Conventional systemic therapies. Conventional systemic therapies used for psoriasis treatment include acitretin, methotrexate, and cyclosporine, which have been used for more than 10 years.2,13

Acitretin is an oral retinoid and is teratogenic, limiting its use in women of childbearing age. Dosing starts at 10 mg/d to 25 mg/d and is increased according to the patient’s ability to tolerate its side effects. However, in the case of generalized pustular psoriasis, it should be started at a high dose and titrated down if a lower dose is effective. Its adverse effects include increases in xerosis and triglyceride level and abnormal liver function tests. Acitretin is also classified as Pregnancy Category X and inappropriate for use in women of childbearing age or men who wish to conceive; in rare cases, the drug has been associated with decreased night vision, skeletal hyperostosis, or pseudotumor cerebri.13,14 Acitretin is more effective when used in combination with topical vitamin D3 derivatives such as calcipotriene, or phototherapy or biologics. Among the drawbacks of acitretin are that it has a slow onset of action and may only thin psoriatic plaques, rather than effectively eliminating them, when used alone. It is not as effective a monotherapy as methotrexate or cyclosporine at tolerable doses,2,14 but acitretin is helpful in treating specific subtypes of psoriasis, such as generalized, palmoplantar, pustular, and hyperkeratotic psoriasis.14 One advantage of acitretin is that it has less potential for end-organ toxicity than methotrexate or cyclosporine.10

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Methotrexate inhibits DNA replication by disrupting cellular folic acid metabolism and is the oldest systemic therapy for moderate-to-severe psoriasis. Although it is cytostatic, it also leads to reduced T-cell gene expression, increases endogenous levels of adenosine, and decreases antibody responses, which are direct anti-inflammatory effects. Methotrexate is available in 2.5-mg tablets, prescribed as 7.5 mg to 25 mg taken once weekly. Subcutaneous methotrexate, also dosed once weekly, exhibits improved bioavailability, efficacy, and tolerability in patient studies of rheumatoid arthritis.13 Cumulative use of methotrexate increases risk of liver toxicity, but folate supplementation can reduce that risk,15 as well as the risks of bone marrow suppression and gastrointestinal side effects.10 A multicenter, randomized controlled trial found that 40% of subjects achieved a 75% reduction in PASI scores (PASI 75) at 24 weeks.13,16

The most common side effects of methotrexate include nausea, diarrhea, fatigue, and headaches. Additionally, liver function tests should be performed every 4 to 12 weeks, as hepatotoxicity may manifest early as elevated transaminases. 

Guidelines from the American Academy of Dermatology have reduced the need for liver biopsies in patients without risk factors for hepatic fibrosis to every 3.5 g to 4.0 g of total cumulative dose.17 Some European countries have standardized the measurement of classic and newly validated serum biomarkers, such as amino terminal propeptide of type III procollagen. A complete blood count is necessary to screen for myelosuppression and kidney function must be monitored prior to and during use because methotrexate is renally excreted. 

Methotrexate is an abortifacient and classified as Pregnancy Category X; it is also contraindicated during lactation. The drug should be discontinued in both men and women at least 3 months prior to attempting to conceive. 

Methotrexate can be combined with other systemic medications or phototherapy for additive or synergistic responses. Combinations allow for lower doses of the individual drugs and improved overall efficacy.13

Cyclosporine is an oral calcineurin inhibitor that lowers the production of IL-2 and other proinflammatory cytokines that activate T cells. It is used in many immune-mediated disease states, including moderate-to-severe psoriasis. It is typically dosed at 2.5 mg/kg/d to 5.5 mg/kg/d.13 Cyclosporine is fast acting and is therefore considered a first-line treatment for types of pustular psoriasis and erythrodermic psoriasis as a rescue drug. A dose of approximately 5 mg/kg/d has shown a reliable average PASI 75 rate of 70%.13,18

Once a course of cyclosporine is complete, management is switched to a therapy with fewer long-term adverse effects. Long-term use and high doses of cyclosporine are associated with renal damage, hypertension, hypertriglyceridemia, electrolyte abnormalities, and increased risk of squamous and basal cell carcinomas. Therefore, it is used intermittently for no longer than 12 weeks at a time and is effective for management of flares. Baseline laboratory and blood pressure tests are necessary prior to its use. While on the medication, weekly blood pressure measurements and monthly comprehensive metabolic panels with lipids, magnesium, and potassium are necessary. 

