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Background: Long‐term management of moderate‐to‐severe psoriasis is usually discussed in terms of continuous administration; however, there are many situations in clinical practice where treatment may be withdrawn with subsequent retreatment. Objective: To assess the clinical course after ixekizumab treatment withdrawal and retreatment, as well as the effectiveness of ixekizumab retreatment, in Japanese patients with plaque psoriasis. Methods: This single‐arm, open‐label study (UNCOVER‐J; NCT01624233) comprised 78 patients with plaque psoriasis. After ixekizumab treatment (160‐mg loading dose, 80 mg every 2 weeks for the first 12 weeks, and then 80 mg every 4 weeks (IXE Q4W) until Week 52), 70 patients achieved a Psoriasis Area Severity Index (PASI)75 response at Week 52. These 70 patients withdrew from ixekizumab treatment from Weeks 52 to 100. Patients who relapsed (PASI ≤50) during the Treatment Withdrawal Period were retreated with IXE Q4W for 192 weeks. Results: At Weeks 52, 76 and 100, PASI75 response rates were 100%, 26% and 7%; PASI90 response rates were 87%, 11% and 3%; and PASI100 response rates were 53%, 0% and 0%. After treatment withdrawal, 87% of patients relapsed; median time to relapse was 143 days. After 12 weeks of retreatment with IXE Q4W, 83% of relapsed patients achieved PASI75, 68% achieved PASI90 and 25% achieved PASI100; improvements were maintained up to 120 weeks of retreatment. Treatment‐emergent adverse events and serious adverse events were reported in 56% and 4% of patients during the Treatment Withdrawal Period, and in 88% and 14% of patients during the Retreatment Period. Conclusion: In patients withdrawn from ixekizumab after achieving PASI75, approximately half relapsed within 5 months of withdrawal; however, most patients recaptured response within 12 weeks, and response was maintained for up to 120 weeks of retreatment. [ABSTRACT FROM AUTHOR]

Background: Erythrodermic and generalized pustular psoriasis are rare, difficult to treat forms of psoriasis. In previous reports, we documented 24‐ and 52‐week findings of an open‐label, phase 3 trial (UNCOVER‐J) of ixekizumab in Japanese patients with erythrodermic or generalized pustular psoriasis; most patients responded to treatment and maintained response through 52 weeks. Objective: To assess the long‐term (>3 years) efficacy and safety of ixekizumab in Japanese patients with erythrodermic or generalized pustular psoriasis. Methods: These subgroup analyses were of a partial population of patients from UNCOVER‐J (NCT01624233; Sponsored by Eli Lilly and Company), specifically those with erythrodermic psoriasis (N = 8) or generalized pustular psoriasis (N = 5). These patients received 160 mg ixekizumab at Week 0, ixekizumab 80 mg every 2 weeks through Week 12, and ixekizumab 80 mg every 4 weeks thereafter up to Week 244. This regimen is consistent with the regimen approved in Japan for plaque, erythrodermic, and generalized pustular psoriasis and psoriatic arthritis. Efficacy assessments included Global Improvement Score (GIS), Psoriasis Area and Severity Index (PASI), dermal symptoms (for patients with generalized pustular psoriasis), Dermatology Life Quality Index (DLQI) and Itch Numeric Rating Scale (NRS). Safety assessments included treatment‐emergent adverse events and adverse events of special interest. Results: Most patients had a GIS of resolved or improved from Week 12 onwards, and all patients had early and sustained improvement in PASI and dermal symptom (generalized pustular psoriasis only) scores. Mean improvements in DLQI and Itch NRS at Week 12 were sustained through Week 244. Ixekizumab was well tolerated over 3 years of treatment in patients with erythrodermic psoriasis or generalized pustular psoriasis, and no new safety concerns were identified. Conclusion: These findings suggest that ixekizumab can be an effective long‐term treatment option for erythrodermic or generalized pustular psoriasis. Linked article: This article is commented on G. Egawa et al., p. 259 in this issue. To view this article visit https://doi.org/10.1111/jdv.15416 [ABSTRACT FROM AUTHOR]

Abstract: Background: Appropriate goal‐oriented treatment strategies are important for optimal treatment outcomes and may prevent under‐treatment. As treatment goals vary by patient, a study to examine treatment goals is more meaningful when patients and their physicians are paired. There has not been any study that examines alignment between paired psoriasis patients and physicians in real‐world clinical practice using skin clearance as a treatment goal indicator. Objectives: To evaluate treatment goal alignment between psoriasis patients and their paired physicians, and to quantitatively identify factors associated with goal misalignment. Methods: The study was a nationwide multicenter cross‐sectional observational study. Subjects were physician‐reported moderate‐to‐severe psoriasis patients with a history of systemic treatments, directly paired with their treating physicians. Subjects completed surveys independently. Treatment goals included seven categories, and patient–physician pairs were grouped as ‘aligned’ or ‘misaligned’ when the answers were the same or different, respectively. Results: A total of 425 pairs (mean response rate, 94.7%) of responses were collected from 54 sites (64.8% general practitioners or clinics; 35.2% university or large hospitals). Treatment goal misalignment was found in 67.9% of the patient–physician pairs. The misalignment was mainly ‘patient predominant’ (60.9%) indicating that patients had higher goals (‘complete clearance’) than physicians. In the multivariate logistic regression analyses, patients’ treatment expectation for ‘complete clearance’ [odds ratio (OR): 1.927; 95% confidential interval (CI): 1.232–3.016] and physician rating of ‘level of understanding on treatment options’ being low (OR: 1.552, 95% CI; 1.082–2.227) were significant factors for treatment goal misalignment. Conclusions: The majority of treatment goal misalignment was found between paired psoriasis patients and their treating physicians in Japan. The most important contributing factors to misalignment were patients’ treatment expectation for ‘complete clearance’ and physicians’ rating of their patients’ ‘level of understanding on treatment options’ being low. [ABSTRACT FROM AUTHOR]

