Background
The cardiovascular safety profile of biologic therapies used for psoriasis is unclear.
Objectives
To compare the risk of major cardiovascular events (CVEs; acute coronary syndrome, ...unstable angina, myocardial infarction and stroke) in patients with chronic plaque psoriasis treated with adalimumab, etanercept or ustekinumab in a large prospective cohort.
Methods
Prospective cohort study examining the comparative risk of major CVEs was conducted using the British Association of Dermatologists Biologics and Immunomodulators Register. The main analysis compared adults with chronic plaque psoriasis receiving ustekinumab with tumour necrosis‐α inhibitors (TNFi: etanercept and adalimumab), whilst the secondary analyses compared ustekinumab, etanercept or methotrexate against adalimumab. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using overlap weights by propensity score to balance baseline covariates among comparison groups.
Results
We included 5468 biologic‐naïve patients subsequently exposed (951 ustekinumab; 1313 etanercept; and 3204 adalimumab) in the main analysis. The secondary analyses also included 2189 patients receiving methotrexate. The median (p25–p75) follow‐up times for patients using ustekinumab, TNFi, adalimumab, etanercept and methotrexate were as follows: 2.01 (1.16–3.21), 1.93 (1.05–3.34), 1.94 (1.09–3.32), 1.92 (0.93–3.45) and 1.43 (0.84–2.53) years, respectively. Ustekinumab, TNFi, adalimumab, etanercept and methotrexate groups had 7, 29, 23, 6 and 9 patients experiencing major CVEs, respectively. No differences in the risk of major CVEs were observed between biologic therapies adjusted HR for ustekinumab vs. TNFi: 0.96 (95% CI 0.41–2.22); ustekinumab vs. adalimumab: 0.81 (0.30–2.17); etanercept vs. adalimumab: 0.81 (0.28–2.30) and methotrexate against adalimumab 1.05 (0.34–3.28).
Conclusions
In this large prospective cohort study, we found no significant differences in the risk of major CVEs between three different biologic therapies and methotrexate. Additional studies, with longer term follow‐up, are needed to investigate the potential effects of biologic therapies on incidence of major CVEs.
Linked Commentary: K. Kridin and A.D. Cohen. J Eur Acad Dermatol Venereol 2020; 34: 668–669. https://doi.org/10.1111/jdv.16345.
Summary
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.
What's already known about this topic?
Research examining acitretin, ciclosporin, fumaric acid esters (FAE) and methotrexate for the treatment of moderate‐to‐severe psoriasis has focused on safety and efficacy in randomized controlled trials.
The persistence and effectiveness of acitretin, ciclosporin, FAE and methotrexate since the introduction of biologic therapies in real‐world clinical practice are poorly understood.
What does this study add?
This systematic review examines the persistence and effectiveness of methotrexate, acitretin, ciclosporin and FAE for moderate‐to‐severe psoriasis.
Data on the persistence and effectiveness of systemic therapies are lacking, particularly for acitretin and ciclosporin.
The definitions of persistence and reporting of effectiveness are inconsistent.
Further good‐quality observational studies are needed to explore the real‐world persistence and effectiveness of systemic treatments used for psoriasis.
Linked Comment: Garcia-Doval and Sbidian. Br J Dermatol 2019; 181:237.
Plain language summary available online
Summary
Background
Patients with psoriasis are often concerned about the risk of serious infection associated with systemic psoriasis treatments.
Objectives
To develop and externally validate a ...prediction model for serious infection in patients with psoriasis within 1 year of starting systemic therapies.
Methods
The risk prediction model was developed using the British Association of Dermatologists Biologic Interventions Register (BADBIR), and the German Psoriasis Registry PsoBest was used as the validation dataset. Model discrimination and calibration were assessed internally and externally using the C‐statistic, the calibration slope and the calibration in the large.
Results
Overall 175 (1·7%) out of 10 033 participants from BADBIR and 41 (1·7%) out of 2423 participants from PsoBest developed a serious infection within 1 year of therapy initiation. Selected predictors in a multiple logistic regression model included nine baseline covariates, and starting infliximab was the strongest predictor. Evaluation of model performance showed a bootstrap optimism‐corrected C‐statistic of 0·64 95% confidence interval (CI) 0·60–0·69, calibration in the large of 0·02 (95% CI −0·14 to 0·17) and a calibration slope of 0·88 (95% CI 0·70–1·07), while external validation performance was poor, with C‐statistic 0·52 (95% CI 0·42–0·62), calibration in the large 0·06 (95% CI −0·25 to 0·37) and calibration slope 0·36 (95% CI −0·24 to 0·97).
