Psoriasis affects 2% of the US population, and approximately 10% of these patients have psoriatic arthritis (PSA). Mean age at onset is 30 years, but the range is from newborn to 100 years. Men and women are affected equally, but women may be affected earlier than men.

US primary care physicians initially see 58% of the estimated 150,000 new cases of psoriasis per year, but dermatologists handle 80% of the 3 million office and hospital visits for psoriasis each year.¹ These facts reinforce the need for general practitioners and internists to recognize the various forms of psoriasis, to keep abreast of safe and effective therapies, and to learn when to refer to a dermatologist, all of which are reviewed in this chapter.

The primary pathologic process likely lies in the immune system, specifically dysregulation of activated T-cell interactions with antigen-presenting cells and overproduction of proinflammatory cytokines. Evidence for this theory derives from the dramatic improvement of severe psoriasis in patients treated with immunosuppressive drugs used in organ transplantation, such as cyclosporine and tacrolimus.

Although a single disease, psoriasis has several morphologic expressions and a full range of severity. The form that psoriasis takes in a patient depends on a combination of genetic influences, environmental factors (eg, trauma and climate), associated diseases (especially infections), and concomitant medications. Certain drugs, including lithium, antimalarials, beta adrenergic blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and interferons, have been reported to induce psoriasis or aggravate preexisting disease in some patients. Ethanol abuse may prevent an expected response to appropriate therapy of psoriasis. Emotional stress may also cause cutaneous nerve fibers to release peptides. This can evoke inflammation or proliferation, thereby leading to a flare of psoriasis.

Plaque-type Psoriasis:

Plaque-type psoriasis, or psoriasis vulgaris, is the most common form, occurring in 75% to 80% of all psoriasis patients. A typical fully developed lesion is a well-demarcated, red-violet round or oval plaque. It is 1 cm or larger in diameter and surmounted by white silvery scales, which overlie bony prominences. In darkly pigmented patients, lesions are hyperpigmented with various shades of brown or black, which are accentuated by chronic rubbing or scratching.

Symmetry of distribution of skin lesions is the rule in plaque-type psoriasis. Any part of the body skin may be involved, but the face is frequently spared. The most commonly involved areas are the elbows, knees, scalp, sacrum, umbilicus, intergluteal cleft, and genitalia. All of these areas should be examined carefully because any of them may be the solitary site and the clue to diagnosis. About 70% of patients complain of pruritus, skin pain, or burning, especially when the scalp is involved.

Guttate Psoriasis:

Guttate psoriasis, named for its droplet-shaped lesions, accounts for about 18% of all cases. This type is more common among children and young adults.² Guttate lesions range in diameter from 0.1 cm to 1.0 cm and are not as indurated or scaly as the lesions of plaque-type psoriasis. They predominate on the trunk and proximal areas of the extremities and are more likely to involve the face.

Guttate psoriasis may be the initial manifestation 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.

Some cases of acute guttate flares are believed to have been precipitated by infection with streptococci. Leung et al³ showed that acute guttate psoriasis following streptococcal throat infection in 10 patients was the result of streptococcal 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 carbohydrates, as bacterial antigens.

Pustular Psoriasis:

Pustular psoriasis accounts for about 1.7% of cases. It is characterized by sterile pustules either generalized or localized to the palms and soles. There is a female predominance in localized pustular psoriasis, but the incidence is equal in men and women in the generalized type. The average age at onset for pustular psoriasis is 50 years.

Localized Pustular Psoriasis:

The eruption of localized pustular psoriasis is chronic and recurring. It is recognizable 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, or on both areas. Lesions are observed in all stages of development, including vesicles, vesicopustules, frank pustules, and dried brown maculopapules.

Generalized Pustular Psoriasis
Generalized (von Zumbusch) pustular psoriasis may develop de novo or from preexisting plaque-type psoriasis. It is characterized by fiery-red, irregular patches with round, arcuate, serpiginous borders that are studded with myriad 1-mm to 2-mm superficial pustules. These patches have a predilection for flexural or skin-fold areas such as the armpits, groin, or under the breasts, but may occur anywhere. The tiny pustules coalesce into lakes of pus, desquamate, and form new pustules as the border moves in waves every 24 to 72 hours. Most patients are acutely ill and have fever, leukocytosis, hypocalcemia, and hypoalbuminemia.

Ryan and Baker⁴ reported that 37 (24%) of 155 patients had their first attack of generalized pustular psoriasis within 1 month of either starting or stopping corticosteroids, and they concluded that the steroids provoked the attacks. Other precipitating factors included infection and other drugs. Methotrexate was less effective in patients who previously received systemic corticosteroids. A more recent review⁵ of 208 cases of recurrent generalized pustular psoriasis found that the disease was more likely to have been triggered by corticosteroids in patients with preceding plaque-type psoriasis and by infection in patients without a history of psoriasis.

