Current Therapies for Psoriasis, Part 2

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The rapid changes in the treatment of psoriasis have provided many new options for the approximately 7.5 million Americans who live with psoriasis, of whom 30% may also develop psoriatic arthritis (PsA).1 The tremendous variation in psoriasis—with common, guttate, inverse, pustular, and erythrodermic variants as well as variation in the parts of the body affected by the disease—complicates the treatment decision. Psoriasis not only has a large direct effect on patients’ quality of life; psoriasis is associated with many comorbidities such as obesity, cardiovascular disease, diabetes, and depression. 

The development of new targets for psoriasis treatments have paralleled our growing understanding of immunological pathways involved in the pathogenesis of psoriasis. Our improved understanding of the human factors that contribute to how well people use their medications has also led to major improvements in our ability to control the disease. With new evolving information, both topical and systemic medications, have been developed to selectively take advantage of these developments.2 

Small Molecule Systemic Treatments

Small molecule drugs for psoriasis target a broad range of mediators in the pathogenesis of psoriasis. Aside from apremilast, these drugs have been used for many years in the treatment of psoriasis (Table 3), but the studies on which they were based have not used the same outcome measures as has become standard in psoriasis treatment. 

Table 3

Methotrexate

Methotrexate has been prescribed since the 1970s for psoriasis and is still considered a first-line systemic treatment. Although newer medications are more effective and have fewer side effects, insurance companies may not cover newer therapies unless methotrexate is contraindicated or until it has been tried and failed. Methotrexate is a dihydrofolic acid reductase antagonist and has a greater affinity for the enzyme than does folic acid. Inhibition of folate production decreases T-cell proliferation and causes T-cell apoptosis. Methotrexate also suppresses joint inflammation for patients affected by PsA. Most patients take methotrexate orally at a dose of 7.5 to 25 mg weekly (either as a single dose or as 3 doses taken at 12-hour intervals); methotrexate can also be taken by intramuscular or subcutaneous injection. The majority of patients see improvement in their psoriasis after starting methotrexate at 3 to 6 weeks, with maximal improvement occurring at 6 months. In a study published in 2017, the effectiveness of subcutaneous methotrexate was tested in 120 patients with moderate to severe psoriasis in a randomized, placebo-controlled trial. After 16 weeks of treatment, 41% of patients in the treatment group experienced a 75% improvement in their Psoriasis Area Severity Index (PASI 75) score compared with 10% achieving this level of improvement in the placebo group.1,3,4,6

Side effects commonly observed are nausea, vomiting, fatigue, stomatitis, diarrhea, dizziness, fever, and alopecia. Taking 1 mg of folic acid daily may help to protect against some of these side effects. Methotrexate is cleared renally; therefore, patients with kidney disease are prescribed a lower dose or the drug is avoided altogether. One potential serious adverse effect is hepatotoxicity, and patients with a history of liver disease, hyperlipidemia, and obesity are at an increased risk. Liver biopsies are occasionally performed for patients on long-term methotrexate therapy, but current recommendations regarding the frequency of the procedure are controversial as the risk of the procedure may exceed the benefit. In addition, pulmonary fibrosis is a rare side effect but should be considered in any patient taking methotrexate who develops new onset respiratory symptoms. Methotrexate toxicity can also cause serious myelosuppression, and patients should be monitored with complete blood counts (CBCs) regularly. Folinic acid (Leucovorin) given at 20 mg is the reversal agent for acute toxicity and may need to be given at multiple doses every 6 hours until the methotrexate is cleared. Lastly, methotrexate is teratogenic and an abortifacient medication; it is contraindicated during pregnancy and in women who are trying to become pregnant.1,3,4

Cyclosporine

Cyclosporine is an immunosuppressive oral medication that was initially used to prevent rejection in organ transplant patients. Since 1997, it has been prescribed for psoriasis. Cyclosporine decreases IL-2 production and other T-lymphocyte-produced cytokines. Cyclosporine is dosed at 2 to 5 mg/kg per day and causes rapid clearance of psoriasis. While effective and valuable for short-term use, cyclosporine is infrequently prescribed because recurrence is rapid upon discontinuation and because it can cause long-term renal complications. Cyclosporine is generally reserved for acute, short-term treatment to achieve improvement while transitioning to another systemic medication or phototherapy that is safer for long-term disease management.1,3,4

