Full text of DOI:10.2165/00128071-200203030-00003

Am J Clin Dermatol 2002; 3 (3): 159-173
1175-0561/02/0003-0159/$25.00/0
REVIEW ARTICLE
© Adis International Limited. All rights reserved.
Novel Therapies for Psoriasis
Jennifer Cather and Alan Menter
Baylor University Medical Center, Dallas, Texas, USA
Contents
Abstract
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
1. Immunology of Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
2. T Lymphocyte Suppressors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
2.1 Methotrexate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
2.2 Mycophenolate Mofetil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
2.3 Thioguanine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
2.4 Hydroxyurea (Hydroxycarbamide) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
3. Blockade of Interleukin (IL)-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
3.1 Cyclosporine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
3.2 Pimecrolimus (SDZ ASM 981) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
3.3 Tacrolimus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
4. Phototherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
4.1 Ultraviolet B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
4.2 Psoralens and Ultraviolet A (PUVA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
4.3 308nm Excimer Laser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
5. Nuclear Receptor Binders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
5.1 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
5.2 Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
5.3 Retinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
5.3.1 Tazarotene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
5.3.2 Etretinate and Acitretin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
5.3.3 Liarozole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
5.3.4 Bexarotene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
6. Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
6.1 Topical Combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
6.2 Phototherapy Combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
6.2.1 PUVA and Retinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
6.2.2 Cyclosporine and Phototherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
6.2.3 Methotrexate and Phototherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
6.3 Combinations with Cyclosporine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
6.3.1 Cyclosporine and Methotrexate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
6.3.2 Cyclosporine and Hydroxyurea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
6.4 Combinations with Retinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
6.4.1 Retinoids and Topical Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
6.4.2 Retinoids and Hydroxyurea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
6.4.3 Retinoids and Systemic Immunosuppressive Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
7. Investigational Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
7.1 Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
7.1.1 IL-10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
7.1.2 IL-11 (Oprelvekin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
7.2 Anticytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
7.2.1 Tumor Necrosis Factor-α . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
7.2.2 Anti-IL-8 Monoclonal Antibody . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
7.3 Antimetabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
7.4 T Cell Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
7.4.1 Adhesion Molecule Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
7.4.2 T Cell Surface Receptor Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
7.5 Cytotoxic Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
7.6 Photodynamic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

160
Cather & Menter
7.7 Antiangiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
7.8 Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
8. Treatment of Psoriasis or Psoriatic Arthropathy During Pregnancy and Lactation . . . . . . . . . . . . . . . . . . . . . . . . . . 169
9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
The T cell-driven immunopathogenesis of psoriasis has been well recognized since cyclosporine first revo-
Abstract
lutionized the treatment of psoriasis 20 years ago. Almost all investigative and clinical research subsequently,
has concentrated on elucidating the specifics of antigen presentation, T cell interaction and the production of
specific cytokines. The role of the keratinocyte, previously thought to be the primary target cell in psoriasis
pathogenesis, has been relegated to a secondary role and the mechanism of action of systemic methotrexate in
psoriasis has been challenged, the primary role of the T lymphocyte is now well known.
While psoriasis has traditionally been treated ‘ab initio’ with topical medications (corticosteroids, vitamin
D3, and retinoid derivatives), either singly, in combination, or with ultraviolet B (UVB) or psoralens and
ultraviolet A (PUVA) therapy, the role of systemic medications has assumed greater prominence. Thus, three
systemic medications currently are approved worldwide for the treatment of moderate to severe forms of pso-
riasis, namely cyclosporine, methotrexate and acitretin. The first two are likely to give significant clearing
(greater than 75%) in the majority of cases, whereas acitretin is significantly less effective as monotherapy, but
may approach methotrexate and cyclosporine in efficacy, if combined with PUVA or UVB phototherapy. The
main limitations of these three drugs remain organ toxicity, especially hepatic toxicity with methotrexate,
hypertension and nephrotoxicity with cyclosporine, and teratogenecity and mucocutaneous toxicity with
acitretin. Thus, the need for more specific systemic therapy, targeting the T lymphocyte. This has become the
major area of clinical research interest over the past 5 years, with the promise of longer-term disease control
(improved remissions) and less organ toxicities. Currently, there are over 15 of these ‘biologic’ drugs in various
stages of development and clinical trials, either by the subcutaneous, intramuscular or intravenous route. The
three main variables are the rapidity of onset, percentages of improvement and remission rates. Without excep-
tion, these new systemic agents appear to be remarkably free of systemic organ toxicities (liver, renal, bone-
marrow, etc.), with adverse effects being limited to mild flu-like symptoms with the anticipated increase in
infections (e.g., herpes simplex) being either equal to placebo or only marginally increased. Not all these agents
under evaluation give clinical responses equal to methotrexate or cyclosporine (75% or greater clearing in 75%
of cases). In addition, response rates may be slower with some therapies versus others. However, the need for
intermittent administration even by the injectable route, longer remissions, lack of systemic organ toxicities and
the potential for safer usage in females of child-bearing age, make a compelling argument for widespread
acceptance by both patients and the dermatological community. Other modalities under clinical evaluation
include vitamin D and retinoid drugs, topically and systemically, with effects on nuclear receptors, as well as
more specific wavelengths (308 to 311nm) of UVB phototherapy with application for more localized forms of
psoriasis. For the 2 to 3% of the worldwide population of patients with psoriasis the future has never looked
brighter.
For decades psoriasis was considered a disorder driven by
This paper will review psoriasis therapies, new and old, and
introduce newer biologic therapies currently under investigation.
hyperproliferative keratinocytes. The current understanding,
however, is that it is primarily a T lymphocyte-driven process. On
histopathology, there is a proliferation of keratinocytes associated
with infiltrating activated T cells. Cytokines originating from the
activated T cells create the hyperproliferative state. Whether the
keratinocyte, or even the dermal vasculature, in psoriasis have
primary defects is still uncertain. T cells may become activated
after interaction with antigen-presenting cells. Currently, psoria-
sis research and drug development is focused predominantly on
the T lymphocyte and its cytokines, with a smaller group of drugs
targeting angiogenesis and adhesion factors (table I).
