Hot Topic Update: Atopic Dermatitis
A renaissance is underway in the arena of atopic dermatitis (AD), according to Eric L. Simpson, MD, MCR, Oregon Health and Science University, Portland, Orgeon, USA. Hot topics reviewed in AD included anti-itch therapies, phosphodiesterase (PDE) blockers, JAK-STAT pathway blockers, and cytokine pathway blockers. New topical and systemic treatments for AD are bringing substantial improvements in skin clearance and quality of life.
Three novel anti-itch therapies are in phase 2 studies. Asimadoline is an oral kappa-opioid agonist. Tradipitant is anovel neurokinin-1 antagonist that blocks substance P. CM1331 is an interleukin (IL)-31R blocker. In the phase 1b dose-ranging study of CM1331, patients had about a 50% reduction in pruritis with just one subcutaneous injection that was maintained for 8 weeks [Nemoto O et al. Br J Dermatol 2016]. Sleep efficiency was also improved. (See the results of the phase 2 study of CM1331 in our AAD coverage.)
The observation by Hanifin and colleagues that monocytes in AD have high levels of PDE-4 led to studies of PDE4 blockers in this setting. An open-label pilot study of oral apremilast in adults with AD showed a 50% improvement in itch scores at 3 months, and 50% improvement in Dermatology Life Quality Index (DLQI) scores and Eczema Area and Severity Index (EASI) scores at 6 months [Samrao S et al. Arch Dermatol 2012]. Results of the phase 2 study with apremilast in adults with AD will be reported in April 2016.
Two topical PDE-4 inhibitors are being developed. The phase 2 results with OPA-15406 were reported recently, showing that in 121 adolescents and adults with mild-to-moderate AD there was a 31% reduction in EASI scores, compared with 6% with vehicle) and 30% of patients were clear or almost clear with the topical agent versus 10% with vehicle.
Crisaborole is a boron-based, topical PDE-4 inhibitor that significantly improved the proportion of patients who were clear or almost clear at Day 29, compared with vehicle, with at least a 2-step improvement in about 700 patients in the phase 2 study (Figure 1). Pruritus was improved with crisaborole, with a significantly shorter time to improvement with the drug than with vehicle (median 1.37 days vs. 1.70 days, respectively; p<0.001). The improvement in pruritus was maintained to Day 29. (See the results of the phase 3 study of crisaborole in our AAD coverage).
An oral agent called baracitinib that blocks JAK1/2 is now enrolling adults with AD in a phase 2 study.
Topical tofacitinib has been examined in 65 adults who had an 82% reduction in EASI scores, compared with 30% reduction with vehicle, at 4 weeks. Tofacitinib has been approved for rheumatoid arthritis. Levy and colleagues reported an open-label trial of tofacitinib in six adults with recalcitrant AD and demonstrated a 71% reduction in itch, 66% reduction in the Scoring of AD (SCORAD) index, and reduction in sleep loss, with no side effects [Levy L, et al. J Am Acad Dermatol 2015]. Although these data are promising, Dr. Simpson noted that the risk-benefit ratio must be clarified, and information about malignancy, infection, and the need to monitor blood count is needed, because these have been seen in the setting of rheumatoid arthritis.
Dupilumab is a fully human monoclonal antibody that blocks IL-4 and IL-13 signaling. In patients with moderate-to-severe AD, the phase 2b study of dupilumab 300 mg weekly compared with placebo, demonstrated significant (p<0.0001) improvements in the EASI score (73.7%), SCORAD (56.9%), and pruritus (46.9%) at 16 weeks [Thaci D et al. Lancet 2016]. Significant (p<0.0001) reductions were also achieved in quality of life measures: 4.3-point reduction in SCORAD sleep loss and 9.3-point reduction in DLQI.
Successful treatment of AD has been shown to correlate with improvements in anxiety and depression scores. In one study of 94 patients with AD, the HADS-probable anxiety score was reduced to 25% with treatment versus 78% with placebo at 16 weeks. Another study showed that at 16 weeks there was a reduction to 20% with treatment compared with 76% with placebo in the EQ-5D-3L score. Mental health comorbidities can be improved by reducing itch and inflammation and improving sleep.