Identifying the Most Relevant Eczema Area and Severity Index Thresholds from the Patient Perspective in Atopic Dermatitis Treatment.

Relationship between EASI and SCORAD severity assessments for atopic dermatitis

Atopic dermatitis (AD) manifests differently across diverse patient populations, potentially leading to challenges in its assessment and management.1 Additionally, pigment masking may obscure erythema and other AD signs leading to misclassification of AD severity in patients with darker phototypes.2,3 We hypothesized that clinician-reported outcome measures may not perform as well in non-White vs. White patients. To test this, we examined whether clinician-reported outcome measures have weaker correlations with established patient-reported outcome measures across different races or ethnicities. A prospective, dermatology practice-based study was performed in children and adults with AD as defined by the Hanifin-Rajka diagnostic criteria. Patients were enrolled sequentially between January 2014 and September 2019. The study was approved by the institutional review board of Northwestern University. Informed consent was obtained electronically. Electronic surveys were completed by patients/caregivers, including self-identified race and Hispanic ethnicity, Numerical Rating Scale (NRS) for average-itch in the past 7 days, and Patient-Oriented Eczema Measure (POEM). Investigator assessments of AD severity were performed by a dermatologist (J.I.S.) and included the Eczema Area and Severity Index (EASI), and the objective component of SCORAD (oSCORAD). Spearman correlations were performed for POEM and NRS-itch vs. oSCORAD and EASI. Correlation coefficients were interpreted as≥0.70 or ≤ −0.70 = very strong, 0.50 to 0.69 or −0.69 to −0.50 = strong, 0.30 to 0.49 or −0.49 to −0.30 = moderate and 0.10 to 0.29 or −0.29 to −0.10 = weak.4 Overall, 1987 patients were included in the study (age <18 years: 101 [5.08%], ≥ 18 years: 1886 [94.92%]), including 198 (9.96%) Black, 360 (18.12%) Asian, 8 (0.40%) multiracial/other, 1313 (66.08%) White race and 108 (5.44%) Hispanic ethnicity. In White patients, POEM and NRS average-itch had strong correlations with oSCORAD and EASI. Whereas in Black patients, POEM had only moderate correlations with oSCORAD and EASI NRS average-itch had weak-moderate correlations with oSCORAD and EASI. Asian/Pacific Islander patients also had numerically weaker correlations of POEM with oSCORAD and EASI compared to White patients, but strong or very strong correlations of NRS average-itch with oSCORAD and EASI. Patients with Hispanic ethnicity also showed weaker correlations for POEM with oSCORAD and EASI compared to Whites, as well as weaker correlations of NRS average-itch with EASI. The modest correlation observed between PROMs and clinician-reported outcome measures in general highlights the importance of measuring both signs and symptoms to fully describe the severity of AD. This is particularly important in non-White patients who had notably weaker correlations between PROMs and clinician-reported outcome measures. The poor correlation between patient-reported outcome measures and clinician-reported outcome measures may be multifactorial, including pigment masking limiting assessment of erythema and other AD signs in patients with darker phototypes,3 more severe pruritus and morphologic variants occurring in Blacks and Asians/Pacific Islanders that may not adequately be represented in oSCORAD and EASI. AD severity is often underestimated in patients with darker phototypes.3 Future efforts are needed to optimize clinician assessments of AD severity in diverse patient populations.

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.

Atopic dermatitis (AD) is a chronic inflammatory disease that affects approximately 5–10% of the child population and 3–10% of the adult population worldwide.1 It can affect any part of the body indifferently, having a different distribution of eczematous lesions depending on the patient's period of life; in adults, it is common to see lesions on the neck, limbs and trunk; in particular, some patients report involvement of specific sites such as the head and neck region. Based on our clinical experience and the reported data on AD, we have analysed the impact on quality of life according to the Dermatology Life Quality Index (DLQI) to look at the repercussions of the disease on personal and social life.2 Our study analysed the global Eczema Area and Severity Index (EASI) and the partial EASIs related to the different body areas in order to understand which of them is the more predictive of DLQI and if, consequently, the involvement of a single body site could be able to predict the severity of the disease by itself. The involvement of the head and neck site has been previously studied in a Delphi, as indicator of a higher burden of disease,3 and its involvement has been associated with a worsening of the quality of life.4 Patients were prospectively enrolled in the moderate-severe atopic dermatitis service between April 2019 and May 2020 accordingly to the previously described criteria.5 Setting the DLQI > 10 as a cut-off, the different partial EASI was analysed by relating them to the total EASI score with logistic regression analysis. The model was adjusted for the global EASI. The sample examined was composed of 192 patients ≥18 years with AD symptoms for at least 6 months. There were 104 males and 88 females mostly affected by the disease from early childhood (67%). 97% had a history of immunosuppressive systemic drug; 173 (90% of the total) were treated with cyclosporine. Mean eosinophils count was 0.43 (±0.37 109/L). The mean global EASI score was 23.6 (±11.88), the EASI of the specific head-neck site (H&N) was 3.2 (±1.9), the trunk EASI was 6.3 (±4.6), the upper limbs EASI was 5 (±3.2) and the lower limbs EASI was 8.8 (±6.5). The average DLQI in the sample was 15.3 (±6.9). Concerning the trunk, upper and lower limbs, there was no statistically significant association between partial EASI and the perceived quality of life, assessed with DLQI (Table 1). On the other hand, there was a statistically significant association with the DLQI and the H&N EASI (OR = 1.27, p = 0.027; IC 1.02–1.57) (Table 1). In clinical practice, many authors have assisted to a low DLQI even in EASI score lower than 24.3 Since in some countries a EASI score lower than 24 will block the access to biologic new drug for AD, QoL can be strongly impacted. EASI of the H&N has a larger impact on the measured quality of life in these subjects than the trunk and limbs. In daily practice, patients with no H&N involvement should still be assessed using the global EASI score to best quantify the severity of the disease from a clinical point of view. However, when evaluating AD specifically involving the H&N site, we have to consider the DLQI impact and the risk of decreasing the perceived quality of life due to the specific involvement of this site. Therefore, in assessing AD, it could be suggested to consider patients with H&N involvement as suffering from more severe atopic dermatitis than their global EASI score suggests; therefore, the considered treatment options should account for this when pondering about indication to biologic drugs. This study was partially supported by an unconditioned grant from Leo Pharma. The authors have no conflict of interest. SR, BP, MTG, RV, NS and MO performed the research. SR and PQ designed the research study. SR analysed the data. SR, NS, MO and BP wrote the paper.

