psoriasis: a clinical update on diagnosis and new therapies

R E V I E W

C H A R L E S C A M I S A , M D Vice chairman, Department of Dermatology, and head, Section of Clinical Dermatology, Cleveland Clinic

Psoriasis: A clinical update on diagnosis and new therapies

A B S T R A C T Psoriasis varies widely in its clinical expression, from a single fingernail pit to widespread disfiguring skin lesions and disabling arthritis. Treatments are divided into five levels, providing a framework for approaching this disease according to severity and recalcitrance to previous treatment. Powerful immunosuppressive drugs are showing some success in treating severe cases.

KEY P O I N T S Flare-ups of psoriasis can be triggered by trauma, cold weather, infections, drugs, and a compromised immune system.

Topical treatments, especially corticosteroids, are most commonly used, but newer vitamin D3 analogs (eg, calcipotriene) and retinoids (eg, tazarotene) may be more effective.

Phototherapy (ultraviolet B or the combination of psoralen and ultraviolet A) is highly effective for moderate to severe psoriasis.

Systemic therapy with acitretin, methotrexate, or cyclosporine is reserved for the most recalcitrant or severe cases of psoriasis.

Consider referring to a dermatologist if 20% or more of the body surface is involved.

RIMARY CARE PHYSICIANS see 5 8 % of new cases of psoriasis,1'2 although der-

matologists handle 80% of the 1.5 million office and hospital visits for psoriasis each year in the United States.3 This fact, coupled with the current trend toward managed heal th care delivery, reinforces the need for primary care clinicians and internists to recognize the vari-ous forms of psoriasis and to keep abreast of current therapies and their safe and effective use, and when to refer to a dermatologist, all of which this article reviews.

• GENERAL HALLMARKS OF PSORIASIS

Psoriasis is a single disease with several mor-phologic expressions and a full range of sever-ity. The form that psoriasis takes in an indi-vidual pa t ient likely depends on genetic influences, environmental factors (eg, trau-ma and climate), associated diseases (espe-cially infections), medications, and immuno-logic status.

The mean age at onset is 30 years, but the range is the full spectrum of human life. Men and women are affected equally, but women may be affected earlier than men. T h e severi-ty ranges from a single fingernail pit to skin lesions covering the entire body surface and disabling arthritis.

T h e most common pattern is symmetric, inf lammatory, and papulosquamous. T h e classic skin lesions—thick, erythematous, itchy patches covered with silvery scales— usually confirm the diagnosis, but examina-tion of scales using potassium hydroxide to look for hyphal elements (ie, fungal infec-tion), serologic testing to rule out syphilis, and skin biopsy to rule out other inflammato-ry skin diseases such as eczema, pityriasis

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P S O R I A S I S C A M I S A

The cause of psoriasis likely lies in the genome and the immune system

FIGURE 1. T h e classic f u l l y d e v e l o p e d sk in l es ion o f psor ias is v u l g a r i s .

rubra pilaris, drug reactions, and cutaneous T-cell lymphoma.

The Koebner p h e n o m e n o n In some patients, a scratch, burn, or surgical incision leads to a flare-up of psoriasis in the area of the trauma. This effect, known as the Koebner p h e n o m e n o n or i somorphic response, is more likely in patients with unstable psoriasis.

T h e Koebner phenomenon also occurs in lichen planus, vitiligo, and other skin dis-eases. Routine daily trauma may be partly responsible. Cer ta in drugs (eg, l i thium, anti-malarials, beta-adrenergic blockers, calcium channe l blockers, ang io tens in-conver t ing enzyme inhibitors, interferons) have been associated with an "endogenous Koebner phenomenon ," inducing psoriasis or aggra-vating preexisting disease in some patients.4

Emotional stress may also cause cutaneous nerve fibers to release peptides, which can evoke inflammation or proliferation, thereby representing another endogenous Koebner phenomenon. 4

Proposed causes of psoriasis T h e cause of psoriasis is still not known, but experts agree that the lesions are the result of hyperproliferation and abnormal differentia-tion of the epidermis.

T h e primary pathologic process likely lies in the immune system, specifically an aberra-tion in the regulation of interleukin-2, growth factors, or adhesion molecules. Evidence for this theory comes from success in treating severe psoriasis with immunosuppressive drugs used in organ transplantation.4

• CLINICAL EXPRESSIONS OF PSORIASIS

P laque- type psoriasis Plaque-type psoriasis, or psoriasis vulgaris, is the most common form, occurring in 75% to 80% of all psoriasis patients. W h e n fully developed, the lesion is a well-demarcated, red-violet, round or oval plaque 1 cm or larger in diameter surmounted by white silvery scales, overlying bony prominences ( F I G U R E 1 ) .

In darkly pigmented patients, lesions are hyperpigmented with various shades of brown or black, especially if the patient scratches or rubs them.

T h e most commonly involved areas are the elbows, knees, scalp, sacrum, umbilicus, intergluteal cleft, and genitalia, and all of these areas should be examined: any one of them may be the solitary site.

G u t t a t e psoriasis Gut ta te psoriasis, named for its droplet-shaped lesions ( F I G U R E 2 ) , accounts for about 1 8 % of all cases, more commonly among children and young adults.5 Guttate lesions range in diame-ter from 0.1 to 1.0 cm and are not as indurat-ed or scaly as the lesions of plaque-type psori-asis. They predominate on the trunk and prox-imal areas of the extremities and are likely to involve the face.

