Retinoids in the treatment of photoageing: A histological study of topical retinoid efficacy in black skin.

BACKGROUND: Photoageing describes complex cutaneous changes that occur due to chronic exposure to solar ultraviolet radiation (UVR). The 'gold standard' for the treatment of photoaged white skin is all-trans retinoic acid (ATRA); however, cosmetic retinol (ROL) has also proven efficacious. Recent work has identified that black skin is susceptible to photoageing, characterized by disintegration of fibrillin-rich microfibrils (FRMs) at the dermal-epidermal junction (DEJ). However, the impact of topical retinoids for repair of black skin has not been well investigated. OBJECTIVES: To determine the potential of retinoids to repair photoaged black skin. METHODS: An exploratory intervention study was performed using an in vivo, short-term patch test protocol. Healthy but photoaged black volunteers (>45 years) were recruited to the study, and participant extensor forearms were occluded with either 0.025% ATRA (n = 6; 4-day application due to irritancy) or ROL (12-day treatment protocol for a cosmetic) at concentrations of 0.3% (n = 6) or 1% (n = 6). Punch biopsies from occluded but untreated control sites and retinoid-treated sites were processed for histological analyses of epidermal characteristics, melanin distribution and dermal remodelling. RESULTS: Treatment with ATRA and ROL induced significant acanthosis (all p < 0.001) accompanied by a significant increase in keratinocyte proliferation (Ki67; all p < 0.01), dispersal of epidermal melanin and restoration of the FRMs at the DEJ (all p < 0.01), compared to untreated control. CONCLUSIONS: This study confirms that topical ATRA has utility for the repair of photoaged black skin and that ROL induces comparable effects on epidermal and dermal remodelling, albeit over a longer timeframe. The effects of topical retinoids on black photoaged skin are similar to those reported for white photoaged skin and suggest conserved biology in relation to repair of UVR-induced damage. Further investigation of topical retinoid efficacy in daily use is warranted for black skin.

Physical activity is important for cardiovascular health and cardiorespiratory fitness in patients with psoriasis.

BACKGROUND: Patients with psoriasis have a level of physical activity below that recommended for cardiovascular health, which is significantly limited by disease severity and other psoriasis-specific barriers. We hypothesized that physical activity is important for cardiovascular health in patients with psoriasis and that its objective measurement could have clinical utility. AIM: To explore whether physical activity influences the risk of cardiovascular disease (CVD) in patients with psoriasis. METHODS: In total, 242 patients with chronic plaque psoriasis were recruited. History, examination and physical activity were assessed and arteriography, the noninvasive measurement of arterial function, was performed for each participant. RESULTS: We observed a significant relationship between volume of physical activity and the likelihood of future CVD as measured by pulse wave velocity (PWV; P < 0.02). We identified a significant relationship between the diastolic reflection area (DRA) and health-promoting levels of physical activity (P < 0.001), in addition to a significant correlation between DRA and the likelihood of future CVD (P < 0.001). The DRA is a complex, dimensionless variable that describes the intensity of diastolic wave reflection and the duration of diastole, which are key determinants of the blood supply to the left ventricle. Our data suggest that DRA may represent a surrogate marker for cardiorespiratory fitness. CONCLUSION: Our study describes a significant relationship between exercise, cardiorespiratory fitness and PWV, a preclinical indicator of future CVD risk, in patients with psoriasis. The DRA offers a noninvasive, objective measurement of exercise adherence, which could have clinical utility in the future.

The promise and challenges of cell therapy for psoriasis.

The management of moderate-to-severe psoriasis has been transformed by the introduction of biological therapies. These medicines, particularly those targeting interleukin (IL)-17 and IL-23p19, can offer clear or nearly clear skin for the majority of patients with psoriasis, with good long-term drug survival. However, as currently used, none of these therapies is curative and disconcertingly there is a small but increasing number of patients with severe psoriasis who have failed all currently available therapeutic modalities. A similar scenario has occurred in other immune-mediated inflammatory diseases (IMIDs) where treatment options are limited in severely affected patients. In these cases, cell therapy, including haematopoietic stem cell transplantation (HSCT) and mesenchymal stromal cells (MSC), has been utilized. This review discusses the various forms of cell therapy currently available, their utility in the management of IMIDs and emerging evidence for efficacy in severe psoriasis that is unresponsive to biological therapy. Balancing the risks and benefits of treatment vs. the underlying disease is key; cell therapy carries significant risks, costs, regulation and other complexities, which must be justified by outcomes. Although HSCT has anecdotally been reported to benefit severe psoriasis, sometimes with apparent cure, this has mainly been in the setting of other coincidental 'routine' indications. In psoriasis, cell therapies, such as MSC and regulatory T cells, with a lower risk of complications are likely to be more appropriate. Well-designed controlled trials coupled with mechanistic studies are warranted if advanced cell therapies are to be developed and delivered as a realistic option for severe psoriasis.

