Risk of liver fibrosis associated with long-term methotrexate therapy may be overestimated.

BACKGROUND & AIMS: The risk of significant liver fibrosis from prolonged methotrexate (MTX) exposure has been estimated at around 5%, prompting intensive monitoring strategies. However, the evidence is derived from retrospective studies that under-reported risk factors for liver disease. We evaluated the risk of long-term MTX therapy on liver fibrosis in a longitudinal cohort study using two non-invasive markers. METHOD: Between 2014-2021, adult patients diagnosed with rheumatoid arthritis (RA) or psoriasis for ≥2 years were recruited prospectively from six UK sites. The MTX group included patients who received MTX for ≥6 months, whereas the unexposed group included those who never received MTX. All patients underwent full liver profiling, with transient elastography (TE) and enhanced liver fibrosis (ELF) marker measurements. RESULTS: A total of 999 patients (mean age 60.8 ± 12 years, 62.3% females) were included. Of 976 with valid TE values, 149 (15.3%) had liver stiffness ≥7.9 kPa. Of 892 with a valid ELF, 262 (29.4%) had ELF ≥9.8. Age and BMI were independently associated with elevated liver stiffness and ELF. Neither MTX cumulative dose nor duration was associated with elevated liver stiffness. Diabetes was the most significant risk factor associated with liver stiffness ≥7.9 kPa (adjusted odds ratio = 3.19; 95% CI 1.95-5.20; p <0.001). Regular use of non-steroidal anti-inflammatory drugs showed the strongest association with ELF ≥9.8 (odds ratio = 1.76; 95% CI 1.20-2.56; p = 0.003), suggesting the degree of joint inflammation in RA may confound ELF as a non-invasive marker of liver fibrosis. CONCLUSION: The risk of liver fibrosis attributed to MTX itself might have been previously overestimated; there is a need to consider modifying current monitoring guidelines for MTX. IMPACT AND IMPLICATIONS: Current guidelines recommend intensive (2-3 monthly) monitoring strategies for patients on long-term methotrexate therapy due to the potential risk of liver fibrosis. Evaluation of the association using two validated non-invasive markers of liver fibrosis, liver stiffness and enhanced liver fibrosis score, in a large cohort of patients with rheumatoid arthritis or psoriasis shows that the reported risk has previously been overestimated. The clinical focus should be to improve patients' metabolic risk factors, diabetes and BMI, that are independently associated with liver stiffness. There is a need to consider modifying current treatment monitoring guidelines for methotrexate.

Paediatric dermatology teleconsultations: a survey of healthcare professionals in the UK.

The COVID-19 pandemic catapulted dermatology services into a digital era, with the rapid introduction of teleconsultations. The UK National Health Service operational planning guidance recommends ≥ 25% of consultations are delivered remotely. There is a lack of data regarding the acceptability and effectiveness of paediatric dermatology teleconsultations. We surveyed UK healthcare professionals (HCPs) to explore their experiences of teleconsultations in paediatric dermatology, with a focus on follow-up consultations for paediatric eczema (PE), to inform a future clinical trial. There were 119 responses. Pre-pandemic, 37% provided some form of teleconsultation service, rising to 92% post-pandemic. In total, 41% (n = 49) now carry out > 25% of consultations remotely. We found 55% felt teleconsultations were less effective than face-to-face ones for PE follow-up. Eighty HCPs offered teleconsultations for PE. Among the HPCs who offered teleconsultations for PE, the most effective format for follow-up consultations was felt to be telephone with photographs (52/80, 65%). Our results demonstrate varying opinion on the effectiveness and optimal format of paediatric teleconsultations, supporting the need for further research.

How is oral isotretinoin prescribed for the treatment of acne vulgaris? Results from a UK Dermatology Clinical Trials Network (UKDCTN) and British Dermatological Nursing Group (BDNG) survey of health professionals.

We undertook a survey of UK healthcare professionals through the UK Dermatology Clinical Trials Network and British Dermatological Nursing Group to understand clinicians' routine practice of prescribing oral isotretinoin for treatment of acne vulgaris. We also wanted to understand clinicians' experiences and views on prescribing low daily dose regimens. Overall, the survey showed that clinicians adopted a patient-centred approach when deciding isotretinoin dosing. The rationale for using a low-dose regimen varied, but was focused on patient wellbeing during treatment. Some clinicians were concerned that use of a low-dose regimen could be less effective and lead to longer treatment durations. The survey results will be useful to inform a clinical trial investigating the effectiveness and safety of low daily dose isotretinoin for the treatment of acne.

