48-Week Real-World Outcomes of Lebrikizumab Treatment for Atopic Dermatitis: Systemic Therapy-Naive Versus -Experienced Patients.

Sustainability of Early Responses and Achievement of Delayed Responses to Lebrikizumab in Atopic Dermatitis: A 48-Week Japanese Real-World Study.

The main conventional systemic treatments for atopic eczema are methotrexate (MTX) and ciclosporin (CIC). Dupilumab was the first novel systemic agent to enter routine clinical practice. There are no head-to-head randomized controlled trials or real-world studies comparing these agents directly. The aim of this study was to compare the real-world clinical effectiveness and safety of CIC, dupilumab and MTX in atopic eczema. We compared the treatment effectiveness and safety of these systemic agents in a prospective cohort study of adult and paediatric patients recruited into the UK-Irish Atopic Eczema Systemic TherApy Register (A-STAR). Treatment effectiveness measures included Eczema Area and Severity Index (EASI), Patient-Oriented Eczema Measure (POEM), Peak Pruritus Numerical Rating Scale (PP-NRS), Dermatology Life Quality Index (DLQI) and children’s DLQI (cDLQI). The minimum duration of treatment was 28 days, and follow-up was 12 months. Adjusted Cox regression was used to compare the hazards of achieving EASI 50, EASI 75 and EASI 90 (≥ 50%, ≥ 75 and ≥ 90% improvement from baseline) over time, and linear mixed-effects models were used to estimate changes in effectiveness scores. Treatment safety was assessed by examining adverse events at follow-up visits. In total, 488 patients were included: 282 on dupilumab, 149 on MTX and 57 on CIC. CIC and MTX were primarily used first line, while dupilumab was mainly used second line. EASI 50, EASI 75 and EASI 90 were achieved more rapidly in the dupilumab and CIC groups compared with MTX (Table). After adjustment for previous severity, the reductions in EASI, POEM, PP-NRS and DLQI were greater for patients treated with dupilumab compared with MTX. In patients with severe disease the reductions in EASI, POEM and PP-NRS were even greater with CIC. Seven of 13 serious adverse events (SAEs) occurred in 7 of 282 (2%) patients on dupilumab, including 1 event that was considered treatment related: a herpes simplex infection. There were 6 of 13 SAEs reported in 6 of 149 (4%) patients on MTX, including 2 events that were considered treatment related: one herpes simplex infection and 1 joint effusion. There were no SAEs reported in the 57 patients on CIC. This real-world comparison of CIC, dupilumab and MTX in atopic eczema suggests that dupilumab is consistently more effective than MTX, and that CIC is most effective in very severe disease within one follow-up year.TableHazard ratios and 95% confidence intervals between treatment groups of patients achieving EASI 50, EASI 75 and EASI 90ComparisonEASI 50EASI 75EASI 90Dupilumab – methotrexate1.31 (0.93–1.85), P = 0.121.55 (1.02–2.36), P = 0.043.04 (1.53–6.04), P = 0.002Ciclosporin – methotrexate2.22 (1.42–3.47), P < 0.0011.97 (1.11–3.50), P = 0.024.24 (1.86–9.62), P < 0.001Ciclosporin – dupilumab1.69 (1.12–2.57), P = 0.011.27 (0.75–2.17), P = 0.381.39 (0.71–2.73), P = 0.33

Upadacitinib, a Janus kinase 1 (JAK1) inhibitor, is effective for moderate-to-severe atopic dermatitis (AD). Upadacitinib treatment may be discontinued in some patients; however, the effectiveness and safety of retreatment after its withdrawal have not been examined in detail in real-world practice. To evaluate the effectiveness and safety of upadacitinib retreatment after withdrawal in real-world clinical practice for Japanese patients with AD. This retrospective study included 62 Japanese patients with moderate-to-severe AD treated with upadacitinib 15 mg (n = 38) or 30 mg (n = 24). Effectiveness was assessed using the Eczema Area and Severity Index (EASI) and Peak Pruritus Numerical Rating Scale (PP-NRS) before treatment (baseline), at timepoints of discontinuation, at retreatment, and at week 12 after retreatment with upadacitinib. Safety was evaluated through the incidence of treatment-emergent adverse events (TEAEs). EASI and PP-NRS scores significantly decreased at week 12 after upadacitinib retreatment compared with baseline in both the 15-mg and 30-mg groups (P = 0.01 for EASI and PP-NRS in both groups). At week 12 after retreatment, achievement rates of at least a 75%, 90% or 100% reduction in EASI from baseline (EASI 75, EASI 90 or EASI 100, respectively) were 84%, 57% and 19% in the 15-mg group, and 87%, 57% and 17% in the 30-mg group, respectively. TEAEs were mild or moderate, and no serious AEs or deaths were reported. Retreatment with upadacitinib after withdrawal effectively improved clinical signs and pruritus in patients with AD, with a manageable safety profile, supporting its use for long-term management of AD.

