Background: Skin pain in atopic dermatitis (AD) increases with disease severity and is associated with substantial quality of life (QoL) burden. Objectives: The aim of the study was to evaluate abrocitinib efficacy on skin pain and QoL in adults and adolescents with moderate-to-severe AD. Methods: This post hoc analysis included data with abrocitinib administered as monotherapy (pooled phase 2b [NCT02780167] and phase 3 JADE MONO-1 [NCT03349060] and JADE MONO-2 [NCT03575871]) or in combination with topical therapy (phase 3 JADE COMPARE [NCT03720470] and JADE TEEN [NCT03796676]). Patients received oral, once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 or 16 weeks (JADE COMPARE). Skin pain was rated using the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) skin pain Numerical Rating Scale (NRS) item (“How painful was your skin over the past 24 h?”) on a scale from 0 (not painful) to 10 (extremely painful). Itch (Peak Pruritus NRS) and QoL (Dermatology Life Quality Index or Children’s Dermatology Life Quality Index) were assessed. Least squares mean (LSM) change from baseline was analyzed using mixed-effects repeated measures modeling. Results: A total of 1,822 patients (monotherapy pool, n = 942; JADE COMPARE, n = 595; and JADE TEEN, n = 285) were analyzed. LSM change from baseline in PSAAD skin pain score was significantly greater with abrocitinib versus placebo from week 2 through week 12 or 16 across all 3 study populations and occurred in a dose-dependent manner. A greater proportion of patients achieved a ≥4-point improvement from baseline in PSAAD skin pain score with abrocitinib (200 mg and 100 mg) versus placebo in the monotherapy pool (56% and 38% vs. 12%; week 12), JADE COMPARE (72% and 52% vs. 26%; week 16), and JADE TEEN (51% and 60% vs. 31%; week 12). Additionally, a greater proportion of patients achieved a stringent threshold of skin pain improvement (PSAAD skin pain score <2) with abrocitinib versus placebo. Adults and adolescents who achieved a ≥4-point improvement in skin pain reported greater QoL improvement than those who did not achieve a ≥4-point improvement. A positive correlation (≥0.3) was observed between skin pain and QoL and separately between skin pain and itch across the 3 study populations. Conclusion: Abrocitinib as monotherapy or in combination with topical therapy improved skin pain and was associated with improved QoL in both adults and adolescents with moderate-to-severe AD across all evaluated studies.

Skin pain is a common and bothersome symptom of atopic dermatitis (AD) [1‒4] and increases in prevalence and severity with disease progression [5‒10]. Although itch is typically identified as the hallmark symptom of AD, the frequency of skin pain has often been underestimated. Previous studies showed approximately 40–80% of patients with AD experienced daily or periodic occurrences of skin pain, which is typically associated with itch in most patients but can also occur independently [2]. In a large cross-sectional, prospective cohort study of Danish patients with dermatologist-verified diagnosis of AD, higher skin pain scores were observed in the palmar, chest, and plantar areas [8]. A substantial proportion of patients with AD who had concomitant pain and itch described skin pain as related to scratching, burning, and stinging, occurring in the presence or absence of lesions or excoriations [5]. Temporary stinging and burning sensation were also reported in patients with AD following treatment with topical calcineurin and phosphodiesterase 4 inhibitors [12].

From a patient’s perspective, itch and skin pain are the most important symptoms of AD when assessing treatment efficacy [14]. Similar to itch, skin pain in AD is associated with a profound negative impact on patients’ quality of life (QoL) [5], including sleep and mood disturbances and other AD-associated comorbidities such as anxiety [15]. In a social media analysis of patient experiences of AD, pain was often mentioned in conjunction with poor sleep quality and psychological effects related to sleep impairment [16].

While most treatments for AD focus on improvements in itch and skin clearance, few evaluated skin pain in patients [17]. Abrocitinib is an oral, once-daily, Janus kinase 1 (JAK1)–selective inhibitor approved for the treatment of adult and adolescent patients with moderate-to-severe AD [18‒20]. The efficacy of abrocitinib was established in multiple clinical trials, with patients achieving clinically meaningful improvements in skin clearance and patient-reported outcomes, including itch [21‒25]. The effect of abrocitinib on skin pain and patients’ QoL associated with skin pain has not been determined. This post hoc analysis examines the efficacy of abrocitinib on skin pain among adults and adolescents with moderate-to-severe AD in the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) clinical development program using the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD), an 11-item-validated instrument for comprehensive assessment of symptom severity [26]. QoL outcomes in patients with and without skin pain improvement were also assessed.

Patients and Treatment

This post hoc analysis included data from five clinical trials with abrocitinib administered as monotherapy (pooled phase 2b [NCT02780167] [21] and phase 3 JADE MONO-1 [NCT03349060] [22] and JADE MONO-2 [NCT03575871]) [23] or in combination with topical therapy (phase 3 JADE COMPARE [NCT03720470] [24] and phase 3 JADE TEEN [NCT03796676] [25]). Eligible patients were aged 12–17 years (JADE TEEN), ≥12 years (JADE MONO-1 and JADE MONO-2), or ≥18 years (phase 2b and JADE COMPARE) with a clinical diagnosis of moderate-to-severe AD, defined as having an Investigator’s Global Assessment (IGA) score of ≥3, Eczema Area and Severity Index score of ≥12 [phase 2b] or ≥16 [phase 3], percentage of body surface area affected ≥10, and Peak Pruritus Numerical Rating Scale (PP-NRS) score of ≥4 (phase 3 studies only). The PP-NRS was used with permission of Regeneron Pharmaceuticals, Inc., and Sanofi, which developed the instrument [27]. Patients had AD for 1 or more years prior to enrollment in each respective study and had inadequate response to topical medicated therapy for at least 4 weeks or required systemic therapy to control AD. Further details of these studies were published previously [21‒25].

