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Background Skin pain is a common and burdensome symptom of atopic dermatitis (AD), and its severity increases with disease progression. The Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) is a validated 11-item patient-reported instrument developed in accordance with regulatory agency guidance for assessment of the daily symptoms of patients with AD, including skin pain. Objective To establish content validity and evaluate the psychometric properties of the skin pain numerical rating scale (NRS) item of the PSAAD. Methods: The skin pain NRS is a single-item measure from the PSAAD and is used to assess skin pain severity over the past 24 hours with the question "How painful was your skin over the past 24 hours?" on a 10-point scale from 0 (not painful) to 10 (extremely painful). A qualitative validation analysis consisting of concept elicitation (CE) interviews; electronic completion of the PSAAD measure, including the skin pain NRS; and cognitive debriefing (CD) interviews was conducted for adults and adolescents with mild-to-severe AD. Evaluation of psychometric properties of the skin pain NRS--including test-retest reliability, estimation of meaningful within-patient change (MWPC), known-group validity, ability to detect change, construct validity, quality of completion, and ceiling and floor effects--was conducted based on a post hoc qualitative and quantitative analysis of pooled data, with skin pain NRS as part of the PSAAD in the abrocitinib monotherapy phase 3 trials JADE MONO-1 (NCT03349060) and JADE MONO-2 (NCT03575871). Data from patients (≥12 years of age) with moderate-to-severe AD were pooled across all treatment arms. Results: Among 30 CE interviews (adolescents [12-17 years], n=15; adults [≥18 years], n=15) conducted over 2 rounds of testing, 20 of 30 (67%) patients reported skin pain. During CD interviews (n=30), 100% of patients interpreted the skin pain NRS item as intended, and 73% reported it as relevant. The psychometric validation analysis included 736 patients (JADE MONO-1, N=347; JADE MONO-2, N=389). The test-retest reliability of the skin pain NRS was evidenced by large intraclass correlation coefficients (ICC; 0.76 and 0.72 in JADE MONO-1 and MONO-2, respectively) for a single daily skin pain score, which increased to 0.93 and 0.91 for a measurement averaging at least 4 scores per week. Convergent validity was demonstrated by correlations between skin pain and other clinician- and patient-reported AD measures (median correlation >0.4 starting at week 4). The skin pain NRS distinguished between "clear" and "severe" disease severity groups, assessed using the Patient Global Assessment (PtGA) and Investigator's Global Assessment (IGA) as continuous and categorical anchors (P<0.0001); differences were also significant among other disease severity groups using the PtGA and IGA as continuous anchors (P<0.0001). Based on the PtGA and IGA anchor analysis, the estimated MWPC was 1.9 and ranged from 2.7 to 3.9 points using the empirical cumulative distribution function analysis. Ability to detect change was demonstrated by linear relationships between disease severity measures and skin pain scores (correlation of ≥0.5 between the skin pain NRS and the PtGA). More than 90% of patients provided at least 4 daily skin pain scores each week. No floor or ceiling effects were observed. Conclusions: The qualitative and quantitative data from initial PSAAD development and psychometric evaluation of the skin pain NRS from the PSAAD support its content validity, reliability, construct validity, and ability to detect change. These findings corroborate the 4-point improvement in skin pain as the adequate and meaningful cut-off to define a skin pain responder in JADE MONO-1 and MONO-2. [ABSTRACT FROM AUTHOR]

