE) and infection occurring in each dosing scheme. Majority of adverse events were
mild to moderate in severity. As mentioned, a risk of malignancy was conferred to patients on
this medication. One meta-analysis of 15,418 individuals on anti-TNF therapy demonstrated only
0.84% of these patients received a cancer diagnosis (excluding non-melanoma skin cancer).136
Adalimumab
The 52-week REVEAL study consisted of three periods.102 In the initial period, subjects
(n = 1212) were randomized to receive placebo or active drug (80 mg loading dose followed by
40 mg injections biweekly). At week 16, PASI 75/90/100 for the treatment group was 71/37/14%,
respectively. Next, subjects who achieved a PASI 75 (n = 606) at week 16 continued into an
open-label period. During this period injections of 40 mg were administered biweekly through
week 31. Placebo assigned subjects from the first period were administered the loading dose
on week 16, and continued onto 40 mg biweekly dosage. At week 33, 84% achieved a PASI 75
and continued to the final period consisting of a re-randomized to either placebo or continued
adalimumab injections. Following re-randomization, the percentage of patients losing adequate
response was significantly greater in placebo (28%) compared to active treatment (5%), p < 0.001.
Not surprising, the time it took for loss of response was much shorter for subjects on placebo.
In the long-term extension, 840 patients from REVEAL and three other trials were contin-
ued on adalimumab.137 Of the patients who continued into the extension and had been on
adalimumab for the duration of the REVEAL study, PASI 75/90/100 scores at week 160 were
76/50/31%, respectively.
Safety of the drug was demonstrated in both trials. Only 2% of subjects in the REVEAL study
discontinued treatment due to an AE. The only infections occurring at rates greater than 2%
in the treatment groups included upper respiratory infection, nasopharyngitis, and sinusitis.
Rates of malignancy, serious infections, and serious adverse events (SAE) were comparable
between treatment and placebo groups. Adalimumab was associated with increased risks of
non-melanoma skin cancer as had been described in other clinical trials. Similar data was
demonstrated in the long-term extension.
Infliximab
In EXPRESS 1, 378 subjects were randomized in a 4:1 ratio to receive infliximab at 5 mg/kg
or placebo for 50 weeks.103 At week 24, subjects in the placebo arm blindly enter into ac-
tive treatment receiving infliximab 5 mg/kg infusions for the remainder of the study. The
active treatment arm significantly outperformed placebo in PASI 75/90 and physician global
assessment scores (all p < 0.0 0 01). Within the treatment arm at week 10, PASI 75/90 scores
were 80/57%, respectively. Response was well maintained to week 24 with PASI 75/90 scores
of 82/58%. By week 50, analysis of only patients on infliximab for the entirety of the study
revealed decreasing PASI 75/90 scores of 61/45%.
The EXPRESS 2 trial aimed to examine the effect of intermittent versus continuous mainte-
nance dosing.104 To accomplish this the trial was split into an initial treatment period where
subjects were randomized to receive infliximab at 3 mg/kg, 5 mg/kg, or placebo at weeks 0, 2,
and 6. At week 10 PASI 75 for the 3 mg/kg and 5 mg/kg cohort was 70% and 76% respectively.
In the second period subjects initiated on infliximab and achieved a PASI 75 were randomized
to receive dosing every 8 weeks, or intermittent dosing. Subjects in the intermittent dosing
group received treatment during visits if they lost their PASI 75. Subjects dosed every 8 weeks
maintained their response more successfully than the intermittent dosing group for both 3 and
5 mg/kg concentrations. At week 50, PASI 75/90 scores for the 5 mg/kg cohort dosed every 8
weeks was 55/34% respectively. In comparison, the 5 mg/kg cohort dosed intermittently had
PASI scores of 38/10%. PASI scores were lower for 3 mg/kg groups, but exhibited a similar trend
when comparing continuous and intermittent dosing schemes.
Infliximab was well tolerated in these subjects. Comparison of AE rates at week 24 revealed
a slightly higher percentage in the active treatment (82%) versus placebo groups (71%). Most
common AE included upper respiratory infections, headache and fatigue. In the infliximab
groups from EXPRESS 1 three serious infections occurred. In EXPRESS 2, AE rates were com-
parable between the continuous and intermittent infusion cohorts. Through week 50, only 2
malignancies occurred after excluding squamous cell or basal cell cancers of the skin (n = 10).
Of note, all 10 of these subjects with skin cancers had prior phototherapy.
Certolizumab pegol
CIMPASI-1 and CIMPASI-2 are the phase 3 trials that demonstrated the efficacy and safety of
certolizumab pegol (CZP).138 These replicate trials randomized 461 subjects to receive 400 mg
CZP every 2 weeks, 200 mg CZP every 2 weeks (following 400 mg injections at week 0, 2, and
4), or placebo every 2 weeks in a 2:2:1 ratio. At week 16 the PASI 75/90/100 scores in subjects
receiving the 400 mg of CZP every 2 weeks from CIMPASI-1 were 76/44/13%. In the 200 mg
cohort these scores were 66/36/14%. In comparison, the PASI scores in the 400 mg and 200 mg
cohorts from CIMPASI-2 were 83/55/19% and 81/53/15%. By week 48, subjects in CIMPASI-1
receiving 400 mg vs 200 mg of CZP experienced higher PASI 75/90/100 scores (87/60/24% vs
67/43/22%). In CIMPASI-2, respective scores were achieved in 81/62/38% vs 79/60/31%.
A third phase 3 trial, CIMPACT, included an etanercept active comparator group.139 By week
12, 400 mg of CZP was found to be superior and 200 mg of CZP non-inferior to etanercept.
PASI 75/90/100 for these three cohorts at week 12 were 67/34/NA% (400 mg CZP) vs 61/31/NA%
(200 mg CZP) vs 53/27/NA% (etanercept).
As previously mentioned, the CRIB and CRADLE studies demonstrated minimal to no pla-
cental and breastmilk transfer of certolizumab pegol. The structure of CZP is what prevents this
transfer. Because certolizumab is an Fc-free biologic it cannot bind to the neonatal Fc receptor
for IgG responsible for transfer across the placenta.138
Safety of certolizumab pegol was well demonstrated and similar to other biologics. As with
all TNF-inhibitors, the same warnings and precautions should be followed. In CIMPASI-1 rates
of SAE through week 16 were similar between placebo and 200 mg CZP cohorts, but slightly
higher in the 400 mg CZP cohort (2.0% vs 2.1% vs 5.7%). A similar trend was found in CIMPASI-2
with SAEs occurring in 0%, 2.2%, and 4.6%. The most common AEs reported in this medication
included nasopharyngitis and upper respiratory infection. Rate of malignancy through week 48
for the 400 mg cohort was low in both trials (0.7% and 0.8%). Both cases represented a basal
cell carcinoma.
Ustekinumab
In PHOENIX-1 766 subjects were randomized to receive 45 mg of ustekinumab, 90 mg of