Systematic review examining changes over time and variation in the incidence and prevalence of psoriasis by age and gender.

BACKGROUND: There is a lack of any overview of changes over time and variation in the epidemiology of psoriasis with age and between genders. OBJECTIVES: To perform a systematic review of published population-based studies on variations in psoriasis incidence and prevalence with age and between genders, and to explore trends in psoriasis epidemiology over time. METHODS: Eleven electronic and regional databases were searched from their inception dates to October 2019. No language restrictions were applied. Studies were eligible if they reported on changes in psoriasis incidence and/or prevalence over time and/or by age group and gender. RESULTS: In total 308 papers were critically appraised, from which 90 studies from 22 countries were included. Incidence data confirmed a clear bimodal age pattern in psoriasis onset, with the first and second peaks at around 30-39 and 60-69 years of age, respectively, and evidence suggesting that it presents slightly earlier in women than in men. Prevalence data showed an increasing trend with age until around 60 or 70 years, after which it decreases. Although there was lack of agreement on specific gender differences in psoriasis incidence and prevalence, a slight male predominance was reported in several studies. Studies worldwide suggested a stable or slightly decreasing trend in psoriasis incidence, while an increasing trend in psoriasis prevalence has been consistently reported. One particular challenge faced was the vastly different methodologies used in the included studies, which contributed to some of the heterogeneity of the results. CONCLUSIONS: Studies on changes over time in the occurrence of psoriasis have contributed to a greater appreciation of the increasing burden of the disease. However, further research is required to determine the reasons driving the increase in psoriasis prevalence over time.

Risk of hospitalization and death due to infection in people with psoriasis: a population-based cohort study using the Clinical Practice Research Datalink.

BACKGROUND: Psoriasis is associated with risk factors for serious infections, but the independent relationship between psoriasis and serious infection is as yet unclear. OBJECTIVES: To determine whether people with psoriasis have a higher risk of hospitalization due to any infection, respiratory infections, soft-tissue and skin infections, or a higher risk of death due to infection. METHODS: We conducted a cohort study of people (≥ 18 years) with psoriasis using the UK Clinical Practice Research Datalink (CPRD GOLD) linked to Hospital Episode Statistics (HES) and Office for National Statistics (ONS) mortality records between 1 April 2003 and 31 December 2016, and matched with up to six comparators on age, sex and general practice. Hospitalization was ascertained from HES records; death was ascertained from ONS mortality records. Stratified Cox proportional hazard models were estimated, with stepwise adjustment in different models for potential confounders or mediators between psoriasis and serious infection. RESULTS: There were 69 315 people with psoriasis and 338 620 comparators who were followed up for a median (interquartile range) of 4·9 (5·9) and 5·1 (6·3) years, respectively. People with psoriasis had a higher incidence rate of serious infection [20·5 per 1000 person-years, 95% confidence interval (CI) 20·0-21·0, n = 7631] compared with those without psoriasis (16·1 per 1000 person-years, 95% CI 15·9-16·3, n = 30 761). The fully adjusted hazard ratio for the association between psoriasis and serious infection was 1·36 (95% CI 1·31-1·40), with similar results across the other outcomes. CONCLUSIONS: Psoriasis is associated with a small increase in the risk of serious infection. Further research is needed to understand how psoriasis predisposes to a higher risk of infection.

Alcohol misuse is associated with poor response to systemic therapies for psoriasis: findings from a prospective multicentre cohort study.

BACKGROUND: Factors that might influence response to systemic treatment for moderate-to-severe psoriasis are varied, and generally, are poorly understood, aside from high bodyweight, suggesting that other unidentified factors may be relevant in determining response to treatment. The impact of alcohol misuse on treatment response has not been previously investigated. OBJECTIVES: To investigate whether alcohol misuse is associated with poor response to treatment for psoriasis. METHODS: This was a prospective cohort study in which response to systemic therapies was assessed using the Psoriasis Area and Severity Index (PASI). The CAGE (Cut down, Annoyed, Guilty, Eye opener) questionnaire was used to screen for alcohol misuse. A multivariable factional polynomial linear regression model was used to examine factors associated with change in PASI between baseline and follow-up. RESULTS: The cohort comprised 266 patients (biologic cohort, n = 134; conventional systemic cohort, n = 132). For the entire cohort, the median (interquartile range) PASI improved from 13 (10·0-18·3) at baseline to 3 (1·0-7·5) during follow-up. A higher CAGE score [regression coefficient: 1·40, 95% confidence interval (CI) 0·04-2·77]; obesity (1·84, 95% CI 0·48-3·20); and receiving a conventional systemic rather than a biologic therapy (4·39, 95% CI 2·84-5·95) were significantly associated with poor response to treatment; whereas a higher baseline PASI (-0·83, 95% CI -0·92 to -0·74) was associated with a better response to treatment. CONCLUSIONS: The poor response to therapy associated with alcohol misuse and obesity found in people with psoriasis calls for lifestyle behaviour change interventions and support as part of routine clinical care. Targeting interventions to prevent, detect and manage alcohol misuse among people with psoriasis is needed to minimize adverse health consequences and improve treatment response.

Patient preferences for stratified medicine in psoriasis: a discrete choice experiment.

BACKGROUND: New technologies have enabled the potential for stratified medicine in psoriasis. It is important to understand patients' preferences to enable the informed introduction of stratified medicine, which is likely to involve a number of individual tests that could be collated into a prescribing algorithm for biological drug selection to be used in clinical practice. OBJECTIVES: To quantify patient preferences for an algorithm-based approach to prescribing biologics ('biologic calculator') in psoriasis. METHODS: An online survey comprising a discrete choice experiment (DCE) was conducted to elicit the preferences of two purposive samples of adults living with psoriasis in the UK, identified from a psoriasis patient organization (Psoriasis Association) and an online panel provider (Dynata). Respondents chose between two biologic calculators and conventional prescribing described using five attributes: treatment delay; positive predictive value; negative predictive value; risk of infection; and cost saving to the National Health Service. Each participant selected their preferred alternative from six hypothetical choice sets. Additional data, including sociodemographic characteristics, were collected. Choice data were analysed using conditional logit and fully correlated random parameters logit models. RESULTS: Data from 212 respondents (67 from the Psoriasis Association and 145 from Dynata) were analysed. The signs of all estimated coefficients were consistent with a priori expectations. Respondents had a strong preference for a high predictive accuracy and avoiding serious infection, but there was evidence of systematic differences in preferences between the samples. CONCLUSIONS: This study indicates that individuals with psoriasis would value a biologic calculator and suggested that such a biologic calculator should have sufficient accuracy to predict future response and risk of serious infection from the biologic.

The risk of malignancy in patients with secukinumab-treated psoriasis, psoriatic arthritis and ankylosing spondylitis: analysis of clinical trial and postmarketing surveillance data with up to five years of follow-up.

BACKGROUND: Data on the use of biologic therapy and malignancy risk are inconsistent due to limited long-term robust studies. OBJECTIVES: To assess the malignancy risk in patients with secukinumab-treated psoriasis, psoriatic arthritis (PsA) and ankylosing spondylitis (AS). METHODS: This integrated safety analysis from both the secukinumab clinical trial programme and postmarketing safety surveillance data included any patient receiving at least one approved dose of secukinumab with a maximum of 5 years of follow-up. Safety analyses evaluated the rate of malignancy using exposure-adjusted incidence rates [EAIR; incidence rates per 100 patient treatment-years (PTY)]. Standardized incidence ratios (SIRs) were reported using the Surveillance, Epidemiology, and End Results Program (SEER) database as a reference population. Crude incidence of malignancy was also reported using postmarketing surveillance data. RESULTS: Safety data from 49 clinical trials with secukinumab-treated patients were included: 10 685 patients with psoriasis, 2523 with PsA and 1311 with AS. Across indications over a 5-year period, the EAIR of malignancy was 0·85 per 100 PTY [95% confidence interval (CI) 0·74-0·98] in secukinumab-treated patients, corresponding to 204 patients per 23 908 PTY. Overall, the observed vs. expected number of malignancies from secukinumab clinical trial data were comparable, as indicated by an SIR of 0·99 (95% CI 0·82-1·19) across indications. The estimated crude cumulative incidence reporting rate per 100 PTY for malignancy was 0·27 in the postmarketing surveillance data across indications with a cumulative exposure of 285 811 PTY. CONCLUSIONS: In this large safety analysis, the risk of malignancy was low for up to 5 years of secukinumab treatment. These data support the long-term use of secukinumab in these indications.

Five-year maintenance of clinical response and health-related quality of life improvements in patients with moderate-to-severe psoriasis treated with guselkumab: results from VOYAGE 1 and VOYAGE 2.