Conclusions
We present the first results of the development of a multivariable prediction model. This model may help patients and dermatologists in the U.K. and the Republic of Ireland to identify modifiable risk factors and inform therapy choice in a shared decision‐making process.
What's already known about this topic?
Patients and their clinicians are often concerned about the risk of serious infection associated with biological therapies for the treatment of psoriasis.
However, there are no current tools available to estimate an individual's risk of serious infection when starting a systemic therapy.
What does this study add?
This study found that the serious infection risk prediction model had good calibration and moderate discrimination
The model included chronic obstructive pulmonary disease, alcohol intake, number of comorbidities and employment status, in addition to age, sex, Psoriasis Area and Severity Index, choice of starting therapy and body mass index.
These are the first results of the multivariable prediction model, which may help patients and dermatologists in the U.K. and the Republic of Ireland to identify modifiable risk factors and inform therapy choice in a shared decision‐making process.
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Hypoxia-inducible factor-1 (HIF-1) mediates the transcriptional response to hypoxic stress, promoting tumour progression and survival. This study investigated the acute effects of the small-molecule ...HIF-pathway inhibitor NSC-134754.
Human PC-3LN5 prostate cancer cells were treated with NSC-134754 for 24 h in hypoxia. Orthotopic prostate tumour-bearing mice were treated with a single dose of NSC-134754 for 6, 24 or 48 h. Treatment response was measured using magnetic resonance spectroscopy and imaging. Ex-vivo histological validation of imaging findings was also sought.
In vitro, NSC-134754 significantly reduced lactate production and glucose uptake (P<0.05), while significantly increasing intracellular glucose (P<0.01) and glutamine uptake/metabolism (P<0.05). Increased glutamine metabolism was independent of c-Myc, a factor also downregulated by NSC-134754. In vivo, a significantly higher tumour apparent diffusion coefficient was determined 24 h post-treatment (P<0.05), with significantly higher tumour necrosis after 48 h (P<0.05). NSC-134754-treated tumours revealed lower expression of HIF-1α and glucose transporter-1, at 6 and 24 h respectively, while a transient increase in tumour hypoxia was observed after 24 h. Vessel perfusion/flow and vascular endothelial growth factor levels were unchanged with treatment.
NSC-134754 induces metabolic alterations in vitro and early anti-tumour activity in vivo, independent of changes in vascular function. Our data support the further evaluation of NSC-134754 as an anti-cancer agent.
Seventy six senior academics from 11 countries invite The BMJ’s editors to reconsider their policy of rejecting qualitative research on the grounds of low priority. They challenge the journal to ...develop a proactive, scholarly, and pluralist approach to research that aligns with its stated mission
Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor with anti-microbial properties found in mucosal fluids. It is expressed during cutaneous wound healing. Impaired healing ...states are characterized by excessive proteolysis and often bacterial infection, leading to the hypothesis that SLPI may have a role in this process. We have generated mice null for the gene encoding SLPI (Slpi), which show impaired cutaneous wound healing with increased inflammation and elastase activity. The altered inflammatory profile involves enhanced activation of local TGF-beta in Slpi-null mice. We propose that SLPI is a pivotal endogenous factor necessary for optimal wound healing.
