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.

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.

Secukinumab for patients failing previous tumour necrosis factor-α inhibitor therapy: results of a randomized open-label study (SIGNATURE).

BACKGROUND: Efficacy data on therapies for patients with psoriasis who have failed tumour necrosis factor (TNF)-α inhibitor therapy is limited. OBJECTIVES: To determine the effectiveness and tolerability of secukinumab, an interleukin (IL)-17A inhibitor, in patients with moderate/severe chronic plaque psoriasis with documented efficacy failure of TNF-α inhibitor therapy (SIGNATURE study). METHODS: This was a randomized, open-label, noncomparator study in 53 dermatology centres in the U.K. and Republic of Ireland. Patients were randomized 1 : 1 to receive secukinumab 300 mg or 150 mg subcutaneously every week for 4 weeks, then 4-weekly thereafter. Patients were stratified by their prior efficacy failure with TNF-α inhibitors. Only patients who started and stayed on the same dose at each time point were included for efficacy assessments. RESULTS: In total, 233 patients were analysed. The primary end point was met, with a statistically significant improvement in response rates [75% reduction in Psoriasis Area and Severity Index (PASI 75)] from baseline to week 16 in both secukinumab 300 mg and 150 mg dose groups [77 of 118 patients (65·3%) and 51 of 115 patients (44·3%), respectively; P < 0·0001]. After 72 weeks, in patients starting and remaining on 300 mg, 77% (54 of 70) achieved PASI 75. Improvements in Dermatology Life Quality Index from baseline to week 16 occurred and were maintained up to 72 weeks. The safety profile was generally consistent with previous secukinumab studies, although a higher incidence of some adverse events (e.g. candida infections) was observed. CONCLUSIONS: This study provides evidence of efficacy and safety of secukinumab for treatment of patients with psoriasis who failed prior TNF-α inhibitor therapy. This study represents a 'real-world' population, providing reassurance that secukinumab is a treatment option in this difficult-to-treat population. What's already known about this topic? Conventional systemic nonbiological and tumour necrosis factor (TNF)-α inhibitor therapies for plaque psoriasis have not fully met patients' needs. There is a lack of data to support the treatment pathways for patients with psoriasis who have inadequate responses to TNF-α inhibitor therapy. Secukinumab, a recombinant high-affinity fully human monoclonal anti-human interleukin-17A antibody of the IgG1/κ-class, has shown excellent safety and efficacy in the treatment of moderate-to-severe psoriasis. What does this study add? This is the first study evaluating treatment with biologics after prior efficacy failure of TNF-α inhibitor therapy as defined by the U.K. National Institute for Health and Care Excellence criteria. Secukinumab is an effective treatment in this difficult-to-treat patient population. This study provides important practical information for clinicians managing psoriasis. Adverse events were consistent with the phase III programme for secukinumab, although some adverse events, e.g. candida, were increased.

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.

What does acne genetics teach us about disease pathogenesis?

BACKGROUND: Acne vulgaris is a highly prevalent inflammatory skin disorder with a complex pathogenesis, characterized by comedones, papules, pustules and nodules. Familial preponderance clearly indicates a genetic basis for acne vulgaris, but until recently solid genetic associations were lacking. RESULTS: The advent of high-resolution genotyping array technologies has allowed for large-scale studies with both family-based and cross-sectional designs. These studies have revealed genetic loci encompassing genes that could be active in biological pathways and processes underlying acne vulgaris. However, specific functional consequences of those variants remain elusive. In parallel, investigations into rare disorders and syndromes that incorporate features of acne or acne-like lesions have recently accelerated our understanding of disease pathogenesis. The genes revealed by these rare disorders highlight mechanisms cardinal for pilosebaceous biology and therefore anchor our insights from genetic association studies for acne vulgaris. CONCLUSIONS: The next phase of research will require more in-depth mechanistic investigations of loci and genes implicated in acne phenotypes to define the key molecular players driving the disorder. Concurrently, new treatments for acne vulgaris could be developed by dissecting the candidate molecular pathways to identify druggable targets.

