Topical tacrolimus 0.1% ointment for treatment of cutaneous Crohn's Disease

Peer reviewedPublisher PD

An observational prospective study of topical acidified nitrite for killing methicillin-resistant Staphylococcus aureus (MRSA) in contaminated wounds

Background Endogenous nitric oxide (NO) kills bacteria and other organisms as part of the innate immune response. When nitrite is exposed to low pH, NO is generated and has been used as an NO delivery system to treat skin infections. We demonstrated eradication of MRSA carriage from wounds using a topical formulation of citric acid (4.5%) and sodium nitrite (3%) creams co-applied for 5 days to 15 wounds in an observational prospective pilot study of 8 patients. Findings Following treatment with topical citric acid and sodium nitrite, 9 of 15 wounds (60%) and 3 of 8 patients (37%) were cleared of infection. MRSA isolates from these patients were all sensitive to acidified nitrite in vitro compared to methicillin-sensitive S. aureus and a reference strain of MRSA. Conclusions Nitric oxide and acidified nitrite offer a novel therapy for control of MRSA in wounds. Wounds that were not cleared of infection may have been re-contaminated or the bioavailability of acidified nitrite impaired by local factors in the tissue

Comparison of the two most commonly used treatments for pyoderma gangrenosum: results of the STOP GAP randomised controlled trial

Objective To determine whether ciclosporin is superior to prednisolone for the treatment of pyoderma gangrenosum, a painful, ulcerating skin disease with a poor evidence base for management. Design Multicentre, parallel group, observer blind, randomised controlled trial. Setting 39 UK hospitals, recruiting from June 2009 to November 2012. Participants 121 patients (73 women, mean age 54 years) with clinician diagnosed pyoderma gangrenosum. Clinical diagnosis was revised in nine participants after randomisation, leaving 112 participants in the analysis set (59 ciclosporin; 53 rednisolone). Intervention Oral prednisolone 0.75 mg/kg/day compared with ciclosporin 4 mg/kg/day, to a maximum dose of 75 and 400 mg/day, respectively. Main outcome measures The primary outcome was speed of healing over six weeks, captured using digital images and assessed by blinded investigators. Secondary outcomes were time to healing, global treatment response, resolution of inflammation, self reported pain, quality of life, number of treatment failures, adverse reactions, and time to recurrence. Outcomes were assessed at baseline and six weeks and when the ulcer had healed (to a maximum of six months). Results Of the 112 participants, 108 had complete primary outcome data at baseline and six weeks (57 ciclosporin; 51 rednisolone). Groups were balanced at baseline. The mean (SD) speed of healing at six weeks was −0.21 (1.00) cm2/day in the ciclosporin group compared with −0.14 (0.42) cm2/day in the prednisolone group. The adjusted mean difference showed no between group difference (0.003 cm2/day, 95% confidence interval −0.20 to 0.21; P=0.97). By six months, ulcers had healed in 28/59 (47%) participants in the ciclosporin group compared with 25/53 (47%) in the prednisolone group. In those with healed ulcers, eight (30%) receiving ciclosporin and seven (28%) receiving prednisolone had a recurrence. Adverse reactions were similar for the two groups (68% ciclosporin and 66% prednisolone), but serious adverse reactions, especially infections, were more common in the prednisolone group. Conclusion Prednisolone and ciclosporin did not differ across a range of objective and patient reported outcomes. Treatment decisions for individual patients may be guided by the different side effect profiles of the two drugs and patient preference. Trial registration Current Controlled Trials ISRCTN35898459

Low-Dose Vitamin D3 Supplementation Does Not Affect Natural Regulatory T Cell Population but Attenuates Seasonal Changes in T Cell-Produced IFN-γ : results from the D-SIRe2 randomised controlled trial

ACKNOWLEDGMENTS We gratefully acknowledge all participants, the assistance of Karen Secombes for sample collection, Megan Forrester for advising on cytokine and flow cytometry analyses, and Rebecca Barr for packaging and blinding the supplement capsules. Vit D3 supplements were donated by Pure Encapsulations (Sudbury, MA). FUNDING Pathways to a healthy lifestyle studentship, RANK prize funding (WM), University of Aberdeen Development fund (HM), NHS endowments EA0702 (AO), Rural and Environment Science and Analytical Services Division of the Scottish government (RESAS) (FT). This research was funded in whole, or in part, by the Wellcome Trust [Grant number 094847/Z/10/Z]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.Peer reviewe

Infliximab is associated with an increased risk of serious infection in patients with psoriasis in the UK and Republic of Ireland: results from the British Association of Dermatologists Biologic Interventions Register (BADBIR)

