Raut 2013

Critical Reviews™ in Therapeutic Drug Carrier Systems, 30(3), 183–216 (2013)
Psoriasis Clinical Implications and

Treatment: A Review
Ashlesha S. Raut, Rashmi H. Prabhu, & Vandana B. Patravale*
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Na-

thalal Parekh Marg, Matunga, Mumbai 400 019, India
*Address all correspondence to: Vandana B. Patravale: Department of Pharmaceutical Sciences and Technology, Institute
of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai 400 019, India; Tel.: 91-22-3361 2217; Fax: 91-22-
3361 1020; E-mail: vbp_muict@yahoo.co.in
ABSTRACT: Psoriasis is a common skin disorder affecting the population worldwide. It is

a T-cell mediated autoimmune disorder leading to keratinocyte hyperproliferation. Psoriasis
has genetic predisposition that is further aggravated by certain stimulating factors. In spite
of significant advances in understanding the pathogenesis of psoriasis, the exact etiology
of the disease remains unknown. The clinical manifestations of this disease include various
forms that affect different parts of the body. Treatment options vary according to the mode
of application or severity of the disease. Earlier treatments have included application of
emollients or keratolytic agents to hydrate the skin or shed off the skin. But later treatments
have been modified to treat the underlying T-cell proliferation. Hence, topical treatments
like coal tar, vitamin D, retinoids, topical calcineurin inhibitors for treating mild psoriasis,
systemic treatments including methotrexate, cyclosporine, acitretin, hydroxyurea, as well as
light therapy for severe psoriasis have become more prominent. Current treatment modali-
ties are associated with the risk of serious side effects from prolonged treatment. Combina-
tions of these therapies have provided effective and rapid modalities to suppress the disease
and reduce the side effects of treatment. In addition, newer carrier systems for conventional
drugs are being developed to improve the effectiveness of treatment and reduce the side ef-
fects. Development of biologics and gene therapy have revolutionized the treatment of this
skin disease. Although an array of therapies to suppress the psoriatic condition exists, none
are curative.
KEY WORDS: Psoriasis, immunopathogenesis, clinical types, treatment, novel delivery systems
I. INTRODUCTION
Psoriasis is a chronic, T-cell mediated autoimmune disorder that is accompanied by

substantial physical and psychosocial distress.1 The term psoriasis was coined by the
Viennese dermatologist Ferdinand von Hebra.2 The name psoriasis is derived from the
Greek word psora which means to itch.3 The prevalence rate of psoriasis around the
world is estimated to be around 2%.4 The primary cause of the disease was originally
thought to be keratinocyte hyperproliferation, which leads to abnormal differentiation
and impaired barrier function, because the clinical appearance of psoriasis is largely a
result of epidermal changes. This apparent discrepancy vanished in the late 1970s and
early 1980s with the identification of T lymphocytes and macrophages in dermal inflam-
0743-4863/13/$35.00 ©2013 Begell House, Inc. www.begellhouse.com 183

184 Raut, Prabhu, & Patravale
matory infiltrates as the major cell types. The view of the pathogenesis of psoriasis then
shifted to that of an immune-mediated disease.5
Current treatments for psoriasis are associated with limited efficacy and problems
such as inconvenience, organ toxicity, and broad-band immunosuppression. Hence, there
is a demand for new therapeutic approaches that are more convenient, effective, safe,
and immunologically selective. Recognition of the central role played by T cells in the
pathogenesis of this disease has led to the reappraisal of therapeutic mechanisms of most
drugs used to treat psoriasis. Newer biological drugs are designed to selectively interfere
with immune mechanisms that induce psoriasis. 6,7 Investigation of novel drug delivery
systems for psoriasis treatment is increasing.8 Gene therapies are also moving toward
providing additional treatment options for psoriasis.9 The effects of psoriasis extend well
beyond the physical symptoms and influence other spheres of life. The social, psycholog-
ical, and financial impacts of psoriasis are much deeper than its physical appearance.10–12
II. SEVERITY
The severity of psoriasis can be assessed by commonly used measures, namely the Psoriasis
Area Severity Index (PASI), the Psoriasis Global Assessment (PGA), and the Lattice System
Physician’s Global Assessment (LS-PGA). Scales for measuring the severity of psoriasis are
generally based on the following factors: the proportion of body surface area affected, dis-
ease activity (degree of plaque redness, thickness and scaling), response to previous thera-
pies, and the impact of the disease on the person. Depending on PASI, psoriasis is usually
graded as mild (affecting <3% of the body), moderate (affecting 3–10% of the body), or
severe (affecting a major portion of the body). The PGA provides a single estimate of the
patient’s overall severity of disease using a 7-point scale from clear to severe (Table 1).
The Lattice System Physician’s Global Assessment (LS-PGA) involves two steps.
In the first step, the percentage of body surface involved is assessed using a 7-point
scale, and in the second step, using a 4-point scale, the average plaque qualities of thick-
ness, erythema, and scale are assessed. A final rating of the severity from clear to very
severe is determined by combining the scores of percentage of body surface and aver-
age plaque qualities in a lattice, which is typically performed using a computerized
algorithm. Compared to PASI and PGA, LS-PGA is a standardized, reliable measure
of therapeutic effect in psoriasis.13 These severity grading parameters are particularly
important in choosing a therapeutic treatment strategy.
Table 1. Description of Psoriasis Global Assessment (PGA)

Severe Very marked plaque elevation, scaling, and/or erythema
Moderate to severe Marked plaque elevation, scaling, and/or erythema
Moderate Moderate plaque elevation, scaling, and/or erythema
Mild to moderate Intermediate between moderate and mild
Mild Slight plaque elevation, scaling, and/or erythema
Almost clear Intermediate between mild and clear
Clear No signs of psoriasis (postinflammatory hyperpigmentation may be
present)
Critical Reviews™ in Therapeutic Drug Carrier Systems

Psoriasis - Clinical Implications and Treatment 185
III. EPIDEMIOLOGY
Although psoriasis occurs worldwide, its prevalence varies with race and geographical
location. The prevalence in Norway and the Arctic (5–12%) is highest, with intermedi-
ate prevalence in Northern Europe and the United States, where the peak approaches 3%
of the population. Psoriasis is moderately prevalent in Central Europe (1.5%) and less
prevalent in the Asian population and among North American Indians and Western Af-
ricans (0–0.3%). The lower prevalence of the disease observed among black Americans
(0.45–0.7%) when compared to the remainder of the US population (1.4–4.6%) further
demonstrates the influence of ethnic factors.14,15
Psoriasis can occur at any age, and the presentation of disease has been reported at
birth and in people of advanced age.16 Psoriasis is equally prevalent in both males and
females.14 In psoriasis, the contribution of the different genetic factors varies depend-
ing upon the patient subgroup based on the age at onset. Using serological markers,
two types of psoriasis exist: type I psoriasis has an early age at onset of <40 years with
positive family history and an association with HLA (human leukocyte antigens) alleles,
whereas type II psoriasis is of later onset (>40 years) with less or no family history and
no association with HLA.17,20
Plaque-type psoriasis is the most common form of the disease, occurring in more
than 80% of cases. Guttate psoriasis occurs in approximately 10% of patients with psoria-
sis, and erythrodermic and pustular psoriasis each occur in fewer than 3% of patients.18,19
IV. GENETICS OF PSORIASIS
The mode of inheritance pattern of psoriasis remains unclear and may be variable. The dis-
ease develops in approximately 50% of siblings of persons with psoriasis when both parents
are affected, in 16% when only one parent has psoriasis, and in 8% when neither parent is
affected. A positive family history is found in as many as 71% of patients with childhood
disease.14 Genetic factors related to susceptibility to this disease includes the following.
IV.A. HLA Molecules
The processes leading to all autoimmune diseases involve the human leukocyte antigen
(HLA) system, which is genetically regulated. HLA molecules are designed to pick off
parts of antigens and present them on the surface of a cell so that the various infection-
fighting factors in the immune system can recognize and destroy them. Malfunction of
this system is at the root of most immune disorders, including psoriatic arthritis.14
IV.B. Psoriasis Susceptibility genes (PSORS)
To date, 19 different putative loci for genetic susceptibility to the disease have been iden-
tified. These loci are located on different chromosomes and are designated as PSORS1-7
(psoriasis susceptibility 1–7), and PSORS9. The remaining loci have not yet been des-
Volume 30, Number 3, 2013

ignated. Of particular interest are the genes located in the regions on specific chromo-
somes that are linked to HLA and tumor necrosis factor (TNF), an immune component
strongly associated with psoriasis.21
V. EXACERBATING FACTORS FOR PSORIASIS
Expression of the dominant gene, which lies dormant, is triggered by certain factors as
discussed below such as environmental factors, stimuli, certain drugs, chemicals and
weather.22,23
V.A. Endocrine Factors
Incidence of psoriasis peaks at puberty and menopause and may be exacerbated by preg-
nancy, premenstrual cycle, and high doses of estrogen.24
V.B. Metabolic Factors
Hypocalcaemia may precipitate psoriasis.24
V.C. Drugs
A number of drugs can worsen or induce pre-existing latent psoriasis: the anti-malarial
drug chloroquine, angiotensin-converting enzyme (ACE) inhibitors, progesterone used
in female hormone therapies, lithium, indomethacin [a non-steroidal anti-inflammatory
drug (NSAID)],tetracyclines, beta blockers, interferons and corticosteroid withdrawal.24,25
V.D. Skin Injuries and the Köbner Response
The Köbner response is a delayed response to skin injuries, in which psoriasis develops
later on at the site. In some cases, even mild abrasions can cause an eruption, which may
be a factor in the frequency of occurrence of psoriasis on the elbows or knees.26 Pre-
existing psoriasis can be further exacerbated by surgical trauma.27
V.E. Psychogenic Factors (Stress and Emotion)
Stress, unexpressed anger, and emotional disorders including depression and anxiety are
strongly associated with psoriasis flare-ups.28
V.F. Environmental Triggers
Cold, dry weather is a common precipitant of psoriasis flare-ups, while hot, damp, sunny
weather helps relieve the problem in most patients. Sunlight plays a dual role by flaring
up and relieving the psoriasis in some patients.25

