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BACKGROUND: The main conventional systemic atopic dermatitis (AD) treatments are methotrexate (MTX) and ciclosporin (CyA). Dupilumab was the first novel systemic agent to enter routine clinical practice. There are no head-to-head randomised controlled trials or real-world studies comparing these agents directly. Network meta-analyses provide indirect comparative efficacy and safety data and have shown strong evidence for dupilumab and CyA. OBJECTIVES: The aim of this study was to compare the real-world clinical effectiveness and safety of CyA, dupilumab and MTX in AD. METHODS: We compared the effectiveness and safety of these systemic agents in a prospective observational 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). 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 over time, and linear mixed-effects models were used to estimate changes in efficacy scores. Treatment safety was assessed by examining adverse events (AEs) at follow-up visits. RESULTS: 488 patients (n=311 adults and n=177 children/adolescents) on dupilumab (n=282), methotrexate (n=149), or CyA (n=57) were included. CyA and MTX were primarily used first line, while dupilumab was mainly a second line systemic as per UK National Institute of Clinical and Care Excellence (NICE) recommendations. EASI-50, EASI-75 and EASI-90 were achieved more rapidly in the dupilumab and CyA groups compared to MTX. After adjustment for previous severity, the reduction in EASI, POEM, PP-NRS and DLQI was greater for patients treated with dupilumab compared to MTX. In severe patients the reduction in EASI, POEM, and PP-NRS was even greater with CyA. The incidence of AEs was similar across groups (734, 654 and 594 per 10,000 person-month on CyA, dupilumab and MTX respectively). CONCLUSIONS: This real-world comparison of CyA, dupilumab and MTX in AD suggests that dupilumab is consistently more effective than MTX and that CyA is most effective in very severe disease within one follow-up year.
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BACKGROUND: Palmoplantar pustulosis (PPP) is an inflammatory skin disorder that mostly affects smokers and manifests with painful pustular eruptions on the palms and soles. Although the disease can present with concurrent plaque psoriasis, TNF and IL-17/IL-23 inhibitors show limited efficacy. There is therefore a pressing need to uncover PPP disease drivers and therapeutic targets. OBJECTIVES: We sought to identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis. METHODS: We performed a genome-wide association meta-analysis of 3 North-European cohorts (n = 1,456 PPP cases and 402,050 controls). We then used the scGWAS program to investigate the cell-type specificity of the association signals. We also undertook genetic correlation analyses to examine the similarities between PPP and other immune-mediated diseases. Finally, we applied Mendelian randomization to analyze the causal relationship between cigarette smoking and PPP. RESULTS: We found that PPP is not associated with the main genetic determinants of plaque psoriasis. Conversely, we identified genome-wide significant associations with the FCGR3A/FCGR3B and CCHCR1 loci. We also observed 13 suggestive (P < 5 × 10-6) susceptibility regions, including the IL4/IL13 interval. Accordingly, we demonstrated a significant genetic correlation between PPP and TH2-mediated diseases such as atopic dermatitis and ulcerative colitis. We also found that genes mapping to PPP-associated intervals were preferentially expressed in dendritic cells and often implicated in T-cell activation pathways. Finally, we undertook a Mendelian randomization analysis, which supported a causal role of cigarette smoking in PPP. CONCLUSIONS: The first genome-wide association study of PPP points to a pathogenic role for deregulated TH2 responses and cigarette smoking.
