European guideline (EuroGuiDerm) on atopic eczema - part II: non-systemic treatments and treatment recommendations for special AE patient populations.

The evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. This second part of the guideline includes recommendations and detailed information on basic therapy with emollients and moisturizers, topical anti-inflammatory treatment, antimicrobial and antipruritic treatment and UV phototherapy. Furthermore, this part of the guideline covers techniques for avoiding provocation factors, as well as dietary interventions, immunotherapy, complementary medicine and educational interventions for patients with atopic eczema and deals with occupational and psychodermatological aspects of the disease. It also contains guidance on treatment for paediatric and adolescent patients and pregnant or breastfeeding women, as well as considerations for patients who want to have a child. A chapter on the patient perspective is also provided. The first part of the guideline, published separately, contains recommendations and guidance on systemic treatment with conventional immunosuppressive drugs, biologics and janus kinase (JAK) inhibitors, as well as information on the scope and purpose of the guideline, and a section on guideline methodology.

European guideline (EuroGuiDerm) on atopic eczema: part I - systemic therapy.

The evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. This first part of the guideline includes general information on its scope and purpose, the health questions covered, target users and a methods section. It also provides guidance on which patients should be treated with systemic therapies, as well as recommendations and detailed information on each systemic drug. The systemic treatment options discussed in the guideline comprise conventional immunosuppressive drugs (azathioprine, ciclosporin, glucocorticosteroids, methotrexate and mycophenolate mofetil), biologics (dupilumab, lebrikizumab, nemolizumab, omalizumab and tralokinumab) and janus kinase inhibitors (abrocitinib, baricitinib and upadacitinib). Part two of the guideline will address avoidance of provocation factors, dietary interventions, immunotherapy, complementary medicine, educational interventions, occupational and psychodermatological aspects, patient perspective and considerations for paediatric, adolescent, pregnant and breastfeeding patients.

Global Guidelines in Dermatology Mapping Project (GUIDEMAP): a scoping review of dermatology clinical practice guidelines.

BACKGROUND: Clinical practice guidelines (CPGs) play a critical role in standardizing and improving treatment outcomes based on the available evidence. It is unclear how many CPGs are available globally to assist clinicians in the management of patients with skin disease. OBJECTIVES: To search for and identify CPGs for dermatological conditions with the highest burden globally. METHODS: We adapted a list of 12 dermatological conditions with the highest burden from the Global Burden of Disease (GBD) study 2019. A systematic literature search was done to identify CPGs published between October 2014 to October 2019. The scoping review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. RESULTS: A total of 226 CPGs were included. Melanoma had the greatest representation in the CPGs, followed by dermatitis and psoriasis. Skin cancers had a relatively high CPG representation but with lower GBD disease burden ranking. There was an uneven distribution by geographical region, with resource-poor settings being under-represented. The skin disease categories of the CPGs correlated weakly with the GBD disability-adjusted life-years metrics. Eighty-nine CPGs did not have funding disclosures and 34 CPGs were behind a paywall. CONCLUSIONS: The global production of dermatology CPGs showed wide variation in geographical representation, article accessibility and reporting of funding. The number of skin disease CPGs were not commensurate with its disease burden. Future work will critically appraise the methodology and quality of dermatology CPGs and lead to the production of an accessible online resource summarizing these findings.

Topical corticosteroid vehicle composition and implications for clinical practice.

This narrative review highlights the therapeutic significance of topical corticosteroid (TCS) vehicles and provides subsequent guidance to improve clinical and research outcomes. A greater understanding of the relationship between the topical vehicle, corticosteroid and skin is needed to ensure safer, more effective treatment for patients. Topical vehicles are not inert and can affect TCS bioavailability, due to the ability of their composition to positively or negatively influence skin status and change the physiochemical characteristics of an inherent corticosteroid. However, this principle is not commonly understood, and has contributed to inconsistencies in potency classification systems. This review provides an insight into the research methods and standardization needed to determine TCS product bioavailability. It identifies formulation components responsible for vehicle composition that underpin the quality, stability, compounding and functionalities of vehicle ingredients. This helps to contextualize how topical vehicles can be responsible for clinically significant effects, and how their composition gives products unique properties. In turn, this facilitates a more in-depth understanding of which resources offer information to inform the best selection of TCS products and why products should be prescribed by brand or manufacturer. This review will better equip clinicians and formulary teams to appraise products. It will also inform prescribing of Specials and why products should not be manipulated. The recommendations, accompanied by patient perspectives on using TCS products, assist clinical decision-making. They also identify the need for research into concomitant application of TCS products with other topical therapies.