V.G. Infection
Infections caused by viruses (human immunodeficiency virus (HIV) 29 and human papil-
lomaviruses (HPV) or bacteria (streptococcal infection and Helicobacter pylori infec-
tion) can trigger some cases of psoriasis.30
V.H. Alcohol and Smoking
Alcohol seems to have a greater influence on the progression of psoriasis in men, where-
as the association between smoking and psoriasis seems to be stronger in women.31
V.I. Obesity
A network of pro-inflammatory cytokines (especially TNF-α) play an important role in

the pathophysiology of both obesity and psoriasis; hence, the two are interlinked. 32,33
VI. PATHOGENESIS
Psoriatic skin is scaly and inflamed with plaques compared with healthy skin.34 The
pathogenesis of psoriasis is regarded to be outcome of activation of lesional and/or cir-
culating immune cells and their secreted products such as cytokines, chemokines and
growth factors, ultimately leading to keratinocyte hyperproliferation, epidermal thick-
ening, and angiogenesis with marked dilatation of blood vessels.35,36
VI.A. Concept of Psoriasis as a T-Cell Mediated Disease
The number of T lymphocytes and macrophages in psoriatic plaques has been observed to
increase compared to normal tissue. Monoclonal antibody probes have shown the T cells to
have CD4+ and CD8+ markers, with TH1 (T- helper cell type 1) cells concentrated in the dermis
and type 1 cytotoxic T-cells in the psoriatic epidermis. These T cells also carry the CD45RO
markers. Both CD4+ and CD8+ T cells in psoriasis produce mainly type-1 cytokines.1,2,37
VI.B. Immunopathogenesis
The pathogenesis of this disease at the cellular level can be more extensively described
and characterized within the context of an inflammatory model.1,2,38,39 These events can
be sequenced as shown in Figure 1.
1. APC Activation
Antigen presenting cells (APCs) such as epidermal Langerhans cells and dermal den-
dritic cells are activated by exogenous or endogenous antigen(s) and migrate from
the skin to lymph nodes, where they encounter and activate naive CDRA45+ T cells.1

188
FIGURE 1. Inflammatory model to illustrate pathogenesis of psoriasis (Modified from Ref no 1). (1) Antigens activate APCs and migrate to lymph
nodes. (2) APCs interact with and activate naive CDRA45+ T cells via signals 1 and 2 in the lymph node. (3) Activated CDRO45+ T cells secrete
proinflammatory cytokines and proliferate/differentiate into T1 central effector and memory T cells; expression of surface CLA allows memory T
cells to traffic towards skin via blood vessels. (4) Inflammatory region releases chemotactic factor that attracts T cells, interacts with endothelial
cells leading to T cell extravasation. (5) Proinflammatory cytokines released from infiltrating T cells induces keratinocyte hyperproliferation and

Raut, Prabhu, & Patravale
additional production of chemotactic factors.

2. T-Cell Activation
T-cell activation is a multistep process described as follows.
a. Step 1 (binding)
Contact between the APC and T cell is initially stabilized by immune cell adhesion mol-
ecule (ICAM)-1 and leukocyte function antigen (LFA)-1 interactions between the two
cells, respectively.
b. Step 2 (primary stimulation/signal 1)

The binding allows for antigen-major histocompatibility complexes (MHC) on the sur-
face of APCs interact with T-cell receptors and CD4/CD8 co-receptors on the surface of
T cells and generate signal 1.1
c. Step 3 (costimulation/signal 2)
Additional interactions also take place between the T cell and APC, together described
as ‘accessory’ or ‘costimulatory’ signals. These are critical for optimal activation of the
T lymphocyte. In the absence of costimulation, the degree of responsiveness of the cell
is very limited (anergetic), or the cell itself may undergo apoptosis. These costimulatory
signals are not antigen specific. Costimulatory interactions include LFA3 with CD2,
CD40 with CD40L, and B7 (CD80 and CD86) on the APC with CD28 on the T cell.1,39
3. Proliferation\Differentiation of T Cells
Activated T cells are induced to secrete a number of cytokines such as interleukin (IL)-2,
tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFNγ), and IL-12, which allow
for their subsequent proliferation and differentiation into CD45RO+ type 1 central and
effector memory cells.40,41
4. Migration of T Cells
T cells acquire a surface protein termed cutaneous lymphocyte–associated antigen

(CLA). This is an adhesion molecule that mediates attachment of the T cell to the endo-
thelial cells of the dermal vasculature through E selectin and P selectin, with subsequent
entry into the skin. The process also involves triggering many chemokines and binding
of integrins, such as vascular cell adhesion molecule, ICAM-1, and LFA-1.42
5. Effects of T Cells on Site
The TH1 and type 1 cytotoxic T cells release high levels of IFN-γ and TNF-α once in
the dermis, which induces ICAM-1, CD40, and major histocompatibility complex II
proteins on the keratinocytes. Keratinocyte hyperproliferation is activated by T cells
located intra-epidermally, thereby accelerating epidermal growth occurring in the re-

generative pathway. The cytokines, which are secreted by different cells in the local
environment of the psoriatic plaque, is suggested to be associated with the pheno-
typic responses observed in psoriasis. TNF-α is known to stimulate the keratinocyte
production of type 1 vasoactive intestinal peptide receptor mRNA. Such vasoactive
intestinal peptide functions by inducing keratinocyte proliferation and stimulating the
production of proinflammatory cytokines such as IL-6, IL-8, and RANTES (regulated
upon expression, normal T cell expressed and secreted).6 Primary cytokine IL-1 has
been shown to be expressed in psoriatic lesional skin.43 These cytokines from intraepi-
dermal T cells are mitogenic in nature thereby stimulating the proliferation of kerati-
nocytes. TNF-α increases plasminogen activator inhibitor type 2, a serine proteinase
inhibitor, which confers protection to the cells from apoptosis, leading to increase in
keratinocyte longevity and thickening the epidermis. The other mechanism for kera-
tinocyte hyperplasia is postulated to be due to wound-reparative phenomenon, which
is actuated by intercellular disruption caused by T-cell entry into the epidermis. This
process of wound repair involves the stimulation of mitogenic cytokines and recep-
tors on keratinocytes such as epidermal growth factor, insulin like growth factor 1,
and keratinocyte growth factor pathways as implicated in regenerative hyperplasia.6,44
The other features of a psoriatic lesion, such as vascular proliferation and neutro-
phil infiltration, are also caused by the action of the other cytokines such as vascular
endothelial growth factor (VEGF) and IL-8 from keratinocytes on endothelium and
polymorphonuclear leucocyte recruitment.35
VII. CLINICAL FEATURES OF TYPES OF PSORIASIS
The various types and presentation of psoriasis are outlined in Table 2.22,23,45–51
VIII. TREATMENT
The history of psoriasis is littered with treatments which received brief notoriety at
particular time periods or within certain geographical regions but have fallen out of
favor with time. Accordingly, topical treatment is considered to be the safest option and
is widely used for mild psoriasis followed by systemic and phototherapies, which are
used for moderate to severe psoriasis.52 Biologics is a rapidly developing treatment field,
this modality provides the most effective options. Combinations of these various agents
rapidly improve the disease state and reduce side effects.53
Along with the severity of disease and the area affected, other factors are consid-
ered in selecting a treatment: age, gender, comorbid disease, pregnancy consideration,
and other medications.54 Drug-delivery strategies exhibit potential in optimizing the
efficacy of therapeutic agents by either modulating their physicochemical and biophar-
maceutical properties or minimizing or eliminating the side effects associated with
them, thereby conferring better patient compliance as well. Novel drug delivery sys-
tems employ an array of carriers such as liposomes, transferosomes, ethosomes, micro/
nanoemulsions, niosomes, cubosomes, solid lipid nanoparticles, nanostructured lipid