Skin pain is a common and bothersome symptom of atopic dermatitis (AD) that is associated with a substantial burden. To assess the efficacy of abrocitinib vs. dupilumab on skin pain in patients with moderate-to-severe AD. Data from patients aged ≥18 years who received oral abrocitinib 200 mg once daily (QD) or subcutaneous dupilumab 300 mg once every 2 weeks in combination with topical therapy in the phase 3 trials JADE COMPARE (NCT03720470) and JADE DARE (NCT04345367) were analysed. Data from patients who received abrocitinib 100 mg QD or placebo in the JADE COMPARE trial were also included in this analysis. Patients rated their skin pain using the Skin Pain Numerical Rating Scale (NRS) item of the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) instrument ['How painful was your skin over the past 24 h?' on a scale from 0 (not painful) to 10 (extremely painful) ] in JADE COMPARE or the Skin Pain Numerical Rating Scale [SP-NRS, which queried patients for the severity of their 'worst skin pain' in the past 24 h on a scale from 0 (no skin pain) to 10 (worst skin pain imaginable)] in JADE DARE. Least squares mean (LSM) changes from baseline and proportions of patients who achieved a ≥4-point improvement from baseline in PSAAD skin pain score or SP-NRS were assessed through Week 16 (JADE COMPARE) or Week 26 (JADE DARE). The JADE COMPARE analysis (Skin Pain NRS item of the PSAAD) was performed post hoc, whereas the JADE DARE analysis (SP-NRS) was prespecified. At Week 2 of JADE COMPARE, LSM change from baseline in PSAAD skin pain score was greater with abrocitinib 200 mg [−2.8 (95% CI, −3.1, −2.5)] than with abrocitinib 100 mg [−2.1 (−2.3, −1.8)], dupilumab [−2.0 (−2.3, −1.8)], or placebo [−1.3 (−1.6, −0,9)]; improvements were sustained through Week 16 of treatment with abrocitinib 200 mg [−4.1 (−4.4, −3.8)], abrocitinib 100 mg [−3.3 (−3.6, −3.0)] and dupilumab [−4.0 (−4.2, −3.7)] compared with placebo [−1.8 (−2.2, −1.4)]. In JADE DARE, LSM change from baseline in SP-NRS was significantly greater with abrocitinib 200 mg vs. dupilumab at Week 2 [−3.7 (−3.9, −3.4) vs. −2.6 (−2.8, −2.3); P < 0.0001] and week 12 [−4.5 (−4.7, −4.2) vs. −4.0 (−4.3, −3.8); P = 0.0116]; no significant differences were observed between the treatment arms at Week 16 [−4.4 (−4.7, −4.2) vs. −4.2 (−4.4, −4.0); P = 0.16], Week 20 [−4.8 (−5.0, −4.5) vs. −4.5 (−4.7 vs. −4.2); P = 0.06] or Week 26 [−4.5 (−4.8, −4.3)] vs. −4.3 (−4.6, −4.1); P = 0.27]. The proportions of patients who achieved a ≥4-point improvement in PSAAD skin pain score at week 2 of JADE COMPARE were greater with abrocitinib 200 mg (43%) than with abrocitinib 100 mg (23%), dupilumab (24%) or placebo (14%). At Week 16, these proportions increased to 76% (abrocitinib 200 mg), 57% (abrocitinib 100 mg) and 70% (dupilumab) compared with placebo (29%). In JADE DARE, the proportions of patients who achieved a ≥4-point improvement in SP-NRS were significantly greater with abrocitinib 200 mg vs. dupilumab at Week 2 (58% vs. 36%; P < 0.0001) and Week 12 (71% vs. 61%; P = 0.0098) but not at subsequent timepoints. Similar to previous findings on the effect of abrocitinib on itch, these results suggest that abrocitinib 200 mg provides greater early skin pain relief in patients with moderate-to-severe AD compared with dupilumab, but the difference between the treatments diminishes with time. At earlier time points, skin pain improvement with abrocitinib 100 mg was similar to that with dupilumab. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with itch, eczematous lesions and impaired quality of life (QoL). Although the frequency of skin pain in AD is often underestimated, it is associated with a substantial health burden, similar to itch and is known to contribute to sleep disruption and mood disturbance. Abrocitinib is an oral, once-daily, selective Janus kinase-1 inhibitor approved for the treatment of moderate-to-severe AD. In phase 3 clinical trials JADE MONO-1 (NCT03349060) and JADE MONO-2 (NCT03575871), abrocitinib demonstrated rapid relief from itch and skin pain, as well as meaningful improvements in QoL compared with placebo. The interrelationships between abrocitinib treatment and improvements in itch, skin pain and QoL have not yet been investigated. This mediation analysis aimed to characterize the effect of abrocitinib treatment via itch and skin pain on dermatology-specific QoL in patients with AD. Data from JADE MONO-1 and JADE MONO-2 were pooled in this analysis. Adult patients with moderate-to-severe AD received abrocitinib (200 or 100 mg) as monotherapy or placebo for 12 weeks. Three separate models were evaluated whereby QoL was assessed using the Dermatology Life Quality Index (DLQI) score, and itch and skin pain were assessed via the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) items #1 (How itchy was your skin over the past 24 h?) and #2 (How painful was your skin over the past 24 h?), respectively. The cross-sectional mediation model (CSMM) was run separately at weeks 2, 4, 8 and 12 using all available data at each timepoint. The longitudinal