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.

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.

The use of psoriasis biomarkers, including trajectory of clinical response, to predict clearance and remission duration to UVB phototherapy.

BACKGROUND: Remission duration and treatment response following phototherapy for psoriasis are highly variable and factors influencing these are poorly understood. OBJECTIVES: Our primary outcome was to investigate whether selected clinical/serum biomarkers were associated with remission duration, and secondly with psoriasis clearance at the end of phototherapy. In addition, we looked at whether early trajectory of UVB clearance was associated with final clearance outcome. METHODS: We performed a prospective cohort study of 100 psoriasis patients, routinely prescribed Narrowband UVB and measured selected clinical and biochemical biomarkers, including weekly PASI (psoriasis area and severity index) scores. Patients were followed up for 18 months. RESULTS: The median time to relapse was 6 months (95% CI 5-18) if PASI90 was achieved, and 4 months (95% CI 3-9) if less than PASI90 was achieved. Achieving PASI100 did not result in prolonged remission. On UVB completion, the median final PASI (n = 96) was 1.0 (IQR 0.5, 1.6) with 78 (81%) achieving PASI75 and 39 (41%) achieving PASI90. Improved PASI90 response was significantly associated with lower BMI, higher baseline PASI, non-smoking status and lower cumulative NbUVB. Serum levels of C-reactive protein (CRP) and vitamin D were not associated with clearance or remission duration. Early treatment response from weeks 2-3 was predictive of final outcome. For example, achieving PASI30 at week 3 was significantly associated with PASI90 at the end of the course [36/77 (51%) vs. 2/24 (8%), P < 0.001]. CONCLUSIONS: Raised BMI and positive smoking status predicted poorer phototherapy response. For the first time, we have shown that PASI clearance trajectory over the first 2-3 weeks of UVB, can predict psoriasis clearance. This is an important new step towards developing psoriasis personalized prescribing, which can now be formally tested in clinical trials. These simple clinical measures can be used to inform patient treatment expectations; allowing treatment modifications and/or switching to alternative therapies.

Drug survival of adalimumab, ustekinumab and secukinumab in patients with psoriasis: a prospective cohort study from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR).

BACKGROUND: Real-world biologic drug survival is an important proxy measure for effectiveness. Predictors of drug survival may help patients with psoriasis choose between biologic therapies. OBJECTIVES: (i) To assess the relative drug survival of adalimumab, ustekinumab and secukinumab in patients with psoriasis. (ii) To investigate predictors of biologic drug survival. METHODS: A prospective cohort study was performed in the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) between November 2007 and August 2019. We performed survival analysis and fitted a flexible parametric survival model for biologic discontinuation due to ineffectiveness. RESULTS: In total 9652 patients were included: 5543 starting on adalimumab (57·4%), 991 on secukinumab (10·3%) and 3118 on ustekinumab (32·3%). The overall drug survivals of adalimumab, secukinumab and ustekinumab in year 1 were 0·78 [95% confidence interval (CI) 0·77-0·79], 0·88 (95% CI 0·86-0·91) and 0·88 (95% CI 0·87-0·89), respectively. The adjusted hazard ratios (adjHRs) for discontinuation of adalimumab and secukinumab compared with ustekinumab were 2·11 (95% CI 1·76-2·54) and 0·67 (95% CI 0·40-1·11), respectively. The presence of psoriatic arthritis predicted for survival in the adalimumab and secukinumab cohorts (adjHR 0·67, 95% CI 0·51-0·88 and 0·70, 95% CI 0·40-1·24, respectively), but for discontinuation in the ustekinumab cohort (adjHR 1·42, 95% CI 1·12-1·81). Previous exposure to biologic therapies predicted for discontinuation in the ustekinumab and secukinumab cohorts (adjHR 1·54, 95% CI 1·26-1·89 and 1·49, 95% CI 0·91-2·45, respectively) and for survival in the adalimumab cohort (adjHR 0·71, 95% CI 0·55-0·92). CONCLUSIONS: Secukinumab and ustekinumab have similar sustained drug survival, while adalimumab has a lower drug survival in patients with psoriasis. Psoriatic arthritis and previous biologic experience were predictors with differential effects between the biologic therapies. What is already known about this topic? There is conflicting evidence over the real-world drug survival of secukinumab in patients with psoriasis. Data from registries to date suggest that secukinumab has a lower drug survival than that reported from clinical trials. What does this study add? This study found that secukinumab and ustekinumab had similar sustained drug survival in the real world, while the drug survival of adalimumab was lower, suggesting that the real-world drug survival of secukinumab is higher than previously reported. We found that psoriatic arthritis and previous biologic experience had differential effects on drug discontinuation in the three biologic cohorts. These predictors may help patients and clinicians choose the most appropriate biologic therapy.

