British Journal of Dermatology

doi: 10.1093/bjd/ljae360.021pmid: N/A

Pustular psoriasis is a devastating subtype of psoriasis associated with significant morbidity and mortality. Pustular psoriasis is the only form of psoriasis that shows prominent sex bias, with the majority of cases found in women. Pustular psoriasis, and to a lesser extent plaque psoriasis, is characterized by the prominent involvement of the IL-36 family of cytokines, which consists of three pro-inflammatory cytokines: IL-36A, IL-36B and IL-36G, and the IL-36 receptor antagonist (IL-36RA/IL36RN). All three IL-36 members and the IL-36 receptor antagonist are increased (5- to 10-fold) in psoriatic skin. Single-cell and spatial-seq data demonstrated that IL-36 responses are primarily localized to the supraspinous compartment of the epidermis and strongly correlate with and act downstream of both IL-17A and TNF responses. CRISPR/Cas9 targeted knocking out of each IL-36 family member in keratinocytes demonstrates that both IL36G and IL36R KOs, but not IL36A KO, suppress both IL-17A and TNF responses (P < 0.001). Notably, the suppressive role of IL36G KO occurred in the absence of neutrophil proteases, which have been considered primary activators of the IL-36 axis in the skin. Bulk RNA-seq data from primary keratinocytes (n = 47) showed marked sex bias in IL-36G response, with female keratinocytes having a more robust pro-inflammatory response to IL-36G compared with male keratinocytes (P < 0.001). Furthermore, female keratinocytes showed higher expression of the type I IFN, IFNK (P < 0.001; FC-3.84), and IFN signature genes, such as MX1 (P < 0.001; FC-4.78), indicating an association between IFN-κ and the IL-36 axis in female keratinocytes. These data provide novel insights into IL-36 biology, demonstrate its role in amplifying IL-17 and TNF responses in the epidermis, and suggest that the sex bias of IL-36 response may contribute to the marked female bias of pustular forms of psoriasis.

doi: 10.1093/bjd/ljae360.128pmid: N/A

The extracellular matrix (ECM) is a non-cellular network in all tissues and organs. Collagens are the most abundant proteins in the ECM, and their role is to maintain the tissue architecture of the different layers of the skin. Blood-based biomarkers of ECM fragments have previously been shown to be diagnostic and pharmacodynamic in psoriatic arthritis (PsA) and spondylarthritis. This study aimed to investigate whether ECM biomarkers can differentiate between patients with moderate-to-severe psoriasis (PSO) and healthy controls (HCs) and to determine the potential of ECM biomarkers as pharmacodynamic biomarkers in patients with PSO. This was a case–control study of patients with moderate-to-severe PSO, defined as psoriasis area and severity index (PASI) ≥8, not receiving systemic anti-psoriatic treatment at inclusion, and age-, sex- and body mass index-matched HCs. From each participant, EDTA plasma was collected at inclusion and 3–6 months after successful treatment response (defined as PASI ≤ 2 after treatment) with adalimumab. A panel of 11 ECM biomarkers was measured in EDTA plasma using validated ELISAs and Immunodiagnostic systems automated chemiluminescent assays. A P-value below 0.05 was considered statistically significant. The differences in biomarker levels between patients with PSO and HC were analysed using an unpaired t-test. The pharmacodynamic effect in patients with PSO with successful treatment response (PASI ≤ 2), was analysed using a paired t-test. Pearson correlation was used to detect any potential association between biomarkers and PASI severity. The study comprised 59 patients with PSO and 52 HC. The median PASI among patients with PSO was 10.0 (8.0–36.8), and 15% (9 patients) had physician-diagnosed PsA. We observed significantly elevated levels of PRO-C3, assessing tissue fibrosis (P = 0.028), and PRO-C4, assessing epidermal basement membrane turnover (P = 0.014), in patients with PSO compared with HC. No differences were observed in the remaining biomarker levels between patients with PSO and HC. Furthermore, no correlations were identified between PASI and biomarker levels. A significantly elevated level of ELP-3 (P = 0.024), indicative of neutrophil activity and elastin degradation, was observed in the nine patients with PSO having PsA compared with HC. Notably, the successful treatment of nine patients with PSO using adalimumab did not significantly change PRO-C3 and PRO-C4 levels. The results demonstrated that the levels of PRO-C3 and PRO-C4 were elevated in patients with PSO compared with HC. However, treatment of psoriasis did not modulate these biomarkers. Our findings underline the need for further research to explore the potential of ECM biomarkers in psoriasis.

