Summary
Background
A validated tool for the dynamic severity assessment of hidradenitis suppurativa/acne inversa (HS) is lacking.
Objectives
To develop and validate a novel dynamic scoring system to ...assess the severity of HS.
Methods
A Delphi voting procedure was conducted among the members of the European Hidradenitis Suppurativa Foundation (EHSF) to achieve consensus towards an initial HS Severity Score System (HS4). Strengths and weaknesses of HS4 were examined by a multicentre prospective study. Multivariate logistic regression, discriminant analysis and receiver operating characteristic curves, as well as examination for correlation (Spearman's rho) and agreement (Cohen's kappa) with existing scores, were engaged to recognize the variables for a new International HS4 (IHS4) that was established by a second Delphi round.
Results
Consensus HS4 was based on number of skin lesions, number of skin areas involved and Dermatology Life Quality Index (DLQI), and was evaluated by a sample of 236 patients from 11 centres. Subsequently, a multivariate regression model calculated adjusted odds ratios for several clinical signs. Nodules, abscesses and draining tunnels resulted as the scoring variables. Three candidate scores were presented to the second Delphi round. The resulting IHS4 score is arrived at by the number of nodules (multiplied by 1) plus the number of abscesses (multiplied by 2) plus the number of draining tunnels (multiplied by 4). A total score of 3 or less signifies mild, 4–10 signifies moderate and 11 or higher signifies severe disease. Cohen's kappa was fair (κ = 0·32) compared with Hurley classification, and moderate (κ = 0·49) compared with Expert Opinion. Correlation was good (ρ > 0·6) with Hurley classification, Expert Opinion, Physician's Global Assessment and Modified Sartorius score, and moderate for DLQI (ρ = 0·36).
Conclusions
The novel IHS4 is a validated tool to dynamically assess HS severity and can be used both in real‐life and the clinical trials setting.
What's already known about this topic?
The modified Sartorius score, Hurley classification and Physician's Global Assessment have been used to assess severity of hidradenitis suppurativa.
However, these are often either difficult to use in daily clinical practice or static and generally poorly validated.
What does this study add?
The proposed score is a systematically constructed, validated and simple tool to assess disease severity, and can be adapted both to clinical research and daily practice.
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Summary
Background
Evidence for the effectiveness of vitiligo treatments is limited.
Objectives
To determine the effectiveness of (i) handheld narrowband UVB (NB‐UVB) and (ii) a combination of potent ...topical corticosteroid (TCS) and NB‐UVB, compared with TCS alone, for localized vitiligo.
Methods
A pragmatic, three‐arm, placebo‐controlled randomized controlled trial (9‐month treatment, 12‐month follow‐up). Adults and children, recruited from secondary care and the community, aged ≥ 5 years and with active vitiligo affecting < 10% of skin, were randomized 1 : 1 : 1 to receive TCS (mometasone furoate 0·1% ointment + dummy NB‐UVB), NB‐UVB (NB‐UVB + placebo TCS) or a combination (TCS + NB‐UVB). TCS was applied once daily on alternating weeks; NB‐UVB was administered on alternate days in escalating doses, adjusted for erythema. The primary outcome was treatment success at 9 months at a target patch assessed using the participant‐reported Vitiligo Noticeability Scale, with multiple imputation for missing data. The trial was registered with number ISRCTN17160087 on 8 January 2015.
Results
In total 517 participants were randomized to TCS (n = 173), NB‐UVB (n = 169) and combination (n = 175). Primary outcome data were available for 370 (72%) participants. The proportions with target patch treatment success were 17% (TCS), 22% (NB‐UVB) and 27% (combination). Combination treatment was superior to TCS: adjusted between‐group difference 10·9% (95% confidence interval 1·0%–20·9%; P = 0·032; number needed to treat = 10). NB‐UVB alone was not superior to TCS: adjusted between‐group difference 5·2% (95% CI − 4·4% to 14·9%; P = 0·29; number needed to treat = 19). Participants using interventions with ≥ 75% expected adherence were more likely to achieve treatment success, but the effects were lost once treatment stopped. Localized grade 3 or 4 erythema was reported in 62 (12%) participants (including three with dummy light). Skin thinning was reported in 13 (2·5%) participants (including one with placebo ointment).