The global burden of atopic dermatitis: lessons from the Global Burden of Disease Study 1990-2017.

BACKGROUND: The Global Burden of Disease (GBD) Study provides an annually updated resource to study disease-related morbidity and mortality worldwide. OBJECTIVES: Here we present the burden estimates for atopic dermatitis (AD), including data from inception of the GBD project in 1990 until 2017. METHODS: Data on the burden of AD were obtained from the GBD Study. RESULTS: Atopic dermatitis (AD) ranks 15th among all nonfatal diseases and has the highest disease burden among skin diseases as measured by disability-adjusted life-years (DALYs). Overall, the global DALY rate for AD in 1990 was 121 [95% uncertainty interval (UI) 65·4-201] and remained similar in 2017 at 123 (95% UI 66·8-205). The three countries with the highest DALY rates of AD were Sweden (327, 95% UI 178-547), the UK (284, 95% UI 155-478) and Iceland (277, 95% UI 149-465), whereas Uzbekistan (85·1, 95% UI 45·2-144), Armenia (85·1, 95% UI 45·8-143) and Tajikistan (85·1, 95% UI 46·1-143) ranked lowest. CONCLUSIONS: The global prevalence rate of AD has remained stable from 1990 to 2017. However, the distribution of AD by age groups shows a bimodal curve with the highest peak in early childhood, decreasing in prevalence among young adults, and a second peak in middle-aged and older populations. We also found a moderate positive correlation between a country's gross domestic product and disease burden. GBD data confirm the substantial worldwide burden of AD, which has remained stable since 1990 but shows significant geographical variation. Lifestyle factors, partially linked to affluence, are likely important disease drivers. However, the GBD methodology needs to be developed further to incorporate environmental risk factors, such as ultraviolet exposure, to understand better the geographical and age-related variations in disease burden.

Identifying and appraising patient-reported outcome measures on treatment satisfaction in acne: a systematic review.

BACKGROUND: After dermatitis, acne is the next skin disease to contribute most to the burden of skin diseases worldwide. Recently, seven core outcome domains have been identified, which together form an Acne Core Outcome Set (ACORN). One of these was satisfaction with acne treatment. OBJECTIVES: To identify studies that described the development of patient-reported outcome measures (PROMS), evaluated one or more measurement properties of a PROM, or evaluated the interpretability of a PROM in patients with acne regarding treatment satisfaction. METHODS: The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) search strategy for identifying PROMS on acne treatment satisfaction was used. We searched PubMed, MEDLINE, Embase, LILACS, Web of Science, Cochrane Library, Emcare, PsycINFO and Academic Search premier (June 2020). Study selection, data extraction and assessment of methodological quality according to COSMIN guidance were carried out independently by two authors. RESULTS: Only one study could be included, describing the development of a treatment satisfaction measure in patients with acne. The development was assessed as inadequate and data on measurement properties were lacking. Additionally, we found 188 studies reporting treatment satisfaction solely as an outcome, using a wide variety of methods, none of them standardized or validated. CONCLUSIONS: We could not find a PROM on treatment satisfaction to recommend for a core outcome set in acne. There is an unmet need for a PROM on treatment satisfaction in acne that is robustly developed, designed and validated.

TREatment of ATopic eczema (TREAT) Registry Taskforce: protocol for a European safety study of dupilumab and other systemic therapies in patients with atopic eczema.