Where are we with developing diagnostic criteria for skin diseases? Mapping the evidence in 2021.

The breadth and scope of dermatological diagnostic criteria is currently unknown. We created a map of diagnostic criteria to provide a panoramic view of past and ongoing research to develop dermatological diagnostic criteria. We analysed studies for which the primary research aim was to develop, validate or critically appraise diagnostic criteria for dermatological conditions identified with a PubMed search conducted in July 2021. The researched skin diseases were grouped based on similarities in pathogenesis. In total, 166 studies covering 104 skin diseases were included in the data extraction. The two largest disease categories were autoimmune diseases (17%) and rare disorders and genetic syndromes (17%). Of the total studies analysed, 28% included a type of validation and 64% provided diagnostic accuracy data. This map of diagnostic criteria covers a vast range of dermatological conditions, but many common skin diseases were under-represented. We plan to update the map and make it available for all health professionals and researchers.

On the definition of dermatological disease. Part 2: approaches for defining dermatological diseases.

In Part 1 of this two-part review, conceptual frameworks for defining skin diseases were articulated. In this review, the main approaches that can be used to develop diagnostic criteria for skin disease are summarized, using atopic dermatitis (AD) as an example. Different frameworks for defining skin disease for research purposes are articulated, including statistical, prognostic, operational, clinical and epidemiological approaches. All share the common aim of attempting to develop criteria that enable meaningful comparisons between groups of people. The desirable attributes of a good definition are described: diagnostic criteria should measure what they are meant to measure; the results should be the same for different assessors; the criteria should be coherent with what is known about that disease; they should reflect some degree of morbidity and not pick up subclinical disease; they should be easy to administer; and they should be applicable to a range of people of different ages, sexes/genders and ethnicities. Consensus-based criteria are contrasted with epidemiological derivation methods that assess the performance of diagnostic criteria in relation to a reference standard. The sensitivity and specificity of a disease definition is explained, along with how the trade-off between these two properties can vary, depending on the purpose of the study and the study setting. The review closes with some reflections on when it is appropriate to consider splitting a disease into more than one category and how diagnostic criteria can be interpreted in the clinical setting.

Comparison of three screening tools to detect psoriatic arthritis in patients with psoriasis (CONTEST study).

BACKGROUND: Multiple questionnaires to screen for psoriatic arthritis (PsA) have been developed but the optimal screening questionnaire is unknown. OBJECTIVES: To compare three PsA screening questionnaires in a head-to-head study using CASPAR (the Classification Criteria for Psoriatic Arthritis) as the gold standard. METHODS: This study recruited from 10 U.K. secondary care dermatology clinics. Patients with a diagnosis of psoriasis, not previously diagnosed with PsA, were given all three questionnaires. All patients who were positive on any questionnaire were invited for a rheumatological assessment. Receiver operating characteristic (ROC) curves were used to compare the sensitivity, specificity and area under the curve of the three questionnaires according to CASPAR criteria. RESULTS: In total, 938 patients with psoriasis were invited to participate and 657 (70%) patients returned the questionnaires. One or more questionnaires were positive in 314 patients (48%) and 195 (62%) of these patients attended for assessment. Of these, 47 patients (24%) were diagnosed with PsA according to the CASPAR criteria. The proportion of patients with PsA increased with the number of positive questionnaires (one questionnaire, 19·1%; two, 34·0%; three, 46·8%). Sensitivities and specificities for the three questionnaires, and areas under the ROC curve were, respectively: Psoriatic Arthritis Screening Evaluation (PASE), 74·5%, 38·5%, 0·594; Psoriasis Epidemiology Screening Tool (PEST), 76·6%, 37·2%, 0·610; Toronto Psoriatic Arthritis Screen (ToPAS), 76·6%, 29·7%, 0·554. The majority of patients with a false positive response had degenerative or osteoarthritis. CONCLUSION: Although the PEST and ToPAS questionnaires performed slightly better than the PASE questionnaire at identifying PsA, there is little difference between these instruments. These screening tools identify many cases of musculoskeletal disease other than PsA.

Managing acne vulgaris: an update.

Acne vulgaris is very common and can have significant negative impact on people. While sometimes a transient problem, acne may persist for many years and often leads to permanent scars or pigment changes. Guidelines unanimously advise topical treatments as first-line, although differ in recommending either topical benzoyl peroxide or topical retinoid (mainly adapalene) alone or in combination. Guidance published by the National Institute for Health and Care Excellence advises counselling patients regarding avoidance of skin irritation when starting topical treatments and promoting adherence (treatments take 6-8 weeks to work). Oral antibiotics are currently overprescribed for acne but have a role when coprescribed with a non-antibiotic topical treatment. Hormonal treatments, such as the combined contraceptive pill, are also effective and there is growing evidence for the use of spironolactone for women with persistent acne. Recent guidance from the Medicines and Healthcare products Regulatory Agency regarding isotretinoin has implications for specialist prescribing and monitoring, and increasing public awareness of potential risks of mental health problems and sexual dysfunction. Although acne is associated with psychiatric disorder, the mental health effects of isotretinoin remain controversial.