Objective: To evaluate efficacy and safety of lebrikizumab combined with topical corticosteroids (TCS) in Japanese patients with moderate-to-severe atopic dermatitis (AD)., Methods: Phase 3, randomized, double-blind, placebo-controlled study (ADhere-J; NCT04760314) conducted at 37 centers in Japan (March 2021-February 2023), comprising 16-week induction (reported herein) and 52-week maintenance periods. Overall, 286 patients aged ≥12 years and ≥40 kg were randomized (interactive web response system) to subcutaneous placebo, lebrikizumab 250 mg every 4 weeks (Q4W), or lebrikizumab 250 mg every 2 weeks (Q2W) with TCS (82, 81, and 123 patients, respectively). Coprimary endpoints were proportions of patients achieving (1) Investigator's Global Assessment score of 0 or 1 (IGA [0,1]) with ≥2-point improvement from baseline, and (2) ≥75% improvement from baseline in Eczema Area and Severity Index (EASI 75) at week 16., Results: At week 16, compared with placebo, a significantly greater proportion of the lebrikizumab Q4W and Q2W groups achieved IGA (0,1) (6.1% vs. 29.1% and 33.4%, respectively; both p  < 0.001) and EASI 75 (13.4% vs. 47.2% and 51.2%, respectively; both p  < 0.001). Serious adverse events (AEs) occurred in 2.4%, 0%, and 0.8% of placebo, lebrikizumab Q4W and Q2W groups, respectively. Common treatment-emergent AEs, including pyrexia (placebo: 15.9%; lebrikizumab Q4W/Q2W: 18.5%/20.3%), conjunctivitis allergic (placebo: 4.9%; lebrikizumab Q4W/Q2W: 12.3%/17.1%), and conjunctivitis (placebo: 2.4%; lebrikizumab Q4W/Q2W: 6.2%/9.8%), were more frequent with lebrikizumab; most were mild or moderate., Conclusion: Consistent with global data, lebrikizumab demonstrated clinical improvements with a positive benefit-risk profile in Japanese adults and adolescents with moderate-to-severe AD through 16 weeks.

Background: This study evaluated the level of burden in pediatric and adolescent atopic dermatitis (AD) patients in Japan, the associated burden on caregivers/families, and whether this burden varied with age., Methods: Data were drawn from the Adelphi Pediatric AD Disease Specific Programme (DSP)™, a cross-sectional survey of physicians and their patients conducted in Japan between July and December 2022. Physicians reported patient demographics, clinical characteristics, disease burden, and current/previous therapies. Patients and/or caregivers reported perceived disease severity and impact of AD, including the Children's Dermatology Life Quality Index (CDLQI) and Dermatitis Family Impact questionnaire (DFI)., Results: Overall, 55 physicians provided data for 537 AD patients aged ≤17. Mean (SD) overall scores for CDLQI, POEM, and DFI were 9.3 (6.3), 8.3 (6.8), and 11.7 (7.2), respectively. Age was associated with higher patient and/or caregiver-reported CDLQI scores, which increased by 0.543 points per year of age (P = 0.01). Patients with severe disease reported a more significant impact on quality of life factors compared with mild patients (P < 0.001). Age was associated with higher caregiver-reported burden, with DFI scores increasing by 0.325 per year (P = 0.01). Physician-reported impact on caregivers showed that age was significantly associated with increased burden on sleep, daily activities, work, and mood (P < 0.05), with disease severity associated with impact across all factors (P < 0.01)., Conclusions: Both increasing age and disease severity were associated with the increased impact of AD on patients and their caregivers. Disease control/modification through appropriate therapeutic intervention at a younger age may relieve the burden of pediatric AD on patients and their families., (© 2024 The Author(s). International Journal of Dermatology published by Wiley Periodicals LLC on behalf of the International Society of Dermatology.)