1. Immunology of Psoriasis
The majority of T cell-mediated inflammatory dermato-
ses can be divided into either T helper cell type 1 (Th1) or Th2
cytokine profiles.[1] In psoriasis there is overexpression of the
proinflammatory Th1 cytokines[2] such as interleukin (IL)-2,
interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα), with
a relative deficiency of the Th2 cytokines IL-4, IL-5, IL-6 and
IL-10.[1,3] Administration of IL-10 shifts cytokine profiles to a Th2
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Am J Clin Dermatol 2002; 3 (3)

Novel Therapies for Psoriasis
161
Table I. Psoriasis therapies current and future
in psoriasis. Other angiogenic factors are increased as well, nota-
bly endothelial cell-stimulating angiogenesis factor and vascular
endothelial growth factor.[5]
Targeting the T lymphocyte
Antimetabolites
The following sections describe new and existing therapies
for psoriasis.
Activation cascade
inhibition of gene transcription: cyclosporine, sirolimus, tacrolimus
inhibition of inosine monophosphate dehydrogenase: mycophenolate
mofetil
Nucleoside analogs
2. T Lymphocyte Suppressors
leflunomide – pyrimidine synthesis inhibitor and cytokine modulator
T cell surface marker blockers
alefacept
2.1 Methotrexate
daclizumab
Methotrexate, a folic acid analog, inhibits several enzymes,
most importantly dihydrofolate reductase. It was originally uti-
lized in psoriasis therapy because of its nonspecific blockade of
the synthesis of nucleic acids and proteins, and hence its effect
on rapidly dividing keratinocytes. The most significant effect of
methotrexate, however, may be on several inflammatory mecha-
nisms.[6] For example, it promotes apoptosis of activated T lym-
phocytes, it increases the concentration of adenosine and in all
likelihood also has effects on other antigen-presenting cells.[7,8]
Methotrexate has been used for over 30 years to treat all
forms of recalcitrant psoriasis,[9] including chronic plaque, ery-
throdermic,[10] and pustular[11] psoriasis, and psoriatic arthritis.
Prior to initiation, baseline laboratory evaluations and concomi-
tant medications should be reviewed. Medications to avoid in-
clude trimethoprim-sulfamethoxazole, hydrochlorothiazide, in-
domethacin, bendrofluazide and furosemide.[10] To reduce the
unlikely possibility of an idiosyncratic drug reaction, a test dose
of 5mg should be given, with a repeat complete blood count 1
week later. The starting dosage is usually 10 to 15mg per week,
divided into three doses given every 12 hours. The dose can be
slowly titrated up to a maximum of 30mg per week, pending
clinical response.[10] Blood counts and liver function tests are
obtained every 4 weeks until dosage and laboratory evaluations
are stable. One non-blind trial using folic acid 5mg to reduce
adverse effects showed a decrease in gastrointestinal symp-
toms;[12] however no double-blind trials have been performed.
Folic acid 1mg per day is likely to reduce adverse effects, as may
the administration of methotrexate by the parenteral route; this
has particular effects on nausea, vomiting and lassitude. Clinical
response is usually seen within 4 to 8 weeks.
basiliximab
blockade of cutaneous lymphocyte-associated antigen with
fucosyltransferase VII
CTLA4-Ig, a fusion protein that blocks B7-CD28 costimulation
LFA-1 (CD11a and CD18): blockade of CD11a with an antibody
prevents T cell adhesion to ICAM-1
Activated T cell toxins
Denileukin diftitox
Manipulation of T cell cytokines alters T cell differentiation and changes
Th1/Th2 state
IL-10
monoclonal antibody to IL-8
heat-killed Mycobacterium vaccae (SRL-172) induces a transient Th1
response with a compensatory Th2 response
TNFα antagonists
infliximab: a monoclonal antibody to TNFα
etanercept: soluble TNFα receptors that bind excess TNFα
thalidomide: TNFα inhibitor
Intracellular nuclear receptors
retinoids
corticosteroids
vitamin D analogs
Targeting angiogenesis and adhesion factors
Vascular endothelial growth factor is increased and the inhibitor of
angiogenesis, thrombospondin-1, is decreased
Dexrazoxane
Topical paclitaxel
Matrix metalloproteinase inhibitors
ICAM-1 and E-selectin
ICAM = intercellular adhesion molecule; IL = interleukin; LFA = lymphocyte
function-associated antigen; Thx = T helper type x; TNFα = tumor necrosis
factor-α.
Oral lesions (stomatitis), erosive psoriasis lesions and leuko-
penia may be early clues of methotrexate toxicity. If methotrexate
overdose is suspected, folinic acid (leucovorin calcium or
citrovorum factor) at a dose of approximately 20mg is given in-
travenously immediately, then 20mg by mouth every 6 hours,
which is continued until the serum concentration of methotrexate
is below 10–8 mol/L.
pattern and demonstrates clinical efficacy.[3] Overexpression of
IL-8 and its receptor, CXCR2, is typically observed in psoriasis
lesions and is thought to contribute to keratinocyte dysfunction
and to the influx of T cells and neutrophils.[2] In addition, aberrant
production of IL-8 and thrombospondin-1 by psoriatic kera-
tinocytes mediates angiogenesis,[4] which is a prominent feature
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Am J Clin Dermatol 2002; 3 (3)

162
Cather & Menter
2.2 Mycophenolate Mofetil
2.4 Hydroxyurea (Hydroxycarbamide)
This antimetabolite is also considered a second-line agent for
the treatment of psoriasis. Because it lacks renal and hepatic tox-
icity and because it does not adversely affect blood lipids, it is a
good therapeutic option for patients with hepatotoxicity from
methotrexate, or patients with mild renal insufficiency (cyclo-
sporine), cardiopulmonary disease or hyperlipidemia (reti-
noids).[23] Bone marrow suppression is the main toxicity seen
with hydroxyurea (hydroxycarbamide) and may present as ane-
mia, megaloblastic anemia (increased mean corpuscular volume
on blood smear), neutropenia and pancytopenia. Hydroxyurea is
excreted by the kidneys; therefore, bone marrow toxicity is more
likely with declining renal function.
Mycophenolate mofetil is a prodrug of mycophenolic acid.
After oral administration, mycophenolate mofetil is hydrolyzed
to mycophenolic acid, which inhibits de novo purine synthesis,
resulting in antiproliferative effects on T and B lymphocytes.
Mycophenolic acid does not inhibit cytokine (IL-1 and IL-2) pro-
duction in humans.
Mycophenolic acid has been used in psoriasis since the early
1970s.[13-17] Marinari et al.[14] reported that 33 out of 35 patients
had good or excellent responses with dosages ranging from 2.4
to 7.2g per day over 89 months. Epinette et al.[13] reported on 85
patients treated with mycophenolate mofetil at doses averaging 2
to 3g per day for up to 13 years.
In our experience, hydroxyurea has been particularly effec-
tive for palmoplantar psoriasis, often in combination with low-
dose systemic retinoids. The initial dosage is 500 to 1000mg
daily, with an increase to 1 or 2g daily as needed and tolerated.
The most common adverse effects associated with myco-
phenolate mofetil include gastrointestinal complaints, ‘flu-like’
symptoms and bone marrow suppression.[18] In the past, there
were concerns that mycophenolate mofetil usage may be linked
with an increase in lymphoproliferative disorders; however, this
was not seen by Epinette et al.[13] Treatment is normally com-
menced at 1 to 2g per day with increases up to 3 to 4g per day, as
indicated. Mycophenolate mofetil is primarily eliminated by the
kidneys.
3. Blockade of Interleukin (IL)-2
Drugs acting via immunophilins (cyclosporine, sirolimus,
and tacrolimus) prevent the production of cytokines, including
IL-2, by activated T lymphocytes. Thus, these drugs uncouple the
activation of T lymphocytes from the production of IL-2 and
other growth factors.
2.3 Thioguanine
3.1 Cyclosporine
The two most commonly used formulations of cyclospor-
ine[24] include Sandimmune™1 and Neoral™. Sandimmune™
has a highly variable bioavailability, showing maximal absorp-
tion when taken with food. Neoral™, on the other hand, is a newer
formulation with more predictable bioavailability because of its
microemulsion technology and is best given on an empty stom-
ach. Despite this, most patients prefer taking it with food to re-
duce abdominal cramping. Converting patients from Sandi-
mmune™ to Neoral™ may improve efficacy and possibly allow
lower dosages.
Baseline studies before initiating cyclosporine should in-
clude full medical history, laboratory examinations, review of
concomitant medications, and careful blood pressure monitoring.
Additionally, women should have a screening cervical examina-
tion. Cyclosporine is metabolized via the cytochrome P450 3A
system in the liver and small intestine, and therefore multiple
drug interactions are possible. Patients with chronic hepatitis,
HIV infection, renal insufficiency, systemic malignancies and
Patients who have failed to respond to, or cannot tolerate,
other systemic treatments (e.g. excluded from methotrexate treat-
ment because of kidney or liver disease) may have significant
improvement on thioguanine (6-thioguanine).[19] Thioguanine is
the natural metabolite of azathioprine, but appears to be more
effective than its parent compound. The mechanism of action of
thioguanine is the induction of apoptosis in activated T lympho-
cytes.
Murphy et al.[20] treated 20 patients with moderate to severe
plaque-type psoriasis with thioguanine and performed biopsies
after 1 and 2 months of therapy. Eighteen out of 20 patients
showed a significant clinical response, which correlated best with
cutaneous T cell depletion.[20] Significant hematological abnor-
malities may be seen with daily administration, especially in pa-
tients previously treated with methotrexate.[21] Therefore, pulse
administration starting at 40mg twice daily, two to three times a
week, has been studied and found efficacious in a small series
of patients.[22] Hepatic changes may be seen and, rarely, veno-
occlusive disease.
1 Use of tradenames is for product identification only and does not imply
endorsement.
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Am J Clin Dermatol 2002; 3 (3)

Novel Therapies for Psoriasis
163
uncontrolled hypertension are not ideal candidates for cyclospor-
ine, and neither are patients unlikely to be compliant or women
who are planning to get pregnant or breast-feed. However,
cyclosporine is not a teratogen, with premature delivery and
lower birthweight the only likely complications noted in the
transplant pregnancy registry.
All forms of psoriasis have been successfully treated with
cyclosporine, including plaque, pustular, erythrodermic and pso-
riatic arthritis.[25,26] Patients are usually started on 3 mg/kg/day,
given in two divided doses, with dosage titration up to 5
mg/kg/day as needed. Patients must be carefully monitored for
hypertension, renal insufficiency, cutaneous malignancies and
gingival hyperplasia. If serum creatinine increases to greater than
25 to 30% above baseline then the dosage must be decreased
according to standard guidelines, and repeated laboratory results
must be obtained to ensure normalization. Discontinuation of the
medication is mandatory if renal impairment persists.
Short intermittent courses of cyclosporine are more com-
monly employed rather than long-term maintenance therapy
(over 1 to 2 years). Powles et al.[27] reported that 78% of patients
(23/29) treated long term with cyclosporine developed nephro-
toxicity which, upon drug discontinuation, showed improvement
even if patients had been on therapy for 10 years. Powles et al.[27]
performed renal biopsies on patients on Sandimmune™ for 2.5
and 3.5 years and found progressive interstitial fibrosis, which
correlated with the presence of hypertension and increasing pa-
tient age.
In 1992, Jegasothy et al.[38] reported seven patients with se-
vere recalcitrant psoriasis who improved on oral tacrolimus.
Therapy was well tolerated during treatment (up to 14 months),
and dosage reduction controlled the adverse effects of hyperten-
sion and nephrotoxicity. In a larger study, initial dosages of 0.05
mg/kg/day with increases up to 0.15 mg/kg/day were considered
well tolerated and efficacious [psoriasis area severity index
(PASI) score reduction of 83% at week 9] in patients with chronic
plaque psoriasis.[39] Adverse effects included diarrhea (18.5%),
paresthesia (14.8%), insomnia (11%), pharyngitis (11%) and
headache (7.4%).
The metabolic effects of tacrolimus 0.3 mg/kg/day were spe-
cifically studied in seven patients with severe recalcitrant psori-
asis.[40] All patients had some degree of elevation of blood urea
nitrogen and creatinine, with maximal levels noted at week 8.
Median glucose levels were mildly elevated after 4 weeks of ther-
apy. Liver enzymes and lipid levels were essentially without
change. One patient had a mild elevation in blood pressure. In-
vestigators concluded that remissions in psoriasis could be
achieved using systemic tacrolimus with minor metabolic ef-
fects.[40]
4. Phototherapy
Several different phototherapy options are available to patients
with psoriasis, including ultraviolet A (UVA), UVB, narrow
band (311nm) UVB (NB-UVB), psoralens and UVA (PUVA),
and retinoids and PUVA (Re-PUVA). NB-UVB and PUVA pri-
marily target activated T lymphocytes and induce apoptosis.[41-43]
3.2 Pimecrolimus
Pimecrolimus (SDZ ASM 981), a novel ascomycin macro-
lactam derivative, inhibits the proliferation of T cells after antigen-
specific or nonspecific stimulation. It is a specific inhibitor of the
production of proinflammatory cytokines from T cells and mast
cells, and appears in initial studies to be highly effective in pso-
riasis therapy if used systemically or under occlusion.[28-30] If
used without occlusion the drug is ineffective.[31] It is approved
for topical therapy of atopic dermatitis by the US Food and Drug
Administration (FDA).