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BACKGROUND: There are established risk factors for liver fibrosis (LF), but data on the impact of methotrexate on LF in patients with psoriasis are lacking. OBJECTIVES: This cross-sectional study aimed to determine the prevalence of LF in patients with psoriasis and to evaluate the relationship between LF, cumulative methotrexate dose and other LF risk factors. METHODS: Adults with a history of moderate-to-severe chronic plaque psoriasis were recruited between June 2020 and March 2021. Patients underwent transient elastography to evaluate LF. Three values for liver stiffness measurement (LSM) were assessed, indicating mild or worse LF (≥ 7 kPa), moderate or worse LF (≥ 7.9 kPa) and advanced LF (≥ 9.5kPa). Cumulative methotrexate dose and other potential risk factors for LF were assessed. RESULTS: Overall, 240 patients were recruited and 204 participants with valid LSM values were included in the analysis [median age 48â years [interquartile range (IQR) 37-57]; 51% female sex; 56% body mass index (BMI) ≥ 30 (kg m-2) and a median Alcohol Use Disorders Identification Test (AUDIT) score of 4 (IQR 1-7, 23% score ≥ 8)]. In total, 91% had received methotrexate [median duration 36â months (IQR 14-78)]. Prevalence of LF was 36%, 25% and 17% using LSM ≥ 7 kPa, ≥ 7.9 kPa and ≥ 9.5 kPa, respectively. There was no association between cumulative methotrexate dose [median 2.16 (IQR 0.93-5.2)] and continuous LSM values [unstandardized coefficient 0.16, 95% confidence interval (CI) -0.49 to 0.82, P = 0.626] or using the categorical LSM cutoff values: ≥ 7 kPa [unadjusted odds ratio 1.06 (95% CI 0.97-1.15), P = 0.192], ≥ 7.9 kPa [unadjusted odds ratio 1.03 (95% CI 0.94-1.12), P = 0.577] and ≥ 9.5 kPa (unadjusted odds ratio 1.01, 95% CI 0.91-1.12; P = 0.843). The following risk factors were associated with higher LSM values: BMI (P ≤ 0.001), waist circumference (P ≤ 0.001), metabolic syndrome (P ≤ 0.001), AUDIT score (P = 0.020) and FIB-4 score (P = 0.03). BMI ≥ 28, diabetes and metabolic syndrome were shown to be better predictors of LF compared with FIB-4 score. CONCLUSIONS: This study confirms a high prevalence of significant LF in patients with psoriasis. Cumulative methotrexate dose was not associated with LF. Patients with BMI ≥ 28, metabolic syndrome and diabetes are at higher risk for LF. These risk factors may help to identify when a more detailed liver health assessment is needed.
Psoriasis is a common inflammatory skin disease affecting 3% of the UK population. People with psoriasis appear to have higher rates of liver fibrosis (scarring in the liver from injury or inflammation) compared with people without psoriasis. There are several risk factors for increasing chances of developing liver fibrosis, including obesity, alcohol and diabetes; however, there have been some concerns that methotrexate (a medicine used to treat psoriasis) could also contribute to liver fibrosis. The majority of people needing systemic therapy (such as oral medicines) will try methotrexate first as per National Institute for Health and Care Excellence (NICE) guidance. In this study carried out in the UK, we aimed to look at the relationship between the cumulative dose (total over time) of methotrexate and liver fibrosis and the relationship between other risk factors and liver fibrosis (e.g. body mass index (BMI) (a measure that uses your height and weight to work out whether your weight is healthy), diabetes, alcohol intake and metabolic syndrome (a combination of diabetes, high blood pressure and obesity)). Liver fibrosis was measured using transient elastography, which is a non-invasive technique similar to an ultrasound. We also aimed to find out whether the clinical risk factors for liver fibrosis and a simple test called a 'FIB-4 score' (measured using blood test values and age) can predict a person's chance of developing liver fibrosis, in order to determine which people will benefit most from transient elastography. From our results, we were able to confirm that liver scarring is prevalent in our patients with psoriasis. We did not find an association between cumulative methotrexate and liver scarring. However, BMI, diabetes, metabolic syndrome and FIB-4 score were associated with liver scarring. We found that BMI ≥ 28, metabolic syndrome and diabetes can be used to identify patients who require a liver health assessment. Overall, the study findings suggest that cumulative methotrexate dose is not associated with liver fibrosis in people with a history of moderate-to-severe psoriasis.