BACKGROUND: Psoriasis is a chronic disease requiring long-term therapy. OBJECTIVES: Physician- and patient-reported outcomes were evaluated through week 252 in VOYAGE 1 and VOYAGE 2. METHODS: In total, 1829 patients were randomized at baseline to receive guselkumab 100 mg every 8 weeks, placebo or adalimumab. Patients receiving placebo crossed over to guselkumab at week 16. Patients receiving adalimumab crossed over to guselkumab at week 52 in VOYAGE 1, and randomized withdrawal and retreatment occurred at weeks 28-76 in VOYAGE 2; all patients then received open-label guselkumab through week 252. Efficacy and health-related quality of life (HRQoL) endpoints were analysed through week 252. Safety was monitored through week 264. RESULTS: The proportions of patients in the guselkumab group who achieved clinical responses at week 252 in VOYAGE 1 and VOYAGE 2, respectively, were 84·1% and 82·0% [≥ 90% improvement in Psoriasis Area and Severity Index (PASI)]; 82·4% and 85·0% [Investigator's Global Assessment (IGA) 0 or 1]; 52·7% and 53·0% (100% improvement in PASI) and 54·7% and 55·5% (IGA 0). HRQoL endpoints were achieved as follows: 72·7% and 71·1% of patients (Dermatology Life Quality Index 0 or 1: no effect on patient's life); 42·4% and 42·0% [Psoriasis Symptoms and Signs Diary (PSSD) symptom score = 0] and 33·0% and 31·0% (PSSD sign score = 0). As measured in VOYAGE 2 only, approximately 45% of patients achieved ≥ 5-point reduction in Short Form-36 physical and mental component scores, and 80% reported no anxiety or depression (Hospital Anxiety and Depression Scale scores < 8). Similar findings were reported for adalimumab crossovers. These effects were maintained from week 52 in VOYAGE 1 and week 100 in VOYAGE 2. No new safety signals were identified. CONCLUSIONS: Guselkumab maintains high levels of clinical response and improvement in patient-reported outcomes through 5 years in patients with moderate-to-severe psoriasis.

Efficacy of secukinumab and adalimumab in patients with psoriatic arthritis and concomitant moderate-to-severe plaque psoriasis: results from EXCEED, a randomized, double-blind head-to-head monotherapy study.

BACKGROUND: Secukinumab [an interleukin (IL)-17A inhibitor] has demonstrated significantly higher efficacy vs. etanercept (a tumour necrosis factor inhibitor) and ustekinumab (an IL-12/23 inhibitor) in patients with moderate-to-severe plaque psoriasis. OBJECTIVES: To report 52-week results from a prespecified analysis of patients with active psoriatic arthritis (PsA) having concomitant moderate-to-severe plaque psoriasis from the head-to-head EXCEED monotherapy study comparing secukinumab with adalimumab. METHODS: Patients were randomized to receive secukinumab 300 mg via subcutaneous injection at baseline, week 1-4, and then every 4 weeks until week 48 or adalimumab 40 mg via subcutaneous injection every 2 weeks from baseline until week 50. Assessments in patients with concomitant moderate-to-severe psoriasis, defined as having affected body surface area > 10% or Psoriasis Area and Severity Index (PASI) ≥ 10 at baseline, included musculoskeletal, skin and quality-of-life outcomes. Missing data were handled using multiple imputation. RESULTS: Of the 853 patients [secukinumab (N = 426), adalimumab (N = 427)], 211 (24·7%) had concomitant moderate-to-severe psoriasis [secukinumab (N = 110, 25·8%), adalimumab (N = 101, 23·7%)]. Up to week 50, 5·5% of patients discontinued secukinumab vs.17·8% in the adalimumab group. The proportion of patients who achieved American College of Rheumatology (ACR) 20 response was 76·4% with secukinumab vs. 68·3% with adalimumab (P = 0·175), PASI 100 response was 39·1% vs. 23·8% (P = 0·013), and simultaneous improvement in ACR 50 and PASI 100 response at week 52 was 28·2% vs. 17·7%, respectively (P = 0·06). Secukinumab demonstrated consistently higher responses vs. adalimumab across skin endpoints. CONCLUSIONS: This prespecified analysis in PsA patients with concomitant moderate-to-severe plaque psoriasis in the EXCEED study provides further evidence that IL-17 inhibitors offer a comprehensive biological treatment to manage the concomitant features of psoriasis and PsA.

Defining trajectories of response in patients with psoriasis treated with biologic therapies.

BACKGROUND: The effectiveness and cost-effectiveness of biologic therapies for psoriasis are significantly compromised by variable treatment responses. Thus, more precise management of psoriasis is needed. OBJECTIVES: To identify subgroups of patients with psoriasis treated with biologic therapies, based on changes in their disease activity over time, that may better inform patient management. METHODS: We applied latent class mixed modelling to identify trajectory-based patient subgroups from longitudinal, routine clinical data on disease severity, as measured by the Psoriasis Area and Severity Index (PASI), from 3546 patients in the British Association of Dermatologists Biologics and Immunomodulators Register, as well as in an independent cohort of 2889 patients pooled across four clinical trials. RESULTS: We discovered four discrete classes of global response trajectories, each characterized in terms of time to response, size of effect and relapse. Each class was associated with differing clinical characteristics, e.g. body mass index, baseline PASI and prevalence of different manifestations. The results were verified in a second cohort of clinical trial participants, where similar trajectories following the initiation of biologic therapy were identified. Further, we found differential associations of the genetic marker HLA-C*06:02 between our registry-identified trajectories. CONCLUSIONS: These subgroups, defined by change in disease over time, may be indicative of distinct endotypes driven by different biological mechanisms and may help inform the management of patients with psoriasis. Future work will aim to further delineate these mechanisms by extensively characterizing the subgroups with additional molecular and pharmacological data.

A head-to-head comparison of ixekizumab vs. guselkumab in patients with moderate-to-severe plaque psoriasis: 24-week efficacy and safety results from a randomized, double-blinded trial.

BACKGROUND: Significantly more patients with moderate-to-severe plaque psoriasis treated with the interleukin (IL)-17A inhibitor ixekizumab vs. the IL-23p19 inhibitor guselkumab in the IXORA-R head-to-head trial achieved 100% improvement in Psoriasis Area and Severity Index (PASI 100) at week 12. OBJECTIVES: To compare skin and nail clearance and patient-reported outcomes for ixekizumab vs. guselkumab, up to week 24. METHODS: IXORA-R enrolled adults with moderate-to-severe plaque psoriasis, defined as static Physician's Global Assessment ≥ 3, PASI ≥ 12 and involved body surface area ≥ 10%. Statistical comparisons were performed using the Cochran-Mantel-Haenszel test stratified by pooled site. Time-to-first-event comparisons were performed using Kaplan-Meier analysis, and P-values were generated using adjusted log-rank tests stratified by treatment group. Cumulative days at clinical and patient-reported responses were compared by ancova. The trial was registered with ClinicalTrials.gov (NCT03573323). RESULTS: Of the 1027 patients randomly assigned, 90% completed the trial (465 of 520 ixekizumab and 459 of 507 guselkumab). As early as week 2 and through week 16, more patients on ixekizumab achieved PASI 100 (P < 0·01). At week 24, ixekizumab was noninferior to guselkumab (50% vs. 52%, difference -2·3%), with no statistically significant difference in PASI 100 (P = 0·41). More patients receiving ixekizumab showed completely clear nails at week 24 (52% vs. 31%, P = 0·007). The median time to first PASI 50/75/90 and PASI 100 were 2 and 7·5 weeks shorter, respectively, for patients on ixekizumab vs. guselkumab (P < 0·001). Patients on ixekizumab also had a greater cumulative benefit, with more days at PASI 90 and 100, with Dermatology Life Quality Index of 0 or 1, and itch free (P < 0·05). The frequency of serious adverse events was 3% for each group, with no new safety signals. CONCLUSIONS: Ixekizumab was noninferior to guselkumab in complete skin clearance and superior in clearing nails at week 24. Ixekizumab cleared skin more rapidly in patients with moderate-to-severe plaque psoriasis, with a greater cumulative benefit, than guselkumab. Overall, the safety findings were consistent with the known safety profile for ixekizumab.

Risk-mitigating behaviours in people with inflammatory skin and joint disease during the COVID-19 pandemic differ by treatment type: a cross-sectional patient survey.

BACKGROUND: Registry data suggest that people with immune-mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse coronavirus disease 2019 (COVID-19) outcomes compared with patients receiving no systemic treatments. OBJECTIVES: We used international patient survey data to explore the hypothesis that greater risk-mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation. METHODS: Online surveys were completed by individuals with psoriasis (globally) or rheumatic and musculoskeletal diseases (RMDs) (UK only) between 4 May and 7 September 2020. We used multiple logistic regression to assess the association between treatment type and risk-mitigating behaviour, adjusting for clinical and demographic characteristics. We characterized international variation in a mixed-effects model. RESULTS: Of 3720 participants (2869 psoriasis, 851 RMDs) from 74 countries, 2262 (60·8%) reported the most stringent risk-mitigating behaviour (classified here under the umbrella term 'shielding'). A greater proportion of those receiving targeted therapies (biologics and Janus Kinase inhibitors) reported shielding compared with those receiving no systemic therapy [adjusted odds ratio (OR) 1·63, 95% confidence interval (CI) 1·35-1·97]. The association between targeted therapy and shielding was preserved when standard systemic therapy was used as the reference group (OR 1·39, 95% CI 1·23-1·56). Shielding was associated with established risk factors for severe COVID-19 [male sex (OR 1·14, 95% CI 1·05-1·24), obesity (OR 1·37, 95% CI 1·23-1·54), comorbidity burden (OR 1·43, 95% CI 1·15-1·78)], a primary indication of RMDs (OR 1·37, 95% CI 1·27-1·48) and a positive anxiety or depression screen (OR 1·57, 95% CI 1·36-1·80). Modest differences in the proportion shielding were observed across nations. CONCLUSIONS: Greater risk-mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID-19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence-based patient communication on risk-mitigation strategies and may help inform updated public health guidelines as the pandemic continues.

