ABSTRACT
BACKGROUND: Atopic dermatitis (AD) is the most common inflammatory skin condition which affects all ages. New therapies, including the monoclonal antibody therapy dupilumab, offer excellent efficacy. However, in clinical trials, and emphasised in real-world observations, the unexpected increased frequency of ocular adverse effects became apparent. The effectiveness of dupilumab and the unpredictability of ocular adverse effects mean that clinicians need guidance on counselling patients prior to treatment and on managing them if they arise. OBJECTIVES: The British Association of Dermatologists (BAD) and Royal College of Ophthalmologists collaborated on this consensus guidance on managing dupilumab-related ocular surface disorders (DROSD). METHODS: A multidisciplinary group was formed of adult and paediatric dermatologists and ophthalmologists with DROSD expertise, patient representation, and BAD Clinical Standards Unit. A literature search was conducted, and the results reviewed. All recommendations were reviewed, discussed and voted on. RESULTS: The recommendations pertain to dermatology and ophthalmology management, and apply to all ages, unless otherwise stated. Importantly, initiation of dupilumab for AD should not be delayed for most eye disorders except acute new problems, e.g. infections, or potentially severe conditions, e.g. a history of corneal transplant (ophthalmology advice should be sought first). There is insufficient evidence to recommend lubricant drops prophylactically. Dermatologists should assess eye complaints to diagnose DROSD; a severity grading system is provided. DROSD management differs slightly in those aged <7 years as ocular complications may affect neuro-ocular development; therefore, irrespective of DROSD severity, this population should be referred for ophthalmology advice. In those aged ≥7 years, dermatologists should feel confident to trial treatment and reserve ophthalmology advice for severe or non-responding cases. Discussion about dupilumab withdrawal should be prompted by a significant impact on quality of life, threat to sight, or other complications. CONCLUSIONS: Although dupilumab is a highly effective agent for treating AD, the risk of ocular adverse effects should not inhibit clinicians or patients from using it, but clinicians should be aware of them. If a patient develops DROSD, there are clear pathways to assess severity and offer initial management; where ineffective, dermatologists should assess the urgency and seek advice from or initiate referral to ophthalmology. While the evidence reviewed for these guidelines reflects the extensive literature on dupilumab, we believe our advice has relevance for ocular surface disorders in atopic dermatitis (AD) patients treated with tralokinumab and lebrikizumab.
ABSTRACT
BACKGROUND: UK guidelines for managing adults with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), published by the British Association of Dermatologists (BAD) in 2016, outline a set of audit standards. OBJECTIVES: To audit current management of SJS/TEN in adults against standards in the BAD guidelines. METHODS: BAD members were invited to submit data on five consecutive adults with SJS/TEN per department over an 8-week period in 2022. RESULTS: Thirty-nine dermatology centres in the UK (29%) participated, and data for 147 adults with SJS/TEN were collected. Within 24â h of the diagnosis being made or suspected, the following were documented, per 147 submitted cases: Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN) for 76 (52%), list of medications for 113 (77%) and timelines for commencement/alterations of medications for 104 (71%). The initial assessment was documented of the eyes by an ophthalmologist in 71 (48%), of the mouth in 130 (88%), of the genital skin in 103 (70%) and of the urinary tract in 93 (63%). During the first 10â days after a suspected or confirmed diagnosis of SJS/TEN, daily assessments of the mouth were documented in 26 of 147 cases (18%), of the eyes in 12 (8%), and of the urinary tract and genital skin in 14 (10%). At discharge, a drug was declared to be the cause of SJS/TEN for 130 of 147 cases (88%), while 9 (6%) were thought to be secondary to infection. Eleven of 147 (8%) had no response to this question. Documentation regarding advice was present on avoidance of the culprit drug in 76 of 130 declared SJS/TEN cases (58%), and on requesting a MedicAlert® bracelet/amulet in 9 of the 147 cases (6%). CONCLUSIONS: This audit suggests that a clinical review checklist might be needed to enable colleagues to maintain standards outlined in the guidelines, including documentation of SCORTEN, daily assessments of mucosal areas, and advice to avoid culprit drug(s) and to request a MedicAlert® bracelet/amulet.
Subject(s)
Practice Guidelines as Topic , Stevens-Johnson Syndrome , Stevens-Johnson Syndrome/therapy , Stevens-Johnson Syndrome/diagnosis , Humans , Adult , United Kingdom , Male , Female , Middle Aged , Clinical Audit , Aged , Severity of Illness Index , Young Adult , Dermatology/standards , Aged, 80 and overSubject(s)
Anus Neoplasms , Bowen's Disease , Carcinoma, Squamous Cell , Skin Neoplasms , Squamous Intraepithelial Lesions , Humans , Carcinoma, Squamous Cell/diagnosis , Carcinoma, Squamous Cell/therapy , Carcinoma, Squamous Cell/pathology , Bowen's Disease/diagnosis , Bowen's Disease/therapy , Bowen's Disease/pathology , Skin Neoplasms/diagnosis , Skin Neoplasms/therapy , Skin Neoplasms/pathology , DermatologistsABSTRACT
BACKGROUND: Erosive pustular dermatosis of the scalp (EPDS) is a chronic condition characterized by erosive plaques and subsequent scarring alopecia as a result of local trauma or inflammation. A number of therapeutic approaches have been described in the literature but there is no consensus of opinion on optimal treatment of the disease. OBJECTIVES: To provide evidence-based recommendations for topical and systemic treatment of adult patients with EPDS by performing a systematic review. METHODS: The MEDLINE, MEDLINE In-Process, Embase and Cochrane databases were searched from inception to 26 June 2019 in accordance with the PRISMA guidelines for studies involving adult patients treated for EPDS with at least one reported response to treatment. The study was registered on PROSPERO. Texts were reviewed independently by two authors. The risk of bias and quality of the studies were assessed using the Quality Appraisal Checklist for Case Series Studies. RESULTS: In total 75 studies were included, involving 168 patients. Many treatments have been reported in the literature, with varying degrees of therapeutic success. The results were highly heterogeneous and methodological quality was very low. We were unable to perform a meta-analysis on the data. CONCLUSIONS: The limited available evidence supports use of topical corticosteroids, with or without oral zinc, followed by maintenance therapy with topical calcineurin inhibitors as being effective in managing this condition. Topical photodynamic therapy is also potentially beneficial in the management of EPDS. Prospective, comparative, randomized controlled trials are required in order to provide further evidence to guide treatment.