Psoriasis treat to target: defining outcomes in psoriasis using data from a real-world, population-based cohort study (the British Association of Dermatologists Biologics and Immunomodulators Register, BADBIR).

BACKGROUND: The 'treat to target' paradigm improves outcomes and reduces costs in chronic disease management but is not yet established in psoriasis. OBJECTIVES: To identify treatment targets in psoriasis using two common measures of disease activity: Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA). METHODS: Data from a multicentre longitudinal U.K. cohort of patients with psoriasis receiving systemic or biologic therapies (British Association of Dermatologists Biologics and Immunomodulators Register, BADBIR) were used to identify absolute PASI thresholds for 90% (PASI 90) and 75% (PASI 75) improvements in baseline disease activity, using receiver operating characteristic curves. The relationship between PGA (clear, almost clear, mild, moderate, moderate-severe, severe) and PASI (range 0-72) was described, and the concordance between absolute and relative definitions of response was determined. The same approach was used to establish treatment response and eligibility definitions based on PGA. RESULTS: Data from 13 422 patients were available (58% male, 91% white ethnicity, mean age 44·9 years), including over 23 000 longitudinal PASI and PGA scores. An absolute PASI ≤ 2 was concordant with PASI 90 and an absolute PASI ≤ 4 was concordant with PASI 75 in 90% and 88% of cases, respectively. These findings were robust to subgroups of timing of assessment, baseline disease severity and treatment modality. PASI and PGA were strongly correlated (Spearman's rank correlation coefficient 0·92). The median PASI increased from 0 (interquartile range 0-0, range 0-23) to 19 (interquartile range 15-25, range 0-64) for PGA clear to severe, respectively. PGA clear/almost clear was concordant with PASI ≤ 2 in 90% of cases, and PGA moderate-severe severe was concordant with the National Institute for Health and Care Excellence PASI eligibility criteria for biologics in 81% of cases. CONCLUSIONS: An absolute PASI ≤ 2 and PGA clear/almost clear represent relevant disease end points to inform treat-to-target management strategies in psoriasis. What's already known about this topic? The most commonly used relative disease activity measure in psoriasis is ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90); however, it has several limitations including dependency on a baseline severity assessment. Defining an absolute target disease activity end point in psoriasis has the potential to improve patient outcomes and reduce costs, as demonstrated by treat-to-target approaches in other chronic diseases such as hypertension and diabetes. The Physician's Global Assessment (PGA) is a popular alternative measure of psoriasis severity in daily practice; however, its utility has not been formally assessed with respect to PASI. What does this study add? An absolute PASI ≤ 2 corresponds with PASI 90 response and is a relevant disease end point for treat-to-target approaches in psoriasis. There is a strong correlation between PASI and PGA. PGA moderate-severe/severe may serve as an alternative eligibility criterion for biologics to PASI-based definitions, and PGA clear/almost clear is an appropriate alternative absolute treatment end point. What are the clinical implications of this work? Absolute PASI ≤ 2 and PGA clear/almost clear represent relevant disease end points to inform treat-to-target management strategies in psoriasis.

