Inflammatory memory in psoriasis: From remission to recurrence.

The routine use of targeted systemic immunomodulatory therapies has transformed outcomes for people with severe psoriasis, with skin clearance (clinical remission) rates up to 60% at 1 year of biologic treatment. However, psoriasis may recur following drug withdrawal, and as a result, patients tend to continue receiving costly treatment indefinitely. Here, we review research into the "inflammatory memory" in resolved psoriasis skin and the potential mechanisms leading to psoriasis recurrence following drug withdrawal. Research has implicated immune cells such as tissue resident memory T cells, Langerhans cells, and dermal dendritic cells, and there is growing interest in keratinocytes and fibroblasts. A better understanding of the interactions between these cell populations, enabled by single cell technologies, will help to elucidate the events underpinning the shift from remission to recurrence. This may inform the development of personalized strategies for sustaining remission while reducing long-term drug burden.

A genome-wide meta-analysis of palmoplantar pustulosis implicates TH2 responses and cigarette smoking in disease pathogenesis.

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.

The association of age at psoriasis onset and HLA-C*06:02 with biologic survival in patients with moderate-to-severe psoriasis: a cohort study from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR).

BACKGROUND: Few studies have used real-world data to investigate the association between biologic therapy survival and age at psoriasis onset or HLA-C*06:02 status in patients with moderate-to-severe psoriasis. The robustness of these studies is limited by small sample size, short follow-up and diverse safety and effectiveness measures. OBJECTIVES: To describe biologic survival and explore whether the response to biologics is modified by age at psoriasis onset or HLA-C*06:02 status in patients with moderate-to-severe psoriasis. METHODS: Data from patients in the UK and the Republic of Ireland registered in the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) from 2007 to 2022 on a first course of adalimumab, etanercept, secukinumab or ustekinumab with at least 6 months' follow-up and a subset of BADBIR patients with available HLA-C*06:02 information registered to Biomarkers and Stratification To Optimise outcomes in Psoriasis (BSTOP) were analysed. Patients aged ≥ 50 years at treatment initiation were classified into early-onset psoriasis (EOP) (presenting in patients ≤ 40 years of age) and late-onset psoriasis (LOP) (presenting in patients > 40 years of age). BADBIR patients with available information in BSTOP were categorized as HLA-C*06:02- or HLA-C*06:02 + . Biologic survival was defined as treatment discontinuation associated with ineffectiveness or occurrence of adverse events (AEs). Adjusted survival function and hazard ratio (aHR) with 95% confidence interval (CI) were estimated using a flexible parametric model to compare discontinuing therapy between age at psoriasis onset and HLA-C*06:02 groups. Each model included exposure (biologics), effect modifier (age at onset or HLA-C*06:02 status), interaction terms and several baseline demographic, clinical and disease severity covariates. RESULTS: Final analytical cohorts included 4250 patients in the age at psoriasis onset group [2929 EOP (69%) vs. 1321 LOP (31%)] and 3094 patients in the HLA-C*06:02 status group [1603 HLA-C*06:02+ (52%) vs. 1491 HLA-C*06:02- (48%)]. There was no significant difference between EOP and LOP in drug survival associated with ineffectiveness or AEs for any biologics. However, compared with patients who were HLA-C*06:02-, patients who were HLA-C*06:02 + were less likely to discontinue ustekinumab for reasons associated with ineffectiveness (aHR 0.56, 95% CI 0.42-0.75). CONCLUSIONS: HLA-C*06:02, but not age at psoriasis onset, is a predictive biomarker for biologic survival in patients with psoriasis. Findings from this large cohort provide further, important information to aid clinicians using biologic therapies to manage patients with psoriasis.

Acceptability of 'as needed' biologic therapy in psoriasis: insights from a multi-stakeholder mixed methods study.

OBJECTIVES: Biologic therapies have led to increasing numbers of patients with psoriasis who have clear or nearly clear skin. Current practice is that biologic therapy is continued indefinitely in these patients, contributing to a substantial long-term drug and healthcare burden. 'As needed' biologic therapy in psoriasis may address this, however our understanding of patient and clinician perceptions of this strategy is limited. METHODS: We first conducted UK-wide online scoping surveys of patients with psoriasis and dermatology clinicians to explore their views on 'as needed' biologic therapy. Using topic guides informed by these survey findings, we then carried out qualitative focus groups with patients and clinicians. Themes were identified using reflexive thematic analysis. RESULTS: Of 67 patients and 27 clinicians completing the scoping surveys, 67% (43/64) and 78% (21/27), respectively, supported the use of 'as needed' biologic therapy. Respondents highlighted advantages such as a reduction in healthcare burden and greater ownership of care. Challenges included logistics of 'as needed' drug provision and potential risks of disease flare and drug immunogenicity. Focus groups comprised 15 patients with psoriasis (9 female [60%], average disease duration 32 years [range 9-64 years]) and 9 dermatology clinicians (8 female [89%], average dermatology experience 20 years [range 8-33 years]). Both patients and clinicians felt that an 'as needed' treatment approach will deliver a reduction in treatment burden and present an opportunity for patient-led ownership of care. Both groups highlighted the importance of ensuring ongoing access to medication and discussing the potential impact of psoriasis recurrence. Patient preferences were influenced by their lived experiences, particularly previous difficulties with medication delivery logistics and establishing disease control. Clinician perspectives were informed by personal experience of their patients adapting their own dosing schedules. Clinicians highlighted the importance of targeted patient selection for an 'as needed' approach, ongoing disease monitoring, and prompt re-access to medications upon psoriasis recurrence. CONCLUSION: These data indicate that 'as needed' biologic therapy in psoriasis is acceptable for both patients and clinicians. Formal assessment of clinical effectiveness and cost effectiveness is warranted, to enable the real-world potential of this approach to be realised.

Defining disease severity in atopic dermatitis and psoriasis for the application to biomarker research: an interdisciplinary perspective.

More severe atopic dermatitis and psoriasis are associated with a higher cumulative impact on quality of life, multimorbidity and healthcare costs. Proactive, early intervention in those most at risk of severe disease may reduce this cumulative burden and modify the disease trajectory to limit progression. The lack of reliable biomarkers for this at-risk group represents a barrier to such a paradigm shift in practice. To expedite discovery and validation, the BIOMarkers in Atopic Dermatitis and Psoriasis (BIOMAP) consortium (a large-scale European, interdisciplinary research initiative) has curated clinical and molecular data across diverse study designs and sources including cross-sectional and cohort studies (small-scale studies through to large multicentre registries), clinical trials, electronic health records and large-scale population-based biobanks. We map all dataset disease severity instruments and measures to three key domains (symptoms, inflammatory activity and disease course), and describe important codependencies and relationships across variables and domains. We prioritize definitions for more severe disease with reference to international consensus, reference standards and/or expert opinion. Key factors to consider when analysing datasets across these diverse study types include explicit early consideration of biomarker purpose and clinical context, candidate biomarkers associated with disease severity at a particular point in time and over time and how they are related, taking the stage of biomarker development into account when selecting disease severity measures for analyses, and validating biomarker associations with disease severity outcomes using both physician- and patient-reported measures and across domains. The outputs from this exercise will ensure coherence and focus across the BIOMAP consortium so that mechanistic insights and biomarkers are clinically relevant, patient-centric and more generalizable to current and future research efforts.

Atopic dermatitis (AD), and psoriasis are long-term skin conditions that can significantly affect people's lives, especially when symptoms are severe. Approximately 10% of adults and 20% of children are affected by AD, while psoriasis affects around 5% of people in the UK. Both conditions are associated with debilitating physical symptoms (such as itch) and have been linked to depression and anxiety. Biomarkers are naturally occurring chemicals in the human body and have potential to enhance the longer-term management of AD and psoriasis. Currently, there are no routinely used biomarkers that can identify people who experience or will go on to develop severe AD and psoriasis. For this reason, research is under way to understand which biomarkers are linked to severity. In this study, a multidisciplinary team of skin researchers from across Europe, along with patient groups, discussed the complexities of studying severity-related biomarkers. We identified a number of severity measurement approaches and there were recommendations for future biomarker research, including (i) considering multiple measures as no single measure can encompass all aspects of severity, (ii) exploring severity measures recorded by both healthcare professionals and patients, as each may capture different aspects, and (iii) accounting for influencing factors, such as different treatment approaches, that may impact AD and psoriasis severity, which make it challenging to compare findings across studies. Overall, we anticipate that the insights gained from these discussions will increase the likelihood of biomarkers being effectively applied in real-world settings, to ultimately improve outcomes for people with AD and psoriasis.

Integrated proteomics and genomics analysis of paradoxical eczema in psoriasis patients treated with biologics.