ustekinumab, or placebo.112 At week 12 subjects receiving 45 mg or 90 mg of drug experienced
the following PASI 75/90/100 scores: 67/42/13% vs 66/37/11%. Subjects on placebo then crossed
into active treatment until week 40 with similar response as those initially randomized to
treatment. Maximum efficacy in patients on ustekinumab from the beginning of the trial
was experienced around week 24. Lastly, patients meeting a PASI 75 response at week 40
entered a randomized withdrawal phase. The median time to loss of the PASI 75 response was
approximately 15 weeks.
PHOENIX-2 randomized 1230 subjects into the same groups as PHOENIX-1.111 At week 12,
the percent of subjects achieving a PASI 75/90/100 in the 45 mg group was 67/42/18%. In the
90 mg group these numbers increased to 76/51/18%. At week 28, these PASI 75/90/100 scores
for the 45 mg and 90 mg groups increased to 71/49/21% vs 79/56/29%.
The ACCEPT trial exchanged the placebo group for an active comparator, etanercept.110 They
randomized 903 subjects. The 45 mg and 90 mg ustekinumab groups both showed superiority
compared to subjects on etanercept.
A 5-year follow-up of subjects in the PHOENIX-2 trial showed at week 244 that 77% and 79%
of subjects achieved a PASI 75 in the 45 mg and 90 mg groups respectively.
Again, nasopharyngitis, URI, headache, and arthralgia were most commonly experienced AEs.
Rates of discontinuation due to AE were similar across treatment and placebo groups. Rates of
AE, SAE, and discontinuation did not exhibit any dose response. Following maintenance injec-
tions to week 76, no increase in MACE, SAEs, AEs, serious infection, or malignancy was found.
Secukinumab
The ERASURE trial was a 52-week study and randomized 738 subjects to receive placebo,
300 mg of drug, or 150 mg of drug.140 Subjects receiving 300 mg of secukinumab were more
likely to achieve PASI endpoints compared to the 150 mg group. At week 12 examination of the
30 0 mg group, PASI 75/90/10 0 was 82/59/29%. In the 150 mg group PASI 75/90/100 scores were
achieved by 72/39/13%. At week 52, PASI 90/100 for the 300 mg group was well maintained at
60/39%.
The FIXTURE trial was identical in design with the exception of an etanercept comparison
group.140 In total, 1,306 subjects were randomized. Comparison of the 300 mg secukinumab
group vs etanercept group revealed the following respective PASI 75/90/100 scores: 77/54/24%
vs 27/21/4%.
The SCULPTURE trial was a 52-week study that extended for an additional 2 years to exam-
ine long-term outcomes.141 Of the 168 subjects who received 300 mg of secukinumab every 4
weeks for 3 years, 64% had a PASI 90 score and 43% a PASI 100.
The most frequently experienced AEs were nasopharyngitis, headache, and diarrhea during
induction. Overall the percentage of patients experiencing an AE was similar between the
300 mg group, 150 mg group, and etanercept group (56%, 58%, and 58% respectively). Likewise,
the rates of SAEs were similar between the groups (6.8, 6.0, and 7.0 respectively per 100-patient
years). Exposure-related malignancy rates showed no clinically significant difference between
drug and placebo groups.
Ixekizumab
The UNCOVER-1 trial lasted 12 weeks and randomized a total of 1,296 subjects to receive
80 mg every 2 weeks, 80 mg every 4 weeks, or placebo.117 Subjects dosed every 2 weeks
experienced better outcomes than every 4 weeks. 82% from the 2-week cohort and 76% from
the 4-week cohort achieved a physician global assessment score of 0 (clear) or 1 (almost clear)
at week 12. Additionally, comparing 2-week vs 4-week dosing after 12 weeks of treatment,
revealed PASI 75/90/100 of 89/71/35% vs 83/65/34%
UNCOVER-2 randomized 1224 subjects into similar groups as UNCOVER-1 but with an
additional group assigned to 50 mg of etanercept twice weekly.116 Subjects dosed every 2 weeks