Epidermal autophagy and beclin 1 regulator 1 and loricrin: a paradigm shift in the prognostication and stratification of the American Joint Committee on Cancer stage I melanomas.

BACKGROUND: The updated American Joint Committee on Cancer (AJCC) staging criteria for melanoma remain unable to identify high-risk stage I tumour subsets. OBJECTIVES: To determine the utility of epidermal autophagy and beclin 1 regulator 1 (AMBRA1)/loricrin (AMLo) expression as a prognostic biomarker for AJCC stage I cutaneous melanoma. METHODS: Peritumoral AMBRA1 expression was evaluated in a retrospective discovery cohort of 76 AJCC stage I melanomas. AMLo expression was correlated with clinical outcomes up to 12 years in two independent powered, retrospective validation and qualification cohorts comprising 379 AJCC stage I melanomas. RESULTS: Decreased AMBRA1 expression in the epidermis overlying primary melanomas in a discovery cohort of 76 AJCC stage I tumours was associated with a 7-year disease-free survival (DFS) rate of 81·5% vs. 100% survival with maintained AMBRA1 (P < 0·081). Following an immunohistochemistry protocol for semi-quantitative analysis of AMLo, analysis was undertaken in validation (n = 218) and qualification cohorts (n = 161) of AJCC stage I melanomas. Combined cohort analysis revealed a DFS rate of 98·3% in the AMLo low-risk group (n = 239) vs. 85·4% in the AMLo high-risk cohort (n = 140; P < 0·001). Subcohort multivariate analysis revealed that an AMLo hazard ratio (HR) of 4·04 [95% confidence interval (CI) 1·69-9·66; P = 0·002] is a stronger predictor of DFS than Breslow depth (HR 2·97, 95% CI 0·93-9·56; P = 0·068) in stage IB patients. CONCLUSIONS: Loss of AMLo expression in the epidermis overlying primary AJCC stage I melanomas identifies high-risk tumour subsets independently of Breslow depth. What's already known about this topic? There is an unmet clinical need for biomarkers of early-stage melanoma. Autophagy and beclin 1 regulator 1 (AMBRA1) is a proautophagy regulatory protein with known roles in cell proliferation and differentiation, and is a known tumour suppressor. Loricrin is a marker of epidermal terminal differentiation. What does this study add? AMBRA1 has a functional role in keratinocyte/epidermal proliferation and differentiation. The combined decrease/loss of peritumoral AMBRA1 and loricrin is associated with a significantly increased risk of metastatic spread in American Joint Committee on Cancer (AJCC) stage I tumours vs. melanomas, in which peritumoral AMBRA1 and loricrin are maintained, independently of Breslow depth. What is the translational message? The integration of peritumoral epidermal AMBRA1/loricrin biomarker expression into melanoma care guidelines will facilitate more accurate, personalized risk stratification for patients with AJCC stage I melanomas, thereby facilitating stratification for appropriate follow-up and informing postdiagnostic investigations, including sentinel lymph node biopsy, ultimately resulting in improved disease outcomes and rationalization of healthcare costs.

Pruritus secondary to primary biliary cholangitis: a review of the pathophysiology and management with phototherapy.