BACKGROUND: Few studies have explored the immunology and genetic risk of paradoxical eczema occurring as an adverse event of biologic therapy in patients with psoriasis. OBJECTIVES: We sought to describe the systemic inflammatory signature of paradoxical eczema using proteomics and explore whether this is genetically mediated. METHODS: This study used the Olink Target 96 Inflammation panel on 256 serum samples from 71 patients with psoriasis and paradoxical eczema, and 75 controls with psoriasis to identify differentially expressed proteins and enriched gene sets. Case samples from 1 or more time points (T1 prebiologic, T2 postbiologic, and T3 postparadoxical eczema) were matched 1:1 with control samples. Genes contributing to enriched gene sets were selected, and functional single nucleotide polymorphisms used to create polygenic risk scores in a genotyped cohort of 88 paradoxical eczema cases and 3124 psoriasis controls. RESULTS: STAMBP expression was lower in cases at T1 than in controls (log-fold change: -0.44; adjusted P = .022); no other proteins reached statistical significance at equivalent time points. Eleven gene sets including cytokine and chemokine pathways were enriched in cases at T2 and 10 at T3. Of the 39 proteins contributing to enriched gene sets, the majority are associated with the atopic dermatitis serum proteome. A polygenic risk score including 38 functional single nucleotide polymorphisms linked to enriched gene sets was associated with paradoxical eczema (adjusted P = .046). CONCLUSIONS: The paradoxical eczema systemic inflammatory proteome trends toward atopic dermatitis at a gene-set level and is detectable before onset of the phenotype. This signature could be genetically determined.

Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease.

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031-2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031-2A>C;c.2031-2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031-2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031-2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10-6 and p = 3.6 × 10-5, respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10-10. Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.

Common mental health disorders in adults with inflammatory skin conditions: nationwide population-based matched cohort studies in the UK.

BACKGROUND: Psoriasis and atopic eczema are common inflammatory skin diseases. Existing research has identified increased risks of common mental disorders (anxiety, depression) in people with eczema and psoriasis; however, explanations for the associations remain unclear. We aimed to establish the risk factors for mental illness in those with eczema or psoriasis and identify the population groups most at risk. METHODS: We used routinely collected data from the UK Clinical Practice Research Datalink (CPRD) GOLD. Adults registered with a general practice in CPRD (1997-2019) were eligible for inclusion. Individuals with eczema/psoriasis were matched (age, sex, practice) to up to five adults without eczema/psoriasis. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for hazards of anxiety or depression in people with eczema/psoriasis compared to people without. We adjusted for known confounders (deprivation, asthma [eczema], psoriatic arthritis [psoriasis], Charlson comorbidity index, calendar period) and potential mediators (harmful alcohol use, body mass index [BMI], smoking status, and, in eczema only, sleep quality [insomnia diagnoses, specific sleep problem medications] and high-dose oral glucocorticoids). RESULTS: We identified two cohorts with and without eczema (1,032,782, matched to 4,990,125 without), and with and without psoriasis (366,884, matched to 1,834,330 without). Sleep quality was imbalanced in the eczema cohorts, twice as many people with eczema had evidence of poor sleep at baseline than those without eczema, including over 20% of those with severe eczema. After adjusting for potential confounders and mediators, eczema and psoriasis were associated with anxiety (adjusted HR [95% CI]: eczema 1.14 [1.13-1.16], psoriasis 1.17 [1.15-1.19]) and depression (adjusted HR [95% CI]: eczema 1.11 [1.1-1.12], psoriasis 1.21 [1.19-1.22]). However, we found evidence that these increased hazards are unlikely to be constant over time and were especially high 1-year after study entry. CONCLUSIONS: Atopic eczema and psoriasis are associated with increased incidence of anxiety and depression in adults. These associations may be mediated through known modifiable risk factors, especially sleep quality in people with eczema. Our findings highlight potential opportunities for the prevention of anxiety and depression in people with eczema/psoriasis through treatment of modifiable risk factors and enhanced eczema/psoriasis management.

Uptake of tumour necrosis factor-alpha inhibitor biosimilars for psoriasis: a drug utilization study from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR).