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Técnicas de Imagem por Elasticidade , Cirrose Hepática , Metotrexato , Psoríase , Humanos , Metotrexato/efeitos adversos , Metotrexato/administração & dosagem , Psoríase/tratamento farmacológico , Psoríase/epidemiologia , Psoríase/diagnóstico , Feminino , Masculino , Pessoa de Meia-Idade , Cirrose Hepática/epidemiologia , Cirrose Hepática/induzido quimicamente , Estudos Transversais , Adulto , Fatores de Risco , Prevalência , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/administração & dosagem , Índice de Gravidade de Doença , Relação Dose-Resposta a DrogaRESUMO
Importance: Biologics used for plaque psoriasis have been reported to be associated with an atopic dermatitis (AD) phenotype, or paradoxical eczema, in some patients. The risk factors for this are unknown. Objective: To explore risk of paradoxical eczema by biologic class and identify factors associated with paradoxical eczema. Design, Setting, and Participants: This prospective cohort study used data from the British Association of Dermatologists Biologics and Immunomodulators Register for adults treated with biologics for plaque psoriasis who were seen at multicenter dermatology clinics in the UK and Ireland. Included participants were registered and had 1 or more follow-up visits between September 2007 and December 2022. Exposures: Duration of exposure to tumor necrosis factor (TNF) inhibitors, interleukin (IL) 17 inhibitors, IL-12/23 inhibitors, or IL-23 inhibitors until paradoxical eczema onset, treatment discontinuation, last follow-up, or death. Main Outcomes and Measures: Incidence rates of paradoxical eczema, paradoxical eczema risk by biologic class, and the association of demographic and clinical variables with risk of paradoxical eczema were assessed using propensity score-weighted Cox proportional hazards regression models. Results: Of 56â¯553 drug exposures considered, 24â¯997 from 13â¯699 participants were included. The 24â¯997 included exposures (median age, 46 years [IQR, 36-55 years]; 57% male) accrued a total exposure time of 81â¯441 patient-years. A total of 273 exposures (1%) were associated with paradoxical eczema. The adjusted incidence rates were 1.22 per 100â¯000 person-years for IL-17 inhibitors, 0.94 per 100â¯000 person-years for TNF inhibitors, 0.80 per 100â¯000 person-years for IL-12/23 inhibitors, and 0.56 per 100â¯000 person-years for IL-23 inhibitors. Compared with TNF inhibitors, IL-23 inhibitors were associated with a lower risk of paradoxical eczema (hazard ratio [HR], 0.39; 95% CI, 0.19-0.81), and there was no association of IL-17 inhibitors (HR, 1.03; 95% CI, 0.74-1.42) or IL-12/23 inhibitors (HR, 0.87; 95% CI, 0.66-1.16) with risk of paradoxical eczema. Increasing age (HR, 1.02 per year; 95% CI, 1.01-1.03) and history of AD (HR, 12.40; 95% CI, 6.97-22.06) or hay fever (HR, 3.78; 95% CI, 1.49-9.53) were associated with higher risk of paradoxical eczema. There was a lower risk in males (HR, 0.60; 95% CI, 0.45-0.78). Conclusions and Relevance: In this study, in biologic-treated patients with psoriasis, paradoxical eczema risk was lowest in patients receiving IL-23 inhibitors. Increasing age, female sex, and history of AD or hay fever were associated with higher risk of paradoxical eczema. The overall incidence of paradoxical eczema was low. Further study is needed to replicate these findings.
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Produtos Biológicos , Eczema , Psoríase , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Biológicos/efeitos adversos , Produtos Biológicos/efeitos adversos , Dermatite Atópica , Eczema/induzido quimicamente , Eczema/epidemiologia , Interleucina-12 , Interleucina-17 , Interleucina-23 , Estudos Prospectivos , Psoríase/tratamento farmacológico , Psoríase/epidemiologia , Rinite Alérgica Sazonal , Inibidores do Fator de Necrose Tumoral/uso terapêuticoRESUMO
BACKGROUND: Combined expression of the autophagy-regulatory protein AMBRA1 (activating molecule in Beclin1-regulated autophagy) and the terminal differentiation marker loricrin in the peritumoral epidermis of stage I melanomas can identify tumour subsets at low risk of -metastasis. OBJECTIVES: To validate the combined expression of peritumoral AMBRA1 and loricrin (AMBLor) as a prognostic biomarker able to identify both stage I and II melanomas at low risk of tumour recurrence. METHODS: Automated immunohistochemistry was used to analyse peritumoral AMBRA1 and loricrin expression in geographically distinct discovery (n = 540) and validation (n = 300) cohorts of nonulcerated American Joint Committee on Cancer (AJCC) stage I and II melanomas. AMBLor status was correlated with clinical outcomes in the discovery and validation cohorts separately and combined. RESULTS: Analysis of AMBLor in the discovery cohort revealed a recurrence-free survival (RFS) rate of 95.5% in the AMBLor low-risk group vs. 81.7% in the AMBLor at-risk group (multivariate log-rank, P < 0.001) and a negative predictive value (NPV) of 96.0%. In the validation cohort, AMBLor analysis revealed a RFS rate of 97.6% in the AMBLor low-risk group vs. 78.3% in the at-risk group (multivariate log-rank, P < 0.001) and a NPV of 97.6%. In a multivariate model considering AMBLor, Breslow thickness, age and sex, analysis of the combined discovery and validation cohorts showed that the estimated effect of AMBLor was statistically significant, with a hazard ratio of 3.469 (95% confidence interval 1.403-8.580, P = 0.007) and an overall NPV of 96.5%. CONCLUSIONS: These data provide further evidence validating AMBLor as a prognostic biomarker to identify nonulcerated AJCC stage I and II melanoma tumours at low risk of disease recurrence.
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Melanoma , Proteínas de Membrana , Neoplasias Cutâneas , Humanos , Estados Unidos , Melanoma/patologia , Prognóstico , Recidiva Local de Neoplasia/patologia , Epiderme/metabolismo , Biomarcadores , Estadiamento de Neoplasias , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
BACKGROUND: The population prevalence of multimorbidity (the existence of at least 2 or more long-term conditions [LTCs] in an individual) is increasing among young adults, particularly in minority ethnic groups and individuals living in socioeconomically deprived areas. In this study, we applied a data-driven approach to identify clusters of individuals who had an early onset multimorbidity in an ethnically and socioeconomically diverse population. We identified associations between clusters and a range of health outcomes. METHODS AND FINDINGS: Using linked primary and secondary care data from the Clinical Practice Research Datalink GOLD (CPRD GOLD), we conducted a cross-sectional study of 837,869 individuals with early onset multimorbidity (aged between 16 and 39 years old when the second LTC was recorded) registered with an English general practice between 2010 and 2020. The study population included 777,906 people of White ethnicity (93%), 33,915 people of South Asian ethnicity (4%), and 26,048 people of Black African/Caribbean ethnicity (3%). A total of 204 LTCs were considered. Latent class analysis stratified by ethnicity identified 4 clusters of multimorbidity in White groups and 3 clusters in South Asian and Black groups. We found that early onset multimorbidity was more common among South Asian (59%, 33,915) and Black (56% 26,048) groups compared to the White population (42%, 777,906). Latent class analysis revealed physical and mental health conditions that were common across all ethnic groups (i.e., hypertension, depression, and painful conditions). However, each ethnic group also presented exclusive LTCs and different sociodemographic profiles: In White groups, the cluster with the highest rates/odds of the outcomes was predominantly male (54%, 44,150) and more socioeconomically deprived than the cluster with the lowest rates/odds of the outcomes. On the other hand, South Asian and Black groups were more socioeconomically deprived than White groups, with a consistent deprivation gradient across all multimorbidity clusters. At the end of the study, 4% (34,922) of the White early onset multimorbidity population had died compared to 2% of the South Asian and Black early onset multimorbidity populations (535 and 570, respectively); however, the latter groups died younger and lost more years of life. The 3 ethnic groups each displayed a cluster of individuals with increased rates of primary care consultations, hospitalisations, long-term prescribing, and odds of mortality. Study limitations include the exclusion of individuals with missing ethnicity information, the age of diagnosis not reflecting the actual age of onset, and the exclusion of people from Mixed, Chinese, and other ethnic groups due to insufficient power to investigate associations between multimorbidity and health-related outcomes in these groups. CONCLUSIONS: These findings emphasise the need to identify, prevent, and manage multimorbidity early in the life course. Our work provides additional insights into the excess burden of early onset multimorbidity in those from socioeconomically deprived and diverse groups who are disproportionately and more severely affected by multimorbidity and highlights the need to ensure healthcare improvements are equitable.
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Multimorbidade , Aceitação pelo Paciente de Cuidados de Saúde , Adulto Jovem , Humanos , Masculino , Adolescente , Adulto , Feminino , Estudos Transversais , Análise por Conglomerados , Reino Unido/epidemiologiaRESUMO
PURPOSE: To identify the incidence, risk factors, demographics, and clinical profile of dupilumab-induced ocular surface disease (DIOSD) in patients with atopic dermatitis (AD), propose a standardised treatment protocol (STP) and evaluate the response. METHODS: Prospective case series of AD patients treated in the Dermatology Department, Royal Victoria Infirmary, Newcastle upon Tyne, UK developing ocular symptoms after commencing Dupilumab between September 2018 and February 2020. A standard history and examination protocol were used including subjective symptom severity grading and Ocular Surface Disease Index (OSDI) questionnaire on each visit. Standard treatment was prescribed, and response evaluated. RESULTS: 32 of 113 included patients (28.31%) developed DIOSD, of which 20 (62.5%) were referred to the Cornea Service. Median age was 38.0 years (IQR 26.8; range 19-74). Male to female ratio was 1:1. Average time to onset of ocular symptoms from starting dupilumab was 9.2 weeks (IQR 8.8; range 0.1-40). 90% patients had bilateral conjunctival inflammation and blepharitis at presentation. Significant improvement in the subjective severity scale and the median OSDI score (from 34.0 to 10.2) was noted in response to topical eye treatment. Dupilumab was discontinued in none. CONCLUSIONS: DIOSD is not uncommon although, with timely referral and appropriate topical treatment better clinical outcome and patient satisfaction can be achieved without the need to discontinue Dupilumab. Prior allergic conjunctivitis did not affect the incidence or severity of DIOSD. Further prospective studies with longer follow-up and more focus on possible disease mechanism such as goblet cell related changes and immune response are needed.
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BACKGROUND: Real-world data evaluating effectiveness and persistence of systemic therapies for patients with psoriasis are limited. Objectives To determine the effectiveness and persistence of acitretin, ciclosporin, fumaric acid esters (FAEs) and methotrexate in patients with moderate-to-severe psoriasis. METHODS: Data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR), a prospective, multicentre pharmacovigilance register of patients with moderate-to-severe psoriasis receiving biologic and/or conventional systemic therapies, were analysed. Eligible patients were ≥ 16â years of age receiving a first course of acitretin, ciclosporin, FAEs or methotrexate between 2007 and 2021 with ≥ 6 months' follow-up. Effectiveness was defined as achieving absolute Psoriasis Area and Severity Index (aPASI) ≤ 2 reported ≥ 4 weeks after treatment start date until date of cessation. To identify baseline clinical variables associated with treatment effectiveness, we used multivariable logistic regression models estimating the adjusted odds ratio (aOR) of achieving aPASI ≤ 2. To describe drug persistence associated with ineffectiveness, occurrence of adverse events or other reasons for discontinuation, survival estimates with 95% confidence intervals (CIs) were obtained using a flexible parametric model. Results were obtained using multiple imputed data. RESULTS: In total, 5430 patients were included in the analysis. Overall, 1023 (19%) patients were receiving acitretin, 1401 (26%) patients were on ciclosporin, 347 (6%) patients were on FAEs, and 2659 (49%) patients were receiving methotrexate at registration. The proportion of patients who achieved aPASI ≤ 2 was lower for those treated with acitretin [n = 118 (21%)] compared with those receiving ciclosporin [n = 233 (34%)], FAEs [n = 43 (29%)] and methotrexate [n = 372 (32%)]. Factors associated with ineffectiveness included prior experience to previous nonbiologic systemic therapies (acitretin) (aOR 0.64, 95% CI 0.42-0.96), male sex (methotrexate) (aOR 0.58, 95% CI 0.46-0.74), comorbidities (aOR 0.70, 95% CI 0.51-0.97) and alcohol consumption (≤ 14 units per week) (ciclosporin) (aOR 0.70, 95% CI 0.50-0.98). Persistence associated with all reasons for discontinuation showed better survival for methotrexate compared with acitretin, ciclosporin and FAEs cohorts at 12â months [survival estimate 46.1 (95% CI 44.0-48.3), 31.9 (95% CI 29.4-34.7), 30.0 (95% CI 27.5-32.4) and 35.0 (95% CI 29.9-40.9), respectively]. CONCLUSIONS: The real-world effectiveness and persistence of acitretin, ciclosporin, FAEs and methotrexate were generally low. Previous nonbiologic systemic therapies, male sex, comorbidities and alcohol consumption were risk factors associated with treatment ineffectiveness.
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Fármacos Dermatológicos , Psoríase , Humanos , Masculino , Metotrexato/uso terapêutico , Acitretina/efeitos adversos , Ciclosporina/uso terapêutico , Estudos de Coortes , Estudos Prospectivos , Fumaratos/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Psoríase/tratamento farmacológico , Psoríase/induzido quimicamente , Fatores Biológicos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Adjuvantes Imunológicos/uso terapêutico , Resultado do TratamentoRESUMO
Targeted biologic therapies can elicit an undesirable host immune response characterized by the development of antidrug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is adalimumab, a tumor necrosis factor inhibitor. This study aimed to identify genetic variants that contribute to the development of ADA against adalimumab, thereby influencing treatment failure. In patients with psoriasis on their first course of adalimumab, in whom serum ADA had been evaluated 6-36 months after starting treatment, we observed a genome-wide association with ADA against adalimumab within the major histocompatibility complex (MHC). The association signal mapped to the presence of tryptophan at position 9 and lysine at position 71 of the HLA-DR peptide-binding groove, with both residues conferring protection against ADA. Underscoring their clinical relevance, these residues were also protective against treatment failure. Our findings highlight antigenic peptide presentation via MHC class II as a critical mechanism in the development of ADA against biologic therapies and downstream treatment response.
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Estudo de Associação Genômica Ampla , Psoríase , Humanos , Adalimumab/uso terapêutico , Anticorpos , Antígenos HLA-DRRESUMO
Background: Few data exist on differences in treatment effectiveness and safety in atopic dermatitis patients of different skin types. Objective: To investigate treatment outcomes of dupilumab, methotrexate, and ciclosporin, and morphological phenotypes in atopic dermatitis patients, stratified by Fitzpatrick skin type. Methods: In an observational prospective cohort study, pooling data from the Dutch TREAT (TREatment of ATopic eczema) NL (treatregister.nl) and UK-Irish A-STAR (Atopic eczema Systemic TherApy Register; astar-register.org) registries, data on morphological phenotypes and treatment outcomes were investigated. Results: A total of 235 patients were included (light skin types [LST]: Fitzpatrick skin type 1-3, n = 156 [Ethnicity, White: 94.2%]; dark skin types [DST]: skin type 4-6, n = 68 [Black African/Afro-Caribbean: 25%, South-Asian: 26.5%, and Hispanics: 0%]). DST were younger (19.5 vs 29.0 years; P < .001), more often had follicular eczema (22.1% vs 2.6%; P < .001), higher baseline Eczema Area and Severity Index (EASI) scores (20.1 vs 14.9; P = .009), less allergic contact dermatitis (30.9% vs 47.4%; P = .03), and less previous phototherapy use (39.7% vs 59.0%; P = .008). When comparing DST and LST corrected for covariates including baseline EASI, DST showed greater mean EASI reduction between baseline and 6 months with only dupilumab (16.7 vs 9.7; adjusted P = .032). No differences were found for adverse events for any treatments (P > .05). Limitations: Unblinded, non-randomized. Conclusion: Atopic dermatitis differs in several characteristics between LST and DST. Skin type may influence treatment effectiveness of dupilumab.
