Lebrikizumab vs Other Systemic Monotherapies for Moderate-to-Severe Atopic Dermatitis: Network Meta-analysis of Efficacy

Abrocitinib, a selective Janus kinase (JAK)-1 inhibitor, is approved for the treatment of moderate-to-severe atopic dermatitis (AD). Although several real-world studies evaluated the safety and efficacy of abrocitinib, most have been limited by small sample sizes, and there are limited data on South Korean patients with AD. In addition, real-world comparative data across oral JAK inhibitors for AD remain limited. We conducted a retrospective, single-center cohort study at the National Medical Center in Seoul, Korea. Patients aged ≥ 12years with moderate-to-severe AD (baseline EASI ≥ 7) who initiated abrocitinib between September 2022 and April 2024 were included in the primary cohort; additional cohorts treated with upadacitinib or baricitinib during predefined periods were analyzed for between-drug comparisons. Efficacy was assessed at baseline, week2, and week16 using the Eczema Area and Severity Index (EASI) and patient-reported outcomes (PROs). Safety was evaluated by adverse events (AEs), physical examinations, and laboratory tests. Of the 66 patients enrolled, 57 patients completed 16weeks of abrocitinib treatment in the analysis. The mean EASI score significantly decreased after 16weeks. At week16, 94.4%, 72.2%, and 25.9% of patients with AD achieved EASI-50, -75, and -90, respectively. Additionally, of the 21 patients who had previously experienced biologics or other JAK inhibitors, 95.5%, 72.7%, and 22.7% achieved EASI-50, -75, and -90, respectively. Further analysis of the EASI breakdown showed improvements of more than 80% across all body regions, with the lower extremities showing the greatest reduction (87.5%) and lichenification exhibiting the highest symptom improvement (89.7%). In descriptive, unadjusted comparisons, abrocitinib showed numerically higher EASI-50 and EASI-75 response rates at week16 than upadacitinib and baricitinib. Acne was the most frequent adverse event with abrocitinib (43.9%), followed by urticaria (24.6%) and herpes simplex infection (12.3%); no dose reductions or treatment discontinuations due to adverse events occurred. Abrocitinib demonstrates real-world efficacy and safety in moderate-to-severe AD, including patients with inadequate responses to other dupilumab or JAK inhibitors, including those with prior exposure to biologics or other JAK inhibitors.

Janus kinase (JAK) inhibitors have become promising treatments for atopic dermatitis (AD), however no study directly comparing JAK inhibitors with each other has been reported. We conducted this network meta‐analysis to determine the comparative efficacy and safety of three common oral JAK inhibitors including abrocitinib, baricitinib, and upadacitinib for moderate‐to‐severe AD. We first identified eligible studies from published meta‐analyzes, then we searched PubMed to obtain additional studies published between February and July 2021. Clinical efficacy and safety were evaluated as primary and secondary outcome, respectively. After extracting data and assessing methodological quality, we utilized ADDIS 1.4 software to conduct pair‐wise and network meta‐analyzes. Ten eligible studies were included in the final analysis. Pooled results that abrocitinib, baricitinib, and upadacitinib obtained higher investigator global assessment (IGA), eczema area, and severity index (EASI) response, however abrocitinib and upadacitinib caused more treatment‐emergent adverse events (TEAEs) regardless of doses, compared with placebo. Network meta‐analyzes revealed that upadacitinib 30 mg was superior to all regimens and upadacitinib 15 mg was better than remaining regimens except for abrocitinib 200 mg in terms of IGA and EASI response. Moreover, abrocitinib 200 mg was superior to abrocitinib 100 mg, baricitinib 1 mg, 2 mg, and 4 mg for clinical efficacy. However, upadacitinib 30 mg caused more TEAEs. Abrocitinib, baricitinib, and upadacitinib were consistently effective therapies in adult and adolescent patients with AD; however, upadacitinib 30 mg may be the optimal option in short‐term studies. More efforts should be done to reduce the risk of TEAEs caused by upadacitinib 30 mg.