Table 2. Clinical Types of Psoriasis

Types of Psoriasis Description Occurrence
Plaque Psoriasis Symmetrical, well-demarcated, Patches on the elbows, knees,
red-violet round or oval plaque lower back, scalp, palms, soles,
genitals (occasional)
Psoriatic Arhtritis (PsA) A. Symmetric PsA Affects the whole body causing
B. Asymmetric PsA stiff, tender and inflamed joints
C. Distal Interphalangeal
Predominant (DIP)
D. PsA in the Spine
E. Arthritis Mutilans
Guttate Psoriasis Droplet-shaped lesions caused Occurs over the trunk and often
by streptococcal infection on the arms, legs
Generalized Erythroder- Inflamed erythema and wide- Affects nearly the whole body
mic Psoriasis spread scaling
Pustular Psoriasis Patches become pus-filled Patches appear on entire body
A. Generalized and blister-like, fiery-red, and in Generalized type,
B. Palmoplantar irregular . pustules appear on the hands
and feet in Palmoplantar type.
Hands and Feet Psoriasis Physical handicap, painful fis- Splitting occurs over the fin-
suring and splitting gertip and heels, scaling occur
over the knuckles.
Flexural and Genital Lesions are erythematous, Axillae, groins, umbilicus and
Psoriasis shiny deep pink plaques. genitalia are involved.
Nail Psoriasis Pitting of the nail plate, subun- Fingernails are affected more
gual hyperkerastosis (depo- often than toenails.
sition of material under nail
plate), Onycholysis (nail plate
separate from nail bed)
Facial Psoriasis Sebopsoriasis, scaly erythema- Most common site is the frontal
tous lesions hairline, forehead, eyebrows
and nasolabial folds
Scalp Psoriasis Well-defined pale red plaques Affecting scalp mainly in
with a thick surface of silvery younger patients causing local
scales alopecia
carriers, and polymeric systems.. These systems provide protection to the drug as it is
delivered, are mainly biocompatible in nature, and allow passive targeting.8 Advances
in drug carrier systems which have been explored for antipsoriatic drugs are also re-
viewed here.
VIII.A. Systemic Therapies
The array of systemic medications used in the treatment of psoriasis is rapidly expand-
ing. USFDA-approved systemic treatments include methotrexate, retinoids, and cy-
closporine, while other approved drugs include mycophenolate mofetil, hydroxyurea,
6-thioguanine and sulfasalazine, which are also administered systemically.55,56

1. Cyclosporine (Neoral®)
Cyclosporine induces immunosuppression by inhibiting the first phase of T-cell activa-

tion. Cyclosporine binds to an immunophilin called cyclophilin to form a complex which
then binds to and inhibits the enzyme calcineurin, a calcium-activated phosphatase.
Calcineurin inhibition, in turn, results in the blockage of signal transduction pathways,
which ultimately inhibits the production of cytokines such as IL-2 and interferon-γ.57
Currently, marketed preparation of cyclosporine (Neoral®) is in the form of microemul-
sion pre-concentrate in solution in soft gelatin capsules.58 Administered as a starting
dose of 5 mg/kg/day in divided doses (starting 2.5 mg/kg/day and increasing at 2–4-
week intervals up to 5 mg/kg/day), followed by a daily maintenance dose of 0.5–1 mg/
kg. Adverse effects include nephrotoxicity, electrolyte imbalance (hyperkalemia, hy-
pomagnesemia, hyperuricemia), elevation of cholesterol and triglyceride levels, skin
alteration, and gastric irritations.59,60
Encapsulating the drug into a liposomal formulation (comprising of phosphatidyl-
choline, phosphatidylglycerol and cyclosporin) reduced dose-dependent side effects.61
Furthermore, the stability of this liposomal formulation was improved by combining it
with hyaluronic acid 62 or formulating it as a self emulsifying delivery system (SEDDS)
or spontaneous emulsion (comprised of cyclosporine, ethanol ethyl oleate, and polyoxy-
ethylene glycerol trioleate).63 Oral bioavailability of cyclosporine can be improved by
formulating it as an aqueous dispersion containing nanoparticles of cyclosporin in an
amorphous form with good bioavailability.64 Pro-dispersion liposphere formulation of
cyclosporine has been developed by Avramoff et al., which is a homogeneous solution
of cyclosporine in a mixture of surfactants, phospholipids, and ethyl acetate that spon-
taneously disperses in water.65 A clinical study (a randomized, open-label, two-period,
two-treatment crossover study) was designed to compare the in vivo bioequivalence of
this liposphere formulation with the commercial product Neoral.66 Interestingly, both of
the cyclosporine formulations were found to be bioequivalent and could be interchanged
without dosage adjustment.65,66 Murdan et al. investigated non-lipidic self-dispersing
delivery systems, namely amphiphilogel (hydrophobic, hydrophilic gel containing etha-
nol), its aqueous dispersion, and its gel-based emulsion for oral delivery of cyclospo-
rine. The ampiphilogel and gel-based emulsion systems, incorporating cyclosporine
were found to be bioequivalent to Neoral® , except the hydrophilic type ampiphilogel.
The probable reason for the high drug absorption of bioequivalent formulations is the
ability of the gels to keep the drug in a solubilized form when the gel interacts with the
aqueous gastric contents. In contrast, low drug absorption of hydrophilic ampiphilo-
gel is attributed to the absence of the lipophilic environment in which the drug exists
in solubilized form and is more available for absorption.67 An open-label, randomized,
three-period crossover study was designed to assess the comparative bioavailability of
cyclosporine from gel-based emulsion (GEM) and Neoral. Suprisingly, despite the aver-
age particle size of this delivery system being a thousand times greater than that of the
microemulsion system (Neoral), the gel-based emulsion still proved to be bioequivalent.
This comparable bioavailabilty of GEM was postulated to be related to either physical

factors (i.e., GEM could exhibit the ability to overcome the unstirred water layer in
the small intestinal lumen and adherence to intestinal wall provides sufficient time and
requisite concentration gradient for cyclosporine absorption) or formulation factors (i.e.,
GEM formulations are mainly based on non-ionic surfactants, which could affect drug
permeation/absorption through the intestine).68 Cyclosporine-loaded SLNs (consisting
of stearic acid, phosphatidylcholine, and taurocholate), slow-release carriers of cyclo-
sporine, have been proposed to be exploited for various routes, particularly the duodenal
route.69 Lecithin vesicles were investigated as a carrier for oral delivery of cyclosporine
A. This carrier was found to enhance the absorption of cyclosporine A and was found
to be bioequivalent with Neoral. These vesicular systems facilitate drug penetration
through the intestinal mucosal layer and, due to small size and presence of lecithin
in vesicles, promote drug absorption.70 Taking advantage of the permeation-enhancing
property of cubosomes, they were exploited to improve oral delivery of cyclosporine A.
This study revealed that the bioavailability of cubic nanoparticles was enhanced more
significantly than in a micreoemulsion-based system (i.e., Neoral). The mechanism for
enhanced oral delivery of cyclosporine A through cubosomes is likely due to transport
of cubic nanoparticles across the membrane, enhanced contact with the cell surface, and
absorption through the lipid digestion process.71
2. Methotrexate (Rheumatrex®)
Methotrexate inhibits replication and function of T and B cells and suppresses the secre-
tion of cytokines such as IL-1, IFN-α, and TNF-α. Methotrexate also suppresses epi-
dermal cell division in psoriasis by competitively inhibiting the enzyme dihydrofolate
reductase, resulting in inhibition of DNA synthesis and arrest of cell division in the S
phase.72 It is available as a tablet and dosing frequency is 0.2–0.4 mg/kg/week to a maxi-
mum of 0.5 mg/kg/week or 30 mg/week. Fatigue, headache, chills, dizziness, fever, nau-
sea, anorexia, are common side effects. More serious effects include fibrosis, cirrhosis,
hematologic side effects (leucopenia, anemia), acute hypersensitivity, dermatological
side effects, depression, abortifacient and teratogenic side effects in females, and oligo-
spermia in males.73
3. Mycophenolate mofetil (CellCept®)
Mycophenolate mofetil is a semisynthetic prodrug derivative of mycophenolic acid.

