Clinical Pearls & Morning Reports
Published July 15, 2020
Lebwohl et al. conducted a phase 2b trial that evaluated the efficacy and safety of two dose levels of roflumilast cream (which contains a phosphodiesterase type 4 [PDE-4] inhibitor) for the treatment of plaque psoriasis. Read the NEJM Original Article here.
Q: What are the main treatments for psoriasis?
A: High-potency topical glucocorticoids and vitamin D derivatives are the main treatments for psoriasis. Glucocorticoids are effective in the treatment of psoriasis, but their use is usually limited to no more than 2 to 8 weeks, and they may be associated with adverse events that resolve slowly, such as skin atrophy, or that are irreversible with long-term use, such as striae. Vitamin D derivatives are less efficacious than topical glucocorticoids and can cause local irritation. Topical calcineurin inhibitors are not approved for the treatment of psoriasis but have been used off-label to treat facial and intertriginous psoriasis.
Q: Have PDE-4 inhibitors been previously used for the treatment of psoriasis?
A: PDE-4 is an enzyme that maintains intracellular levels of cyclic adenosine monophosphate (cAMP) and mediates biologic responses to extracellular stimuli in numerous cell types, including immune cells. PDE-4 activity is greater in psoriatic skin than in healthy skin, and inhibition of PDE-4 results in down-regulation of immune modulators, including tumor necrosis factor α, interferon-γ, interleukin-17, and interleukin-23. The oral PDE-4 inhibitor apremilast has been approved for the treatment of moderate-to-severe plaque psoriasis, and crisaborole ointment has been approved for the treatment of atopic dermatitis; however, topical PDE-4 inhibitors are currently not approved for the treatment of psoriasis.
A: This phase 2b trial of roflumilast cream showed greater reductions in psoriasis signs and symptoms than placebo vehicle cream at 6 weeks. Patients were randomly assigned in a 1:1:1 ratio to receive roflumilast 0.3% cream, roflumilast 0.15% cream, or vehicle (placebo) cream, applied once daily to affected skin areas for 12 weeks. The primary efficacy outcome was an investigator’s global assessment (IGA) status of clear or almost clear (score of 0 or 1) at week 6. The primary efficacy outcome was observed in 28% of the patients in the roflumilast 0.3% group, in 23% of those in the roflumilast 0.15% group, and in 8% of those in the vehicle group (P<0.001 and P=0.004 vs. vehicle for roflumilast 0.3% and 0.15%, respectively). Among the approximately 15% of patients overall who had baseline intertriginous psoriasis of at least mild severity, an IGA score indicating clear or almost clear plus a 2-grade improvement in the intertriginous-area IGA score occurred at week 6 in 73% of the patients in the roflumilast 0.3% group, in 44% of those in the roflumilast 0.15% group, and in 29% of those in the vehicle group. By week 12, a total of 14 of 15 patients (93%) treated with roflumilast 0.3% had an intertriginous-area IGA score of 0 (clear), as compared with 3 of 17 patients (18%) in the vehicle group. Longer and larger trials are necessary to determine the effectiveness and safety of roflumilast.
A: Adverse events that were considered by the investigators to be related to the intervention were reported in 6% of the patients receiving roflumilast 0.3%, in 3% of those receiving roflumilast 0.15%, and in 7% of those receiving vehicle. The incidence of application-site reactions (in four patients receiving roflumilast 0.3%, in one receiving roflumilast 0.15%, and in five receiving vehicle), gastrointestinal adverse events such as nausea and diarrhea (in three, two, and three, respectively), and psychiatric adverse events (in three, two, and three, respectively) was similar in the roflumilast groups and the vehicle group.