Anakinra for palmoplantar pustulosis: results from a randomized, double-blind, multicentre, two-staged, adaptive placebo-controlled trial (APRICOT).

BACKGROUND: Palmoplantar pustulosis (PPP) is a rare, debilitating, chronic inflammatory skin disease that affects the hands and feet. Clinical, immunological and genetic findings suggest a pathogenic role for interleukin (IL)-1. OBJECTIVES: To determine whether anakinra (an IL-1 receptor antagonist) delivers therapeutic benefit in PPP. METHODS: This was a randomized (1 : 1), double-blind, two-staged, adaptive, UK multicentre, placebo-controlled trial [ISCRTN13127147 (registered 1 August 2016); EudraCT number: 2015-003600-23 (registered 1 April 2016)]. Participants had a diagnosis of PPP (> 6 months) requiring systemic therapy. Treatment was 8 weeks of anakinra or placebo via daily, self-administered subcutaneous injections. Primary outcome was the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. RESULTS: A total of 374 patients were screened; 64 were enrolled (31 in the anakinra arm and 33 in the placebo arm) with a mean (SD) baseline PPPASI of 17·8 (10·5) and a PPP investigator's global assessment of severe (50%) or moderate (50%). The baseline adjusted mean difference in PPPASI favoured anakinra but did not demonstrate superiority in the intention-to-treat analysis [-1·65, 95% confidence interval (CI) -4·77 to 1·47; P = 0·30]. Similarly, secondary objective measures, including fresh pustule count (2·94, 95% CI -26·44 to 32·33; favouring anakinra), total pustule count (-30·08, 95% CI -83·20 to 23·05; favouring placebo) and patient-reported outcomes, did not show superiority of anakinra. When modelling the impact of adherence, the PPPASI complier average causal effect for an individual who received ≥ 90% of the total treatment (48% in the anakinra group) was -3·80 (95% CI -10·76 to 3·16; P = 0·285). No serious adverse events occurred. CONCLUSIONS: No evidence for the superiority of anakinra was found. IL-1 blockade is not a useful intervention for the treatment of PPP.

Research priorities and identification of a health-service delivery model for psoriasis from the UK Psoriasis Priority Setting Partnership.

BACKGROUND: Psoriasis impacts the health and psychosocial functioning of patients, conferring a significant economic burden on healthcare systems. There remain unmet needs in psoriasis care, which if addressed by research, could improve clinical outcomes. AIM: To research priorities and identify a health service delivery model from the UK Psoriasis Priority Setting Partnership (PsPSP). METHODS: Between July 2017 and November 2018, we invited people with lived experience of psoriasis and healthcare professionals to (i) identify unmet needs, and (ii) prioritize the order in which these should be addressed by research. We collaborated with the Psoriasis Association and used methodology established by the James Lind Alliance, which pioneers the joint setting of research priorities by patients and clinicians worldwide. RESULTS: In our initial harvesting survey (Survey 1), 2133 questions were submitted by 805 individuals. Submissions that had not been answered by research (true uncertainties) were supplemented with evidence gaps from systematic reviews/guidelines published in the previous 5 years and refined to produce 55 indicative questions. Voting in Survey 2, by 1154 individuals, enabled a shortlist of questions, which were prioritized during the final workshop to produce a top 20 list of research questions. Submissions on health service delivery (5.8% of the total submissions), which were analysed separately, described a blueprint for psoriasis care. CONCLUSIONS: The PsPSP will inform the translational research agenda, ensuring that future research is relevant for the needs of people with psoriasis and those who manage the disease. Submissions on health service delivery describe a model of holistic, patient-focused care providing high-quality, effective management for patients with psoriasis.

The incidence of psoriasis in Chile: an analysis of the National Waiting List Repository.