Both clinician-reported outcome measures (CROMs) measures and patient-reported outcome measures (PROMs) are applied to evaluate outcomes in rehabilitation settings. The previous data show only a low to moderate correlation between these measures. Relationships between functional performance measures (Clinician-Reported Outcome Measures, CROMs) and Patient-Reported Outcome Measures (PROMs) were analysed in rehabilitation patients with traumatic injuries of the lower limb. A cohort of 315 patients with 3 subgroups (127 hip, 101 knee and 87 ankle region) was analysed before and after 3 weeks of inpatient rehabilitation. All three groups showed significant improvements in PROMs with low to moderate effect sizes. Moderate to high effect sizes were found for CROMs. Correlation coefficients between CROMs and PROMs were low to moderate. The performance consistency between PROMs and CROMs ranged from 56.7% to 64.1%. In this cohort of rehabilitation patients with traumatic injuries, CROMs showed higher effect sizes than PROMs. When used in combination, patient-reported outcome and performance measures contribute to collecting complementary information, enabling the practitioner to make a more accurate clinical evaluation of the patient’s condition.

The Comparison between Objective and Subjective Severity Scores of Atopic Dermatitis

Introduction: Upadacitinib has demonstrated high and rapid rates of efficacy in adolescent and adult patients with moderate-to-severe atopic dermatitis (AD) as assessed by the Eczema Area and Severity Index (EASI). This post hoc analysis assessed the EASI response in four anatomical regions for patients with moderate-to-severe AD treated with upadacitinib compared to dupilumab over 24 weeks. Methods: Data from patients randomized 1:1 to receive upadacitinib 30 mg extended-release tablet orally once daily or dupilumab 300 mg by subcutaneous injection every 2 weeks after a loading dose of 600 mg in the Heads Up study were analyzed for achievement of ≥75%, ≥90%, or 100% reduction of EASI in four body regions: (1) head and neck, (2) trunk (including genitals), (3) upper limbs, and (4) lower limbs (including buttocks) at each study visit through week 24. Patient response data from the Head and Neck Patient Global Impression of Severity (HN-PGIS) were also analyzed at each study visit for comparison of upadacitinib to dupilumab. Results: Greater proportions of patients treated with upadacitinib versus dupilumab achieved skin clearance rates of ≥75% (EASI 75) at week 1 and higher clearance rates of ≥90% (EASI 90) or 100% (EASI 100) by week 4 or earlier in all four body regions. This difference was maintained at each visit through week 24 for both EASI 90 and EASI 100. Patient responses on the HN-PGIS indicated that a greater proportion of patients (nominal p value <0.05) treated with upadacitinib compared to dupilumab reported that AD symptoms in the head and neck region were absent or minimal as early as week 1. Conclusion: Compared to dupilumab, upadacitinib treatment provided higher rates of rapid, sustained efficacy for the head and neck, trunk, upper limbs, and lower limbs for the treatment of moderate-to-severe AD as measured by the EASI and supported by patient responses. Introduction: Upadacitinib has demonstrated high and rapid rates of efficacy in adolescent and adult patients with moderate-to-severe atopic dermatitis (AD) as assessed by the Eczema Area and Severity Index (EASI). This post hoc analysis assessed the EASI response in four anatomical regions for patients with moderate-to-severe AD treated with upadacitinib compared to dupilumab over 24 weeks. Methods: Data from patients randomized 1:1 to receive upadacitinib 30 mg extended-release tablet orally once daily or dupilumab 300 mg by subcutaneous injection every 2 weeks after a loading dose of 600 mg in the Heads Up study were analyzed for achievement of ≥75%, ≥90%, or 100% reduction of EASI in four body regions: (1) head and neck, (2) trunk (including genitals), (3) upper limbs, and (4) lower limbs (including buttocks) at each study visit through week 24. Patient response data from the Head and Neck Patient Global Impression of Severity (HN-PGIS) were also analyzed at each study visit for comparison of upadacitinib to dupilumab. Results: Greater proportions of patients treated with upadacitinib versus dupilumab achieved skin clearance rates of ≥75% (EASI 75) at week 1 and higher clearance rates of ≥90% (EASI 90) or 100% (EASI 100) by week 4 or earlier in all four body regions. This difference was maintained at each visit through week 24 for both EASI 90 and EASI 100. Patient responses on the HN-PGIS indicated that a greater proportion of patients (nominal p value <0.05) treated with upadacitinib compared to dupilumab reported that AD symptoms in the head and neck region were absent or minimal as early as week 1. Conclusion: Compared to dupilumab, upadacitinib treatment provided higher rates of rapid, sustained efficacy for the head and neck, trunk, upper limbs, and lower limbs for the treatment of moderate-to-severe AD as measured by the EASI and supported by patient responses.

