Corinna Dressler

Immune checkpoint blockade for unresectable or metastatic uveal melanoma: A systematic review

BACKGROUNDnThe use of immune checkpoint blockade (ICB) for uveal melanoma (UM) is little established. The aim of this review was to provide a comprehensive overview on the efficacy, safety, and tolerability of ICB in patients with UM.nnnMETHODSnWe performed a systematic literature research covering MEDLINE, Embase and CENTRAL. Abstracts of pertinent conferences and trial registers were handsearched for relevant studies.nnnRESULTSnOut of 1327 records initially identified, 12 eligible studies were included in the qualitative synthesis. They comprised 7 expanded access or named patient programs (n=162), 4 phase II trials (n=171), and 1 phase Ib trial (sample size unknown), while no randomized controlled trial was found. Ipilimumab monotherapy was assessed at 3mg/kg in 5 trials (n=186) with a response rate of 0 to 5%. Two reports investigated ipilimumab at 10mg/kg (n=45) with radiological responses observed in 0 to 6.5%. The median progression-free survival (PFS) was below 3months and the median overall survival was 5.2-9.8months for ipilimumab monotherapy. Severe immune-related adverse events occurred at a frequency comparable to cutaneous melanoma (6 to 36%). Two studies investigated pembrolizumab (2mg/kg) and nivolumab (3mg/kg) with overall response rates of 30% and 6%, respectively. Data on combined ipilimumab and programmed cell death protein 1 inhibition were available from one expanded access program, but no response was observed with a median PFS of 2.9months.nnnCONCLUSIONSnUM is little responsive to ipilimumab regardless of dosage schemes. Sound randomized clinical trials are needed to evaluate the efficacy of combined ICB in patients with UM.

Executive summary of the methods report for ‘The EAACI/GA2LEN/EDF/WAO Guideline for the Definition, Classification, Diagnosis and Management of Urticaria. The 2017 Revision and Update’

To the Editor, For the revision and update of the EAACI/GA2LEN/EDF/WAO guideline on urticaria, we defined and followed a structured process as recommended by national and international guideline development manuals and took the Appraisal of Guidelines Research and Evaluation (AGREE II) Instrument into account. The full methods report can be found in the online Appendix S1. Experts representing 44 international societies were nominated. The experts were responsible to define key questions and select relevant outcomes using an online survey tool. Secondly, a systematic review protocol was developed specifying the search strategy, three databases, the inclusion/exclusion criteria, the outcomes and study appraisal methods, data collection and synthesis procedures. The methods as recommended by Cochrane, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group were adhered to. Record screening, data extraction and study appraisal were carried out twice and independently by two methodologists. Risk ratios, mean difference and corresponding confidence intervals were calculated, and whenever appropriate, metaanalysis was performed using Review Manager. The Cochrane Risk of Bias Assessment tools was used, and we evaluated the certainty of the evidence as postulated by GRADE using GRADEpro GDT. A summary of the four possible GRADE rating can be seen in Table 1. Furthermore, we developed evidence-to-decision frameworks (EtD) providing a concise overview of the available evidence including other, relevant context factors. The literature search took place on 1st June 2016. A total of 8090 records were identified and screened in two phases by two methodologists. A total of 65 studies could be included, and we created 31 GRADE evidence profiles. Recommendations were drafted using standardized wording (Table 2). Additionally, the experts drafted recommendations for all remaining key questions and those for which no evidence could be identified. A preconsensus conference voting on the recommendation took place. Results and feedback were integrated. The draft recommendations and EtD frameworks were made available online to all conference participants ahead of time. On 1st December 2016, the consensus conference took place with over 250 participants. Each recommendation was voted on using a structured, nominal group technique process: presentation of the available evidence/GRADE profile, presentation of the draft recommendation, open discussion, voting and/or generating alternative phrasing, final voting. Green and red cards were used to vote for or against a suggested recommendation. Consensus levels had been predefined as: >90% agreement strong consensus, 70%-89% consensus. Voting results were documented, and each recommendation passed (at least 75% agreement). An internal and an external review of the final guideline was conducted.

Chronic inducible urticaria: A systematic review of treatment options

Background Chronic inducible urticaria (CindU) is a condition characterized by the appearance of recurrent wheals, angioedema, or both as a response to specific and reproducible triggers. Objective We sought to systematically assess evidence on the efficacy and safety of treatment options for CindU. Results were used to inform the 2017 update of “The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.” Methods Randomized controlled trials and controlled intervention studies were searched systematically in various databases. Included studies were evaluated with the Cochrane Risk of Bias tool. Where possible, results from single studies were meta‐analyzed, applying the Mantel‐Haenszel approach by using a random‐effects model (Der Simonian–Laird). Results We identified 30 studies that included patients with cold urticaria, symptomatic dermographism, delayed‐pressure urticaria, or cholinergic urticaria. No studies on other forms of CindU were eligible. Risk of bias was often rated as unclear or high. Overall, second‐generation antihistamines were more effective than placebo, and available data indicate that updosing might be effective. Omalizumab proved effective in patients with symptomatic dermographism, who did not respond to antihistamines. Detailed results are given for each type of CindU. Conclusions The available evidence is limited by small samples, heterogeneous efficacy outcomes, and poor reporting quality in many of the included studies. The findings are congruent with the suggested stepwise approach to treating CindUs. However, the data do not allow for drawing specific conclusions for specific subtypes of CindU.