All patients included in this analysis received oral, once-daily abrocitinib 200 mg or 100 mg or placebo for 12 weeks or 16 weeks (in JADE COMPARE). The JADE COMPARE study also included dupilumab 300 mg as an active comparator treatment arm, which was administered subcutaneously every other week (after a loading dose of 600 mg). Data from the dupilumab treatment arm of JADE COMPARE study [24] and the head-to-head JADE DARE (NCT04345367) study [28] are not shown here and will be reported separately.

Assessments

Efficacy Assessments

Skin pain was assessed using the validated PSAAD instrument (© 2016 Pfizer Inc., all rights reserved) [26]. Patients rated their skin pain over the past 24 h via the PSAAD skin pain item (“How painful was your skin over the past 24 h?”) on an NRS from 0 (not painful) to 10 (extremely painful). Responses were recorded daily throughout the treatment period using an electronic diary. Weekly skin pain scores were obtained by averaging the daily values over the past week.

Least squares mean (LSM) change from baseline in the PSAAD skin pain NRS score was assessed in all patients and in the subset of IGA nonresponders through week 12 or 16. IGA nonresponders were defined as patients who did not achieve an IGA score of 0 (clear) or 1 (almost clear) with a ≥2-point improvement from baseline. A 4-point change on the 0–10 skin pain NRS item of the PSAAD was estimated to demonstrate a clinically meaningful response in skin pain severity in patients with moderate-to-severe AD based on the validated skin pain NRS instrument [29]. Therefore, the proportion of patients with a ≥4-point improvement from baseline on the skin pain NRS item of the PSAAD was assessed in those who had a score of ≥4 at baseline. Patients with AD report suffering from persistent skin pain even when under treatment for AD due to the severity of their AD [30], suggesting that the minimal clinically important difference of a 4-point improvement from baseline may still leave some patients with burdensome skin pain. From a patient’s perspective, itch and pain are the two most important factors when assessing treatment response [14]. Assessment of AD treatments for efficacy on itch using the validated PP-NRS instrument often includes the achievement of a score of <2 on the PP-NRS (PP-NRS 0/1, indicating little to no itch) as a clinically important endpoint for patients with AD. The achievement of a score of <2 (indicating not painful/very little pain) on the validated skin pain NRS instrument is also gaining acceptance as an important clinical endpoint from the perspective of patients with AD. To assess the stringent efficacy response of abrocitinib at higher thresholds of skin pain improvement, the proportion of patients who achieved a score <2 (indicating not painful) on the skin pain NRS item of the PSAAD was evaluated in patients with a score of ≥2 at baseline. Other assessments were the number of days with a skin pain score of <2 on the PSAAD skin pain NRS and Pearson correlation coefficients between PSAAD skin pain score and PP-NRS score.

QoL Assessments

QoL outcomes were assessed using dermatologic disease-specific instruments (Dermatology Life Quality Index [DLQI] in adults and Children’s Dermatology Life Quality Index [CDLQI] in adolescents) [32]. LSM change from baseline in DLQI (in adults) or CDLQI (in adolescents) was assessed in those who achieved or did not achieve a ≥4-point improvement from baseline in the skin pain NRS item of the PSAAD through week 12 or 16. Pearson correlation coefficients between PSAAD skin pain score and DLQI/CDLQI score were also assessed.

Statistical Analysis

Baseline characteristics were summarized using descriptive statistics. Mixed-effects repeated measures modeling was employed in the analysis of LSM change from baseline in the PSAAD skin pain score. Continuous endpoints were analyzed based on all observed data. For the binary endpoints (i.e., determining the proportions of responders), data were analyzed using the nonresponder imputation method. Missing data due to study discontinuation were imputed as nonresponders. Any observations that were missing intermittently remained missing in the analysis. The estimates and confidence intervals for treatment differences were calculated based on the Cochran-Mantel-Haenszel-weighted average and the normal approximation of binomial proportions. Nominal p values at the <0.05 significance level were calculated for differences between abrocitinib and placebo. Statistical comparisons were not controlled for multiplicity.

Baseline Demographics and Disease Characteristics

In total, 942 patients from the pooled monotherapy population, 595 patients from JADE COMPARE, and 285 patients from JADE TEEN were included in this analysis (Table 1). The mean age was 35 years in the monotherapy pool, 38 years in JADE COMPARE, and 15 years in the JADE TEEN population. The mean duration of AD was 23 years both in the pooled monotherapy and JADE COMPARE populations and 10 years in the JADE TEEN population. Baseline IGA, Eczema Area and Severity Index, percentage of body surface area affected, and PP-NRS scores were balanced across the treatment arms in all evaluated studies (Table 1).

Table 1.