Background: Moderate-to-severe atopic dermatitis (AD) impacts patients' quality of life (QOL). More treatment options are urgently needed to manage this chronic disease. Lebrikizumab is a monoclonal antibody that binds to IL-13, a key mediator in AD pathogenesis. In Japanese patients, lebrikizumab has been evaluated through week (W) 16 in the randomized, placebo-controlled, phase III ADhere-J study., Objectives: To evaluate long-term efficacy and safety of lebrikizumab in combination with topical corticosteroids (TCS) in the ADhere-J study., Methods: Patients aged ≥12 years and weighing ≥40 kg with moderate-to-severe AD, and receiving either subcutaneous lebrikizumab 250 mg every 2 weeks (Q2W)/every 4 weeks (Q4W) or placebo during the 16-week induction period, were evaluated during the long-term maintenance period from W16 to W68. Responders achieved co-primary endpoints at W16: Investigator's Global Assessment score of 0 or 1 (IGA [0,1]) with ≥2-point improvement from baseline, and/or ≥75% improvement from baseline in Eczema Area and Severity Index (EASI 75). In this analysis, W16 responders received lebrikizumab 250 mg Q2W or Q4W combined with TCS during the maintenance period (maintenance primary population; MPP); W16 per-protocol nonresponders received lebrikizumab Q2W with TCS (maintenance escape population; MEP). Major endpoints included IGA (0,1) with ≥2-point improvement from baseline and EASI 75 through W68. Other outcomes included QOL, itch, and serum thymus and activation-regulated chemokine., Results: At W68, 66-81% of 103 patients in the MPP and 32-38% of 168 patients in the MEP achieved IGA (0,1) with ≥2-point improvement from baseline. EASI 75 was maintained by 83-89% of patients in the MPP, while 71-80% of patients in the MEP achieved this outcome by W68. Across treatment arms, patients in the MPP tended to maintain improvements recorded at W16, while patients in the MEP steadily improved across the maintenance period. No new safety signals were reported, and most treatment-emergent adverse events were mild or moderate in severity in both populations. Safety outcomes were consistent with previous reports for lebrikizumab treatment in global studies., Conclusions: These results support the use of lebrikizumab in combination with TCS for moderate-to-severe AD in the Japanese population over the long term., Clinical Trial Registration: ClinicalTrials.gov (NCT04760314)., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Lebrikizumab has previously demonstrated efficacy in Phase 3 trials: ADvocate1 and ADvocate2 (as monotherapy), ADhere, and ADhere-J (in combination with topical corticosteroids). Here, the impact of lebrikizumab combined with low- to mid-potency topical corticosteroids on patient-reported outcomes at 16 weeks in Japanese patients with moderate-to-severe atopic dermatitis is evaluated. Eligible patients (n = 286) were randomized 2:2:3 to receive placebo+ topical corticosteroids, 250 mg lebrikizumab every 4 weeks (LEBQ4W+topical corticosteroids, 500 mg loading dose at baseline), or 250 mg lebrikizumab every 2 weeks (LEBQ2W+ topical corticosteroids, 500 mg loading dose at baseline and Week 2) by subcutaneous injection. All PRO endpoints for the study were met; patients in the lebrikizumab in combination with topical corticosteroids groups demonstrated statistically significant and clinically meaningful improvements compared with placebo in combination with topical corticosteroids in Skin Pain NRS, DLQI, POEM, WPAI-AD, and SCORAD scales. Lebrikizumab combined with topical corticosteroids compared with placebo+topical corticosteroids improved patient-reported outcomes in Japanese patients with moderate-to-severe atopic dermatitis.

Background and Objective: Real-world evidence on persistence of interleukin-17 inhibitors (IL-17i) as a drug class among Japanese patients with psoriasis is lacking. Hence, we aimed to describe persistence rates of IL-17is among patients with psoriasis including psoriasis vulgaris (PsO), psoriatic arthritis (PsA), and generalized pustular psoriasis (GPP) or erythrodermic psoriasis (EP) in Japan., Methods: We analyzed claims data from the Medical Data Vision database. Patients ≥15 years old with a psoriasis diagnosis and an IL-17i prescription between November 2016 and August 2020 were included and followed through August 2021. Persistence rates of the IL-17i class among patients with psoriasis and its subtypes (PsO, PsA, and GPP or EP), and persistence rates of ixekizumab, secukinumab, or brodalumab among patients with PsO or PsA were analyzed using Kaplan-Meier method. Analyses were conducted in the bio-naïve and bio-experienced subgroups., Results: The IL-17i class had >50% persistence rates up to 36 months among patients with psoriasis and its subtypes (PsO, PsA, and GPP or EP). 36-Month persistence rates for ixekizumab, secukinumab, and brodalumab were 46.2% to 57.7% in patients with PsO and 43.0% to 48.4% in patients with PsA. Across analyses, bio-naïve patients demonstrated similar or greater persistence rates than bio-experienced patients., Conclusion: IL-17is' persistence rates over 36 months were >50% among patients with psoriasis and its subtypes (PsO, PsA, and GPP or EP) in Japan.

Introduction: Baricitinib is an oral selective Janus kinase (JAK)1/JAK2 inhibitor approved in Japan and the European Union for the treatment of atopic dermatitis (AD). The aim of this study is to report pooled safety data for baricitinib in the Japanese subpopulation of the clinical development program in moderate-to-severe AD., Methods: This analysis included participant-level safety data from five double-blind, randomized clinical studies and one double-blind, randomized, long-term extension study, reported in three datasets for the Japanese subpopulation: (1) placebo-controlled, (2) baricitinib 2 mg and 4 mg extended (&quot;2-mg-4-mg extended&quot;), and (3) all baricitinib doses (&quot;All-bari-AD&quot;). The data cutoff was 13 December 2019. Safety outcomes included treatment-emergent adverse events, adverse events of special interest, and abnormal laboratory changes. Proportions of participants with events and incidence rates were calculated., Results: Data were collected for 341 participants from Japan who received baricitinib for 371.7 participant-years (median duration 371.0 days). In the placebo-controlled dataset, the frequencies of serious infections and herpes zoster were low and similar between treatment groups, and the incidence of treatment-emergent infections, in particular herpes simplex, was higher in the baricitinib groups compared with the placebo group. No gastrointestinal perforations, tuberculosis, positively adjudicated cardiovascular events, deep vein thrombosis, or pulmonary embolism were reported with exposure up to 2 years in the All-bari-AD dataset. There were no deaths in the Japanese subpopulation., Conclusions: This integrated safety analysis in the subpopulation of Japanese participants is consistent with the established safety profile of baricitinib in the global study population with moderate-to-severe AD., Gov Identifiers: NCT02576938, NCT03334396, NCT03334422, NCT03428100, NCT03733301, and NCT03334435., (© 2022. The Author(s).)

