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.

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.

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.

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.

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.

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.

The quest for psoriasis susceptibility genes in the postgenome-wide association studies era: charting the road ahead.

The International Psoriasis Council, a global nonprofit organization dedicated to advancing psoriasis research and treatment, organized its inaugural genetics workshop in Montreal, on 12 October 2011. The presentations included a summary of the remarkable progress achieved through the implementation of genome-wide association studies, which have highlighted key pathogenic pathways for psoriasis. Ongoing meta-analyses are identifying further susceptibility genes, bringing the number of known loci close to 40. The functional characterization of low-risk alleles is proving problematic, but next-generation sequencing approaches are expected to identify rare deleterious variants, which will be easier to investigate. Elucidating the genetic architecture of psoriasis will have major implications in terms of understanding disease mechanisms and predicting response to treatment.

Infliximab for the treatment of psoriasis in the U.K.: 9 years' experience of infusion reactions at a single centre.

BACKGROUND: Infliximab is an antitumour necrosis factor-α chimeric monoclonal antibody that is an established treatment for severe chronic plaque psoriasis. The recommended administration of a 2-h infusion followed by 2 h of monitoring is practised due to the potential occurrence of infusion reactions. However, accelerated infusions and shortened monitoring periods are used in patients with rheumatological disorders and inflammatory bowel disease without an increase in adverse events. OBJECTIVES: To review the standard infliximab infusion protocol, the incidence of acute infusion reactions, the use of concomitant methotrexate and the clinical relevance of the 2-h postinfusion monitoring period. METHODS: A retrospective case note and pharmacy database review of all infliximab infusions administered to patients with psoriasis at a tertiary dermatology centre was carried out. RESULTS: Fifty-nine consecutive patients received a total of 858 infliximab infusions (range 1-43 infusions per patient) between January 2001 and June 2010. The incidence of infusion reactions was 1.5%, affecting 16.9% of patients and occurring between the first and eleventh infusions. Mild, moderate and severe acute reactions occurred in 0.6% (n=5), 0.3% (n=3) and 0.3% (n=3) of infliximab infusions, respectively. Thirty-three patients (56%) received concomitant systemic treatments during part of or throughout the infliximab treatment, including 24 (41%) on methotrexate (5-20 mg weekly). The prevalence of infusion reactions in patients receiving infliximab alone was 27% compared with 4% in those receiving concomitant methotrexate (P=0.05). All infusion reactions were managed as per our trust protocol with only one infusion reaction occurring in the postinfusion period (10 min after infusion completion). CONCLUSION: The risk of infusion reactions in our cohort of patients was low, with the majority occurring early in the treatment cycle. Concomitant methotrexate may reduce this risk. A shortened postinfusion monitoring period can be safely considered.

Methotrexate polyglutamates as a marker of patient compliance and clinical response in psoriasis: a single-centre prospective study.

BACKGROUND: Methotrexate is activated by the sequential addition of glutamic acid residues to form methotrexate polyglutamates (MTXPG(1-5)). MTXPG(1-5) inhibit enzymes of the folate-purine-pyrimidine pathways, and longer-chain MTXPG(3-5) species are more active. OBJECTIVES: To determine the pattern of erythrocyte MTXPG(1-5) in patients initiated on oral methotrexate for psoriasis, and to investigate the potential utility of MTXPGs as markers of compliance and/or clinical response. METHODS: This was a single-centre, prospective study of 55 adult patients with chronic plaque psoriasis initiated on weekly oral methotrexate. Erythrocyte MTXPG(1-5) concentrations were measured (at weeks 4, 8, 12, 24 and 52) using high-performance liquid chromatography. Methotrexate responders achieved ≥ 50% improvement in Psoriasis Area and Severity Index or physician's global score of 'clear'/'nearly clear' at 24 weeks. RESULTS: MTXPG levels were measured in 14-33 patients at each time point. All MTXPG(1-5) species were detected at week 4 of therapy. Steady state for long-chain MTXPG(3-5) and total MTXPG(1-5) was achieved by week 24. MTXPG(3) emerged as the predominant MTXPG species (from week 12 onwards) and reflected overall polyglutamate status (correlating strongly with MTXPG(2-5) , MTXPG(3-5) and MTXPG(4-5) ; R = 0·76-0·95, P < 1·55 × 10(-5)). Age, renal function and sex were not significant determinants of MTXPG(3) concentration. No significant association was identified between MTXPG and adverse events or responder status. CONCLUSIONS: This is the first study to demonstrate the prospective accumulation of MTXPG(1-5) in patients with psoriasis. The detection of MTXPGs early in therapy and the establishment of a steady state with continuous treatment may offer measuring of MTXPG as a test to monitor patient compliance with therapy. Larger studies are required to determine the role of MTXPG as a potential biomarker of clinical response.

A prospective case-controlled cohort study of endothelial function in patients with moderate to severe psoriasis.