In adults with moderate-to-severe atopic dermatitis (AD), rocatinlimab demonstrated significant and progressive improvement in clinical measures of disease severity compared with placebo. This post hoc analysis of a phase2b study was undertaken to understand the disease burden and to assess the impact of rocatinlimab on patient-reported outcomes (PROs). This analysis used baseline data from a multicenter, randomized, double-blind study of adults with moderate-to-severe AD, who completed a Worst Pruritus numerical rating scale (NRS), Sleep Disturbance NRS, and the Dermatology Life Quality Index (DLQI). A mixed model for repeated measures was used to estimate changes in PRO scores from baseline; scores were also compared with clinically meaningful change benchmarks. The analysis included 267 subjects, mean (SD) age 37.9 (14.7) years, 40.8% female; 55.1% grade3 and 44.9% grade4 Investigator Global Assessment for AD. Mean (SD) scores were: Worst Pruritus NRS 7.5 (1.9), Sleep Disturbance NRS 5.5 (2.9), DLQI total score 12.6 (7.1). Worst Pruritus and Sleep NRS scores had low positive correlations with SCORing AD (SCORAD) score (r = 0.44, r = 0.45 respectively) and negligible correlations with Eczema Area and Severity Index (EASI) score and area affected (r < 0.30). DLQI score varied by sex, study country, race, age, longer disease duration, disease severity (EASI and SCORAD), presence of asthma, and Worst Pruritus NRS, Sleep disturbance NRS, and DLQI scores. Rocatinlimab showed benefit on all three PROs, with significant improvements from baseline at the end of the double-blind period (week18) and active treatment extension (week36). Benefits were maintained over 20weeks' post-treatment follow-up. The benefit of rocatinlimab treatment on PROs is rapid and maintained for at least 20weeks following treatment completion. This analysis demonstrates the importance of characterizing the burden of moderate-to-severe AD from the patient's perspective, alongside clinical disease measures, to develop a fuller picture of treatment benefit. ClinicalTrials.gov identifier, NCT03703102.

Objectives Baricitinib has shown efficacy and a favorable safety profile in randomized trials for moderate-to-severe atopic dermatitis (AD), but real-world evidence is limited. We conducted a multicenter, retrospective and prospective study aimed at evaluating the long-term effectiveness and safety profile of baricitinib in the treatment of adult patients affected from AD, with the additional goal of identifying potential predictors of treatment response. Methods We included adult AD patients treated with baricitinib between January 2023 and November 2024 at five Italian tertiary centers. Disease severity and patient-reported outcomes, including the Eczema Area and Severity Index (EASI), Body Surface Area (BSA), Itch Numeric Rating Scale (Itch-NRS), Sleep Numeric Rating Scale (Sleep-NRS), Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), and Minimal Disease Activity (MDA, defined as EASI ≤3 and Itch-NRS ≤1), were assessed at baseline and weeks 4, 16, 32, and 52. Results The 52 patients enrolled showed significant and sustained improvements in physician- (BSA, EASI) and patient-reported outcomes (Itch-NRS, Sleep-NRS, DLQI, POEM). At week 16, atopic comorbidities increased the odds of achieving MDA (OR: 10.9; p = 0.033), whereas head and neck involvement reduced the likelihood of response (OR: 0.07 p = 0.028). Thirty-two mild to moderate adverse events occurred in 28 patients, none requiring treatment discontinuation. Conclusion In this real-world study, baricitinib provided substantial long-term effectiveness with a favorable safety profile in moderate-to-severe AD, and atopic comorbidities emerged as a predictor of optimal clinical response at week 16.

Interobserver Agreement of the Eczema Area and Severity Index for Atopic Dermatitis Severity Assessment: A Real-World Evidence Study.

CBP-201 is a next-generation monoclonal antibody targeting the IL-4Rα subunit. Rapid efficacy with CBP-201 was demonstrated in global phase 2 (WW001) and China-only pivotal trials (CN002) in patients with moderate-to-severe atopic dermatitis (AD). Previous studies of AD therapy demonstrated similar efficacy between moderate and severe disease, with a trend toward greater improvement in moderate patients. It is unknown whether there are differences in clinical response to CBP-201 with moderate vs.severe AD. We report post hoc efficacy analyses at Week 16 with CBP-201 300 mg from WW001 in baseline severity subgroups, based on validated Investigator Global Assessment (vIGA™) scores of 3 (moderate) and 4 (severe). In WW001 (NCT04444752), adults with moderate-to-severe AD were enrolled in a RDBPC 16-week trial of subcutaneous CBP-201 or placebo. For post hoc analysis, data for 300 mg every 2- and 4-week dose regimens were pooled. Investigators assessed AD severity using Eczema Area and Severity Index (EASI), SCORing AD (SCORAD), percent Body Surface Area (BSA) of AD involvement and vIGA. Patient-reported outcomes were assessed with the Dermatology Life Quality Index (DLQI) and Patient Oriented Eczema Measure (POEM). Least squares mean (LSM) score changes were analysed using ANCOVA modeling (including treatment, baseline score and baseline vIGA), with missing data interpolated by last observation carried forward. Responder endpoints were analysed using Clopper–Pearson methodology and, for missing values, nonresponder imputation. P-values are for CBP-201 vs. placebo, per baseline severity subgroup, at Week 16. At baseline, 113 patients had moderate AD (n = 74 CBP-201, n = 39 placebo) and 56 patients had severe AD (n = 39 CBP-201, n = 17 placebo). Baseline EASI scores were lower in the moderate subgroup [mean (SD): CBP-201, 21.5 (7.0); placebo, 22.2 (6.3)] vs. the severe subgroup [CBP-201, 33.6 (11.9); placebo, 31.9 (10.8)]. In both the moderate and severe AD subgroups, significant improvements with CBP-201 vs. placebo were observed. Except for the proportion of patients achieving vIGA 0/1, numerically greater CBP-201 responses were observed in patients with severe vs. moderate AD at Week 16; placebo responses were comparable per subgroup. In the severe and moderate subgroups, LSM SCORAD scores decreased by −42.8% (severe) and −29.8% (moderate), and LSM percent BSA decreased by −29.8% and −17.3%, respectively. Clinically meaningful 2-point improvement in vIGA was reported for 48.7% and 27.0% of patients with severe and moderate AD, respectively. The proportions of patients achieving vIGA 0/1, with 2-point improvement, were 20.5% and 27.0% with severe and moderate AD, respectively. Numerically greater proportions of patients with