BACKGROUND: Tumour necrosis factor-alpha inhibitors (TNFi) have revolutionized the treatment of moderate-to-severe psoriasis. Following patent expiry of the originator biologics, TNFi biosimilars became available, presenting the opportunity for significant reductions in drug costs. OBJECTIVES: To describe the uptake of TNFi biosimilars for psoriasis treatment in the UK and Ireland. METHODS: This observational cohort study utilizes data from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR), a national pharmacovigilance study register for patients with psoriasis on systemic treatments. We analysed biosimilar uptake trends over time in nine geographical regions of England along with Wales, Scotland, Northern Ireland and the Republic of Ireland. We assessed the incidence of switching to biosimilars in an originator-user cohort (switchers). Patients on originators infliximab, etanercept and adalimumab at the time originator patents expired, entered the cohort on 1 February 2015, August 2015 and October 2018, respectively, and were followed up until 31 October 2021. Trends in biosimilar initiations were assessed in an adalimumab-naïve cohort who started adalimumab between 1 October 2018 and 31 July 2019 (starters). We assessed the associations between patient factors and originator-to-biosimilar switching and biosimilar initiation using a multivariable Cox regression model and a multivariable logistic regression model, respectively. RESULTS: Included in the originator-user cohort were 4202 patients (209 on infliximab, 742 on etanercept and 3251 on adalimumab). For infliximab, etanercept and adalimumab, respectively, the cumulative incidence of originator-to-biosimilar switching increased with time to 14.8%, 23.6% and 66.6% after 3 years. Across geographical regions, 3-year switching rates varied from 0% to 43.7% for infliximab; from 0% to 40.4% for etanercept; and from 12.5% to 84.3% for adalimumab. Out of the 528 patients included in the adalimumab-naïve cohort, 67.8% started on biosimilars. Originator-to-biosimilar switching and biosimilar initiation were more common in men and in patients who had lower Psoriasis Area and Severity Index at cohort entry. CONCLUSIONS: The uptake of biosimilars increased over time and varied considerably across the UK and Ireland; adalimumab had the highest biosimilar uptake rate compared with that of other TNFi drugs.

Effectiveness and survival of methotrexate versus adalimumab in patients with moderate-to-severe psoriasis: a cohort study from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR).

BACKGROUND: Most information on the comparative effectiveness and survival of methotrexate (MTX) and adalimumab (ADA) in the treatment of psoriasis is from randomized control trials and may not translate to the everyday clinical setting. OBJECTIVES: To determine the real-world effectiveness and survival of MTX and ADA in patients with moderate-to-severe psoriasis registered in the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR). METHODS: Eligible patients were registered in BADBIR, ≥ 16 years of age and receiving a first course of MTX or ADA between September 2007 and December 2021, with ≥ 6 months of follow-up. Effectiveness was defined as achieving an absolute Psoriasis Area and Severity Index (PASI) ≤ 2 reported ≥ 13 weeks after the treatment start date until the stop date. The average treatment effect (ATE) was estimated using inverse probability of treatment weighting with propensity score, including baseline covariates. ATE results were presented as risk ratios (RR). A flexible parametric model was used to estimate adjusted standardized average survival, defined as treatment discontinuation associated with ineffectiveness or the occurrence of adverse events (AEs) at 6, 12 and 24 months. Restricted mean survival time (RMST) at 2 years of treatment exposure was calculated. RESULTS: In total, 6575 patients (median age 44 years; 44% female) were analysed; 2659 (40.4%) were prescribed MTX and 3916 (59.5%) ADA. The proportion of patients achieving PASI ≤ 2 was higher in the ADA cohort (77.4%) than in the MTX cohort (37.4%). ADA was more effective than MTX [RR 2.20, 95% confidence interval (CI) 1.98-2.45]. Overall survival associated with ineffectiveness or AEs was lower in the MTX cohort than in the ADA cohort at 6 months [survival estimate 69.7 (95% CI 67.9-71.5) vs. 90.6 (95% CI 89.8-91.4)], 1 year [survival estimate 52.5 (95% CI 50.4-54.8) vs. 80.6 (95% CI 79.5-81.8)] and 2 years [survival estimate 34.8 (95% CI 32.5-37.2) vs. 68.6 (95% CI 67.2-70.0)]. The difference in RMST (years) overall, or when stratified by ineffectiveness and AEs, was 0.53 (95% CI 0.49-0.58), 0.37 (95% CI 0.33-0.42) and 0.29 (95% CI 0.25-0.33), respectively. CONCLUSIONS: Patients on ADA were twice as likely to be clear or nearly clear of psoriasis and were less likely to discontinue their medication than patients on MTX. Findings from this real-world cohort provide important information to aid clinicians managing patients with psoriasis.

Factors associated with depression, anxiety and severe mental illness among adults with atopic eczema or psoriasis: a systematic review and meta-analysis.