BACKGROUND: There is well-documented evidence that patients with moderate and severe psoriasis have a significantly increased risk of cardiovascular disease (CVD). While this risk can, at least in part, be attributed to the high prevalence of traditional risk factors in the population with psoriasis, some epidemiological evidence suggests it may be independent of these. OBJECTIVES: This prospective, case-controlled study investigates whether psoriasis is a risk factor for CVD using two, validated, sensitive markers of CVD, endothelial dysfunction and high-sensitivity C-reactive protein (hsCRP). METHODS: Patients were recruited from a tertiary referral psoriasis clinic and exclusion criteria included established CVD and/or conventional risks for CVD. Preclinical CVD was assessed using flow-mediated brachial artery dilatation, which measures endothelial dysfunction, and hsCRP, a serological marker of atherosclerosis. RESULTS: Sixty-four patients (22%) out of a total of 285 consecutive patients attending the severe psoriasis clinic were entered into the study. One hundred and sixty-one (56%) were excluded following identification of cardiovascular risk; 39 of the 161 (24%) had at least two cardiovascular risk factors. A further 16 (6%) patients were excluded because of established CVD. No statistically significant difference in endothelial dysfunction was observed between patients with psoriasis (n = 60) and healthy controls (n = 117) (P = 0·508). The hsCRP level was, however, significantly elevated in the psoriasis group (2·828 mg L(-1), SEM 0·219; controls 0·728 mg L(-1), SEM 0·142; P < 0·05). CONCLUSION: This large, investigative study is the first to assess endothelial function in patients with psoriasis after exclusion of traditional risk factors for CVD. These data suggest that psoriasis per se is not a risk factor for CVD and that elevated hsCRP is possibly independent of atheroma risk. There was a high prevalence of traditional risk factors in our population with severe psoriasis.

A retrospective cohort study of the impact of biologic therapy initiation on medical resource use and costs in patients with moderate to severe psoriasis.

BACKGROUND: Biologic therapy has become established as an important treatment option in patients with severe psoriasis, but is significantly more expensive in terms of drug costs than traditional treatment options. Relatively little is known about the total healthcare cost of treating severe psoriasis in daily clinical practice and what the budgetary impacts of such high-cost drugs are when compared with standard systemic therapy. OBJECTIVES: To describe the impact of biologic therapy introduction on the use of medical resources, costs and where available, outcomes in patients with moderate to severe psoriasis. METHODS: Data were extracted from case notes of a sequential patient cohort with psoriasis attending a tertiary referral severe psoriasis service and initiated on biologics (adalimumab, efalizumab, etanercept or infliximab) for treatment of their psoriasis. Data on hospital resource use (inpatient, outpatient, day ward, accident and emergency visits and phototherapy sessions) and drug usage (systemic nonbiologic and biologic psoriasis therapies and supportive drugs) were collected for 12 months prior to, and at least 6 months following initiation of biologic therapy. Outcome was measured using the Psoriasis Area and Severity Index (PASI). Differences in resource use and associated costs and outcomes, between 12 months before and after initiation of biologic therapy, were tested using Wilcoxon paired sign tests for continuous data and the McNemar test for categorical data. Confidence intervals (CI) around treatment costs were constructed using a 5000-sample bootstrap analysis. RESULTS: The primary analysis population comprised 76 patients completing 12 months of biologic therapy: 71% males; mean age at time of study 47·3 years (range 23-74); mean duration of psoriasis 24·7 years (range 5·3-45·5). Significant reductions (P < 0·05) in the year following initiation of biologic therapy were observed for all hospital resource use categories, with mean annual costs reduced by £1682 (95% CI -3182 to -182·2; P = 0·05). Mean annual drug costs increased by £9456 (95% CI 8732-10,182; P < 0·001). Mean PASI fell by 8·9 points from 18·7 to 9·8 (95% CI -10·8 to -7·1; P < 0·001). CONCLUSIONS: Total healthcare costs associated with treatment of severe psoriasis with biologic therapy are significantly greater than with traditional systemic therapy. However, some of these are offset by substantial reductions in the number and length of hospital admissions and use of photo- and systemic therapy, and result in significantly improved patient outcome (as inferred by improvement in PASI).

Antinuclear antibodies associate with loss of response to antitumour necrosis factor-alpha therapy in psoriasis: a retrospective, observational study.

BACKGROUND: An increasing number of patients with severe psoriasis are failing to respond to antitumour necrosis factor (TNF)-alpha therapy (etanercept, infliximab and adalimumab). OBJECTIVES: We observed that many of these patients developed antinuclear antibodies (ANA) and antidouble-stranded DNA (anti-dsDNA) antibodies while on treatment prompting us to investigate whether their development is associated with anti-TNF treatment failure. METHODS: All patients with psoriasis who had received anti-TNF therapies were identified and their blood results and treatment histories were obtained from electronic patient records and case notes. RESULTS: A total of 97 patients had been treated with anti-TNF agents (60 were on their first agent, 22 had been on and stopped one agent, nine had been on and stopped two agents and six had been on and stopped all three agents). ANA developed in 17% of patients on their first treatment, 54% of patients who had failed one treatment, 78% of patients who had failed two treatments and 83% of patients who had failed all three treatments. Anti-dsDNA antibodies developed in 2%, 27%, 33% and 83% of patients from the same respective groups. Significantly, the antibodies developed before treatment had failed with all three agents and their development was not related to the total time that patients had been on anti-TNF therapy. CONCLUSIONS: This study suggests that the development of ANA and anti-dsDNA antibodies on anti-TNF treatment may act as a marker of forthcoming treatment failure. Large-scale prospective studies are required to assess the importance of this observation.