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.

Immunogenicity of biologic therapies in psoriasis: Myths, facts and a suggested approach.

With biologic drugs dominating the therapeutic space for severe immune-mediated inflammatory disease, it is critical for clinicians to be familiar with the concept of drug immunogenicity, with the potential for our patients to develop antidrug antibodies (ADA) of clinical relevance. Whilst there are clear differences between different therapeutic biologics in terms of reported ADA rates, there is no accepted dermatology guideline or grouping of drugs by risk of clinically relevant ADA, nor a consensus on approach to ADA management. This is partly because making valid comparisons of immunogenicity across drugs is fundamentally flawed: the differing types of ADA assay, trial design and included patient population - as well as the molecular structure of the biologic molecules themselves - are all highly influential on reported ADA prevalence and impact on clinical response. Therefore, the first part of this article aims to give an overview of ADA that also clarifies common misconceptions on the subject, whilst the second part of this article outlines Phase III immunogenicity data on commonly used biologics for psoriasis, the most common dermatological indication. Based on this, and acknowledging current limitations in available evidence, we propose a working categorization of biologics together with a broad approach to management: Group 1 - biologics with higher risk of clinically relevant ADA; Group 2 - biologics with lower risk of clinically relevant ADA; and Group 3 - biologics with no established risk of clinically relevant ADA. However, these groupings represent a working concept only; more research is required, using comparable ADA assays and consistent reporting of related outcomes. Finally, there is an urgent need for better characterization of individuals at particular risk of developing ADA to inform future clinical decision-making.

Atopic dermatitis: the skin barrier and beyond.

BACKGROUND: Atopic dermatitis is the most common chronic inflammatory skin disorder, affecting up to 20% of children and 10% of adults in industrialized countries. This highly debilitating condition poses a considerable burden to both the individual and society at large. The pathophysiology of atopic dermatitis is complex, encompassing both genetic and environmental risk factors. METHODS: This is a narrative review based on a systematic literature search. CONCLUSIONS: Dysregulation of innate and adaptive immunity plays a key role; however, recent epidemiological, genetic and molecular research has focused interest on skin barrier dysfunction as a common precursor and pathological feature. Current understanding of the aetiology of atopic dermatitis highlights disruption of the epidermal barrier leading to increased permeability of the epidermis, pathological inflammation in the skin, and percutaneous sensitization to allergens. Thus, most novel treatment strategies seek to target specific aspects of the skin barrier or cutaneous inflammation. Several studies have also shown promise in preventing atopic dermatitis, such as the early use of emollients in high-risk infants. This may have broader implications in terms of halting the progression to atopic comorbidities including food allergy, hay fever and asthma.

Subcutaneous methotrexate in patients with moderate-to-severe psoriasis: a critical appraisal.

AIM: Warren et al. set out to assess the effect of an intensified dosing schedule of subcutaneous methotrexate in patients with moderate-to-severe chronic plaque psoriasis. SETTING AND DESIGN: This was a prospective, double-blind, randomized (3 : 1), placebo-controlled study, conducted across 16 centres in Germany, France, the Netherlands and the U.K. STUDY EXPOSURE: Methotrexate-naive adults with a diagnosis of moderate-to-severe chronic plaque psoriasis for at least 6 months before baseline were randomly assigned to receive weekly subcutaneous injections of either methotrexate at a starting dose of 17·5 mg, or placebo for 16 weeks (first phase). Dose escalation to 22·5 mg per week was implemented after 8 weeks if patients did not achieve ≥ 50% improvement in Psoriasis Area and Severity Index (PASI 50). Treatment was combined with folic acid 5 mg per week. The first phase of the study was followed by an open-label period from 16 to 52 weeks (second phase), in which both groups received weekly methotrexate injections. At week 24, dose escalation to 22·5 mg per week was possible in patients not achieving PASI 50. OUTCOMES: Psoriasis severity was measured using PASI. The authors also used two other psoriasis severity measures and two quality-of-life measures, looked at safety indices and performed a substudy analysing paired skin biopsies at baseline and week 16 (histopathology, immunohistochemistry and expression of interleukin-17A, interferon-γ and tumour necrosis factor-α). PRIMARY OUTCOME MEASURES: The primary outcome was the proportion of patients reaching PASI 75 at week 16. RESULTS: In total 120 patients were included in this trial, most of whom were middle-aged white men with long-standing psoriasis, and the mean body mass index was 30·1 kg m-2 . PASI 75 was achieved in 41% of patients receiving methotrexate vs. 10% of patients receiving placebo (relative risk 3·93, 95% confidence interval 1·31-11·81; P = 0·0026) at week 16. Subcutaneous methotrexate was generally well tolerated, with no serious adverse events related to this treatment over the 52-week study. CONCLUSION: Warren et al. conclude that the 52-week risk-benefit profile of subcutaneous methotrexate is favourable in patients with psoriasis.

