Psoriasis – Cleveland Clinic Center for Continuing Education

Definition and Etiology

Psoriasis is a common; typically chronic papulosquamous skin disease that may be associated with a seronegative spondyloarthropathy. The etiology of psoriasis is unknown.

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Psoriasis affects 2% of the U.S. population, and about 11% of these patients have psoriatic arthritis (PsA). Psoriasis may begin at any age however generally there are two peaks of onset, the first at 20-30 years and the second at 50-60 years. Men and women are equally affected.

U.S. primary care physicians initially see 58% of the estimated 150,000 new cases of psoriasis per year, however dermatologists manage 80% of the 3 million office and hospital visits for psoriasis each year.

The type and clinical manifestations of psoriasis in a patient depend on a combination of genetic influences, environmental factors (i.e. trauma and climate) and associated diseases (particularly bacterial infections). Additionally, certain medications, notably lithium, antimalarials, beta blockers, interferon, and ethanol (if abused) have been reported to induce psoriasis or exacerbate preexisting disease in some patients. Emotional stress may also lead to psoriasis flares.

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Psoriasis is associated with the metabolic syndrome and cardiovascular (CV) disease. Psoriasis patients are not only more likely to have CV risk factors but severe psoriasis may serve as an independent risk factor for CV mortality.

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Psoriatic skin lesions are the result of inflammation in the dermis and hyperproliferation with abnormal differentiation of the epidermis. The primary pathologic process is most likely dysregulation of activated T cell interactions with antigen-presenting cells and overproduction of pro-inflammatory cytokines such as interferon- and tumor necrosis factor- (TNF- ). Evidence for this theory derives from the dramatic improvement of severe psoriasis in patients treated with immunosuppressive therapies such as cyclosporine (a potent T cell inhibitor used to prevent transplant rejection) or with TNF- inhibitors (used in other inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis and ankylosing spondylitis).

Recently, additional cytokine mediators, IL-12 and IL-23, have been linked to psoriasis as they promote differentiation of nave CD4+ lymphocytes into Th1 and Th17 cells respectively. The U.S Food and Drug Administration (FDA) has recently approved a novel therapy for psoriasis targeting Il-12 and IL-23, which will be discussed in the therapy section.

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Although considered a single disease, psoriasis has several morphologic expressions and a full range of severity.

Plaque-type psoriasis, or psoriasis vulgaris, is the most common form, occurring in about 80% of all psoriasis patients. A typical lesion is a well-demarcated, red-violet plaque with adherent white silvery scales (Fig. 1).

Lesions are typically symmetrical and the face is usually spared. The most commonly involved areas are the elbows and knees, scalp, sacrum, umbilicus, intergluteal cleft, and genitalia. In addition to physical trauma (Koebner phenomenon), other causes of cutaneous injury such as viral exanthems or sunburn may elicit the formation of any type of psoriatic lesion. About 70% of patients complain of pruritus, skin pain, or burning, especially when the scalp is involved. A characteristic finding, coined Auspitz sign, is pinpoint bleeding when psoriatic scale is lifted and correlates with histologic elongation of dermal papillae vessels in combination with suprapapillary epidermal thinning.

Guttate psoriasis (Fig. 2), named for its small droplet-shaped lesions, accounts for about 18% of all cases. This type is more common among children and young adults and is more likely to involve the face. Patients frequently have a history of a preceding upper respiratory tract infection or pharyngitis, particularly Group A Streptococcus. Some cases of acute guttate flares following streptococcal infection are precipitated by its superantigen exotoxin.

Pustular psoriasis (Fig. 3 and B) accounts for approximately 1.7% of cases. It is characterized by sterile pustules, which may be generalized or localized to the palms and soles. There is a female predominance in localized pustular psoriasis, however the incidence is equal in men and women in the generalized type. The average age at onset for pustular psoriasis is 50 years. Pregnancy and rapid tapering of systemic corticosteroids are known triggers. Generalized pustular psoriasis in pregnancy is also known as impetigo herpetiformis. Impetigo herpetiformis and generalized pustular psoriasis must be treated more aggressively because untreated, may lead to serious complications such as sepsis and bacterial superinfection.

Inverse psoriasis involves intertriginous areas (i.e skin folds of axilla, inguinal, intergluteal and inframammary regions). Plaques are typically pink to red and minimally scaly. Lesions may mimic cutaneous candidiasis however satellite lesions (if present) distinguish candidiasis from inverse psoriasis. Consider inverse psoriasis if candidiasis is recalcitrant to appropriate therapies.