Introduction & Objectives: Upadacitinib (UPA), a selective oral Janus kinase (JAK) inhibitor, and dupilumab (DUPI), a monoclonal antibody targeting interleukin-4Rα, are both treatments approved for patients with moderate-to-severe Atopic Dermatitis (AD). Results from a phase 3b/4 trial (Level Up NCT05601882) indicated that UPA was superior to DUPI in simultaneously achieving the stringent endpoints of Eczema Area and Severity Index (EASI) improvement of ≥90% from baseline (EASI 90) and a Worst Pruritus Numerical Rating Scale score of 0/1 (WP-NRS 0/1) at Week 16. In this post-hoc analysis, we analyzed the median time (days) spent in response states based on EASI 90 and/or WP-NRS 0/1 in patients either receiving UPA or DUPI over a 16-week period. Materials & Methods: The Level Up study was a phase 3b/4 head-to-head global, randomized, open-label, efficacy assessor blinded, multicenter study comparing UPA vs DUPI in adolescents and adults with moderate-to-severe AD. Patients were randomized to UPA 15 mg or DUPI per its label for 16 weeks of treatment. Patients on UPA 15 mg were dose-escalated to 30 mg starting at Week 4 if they had a <EASI 50 response, or a <4-point WP-NRS improvement from baseline. Patients taking UPA 15 mg who did not achieve EASI 75 starting at Week 8 similarly had their dose increased to 30 mg. Starting at Week 4, rescue with topical therapy was optional and per investigator’s discretion if protocol criteria were met. The current analyses assessed the number and proportion of days patients spent with clear or nearly-clear skin (EASI 90) and/or no/minimal itch (WP-NRS 0/1), with comparisons made at the median (50th percentile) and upper quartile (75th percentile). Missing data at study visits were imputed using non-responder imputation with multiple imputations. Results: Participants included 458 patients receiving UPA and 462 receiving DUPI. Cumulatively over a course of 16 weeks, patients taking UPA vs DUPI spent a greater number of days at EASI 90 and WP-NRS 0/1. Over 16 weeks (112 days), 1 in 2 patients (ie, median or 50th-percentile) spent at least 28.0 days at EASI 90 with UPA vs 0 days with DUPI, while 1 in 4 patients spent at least 64.4 days with UPA vs 25.7 days with DUPI. For days at WP-NRS 0/1 with UPA vs DUPI, 1 in 2 patients spent at least 11.3 vs 0.4 days with no/minimal itch respectively; and 1 in 4 patients (ie, upper quartile or 75th-percentile) spent at least 57.2 vs 17.0 days with UPA vs DUPI, respectively. Similar patterns were observed in the number of days simultaneously achieving both EASI 90 and WP-NRS 0/1, as well the proportion of days spent in these responses. Conclusion: Treatment of moderate-to-severe AD with UPA per label resulted in a greater number or proportion of days spent with EASI 90 and/or WP-NRS 0/1 compared with DUPI over 16 weeks. These results highlight differences in lived day- to-day skin disease and itch symptom burden over the course of treatment and can be used to inform shared decision-making discussions between patients and physicians.

The ORAL Surveillance trial showed a potentially higher incidence of malignancy and major adverse cardiovascular events (MACEs) associated with tofacitinib than those associated with tumor necrosis factor (TNF) inhibitors (TNFis). However, few studies have compared the safety of non-TNFis or other Janus kinase (JAK) inhibitors (JAKis). This study was aimed at comparing the incidence rates (IRs) of malignancies and MACEs in patients with rheumatoid arthritis (RA) treated using interleukin-6 (IL-6) inhibitors (IL-6is) or JAKis. We retrospectively analyzed 427 patients with RA who were treated using an IL-6i (n = 273) or a JAKi (n = 154). We determined the IRs of malignancy and MACEs, and the standardized incidence ratio (SIR) of malignancies and investigated factors related to malignancy and MACEs. After adjusting the clinical characteristic imbalance by propensity score matching (PSM), we compared the IRs of adverse events between the JAKi and IL-6i groups. After PSM, the observational period was determined to be 605.27 patient-years (PY), and the median observational period was determined to be 2.28 years. We identified seven cases of malignancy (IR: 2.94 per 100 PY) in the JAKi-treated group and five cases (IR: 1.36 per 100 PY) in the IL-6i-treated group after PSM. The IR of MACEs was 2.56 and 0.83 (per 100 PY) in the JAKi- and IL-6i-treated groups. The IRRs of JAKi-treated patients versus IL-6i-treated patients were 2.13 (95% confidence interval (CI): 0.67-7.42) for malignancy and 3.03 (95% CI: 0.77-15.21) for MACE. There were no significant differences in IRR for malignancy and MACE between both groups after PSM. Univariate and multivariable Cox regression analyses revealed that older age and JAKi use were independent risk factors for malignancy, while older age, hypertension, and JAKi use were independent risk factors for MACEs. The overall malignancy SIR was significantly higher in the JAKi-treated group compared to the general population (2.10/100 PY, 95% CI: 1.23-2.97). The IRs of malignancy and MACE in patients with RA after PSM were comparable between IL-6i-treated and JAKi-treated patients. However, the SIR of malignancy in JAKi treatment was significantly higher than in the general population; therefore, further safety studies comparing JAKi to non-TNFi biologic disease-modifying antirheumatic drugs (bDMARDs) are needed.