Baseline demographics and disease characteristics

Pooled monotherapyJADE COMPAREJADE TEEN
placebo (N = 210)abrocitinib, 100 mg (N = 369)abrocitinib, 200 mg (N = 363)placebo (N = 131)abrocitinib, 100 mg (N = 238)abrocitinib, 200 mg (N = 226)placebo (N = 96)abrocitinib, 100 mg (N = 95)abrocitinib, 200 mg (N = 94)
Age, years, mean (SD) 35.0 (15.0) 35.9 (15.8) 34.1 (16.4) 37.4 (15.2) 37.3 (14.8) 38.8 (14.5) 14.8 (1.7) 15.1 (1.8) 14.7 (1.8) 
Age group, n (%) 
 12–17 years 25 (11.9) 51 (13.8) 48 (13.2) 0 (0) 0 (0) 0 (0) 95 (99.0) 95 (100.0) 94 (100.0) 
 18–64 years 178 (84.8) 297 (80.5) 289 (79.6) 121 (92.4) 224 (94.1) 211 (93.4) 1 (1.0)a 0 (0) 0 (0) 
 >65 years 7 (3.3) 21 (5.7) 26 (7.2) 10 (7.6) 14 (5.9) 15 (6.6) 0 (0) 0 (0) 0 (0) 
Duration of AD, years, mean (SD) 23.5 (15.2) 23.7 (16.1) 22.0 (15.1) 21.4 (14.4) 22.7 (16.3) 23.4 (15.6) 10.5 (4.8) 9.8 (5.4) 9.7 (5.3) 
IGA score, n (%) 
 Moderate (IGA = 3) 132 (62.9) 228 (61.8) 231 (63.6) 88 (67.2) 153 (64.3) 138 (61.1) 57 (59.4) 57 (60.0) 61 (64.9) 
 Severe (IGA = 4) 78 (37.1) 141 (38.2) 132 (36.4) 43 (32.8) 85 (35.7) 88 (38.9) 39 (40.6) 38 (40.0) 33 (35.1) 
EASI score, mean (SD) 27.6 (11.8) 29.4 (12.4) 29.0 (13.4) 31.0 (12.6) 30.3 (13.5) 32.1 (13.1) 29.2 (12.7) 31.0 (12.8) 29.5 (12.2) 
%BSA affected, mean (SD) 45.8 (22.1) 48.6 (22.5) 47.2 (23.6) 48.9 (24.9) 48.1 (23.1) 50.8 (23.0) 45.8 (22.4) 51.2 (21.7) 48.7 (21.7) 
PP-NRS score 
 Mean (SD) 7.0 (1.9) 7.1 (1.9) 7.0 (1.9) 7.1 (1.8) 7.1 (1.7) 7.6 (1.5) 7.2 (1.7) 7.0 (1.8) 6.8 (2.0) 
 Median (IQR) 7.0 (6.0–8.0) 7.0 (6.0–8.0) 7.0 (6.0–8.0) 7.0 (6.0–8.0) 7.0 (6.0–8.0) 8.0 (7.0–9.0) 7.0 (6.0–8.0) 7.0 (6.0–8.0) 7.0 (6.0–8.0) 
 Range 2.0–10.0 0.0–10.0 0.0–10.0 2.0–10.0 2.0–10.0 4.0–10.0 4.0–10.0 3.0–10.0 1.0–10.0 
Evaluable for the PSAAD skin pain NRSb, n 171 314 317 123 213 217 84 88 82 
 Mean (SD) 5.6 (2.4) 5.6 (2.6) 5.6 (2.6) 5.3 (2.7) 5.4 (2.6) 5.8 (2.4) 5.1 (2.8) 4.8 (2.5) 5.0 (2.7) 
 Median (IQR) 5.7 (3.9–7.4) 6.0 (3.7–7.5) 6.0 (3.7–7.5) 5.3 (3.1–7.8) 5.9 (3.5–7.2) 6.3 (4.1–7.6) 5.2 (3.2–7.2) 5.0 (3.0–6.7) 5.3 (2.8–7.0) 
 Patients with weekly average PSAAD skin pain score <2, n (%) 9 (5.3) 33 (10.5) 32 (10.1) 15 (12.2) 32 (15.0) 21 (9.7) 12 (14.3) 12 (13.6) 12 (14.6) 
 Patients with weekly average PSAAD skin pain score ≥2 to ≤7, n (%) 109 (63.7) 181 (57.6) 186 (58.7) 66 (53.7) 125 (58.7) 123 (56.7) 50 (59.5) 57 (64.8) 50 (61.0) 
 Patients with weekly average PSAAD skin pain score >7, n (%) 53 (31.0) 100 (31.8) 99 (31.2) 42 (34.1) 56 (26.3) 73 (33.6) 22 (26.2) 19 (21.6) 20 (24.4) 
Evaluable for DLQIc, n 184 315 311 131 238 226 NA NA NA 
 Mean (SD) 14.3 (7.2) 15.1 (7.1) 14.4 (6.6) 15.2 (6.9) 15.5 (6.4) 16.3 (6.6) NA NA NA 
Evaluable for CDLQId, n 24 48 47 NA NA NA 96 95 94 
 Mean (SD) 12.5 (6.3) 12.4 (6.4) 13.1 (5.5) NA NA NA 14.0 (6.7) 14.3 (6.1) 13.6 (7.0) 
HADSe anxiety scale score, mean (SD) 6.6 (4.0) 6.0 (4.3) 5.8 (4.0) 5.3 (3.9) 5.3 (3.9) 5.5 (3.8) 5.7 (3.7) 5.7 (4.1) 5.2 (4.3) 
HADSe depression scale score, mean (SD) 4.5 (3.6) 4.3 (4.0) 4.2 (3.8) 4.1 (3.7) 4.0 (3.3) 3.9 (3.4) 3.8 (3.4) 3.7 (3.3) 3.3 (2.8) 
