SYSTEMIC THERAPY FOR PSORIASIS

Abstract and Introduction

Abstract

Psoriasis therapy has changed dramatically in the past decade with the introduction of biologic therapy. The treatment of
moderate to severe psoriasis is reviewed. Phototherapy, conventional systemic therapy, and biologic therapy are
discussed including practical tips for administering each agent. Overall approaches to treatment are discussed along with
special circumstances where individual therapies have advantages.

Introduction

Psoriasis is a common chronic inflammatory disorder primarily affecting the skin. Clinical manifestations range from a few
small scaly plaques to involvement of nearly the entire skin surface. Psoriasis is frequently associated with arthritis. In
addition patients with severe psoriasis have a higher risk of myocardial infarction (which may be related to the systemic
inflammation induced by Th1 cytokines) and lymphoma (Gelfand, Neimann, et al., 2006; Gelfand, Shin, et al., 2006).
Physicians in the past have typically based their decision to prescribe systemic therapy on the amount of body surface
area involved. A more recent clinical consensus from the medical board of the National Psoriasis Foundation suggests a
two-tiered approach (treat topically or treat systemically) based on multiple factors including body surface area involved
and the quality of life (Pariser et al., 2007). The use and selection of an appropriate systemic therapy for psoriasis are
discussed.

Ultraviolet B (UVB) Phototherapy

In UVB phototherapy, the skin is exposed to ultraviolet light in the UVB wavelengths (290-320 nm). Patients can receive
this treatment in the office or at home, with ultraviolet light bulbs mounted in a booth or in a panel. Typically, patients are
treated three times a week, starting with a dose according to their skin type or calculated minimal erythema dose. There
are regular dosage increases each session up to the patient's maximum target dose (Zanolli & Feldman, 2005). Patients
continue treatments with further increases or decreases in dose as tolerated until their psoriasis is cleared. Treatment
frequencies and dosing then can usually be tapered to maintain clearance (Boztepe, Karaduman, Sahin, Hayran, &
Kolemen, 2006).

More recently, the UVB spectrum was examined in detail and a narrow range of wavelengths (311-312 nm) was found the
most effective (Diffey & Farr, 1987; Parrish & Jaenicke, 1981). Phototherapy using this narrower range of wave lengths is
called narrow-band UVB (NB-UVB), and the older form of phototherapy using the full UVB spectrum is called broad-band
UVB (BB-UVB). NB-UVB clears lesions faster than BB-UVB, and as a result, fewer treatments are needed (Coven et al.,
1997).

UVB phototherapy, one of the oldest known treatments for psoriasis, enjoys a long record of safety. Over decades of use,
no studies have convincingly shown an increased risk of skin cancer with BB-UVB (Lee, Koo, & Berger, 2005; Stern &
Laird, 1994). However, similar data for NB-UVB is still not yet available. Short-term side effects of both BB-UVB and NB-
UVB include phototoxicity and photosensitivity reactions. These reactions are less likely to occur with NB-UVB but peak
later and last longer (Coven et al., 1997). Phototoxicity within psoriatic lesions is also more common in NB-UVB
(Calzavara-Pinton, Zane, Candiago, & Facchetti, 2000; George & Ferguson 1992). A logistical concern with all forms of
phototherapy is the time and expense required for multiple treatments per week (including insurance co-payments).

Psoralen Plus Ultraviolet A (PUVA)

PUVA uses a photosensitizing agent (8-methoxypsoralen, Oxsoralen®) taken orally or applied topically before exposure
to ultraviolet A (UVA) light (320-400 nm). Treatments are typically given twice a week at the dermatologist's office with a
dosing strategy similar to UVB phototherapy (Collins, Wainwright, Amorim, Lakshmipathi, & Ferguson, 1996).

PUVA is more effective than NB-UVB, and remissions using PUVA last longer (Gordon, Diffey, Matthews, & Farr, 1999;
Yones, Palmer, Garibaldinos, & Hawk, 2006). PUVA treatment frequencies may also be lower than UVB treatment
frequencies, both during clearance of a patient's psoriatic lesions and during a maintenance regimen, thus requiring less
of a time commitment from the patient.