4.1 Ultraviolet B
NB-UVB is superior to broad band UVB when looking at
clinical improvement and histologic reversal of epidermal hyper-
plasia,[44] and in clinical trials appears to be almost as effective
as PUVA in clearing psoriasis.[45] However, remissions do not
appear to be as durable as with PUVA.
4.2 Psoralens and Ultraviolet A (PUVA)
Psoralens such as methoxsalen (8-methoxypsoralen) and 5-
methoxypsoralen have been used both topically (e.g. in bath wa-
ter or painted directly on lesions) and systemically.
Methoxsalen 0.6 mg/kg is metabolized through the liver and
excreted by the kidneys, usually within 12 hours. Therefore, pro-
tection from UV exposure is recommended for 12 hours after it
is ingested. Newer modes of methoxsalen application, like sub-
lingual and rectal, can decrease the time of photosensitivity to 2
hours.[46] Topical methoxsalen, primarily used to avoid the nau-
3.3 Tacrolimus
Tacrolimus has also been approved by the FDA for the top-
ical therapy of atopic dermatitis.[24] Tacrolimus is a smaller com-
pound and penetrates the skin better than cyclosporine.[32-34]
Studies using topical tacrolimus ointment for psoriasis, however,
have been disappointing.[35,36] Efficacy has been seen when
tacrolimus is used under occlusion after removal of psoriasis
scale or used in the treatment of flexural psoriasis.[37]
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sea, headache and ophthalmologic risk associated with systemic
PUVA, has been tried successfully for palmar-plantar psoriasis
and may also be placed in bath water for total body application.
It is associated with minimal, if any, systemic absorption of the
psoralen.[47]
as little as one treatment, with moderately long remissions.[55]
The radiation can be directed to localized lesions, thus sparing
surrounding healthy skin.[55,56] Other similar lasers are currently
under evaluation.
5-Methoxypsoralen is considered an alternative to metho-
xsalen, primarily because of its greater tolerability (lower inci-
dence of nausea and headache) and decreased phototoxicity.[48,49]
The highly variable absorption of 5-methoxypsoralen improves
if it is taken with food, and it is most effective at a dose of ap-
proximately 1.2 mg/kg with light exposure 3 hours postdose.[50]
In addition, a micronized formulation of 5-methoxypsoralen,
which has an increased bioavailability and increased efficacy, is
also available.[51]
In general, the photochemotherapeutic effects of PUVA are
a result of psoralens intercalating between DNA base pairs and,
upon UVA irradiation, covalently binding with pyrimidine bases
of native DNA. Other important effects include normalization of
number, maturation, activation and arrangement of keratinocytes,
reduction of activated antigen-presenting cells, reorganization of
the vascular architecture and elimination of polymorphonuclear
and T lymphocytes.[52]
Patients treated with PUVA tend to have longer remission
rates compared with cyclosporine or methotrexate.[53,54] Vallat et
al.[54] examined biopsies of lesional and nonlesional skin from
patients with psoriasis being treated with bath-PUVA. They
found epidermal and dermal T lymphocytes expressing CD3,
CD4, CD8 and high affinity IL-2 receptor markedly suppressed,
with almost complete elimination of the IL-2 receptor on the sur-
face of T cells in some patients.[54] Since PUVA produces a
greater decrease in T lymphocytes than with any other treatment,
including cyclosporine, it is associated with longer remissions.[53]
PUVA should be administered with caution to patients with
HIV infection, and is contraindicated in pregnancy. Adverse
events reported during PUVA therapy include nausea, vomiting,
headaches, pruritus, acute phototoxic reactions and cutaneous
malignancies.[52] Gastrointestinal symptoms can be reduced if
methoxsalen is taken with food. Acute phototoxic reactions, from
inadvertent overexposure to UVA, may begin with an erythema
as soon as 24 hours after exposure; however, the response peaks
at 48 to 96 hours.[52] Periodic ophthalmologic examination is ad-
vised to monitor for cataract formation.
5. Nuclear Receptor Binders
The molecular composition and function of the gluco-
corticoid, vitamin D, thyroid hormone and retinoid receptors are
all similar.
Retinoids are compounds that bind to and activate one or
more retinoid receptors. There are two groups of retinoid recep-
tors: retinoic acid receptors (RAR) and retinoid X receptors
(RXR). Each group has three isoforms: α, β and γ. In normal skin,
RARα (10%) and RARγ (90%), and RXRα (90%) and RXRβ
(10%), predominate.[57,58] The receptors act in pairs, usually
heterodimers. The molecular structures of the biologically active
forms of vitamin D [calcitriol (1α,25-dihydroxyvitamin D3)] and
vitamin A [tretinoin (all-trans-retinoic acid) and 9-cis-retinoic
acid] are not related. The nuclear receptors for vitamin D (VDR)
and retinoids are, however, members of the same superfamily of
ligand-activated transcription factors. Vitamin D can activate
VDR-RXR or VDR-RAR; however, depending on relative ex-
pression of nuclear receptors, retinoids can have either cos-
timulating or repressing effects. Vitamin D and retinoid signaling
are linked at the level of gene regulation, and this may explain
the similar effects of both hormones on cell proliferation and
differentiation.[59]
5.1 Corticosteroids
New foam vehicles have been designed to enhance delivery
of topical corticosteroids to lesional skin.[60-62] Bethamethasone
valerate foam and clobetasol propionate foam enhance the bio-
availability of the corticosteroid, leading to improved efficacy in
scalp psoriasis without increased toxicity.[62] We have found
these foam preparations to also be helpful and well tolerated in
hand psoriasis.
5.2 Vitamin D
Calcipotriene, a synthetic analog of calcitriol, induces clini-
cal improvement of psoriasis which is heralded by an increase in
IL-10 and concomitant decrease in IL-8.[63] The IL-10 receptor
gene is upregulated 10-fold by calcitriol and 12-fold by calci-
potriol.[64] Calcipotriol acts as an inhibitor of proliferation and as
a promoter of differentiation in epidermal cells.
4.3 308nm Excimer Laser
The XTRAC™ excimer laser is the first FDA-approved laser
for the treatment of psoriasis. In a small study of 12 patients, the
308nm UVB radiation at high fluence cleared the psoriasis with
Tacalcitol (a vitamin D analog available in Europe) cream 4
μg/g once daily is well tolerated and efficacious for long term
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treatment of plaque psoriasis, with no changes in calcium meta-
bolism with treatment up to 20% of body surface area.[65] Only
5.9% of patients discontinued therapy because of irritation.