Leveraging the nice face of Janus kinase inhibition—ruxolitinib cream in atopic dermatitis

Janus kinase (JAK) inhibitors are promising treatments for atopic dermatitis (AD). The aim of this study was to assess the efficacy and safety of JAK inhibitors for AD treatment via the “Grading of Recommendations Assessment, Development, and Evaluation” approach. We identified 15 randomized controlled trials comparing oral or topical JAK inhibitors against placebo to treat AD. A random-effects meta-analysis was performed, and the numbers-needed-to-treat (NNTs)/numbers-needed-to-harm (NNHs) were calculated. Patients treated with JAK inhibitors were associated with higher rates of achieving eczema area and severity index-75 (rate ratio (RR): 2.84; 95% confidence interval (CI): 2.20–3.67; I2: 38.9%; NNT = 3.97), Investigator’s Global Assessment response (RR: 2.99; 95% CI: 2.26–3.95; I2: 0%; NNT = 5.72), and pruritus numerical rating scale response (RR: 2.52; 95% CI: 1.90–3.35; I2: 39.4%; NNT = 4.91) than those treated with placebo. Moreover, patients treated with JAK inhibitors had a higher risk of treatment-emergent adverse events (RR: 1.14; 95% CI: 1.02–1.28; I2: 52%; NNH = 14.80) but not adverse events leading to drug discontinuation. According to the evidence-based results, JAK inhibitors are potentially effective strategies (certainty of evidence: “moderate”) for treating AD with tolerable side effects (certainty of evidence: “low”). Nevertheless, long-term follow-up is required.

The Janus kinase inhibitors (JAKi), abrocitinib, baricitinib and upadacitinib, are novel systemic treatments for patients with moderate-to-severe atopic eczema, typically prescribed as a third-line systemic treatment options in UK practice. We sought to describe the treatment effectiveness and safety of these agents in the UK-Irish Atopic eczema Systemic TherApy Register (A-STAR), a prospective observational register of paediatric and adult patients receiving systemic treatment for atopic eczema. We analysed treatment effectiveness, focusing on Eczema Area and Severity Index (EASI). The minimum duration of treatment was 28 days and the follow-up time was a maximum of 12 months. We calculated the mean follow-up time until EASI 50, 75 and 90 were reached (≥ 50%, ≥ 75% and ≥ 90% improvement from baseline), or the patient terminated follow-up, without conducting formal comparisons between groups. Treatment safety was assessed by calculating incidence rates (IR) of adverse events (AEs) at follow-up. In total, 39 patients receiving abrocitinib, 21 on baricitinib, and 35 on upadacitinib were included. The mean time on treatment was 9.08 months (range 0.69–31.6) for abrocitinib, 8.07 (2.10–32.3) for baricitinib and 10.3 (0.46–27.7) for upadacitinib. Overall, 56% of patients were male, 77% were of White ethnicity, and the mean age was 32.5 years (SD 14.3). The mean baseline EASI was 20.4 (SD 13.8) for abrocitinib, 19.5 (SD 16.9) for baricitinib and 17.4 (SD 12.5) for upadacitinib. The percentage of patients who had had more than three past systemic treatments was 74% (n = 29) for abrocitinib, 76% (n = 16) for baricitinib, and 71% (n = 25) for upadacitinib. The mean follow-up to EASI 75 (in months) was 4.22 for abrocitinib, 4.78 for baricitinib and 4.24 for upadacitinib. EASI 50 and 90 followed similar trends (Table). Overall, 179 AEs were reported. Individually, for abrocitinib, baricitinib and upadacitinib, there were 68 AEs in 28 treatment cycles (IR 856 per 10 000 person-months), 30 AEs in 14 cycles (IR 1375) and 61 AEs in 23 cycles (IR 764), respectively. Serious AE data will also be presented. UK-Irish A-STAR register is a promising vehicle to collect real-world data on JAKi. All three treatments appear effective, even as third- and fourth-line therapy. Larger patient numbers are required for an adequately powered comparative analysis. A-STAR is funded through BADERL, a registered not-for-profit company within the British Association of Dermatologists. BADERL receives income from AbbVie, Eli Lilly and Pfizer for providing pharmacovigilance services. The A-STAR study protocol, study conduct and decisions concerning data analyses, interpretation and publication are made independently of any industry involvement.EASI 50EASI 75EASI 90TreatmentnMean monthsEventsaMean monthsEventsaMean monthsEventsaUpadacitinib253.2088%4.2464%5.1152%Abrocitinib303.2270%4.2253%5.4533%Baricitinib134.0054%4.7831%5.878%aPercentage of cohort achieving outcome.