On the other hand, PUVA has more potential side effects than UVB phototherapy. When 8-methoxypsoralen is given
orally, common side effects include nausea, headaches, and dizziness. These side effects are avoided with the topical
application of psoralen. Patients treated with either oral or topical PUVA may develop phototoxicity with blisters. In
contrast to UVB phototherapy, the long-term use of PUVA has been associated with an increased risk of squamous cell
carcinoma (Henseler, Christophers, Honigsmann, & Wolff, 1987; Stern & Lange, 1988; Stern, Thibodeau, Kleinerman,
Parrish, & Fitzpatrick, 1979).

The concern for the increased risk of skin cancer with long-term use of PUVA and the advent of NB-UVB has led to a
dramatic decrease in the use of PUVA in recent years. The cost of 8-methoxypsoralen (the only psoralen approved for
treating psoriasis in the United States) has also risen significantly (Feldman, Garton, Averett, Balkrishnan, & Vallee,
2003). However, PUVA remains a good treatment option for patients with thick plaques and for patients with darker skin
(who are less likely to clear with UVB phototherapy and are less susceptible to PUVA-induced skin cancer) (Henseler et
al., 1987; Stern et al., 1979; Stern & Lange, 1988).

Methotrexate

Methotrexate is an immunosuppressive agent which blocks DNA synthesis by inhibiting dihydrofolate reductase. It is
typically given either as a single weekly dose of 7.5 to 25 mg per week or divided into three doses each week at 12-hour
intervals (Weinstein & Frost, 1971). Methotrexate is most commonly given via the oral route, however subcutaneous
administration is also an option (Zackheim, 1992). Possible advantages of subcutaneous injections include less nausea
and increased bioavailability. Patients may also be more familiar with self-injection because of the proliferation of that
administration route with biologic therapy.

In addition to nausea, methotrexate can cause anemia and rarely pancytopenia. Both of these side effects can be reduced
with folic acid supplementation (Duhra, 1993; Ortiz et al., 1998). It was previously thought that folic acid supplementation
may reduce the efficacy of methotrexate, but a recent review refutes that claim (Salim, Tan, Ilchyshyn, & Berth-Jones,
2006; Strober & Menon, 2005).

Patients on long-term methotrexate therapy also may develop cirrhosis (Gilbert, Klintmalm, Menter, & Silverman, 1990).
Risk factors for this include pre-existing liver disease, alcohol use, diabetes, and obesity (Langman, Hall, & Todd, 2001).
Although there is relatively little mention of screening for cirrhosis using liver biopsies in the rheumatology literature, this
issue has caused much concern and controversy among dermatologists. Current American Academy of Dermatology
(AAD) guidelines suggest a liver biopsy after each cumulative methotrexate dose of 1.5 g; however, more recent studies
suggest that the first liver biopsy may not be necessary in patients without risk factors until 3.5 to 4 g of methotrexate have
been given (Aithal et al., 2004; Langman et al., 2001).

Other tests of liver function have been investigated in an attempt to decrease the need for liver biopsies. Some recent
studies suggest that liver biopsies can be avoided if PIIINP (procollagen III) levels are consistently normal (Maurice et al.,
2005). Another study showed a seven-fold decrease in biopsies using a PIIINP protocol compared to AAD guidelines
(Chalmers et al., 2005). Unfortunately this test is not approved for use in the United States.
Cyclosporine (Neoral®)

Cyclosporine works by inhibiting T-lymphocyte transcription of IL-2. The long-term use of cyclosporine can be limited by
the two major side effects of renal toxicity and hypertension (Grossman, Chevret, Abi-Rached, Blanchet, & Dubertret,
1996; Mrowietz et al., 1995; Lowe, Wieder, & Rosenbach, 1996; Powles et al., 1998). More recently it has been used in a
short-term approach via intermittent 3 to 4 month intervals, either to obtain a quick response before transitioning to
another agent, or to control a flare in a patient on stable systemic therapy (Finzi, 1996; Ho et al., 2001). Dosing is usually
started at 4 to 5 mg/kg/d and then tapered as clearance is achieved.