doi: 10.1093/bjd/ljae360.107pmid: N/A

Bimekizumab (BKZ) has shown rapid normalization of the psoriatic skin transcriptome and tissue-resident memory T-cell (Trm) signatures by Week (Wk)8, which may promote clinical response durability. Questions remain on the very early/longer-term effects of BKZ on key inflammatory pathways/mechanisms behind observed rapid, high, durable clinical responses in patients with psoriasis and psoriatic arthritis (PsA). We describe a study designed to investigate molecular/cellular changes associated with BKZ responses; we hypothesize that fast, durable, complete normalization of inflammatory biomarkers correlates with rapid, high, long-term clinical responses. BE UNIQUE is an ongoing multicentre Phase 3b study enrolling adults with moderate-to-severe psoriasis [psoriasis area and severity index (PASI) ≥12, body surface area (BSA) ≥10%, IGA ≥3]: 40 without concomitant PsA (Cohort A), 40 with concomitant active PsA (Cohort B). Active PsA is defined as disease meeting Classification Criteria for Psoriatic Arthritis, ≥1 tender joint count and ≥1 swollen joint count (SJC). In Part 1, patients will receive BKZ 320 mg every 4 weeks (Q4W) to Wk16, then Q8W to Wk48. In Part 2 (Wks48–96), patients with PASI = 0 [and low PsA activity for Cohort B (SJC≤1 and no increase in concomitant medications for PsA symptom treatment vs. baseline)] will be randomized 1:1 to BKZ Q8W or Q12W; patients with PASI >0 and/or without low PsA activity will continue on BKZ Q8W. Lesional skin biopsies will be taken at baseline/Wk1/48/96 and non-lesional skin biopsies at baseline/Wk48, with optional synovial tissue biopsy at baseline/Wk48 for Cohort B. Randomized patients with a PASI >3 during Part 2 will enter an escape period and receive BKZ Q8W to study end; a lesional skin biopsy will be taken on escape period entry, rather than Wk96. Biopsies will undergo transcriptomics. Blood samples will be collected. Baseline skin biopsies/blood samples will be taken from a matching Control Cohort (10 healthy individuals). Primary objective: assess gene expression score changes using reverse transcription-polymerase chain reaction of skin biopsies, using preselected genes based on BKZ mechanism of action/psoriatic disease pathways, including CCL20/CXCL1/CXCL8/IL12B/IL17A/IL17C/IL17F/IL23A/IL36A/IL36G/KRT16/S100A7, alongside markers of tissue-specific T-cell populations, for example, Trms. Secondary objective: evaluate BKZ safety/tolerability. Exploratory objectives include investigating BKZ effect on skin and blood bulk/single cell/spatial transcriptomics, BKZ systemic effects on gene/protein expression and BKZ clinical response. BE UNIQUE will enable the exploration of mechanisms underlying rapid, high, durable clinical responses observed with BKZ treatment and whether clinical response durability is associated with molecular/cellular changes in skin, blood and joints in psoriatic disease.