Erythrodermic Psoriasis:

Exfoliative dermatitis or psoriatic erythroderma accounts for only 1% to 2% of all cases of psoriasis, making it the least common form. Erythroderma is generally defined as a scaling pruritic, inflammatory skin eruption that involves all or almost all of the body surface. Erythrodermic psoriasis usually develops gradually or acutely during the course of chronic plaque-type psoriasis, but it may be the first manifestation of psoriasis, even in children. The mean age at onset is about 50 years. Men with the condition outnumber women by 2-3:1. Sterile pustules may develop in some areas of erythrodermic psoriasis. Concomitant psoriatic arthropathy is common.

Precipitating factors for erythrodermic psoriasis include systemic illnesses, emotional stress, and alcoholism. However, the most important ones seem to be related to treatment, especially the inappropriate or excessive use of potent topical, oral, and intramuscular corticosteroids.⁶ Patients are at risk for Staphylococcus aureus septicemia owing to their compromised skin barrier and, in some cases, because of immunosuppressive drug use. Treating S. aureus-infected patients with appropriate intravenous antibiotics may also clear the skin.

Nail Psoriasis:

The nails are involved in up to 50% of psoriasis patients; in patients with PSA, the prevalence exceeds 80%. Fingernails are affected more often than toenails. Pitting of the nail plate is the most common manifestation. The pits tend to be large, deep, and randomly dispersed on the nail plate. Small red spots in the lunula or yellow-brown spots (the oil droplet sign) in the nail bed correspond to early guttate lesions of psoriasis there. The nail plate may thicken, with dispersed deep pitting and ridging, which leads to crumbling. The distal nail plate may separate from the nail bed (onycholysis). Chronic inflammation of the nail matrix may lead to scarring and permanent dystrophy, mimicking onychomycosis, especially when toenails are affected.

Psoriatic Arthritis:

PSA affects up to one-third of patients with psoriasis. PSA is a destructive arthropathy and enthesopathy with some clinical features in common with rheumatoid arthritis (RA). For example, both PSA and RA are chronic diseases that result in damage to bone and synovial membrane, disability, and increased mortality. However, the radiographic appearance of PSA differs from that of RA, particularly with regard to sacroiliac and cervical spine involvement. Arthritis occurs after the onset of the skin eruption in two thirds of cases. The severity of skin and nail involvement does not correlate with the severity of joint disease in patients with PSA, but distal interphalangeal joint involvement is likely to be associated with dystrophy of the adjacent nail. Although the systemic agents used to treat psoriasis are often appropriate for PSA, the specific management of PSA is beyond the scope of this article.

The classic clinical skin lesions—thick, erythematous, often pruritic patches covered with silvery scale—usually confirm the diagnosis.

Tests should be conducted to rule out other inflammatory skin diseases that may mimic psoriasis, such as eczema, pityriasis rubra pilaris, drug reactions, and cutaneous T-cell lymphoma. These tests include examination of scales using potassium hydroxide to search for fungal elements, serologic testing to rule out syphilis, and skin biopsy.

Treatments for psoriasis are divided into six levels (Table 1). The choice of treatment depends on the severity of disease and response in the individual patient.

Level 1: Topical Treatments:

Emollients (bland lubricants) should be tried first, followed by keratolytic lotions containing salicylic acid or urea. Because mild to moderate psoriasis generally involves less than 10% of the body surface area (BSA), most patients are treated with a topical corticosteroid combined with a calcipotriene ointment or cream.⁷ Tazarotene, available in a gel or cream formulation, is a third-generation synthetic retinoid that is used in combination with a topical corticosteroid. Irritation is an expected side-effect if tazarotene is used alone. Anthralin cream 1% is an effective psoriasis treatment when applied to extensor areas for 1 hour or less per day, but its use is complicated by staining and irritation to the surrounding skin. Coal tar gels, available without prescription, are more elegant though less efficacious than crude coal tar. Tar may be combined with natural sunlight regimens but should not be used in tanning salons, which use ultraviolet A (UVA) light that can cause "smarting" of the skin.

Caveats About Topical Corticosteroids
Prescribing topical corticosteroids comes with several caveats:

• Common side effects include atrophy, folliculitis, rebound flare-up, and tachyphylaxis.
• Do not apply fluorinated corticosteroids to the face, flexures, or under occlusion because this may lead to acneiform eruption, striae distensae, and increase systemic absorption especially in children.
• When prescribing generics, the ointment formulation is closest to the brand in potency.

Level 2:

Phototherapy is highly effective, clearing 80% to 100% of the skin. However, some maintenance therapy is usually necessary.⁸ The disadvantages to this treatment method are that it requires specialty equipment and care, the need for two or three office visits a week, and is expensive. Additionally, it carries a short-term risk of sunburn and a theoretical long-term risk of skin cancer.