BACKGROUND: Primary biliary cholangitis (PBC) is an autoimmune hepatobiliary disorder characterized by destruction of liver bile ducts leading to intrahepatic cholestasis. It causes intractable pruritus for which ultraviolet (UV)B phototherapy is an experimental treatment when alternative therapies fail. The pathophysiology of cholestatic itch and the mechanism of action of narrowband UVB in this condition remains poorly understood. OBJECTIVES: To summarize the current literature and propose testable hypotheses for the mechanism of action of phototherapy in attenuating itch. METHODS: A focused PubMed search for articles relating to the pathogenesis of itch in cholestatic disease was performed. A total of 3855 articles were screened and 50 were found suitable for literature review. Evidence from this literature review was combined with author expertise in the area. RESULTS: Formulated hypotheses focus on the role of bile salts, autotaxin and specific receptors including G-protein-coupled bile acid receptor, Gpbar1 (also known as TGR5) and the nuclear transcription factor farnesoid X receptor. CONCLUSIONS: Several testable mechanisms through which phototherapy may exert its effects are discussed in this review. The next steps are to carry out an objective assessment of the efficacy of phototherapy in cholestatic pruritus, gain further knowledge on the underlying pathways, and subsequently trial its use against current licensed therapies. Such studies could lead to increased mechanistic understanding, identification of novel therapeutic targets and the potential to refine phototherapy protocols, leading to improved control of itch and quality of life in patients with PBC. What's already known about this topic? Primary biliary cholangitis (PBC) is frequently associated with intractable pruritus for which current treatment options are often unsuccessful. Phototherapy is used as an experimental treatment for PBC-associated pruritus when alternative better-studied treatments fail. What does this study add? This study reviews the current literature on the pathophysiology and management of cholestatic pruritus, an area which remains poorly understood. We propose testable hypotheses of the mechanisms behind the attenuation of cholestatic pruritus with phototherapy.

Identifying demographic, social and clinical predictors of biologic therapy effectiveness in psoriasis: a multicentre longitudinal cohort study.

BACKGROUND: Biologic therapies have revolutionized the treatment of moderate-to-severe psoriasis. However, for reasons largely unknown, many patients do not respond or lose response to these drugs. OBJECTIVES: To evaluate demographic, social and clinical factors that could be used to predict effectiveness and stratify response to biologic therapies in psoriasis. METHODS: Using a multicentre, observational, prospective pharmacovigilance study (BADBIR), we identified biologic-naive patients starting biologics with outcome data at 6 (n = 3079) and 12 (n = 3110) months. Associations between 31 putative predictors and outcomes were investigated in univariate and multivariable regression analyses. Potential stratifiers of treatment response were investigated with statistical interactions. RESULTS: Eight factors associated with reduced odds of achieving ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) at 6 months were identified (described as odds ratio and 95% confidence interval): demographic (female sex, 0·78, 0·66-0·93); social (unemployment, 0·67, 0·45-0·99); unemployment due to ill health (0·62, 0·48-0·82); ex- and current smoking (0·81, 0·66-0·99 and 0·79, 0·63-0·99, respectively); clinical factors (high weight, 0·99, 0·99-0·99); psoriasis of the palms and/or soles (0·75, 0·61-0·91); and presence of small plaques only compared with small and large plaques (0·78, 0·62-0·96). White ethnicity (1·48, 1·12-1·97) and higher baseline PASI (1·04, 1·03-1·04) were associated with increased odds of achieving PASI 90. The findings were largely consistent at 12 months. There was little evidence for predictors of differential treatment response. CONCLUSIONS: Psoriasis phenotype and potentially modifiable factors are associated with poor outcomes with biologics, underscoring the need for lifestyle management. Effect sizes suggest that these factors alone cannot inform treatment selection.

Infliximab is associated with an increased risk of serious infection in patients with psoriasis in the U.K. and Republic of Ireland: results from the British Association of Dermatologists Biologic Interventions Register (BADBIR).