Ivermectin and permethrin for treating scabies.

Background Scabies is an intensely itchy parasitic infection of the skin. It occurs worldwide, but is particularly problematic in areas of poor sanitation, overcrowding, and social disruption. In recent years, permethrin and ivermectin have become the most relevant treatment options for scabies. Objectives To assess the efficacy and safety of topical permethrin and topical or systemic ivermectin for scabies in people of all ages. Search methods We searched the following databases up to 25 April 2017: the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, and IndMED. We searched the World Health Organization International Clinical Trials Registry Platform, the ISRCTN registry, CenterWatch Clinical Trials Listing, ClinicalTrials.gov, TrialsCentral, and the UK Department of Health National Research Register for ongoing trials. We also searched multiple sources for grey literature and checked reference lists of included studies for additional trials. Selection criteria We included randomized controlled trials that compared permethrin or ivermectin against each other for people with scabies of all ages and either sex. Data collection and analysis Two review authors independently screened the identified records, extracted data, and assessed the risk of bias for the included trials. The primary outcome was complete clearance of scabies. Secondary outcomes were number of participants re‐treated, number of participants with at least one adverse event, and number of participants withdrawn from study due to an adverse event. We summarized dichotomous outcomes using risk ratios (RR) with 95% confidence intervals (CI). If it was not possible to calculate the point estimate, we described the data qualitatively. Where appropriate, we calculated combined effect estimates using a random‐effects model and assessed heterogeneity. We calculated numbers needed to treat for an additional beneficial outcome when we found a difference. We assessed the certainty of the evidence using the GRADE approach. We used the control rate average to provide illustrative clearance rates in the comparison groups. Main results Fifteen studies (1896 participants) comparing topical permethrin, systemic ivermectin, or topical ivermectin met the inclusion criteria. Overall, the risk of bias in the included trials was moderate: reporting in many studies was poor. Nearly all studies were conducted in South Asia or North Africa, where the disease is more common, and is associated with poverty. Efficacy Oral ivermectin (at a standard dose of 200 μg/kg) may lead to slightly lower rates of complete clearance after one week compared to permethrin 5% cream. Using the average clearance rate of 65% in the trials with permethrin, the illustrative clearance with ivermectin is 43% (RR 0.65, 95% CI 0.54 to 0.78; 613 participants, 6 studies; low‐certainty evidence). However, by week two there may be little or no difference (illustrative clearance of permethrin 74% compared to ivermectin 68%; RR 0.91, 95% CI 0.76 to 1.08; 459 participants, 5 studies; low‐certainty evidence). Treatments with one to three doses of ivermectin or one to three applications of permethrin may lead to little or no difference in rates of complete clearance after four weeks’ follow‐up (illustrative cures with 1 to 3 applications of permethrin 93% and with 1 to 3 doses of ivermectin 86%; RR 0.92, 95% CI 0.82 to 1.03; 581 participants, 5 studies; low‐certainty evidence). After one week of treatment with oral ivermectin at a standard dose of 200 μg/kg or one application of permethrin 5% lotion, there is probably little or no difference in complete clearance rates (illustrative cure rates: permethrin 73%, ivermectin 68%; RR 0.93, 95% CI 0.74 to 1.17; 120 participants, 1 study; moderate‐certainty evidence). After two weeks of treatment, one dose of systemic ivermectin compared to one application of permethrin lotion may lead to similar complete clearance rates (extrapolated cure rates: 67% in both groups; RR 1.00, 95% CI 0.78 to 1.29; 120 participants, 1 study; low‐certainty evidence). There is probably little or no difference in rates of complete clearance between systemic ivermectin at standard dose and topical ivermectin 1% lotion four weeks after initiation of treatment (illustrative cure rates: oral ivermectin 97%, ivermectin lotion 96%; RR 0.99, 95% CI 0.95 to 1.03; 272 participants, 2 studies; moderate‐certainty evidence). Likewise, after four weeks, ivermectin lotion probably leads to little or no difference in rates of complete clearance when compared to permethrin cream (extrapolated cure rates: permethrin cream 94%, ivermectin lotion 96%; RR 1.02, 95% CI 0.96 to 1.08; 210 participants, 1 study; moderate‐certainty evidence), and there is little or no difference among systemic ivermectin in different doses (extrapolated cure rates: 2 doses 90%, 1 dose 87%; RR 0.97, 95% CI 0.83 to 1.14; 80 participants, 1 study; high‐certainty evidence). Safety Reporting of adverse events in the included studies was suboptimal. No withdrawals due to adverse events occurred in either the systemic ivermectin or the permethrin group (moderate‐certainty evidence). Two weeks after treatment initiation, there is probably little or no difference in the proportion of participants treated with systemic ivermectin or permethrin cream who experienced at least one adverse event (55 participants, 1 study; moderate‐certainty evidence). After four weeks, ivermectin may lead to a slightly larger proportion of participants with at least one adverse event (extrapolated rates: permethrin 4%, ivermectin 5%; RR 1.30, 95% CI 0.35 to 4.83; 502 participants, 4 studies; low‐certainty evidence). Adverse events in participants treated with topical ivermectin were rare and of mild intensity and comparable to those with systemic ivermectin. For this comparison, it is uncertain whether there is any difference in the number of participants with at least one adverse event (very low‐certainty evidence). No withdrawals due to adverse events occurred (62 participants, 1 study; moderate‐certainty evidence). It is uncertain whether topical ivermectin or permethrin differ in the number of participants with at least one adverse event (very low‐certainty evidence). We found no studies comparing systemic ivermectin in different doses that assessed safety outcomes. Authors conclusions We found that for the most part, there was no difference detected in the efficacy of permethrin compared to systemic or topical ivermectin. Overall, few and mild adverse events were reported. Our confidence in the effect estimates was mostly low to moderate. Poor reporting is a major limitation.