BACKGROUND: Evidence suggests an association between atopic eczema (AE) or psoriasis and mental illness; however, the factors associated with mental illness are unclear. OBJECTIVES: To synthesize and evaluate all available evidence on factors associated with depression, anxiety and severe mental illness (SMI) among adults with AE or psoriasis. METHODS: We searched electronic databases, grey literature databases and clinical trial registries from inception to February 2022 for studies of adults with AE or psoriasis. Eligible studies included randomized controlled trials (RCTs), cohort, cross-sectional or case-control studies where effect estimates of factors associated with depression, anxiety or SMI were reported. We did not apply language or geographical restrictions. We assessed risk of bias using the Quality in Prognosis Studies tool. We synthesized results narratively, and if at least two studies were sufficiently homogeneous, we pooled effect estimates in a random effects meta-analysis. RESULTS: We included 21 studies (11 observational, 10 RCTs). No observational studies in AE fulfilled our eligibility criteria. Observational studies in people with psoriasis mostly investigated factors associated with depression or anxiety - one cross-sectional study investigated factors associated with schizophrenia. Pooled effect estimates suggest that female sex and psoriatic arthritis were associated with depression [female sex: odds ratio (OR) 1.62, 95% confidence interval (CI) 1.09-2.40, 95% prediction intervals (PIs) 0.62-4.23, I2 = 24.90%, τ2 = 0.05; psoriatic arthritis: OR 2.26, 95% CI 1.56-3.25, 95% PI 0.21-24.23, I2 = 0.00%, τ2 = 0.00] and anxiety (female sex: OR 2.59, 95% CI 1.32-5.07, 95% PI 0.00-3956.27, I2 = 61.90%, τ2 = 0.22; psoriatic arthritis: OR 1.98, 95% CI 1.33-2.94, I2 = 0.00%, τ2 = 0.00). Moderate/severe psoriasis was associated with anxiety (OR 1.14, 95% CI 1.05-1.25, I2 0.00%, τ2 = 0.00), but not depression. Evidence from RCTs suggested that adults with AE or psoriasis given placebo had higher depression and anxiety scores compared with comparators given targeted treatment (e.g. biologic agents). CONCLUSIONS: Our review highlights limited existing research on factors associated with depression, anxiety and SMI in adults with AE or psoriasis. Observational evidence on factors associated with depression or anxiety in people with psoriasis was conflicting or from single studies, but some identified factors were consistent with those in the general population. Evidence on factors associated with SMIs in people with AE or psoriasis was particularly limited. Evidence from RCTs suggested that AE and psoriasis treated with placebo was associated with higher depression and anxiety scores compared with skin disease treated with targeted therapy; however, follow-up was limited. Therefore, long-term effects on mental health are unclear.

Effectiveness and persistence of acitretin, ciclosporin, fumaric acid esters and methotrexate for patients with moderate-to-severe psoriasis: a cohort study from BADBIR.

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 ≥ 16 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 12 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.

Nonadherence to systemic immune-modifying therapy in people with psoriasis during the COVID-19 pandemic: findings from a global cross-sectional survey.

BACKGROUND: Nonadherence to immune-modifying therapy is a complex behaviour which, before the COVID-19 pandemic, was shown to be associated with mental health disorders in people with immune-mediated diseases. The COVID-19 pandemic has led to a rise in the global prevalence of anxiety and depression, and limited data exist on the association between mental health and nonadherence to immune-modifying therapy during the pandemic. OBJECTIVES: To assess the extent of and reasons underlying nonadherence to systemic immune-modifying therapy during the COVID-19 pandemic in individuals with psoriasis, and the association between mental health and nonadherence. METHODS: Online self-report surveys (PsoProtectMe), including validated screens for anxiety and depression, were completed globally during the first year of the pandemic. We assessed the association between anxiety or depression and nonadherence to systemic immune-modifying therapy using binomial logistic regression, adjusting for potential cofounders (age, sex, ethnicity, comorbidity) and country of residence. RESULTS: Of 3980 participants from 77 countries, 1611 (40.5%) were prescribed a systemic immune-modifying therapy. Of these, 408 (25.3%) reported nonadherence during the pandemic, most commonly due to concerns about their immunity. In the unadjusted model, a positive anxiety screen was associated with nonadherence to systemic immune-modifying therapy [odds ratio (OR) 1.37, 95% confidence interval (CI) 1.07-1.76]. Specifically, anxiety was associated with nonadherence to targeted therapy (OR 1.41, 95% CI 1.01-1.96) but not standard systemic therapy (OR 1.16, 95% CI 0.81-1.67). In the adjusted model, although the directions of the effects remained, anxiety was not significantly associated with nonadherence to overall systemic (OR 1.20, 95% CI 0.92-1.56) or targeted (OR 1.33, 95% CI 0.94-1.89) immune-modifying therapy. A positive depression screen was not strongly associated with nonadherence to systemic immune-modifying therapy in the unadjusted (OR 1.22, 95% CI 0.94-1.57) or adjusted models (OR 1.14, 95% CI 0.87-1.49). CONCLUSIONS: These data indicate substantial nonadherence to immune-modifying therapy in people with psoriasis during the pandemic, with attenuation of the association with mental health after adjusting for confounders. Future research in larger populations should further explore pandemic-specific drivers of treatment nonadherence. Clear communication of the reassuring findings from population-based research regarding immune-modifying therapy-associated adverse COVID-19 risks to people with psoriasis is essential, to optimize adherence and disease outcomes.