BACKGROUND: Patients with psoriasis and clinicians are concerned that infliximab may be associated with a risk of serious infections. OBJECTIVES: To compare the risk of serious infections associated with infliximab in patients with chronic plaque psoriasis against a cohort on nonbiologic systemic therapies. METHODS: A prospective cohort study was performed using data from the British Association of Dermatologists Biologic Interventions Register (BADBIR). Infliximab was compared with nonbiologic systemic therapies, inclusive of any exposure to methotrexate, ciclosporin, acitretin, fumaric acid esters, psoralen-ultraviolet A or hydroxycarbamide. Serious infections were those associated with hospitalization, the use of intravenous antimicrobial therapy and/or those that led to death. Propensity score inverse probability treatment weights were used to adjust for potential confounding from a priori identified covariates. Cox proportional hazards models were calculated to obtain hazard ratios (HRs). RESULTS: In total, 3843 participants were included for analysis up to October 2016. The incidence rates were significantly higher in the infliximab cohort (47·8 per 1000 person-years) [95% confidence interval (CI) 35·7-64·0], compared with 14·2 per 1000 person-years (95% CI 11·5-17·4) in the nonbiologic systemic cohort. Infliximab was associated with an overall increase in the risk of serious infection compared with nonbiologics [adjusted HR (adjHR) 1·95, 95% CI 1·01-3·75] and methotrexate only (adjHR 2·96, 95% CI 1·58-5·57) and a higher risk of serious infection in the first 6 months of therapy (adjHR 3·49, 95% CI 1·14-10·70). CONCLUSIONS: Infliximab is associated with an increased risk of serious infections compared with nonbiologic systemic therapies in patients with psoriasis in the U.K. and the Republic of Ireland.

Persistence and effectiveness of nonbiologic systemic therapies for moderate-to-severe psoriasis in adults: a systematic review.

BACKGROUND: The persistence and effectiveness of systemic therapies for moderate-to-severe psoriasis in current clinical practice are poorly characterized. OBJECTIVES: To systematically review observational studies investigating the persistence and effectiveness of acitretin, ciclosporin, fumaric acid esters (FAE) and methotrexate, involving at least 100 adult patients with moderate-to-severe psoriasis, exposed to therapy for ≥ 3 months. METHODS: MEDLINE, Embase, the Cochrane Library and PubMed were searched from 1 January 2007 to 1 November 2017 for observational studies reporting on persistence (therapy duration or the proportion of patients discontinuing therapy during follow-up) or effectiveness [improvements in Psoriasis Area and Severity Index (PASI) or Physician's Global Assessment (PGA)]. This review was registered with PROSPERO, number CRD42018099771. RESULTS: Of 411 identified studies, eight involving 4624 patients with psoriasis were included. Variations in the definitions and analyses of persistence and effectiveness outcomes prevented a meta-analysis from being conducted. One prospective multicentre study reported drug survival probabilities of 23% (ciclosporin), 42% (acitretin) and 50% (methotrexate) at 1 year. Effectiveness outcomes were not reported for either acitretin or ciclosporin. The persistence and effectiveness of FAE and methotrexate were better characterized, but mean discontinuation times ranged from 28 to 50 months for FAE and 7·7 to 22·3 months for methotrexate. At 12 months of follow-up, three studies reported that 76% (FAE), 53% (methotrexate) and 59% (methotrexate) of patients achieved ≥ 75% reduction in PASI, and one reported that 76% of FAE-exposed patients achieved a markedly improved or clear PGA. CONCLUSIONS: The comparative persistence and effectiveness of acitretin, ciclosporin, FAE and methotrexate in real-world clinical practice in the past decade cannot be well described due to the inconsistency of the methods used.

An observer-blinded randomized controlled pilot trial comparing localized immersion psoralen-ultraviolet A with localized narrowband ultraviolet B for the treatment of palmar hand eczema.