doi: 10.1093/bjd/ljae360.061pmid: N/A

The WHO has highlighted the necessity of gaining a deeper understanding of the global burden of psoriasis. In response to this need, the Global Psoriasis Atlas was established to conduct comprehensive research into the global prevalence and incidence of psoriasis. We aimed to systematically review and present up-to-date data on the incidence of psoriasis, as well as to quantify its prevalence at global, regional, and country-specific levels. Literature searches were updated from 2019 to January 2024, resulting in 48 new studies. Among these, 13 studies reported incidence data, 7 reported only incidence, 6 reported both prevalence and incidence, and the remaining 35 studies reported only prevalence. In total, our updated prevalence analysis included 170 population-based epidemiological studies. A Bayesian hierarchical linear mixed model was employed to estimate the global, regional, and country-specific prevalence of psoriasis. Countries were mapped according to the global burden of disease (GBD) classification, considering geography and income. The data were fitted to a statistical model using Bayesian inference, sampling from a posterior distribution through a Hamiltonian Markov chain Monte Carlo method implemented in the RStanArm package in R (version 4.4.0). The updated review incorporated data from eight new countries and expanded to cover two additional GBD global regions. We observed a global increase in the prevalence of psoriasis, with some variations attributed to the significant expansion with the update of certain very sparse datasets. The crude lifetime prevalence for adults in high-income countries increased from 1.12% [95% confidence interval (CI): 0.39, 2.79] to 1.40% (95% CI: 0.52, 3.25). In the Latin America and Caribbean super-region, prevalence rates appear to have slightly decreased, but this finding is based on a very low evidence base, with no studies on psoriasis prevalence included from Caribbean countries. Most of the newly added studies were from high-income countries, with 70% originating from Western Europe, North America, and high-income Asian countries. The incidence of psoriasis varied from 23.14 per 100 000 person years in Taiwan to 321.0 per 100 000 person years in Italy. The incidence of psoriasis was higher in adults than in children. Seventy-six per cent of countries worldwide lack data on the epidemiology of psoriasis. The prevalence of psoriasis is higher in adults compared with children. Additionally, the distribution of psoriasis varies geographically, with higher frequency observed in high-income countries and regions with older populations. These estimates can assist countries and the international community in making informed public health decisions regarding the appropriate management of psoriasis and in monitoring changes over time.

doi: 10.1093/bjd/ljae360.005pmid: N/A

Psoriasis is a systemic inflammatory condition characterized by inflamed plaques on the skin that is associated with an increased risk of cardiovascular disease (CVD) including myocardial infarction, hypercholesterolaemia, and hypertension. It is hypothesized that the systemic inflammation associated with psoriasis contributes to the development of CVD; however, the precise mechanism(s) and the impact of systemic therapy remain unknown. We previously demonstrated that circulating monocytes from individuals with psoriasis exhibit a hyperactivated adhesive transcriptional gene expression endotype. Additionally, patients with elevated monocyte doublets at baseline had normalization of these levels following treatment with apremilast. This suggests that aberrant adhesive monocytes contribute to CVD in psoriasis and that apremilast may not only be effective at treating cutaneous disease but may also have cardioprotective effects via monocyte modulation. Our goals were to (i) identify the top differentially expressed genes (DEGs) and associated pathways in psoriasis patients circulating CD14+ monocytes following treatment with apremilast through a prospective cohort study, and (ii) determine if psoriasis patients treated with apremilast have a lower relative risk of CVD vs. those treated with topical corticosteroid (TCS) alone through a retrospective cohort analysis. First, we conducted a prospective cohort study of 14 individuals with psoriasis where CD14+ monocytes were negatively selected from whole blood for transcriptome analysis at baseline and 16 weeks post-treatment. Next, a retrospective cohort study using TriNetX was utilized to determine if apremilast treatment in psoriasis is associated with a lower relative risk (RR) for developing CVD within 5 years compared with those receiving TCS. The top DEGs post-treatment included KCNS1, WNT4, and CASS4 (increased) and ID1, ENKUR, and PIM1 (decreased). Key pathways identified were macrophage differentiation, NADPH oxidase complex activation, and lipoprotein clearance. In the retrospective analysis, 9269 individuals in each group (apremilast vs. TCS) were matched for age, sex, body mass index, race, Type 2 diabetes mellitus, nicotine dependence, alcohol-related disorders, chronic kidney disease, aspirin, antilipemic agents and anticoagulation. Comparisons between individuals treated with apremilast vs. TCS revealed that apremilast treatment was associated with a lower RR of new-onset myocardial infarction (0.754; 0.606–0.939), cerebral infarction (0.667; 0.542–0.820), deep vein thrombosis (0.812; 0.662–0.997), and hypertension (0.702; 0.633–0.778). Concordant with the finding that apremilast modified monocytes lipoprotein clearance, apremilast treatment resulted in reduced risk of hypercholesterolaemia (0.671; 0.610–0.738) and elevated low-density lipoprotein (0.628; 0.532–0.742) relative to those receiving TCS alone. In conclusion, apremilast therapy reduces the risk of new-onset CVD, hypertension, and thrombotic events in individuals with psoriasis, which may be mediated by alteration of circulating monocyte reactive oxygen species and lipoprotein clearance.