Background/Objective: Systematic reviews (SRs) with network meta-analysis (NMA) support evidence-based decision-making by enabling both direct and indirect comparisons across multiple interventions. Given the expanding use of Janus kinase (JAK) inhibitors in rheumatoid arthritis (RA), the methodological rigor of SRs with NMA is essential for trustworthy conclusions. This study is aimed at evaluating the methodological quality of SRs with NMA assessing the efficacy and/or safety of JAK inhibitors in RA. Methods: PubMed and Embase were searched for full-text SRs with NMAs evaluating JAK inhibitors as a therapeutic class in RA. Eligible publications were English-language articles reporting efficacy and/or safety outcomes. Narrative reviews, letters, duplicates, reviews focused on a single JAK inhibitor, and reviews without quantitative synthesis were excluded. Three independent reviewers assessed methodological quality using AMSTAR 2. Descriptive statistics were used to summarize findings. Results: Of the 222 records identified, 18 SRs with NMA met the inclusion criteria: 5 focused on efficacy, 5 on safety, and 8 assessed both. The most consistently fulfilled AMSTAR 2 items were a clearly defined PICO question (100%), duplicate study selection (100%), and reporting of conflicts of interest (100%). Common shortcomings included lack of protocol registration (44%), incomplete reporting of the search strategy (39%), and absence of publication bias assessment (50%). Risk-of-bias assessment varied by review focus: all safety reviews complied (100%), compared with 20% of efficacy reviews and 37% of mixed reviews. Conclusions: Most SRs with NMA of JAK inhibitors in RA present relevant methodological limitations, particularly in protocol registration, search reporting, and risk-of-bias assessment. Methodological standards were generally higher in safety-focused reviews, underscoring the need for more consistent and rigorous conduct and reporting, especially in efficacy and mixed reviews, to strengthen confidence in NMA-derived conclusions.

Atopic dermatitis (AD) is a chronic, recurring, inflammatory skin disease characterized by extensive rashes on the body, leading to symptoms such as persistent itching and exudation. There is still a need for safe and effective therapies to improve disease management for uncontrolled moderate-to-severe AD, as current treatments may not adequately control the disease. 611 is a novel monoclonal antibody that targets interleukin (IL)-4Rα. It can selectively bind to IL-4Rα, thereby obstructing the signalling pathways of both IL-4 and IL-13. This action aids in modulating immune function, offering potential relief for conditions such as AD and other related diseases. In this phase II study, the safety and efficacy of 611 was investigated in moderate-to-severe AD in adult patients. In total 93 patients were randomly assigned to three groups: group A received a loading dose of 600 mg of 611 followed by 300 mg every 2 weeks (Q2W), group B received a loading dose of 600 mg of 611 followed by 300 mg every 4 weeks (Q4W), and there was also a placebo group. The primary efficacy endpoint was the proportion of patients with Eczema Area and Severity Index (EASI) 75 response (≥ 75% reduction in score from baseline) at week 16. The results showed positive responses in primary and all secondary endpoints in adult patients with moderate-to-severe AD after treatment with 611. There was a significant difference between 611 and placebo in EASI 75 improvement, with a 60.0% response rate for 611 compared with 15.6% for placebo (P < 0.001). The percentage of patients achieving IGA 0/1 (Investigator’s Global Assessment score of 0 or 1, and ≥ 2-point reduction from baseline) also exhibited a significant difference in the groups receiving 611 or placebo, with rates of 35.5% and 9.4%, respectively (P < 0.05). The other endpoints, including EASI 90, EASI 50, and numerical rating scale reduction by ≥ 4 points, improved more in the groups receiving 611 than for placebo. Regarding safety data in the trial, treatment with 611 showed results comparable with placebo. 611 showed a positive effect in treatment of patients with moderate-to-severe AD in terms of efficacy and safety. 611 has potentially become a promising treatment product targeting IL-4Rα, following on from dupilumab.