The least common form of psoriasis is exfoliative dermatitis or psoriatic erythroderma, which accounts for 1% to 2% of all cases. Erythroderma is defined as a scaling pruritic, erythematous inflammatory skin eruption that involves over 90% of the body surface. Erythrodermic psoriasis may develop gradually or acutely during the course of chronic plaque-type psoriasis, but it may be the first manifestation of psoriasis, even in children. Psoriasis is the most common cause of erythroderma in adults and the second (following drug eruptions) in children. The mean age at onset is approximately 50 years. Men with the condition outnumber women, and concomitant psoriatic arthropathy is common. The most common precipitating factor is the withdrawal of potent topical, oral, and intramuscular corticosteroids. Although psoriasis patients are typically thought to be at decreased risk of cutaneous infection, those with erythrodermic psoriasis may be at risk for Staphylococcus aureus septicemia as a result of their compromised skin barrier therefore it is important for emergent evaluation by a dermatologist. Additionally, erythroderma may result in temperature dysregulation, hypoalbuminemia, and high output cardiac failure.

The nails (Fig. 4) are involved in up to 50% of psoriasis patients; in patients with psoriatic arthritis (PsA), the prevalence exceeds 80%. Pitting of the nail plate is the most common manifestation and is the result of damage to the proximal nail matrix. The pits tend to be large, deep, and randomly dispersed on the nail plate. Distal onycholysis, or lifting of the nail plate, is a common finding in psoriatic nail disease. Yellow-brown dyschromia (oil droplet sign) of the nail bed corresponds to psoriasis in that location and is the result of abnormal keratinization of the nail bed.

PsA affects up to one third of patients with psoriasis and is a destructive arthropathy and enthesopathy. Although PsA may share clinical features with rheumatoid arthritis (involving small and medium sized joints), it most commonly presents as inflammation of the proximal and distal interphalangeal joints in the hands and feet. Arthritis occurs after the onset of skin involvement in two thirds of cases however in 10-15% of patients, it occurs prior to the development of skin lesions. The severity of skin and nail involvement does not correlate with the severity of joint disease in patients with PsA. Early recognition and intervention is important as PsA may lead to loss of function. For this reason, patients with joint involvement are typically treated with more aggressive therapies such as a TNF inhibitor.

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A clinical diagnosis is usually sufficient for classic skin and nail lesions. The differential diagnosis is expansive however with several dermatologic conditions, which may present similarly including: atopic dermatitis, pityriasis rubra pilaris, drug reactions, tinea corporis, secondary syphilis, and cutaneous T cell lymphoma (mycosis fungoides variant). Therefore, it may be necessary to perform skin biopsy, potassium hydroxide (KOH) examination of scales, and serologic evaluations such as RPR and CBC with differential, blood smear and immunophenotyping (CD 4 to CD 8 ratio).

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The choice of treatment depends on the severity of disease and response in the individual patient.

Betamethasone dipropionate 0.05% (Diprolene)

Fluocinonide 0.05% (Lidex)

Desoximetasone 0.25% (Topicort)

PUVA*

Cyclosporine (Gengraf, Neoral, Sandimmune)

Acitretin (Soriatane)

Ustekinumab (Stelara)

Calcipotriol (Dovonex)

calcipotriene (Dovonex)

Calcitriol (Vectical)

Etanercept (Enbrel)

Adalimumab (Humira)

* *(PUVA) Psoralen combined with ultraviolet A.

Patients with limited disease (affecting less than 5% body surface area), not significantly involving the hands, feet or genitalia are treated primarily with class I or II topical corticosteroids. Steroid sparing agents such as calcipotriene, calcitriol (Vitamin D analogues), pimecrolimus and tacrolimus (calcineurin inhibitors) may also be used as monotherapy or in combination with a topical corticosteroid. Patients may complain of burning with application. The U.S. FDA currently recommends pimecrolimus and tacrolimus as second-line agents given potential cancer risk.

Phototherapy is a first line therapy for moderate to severe psoriasis. It may be used as monotherapy or in combination with topical or systemic therapies. There are several disadvantages to this treatment method as it is costly, requires special equipment and necessitates two or three office visits per week. It is advantageous for patients with additional comorbidities that preclude initiation of systemic therapies. Narrow band UVB therapy is the most commonly utilized form of phototherapy. Although more effective toward long term remission of psoriasis, psoralen plus UVA (PUVA) therapy is less utilized given increased risk of melanoma and non-melanoma skin cancers. Caution must also be taken in patients with fair skin, those who are taking photosensitizing medications, those with a history of skin cancer, and those who are chronically immunosuppressed after organ transplantation (as these patients are already at increased risk of non melanoma skin cancer).

Systemic therapy is effective, in treating severe disease (affecting more than 5% body surface area) and disease significantly involving the hands, feet or genitalia, however they have greater potential for toxicity. Systemic treatments for psoriasis are generally prescribed after consultation with a dermatologist.

