Advances in the Treatment of Psoriasis

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Pharmacy Times, Volume 0, 0

Psoriasis is a chronic, hereditarydisease that involves the skinand, in some instances, thejoints. Psoriasis affects between 1% and3% of the population worldwide andnearly 7.5 million individuals in theUnited States alone.1 The NationalPsoriasis Foundation estimates that theoverall therapy costs for this lifelong diseasemay exceed $3 billion annually.Quality-of-life studies have defined theimpact of psoriasis to be as detrimentalto patients as that of cancer, arthritis, orheart disease.2

The immune pathogenesis of psoriasiswas identified nearly 20 years ago. Priorto that time, psoriasis was thought to bean epidermal disease resulting fromabnormal keratinocyte growth and differentiation.The discovery of psoriasis benefitsin a renal transplant patient receivingcyclosporine revolutionized this theoryand precipitated the interest in animmunogenic process.3

Psoriasis is a T-cell-mediated disease.Unidentified antigens cause activation ofT cells, which then proliferate and enterthe systemic circulation. The T cellsmigrate into the skin andrelease a number of cytokines(including tumornecrosis factor alpha[TNF-a] and interferongamma), which cause vascularchanges and interferewith normal keratinocytedevelopment.

The diagnosis of psoriasisis typically ascertainedby a careful patient historyreview and a physicalexamination.4 In rare instances,skin biopsy maybe necessary to identifyhyperproliferation and inflammationof the epidermisand dermis. Other diseasesthat can presentsimilarly to psoriasis includetinea corporis andsubacute cutaneous lupuserythematosus.

Five types of psoriasiscurrently are recognized:plaque, guttate, inverse,erythrodermic, and pustular.Plaque psoriasis is themost common form, occurring in >80%of afflicted individuals.5 Two peak ages ofonset are recognized: 16 to 22 years and57 to 60 years.1 Psoriasis is more commonlyidentified in Caucasian individualsand is more frequent at higher latitudes.5Prevalence is similar between genders.5Hereditary factors also influence the disease.Research on the human genomehas identified the gene locus, PSORS-1,which is accountable for nearly 50% ofthe genetic susceptibility to psoriasis.6

Symptoms

Symptoms of psoriasis can vary butmost commonly include pruritis, erythema,and possibly pain. In the most commonform of the disease, patients arecharacterized by the development ofwell-demarcated plaques with silveryscales on the elbows, knees, or scalp.Between 10% and 30% of individualsafflicted with psoriasis will develop psoriaticarthritis, a related condition thatcauses swelling and tenderness of thejoints and is commonly found in the distalextremities.7

In clinical trials, disease severity isassessed by the percentage of body surfaceinvolved and the resultant effect ona patient's quality of life, using thePsoriasis Area and Severity Index (PASI)scale. Scores range from 1 to 72, with 72being the most severe form of the disease.The goal in studies has been toattain a >75% improvement in PASI scorein order for a new medication to receiveFDA approval.

Conventional Treatment

We will review pharmacotherapy forthe most common form of the disease,plaque psoriasis. Patient education isessential to teach avoidance of factorsthat could cause disease flare-ups(Table 1). Providers need to stress thattherapy is meant to control rather than tocure psoriasis. Several organizationshave excellent Web-based resources,with information appropriate for bothpatients and providers (Table 2).

Topical therapy is the mainstay oftreatment for patients with localized disease.Adherence to topical regimens canbe poor, however. Regular use of emollientagents can help to hydrate and softenthe skin. Tar products and anthralinare no longer favored because of theirnoxious odor and their tendency tocause staining of clothing and skin.

Topical corticosteroids have antiinflammatoryand antiproliferative effectsand are available in many formsand strengths. Corticosteroids havedemonstrated rapid effectiveness andare the most commonly prescribed treatment,despite side effects of cutaneousatrophy, formation of telangiectasia, andhypothalamus-pituitary-adrenal axis suppression.8 Agent selection is based onboth the location and the thickness ofthe plaques. Unfortunately, many patientswill experience disease reactivationonce corticosteroid treatment is discontinued.

Topical calcipotriene, a vitamin D3analogue, and tazarotene, a retinoidanalogue, inhibit epidermal cell proliferationand enhance normal keratinization.The slow onsets of action andfavorable side-effect profiles of theseagents are the reasons for their combinationwith corticosteroid therapy.Their most common side effect is skinirritation, occurring in as many as 25%of patients. Tazarotene should bestrictly avoided in pregnant patientsbecause of its teratogenic effects.

Phototherapy and systemic therapiesare likely treatment options for patientswhose disease is not controlled by topicaltherapy or whose skin involvement issuch that topical therapy is not reasonable(>30% of body surface affected oruse of more than 100 g of a steroidpreparation per day).1,5,9 In many instances,patients will achieve superiorresults if phototherapy is combined withtopical treatments.Oral retinoid productssuch as acitretin also can be combinedwith phototherapy to help reduce thenumber of treatments necessary toachieve remission.

Phototherapy involves controlledexposure to either ultraviolet B or ultravioletA (UVA) light. Psoralen, a prescriptionmedication that has photosensitizingproperties, is given in combination withUVA exposure. Although both therapiesare deemed highly effective, redness orhypopigmentation may occur, and UVAexposure is associated with the developmentof squamous cell carcinoma.

The use of oral immunosuppressivesis limited by their side-effect profiles.Methotrexate inhibits the proliferationof rapidly dividing cells and has a longhistory of use for psoriasis. It commonlycauses nausea and folic acid deficiencyand should be used only in patients withadequate renal function. Long-term useis associated with hepatic fibrosis andcirrhosis, particularly in patients usinghigh-dose regimens or concomitanthepatotoxic agents. Bone marrow suppressioncan occur at any time.Methotrexate is contraindicated inpregnancy.