BackgroundBiologics and Janus kinase (JAK) inhibitors have expanded treatment options for moderate-to-severe atopic dermatitis (AD), but comparative real-world data remain limited.ObjectiveThis study aims to compare disease-related characteristics and outcomes of patients with moderate-to-severe AD treated with biologics or JAK inhibitors (JAKi) in routine clinical practice.Materials and methodsAn ambispective, observational study was conducted across three hospitals in southern Spain. Patients who initiated advanced systemic therapy (AST) between 2019 and 2024 were included in the study. Baseline disease-related variables, clinical severity scores, treatment outcomes, adverse events, and drug survival were assessed. Short-term (16 weeks) and medium-to-long-term (24 and 52 weeks) intervals were considered. Super-responder rates, based on a proposed definition, were also evaluated.ResultsA total of 202 patients were included (134 treated with biologics and 68 with JAK inhibitors). JAK inhibitors produced faster early responses, while biologics achieved greater absolute improvements between weeks 16 and 52, along with longer treatment persistence. The adverse event profiles differed between the drug classes: infections and acne were more common with JAKi, while ocular symptoms were more common with biologics. The difference in super-responder rates between groups was not statistically significant (16.42% vs. 23.53%, p = 0.25443).ConclusionBoth treatment classes were effective and well-tolerated. Differences in response dynamics and safety profiles support individualized treatment decisions.

Janus kinase 2 (JAK2) inhibitors in the treatment of multiple myeloma: modulating the myeloma immune microenvironment.