Objective: Itch is a common symptom of atopic dermatitis (AD), however, there is limited evidence of the frequency and association of skin pain alongside itch. This study assessed the incremental dual burden and impact of itch and skin pain on satisfaction, quality of life and work productivity in patients with AD in Japan., Methods: Data were drawn from the 2020 Adelphi AD Disease Specific Programme, a point-in-time survey of dermatologists ( n  = 56) and their patients with history of moderate/severe AD ( n  = 265). Patients were grouped accordingly: no itch/skin pain (No I/SP, reference group, n  = 89), itch/no skin pain (I-only, n  = 71), and itch and skin pain (I + SP, n  = 26). Descriptive analyses were performed alongside a range of regression models, dependent on outcome variables., Results: I + SP patients had a 4.97-point worse POEM score ( p  = .005) and 14.5% more overall work impairment ( p  = .034) versus the reference group. I-only and I + SP patients were 8.92 and 23.5 times more likely, respectively, to experience sleep disruption on a day-to-day basis (both p  < .001). I + SP patients were 4.6 times more likely to be bothered by their symptoms ( p  = .034), had a mean EASI score 6.7 points higher ( p  = .008) and had 1.39 more areas affected ( p  = .001). I + SP patients were 7.26 times more likely to express dissatisfaction with lack of improvement in their condition and 8 times more likely to be dissatisfied with convenience of treatment (both p  < .05)., Conclusion: This dissatisfaction, alongside variations in reported symptomatic burdens, suggests that physicians could consider alternative and/or novel therapeutic approaches for the management of both itch and skin pain.

Introduction: In 2018, ixekizumab (80 mg every 2 weeks [Q2W] beyond Week 12) received approval in Japan for patients with generalized pustular psoriasis (GPP) and erythrodermic psoriasis (EP). This open-label study evaluated the efficacy and safety of ixekizumab (80 mg Q2W from Week 12 to Week 20) in Japanese patients with GPP and EP., Methods: Seven patients with GPP and five patients with EP were enrolled. An initial dose of 160 mg (subcutaneous [SC] injection) was followed by 80 mg Q2W SC until Week 12. Primary endpoint assessed global improvement score (GIS) by comparing psoriatic findings, Static Physician Global Assessment, Psoriasis Area and Severity Index score, and other evaluations with those at the baseline and were graded as 1 = resolved, 2= improved, 3 = unchanged, and 4 = worsened. Patients who showed GIS = 1 (resolved) at Week 12 completed the study. Patients with GIS ≥ 2 continued to receive ixekizumab 80 mg Q2W until Week 20., Results: At Week 12, four of seven patients with GPP showed "resolved," two showed "improved," and one showed "worsened." Of five patients with EP, one showed "resolved" and four showed "improved." Two patients with GPP and four patients with EP continued ixekizumab treatment until Week 20. At Week 20, one of the two patients with GPP showed "resolved" and one patient showed "improved." All four patients with EP showed "improved." One non-drug related serious adverse event was reported by one patient with EP at Week 12. From Week 12 to Week 20, no adverse events (AEs) were reported in patients with GPP, but two mild AEs were reported in one of the four patients with EP., Conclusions: This study indicates that ixekizumab continuous Q2W dosing is efficacious and safe for patients with GPP and EP., Clinical Trial Registration: NCT03942042., (© 2021. The Author(s).)

Background: Previously, our cross-sectional observational study in Japan revealed high (68%) discordance within treatment goals between psoriasis patients and their physicians., Objective: This secondary analysis aimed to determine whether patient and physician users of biologics have higher treatment goals than users of non-biologics., Methods: A survey for both patients and physicians on background characteristics, disease severity, treatment goals, treatment satisfaction, and health-related quality of life was conducted at 54 sites. Association between treatment goals and biologic/non-biologic users was assessed using ordinal logistic regression models., Results: In total, 449 patient-physician pairs agreed to participate; 425 completed the survey and were analyzed. More biologic users than non-biologic users reported complete clearance (Psoriasis Area and Severity Index 100) as a treatment goal (patient-reported: 23.6% vs. 16.1%; physician-reported: 26.9% vs. 2.2%). Biologic users were significantly associated with higher treatment goals than non-biologic users (patient-reported: 1.8 (1.15-2.87) (odds ratio (9 5% CI)), p = 0.01; physician-reported: 11.0 (5.72-21.01), p < 0.01). Among biologic users, higher treatment goals were associated with higher treatment satisfaction (patient- and physician-rated); lower treatment goals were associated with back lesions and increasing patient age (patient-rated) and higher disease severity (physician-rated)., Conclusion: Use of biologics among patients with psoriasis was associated with higher treatment goals. Further use of biologics contributed to treatment satisfaction. Appropriate treatment goals that are shared among patients and their physicians may improve treatment outcomes.

Objective: Assess patient characteristics, real-world treatment patterns, and health care resource utilization (HCRU) among patients with psoriatic arthritis (PsA) in Japan., Methods: Patients diagnosed with PsA from April 2009 through July 2017 were identified from the Medical Data Vision database. Patient characteristics, treatment patterns, and HCRU were evaluated for these patients., Results: A total of 639 patients met inclusion criteria and were included in the analysis for patients with a PsA diagnosis. Over 12 months following diagnosis, patients received oral NSAIDs (61.7%), conventional synthetic disease-modifying antirheumatic drugs (DMARDs) (55.1%), corticosteroids (35.1%), topical NSAIDs (34.0%), adalimumab (14.7%), infliximab (9.7%), secukinumab (5.0%), ustekinumab (4.5%), ixekizumab (1.6%), and golimumab (1.6%). A total of 227 (35.5%) patients initiated biologic DMARDs (bDMARDs) over the median 25.2 months of study follow-up. Compared with the overall group of patients diagnosed with PsA, patients who initiated bDMARDs had higher median total per-patient health care costs ($27,772 vs. $11,316), lower median per-patient hospitalization costs ($31,164 vs. $39,359), and fewer median hospital days per admission (8.0 vs. 12.0 days)., Conclusion: This study presents knowledge of the current state of patient characteristics, treatment patterns, HCRU, and costs among patients with PsA in Japan. Considering the relatively recent guideline recommendations, the preliminary treatment patterns suggest physicians may be following treatment guidelines.