severe vs. moderate AD experienced EASI responses with CBP-201: EASI-50, 66.7% vs. 54.1%; EASI-75, 53.8% vs. 39.2%; EASI-90, 28.2% vs. 23.0%. Patients with severe vs. moderate AD reported greater improvements in patient reported outcomes with CBP-201: DLQI, −8.7 vs. −7.0; POEM, −12.5 vs. −8.7. Clinically meaningful improvements were observed in patients with AD with either moderate or severe AD after 16 weeks of treatment with CBP-201 300 mg at either 2- or 4-week dosing. There were no differences noted between moderate and severe patients in the placebo treatment group. In most severity readouts, greater proportions of patients with AD with severe disease on study entry experienced clinically meaningful improvements with CBP-201. In future CBP-201 trials, a more severe AD population needs to be examined to determine if this same observation is also noted. Collectively, the WW001 findings support further investigation of CBP-201, at both the 2- and 4-week dosing schedules enrolling larger numbers of moderate and severe patients with AD and with prespecified analyses by baseline AD severity.

Atopic dermatitis (AD) is a common chronic inflammatory disease that places a large burden on the patients, their families and society.1 For all clinical trials for AD, the Harmonizing Outcome Measures for Eczema (HOME) initiative recommended the Eczema Area and Severity Index (EASI) for assessing signs of AD.2 An objective measure to evaluate treatment effect is usually required from regulatory agencies. EASI is therefore commonly used in addition to instruments which assess other domains such as symptoms, control of AD and quality of life. Recently, EASI has been recommended for clinical practice and is used in numerous AD registries globally. The study of Jacobson et al.3 summarizes the current evidence of the validity and reliability of EASI, assessing all relevant measurement properties across different populations. The authors have conducted this important work in a methodologically excellent manner. Their research adheres to COSMIN4 guidelines for patient-reported outcome measures. The study of Jacobson et al.3 is therefore of great importance, as the worldwide widespread use of the EASI requires in depth knowledge of its validity across varying groups of individuals with AD, as well as awareness of the possible limitations in certain populations in order to ensure correct interpretation of outcomes. Despite the initial selection of EASI by the HOME group, the need of further validation studies had been pointed out.2 For example, there was a lack of evidence on the interpretability and feasibility of EASI.2 The recent paper by Jacobson et al.3 explores whether these questions still persist; and answer new occurring questions about the validity in varying groups of individuals with AD defined by severity, age and skin phototype. In severe AD, EASI is considered as valid, while in mild AD, changes in severity might be difficult to assess.5 In mild AD, the measurement error was greater than the MIC and a floor effect has been observed in this subset of patients with mild AD. For individuals with melanin-rich skin, further validation studies might be needed to correctly calculate and interpret the EASI, as the current evidence is still limited although promising. Questions pertain regarding the interpretability of the EASI. Although evaluated in studies with excellent study design, variations in severity strata across different studies suggest that the interpretation of EASI might benefit from further studies for developing strata. EASI is generally considered feasible, especially when performed by trained investigators. The increasing use of EASI in clinical trials, clinical practice and registries has created a demand for technological adaptations and applications. The findings of the Jacobson et al.3 are of high importance for all clinical trials, registries and for clinicians treating children and adults with AD as they help to interpret results from the EASI and highlight remaining challenges. This research fills existing validation gaps and highlights a few remaining questions which are needed to measure outcomes appropriately in children in both clinical trials and routine and thus promote excellence in research and patient care. The results of the current study will enable well-designed studies that are able to address questions which otherwise remain unsolved. None. The authors have no conflict of interest to declare. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Lebrikizumab, a monoclonal antibody targeting interleukin (IL)-13, has demonstrated efficacy and safety in phase III trials for moderate-to-severe atopic dermatitis (AD). However, long-term real-world evidence, particularly in European populations and in difficult-to-treat areas such as the head and neck, remains limited. This study evaluated the 52-week real-world effectiveness and safety of lebrikizumab in patients with moderate-to-severe AD. This retrospective, two-center study included adults and adolescents treated with lebrikizumab according to the approved label. Clinical assessments were performed at baseline and weeks 16, 24, and 52. Effectiveness outcomes included the Eczema Area and Severity Index (EASI) 75/90/100, absolute EASI thresholds, Investigator's Global Assessment (IGA) 0/1, patient-reported outcomes (Peak Pruritus Numerical Rating Scale [PP-NRS] and Sleep Disturbance Numerical Rating Scale [S-NRS]), and minimal disease activity (MDA) defined as the combined endpoint EASI 90 plus PP-NRS 0/1. Head and neck involvement was specifically analyzed. Safety was assessed by recording adverse events (AEs). A total of 123 patients were included (116 adults, 7 adolescents). EASI 75 was achieved by 65.0%, 68.9%, and 82.6% of patients at weeks 16, 24, and 52, respectively. EASI 90 increased from 43.9% at week 16 to 69.6% at week 52, while EASI 100 was observed in 56.5% at week 52. IGA 0/1 was achieved by 82.6% of patients at week 52. Clinically meaningful pruritus improvement (ΔPP-NRS ≥ 4) was observed in 65.2% of patients at week 52, and MDA was achieved by 56.6%. Patients with head and neck AD showed comparable clinical responses to those without involvement of this area, with a marked reduction in head and neck EASI (H&N EASI) over time. Overall, 5.7% of patients reported at least one AE, most commonly mild-to-moderate conjunctivitis, with no new safety signals. In this real-world European cohort, lebrikizumab demonstrated sustained effectiveness and a favorable safety profile over 52weeks, including in patients with head and neck involvement, supporting its long-term use in routine clinical practice.