Natural sunlight and UVA tanning beds are mildly therapeutic. Ultraviolet B (UVB) phototherapy is given by dermatologists in the office or clinic. It is reserved for patients with widespread lesions involving 10% or more of the BSA. Specialized training is necessary for the safe delivery of phototherapy.

The Goeckerman regimen, first described in 1925, used a combination of broadband UVB (290 nm to 320 nm) phototherapy and crude coal tar. However, a 1981 study found that nonerythemogenic protocols of broadband UVB therapy used with a bland ointment, such as petrolatum or mineral oil, was equally as effective at clearing psoriasis. The study showed that the erythema spectrum for UVB was below 300 nm and that the therapeutic action spectrum was between 300 nm and 313 nm.⁹ In 1984 a fluorescent lamp (Philips TL-01) was designed to emit UVB at 311nm to 313nm, which is now known as narrowband UVB. Several studies have shown that narrowband UVB phototherapy is more effective more rapidly than broadband UVB therapy.

Our clinic uses the modified protocol described by Shelk and Morgan¹⁰, treating patients three times weekly until their skin is nearly clear followed by maintenance one to two times weekly. Narrowband UVB phototherapy is probably not as efficacious as PUVA but is perceived to be safer because no internal photosensitizer is used. Moreover, broadband UVB therapy has had a long track record of safety since 1925, whereas PUVA has been found to be associated with squamous cell carcinoma.

Recent US Food and Drug Administration (FDA) approval of the 308-nm xenon chloride excimer laser has enhanced narrowband UVB therapy. In a pilot study of the XTRAC (PhotoMedex)¹¹, psoriasis cleared after 8 treatments; however, 30 narrowband UVB treatments were required to achieve the same effect. The cumulative dose for the laser was one sixth that of narrowband UVB. A second study showed that higher fluences produced significantly better results and fewer recurrences at 4 months follow-up; however, higher fluences may cause blistering reactions. Disadvantages to this modality are that the aperture of the handpiece is 4 cm² (limiting practical use to patients with less than 10% BSA involvement); unproven efficacy in specialized areas such as the scalp, palms, and soles; and unknown long-term side-effects.

When to Refer to a Dermatologist
Consider referring to a dermatologist any patient with moderate to severe psoriasis who does not respond to treatment with emollients, keratolytics, topical steroids, calcipotriene, tazarotene, natural sunlight, or a tanning bed.

What Constitutes Severe Psoriasis?
The traditional method of defining severity of psoriasis relies on estimates of BSA involved without regard to quality-of-life issues. Thus, it is obvious that severe psoriasis includes:

• extensive plaque-type psoriasis involving 20% or more of the BSA
• psoriatic erythroderma
• generalized pustular psoriasis

A broader definition of severe disease includes:

• disabling plaque-type psoriasis involving the face, genitalia, hands, and feet;
• psoriasis complicated by medication change, such as during rotational therapy, or by a need for medication withdrawal, such as that caused by flare due to systemic corticosteroids;
• disabling PSA with skin disease of any extent

The Dermatology Life Quality Index¹² consists of 10 questions that rate the impact of psoriasis on a patient's routine activities at work, school, and home; on social activities; and on mental health. Incorporating quality-of-life parameters into the definition of psoriasis severity allows for an overlapping of estimates of involved BSA, according to a recent position paper.¹³ Doing so results in the following definitions:

Level 3: Systemic:

Although systemic treatments are more effective than level 2 treatments, they are often more expensive and have greater potential for toxicity. Systemic treatments are generally prescribed only by a dermatologist.

Photochemotherapy or PUVA was first reported as a novel treatment for psoriasis in a landmark article in 1974.¹⁴ The photosensitizer, 8-methoxypsoralen (8-MOP), is taken orally 1.5 to 2 hours before UVA exposure. The drug is excited by the UVA irradiation in the 320-nm to 390-nm wavelength range. This produces crosslinking of DNA strands, thereby inhibiting DNA synthesis and epidermal turnover, which leads to healing of psoriasis.

Long-term follow-up of PUVA-treated patients has conclusively demonstrated the carcinogenic potential of PUVA for squamous cell carcinoma with the greatest risk for male genitalia. The latter must now be shielded during treatment. These patients also developed pigmented macules, called PUVA lentigines, in exposed areas. One study group reported that the incidence of malignant melanoma is increased in patients who received more than 250 PUVA treatments and were followed for more than 15 years. Although their results have not been confirmed by other investigators, dermatologists have sought to treat patients with alternatives perceived to be safer, such as bath PUVA.