BACKGROUND: A long-term prospective observational safety study is essential to characterize fully the safety profile of systemic immunomodulating therapies for patients with atopic eczema. The TREatment of ATopic eczema (TREAT) Registry Taskforce offers a large platform to conduct such research using national registries that collect the same data using a predefined core dataset. OBJECTIVES: To present a protocol for a safety study comparing dupilumab with other systemic immunomodulating therapies in children and adults with moderate-to-severe atopic eczema, to assess the long-term safety risk of these therapies in a routine clinical care setting. METHODS: We describe a registry-embedded international observational prospective cohort study. Adult and paediatric patients who start treatment with dupilumab or another systemic immunomodulating agent for their atopic eczema will be included. The primary end point is the incidence of malignancies (excluding nonmelanoma skin cancer) compared between the treatment groups. Secondary end points include other serious adverse events and adverse events of special interest, such as eye disorders and eosinophilia. CONCLUSIONS: This protocol delineates a safety study for dupilumab in adult and paediatric patients with atopic eczema, using a standardized methodological approach across several national registries. The protocol could also be used for other novel systemic immunomodulating therapies, and could provide licensing and reimbursement authorities, pharmaceutical companies and clinicians with safety evidence from a routine clinical care setting. What's already known about this topic? There is a need for long-term data on the safety of systemic immunomodulating therapies in patients with atopic eczema. Regulatory bodies, such as the European Medicines Agency, increasingly stipulate the collection of such data as part of the licensing agreement for new treatments, to assess the new agent's long-term safety profile against established therapies. Large numbers of patients with a long duration of follow-up are necessary in order to detect rare events like malignancies. What does this study add? The TREAT Registry Taskforce offers a platform to conduct such research with a network of multiple national atopic eczema research registries. We present a protocol for an investigator-initiated multicentre safety study comparing dupilumab with other systemic immunomodulating therapies in adults and subsequently adolescents and children with moderate-to-severe atopic eczema. This protocol can be used as a framework for similar studies for other novel systemic immunomodulating therapies across both adult and paediatric populations.

Atopic eczema: burden of disease and individual suffering - results from a large EU study in adults.

BACKGROUND: Atopic eczema (AE, atopic dermatitis) is one of the most common non-communicable inflammatory skin diseases affecting 1-5% of the adult population in Europe with marked impairment in quality of life. In spite of great progress in understanding the pathophysiology of disturbed skin barrier and immune deviation, AE still represents a problem in daily clinical practice. Furthermore, the true impact of AE on individual suffering is often not recognized. OBJECTIVES: With a large European study, we wanted to provide insights into the actual suffering and individual burden of disease in adult patients with AE. METHODS: A total of 1189 adult patients (18-87 years, 56% female) with moderate to severe AE were recruited in nine European countries by dermatologists or allergists together with the help of patient organizations. A computer-assisted telephone interview was performed by experienced interviewers between October 2017 and March 2018. The following instruments were used to assess severity or measure quality of life: Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), Hospital Anxiety and Depression Scale (HADS-D) and a newly developed Atopic Eczema Score of Emotional Consequences (AESEC). Patients were also asked to self-assess the severity of their disease. RESULTS: Despite current treatment, 45% of participants still had actual moderate to very severe AE in POEM. Due to their skin disease, 57% missed at least 1 day of work in the preceding year. DLQI showed moderate to extremely large impairment in 55%. According to HADS-D, 10% scored on or above the threshold of eight points with signs of depressive symptoms. Assessed with AESEC, 57% were emotionally burdened with feelings such as 'trying to hide the eczema', 'feeling guilty about eczema', having 'problems with intimacy' and more. Of persons actually suffering from severe AE, 88% stated that their AE at least partly compromised their ability to face life. CONCLUSIONS: This real-life study shows that adults with a moderate to severe form of AE are suffering more than what would be deemed acceptable. There is a need for increased awareness of this problem among healthcare professionals, policymakers and the general public to support research in the development of new and more effective treatments and provide access to better and affordable health care for affected patients.

TREatment of ATopic eczema (TREAT) Registry Taskforce: consensus on how and when to measure the core dataset for atopic eczema treatment research registries.