Acitretin

Acitretin is a second generation oral systemic retinoid medication that normalizes keratinization. It reduces hyperproliferation and the scale produced in psoriasis and thins psoriatic plaques making topical medications and phototherapy more effective. Although a systemic medication, it is not a treatment for PsA. Acitretin is generally prescribed at 25 to 50 mg either daily or every other day. It is considered first-line therapy for pustular and erythrodermic psoriasis and is also effective in treating plaque psoriasis particularly in combination with phototherapy. In 2 previous studies testing the efficacy of acitretin, 66% and 85% of patients achieved PASI 50, and 34% and 52% achieved PASI 75 after 12 weeks of treatment.11

Common side effects observed are similar to those seen when oral isotretinoin therapy is used for acne and include chelitis, xerosis, headache, joint pain, and alopecia. Other adverse events are elevations in liver enzymes, cholesterol, and triglycerides, so these levels should be routinely monitored. Severe depression can also occur with oral retinoid treatment. Side effects are usually reversible when the medication is stopped. Acitretin is also a teratogen; therefore, it is contraindicated in women who are pregnant, nursing, and in women of childbearing potential. Note: Because of the long half-life of acitretin, it should rarely if ever be used by a woman who might someday become pregnant.1,3,4

Apremilast

Apremilast decreases inflammatory cytokines by inhibiting phosphodiesterase-4. This prevents the conversion of cyclic adenosine monophosphate (cAMP) to AMP; the resulting higher levels of cAMP decrease production of inflammatory cytokines such as TNF-α and IL-23. Apremilast was approved by the FDA in 2014 for the treatment of moderate to severe plaque psoriasis and PsA. It is typically dosed at 30 mg twice a day. In previous clinical trials, 31% of patients taking apremilast achieved PASI 75 after 16 weeks, and about 38% experienced a 20% improvement in their arthritis severity score. Compared with biologics, such as adalimumab (Humira), etanercept (Enbrel), and ustekinumab (Stelara), apremilast is less effective at treating psoriasis; however, apremilast is a reasonable option for patients who do not wish to start an injectable medication. 

The most common side effect is diarrhea; nausea, vomiting, headache, and upper respiratory tract infection are also common. With continued treatment, especially after the first 2 weeks, these adverse effects tend to resolve so patients should be encouraged to continue taking the medication. Although apremilast decreases inflammatory cytokines, an increased risk of opportunistic infection has not been found in clinical trials, and there is no requirement in the label for laboratory monitoring.12 For unknown reasons, 10% to 12% of patients taking apremilast experienced a weight loss of 5% to 10%. In addition, gastroesophageal reflux disease, hypersensitivity, migraine, and suicidal ideation have been observed. This medication has not been studied in pregnancy and is considered pregnancy category C.1-3,6

JAK Inhibitors 

Janus kinases (JAK)—such as JAK1, JAK2, JAK3, and tyrosine kinase 2—are a group of tyrosine kinases found in hematopoietic cells that are responsible for signaling that mediate the signal when cytokines bind to their receptors. By targeting JAKs and interrupting the signaling process, the immune system is modulated and inflammation can be reduced. Tofacitinib (Xeljanz) is a small molecule that has been FDA approved as an oral medication for the treatment of rheumatoid arthritis. It primarily targets JAK3 and has been investigated for its role in the treatment of psoriasis. So far, tofacitnib has been well tolerated and shown rapid results in patients with psoriasis, but there is concern for an increased risk of infection. Another oral medication, baricitinib is an inhibitor of JAK1 and JAK2 and is being studied for its role in the treatment of psoriasis. Side effects associated with these medications are increased risk of infection, elevations in cholesterol and creatinine phosphokinase levels, anemia, neutropenia, and lymphopenia.6,13

Systemic Treatments: Biologics

The introduction of biologic treatments has revolutionized the treatment of patients with moderate to severe psoriasis. As standards for how much improvement can be achieved and how little side effects should be tolerated have become much more stringent, disease clearing has become a realistic expectation for many patients (Table 4).

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