Conclusions
Combination treatment with home‐based handheld NB‐UVB plus TCS is likely to be superior to TCS alone for treatment of localized vitiligo. Combination treatment was relatively safe and well tolerated but was successful in only around one‐quarter of participants.
What is already known about this topic?
Vitiligo is a common condition, and can have a considerable psychological impact.
Topical corticosteroids (TCSs) are standard care for vitiligo. Narrowband ultraviolet B (NB‐UVB) is a widely used treatment, but it is usually only available as full‐body treatment, delivered in secondary care.
Evidence for the use of handheld NB‐UVB in combination with TCSs is very limited.
What does this study add?
For people with localized nonsegmental vitiligo, combination therapy with NB‐UVB and a potent TCS (mometasone furoate 0·1% ointment) is likely to result in improved treatment response compared with potent TCS alone, but was successful in only around one‐quarter of participants.
Both treatments are relatively safe and well tolerated when used over a period of 9 months.
Treatment effects start to be lost soon after cessation of treatment, so ways of maintaining treatment response once treatment is stopped need further investigation
Linked Comment: Wolkerstorfer. Br J Dermatol 2021; 184:790.
Summary
Background
Epidemiology data regarding hidradenitis suppurativa (HS) are conflicting and prevalence estimates vary 80‐fold, from 0·05% in a population‐based study to 4%.
Objectives
To assess ...the hypothesis that previous population‐based studies underestimated true HS prevalence by missing undiagnosed cases.
Methods
We performed a population‐based observational and case–control study using the U.K. Clinical Practice Research Datalink (CPRD) linked to hospital episode statistics data. Physician‐diagnosed cases in the CPRD were identified from specific Read codes. Algorithms identified unrecognized ‘proxy’ cases, with at least five Read code records for boils in flexural skin sites. Validation of proxy cases was undertaken with general practitioner (GP) questionnaires to confirm criteria‐diagnosed cases. A case–control study assessed disease associations.
Results
On 30 June 2013, 23 353 physician‐diagnosed HS cases were documented in 4 364 308 research‐standard records. In total, 68 890 proxy cases were identified, reduced to 10 146 criteria‐diagnosed cases after validation, extrapolated from 107 completed questionnaires (61% return rate). Overall point prevalence was 0·77% 95% confidence interval (CI) 0·76–0·78%. An additional 18 417 cases had a history of one to four flexural skin boils. In physician‐diagnosed cases, odds ratios (ORs) for current smoker and obesity (body mass index > 30 kg m‐2) were 3·61 (95% CI 3·44–3·79) and 3·29 (95% CI 3·14–3·45). HS was associated with type 2 diabetes, Crohn disease, hyperlipidaemia, acne and depression, and not associated with ulcerative colitis or polycystic ovary syndrome.
Conclusions
Contrary to results of previous population‐based studies, HS is relatively common, with a U.K. prevalence of 0·77%, one‐third being unrecognized, criteria‐diagnosed cases using the most stringent disease definition. If individuals with probable cases are included, HS prevalence rises to 1·19%.
What's already known about this topic?
Previous population‐based studies suggest that the prevalence of hidradenitis suppurativa (HS) may be as low as 0·05% but existing studies have not quantified undiagnosed cases.
What does this study add?
Analysis of 4·3 million research‐standard records in the U.K. Clinical Practice Research Datalink demonstrates a HS prevalence of 0·77% using the most stringent disease definition 95% confidence interval (CI) 0·76–0·78%, one‐third being undiagnosed cases, rising to 1·19% (95% CI 1·18–1·20%) if probable cases are included.
Linked Comment: Sbidian. Br J Dermatol 2018; 178:831–832.