BACKGROUND: Hand eczema is a common inflammatory dermatosis that causes significant patient morbidity. Previous studies comparing psoralen-ultraviolet A (PUVA) with narrowband ultraviolet B (NB-UVB) have been small, nonrandomized and retrospective. OBJECTIVES: To conduct an observer-blinded randomized controlled pilot study using validated scoring criteria to compare immersion PUVA with NB-UVB for the treatment of chronic hand eczema unresponsive to topical steroids. METHODS: Sixty patients with hand eczema unresponsive to clobetasol propionate 0·05% were randomized to receive either immersion PUVA or NB-UVB twice weekly for 12 weeks with assessments at intervals of 4 weeks. The primary outcome measure was the proportion of patients achieving 'clear' or 'almost clear' Physician's Global Assessment (PGA) response at 12 weeks. Secondary outcome measures included assessment of the modified Total Lesion and Symptom Score (mTLSS) and the Dermatology Life Quality index (DLQI). RESULTS: In both treatment arms, 23 patients completed the 12-week assessment for the primary outcome measure. In the PUVA group, five patients achieved 'clear' and eight 'almost clear' [intention-to-treat (ITT) response rate 43%]. In the NB-UVB group, two achieved 'clear' and five 'almost clear' (ITT response rate 23%). For the secondary outcomes, median mTLSS scores were similar between groups at baseline (PUVA 9·5, NB-UVB 9) and at 12 weeks (PUVA 3, NB-UVB 4). Changes in DLQI were similar, with improvements in both groups. CONCLUSIONS: In this randomized pilot trial recruitment was challenging. After randomization, there were acceptable levels of compliance and safety in each treatment schedule, but lower levels of retention. Using validated scoring systems - PGA, mTLSS and DLQI - as measures of treatment response, the trial demonstrated that both PUVA and NB-UVB reduced the severity of chronic palmar hand eczema.

Treatment of moderate-to-severe atopic eczema in adults within the U.K.: results of a national survey of dermatologists.

BACKGROUND: Little is known about U.K. dermatologists' treatment approaches towards adult patients with recalcitrant moderate-to-severe atopic eczema. OBJECTIVES: We wanted to learn about (i) treatment approaches used for this disease in the U.K.; (ii) factors that influence treatment decisions and (iii) perceived gaps in evidence on treatment safety and efficacy, and priorities for future trials. METHODS: We conducted an online survey of consultant-level dermatologists in the U.K. RESULTS: Sixty-one respondents from over 30 centres reported on management of moderate-to-severe atopic eczema in adults, outwith the context of an acute flare. Phototherapy or psoralen-ultraviolet A was the most common therapeutic modality chosen first line (46%), and this was usually narrowband ultraviolet B. Systemic therapy was chosen as a first-line approach by 36% of dermatologists. Azathioprine was the commonest drug reported being used as first line followed by oral corticosteroids, ciclosporin and methotrexate. Methotrexate was the most common second-line treatment of respondents. The key factors that influenced decision making on the use of phototherapy and systemic agents were the respondent's clinical experience, results of baseline tests (systemic agents) and knowledge of both efficacy and acute and chronic side-effect profiles. The most important evidence gaps identified were the relative effectiveness of treatments, the alternatives to current approaches and the safety of long-term maintenance treatment. With regard to future trials, respondents suggested that priority should be given to studies involving methotrexate. CONCLUSIONS: While survey study designs have limitations, we found that phototherapy, in particular narrowband ultraviolet B, was respondents' preferred first-line treatment for adults with recalcitrant moderate-to-severe atopic eczema, perhaps reflecting access to, and clinical experience of, this approach. Azathioprine is widely used as a longer-term maintenance treatment.

High prevalence of alcohol use disorders in patients with inflammatory skin diseases.