Mycophenolic acid inhibits purine synthesis in lymphocytes by reversibly and non-
competitively inhibiting the enzyme, inosine monophosphate dehyrogenase (IMPDH),
preventing synthesis of DNA and RNA. Consequently, mycophenolic acid inhibits lym-
phocyte proliferation, antibody production, and the formation of adhesion molecules in
response to antigenic or mitogenic stimulation.74 It is available as a capsule, tablet, or
powder for reconstitution with a dose of 1 to 1.5 g twice daily and maintenance dose of
0.5 g twice daily. Side effects may be gastrointestinal, genitourinary, hematologic, infec-
tious, carcinogenic, and/or teratogenic.75

4. Hydroxyurea (Hydrea®)
Hydroxyurea is a cell cycle–phase antineoplastic agent that inhibits ribonucleotide di-

phosphate reductase, thereby inhibiting DNA synthesis during the S phase of mitosis,
leading to accumulation of cells at the G1 and/or S phases and eventual apoptosis. In
psoriasis, hydroxyurea slows down the kinetics of basal cell replication in the epidermis,
reverses the abnormal keratin proliferation in psoriatic plaques, and inhibits vascular
proliferation in the dermis.57 The initial dose is 1 g/day as 500 mg capsules in a single or
two divided doses. Mycophenolate mofetil commonly causes drug fever, flu-like symp-
toms, dyspepsia, fatigue, constipation, anorexia, and other adverse effects that may be
hematologic, nephrotoxic, cutaneous, neoplastic, and/or teratogenic.76
5. Systemic Retinoids
Retinoids are a class of compounds that comprise vitamin A and its natural and synthetic
analogues. Retinoids bind nuclear receptors (RAR - retinoic acid receptor and RXR- ret-
inoid X receptor) that regulate gene transcription. In vivo, retinoids induce keratinocyte
differentiation and reduce epidermal hyperplasia in psoriasis. The main side effects as-
sociated with retinoids include teratogenicity, elevated liver enzymes, hyperlipidaemia,
hyperostosis, and/or cheilitis.76
a. Acetretin (Soriatane®)
Oral acitretin is currently indicated for the treatment of severe psoriasis in adults. It is a
nuclear receptor binder that reduces the CD25+ T-cell count and keratinocyte prolifera-
tion while enhancing keratinocyte differentiation. The recommended dosage is 25 to 50
mg per day, given as a single dose in capsule form.77
b. Liarozole
Liarozole, an imidazole derivative, is an inhibitor of the cytochrome P450-dependent
metabolism of retinoic acid. Thereby, it reduces 4-hydroxylation of retinoic acid, thus
improving plaque psoriasis symptoms. There is a decrease in the number of CD11+
cells, ICAM-1 expression, and keratinocyte proliferation.77
6. Fumaric acid esters (Fumaderm®)
Fumaric acid esters (also known as fumarates) are a mixture of dimethylfumarate along
with monoethylfumarate salts. The mode of action is mainly an inhibition of T-cell
activity and a shift from a TH1-type response to a type 2 helper T-cell–type pattern.
Fumarates are commonly used in Northern Europe for the treatment of patients with
moderate to severe psoriasis, and they are not approved in the United States. Several
well-designed randomized studies of fumarates demonstrate mean PASI improvement
rates between 50% and 80% after 12 to 16 weeks of treatment when initially dosed at
one pill daily of Fumaderm (containing 120 mg of dimethylfumarate, 87 mg of calcium

monoethylfumarate, 5 mg of magnesium monoethylfumarate, and 3 mg of zinc mono-

ethylfumarate), and the dose is escalated as tolerated up to 6 pills daily.78
7. Leflunomide (Arava®)
Leflunomide is a selective pyrimidine synthesis inhibitor with immunomodulatory and

anti-inflammatory activity. Leflunomide inhibits de novo pyrimidine synthesis, and by
this mechanism preferentially inhibits T-cell activation and proliferation. Leflunomide
offers an efficacious, well-tolerated, safe, and relatively inexpensive therapeutic option
for the treatment of actively inflamed joints and psoriatic skin lesions in patients with
psoriatic arthritis. But its efficacy in other forms of psoriasis is yet to be established.79
8. Thioguanine
Thioguanine is an analogue of the natural purines hypoxanthine and guanine. It was ini-
tially approved for the treatment of leukemia. The efficacy of 6-thioguanine in psoriasis
was evaluated in a retrospective, open-label study of 40 subjects who received 6-thio-
guanine with varying treatment courses and dosages. In this population, 78% achieved
complete or almost complete clearing, 11% showed moderate improvement, and 11%
showed little or no improvement in psoriasis. Reversible bone-marrow suppression was
seen in approximately 66% of subjects. It has been suggested that 6-thioguanine clears
psoriasis by depleting cutaneous T cells by inducing apoptosis. Side effects include bone
marrow suppression, myelosuppression, thrombocytopenia, gastrointestinal side effects,
musculoskeletal effects, elevated liver enzymes, hyperuricemia.80,81
9. Sulfasalazine
The mechanism of action of sulfasalazine in treating psoriasis may be by inhibition

of 5-lipoxygenase.77 An open study of 32 patients with chronic plaque psoriasis treat-
ed with sulfasalazine 3–4 g/day was conducted. Of the 24 patients who completed the
study, 41% showed a moderate improvement and 41% showed a marked improvement.77
VIII.B. Topical Drugs
Topical therapy is mostly used to treat mild psoriasis and is accepted very well by pa-
tients; hence, it is the most widely used mode of drug delivery.52 Emollients, keratolytic
agents, dithranol, and tar were used in earlier times, and changes in formulations, espe-
cially the vehicle, are being considered to bring these products back onto the market.82,83
1. Emollients
Emollients act by hydrating the outer layer of epidermis and allowing the shedding
of scales. It can be applied directly as an aqueous cream or used as a soap substitute

or bath additive. However, it has limited efficacy and sometimes may cause sensitiza-
tion.84
2. Keratolytic Agents
Keratolytic agents include salicylic acid, urea, propylene glycol, and glycolic acids.85
Salicylic acid causes loosening of the outer layer of skin. It is applied as a cream, in
over-the-counter scalp solutions, and in shampoos, and it may cause irritation or toxicity
at high concentration. Urea has been shown to reduce epidermal hyperproliferation and
to induce cell differentiation.86 Currently, a stable, aqueous-based emulsion formulation
comprising urea and salicylic acid is under study. This formulation overcomes the stabil-
ity issues related to the individual formulations of the two compounds.87
3. Dithranol (Micanol®)
Dithranol acts by increasing apoptotic potential of psoriatic keratinocytes.88 A 1–10%

anthralin ointment can be applied once or twice daily. Staining of skin and clothes ac-
companied by irritation limits its patient compliance. Incorporation of dithranol in an
emulsifying oil base (bio-wash-oil) is effective in the treatment of scalp psoriasis.89
Entrapment of dithranol in vesicles such as liposomes and niosomes was found to
be effective in the localized delivery of the drug and also reduced the dose-dependent
side effects like irritation and staining. In an in vitro permeation study, mouse abdominal
skin exhibited enhanced skin permeation with liposomal system compared with a nio-
somal system. Both systems were found to be better than conventional cream formula-
tions.90 Preliminary studies on dithranol liposomal formulation based on phospholipid
exhibited markedly low irritation potential, minimal staining of skin and clothes, and
easy washability in comparison to conventional cream formulations.91 An open-label
as well as a randomized, double-blind, vehicle-controlled study of this novel, stable
aqueous gel based liposomal formulation (lipogel) of dithranol in psoriasis revealed
that a 0.5% dose in a liposome system could clear plaques as well as a 1.15% commer-
cially available dithranol cream. The efficacy advantage of this lipogel is attributed to
the strategic liposomal formulation design that moderated the reactivity of dithranol to
the desired level and also favored an interaction between liposome and skin, precluding
problems of irritation or staining.92 A mixed vesicular system of dithranol tested on pso-
riatic patients was found to be effective and devoid of irritation and staining.93 A phos-
pholipid-based microemulsion system was developed as a novel carrier for improved
topical delivery of dithranol. The developed lecithinized microemulsion system showed
maximum skin permeation, skin permeation flux, and skin retention of the drug.94 Hy-
drophilic silica aerogel was explored as a potential drug carrier system for delivery of
dithranol to enhance its dermal availability by improving its skin penetration properties.
Dithranol adsorbed on hydrophilic silica aerogel exhibited superior penetration behavior
when tested through artificial membranes and human stratum cornea in comparison to
that of the standard ointments (e.g., dithranol in white soft paraffin).95