Maxacalcitol, a vitamin D3 analog, is 10-fold more effective
at suppressing keratinocyte proliferation in vitro than calcipotriol
or tacalcitol.[66] A phase II double-blind, randomized, left vs
right, concentration-response study with once daily topical max-
acalcitol demonstrated a marked improvement or clearance of
psoriasis with maxacalcitol cream 25 μg/g in 55% of patients,
which compared favourably with calcipotriol (46%). Investiga-
tors rated maxacalcitol 25 μg/g as more effective than once-daily
calcipotriol.[66]
A topical cream formulation significantly reduces the irrita-
tion and improves tolerability.[72] Although absorption is consid-
ered minimal, this drug is considered pregnancy category X.
Other topical retinoids for psoriasis are currently in clinical trials.
5.3.2 Etretinate and Acitretin
The active metabolite of etretinate is acitretin, and both com-
pounds are teratogenic.[73] The long half-life of etretinate (about
120 days) limits its use in fertile women, and therefore acitretin,
whose half-life is around 2 to 3 days, was developed and etretinate
was discontinued. Unfortunately, ingestion of ethanol converts
acitretin into etretinate, leading to prolonged exposure to this
teratogen, and fertile women taking acitretin should be informed
about the importance of strict alcohol abstinence.[74]
5.3 Retinoids
Etretinate reduces lesional CD25+ T lymphocytes by 50 to
65%, reduces keratinocyte proliferation and enhances kera-
tinocyte differentiation.[75] Its metabolite, acitretin is one of the
most effective treatments for localized and pustular forms of pso-
riasis at dosages ranging from 0.5 to 0.75 mg/kg/day. Typically,
localized pustular psoriasis responds at half the dose required by
generalized pustular psoriasis. In addition, erythrodermic vari-
ants may respond within 2 to 4 weeks. Chronic plaque psoriasis
is the least responsive to acitretin, requiring up to 6 to 8 weeks
for response when used as monotherapy.
Retinoids work in a variety of ways. They inhibit the tran-
scription factor AP-1, which is a dimeric complex of jun and fos.
RAR interacts with fos or jun to form an inactive complex (termed
‘transexpression’). In addition, after an RAR-RXR heterodimer
is formed, in the presence of RAR-binding retinoids, the RAR
portion can bind with retinoid acid response elements (RAREs)
in the promoter regions of genes regulated by retinoids (termed
‘transactivation’). Tretinoin causes transrepression of genes con-
taining AP-1 response elements and activates genes containing
RAREs. Some synthetic retinoids have differing effects; some
transrepress AP-1 while not affecting RAREs, and these may
have fewer adverse effects.
5.3.3 Liarozole
Liarozole, an inhibitor of the metabolism of tretinoin, is an
effective treatment for psoriasis with the lowest effective dose
being 75mg twice daily.[76]
5.3.1 Tazarotene
Tazarotene (AGN 190168), a new acetylenic retinoid that is
hydrolyzed into the active metabolite tazarotenic acid, is ap-
proved in the US for the topical treatment of both psoriasis and
acne. The systemic bioavailability of the gel after single or mul-
tiple applications is below 1%, and there is no accumulation in
adipose tissue. Steady-state concentrations are seen within 2
weeks. There is a low potential for systemic adverse effects.[67-69]
Tazarotene gel 0.05 and 0.1% is not sensitizing, phototoxic or
photosensitizing.[68]
Once daily application of 0.05 or 0.1% gel gave a 50% re-
duction in PASI after 12 weeks in one large placebo-controlled
study.[70] Once daily application of either gel gives clinical im-
provement similar to twice daily fluocinonide cream at 12 weeks.
Fluocinonide acts more rapidly, but relapse rates are significantly
lower for 0.1% tazarotene.[71] Local irritant reactions (erythema,
pruritus, peeling, burning/stinging and painful skin) are the most
significant adverse effects experienced, and should be discussed
at length with patients prior to starting therapy. In general, pa-
tients with skin type III/IV tolerate tazarotene therapy better than
those with types I/II.
5.3.4 Bexarotene
Bexarotene is considered a ‘rexinoid’ or an RXR-specific
retinoid.[77] The drug binds to and activates RXRs. RXRs are
primarily involved in controlling apoptosis, not cell growth and
proliferation. In the US, bexarotene is approved for the treatment
of cutaneous T cell lymphoma in oral and gel preparations; it is
not currently approved for the treatment of psoriasis.
In a European study, 23 patients with psoriasis were treat-
ed with bexarotene at three dosage levels: 0.5, 1.0 and 2.0
mg/kg/day. Clinical and histologic improvement of psoriasis was
seen after 12 weeks with all dosages.[78] We have used bexarotene
alone and in combination with both NB-UVB and PUVA, with
responses similar to traditional therapy with retinoids + PUVA.
Our initial dosage was approximately 2 mg/kg/day (two 75mg
tablets of bexarotene by mouth at night with food). Approxi-
mately 2 weeks later, phototherapy was initiated. Our patients
previously on etretinate or acitretin report minimal to no cut-
aneous adverse effects, and have signified a preference for
bexarotene.
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Hyperlipidemia and hypothyroidism, both of which are re-
alone.[95] No unusual photosensitivity has been described with
this combination.[96] We have found similar results with PUVA.
versible, may occur with bexarotene with the threshold dosage of
the drug being 75 mg/day. Therefore it is prudent to start
bexarotene only after baseline laboratory results (including a fast-
ing lipid panel and thyroid function panel) are obtained. Diet
management is important in controlling lipids; however, if lipid-
lowering medications are required, atorvastatin rather than
gemfibrozil is helpful. The hypothyroidism induced is a ‘central
hypothyroidism’ and requires monitoring of free thyroxine, not
thyroid-stimulating hormone. Thyroid replacement has not been
required in our patients. Bexarotene is pregnancy category X, and
adequate contraception should be used for 1 month after the last
dose.[79]
6.2.1 PUVA and Retinoids
Pretreatment with aromatic retinoids 2 weeks prior to PUVA
is likely to decrease the amount of UVA required and be more
effective than either treatment alone.[97,98] Thus, acitretin com-
bined with either UVB or PUVA works faster at reduced dosages
than monotherapy with either alone.[98-100]
Since retinoids have been shown to prevent the formation of
premalignant squamous metaplasia on various epithelia, their
combination with PUVA may theoretically reduce the number of
cutaneous malignancies seen with PUVA. In addition, in females
of childbearing age where acitretin is contraindicated, isotretin-
oin or bexarotene may be substituted with similar effect, with 1
month of post-treatment pregnancy prevention mandatory.