Summary
The health watchdog NICE recommends that patients with moderate‐to‐severe psoriasis should try at least two non‐biologic systemic therapies before they are eligible for biologic drugs. ...Unfortunately, there are few studies which compare different drugs and give information about how long they are effective. The authors, based in several major centres in the UK, performed a systematic review (a type of high quality way of reviewing the scientific research) of the major non‐biologic drugs used in psoriasis, using databases including MEDLINE, PubMed and Embase. They identified 411 studies, of which 8 had recruited more than 100 patients who were included in the study, representing 4624 patients. Discontinuation because of adverse events (unwanted side effects) was commoner with treatments called fumaric acid esters (43‐46%) than with methotrexate (22%). In one study, 50% remained on methotrexate, 42% on acitretin but only 22% on ciclosporin after one year; however, this may reflect the fact that ciclosporin is generally used in short courses because of increased toxicity in long term use. In other studies, the mean time for discontinuing methotrexate ranged from 7.7 to 22.3 months, whereas for fumaric acid esters it was 28 to 50 months. 76% of patients on fumaric acid esters and 59% on methotrexate achieved a reduction in Psoriasis Area and Severity Index (PASI score) of greater than 75%. PASI is used to record the redness, thickness and scaling of a patient's psoriasis and to measure how well a treatment works, as a reduction in the PASI score means a reduction in these symptoms; for example PASI 75 means the patient has a 75% or more reduction in their PASI score from the start. The authors concluded that it was difficult to compare the available studies because they used different methods of analysis, and stressed the need for long term observational studies (i.e. where researchers observe the effect of a treatment without trying to change who is or isn't exposed to it) of good quality.
Linked Article: Mason et al. Br J Dermatol 2019; 181:256–264
The hypoxic areas of solid cancers represent a negative prognostic factor irrespective of which treatment modality is chosen for the patient. Still, after almost 80 years of focus on the problems ...created by hypoxia in solid tumours, we still largely lack methods to deal efficiently with these treatment-resistant cells. The consequences of this lack may be serious for many patients: Not only is there a negative correlation between the hypoxic fraction in tumours and the outcome of radiotherapy as well as many types of chemotherapy, a correlation has been shown between the hypoxic fraction in tumours and cancer metastasis. Thus, on a fundamental basis the great variety of problems related to hypoxia in cancer treatment has to do with the broad range of functions oxygen (and lack of oxygen) have in cells and tissues. Therefore, activation-deactivation of oxygen-regulated cascades related to metabolism or external signalling are important areas for the identification of mechanisms as potential targets for hypoxia-specific treatment. Also the chemistry related to reactive oxygen radicals (ROS) and the biological handling of ROS are part of the problem complex. The problem is further complicated by the great variety in oxygen concentrations found in tissues. For tumour hypoxia to be used as a marker for individualisation of treatment there is a need for non-invasive methods to measure oxygen routinely in patient tumours. A large-scale collaborative EU-financed project 2009-2014 denoted METOXIA has studied all the mentioned aspects of hypoxia with the aim of selecting potential targets for new hypoxia-specific therapy and develop the first stage of tests for this therapy. A new non-invasive PET-imaging method based on the 2-nitroimidazole
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F-HX4 was found to be promising in a clinical trial on NSCLC patients. New preclinical models for testing of the metastatic potential of cells were developed, both in vitro (2D as well as 3D models) and in mice (orthotopic grafting). Low density quantitative real-time polymerase chain reaction (qPCR)-based assays were developed measuring multiple hypoxia-responsive markers in parallel to identify tumour hypoxia-related patterns of gene expression. As possible targets for new therapy two main regulatory cascades were prioritised: The hypoxia-inducible-factor (HIF)-regulated cascades operating at moderate to weak hypoxia (<1% O
2
), and the unfolded protein response (UPR) activated by endoplasmatic reticulum (ER) stress and operating at more severe hypoxia (<0.2%). The prioritised targets were the HIF-regulated proteins carbonic anhydrase IX (CAIX), the lactate transporter MCT4 and the PERK/eIF2α/ATF4-arm of the UPR. The METOXIA project has developed patented compounds targeting CAIX with a preclinical documented effect. Since hypoxia-specific treatments alone are not curative they will have to be combined with traditional anti-cancer therapy to eradicate the aerobic cancer cell population as well.
We constructed maps for eight chromosomes (1, 6, 9, 10, 13, 20, X and (previously) 22), representing one-third of the genome, by building landmark maps, isolating bacterial clones and assembling ...contigs. By this approach, we could establish the long-range organization of the maps early in the project, and all contig extension, gap closure and problem-solving was simplified by containment within local regions. The maps currently represent more than 94% of the euchromatic (gene-containing) regions of these chromosomes in 176 contigs, and contain 96% of the chromosome-specific markers in the human gene map. By measuring the remaining gaps, we can assess chromosome length and coverage in sequenced clones.
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