Does weight loss reduce the severity and incidence of psoriasis or psoriatic arthritis? A Critically Appraised Topic.

CLINICAL QUESTION: Does weight loss reduce the severity and incidence of psoriasis or psoriatic arthritis (PsA) in obese individuals? BACKGROUND: Obesity presents a rising public health challenge and is more prevalent among individuals with psoriasis or PsA than in the general population. Longitudinal population-based studies suggest a causal role for obesity in psoriasis and PsA onset and that obesity drives greater disease severity. METHODS: We systematically reviewed evidence within the MEDLINE, Embase and CENTRAL databases and clinical trials registries examining lifestyle, pharmacological and surgical weight loss interventions in the treatment and prevention of psoriasis and PsA in obese individuals. Meta-analysis was conducted using random-effects models, followed by sensitivity analyses. RESULTS: Of 176 full-text articles reviewed, 14 met the inclusion criteria. Meta-analysis of six randomized control trials (RCTs) confirmed that weight loss following lifestyle interventions (diet or physical activity) improves psoriasis compared with control [mean change in Psoriasis Area and Severity Index -2·59, 95% confidence interval (CI) -4·09 to -1·09; P < 0·001]. One RCT demonstrated a greater likelihood of achieving minimal PsA activity following diet-induced weight loss (odds ratio 4·20, 95% CI 1·82-9·66; P < 0·001). Three studies of pharmacological treatments reported conflicting results, and no RCTs of bariatric surgery were identified. Two cohort studies suggested that bariatric surgery, particularly gastric bypass, reduces the risk of developing psoriasis (hazard ratio 0·52, 95% CI 0·33-0·81; P < 0·01). CONCLUSIONS: These limited data indicate that weight loss can improve pre-existing psoriasis and PsA, and prevent the onset of psoriasis in obese individuals. Together with the National Institute for Health and Care Excellence obesity guidance, this informed a local obesity screening and management pathway, providing multidisciplinary weight loss interventions alongside conventional skin-focused care for patients with psoriasis.

A standardization approach to compare treatment safety and effectiveness outcomes between clinical trials and real-world populations in psoriasis.

BACKGROUND: Patients recruited in randomized controlled trials (RCTs) for biologic therapies in psoriasis are not fully representative of the real-world psoriasis population. OBJECTIVES: Firstly, to investigate whether patient characteristics are associated with being included in a psoriasis RCT. Secondly, to estimate the differences in the incidence of severe adverse events (SAEs) and the response rate between RCT and real-world populations of patients on biologic therapies for psoriasis using a standardization method. METHODS: Data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) were appended to individual participant-level data from two RCTs assessing ustekinumab in patients with psoriasis. Baseline variables were assessed for association of being in an RCT using a multivariable logistic regression model. Propensity score weights were derived to reweigh the registry population so that variables had the distribution of the trial population. We measured the C-statistic of the model with trial status as the dependent variable, and the risk differences in the incidence rate of SAEs in the first year and Psoriasis Area and Severity Index (PASI) after 6 months in the BADBIR cohort before and after weighting. RESULTS: In total 6790 registry and 2021 RCT participants were included. The multivariable logistic regression model had a C-statistic of 0.82 [95% confidence interval (CI) 0.81-0.83]. The risk differences for the incidence rate of SAEs and the proportion of patients with PASI < 1.5 were 9.27 (95% CI -3.91-22.5) per 1000 person-years and 0.95 (95% CI -1.98-4.15), respectively. CONCLUSIONS: Our results suggest that RCTs of biologic therapies in patients with psoriasis are not fully representative of the real-world population, but this lack of external validity does not account for the efficacy-effectiveness gap. What's already known about this topic? Patients with psoriasis who would not be eligible for randomized controlled trials (RCTs) investigating biologic therapies have a greater risk of serious adverse events and lower treatment effectiveness than patients who would have been eligible. What does this study add? Baseline patient characteristics were shown to be predictive of whether a patient would have been eligible for enrolment in an RCT for psoriasis biologic therapy. We did not find any efficacy-effectiveness gap between the sample representative of the real-world population of patients with psoriasis and the sample representative of the RCT population. Factors outside of baseline patient characteristics, such as observer effect and higher adherence in RCTs, may be more influential in any efficacy-effectiveness gap between trial and real-world populations of patients with psoriasis.