A real-world study of the longitudinal course of skin pain in adult atopic dermatitis

Dupilumab, an IgG4 mAb targeting the IL-4 receptor alpha (IL-4Rα), substantially improves disease severity in patients with atopic dermatitis (AD) (Gooderham et al., 2018Gooderham M.J. Hong H.C. Eshtiaghi P. Papp K.A. Dupilumab: a review of its use in the treatment of atopic dermatitis.J Am Acad Dermatol. 2018; 78: S28-S36Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). A recent daily practice study indicates that dose reduction of dupilumab might be successfully applied in patients with controlled AD (Spekhorst et al., 2022Spekhorst L.S. Bakker D. Drylewicz J. Rispens T. Loeff F. Boesjes C.M. et al.Patient-centered dupilumab dosing regimen leads to successful dose reduction in persistently controlled atopic dermatitis.Allergy. 2022; 77: 3398-3407Crossref PubMed Scopus (12) Google Scholar). Spekhorst et al., 2022Spekhorst L.S. Bakker D. Drylewicz J. Rispens T. Loeff F. Boesjes C.M. et al.Patient-centered dupilumab dosing regimen leads to successful dose reduction in persistently controlled atopic dermatitis.Allergy. 2022; 77: 3398-3407Crossref PubMed Scopus (12) Google Scholar showed that prolongation of the injection interval up to 6 weeks resulted in sustained disease control in patients with AD with low disease activity after 52 weeks of dupilumab treatment. However, the associated immunologic effects of interval prolongation are currently unknown. Therefore, we studied the effects of interval prolongation on dupilumab serum levels, the IL-4Rα occupancy, (skin-homing) T-cell function, and serum thymus and regulated chemokine levels in patients with AD in whom the dupilumab interval was prolonged. All included patients participated in the Dutch BioDay registry and signed informed consent for extraction of data from the registry. In addition, all included patients gave their consent for collection of blood samples during the treatment according to our biobank protocol, which has been approved by the Medical Ethical Committee of the University Medical Center Utrecht (approval number 17-884). After 1 year of treatment with the standard dose of dupilumab, the dosing interval was prolonged according to the protocol described previously (Spekhorst et al., 2022Spekhorst L.S. Bakker D. Drylewicz J. Rispens T. Loeff F. Boesjes C.M. et al.Patient-centered dupilumab dosing regimen leads to successful dose reduction in persistently controlled atopic dermatitis.Allergy. 2022; 77: 3398-3407Crossref PubMed Scopus (12) Google Scholar). In brief, a patient-centered dosing regimen that is guided by the Eczema Area and Severity Index (EASI) was applied, in which patients were eligible for dose reduction in cases of EASI ≤ 7, indicating mild disease activity or less, for at least 6 months. Patients with AD who prolonged the interval from 300 mg dupilumab subcutaneously every 2 weeks (Q2W) to every 4 weeks (Q4W), and eventually every 6 weeks (Q6W), were retrospectively enrolled in this study. Blood samples were collected from patients before the initiation of treatment (baseline) and during treatment at time points when patients were treated with dupilumab Q2W, Q4W, and Q6W for at least 3 months. PBMCs from a total of 11 patients and healthy controls were available for analyses. The EASI was used to assess disease severity and to evaluate clinical effectiveness. In addition, serum thymus and regulated chemokine levels, currently the best performing and most accepted biomarker for disease severity in AD (Thijs et al., 2015Thijs J. Krastev T. Weidinger S. Buckens C.F. de Bruin-Weller M. Bruijnzeel-Koomen C. et al.Biomarkers for atopic dermatitis: a systematic review and meta-analysis.Curr Opin Allergy Clin Immunol. 2015; 15: 453-460Crossref PubMed Scopus (162) Google Scholar), were measured. PBMCs were isolated and analyzed using flow cytometry. The quantification of total dupilumab levels in serum was performed with a validated liquid chromatography-tandem mass spectrometry analysis (Amrani et al., 2021Amrani M.E. Gerencser L. Huitema A.D.R. Hack C.E. van Luin M. van der Elst K.C.M. A generic sample preparation method for the multiplex analysis of seven therapeutic monoclonal antibodies in human plasma or serum with liquid chromatography-tandem mass spectrometry.J Chromatogr A. 2021; 1655: 462489Crossref PubMed Scopus (10) Google Scholar). Detailed methods related to laboratory assessments and statistical analysis are described in this letter's online repository. We included a total of 11 patients with AD. All clinical characteristics are shown in Table 1. In addition, a total of 11 healthy adult volunteers were included in the analyses. An overview of the study design, peripheral blood collection, and laboratory assessments is presented in Figure 1a.Table 1Baseline CharacteristicsClinical CharacteristicsTapering Patients (n = 11)Healthy Control (n = 11)Age at start, y, median (IQR)37 (33–49.5)29 (27–31)Male, n (%)6 (54.54)4 (36.36)Atopic comorbidities, n (%) Allergic asthma4 (36.36)— Allergic rhinitis10 (90.90)— Allergic conjunctivitis7 (63.63)— No atopic comorbidities1 (9.09)—Food allergy, n (%)7 (63.63)—Age of onset, n (%) Children8 (72.72)— Adolescent2 (18.18)— Adult1 (9.09)—Previous use of systemic immunosuppressive medication Cyclosporine10 (90.90)— Methotrexate4 (36.36)— Azathioprine1 (9.09)— Mycophenolate mofetil1 (9.09)—EASI score at baseline, median (IQR)12.00 (9.40–24.5)— EASI score at prolongation to Q4W, median (IQR)0.95 (0.57–2.87)— EASI score at prolongation to Q6W, median (IQR)1.10 (0.82–1.92)—TARC levels at baseline, median (IQR)1392 (779–4272)—Median duration on interval in days (IQR)— 1×/2 wk366 (112–376) 1×/4 wk210 (178–285) 1×/6 wk178 (98–191)Abbreviations: EASI, Eczema Area Severity Index; IQR, interquartile range; Q4W, every 4 weeks; Q6W, every 6 weeks. Open table in a new tab Abbreviations: EASI, Eczema Area Severity Index; IQR, interquartile range; Q4W, every 4 weeks; Q6W, every 6 weeks. As expected, the dupilumab interval prolongation resulted in a significant decrease in dupilumab serum levels in all patients (Figure 1b). Dupilumab surface binding (anti-IgG4) to both CD19+ B cells and CD4+ T cells also gradually decreased with interval prolongation. During treatment with dupilumab Q2W and Q4W, IL-4Rα expression remained undetectable, regardless of the number of days between the last dupilumab injection and the blood draw, and despite lower levels of dupilumab in the serum for the Q4W interval. Importantly, during treatment with dupilumab Q6W, the IL-4Rα became fully or partly detectable again if the time between the injection of dupilumab and the blood draw was 40 days or longer (Figure 1c). These results indicate that around an interval of 40 days, a tipping point occurs where dupilumab is no longer (fully) saturating IL-4Rα on circulating lymphocytes. This was accompanied by clinical and immunological changes. A significant decrease in EASI scores was seen during all dosing intervals compared with baseline, but EASI scores slightly increased in 8 of 11 patients when extending the interval from Q4W to Q6W (Figure 1d). The same applied to serum thymus and regulated chemokine levels (Figure 1e). In addition, IL-4 and IL-13 levels increased slightly during interval prolongation in some patients, and the percentage of proliferating (Ki67+) skin-homing (C-C chemokine receptor type 4 +, Cutaneous Lymphocyte Antigen +) CD4+ T cells increased significantly when extending the interval from Q4W to Q6W (Figure 1f). No significant changes were found in the production of T helper types 1, 17, and 22-related cytokines by skin-homing T cells during interval prolongation (data not shown). This study confirms the strong functional immunological effects of dupilumab treatment as previously presented by Bakker et al., 2021Bakker D.S. van der Wal M.M. Heeb L.E.M. Giovannone B. Asamoah M. Delemarre E.M. et al.Early and long-term effects of dupilumab treatment on circulating T-cell functions in patients with moderate-to-severe atopic dermatitis.J Invest Dermatol. 2021; 141: 1943-1953.e13Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar. Complementary to this study, we showed that the IL-4Rα was still undetectable when prolonging the interval from Q2W to Q4W, regardless of the number of days since the latest injection of dupilumab. There seems to be a clear tipping point within Q4W to Q6W at which the receptor becomes detectable again. This is likely the result of reduced dupilumab binding, but additional changes in surface IL-4Rα receptor expression upon dupilumab withdrawal cannot be ruled out. Although no signs of receptor internalization or reduced expression of the receptor were observed in the previous study by Bakker et al., 2021Bakker D.S. van der Wal M.M. Heeb L.E.M. Giovannone B. Asamoah M. Delemarre E.M. et al.Early and long-term effects of dupilumab treatment on circulating T-cell functions in patients with moderate-to-severe atopic dermatitis.J Invest Dermatol. 2021; 141: 1943-1953.e13Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, the recently published study by Heeb and Boyman, 2023Heeb L.E.M. Boyman O. Comprehensive analysis of human IL -4 receptor subunits shows compartmentalization in steady state and dupilumab treatment.Allergy. 2023; 78: 1073-1087Crossref PubMed Scopus (7) Google Scholar shows that engagement of IL-4Rα by dupilumab may result in the internalization of the antibody and decreased total IL-4Rα expression. IL-4Rα surface expression may therefore be restored when dupilumab serum levels drop. In the 3 patients of our cohort in whom the IL-4Rα became detectable again during Q6W, the lowest levels of dupilumab in serum were measured. This suggests that a certain concentration of dupilumab in the serum is required for IL-4Rα saturation. Our clinical experience after using this protocol for several years is that patients treated with dupilumab Q6W often report symptoms such as redness and itch in the week before the new dupilumab injection should be given. This is in line with the returning detectability of the IL-4Rα after 40 days. In addition, there are some patients in whom it seems impossible to extend the interval to longer than 2 weeks to maintain good clinical effects. It could be hypothesized that one of the mechanisms for the lack of response includes subtherapeutic drug concentrations secondary to enhanced clearance. For future research, it would be interesting to examine these patient groups to further optimize biologic therapy. In conclusion, our study supports the idea to consider interval prolongation of dupilumab from Q2W to Q4W in patients with AD in whom the disease