Objectives: High treatment satisfaction in both patients and physicians is an important factor in improving quality of life in psoriasis patients. This study aimed to evaluate treatment satisfaction alignment between psoriasis patients and physicians and to identify factors associated with satisfaction misalignment, especially "physician-predominant" misalignment., Methods: This is a nationwide multicenter cross-sectional study. Subjects were paired moderate to severe psoriasis outpatients and their physicians. Treatment satisfaction was evaluated on a scale from 0 to 10. Subjects were defined as "misaligned" when the difference in treatment satisfaction was over ±1 between the patient-physician pair., Results: A total of 425 pairs were collected from 54 facilities in Japan. The mean patient age and disease duration were 56.5 years and 18.7 years, respectively. The mean physician age was 50.6 years and 69.6% of physicians specialized in psoriasis. Treatment satisfaction misalignment was found in 49.9% of the patient-physician pairs. Among misaligned pairs, 43.6% were "physician-predominant" pairs. In the multivariate logistic regression analyses, "treatment is effective" was the most important reason for treatment satisfaction (odds ratio [OR]: 35.5; 95% confidence interval [CI]: 5.43, 231.78). Symptoms in the genital area (OR: 10.2; 95% CI: 2.55, 40.93) and lack of understanding of treatment options by patients (OR: 7.5; 95% CI: 2.19, 25.94) were key factors leading to "physician-predominant" status., Conclusions: The results suggest that genital psoriasis plays an important role in treatment satisfaction from the patient perspective, and illustrate the importance of communication between patients and physicians which potentially resolves these factors and improves misalignment.

Introduction: The content validity and treatment success thresholds of clinical outcome assessments (COAs) for alopecia areata (AA)-including the Alopecia Areata-Investigator Global Assessment™ (AA-IGA™), Scalp Hair Assessment Patient-Reported Outcome™ (PRO), and clinician-reported outcome (ClinRO) and PRO measures for eyebrows, eyelashes, eye irritation, and nails-were established in interviews with dermatologists and patients in North America. This study aimed to confirm the content validity and treatment success thresholds of these measures with clinicians and patients in Japan., Methods: Qualitative interviews were conducted in Japan with dermatologists with AA expertise and adults with AA who experienced ≥ 50% scalp hair loss. Interviews included concept elicitation and cognitive interview questions. Data were analyzed using thematic and framework techniques., Results: Seven dermatologists and 15 patients participated. Scalp hair loss was the most important sign/symptom of AA and the greatest treatment priority. Dermatologists and patients understood the AA-IGA™, Scalp Hair Assessment PRO™, and other COAs, and found these measures to be appropriate, relevant, and clinically meaningful. Dermatologists and patients confirmed that achieving ≤ 20% scalp hair loss (AA-IGA™/Scalp Hair Assessment PRO™ categories 0 or 1) indicated treatment success for patients with ≥ 50% scalp hair loss. Categories 0 or 1 on the other COAs represented treatment success., Conclusion: This study confirmed the content validity and treatment success thresholds of the AA-IGA™, Scalp Hair Assessment PRO™, and other ClinRO and PRO measures for AA in Japan. These findings were aligned with interview results in North America and support the use of these measures in AA treatment studies.

Introduction: Ixekizumab has demonstrated rapid onset of action, high levels of skin clearance, and improvements in quality of life in patients with moderate-to-severe psoriasis, including plaque, erythrodermic, or generalized pustular psoriasis., Methods: This was a post hoc analysis of UNCOVER-J, a phase 3, multicenter, single-arm, open-label study of ixekizumab for treatment of Japanese patients with psoriasis. The objective was to assess the proportion of patients who achieved Dermatology Life Quality Index (DLQI) (0,1) and Itch Numeric Rating Scale (NRS) (0) at weeks 4 and 12 according to Psoriasis Area and Severity Index (PASI) percentage improvement levels. All intent-to-treat patients with plaque, erythrodermic, or generalized pustular psoriasis were analyzed., Results: A total of 91 patients were treated with ixekizumab and included in the analysis. Rapid improvements in PASI at weeks 4 and 12 were associated with improvements in DLQI (0,1) response at week 4 and at week 12. Complete skin clearance (PASI 100) achieved either at week 4 or week 12 was associated with a higher Itch NRS (0) response at week 12., Conclusions: Patients with rapid improvement in clinical symptoms of psoriasis had better patient outcomes than those with slower responses. These findings highlight the clinical importance of achieving a fast response in patients with psoriasis, which may lead to better treatment outcomes., Trial Registration: ClinicalTrials.gov identifier, NCT01624233.

BACKGROUND: Injection-site reactions (ISRs) are reported with biologic therapies. The objective of this study was to comprehensively characterize ISRs among moderate-to-severe psoriasis patients treated with ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A.

METHODS: ISRs are presented from UNCOVER-1, UNCOVER-2, and UNCOVER-3 (12 weeks) and all ixekizumab-exposed patients in 11 controlled and uncontrolled trials (156 weeks).

RESULTS: At week 12, reported ISR frequency with 80 mg ixekizumab every 2 weeks (IXE Q2W, 16.8%) was comparable with etanercept twice weekly (16.4%); both were significantly higher than placebo (3.3%). With IXE Q2W, ISRs were mild (12.3%), moderate (3.9%), or severe (0.7%), typically reported in the first 2 weeks (median onset, 6.6 days), and most commonly characterized as nonspecified, erythema, and pain. Generally, erythema onset was delayed, whereas pain occurred around drug administration. Discontinuation from ixekizumab due to ISRs (0.4%) occurred in the first 12 weeks. After 2 weeks, ISR frequency decreased and remained stable (≤4.2%) through week 156. No ISR-related serious adverse events were reported in ixekizumab-treated patients. ISR data were solicited if patients reported injection-associated events. Since nonspecified ISR was the most commonly reported term, specific types might be underreported.