doi: 10.1093/bjd/ljae360.082pmid: N/A

The efficacy and safety of guselkumab, a fully human IL-23p19-subunit inhibitor, has been established in DISCOVER-1 and -2 studies. This post hoc analysis evaluates guselkumab efficacy through Week (W)100 in Bionaive psoriatic arthritis (PsA) patients with severe disease activity (DA) based on a range of composite and patient-reported outcomes. In DISCOVER-2, Bionaive adults with active PsA (≥5 swollen and ≥5 tender joints, CRP ≥0.6 mg/dL) received (1:1:1) guselkumab 100 mg every 4W (Q4W); guselkumab 100 mg at W0, W4, Q8W; or placebo with crossover to guselkumab Q4W at W24. Severe DA was defined by clinical DA Index for PsA (cDAPSA >27), PsA DA Score (PASDAS ≥5.4), and patient global assessment (PtGA ≥80 mm) criteria. Least square mean (LSM) changes from baseline were estimated with mixed models for repeated measures, adjusted for treatment group, baseline outcome levels, and study stratification factors (baseline csDMARD use, high-sensitivity serum CRP). Among 739 DISCOVER-2 patients, 648 (88%), 639 (86%), and 218 (29%) met cDAPSA (mean = 49.5), PASDAS (mean = 6.8), and PtGA (mean = 89.0) criteria for severe DA. Baseline characteristics and treatment groups were generally consistent across severe DA cohorts, except guselkumab Q4W group had a higher proportion of males and dactylitis than placebo. In multivariate analyses, irrespective of the severe DA cohort, significantly greater improvements were observed in guselkumab-treated patients vs. placebo in all evaluated endpoints (largest effect observed in severe PtGA cohort). Guselkumab showed clinically meaningful improvements at W2 for cDAPSA (guselkumab Q4W: −5.9; Q8W: −7.2; placebo: −5.0) and W8 for PASDAS (guselkumab Q4W: −1.5; Q8W: −1.5; placebo: −0.9) and PtGA (guselkumab Q4W: −30.0; Q8W: −32.1; placebo: −17.4). The LSM differences between guselkumab Q4W/Q8W and placebo were enhanced through W24 across severe DA cohorts, at which time further improvements with guselkumab occurred, resulting in significant (P < 0.001) differences of −9.8/−9.0 for cDAPSA, −1.1/−1.1 for PASDAS, and −24.0/−20.2 for PtGA. Further improvements were observed through 2 years of guselkumab treatment in all evaluated outcomes (LSM difference from BL: ΔcDAPSA, ∼−36; ΔPASDAS, ∼−3.6; ΔPtGA, ∼−56) representing ∼73%, ∼53%, and ∼63% improvements in joint DA, PsA activity across domains, and patient-reported overall DA. Guselkumab demonstrated rapid (W2 for joint and W8 for overall DA) and clinically meaningful improvements in DA in Bionaive PsA patients with severe DA in a range of joint-focused and multi-domain outcomes; these improvements were further enhanced by W24 and sustained through 2 years. Overall, findings support the use of guselkumab in PsA patients with severe DA.

doi: 10.1093/bjd/ljae360.046pmid: N/A

The prevalence of Psoriasis in African populations ranges from 0.05 to 1%, compared with 2–3% reported in Caucasian populations.1,2 Some postulate that the low prevalence in African studies may be due to missed or misdiagnoses as tinea corporis or non-specific dermatitis by non-dermatologists due to a scarcity of dermatologists and dermatopathologists.1,2 Information on psoriasis in Nigerians is needed, being the most populous dark-skinned nation in the world, as clinical and genetic variations could influence therapeutic approaches to its management. This project was to develop a psoriasis registry, the first in Nigeria, that will document psoriasis patients’ clinical, epidemiological and biochemical characteristics. Our Roadmap included developing the Psoriasis Registry team, writing the proposal, and seeking ethics clearance from the National Human Research and Ethics Committee of Nigeria and the committees at the participating centres. Investigators were trained on diagnosis, assessment, and instruments, including PASI, DLQI, and body surface area, as well as datasheets and protocols and data entry into the website https://psoriasis.org.ng. Bimonthly meetings are held to assess the challenges and progress. This collaborative effort comprised the principal investigator (PI), three co-PIs, and over 60 co-investigators from Dermatology clinics across Nigeria’s six geopolitical regions. The proposal and protocols have received approval from the National Human Research and Ethics Committee of Nigeria (NHREC/01/01/2007 – 08/11/202333). Data entry started in January, and we are about 6 months into the project. Preliminary results show about equal frequencies of psoriasis in both males and females. Chronic plaque psoriasis is the most common clinical type, and all the clinical types have been documented. This study, with the cohort developed, will form the foundation for further studies of psoriasis in Nigeria, particularly genetic studies. It will potentially improve the understanding and management of psoriasis across Nigeria’s six geopolitical zones and the skin of colour population.