Gut ta te psoriasis may be the initial mani-festation of psoriasis, or it may represent an acute flare of preexisting chronic plaque-type psoriasis. Patients frequently have a history of upper respiratory tract infection, laryngitis, or tonsillitis.

Streptococci and guttate psoriasis. Some cases of acute guttate flares are believed to have been precipitated by infection with groups A, C, and G streptococci.6 Leung et al7 showed that acute guttate psoriasis follow-ing streptococcal th roa t infec t ion in 10 pa t ien ts was the result of s t reptococcal exotoxin C, which acts as a superantigen and activates CD4 + and CD8 + T cells in the lesions and the areas around them. Researchers hypothesize that these T cells persist in the skin of patients who go on to develop chronic plaque-type psoriasis, because the T cells mistakenly recognize skin autoantigens such as keratins and carbohy-drates as bacterial antigens.

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Pustular psoriasis Pustular psoriasis accounts for perhaps 1.7% of cases.4 It is characterized by sterile pus-tules either localized to the palms and soles or generalized. T h e average age at onset is 50 years.

Localized pustular psoriasis. T h e erup-tion is chronic and recurring and is recogniz-able by yellowish pustules on a background of redness and scaling on the palm (thenar and hypothenar eminences) or on the instep of the sole and side of the heel ( F I G U R E 3 ) , or on both areas. Lesions are observed in all stages of development, including vesicles, vesico-pustules, frank pustules, and dried brown maculopapules. There is a female predomi-nance.

Generalized (von Zumbusch) pustular psoriasis may develop de novo or from preex-isting plaque-type psoriasis and is character-ized by fiery-red, irregular patches with round, arcuate, serpiginous borders, over which are seen tens of thousands of 1-mm to 2-mm superficial pustules (F I G U R E 4 ) . These tend to occur in flexural or skin-fold areas (armpits, groin, under the breasts) but may occur any-where. T h e pustules coalesce into lakes of pus, desquamate, and form new pustules as the bor-der moves in waves every 24 to 72 hours. Most patients have fever, leukocytosis, hypocal-cemia, and hypoalbuminemia. T h e incidence is equal in men and women.

Ryan and Baker8 reported that 37 (24%) of 155 patients had their first attack of generalized pustular psoriasis within 1 month of either starting or stopping systemic corticosteroids, and they concluded that the steroids provoked the attacks. Other precipitating factors includ-ed infection and other drugs. Methotrexate was less effective in patients who previously received systemic corticosteroids.

Ohkawara et al9 recently reviewed 208 cases of recurrent generalized pustular psoria-sis and found that cases in patients with pre-ceding plaque-type psoriasis were more likely to have been triggered by corticosteroids, whereas cases in patients without a history of psoriasis were more likely to have been trig-gered by infection.

Erythrodermic psoriasis Exfoliative dermatitis or psoriatic erythroder-

FIGURE 2. G u t t a t e psor ias is o n t h e u p p e r back r e p r e s e n t i n g a n a c u t e f l a r e o f p r e e x -i s t i n g c h r o n i c psor ias is o f t h e l o w e r back a n d b u t t o c k s . Streptococcal

infection may precipitate flare-ups of guttate psoriasis

FIGURE 3. Loca l i zed p u s t u l a r psor iasis o f t h e soles.

ma accounts for only 1% to 2% of all cases of psoriasis, making it the least common form.

Erythroderma in general is defined as a scaling pruritic, inflammatory process of the skin that involves all or almost all of the body surface. Erythrodermic psoriasis (F I G U R E 6 ) usu-ally develops gradually or acutely during the

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Up to 50% of psoriasis patients have nail involvement

FIGURE 4. G e n e r a l i z e d p u s t u l a r psor ias is o f v o n Z u m b u s c h s h o w i n g w a v e s o f a n n u l a r p i n p o i n t pus tu les f o l l o w e d by d e s q u a m a t i o n .

course of chronic plaque-type psoriasis, but it may be the first manifestation of psoriasis, even in children. T h e mean age at onset is about 50 years. Male patients outnumber female patients. Sterile pustules may develop in some areas of erythrodermic psoriasis. In patients with the most unstable cases (ie, those with inflammation), generalized pustu-lar psoriasis may develop. Concomitant psori-atic arthropathy is common.

Precipitating factors for erythrodermic psoriasis include systemic illnesses, emotional stress, and alcoholism, but the most important ones seem to be related to treatment, especial-ly the inappropriate or excessive use of potent topical, oral, and intramuscular corticos-teroids.10

Patients are at risk for Staphylococcus aureus septicemia owing to their compromised skin barrier and, in some, because of immuno-suppressive drugs.11

Nail psoriasis Up to 50% of patients with psoriasis have involvement of the nails; in patients with pso-riatic arthritis the incidence is more than 80%.12

Fingernails are affected more of ten than toenails. Pitting of the nail plate is the most common manifestation. T h e pits tend to be large, deep, and randomly dispersed on the nail plate. Small red spots in the lunula or yel-low-brown spots (the "oil droplet" sign) in the nail bed correspond to early guttate lesions of psoriasis there. T h e nail plate may thicken, with dispersed deep pitting and ridging, which

causes crumbling. The distal nail plate may separate from the nail bed (onycholysis). Splinter hemorrhages are very common after minor trauma.