BackgroundPatients with psoriasis and clinicians are concerned that infliximab may be associated with a risk of serious infections.ObjectivesTo compare the risk of serious infections associated with infliximab in patients with chronic plaque psoriasis against a cohort on nonbiologic systemic therapies.MethodsA prospective cohort study was performed using data from the British Association of Dermatologists Biologic Interventions Register (BADBIR). Infliximab was compared with nonbiologic systemic therapies, inclusive of any exposure to methotrexate, ciclosporin, acitretin, fumaric acid esters, psoralen‐ultraviolet A or hydroxycarbamide. Serious infections were those associated with hospitalization, the use of intravenous antimicrobial therapy and/or those that led to death. Propensity score inverse probability treatment weights were used to adjust for potential confounding from a priori identified covariates. Cox proportional hazards models were calculated to obtain hazard ratios (HRs).ResultsIn total, 3843 participants were included for analysis up to October 2016. The incidence rates were significantly higher in the infliximab cohort (47·8 per 1000 person‐years) [95% confidence interval (CI) 35·7–64·0], compared with 14·2 per 1000 person‐years (95% CI 11·5–17·4) in the nonbiologic systemic cohort. Infliximab was associated with an overall increase in the risk of serious infection compared with nonbiologics [adjusted HR (adjHR) 1·95, 95% CI 1·01–3·75] and methotrexate only (adjHR 2·96, 95% CI 1·58–5·57) and a higher risk of serious infection in the first 6 months of therapy (adjHR 3·49, 95% CI 1·14–10·70).ConclusionsInfliximab is associated with an increased risk of serious infections compared with nonbiologic systemic therapies in patients with psoriasis in the U.K. and the Republic of Ireland

Risk of major cardiovascular events in patients with psoriasis receiving biologic therapies: a prospective cohort study

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

Risks of basal cell and squamous cell carcinoma in psoriasis patients after treatment with biologic vs non‐biologic systemic therapies

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Current patch test results with the European baseline series and extensions to it from the 'European Surveillance System on Contact Allergy' network, 2007-2008

BACKGROUND: The pattern of contact sensitization to the supposedly most important allergens assembled in the baseline series differs between countries, presumably at least partly because of exposure differences. Objectives. To describe the prevalence of contact sensitization to allergens tested in consecutive patients in the years 2007 and 2008, and to discuss possible differences. METHODS: Data from the 39 departments in 11 European countries comprising the European Surveillance System on Contact Allergy network (www.essca-dc.org) in this period have been pooled and analysed according to common standards. RESULTS: Patch test results with the European baseline series, and country-specific or department-specific additions to it, obtained in 25 181 patients, showed marked international variation. Metals and fragrances are still the most frequent allergens across Europe. Some allergens tested nationally may be useful future additions to the European baseline series, for example methylisothiazolinone, whereas a few long-term components of the European baseline series, namely primin and clioquinol, no longer warrant routine testing. CONCLUSIONS: The present analysis points to 'excess' prevalences of specific contact sensitization in some countries, although interpretation must be cautious if only few, and possibly specialized, centres are representing one country. A comparison as presented may help to target in-depth research into possible causes of 'excess' exposure, and/or consideration of methodological issues, including modifications to the baseline series

Development and validation of a multivariable risk prediction model for serious infection in patients with psoriasis receiving systemic therapy

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

Efficacy and safety of ciclosporin versus methotrexate in the treatment of severe atopic dermatitis in children and young people (TREAT): a multicentre parallel group assessor-blinded clinical trial

Background: Conventional systemic drugs are used to treat children and young people (CYP) with severe atopic dermatitis (AD) worldwide, but no robust randomized controlled trial (RCT) evidence exists regarding their efficacy and safety in this population. While novel therapies have expanded therapeutic options, their high cost means traditional agents remain important, especially in lower-resource settings. Objectives: To compare the safety and efficacy of ciclosporin (CyA) with methotrexate (MTX) in CYP with severe AD in the TREatment of severe Atopic Eczema Trial (TREAT) trial. Methods: We conducted a parallel group assessor-blinded RCT in 13 UK and Irish centres. Eligible participants aged 2–16 years and unresponsive to potent topical treatment were randomized to either oral CyA (4 mg kg–1 daily) or MTX (0.4 mg kg–1 weekly) for 36 weeks and followed-up for 24 weeks. Co-primary outcomes were change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to first significant flare (relapse) after treatment cessation. Secondary outcomes included change in quality of life (QoL) from baseline to 60 weeks; number of participant-reported flares following treatment cessation; proportion of participants achieving ≥ 50% improvement in Eczema Area and Severity Index (EASI 50) and ≥ 75% improvement in EASI (EASI 75); and stratification of outcomes by filaggrin status. Results: In total, 103 participants were randomized (May 2016–February 2019): 52 to CyA and 51 to MTX. CyA showed greater improvement in disease severity by 12 weeks [mean difference in o-SCORAD –5.69, 97.5% confidence interval (CI) –10.81 to –0.57 (P=0.01)]. More participants achieved ≥ 50% improvement in o-SCORAD (o-SCORAD 50) at 12 weeks in the CyA arm vs. the MTX arm [odds ratio (OR) 2.60, 95% CI 1.23–5.49; P=0.01]. By 60 weeks MTX was superior (OR 0.33, 95% CI 0.13–0.85; P=0.02), a trend also seen for ≥ 75% improvement in o-SCORAD (o-SCORAD 75), EASI 50 and EASI 75. Participant-reported flares post-treatment were higher in the CyA arm (OR 3.22, 95% CI 0.42–6.01; P=0.02). QoL improved with both treatments and was sustained after treatment cessation. Filaggrin status did not affect outcomes. The frequency of adverse events (AEs) was comparable between both treatments. Five (10%) participants on CyA and seven (14%) on MTX experienced a serious AE. Conclusions: Both CyA and MTX proved effective in CYP with severe AD over 36 weeks. Participants who received CyA showed a more rapid response to treatment, while MTX induced more sustained disease control after discontinuation