doi: 10.1093/bjd/ljae360.020pmid: N/A

The psoriasis area and severity index (PASI) is the gold standard for assessing psoriasis severity but is time-consuming, subjective, poorly reproducible, and requires face-to-face interaction between clinician and patient. Automating PASI assessments using deep learning-based image analysis may provide a more objective, efficient measure of disease severity in trial and real-world settings. Most studies have used Convolutional Neural Networks.1 However, Vision Transformers (ViTs) are sophisticated deep learning models that have shown unprecedented capabilities in image analysis, including classifying skin lesions from dermoscopic images and 3D image (computed tomography/magnetic resonance imaging scan) analysis. We sought to develop and evaluate a ViT model for automated PASI using images. Following consent, adults with chronic plaque psoriasis were recruited via a UK national specialized psoriasis service (04/2021–05/2024). Professional studio photographs (five standardized views) and self-taken photographs (three views) were captured. Two blinded, independent face-to-face physician PASI measures were recorded, with the first rater used as the primary reference value. Fitzpatrick Skin Type and Physician Global Assessment (PGA) were also noted. We trained our ‘MultiViT’ model over 300 epochs and tested using an 80:20 split of the participants. MultiViT advances beyond standard ViTs by handling multiple images and resolutions simultaneously. Mean absolute error (MAE) was used to assess prediction accuracy and compare the standard ViT models with the MultiViT. We captured 1109 images from 152 participants; 63% were male, median age of 45.5 years [interquartile range (IQR) 33.75–57.0], median body mass index of 29.68, 84% Fitzpatrick Skin Types I–IV, and 16% V and VI. The majority (76%) had mild-to-moderate disease (PGA ≤3); median PASI was 8.2 (IQR 5.7–12.7). The MultiViT model demonstrated an MAE of 3.88 for predicting PASI from skin images vs. 5.13 for the standard ViT. When stratified by skin type, I–IV performed better than V and VI (MAE of 2.80 and 8.17, respectively), and by disease severity, PGA ≤3 performed better than PGA >3 (MAE of 1.97 and 9.13, respectively). Our findings suggest the MultiViT model offers potential for automated psoriasis severity assessments from skin images, with favourable prediction accuracy despite a small dataset. An expanded and more diverse (Fitzpatrick Skin Type, severity) dataset will enable further refinement, validation and testing of the MultiViT model in trial and real-world settings. Future integration into a smartphone application will facilitate self-monitoring of psoriasis and healthcare efficiency for improved health and cost outcomes in psoriasis.

