Clinical consequences of antibody formation, serum concentrations, and HLA-Cw6 status in psoriasis patients on Ustekinumab

Background: Ustekinumab for the treatment of psoriasis is currently administered in a standard dosing regimen. However, some patients tend to benefit from alternative dosing regimens, a step toward personalized medicine. Methods: To investigate the role of ustekinumab serum concentrations, anti-ustekinumab antibodies [AUA] and HLA-Cw6 status as tools for optimizing ustekinumab treatment, a multicenter prospective cohort study was conducted at an academic hospital with affiliated nonacademic hospitals in Belgium (cohort 1) and 2 academic hospitals in the Netherlands (cohort 2 and 3). Patients with plaque-type psoriasis were eligible if treated with ustekinumab for >16 weeks. Serum samples and Psoriasis Area and Severity Index scores were obtained at baseline, week 16, 28, 40, 52, and/or >64 of ustekinumab treatment. Results: A total of 137 patients with 229 observations for serum concentrations and AUA and 61 observations for HLA-Cw6 status were included. Presence of AUA (prevalence of 8.7%) was significantly associated with a diminished clinical response (P = 0.032). The median ustekinumab trough concentration was 0.3 mcg/mL (<0.02-3.80). No differences in serum concentrations were observed between moderate to good responders and nonresponders (P = 0.948). Serum trough concentrations were not affected by methotrexate comedication. Prevalence of HLA-Cw6 positivity was 41% with no statistically significant difference in clinical response between HLA-Cw6-positive and HLA-Cw6-negative patients (P = 0.164). Conclusions: The presence of AUA was associated with treatment failure in this patient population; measurement of AUA may therefore be a candidate marker for personalized pharmacotherapy. The clinical utility of ustekinumab serum trough concentrations or HLA-Cw6 status determination remains less clear. Further exploration on the potential of measuring ustekinumab serum concentrations and other biomarkers in predicting therapy outcomes should be encouraged

How to write a Critically Appraised Topic: evidence to underpin routine clinical practice

Critically appraised topics (CATs) are essential tools for busy clinicians who wish to ensure that their daily clinical practice is underpinned by evidence-based medicine. CATs are short summaries of the most up-to-date, high-quality available evidence that is found using thorough structured methods. They can be used to answer specific, patient-orientated questions that arise recurrently in real-life practice. This article provides readers with a detailed guide to performing their own CATs. It is split into four main sections reflecting the four main steps involved in performing a CAT: formulation of a focused question, a search for the most relevant and highest-quality evidence, critical appraisal of the evidence and application of the results back to the patient scenario. As well as helping to improve patient care on an individual basis by answering specific clinical questions that arise, CATs can help spread and share knowledge with colleagues on an international level through publication in the evidence-based dermatology section of the British Journal of Dermatolog

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

BackgroundComparative, 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.ObjectivesTo 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.MethodsProposals 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.ResultsA 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.ConclusionsThis 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)

Report from the third international consensus meeting to harmonise core outcome measures for atopic eczema/dermatitis clinical trials (HOME).

This report provides a summary of the third meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in San Diego, CA, U.S.A., 6-7 April 2013 (HOME III). The meeting addressed the four domains that had previously been agreed should be measured in every eczema clinical trial: clinical signs, patient-reported symptoms, long-term control and quality of life. Formal presentations and nominal group techniques were used at this working meeting, attended by 56 voting participants (31 of whom were dermatologists). Significant progress was made on the domain of clinical signs. Without reference to any named scales, it was agreed that the intensity and extent of erythema, excoriation, oedema/papulation and lichenification should be included in the core outcome measure for the scale to have content validity. The group then discussed a systematic review of all scales measuring the clinical signs of eczema and their measurement properties, followed by a consensus vote on which scale to recommend for inclusion in the core outcome set. Research into the remaining three domains was presented, followed by discussions. The symptoms group and quality of life groups need to systematically identify all available tools and rate the quality of the tools. A definition of long-term control is needed before progress can be made towards recommending a core outcome measure

Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial

markdownabstract__Background:__ The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory diseases. __Methods:__ This is an investigator-initiated, multicenter randomized controlled trial (RCT) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis. The primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability, and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. A total of 93 patients is desired to meet an adequate sample size. In our experience, the main limitation for recruitment is prior adalimumab therapy and intolerability or toxicity for methotrexate in the past. __Discussion:__ OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable clinical data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analyzed in order to support the development of a more personalized approach for this targeted therapy. Trial registration:NTR4499. Registered on 7 April 2014

Patients with atopic dermatitis with filaggrin loss-of-function mutations show good but lower responses to immunosuppressive treatment

Filaggrin (FLG) mutations are a strong risk factor to develop atopic dermatitis (AD). However, the relationship between FLG mutations and treatment outcome in AD has not been thoroughly studied. To investigate whether FLG mutations influence immunosuppressive treatment outcome in AD, we studied the effect of FLG mutations in patients with severe AD participating in a single blinded randomized controlled trial (RCT) with methotrexate (MTX) or azathioprine (AZA) during a 24 weeks treatment regimen.((1)) Two years after randomization buccal mucosa swabs were collected from 36 of the 42 RCT patients (86%) to determine the FLG genotype status (R501X, 2282del4, R2447X, S3247X and 3321delA mutations). This article is protected by copyright. All rights reserve

Definition of treatment goals for moderate to severe psoriasis: a European consensus

Patients with moderate to severe psoriasis are undertreated. To solve this persistent problem, the consensus programme was performed to define goals for treatment of plaque psoriasis with systemic therapy and to improve patient care. An expert consensus meeting and a collaborative Delphi procedure were carried out. Nineteen dermatologists from different European countries met for a face-to-face discussion and defined items through a four-round Delphi process. Severity of plaque psoriasis was graded into mild and moderate to severe disease. Mild disease was defined as body surface area (BSA) &lt;= 10 and psoriasis area and severity index (PASI) &lt;= 10 and dermatology life quality index (DLQI) &lt;= 10 and moderate to severe psoriasis as (BSA &gt; 10 or PASI &gt; 10) and DLQI &gt; 10. Special clinical situations may change mild psoriasis to moderate to severe including involvement of visible areas or severe nail involvement. For systemic therapy of plaque psoriasis two treatment phases were defined: (1) induction phase as the treatment period until week 16; however, depending on the type of drug and dose regimen used, this phase may be extended until week 24 and (2) maintenance phase for all drugs was defined as the treatment period after the induction phase. For the definition of treatment goals in plaque psoriasis, the change of PASI from baseline until the time of evaluation (Delta PASI) and the absolute DLQI were used. After induction and during maintenance therapy, treatment can be continued if reduction in PASI is &gt;= 75%. The treatment regimen should be modified if improvement of PASI is &lt;50%. In a situation where the therapeutic response improved &gt;= 50% but &lt;75%, as assessed by PASI, therapy should be modified if the DLQI is &gt;5 but can be continued if the DLQI is &lt;= 5. This programme defines the severity of plaque psoriasis for the first time using a formal consensus of 19 European experts. In addition, treatment goals for moderate to severe disease were established. Implementation of treatment goals in the daily management of psoriasis will improve patient care and mitigate the problem of undertreatment. It is planned to evaluate the implementation of these treatment goals in a subsequent programme involving patients and physicians

Report from the fourth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative)

This article is a report of the fourth meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in Malmö, Sweden on 23–24 April 2015 (HOME IV). The aim of the meeting was to achieve consensus over the preferred outcome instruments for measuring patient-reported symptoms and quality of life for the HOME core outcome set for atopic eczema (AE). Following presentations, which included data from systematic reviews, consensus discussions were held in a mixture of whole group and small group discussions. Small groups were allocated a priori to ensure representation of different stakeholders and countries. Decisions were voted on using electronic keypads. For the patient-reported symptoms, the group agreed by vote that itch, sleep loss, dryness, redness/inflamed skin and irritated skin were all considered essential aspects of AE symptoms. Many instruments for capturing patient-reported symptoms were discussed [including the Patient-Oriented SCOring Atopic Dermatitis index, Patient-Oriented Eczema Measure (POEM), Self-Administered Eczema Area and Severity Index, Itch Severity Scale, Atopic Dermatitis Quickscore and the Nottingham Eczema Severity Score] and, by consensus, POEM was selected as the preferred instrument to measure patient-reported symptoms. Further work is needed to determine the reliability and measurement error of POEM. Further work is also required to establish the importance of pain/soreness and the importance of collecting information regarding the intensity of symptoms in addition to their frequency. Much of the discussion on quality of life concerned the Dermatology Life Quality Index and Quality of Life Index for Atopic Dermatitis; however, consensus on a preferred instrument for measuring this domain could not be reached. In summary, POEM is recommended as the HOME core outcome instrument for measuring AE symptoms