Diagnosing liver fibrosis: a narrative review of current literature for dermatologists.

Chronic liver disease is a growing problem worldwide due to obesity, alcohol-related liver disease and viral hepatitis. Liver fibrosis is generally asymptomatic and patients may not present until they have advanced cirrhosis, when the scope for reversibility is limited. Identification of asymptomatic individuals at an early stage is fundamental to reversing the rising toll of liver-related morbidity and mortality. Awareness of liver disease and the techniques for diagnosis is important for dermatologists, not only due to the burden of disease in the general population but also because some dermatology cohorts may have an elevated risk. For example, there is an increased prevalence of metabolic syndrome and excess alcohol use in those with psoriasis and hidradenitis suppurativa. In isolation, standard liver function tests lack sensitivity to detect advanced fibrosis and cirrhosis and are of limited value. Traditionally diagnosis has relied on liver biopsy, which remains the gold standard but is both costly and invasive. There have been several recent advances in the development of noninvasive alternatives. These include scoring systems combining clinical and conventional laboratory parameters for use as screening tools, direct serum biomarkers of fibrogenesis and tissue elastography using both ultrasound (Fibroscan) and magnetic resonance. This review summarizes current and future noninvasive diagnostic techniques for evaluation of liver fibrosis.

Screening for anxiety and depression in people with psoriasis: a cross-sectional study in a tertiary referral setting.

BACKGROUND: National Institute for Health and Care Excellence guidance recommends assessment of psychological and social well-being in people with psoriasis. OBJECTIVES: To screen systematically for depression and anxiety in patients with psoriasis in routine clinical practice and to identify at-risk groups for psychiatric morbidity. METHODS: Consecutive patients attending a single, tertiary centre over a 10-month period were invited to complete the Patient Health Questionnaire Depression Scale (PHQ-9), Generalized Anxiety Disorder Scale (GAD-7) and Dermatology Life Quality Index (DLQI) as part of IMPARTS: Integrating Mental and Physical Healthcare: Research, Training and Services. Information on demographics, treatment and clinical disease severity was collated from electronic patient records. Regression models were used to identify at-risk groups for psychiatric morbidity. RESULTS: Of 607 patients included (56·2% on biologics), 9·9% (95% confidence interval 7·5-12·3%) screened positive for major depressive disorder (MDD) and 13·1% (79/604) (95% confidence interval 10·4-15·8%) for generalized anxiety disorder (GAD; GAD-7 score > 9). Suicidal ideation was reported in 35% of those with MDD; DLQI was < 10 in 38·3% and 45·6% cases of MDD and GAD, respectively. After adjusting for covariates, the risk of MDD or GAD was significantly higher in women and those with severe clinical disease, psoriatic arthritis and previous depression/anxiety. The risk of GAD was significantly increased with Asian ethnicity and use of topical treatments only. CONCLUSIONS: Systematic screening for anxiety and depression identifies clinically important levels of depression and anxiety that may be missed using DLQI data alone. Women and those with severe disease, psoriatic arthritis and/or a prior history of psychiatric morbidity may be at particular risk.

European consensus statement on phenotypes of pustular psoriasis.