Pooled monotherapyJADE COMPAREJADE TEEN
placebo (N = 210)abrocitinib, 100 mg (N = 369)abrocitinib, 200 mg (N = 363)placebo (N = 131)abrocitinib, 100 mg (N = 238)abrocitinib, 200 mg (N = 226)placebo (N = 96)abrocitinib, 100 mg (N = 95)abrocitinib, 200 mg (N = 94)
Age, years, mean (SD) 35.0 (15.0) 35.9 (15.8) 34.1 (16.4) 37.4 (15.2) 37.3 (14.8) 38.8 (14.5) 14.8 (1.7) 15.1 (1.8) 14.7 (1.8) 
Age group, n (%) 
 12–17 years 25 (11.9) 51 (13.8) 48 (13.2) 0 (0) 0 (0) 0 (0) 95 (99.0) 95 (100.0) 94 (100.0) 
 18–64 years 178 (84.8) 297 (80.5) 289 (79.6) 121 (92.4) 224 (94.1) 211 (93.4) 1 (1.0)a 0 (0) 0 (0) 
 >65 years 7 (3.3) 21 (5.7) 26 (7.2) 10 (7.6) 14 (5.9) 15 (6.6) 0 (0) 0 (0) 0 (0) 
Duration of AD, years, mean (SD) 23.5 (15.2) 23.7 (16.1) 22.0 (15.1) 21.4 (14.4) 22.7 (16.3) 23.4 (15.6) 10.5 (4.8) 9.8 (5.4) 9.7 (5.3) 
IGA score, n (%) 
 Moderate (IGA = 3) 132 (62.9) 228 (61.8) 231 (63.6) 88 (67.2) 153 (64.3) 138 (61.1) 57 (59.4) 57 (60.0) 61 (64.9) 
 Severe (IGA = 4) 78 (37.1) 141 (38.2) 132 (36.4) 43 (32.8) 85 (35.7) 88 (38.9) 39 (40.6) 38 (40.0) 33 (35.1) 
EASI score, mean (SD) 27.6 (11.8) 29.4 (12.4) 29.0 (13.4) 31.0 (12.6) 30.3 (13.5) 32.1 (13.1) 29.2 (12.7) 31.0 (12.8) 29.5 (12.2) 
%BSA affected, mean (SD) 45.8 (22.1) 48.6 (22.5) 47.2 (23.6) 48.9 (24.9) 48.1 (23.1) 50.8 (23.0) 45.8 (22.4) 51.2 (21.7) 48.7 (21.7) 
PP-NRS score 
 Mean (SD) 7.0 (1.9) 7.1 (1.9) 7.0 (1.9) 7.1 (1.8) 7.1 (1.7) 7.6 (1.5) 7.2 (1.7) 7.0 (1.8) 6.8 (2.0) 
 Median (IQR) 7.0 (6.0–8.0) 7.0 (6.0–8.0) 7.0 (6.0–8.0) 7.0 (6.0–8.0) 7.0 (6.0–8.0) 8.0 (7.0–9.0) 7.0 (6.0–8.0) 7.0 (6.0–8.0) 7.0 (6.0–8.0) 
 Range 2.0–10.0 0.0–10.0 0.0–10.0 2.0–10.0 2.0–10.0 4.0–10.0 4.0–10.0 3.0–10.0 1.0–10.0 
Evaluable for the PSAAD skin pain NRSb, n 171 314 317 123 213 217 84 88 82 
 Mean (SD) 5.6 (2.4) 5.6 (2.6) 5.6 (2.6) 5.3 (2.7) 5.4 (2.6) 5.8 (2.4) 5.1 (2.8) 4.8 (2.5) 5.0 (2.7) 
 Median (IQR) 5.7 (3.9–7.4) 6.0 (3.7–7.5) 6.0 (3.7–7.5) 5.3 (3.1–7.8) 5.9 (3.5–7.2) 6.3 (4.1–7.6) 5.2 (3.2–7.2) 5.0 (3.0–6.7) 5.3 (2.8–7.0) 
 Patients with weekly average PSAAD skin pain score <2, n (%) 9 (5.3) 33 (10.5) 32 (10.1) 15 (12.2) 32 (15.0) 21 (9.7) 12 (14.3) 12 (13.6) 12 (14.6) 
 Patients with weekly average PSAAD skin pain score ≥2 to ≤7, n (%) 109 (63.7) 181 (57.6) 186 (58.7) 66 (53.7) 125 (58.7) 123 (56.7) 50 (59.5) 57 (64.8) 50 (61.0) 
 Patients with weekly average PSAAD skin pain score >7, n (%) 53 (31.0) 100 (31.8) 99 (31.2) 42 (34.1) 56 (26.3) 73 (33.6) 22 (26.2) 19 (21.6) 20 (24.4) 
Evaluable for DLQIc, n 184 315 311 131 238 226 NA NA NA 
 Mean (SD) 14.3 (7.2) 15.1 (7.1) 14.4 (6.6) 15.2 (6.9) 15.5 (6.4) 16.3 (6.6) NA NA NA 
Evaluable for CDLQId, n 24 48 47 NA NA NA 96 95 94 
 Mean (SD) 12.5 (6.3) 12.4 (6.4) 13.1 (5.5) NA NA NA 14.0 (6.7) 14.3 (6.1) 13.6 (7.0) 
HADSe anxiety scale score, mean (SD) 6.6 (4.0) 6.0 (4.3) 5.8 (4.0) 5.3 (3.9) 5.3 (3.9) 5.5 (3.8) 5.7 (3.7) 5.7 (4.1) 5.2 (4.3) 
HADSe depression scale score, mean (SD) 4.5 (3.6) 4.3 (4.0) 4.2 (3.8) 4.1 (3.7) 4.0 (3.3) 3.9 (3.4) 3.8 (3.4) 3.7 (3.3) 3.3 (2.8) 