BACKGROUND: Comparative, real-life and long-term evidence on the effectiveness and safety of phototherapy and systemic therapy in moderate-to-severe atopic eczema (AE) is limited. Such data must come from well-designed prospective patient registries. Standardization of data collection is needed for direct comparisons and data pooling. OBJECTIVES: To reach a consensus on how and when to measure the previously defined domain items of the TREatment of ATopic eczema (TREAT) Registry Taskforce core dataset for research registries for paediatric and adult patients with AE. METHODS: Proposals for the measurement instruments were based on recommendations of the Harmonising Outcome Measures for Eczema (HOME) initiative, the existing AE database of TREATgermany, systematic reviews of the literature and expert opinions. The proposals were discussed at three face-to-face consensus meetings, one teleconference and via e-mail. The frequency of follow-up visits was determined by an expert survey. RESULTS: A total of 16 experts from seven countries participated in the 'how to measure' consensus process and 12 external experts were consulted. A consensus was reached for all domain items on how they should be measured by assigning measurement instruments. A minimum follow-up frequency of initially 4 weeks after commencing treatment, then every 3 months while on treatment and every 6 months while off treatment was defined. CONCLUSIONS: This core dataset for national AE research registries will aid in the comparability and pooling of data across centres and country borders, and enables international collaboration to assess the long-term effectiveness and safety of phototherapy and systemic therapy used in patients with AE. What's already known about this topic? Comparable, real-life and long-term data on the effectiveness and safety of phototherapy and systemic therapy in patients with atopic eczema (AE) are needed. There is a high diversity of outcomes and instruments used in AE research, which require harmonization to enhance comparability and allow data pooling. What does this study add? Our taskforce has reached international consensus on how and when to measure core domain items for national AE research registries. This core dataset is now available for use by researchers worldwide and will aid in the collection of unified data. What are the clinical implications of this work? The data collected through this core dataset will help to gain better insights into the long-term effectiveness and safety of phototherapy and systemic therapy in AE and will provide important information for clinical practice. Standardization of such data collection at the national level will also allow direct data comparisons and pooling across country borders (e.g. in the analysis of treatment-related adverse events that require large patient numbers).

Interventions for rosacea based on the phenotype approach: an updated systematic review including GRADE assessments.

BACKGROUND: Rosacea is a common chronic facial dermatosis. Classification of rosacea has evolved from subtyping to phenotyping. OBJECTIVES: To update our systematic review on interventions for rosacea. METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index and ongoing trials registers (March 2018) for randomized controlled trials. Study selection, data extraction, risk-of-bias assessment and analyses were carried out independently by two authors. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to assess certainty of evidence. RESULTS: We included 152 studies (46 were new), comprising 20 944 participants. Topical interventions included brimonidine, oxymetazoline, metronidazole, azelaic acid, ivermectin and other topical treatments. Systemic interventions included oral antibiotics, combinations with topical treatments or other systemic treatments. Several studies evaluated laser or light-based treatment. We present the most current evidence for rosacea management based on a phenotype-led approach. CONCLUSIONS: For reducing temporarily persistent erythema there was high-certainty evidence for topical brimonidine and moderate certainty for topical oxymetazoline; for erythema and mainly telangiectasia there was low-to-moderate-certainty evidence for laser and intense pulsed light therapy. For reducing papules/pustules there was high-certainty evidence for topical azelaic acid and topical ivermectin; moderate-to-high-certainty evidence for doxycycline 40 mg modified release (MR) and isotretinoin; and moderate-certainty evidence for topical metronidazole, and topical minocycline and oral minocycline being equally effective as doxycycline 40 mg MR. There was low-certainty evidence for tetracycline and low-dose minocycline. For ocular rosacea, there was moderate-certainty evidence that oral omega-3 fatty acids were effective and low-certainty evidence for ciclosporin ophthalmic emulsion and doxycycline.

AGREE II assessments of recent acne treatment guidelines: how well do they reveal trustworthiness as defined by the U.S. Institute of Medicine criteria?