Of the two psoralens available for PUVA therapy, a single
study found the combination of 5-methoxypsoralen and etretinate
to be more effective than methoxsalen and etretinate.[101]
6. Combination Therapy
Rotational therapy, with agents having different toxicities,
has been advocated to reduce the amount of long-term toxicity
from an individual treatment while maximizing the duration of
remission.[80,81] Several agents have been used effectively in
combination.[82]
6.2.2 Cyclosporine and Phototherapy
Phototherapy is generally contraindicated while a patient is
on cyclosporine because of immunosuppression and increased
risk of skin cancers.[102,103] A short overlap may be necessary
when rotating off cyclosporine on to PUVA or UVB.
6.1 Topical Combinations
Calcipotriene and halobetasol propionate,[83] as well as taza-
rotene and moderate-to-high-potency corticosteroids,[84] each
once a day, are more effective than either agent alone.
6.2.3 Methotrexate and Phototherapy
Phototherapy has been used in combination with methotrex-
ate to limit the cumulative dose of methotrexate; however, pro-
longed phototoxicity, i.e. methotrexate-induced ‘recall’ of UV-
induced erythema, has occasionally been associated with this
regimen.[82,104] This combination should be reserved for short
courses in refractory psoriasis, since some authors have ques-
tioned the possibility of synergistic carcinogenic effects from
these two therapies.[105]
6.2 Phototherapy Combinations
Both UVB and PUVA have been used with topical and
systemic agents with good results.[82,85-87] Topical calcipo-
triol/calcipotriene enhances both UVB and PUVA.[88] Calcipo-
triol and tacalcitol have been beneficial when combined with pho-
totherapy (broad band and NB-UVB).[89] Calcipotriol therapy is
more effective when UVB therapy is added to it,[89] and UVB
therapy alone is not as effective as UVB therapy with calci-
potriol.[88,90] Of note, calcipotriol should be introduced with cau-
tion to patients already receiving phototherapy, as the medication
can cause photosensitivity.[91] The medication should only be ap-
plied after light therapy, not before, since it may have pho-
toprotective effects for UVA and UVB,[87,92-94] and the medica-
tion is degraded by UVA.[92] Hyperpigmentation has been seen
at the site of calcipotriol application if the agent is applied before
PUVA.[93,94]
6.3 Combinations with Cyclosporine
6.3.1 Cyclosporine and Methotrexate
Rheumatologists have used cyclosporine with methotrexate
for years for the treatment of rheumatoid arthritis.[106,107] Clark
et al.[108] successfully used low dose cyclosporine combined with
methotrexate to treat 19 patients with severe recalcitrant psoria-
sis. We have effectively treated over 60 patients with this regimen
and have found no drug interactions with these drugs when used
in combination at low doses (unpublished observations).
Tazarotene gel enhances UVB phototherapy.[95,96] Patients
treated with tazarotene and UVB had a ≥50% improvement in
psoriatic lesions after 32 days, compared with 67 days with UVB
6.3.2 Cyclosporine and Hydroxyurea
Cyclosporine + hydroxyurea[109] has also been shown to be
beneficial for severe recalcitrant psoriasis.
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6.4 Combinations with Retinoids
(n = 5)]. Clinical response was seen in all but one patient, with a
decrease in PASI of 55.3 11.5% (mean standard error).[121]
There was a decreased response in the delayed-type hypersensi-
tivity reaction to recall antigens, suggesting immunosuppres-
sion.[121]
Combination therapies are often required with retinoids, given
their slow onset of action and incomplete clearing achieved.
6.4.1 Retinoids and Topical Therapy
Combinations with various topical agents, such as cortico-
7.1.2 IL-11 (Oprelvekin)
Recombinant humanized IL-11(oprelvekin) modulates
steroids, anthralin and calcipotriene ointment (0.005%), also lead
to reduced dosages and shorter courses of the combination being
needed.[110-113]
macrophages and Th1 lymphocyte function in cell culture,
and shows anti-inflammatory activity in animal models.[115]
Subcutaneous delivery of recombinant IL-11 in a phase I dose-
escalation clinical trial improved psoriasis in 7 of the 12 patients
treated.[122] Clinical response was associated with a decrease in
proinflammatory cytokines (TNFα, IFNγ, IL-8, IL-12) and an
increase in IL-8.[122]
6.4.2 Retinoids and Hydroxyurea
In our experience, hyperkeratotic palmar-plantar psoriasis,
only partially improved with systemic retinoids, frequently re-
sponds to the addition of hydroxyurea at dosages up to 500mg
twice daily.
6.4.3 Retinoids and Systemic Immunosuppressive Drugs
Oral retinoids have been used successfully with both cyclo-
7.2 Anticytokines
sporine[114] and methotrexate,[115] with minimal drug interactions
reported. However, one case of increased hepatotoxicity from the
combination of acitretin and methotrexate has been reported,
which prompts caution.[116,117]
7.2.1 Tumor Necrosis Factor-α
TNFα, a proinflammatory cytokine, is elevated in the skin
and joints of patients with psoriasis and psoriatic arthritis. The
two anti-TNFα medications used successfully for psoriatic arthri-
tis and psoriasis are etanercept and infliximab.[123] These medi-
cations can be used alone or in combination with methotrexate.
A randomized, double-blind, placebo-controlled, 12-week study
assessed the efficacy and tolerability of etanercept (twice-weekly
subcutaneous injections of 25mg) versus placebo in 60 patients
with psoriasis and psoriatic arthritis.[123] Patients treated with
etanercept had a median PASI improvement of 46%, and 5 out of
19 (26%) had 75% improvement.[123] The drug was well toler-
ated.
7. Investigational Drugs
7.1 Cytokines
7.1.1 IL-10
There is a relative deficiency of IL-10 in psoriasis.[3,118] Pa-
tients on antipsoriatic therapy show a higher expression of IL-10
mRNA by peripheral blood mononuclear cells,[119] suggesting
that IL-10 may have an antipsoriatic effect.