Introduction/Background Tralokinumab is a high-affinity monoclonal antibody that specifically targets IL-13, a driver of inflammation in atopic dermatitis (AD). The ECZTRA 1, 2, 3, and 6 trials demonstrated that tralokinumab is efficacious and safe in adults and adolescents; however, real-world evidence on tralokinumab use is limited. Objectives To assess the change from baseline in clinician-assessed and patient-reported outcomes (PROs) among US adults with AD following 6 months of persistent tralokinumab use after treatment initiation in the CorEvitas AD registry. Methods The CorEvitas AD Registry is a prospective, non-interventional registry launched in July 2020 for adult AD patients under the care of a licensed dermatologist or qualified dermatology practitioner. This analysis includes US patients enrolled in the CorEvitas AD registry who initiated tralokinumab between February 1, 2022 and May 31, 2023, had baseline data, and were persistent on tralokinumab at the 6-month follow-up (defined as a visit occurring 5 to 9 months from tralokinumab initiation). Baseline data were summarized using descriptive statistics and stratified by advanced systemic therapy (AST) experience (defined as any previous history of dupilumab, abrocitinib, or upadacitinib). Outcome measures collected included: validated Investigator’s Global Assessment for atopic dermatitis (vIGA-ADTM), ≥50%/≥75% improvement in Eczema Area and Severity Index (EASI) (EASI-50/75), ≥4-point improvement in Dermatology Life Quality Index (DLQI), ≥3-point improvement in mean weekly pruritis numerical rating scale, and mean change in Work Productivity and Activity Impairment (WPAI). Results Among the 60 patients in this analysis, the mean age was 49.1 years and mean AD duration was 15.0 years. The majority of patients were female (34/60, 56.7%), White (51/60, 85.0%), worked full-time (38/60, 63.3%), and AST-naïve (44/60, 73.3%). At baseline, the majority of patients had moderate-to-severe AD based on EASI (EASI≥ 7, 40/60, 67%) and vIGA-ADTM (vIGA-ADTM 3: 50/60, 83.3%; vIGA-ADTM 4: 4/60, 6.7%). Disease severity was lower in AST-experienced patients, all of whom were dupilumab-experienced. A notable proportion of patients experienced improvements in clinician-assessed endpoints and PROs from baseline to 6 months: vIGA-ADTM ≤1 from 6.7% (4/60) to 55.0% (33/60), EASI ≤7 from 33.3% (20/60) to 85.0% (51/60), and DLQI ≤5 from 38.3% (23/60) to 66.7% (40/60). Among patients with EASI ≥7.1 at baseline, 85.0% (34/40) achieved EASI-50 (AST-naïve: 90.9%, 30/33; AST-experienced: 57.1%, 4/7) and 77.5% (31/40) achieved EASI-75 (AST-naïve: 84.8%, 28/33; AST-experienced: 42.9%, 3/7) at the 6-month follow-up. In patients with vIGA-ADTM of 3 or 4 at baseline, 79.6% (43/54) achieved EASI-50 (AST-naïve: 83.3%, 35/42; AST-experienced: 66.7%, 8/12) and 66.7% (36/54) achieved EASI-75 (AST-naïve: 76.2%, 32/42; AST-experienced: 33.3%, 4/12) at follow-up. Among patients with baseline DLQI ≥4, 71.4% (30/42) achieved ≥4-point improvement at follow-up (AST-naïve: 78.1%, 25/32; AST-experienced: 50.0%, 5/10). Of patients with baseline mean weekly pruritus NRS ≥3, 69.8% (37/53) achieved ≥3-point improvement at follow-up (AST-naïve: 70.0%, 28/40; AST-experienced: 69.2%, 9/13). Among the 40 patients employed at both baseline and follow-up visit, improvements were reported in WPAI. Percent impairment at work due to AD decreased by 14.8% (95% CI: -25.6%; -3.9%) and percent overall work impairment due to AD decreased by 15.7% (95% CI: -26.4%; -5.0%). For all 60 patients, non-work activity impairment due to AD decreased by 14.5% (95% CI: -23.9%; -5.1%). Conclusions In this real-world study, patients with AD experienced notable improvements in both clinician-assessed and patient-reported outcomes after 6-months of persistent tralokinumab treatment, regardless of prior AST therapy use. All 16 AST-experienced patients had prior use of dupilumab. These findings support the therapeutic potential of tralokinumab for AD patients, highlighting the need for future studies with longer follow-up period and larger sample size.

Janus kinase (JAK) inhibitors are being increasingly used in inflammatory bowel diseases (IBDs). In the present review we raise a series of practical questions on JAK inhibitors in IBD and provide clear and concise answers. We performed a bibliographic search to identify studies assessing the role of JAK inhibitors in IBD. The key conclusions are summarized as follows. Upadacitinib has shown favorable efficacy outcomes in ulcerative colitis relative to other JAK inhibitors, although this conclusion requires confirmation through randomized trials. Extended induction can benefit patients with partial response. Real-world data support the use of JAK inhibitors in pediatric and older adults with IBD. JAK inhibitor efficacy appears unaffected by body mass index. JAK inhibitors may offer considerably high colectomy-free rates in acute severe ulcerative colitis. Interruption of therapy should be cautious, as maintenance seems key to sustained remission. Dose re-escalation can recapture response in over half of patients with loss of efficacy. Switching between JAK inhibitors, especially from tofacitinib to upadacitinib, is a viable strategy. Upadacitinib appears promising in the treatment of refractory perianal fistulizing Crohn's disease. JAK inhibitors may also be an option in refractory pouchitis. Combination therapy with JAK inhibitors and biologics may be beneficial in refractory IBD, though more studies are needed. JAK inhibitors appear effective in some extraintestinal dermatologic manifestations. Pretreatment screening for latent tuberculosis is advised. JAK inhibitors cause reversible, dose-dependent cholesterol increases without consistent evidence of a clear impact on cardiovascular risk, but monitoring is advised. Use in pregnancy is discouraged due to potential risks, and breastfeeding is contraindicated because of drug excretion in milk.