Protocol for a case-control diagnostic accuracy study to develop diagnostic criteria for psoriasis in children (DIPSOC study): a multicentre study recruiting in UK paediatric dermatology clinics.

INTRODUCTION: Diagnosing psoriasis in children can be challenging. Early and accurate diagnosis is important to ensure patients receive psoriasis specific treatment and monitoring. It is recognised that the physical, psychological, quality of life, financial and comorbid burden of psoriasis are significant. The aim of this study is to develop clinical examination and history-based diagnostic criteria for psoriasis in children to help differentiate psoriasis from other scaly inflammatory rashes. The criteria tested in this study were developed through a consensus study with a group of international psoriasis experts (International Psoriasis Council). METHODS AND ANALYSIS: Children and young people (<18 years) with psoriasis (cases) and other scaly inflammatory skin diseases (controls) diagnosed by a dermatologist are eligible for recruitment. All participants complete a single research visit including a diagnostic criteria assessment by a trained investigator blinded to the participant's diagnosis. The reference standard of a dermatologist's diagnosis is extracted from the medical record. Sensitivity and specificity of the consensus derived diagnostic criteria will be calculated and the best predictive criteria developed using multivariate logistic regression. ETHICS AND DISSEMINATION: Health Regulatory Authority and National Health Service Research Ethics Committee approvals were granted in February 2017 (REC Ref: 17/EM/0035). Dissemination will be guided by stakeholders; patients, children and young people, dermatologists, primary care and paediatric rheumatologists. The aim is to publish the study results in a high-quality peer-reviewed journal, present the findings at international academic meetings and disseminate more widely through social media and working with patient associations. TRIAL REGISTRATION NUMBER: ISRCTN98851260.

Cochrane Reviews and Dermatological Trials Outcome Concordance: Why Core Outcome Sets Could Make Trial Results More Usable.

Evidence-based health care requires that relevant outcomes for patients are included in clinical trials investigating treatment effects, allowing subsequent systematic reviews to summarize all relevant evidence to guide clinical practice. Currently, no gold standard of outcome choice for dermatology trials and reviews exists. We systematically assessed concordance between efficacy outcomes in a random sample of 10 Cochrane Skin systematic reviews and the 220 dermatology trials included. Reviews did not include 742 (68%) of the 1,086 trial outcomes. Of the 60 outcomes the reviews sought, 17 (28%) were not reported in any trial, while 12 were assessed in <50% of trials. For 11 of 23 (48%) primary review outcomes, meta-analysis was impossible, because trial outcomes were absent or unclear. This small overlap of review/trial outcomes could suggest that trials are not measuring the outcomes perceived to be the most important by patients, clinicians, systematic reviewers, and trialists. The lack of standardized outcome measures, poor reporting of outcomes in trials, and low concordance of outcomes between reviews and primary studies could be improved by the development and implementation of Core Outcome Sets. These are an agreed-upon minimum set of key outcomes, for specified conditions, to be reported in all trials.

Long-term topical corticosteroid use and risk of skin cancer: a systematic review.

