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    A new class steps forward

    PDE inhibitors are small molecules making a big impact

     

    Counsel thoroughly

    In all trials, says Dr. Chapman, patients tend to tolerate apremilast well. Nevertheless, "The gastrointestinal side effects are real. Patients may get diarrhea or an upset stomach. And if you don't counsel them about this, they're going to stop treatment." After two to four weeks, he added, the gastrointestinal upset resolves in more than 75% of patients. "Occasionally I may decrease the dose from two 30 mg tablets to one per day to get them through the first month."

    Apremilast's packaging also warns of an increased risk of depression. However, says Dr. Chapman, "I have an issue with the whole idea because our patients with psoriasis are already depressed." Physicians must consider baseline depression levels in these patients when assessing whether apremilast raises this risk, he says. "I have not had any cases in which apremilast exacerbated depression. I tend to ask a few more questions these days," after receiving a manufacturer's letter cautioning that many patients who go on apremilast are already taking selective serotonin reuptake inhibitors.

    Additionally, he says, 20% of patients lose at least 5% of their body weight while on apremilast. Although packaging presents weight-loss as a negative side effect, "Most people don't mind it." One of his patients experienced a 15% weight loss, prompting a malignancy workup, which was negative, and a reduction in her dose. "She has maintained response, and the 15% weight loss, and it's been a year." Physicians also should know that taking apremilast with anti-seizure drugs or rifampin lowers apremilast blood levels, Dr. Chapman says.

    Another PDE4 inhibitor, crisaborole 2% ointment, is approved for topical use in patients with atopic dermatitis (AD) as young as two years old. As a nonsteroidal treatment, Dr. Chapman says, "It's not going to be the medication for your most severe cases, but it certainly has a role in atopic dermatitis." In pivotal trials, around 1/3 of patients achieved investigator global assessments of clear or almost clear.7 Going forward, "We may need to increase the dosing a bit for atopic dermatitis. Those clinical trials will happen."

    As dermatologists grow comfortable with PDE inhibitors, he added, "We'll take these new medications and do what we do best, which is to use them (off-label) for other indications, change the dosing, grind them up into an ointment – we'll figure out the best ways to use them."

    Presently, he says, apremilast is being studied in inflammatory bowel disease, Behcet's disease and pediatric psoriasis. "I also believe it might be a great drug for hidradenitis suppurativa (HS)." Case reports suggest that apremilast can soothe allergic contact dermatitis enough that patients can undergo patch testing,8 and that apremilast modestly improves erythrodermic psoriasis (although in this case apremilast-induced atrial fibrillation limited its utility).9 "You can see how dermatologists are starting to experiment with the medication."

    Disclosures: Dr. Chapman is a consultant for Celgene, maker of apremilast.

    References

    1. Papp KReich KLeonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015;73(1):37-49.

    2. Paul C, Cather J, Gooderham M, et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol. 2015;173(6):1387-99.

    3. Reich KGooderham MGreen L, et al. The efficacy and safety of apremilast, etanercept and placebo in patients with moderate-to-severe plaque psoriasis: 52-week results from a phase IIIb, randomized, placebo-controlled trial (LIBERATE). J Eur Acad Dermatol Venereol. 2017;31(3):507-517.

    4. Armstrong AWBetts KASundaram MThomason DSignorovitch JE. Comparative efficacy and incremental cost per responder of methotrexate versus apremilast for methotrexate-naïve patients with psoriasis. J Am Acad Dermatol. 2016;75(4):740-6.

    5. Edwards CJBlanco FJCrowley J, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3). Ann Rheum Dis. 2016;75(6):1065-73.

    6. Kavanaugh AMease PJGomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014;73(6):1020-6.

    7. Paller ASTom WLLebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75(3):494-503.

    8. West CE, Fowler JF. Clearance of erythroderma in a patient on apremilast and positive patch test reactions while on treatment. Dermatitis. 2016;27(6):392.

    9. Arcilla J, Joe DKim JKim YTruong VNJaipaul N. Erythrodermic psoriasis treated with apremilast. Dermatol Reports. 2016;8(1):6599. 

    John Jesitus
    John Jesitus is a medical writer based in Westminster, CO.

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