In bath PUVA, the 8-MOP solution is dissolved in bath water, and the patient is soaked for 30 minutes before UVA exposure. Systemic absorption is negligible, and it is not necessary for the patient to wear UV protective glasses for the remainder of the day. The psoralen must be dispensed in the office. Most offices are not set up to give full body baths, however, this treatment is highly effective for psoriasis of the palms and soles, which is usually recalcitrant. Palms and soles are soaked in basins in an examination room and followed by twice-weekly exposure to hand-foot UVA-delivery units. The formula is 0.4 mL of 1% methoxsalen (Oxsoralen) solution diluted in 1.5 L tap water.¹⁵ If necessary, this treatment can be enhanced with 10-25 mg daily acitretin, an oral retinoid.

Oral Retinoid Therapy: Special Considerations
Retinoids are naturally or synthetically derived from Vitamin A (retinol) and have anti-inflammatory, antikeratinizing, and antiproliferative effects on the skin. Acitretin is the only oral retinoid approved for psoriasis therapy in the United States. The drug has demonstrated good to excellent therapeutic results, especially in combination with other conventional treatments.

• Adverse Effects of Oral Retinoids
  Although oral retinoids have numerous side effects, they are generally not serious, except for teratogenicity. The most common and frequently troublesome side effects are dryness of the skin and mucous membranes, hair loss, and nail changes. Patients taking acitretin for years may develop diffuse idiopathic skeletal hyperostosis-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.
  
  
• Lipid Effects
  Retinoids cause hyperlipidemia, especially elevations of serum triglyceride, and decreases in high-density lipoprotein cholesterol. Experimental evidence supports the hypothesis that retinoids induce increased synthesis of apoprotein B and triglycerides. Fish oil supplements given to patients receiving acitretin significantly decrease triglyceride levels. Gemfibrozil or atorvastatin calcium are useful for treating patients with hyperlipidemia due to acitretin who do not respond to dietary manipulation and dose reductions of acitretin.¹⁶
  
  
• Use In Pregnancy
  Acitretin is reserved for men or for women who are not of childbearing age. Fertile women with severe psoriasis who take acitretin must follow two-method contraception or abstinence and have monthly pregnancy tests. Acitretin may be converted to etretinate, which has a long half-life and is stored in fat. Therefore, the manufacturer's guidelines warn that patients must abstain from drinking alcohol during treatment and must not conceive for 3 years after terminating treatment.

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 have confirmed that methotrexate is superior to placebo in improving skin manifestations and joint symptoms in psoriatic patients. A good to excellent response (50% to 100% clearing of psoriasis) occurred in 70% of patients with severe disease treated with a single weekly oral dose of methotrexate (20 mg to 37.5 mg).¹⁷ A recent randomized control trial comparing methotrexate to cyclosporine in the treatment of moderate to severe psoriasis showed that 30-40% of patients in both groups achieved almost complete clearing after 16 weeks. The difference was not statistically significant, but 12 patients in the methotrexate group and 1 patient in the cyclosporine group were withdrawn because of abnormal liver function tests.¹⁸

• Adverse Effects
  The most common adverse effects of methotrexate therapy are nausea, anorexia, fatigue, headache, and alopecia. Oral ulcerations generally do not occur when methotrexate is used at recommended doses. If they do occur, oral ulcerations 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.
  
  
• Monitoring for Liver Damage
  During Methotrexate Therapy
  Hepatotoxicity is the primary clinical concern when planning long-term methotrexate therapy. 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 RA patients taking methotrexate, recommendations for liver biopsy from different organizations differ. For example, the American 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. Many rheumatologists have adopted the same guidelines for monitoring patients with PSA. On the other hand, 1988 guidelines from the American Academy of Dermatology recommended a liver biopsy at baseline. However, a 1998 consensus conference¹⁹ eliminated this recommendation, except when the patient has significant risk factors.

  The initial liver biopsy is done after a 1-g to 1.5-g cumulative dose and is repeated after 3-g and 4-g cumulative doses. Liver biopsy should not be performed in elderly patients, during acute illness, in patients with limited life expectancy, or in patients with medical conditions that contraindicate the procedure.
  
  

• Folic Acid
  Folic acid supplementation 1 mg/day is recommended because it mitigates the gastrointestinal effects of methotrexate (nausea, diarrhea, elevated liver enzymes) without altering its efficacy. It also prevents megaloblastic anemia due to folic acid deficiency.

Cyclosporine Therapy for Psoriasis:
Special Considerations
Cyclosporine is very effective for psoriasis, but it does not cure it and does not induce remissions that are more durable than those achieved with PUVA therapy, for example. To maintain a prolonged remission, one must continue giving cyclosporine or change to another systemic therapy. Stopping cyclosporine or giving a suboptimal dose allows skin lesions to recur at a rate and severity consistent with the natural history of an individual's disease.