Pustular psoriasis (PP) is a group of inflammatory skin conditions characterized by infiltration of neutrophil granulocytes in the epidermis to such an extent that clinically visible sterile pustules develop. Because of clinical co-incidence, PP is currently grouped with psoriasis vulgaris (PV). However, PP and PV are phenotypically different, respond differently to treatments and seem to be distinct on the genetic level. In contrast to PV, the phenotypes of PP are not well defined. Descriptions of each form of PP are discordant among standard dermatology textbooks [Saurat Dermatologie 2016, Rook's Dermatology 2016, Fitzpatrick's 2012 and Braun-Falco 2012], encumbering the collection of phenotypically well-matched groups of patients as well as clinical trials. The European Rare and Severe Psoriasis Expert Network (ERASPEN) was founded to define consensus criteria for diagnosis, deeply phenotype large groups of PP patients, analyse the genetics and pathophysiology and prepare for prospective clinical trials. This work reviews historical aspects of these conditions, new genetic findings and presents our initial considerations on the phenotypes of PP and a consensus classification of clinical phenotypes that will be used as a baseline for further, prospective studies of PP. Generalized pustular psoriasis (GPP) is defined as primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustulation is restricted to psoriatic plaques). GPP can occur with or without systemic inflammation, with or without PV and can either be a relapsing (>1 episode) or persistent (>3 months) condition. Acrodermatitis continua of Hallopeau (ACH) is characterized by primary, persistent (>3 months), sterile, macroscopically visible pustules affecting the nail apparatus. Palmoplantar pustulosis (PPP) has primary, persistent (>3 months), sterile, macroscopically visible pustules on palms and/or soles and can occur with or without PV.

Identification of loci associated with late-onset psoriasis using dense genotyping of immune-related regions.

BACKGROUND: Chronic plaque psoriasis can be subdivided into two groups according to the age of onset: type 1 (early onset, before 40 years) and type 2 (late onset, at or beyond 40 years). So far, 36 genetic loci have been associated with early-onset psoriasis in genome-wide association studies of white populations, while few studies have investigated genetic susceptibility to late-onset psoriasis. OBJECTIVES: To characterize the genetics underpinning late-onset psoriasis. METHODS: We genotyped 543 cases of late-onset psoriasis and 4373 healthy controls using the Immunochip array, a dense genotyping chip containing single-nucleotide polymorphisms previously associated with autoimmune diseases. Imputation using SNP2HLA and stepwise logistic regression analysis was performed for markers spanning the human leucocyte antigen gene region. RESULTS: Two loci (HLA-C and IL12B) previously associated with early-onset psoriasis showed significant association at a genome-wide threshold in the current study (P < 5 × 10(-8)). Six more loci (TRAF3IP2, IL23R, RNF114, IFIH1, IL23A and HLA-A) showed study-wide significant association (P < 2·3 × 10(-5); calculated using Genetic type 1 error calculator). Additionally, we identified an association at IL1R1 on chromosome 2q13, which is not associated with early-onset disease. CONCLUSIONS: This is the largest study to date of genetic loci in late-onset psoriasis, and demonstrates the overlap that exists with early-onset psoriasis. It also suggests that some loci are associated exclusively with late-onset psoriasis.

Demographics and disease characteristics of patients with psoriasis enrolled in the British Association of Dermatologists Biologic Interventions Register.