BACKGROUND: There is a known association between psoriasis and heavy alcohol consumption. The association between heavy alcohol consumption and other inflammatory skin diseases remains to be defined. OBJECTIVES: To examine the prevalence of heavy drinking using the Alcohol Use Disorders Identification Test (AUDIT) in patients with inflammatory skin disease. METHODS: We conducted an observational cross-sectional study in a single hospital outpatient department. We recruited 609 patients with either psoriasis, eczema, cutaneous lupus or other inflammatory disorders, and a reference population with skin lesions. Primary outcome was the proportion of patients in each group with an alcohol use disorder (AUD). RESULTS: The observed prevalence of AUD was 30·6% in patients with psoriasis, 33·3% in those with eczema, 12·3% in those with cutaneous lupus, 21·8% in those with other inflammatory disease and 14·3% in those with non-inflammatory disease. Odds ratios (OR) for AUD in patients in the inflammatory groups compared with those in the noninflammatory groups, adjusted for age and sex, were as follows: psoriasis 1·65 [95% confidence interval (CI) 0·86-3·17], eczema 2·00 (95% CI 1·03-3·85), lupus 1·03 (95% CI 0·39-2·71), other inflammatory disease 1·32 (95% CI 0·68-2·56). ORs were reduced if also adjusted for Dermatology Life Quality Index (DLQI). The prevalence of DLQI ≥ 11 was 31·1% for psoriasis, 43·7% for eczema, 17·5% for cutaneous lupus, 17·2% for other inflammatory disease and 2·8% for noninflammatory disease. CONCLUSIONS: Patients with eczema attending a hospital clinic have been shown to have high levels of AUD of a similar level to patients with psoriasis and higher than patients with noninflammatory skin diseases.

Comparative effectiveness of biological therapies on improvements in quality of life in patients with psoriasis.

BACKGROUND: Evidence of the comparative effectiveness of biological therapies for psoriasis on health-related quality of life (HRQoL) in routine clinical practice is limited. OBJECTIVES: To examine the comparative effectiveness of adalimumab, etanercept and ustekinumab on HRQoL in patients with psoriasis, and to identify potential predictors for improved HRQoL. METHODS: This was a prospective cohort study in which changes in HRQoL were assessed using the Dermatology Life Quality Index (DLQI) and EuroQoL-5D (EQ-5D) at 6 and 12 months. Multivariable regression models were developed to identify factors associated with achieving a DLQI of 0/1 and improvements in the EQ-5D utility score. RESULTS: In total, 2152 patients with psoriasis were included, with 1239 patients on adalimumab, 517 on etanercept and 396 on ustekinumab; 81% were biologic naïve. For the entire cohort, the median (interquartile range) DLQI and EQ-5D improved from 18 (13-24) and 0·73 (0·69-0·80) at baseline to 2 (0-7) and 0·85 (0·69-1·00) at 6 months, respectively (P < 0·001). Similar improvements were achieved at 12 months. At 12 months, multivariable regression modelling showed that female sex, multiple comorbidities, smoking and a higher DLQI or a lower EQ-5D utility score at baseline predicted a lower likelihood of achieving a DLQI of 0/1 or improvement in the EQ-5D. Compared with adalimumab, patients receiving etanercept, but not ustekinumab, were less likely to achieve a DLQI of 0/1. There was no significant difference between the biological therapies in EQ-5D improvement. CONCLUSIONS: In routine clinical practice biological therapies produce marked improvement in HRQoL, which is influenced by the choice of biological therapy, baseline impairment in HRQoL, lifestyle characteristics and comorbidities. These findings should help inform selection of optimal biological therapy for patients related to improvements in HRQoL.

Patterns of biologic therapy use in the management of psoriasis: cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR).

BACKGROUND: Treatment modifications, including dose escalations, dose reductions, switches, discontinuations and restarts of biologics may be necessary in the management of psoriasis but the patterns of usage are incompletely defined. OBJECTIVES: To examine the treatment utilization patterns of adalimumab, etanercept and ustekinumab among biologic-naïve and non-naïve patients with psoriasis enrolled in the British Association of Dermatologists Biologic Interventions Register (BADBIR). METHODS: The study cohort included adults with chronic plaque psoriasis who were followed up for ≥ 12 months. Treatment modifications were assessed during the first year of therapy. The time-trend method, comparing the cumulative dose (CD) patients received with the recommended cumulative dose (RCD), was used to assess dosing patterns. Concomitant use of other systemic treatments was also examined. RESULTS: In total, 2980 patients (adalimumab: 1675; etanercept: 996; ustekinumab: 309) were included; 79·2% were biologic-naïve. Over 12 months, 77·4% of patients continued the biologic, 2·6% restarted therapy after a break of ≥ 90 days, 2·5% discontinued, and 17·5% switched biologic therapy. Most patients (85·7%) received the RCD of the biologic, although 8·1% were exposed to a higher CD. In total, 749 (25·1%) patients used conventional systemic therapies concomitantly with a biologic at some stage; methotrexate was used most commonly (458; 61·2%). Of those using combination therapy, 454 (60·6%) continued the use of the conventional systemic therapy for > 120 days after the start of the biologic. CONCLUSIONS: More than one-third of patients experienced treatment modifications within the first year of initiating a biologic. Conventional systemic therapies, particularly methotrexate, were commonly used concurrently, which should be considered when evaluating treatment response and adverse events to biologics in real-world observational studies.