Cyclosporine interferes directly with T-cell activation and with communication with antigen-presenting cells, inhibiting the synthesis or expression of interleukin-1, interleukin-2, and interleukin-2 receptor. In psoriatic lesions, cyclosporine also inhibits the epidermal cytokine network.

Because 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. Nephrotoxicity and hypertension are the two most serious side effects of cyclosporine therapy. They require baseline evaluation, constant monitoring, and intervention (medical treatment, dose reduction, or discontinuation of cyclosporine). Manufacturers state that treatment is safe for 1 year, but a consensus conference extended that to 2 years.²⁰ Another possibly safer approach is intermittent therapy with cyclosporine. At the end of the treatment period, the patient should be gradually tapered off cyclosporine and switched to another systemic agent. This is called rotational therapy. Combined methotrexate and cyclosporine has been used safely to treat graft-versus-host disease, RA, and severe psoriasis.

Levels 4 and 5: Experimental Treatments:

Treatments in levels 4 and 5 are not approved by the FDA. Level 4 treatments are slightly to moderately effective but are less toxic than level 5 treatments. Level 5 treatments are reserved for the most severe and recalcitrant cases, including PSA. Level 6 treatments are the biologic immunomodulators some of which are currently FDA-approved for psoriasis, PSA, and other indications.

Vitamin D₃ and Analogs
Topical vitamin D₃ (calcitriol) and the topical synthetic analogs calcipotriene and tacalcitol are effective for plaque-type psoriasis and are free of any serious toxicity.²¹ In double-blind studies, patients applied calcipotriene to one side of their body and corticosteroids to the other side. Calcipotriene was equivalent to or better than medium-strength and potent corticosteroid ointments, without the risk of skin atrophy or rebound flare-ups on discontinuation of therapy.

In open trials, patients taking oral calcitriol showed dramatic improvement but experienced significant hypercalcemia, hypercalciuria, and nephrotoxicity. No placebo-controlled study of oral calcitriol alone has been conducted; however, when combined with 21 erythemogenic ultraviolet B treatments, oral calcitriol had no additive effect compared with placebo.

Hydroxyurea in Recalcitrant Psoriasis
The antimetabolite hydroxyurea plays a minor role in the treatment of recalcitrant psoriasis. In one prospective nonrandomized series at a dose of 1-1.5 g/day for a median of 36 weeks, more than half the patients achieved at least a 70% reduction in the Psoriasis Area and Severity Score (PASI).²² Adverse reactions are common, notably cytopenia and macrocytosis. Hydroxyurea is not effective for pustular or erythrodermic psoriasis or PSA.

Thiopurine Antimetabolites
Thiopurine antimetabolites, such as azathioprine, mercaptopurine (6-mercaptopurine, 6-MP), and thioguanine (6-thioguanine, 6-TG), are used as immunosuppressive and steroid-sparing agents for many diseases. All inhibit DNA synthesis. Azathioprine is metabolized to 6-MP, which is then converted to 6-MP ribotide. The main side effects of treatment with thiopurine antimetabolites are gastrointestinal and hematologic events.

In a study of azathioprine in 29 patients with severe plaque-type psoriasis as well as erythroderma and pustular variants, 19 (66%) benefited from treatment. A 50% to 100% improvement was seen after treatment with doses of 75 mg/day to 200 mg/day.²³

In a study of 6-TG in patients with recalcitrant plaque-type psoriasis, marked improvement occurred in 50% to 70% of patients treated with a pulse-dosing schedule of 120 mg twice weekly to 160 mg thrice weekly.²⁴ Palmoplantar psoriasis and generalized pustular psoriasis may also respond well to 6-TG. The response is usually evident within 12 weeks of therapy initiation. The chief toxicity of 6-TG is myelosuppression.

Mycophenolic Acid
Mycophenolic acid inhibits de novo synthesis of guanosine nucleotide, thereby selectively suppressing proliferation of T and B lymphocytes. The main side effects are gastrointestional and genitourinary events, and the incidence of herpes zoster also is increased. Double-blind placebo-controlled trials have confirmed its efficacy in psoriasis. After 12 weeks of treatment, mean severity scores decreased by 68%. Patients were subsequently treated with 1.6 g/day to 4.8 g/day for 2 years.²⁵ Although monotherapy with mycophenolate mofetil (MMF, CellCept) has been disappointing in anecdotal reports, it may allow the use of lower and safer doses of cyclosporine when used in combination.²⁶

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

In a double-blind study, 17 psoriasis patients received sulfasalazine 3 g/day to 4 g/day. Of these, seven had a marked response, seven had a moderate response, and three had a minimal response.²⁷ Common side effects of sulfasalazine treatment are anorexia, nausea, vomiting, fatigue, headaches, and cutaneous eruptions. Although usually not severe, these side effects frequently lead to discontinuation of treatment before any therapeutic benefit can occur. The incidence of drug-induced rash may be as high as 18%.