Maintenance of Early Responses and Delayed Responses to Tralokinumab Treatment in Moderate-to-Severe Atopic Dermatitis: A 48-Week Real-World Study.

Primary results of the JADE DARE trial (NCT04345367) demonstrated that abrocitinib was superior to dupilumab in reducing the signs and symptoms of moderate-to-severe atopic dermatitis (AD). This post hoc analysis evaluated the efficacy and safety of abrocitinib in patients with moderate-to-severe AD who were responders or nonresponders to dupilumab using various definitions of response. Data included dupilumab-treated patients from JADE DARE who switched to abrocitinib 200mg when enrolled in the ongoing JADE EXTEND trial (NCT03422822). For this analysis, various response criteria at Week 26 of JADE DARE were defined post hoc based on Investigator's Global Assessment (IGA), Eczema Area and Severity Index (EASI), Peak Pruritus Numerical Rating Scale (PP-NRS), and Dermatology Life Quality Index (DLQI) scores or responses. Efficacy was analyzed at Week 12 of JADE EXTEND based on patients' fulfillment of the various response criteria at Week 26 of JADE DARE. EASI scores and percentage changes from baseline in EASI and PP-NRS at Week 26 in JADE DARE were compared with the corresponding scores and percentage changes at Week 12 in EXTEND. Safety was assessed. Of 365 dupilumab-treated patients in JADE DARE, 316 were enrolled in JADE EXTEND and 312 received abrocitinib 200mg. Most dupilumab responders for IGA, EASI, PP-NRS, and DLQI at DARE Week 26 maintained their responses 12weeks after switching to abrocitinib, while a considerable proportion of IGA, EASI, PP-NRS, or DLQI dupilumab nonresponders gained response after switching to abrocitinib. Lower EASI scores and greater percentage changes from baseline in EASI and PP-NRS scores were observed with abrocitinib at EXTEND Week 12 than with dupilumab at DARE Week 26. No new safety signals were observed. Abrocitinib 200mg may be an effective treatment option for patients with moderate-to-severe AD who do not achieve an optimal response with dupilumab treatment. Clinicaltrials.gov: NCT04345367 (JADE DARE) and NCT03422822 (JADE EXTEND).

Atopic dermatitis is characterized by persistent eczema and pruritus. Janus kinase inhibitors, including upadacitinib, are effective treatments for moderate-to-severe atopic dermatitis. If patients do not respond well to a certain dose of a Janus kinase inhibitor, increasing the dose may improve their treatment responsiveness. We assessed the outcomes of a dose increase in upadacitinib from 15 mg to 30 mg for Japanese patients with moderate-to-severe atopic dermatitis. In 23 patients who showed insufficient responses to upadacitinib 15-mg treatment, the dose of upadacitinib was increased to 30 mg. We evaluated total Eczema Area and Severity Index (EASI), EASI on the head and neck, trunk, upper, or lower limbs, EASI of erythema, edema/papulation, excoriation, or lichenification, and Peak Pruritus Numerical-Rating Scale at baseline (onset of upadactinib 15 mg), week 0 (time of increase), and weeks 4 and 12 after the increase. Total EASI, EASI on each anatomical site, EASI of each clinical sign, and Peak Pruritus Numerical-Rating Scale were markedly reduced at weeks 4 or 12 compared with week 0. After the dose increase, the achievement rates of EASI 75 and EASI 90 significantly improved; EASI 75 4.3%, 68.2%, and 66.7%; EASI 90 0%, 18.2%, and 38.1% at weeks 0, 4, and 12, respectively. These results suggest that upadacitinib 30 mg can ameliorate rash and pruritus insufficiently improved by upadacitinib 15 mg, and that the dose increase to 30 mg may be considered as atreatment option for patients with atopic dermatitis with a limited response to upadacitinib 15 mg.