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BACKGROUND: The TREatment of ATopic eczema (TREAT) Registry Taskforce is a collaborative international network of registries collecting data of atopic eczema (AE) patients receiving systemic and phototherapy with the common goal to provide long-term real-world data on the effectiveness, safety and cost-effectiveness of therapies. A core dataset, consisting of domains and domain items with corresponding measurement instruments, has been developed to harmonize data collection. OBJECTIVES: We aimed to give an overview of the status and characteristics of the eight established TREAT registries, and to perform a mapping exercise to examine the degree of overlap and pooling ability between the national registry datasets. This will allow us to determine which research questions can be answered in the future by pooling data. METHODS: All eight registries were asked to share their dataset and information on the current status and characteristics. The overlap between the core dataset and each registry dataset was identified (according to the domains, domain items and measurement instruments of the TREAT core dataset). RESULTS AND CONCLUSIONS: A total of 4702 participants have been recruited in the eight registries as of 1st of May 2022. Of the 69 core dataset domain items, data pooling was possible for 69 domain item outcomes in TREAT NL (the Netherlands), 61 items in A-STAR (UK and Ireland), 38 items in TREATgermany (Germany), 36 items in FIRST (France), 33 items in AtopyReg (Italy), 29 items in Biobadatop (Spain), 28 items in SCRATCH (Denmark) and 20 items in SwedAD (Sweden). Pooled analyses across all registries can be performed on multiple important domain items, covering the main aims of analysing data on the (cost-)effectiveness and safety of AE therapies. These results will facilitate future comparative or joint analyses.
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Dermatite Atópica , Eczema , Humanos , Dermatite Atópica/terapia , Sistema de Registros , Alemanha , Fototerapia , EspanhaRESUMO
BACKGROUND: The application of artificial intelligence (AI) to whole slide images has the potential to improve research reliability and ultimately diagnostic efficiency and service capacity. Image annotation plays a key role in AI and digital pathology. However, the work-streams required for tissue-specific (skin) and immunostain-specific annotation has not been extensively studied compared with the development of AI algorithms. OBJECTIVES: The objective of this study is to develop a common workflow for annotating whole slide images of biopsies from inflammatory skin disease immunostained with a variety of epidermal and dermal markers prior to the development of the AI-assisted analysis pipeline. METHODS: A total of 45 slides containing 3-5 sections each were scanned using Aperio AT2 slide scanner (Leica Biosystems). These slides were annotated by hand using a commonly used image analysis tool which resulted in more than 4000 images blocks. We used deep learning (DL) methodology to first sequentially segment (epidermis and upper dermis), with the exclusion of common artefacts and second to quantify the immunostained signal in those two compartments of skin biopsies and the ratio of positive cells. RESULTS: We validated two DL models using 10-fold validation runs and by comparing to ground truth manually annotated data. The models achieved an average (global) accuracy of 95.0% for the segmentation of epidermis and dermis and 86.1% for the segmentation of positive/negative cells. CONCLUSIONS: The application of two DL models in sequence facilitates accurate segmentation of epidermal and dermal structures, exclusion of common artefacts and enables the quantitative analysis of the immunostained signal. However, inaccurate annotation of the slides for training the DL model can decrease the accuracy of the output. Our open source code will facilitate further external validation across different immunostaining platforms and slide scanners.
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Inteligência Artificial , Dermatopatias , Humanos , Imuno-Histoquímica , Reprodutibilidade dos Testes , SoftwareRESUMO
Despite increased understanding about psoriasis pathophysiology, currently there is a lack of predictive computational models. We developed a personalisable ordinary differential equations model of human epidermis and psoriasis that incorporates immune cells and cytokine stimuli to regulate the transition between two stable steady states of clinically healthy (non-lesional) and disease (lesional psoriasis, plaque) skin. In line with experimental data, an immune stimulus initiated transition from healthy skin to psoriasis and apoptosis of immune and epidermal cells induced by UVB phototherapy returned the epidermis back to the healthy state. Notably, our model was able to distinguish disease flares. The flexibility of our model permitted the development of a patient-specific "UVB sensitivity" parameter that reflected subject-specific sensitivity to apoptosis and enabled simulation of individual patients' clinical response trajectory. In a prospective clinical study of 94 patients, serial individual UVB doses and clinical response (Psoriasis Area Severity Index) values collected over the first three weeks of UVB therapy informed estimation of the "UVB sensitivity" parameter and the prediction of individual patient outcome at the end of phototherapy. An important advance of our model is its potential for direct clinical application through early assessment of response to UVB therapy, and for individualised optimisation of phototherapy regimes to improve clinical outcome. Additionally by incorporating the complex interaction of immune cells and epidermal keratinocytes, our model provides a basis to study and predict outcomes to biologic therapies in psoriasis.