%BSA, percentage of body surface area; CDLQI, Children’s Dermatology Life Quality Index; DLQI, Dermatology Life Quality Index; HADS, Hospital Anxiety and Depression Scale; IQR, interquartile range; NA, not applicable; PP-NRS, Peak Pruritus Numerical Rating Scale; PSAAD, Pruritus and Symptoms Assessment for Atopic Dermatitis; SD, standard deviation.

aIn JADE TEEN, 1 patient aged 18 years was enrolled, which was a protocol deviation.

bPatients rated their skin pain in relation to their AD from 0 (not painful) to 10 (extremely painful).

cDLQI scores range from 0 to 30, with a score of 0–1 indicating no effect, 2–5 a small effect, 6–10 a moderate effect, 11–20 a very large effect, and 21–30 an extremely large effect.

dCDLQI scores range from 0 to 30, with a score of 0–1 indicating no effect, 2–6 a small effect, 7–12 a moderate effect, 13–18 a very large effect, and 19–30 an extremely large effect.

eHADS scores range from 0–21; a score of 0–7 is considered normal, 8–10 as borderline abnormal, and 11–21 as abnormal.

Across the 3 populations, 21–29% of patients experienced high skin pain (weekly mean score of >7 on the skin pain NRS item of the PSAAD) at baseline, and 8–13% of patients reported low skin pain (weekly mean score <2 on the skin pain item of the PSAAD; Table 1). Patients with high skin pain at baseline had more severe symptoms of AD than those with low skin pain (online suppl. Table. S1; for all online suppl. material, see https://doi.org/10.1159/000535285). The severity of itch was associated with the intensity of skin pain at baseline (online suppl. Table S2). Patients with high itch (PP-NRS ≥7) had high baseline scores on the skin pain NRS item of the PSAAD, and those with low or moderate itch (PP-NRS <7) had low baseline scores on the skin pain NRS item of the PSAAD.

Skin Pain Improvement

LSM change from baseline in the PSAAD skin pain score was significantly greater with both doses of abrocitinib versus placebo (nominal p < 0.05) as early as week 1 and sustained through week 12 or 16 across all 3 study populations (Fig. 1). These improvements with abrocitinib, administered as monotherapy or in combination with topical therapy, occurred in a dose-dependent manner (Fig. 1).

Fig. 1.

LSM change from baseline in the PSAAD skin pain score. *Nominal p < 0.05 for abrocitinib versus placebo; not controlled for multiplicity. n indicates the number included in analysis. CfB, change from baseline; LSM, least squares mean; PSAAD, Pruritus and Symptoms Assessment for Atopic Dermatitis.

Fig. 1.

LSM change from baseline in the PSAAD skin pain score. *Nominal p < 0.05 for abrocitinib versus placebo; not controlled for multiplicity. n indicates the number included in analysis. CfB, change from baseline; LSM, least squares mean; PSAAD, Pruritus and Symptoms Assessment for Atopic Dermatitis.

Close modal

Skin pain improvement with abrocitinib was largely similar between adults and the adolescent population both from the TEEN study (Fig. 1) and the pooled monotherapy study (online suppl. Fig. S1). In a subset of patients who were classified as nonresponders on the IGA scale (i.e., did not achieve IGA 0/1 with a ≥2-point improvement from baseline), LSM change in the PSAAD skin pain score was greater with abrocitinib 200 mg and abrocitinib 100 mg versus placebo at week 2, with sustained improvement observed through week 12 or 16 across all studies (online suppl. Fig. S2). Among patients with a PSAAD skin pain score of ≥4 at baseline, a greater proportion achieved a ≥4-point improvement in skin pain with abrocitinib compared with placebo across the three study populations (Fig. 2).

Fig. 2.

Proportion of patients achieving a ≥4-point improvement in the PSAAD skin pain score. *Nominal p < 0.05 for abrocitinib versus placebo; not controlled for multiplicity. Analysis includes patients with a PSAAD skin pain score of ≥4 at baseline. If a patient withdrew from the study, the patient was considered a nonresponder after that point. Evaluable patients (n) were those in the nonresponder imputation analysis set at the specified visit, and the percentage of responders was calculated based on the number of evaluable patients. PSAAD, Pruritus and Symptoms Assessment for Atopic Dermatitis.

Fig. 2.

Proportion of patients achieving a ≥4-point improvement in the PSAAD skin pain score. *Nominal p < 0.05 for abrocitinib versus placebo; not controlled for multiplicity. Analysis includes patients with a PSAAD skin pain score of ≥4 at baseline. If a patient withdrew from the study, the patient was considered a nonresponder after that point. Evaluable patients (n) were those in the nonresponder imputation analysis set at the specified visit, and the percentage of responders was calculated based on the number of evaluable patients. PSAAD, Pruritus and Symptoms Assessment for Atopic Dermatitis.

Close modal

In the pooled monotherapy cohort, the proportion of patients with a ≥4-point improvement in the PSAAD skin pain score was greater with abrocitinib 200 mg (56.3%) and abrocitinib 100 mg (38.3%) than placebo (12.0%; nominal p < 0.05 for both) at week 12. Similarly, the proportion of patients with a ≥4-point improvement in the PSAAD skin pain score with abrocitinib 200 mg and abrocitinib 100 mg was greater than placebo in JADE COMPARE at week 16 (71.5% and 51.5% vs. 26.2%; nominal p < 0.05 for both) and JADE TEEN at week 12 (51.2% and 59.5% vs. 31.3%; nominal p < 0.05 for abrocitinib 100 mg vs. placebo). Improvements with abrocitinib occurred in a dose-dependent manner at all timepoints in the pooled monotherapy and JADE COMPARE studies but were variable in the JADE TEEN study.