4. Tar
Tar appears to exert its antipsoriatic actions through suppression of DNA synthesis and
subsequent reduction of mitotic activity in the basal layer of the epidermis. Coal tar has
been a very popular traditional treatment for various types of psoriasis (scalp, hand, and
foot) for more than a century. Coal tar exists in various preparations including crude
coal tar, coal tar ointment, and coal tar solution. These products have been poorly toler-
ated by patients due to staining of the clothing, skin, and hair as well as a malodorous
tar smell.30
Coal tar 2% foam (Scytera® Foam) is a novel coal tar formulation in a foam vehicle.
Staining and smell of coal tar preparations is eliminated when formulated as spray or
foam containing an alcoholic extract of coal tar.96,97 Phospholipid (lecithin)-based coal
tar formulation was developed with resultant improved efficacy and patient compliance
due to its non-staining, non-irritant attributes. Superior anti-psoriatic activity was exhib-
ited by lecithin-based formulation in comparison to conventional coal tar preparation on
evaluation in a mouse tail model.98,99
5. Corticosteroids (Synacort®, Aclovate®, and Cloderm®)
Corticosteroids are the first immunomodulators that were available in topical formu-
lations. Immunosuppressive effects of corticosteroids are mediated by regulation of
corticosteroid-responsive genes. At the cellular level, corticosteroids bind with cyto-
plasmic corticosteroid (or glucocorticoid) receptors to form a steroid-receptor com-
plex, which then translocates into the nucleus, where it binds to the glucocorticoid-
responsive element in corticosteroid-responsive target genes to either stimulate or
inhibit transcription and thus protein synthesis. Corticosteroids inhibit the transcrip-
tion of various proinflammatory cytokine genes including those for interleukin (IL)-1,
IL-2, IL-6, interferon gamma (IFN-γ), and tumor necrosis factor-alpha.100,101 Corti-
costeroids are available in cream, gel, or ointment formulations and are marketed
according to their potencies into 7 class from superpotent to least potent.102 Risk of
cutaneous atrophy, acneiform eruptions, perioral dermatitis, hypopigmentation, tachy-
phylaxis, viral infections is commonly seen with corticosteroid therapy. Discontinua-
tion or withdrawal of treatment with corticosteroids often causes transiently improved
skin lesions to flare up.103 A novel thermolabile, low-
residue foam vehicle, VersaFoam (Connetics Corp, Palo Alto, Calif), containing two
corticosteroids, betamethasone valerate and clobetasol propionate, have been devel-
oped to bypass the barrier function of the skin and provide better penetration (and this
treatment is cosmetically acceptable).104,105 Traditionally used in an ointment vehicle
for psoriasis, clobetasol propionate 0.05% is also available in spray, foam, lotion,
and shampoo formulations, which ensures improved patient convenience and accep-
tance.106 Recently, a new formulation containing 8% clobetasol-17-propionate in a co-
lourless nail lacquer vehicle has shown good results in the control of nail psoriasis.107
Poly (D,L-lactic-co-glycolic acid) (PLGA) microspheres formulated in an emulgel

base for topical delivery of clobetasol propionate has been investigated by Badilli et
al. Encapsulation of clobetasol propionate in PLGA microspheres delayed the drug
release from emulgel formulation and is expected to reduce topical and systemic side
effects associated with this corticosteroid. Also, prolonged release of drug from this
microparticulate system is expected to increase the efficiency of psoriasis treatment.108
In vitro permeation study of betamethasone 17-valerate (BMV) formulated in mono-
stearin-based solid lipid nanoparticles (SLN) was performed on human epidermis.
The results showed remarkable controlled-release properties and significant deposi-
tion in the epidermis. More importantly, this system exhibited lower skin permeation
and preferential targeting of BMV in the human epidermis compared to commercial
lotions and drug suspensions. Thus, localization of corticosteroid in the upper layers
of the skin enabled formation of drug reservoir in epidermal layer (disease site) and
also minimized systemic absorption of such corticosteroid.109 Epidermal targeting of
clobetasol-17-propionate (CP) was also achieved using lecithin/chitosan nanoparti-
cles as a carrier system, when permeation was assessed across pig ear skin. CP-loaded
nanoparticles formulated in a chitosan gel base provided the same amount of CP in
skin when compared to commercial creams, although the former system contained 10
times less CP. Thus, a remarkable reduction in side effects and improved risk-benefit
ratio for topically applied CP can be obtained using such a carrier system.110
6. Retinoic Acid (Tazorac®)
Tazarotene is a topically applied acetylenic retinoid that has been licensed for use in pso-
riasis. Like all the retinoids, it modulates keratinocyte proliferation and differentiation
by binding to retinoic acid receptors (RARs), the probable molecular target of retinoid
action in adult human skin. The cream or gel formulation is applied once daily, usually
at bedtime for 12 weeks. Possible side effects include irritancy, limited efficacy, terato-
genic effect, pruritis, burning, dryness, peeling, and erythema.111,112
7. Vitamin D3 Analogues (Dovonex®)
1, 25-dihydroxyvitamin D3 (calcitriol) is the hormonally active form of Vitamin D. It

acts on the vitamin D receptor (VDR) on keratinocytes. VDR binds to and activates tran-
scription of genes that influence growth, differentiation, and inflammation in keratino-
cytes. Calcitriol has also been shown to have immunomodulatory effects on monocytes,
macrophages, T cells, and dendritic cells. It is believed that through these mechanisms
vitamin D actively treats psoriatic skin lesions topically.113,114 Tacalcitol is a new vitamin
D derivative that is effective against psoriasis vulgaris. Ointment, cream, scalp solution
is generally applied twice a day and may cause local side effects including irritation, risk
of hypercalciuria, and hypercalcemia.115
Topical liposomal formulation of vitamin D and its derivatives is less greasy (lead-
ing to better patient compliance), with enhancement of its penetration capabilities and
skin hydration. If used as gel-based formulation, carbomer or xanthan gum is used as

gelling agent or can be used simply as dispersion agent.116 Nanostructured lipid carriers
loaded with both methotrexate and calcipotriol have demonstrated enhanced drug per-
meation and have limited skin irritation in animal models.117 Liposomes encapsulating
1,25-dihydroxyvitamin D3 were found to be superior in efficacy and safety in compari-
son to the free drug.118
The evidence that psoriasis is a systemic disease suggests merit in revisiting sys-
temic oral vitamin D for treatment of the inflammatory pathogenesis of psoriasis. Perez
et al. established that 88% of 85 psoriasis patients treated with oral vitamin D had im-
provement in their psoriasis, 26.5% had complete clearance, 36.2% had moderate im-
provement, and 25.3% had slight improvement.119
8. Topical Calcineurin Inhibitors TCI (Protopic®, Elidel®, and

Rapamune®)
This class of drugs includes ascomycins like tacrolimus, pimecrolimus, and sirolimus.
Normally, interaction of an antigen/allergen with the T-lymphocyte receptor results in
an increase in cytosolic calcium, which then forms a complex with the calcium-binding
protein calmodulin that activates calcineurin. Activated calcineurin catalyzes the de-
phosphorylation of NF-AT (nuclear factor of activated T cells), which then moves into
the nucleus to regulate the transcription of various genes. TCI disrupts this intracellu-
lar signaling by forming a complex with macrophilin-12 and calcium-calmodulin. This
complex inhibits activity of calcineurin, thereby preventing the dephosphorylation of
NF-AT and interfering with its ability to regulate gene transcription. It is generally avail-
able as an ointment and is applied to the affected area twice daily. General side effects
may include transient burning sensation and teratogenic effects.120,121
Tacrolimus-loaded colloidal-modified nanolipid carrier (MNLC) (involving the
use of lipophilic solubilizers) provided enhanced effectiveness and improved per-
formance in terms of stability and skin localization of tacrolimus for topical appli-
cation. Higher in vitro drug release, skin permeation, and in vivo bioavailability
with dermatopharmacokinetic approach in guinea pigs was observed in comparison
to commercial ointment Protopic® as a reference. This nanocarrier formulation was
found to be less skin irritating than the reference product and also allowed for enhanced
encapsulation efficiency.122 A preclinical animal study on topical liposomal delivery of
tacrolimus resulted in higher skin concentrations of drug than was achieved by sys-
temic administration.123 Li et al. compared delivery capability of tacrolimus-loaded
ethosomes and liposomes. Higher encapsulation efficiency and dermal accumulation of
tacrolimus was found with ethosomes in contrast to liposomes, leading to the conclu-
sion that the high entrapment capability of ethosomes promotes more skin permeation
of drug and results in accumulation at the target site.124 Colloidal carrier systems (oil-
in-water microemulsions) have been potentially developed for dermal targeting of ta-
crolimus. Ex vivo permeation study on human skin revealed that rapid and higher drug
accumulation in target site dermis was observed with colloidal system in comparison
to standard ointment.125