Kidney disease in moderate-to-severe psoriasis: a critical appraisal.

AIM: Using a population-based cohort, Wan et al. examined the risk of moderate-to-advanced (stage 3-5) chronic kidney disease (CKD) in patients with psoriasis. SETTING AND DESIGN: A population-based cohort was constructed using The Health Improvement Network (THIN) database. THIN is an electronic primary healthcare records database containing routinely collected medical diagnosis and drug prescribing data on > 9 million patients in the U.K. Data were collected prospectively on 143 883 adults (aged 18-90 years) with psoriasis. Of these, 7354 had severe psoriasis, as defined by prescription codes for systemic medication or treatment codes for phototherapy. Patients with psoriasis were matched with up to five nonpsoriasis age- and practice-matched controls. Patients with a diagnosis of CKD before study entry were excluded. In addition, baseline data from the Incident Health Outcomes and Psoriasis Events (iHOPE) study, a cohort of 8731 primary care patients aged 25-64 years with psoriasis, was included. Psoriasis severity was categorized according to body surface area (BSA) involvement as estimated by general practitioners. A similar method using a patient-reported BSA assessment tool was previously validated by the same group. Patients were matched by age and practice with 10 nonpsoriasis controls. STUDY EXPOSURE: Psoriasis, identified on the basis of a recorded diagnostic code for psoriasis. OUTCOMES: Incident CKD was defined as the presence of a recorded diagnostic code consistent with moderate-to-advanced (stage 3-5) CKD or laboratory parameters consistent with the diagnosis (estimated glomerular filtration rate < 60 mL min(-1)  1·73 m(-2) ) during follow-up. Prevalent CKD (as defined above) in the cross-sectional data from the iHOPE study. RESULTS: The adjusted hazard ratios for incident CKD were 1·05 [95% confidence interval (CI) 1·02-1·07], 0·99 (95% CI 0·97-1·02) and 1·93 (95% CI 1·79-2·08) in the overall, mild and severe psoriasis groups, respectively. In the nested cross-sectional study (iHOPE) the adjusted prevalence odds ratios for CKD were 0·89 (95% CI 0·72-1·10), 1·36 (95% CI 1·06-1·74) and 1·58 (95% CI 1·07-2·34) in the mild, moderate and severe psoriasis groups, respectively. CONCLUSIONS: Moderate-to-severe psoriasis is associated with an increased risk of moderate-to-advanced CKD, independently of traditional risk factors.

Translating translation into patient benefit for atopic eczema.

This review considers, in the context of British Skin Foundation (BSF)-funded translational research into atopic eczema conducted in Newcastle, the complex interactions between clinical and non-clinical scientists in both academia and industry and how this may have impacted on clinical care. However, research in individual centres does not occur in isolation and clinically relevant outcomes from collaborative research are increasingly supported through regional and national networks. This is illustrated by our trial of azathioprine in adults with atopic eczema conducted across centres in the North East of England that employed pharmacogenetic dosimetry. Correspondingly the formation of a UK Translational Network for Translational Research in Dermatology (UK TREND) has facilitated the development of a UK-wide network to support atopic eczema projects based on an e-Delphi prioritisation exercise.