experienced similar PASI and PGA scores at week 12 as previously reported (PASI 75/90/100:
90/71/41%, and PGA of 0 or 1: 83%). Similarly, the every 4-week dosing group was comparable
to UNCOVER 1 data (PASI 75/90/100: 78/60/31%, and PGA of 0 or 1: 73%). The etanercept group
in this study achieved a PGA score of 0 or 1 in 36% and a PASI 75/90/100 of 42/19/5%.
Following week 12, subjects with a PGA score of 0 or 1 from UNCOVER 1 and 2 were
randomized to receive placebo, ixekizumab every 12 weeks, or ixekizumab every 4 weeks until
week 60. Of subjects receiving every 4-week injections, 74% maintained their PGA score at week
60, whereas only 39% and 7% of the every 12-week and placebo groups maintained their score.
UNCOVER-3 randomized 1,346 subjects and was a long-term study.116 At week 60 PASI
75/90/100 for patients on ixekizumab were obtained in 83/73/55%.
Safety analysis of these three trials revealed the most common adverse events included
nasopharyngitis, URI, injection site reactions, and headache. Rates of serious adverse events
were similar between ixekizumab and placebo groups. During the induction phase, there were
no differences in exposure-adjusted incidence rates of cancer, major adverse cardiac events
(MACE) or cerebrovascular events between the ixekizumab and placebo groups. In UNCOVER-2
and UNCOVER-3, similar rates of infection (26% vs 22%) and non-fatal SAEs (2% vs 2%) were
found between the ixekizumab group and etanercept group respectively.
Brodalumab
In AMAGINE-1 661 subjects were randomized to receive 140 mg of drug, 210 mg of drug, or
placebo every 2 weeks.120 Subjects receiving 210 mg of active drug outperformed other groups
and at week 12. Within the group administered 210 mg, 83/70/42% obtained PASI 75/90/100
scores.
Examination of AMAGINE-2 and AMAGINE-3 together included 3,712 total randomized
patients.121 These studies utilized the same groups as AMAGINE-1 with addition of an ustek-
inumab group. In AMAGINE-2, Week 12 and 52 PASI 75/90/100 scores for patients receiving
210 mg of drug were 86/70/44% and 80/75/56%. In AMAGINE-3, these scores were 85/69/37% and
80/73/53%. In comparison, the ustekinumab group in these two studies experienced a lower per-
centage of subjects obtaining a PASI 75/90/100 (AMAGINE-2: 7-/61/22%; AMAGINE-3: 69/57/19%).
Like the other anti-IL-17A antibodies, the most frequent AEs reported for brodalumab
included nasopharyngitis, URI, headache, and arthralgia. SAEs through the entirety of the study
occurred at a rate of 8.3 in subjects treated with brodalumab and 13.0 with ustekinumab within
AMAGINE-2; rates of 7.9 and 4.0 respectively were found in AMAGINE-3.
Guselkumab
In VOYAGE 1 a total of 837 patients were randomized to placebo, guselkumab 100 mg every
8 weeks, or adalimumab 40 mg every 2 weeks.142 At week 16, PASI 75/90/100 scores for the
guselkumab group were 91/73/37%. By week 48, these scores were changed to 88/76/47%. PASI
75/90/100 for the adalimumab group at week 16 (73/50/17%) and at week 48 (63/48/23%) were
lower than the guselkumab group.
VOYAGE 2 was designed similarly to VOYAGE 1, but contained a randomized withdrawal and
re-treatment group starting at week 28.143 Only subjects who achieved a PASI 90 were included
in the withdrawal and re-treatment period. Of the patients randomized into the withdrawal
group after week 24, the median time to loss of PASI 90 was approximately 15.2 weeks.
The most common AEs were infection including nasopharyngitis and URI. Rates of infection
for placebo, guselkumab, and adalimumab groups were 19%, 22%, and 23% respectively. At the
end of study, the percentage of patients experiencing a SAE was similar for the guselkumab and
adalimumab groups (4.9% vs 4.5%). Rates of serious infections, MACE, and malignancy were low
across all groups.
