Psoriasis: Evolving treatment for a complex disease
ABSTRACTThe cutaneous manifestations of psoriasis can vary in morphology and severity, and therapy should be tailored accordingly. Biologic agents are important new options for treating patients with the most severe forms of the disease. All physicians should be aware that severe psoriasis may increase cardiovascular morbidity and the risk of death, and preventive strategies for patients with severe disease should be considered.
KEY POINTS
- Studies in the past 10 years have uncovered a link between psoriasis, metabolic syndrome, and cardiovascular disease. Interestingly, the risk grows less with age; patients at greatest risk are young men with severe psoriasis.
- The most common presentation of psoriasis is plaque psoriasis. However, there are several other clinical variations of psoriasis, each of which has a distinct response to treatment and may be associated with significant systemic symptoms.
- Tumor necrosis factor inhibitors should be considered first-line in the treatment of psoriatic arthritis.
- Phototherapy and systemic medications including methotrexate, acitretin (Soriatane), cyclosporine (Gengraf, Neoral, Sandimmune), and biologic agents are the most effective treatments for moderate-to-severe psoriasis.
ORAL THERAPIES FOR SEVERE PSORIASIS
Patients who have severe psoriasis—ie, affecting more than 5% of the body surface or debilitating disease affecting the palms, soles, or genitalia—are best managed with systemic medications, especially if they do not have access to phototherapy.20
Methotrexate
In 1972, the US Food and Drug Administration (FDA) approved methotrexate for treating severe psoriasis.42 In studies of methotrexate at doses of 15 to 20 mg weekly, 36% to 68% of patients with severe plaque psoriasis achieved a PASI-75 score.40,42,47
,Dosages of methotrexate for treating severe psoriasis range from 7.5 to 25 mg once a week. Patients should also receive a folate supplement of 1 to 5 mg every day except the day they take methotrexate. The folate is to protect against gastrointestinal side effects, bone marrow suppression, and hepatic toxicity associated with methotrexate.
Other side effects of methotrexate include pulmonary fibrosis and stomatitis. Pregnancy, nursing, alcoholism, chronic liver disease, immunodeficiency syndromes, bone-marrow hypoplasia, leukopenia, thrombocytopenia, anemia, and hypersensitivity to methotrexate are all contraindications to methotrexate use.
The National Psoriasis Foundation, in its 2009 guidelines for the use of methotrexate in treating psoriasis,48 recommends obtaining a complete blood cell count with platelets, blood urea nitrogen, creatinine, and liver function tests at baseline and at 1- to 3-month intervals thereafter.
Liver biopsies were previously recommended for patients receiving methotrexate long-term when the cumulative dose of therapy reached 1.5 g. However, given the invasive nature of the liver biopsy procedure and the low incidence of methotrexate-induced hepatotoxicity, this recommendation has been revised.
For patients with no significant risk factors for hepatic toxicity (eg, obesity, diabetes, hyperlipidemia, hepatitis, or history of or current alcohol consumption) and normal liver function tests, liver biopsy should be considered when a cumulative methotrexate dose of 3.5 to 4.0 g is reached. Alternatively, one may choose to continue to monitor the patient without liver biopsy or to switch to another medication, if possible.42,48
Patients at high risk should be monitored more carefully, and liver biopsy should be considered soon after starting methotrexate and repeated after every 1.0 to 1.5 g.48
No reliable noninvasive measures to evaluate for liver fibrosis are routinely available in the United States. Serial measurements of serum type III procollagen aminopeptide have been reported to correlate with the risk of developing liver fibrosis; however, this test is readily available only in Europe.49
Cyclosporine
Cyclosporine (Gengraf, Neoral, Sandimmune) is very effective for treating psoriasis, especially erythrodermic psoriasis. It is often used only short-term or as a bridge to other maintenance therapies because it has a rapid onset and because long-term therapy (3 to 5 years) is associated with a risk of glomerulosclerosis.50
Cyclosporine works by decreasing T-cell activation by binding cyclophilin, which leads to inhibition of transcription of calcineurin and nuclear factor of activated T cells.51 Given at doses of 2.5 to 5 mg/kg/day, cyclosporine has been shown to result in rapid improvement in up to 80% to 90% of psoriatic patients.52,53
The initial recommended dose of cyclosporine is usually 2.5 to 3 mg/kg/day in two divided doses, which is maintained for 4 weeks and then increased by 0.5 mg/kg/day until the disease is stable.42
Nephrotoxicity and hypertension are cyclosporine’s most serious side effects. Blood urea nitrogen, creatinine, and blood pressure should be monitored at baseline and then twice a month for the first 3 months and once monthly thereafter. Liver function tests, complete blood cell count, lipid profile, magnesium, uric acid, and potassium should also be checked every month.
Cyclosporine also increases the risk of cutaneous squamous cell carcinoma, especially in patients who have received psoralen plus ultraviolet A treatment.42
Patients with hypersensitivity to cyclosporine, a history of chronic infection (eg, tuberculosis, hepatitis B, hepatitis C), renal insufficiency, or a history of systemic malignancy should not receive cyclosporine.