is well-controlled. The transition from dupilumab Q4W to Q6W seems to be an important biological tipping point and marks the window through which disease activity may show the first signs of relapse, at least in some patients. All included patients participated in the Dutch BioDay registry and signed informed consent for extraction of data from the registry. In addition, all included patients gave their consent for collection of blood samples during the treatment according to our biobank protocol, which has been approved by the Medical Ethical Committee of the University Medical Center Utrecht (approval number 17-884). The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. No large datasets were generated and/or analyzed during the current study. Coco Dekkers: http://orcid.org/0000-0002-2344-6860 M. Marlot van der Wal: http://orcid.org/0000-0003-4554-9059 Mohsin El Amrani: http://orcid.org/0000-0001-8276-0860 Matthijs van Luin: http://orcid.org/0000-0001-6172-887X Daphne S. Bakker: http://orcid.org/0000-0002-0193-5794 Marjolein de Bruin-Weller: http://orcid.org/0000-0002-1249-6993 Femke van Wijk: http://orcid.org/0000-0001-8343-1356 DSB is a speaker for Sanofi Genzyme, Janssen, and Leo Pharma. MB is a consultant, advisory board member, and/or speaker for AbbVie, Almirall, Arena, Aslan, Eli Lilly, Galderma, Janssen, Leo Pharma, Pfizer, Regeneron, and Sanofi Genzyme. FW is a speaker and/or consultant for Janssen, Johnson & Johnson, and Takeda. She has received research funding from Leo Pharma, Takeda, Galapagos, Sanofi, and Bristol-Myers Squibb, all unrelated to this research. The remaining authors state no conflict of interest. CD, MMVDW, MEA, MVL, DSB, MDBW, and FVW have made substantial contributions to conception and design, the acquisition of data, or the analysis and interpretation of data. All authors have been involved in drafting the manuscript or revising it critically and have given their final approval of the version to be published. Patients included in this manuscript participated in the BioDay registry sponsored by Sanofi Genzyme. Conceptualization: CD, MMVDW, DSB, MDBW, FVW; Formal Analysis: CD, MMVDW, MEA; Funding Acquisition: FVW, MDBW; Investigation: CD, MMVDW, MEA; Methodology: MMVDW, MEA; Resources: CD, MMVDW, MEA; Supervision: MDBW, FVW; Validation: FVW; Visualization: CD, MMVDW; Writing - Original Draft Preparation: CD, MMVDW; Writing - Review and Editing: MEA, MVL, DSB, MDBW, FVW All included patients participated in the Dutch BioDay registry, which is a large prospective registry that contains daily practice data regarding dupilumab for the treatment of atopic dermatitis (ClinicalTrials.gov identifier: NCT03549416, retrospectively registered 08 June 2018). All patients were treated with dupilumab in daily practice under our biobank protocol, which has been approved by the Medical Ethical Committee of the University Medical Center Utrecht (approval number 17-884), and gave their consent for the collection of blood samples during treatment. At baseline, patients received a loading dose of 600 mg dupilumab, followed by a standard maintenance dose of 300 mg dupilumab every 2 weeks during the first year of treatment. After 1 year of treatment with the standard dose of dupilumab, the dosing interval was prolonged according to the protocol described previously (Spekhorst et al., 2022Spekhorst L.S. Bakker D. Drylewicz J. Rispens T. Loeff F. Boesjes C.M. et al.Patient-centered dupilumab dosing regimen leads to successful dose reduction in persistently controlled atopic dermatitis.Allergy. 2022; 77: 3398-3407Crossref PubMed Scopus (12) Google Scholar). The injection intervals were stepwise prolonged and guided by the Eczema Area and Severity Index score. In the case of an Eczema Area and Severity Index ≤ 7, indicating mild disease activity or less, for at least 6 months, patients were eligible for dose reduction. If patients remained in a state of controlled disease (Eczema Area and Severity Index ≤ 7), the dosage was further reduced. At any time, the actual decision for dose reduction of dupilumab was based on shared decision-making between the patient and the physician. Patients with moderate-to-severe atopic dermatitis prolonged the interval from 300 mg dupilumab subcutaneously every 2 weeks to 300 mg dupilumab subcutaneously every 4 weeks, and eventually 300 mg dupilumab subcutaneously every 6 weeks, were retrospectively enrolled in this longitudinal study. Blood samples were collected from patients before initiation of dupilumab treatment (baseline) and during dupilumab treatment at time points when patients were treated with dupilumab every 2, 4, and 6 weeks for at least 3 months. From a total of 11 patients, PBMCs as well as serum samples were available for analyses. Blood samples from 11 healthy adult volunteers without atopic dermatitis or any other atopic disease were obtained from the Mini Donor Service at the University Medical Center Utrecht, The Netherlands. Clinical data were extracted from the BioDay registry. All patients signed written informed consent, adhering to the principles of the Declaration of Helsinki. The Eczema Area and Severity Index score was used to assess disease severity and to evaluate the clinical effectiveness. In addition, thymus and regulated chemokine levels, currently the best performing and most accepted biomarker for disease severity in atopic dermatitis (Thijs et al., 2015Thijs J. Krastev T. Weidinger S. Buckens C.F. de Bruin-Weller M. Bruijnzeel-Koomen C. et al.Biomarkers for atopic dermatitis: a systematic review and meta-analysis.Curr Opin Allergy Clin Immunol. 