Link with arthropathy. T h e severity of skin and nail involvement does not correlate with the severity of joint disease in patients with psoriatic arthritis. However, psoriatic involvement of the fingernail is significantly associated with arthropathy of the adjacent distal interphalangeal joint. Whereas the most frequent fingernail change is pitting, subun-gual hyperkeratosis is the most common toe-nail change in psoriatic arthritis.

• PSORIASIS THERAPY: A N OVERVIEW

Treatments for psoriasis are divided into five levels ( T A B L E I).4 T h e choice of t reatment depends on the severity and response in the individual patient.

Level 1: Topical t r e a t m e n t s Emollients (bland lubricants) should be tried first, followed by keratolytic lotions. Topical corticosteroids and calcipotriene ointment or cream can be used by internists for psoriasis involving less than 20% of the body surface area. Most nondermatologists would probably not use anthralin, crude coal tar, or tazarotene, as these are inelegant (messy, inconvenient to use, and with a bad odor) and have a high irri-tation potential; coal tar gels, often available over the counter, are more elegant though less efficacious.

Level 2: Phototherapy All forms of phototherapy are highly effective (80% to 100%) at clearing skin, but some maintenance is necessary. Disadvantages are the requirement for specialty care, the need for office visits two or three times a week, expense, maintenance therapy, theoretical short-term risks of sunburn, and long-term risk of skin cancer.

Beyond natural sunlight and tanning beds, phototherapy is given by dermatologists in the office or clinic and is reserved for patients with widespread lesions involving 20% or more of the body surface area. Specialized equipment and training is neces-sary for delivery of phototherapy.

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Phototherapy is highly effective at clearing the skin

T A B L E 1

T r e a t m e n t s f o r p s o r i a s i s Level 1: Topical therapies

Emollients Keratolytics

Salicylic acid Lactic acid Urea

Calcipotriene Anthralin (usually short contact) Corticosteroids

Topical Hydrocolloid occlusive dressing Intralesional injections

Coal tar Tazarotene

Level 2: Phototherapies Natural sunlight Ultraviolet B light Ultraviolet B light + coal tar (Goeckerman regimen)

Ultraviolet B light + anthralin (Ingram regimen)

Ultraviolet B monochromatic light (311 nm) Ultraviolet A light

Level 3: Systemic therapies (high efficacy, high toxicity)

Psoralen + ultraviolet A light Psoralen + ultraviolet A light + ultraviolet B light Acitretin (may be combined with ultraviolet B light or with psoralen + ultraviolet A light)

Methotrexate Cyclosporine

Level 4: Systemic therapy (moderate efficacy, low to moderate toxicity)*

Sulfasalazine Hydroxyurea Calcitriol Antibiotics

Level 5: Innovative systemic therapy (moderate efficacy, high toxicity)*

Azathioprine 6-Thioguanine Mycophenolate mofetil Tacrolimus

*Not approved for psoriasis treatment by the US Food and Drug Administration

Level 3: Systemic t rea tments Systemic treatments are more effective than level 2 treatments but are often more expen-sive and have greater potential for toxicity. (In general, topical therapies are less toxic than phototherapies, which are less toxic than systemic therapies.) Systemic treatments are generally prescribed only by a dermatologist.

Levels 4 and 5: Experimental t r e a t m e n t s Treatments in level 4 and level 5 are no t approved by the U S Food and Drug Administration. Level 4 treatments are weak-ly to moderately effective but are less toxic than level 5 treatments, which are reserved for the most severe and recalcitrant cases, including arthropathy.

W h e n to refer to a dermato log is t Consider referring to a dermatologist if 20% or more of the body surface area is involved; the disease fails to respond to emollients, ker-atolytics, topical steroids, calcipotriene, nat-ural sunlight, or tanning treatment bed; or for any form of pustular or erythrodermic psoria-sis. Whenever possible, avoid using systemic steroids in psoriatic patients.

M a n a g e m e n t of severe psoriasis The management of patients with psoriatic erythroderma or pustular psoriasis includes admission to the hospital for evaluation, sup-portive care, and conservative treatment until the patient is stable enough to receive aggres-sive, conventional antipsoriatic therapy.

Severe psoriasis can usually be controlled eventually with the standard regimen of ultra-violet B light plus coal tar, or with psoralen-ultraviolet A light therapy, acitretin, metho-trexate, or cyclosporine. T h e disease reverts back to its previous state (either plaque-type psoriasis or clear). Systemic and potent topi-cal corticosteroids are to be avoided. A minor-ity of patients remain unstable and have repeated episodes of erythroderma or pustula-tion during their lifetime.

Treating localized pustular psoriasis. Recalcitrance to therapy is the rule for local-ized pustular psoriasis of the palms and soles. Topical keratolytics, corticosteroids, tars, and ultraviolet B light are generally ineffective, and systemic agents such as methotrexate give

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inconsistent results. T h e most effective treat-ment reported to date with the largest number of patients is the aromatic retinoid acitretin, 30 to 50 mg per day by mouth, either alone or combined with psoralen-ultraviolet A thera-py.13 Long-term maintenance therapy is then required to prevent relapse.

