Phosphodiesterase-4 and Janus Kinase Inhibitors

Psoriasis

Q18.3 Apremilast was approved by the US Food and Drug Administration (FDA) initially in March 2014 for treatment of active psoriatic arthritis. Several months later in September 2014, its approved indications expanded to include patients with moderate to severe plaque psoriasis for whom phototherapy or other systemic therapy is appropriate. Subset analyses within its phase 3 registrational studies demonstrate efficacy in specifically treating scalp and nail psoriasis, as well as palmoplantar psoriasis associated with moderate-to-severe plaque psoriasis affecting large areas of the rest of the body.

Apremilast is available as 30 mg tablets and as 10 mg, 20 mg, and 30 mg tablets in a titration pack used at the beginning of therapy and that might reduce gastrointestinal (GI) adverse effects (AE). Patients can take apremilast with or without food, but should not alter the tablet in any way including crushing, splitting, or chewing. Patients with creatinine clearance of less than 30 mL/min should only take apremilast 30 mg daily. No dose adjustment is necessary for geriatric patients or those with hepatic impairment. No laboratory monitoring is required for patients on apremilast therapy.

Q18.4 In patients with moderate to severe plaque psoriasis, Psoriasis Area and Severity Index (PASI)-75 was achieved in 28.8% to 39.8% of patients receiving apremilast compared with 5.3% to 11% in patients receiving placebo after 16 weeks of therapy. Patients, taking apremilast in general, have reported improvements in quality of life measures when compared with patients in matched placebo groups.

After 16 weeks of apremilast therapy, psoriasis patients with nail involvement had 22.5% to 29.0% improvement in the Nail Psoriasis Severity Index (NAPSI) score, compared with 6.5% to 7.1% improvement seen for the placebo population. Further, 40.9% to 46.5% of patients with severe scalp psoriasis who took apremilast 30 mg twice daily achieved a Scalp Physicians Global Assessment (ScPGA) of minimal or clear after 16 weeks. Significant improvements in palmoplantar psoriasis were also noted after 16 weeks of apremilast therapy; 46% of patients with a palmoplantar psoriasis physician global assessment (PPPGA) score of 1 or greater, indicating active disease at baseline achieved a PPPGA score of 0 (clear) compared with 25% of patients receiving placebo. It should be noted that this was a secondary analysis of patients in the phase III study of moderate-to-severe psoriasis, and that these patients did not have palmoplantar psoriasis as the primary feature of their disease. A separate study of patients with palmoplantar psoriasis as their primary disease failed to reach statistical significance at its primary endpoint.

Psoriatic Arthritis

Q18.4 In a study of psoriatic arthritis patients, 32.1% to 38.1% of patients on apremilast 30 mg twice daily achieved American College of Rheumatology (ACR)-20 compared with 18.9% to 19.0% of patients receiving placebo. At 52 weeks, an as observed statistical analysis showed that ACR20 was achieved in 54.6% patients receiving the same dosing.

Off-Label Uses for Apremilast

Although not FDA approved for Behçet disease (BD), randomized clinical trials have shown that BD patients, receiving apremilast, had reduction in the number of oral ulcers, genital ulcers, reduction in pain from oral ulcers and improvement in quality of life measures at 12 weeks. In addition, small pilot studies have showed that apremilast may be of benefit in patients with discoid lupus erythematosus and lichen planus. Recent clinical studies have also shown that more patients with active ulcerative colitis, who receive apremilast, reach clinical remission within 12 weeks than do patients receiving placebo.

Individual reports of apremilast efficacy in treating various other disease states have been published as well; these include pityriasis rubra pilaris, vitiligo and SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome.

Apremilast is also being studied for efficacy and safety in many other dermatologic conditions, including frontal fibrosing alopecia, chronic itch, nummular eczema, hidradenitis suppurativa, AD, contact dermatitis, severe acne, alopecia areata, rosacea, prurigo nodularis, cutaneous sarcoidosis, and vulvodynia. The true efficacy of apremilast in treating these conditions is left to be determined. Indications for apremilast are summarized in Box 18.1 .

Pharmacology and Pharmacokinetics

Apremilast is metabolized in the liver, primarily by cytochrome P-450 (CYP)3A4, but also by CYP1A1 and CYP2A6. Coadministration with potent CYP inducers, including rifampin, phenobarbital, carbamazepine, and phenytoin should be avoided because it may result in decreased apremilast drug levels. A summary of drug interactions that should be considered when prescribing apremilast can be found in Table 18.1 . The apremilast half-life is approximately 6 to 9 hours, necessitating apremilast as twice daily dosing. The drug is excreted primarily through the urine, but a small portion is excreted through the feces.

Contraindications and Adverse Effects

Allergy to apremilast or to any of the ingredients in the formulation is the only absolute contraindication to its use. It has not been studied in pregnant or lactating patients or pediatric populations and, therefore risk in these scenarios cannot be ruled out.