Skin Pain Improvement by Stringent Thresholds

Among patients with a score of ≥2 on the skin pain NRS item of the PSAAD at baseline, a greater proportion achieved a stringent threshold of skin pain improvement (score <2 on the skin pain NRS item of the PSAAD) with abrocitinib versus placebo as early as week 2 and continued to increase through week 12 or 16 across the three study populations (Fig. 3). In the pooled monotherapy cohort, the proportion of patients with skin pain improvement at the stringent threshold was greater with abrocitinib 200 mg (56.2%) and abrocitinib 100 mg (35.7%) than placebo at week 12 (11.3%; nominal p < 0.05 for both). Similarly, a greater proportion of patients achieved a stringent threshold of skin pain improvement with abrocitinib 200 mg and 100 mg than placebo at week 16 in JADE COMPARE (63.4% and 48.7% vs. 28.1%; nominal p < 0.05 for both) and week 12 in JADE TEEN (60.7% and 56.1% vs. 27.9%; nominal p < 0.05 for both).

Fig. 3.

Proportion of patients who achieved a score of <2 on the skin pain numerical rating scale item of the PSAAD. *Nominal p < 0.05 for abrocitinib versus placebo; not controlled for multiplicity. Analysis includes patients with a PSAAD skin pain score of ≥2 at baseline. If a patient withdrew from the study, the patient was considered a nonresponder after that point. Evaluable patients (n) were those in the nonresponder imputation analysis set at the specified visit, and the percentage of responders was calculated based on the number of evaluable patients. PSAAD, Pruritus and Symptoms Assessment for Atopic Dermatitis.

Fig. 3.

Proportion of patients who achieved a score of <2 on the skin pain numerical rating scale item of the PSAAD. *Nominal p < 0.05 for abrocitinib versus placebo; not controlled for multiplicity. Analysis includes patients with a PSAAD skin pain score of ≥2 at baseline. If a patient withdrew from the study, the patient was considered a nonresponder after that point. Evaluable patients (n) were those in the nonresponder imputation analysis set at the specified visit, and the percentage of responders was calculated based on the number of evaluable patients. PSAAD, Pruritus and Symptoms Assessment for Atopic Dermatitis.

Close modal

Across the three study populations, patients reported a greater number of days with skin pain improvement at the stringent threshold (PSAAD skin pain score <2) after treatment with abrocitinib versus placebo (online suppl. Fig. S3). In the pooled monotherapy population, the number of skin pain-free days was 35.8, 24.1, and 8.8 at week 12 after treatment with abrocitinib 200 mg, abrocitinib 100 mg, and placebo, respectively. Similarly, the number of skin pain-free days were greater with abrocitinib 200 mg and abrocitinib 100 mg compared with placebo in JADE COMPARE (55.5 and 42.4 vs. 25.4 days; week 16) and JADE TEEN (33.0 and 30.0 vs. 18.8 days; week 12). At week 12 (or week 16 in JADE COMPARE), a positive correlation (≥0.3) was observed between the PSAAD skin pain score and PP-NRS score, ranging from 0.74 to 0.83 in the pooled monotherapy population, from 0.66 to 0.78 in JADE COMPARE, and from 0.64 to 0.73 in JADE TEEN (Table 2).

Table 2.

Pearson correlation coefficients (95% CI) between the PSAAD skin pain score and PP-NRS or DLQI/CDLQI scores

Pooled monotherapyJADE COMPAREJADE TEEN
placebo (n = 171)abrocitinib, 100 mg (n = 314)abrocitinib, 200 mg (n = 317)placebo (n = 123)abrocitinib, 100 mg (n = 213)abrocitinib, 200 mg (n = 217)placebo (n = 84)abrocitinib, 100 mg (n = 88)abrocitinib, 200 mg (n = 82)
PP-NRS score 
 Week 12/16a 0.74 (0.65–0.82) 0.78 (0.72–0.82) 0.83 (0.79–0.86) 0.77 (0.65–0.85) 0.78 (0.70–0.84) 0.66 (0.55–0.74) 0.64 (0.46–0.76) 0.66 (0.49–0.78) 0.73 (0.58–0.83) 
DLQI/CDLQIb score 
 Week 12/16a 0.61 (0.48–0.71) 0.70 (0.63–0.76) 0.65 (0.57–0.71) 0.56 (0.40–0.69) 0.60 (0.49–0.68) 0.49 (0.37–0.59) 0.51 (0.31–0.66) 0.35 (0.12–0.54) 0.61 (0.44–0.74) 
Pooled monotherapyJADE COMPAREJADE TEEN
placebo (n = 171)abrocitinib, 100 mg (n = 314)abrocitinib, 200 mg (n = 317)placebo (n = 123)abrocitinib, 100 mg (n = 213)abrocitinib, 200 mg (n = 217)placebo (n = 84)abrocitinib, 100 mg (n = 88)abrocitinib, 200 mg (n = 82)
PP-NRS score 
 Week 12/16a 0.74 (0.65–0.82) 0.78 (0.72–0.82) 0.83 (0.79–0.86) 0.77 (0.65–0.85) 0.78 (0.70–0.84) 0.66 (0.55–0.74) 0.64 (0.46–0.76) 0.66 (0.49–0.78) 0.73 (0.58–0.83) 
DLQI/CDLQIb score 
 Week 12/16a 0.61 (0.48–0.71) 0.70 (0.63–0.76) 0.65 (0.57–0.71) 0.56 (0.40–0.69) 0.60 (0.49–0.68) 0.49 (0.37–0.59) 0.51 (0.31–0.66) 0.35 (0.12–0.54) 0.61 (0.44–0.74) 

A Pearson correlation coefficient of ≥0.3 was considered a positive correlation.

CDLQI, Children’s Dermatology Life Quality Index; CI, confidence interval; DLQI, Dermatology Life Quality Index; NA, not applicable; PP-NRS, Peak Pruritus Numerical Rating Scale; PSAAD, Pruritus and Symptoms Assessment for Atopic Dermatitis.

aWeek 16 was assessed in JADE COMPARE.

bCDLQI was assessed in JADE TEEN.