Acitretin (Soriatane®)

Acitretin, like all retinoids, promotes the differentiation of keratinocytes. It is useful in combination with other therapies,
particularly with phototherapy, or as a maintenance therapy after control with a faster-acting agent (Hodulik & Zeichner,
2006; Spuls, Rozenblit, & Lebwohl, 2003). Dosing of acitretin is usually started at 10 to 25 mg per day, with a slow titration
up in dose. Recent studies have shown that adverse events are much more common in high-dose regimens (50 mg daily)
as compared to low-dose regimens (25 mg daily) (Pearce et al., 2006). Higher doses of acitretin are often limited by the
common side effects, including dry lips, dry eyes, xerosis, hair loss, and myalgias. Experienced patients can adjust the
dosing of acitretin themselves de pending on disease activity and side effects.

More serious adverse effects of acitretin include teratogenicity, hepatotoxicity, and hyperlipidemia (Pearce et al., 2006).

Etanercept (Enbrel®)

Etanercept is a fusion protein consisting of two tumor necrosis factor (TNF) receptors linked to the Fc protein of human
immunoglobulin (IgG). It works by inhibiting the pro-inflammatory action of TNF in psoriasis.

Patients inject the medication subcutaneously, with dosing either at 50 mg weekly (either as a single dose or divided into
two doses) or 50 mg twice a week for 12 weeks followed by a decrease to the 50 mg weekly maintenance dosing. The
regimen with higher initial dosing has been shown to clear psoriatic lesions faster; however, a recent study has shown that
patients on both dosing schedules achieve the same endpoint at 1 year (Sterry, 2004). Thus, consideration should be
made to dose patients starting at 50 mg weekly, which is less costly and achieves the same result at 1 year.

A common side effect of etanercept is a transient injection reaction (Zeltser et al., 2001). More serious rare reactions
include serious infections (including tuberculosis), demyelinating disease, aplastic anemia, and an increased incidence of
malignancy (Bongartz et al., 2006; Setoguchi et al., 2006).

With incomplete response to etanercept, it may be combined with other therapies including NB-UVB, acitretin, or
methotrexate (Conley, Nanton, Dhawan, Pearce & Feldman, 2006; Gul et al., 2006). Incomplete responses or failures
may necessitate a switch to infliximab, adalimumab, or efalizumab (Farnsworth, George, & Hsu, 2005; Wick, 2005). Some
studies have suggested that some patients treated with etanercept may lose efficacy over time (Tyring, Poulin, Langley, &
Gordon, 2006). If a previously stable patient on etanercept flares, cyclosporine may be used temporarily to control the
disease (Pedraz, Sanz, & Garcia-Diez, 2007).

Efalizumab (Raptiva®)

Efalizumab is a humanized monoclonal antibody against CD11a and is thought to work by inhibiting T-cell activation and
migration. Weekly subcutaneous injections of the medication are dosed based on the weight of individual patients (0.7
mg/kg once, then 1 mg/kg every week up to a maximum of 200 mg). Efalizumab maintains efficacy in heavier patients and
thus may be more efficacious for that subset of patients compared to medications with fixed dosing (Clark & Lebwohl,
2008). Efalizumab is also distinct in having shown efficacy in hand and foot psoriasis including a placebo-controlled trial
(Fretzin, Crowley, Jones, Young, & Sobell, 2006; Leonardi, Sofen & Krell, 2007).

Flu-like symptoms may accompany the first few injections of efalizumab, with improvement after several doses (Dubertret
et al., 2006). Possible serious adverse events include infections, malignancy, thrombocytopenia, and autoimmune he
molytic anemia.

Patients occasionally may have disease flares while on long-term therapy (Golda, Benham, & Koo, 2006; Hamilton, 2005).
Topical steroids can be used for mild flares, while cyclosporine may be needed for the rare severe flare (Papp, Toth, &
Rosoph, 2006).