Acitretin
Acitretin, an oral retinoid, has been used for several years to treat psoriasis. Its onset is slow, typically ranging from 3 to 6 months, and its effects are dose-dependent. It is most effective as a maintenance therapy, usually after the disease has been stabilized by agents such as cyclosporine, or in combination with other treatments such as phototherapy.42 Acitretin has been shown to be effective in patients with pustular psoriasis.54
Acitretin does not alter the immune system and has not been shown to have significant cumulative toxicities. Serum triglycerides are monitored closely, since acitretin can lead to hypertriglyceridemia.
All retinoids, including acitretin, are in pregnancy category X and should therefore be avoided during pregnancy. Although its half-life is only 49 hours, acitretin may be transformed to etretinate either spontaneously or as a result of alcohol ingestion. Etretinate has a half-life of 168 days and can take up to 3 years to be eliminated from the body. Therefore, acitretin is contraindicated in women who plan to become pregnant or who do not agree to use adequate contraception for 3 years after the drug is discontinued.42
Biologic agents
Advances in our understanding of the pathogenesis of psoriasis have resulted in more specific, targeted therapy.
Alefacept (Amevive) is a human Fc IgG1 receptor fused to the alpha subunit of LFA3. It binds to CD2, blocks costimulatory signaling, and induces apoptosis in activated memory T cells.
Alefacept was the first biologic agent approved by the FDA for the treatment of psoriasis and one of the few biologic agents to induce long-term remission.55 However, its use has declined because few patients achieved significant clearance of their psoriasis and its onset of action was much slower than that of other medications.56
The currently approved biologic therapies commonly used for moderate to severe psoriasis include the TNF-alpha inhibitors and ustekinumab (Stelara).
The TNF-alpha inhibitors include infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). They are generally well tolerated and highly effective. However, TNF-alpha inhibitors and other biologic agents are contraindicated in patients with serious infection, a personal history or a family history in a first-degree relative of demyelinating disease, or class III or IV congestive heart failure. Patients should be screened for active infection, including tuberculosis and hepatitis B, since reactivation has been reported following initiation of TNF-alpha inhibitors.1
Adalimumab is a human monoclonal antibody against TNF-alpha. It binds to soluble and membrane-bound TNF-alpha and prevents it from binding to p55 and p75 cell-surface TNF receptors.
The dosing schedule for adalimumab is 80 mg subcutaneously for the first week, followed by 40 mg subcutaneously the next week, and then 40 mg subcutaneously every 2 weeks thereafter.1
Etanercept is a recombinant human TNF-alpha receptor (p75) protein fused with the Fc portion of IgG1, which binds to soluble TNF-alpha.57 Dosing for etanercept is 50 mg subcutaneously twice weekly for the first 12 weeks, followed by 50 mg weekly thereafter.
Infliximab is a chimeric antibody composed of a human IgG1 constant region fused to a mouse variable region that binds to both soluble and membrane-bound TNF-alpha.58 Infliximab is given as an infusion at a dose of 5 mg/kg over 2 to 3 hours at weeks 0, 2, and 6, and then every 8 weeks thereafter.
Efficacy of TNF inhibitors. There are no specific guidelines for the sequence of initiation of TNF inhibitors because no studies have directly compared the efficacy of these medications. However, response to infliximab is relatively rapid compared with adalimumab and etanercept.
In a phase III clinical trial,59 as many as 80% of patients achieved PASI-75 clearance of their psoriasis after three doses of infliximab. Interestingly, only 61% of patients maintained PASI-75 clearance by week 50. This loss of efficacy of infliximab is also reported with other TNF-alpha inhibitors and is thought to be secondary to the development of antibodies to the drugs. For infliximab, this loss of efficacy is less when infliximab is given continuously rather than on an as-needed basis. Simultaneous treatment with methotrexate is also thought to decrease the development of antibodies to infliximab.60
Ustekinumab is an monoclonal antibody directed against the common p40 subunit of IL-12 and IL-23, which have been shown to be at increased levels in psoriatic lesions and important for the pathogenesis of psoriasis.
Between 66% and 76% of patients treated with ustekinumab achieved significant clearance of their disease after 12 weeks of treatment in two large phase III multicenter, randomized, double-blind, placebo-controlled trials.61,62
Dosing of ustekinumab is weight-based. For those weighing less than 100 kg, ustekinumab is given at 45 mg subcutaneously at baseline, at 4 weeks, and every 12 weeks thereafter. The same dosing schedule is used for those weighing more than 100 kg, but the dose is increased to 90 mg.
Guidelines for monitoring patients while on ustekinumab are similar to those for other biologic agents. Information on long-term toxicities is still being collected. However, injection-site reactions, serious infections, malignancies, and a single case of reversible posterior leukoencephalopathy have been reported.20
While biologic agents are significantly more expensive than the conventional therapies discussed above and insurance coverage for these agents varies, they have demonstrated superior efficacy and may be indicated for patients with recalcitrant moderate to severe psoriasis for whom multiple types of treatment have failed.