Nail psoriasis. N o topical therapy is suc-cessful for nail bed psoriasis. However, injec-tions of triamcinolone acetonide suspension 5 mg/cc diluted with 1% lidocaine into the proximal and lateral nail folds4 may be effec-tive. This procedure is usually done in a der-matologist's office. T h e disadvantages are that it is painful for the patient and tedious for the clinician. The injections must be repeated at monthly intervals until the desired effect is obtained, and then at some less frequent inter-val for maintenance.

Whi le the best systemic medication for nail psoriasis is probably methotrexate, most clinicians would not use it for nail psoriasis alone unless the psoriasis was disabling or destructive.

• ORAL RETINOID THERAPY FOR PSORIASIS: SPECIAL CONSIDERATIONS

Ret inoids are natural ly or synthet ical ly derived from vitamin A (retinol) and have ant i - inf lammatory, ant ikerat inizing, and antiproliferative effects on the skin. T h e two aromat ic retinoids approved for psoriasis therapy are etretinate and acitretin. T h e drugs are given orally but may be combined with topical therapy (not tazarotene) or ultraviolet light. T h e therapeutic results with these drugs have been good to excellent, especially in combination with other con-vent ional treatments.14.15

Etretinate accumulates in adipose tissue and is eliminated slowly after discontinuation. Aci t re t in , the main active metaboli te of etretinate, was developed to avoid these prob-lems. However, tests using a new chromatog-raphy tssay detected etretinate in the plasma and subcutaneous fat of a woman 4-3 years after she stopped taking acitretin,16 indicating that acitretin may in fact be esterified in vivo to etretinate. Alcohol consumption and possi-bly even excess body fat may enhance this reaction.

Adverse effects of oral ret inoids With the exception of teratogenicity, the side effects of oral retinoids, while numerous, are generally not serious. The most common and frequently troublesome side effects are dryness of the skin and mucous membranes, hair loss, and nail changes. Patients taking etretinate or acitretin for years may develop diffuse idio-pathic skeletal hyperostosis-like (dish-like) involvement of the spine. Extraspinal tendon and ligament calcifications are more common. Many of these changes are asymptomatic, and well-established guidelines for monitoring skeletal toxicity are lacking.

A rare idiosyncratic hepatic reaction has been reported in about 1.5% of patients taking etretinate.

Lipid effects. Retinoids cause hyperlipi-demia, especially elevations of serum triglyc-eride and decreases in high-density lipopro-tein cholesterol. Experimental evidence sup-ports the hypothesis that retinoids induce increased synthesis of apoprote in B and triglycerides.17 Fish oil supplements given to patients receiving etretinate or acitretin sig-nificantly decrease triglyceride levels in every patient. Gemfibrozil is also useful in patients with hyperlipidemia due to acitretin who are recalcitrant to dietary manipulation and dose reductions.

U s e in pregnancy. 1 usually reserve acitretin for male patients or for women who are not of childbearing age. Fertile women with severe psoriasis who take acitretin must follow strict two-method contraception or abstinence and have monthly pregnancy tests. New that it is known that acitretin may be converted to etretinate and stored in fat, guidelines recommend that patients abstain from alcohol during treatment and avoid preg-nancy during and for 3 years after terminating treatment.

Tazarotene: A newer, topical ret inoid Tazarotene (Tazorac), a new topical receptor-selective retinoid, alleviates psoriasis by nor-malizing keratinocyte differentiation, inhibit-ing cell proliferation, and decreasing the expression of inflammatory markers. In a study,18 tazarotene gel 0.1% applied once daily for 12 weeks produced a 65% improvement in psoriatic plaques compared with a 30%

Most systemic therapies for psoriasis are effective for psoriatic arthritis

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improvement with vehicle gel (a typical placebo response). Although systemic absorp-tion of tazarotene after topical application is minimal, the product information recom-mends obtaining a pregnancy test before start-ing therapy and using effective contraception during therapy.

U p to 80% of patients developed skin irri-tation while using this agent in studies, and most would probably stop using it unless close-ly followed. Research is continuing into newer receptor-specific drugs that may eventually bypass irritation and teratogenicity.

• METHOTREXATE THERAPY FOR PSORIASIS: SPECIAL CONSIDERATIONS

Methotrexate, first used for psoriasis in 1958, is the antimetabolite most often prescribed by dermatologists for this disease. Double-blind, controlled studies confirmed the superiority of methotrexate compared with placebo in improving skin manifestations, joint symptoms, and function in psoriatic patients. A good to excellent response (50% to 100% clearing of psoriasis) occuned in 70% of patients with severe disease using a single weekly oral dose of methotrexate (20 to 37.5 mg).19

Adverse effects T h e most common adverse effects of methotrexate therapy are nausea, anorexia, fatigue, headache, and alopecia. Oral ulcera-tions generally do not occur at the doses nor-mally used for psoriasis treatment, and if they do, they indicate toxic serum levels due to drug interactions, dehydration, overdose, or deterioration of renal function. Bone marrow depression is also more likely to occur under these circumstances.