9. Topical Delivery of Systemic Agents
a. Cyclosporine
Taking into consideration the systemic toxicity associated with the oral administration
of cyclosporine, attempts were made to investigate the effectiveness of cyclosporine on
topical treatment. A marked reduction in local psoriasis area severity index score oc-
curred, and negligible plasma drug levels were achieved, but only after prolonged dura-
tion of treatment in patients with chronic and stable psoriasis.126 Oil-based, gel-based,
cream-based, and amphiphilic formulations of topical cyclosporine have been effective in
treatment of psoriasis.127 A small double-blind, vehicle-controlled trial showed significant
improvement in chronic plaque psoriatic lesions using a topical cyclosporine formulation
with penetration enhancers [(propylene glycol (18%) and azone (2%)].128 The influence
of various vehicles and enhancers on topical delivery of cyclosporine was investigated
across rat skin in vitro. Enhancement in topical delivery of cyclosporine was achieved
with a vehicle (40% ethanol), whereas pre-treatment of skin with 10% menthol or 0.05%
SLS (sodium lauryl sulphate) as penetration enhancer reduced the lag time for the drug to
reach deeper skin. Researchers have suggested that this approach could prove useful for
topical treatment of psoriasis as enhanced skin accumulation of cyclosporine A was pos-
sible without any significant systemic side effects.129 Incorporation of monoolein (penetra-
tion enhancer) in propylene glycol formulations of cyclosporine A was found to promote
its topical delivery with substantial reduction in transdermal delivery of cyclosporine
A.130 Reverse cubic and hexagonal phases of monoolein were investigated as potential
carriers of cyclosporine A. Both liquid crystalline phases increased the skin penetration
of cyclosporine A; however, skin irritation was reported and needs to be minimized to
make use of this type of carrier system.131 Successful topical delivery of cyclosporine A
was achieved through multicompartmental liposomes and microemulsified systems.132,133
Lecithin vesicular carriers were better carriers for enhanced transdermal delivery of cy-
closporine in comparison to conventional vesicles as was confirmed by in vitro permeation
study. The likely reason for better functioning of lecithin (flexible) vesciles is the penetra-
tion ability of this flexible vesicles through interstices of stratum corneum due to transcuta-
neous hydration and fusion of the vesicles with skin in contrast to conventional vesicles.134
Application of iontophoresis on topical delivery of cyclosporin from lecithin vesicles across
human cadaver skin resulted in appreciable drug transport across skin when compared to
that using a microemulsion system. Interestingly, the lecithin vesicular system proved to be
efficient in transdermal delivery despite having a larger particle size than microemulsion.
This advantage is attributed to the additive effect of iontophoresis and permeation ability of
flexible vesicular structure across the skin.135 The use of low-frequency ultrasound in com-
bination with chemical enhancers for topical transport of cyclosporin A could significantly
enhance the skin accumulation of the drug and optimize the targeting of the drug.136
b. Methotrexate
To minimize systemic exposure and toxicity associated with orally administered metho-
trexate (MTX), topical formulations containing Azone (laurocapram), a skin-penetra-

tion enhancer, have been developed and evaluated.137 Microemulsions of MTX exhib-
ited higher permeation flux than that of drug solution as assessed in mice skin.138A small
clinical trial was carried out to treat psoriatic plaques by topical application of liposome-
entrapped MTX in paraffin wax. Total clearance of psoriatic plaques and complete re-
covery of one patient was achieved in the group treated with liposomal preparation,
whereas no significant improvement was achieved in the control group receiving free
MTX.139 Researchers have highlighted the utility of deformable liposome as carrier sys-
tem for MTX for in vitro transepidermal delivery.140,141 The deformable liposomes exhib-
ited high drug concentration in the epidermis and dermis layers of the skin when tested
for permeability across porcine skin compared to MTX-loaded conventional liposomes.
Such enhanced skin permeability of deformable liposomes over conventional liposomes
was thought to be linked to deformable and elastic attributes imparted by oleic acid to
the carrier and skin penetration property of oleic acid.140 Application of methotrexate
deformable liposome formulation resulted in deposition of 50% administered dose in
the skin by virtue of self-optimizing deformability of the carrier system.141 In a double-
blind placebo-controlled trial in psoriatic patients, MTX-loaded niosomes in chitosan
gel resulted in better clinical efficacy, tolerance, and patient compliance in comparison
to a marked formulation. Lesions treated with niosomal preparation showed marked
improvement over marketed formulations. Also, once daily application of this niosomal
gel may improve compliance of psoriatic patients in contrast to the twice daily applica-
tion of available gel formulations.142 Another double-blind placebo-controlled study on
MTX liposome (LMTX)-incorporated in gel was conducted to treat localized psoriasis.
LMTX gel exhibited zero-order drug release and antipsoriatic activity. Laser irradiation
following the application of LMTX gel profoundly increased drug release. Remark-
ably, 60% of patients treated with LMTX gel did not show recurrence.143 Ethosomes
were also explored as possible carrier for transdermal delivery of MTX, they exhibited
significant skin permeation of MTX due to the presence of ethanol, which provides mal-
leability to the vesicles and enhances skin permeability.144 In one clinical study of MTX-
loaded solid lipid nanoparticles on psoriasis, patients showed improvement in healing of
lesions and reduction of erythema and scaling.145
c. Mycophenolate mofetil
Topical ampiphilic cream formulation of mycophenolate mofetil demonstrated penetra-
tion into excised human skin and conversion into mycophenolic acid enzymatically under
ex vivo conditions. This result suggests the potential of this semisolid preparation as an
alternative to systemic administration of this drug, which is associated with side effects.146
d. Acitretin
Topical administration of acitretin may lessen the risk of systemic toxicity while in-
creasing local bioavailability in the skin. Once daily topical application of acitretin-
loaded nanostructured lipid carrier gel is superior in enhancing the patient compliance
and management of symptoms of psoriasis in comparison to twice daily application of
plain acitretin gel.147

VIII.C. Light Therapy (Phototherapy)
1. Effects of Acute UV Irradiation on the Skin
Irradiation with ultraviolet (UV) light in the B waveband has been recognized to induce
suppression of selected immune responses to antigens encountered shortly after expo-
sure.148 The wavelengths within the action spectrum for psoriasis that produce the best
therapeutic response at suberythemogenic doses of UV light therapy occur between 310
and 315 nm.149
The effects of UV light can result in two main categories of observable changes.
One category consists of rapid changes, which include membrane damage, induction
of cytoplasmic transcription factors, DNA damage, and isomerization of urocanic acid.
The second category of subacute changes includes alteration of antigen-presenting cell
populations and the modification of intracellular and intercellular signaling mecha-
nisms.150 This overall effect creates a change in the environment in the cytokine patterns
of the dermis and epidermis, which is more favorable for development of T helper Th-2
cell–like response as a result of UV effects on the skin.
Urocanic acid (UCA) is one of the major chromophores of UV light in the skin and
is an immune modifier. UVB light within the range of 290 to 341 nm causes UCA to be
isomerized from trans UCA to cis UCA. This effect is maximal between 290 and 310
nm. The transformation from trans to cis UCA is dose dependent until equal parts of
both are present in the skin. The presence of cis UCA helps to promote a change in the
cytokine production from a Th-1 to a Th-2 environment in the skin.151
2. Psoralens and Ultraviolet A Radiation (PUVA) (Oxsoralen®)
PUVA employs a combination of a psoralen drug and ultraviolet A (UVA) radiation. Forms
of psoralen include methoxsalen, 8-methoxypsoralen (8-MOP), or bergapten (5-MOP).
The effectiveness of the treatment is based on a chemical reaction in the skin between
the psoralen and light, which creates redness and inflammation that prevents the psoriasis
disease process. Interaction between psoralen and DNA occurs in the cell, when psoralen
intercalates with the pyrimidine bases of DNA. On exposure to UVA monfunctional cy-
clobutane adducts are formed between psoralen and thymine. This ultimately results in
DNA crosslinking and hence arrests cell division.151,152 Oral methoxsalen (psoralen) and
ultraviolet A radiation (PUVA) may cause erythema and itching. The accidental adverse
reactions such as extensive burns could occasionally occur. PUVA is also carcinogenic,
and cases of skin cancer (malignant melanoma) have been reported.153,154
Baroli et al. have studied the utility of microemulsions for topical delivery of 8-MOP;
their results in a skin permeation study suggest that these systems efficiently promote
localization of 8-MOP in the skin.155 Solid lipid nanoparticles and nanostructured lipid
carriers (NLCs) have been developed for topical psoralen delivery. In this application,
NLCs have demonstrated enhanced skin permeation through hyperproliferative skin
(psoriasis-like skin) in vitro and controlled-release properties.156

3. 308-nm Excimer Laser
The 308-nm excimer laser represents the latest advance in the concept of selective pho-
totherapy. It is similar to narrow band UV, but it emits a monochromatic and coherent
beam of light which can selectively treat a lesion while sparing surrounding healthy
skin.157
VIII.D. Biologics
“Biologic response modifiers,” or biologics, are defined by the US Department of

Health and Human Services as a “generic term for hormones, neuroactive compounds,
and immunoreactive compounds that act at the cellular level.”158 The Food and Drug
Administration’s (FDA) Center for Biologics Evaluation and Research (CBER) further
defines biologic products as those “derived from living material —human, plant, ani-
mal, or microorganism—and used for the treatment, prevention, or cure of disease in
humans.”158 Biologic response modifiers include cytokines and lymphokines, such as
interleukins, interferons, colony-stimulating factors, tumor necrosis factor (TNF), and
other antiproliferative biologic agents.158
Both phototherapy and traditional systemic therapies for psoriasis are associated
with the risk of acute and long-term toxicity, including cancer (cyclosporine, photoche-
motherapy) and teratogenicity (methotrexate and acitretin). Clinical experience indi-
cates that sustaining an acceptable response using phototherapy or traditional systemic
therapies very often requires the use of doses associated with significant cumulative
toxicity. In contrast, biologics have a good efficacy-risk profile because they are specifi-
cally designed to block target molecules involved in the pathogenesis of psoriasis.159
Targeting strategies for treatment of psoriasis with biologics included the following:
Strategy 1: Alterating pathogenic T cell numbers in the periphery, in the skin, or

both by binding to specific receptor on the surface of the T cell induces apoptosis
through a direct signaling mechanism or by activating an accessory cell like a natu-
ral killer cell or macrophage to induce apoptosis in the target.
Strategy 2: Use of a targeted blockade of specific cell–cell interactions inhibits ei-

ther (a) T-cell activation or (b) T-cell migration into the skin.
Strategy 3: Immune deviation occurs when physiologic or super-physiologic doses

of naturally occurring proteins are given to alter the cytokines produced by T cells.
Strategy 4: Monoclonal antibodies or naturally occurring receptors are used to inac-

tivate cytokines that have already been secreted.160,161
The major biologics currently in use include Alefacept, Efalizumab, Etanercept, In-
fliximab, Adalimumab.