BACKGROUND: Psoriasis is a serious and chronic noncommunicable disease. However, the fundamental measure of disease occurrence, the incidence, has been scarcely reported globally. There are no previous studies of psoriasis incidence in Latin America. AIM: To estimate the incidence rates of psoriasis in Chile during 2016 and 2017 using an administrative database, the Waiting List Repository. METHODS: We examined referrals of psoriasis at onset, made by physicians to dermatologists, evaluated the agreement of diagnosis, and estimated the incidence of the disease considering the eligible population at risk. RESULTS: In most cases, the referrals corresponded to incident cases of psoriasis (73.3%; 95% CI: 66.6-79.2). The national incidence rates of psoriasis were 22.1 (95% CI: 21.1-23.1) and 22.7 (95% CI: 21.8-23.6) per 100 000 person-years in 2016 and 2017, respectively. The most common type of psoriasis was the late-onset type. We observed a high variation in the figures throughout the country, with a range from 0.75 (95% CI: 0.3-1.5) per 100 000 person-years in the Metropolitan region to 164.9 (95% CI: 138.6-195.1) per 100 000 person-years in the Aysen region. CONCLUSION: We describe for the first time the incidence of psoriasis in a Latin American country. Our findings could potentially guide collaborations to improve our global understanding of psoriasis in Latin America.

Twelve-week secukinumab treatment is consistently efficacious for moderate-to-severe psoriasis regardless of prior biologic and non-biologic systemic treatment: Post hoc analysis of six randomised trials.

BACKGROUND: The efficacy of biologic therapies is greater among biologic-naïve vs. biologic-experienced psoriasis patients. However, little is known as to whether prior use of other systemic therapies impacts secukinumab efficacy in patients with moderate-to-severe psoriasis. OBJECTIVE: To investigate the impact of prior exposure to systemic therapies upon the efficacy and safety of secukinumab 300 mg for moderate-to-severe psoriasis. METHODS: Post hoc analysis of six randomised controlled trials (RCTs) comparing secukinumab with placebo, ustekinumab or etanercept at 12 weeks of treatment. Data comparing secukinumab with placebo and ustekinumab were meta-analysed, while comparisons between secukinumab and etanercept were from a single RCT. Four subgroups of patients were assessed: (i) naïve to non-biologic systemics (NBS) and biologics; (ii) exposed to NBS but naïve to biologics; (iii) naïve to NBS but exposed to biologics; and (iv) exposed to NBS and biologics. Outcomes of interest included the following: investigator's global assessment (IGA) score, absolute psoriasis area and severity index (PASI) response, PASI 75, PASI 90 and PASI 100 responses, and dermatology life quality index (DLQI). Safety was also assessed. RESULTS: One thousand three hundred and eighty-three patients were included in the secukinumab vs. placebo meta-analysis: 1776 in the secukinumab vs. ustekinumab meta-analysis and 653 in the within-trial analyses of secukinumab vs. etanercept. For all subgroups, secukinumab was significantly more efficacious than placebo for all outcomes measured. Secukinumab generated greater responses in biologic-naïve patients, while prior NBS had a negligible impact on treatment response. Furthermore, secukinumab was more efficacious than both ustekinumab and etanercept on many outcomes, with an even greater difference for biologic-naïve than biologic-exposed patients. Safety results were consistent with individual clinical trial results. CONCLUSIONS: Twelve-week treatment with secukinumab 300 mg is consistently more efficacious than placebo, etanercept and ustekinumab in patients with moderate-to-severe psoriasis, regardless of prior exposure to biologics or NBS. Secukinumab had a comparable safety profile to both etanercept and ustekinumab.

Characteristics and outcomes of patients treated with apremilast in the real world: results from the APPRECIATE study.

BACKGROUND: APPRECIATE is a multinational, observational, retrospective, cross-sectional study in patients treated for psoriasis with apremilast, an oral phosphodiesterase 4 inhibitor. OBJECTIVES: To describe the characteristics of patients with psoriasis treated with apremilast in the clinical setting, to evaluate real-world outcomes of psoriasis treatment with apremilast and to better understand the perspectives of patients and physicians on treatment outcomes. METHODS: In six European countries, patients with chronic plaque psoriasis treated in clinical practice who could be contacted 6 (±1) months after apremilast initiation were enrolled. Patient characteristics, Dermatology Life Quality Index (DLQI) and Psoriasis Area and Severity Index (PASI) were obtained from medical records when available. Outcomes were evaluated using patient/physician questionnaires. RESULTS: In 480 patients at treatment initiation, mean [median; 95% confidence interval (CI)] PASI and DLQI scores were 12.5 (10.7; 11.6-13.4) and 13.4 (13.0; 11.4-14.2), respectively. At 6 (±1) months, 72.3% of patients (n = 347) continued apremilast treatment [discontinuations: lack of efficacy (13.5%), safety (11.7%), other (2.5%)]. In patients continuing treatment, 48.6% achieved a ≥75% reduction in PASI score; mean (95% CI) DLQI score was 5.7 (4.5-6.9), and mean (SD) Patient Benefit Index score was 2.8 (1.2). Physicians perceived clinical improvement in 75.6% of patients. Physicians' perspective on overall success of apremilast in meeting expectations correlated with patients' perception of treatment benefit (r = 0.691). Most commonly reported adverse events (>5% of patients) were diarrhoea, nausea and headache. CONCLUSIONS: Patients in APPRECIATE reported high disease burden despite more moderate skin involvement than those who enrolled in clinical trials of apremilast. Findings from APPRECIATE demonstrate the real-world value of apremilast for psoriasis treatment, as 7 of 10 patients continued therapy and showed notable improvement in disease severity and quality of life 6 (±1) months after apremilast initiation.