M o n i t o r i n g for liver d a m a g e during methot rexa te therapy Hepatotoxicity is the primary clinical concern when planning long-term methotrexate ther-apy. Mild elevations (less than twice the upper limit of normal) of transaminase levels are to be expected during therapy, but these levels do not correlate with hepatic fibrosis.

Because liver disease is less common in rheumatoid arthritis patients taking metho-trexate than in psoriasis pat ients taking

methot rexate , recommendat ions for liver biopsy from different organizations differ. For example, the Amer ican College of Rheumatology does not recommend liver biopsy during treatment unless 5 of 9 or 6 of 12 aspartate aminotransferase levels in a 12-month period are elevated, or unless the serum albumin concentration decreases below normal.2 0 Many rheumatologists have adopt-ed the same guidelines for monitoring patients with psoriatic arthritis. O n the other hand, 1988 guidelines from the American Academy of Dermatology21 recommended a liver biopsy at baseline. However, 1998 guidelines from the same organization22 eliminated this rec-ommendation, unless the patient has signifi-cant risk factors. The initial liver biopsy is done after a 1- to 1.5-g cumulative dose and is repeated after 3- and 4-g cumulative doses. Liver biopsy should not be performed in elder-ly patients, during acute illness, or in patients with limited life expectancy, or if there are medical contraindications to the procedure.

Folic acid. I recommend folic acid supple-mentat ion 1 mg/day because it mitigates the gastrointestinal effects of methotrexate (nau-sea, diarrhea, elevated liver enzymes) without altering its efficacy, and also because it pre-vents megaloblastic anemia due to folic acid deficiency.23

• CYCLOSPORINE THERAPY FOR PSORIASIS: SPECIAL CONSIDERATIONS

Cyclosporine is very effective for psoriasis, but it does not cure it and does not induce remis-sions tha t are more durable than those achieved, for example, with psoralen-ultravio-let A therapy. To maintain a prolonged remis-sion, one must cont inue cyclosporine or change to another systemic therapy. Stopping cyclosporine or giving a suboptimal dose allows skin lesions to recur at a rate and sever-ity consistent with the natural history of an individual's disease.

Cyclosporine interferes directly with T cell activation and communication with anti-gen-presenting cells by inhibiting the synthe-sis or expression of interleukin-1, interleukin-2, and interleukin-2 receptor. In psoriatic lesions, cyclosporine also inhibits the epider-mal cytokine network.

Women of childbearing age taking acitretin must use two birth control methods

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Guidelines differ for liver biopsy during methotrexate treatment

Since cyclosporine therapy is reserved for severe cases of psoriasis and is usually given by a specialist, a detailed discussion of its use is beyond the scope of this paper. T h e two most important side effects of cyclosporine, requiring baseline evaluation, constant mon-itoring, and in te rvent ion (medical treat-ment , dose reduction, or discontinuation of cyclosporine), are nephrotoxicity and hyper-tension.

• EXPERIMENTAL TREATMENTS FOR PSORIASIS

V i tamin D 3 and analogs Vitamin D3 (calcitriol) and the synthetic analogs calcipotriene and tacalcitol, all in top-ical form, are effective for plaque-type psoria-sis and are free of any serious toxicity. 24 In double-blind studies, patients applied cal-cipotriene to one side of their body and corti-costeroids to the other side. Calcipotriene was equivalent to or better than medium and potent corticosteroid ointments without the risk of skin atrophy or rebound flare-ups upon discontinuation of therapy. In open trials,25

patients taking oral calcitriol showed dramat-ic improvement but experienced significant hypercalcemia, hypercalciuria, and nephro-toxicity. N o placebo-controlled study of oral calcitriol alone has been performed. However, oral calcitriol had no additive effect compared with placebo when combined with 21 erythe-mogenic ultraviolet B treatments.2 6

Hydroxyurea in recalci trant psoriasis T h e antimetabolite hydroxyurea plays a minor role in the treatment of recalcitrant psoriasis. In one trial,27 60% percent of pat ients achieved "complete to near complete clear-ing" with a starting dose of 1.5 g daily and a maintenance dose ranging from 0.5 to 1.5 g daily. Adverse reactions are common, notably cytopenia and macrocytosis. Hydroxyurea is not effective for pustular or erythrodermic psoriasis or psoriatic arthritis.

Thiopur ine an t imetabo l i t es Thiopurine antimetabolites—ie, azathioprine, mercaptopurine (6-mercaptopurine, 6-MP), and thioguanine (6-thioguanine, 6 -TG)—are used as immunosuppressive and steroid-spar-

ing agents for many diseases. All inhibit D N A synthesis. Azathioprine is metabolized to 6-MP, which is then converted to 6-MP ribotide.

In a study of azathioprine in 29 patients with severe plaque-type psoriasis as well as ery-throderma and pustular variants, 19 (66%) of 29 benefited with 50% to 100% improvement on doses of 75 to 200 mg/day.28 T h e main side effects are gastrointestinal and hematologic.

In a study of 6-TG in patients with recal-citrant plaque-type psoriasis, marked improve-ment occurred in 50% to 70% of patients treated with a pulse-dosing schedule of 120 mg twice weekly to 160 mg thrice weekly.29

Palmoplantar pustulosis and generalized pus-tular psoriasis may also respond very well to 6-T G . 3 0 T h e response is usually evident within 12 weeks of starting therapy. T h e chief toxici-ty of 6 -TG is myelosuppression.