Infliximab (Remicade®)

Infliximab is a chimeric monoclonal antibody against TNF, with human constant regions and murine variable regions. It is
the most effective biologic agent for treating psoriasis at the usually prescribed doses (Menter, Feldman, et al., 2007;
Menter, Papp, et al., 2007; Reich et al., 2005). Since dosing is weight based (start 5 mg/kg on weeks 0, 2, and 6, then 5
mg/kg every 8 weeks), it may be given more consideration when treating heavier patients. Infliximab is administered
intravenously, and access to an infusion clinic is necessary when starting this medication.

Patients receiving infliximab infusions may develop an infusion reaction which uncommonly re quires discontinuation of
the medication (Cheifetz et al., 2003; Leonardi, Guzzo, Reich, &Li, 2007; Wasserman et al., 2004). More unusual adverse
events include serious infections (including tuberculosis), hepatotoxicity, hematologic suppression, neurologic disease, a
lupus-like syndrome, and an increased incidence of malignancy (Bongartz et al., 2006; Setoguchi et al., 2006).

One concern of infliximab is loss of efficacy over periods as short as 6 to 12 months (Krathen, Berthelot, & Hsu, 2006;
Papp, 2006). In a recent study, patients who responded to infliximab but did not maintain this response had a drop in
detectable serum infliximab levels at the time of infusion (Bendtzen et al., 2006). This can be associated with the
formation of antibodies to infliximab. Administration of infliximab with methotrexate may decrease antibody formation
(Bendtzen et al., 2006). If a patient begins to show a loss of efficacy while on infliximab, the frequency of infusions may be
increased (Berger, Edelsberg, Li, Maclean, & Oster, 2005).

Adalimumab (Humira®)

Adalimumab is a monoclonal antibody against TNF. It is approved for the treatment of psoriatic arthritis, rheumatoid
arthritis, and ankylosing spondylitis, and was recently approved for the treatment of psoriasis. The approved dose for
psoriasis is 80 mg at week 0, then 40 mg 1 week later, and then 40 mg every other week. Phase III trials showed
excellent results in the treatment of psoriasis (Menter, Papp, et al., 2007). A placebo-controlled trial comparing
methotrexate to adalimumab revealed a significant advantage with adalimumab (Saurat et al., 2006).

Patients may develop an injection site reaction with adalimumab. Serious reactions include serious infections (including
tuberculosis), demyelinating disease, bone marrow suppression, and an increased incidence of malignancy.

Alefacept (Amevive®)

Alefacept is a fusion protein combining the binding portion of lymphocyte function-associated antigen-3 with the Fc portion
of IgG. It inhibits T-cell activation and induces T-cell apoptosis. Alefacept often is used with other therapies such as
methotrexate or phototherapy (Koo, Bagel, Sweetser, & Ticho, 2006; Ortonne, Khemis, Koo, & Choi, 2005; Scheinfeld,
2005). Alefacept offers a potential advantage in that patients who respond well often will maintain that response off
therapy for a period of many months (Gordon & Langley, 2003).
Alefacept is usually given as a weekly intramuscular dose of 15 mg in courses of 12 weeks. Courses may be repeated
after a rest period of 12 weeks (Menter et al., 2006). CD4 counts are monitored throughout therapy with alefacept. More
recent suggested schedules reveal less-frequent monitoring is required.

Patients on alefacept may develop injection site reactions. Serious adverse events include malignancy and infection.

Therapeutic Approach

In deciding which therapy to use, many important factors must be considered, including safety, efficacy, availability, and
cost. Long-term side effects will, of course, become better known as experience with each therapy grows. In particular,
biologic medications are already in their 2nd decade of use in rheumatology, but there is much less experience than with
more traditional therapies. Comparisons of efficacy between therapies are hampered by the lack of quality comparative
clinical trials. Clinicians are left with comparing studies which, for the most part, differ in patient population, data collection,
and statistical methods. Availability of specific therapies differs depending on location: phototherapy requires ultraviolet
light units and infliximab infusions require access to an infusion clinic. Availability of biologic therapies in particular is
influenced by their relatively high cost and resulting difficulties with insurance coverage.