CONCLUSIONS: ISRs have been reported with ixekizumab during clinical trials. These reactions are typically tolerable, manageable, and decrease over time.

Clinicaltrials.gov: NCT01474512 (UNCOVER-1); NCT01597245 (UNCOVER-2); NCT01646177 (UNCOVER-3); NCT01777191 (UNCOVER-A); NCT01624233 (UNCOVER-J); NCT01107457 (I1F-MC-RHAJ); NCT02561806 (I1F-MC-RHBS); NCT02387801 (I1F-US-RHBO);NCT02513550 (I1F-MC-RHBP); NCT02634801 (I1F-EW-RHBZ)

J Drugs Dermatol. 2018;17(2):200-206.

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The present study describes a subgroup analysis of 33 Japanese patients participating in UNCOVER-1, an international, placebo-controlled, phase 3 study of ixekizumab in patients with moderate-to-severe psoriasis. Patients were randomized to a placebo (n = 13) or ixekizumab 80 mg every 4 (IXEQ4W, n = 12) or 2 (IXEQ2W, n = 8) weeks, from week 0-12. At week 12, ixekizumab-treated patients with a static Physician Global Assessment score 0 or 1 (sPGA [0,1]; n = 16) were re-randomized to a placebo (n = 6), ixekizumab 80 mg every 12 (IXEQ12W, n = 5) or 4 (IXEQ4W, n = 5) weeks, from week 12-60. At week 12, more ixekizumab-treated versus placebo-treated patients achieved sPGA (0,1) (≥66.7% vs 0%), ≥75% improvement in Psoriasis Area and Severity Index (≥75% vs 0%), and sPGA (0) or 100% improvement in Psoriasis Area and Severity Index (both ≥33.3% vs 0%), with improved symptoms and quality of life. At week 60, 100% (IXEQ4W), 40.0% (IXEQ12W) and 16.7% (placebo) had maintained sPGA (0,1). From week 0-12, treatment-emergent adverse events were 76.9% (placebo), 75.0% (IXEQ4W) and 87.5% (IXEQ2W), and from week 12-60 were 66.7% (placebo) and 100% (IXEQ12W, IXEQ4W). Ixekizumab-treated patients had no severe treatment-emergent adverse events, and one serious TEAE (IXEQ4W); infection was the most frequent treatment-emergent adverse event. In conclusion, ixekizumab for 60 weeks was effective and safe for Japanese patients with moderate-to-severe psoriasis, in line with the overall findings from UNCOVER-1., (© 2017 Eli Lilly Japan KK. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

The impact on survival of a second primary melanoma (SPM) is unclear. We used our melanoma center's database to examine clinicopathologic risk factors and outcomes of stage 0 to IV cutaneous melanoma in patients with one versus two primaries. Among 12,325 patients with primary melanoma, 969 (7.86%) developed SPM. SPMs were significantly thinner than autologous primary melanomas (P = 0.01), and 451 SPM patients had better overall and melanoma-specific survival than 451 prognostically matched non-SPM patients (P < 0.0001 and 0.0001, respectively) at a median follow-up of 142.37 months. Patients with cutaneous melanoma are at high risk for development of SPM, but the development of SPM does not seem to impair survival.

Background: Retrospective data indicate that immunoprofiling of T cell markers can be prognostic in colon cancer. Prospective T cell immunoprofiling of colon cancer has not been well defined for patients whose lymph nodes are ultrastaged., Study Design: A prospective cohort was selected from patients enrolled in an ongoing phase II multicenter trial of nodal ultrastaging for colon cancer. Primary tumor specimens from 89 patients were analyzed by immunohistochemistry for the T cells CD3(+), CD4(+), CD8(+), and FOXP3(+). Lymphocyte populations were quantified with digital image analysis. Results were examined for their association with 5-year disease-free survival along with TNM stage and clinicopathologic variables., Results: Longer disease-free survival was associated with higher CD3(+) counts at the invasive margin (IM) (p = 0.005), higher CD8(+) counts at the tumor center (TC) and IM (p = 0.002), a lower CD4(+)/CD8(+) ratio at the TC+IM (p = 0.027), and a higher CD8(+)/FOXP3(+) ratio at the TC+IM (p = 0.020). After multivariable analysis, CD8(+) at the TC+IM (p = 0.002), the CD8(+)/FOXP3(+) ratio at the TC+IM (p = 0.004), and the number of tumor-positive lymph nodes (p = 0.003) remained significant., Conclusions: This is the first prospective demonstration of the prognostic utility of immunoprofiling in colon cancer after nodal ultrastaging. Staging based on tumor immunoprofile can augment TNM staging and provide targets for specific immunotherapies., (Copyright © 2016. Published by Elsevier Inc.)

Background: Although AJCC/TNM staging remains the gold standard for prognostic assessment of colon cancer, stage-specific outcomes vary. We therefore prospectively evaluated the prognostic role of immunoprofiling., Methods: Our cohort included 35 patients from an ongoing prospective trial of ultrastaging for colon cancer. Specimens were analyzed for T cell markers (CD3, CD4, CD8, and FoxP3). The number of tumor-infiltrating lymphocytes was analyzed at the tumor's margin and center and correlated with AJCC/TNM stage, clinicopathologic variables, and disease-free survival., Results: There was a significant inverse association between number of CD3(+) cells in the tumor center and tumor stage (P = 0.05). The tumor center/margin ratio of CD3(+) cells also showed an inverse but non-significant relationship with nodal involvement (P = 0.07). Body mass index was inversely associated with numbers of CD3(+)(P = 0.04) and CD8(+)(P = 0.02) cells. Longer disease-free survival was correlated with higher CD8+ counts (P = 0.07), lower CD4(+)/CD8(+) ratios (P = 0.008), and higher CD8(+)/FoxP3(+) ratios (P = 0.02)., Conclusions: This is the first prospective validation of immunoprofiling in patients whose colon cancer is staged with strict surgical and pathology quality measures. The apparent correlation between immunophenotypic response and clinical outcome warrants evaluation in a larger prospective trial.

Melanoma-associated chondroitin sulfate proteoglycan (MCSP; also called HMW-MAA, CSPG4, NG2, MSK16, MCSPG, MEL-CSPG, or gp240) is a well characterized melanoma cell-surface antigen. In this study, a new bispecific T-cell engaging (BiTE) antibody that binds to MCSP and human CD3 (MCSP-BiTE) was tested for its cytotoxic activity against human melanoma cell lines. When unstimulated peripheral mononuclear blood cells (PBMCs) derived from healthy donors were cocultured with melanoma cells at effector:target ratios of 1:1, 1:5, or 1:10, and treated with MCSP-BiTE antibody at doses of 10, 100, or 1000 ng/mL, all MCSP-expressing melanoma cell lines (n=23) were lysed in a dose-dependent and effector:target ratio-dependent manner, whereas there was no cytotoxic activity against MCSP-negative melanoma cell lines (n=2). To investigate whether T cells from melanoma patients could act as effector cells, we cocultured unstimulated PBMCs with allogeneic melanoma cells from 13 patients (4 stage I/II, 3 stage III, and 6 stage IV) or with autologous melanoma cells from 2 patients (stage IV). Although cytotoxic activity varied, all 15 PBMC samples mediated significant redirected lysis by the BiTE antibody. When PBMC or CD8 T cells were prestimulated by anti-CD3 antibody OKT-3 and interleukin-2, the MCSP-BiTE concentrations needed for melanoma cell lysis decreased up to 1000-fold. As MCSP is expressed on most human melanomas, immunotherapy with MCSP/CD3-bispecific antibodies merits clinical investigation.

There are no standard methods to predict response to treatment or outcome of stage IV melanoma. Our previous assessment of peripheral blood mononuclear cells (PBMC) from immunized patients demonstrated that interleukin (IL)-10 expression might be associated with prognosis. However, PBMC are a mixture of CD4+ cells, CD8+ cells, and monocytes. This study identified the subset of PBMC responsible for IL-10 expression and evaluated the prognostic value of IL-10 expression in immunized stage IV patients. Eighty-seven patients with stage IV melanoma were randomly selected from our database. All patients had received an allogeneic melanoma whole-cell vaccine (Canvaxin) after complete resection of clinical disease. Blood samples had been collected serially during Canvaxin administration and cryopreserved. Intracellular IL-10 expression was assessed by double staining fluorescence-activated cell sorter. CD14+ monocytes are the predominant PBMC producing IL-10. Sixteen weeks after treatment (week 16), IL-10 levels were significantly (P=0.02) higher in poor-survival patients than those with favorable outcomes. Patients were separated into 2 groups on the basis of the CD14+ monocyte IL-10 response: either increasing or decreasing IL-10 expression from preimmunization (week 0) to week 16 blood draws. Patients with increasing IL-10 levels had significantly shorter survival than those whose IL-10 levels decreased at week 16 (P<0.0001). Multivariate analysis demonstrated that trends in IL-10 levels inversely correlated with survival (P<0.0001). We conclude that CD14+ monocytes are the dominant cellular source of IL-10 among PBMC and that changes in IL-10 expression may serve as an immunologic-based surrogate for predicting outcome for stage IV patients after surgical resection.

Purpose: Identification of regional node metastasis is important for accurate staging and optimal treatment of early melanoma. We hypothesize that the nodal profile of immunoregulatory cytokines can confirm the identity of the first tumor-draining regional node, i.e., the sentinel node (SN) and indicate its tumor status., Experimental Design: RNA was extracted from freshly dissected and preserved nodal tissue of 13 tumor-negative SNs, 10 tumor-positive SNs (micrometastases <2 mm), and 11 tumor-negative non-SNs (NSN). RNA was converted into cDNA and then amplified by PCR. Expression of 96 cytokines and chemokines was assessed using cDNA microarray and compared by using hierarchical clustering., Results: Fifty-seven genes were expressed at significantly (P < 0.05) different levels in SNs and NSNs (4 genes had higher expression, and 53 genes had lower expression in SNs). Expression levels of interleukin-13 (IL-13), leptin, lymphotoxin beta receptor (LTbR), and macrophage inflammatory protein 1b (MIP1b) were significantly higher (P < 0.04, P < 0.01, P < 0.05, and P < 0.01, respectively), and expression level of IL-11Ra was lower (P < 0.03) for tumor-positive as compared with tumor-negative SN. Receiver-operator characteristics curve analyses showed that the area under the curve (AUC) for IL-13, leptin, LTbR, MIP1b, and IL-11Ra was 0.79, 0.83, 0.75, 0.81, and 0.77, respectively. The AUC for the five genes in combination was 0.973, suggesting high concordance of gene-expression profiles with SN staging., Conclusions: SNs have a different immunoregulatory cytokine profile than NSNs. The cytokine profile of tumor-positive SNs; increased expression of IL-13, leptin, LTbR, and MIP1b and decreased expression of IL-11Ra, may provide clues to the local tumor lymph node interaction seen in the earliest steps of melanoma metastasis.

Hypothesis: Intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) has become an increasingly popular surgical technique for staging the regional lymph nodes in early-stage melanoma. The technique of LM/SL has potentially great advantage for the groin, where the morbidity of superficial groin dissection or iliac dissection can be high. The surgical management of these basins is unknown for patients with tumor-positive sentinel lymph nodes (SNs)., Design: Cohort of successive patients undergoing LM/SL over 18 years. Those patients found to have tumor-positive SNs underwent sentinel complete lymph node dissection. Postoperatively, patients were followed up on a routine basis with serial examinations and chest radiography. The median follow-up was 50 months., Setting: Tertiary cancer center., Patients: The technique of LM/SL was performed for 431 consecutive patients. Sentinal lymph nodes were identified in each case. Patients with tumor-positive SNs underwent sentinel complete lymph node dissection., Intervention: Cutaneous lymphoscintigraphy and blue dye with or without use of the gamma probe-directed LM/SL. Sentinel lymph nodes were examined by hematoxylin-eosin staining and immunohistochemistry staining with HMB-45 and S100 protein. Only patients with tumor-positive SNs had sentinel complete lymph node dissection. Main Outcome Measure Computer-assisted database with statistical analyses using log-rank tests and Cox regression models., Results: Of the 431 patients, 264 (61%) were women and the median age was 50 years (age range, 15-89 years). A majority (86%) of the primary tumors were on the lower extremities, 54% were of Clark level IV or V, and there was a mean +/- SD thickness of 1.89 +/- 1.59 mm (range, 0.30-14.00 mm). Ninety-three patients (21%) were found to have tumor-positive SNs. After LM/SL and sentinel complete lymph node dissection, 62 patients (67%) were found to have a single tumor-positive lymph node, 25 (27%) had 2 tumor-positive lymph nodes, and 6 (6%) had 3 or more tumor-positive lymph nodes. Only 12 patients (4%) with tumor-negative SNs have had recurrence in the dissected basin. The 5-year overall survival was significantly better for patients with tumor-negative lymph nodes (mean +/- SD 5-year overall survival, 94% +/- 5%) than for patients with tumor-positive lymph nodes (mean +/- SD 5-year overall survival, 75% +/- 4%) (P < .01). The tumor status of the Cloquet lymph node was predictive of the tumor status of the iliac lymph nodes. Multivariate analyses with a Cox regression model identified tumor-positive SN (P = .001), primary tumor thickness (P = .03), and ulceration (P = .001) as being predictive of survival. Sex, age, Clark level, and primary site were not significant (P > .05)., Conclusions: Our results demonstrate the prognostic significance of LM/SL for early-stage melanoma draining to the groin basin. The accuracy of LM/SL measured by the rare recurrences suggests that this surgical procedure should become standard for patients with early-stage melanoma of the lower extremities and trunk. Sampling of the Cloquet node should be used to determine the need for iliac dissection when a tumor-positive SN is identified in the groin.

Purpose: Approximately 20% of sentinel node (SN) positive melanoma patients have additional non-SN (NSN) metastasis. The rationale for this study was to identify the factors associated with additional nodal disease, as a method to determine which patients may most benefit from completion lymph node dissection (CLND)., Patients and Methods: During 1990 to 2002, 1,599 patients have undergone SN biopsy at our institute. 19.5% underwent CLND for tumor-positive SN. One hundred ninety-one of these patients had clinicopathologic information available for review. Univariate analyses used chi2 test, Wilcoxson rank sum test, and chi2 test for trend. Multivariate analyses used logistic regression and Wald test., Results: Forty-six (24%) patients had tumor-positive NSN. Univariate analyses showed that primary thickness (Breslow and Clark), primary site, SN tumor size, and number of tumor-positive SNs were significantly associated with tumor-positive NSN. Multivariate analysis (167 patients), confirmed that Breslow and SN tumor size were independently predictive. Sex, histology, ulceration, mitotic index, and SN basin location were not predictive. Risk stratification by the number of prognostic factors present (Breslow > or = 3 mm and SN tumor size > or = 2 mm) showed that probability of finding tumor-positive NSN was 12.3% in the low-risk group (0 factors), 30.9% in the intermediate-risk group (1 factor), and 41.9% in the high-risk group (2 factors)., Conclusion: Thicker primary and larger SN tumor size are factors that correlate best with tumor-positive NSN. Although none of these factors are absolutely predictive of residual nodal disease, these factors must be strongly considered if the SN contains metastasis, as they provide enhanced risk assessment for NSN tumor-positivity.

Expression of thymidine phosphorylase (TP) is often associated with tumor angiogenesis and / or prognosis in patients. Further, infiltration of macrophages is closely correlated with the depth of tumor and angiogenesis in melanomas. In this study, we examined the expression of TP and an activated macrophage-specific enzyme, heme oxygenase-1 (HO-1), involved in malignancy in 22 cases with melanomas. TP was strongly expressed not only in CD68-positive macrophages in and around tumors, but also in S100 protein-positive melanoma cells, fibroblasts and keratinocytes. By contrast, HO-1 was specifically expressed in macrophages, but only slightly in melanoma cells and other cell types in the stroma of melanomas. We thus observed apparent co-expression of TP and HO-1 in macrophages infiltrating in the late stage of malignant melanomas. There appeared increasing numbers of TP-positive cells in Clark level IV and V melanoma compared with Clark level I (in situ) melanoma, and there was also a close correlation between numbers of TP-positive cells and HO-1-positive cells. Both TP- and HO-1-positive macrophages could be observed in the stroma in and around tumors in vertical growth melanomas.