Acta Dermato-Venereologica 99-9CompleteContent | Page 6
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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).
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Journal Compilation © 2019 Acta Dermato-Venereologica.