Tildrakizumab
The first study, reSURFACE 1, was a three-part study running a total of 3 years.122 In
the first part, trial sites randomized 772 patients in a 2:2:1 fashion to receive 200 mg of
tildrakizumab, 100 mg of tildrakizumab, or placebo for 12 weeks. At week 12, subjects on
tildrakizumab achieved much greater rates of PASI 75 and PGA scores of 0 or 1 compared
to placebo (p < 0.0 0 01). In the 20 0 mg dosing group, the percentage who achieved a PASI
75/90,100 at week 12 was 62/35/14%; rates in the 100 mg tildrakizumab group were similar
at 64/35/42%. In part two, the placebo group was re-randomized to either 100 mg or 200 mg
of tildrakizumab at week 12. These subjects exhibited similar response as subjects initially
exposed to tildrakizumab. Finally, part three consisted of a randomization to one of two arms
beginning at week 28. The first consisted of tildrakizumab 200 mg or treatment withdrawal. The
second arm was treated with tildrakizumab 100 mg or withdrawn from treatment. If subjects
withdrawn from treatment relapsed, they resumed treatment with the dose of tildrakizumab
used in their perspective arm. Of the patients re-randomized to placebo, 57% from the 200 mg
group and 49% from the 100 mg group maintained their PASI 75 response until week 64 (36
weeks following discontinuation of drug from part two of study).
The second study, reSURFACE 2, was a similar three-part design to reSURFACE 1, but included
an active comparator group randomized to etanercept.122 As expected, tildrakizumab groups sig-
nificantly outperformed placebo groups. Importantly, the 200 mg tildrakizumab group achieved
significantly higher rates of PASI 75compared to the etanercept group. A significant difference
in PASI 75 only was found when comparing the 100 mg tildrakizumab to etanercept groups.
Adverse events related to the study medication were comparable to the other biologics.
Nasopharyngitis was the most commonly reported in both trials. Severe infections, malignancy,
and drug-related hypersensitivity were all extremely rare occurring in <1%.
Conclusion
Psoriasis is a complex disease that negatively impacts patients physically and emotionally
in a myriad of ways. Public awareness of the condition has improved over time; however, con-
tinued education is necessary to reduce the social impacts and stigma of psoriasis. Fortunately,
research has produced therapeutics that have achieved unparalleled results in the treatment
of psoriasis. Nearly a decade ago, complete or nearly complete reduction in skin lesions were
unheard of. Today, biologics continue to push the envelope of possibility; achieving 90% or 100%
reductions have become an achievable goal rather than a hope or dream. Biologics have rapidly
become the premier class of treatment in patients with moderate to severe psoriasis. As trials
continue to demonstrate the safety and efficacy of these medications, hopefully physicians will
become more familiar and comfortable in their use.
Financial disclosures
Eric Schadler has served as a sub-investigator for clinical studies sponsored by companies
that manufacture drugs used for the treatment of psoriasis including AbbVie, Boehringer-
Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Novartis, and UCB.
Dr. Stephanie Mehlis has served as a consultant and/or paid speaker for and/or served as
principal investigator in clinical studies sponsored by companies that manufacture drugs used
for the treatment of psoriasis including AbbVie, Amgen, Boehringer-Ingelheim, Bristol Myers
Squibb, Celgene, Eli Lilly, GlaxoSmithKline, Janssen, Maruho, Novartis, Pfizer, and UCB.
Dr. Bernhard Ortel has no financial disclosures.
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U 7 Biologics For The Primary Care Physician Review and Treatment of Psoriasis

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Disease-a-Month 65 (2019) 51–90

Contents lists available at ScienceDirect

journal homepage: www.elsevier.com/locate/disamonth

Biologics for the primary care physician:

Psoriasis is a chronic inﬂammatory disease that affects ap-

ically based on characteristic history and physical examina-

Psoriasis is a chronic inﬂammatory disease historically considered a condition of the skin.

Loci Name Location

Trauma Sunlight (UV light)

The genetic component of psoriasis serves as a “primer” in disease development. Triggering

Infections have been implicated in the pathogenesis of numerous diseases by triggering

Alcohol and smoking

Clinical classiﬁcation and features

Psoriasis vulgaris, more commonly referred to as plaque psoriasis, is characterized by erythe-

As the name implies, pustular psoriasis is characterized by numerous pustules overlying an

Erythrodermic psoriasis can be a result of an escalation of preexisting psoriasis, discontinu-

Fig. 2. Psoriasis plaques may be associated with signiﬁcant erythema.

IL-17 is a proinﬂammatory, homodimeric glycoprotein discovered in 1993.39 Six homogenous

IL-23 is a pro-inﬂammatory heterodimeric glycoprotein discovered in 20 0 0.46 The cytokine

Tumor necrosis factor-α

TNF-α is a pro-inﬂammatory cytokine secreted primarily by macrophages and activated

Psoriatic arthritis (PsA)

Psoriatic arthritis is a seronegative spondyloarthropathy occurring in patients with psoriasis,

Co-morbidity Screening recommendations?54 , ∗

Obesity & type 2 diabetes mellitus

Inﬂammatory bowel disease

Ophthalmic complications of psoriasis may occur at numerous anatomic locations including

information of their disease resulting in poorer adherence to treatments.93 A survey by Brown

Severity of disease is the critical determination when choosing an appropriate therapeutic.

E.D. Schadler et al. / Disease-a-Month 65 (2019) 51–90

E.D. Schadler et al. / Disease-a-Month 65 (2019) 51–90

Adalimumab (Humira®, AbbVie). Adalimumab is a monoclonal antibody against TNF-α . It func-

Inﬂiximab (Remicade®, Janssen Pharmaceutica). Inﬂiximab is a monoclonal anti-TNF-α antibody

IL -12/IL -23 inhibitors

Brodalumab (Siliq®; Valeant Pharmaceuticals). Brodalumab is a monoclonal antibody directed

Selective IL-23 inhibitors

Tildrakizumab (Ilumya®, Sun Pharmaceutical Industries Ltd.). Tildrakizumab is an IgG humanized

Biologics in the pipeline

Management of patients on biologics

Oral systemics (non-biologic)

Landmark clinical trials

would experience a sustained response following a dose reduction to 25 mg twice weekly.

In PHOENIX-1 766 subjects were randomized to receive 45 mg of ustekinumab, 90 mg of

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