Methotrexate (MTX) is the antimetabolite most often prescribed by dermatologists for moderate-to-severe psoriasis. Hepatotoxicity is the primary clinical concern when planning long-term methotrexate therapy. Mild transaminase elevations (less than twice the upper limit of normal) are to be expected during therapy, but these levels do not correlate with hepatic fibrosis. A 2009 consensus conference advocates following the American College of Rheumatology guidelines for patients with no risk factors for liver injury and recommend considering liver biopsy or switching to another treatment after 3.5 to 4 g to total cumulative methotrexate dosage. Folic acid (FA) supplementation at 1 mg daily is recommended to abate the gastrointestinal side effects of methotrexate without reducing efficacy (although many providers hold FA on the day of MTX therapy). It also helps to prevent megaloblastic anemia.

Cyclosporine is particularly useful for erythrodermic psoriasis as it takes effect rather quickly. Nephrotoxicity and hypertension are the two most serious side effects of cyclosporine therapy and should be monitored closely. Hyperlipidemia is also a potential side effect and given an already increased risk of CV disease in patients with severe psoriasis, fasting lipid profiles should be obtained regularly.

The biologic immunomodulators are monoclonal antibodies and fusion proteins that represent a paradigm shift in the treatment of moderate-to-severe psoriasis. These compounds were designed to antagonize cell-cell interactions, memory-effector T cells, or pro inflammatory cytokines.

Alefacept is a fusion protein composed of leukocyte function antigen-3 and human immunoglobulin 1 (IgG1). Alefacept was the first biologic to receive FDA approval for psoriasis in 2003. Although not mandated by the FDA, its pharmaceutical company voluntarily pulled alefacept from manufacturing and distribution in November 2011.

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. Efalizumab was approved by the FDA for psoriasis in 2003. After three cases of progressive multifocal leukoencephalopathy caused by the JC virus were reported in association with efalizumab therapy for psoriasis, the manufacturer voluntarily withdrew the drug from the U.S. market in June 2009.

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 FDA approved for RA, PsA, ankylosing spondylitis, and chronic to severe plaque psoriasis in adults. Etanercept is given at a starting dose of 50 mg injected subcutaneously (SQ) twice weekly for 12 weeks followed by 50 mg once weekly for maintenance of moderate to severe chronic plaque psoriasis. For PsA, 50mg is injected SQ weekly.

Infliximab is a chimeric (human-mouse) monoclonal antibody that binds TNF. It is FDA approved for rheumatoid and psoriatic arthritis and Crohn's disease with and without methotrexate (MTX). For the treatment of severe plaque psoriasis and PsA (with or without MTX), infliximab is delivered by an intravenous infusion over a 2-hour period at weeks 0, 2, and 6 followed by maintenance infusions every 8 weeks. The serious immediate infusion reaction rate is 1%, and about 1% of patients experience delayed hypersensitivity reactions consisting of myalgia, arthralgia, fever, or skin eruption. Neutralizing antibodies are formed in about 20% of patients treated for 1 year, which can result in dose creep, whereby dose escalation or more frequent dosing of infliximab becomes necessary to keep symptoms under control. Concomitant methotrexate administration reduces the development of antichimeric antibodies.

Adalimumab is a human anti-TNF monoclonal antibody that blocks the interaction of TNF with the p55 and p75 cell-surface receptors. It is FDA approved for plaque psoriasis, PsA, ankylosing spondylitis, Crohn's disease, ulcerative colitis, juvenile idiopathic arthritis, and rheumatoid arthritis. For moderate to severe plaque psoriasis, it is given at a starting dose of 80mg SQ, followed by 40mg SQ every other week beginning one week after the initial dose. For PsA, 40mg of adalimumab is administered every other week as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDS).

Ustekinumab utilizes monoclonal antibodies directed against the p40 subunit of cytokines IL-12 and IL-23, which have been recently described as significant mediators of psoriasis. In September 2009, ustekinumab obtained FDA approval for the treatment of moderate to severe plaque psoriasis. It is also used to treat moderate to severe Crohn's disease that is resistant to TNF inhibitors. For patients weighing 100kg or less, 45mg is injected SQ initially, 4 weeks later, then every 12 weeks thereafter. Patients weighing greater than 100kg may receive 90mg SQ initially, 4 weeks later, followed by every 12 weeks thereafter.

The greatest theoretical risks associated with the biologic immunomodulators are serious infections, particularly granulomatous, and increased rates of malignancy, particularly the lymphoproliferative diseases. To date, controlled trials and postmarketing 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. Although the risk for reactivating tuberculosis is considered greater for infliximab and adalimumab than with etanercept, a baseline tuberculin skin test (PPD) is recommended for all biologic immunomodulator therapies. Additional laboratory evaluation should include: hepatitis B screening, hepatic function panel and complete blood count with differential.

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Psoriasis - Cleveland Clinic Center for Continuing Education