Care of the Postpartum Patient in the Emergency Department: A Systematic Review with Implications for Maternal Mortality.

OBJECTIVE: Approximately one-third of maternal deaths occur postpartum. Little is known about the intersection between the postpartum period, emergency department (ED) use, and opportunities to reduce maternal mortality. The primary objectives of this systematic review are to explore the incidence of postpartum ED use, identify postpartum disease states that are evaluated in the ED, and summarize postpartum ED use by race/ethnicity and payor source. STUDY DESIGN: We searched PubMed, Embase, Cumulative Index of Nursing and Allied Health Literature (CINAHL), ClinicalTrials.gov, Cochrane CENTRAL, Social Services Abstracts, and Scopus from inception to September 19, 2019. Each identified abstract was screened by two authors; the full-text manuscripts of all studies deemed to be potential candidates were then reviewed by the same two authors and included if they were full-text, peer-reviewed articles in the English language with primary patient data reporting care of a female in the ED in the postpartum period, defined as up to 1 year after the end of pregnancy. RESULTS: A total of 620 were screened, 354 records were excluded and 266 full-text articles were reviewed. Of the 266 full-text articles, 178 were included in the systematic review; of these, 108 were case reports. Incidence of ED use by postpartum females varied from 4.8 to 12.2% in the general population. Infection was the most common reason for postpartum ED evaluation. Young females of minority race and those with public insurance were more likely than whites and those with private insurance to use the ED. CONCLUSION: As many as 12% of postpartum women seek care in the ED. Young minority women of lower socioeconomic status are more likely to use the ED. Since approximately one-third of maternal deaths occur in the postpartum period, successful efforts to reduce maternal mortality must include ED stakeholders. This study is registered with the Systematic Review Registration (identifier: CRD42020151126). KEY POINTS: · Up to 12% of postpartum women seek care in the ED.. · One-third of maternal deaths occur postpartum.. · Maternal mortality reduction efforts should include ED stakeholders..

Single-cell analysis implicates TH17-to-TH2 cell plasticity in the pathogenesis of palmoplantar pustulosis.

BACKGROUND: Palmoplantar pustulosis (PPP) is a severe inflammatory skin disorder characterized by eruptions of painful, neutrophil-filled pustules on the palms and soles. Although PPP has a profound effect on quality of life, it remains poorly understood and notoriously difficult to treat. OBJECTIVE: We sought to investigate the immune pathways that underlie the pathogenesis of PPP. METHODS: We applied bulk and single-cell RNA sequencing (RNA-Seq) methods to the analysis of skin biopsy samples and peripheral blood mononuclear cells. We validated our results by flow cytometry and immune fluorescence microscopy RESULTS: Bulk RNA-Seq of patient skin detected an unexpected signature of T-cell activation, with a significant overexpression of several TH2 genes typically upregulated in atopic dermatitis. To further explore these findings, we carried out single-cell RNA-Seq in peripheral blood mononuclear cells of healthy and affected individuals. Memory CD4+ T cells of PPP patients were skewed toward a TH17 phenotype, a phenomenon that was particularly significant among cutaneous lymphocyte-associated antigen-positive skin-homing cells. We also identified a subset of memory CD4+ T cells that expressed both TH17 (KLRB1/CD161) and TH2 (GATA3) markers, with pseudotime analysis suggesting that the population was the result of TH17 to TH2 plasticity. Interestingly, the GATA3+/CD161+ cells were overrepresented among the peripheral blood mononuclear cells of affected individuals, both in the single-cell RNA-Seq data set and in independent flow cytometry experiments. Dual-positive cells were also detected in patient skin by immune fluorescence microscopy. CONCLUSIONS: PPP is associated with complex T-cell activation patterns and may explain why biologic drugs that target individual T helper cell populations have shown limited therapeutic efficacy.

Biomarkers of disease progression in people with psoriasis: a scoping review.