Atopic dermatitis (AD) is a chronic skin disease characterized by type 2-skewed immune responses, and significantly influenced by cytokines dependent on Janus kinases (JAKs). Upadacitinib, a JAK1 inhibitor, is effective for moderate-to-severe AD. This study aims to identify biomarkers that reflect long-term therapeutic effects of upadacitinib 15 mg or 30 mg. A retrospective study from August 2021 to July 2023 included 213 AD patients treated with upadacitinib 15 mg and 70 AD patients with 30 mg. We analyzed eczema area and severity index (EASI), peak pruritus-numerical rating scale (PP-NRS), serum immunoglobulin E (IgE), thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), and total eosinophil count (TEC) at weeks 0, 4, 12, 24, 36, and 48 of treatment. Both treatments with upadacitinib 15 mg and 30 mg significantly reduced EASI and PP-NRS scores over week 4 to 48 compared to baseline. Upadacitinib 15 mg or 30 mg treatment significantly decreased TEC compared to baseline through week 4 to 36 or week 4 to 48, respectively. The percent reduction of TEC correlated with those of EASI and PP-NRS through week 4 to 48 of treatment with upadacitinib 15 mg, or through week 12 to 48 with 30 mg, respectively. After adjusting for % reductions of other laboratory markers, the significance of correlations was preserved at weeks 36 and 48 of 15 mg treatment, while at weeks 4 and 36 of 30 mg treatment. The % reduction of TEC correlated with those of EASI and PP-NRS during upadacitinib treatment, indicating its potential as a biomarker reflecting treatment responses to upadacitinib in AD patients. However, the variability of significant correlation during treatment indicates that further inspection is needed for its usefulness in monitoring responses to upadacitinib treatment for AD.

PurposeTo investigate the therapeutic effectiveness and safety of Janus kinase 1 inhibitor upadacitinib in adolescent patients with atopic dermatitis (AD).Patients and MethodsThis study examined therapeutic effectiveness and safety of upadacitinib for 39 Japanese adolescent patients (aged 12–17 years) diagnosed with moderate-to-severe AD from August 2021 to January 2023. The patients were treated with upadacitinib 15 mg/day plus twice daily topical corticosteroids. Total eczema area and severity index (EASI) or EASI on head and neck, upper limbs, lower limbs, and trunk or for erythema, edema/papulation, excoriation, or lichenification, atopic dermatitis control tool (ADCT), peak pruritus-numerical rating scale (PP-NRS), and laboratory indexes were assessed at weeks 0, 4, and 12 of treatment. Treatment-emergent adverse events were recorded.ResultsTotal EASI or EASI on 4 anatomical sites or for 4 rash types, ADCT, and PP-NRS were significantly reduced at week 4 and 12 compared to week 0. The achievement rates at weeks 4 or 12 were 64.1% or 62.5% for EASI 75, 93.5% or 73.1% for ADCT <7-point, and 80.6% or 60% for PP-NRS ≥4-point improvement, respectively, indicating their peak at week 4 and slight decrease at week 12. The percent reduction of EASI for excoriation was higher than that for lichenification or edema/papulation at week 4 or week 12, respectively. The percent reductions of EASI for erythema and edema/papulation on head and neck were lower than those on lower limbs at week 12. Total eosinophil counts (TEC) and IgE reduced at week 4 compared to week 0 while TARC, IgE, TEC, and LDH increased at week 12 compared to week 4.ConclusionThese results suggest therapeutic effectiveness and tolerability of upadacitinib and support its therapeutic usefulness for adolescent AD patients.