A lower dose of sulfasalazine than is needed for cutaneous psoriasis may be effective for arthropathy. Results of large multicenter double-blind studies of sulfasalazine at 2 g/day for PSA showed trends favoring a response to sulfasalazine, with decreased pain and decreased erythrocyte sedimentation rate.²⁸

Tacrolimus
The macrolide lactone tacrolimus (Prograf), formerly known as FK506, is an immunosuppressive drug that inhibits T lymphocyte activation, but is chemically unrelated to cyclosporine. Results from the first double-blind trial of tacrolimus in the treatment of plaque-type psoriasis showed that, after 9 weeks, the drug was effective in improving the disease severity index by 83%.²⁹ Doses ranged from 0.05 mg/kg/day to 0.15 mg/kg/day. Mild hypertension and mild to moderate renal dysfunction developed infrequently. Additional studies with larger numbers of patients treated long-term will be necessary to elucidate optimal dosing schedules and the toxicity profile of systemic tacrolimus. Tacrolimus ointment is not effective for psoriasis. A chemically related compound called pimecrolimus was used to treat psoriasis in a phase 2 double-blind placebo-controlled trial. At a dosage of 30 mg twice daily, the PASI score was reduced by 75% after four weeks of treatment with minimal toxicity.³⁰

Level 6: Biologic Immunomodulators:

The scientific evidence supports that immune mechanisms play a role in psoriasis, eg, activated T cells in the dermis and epidermis, clinical response to immunosuppressives and to chemotherapy that targets interleukin-2 receptors expressed on activated T-cells, and the high blood and skin levels of proinflammatory cytokines such as interferon-gamma and tumor necrosis factor-alpha (TNF). The Level 6 designer molecules comprised of monoclonal antibodies and fusion proteins represent the new paradigm of treatment of moderate-to-severe psoriasis of the 21st century. These compounds are designed to antagonize cell-cell interactions, memory-effector T-cells, and proinflammatory cytokines.³¹

Alefacept
Alefacept is fusion protein composed of leukocyte function antigen-3 and human IgG1 domains that is administered as a once weekly intramuscular dose of 15 mg for 12 weeks. In double-blind placebo-controlled phase 3 studies, 21% of patients achieved >75% improvement at 14 weeks compared to 5% receiving placebo.³² Alefacept received FDA approval for psoriasis in 2003. Reduction in numbers of memory-effector (CD45RO+) T-cells is associated with response to therapy, and it is recommended to monitor CD4 counts weekly during therapy. Novel dosing schedules and combinations are under study with hopes of improving efficacy. No serious side effects have been encountered, and no rebound of psoriasis occurs after stopping alefacept.

Efalizumab
Efalizumab is a humanized monoclonal antibody directed against the CD-11a subunit of leukocyte function antigen-1( LFA-1) expressed on T cells. By blocking the interaction of LFA-1 and its ligand intercellular adhesion molecule-1, T-cell activation and migration into psoriatic plaques are decreased. In phase 3 trials, efalizumab administered as 1mg/kg once weekly as a subcutaneous injection achieved >75% improvement after 12 weeks in 27% of patients compared to 4% receiving placebo.³³ Efalizumab was approved by the FDA for psoriasis in 2003. It is recommended to monitor platelet counts for the first few months of therapy and to continue therapy in order to maintain the response. About 10% of patients experience a flare of their disease either during or after abruptly stopping efalizumab.

Tumor Necrosis Factor Inhibitors
Etanercept is a cloned and engineered fusion protein made of two p75 TNF receptors and the Fc portion of human IgG. It binds and inactivates TNF and prevents its significant proinflammatory effects in the target tissue of skin and joints. Etanercept is a disease modifying anti-rheumatic drug that is FDA-approved for rheumatoid and psoriatic arthritis with and without methotrexate. In the pivotal phase 3 studies of etanercept in psoriasis, 25 mg administered twice weekly by subcutaneous injection and 50 mg twice weekly gave >75% improvement in 34% and 49% of patients respectively after 12 weeks compared to 4% receiving placebo.³⁴ Etanercept was approved for psoriasis by the FDA in 2004 at a starting dose of 50 mg twice weekly for 12 weeks followed by 25 mg twice weekly for maintenance. In studies, only wheal-like injection site reactions occurred at higher frequency with etanercept than placebo. Infrequent associations of new onset or aggravation of demyelinating diseases, congestive heart failure, and aplastic anemia have been observed without assigning cause and effect.