QoL Improvements

LSM change from baseline in DLQI/CDLQI scores was greater in the subset of adult and adolescent patients who achieved a ≥4-point improvement in the PSAAD skin pain score than those who did not achieve a 4-point improvement across all evaluated studies (Fig. 4). At week 12 (or week 16 in JADE COMPARE), a positive correlation (≥0.3) was observed between the PSAAD skin pain score and DLQI/CDLQI, ranging from 0.61 to 0.70 in the pooled monotherapy population, from 0.49 to 0.60 in JADE COMPARE, and from 0.35 to 0.61 in JADE TEEN (Table 2).

Fig. 4.

LSM change from baseline in DLQI/CDLQI among patients who did or did not achieve a ≥4-point improvement in the PSAAD skin pain score. *Nominal p < 0.05 for abrocitinib versus placebo; not controlled for multiplicity. n indicates the number included in analysis at each time point. DLQI is shown for adults in the pooled monotherapy and JADE COMPARE populations; CDLQI is shown for adolescents in JADE TEEN. CDLQI, Children’s Dermatology Life Quality Index; DLQI, Dermatology Life Quality Index; PSAAD, Pruritus and Symptoms Assessment for Atopic Dermatitis.

Fig. 4.

LSM change from baseline in DLQI/CDLQI among patients who did or did not achieve a ≥4-point improvement in the PSAAD skin pain score. *Nominal p < 0.05 for abrocitinib versus placebo; not controlled for multiplicity. n indicates the number included in analysis at each time point. DLQI is shown for adults in the pooled monotherapy and JADE COMPARE populations; CDLQI is shown for adolescents in JADE TEEN. CDLQI, Children’s Dermatology Life Quality Index; DLQI, Dermatology Life Quality Index; PSAAD, Pruritus and Symptoms Assessment for Atopic Dermatitis.

Close modal

This post hoc analysis of JADE clinical trials demonstrated rapid and sustained improvement in skin pain with abrocitinib in both adult and adolescent patients with moderate-to-severe AD. Skin pain improvements occurred as early as week 1 and were sustained through week 12 or 16 with abrocitinib administered as monotherapy or in combination with topical therapy in a dose-dependent manner.

Abrocitinib as monotherapy or combination therapy demonstrated efficacy on skin pain, with 38–72% of patients across all evaluated studies achieving a ≥4-point improvement on the skin pain NRS item of the PSAAD. In a comparable study population, treatment with approved doses of 2 mg and 4 mg baricitinib, another oral JAK-selective inhibitor, resulted in 15–49% of patients achieving a ≥4-point improvement from baseline in the skin pain NRS score when administered as monotherapy or combination therapy [34]. A direct comparison of the two therapies is limited by differences in clinical trial designs and methods of skin pain assessment. Nevertheless, results from both studies underscore the efficacy with JAK inhibitors, including abrocitinib, in both adults and adolescents whose AD was poorly controlled despite previous treatment with various traditional, systemic immunosuppressive agents.

Approximately half the patients who had a baseline score of ≥2 on the skin pain NRS item of the PSAAD experienced skin pain improvement at stringent thresholds at the end of the 12- or 16-week treatment period with abrocitinib. Notably, these results were achieved in patients with substantial skin pain at baseline; 89% of all evaluable patients across the three studies had a score of ≥2 on the skin pain item of the PSAAD instrument. Furthermore, skin pain improvement with abrocitinib occurred even in the absence of IGA response, highlighting its broad treatment effect. This also suggests that, in some patients with AD, skin pain may be a distinct symptom which occurs independently of lesion severity, although further study is warranted to fully elucidate this relationship.

Improvement in skin pain was also associated with improvement in QoL in both adults and adolescents across the study populations. Given the profound negative impact of skin pain on patients’ QoL, including their psychological and physical well-being [5], these findings may facilitate optimal treatment management for moderate-to-severe AD.

The mechanism of skin pain in AD is poorly understood [30]. Some studies showed a relationship between skin pain and itch [10], whereas others have reported pain to be a distinct symptom from itch [5]. Our analysis indicates an apparent, albeit modest, correlation between itch improvement and skin pain improvement. This is consistent with other studies, which also showed modest correlation between skin pain and itch [6]. Additionally, the presentation of pain in AD is highly variable among adults and adolescents [2]. In a study of patients with AD, 64% of adults described their pain as burning and 25% described it as stinging, compared with 40% and 67% of adolescents, respectively [2]. Although the type of pain was not assessed in this analysis, both adults and adolescents had largely similar improvements in skin pain as measured with the skin pain NRS item of the PSAAD instrument. Although the molecular mechanisms for itch in AD have been identified, the pathways that drive pain in patients with AD have not been fully elucidated. These findings notwithstanding, it has been shown that JAK1-selective inhibitors directly mediate the signaling of multiple inflammatory cytokines, including interleukin (IL)-31, IL-4, IL-13, and thymic stromal lymphopoietin, that are associated with inducing itch and related symptoms [35]. IL-4 [36] and IL-13 [37] are also known to sensitize a subset of neurons involved in pain and itch perpetuation. The targeted inhibition of these cytokines by abrocitinib may explain the broad and robust treatment efficacy observed in patients with moderate-to-severe AD.

One of the limitations of this study is the post hoc nature of assessments and the relatively small sample sizes of the subgroups. Statistical comparisons were not adjusted for multiplicity. PSAAD is a patient-reported measure and is inherently subjective. Use of topical calcineurin or phosphodiesterase 4 inhibitors in the JADE COMPARE study may have contributed to the skin pain in patients; however, the effect was likely minimal because >90% of patients were treated with topical corticosteroids. Relief in the symptoms of AD other than skin pain may also have contributed to patients’ QoL improvements. Nevertheless, this analysis adds to the accumulating evidence that abrocitinib can improve the most bothersome symptoms of AD rapidly and in a sustained manner.