Subject(s)
Scalp Dermatoses , Scalp , Alopecia , Calcineurin Inhibitors , Humans , Prospective Studies , Scalp Dermatoses/drug therapySubject(s)
Delivery of Health Care/standards , Eczema/therapy , Child , Child, Preschool , Clinical Audit , Disease Management , Eczema/diagnosis , Female , Guideline Adherence/standards , Humans , Infant , Infant, Newborn , Male , United KingdomABSTRACT
Multiple biologic treatments are licensed for psoriasis. The lack of head-to-head randomized controlled trials makes choosing between them difficult for patients, clinicians, and guideline developers. To establish their relative efficacy and tolerability, we searched MEDLINE, PubMed, Embase, and Cochrane for randomized controlled trials of licensed biologic treatments for skin psoriasis. We performed a network meta-analysis to identify direct and indirect evidence comparing biologics with one another, methotrexate, or placebo. We combined this with hierarchical cluster analysis to consider multiple outcomes related to efficacy and tolerability in combination for each treatment. Study quality, heterogeneity, and inconsistency were evaluated. Direct comparisons from 41 randomized controlled trials (20,561 participants) were included. All included biologics were efficacious compared with placebo or methotrexate at 3-4 months. Overall, cluster analysis showed adalimumab, secukinumab, and ustekinumab were comparable in terms of high efficacy and tolerability. Ixekizumab and infliximab were differentiated by very high efficacy but poorer tolerability. The lack of longer term controlled data limited our analysis to short-term outcomes. Trial performance may not equate to real-world performance, and so results need to be considered alongside real-world, long-term safety and effectiveness data. These data suggest that it is possible to discriminate between biologics to inform clinical practice and decision making (PROSPERO 2015:CRD42015017538).
Subject(s)
Biological Factors/therapeutic use , Biological Therapy/methods , Psoriasis/drug therapy , Humans , Network Meta-AnalysisABSTRACT
A comprehensive evaluation of the risk of serious infections in biologic therapies for psoriasis is lacking. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) and prospective cohort studies reporting serious infections in people taking any licensed biologic therapy for psoriasis compared with those taking placebo, nonbiologic therapy, or other biologic therapies. The quality of the studies was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. No significant heterogeneity was detected in data from 32 RCTs (n = 13,359 participants) and one cohort study (n = 4,993 participants). In adults, low- to very-low-quality RCT data showed no significant difference between any biologic therapy and placebo at weeks 12-16 (overall pooled Peto odds ratio = 0.71, 95% confidence interval = 0.36-1.41) and weeks 20-30 (odds ratio = 2.27, 95% confidence interval = 0.45-11.49). No significant differences were found in any of the other comparisons in underpowered RCT data. Prospective cohort study data of low quality suggests that only adalimumab (adjusted hazard ratio [adjHR] = 2.52, 95% confidence interval = 1.47-4.32) was associated with a significantly higher risk of serious infection compared with retinoid and/or phototherapy in adults. No association between biologic therapies and serious infections in patients with psoriasis who were eligible for RCTs was detected. Further observational studies are needed to inform the uncertainty around this risk in the real world.
Subject(s)
Biological Products/therapeutic use , Infections/complications , Psoriasis/complications , Psoriasis/therapy , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Biological Therapy , Humans , Methotrexate/therapeutic use , Odds Ratio , Phototherapy/methods , Proportional Hazards Models , Randomized Controlled Trials as Topic , Retinoids/therapeutic use , Risk Factors , Time Factors , Ustekinumab/therapeutic useABSTRACT
Synthetic approaches to the lantibiotics, a family of thioether-bridged antimicrobial peptides, require flexible synthetic routes to a variety of orthogonally protected derivatives of lanthionine 1. The most direct approaches to lanthionine involve the reaction of cysteine with an alanyl beta-cation equivalent. Several possibilities exist for the alanyl beta-cation equivalent, including direct activation of serine under Mitsunobu conditions: however, the low reactivity of sulfur nucleophiles in the Mitsunobu reaction has previously precluded its use in the synthesis of the lantibiotics. We report here a new approach to the synthesis of protected lanthionine, using a novel variant of the Mitsunobu reaction in which catalytic zinc tartrate is used to enhance the nucleophilicity of the thiol. In the course of these studies, we have also demonstrated that the synthesis of lanthionine from trityl-protected beta-iodoalanines is prone to rearrangement, via an aziridine, to give predominantly trityl-protected alpha-iodo-beta-alanines, and hence norlanthionines, as the major products.
Subject(s)
Alanine/analogs & derivatives , Alanine/chemical synthesis , Anti-Bacterial Agents/chemical synthesis , Peptides , Alanine/chemistry , Anti-Bacterial Agents/chemistry , Molecular Structure , Stereoisomerism , SulfidesABSTRACT
Two diastereomeric analogues of ring C of nisin incorporating a novel norlanthionine residue have been synthesized via a triply orthogonal protecting group strategy. A full structural study was carried out by NMR, which elucidated the conformational properties of the two peptides and enabled the identity of each diastereoisomer to be proposed.