Report from the fifth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative)

This is the report from the fifth meeting of the Harmonising Outcome Measures for Eczema initiative (HOME V). The meeting was held on 12–14 June 2017 in Nantes, France, with 81 participants. The main aims of the meeting were (i) to achieve consensus over the definition of the core domain of long-term control and how to measure it and (ii) to prioritize future areas of research for the measurement of the core domain of quality of life (QoL) in children. Moderated whole-group and small-group consensus discussions were informed by presentations of qualitative studies, systematic reviews and validation studies. Small-group allocations were performed a priori to ensure that each group included different stakeholders from a variety of geographical regions. Anonymous whole-group voting was carried out using handheld electronic voting pads according to predefined consensus rules. It was agreed by consensus that the long-term control domain should include signs, symptoms, quality of life and a patient global instrument. The group agreed that itch intensity should be measured when assessing long-term control of eczema in addition to the frequency of itch captured by the symptoms domain. There was no recommendation of an instrument for the core outcome domain of quality of life in children, but existing instruments were assessed for face validity and feasibility, and future work that will facilitate the recommendation of an instrument was agreed upon. The Harmonising Outcome Measures for Eczema (HOME) initiative is an international group working together to develop a core outcome set (COS) for clinical trials in eczema (synonymous with atopic eczema and atopic dermatitis). HOME is coordinated from the Centre of Evidence Based Dermatology, University of Nottingham, U.K. Participation in HOME is open to anyone with an interest in outcomes for eczema. A COS is the agreed upon minimum set of instruments that should be included in all clinical trials for a particular condition. Use of a COS does not preclude using other instruments; other domains and instruments can also be included to meet the specific requirements of individual trials. COS initiatives are active across many fields of medicine and should enable better synthesis of trial data and reduce selective outcome reporting bias. The HOME initiative follows the best current guidance on developing a COS. Four core domains have been identified: clinician-reported signs; patient-reported symptoms; quality of life; and long-term control. The core outcome measurement instruments for clinician-reported signs and patient-reported symptoms have been established: the Eczema Area and Severity Index (EASI) for measuring clinician reported signs was agreed on at the HOME III meeting, and the Patient-Oriented Eczema Measure (POEM) was chosen to measure patient-reported symptoms at the HOME IV meeting. This is a report from the fifth consensus meeting of the HOME initiative (HOME V), which was held on 12–14 June 2017 in Nantes, France. The local organizers were Sebastien Barbarot and Jean-Francois Stalder of Nantes University Hospital, France

Initial results of secukinumab drug survival in patients with psoriasis: A multicentre daily practice cohort study

Interleukin 17-antagonist secukinumab demonstrated high efficacy for treatment of psoriasis in randomized controlled trials. However, performance in daily practice may differ from trials. Drug survival is a comprehensive outcome covering effectiveness and safety, suitable for analyses of daily practice. The aim of this study was to evaluate drug survival of secukinumab in a daily practice psoriasis cohort. Data were collected from 13 hospitals. Drug survival was analysed using Kaplan–Meier survival curves, split for reason of discontinuation. In total, 196 patients were included (83% biologic experienced). Overall, 12 and 18 months drug survival of secukinumab was 76% and 67%, respectively, and was mostly determined by ineffectiveness. There was a trend towards shorter drug survival in women and in biologic experienced patients. Thirteen percent of patients experienced at least one episode of fungal infection. This is one of the first studies of drug survival of secukinumab in patients with psoriasis treated in daily practice