Mycophenol ic acid Mycophenolic acid inhibits de novo synthesis of guanosine nucleotide, thereby selectively suppressing proliferation of T and B lympho-cytes.31 Double-blind placebo-controlled trials confirmed its efficacy in psoriasis (68% decrease in mean severity scores) after 12 weeks, and patients were subsequently treated with 1.6 to 4-8 g/day for 2 years.32 T h e main side effects are gastrointestinal and genitouri-nary. T h e incidence of herpes zoster was increased. T h e sponsor discont inued the national clinical trial in 1977.

steroid-sparing agent for Sulfasalazine Sulfasalazine is inflammatory bowel disease and is also a sec-ond-line therapy for rheumatoid arthritis and ankylosing spondylitis. It may have anti-inflammatory activity in these diseases and psoriasis by inhibiting 5-lipoxygenase.

In a double-blind study,33 17 patients with psoriasis received sulfasalazine 3 to 4 g/day. Of these, 7 had a marked response, 7 had a mod-erate response, and 3 had a minimal response.

Side effects (anorexia, nausea, vomiting, fatigue, headaches, cutaneous eruptions) are common and, while usually not severe, fre-quently lead to discontinuation of treatment before any therapeutic benefit can occur. T h e incidence of drug-induced rash may be as high as 18%.

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A lower dose of sulfasalazine than is needed for cutaneous psoriasis may he effective for arthropathy. Two large multicenter double-blind studies of sulfasalazine at 2 g/day for psori-atic arthritis showed trends favoring a response to sulfasalazine, with decreased pain and decreased erythrocyte sedimentation r a t e . 5 4 , 3 5

Tacrolimus T h e macrolide lactone tacrolimus (Prograf), formerly known as FK506, is an immunosup-pressive drug chemically unrelated to

cyclosporine that inhibits T lymphocyte acti-vation. T h e first double-blind trial36 showed that tacrolimus was effective in improving severe plaque-type psoriasis by 83% after 9 weeks at doses of 0.05 to 0.15 mg/kg/day. Mild hypertension and mild to moderate renal dys-function developed infrequently. Additional studies with larger numbers of patients treated long-term will be necessary to elucidate opti-mal dosing schedules and the toxicity profile of systemic tacrolimus. Tacrolimus ointment has proven ineffective in psoriasis.37 •

• REFERENCES 1. K i r s n e r RS, F e d e r m a n DG. M a n a g e d ca re : T h e d e r m a t o l o g i s t as a p r i -

m a r y c a r e p r o v i d e r . J A m A c a d D e r m a t o l 1995; 3 3 : 5 3 5 - 5 3 7 . 2 . B o h m M , V o o r h e e s J, a n d t h e C o m m i t t e e o n Psor ias is . W h i t e p a p e r o n

h o s p i t a l i z a t i o n f o r psor ias is ca re . J A m A c a d D e r m a t o l 1984 ; 1 0 : 8 4 2 - 8 5 1 .

3. S t e r n RS. U t i l i z a t i o n o f o u t p a t i e n t c a r e f o r psor ias is . J A m A c a d D e r m a t o l 1996 ; 3 5 : 5 4 3 - 5 4 5 .

4 . C a m i s a C. H a n d b o o k o f Psoriasis. M a i d e n , M A : B l a c k w e l l Sc ience, 1998. 5. N a n d a A , K a u r S, K a u r I, K u m a r B. C h i l d h o o d psor ias is : a n e p i d e m i o -

l o g i c s u r v e y o f 112 p a t i e n t s . P e d i a t r D e r m a t o l 1990 ; 7 : 1 9 - 2 1 . 6. H e n d e r s o n CA , H i g h e t AS . A c u t e psor ias is a s s o c i a t e d w i t h L a n c e f i e l d

g r o u p C a n d g r o u p G c u t a n e o u s s t r e p t o c o c c a l I n f e c t i o n s . Br J D e r m a t o l 1988 , 1 1 8 : 5 5 9 - 5 6 2 .

7. L e u n g DY, T r a v e r s e JB, G i o r n o R, e t a l . E v i d e n c e f o r a s t r e p t o c o c c a l s u p e r a n t i g e n - d r i v e n p rocess i n a c u t e g u t t a t e psor ias is . J C l i n Inves t 1985 ; 9 6 : 2 1 0 6 - 2 1 1 2 .

8. R y a n TJ, B a k e r H. T h e p r o g n o s i s o f g e n e r a l i z e d p u s t u l o p s o r i a s i s . Br J D e r m a t o l 1 9 7 1 ; 8 5 : 4 0 7 - 4 1 1 .

9. O h k a w a r a A , Y a s u v a H, K o b a y a s h i H, e t a l . G e n e r a l i z e d p u s t u l a r pso -r iasis i n J a p a n : t w o d i s t i n c t g r o u p s f o r m e d b y d i f f e r e n c e s a n d s y m p -t o m s a n d g e n e t i c b a c k g r o u n d . A c t a D e r m V e n e r e o l 1996 ; 7 6 : 6 8 - 7 1 .