BACKGROUND: Up-to-date, trustworthy guidelines are a widely relied upon means of promoting excellent patient care. OBJECTIVES: To determine the quality of recently published acne treatment guidelines by utilizing the Appraisal of Guidelines for Research and Evaluation (AGREE) II Reporting Checklist, the U.S. Institute of Medicine's (IOM) criteria of trustworthiness, the red flags of Lenzer et al. and CheckUp. METHODS: Systematic searches were conducted in bibliographic databases, guideline depositories and using Google to identify acne treatment guidelines published since 2013. Six assessors independently scored each guideline using the AGREE II Reporting Checklist. Guidelines were concomitantly assessed for trustworthiness using the IOM criteria and for the red flags of Lenzer et al., indicative of potential bias. Updates were screened using CheckUp. RESULTS: Eight guidelines were identified, two of which were updates. Lowest scoring AGREE II domains across all guidelines were applicability (six poor, one fair, one average) and rigour (four poor, one fair, three average). Two of the three highest-scoring guidelines were developed using AGREE II. No guideline fully met each IOM criterion and all raised at least one red flag indicative of potential bias. One updated guideline did not address seven of 16 items on CheckUp and the other did not address four. Patient involvement in guideline development was minimal. CONCLUSIONS: Use of the AGREE II instrument during guideline development did not have as great an effect on guideline quality as might be expected. There is considerable room for improvement in acne treatment guidelines in order to satisfy the IOM trustworthiness criteria and avoid bias.

Emollients and moisturizers for eczema: abridged Cochrane systematic review including GRADE assessments.

Eczema is a chronic inflammatory skin disorder with considerable impact on quality of life. Emollients or moisturizers are widely recommended, but are these effective and safe? We searched for randomized controlled trials (RCTs) in the Cochrane Skin Group Specialised Skin Register, CENTRAL in The Cochrane Library, MEDLINE, Embase, LILACS, the GREAT database and five trial registers to December 2015. We included 77 RCTs with 6603 participants. Seven studies (9%) were at low risk of bias, 34 (44%) had unclear risk and 36 (47%) were at high risk. The quality of the evidence was mainly low or moderate for the prespecified outcomes. The most important comparison, 'moisturizer vs. no moisturizer', showed improved Scoring Atopic Dermatitis values in the moisturizer group compared with no moisturizer [mean difference -2·42, 95% confidence interval (CI) -4·55 to -0·28], but did not meet the minimal important difference of 8·7. Fewer flares were seen (risk ratio 0·40, 95% CI 0·23-0·70) and the rate of flares was reduced (hazard ratio 3·74, 95% CI 1·86-7·50). The groups applying moisturizer used less topical corticosteroids over 6-8 weeks (mean difference -9·30 g, 95% CI 15·3 to -3·27). Glycyrrhetinic acid-, urea- and glycerol-containing creams worked better than their controls (vehicle, placebo or no moisturizer) according to both participants and physicians. More flares were reported with moisturizer alone than when combined with twice-weekly fluticasone propionate (risk ratio 2·17, 95% CI 1·55-3·11). Adding moisturizers to topical anti-inflammatory treatment was more effective than anti-inflammatory treatment alone and resulted in fewer flares.

[Cryptococcal sepsis simulating miliary tuberculosis in malignant lymphoma]. / Kryptokokkensepsis unter dem Bild einer Miliartuberkulose bei malignem Lymphom.

A malignant non-Hodgkin lymphoma (Cb-Cc) stage IVb was diagnosed in a man of 71 years of age. He was subjected to polychemotherapy. The mediastinum was irradiated. Cortisone therapy was performed because of irradiation pneumonitis. A highly febrile disease pattern developed with increasing dyspnoea while displaying the signs and symptoms of a miliary pulmonary disease. The treatment course was directed at combatting miliary tuberculosis. The patient died from cardiorespiratory failure. The postmortem examination supplied proof of cryptococcal sepsis. The differential diagnosis is discussed.