In conclusion, abrocitinib provided rapid and sustained improvement in skin pain and QoL in adult and adolescent patients with moderate-to-severe AD and may fulfill an unmet need for a systemic treatment to alleviate both itch and skin pain in AD. Further research is warranted to better understand and define skin pain as well as its relationship to AD severity, itch, and QoL outcomes in patients with AD.

Abrocitinib improves skin pain and QoL in adults and adolescents with AD.

Editorial/medical writing support under the guidance of authors was provided by Amanda Mabhula, PhD, and Renee Gordon, PhD, at ApotheCom, San Francisco, CA, USA, in accordance with Good Publication Practice (GPP 2022) guidelines (Ann Intern Med. 2022; 10.7326/M22-1460).

This research was conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonization Good Clinical Practice guidelines. All patients provided written informed consent. For underaged patients, written informed consent was obtained from the patient’s parent(s) or legal guardian. The clinical trial protocols were approved by the Institutional Review Board or Ethics Committee at each study site, and all local regulatory requirements were followed. All clinical trials included in this analysis were registered prior to recruitment in ClinicalTrials.gov (phase 2b [NCT02780167]; JADE MONO-1 [NCT03349060]; JADE MONO-2 [NCT03575871]; JADE COMPARE [NCT03720470]; and JADE TEEN [NCT03796676]).

J.P.T. is an advisor for Pfizer Inc., AbbVie, Almirall, Arena Pharmaceuticals, Coloplast, OM Pharma, Aslan Pharmaceuticals, Union Therapeutics, Eli Lilly and Company, LEO Pharma, Regeneron, and Sanofi Genzyme; is a speaker for Pfizer Inc., AbbVie, Almirall, Eli Lilly and Company, LEO Pharma, Regeneron, and Sanofi Genzyme; and received research grants from Pfizer Inc., Regeneron, and Sanofi Genzyme. A.B. reports consultancy and travel grants with AbbVie, Almirall, Eli Lilly and Company, Galderma, Janssen, LEO Pharma, Novartis, Sanofi, and UCB. S.S. is an investigator for Dermasence, Galderma, GSK, Kiniksa, Menlo Therapeutics, Novartis, Trevi Therapeutics, Sanofi, and Vanda; is a member of scientific advisory boards, a consultant and/or a speaker for Pfizer Inc., AbbVie, Almirall, Beiersdorf, Bellus Health, Benevolent, Bionorica, Cara, Clexio, Escient, Galderma, Grünenthal, Kiniksa, LEO Pharma, Lilly, L’Oréal, Menlo Therapeutics, Sanofi, Trevi Therapeutics, P.G. Unna Academy, and Vifor. C.C. is an investigator for Pfizer Inc., AbbVie, Eli Lilly and Company, La Roche Posay, Novartis, and Sanofi; is an advisor for Pfizer Inc., AbbVie, CeraVe, Eli Lilly and Company, Janssen, Novartis, and Sanofi; is a speaker for Pfizer Inc., AbbVie, CeraVe, Eli Lilly and Company, Eucerin, Galderma, ISDIN, Janssen, La Roche Posay, Novartis, and Sanofi; and receives grants for investigation from Pfizer Inc. L.M. is an investigator for Pfizer Inc., AbbVie, Galderma, Kiniksa, Lilly, Menlo Therapeutics, Novartis, Sanofi, and Trevi Therapeutics; and is a consultant for AbbVie, Beiersdorf, Clexio, Galderma, Lilly, Menlo Therapeutics, Novartis, Sanofi, Sienna Biopharmaceuticals, and Trevi Therapeutics. B.S.K. is a consultant and advisor for Pfizer Inc., AbbVie, Boehringer Ingelheim, Cara Therapeutics, Kiniksa, Menlo Therapeutics, and Sanofi-Regeneron; has received research grants from Cara Therapeutics, Celgene, and LEO Pharma; and is a founder and stockholder in Nuogen Pharma. P.B., G.C., D.E.M., M.W., J.A., and E.G. are employees and stockholders of Pfizer Inc. J.I.S. has served as an investigator for Celgene, Eli Lilly and Company, F. Hoffmann-LaRoche, Menlo Therapeutics, Realm Therapeutics, Regeneron, and Sanofi; as a consultant for Pfizer Inc., AbbVie, Anacor, AnaptysBio, Arena Pharmaceuticals, Dermavant, Dermira, Eli Lilly and Company, Galderma, GlaxoSmithKline, Glenmark, Incyte, Kiniksa Pharmaceuticals, LEO Pharma, Menlo Therapeutics, Novartis, Realm Therapeutics, Regeneron, and Sanofi; and as a speaker for Regeneron and Sanofi.

This study was funded by Pfizer Inc., New York, NY, USA. Editorial/medical writing support for this manuscript (provided by ApotheCom) was funded by Pfizer Inc., New York, NY, USA.

Jacob Thyssen, Anthony Bewley, Sonja Ständer, Carla Castro, Laurent Misery, Brian S. Kim, Gary Chan, Daniela E. Myers, Melissa Watkins, Justine Alderfer, Erman Güler, and Jonathan I. Silverberg contributed to the study design and data analysis and interpretation. Pinaki Biswas contributed to the data analysis and interpretation and conducted the statistical analysis. All authors participated in drafting and revising the manuscript and approved the final version for submission. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Upon request and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual deidentified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information. Further inquiries can be directed to the corresponding author.

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