In a pilot study involving three patients, daily subcutaneous
administration of IL-10 8 μg/kg/day demonstrated clinical effi-
cacy and acceptable tolerability.[119] IL-10 caused a type-2 cytok-
ine shift (increasing IL-4, IL-5 and IL-10), as well as decreased
expression of human leukocyte antigen (HLA)-DR and IL-
12.[119] In addition, IL-10 therapy induced a downregulation of
the epidermal IL-8/CXCR2 pathway and a reversal of abnormal
keratinocyte proliferation and differentiation.[2]
Severe psoriatic arthritis has been treated successfully with
infliximab, given by the intravenous route.[124] Additionally, in-
fliximab has been used in one patient with psoriasis without ar-
thritis, which resulted in a dramatic decrease in the psoriasis skin
lesions.[125] Further studies are ongoing with these two medica-
tions, both of which are currently approved in the US for rheu-
matoid arthritis. Etanercept was approved by the FDA in Jan 2002
for use in psoriatic arthritis.
The antipsoriatic effect of recombinant human IL-10 is re-
lated to modulation of circulating immune cells rather than a di-
rect effect on human keratinocytes.[2,118,120] A phase II pilot study
involving three patients with psoriasis treated with recombinant
human IL-10 8 μg/kg/day over 24 days demonstrated clinical
efficacy and an acceptable tolerability profile.[3] In another phase
II study, ten patients with psoriasis were given subcutaneous in-
jections of recombinant IL-10 at two different administration
regimens [8 μg/kg daily (n = 5) or 20 μg/kg three times a week
7.2.2 Anti-IL-8 Monoclonal Antibody
ABX-IL8, a fully humanized immunoglobulin (Ig) G2
monoclonal antibody directed against IL-8, has been used to treat
psoriasis.[126] In dose-escalation trials there were no serious or
unexpected adverse events, specifically no capillary leak syn-
drome, and no immunogenicity was detected. The half-life is ap-
proximately 3 weeks for doses of 1 and 3 mg/kg, suggesting the
benefit of longer remissions.
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7.3 Antimetabolites
of human IgG-1. Its immune modulating effect results from in-
teraction with the CD2 receptor, which competitively inhibits the
binding of CD2+ cells to LFA-3+ cells.[135] All patients who re-
ceived alefacept had a transient decrease in lymphocytes express-
ing CD2, CD4 and CD8; however, no change was seen in CD19+
lymphocytes.[135,136] More specifically, the greatest reduction
was seen in the memory/effector lymphocytes (CD45RO+) com-
pared with naïve lymphocytes (CD45RA+), which may be be-
cause of stronger CD2 expression on memory cells. Psoriasis
patients treated with alefacept had an improved quality of life[137]
and responses that prompted further investigation.[138] In a phase
II randomized, double-blind, placebo-controlled trial, alefacept
resulted in a 53% mean reduction in PASI at the two higher dos-
age levels, and 17% of these patients were judged clear or almost
clear.[139] Alefacept was well tolerated and there were no in-
creases in infection rate, cytokine release or capillary-leak syn-
dromes. Response rates increased with greater serum concentra-
tions. The pharmacokinetics of alefacept have been studied in a
small number of patients.[140] The elimination half-life is approx-
imately 5 weeks and weekly administration gives predictable
concentrations, again suggesting longer remissions.
Leflunomide is the newest disease-modifying antirheumatic
drug approved for rheumatoid arthritis, it inhibits dihydroorotate
dehydrogenase, thereby decreasing biosynthesis. We have seen
this drug decrease psoriatic skin and joint disease in two of our
patients. Leflunomide, in vitro, decreases the receptor for the pro-
inflammatory cytokine IL-8 and increases the receptor for the
anti-inflammatory receptor IL-10.[127]
All patients require an oral loading dose of 100mg daily for
three doses, followed by a daily dose of 20mg. This medication
is pregnancy category X, and also should not be used in patients
with hepatic insufficiency or patients with hepatitis B or C. After
stopping leflunomide, cholestyramine or charcoal must be given,
otherwise it may take up to 2 years to reduce the concentration
down to nonteratogenic levels, given its long half-life (about 2
weeks). Theoretically, immunosuppression is possible with this
medication.
The most common adverse events associated with leflunom-
ide include diarrhea, alopecia, increased liver function tests and
rash. The usefulness of this medication in psoriasis remains un-
known at this time.
CTLA4Ig is a chimeric fusion protein that blocks the activa-
tion of T cells by interrupting the interaction between B7 on
antigen-presenting cells and CD28 and CD152 (cytotoxic T lym-
phocyte-associated antigen-4) receptors on T cells. One nonblind
dose escalation trial has shown the utility of this medication for
the treatment of psoriasis. Of the 43 study participants, 46%
achieved a ≥50% sustained improvement, which was greatest at
higher doses.[141] Clinical improvement using CTLA4Ig is asso-
ciated with a decrease in lesional T cells and decreased prolifer-
ation of keratinocytes, with no increase in T cell apoptosis.[141]
Therefore, the reduction in T cells was likely to be because of
inhibition of T cell activation, proliferation and recruitment. In
addition, there was decreased activation of dendritic cells and
vascular endothelium.[142]
7.4 T Cell Activation
7.4.1 Adhesion Molecule Blockers
The lymphocyte function-associated antigen (LFA)-1, lo-
cated on T cells, interacts with intercellular adhesion molecule
(ICAM)-1 on antigen-presenting cells. LFA-1 is composed of two
subunits: CD11a and CD18. Monoclonal antibodies against LFA-
1 or one of its ligands inhibit T cell activation in vitro.[128] The
upregulation of ICAM-1 on keratinocytes and its interaction with
LFA-1 on T cells[129] lends to a possible benefit with an LFA
blocker.
CD11a is a leucocyte integrin which plays a major role in T
cell activation and emigration into the skin. Anti-CD11a
(Hu1124) is a humanized IgG-1 version of the murine anti-
CD11a monoclonal antibody MHM24, which recognizes human
and chimpanzee CD11a. Hu1124 given in 8-weekly doses of 0.3
mg/kg intravenously is well tolerated and reduces the signs of
moderate-to-severe plaque psoriasis.[130] Clinical and histologic
improvement induced by Hu1124 may be because of decreased
T cell activation, T cell migration and T cell cytokine production.