BACKGROUND: The British Association of Dermatologists Biologic Interventions Register (BADBIR) is a prospective, observational cohort designed to assess the long-term safety of biologic and conventional systemic therapies used for adults with moderate-to-severe psoriasis in the U.K. and Republic of Ireland. OBJECTIVES: To describe the demographics, disease severity and comorbidities of patients with psoriasis on enrolment into BADBIR, and to highlight differences in those commencing biologics compared with those on conventional systemic therapies. METHODS: Baseline data were collected from 151 dermatology departments in the U.K. and Republic of Ireland. Descriptive analysis was conducted. RESULTS: As of August 2014, 8399 patients were registered with BADBIR; 5065 (60%) received biologics, of whom 52·8% received adalimumab, 24·6% etanercept, 18·7% ustekinumab and 3·9% infliximab. In the comparator cohort 44·1% received methotrexate, 23·1% ciclosporin, 18·0% acitretin and 7·6% fumaric acid esters. Overall 4897 (58%) were male. Patients on biologics had a higher mean ± SD age and disease duration than patients on conventional systemic therapies (46·3 ± 12·7 vs. 44·3 ± 14·3 years and 23·0 ± 12·6 vs. 19·0 ± 13·4 years, respectively; both P < 0·001). Mean body mass index, Psoriasis Area and Severity Index and Dermatology Life Quality Index scores for patients on biologics were higher than for those on conventional systemic therapies (31·0 ± 7·2 vs. 30·1 ± 7·3 kg m(-2) ; 16·4 ± 8·3 vs. 15·5 ± 7·9 and 17·4 ± 7·5 vs. 15·0 ± 7·1, respectively; all P < 0·001). In total 71% of all patients had comorbidities and 47% had more than one comorbidity. The most frequent comorbidities were obesity (42·1%), hypertension (25·7%), depression (22·1%) and psoriatic arthritis (17·1%). CONCLUSIONS: BADBIR is an invaluable resource to study the safety and effectiveness of both biologic and conventional systemic therapies. Understanding differences in baseline characteristics between cohorts is crucial in undertaking future pharmacovigilance studies.

Diagnostic accuracy of noninvasive markers of liver fibrosis in patients with psoriasis taking methotrexate: a systematic review and meta-analysis.

People with psoriasis taking methotrexate may be at increased risk of developing liver fibrosis compared with the general population. Noninvasive methods of detecting fibrosis have been widely adopted but their clinical utility is uncertain. To evaluate the diagnostic accuracy of noninvasive methods to detect fibrosis compared with liver biopsy (reference standard) in people with psoriasis taking methotrexate. A systematic search using Ovid/Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library and Clinical Trials Register was performed. Diagnostic cohorts or case-control studies of adults taking or being considered for methotrexate therapy were considered. Study quality was evaluated using the Quality Assessment tool for Diagnostic Accuracy Studies (QUADAS-2). Pooled data analysis was performed using RevMan 5.1. Bayesian meta-analysis was conducted using Markov chain Monte Carlo simulation. Seventeen studies were included. Sensitivity and specificity were 38% and 83% for standard liver function tests (LFTs), 74% and 77% for procollagen-3 N-terminal peptide (P3NP), 60% and 80% for Fibroscan(®) (Echosens, France, www.echosens.com), and 55% and 49% for ultrasound. Confidence in these results is limited owing to low-quality data; old, small studies displayed significant selection bias and significant variation in the prevalence of fibrosis. No studies were identified evaluating recently developed markers. The clinical utility of LFTs, P3NP and liver ultrasound is poor. Therefore if these tests are used in isolation, a significant proportion of patients with liver fibrosis may remain unidentified. Larger prospective studies are required in this population to validate newer non-invasive methods.

Methotrexate and liver fibrosis in people with psoriasis: a systematic review of observational studies.

Methotrexate (MTX) is an effective treatment for psoriasis but concerns regarding the development of liver fibrosis prevent optimal use. The primary objective of this systematic review was to assess whether MTX use increases the risk of developing fibrosis in people with psoriasis. Searches were performed on Medline, Embase, the Cochrane Database and Clinical Trials Register from inception until September 2013 for studies including at least two liver biopsies in people with psoriasis. Double extraction using predefined data fields was performed. Randomized controlled trials and observational studies were considered. Statistical analysis was performed using Review Manager 5. Quality of observational studies was assessed using a study quality bias checklist. Eight observational studies met the inclusion criteria (n = 429 patients). The pooled risk difference (RD) of developing significant liver fibrosis was 0·09 [95% confidence interval (CI) -0·03 to 0·20]. The RD for developing 'any fibrosis' was 0·22 (95% CI 0·04-0·41). The RD for cirrhosis was 0·04 (95% CI 0·02-0·07). There was no clear association between cumulative dose of MTX and fibrosis. Obesity, diabetes and alcohol use were under-reported. The quality of the included studies was weak and the degree of selection bias means the results are not generalizable to all patients with psoriasis taking MTX. High-quality, population-based studies that consider potential confounders common in psoriasis population are justified for better prediction of the subset of patients at risk of liver fibrosis. In this highly selected review population, MTX use appears to contribute to the development of 'any' fibrosis without clear evidence of risk stratifiers.