10. B o y d AS, M e n t e r A . E r y t h r o d e r m i c psoriasis. P r e c i p i t a t i n g fac to rs , course , a n d p r o g n o s i s in 50 p a t i e n t s . J A m A c a d D e r m a t o l 1989; 2 1 : 9 8 5 - 9 9 1 .

11. M c F a d y e n T, Lye l l A . Success fu l t r e a t m e n t o f g e n e r a l i z e d p u s t u l a r pso-r ias is ( v o n Z u m b u s c h ) b y s y s t e m i c a n t i b i o t i c s c o n t r o l l e d by a b l o o d cu l -t u r e . Br J D e r m a t o l 1971; 8 5 : 2 7 4 - 2 7 6 .

12. J o n e s S M , A r m a s JB, C o h e n M G , e t a l . P s o r i a t i c a r t h r i t i s : o u t c o m e o f d i s e a s e s u b s e t s In r e l a t i o n s h i p o f j o i n t d i s e a s e t o n a i l a n d s k i n d i s e a s e . B r J R h e u m a t o l 1 9 9 4 ; 3 3 : 8 3 4 - 8 3 9 .

13. R o s e n K, M o b a k e n H, S w a n b e c k B. P U V A , e t r e t i n a t e , a n d P U V A - e t r e t l -n a t e t h e r a p y f o r p u s t u l o s i s p a l m o p l a n t a r i s . A r c h D e r m a t o l 1987 ; 1 2 3 : 8 8 5 - 8 8 9 .

14. El l is C N , V o o r h e e s JJ. E t r e t i n a t e t h e r a p y . J A m A c a d D e r m a t o l 1987 ; 1 6 : 2 6 7 - 2 9 1 .

15. G o l d f a r b M J , El l is CN, G u p t a A K , e t a l . A c i t r e t i n i m p r o v e s psor ias i s i n a d o s e - d e p e n d e n t f a s h i o n . J A m A c a d D e r m a t o l 1988 ; 1 8 : 6 5 5 - 6 6 2 .

16. M a i e r H, H o n i g s m a n n H. C o n c e n t r a t i o n o f e t r e t i n a t e i n p l a s m a a n d s u b c u t a n e o u s f a t i n 10 f e m a l e p a t i e n t s w i t h l o n g t e r m a c i t r e t i n t r e a t -m e n t [ a b s t r a c t ] , Br J D e r m a t o l 1996 ; 135 :837 .

17. A s h l e y J M , L o w e NJ, El l is CN. R e t i n o i d s a n d a l t e r a t i o n s i n l i p i d m e t a b -o l i s m . In: R o e n i g k H H Jr, M a l b a c h HI, eds. Psor iasis. 2 n d e d . N e w Y o r k : M a r c e l D e k k e r , 1 9 9 1 : 7 4 9 - 7 5 5 .

18. W e i n s t e i n G G . S a f e t y , e f f i c a c y , a n d d u r a t i o n o f t h e r a p e u t i c e f f e c t o f t a z a r o t e n e u s e d i n t h e t r e a t m e n t o f p l a q u e p s o r i a s i s . Br J D e r m a t o l 1 9 9 6 ; 1 3 5 S u p p l 4 9 : 3 2 - 3 6 .

19. R o e n i g k H H Jr, B e r g f e l d WF, C u r t i s G H . M e t h o t r e x a t e f o r pso r ias i s i n w e e k l y o r a l doses . A r c h D e r m a t o l 1969 ; 9 9 : 8 6 - 9 3 .

20 . H a s s a n W . M e t h o t r e x a t e a n d l i ve r t o x i c i t y : r o l e o f s u r v e i l l a n c e l i ve r b i o p s y : c o n f l i c t b e t w e e n g u i d e l i n e s f o r r h e u m a t o l o g i s t s a n d d e r m a t o l -og i s t s . A n n R h e u m Dis 1996 ; 5 5 : 2 7 3 - 2 7 5 .

21 . R o e n i g k H H Jr, A u e r b a c h R, M a i b a c h HI, W e i n s t e i n G D . M e t h o t r e x a t e i n psor ias is : r ev i sed g u i d e l i n e s . J A m A c a d D e r m a t o l 1988; 1 9 : 1 4 5 - 1 5 6 .

22. R o e n i g k H H Jr, A u e r b a c h R, M a i b a c h HI , e t a l . M e t h o t r e x a t e i n p s o r i a -sis: c o n s e n s u s c o n f e r e n c e . J A m A c a d D e r m a t o l 1998 ; 3 8 : 4 7 8 - 4 8 5 .

23. M o r g a n SL, B a g g o t t JE, V a u g h n W H , e t a l . S u p p l e m e n t a t i o n w i t h f o l i c a c i d d u r i n g M e t h o t r e x a t e t h e r a p y f o r r h e u m a t o i d a r t h r i t i s . A d o u b l e -b l i n d p l a c e b o - c o n t r o l l e d t r i a l . A n n I n t e r n M e d 1994 ; 1 2 1 : 8 3 3 - 8 4 1 .

