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756 CLINICAL REPORT Direct and Indirect Effects of Crisaborole Ointment on Quality of Life in Patients with Atopic Dermatitis: A Mediation Analysis Eric L. SIMPSON 1 , Gil YOSIPOVITCH 2 , Andrew G. BUSHMAKIN 3 , Joseph C. CAPPELLERI 3 , Thomas LUGER 4 , Sonja STÄNDER 5 , Wynnis L. TOM 6,7 , William C. PORTS 3 , Michael A. ZIELINSKI 8 , Anna M. TALLMAN 9 , Huaming TAN 3 and Robert A. GERBER 3 Oregon Health and Science University, Portland, OR, 2 University of Miami, Miller School of Medicine, Miami, FL, 3 Pfizer Inc, Groton, CT, USA, University Hospital Münster, 5 Center for Chronic Pruritus, University Hospital Münster, Münster, Germany, 6 University of California, 7 Rady Children’s Hospital-San Diego, San Diego, CA, 8 Pfizer Inc, Collegeville, PA, and 9 Pfizer Inc, New York, NY, USA (at the time of the analysis) 1 4 Crisaborole ointment is a nonsteroidal phosphodieste- rase 4 inhibitor for the treatment of mild to moderate atopic dermatitis. Using pooled data from two phase 3 studies (NCT02118766/NCT02118792), mediation modeling determined the interrelationship among pruritus, quality of life (QoL), and treatment. Patients aged ≥ 2 years received crisaborole ointment, 2%, or vehicle twice daily for 28 days. QoL measures were Dermatology Life Quality Index (DLQI) (≥ 16 years) and Children’s Dermatology Life Quality Index (CDLQI) (2–15 years). Pruritus was assessed by the Severity of Pruritus Scale (4-point scale from 0 to 3). The in- direct effect of crisaborole on QoL mediated through its effect on pruritus was 51% (DLQI model, p  < 0.05) and 72% (CDLQI model, p  < 0.05). Direct effect (other effects) on QoL was 49% (DLQI model, p  < 0.05) and 28% (CDLQI model, p  >  0.05). Mediation modeling shows that crisaborole affects QoL mostly indirectly through pruritus severity reduction. Key words: crisaborole; atopic dermatitis; quality of life; mediation; pruritus. Accepted Mar 21, 2019; E-published Mar 21, 2019 Acta Derm Venereol 2019; 99: 756–761. Corr: Eric L. Simpson, MD, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR 97225, USA. E-mail: [email protected] A topic dermatitis (AD) is a chronic inflammatory skin disease characterized by intensely pruritic eczematous lesions (1, 2). Pruritus is the predominant symptom of AD; approximately 91% of patients with AD report daily pruritus (3). The precise mechanism of AD-associated pruritus is complex and continues to be investigated; however, it is thought to be caused by various inflammatory and noninflammatory stimuli (4). AD-associated pruritus has a significant impact on quality of life (QoL) in children and adults (5), and, as a result, a central goal of treatment is rapid relief of pruritus flares and long-term symptom control (4). Until recently, initial pharmaceutical treatment of AD involved topical corticosteroids (TCSs) or topical calcineurin inhibitors (TCIs), but there are potential limitations to their use (6–8). TCSs are the mainstay of AD treatment and are effective in treating active inflam­ matory disease (6–8). However, their broad mechanism of action can lead to adverse effects, such as skin atrophy, doi: 10.2340/00015555-3181 Acta Derm Venereol 2019; 99: 756–761 SIGNIFICANCE Atopic dermatitis, a skin disease characterized by inflam- mation and itching, has a significant impact on a patient’s quality of life. Mediation modeling can be used to find if a causal factor influences an outcome factor through a third factor, the mediator. The mediation analysis presented here shows that quality of life in patients with atopic dermatitis is mostly influenced by the effect of the treatment on itching. particularly with more potent agents. Such adverse ef­ fects have resulted in “steroid phobia” or a hesitancy of patients to use these agents (9–11). TCIs reduce body surface area involvement and signs and symptoms of AD; however, efficacy is comparable with that of low- or mid- potency TCSs (6–8). The most common adverse event with TCIs is burning and stinging, which can preclude their use in many patients, especially in children (12). As a result, there is a need for new, effective, nonsteroidal treatments that address inflammation and pruritus. Crisaborole ointment is a nonsteroidal phosphodies­ terase 4 (PDE4) inhibitor for the treatment of mild to moderate AD. Crisaborole, a novel boron-containing mo­ lecule approved to treat mild to moderate AD in patients aged ≥ 2 years, reduces pro-inflammatory cytokines via a unique mechanism of action through inhibition of PDE4 (13–15). In 2 identically designed phase 3 clinical studies (AD-301: NCT02118766; AD-302: NCT02118792), crisaborole ointment, 2%, improved global disease severity and all measured signs and symptoms of AD in significantly more patients compared with vehicle; application site pain was the most common treatment- related adverse event (13). In prespecified and post hoc analyses, crisaborole oint­ ment also reduced the severity of pruritus in significantly more patients compared with vehicle ointment at day 29 and at week 4 of the studies (p = 0.005 and p < 0.001, respectively) (13, 16, 17). A qualitative and psychometric analysis of the Severity of Pruritus Scale (SPS), a 4-point rating scale ranging from 0 (“no itching”) to 3 (“bother­ some itching/scratching which is disturbing sleep”), used in the phase 3 studies was recently completed and supported the validity of the measure for use in AD (18). Greater mean improvement in QoL was also observed with crisaborole compared with vehicle at day 29 (19). This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica.