Baricitinib Improvement Across Regions in Atopic Dermatitis Patients with Baseline Body Surface Area up to 40% and Severe Itch.

INTRODUCTION: Patients with moderate-to-severe atopic dermatitis (AD) who are most likely to respond to the Janus kinase (JAK) 1/2 inhibitor baricitinib (BARI) are known to have an impacted body surface area (BSA) ≤ 40% and severe itch (numerical rating scale [NRS] ≥ 7], collectively termed 'BARI itch-dominant' patients. Our objective is to build on our previous work by providing a body region-specific, clinical characterization of the BARI itch-dominant patient at baseline and their response to BARI 4 mg. METHODS: BREEZE-AD7 was a phase 3 trial in adults with moderate-to-severe AD receiving placebo or 2 mg or 4 mg BARI in combination with topical corticosteroids. Assessing only data from BARI itch-dominant patients, we summarized the baseline characteristics and conducted body region-specific analyses on Eczema Area and Severity Index (EASI) data in order to report the response to placebo versus BARI 4 mg within this patient subtype. RESULTS: BARI 4 mg was highly effective across all body regions; at week 16, 75% improvement was seen in EASI scores (EASI75), and response rates with BARI 4 mg (head/neck, 58.3%; trunk, 69.2%; upper extremities, 61.5%; lower extremities, 87.5%) all exceeded those with placebo (head/neck: 37.5%; trunk, 40.6%; upper extremities, 18.8%; lower extremities, 40.6%) as well as the overall EASI75 rates of the intent-to-treat (ITT) population (BARI, 48.0%; placebo, 23.0%). At baseline, most BARI itch-dominant patients presented with involvement of all regions (mean regional BSA 22.7%-40.3%), highest in the head and neck, mean EASI region scores of 15.7-24.0, and considerably severe sign ratings (mean EASI sub-scores: 1.4-2.3, out of 3), especially for erythema. CONCLUSION: BARI itch-dominant patients exhibit AD involvement across all body regions and considerable sign severity, especially erythema. In response to BARI 4 mg, EASI quickly improved across regions, substantially more so in this subtype than in the ITT population.

Real world evidence: patients with alopecia areata in Italy.

BACKGROUND: This real-world analysis aimed at characterizing patients hospitalized for alopecia areata (AA) in Italy, focusing on comorbidities, treatment patterns and the economic burden for disease management. METHODS: Administrative databases of healthcare entities covering 8.9 million residents were retrospectively browsed to include patients of all ages with hospitalization discharge diagnosis for AA from 2010 to 2020. The population was characterized during the year before the first AA-related hospitalization (index-date) and followed-up for all the available successive period. AA drug prescriptions and treatment discontinuation were analyzed during follow-up. Healthcare costs were also examined. RESULTS: Among 252 patients with AA (mean age 32.1 years, 40.9% males), the most common comorbidities were thyroid disease (22.2%) and hypertension (21.8%), consistent with literature; only 44.4% (112/252) received therapy for AA, more frequently with prednisone, triamcinolone and clobetasol. Treatment discontinuation (no prescriptions during the last trimester) was observed in 86% and 88% of patients, respectively at 12 and 24-month after therapy initiation. Overall healthcare costs were 1715€ per patient (rising to 2143€ in the presence of comorbidities), mostly driven by hospitalization and drugs expenses. CONCLUSIONS: This first real-world description of hospitalized AA patients in Italy confirmed the youth and female predominance of this population, in line with international data. The large use of corticosteroids over other systemic therapies followed the Italian guidelines, but the high discontinuation rates suggest an unmet need for further treatment options. Lastly, the analysis of healthcare expenses indicated that hospitalizations and drugs were the most impactive cost items.

Effectiveness of Biologics, Patient-Reported Outcomes, and Clinical Photography in a Subset of Patients with Moderate-to-Severe Psoriasis: Week 12 Results from the Psoriasis Study of Health Outcomes (PSoHO).

Purpose: Since skin is highly accessible, clinical photography is a useful tool to visually substantiate the real-world effectiveness outcomes of biologic-treated adults with moderate-to-severe psoriasis (PsO). We report the effectiveness and patient-reported outcomes at Week 12 between anti-interleukin (IL)-17A biologics and other biologics as well as ixekizumab and guselkumab in patients with available clinical photography at baseline and Week 12. Patients and Methods: The Psoriasis Study of Health Outcomes (PSoHO) is an international, non-interventional, cohort study investigating the effectiveness of biologics in adults with moderate-to-severe psoriasis at Week 12. Outcomes included the proportion of patients who achieved 90% improvement in Psoriasis Area and Severity Index (PASI90) and/or static Physician Global Assessment (sPGA) 0/1 (primary endpoint), PASI100, PASI90, Dermatology Life Quality Index (DLQI), and Itch Numeric Rating Scale (NRS) (secondary endpoints) at Week 12. Data are reported descriptively. Results: This analysis included 59 biologic-treated (23 anti-IL-17A; 36 other biologics) patients with available clinical photographs from the overall PSoHO study (n=1981). At baseline, the mean (standard deviation [SD]) age was 45.7 (11.1) years, 71.2% were male, 52.5% were bio-experienced and the median (interquartile range) duration of disease was 10.5 (12.4) years. Mean (SD) PASI was 16.9 (9.3) and sPGA was 3.5 (0.8). At Week 12, 65.2%/47.2% of the anti-IL-17A/other biologics cohort achieved the primary outcome. Response rates for PASI90/100 were numerically higher with anti-IL-17A than with other biologics. Patients receiving anti-IL-17A had numerically better outcomes for DLQI 0/1 and Itch NRS than those receiving other biologics at Week 12. Clinical photographs confirmed skin improvements in ixekizumab- and guselkumab-treated patients. Conclusion: This subgroup analysis showed that anti-IL-17A biologics are effective at rapidly improving signs and symptoms of PsO and improving quality of life. Additionally, serial photography provided visual evidence of biologic treatment response over time.

Cost-effectiveness analysis of baricitinib versus dupilumab for moderate to severe atopic dermatitis: an Italian healthcare system perspective.

AIMS: To assess, within the Italian healthcare system, the cost-effectiveness of baricitinib versus dupilumab, both in combination with topical corticosteroids (TCS), in adults with moderate to severe atopic dermatitis (AD) who are eligible for but have failed, have contraindications to, or cannot tolerate ciclosporin. MATERIALS AND METHODS: Using the perspective of the Italian healthcare payer, direct medical costs associated with each intervention were estimated over a lifetime horizon. A Markov cohort model utilized the proportions of patients with ≥75% improvement Eczema Area and Severity Index obtained from clinical trials. Health outcomes were evaluated in quality-adjusted life years (QALYs) to assess the cost effectiveness of baricitinib against a willingness-to-pay threshold of €35,000 per QALY gained. RESULTS: In the base case, with secondary censoring applied, patients treated with dupilumab or baricitinib, in combination with TCS, accumulated total costs of €135,780 or €129,586, and total QALYs of 18.172 or 18.133, respectively. The incremental cost-effectiveness ratio of dupilumab versus baricitinib was estimated at €160,905/QALY. LIMITATIONS: Core assumptions were needed to extrapolate available short-term clinical trial data to lifelong data, adding uncertainty. Benefits of baricitinib seen in clinical trials and not assessed in dupilumab clinical trials were not included. Discontinuation rates for each treatment were derived from different sources potentially introducing bias. Results may not be generalizable to other populations. CONCLUSIONS: This cost-effectiveness analysis shows that, from the Italian healthcare payer perspective, in the treatment of patients with moderate to severe AD who have experienced failure on, are intolerant to, or have contraindication to ciclosporin, dupilumab cannot be considered cost-effective when compared with baricitinib. Given its oral administration, favorable risk/benefit profile and lower acquisition cost compared with dupilumab, baricitinib may offer a valuable, cost-effective treatment option-after failure on conventional systemic agents-for patients with moderate to severe AD in Italy.

Baricitinib is the first oral systemic treatment for patients with moderate to severe atopic dermatitis (AD). The drug was effective for treating patients with AD in clinical trials, producing improvements in skin inflammation, itch, sleep disturbances due to itch and skin pain, as well as the quality of life of patients. However, it is important to ensure that healthcare funds are well spent. We therefore compared the cost-effectiveness of baricitinib, with another new systemic treatment for AD, dupilumab, (both in combination with topical corticosteroids) in patients with moderate to severe AD who are eligible for but have failed or are unable to take ciclosporin, in Italy. We found that using dupilumab to treat these patients with AD cost more than using baricitinib, although dupilumab was more effective. Combining these considerations showed that the cost of obtaining the additional benefit from dupilumab over baricitinib was not cost-effective for the Italian healthcare system. Baricitinib may be a better treatment option because it is given orally, has a favorable balance between the risks and benefits of treatment, and costs less than dupilumab.

Ixekizumab is effective in the long-term management in moderate-to-severe plaque psoriasis: results from an Italian retrospective cohort study (the LOTIXE study).

PURPOSE: Ixekizumab is a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A approved for the treatment of moderate-to-severe plaque psoriasis. The objective of this study was to describe the real-world long-term effectiveness of ixekizumab in patients with plaque psoriasis in Italy. MATERIALS AND METHODS: A retrospective study was conducted in patients affected by moderate-to-severe plaque psoriasis who were continuously treated with ixekizumab for at least 12 months. Patient data was obtained at 4-weeks, 12-weeks and 6-, 12-, 18- and 24-months after baseline (June 2017 and September 2019) from 10 sites. Results were analyzed by complete case approach, with sensitivity analysis performed to evaluate the impact of missing data. RESULTS: A total of 198 patients were enrolled in the study. At Month 24, 94.3% of patients achieved PASI75 response, while 85.1 and 71.8% achieved PASI90 and PASI100, respectively; and 91.1% of the patients achieved absolute PASI score ≤2. Patients experienced psoriasis improvement at 4 weeks after starting treatment, and improvement was maintained with continued ixekizumab use. The quality of life of patients also improved significantly starting at Week 12, with sustained effect in the long term. CONCLUSION: This 24-month observational cohort study confirmed that ixekizumab is effective in the long-term management of patients with moderate-to-severe plaque psoriasis.

Analysis of Drug Utilization in Patients with Psoriasis: A Real-World Retrospective Study Among the Italian Population.

Purpose: An Italian real-world retrospective study was conducted in patients with psoriasis (PSO) to evaluate their characteristics, treatment patterns, and biological/targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) drug utilization. Patients and Methods: The retrospective analysis was carried out on real-world data collected from administrative databases of selected Italian health-departments; the dataset covered approximately 22% of the Italian population. PSO patients (identified by PSO hospitalization, and/or active exemption code and/or a topical anti-psoriatic medication prescription) were included. In prevalent patients identified during 2017-2018-2019-2020, baseline characteristics and treatment patterns were investigated. Moreover, b/tsDMARD drug utilization (focusing on persistence, monthly dosage, and mean duration between prescriptions) was evaluated in bionaïve patients included during 2015 and 2018. Results: PSO was diagnosed in 241,552 (in 2017), 269,856 (in 2018), 293,905 (in 2019) and 301,639 (in 2020) patients. At the index date, almost 50% of patients had not received systemic medications, and 2% had received biological treatment. Among the b/tsDMARD-treated patients, a decrease in the use of tumour necrosis factor (TNF) inhibitors (60.0-36.4%, from 2017 to 2020) and an increase in the use of interleukin (IL) inhibitors (36.3-50.6%, from 2017 to 2020) were observed. In 2018, the persistence rates of TNF inhibitors and IL inhibitors in bionaïve patients ranged from 60.8-79.7% and 83.3-87.9%, respectively. Conclusion: This real-world study of PSO drug utilization in Italy showed that a significant number of patients were not treated with systemic medications and only 2% of patients were treated with biologics. An increase in the use of IL inhibitors and a decrease in the prescription of TNF inhibitors over years were found. Patients treated with biologics were highly persistent with treatment. These data provide insight into routine clinical practice for PSO patients in Italy, suggesting that the optimization of treatment for PSO still represents an unmet medical need.

GLUT1 Expression in Tumor-Associated Neutrophils Promotes Lung Cancer Growth and Resistance to Radiotherapy.

Neutrophils are the most abundant circulating leucocytes and are essential for innate immunity. In cancer, pro- or antitumor properties have been attributed to tumor-associated neutrophils (TAN). Here, focusing on TAN accumulation within lung tumors, we identify GLUT1 as an essential glucose transporter for their tumor supportive behavior. Compared with normal neutrophils, GLUT1 and glucose metabolism increased in TANs from a mouse model of lung adenocarcinoma. To elucidate the impact of glucose uptake on TANs, we used a strategy with two recombinases, dissociating tumor initiation from neutrophil-specific Glut1 deletion. Loss of GLUT1 accelerated neutrophil turnover in tumors and reduced a subset of TANs expressing SiglecF. In the absence of GLUT1 expression by TANs, tumor growth was diminished and the efficacy of radiotherapy was augmented. Our results demonstrate the importance of GLUT1 in TANs, which may affect their pro- versus antitumor behavior. These results also suggest targeting metabolic vulnerabilities to favor antitumor neutrophils. SIGNIFICANCE: Lung tumor support and radiotherapy resistance depend on GLUT1-mediated glucose uptake in tumor-associated neutrophils, indicating that metabolic vulnerabilities should be considered to target both tumor cells as well as innate immune cells. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2345/F1.large.jpg.

Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growth.

Glucose utilization increases in tumors, a metabolic process that is observed clinically by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET). However, is increased glucose uptake important for tumor cells, and which transporters are implicated in vivo? In a genetically-engineered mouse model of lung adenocarcinoma, we show that the deletion of only one highly expressed glucose transporter, Glut1 or Glut3, in cancer cells does not impair tumor growth, whereas their combined loss diminishes tumor development. 18F-FDG-PET analyses of tumors demonstrate that Glut1 and Glut3 loss decreases glucose uptake, which is mainly dependent on Glut1. Using 13C-glucose tracing with correlated nanoscale secondary ion mass spectrometry (NanoSIMS) and electron microscopy, we also report the presence of lamellar body-like organelles in tumor cells accumulating glucose-derived biomass, depending partially on Glut1. Our results demonstrate the requirement for two glucose transporters in lung adenocarcinoma, the dual blockade of which could reach therapeutic responses not achieved by individual targeting.