Infliximab is a chimeric (human-mouse) monoclonal antibody that binds TNF. It is FDA-approved for rheumatoid arthritis and Crohn's disease with and without methotrexate. It is delivered by an intravenous infusion over a 2-hour period. Phase 2 trials of infliximab as monotherapy have indicated high efficacy for this drug. Gottlieb et al³⁵ reported the results after treating 249 patients at week 0, 2, and 6 with placebo, 3 mg/kg, or 5 mg/kg infliximab infusions given at weeks 0, 2, and 6. The proportion of patients achieving >75% improvement in the severity score at 10 weeks was 6, 72, and 88%, respectively. Infusion reactions occur in about 20% of patients and usually consist of fever, chills, urticaria, pruritus, and less frequently, chest pain, hypotension, hypertension, and dyspnea. Neutralizing antibodies are formed which may result in a serum-sickness-like reaction, and more commonly "dose creep," whereby dose escalation of infliximab becomes necessary to keep symptoms under control. Concomitant methotrexate administration reduces the development of anti-chimeric antibodies.

A human anti-TNF monoclonal antibody, adalimumab, currently approved for rheumatoid arthritis, is under development for psoriasis and PSA as an alternate week subcutaneous injection.

The greatest theoretical risks associated with the new biologic immunomodulating agents discussed here are serious infections and increased rate of malignancy, particularly the lymphoproliferative diseases. To date, controlled trials or post-marketing surveillance studies have not conclusively demonstrated a higher than expected frequency of lymphomas in patients who have been treated the longest with anti-TNF agents, however, the risk for reactivating tuberculosis is considered greater for infliximab than etanercept. Therefore, screening for tuberculosis is required before administering infliximab.

The management of patients with psoriatic erythroderma or pustular psoriasis includes admission to the hospital for evaluation, supportive care, and conservative treatment until the patient is stable enough to receive aggressive, conventional antipsoriatic therapy.

Severe psoriasis can usually be controlled eventually with the standard regimen of PUVA, acitretin, methotrexate, or cyclosporine. The biologic immunomodulators have been systematically studied only in moderate to severe plaque-type psoriasis, so it is not possible to extrapolate the results to the most severe variants. The disease usually reverts back to its previous state (either plaque-type psoriasis or clear). Systemic and potent topical corticosteroids should be avoided. A small number of patients remain unstable and have repeated episodes of erythroderma or pustulation during their lifetime.

Localized Pustular Psoriasis:

Recalcitrance to therapy is the rule for localized pustular psoriasis of the palms and soles. Topical keratolytics, corticosteroids, tars, and UVB light are generally ineffective; and systemic agents, such as methotrexate, give inconsistent results. To date, the most effective treatment for the largest number of patients is acitretin 30 mg to 50 mg per day by mouth, either alone or combined with PUVA. Low-dose cyclosporine may also be effective, but long-term maintenance therapy is then required to prevent relapse.

Nail Psoriasis:

Nail disease improves with any systemic treatment that also improves the skin. The only topical therapy shown to improve nail psoriasis (pitting and onycholysis) is tazarotene 0.1% gel once daily for 24 weeks.³⁶ Injections of triamcinolone acetonide suspension 5 mg/mL diluted with 1% lidocaine into the proximal and lateral nail folds may be effective for nail bed psoriasis. This procedure is usually done in a dermatologist's office. The 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 a less-frequent interval for maintenance.

Return to Medicine Index

1. Stern RS. Utilization of outpatient care for psoriasis. J Am Acad Dermatol. 1996;35:543-545.
   
   
2. Nanda A, Kaur S, Kaur I, Kumar B. Childhood psoriasis: an epidemiologic survey of 112 patients. Pediatr Dermatol. 1990;7:19-21.
   
   
3. Leung DY, Travers JB, Giorno R, et al. Evidence for a streptococcal superantigen-driven process in acute guttate psoriasis. J Clin Invest. 1995;96:2106-2112.
   
   
4. Ryan TJ, Baker H. The prognosis of generalized pustular psoriasis. Br J Dermatol. 1971;85:407-411.
   
   
5. Ohkawara A, Yasuda H, Kobayashi H, et al. Generalized pustular psoriasis in Japan: two distinct groups formed by differences in symptoms and genetic background. Acta Derm Venereol. 1996;76:68-71.
   
   
6. Boyd AS, Menter A. Erythrodermic psoriasis. Precipitating factors, course, and prognosis in 50 patients. J Am Acad Dermatol. 1989;21:985-991.
   
   
7. Lebwohl M, Ali S. Treatment of psoriasis. Part 1. Topical therapy and phototherapy. J Am Acad Dermatol. 2001;45:487-498.
   