Given these limitations, we approach patients with psoriasis who require systemic therapy by performing a complete
history and cutaneous examination. If there are no contraindications we generally start with NB-UVB with or without
acitretin. If phototherapy is not an option due to logistical issues, methotrexate is usually started. For many patients these
conventional treatments are very effective. If there is not an adequate response after approximately 12 weeks then
patients may be switched to the alternative therapy or switched to a biologic medication. Occasionally PUVA is considered
for patients with extremely thick plaques or patients with type V or VI skin. Cyclosporine is usually reserved for short-term
treatment of flares, followed by transitioning to other therapies for long-term control.

In choosing a biologic medication, several situations may point to the use of one over another. Etanercept is the most-
used biologic medication for psoriasis, in part because dermatologists have the most accumulated experience with it. In
particular, biologic medications are already in their second decade of use in rheumatology, but there is still much less
experience with them than with more traditional therapies in the treatment of psoriasis. Obese patients may experience
better efficacy with medications dosed using weight-based calculations (efalizumab or infliximab) (Clark & Lebwohl, 2008;
Strober, Gottleib, Leonardi, & Papp, 2006; Reich et al., 2006). Efalizumab also has shown efficacy in hand and foot
psoriasis (Fretzin et al., 2006; Leonardi, Stofen et al., 2007). Infliximab is one of the most efficacious therapies for
psoriasis and in addition works very quickly. This may be the best treatment for patients with extremely severe psoriasis
and in patients where hospitalization is a consideration. Adalimumab has also shown impressive results and was
approved for the treatment of psoriasis in January 2008. Prior authorization requirements may restrict its use to patients
with psoriatic arthritis. Alefacept is useful in particular because a subset of patients has shown remarkable clearing of
resistant psoriasis when it was given followed by narrow-band UVB therapy (Koo et al., 2006; Ortonne et al., 2005;
Scheinfeld, 2005). Of note in patients who also have psoriatic arthritis, the biologics affecting TNF (etanercept, infliximab,
and adalimumab) have all been FDA-approved for use in those patients.

As discussed, several longer-term trials have shown some loss of efficacy when using biologic medications, in particular
etanercept and infliximab. It may then become necessary to switch those patients to a different biologic medication. There
are two different options: changing to a medication in the same class (from a TNF inhibitor to another TNF inhibitor), or
changing to a medication in a different class (from a TNF inhibitor to a T-cell agent such as efalizumab or alefacept).
There is no strong evidence in the literature to differentiate between these two options at this time. Data exists in the
rheumatologic literature showing efficacy when switching be tween TNF-inhibiting agents (Cohen et al., 2005). There is
also anecdotal evidence of efficacy when switching from a TNF-inhibiting agent to a medication with a different
mechanism of action or vice versa.
Conclusion

Psoriasis is a disease that can seriously impact the quality of life of those affected. However, the number of therapeutic
options continues to grow and our understanding of each therapy continues to expand. This allows us to provide better
care for our patients and improve their quality of life.

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Authors and Disclosures

Melvin Lee, MD, Dermatology Resident, State University of New York at Buffalo, School of Medicine and Biomedical
Sciences, Department of Dermatology, Buffalo, NY.

Robert E. Kalb, MD, Clinical Associate Professor, Department of Dermatology, SUNY at Buffalo School of Medicine,
Buffalo Medical Group, P.C., Buffalo, NY.

Disclosure: Dr. Kalb has served as a consultant and/or speaker for Abbott, Amgen, Centocor, Genentech, Stiefel, and
Warner Chilcott. Dr. Lee reported no actual or potential conflict of interest in relation to this continuing nursing education
article.

The Editor, Marcia J. Hill, MSN, RN, disclosed that she is an employee of Genentech.

Dermatology Nursing. 2008;20(2):105-111. © 2008 Jannetti Publications, Inc.

All other Dermatology Nursing Editorial Board members reported no actual or potential conflict of interest in relation to this
continuing nursing education article.