Effect of baseline disease severity on achievement of treatment target with apremilast: results from a pooled analysis.

BACKGROUND: Treating to absolute treatment targets rather than relative measures such as Psoriasis Area and Severity Index (PASI)-75 is emerging as an important clinical concept included in psoriasis guidelines and clinical practice. Achieving treatment targets is associated with achievement of long-term outcomes. OBJECTIVE: To evaluate the relationship between psoriasis severity, disease characteristics and achievement of PASI ≤2 with apremilast in a pooled analysis of the phase 3 ESTEEM 1 and 2 (NCT01194219 and NCT01232283), phase 3b LIBERATE (NCT01690299) and phase 4 UNVEIL (NCT02425826) clinical trials. METHODS: Pooled data from patients with moderate-to-severe plaque psoriasis randomized to apremilast 30 mg BID were analysed by baseline PASI quartiles (Q1: 2.4-13.1; Q2: 13.2-15.9; Q3: 16.0-20.0; Q4: 20.1-57.8). Assessments included PASI, Dermatology Life Quality Index (DLQI), Scalp Physician's Global Assessment (ScPGA; ScPGA ≥1) and target (worst) Nail Psoriasis Severity Index (NAPSI; NAPSI ≥1). RESULTS: Of 1062 patients, 963 had ScPGA ≥1 and 643 had NAPSI ≥1; 771 patients with baseline and Week 32 PASI assessments were included in analyses of Week 32 PASI target achievement. Rates of PASI ≤2 at Week 32 were greater in lower PASI quartiles (Q1: 43.5%; Q2: 31.2%; Q3: 26.8%; Q4: 18.4%). Most patients achieving PASI ≤2 target (83.6%) achieved DLQI ≤5 at Week 32; 59.3% of patients who did not achieve PASI ≤2 target achieved DLQI ≤5. At Week 32, mean improvements in ScPGA and NAPSI were similar with more moderate vs. more severe disease (ScPGA, range: 1.1-1.4; NAPSI, range: 1.6-2.5). In a subgroup analysis, achievement of PASI ≤2 target was higher in the lowest PASI quartile and with disease duration <5 years. CONCLUSIONS: Greater achievement of PASI ≤2 was observed in patients with more moderate vs. more severe skin disease. Apremilast may be particularly beneficial in more moderate disease early in the treatment paradigm.

Distinctive clinical and histological characteristics of atrophic and hypertrophic facial photoageing.

BACKGROUND: Photoageing describes complex cutaneous changes which occur following chronic exposure to solar ultraviolet radiation (UVR). Amongst White Northern Europeans, facial photoageing appears as distinct clinical phenotypes: 'hypertrophic' photoageing (HP) and 'atrophic' photoageing (AP). Deep, coarse wrinkles predominate in individuals with HP, whereas those with AP have relatively smooth, unwrinkled skin with pronounced telangiectasia. AP individuals have an increased propensity for developing keratinocyte cancers. OBJECTIVES: To investigate whether histological differences underlie these distinct phenotypes of facial photoageing. METHODS: Facial skin biopsies were obtained from participants with AP (10 M, 10 F; mean age: 78.7 years) or HP (10 M, 10 F; mean age: 74.5 years) and were assessed histologically and by immunohistochemistry. RESULTS: Demographic characterization revealed 95% of AP subjects, as compared to 35% with HP, were Fitzpatrick skin type I/II; of these, 50% had a history of one or more keratinocyte cancers. There was no history of keratinocyte cancers in the HP cohort. Analysis of UVR-induced mitochondrial DNA damage confirmed that all volunteers had received similar lifetime cumulative doses of sun exposure. Histologically, male AP had a significantly thicker epidermis than did AP females or those of either sex with HP. HP facial skin exhibited severe solar elastosis, whereas in AP facial skin, solar elastosis was apparent only in females. Loss of papillary dermal fibrillin-rich microfibrils occurred in all HP and AP female subjects, but not in AP males. Furthermore, male AP had a significant reduction in collagen VII at the dermal-epidermal junction than did AP females or those of either sex with HP. CONCLUSIONS: This study provides further evidence that AP and HP represent distinct clinical and histological entities. Knowledge of these two phenotypes is clinically relevant due to the increased prevalence of keratinocyte cancers in those - particularly males - with the AP phenotype.