Methotrexate vs. ciclosporin in the treatment of severe atopic dermatitis in children: a critical appraisal.

AIM: El-Khalawany et al. (Eur J Pediatr 2012; 172: 351-6) aimed to compare the efficacy and safety of methotrexate vs. ciclosporin in the treatment of children with severe atopic eczema. SETTING AND DESIGN: This multicentre, parallel group (ratio 1 : 1), randomized controlled trial was conducted in a secondary care setting in Egypt. STUDY EXPOSURE: Children with severe atopic eczema were randomly assigned to receive either methotrexate (7.5 mg weekly) or ciclosporin (2.5 mg kg(-1) daily) for 12 weeks, followed by a 12-week follow-up period. OUTCOMES: Eczema severity was measured using the SCORing of Atopic Dermatitis (SCORAD) index. The authors also recorded the number of patients on each therapy experiencing adverse effects. PRIMARY OUTCOME MEASURES: The primary outcome was the mean change in SCORAD after 12 weeks of treatment. RESULTS: Forty patients with a mean age of 11.6 ± 1.52 years were included in the trial. At week 12, patients in the methotrexate group had a mean ± SD absolute reduction in SCORAD of 26.25 ± 7.03, compared with 25.02 ± 8.21 in the ciclosporin group (P = 0.93). Both drugs were associated with minor adverse effects, none of which necessitated changing the treatment regimen. CONCLUSIONS: El-Khalawany et al. conclude that both methotrexate and ciclosporin in low doses are clinically effective, relatively safe, and well tolerated as treatments for severe atopic eczema in children.

Does early life exposure to antibiotics increase the risk of eczema? A systematic review.

A number of studies have suggested that early life exposure to antibiotics can lead to an increased risk of developing eczema. This systematic review and meta-analysis of observational studies, involving children or young adults aged 0-25 years, assessed the impact of antibiotic exposure either in utero or during the first 12 months of life on subsequent eczema risk. Twenty studies examined the association between prenatal and/or postnatal exposure to antibiotics and development of eczema. The pooled odds ratio (OR) for the 17 studies examining postnatal antibiotic exposure was 1.41 [95% confidence interval (CI) 1.30-1.53]. The pooled OR for the 10 longitudinal studies was 1.40 (95% CI 1.19-1.64), compared with a pooled OR of 1.43 (95% CI 1.36-1.51) for the seven cross-sectional studies. There was a significant dose-response association, suggesting a 7% increase in the risk of eczema for each additional antibiotic course received during the first year of life [pooled OR 1.07 (95% CI 1.02-1.11)]. Finally, the pooled OR for the four studies relating to antenatal exposure was 1.30 (95% CI 0.86-1.95). We conclude that exposure to antibiotics in the first year of life, but not prenatally, is more common in children with eczema.

Should testosterone replacement be offered to hypogonadal men treated previously for prostatic carcinoma?

Androgen administration can cause prostate cancer progression, and androgen deprivation therapy is a commonly used therapeutic modality in the treatment of prostate cancer. In trying to answer the posed clinical question, this article reviews the risks and benefits of testosterone replacement therapy in this setting and the published data from clinical series. Recommendations are made based on the available evidence.

Matched glucose responses to insulin administered subcutaneously and intravenously. Evidence for subcutaneous inactivation of insulin.

A new technique of programmed intravenous insulin infusion at a series of decreasing rates has been used to imitate the magnitude and time course of biological responses obtained by the subcutaneous route. Groups of normal rats prepared with indwelling venous cannulae were injected subcutaneously with soluble porcine insulin, 0.4 U/kg. The pattern of the resulting hypoglycaemic response was subsequently matched by a 2-hour intravenous insulin infusion at rates decreasing stepwise from 0.3 to 0.05 U kg-1h-1. The total amount of insulin infused intravenously was only 50% of that required subcutaneously. In addition, subcutaneous or intravenous infusions of insulin at 0.05 U kg-1h-1 were given to two groups of rats from the same batch. When both infusions were continued until plateau responses were reached, a significantly greater lowering of plasma glucose was caused by the intravenous route. These results suggest that when insulin is given subcutaneously significant inactivation of the insulin occurs at or near the injection site.