BACKGROUND: Identification of those at risk of more severe psoriasis and/or associated morbidities offers opportunity for early intervention, reduced disease burden and more cost-effective healthcare. Prognostic biomarkers of disease progression have thus been the focus of intense research, but none are part of routine practice. OBJECTIVES: To identify and catalogue candidate biomarkers of disease progression in psoriasis for the translational research community. METHODS: A systematic search of CENTRAL, Embase, LILACS and MEDLINE was performed for relevant articles published between 1990 and December 2021. Eligibility criteria were studies involving patients with psoriasis (any age, n ≥ 50) reporting biomarkers associated with disease progression. The main outcomes were any measure of skin severity or any prespecified psoriasis comorbidity. Data were extracted by one reviewer and checked by a second; studies meeting minimal quality criteria (longitudinal design and/or use of methods to control for confounding) were formally assessed for bias. Candidate biomarkers were identified by an expert multistakeholder group using a majority voting consensus exercise, and mapped to relevant cellular and molecular pathways. RESULTS: Of 181 included studies, most investigated genomic or proteomic biomarkers associated with disease severity (n = 145) or psoriatic arthritis (n = 30). Methodological and reporting limitations compromised interpretation of findings, most notably a lack of longitudinal studies, and inadequate control for key prognostic factors. The following candidate biomarkers with future potential utility were identified for predicting disease severity: LCE3D, interleukin (IL)23R, IL23A, NFKBIL1 loci, HLA-C*06:02 (genomic), IL-17A, IgG aHDL, GlycA, I-FABP and kallikrein 8 (proteomic), tyramine (metabolomic); psoriatic arthritis: HLA-C*06:02, HLA-B*27, HLA-B*38, HLA-B*08, and variation at the IL23R and IL13 loci (genomic); IL-17A, CXCL10, Mac-2 binding protein, integrin b5, matrix metalloproteinase-3 and macrophage-colony stimulating factor (proteomic) and tyramine and mucic acid (metabolomic); and type 2 diabetes mellitus: variation in IL12B and IL23R loci (genomic). No biomarkers were supported by sufficient evidence for clinical use without further validation. CONCLUSIONS: This review provides a comprehensive catalogue of investigated biomarkers of disease progression in psoriasis. Future studies must address the common methodological limitations identified herein to expedite discovery and validation of biomarkers for clinical use. What is already known about this topic? The current treatment paradigm in psoriasis is reactive. There is a need to develop effective risk-stratified management approaches that can proactively attenuate the substantial burden of disease. Prognostic biomarkers of disease progression have therefore been the focus of intense research. What does this study add? This review is the first to scope, collate and catalogue research investigating biomarkers of disease progression in psoriasis. The review identifies potentially promising candidate biomarkers for further investigation and highlights common important limitations that should be considered when designing and conducting future studies in this area.

Biomarkers of systemic treatment response in people with psoriasis: a scoping review.

BACKGROUND: Responses to the systemic treatments commonly used to treat psoriasis vary. Biomarkers that accurately predict effectiveness and safety would enable targeted treatment selection, improved patient outcomes and more cost-effective healthcare. OBJECTIVES: To perform a scoping review to identify and catalogue candidate biomarkers of systemic treatment response in psoriasis for the translational research community. METHODS: A systematic search of CENTRAL, Embase, LILACS and MEDLINE was performed for relevant articles published between 1990 and December 2021. Eligibility criteria were studies involving patients with psoriasis (any age, n ≥ 50) reporting biomarkers associated with systemic treatment response. The main outcomes were any measure of systemic treatment efficacy or safety. Data were extracted by one reviewer and checked by a second; studies meeting minimal quality criteria (use of methods to control for confounding) were formally assessed for bias. Candidate biomarkers were identified by an expert multistakeholder group using a majority voting consensus exercise and mapped to relevant cellular and molecular pathways. RESULTS: Of 71 included studies (67 studying effectiveness outcomes and eight safety outcomes; four studied both), most reported genomic or proteomic biomarkers associated with response to biologics (48 studies). Methodological or reporting limitations frequently compromised the interpretation of findings, including inadequate control for key covariates, lack of adjustment for multiple testing, and selective outcome reporting. We identified candidate biomarkers of efficacy to tumour necrosis factor inhibitors [variation in CARD14, CDKAL1, IL1B, IL12B and IL17RA loci, and lipopolysaccharide-induced phosphorylation of nuclear factor (NF)-κB in type 2 dendritic cells] and ustekinumab (HLA-C*06:02 and variation in an IL1B locus). None were supported by sufficient evidence for clinical use without further validation studies. Candidate biomarkers were found to be involved in the immune cellular crosstalk implicated in psoriasis pathogenesis, most notably antigen presentation, T helper (Th)17 cell differentiation, positive regulation of NF-κB, and Th17 cell activation. CONCLUSIONS: This comprehensive catalogue provides a key resource for researchers and reveals a diverse range of biomarker types and outcomes in the included studies. The candidate biomarkers identified require further evaluation in methodologically robust studies to establish potential clinical utility. Future studies should aim to address the common methodological limitations highlighted in this review to expedite discovery and validation of biomarkers for clinical use. What is already known about this topic? Responses to the systemic treatments commonly used to treat psoriasis vary. Biomarkers that accurately predict effectiveness and safety would enable targeted treatment selection, improved patient outcomes and more cost-effective healthcare. What does this study add? This review provides a comprehensive catalogue of investigated biomarkers of systemic treatment response in psoriasis. A diverse range of biomarker types and outcomes was found in the included studies, serving as a key resource for the translational research community.

