Small molecule therapies. Apremilast is a small, oral phosphodiesterase-4 (PDE4) inhibitor effective for the treatment of psoriasis and psoriatic arthritis;2 it showed a minimum 75% reduction in PASI scores in approximately 30% of subjects dosed at 30 mg twice daily after 16 weeks. PDE4 is active in the immune cells and keratinocytes and increases the production of inflammatory cytokines, so its inhibition improves inflammation in psoriasis. Patients in apremilast trials may have had side effects of nausea, vomiting, diarrhea, headaches, and upper respiratory tract infections, but no significant laboratory changes are seen in those taking apremilast, so no monitoring is necessary.13,28 One interesting side effect seen in 10% of subjects treated with apremilast was a decrease of 5% to 10% in body weight at baseline, the cause of which remains unknown.29
Janus kinase (JAK) inhibitors, such as tofacitinib (a JAK1/JAK3 inhibitor), have recently gained approval for use in rheumatoid arthritis and show promise in the treatment of psoriasis. JAK molecules are proteins within cells that transmit signals from extracellular cytokines to the cellular nucleus. By inhibiting JAK, cytokine effects on the cell are reduced. Tofacitinib thus interrupts signaling via several interleukin receptors, such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.13,30 Tofacitinib has undergone phase 3 multicenter trials for psoriasis, which showed an average week-16 PASI 75 response of approximately 40% at 5 mg twice daily and approximately 60% at 10 mg twice daily. Furthermore, oral tofacitinib, 10 mg twice daily showed noninferiority to etanercept dosed at 50 mg subcutaneously twice weekly. Unlike apremilast, tofacitinib has shown laboratory abnormalities, especially when doses are more than 5 mg twice daily. Cytopenias and anemias, increased liver enzyme test abnormalities, and increased cholesterol and creatinine levels have been reported in a small number of patients, but have all been reversed with discontinuation of the drug. Additionally, patients on tofacitinib have increased rates of herpes zoster outbreaks, infections, and certain malignancies, prompting a boxed FDA warning. Patients prescribed this medication should therefore receive regular monitoring of their laboratory results so that abnormalities can be addressed early with a dose reduction or complete discontinuation of the medication.13,31
Second-tier systemic agents. The following agents have not been approved by the FDA for treatment of psoriasis and are reserved only for those cases refractory to the aforementioned medications due to their significant side effect profiles and drug-drug interactions: mycophenolate mofetil, leflunomide, fumaric acid esters, hydroxyurea, 6-thioguanine, and sulfasalazine.13 Of note, fumaric acid esters are approved for psoriasis treatment in several other countries,2 but larger randomized, double-blind controlled trials are necessary to confirm the extent of their efficacy. Mycophenolate mofetil has shown substandard efficacy as a monotherapy, but may be used in those who cannot tolerate other medications or in combination with other treatment regimens. Leflunomide may prove helpful as an adjunctive medication for those patients also suffering from psoriatic arthritis. A majority of second-tier systemic agents are antimetabolites and thus, contraindicated in pregnant women. Furthermore, many require frequent monitoring of laboratory values due to their substandard safety profiles and lower quality of data available on their utility in psoriasis treatment specifically.13
Due to hormonal changes, most women have symptomatic improvement of their psoriatic symptoms during pregnancy. For those women who do require therapy during pregnancy, topical agents such as corticosteroids are preferred. UV-B phototherapy is safe to use in pregnant women with moderate-to-severe disease.12,32 Although more data are necessary, biologic agents are the favored systemic medications for pregnant patients whose disease is not well-controlled with topical agents or phototherapy, including bath PUVA.32 Cyclosporine is classified as a Pregnancy Category C agent, so its potential benefits may warrant its use.