1. Alefacept (Amevive®)
Alefacept is a chimeric fusion protein combining a portion of human immunoglobu-

lin (IgG) and the binding site of lymphocyte function-associated antigen-3 (LFA-3).
It binds to CD2, the partner molecule of LFA-3 located on the surface of T cells, thus
inhibiting memory T-cell activation and proliferation. Alefacept also enhances binding
between natural killer cells and T cells, resulting in T-cell apoptosis.
2. Efalizumab (Raptiva®)
Efalizumab is a recombinant humanized monoclonal antibody directed against the T-cell

surface molecule CD11a. The CD11a and CD18 proteins together form lymphocyte-
function-associated antigen-1 (LFA-1). Binding of efalizumab to CD11a blocks the in-
teraction between LFA-1 and intracellular adhesion molecule-1 (ICAM-1), its partner
molecule on the surface of antigen-presenting cells (APCs). Psoriasis-inducing T cells
are thereby prevented from being activated in the lymph nodes or from being reactivated
in the dermis and epidermis.
3. TNFα inhibitors: Etanercept, Infliximab, and Adalimumab
Tumor necrosis factor-a (TNF-α) is a proinflammatory cytokine found in increased con-

centrations in the joints and skin. Endogenous skin cells and activated leukocytes se-
crete TNF-α, which binds to target receptors that are found on almost every cell of the
body. TNF plays an active role in leukocyte recruitment, migration, and activation. Leu-
kocytes activated by TNF secrete more cytokines, creating an inflammatory cascade.
The biologic agents that block TNF include etanercept, infliximab, and adalimumab.
a. Etanercept (Enbrel®)
Etanercept is a fusion protein consisting of two TNF receptors fused to the Fc portion
of human IgG antibody. This construct creates an exogenous TNF receptor and pre-
vents excess TNF from binding to cell-bound receptors, resulting in a reduction in the
amounts of active TNF and mitigation of TNF-mediated diseases such as rheumatoid
arthritis and psoriasis.
b. Infliximab (Remicade®)
Infliximab is a monoclonal chimeric antibody composed of murine variable regions
that binds specifically to TNF-α and neutralize its activity. The mechanism is linked to
the human IgG1, which constantly prevents the firm adhesion of the leukocyte to the
vessel wall.
c. Adalimumab (Humira®)
Adalimumab is a fully human monoclonal antibody that specifically binds to TNF-α,
blocking its interaction with the p55 and p75 cell surface TNF receptors.162–164

The various dosage forms and the dosages of the FDA-approved biologics used,
along with their side effects, are highlighted in Table 3.165–167
The chief risks associated with the biologic therapy for moderate and severe psoria-
sis include exacerbation or rebound of psoriasis, thrombopenia, tuberculosis, and other
infections.159
VIII.E. Combination Therapies
Psoriasis is a systemic disease with genetically and immunologically modulated compo-

nents, and therapy must be individualized to each patient. Remission can be difficult to
achieve and to sustain, especially with one-dimensional monotherapy. Because psoriasis
is episodic, chronic, and essentially incurable, both acutely acting agents and those ef-
fective as long-term maintenance agents are needed.
Compounding the problem of picking a regimen is the fact that safety tends to be
inversely proportional to efficacy and/or convenience. The monotherapies that clear
Table 3. FDA-approved Biologics used in Psoriasis

Supplied As
Drug (Dosage Form) Dosage Side Effects
Alefacept Powder for injection, IV/IM 7.5 mg once Common: dizziness,
Amevive® lyophilized 7.5 mg weekly as an IV bolus nausea, chills, rhinitis,
Powder for injection, or 15 mg once weekly lymphopenia, and cough
lyophilized 15 mg as an IM injection for 12
weeks
Efalizumab Powder for injection, SC Single 0.7 mg/kg Common: headache,
Raptiva® lyophilized 150 mg conditioning dose fol- fever, chills, nausea,
(designed to deliver lowed by weekly dose myalgia, leukocytosis,
125 mg/1.25 mL) of 1 mg/kg (max single lymphocytosisSevere:
dose, 200 mg) thrombocytopenina
Etanercept Injection 50 mg/mL SC 50 mg twice weekly Headache, fatigue, rhinitis,
Enbrel® Powder for injection, for 3 months followed by development of autoim-
lyophilized 25mg maintenance dose of 50 mune antibodies; severe
mg/wk opportunistic infections,
malignancy, hematologic
reactions
Infliximab Powder for injection IV 5 mg/kg as an induc- Common: headache, nau-
Remicade® 100 mg (500 mg tion regimen at 0, 2, sea, diarrhea, injection site
sucrose and 6 wk, followed by a reaction, development of
maintenance regimen of autoimmune and antichi-
5 mg/kg for 8 wk meric antibodies
Severe: opportunistic
infections, malignancy
Adalimumab Injection 40 mg per SC 40 mg every other Headache, nausea,
Humira® 0.8 mL week elevated triglycerides,
cough, sinus congestion,
injection site pain, and fa-
tigue, severe opportunistic
infections

psoriasis most quickly and conveniently are among the most toxic. Those that have the
safest therapeutic profile tend to work relatively slowly and incompletely and/or incon-
veniently. The answer to this potential dilemma is to use more than one agent, either in
combination or as part of sequential or rotational therapy. In fact, certain combinations
of treatments are synergistic, with combined effectiveness and/or safety beyond that of
each agent alone.
1. Conventional Combination Therapy
Conventional combination therapy combines two or more agents with synergistic or com-
plementary action, allowing lower-dose, toxicity-sparing regimens of each of the agents.
2. Rotational Therapy
Rotational therapy is another strategy for combining treatments. Patients are moved
from one monotherapy agent to another in an effort to minimize cumulative dosage and
forestall toxicities. The concept of rotational therapy was originally proposed by Wein-
stein and White.
3. Sequential Therapy
Sequential therapy is a strategy designed to optimize initial efficacy and then to lead to a safe
maintenance regimen using specific combinations in a deliberate sequence. The three-step
treatment strategy optimizes outcome through the scheduled use of topical agents (for
mild to moderate psoriasis) or systemic and/or photo-therapeutic agents (for moderate
to severe disease). The strategy consists of (a) the clearing phase, involving the use of a
powerful, rapid-acting agent, such as cyclosporine often at the maximum dermatologic
dose; (b) the transitional phase, in which a well-tolerated, safe maintenance agent such
as acitretin is introduced and administered concurrently with the clearing agent, which
is gradually tapered; and (c) the maintenance phase, in which the patient remains on the
maintenance drug with additional therapy.168
Recent studies have revealed the efficacy of combinations of biologic and tradi-
tional agents, especially with the TNF-α inhibitors, including etanercept, infliximab, and
adalimumab.169 One of the formulations that uses the combination therapy approach is
Taclonex®; it combines two of the widely used psoriasis treatments: a corticosteroid to
treat inflammation and a form of vitamin D to control cell growth.170
VIII.F. Gene Therapy
Since psoriasis is considered to have key genetic underpinnings, the application of gene
therapy to treat the disease arises as a valid approach.9 Attenuation of psoriasis is also
possible using cytokines that suppress T-cell–mediated immune response. The cytokine
IL-4 (interleukin-4) is the only cytokine capable of inducing a Th2 phenotype, which