Factors associated with adverse COVID-19 outcomes in patients with psoriasis-insights from a global registry-based study.

BACKGROUND: The multimorbid burden and use of systemic immunosuppressants in people with psoriasis may confer greater risk of adverse outcomes of coronavirus disease 2019 (COVID-19), but the data are limited. OBJECTIVE: Our aim was to characterize the course of COVID-19 in patients with psoriasis and identify factors associated with hospitalization. METHODS: Clinicians reported patients with psoriasis with confirmed/suspected COVID-19 via an international registry, Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection. Multiple logistic regression was used to assess the association between clinical and/or demographic characteristics and hospitalization. A separate patient-facing registry characterized risk-mitigating behaviors. RESULTS: Of 374 clinician-reported patients from 25 countries, 71% were receiving a biologic, 18% were receiving a nonbiologic, and 10% were not receiving any systemic treatment for psoriasis. In all, 348 patients (93%) were fully recovered from COVID-19, 77 (21%) were hospitalized, and 9 (2%) died. Increased hospitalization risk was associated with older age (multivariable-adjusted odds ratio [OR] = 1.59 per 10 years; 95% CI = 1.19-2.13), male sex (OR = 2.51; 95% CI = 1.23-5.12), nonwhite ethnicity (OR = 3.15; 95% CI = 1.24-8.03), and comorbid chronic lung disease (OR = 3.87; 95% CI = 1.52-9.83). Hospitalization was more frequent in patients using nonbiologic systemic therapy than in those using biologics (OR = 2.84; 95% CI = 1.31-6.18). No significant differences were found between classes of biologics. Independent patient-reported data (n = 1626 across 48 countries) suggested lower levels of social isolation in individuals receiving nonbiologic systemic therapy than in those receiving biologics (OR = 0.68; 95% CI = 0.50-0.94). CONCLUSION: In this international case series of patients with moderate-to-severe psoriasis, biologic use was associated with lower risk of COVID-19-related hospitalization than with use of nonbiologic systemic therapies; however, further investigation is warranted on account of potential selection bias and unmeasured confounding. Established risk factors (being older, being male, being of nonwhite ethnicity, and having comorbidities) were associated with higher hospitalization rates.

In chronic plaque psoriasis, roflumilast cream safely increased likelihood of clear or almost clear state at 6 weeks.

SOURCE CITATION: Lebwohl MG, Papp KA, Stein Gold L, et al. Trial of roflumilast cream for chronic plaque psoriasis. N Engl J Med. 2020;383:229-39. 32668113.

Randomized Controlled Trials of Headache Treatments in Pregnancy: A Systematic Review.

OBJECTIVE: Headaches affect 88% of reproductive-aged women. Yet data are limited addressing treatment of headache in pregnancy. While many women experience improvement in pregnancy, primary and secondary headaches can develop. Consequently, pregnancy is a time when headache diagnosis can influence maternal and fetal interventions. This study was aimed to summarize existing randomized control trials (RCTs) addressing headache treatment in pregnancy. STUDY DESIGN: We searched PubMed, CINAHL, EMBASE, ClinicalTrials.gov, Cochrane Library, CINAHL, and SCOPUS from January 1, 1970 through June 31, 2019. Studies were eligible if they were English-language RCTs addressing treatment of headache in pregnancy. Conference abstracts and studies investigating postpartum headache were excluded. Three authors reviewed English-language RCTs addressing treatment of antepartum headache. To be included, all authors agreed each article to meet the following criteria: predefined control group, participants underwent randomization, and treatment of headache occurred in the antepartum period. If inclusion criteria were met no exclusions were made. Our systematic review registration number was CRD42019135874. RESULTS: A total of 193 studies were reviewed. Of the three that met inclusion criteria all were small, with follow-up designed to measure pain reduction and showed statistical significance. CONCLUSION: Our systematic review of RCTs evaluating treatment of headache in pregnancy revealed only three studies. This paucity of data limits treatment, puts women at risk for worsening headache disorders, and delays diagnosis placing both the mother and fetus at risk for complications.