OBJECTIVE: The objective of this systematic review was to synthesize available research evidence to determine the risk of skin cancer in patients with long-term use of topical corticosteroids (TCS). INTRODUCTION: Topical corticosteroids are one of the most commonly prescribed medicines in dermatology and the mainstay of the treatment of atopic dermatitis and other skin conditions such as psoriasis. They are often required for months or years to control the disease and ultimately restore patients' quality of life. In some patients, TCS may have a local immunosuppressive effect and theoretically increase the risk of skin cancer, whilst on the other hand TCS may decrease the risk of skin cancer in patients where TCS are used to treat inflammatory skin disease. To date, no systematic review has been performed to collate evidence on the effect of long-term TCS use on the risk of skin cancer. INCLUSION CRITERIA: This review considered studies that included people of all ages, genders and ethnicities, including HIV and transplant participants or participants with genetic diseases (for example, Gorlin-Goltz syndrome) This review considered studies that evaluated long-term use of topical corticosteroids. "Long-term" was defined as using TCS more than once a week for a month or longer. The review included cohort, cross-sectional and case-control observational studies exploring the association between the stated intervention and outcomes. The primary outcome measures of interest were: non-melanoma skin cancer (keratinocyte carcinoma), cutaneous squamous cell carcinoma (cSSC), basal cell carcinoma (BCC) or melanoma skin cancer. Genital and oral skin cancers are considered to be slightly different so we did not include them in this review. METHODS: We performed a comprehensive search of MEDLINE, Embase and LILACS on November 9, 2017 to identify observational epidemiological studies assessing the association between long-term TCS use and skin cancer. We also searched EThOS at the British Library and three drug safety databases to identify unpublished work. The titles, abstracts and full text identified from the search were assessed independently by two authors against pre-specified inclusion/exclusion criteria. Methodological quality was not assessed as no articles were found which met the inclusion criteria. Data extraction was not possible as no articles were found which met the inclusion criteria. It was not possible to complete data synthesis as no articles were found which met the inclusion criteria. RESULTS: A total of 1703 potentially relevant studies were identified following a comprehensive electronic search. After abstract and title screening, 51 full texts were assessed for eligibility criteria. Of these, no study met the inclusion criteria. No additional records were identified from searching unpublished literature. CONCLUSIONS: We did not find any studies that could help us establish if long-term TCS use is associated with skin cancer. Future research using primary care databases might give a better understanding regarding long-term use of TCS and skin cancer.

Long-term topical corticosteroid use and risk of skin cancer: a systematic review protocol.

REVIEW QUESTION/OBJECTIVE: The objective of this systematic review is to synthesize the best available research evidence to determine the risk of skin cancer in patients on long-term use of topical corticosteroids. Specifically the review question is: In people using long-term (regular use over one month) topical corticosteroids, what is the risk of developing skin cancer (clinically or histologically confirmed basal cell carcinoma, squamous cell carcinoma or melanoma)?

Development and testing of new candidate psoriatic arthritis screening questionnaires combining optimal questions from existing tools.

OBJECTIVE: Several questionnaires have been developed to screen for psoriatic arthritis (PsA), but head-to-head studies have found limitations. This study aimed to develop new questionnaires encompassing the most discriminative questions from existing instruments. METHODS: Data from the CONTEST study, a head-to-head comparison of 3 existing questionnaires, were used to identify items with a Youden index score of ≥0.1. These were combined using 4 approaches: CONTEST (simple additions of questions), CONTESTw (weighting using logistic regression), CONTESTjt (addition of a joint manikin), and CONTESTtree (additional questions identified by classification and regression tree [CART] analysis). These candidate questionnaires were tested in independent data sets. RESULTS: Twelve individual questions with a Youden index score of ≥0.1 were identified, but 4 of these were excluded due to duplication and redundancy. Weighting for 2 of these questions was included in CONTESTw. Receiver operating characteristic (ROC) curve analysis showed that involvement in 6 joint areas on the manikin was predictive of PsA for inclusion in CONTESTjt. CART analysis identified a further 5 questions for inclusion in CONTESTtree. CONTESTtree was not significant on ROC curve analysis and discarded. The other 3 questionnaires were significant in all data sets, although CONTESTw was slightly inferior to the others in the validation data sets. Potential cut points for referral were also discussed. CONCLUSION: Of 4 candidate questionnaires combining existing discriminatory items to identify PsA in people with psoriasis, 3 were found to be significant on ROC curve analysis. Testing in independent data sets identified 2 questionnaires (CONTEST and CONTESTjt) that should be pursued for further prospective testing.

Antagonism of the interleukin-1 receptor following traumatic brain injury in the mouse reduces the number of nitric oxide synthase-2-positive cells and improves anatomical and functional outcomes.

Interleukin (IL)-1beta plays an important role in the inflammatory response that results from traumatic brain injury and antagonism of the actions of this cytokine can affect outcome. We subjected male mice to aseptic cryogenic injury and assessed recovery through anatomical, histological and functional measures following treatment with recombinant mouse IL-1 receptor antagonist (IL-1ra). A single dose (1 microg, i.c.v.) at the time of injury reduced lesion volume 3 days later, as assessed by Nissl staining, and also the number (30%) of FluoroJade-positive degenerating neurones. Mice treated with IL-1ra performed better on the beam balance and in the grid test as compared with vehicle-treated animals. Furthermore, IL-1ra-treated animals showed fewer (40%) nitric oxide synthase-2-positive cells in and around the lesion. These data suggest that activation of the IL-1 receptor following trauma contributes to the pathology and that antagonism can reduce both anatomical and functional consequences of neuroinflammation.