Subcutaneous administration of humanized anti-CD11a blocks
T cell-dependent functions mediated by LFA-1 and reverses
disease-defining pathology.[130-134]
7.4.2 T Cell Surface Receptor Blockers
Daclizumab is a humanized antibody to the α-subunit (CD25)
of the IL-2 receptor, and blocks normal IL-2 binding to this re-
ceptor.[143] Eighteen of 19 psoriasis patients (12 male and 7 fe-
male) treated with daclizumab finished the study, with a mean
reduction in PASI by 30% at 8 weeks. Variable desaturation of
the receptors occurred after 4 weeks, which correlated with return
of disease.[143]
Basiliximab is a chimeric human/mouse antibody directed
against the IL-2 receptor that has been used to treat severe recal-
citrant psoriasis in combination with cyclosporine.[144,145]
Alefacept (LFA3-TIP) is a recombinant 115kD dimeric
glycosylated protein that consists of the first extracellular domain
of human LFA-3 fused to the hinge and CH2 and CH3 sequences
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Novel Therapies for Psoriasis
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OKTcdr4a, a humanized anti-CD4 IgG4 monoclonal anti-
body, has been used in one pilot, multicenter, multiple-dose,
placebo-controlled study in the treatment of moderate to severe
psoriasis.[146] Infusions were well tolerated, and in the higher
dose group (750 mg/course) the PASI fell by a mean of 17.4 to
7.7. Sustained CD4 saturation was not required for a response.
IDEC-114 is a primatized anti-B7.1 monoclonal antibody
that binds to the high affinity B7.1 (CD80) receptor found on
antigen-presenting cells and certain activated T cells present in
psoriasis. The interaction between CD28 and CD80 provides a
secondary signal for T cell activation. After T cells are activated,
CTLA-4 is upregulated on the cell surface and then CTLA-4
may interact with CD80, leading to T cell deactivation. IDEC-
114 blocks the CD28/CD80 interaction without affecting the
CTLA/CD80 interaction. A preliminary single-dose study showed
clinical and histologic improvement in psoriasis with good toler-
ability,[147] with subsequent studies under way.
Topical application of 5-aminolevulinic acid in single[151] or
multiple[152] applications has shown clinical efficacy; however,
patient responses and discomfort (burning and stinging) are un-
predictable. Verteporfin, a second generation benzoporphyrin
derivative, has been shown to be efficacious in treating pso-
riasis.[153] Verteporfin is activated by longer, more penetrating,
wavelengths of light and has a shorter duration of cutaneous pho-
tosensitivity.
7.7 Antiangiogenesis
Extracts of shark cartilage prepared by homogenization and
ultrafiltration to derive the active agent AE-941 were found to
cause a dose-dependent inhibition of embryonic neovasculariza-
tion and collagenase activity.[154] Topical AE-941 had a benefi-
cial effect in psoriasis, most likely because of its antiangiogenic
and anti-inflammatory properties.[154]
7.8 Miscellaneous
7.5 Cytotoxic Therapies
Peptide T, a short peptide fragment with immune modulating
effects, is under investigation.[155]
As discussed above (in section 1), the majority of T cells in
lesions of psoriasis are activated T cells expressing the IL-2 re-
ceptor (CD25).[148] Denileukin diftitox (DAB389IL-2) is a fusion
toxin composed of the amino acid sequences for diphtheria toxin,
followed by sequences for IL-2. The fusion toxin is taken up
selectively by cells which express the high affinity IL-2 receptor,
primarily activated T lymphocytes.
Gottleib et al.[149] noted that clinical responses with denileukin
diftitox correlated with the reduction in T lymphocytes in lesional
skin, suggesting a primary immune, but not keratinocyte, patho-
genic basis for psoriasis. Additional phase II studies, using a dif-
ferent administration regimen, did not show a significant differ-
ence between placebo and denileukin diftitox.[150] Adverse
effects included fever, chills, headache, myalgias and elevation
of transaminase. One patient with psoriasis developed an arterial
thrombosis from vasospasm and a coagulopathy. Currently, the
role of this drug in the treatment of psoriasis is unknown; how-
ever, there may be a subset of patients, e.g. those with psoriatic
arthritis, who would benefit, given the fact that prolonged clear-
ing has been seen in some patients.
8. Treatment of Psoriasis or Psoriatic Arthropathy
During Pregnancy and Lactation
During pregnancy or times when pregnancy is possible, NB-
UVB or cyclosporine are the therapies of choice for severe disease.
During pregnancy, if systemic nonsteroidal anti-inflammatory
agents are required for psoriatic arthropathy, they may be used
until the last 6 weeks.[156] Additionally, for psoriatic arthropathy,
sulfasalazine and cyclosporine may be continued cautiously with-
out risk of teratogenicity, and prednisone and sulfasalazine, but
not cyclosporine, may be continued cautiously during lactation.
Men taking methotrexate, sulfasalazine, or cyclosporine should be
aware of the possibilities of infertility and teratogenicity.[157]
9. Conclusion
As the genetics, and hence the immunopathogenesis, of pso-
riasis becomes clearer, the whole spectrum of new and novel
therapies discussed in this review will be further delineated and
more precisely targeted; furthermore, disease subtype-specific
therapies, e.g. for palmar-plantar disease and psoriatic arthritis,
will be identified. The goal of more rapid induction of clearance
and longer maintenance of remissions, as utilized in cancer ther-
apy, will be realized, leading to significant improvement in pa-
tient quality of life. The future of therapy for this genetic and
autoimmune systemic disease is indeed very exciting.
7.6 Photodynamic Therapy
Photodynamic therapy relies on the use of light-sensitive
molecules called photosensitizers, coupled with the appropriate
wavelength of light, causing photoactivation and the formation
of singlet oxygen. Singlet oxygen accumulation produces per-
oxidative reactions, leading to cell damage and death.
© Adis International Limited. All rights reserved.
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170
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23. Boyd AS, Neldner KH. Hydroxyurea therapy. J Am Acad Dermatol 1991; 25
(3): 518-24
Acknowledgments
Jennifer Cather is in receipt of a grant from Baylor University Medical
24. Cather JC, Abramovits W, Menter AM. Cyclosporine and tacrolimus use in der-
matology. Dermatol Clin 2001; 19 (1): 119-37
Center, Dallas. Alan Menter has nil funding except for administration. Au-
thors have performed clinical research studies for Genentech, Biogen, Idec,
Abgenix, Allergan, Immunex, Centocor and Ligand.
25. Mrowietz U, Ruzicka T. Cyclosporine A for psoriasis. Dermatol Ther 1999; 11: 60-6
26. Mueller W, Herrmann B. Cyclosporine A for psoriasis [letter]. N Engl J Med 1979;
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Correspondence and reprints: Dr Alan Menter, 5310 Harvest Hill Road, Suite
260, Dallas, TX 75230, USA.
E-mail: research@texasderm.com
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Am J Clin Dermatol 2002; 3 (3)