Previous post hoc analyses of randomized controlled trial data demonstrated that more patients with atopic eczema (AE) on Janus kinase (JAK) inhibitors achieve ‘super response’ (defined as total or nearly total clearance of AE) compared with dupilumab. However, there is a lack of head-to-head comparisons between conventional and novel systemic medications in patients with AE achieving super response in a real-world setting. The aim of this analysis was to explore the association between systemic medications used in patients with AE and patients achieving super response in the UK–Irish Atopic Eczema Systemic Therapy Register (A-STAR). A-STAR is a multicentre prospective observational register in the UK and Ireland aimed at evaluating the real-world effectiveness and safety of systemic treatments in AE. Patients in A-STAR who initiated conventional systemics (oral or subcutaneous methotrexate or ciclosporin), dupilumab or a JAK1 inhibitor (abrocitinib or upadacitinib) were included in this analysis. The outcomes assessed were Eczema Area and Severity Index (EASI), Peak Pruritus Numerical Rating Scale (PP-NRS) and Children’s Dermatology Life Quality Index or Dermatology Life Quality Index (C/DLQI). Patients were stratified by the medications prescribed at baseline. Super response was defined as achieving ≥ 90% improvement in EASI (EASI 90), PP-NRS of 0 or 1 (PP-NRS 0/1) and C/DLQI of 0 or 1 (C/DLQI 0/1) at any timepoint during the follow-up (censored at 500 days). Cox regression was used to assess the association between systemic medication exposure and time to achieve super response. Methotrexate was used as a reference medication. Hazard ratios and 95% confidence intervals were estimated. Risk estimates were adjusted for baseline EASI, C/DLQI, PP-NRS, ethnicity, age, sex, education level, age of AE onset, number of prior systemic treatments, concomitant oral corticosteroids and Fitzpatrick skin type. In total 649 patients were included in the analysis. The medications used were methotrexate (n = 157), ciclosporin (n = 48), dupilumab (n = 299) and JAK1 inhibitors (n = 88). The patients’ mean age was 28.7 years (SD 15.6), the mean (SD) baseline EASI was 18.2 (12.3), mean (SD) baseline PP-NRS 6.5 (2.5) and mean (SD) baseline C/DLQI 14.4 (8.1). The results for the Cox regression are summarized in the Table. Using methotrexate as the reference, both dupilumab and JAK1 inhibitors were associated with significantly more patients achieving super response in crude and adjusted models. In conclusion, treatment with dupilumab and JAK1 inhibitors is associated with a higher proportion of patients with AE achieving super response, compared with methotrexate, despite these treatments being mainly used after failure of conventional systemic medication.TableAssociation between novel systemic immunomodulatory medications and achieving super response in patients with moderate-to-severe AE. Data are expressed as the hazard ratio (95% confidence interval) CrudeAdjustedMethotrexate1 (reference)1 (reference)Ciclosporin2.25 (0.59–8.52)2.79 (0.56–13.9)Dupilumab2.20 (1.04–4.69)3.03 (1.23–7.46)JAK1 inhibitors2.75 (1.58–8.36)5.89 (2.09–16.6)

Background Atopic dermatitis (AD) is a chronic eczematous disease with severe pruritus. Janus kinase (JAK) inhibitors, upadacitinib, baricitinib, and abrocitinib, are systemic treatments for AD. The outcomes of switching from one JAK inhibitor to another have not been examined. Objectives We assessed the outcomes of switching from baricitinib 4 mg to upadacitinib 30 mg in Japanese patients with moderate-to-severe AD. Methods Twenty patients treated with baricitinib 4 mg, showing insufficient response or adverse events, were switched to treatment with upadacitinib 30 mg. We evaluated total eczema area and severity index (EASI), EASI at head and neck, trunk, upper, or lower limbs, EASI of erythema, edema/papulation, excoriation, or lichenification, and peak pruritus numerical-rating scale (PP-NRS) at baseline (start of baricitinib), weeks 0 (time of switching), and 4 and 12 after switching. Results Total EASI, EASI at each anatomical site, EASI of each clinical sign, and PP-NRS were markedly reduced at weeks 4 or 12 compared to week 0. Achievement rates of more than 75% or 90% reduction of EASI from baseline significantly improved after switching. Conclusions Switching from baricitinib 4 mg to upadacitinib 30 mg effectively improved rash and pruritus.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with severe itch. The eosinophil-to-lymphocyte ratio (ELR), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) are reported to reflect itch or the severity of AD. We examined if these parameters may act as indicators for therapeutic effects of the Janus kinase 1 inhibitor upadacitinib for patients with AD in real-world clinical practice. Between August 2021 and September 2023, 65 Japanese patients (aged ≥ 12 years) with moderate to severe AD were treated with 15 mg/day of oral upadacitinib, plus twice daily topical corticosteroids. Before treatment, the baseline ELR, NLR, MLR, and PLR levels positively correlated with the eczema area and severity index (EASI), while the baseline NLR and PLR levels positively correlated with the peak pruritus-numerical rating scale (PP-NRS). After upadacitinib treatment, ELR and NLR remarkably decreased at week 4 and the reduced levels were maintained until week 24, in parallel with EASI and PP-NRS, while MLR and PLR transiently reduced at week 4, but returned to baseline levels after week 12. The percent reduction of ELR significantly correlated with the percent reductions of EASI and PP-NRS at weeks 4, 12, and 24 of upadacitinib treatment. ELR may act as an indicator for the improvement of clinical signs and itch by upadacitinib treatment in AD.