   
8. Honigsmann H. Phototherapy for psoriasis. Clin Exp Dermatol. 2001;26:343-350.
   
   
9. Parrish JA, Jaenicke KF. Action spectrum for phototherapy of psoriasis. J Invest Dermatol. 1981;76:359-362.
   
   
10. Shelk J, Morgan P. Narrow-band UVB: a practical approach. Dermatol Nurs. 2000;12:407-411.
    
    
11. Spann CT, Barbagallo J, Weinberg JM. A review of the 308-nm excimer laser in the treatment of psoriasis. Cutis. 2001;68:351-352.
    
    
12. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19:210-216.
    
    
13. Krueger GG, Feldman SR, Camisa C, et al. Two considerations for patients with psoriasis and their clinicians: what defines mild, moderate, and severe psoriasis? What constitutes a clinically significant improvement when treating psoriasis? J Am Acad Dermatol. 2000;43:281-285.
    
    
14. Parrish JA, Fitzpatrick TB, Tanenbaum L, Pathak MA. Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light. N Engl J Med. 1974;291:1207-1211.
    
    
15. Helm TN, Camisa C. "Psoralens and photochemotherapy (PUVA)". In: Handbook of Psoriasis, ed.2, Camisa C (ed), 2004, Blackwell, Oxford, UK, pp.191-214.
    
    
16. Lebwohl M, Ali S. Treatment of psoriasis. Part 2. Systemic therapies. J Am Acad Dermatol. 2001;45:649-661.
    
    
17. Roenigk HH Jr, Bergfeld WF, Curtis GH. Methotrexate for psoriasis in weekly oral doses. Arch Dermatol. 1969;99:86-93.
    
    
18. Heydendael VM, Spuls PI, Opmeer BC, et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med. 2003; 349:658-665.
    
    
19. Roenigk HH Jr, Auerbach R, Maibach H, Weinstein G, Lebwohl M. Methotrexate in psoriasis: consensus conference. J Am Acad Dermatol. 1998;38:478-485.
    
    
20. Lebwohl M, Ellis C, Gottlieb A, Koo J, Krueger G, Linden K, et al. Cyclosporine consensus conference: with emphasis on the treatment of psoriasis. J Am Acad Dermatol. 1998;39:464-475.
    
    
21. van De Kerkhof PC. New developments in the treatment of psoriasis. Skin Pharmacol Appl Skin Physiol. 2001;14:129-135.
    
    
22. Kumar B, Saraswat A, Kaur I. Rediscovering hydroxyurea: its role in recalcitrant psoriasis. Int J Dermatol. 2001;40:530-534.
    
    
23. Duvivier A, Munro DD, Verbov J. Treatment of psoriasis with azathioprine. Br Med J. 1974;1:49-51.
    
    
24. Silvis NG, Levine N. Pulse dosing of thioguanine in recalcitrant psoriasis. Arch Dermatol. 1999;135:433-437.
    
    
25. Epinette WW, Parker CM, Jones EL, Greist MC. Mycophenolic acid for psoriasis. A review of pharmacology, long-term efficacy, and safety. J Am Acad Dermatol. 1987;17:962-971.
    
    
26. Ameen M, Smith HR, Barker JN. Combined mycophenolate mofetil and cyclosporine therapy for severe recalcitrant psoriasis. Clin Exp Dermatol. 2001;26:480-483.
    
    
27. Gupta AK, Ellis CN, Seigel MT, et al. Sulfasalazine improves psoriasis. A double-blind analysis. Arch Dermatol. 1990;126:487-493.
    
    
28. Combe B, Gouipille P, Kuntz JL, et al. Sulfasalazine in psoriaitic arthritis: a randomized, multi-centre, placebo-controlled study. Br J Rheumatol. 1996;35:664-668.
    
    
29. European FK 506 Multi-centre psoriasis study group. Systemic tacrolimus (FK-506) is effective for the treatment of psoriasis in a double-blind, placebo-controlled study. Arch Dermatol. 1996;132:419-423.
    
    
30. Rappersberger K, Komar M, Ebelin ME, et al. Pimecrolimus identifies a common genomic anti-inflammatory profile, is clinically highly effective in psoriasis and is well tolerated. J Invest Dermatol. 119;876-887, 2002.
    
    
31. Granstein RD. New treatments for psoriasis. N Engl J Med. 2001;345:284-287.
    
    
32. Ellis CN, Krueger GG. Alefacept Clinical Study Group. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med. 2001;345:248-255.
    
    
33. Lebwohl M, Tyring SK, Hamilton TK, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med. 2003;349:2004-2013.
    
    
34. Leonardi C, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003;349:2014-2022.
    
    
35. Gottlieb AB, Evans R, Li S, et al. Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2004;51:534-42.
    
    
36. Scher RK, Stiller M, Zhu YI. Tazarotene 0.1% gel in the treatment of fingernail psoriasis: a double-blind, randomized, vehicle-controlled study. Cutis. 2001;68:355-358.

This information is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options of a specific patient's medical condition.

In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this web site.