PDG2 Evaluating the Severity of Atopic Dermatitis (AD) in Children and Adults: Mapping of Investigator's Static Global Assessment (ISGA) to Eczema Area and Severity INDEX (EASI) in Phase 3 Studies of Crisaborole, 2%

Introduction/Background Atopic dermatitis (AD) is a chronic, recurrent, immune-mediated inflammatory disease associated with burdensome symptoms including itch, skin pain, sleep disruption, as well as reduced quality of life (QoL).1 It is therefore important to consider signs, symptoms, and QoL impairments when evaluating long-term benefits of AD treatments. Upadacitinib is an oral selective Janus kinase inhibitor approved to treat moderate-to-severe AD.2 Objective To evaluate the effects of upadacitinib monotherapy on skin and patient-reported outcomes (PROs) in patients with moderate-to-severe AD over 140 weeks. Methods Measure Up 1 (NCT03569293) and Measure Up 2 (NCT03607422) were replicate, multicenter, phase 3 studies evaluating once-daily oral upadacitinib monotherapy for adolescents (aged 12–17 years) and adults (aged ≥ 18 years) with moderate-to-severe AD.3,4 At baseline, patients were randomized 1:1:1 to upadacitinib 15 mg, upadacitinib 30 mg, or placebo. In this analysis, data for patients who were randomized to upadacitinib 15 mg or upadacitinib 30 mg at baseline in Measure Up 1 and Measure Up 2 were integrated and reported based on observed cases from week 16 (the end of the double-blind period) through week 140 of the blinded extension period; week 16 data for patients randomized to placebo were also reported. Assessments included itch (Worst Pruritus Numerical Rating Scale [WP-NRS]); Eczema Area and Severity Index (EASI); skin pain (AD Symptom Scale [ADerm-SS] Skin Pain); skin symptoms (ADerm-SS 7-item Total Symptom Score [TSS-7]); skin symptom severity (Patient-Oriented Eczema Measure [POEM]); QoL (Dermatology Life Quality Index [DLQI; patients aged ≥ 16 years], and Children’s DLQI [CDLQI; patients aged < 16 years]); and sleep, daily activities, and emotional state (AD Impact Scale [ADerm-IS]). Assessed outcomes included achievement of (1) minimal clinically important differences vs baseline (WP-NRS, ADerm-SS Skin Pain, and POEM improvement ≥ 4; ADerm-SS TSS-7 improvement ≥ 28; ADerm-IS Sleep, Daily Activities, and Emotional State improvements ≥ 12, ≥ 14, and ≥ 11, respectively), (2) no/minimal disease burden or impact (WP-NRS 0/1, ≥ 90% improvement from baseline in EASI [EASI 90], DLQI 0/1,and CDLQI 0/1), and (3) simultaneous achievement of EASI 90 and WP-NRS 0/1, an endpoint that aligns with the recently proposed minimal disease activity concept.5 Results Data for 1213 patients (upadacitinib 15 mg, n = 603; upadacitinib 30 mg, n = 610), including 241 adolescents (19.9%) and 972 adults (80.1%), from Measure Up 1 and Measure Up 2 were analyzed. At week 16, over 50% of patients receiving either dose of upadacitinib reported clinically meaningful improvements in PROs; among patients receiving upadacitinib 15 mg and upadacitinib 30 mg, 36.7% and 53.1% achieved WP-NRS 0/1, while 29.0% and 44.1% achieved DLQI 0/1, and 23.5% and 50.0% achieved CDLQI 0/1, respectively. Response rates at week 16 were sustained or improved further through week 140. At week 140, the proportion of patients treated with upadacitinib 15 mg and upadacitinib 30 mg from baseline who achieved clinically meaningful improvements were 64.8% and 70.9% for itch, 74.6% and 81.5% for skin pain, 67.6% and 75.4% for skin symptoms, 89.0% and 94.2% for skin symptom severity, 76.5% and 84.0% for sleep, 79.2% and 84.0% for daily activities, and 78.6% and 82.7% for emotional state, respectively. At week 140, achievement rates with upadacitinib 15 mg and upadacitinib 30 mg were 45.1% and 51.4% for WP-NRS 0/1, 67.3% and 75.6% for EASI 90, 40.5% and 47.1% for simultaneous EASI 90 and WP-NRS 0/1 achievement, 40.2% and 48.5% for DLQI 0/1, and 35.7% and 65.0% for CDLQI 0/1, respectively. Conclusions Patients with moderate-to-severe AD experienced sustained improvements in skin signs/symptoms through 140 weeks while receiving upadacitinib. Rates of long-term PRO improvements were numerically higher with upadacitinib 30 mg compared with upadacitinib 15 mg.