Validity of noninvasive markers of methotrexate-induced hepatotoxicity: a retrospective cohort study.

BACKGROUND: Methotrexate is a cost-effective systemic treatment for moderate-to-severe psoriasis, but the perceived risk of associated liver fibrosis prevents optimal use. Procollagen III aminoterminal propeptide (PIIINP) is a widely adopted noninvasive biomarker of liver fibrosis; however, its clinical utility is narrow owing to limited evidence of performance and the need for serial measurement. The Enhanced Liver Fibrosis (ELF) assay is a validated biomarker of liver fibrosis. OBJECTIVES: To evaluate the diagnostic accuracy of the ELF test compared with PIIINP for the diagnosis of liver fibrosis in a cohort of patients with psoriasis treated with methotrexate. METHODS: A retrospective cohort study comparing the diagnostic accuracy of PIIINP and ELF in detecting liver fibrosis in patients treated with methotrexate. Liver biopsy was the reference standard. RESULTS: Twenty-seven patients were identified and included in the study. The diagnostic accuracies [area under the receiver operating curve (AUROC)] of serial PIIINP and serial ELF were 0·589 [95% confidence interval (CI) 0·379-0·800] and 0·643 (95% CI 0·391-0·895), respectively, for mild fibrosis; and 0·576 (95% CI 0·237-0·916) and 0·674 (95% CI 0·421-0·927) for at least moderate fibrosis. The AUROC values for single PIIINP and single ELF were 0·582 (95% CI 0·363-0·801) and 0·693 (95% CI 0·482-0·904), respectively, for mild fibrosis; and 0·667 (95% CI 0·363-0·971) and 0·806 (95% CI 0·564-1·000) for at least moderate fibrosis. CONCLUSIONS: This pilot study suggests that ELF may be at least equivalent or possibly superior to PIIINP in the detection of liver fibrosis in patients with psoriasis treated with methotrexate, and supports further investigations into the performance of ELF in this clinical setting.

Genetic markers of treatment response to tumour necrosis factor-α inhibitors in the treatment of psoriasis.

BACKGROUND: Anti-tumour necrosis factor (TNF)-α therapies have revolutionized the treatment of psoriasis; however, up to 50% of patients do not respond satisfactorily. Identification of pharmacogenetic markers of treatment response is an important stop in the development of individually tailored treatment. The objective of this study was to assess the association of human leucocyte antigen (HLA)-C, killer immunoglobulin receptor (KIR) and vitamin D receptor (VDR) genotypes with response to treatment by etanercept and adalimumab. METHODS: This was a study of 138 patients with severe chronic plaque psoriasis who were treated with etanercept and/or adalimumab. Patients were classified as responders if they achieved a 75% reduction in PASI (PASI75) or were almost clear of psoriasis after 24 weeks of therapy. The frequencies of HLA-C and KIR haplotypes and VDR polymorphisms were compared in responders and nonresponders. The frequency of all HLA-C and KIR genotypes were compared between the 138 patients with psoriasis and 247 healthy donors. RESULTS: The number of patients classified as responders was 46 of 94 (49%) in the etanercept group and 50 of 76 (66%) in the adalimumab group. None of the HLA-C, KIR or VDR genotypes examined was predictive of treatment response. Compared with healthy controls, patients with psoriasis were more likely to have the HLA-C*06 genotype (P < 0.001) and less likely to have the HLA-C*07 genotype (P < 0.001), whereas there was no significant difference in frequencies of any KIR subtype. CONCLUSIONS: Using the candidate gene approach to identify biomarkers of treatment response in psoriasis may have limited utility. This was a small study with limited power. Future larger studies are needed to further examine these findings and to explore alternative approaches to identify predictors of treatment response to biological agents.