Cyclosporine has many relative contraindications and is metabolized through the cytochrome P450 liver system; thus, it is important to be aware of a patient’s medical history, diagnoses, and current medications and potential interactions prior to its use.2,10,13 Because cyclosporine can only be used temporarily, it is often combined with or titrated down while also using overlapping therapy, such as methotrexate, acitretin, or biologic agents.13

Biologic agents. The biologic agents are a newer class of medications available to patients with moderate-to-severe psoriasis and are effective long-term treatment options. They have increased safety, efficacy, and tolerability when compared with the classical agents, especially because they show no cumulative toxicity or significant interactions with other drugs. As a result, they are no longer reserved as second-line treatments, but their cost may delay their use until after conventional therapies have been exhausted.2

The risks of biologics include a small increase in opportunistic infections, so they should not be used in immunocompromised individuals or those with active infections. Patients should be tested for latent tuberculosis prior to use. Common side effects include flu-like symptoms and injection site reactions. Cost, the severity of disease, and the medical history of the individual patient should determine their use.2,10

TNF-α inhibitors approved for use in moderate-to-severe psoriasis and psoriatic arthritis include etanercept, adalimumab, and infliximab. Given their mechanism of immunosuppression, they share a heightened risk of causing infection (including sepsis and tuberculosis), autoimmune disorders (eg, lupus), and lymphoma.2 Etanercept reaches a PASI 75 in a majority of patients at 24 weeks when dosed at 50 mg twice weekly and then reduced to 50 mg/wk after 12 weeks. The twice-weekly dosing can be maintained if the patient’s improvement is inadequate after 24 weeks.10 Adalimumab and infliximab are administered subcutaneously and have shown effective control of plaque psoriasis and rapid onset of action, respectively. A loading dose of 80 mg of adalimumab is followed 1 week later by 40-mg injections every other week. For infliximab, 3 intravenous induction infusions (5 mg/kg) are given at weeks 0, 2, and 6, with infusions thereafter every 8 weeks. Adalimumab and infliximab have shown greater efficacy than methotrexate with regard to PASI score improvement.10,19,20 Furthermore, infliximab has the greatest short-term efficacy and most rapid onset of action, followed closely by adalimumab and ustekinumab, making it an ideal medication for treatment of erythrodermic psoriasis.21

Alefacept is a biologic agent approved for use in patients with psoriasis and interferes directly with T-cell surface proteins, such as CD2 and its costimulatory molecule, thereby triggering the apoptosis of pathogenic T lymphocytes. Alefacept carries the risk of CD4 T lymphocyte depletion, so CD4 counts must be regularly checked; alefacept should be discontinued when the count is less than 250 CD4 T cells/uL. Like cyclosporine, alefacept is prescribed for intermittent 12-week courses, leading to a 50% to 75% reduction in PASI scores in approximately 25% of patients, an effect that may last for more than 12 months. Each course can be repeated twice a year. As long as CD4 counts are regularly supervised, alefacept has shown few adverse effects10,22 and is often combined with phototherapy regimens for increased efficacy.23

Ustekinumab is a human monoclonal antibody that blocks IL-12 and IL-23 and has been approved for the treatment of psoriasis and psoriatic arthritis. By blocking these interleukins, ustekinumab interrupts the development of Th17 lymphocytes involved in the psoriasis inflammatory process. Trials have shown no significant risks due to its method of immunosuppression, but long-term data are lacking.10,24 After 2 initial doses of 45 mg at weeks 0 and 4, health care providers give patients an injection of the same dose once every 12 weeks for those weighing 100 kg or less. Patients weighing more than 100 kg are given 90-mg injections every 12 weeks. In 67% to 81% of patients who have a prolonged response, PASI 75 was reached, and many achieved a reduction in PASI scores of 50% by week 2.10,25,26

Secukinumab is a human monoclonal antibody that is approved by the U.S. Food and Drug Administration (FDA) for psoriasis; the drug targets IL-17A, a cytokine produced by TH17 and other immune system cells.2,27 At a subcutaneously administered dose of 3 mg/kg, it has been shown to reduce the PASI score by 58% in 1 month and sustain this improvement by week 12, at which point the average PASI score reduction was 63%. In randomized control trials, more patients on secukinumab reached PASI 75 at week 12 than with either placebo or etanercept. Patients received either 150 mg or 300 mg of the medication once weekly for 5 weeks, then once every 4 weeks. Although secukinumab has been shown to increase risk of infection, its rates and severity of infection are no higher than those of etanercept. Brodalumab and ixekizumab are 2 other IL-17 inhibitors that are currently undergoing phase 3 randomized, controlled trials and clinical trials, respectively.27