can selectively antagonize the effect of psoriasis-inducing T cells, i.e., Th1 cells. A
clinical trial of IL-4 in patients with severe psoriasis demonstrated that such a pleiotro-
pic cytokine can succeed in inhibiting human psoriasis.171 Li et al. investigated the anti-
psoriatic effect of transdermal delivery of IL-4 plasmid using ultradeformable cationic
liposomes in a K14-VEGF transgenic mouse model (psoriasis model). Daily applica-
tion of 15 µg of plasmid DNA could successfully cure psoriasis.172 A novel transdermal
delivery technique was explored for treatment of psoriasis. This technique involves the
use of the IL-4 expression plasmid (pIL-4) with dimethylsulfoxide as a penetration
enhancer. Appreciable IL-4 levels were detected in both epidermis and dermis. The
antipsoriatic efficiency of this treatment was tested in mice, and it relieved the psoriasis
symptoms.173 Keratin 17 (K17), an intermediate filament protein, is highly expressed
only in psoriatic lesions and has been implicated to have a role in the pathogenesis of
the disease. Chang et al. downregulated K17 using antisense oligodeoxynucleotides
(ASODN) and an RNA interference (siRNA) technique as a novel and potential treat-
ment option for psoriasis. They investigated the effect of topically applied K-17–spe-
cific ASODN and liposome-encapsulated siRNA in psoriasis-induced murine models.
Downregulation of K-17 expression was observed with this therapy, which inhibited
proliferation and induced apoptosis in keratinocytes.174 Targeting angiogenesis by non-
viral somatic (antiangiogenic) gene therapy was found to be a highly efficient in the
treatment of psoriasis, as it is assumed that direct targeting of angiogenesis could halt
the psoriatic disease process.175
VIII.G. Future Drugs
Along with the aforementioned drugs, many other drugs are being evaluated for their
safety in psoriatic conditions. These mainly include the biologics, which are still in the
initial phases of research or in some phase of the clinical trial but are not yet approved
for human use.176,177 Other future or new drugs include a novel vitamin D3 anologue, a
polypeptide.178,179 The response of T cells in psoriasis to streptococcal peptidoglycan
may make it a favorable candidate for vaccination.180 A summary of these new drugs is
given in Table 4.
VIII.H. Alternative Therapies
Apart from conventional therapies, a few other therapies have been used to treat psoria-
sis. Although no scientific data have accumulated to support them, the extensive use of
these alternative therapies indicates a certain level of effectiveness.
Climatotherapy involves living in particular climate. The Dead Sea is one of the
most popular locations for this type of treatment.181 In Turkey, doctor fish C. macrosto-
mus and Garra rufa, which live in the outdoor pools of spas, feed on the psoriatic skin
of people with psoriasis without affecting normal skin.182 Balneo-phototherapy includes
treating chronic skin disease by bathing in magnesium-rich Dead Sea salts or Epsom
salts and exposing affected skin areas to ultraviolet light.183 Cryosurgery involves the

Table 4. New Drugs in Treatment of Psoriasis

Nature
(Pharmacologic
Molecular Name Agent) Mechanism of Action Stage
Anakinra, Anti-IL1 Competes with IL-1 for Preclinical
AMG 108 binding to receptor I
Tocilizumab Anti-IL6 Prevents IL-6 receptor from Preclinical
binding its ligand IL-6
Rituximab Anti- CD20 Antibody-dependent cellu- Phase I completed
lar cytotoxicity (ADCC)-me-
diated depletion of selected
B cell populations
Epratuzumab Anti- CD22 ADCC-mediated depletion Preclinical
of selected B cell popula-
tions
Daclizumab Anti- CD25 Blocks binding of IL-2 to its Phase II completed
receptor
Basiliximab Anti- CD25 Antibody directed against Preclinical
the IL-2 receptor
Abatacept CTLA41g Inhibition of B and T cell Phase II completed
cooperation by blocking
CD28-B7 interaction
Belimumab Anti BLys (beta lym- Neutralization of soluble Preclinical
phocyte stimulator) BLyS
LJP 394 Tolerogenic Induction of antigen-specif- Preclinical
(Abetimus sodium) agents(synthetic ic tolerance to dsDNA and
molecules) targeted the consequent reduction
to B lymphocyte of anti-dsDNA antibodies
surface production
Eculizumab Anti-C5 Blockade of complement Preclinical
cascade by binding to C5
component
Oprelvekin Recombinant hu- Modulates macrophages Preclinical
manized IL-11 and type-1 T lymphocyte
function
SMART anti-INF-α Anti-INF-α human- Binds and inactivates the Preclinical
ized monoclonal proinflammatory cytokine
antibody INF-α
Polypeptide T Octapeptide Shows affinity for the CD4 Preclinical
receptor, especially in pa-
tients with HIV infection
Psoraxine Vaccine Act against streptococcal Preclinical
infections
withdrawal of heat from tissue into a heat sink, causing several changes in the treated
tissue that aid in the ultimate destruction of the targeted cutaneous lesion.184 Finally, a
healthy lifestyle and optimum hygiene are key to protection from the disease.

IX. CONCLUSION
Keeping in mind the background of the disease, persistent attempts have been made to
improvise the present scenario with regard to treating the psoriasis. Advances in the last
decade in terms of understanding the pathogenesis of the disease have further broadened
the scope of new applications, especially using biologics. Newer biologics mentioned
are in the research stage. Research is also underway to improve drug delivery by mak-
ing newer formulations of existing drug molecules. The advent of nanotechnology has
highly impacted its use in formulations with regard to its drug efficacy and performance.
More drug combinations are being tried to improve efficacy and reduce dosages. Fi-
nally, analyzing the gene expression patterns of patients could prove helpful in under-
standing the basic corrective mechanisms underlying effective therapeutic approaches.
Thus genetic research could yield a major breakthrough in the development of other
more effective therapeutic strategies for the treatment of psoriasis.
ACKNOWLEDGMENTS
Authors are thankful to University Grant Commission (UGC) for providing research
fellowship and Department of Science and Technology (DST) for providing INSPIRE
fellowship.
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Critical Reviews™ in Therapeutic Drug Carrier Systems, 30(3), 183–216 (2013)

Psoriasis Clinical Implications and

Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Na-

ABSTRACT: Psoriasis is a common skin disorder affecting the population worldwide. It is

Psoriasis is a chronic, T-cell mediated autoimmune disorder that is accompanied by

0743-4863/13/$35.00 ©2013 Begell House, Inc. www.begellhouse.com 183

Table 1. Description of Psoriasis Global Assessment (PGA)

Critical Reviews™ in Therapeutic Drug Carrier Systems

IV. GENETICS OF PSORIASIS

IV.A. HLA Molecules

IV.B. Psoriasis Susceptibility genes (PSORS)

Volume 30, Number 3, 2013

V. EXACERBATING FACTORS FOR PSORIASIS

V.A. Endocrine Factors

V.B. Metabolic Factors

Hypocalcaemia may precipitate psoriasis.24

V.D. Skin Injuries and the Köbner Response

V.E. Psychogenic Factors (Stress and Emotion)

V.F. Environmental Triggers

Critical Reviews™ in Therapeutic Drug Carrier Systems

V.H. Alcohol and Smoking

A network of pro-inflammatory cytokines (especially TNF-α) play an important role in

VI.A. Concept of Psoriasis as a T-Cell Mediated Disease

Volume 30, Number 3, 2013

Critical Reviews™ in Therapeutic Drug Carrier Systems

additional production of chemotactic factors.

T-cell activation is a multistep process described as follows.

b. Step 2 (primary stimulation/signal 1)

T cells acquire a surface protein termed cutaneous lymphocyte–associated antigen

5. Effects of T Cells on Site

Volume 30, Number 3, 2013

VII. CLINICAL FEATURES OF TYPES OF PSORIASIS

Critical Reviews™ in Therapeutic Drug Carrier Systems

Table 2. Clinical Types of Psoriasis

VIII.A. Systemic Therapies

Volume 30, Number 3, 2013

Cyclosporine induces immunosuppression by inhibiting the first phase of T-cell activa-

Critical Reviews™ in Therapeutic Drug Carrier Systems

3. Mycophenolate mofetil (CellCept®)

Mycophenolate mofetil is a semisynthetic prodrug derivative of mycophenolic acid.

Volume 30, Number 3, 2013

Hydroxyurea is a cell cycle–phase antineoplastic agent that inhibits ribonucleotide di-

6. Fumaric acid esters (Fumaderm®)

Critical Reviews™ in Therapeutic Drug Carrier Systems

monoethylfumarate, 5 mg of magnesium monoethylfumarate, and 3 mg of zinc mono-

Leflunomide is a selective pyrimidine synthesis inhibitor with immunomodulatory and

The mechanism of action of sulfasalazine in treating psoriasis may be by inhibition

VIII.B. Topical Drugs

Volume 30, Number 3, 2013

Dithranol acts by increasing apoptotic potential of psoriatic keratinocytes.88 A 1–10%

Critical Reviews™ in Therapeutic Drug Carrier Systems

5. Corticosteroids (Synacort®, Aclovate®, and Cloderm®)

Volume 30, Number 3, 2013

6. Retinoic Acid (Tazorac®)

7. Vitamin D3 Analogues (Dovonex®)

1, 25-dihydroxyvitamin D3 (calcitriol) is the hormonally active form of Vitamin D. It

Critical Reviews™ in Therapeutic Drug Carrier Systems

8. Topical Calcineurin Inhibitors TCI (Protopic®, Elidel®, and

Volume 30, Number 3, 2013

9. Topical Delivery of Systemic Agents

Critical Reviews™ in Therapeutic Drug Carrier Systems

Volume 30, Number 3, 2013

VIII.C. Light Therapy (Phototherapy)