2015; 15: 453-460Crossref PubMed Scopus (162) Google Scholar), were measured in routine care using Quantikine ELISA immunoassays (R&D Systems, Minneapolis, MN). PBMCs were isolated using Ficoll-Paque (GE Healthcare, Eindhoven, The Netherlands) density gradient centrifugation. PBMCs were frozen in RPMI 1640 medium supplemented with 2 mM L-glutamine, 100 IU/ml penicillin-streptomycin, 20% fetal bovine serum, and 10% DMSO (Sigma-Aldrich, Saint Louis, MO), and stored at −196 °C until use. PBMCs were thawed in a 37 °C water bath, washed, and resuspended in RPMI 1640 medium (Gibco, Grand Island, NY) containing 10% fetal bovine serum with the addition of L-glutamine and penicillin-streptomycin. 1,000,000 PBMCs were plated in round-bottom 96-well plates. To determine cell death, eBioscience Fixable Viability Dye eFluor 506 (Invitrogen, Carlsbad, CA) in PBS was used. Surface staining of multiple T- and B-cell markers (Supplementary Tables S1 and S2) was performed for 25 minutes at 4 °C. Surface staining of IL-4 receptor alpha (CD124) phycoerythrin (PE) was performed for 25 minutes at 37 °C. For intracellular and nuclear staining, cells were fixed and permeabilized using eBioscience Fixation and Permeabilization buffers (Invitrogen) and stained for Ki67 AF467. For intracellular cytokine production, cells were first stimulated with phorbol 12-myristate 13-acetate (20 ng/ml) (Sigma-Aldrich, Saint Louis, MO) and ionomycin (1.0 mg/ml) (Sigma-Aldrich, Saint Louis, MO) for a total of 4 hours. Golgistop (1/1,500) (BD Biosciences, San Jose, CA) was added for the last 3.5 hours of cell culture. Afterward, cells were incubated with the fixable viability dye and surface antibodies (Supplementary Tables S3 and S4) and then fixed, permeabilized, and intracellularly stained with IFN-γ PE-Cy7, IL-4 BV711, IL-5 PE, IL-13 PerCP-Cy5.5, IL-17A APC, IL-22 APC, and TNF-α PE-Cy7. Stained cells were resuspended in PBS containing 2% FBS and 0.1% sodium azide (Sigma-Aldrich). Data acquisition was performed on a FACS LSR Fortessa (BD Biosciences), and data were analyzed using FlowJo Software (version 10.8) (Tree Star, Ashland, OR). The quantification of total dupilumab levels in serum was performed with a validated liquid chromatography-tandem mass spectrometry analysis at the department of Clinical Pharmacy (UMC Utrecht, The Netherlands) (Amrani et al., 2021Amrani M.E. Gerencser L. Huitema A.D.R. Hack C.E. van Luin M. van der Elst K.C.M. A generic sample preparation method for the multiplex analysis of seven therapeutic monoclonal antibodies in human plasma or serum with liquid chromatography-tandem mass spectrometry.J Chromatogr A. 2021; 1655: 462489Crossref PubMed Scopus (10) Google Scholar). Statistical analyses were performed using SPSS (for Windows, version 25.0, SPSS, Chicago, IL) and Prism (version 9.3.463, GraphPad Software, San Diego, CA). For the comparison of healthy controls with tapering patients or disease controls, the chi-square test was used for categorical variables and the Mann-Whitney U test was used for continuous variables. The Wilcoxon signed-rank test was used to compare two continuous variables in the same patients. P-values < 0.05 were considered statistically significant.Supplementary Table S1Flowcytometry Panel Overview (Panel 3)Antigen/TargetFluorochromeCloneDilutionCompanyCatalog NumberFixable Viability DyeeF506—1000Thermo Fisher Scientific15560607CD3BV605UCHT1100BioLegend300460CD4BV785RPA-T450BioLegend300554CD8APC-Cy7SK150BD557834CD45ROECDUCHL112.5Beckman CoulterB49192CLAPBHECA-452200BioLegend321308CCR4FITC20541016.7R&DFAB1567FKi67AF647B5650BD558615 Open table in a new tab Supplementary Table S2Flowcytometry Panel Overview (Panel 4)Antigen/TargetFluorochromeCloneDilutionCompanyCatalog NumberFixable Viability DyeeF780—1000Thermo Fisher Scientific13539140CD3BV605UCHT1100BioLegend300460CD4BV785RPA-T450BioLegend300554CD8PE-Cy7SK1200BD335822CD19AF700HIB1950eBioscience56-0199-42IL-4Ra (CD124)PEG077F650BioLegend355004IgG4BiotinHP602550InvitrogenA10663StreptavidineAPC—100Thermo Fisher Scientific17-4317 Open table in a new tab Supplementary Table S3Flowcytometry Panel Overview (Panel 1)Antigen/TargetFluorochromeCloneDilutionCompanyCatalog NumberFixable Viability DyeeF506—1000Thermo Fisher Scientific15560607CD3BV605UCHT1100BioLegend300460CD4BV785RPA-T450BioLegend300554CD8APC-Cy7SK150BD557834CLAPBHECA-452200BioLegend321308CCR4FITC20541016.7R&DFAB1567FCCR10PE31430550R&DFAB3478PIL-4BV711MP4-25D212.5BD564112IL-13PerCP-Cy5.5JES10-5A250Sony Biotechnology3109555IL-22APCIL22JOP40Thermo Fisher Scientific17-7222IFNyPE-Cy74S.B3200BD557844 Open table in a new tab Supplementary Table S4Flowcytometry Panel Overview (Panel 2)Antigen/TargetFluorochromeCloneDilutionCompanyCatalog NumberFixable Viability DyeeF506—1000Thermo Fisher Scientific15560607CD3BV605UCHT1100BioLegend300460CD4BV785RPA-T450BioLegend300554CD8APC-Cy7SK150BD557834CLAPBHECA-452200BioLegend321308CCR4FITC20541016.7R&DFAB1567FIL-5PEJES1-39D1050BioLegend500904IL-17AAPCBL16850BioLegend512333TNFaPE-Cy7Mab11400eBioscience25-7349-82 Open table in a new tab