24. B e i e n N K , B j e r k e JR, R o s s m a n n - R i n g d a h l I, J a c k s o n H B . O n c e - d a i l y t r e a t m e n t o f p s o r i a s i s w i t h t a c a l c i t o l c o m p a r e d w i t h t w i c e d a i l y t r e a t m e n t w i t h c a l c i p o t r i o l . A d o u b l e - b l i n d t r i a l . B r J D e r m a t o l 1 9 9 7 ; 1 3 7 : 5 8 1 - 5 8 6 .

25. P e r e z A , R a a b R, C h e n TC, e t a l . S a f e t y a n d e f f i c a c y o f o r a l c a l c i t r i o l (1 , 2 5 - d i h y d r o x y v i t a m i n D 3 ) f o r t h e t r e a t m e n t o f p s o r i a s i s . Br J D e r m a t o l 1 9 9 6 ; 1 3 4 : 1 0 7 0 - 1 0 7 8 .

26. P r y s t o w s k i JH, K n o b l e r EH, M u z i o PJ. O r a l c a l c i t r i o l d o e s n o t a u g m e n t U V B p h o t o t h e r a p y f o r p l a q u e psor ias is . J A m A c a d D e r m a t o l 1996; 3 5 : 2 7 2 - 2 7 4 .

27. L a y t o n A M , S h e e h a n - D a r e RA, G o o d f i e l d M J D , C o t t e r i l l JA . H y d r o x y u r e a i n t h e m a n a g e m e n t o f t h e r a p y r e s i s t a n t pso r ias i s . Br J D e r m a t o l 1989 ; 1 2 1 : 6 4 7 - 6 5 3 .

28. D u v i v i e r A , M u n r o D D , B e r b o v J. T r e a t m e n t o f pso r i as i s w i t h a z a t h i o -p r i n e . Br M e d J 1974; 1 : 4 9 - 5 1 .

29. S i l v i s N G , L e v i n e N . Pu l se d o s i n g o f t h i o g u a n i n e i n r e c a l c i t r a n t p s o -r ias is . A r c h D e r m a t o l 1 9 9 9 ; 1 3 5 : 4 3 3 - 4 3 7 .

30. Z a c k h e i m HS, G l o g a u RG, F isher D A , M a i b a c h HI . 6 - T h i o g u a n i n e t r e a t m e n t o f psor ias is : e x p e r i e n c e i n 81 p a t i e n t s . J A m A c a d D e r m a t o l 1994 ; 3 0 : 4 5 2 - 4 5 8 .

31. K i t c h i n JES, P o m e r a n z K, Pak G, e t a l . R e d i s c o v e r i n g m y c o p h e n o l i c ac id : a r e v i e w o f its m e c h a n i s m , s ide e f f e c t s , a n d i ts p o t e n t i a l uses. J A m A c a d D e r m a t o l 1997; 3 7 : 4 4 5 - 4 4 9 .

32. E p i n e t t e W W , P a r k e r C M , J o n e s EL, G r e i s t M C . M y c o p h e n o l i c ac i d f o r psor ias is , a r e v i e w o f p h a r m a c o l o g y , l o n g - t e r m e f f i c a c y , a n d sa fe t y . J A m A c a d D e r m a t o l 1987 ; 1 7 : 9 6 2 - 9 7 1 .

33. G u p t a A K , Ell is CN, S i e g e l MT , e t a l . S u l f a s a l a z i n e i m p r o v e s psor ias is . A d o u b l e - b l i n d ana lys is . A r c h D e r m a t o l 1990 ; 1 2 6 : 4 8 7 - 4 9 3 .

34. G u p t a A K , G r o v e r JS, H a m i l t o n TA, e t a l . S u l f a s a l a z i n e t h e r a p y f o r p s o r i a t i c a r t h r i t i s : A d o u b l e - b l i n d , p l a c e b o - c o n t r o l l e d t r i a l . J R h e u m a t o l 1 9 9 5 ; 2 2 : 8 9 4 - 8 9 8 .

35. C o m b e B, G o u i p i l l e P, K u n t z JL, e t a l . S u l f a s a l a z i n e i n p s o r i a t i c a r t h r i t i s : a r a n d o m i z e d , m u l t i - c e n t r e , p l a c e b o - c o n t r o l l e d s t u d y . Br J R h e u m a t o l 1 9 9 6 ; 3 5 : 6 6 4 - 6 6 8 .

36. E u r o p e a n FK 5 0 6 M u l t i - c e n t r e P s o r i a s i s S t u d y G r o u p . S y s t e m i c t a c r o l i m u s ( F K - 5 0 6 ) is e f f e c t i v e f o r t h e t r e a t m e n t f o r p s o r i a s i s i n a d o u b l e - b l i n d , p l a c e b o - c o n t r o l l e d s t u d y . A r c h D e r m a t o l 1 9 9 6 ; 1 3 2 : 4 1 9 - 4 2 3 .

37. Z o n n e v e l d I M , R u b i n s A , J a b l o n s k a S, e t a l . T o p i c a l t a c r o l i m u s is n o t e f f e c t i v e i n c h r o n i c p l a q u e psor ias is : a p i l o t s t u d y . A r c h D e r m a t o l 1998 ; 1 3 4 : 1 1 0 1 - 1 1 0 2 .

ADDRESS: Charles Camisa, MD, Department of Dermatology, A61, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195.

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psoriasis: a clinical update on diagnosis and new therapies

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