doi: 10.1093/bjd/ljae360.100pmid: N/A

Bimekizumab was approved by the European Medicines Agency for the treatment of moderate-to-severe plaque psoriasis in August 2021. Bimekizumab is the only biologic that exerts specific inhibition of interleukin (IL)-17A and IL-17F. Few real-world studies have assessed the drug survival of bimekizumab. We assessed the 1-year all-cause drug survival of the tumour necrosis factor (TNF)-α inhibitor adalimumab, the IL-12/23 inhibitor ustekinumab, the IL-17 inhibitors secukinumab, ixekizumab, brodalumab, and bimekizumab, and the IL-23 inhibitor guselkumab. We used data on adult patients with psoriasis that were extracted from a nationwide prospective psoriasis database in February 2024. Survival functions were estimated using the Kaplan–Meier method. Hazard ratios (HRs) were estimated using a Cox proportional hazards model adjusted for the a priori-defined covariates age, sex, body weight, psoriatic arthritis (PsA), and previous number of biologics. Proportional hazards and linearity were assessed using the cumulative residuals. If the proportionality assumption was violated, we explored the time-varying effects of covariates. We included 4165 patients with 6554 treatment series. There were 3064 treatment series with adalimumab, 1498 with ustekinumab, 856 with secukinumab, 555 with ixekizumab, 195 with brodalumab, 192 with bimekizumab, and 194 with guselkumab. The crude 1-year all-cause drug survival was highest for bimekizumab (83.7%) followed by ustekinumab (79.2%), guselkumab (76.5%), ixekizumab (73.9%), adalimumab (71.4%), secukinumab (70.1%), and brodalumab (60.3%). In the Cox proportional hazards model, we found that bimekizumab had a significantly lower discontinuation hazard than all the other investigated biologics except guselkumab [HR, 1.26; 95% confidence interval (CI), 0.76–2.09]. Compared with bimekizumab, the HR was 1.55 (95% CI, 1.00–2.39) for ixekizumab, 1.56 (95% CI, 1.03–2.38) for ustekinumab, 2.25 (95% CI, 1.48–3.43) for secukinumab, 2.61 (95% CI, 1.65–4.13) for brodalumab, and 2.65 (95% CI, 1.75–4.01) for adalimumab. The analysis found that sex and PsA had time-varying effects. The hazard was 135% higher for females compared with males (HR, 2.35; 95% CI, 1.95–2.84) in the first 100 days and, among those still on treatment after 100 days, the HR decreased to 1.57 (95% CI, 1.40–1.78). In the first 100 days, PsA was protective (HR, 0.69; 95% CI, 0.56–0.86) but PsA had no protective effect for those still on treatment after 100 days (HR, 0.98; 95% CI, 0.86–1.11). In conclusion, bimekizumab had the highest 1-year all-cause drug survival compared with adalimumab, ustekinumab, secukinumab, ixekizumab, and brodalumab but not guselkumab. Data on the long-term drug survival of bimekizumab, as well as the drug survival associated with effectiveness and safety, are needed.

doi: 10.1093/bjd/ljae360.030pmid: N/A

Following the advent of biologic therapies for chronic plaque psoriasis, achieving clear/nearly clear skin (disease control) has become a realistic goal. Patients currently continue high-cost biologic therapy indefinitely once they have achieved disease control, which leads to a long-term drug and healthcare burden. Clinical trial data indicate that some individuals can maintain disease control with less frequent doses, especially those who have higher serum drug concentrations, indicating a role for therapeutic drug monitoring (TDM) in guiding dosing decisions. To enable real-world implementation of TDM-guided precision dosing of biologics, we developed, validated, and beta-tested an online interactive TDM dashboard, powered by a pharmacokinetic (PK) model. We searched for population PK models of the exemplar psoriasis biologic risankizumab in PKPDAI and PubMed databases. We externally validated the PK model using an independent multicentre real-world UK psoriasis dataset (n = 50 patients, BSTOP study) prior to embedding it within an online R Shiny interactive dashboard. Two rounds of beta-testing of the TDM dashboard were performed with healthcare professionals to assess usability. A two-compartment PK model with first-order absorption and elimination processes was identified. The PK model was based on Phase I–III trial data and adopted a nonlinear mixed effects approach (13 123 observations from 1899 patients; 71% male; median age, 47; median weight, 97 kg; Suleiman et al., Clin Pharmacokinet 2019). We integrated the model into an online R Shiny interactive dashboard, which generates a personalized dosing interval for risankizumab. The model is used as a Bayesian prior, to predict individual patient parameters using their serum drug concentrations, dose history and other covariates (weight, serum concentrations of anti-drug antibody, albumin and creatinine). Individual predictions were externally validated (mean absolute error 0.95 mg/L; mean percentage error 17.6%; root mean square error 1.7 mg/L; R2 0.8). Beta-testing sessions with 29 clinicians (58% female; mean age 41; 33% doctor; 42% nurse) from 8 UK dermatology centres showed above-average usability of the dashboard (mean System Usability Scale score 72/100, rating ‘good’). All participants evaluated the dashboard as user-friendly and rated it acceptable or completely acceptable. Mean time to generate a dosing interval using the dashboard was 1.9 min (SD 1.2). Mean time to generate a dosing interval using the dashboard was 1.9 min (SD 1.2). Our study provides a novel pipeline for the implementation of TDM-enabled precision dosing of biologics in real-world practice. Our user-friendly online TDM dashboard has the potential to incorporate other biologic therapies and can be extended across disease contexts (including non-response and other immune-mediated inflammatory diseases) for maximal real-world health benefits and cost saving.