mediation model (LMM), which does not assume independence among measurements of itch, skin pain and DLQI at each timepoint, estimated relationships using all available data from all weeks simultaneously. Based on the results of the CSMM and LMM, a pseudosteady-state model, in which the relationship among variables was assumed to be the same across timepoints, was applied. Effects with P<0.05 were considered statistically significant. In the CSMM, the indirect effect of abrocitinib on DLQI mediated via itch was considered approximately stable (24–30%) for the first 8 weeks before increasing at week 12 (42%), while the indirect effect mediated via skin pain was considered approximately stable from week 2 to week 12 (33–41%). In the LMM, the indirect effect of abrocitinib treatment on DLQI mediated via both itch and skin pain was considered approximately stable from week 2 to week 12 (17–26% and 42–48%, respectively). The cross-sectional and longitudinal models were generally consistent and indicated a pseudo-steady-state period between weeks 2 and 12. Using the pseudo-steady-state model, the direct effect of abrocitinib on DLQI was estimated to be 34.8% (P<0.0001), and the indirect effects mediated via itch and skin pain were estimated to be 19.5% and 45.8%, respectively (P≤0.0001 for both). Improvements in dermatology-specific QoL with abrocitinib are mostly mediated indirectly via a reduction in skin pain and less so by relief of itch. These findings warrant further research to examine to what extent patients consider itch and skin pain as separate concepts in terms of their impact on dermatology-specific QoL. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by intense itch, skin pain and impaired quality of life. Skin pain is a common and bothersome symptom of AD and increases in prevalence and intensity with worsening disease severity. Abrocitinib is an oral, once-daily, selective Janus kinase-1 inhibitor approved for the treatment of moderate-to-severe AD. Abrocitinib treatment resulted in improvements in skin clearance as well as rapid itch reduction in patients with moderate-to-severe AD across multiple phase 3 studies. Work productivity loss and activity impairment were assessed in the phase 3 JADE MONO-2 (NCT03575871) trial, with greater improvements being associated with abrocitinib treatment compared with placebo. The mechanism(s) through which abrocitinib reduces work productivity loss and activity impairment are unclear. To describe the interrelationships among abrocitinib treatment, itch, skin pain, and work productivity and activity impairment using a mediation modelling analysis in patients with AD. Data from adult patients treated with abrocitinib monotherapy (200 or 100 mg) or placebo in JADE MONO-2 were included in this analysis. As separate outcomes, work productivity loss and activity impairment (outcome variables) were measured by the Work Productivity and Activity Impairment Questionnaire: Atopic Dermatitis version 2.0 (WPAI-AD 2.0). Itch and skin pain (mediator variables) were evaluated using the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) item #1 (How itchy was your skin over the past 24 h?) and item #2 (How painful was your skin over the past 24 h?), respectively. Mediation modelling was conducted independently for work productivity loss and activity impairment. All available data at week 12 were used in the modelling. Effects with P<0.05 were considered statistically significant. The direct effects of abrocitinib were estimated to be 7.3% (P=0.779) and 17.5% (P=0.258) on work productivity loss and activity impairment, respectively. The indirect effects of abrocitinib treatment on work productivity loss and, separately, on activity impairment mediated via itch were estimated to be 50.6% (P=0.017) and 20.9% (P=0.062), respectively, and via skin, pain were estimated to be 42.1% and 61.5%, respectively, (P<0.05 for both). The indirect effect of abrocitinib treatment on work productivity loss is mediated approximately equally through the reduction in itch severity and skin pain. The effect of abrocitinib treatment on activity impairment is mostly mediated indirectly through the reduction of skin pain, along with a smaller indirect contribution from the reduction in itch. These findings support further research into the extent that patients consider itch and skin pain as separate concepts in terms of their impact on work productivity. [ABSTRACT FROM AUTHOR]