Relationship between EASI and SCORAD severity assessments for atopic dermatitis

Background:The pathogenesis of atopic dermatitis (AD) involves various mediators, including cytokines and chemokines, which are produced by immune cells, such as dendritic cells and lymphocytes, and non-immune cells, such as epidermal cells. Several mediators, including thymus and activation-regulated chemokine (TARC), are used as biomarkers for AD severity and activity. However, additional local and systemic biomarkers of AD are required.Methods:This study will include 10 male patients with AD and 5 healthy adult males (age range: 20–80 years). The Eczema Area and Severity Index will be used to objectively evaluate the clinical findings. In addition, the severity of eruptions will be assessed on a 5-point scale by scoring symptoms (erythema, edema/papules, oozing/crusting, excoriation, lichenification, and xerosis), and the total intensity will be calculated by adding the symptom scores together. Subjective symptoms will be assessed using a peak pruritus numerical rating scale. Laboratory tests, including measurements of peripheral eosinophil count and serum total immunoglobulin E, TARC, and lactate dehydrogenase levels, will be performed. Using blood samples and extracts of stratum corneum samples obtained by tape stripping, we will conduct an exploratory analysis of protein expression using an antibody array to identify mediators whose levels are significantly altered in patients with AD. After 4 to 8 weeks, blood samples and stratum corneum samples will be collected again from AD patients. Moreover, we will examine whether the candidate proteins can be quantified using enzyme-linked immunosorbent assays.Discussion:This is an important study exploring potential local and systemic biomarkers of AD. The results of this study will be clinically meaningful for the discovery of new biomarkers for diagnosing and assessing the severity of AD.

Background. Atopic dermatitis control tool (ADCT) is a patient‐reported measure to assess disease control of atopic dermatitis (AD), consisting of the severity of symptoms, itch duration, bother, sleep, daily activities, and mood/emotions. Objectives. We evaluated the alterations of total and individual ADCT item scores during treatment with Janus kinase 1 inhibitor upadacitinib in AD patients. Methods. Forty‐seven patients aged ≥12 years with moderate‐to‐severe AD were treated with oral upadacitinib 15 mg/day plus topical corticosteroids. Total and individual ADCT item scores, eczema area, and severity index (EASI) and peak pruritus numerical rating scale (PP‐NRS) were evaluated. Results. Before treatment, total ADCT correlated with EASI and PP‐NRS. The median percent reduction at months 1, 3, and 6 of upadacitinib treatment was 80%, 76.2%, and 67.4% in total ADCT, 75.28%, 85.06%, and 81.73% in EASI, 66.67%, 75%, and 75% in PP‐NRS, respectively, and percent reduction of total ADCT correlated with that of EASI and PP‐NRS except for no correlations with that of EASI at month 1. The percent reduction of ADCT no.4 was the highest among the 6 items. Conclusions. These results suggest that changes in ADCT reflect the therapeutic effects of upadacitinib and that ADCT can be a treatment target for upadacitinib therapy. Upadacitinib might preferentially improve sleep disturbance.

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