S3 Guideline for the treatment of psoriasis vulgaris, update - Short version part 2 - Special patient populations and treatment situations: S3 Psoriasis guideline

The German guideline for the treatment of psoriasis vulgaris was updated using GRADE methodology. The guideline is based on a systematic literature review completed on December 1, 2016, and on a formal consensus and approval process. The second part of this short version of the guideline covers the following special patient populations and treatment situations: tuberculosis screening before and during psoriasis treatment, choice of psoriasis treatment for individuals wishing to have children, as well as during pregnancy and breast‐feeding, and patients with joint involvement and vaccinations. In addition, recommendations on the choice of treatment are presented for patients with the following comorbidities: hepatitis and other hepatic impairment, HIV, malignancies, neurological and psychiatric disorders, ischemic heart disease and congestive heart failure, diabetes mellitus, renal impairment and inflammatory bowel disease.

S3-Leitlinie zur Therapie der Psoriasis vulgaris Update - Kurzfassung Teil 1 - Systemische Therapie: S3-Leitlinie Psoriasis

Die deutsche Psoriasis‐Leitlinie zur Behandlung der Psoriasis vulgaris wurde unter Verwendung der GRADE‐Methodik aktualisiert. Die Leitlinie wurde aufbauend auf einer systematischen Literaturrecherche (letzte Update‐Recherche am 01.12.2016) entwickelt und in einem formalen Konsensus‐ und Freigabeverfahren verabschiedet. Der erste Teil dieser Kurzfassung stellt die Empfehlungen zu den von der Expertengruppe als relevant befundenen und zum Zeitpunkt der Konsensuskonferenz zugelassenen Therapien dar (Acitretin, Adalimumab, Apremilast, Ciclosporin, Etanercept, Fumarsäureester, Infliximab, Methotrexat, Secukinumab, Ustekinumab). Die Leitlinie gibt Hinweise zu Management und Überwachung der eingeschlossenen Therapieoptionen.

Off-label prescriptions and decisions on reimbursement requests in Germany – a retrospective analysis

“Off‐label use” is defined as the prescription of pharmaceutical products outside their approved indications. Rare diseases frequently lack “on‐label” treatment options. In order to avoid reimbursement claims following the prescription of off‐label drugs, physicians in Germany can – on a case‐by‐case basis – file an application for cost coverage with the competent health insurance prior to treatment initiation.

Prioritising topics in guideline development - Results of a two-phase online survey of dermatologist members of the EADV

Most clinical guidelines in dermatology are encyclopaedic, covering a disease and its aetiology, diagnosis, treatment and prevention in their entirety. The usability and uptake of guideline recommendations might be improved by guidelines that are more concise and address specific questions ranked by users according to their perceived importance.

S3 Guideline for the treatment of psoriasis vulgaris, update - Short version part 1 - Systemic treatment: S3 Psoriasis guideline

The German guideline for the treatment of psoriasis vulgaris was updated using GRADE methodology. The guideline is based on a systematic literature review completed on December 1, 2016, and on a formal consensus and approval process. The first section of this short version of the guideline covers systemic treatment options considered relevant by the expert panel and approved in Germany at the time of the consensus conference (acitretin, adalimumab, apremilast, cyclosporine, etanercept, fumaric acid esters, infliximab, methotrexate, secukinumab and ustekinumab). Detailed information is provided on the management and monitoring of the included treatment options.

Umgang mit Antithrombotika bei Operationen an der Haut vor und nach Publikation der entsprechenden S3-Leitlinie: Antithrombotika bei dermatochirurgischen Eingriffen

Laut einer Befragung im Jahre 2012 war der Umgang mit Antithrombotika bei dermatochirurgischen Eingriffen in Deutschland sehr heterogen. 2014 wurde erstmals eine evidenzbasierte Leitlinie zu diesem Thema veröffentlicht.