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Psoríase , Terapia Ultravioleta , Simulação por Computador , Citocinas , Humanos , Estudos Prospectivos , Psoríase/tratamento farmacológico , Resultado do TratamentoAssuntos
Aterosclerose , Psoríase , Humanos , Calgranulina A , Calgranulina B , Biomarcadores , Psoríase/diagnósticoRESUMO
Importance: Drug survival of biologic therapies for psoriasis is a proxy for longer-term treatment effectiveness and safety. Patient factors that are associated with the survival of each biologic differently (effect modifiers) may inform the decision to choose between biologics. Objective: To assess the drug survival associated with the effectiveness and safety of commonly used biologics for psoriasis in the UK and Ireland and identify effect modifiers for these biologics and their survival. Design, Setting, and Participants: We conducted a prospective cohort study of patients with psoriasis using data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) between November 2007 and August 2021. Exposures: Adalimumab, ustekinumab, secukinumab, guselkumab, ixekizumab. Main Outcomes and Measures: We conducted a survival analysis and fitted separate flexible parametric models for drug survival as a proxy for effectiveness and safety. Results: A total of 16â¯122 treatment courses were included: 6607 (41.0%) in which treatment with adalimumab was initiated, 5405 (33.5%) with ustekinumab, 2677 (16.6%) with secukinumab, 730 (4.5%) with guselkumab, and 703 (4.4%) with ixekizumab. The crude survival functions at year 1 for measures of effectiveness for treatment with adalimumab was 0.81 (95% CI, 0.80-0.82), 0.89 for ustekinumab (95% CI, 0.88-0.89), 0.86 for secukinumab (95% CI, 0.85-0.87), 0.94 for guselkumab (95% CI, 0.92-0.96), and 0.86 for ixekizumab (95% CI, 0.83-0.89). The adjusted survival curves from the multivariable model for effectiveness showed that treatment with guselkumab had the higher survival (adjusted hazard ratio, 0.13; 95% CI, 0.03-0.56) and adalimumab had the lower survival (adjusted hazard ratio, 2.37; 95% CI, 2.03-2.76) compared with ustekinumab. Secukinumab and ixekizumab had similar survival curves over time. Psoriatic arthritis, previous biologic exposure, nail involvement, and ethnicity were effect modifiers for survival in association with treatment effectiveness. The crude survival functions at year 1 for safety were 0.91 for treatment with adalimumab (95% CI, 0.90-0.91), 0.94 for ustekinumab (95% CI, 0.94-0.95), 0.94 for secukinumab (95% CI, 0.92-0.94), 0.96 for guselkumab (95% CI, 0.94-0.98), and 0.92 for ixekizumab (95% CI, 0.89-0.94). Guselkumab, ustekinumab, and secukinumab had similar adjusted survival curves for safety, while adalimumab (adjusted hazard ratio, 1.66; 95% CI, 1.46-1.89) and ixekizumab (adjusted hazard ratio, 1.52; 95% CI, 1.13-2.03) had lower survival compared with ustekinumab. Conclusions and Relevance: The results of this cohort study suggest that guselkumab had the highest drug survival in BADBIR of the included biologics for treatment persistence that was associated with effectiveness, and guselkumab had highest drug survival for safety compared with other biologics except ustekinumab. Psoriatic arthritis, nail involvement, previous biologic exposure, and ethnicity were effect modifiers for biologics and their survival in association with treatment effectiveness. This information on longer-term treatment persistence, safety, and tolerability may help patients and their clinicians make an informed decision to initiate treatment with a biologic therapy.