Cyclosporine decreases the productionof inflammatory cytokines, but it isassociated with hypertension, nephrotoxicity,and disease relapse after discontinuation.It also is associated withmultiple drug interactions, includingazole antifungals, nondihydropyridinecalcium channel blockers, erythromycin,and statins. Interactions with otheragents such as tacrolimus and mycophenolateare still under review.

Biologic Therapy

Biologic therapies for psoriasis thathave emerged over the past 5 yearsrepresent a promising new area in thetreatment of moderate-to-severe psoriasis.These immunosuppressive therapiesare designed to target the cells thatare responsible in the pathogenesis ofthe disease, such as T cells and cytokineTNF-a. Inconvenience and dissatisfactionassociated with topical and oraltherapies have greatly increased patientdemand for these injectable products.Multiple randomized clinical trials supportthe efficacy of biologic therapy incomparison with placebo. No trials havebeen conducted, however, demonstratingtheir efficacy in comparison withone another or with other less invasivetherapies. Unfortunately, the long-termeffectiveness of biologic therapies hasyet to be defined.

Alefacept

Alefacept (Amevive) was the first biologictherapy approved for the treatmentof moderate-to-severe chronic plaquepsoriasis. It inhibits the activation of Tcells, while also selectively eliminatingmemory T cells implicated in psoriasis.Alefacept is administered as a 7.5-mgintravenous (IV) bolus or a 15-mg intramuscularinjection at once-weekly officevisits for 12 weeks.

Chills have occurred in >5% of patientsduring IV administration. T-cell countsshould be performed weekly to monitorthe number of CD4+ T lymphocytes.Therapy may need to be discontinued ifthe CD4+ count falls below 250 cells/?Lduring a 1-month period.

A second 12-week course can begiven if at least 12 weeks have passedsince completion of the first course.Alefacept has reduced disease severityby 75% in up to 40% of patients, withremissions lasting as long as 1 year.2There are currently no data to supportgiving more than 2 cycles of alefacepttreatment.

Efalizumab

Efalizumab (Raptiva) is an anti-CD11aIgG1 antibody that inhibits the activationand migration of T lymphocytes. In contrastto alefacept, efalizumab shouldbe taken continuously, because the resultsare reversible on discontinuation.Efalizumab is self-administered as aonce-weekly subcutaneous (SC) injectionof 1 mg/kg, following a 1-time conditioningdose of 0.7 mg/kg.

Because of the 0.3% incidence ofthrombocytopenia observed in a clinicaltrial, monitoring of platelet counts is recommended.Other side effects includeinfluenza-like symptoms and transientpruritic skin eruptions in previously uninvolvedflexural sites.Efalizumab has demonstrated clearingof psoriatic lesions in up to 33% ofpatients after 12 weeks of therapy. Longtermefficacy data are limited to 27months.2

Infliximab

Infliximab (Remicade) is approved forchronic-severe plaque psoriasis and psoriaticarthritis. It is an anti-TNF-achimeric monoclonal antibody that has along history of success in patients withrheumatoid arthritis and Crohn's disease.

TNF-ais implicated in the pathogenesisof psoriasis by inducing the synthesisof many cytokines, resulting in inflammationand abnormal growth of skin cells.Infliximab has demonstrated skin clearingin up to 90% of plaque psoriasispatients after 10 weeks of therapy.2

The drug is administered as a slow IVinfusion of 5 mg/kg over 2 hours. Infusionsare repeated at 2 weeks, 6 weeks,and every 8 weeks thereafter. An infusion-related reaction occurs in as manyas 20% of patients and is the most commonside effect experienced. There is a"black-box" warning regarding thepotential risk of infection with the use ofinfliximab.

It is recommended that patients begiven a tuberculin skin test prior to theinitiation of drug therapy to rule outlatent infection. Infliximab should not beadministered to patients with activeinfections or demyelinating diseases andshould be used with caution in patientswith congestive heart failure.

Etanercept

The effectiveness of etanercept(Enbrel), another anti-TNF-aantibody, hasbeen demonstrated in psoriatic arthritisand chronic moderate-to-severe plaquepsoriasis. Etanercept is self-administeredas a once-weekly 50-mg SC injection.Patients using etanercept for plaque psoriasisshould initiate it with a 3-monthphase in of 50-mg SC twice weekly.

More than 50% of patients haveachieved skin clearing of their plaquepsoriasis after 12 weeks of treatment.Long-term efficacy has not been establishedbeyond 2 years of therapy.2Etanercept has a side-effect profile andsafety concerns similar to those withinfliximab.

Conclusion

Psoriasis is a lifelong disease with aprofound burden on the affected individuals.Most patients will require topicaltherapy in addition to lifestyle modification.Oral immunosuppressives or phototherapiesare a more aggressive treatmentstrategy for the small percentageof patients whose disease is inadequatelycontrolled by topical medications.

Biologic therapy offers a treatmentoption that targets instigators of diseaseactivity. The high cost of injectible therapymay be offset by decreased overallhealth care utilization and improvementsin quality of life in patients who requirethis level of management.

Dr. Pechie is a clinical pharmacist withMemorial Hospital of Rhode Island. Dr.Hull is a pharmacist with Stop andShop Pharmacy. Ms. Hayden is managerof analytical services with AdvancedPharmacy Concepts.

For a list of references, send a stamped, selfaddressedenvelope to: References Department,Attn. A. Rybovic, Pharmacy Times, AscendMedia Healthcare, 103 College Road East,Princeton, NJ 08540; or send an e-mailrequest to: arybovic@ascendmedia.com.