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On May 21, 2019 at 03:02:29 UTC Advanced LIGO and Advanced Virgo observed a short duration gravitational-wave signal, GW190521, with a three-detector network signal-to-noise ratio of 14.7, and an ...estimated false-alarm rate of 1 in 4900 yr using a search sensitive to generic transients. If GW190521 is from a quasicircular binary inspiral, then the detected signal is consistent with the merger of two black holes with masses of 85_{-14}^{+21} M_{⊙} and 66_{-18}^{+17} M_{⊙} (90% credible intervals). We infer that the primary black hole mass lies within the gap produced by (pulsational) pair-instability supernova processes, with only a 0.32% probability of being below 65 M_{⊙}. We calculate the mass of the remnant to be 142_{-16}^{+28} M_{⊙}, which can be considered an intermediate mass black hole (IMBH). The luminosity distance of the source is 5.3_{-2.6}^{+2.4} Gpc, corresponding to a redshift of 0.82_{-0.34}^{+0.28}. The inferred rate of mergers similar to GW190521 is 0.13_{-0.11}^{+0.30} Gpc^{-3} yr^{-1}.
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Summary
The recent hidradenitis suppurativa (HS) Cochrane review identified outcome measure heterogeneity as an important issue to address when designing future HS trials. Our objective was to follow ...the Harmonising Outcome Measures for Eczema (HOME) roadmap, by performing a systematic review of HS outcome measure instruments to inform the development of an HS core outcome set. We performed a systematic review to identify validation evidence for outcome measure instruments used in HS randomized controlled trials (RCTs), and assessed the methodological quality of all HS outcome measure validity studies using the COnsensus‐based Standards for the selection of health Measurement INstruments (COSMIN) checklist. The 12 RCTs included in the Cochrane review utilized 30 outcome measure instruments, including 16 physician‐reported instruments, 11 patient‐reported instruments and three composite measures containing elements of both. Twenty‐seven (90%) of the instruments lacked any validation data. Two further instruments have been developed and partially validated. Of the seven studies meeting our inclusion criteria, six were of ‘fair’ or ‘poor’ methodological quality, in part because most of the studies were not primarily designed for instrument validation. The HiSCR instrument is supported by good‐quality validation data, but there are gaps, including assessment of internal consistency, inter‐rater reliability and minimal clinically important difference, and convergent validity fell below the acceptable range for some comparisons. Multiple, usually unvalidated, outcome measure instruments have been used in HS RCTs. Where validation evidence is available there are issues of low methodological quality or incomplete validity assessment and so, currently, no instruments can be fully recommended.
What's already known about this topic?
The recent hidradenitis suppurativa (HS) Cochrane review identified heterogeneity of outcome measure instruments as an important obstacle in the design of future HS trials.
The Harmonising Outcome Measures for Eczema (HOME) initiative provides a roadmap for developing a core outcomes set in HS.
What does this study add?
Twenty‐seven of the 30 outcome measure instruments used in HS randomized controlled trials are not supported by any formal validation data.
Where available, validation evidence is generally of relatively low methodological quality, or remains incomplete, and so no instruments can be fully recommended currently.
Linked Comment: van der Zee et al. Br J Dermatol 2016; 175:242.
Summary
Background
Monitoring disease activity over time is a prerequisite for clinical practice and research. Valid and reliable outcome measurement instruments (OMIs) and staging systems provide ...researchers and clinicians with benchmark tools to assess the primary and secondary outcomes of interventional trials and to guide treatment selection properly.
Objectives
To investigate inter‐rater reliability and agreement in instruments currently used in hidradenitis suppurativa (HS), with dermatologists experienced in HS as the rater population of interest.
Methods
In a prospective completely balanced design, 24 patients with HS underwent a physical examination by 12 raters (288 assessments) using nine instruments. The results were analysed using generalized linear mixed models.
Results
For the staging systems, the study found good inter‐rater reliability for Hurley staging in the axillae and gluteal region, moderate inter‐rater reliability for Hurley staging in the groin and for Physician's Global Assessment, and fair inter‐rater reliability for refined Hurley staging and the International HS Severity Scoring System. For all the tested OMIs, the observed intervals for limits of agreement were very wide relative to the ranges of the scales.
Conclusions
The very wide intervals for limits of agreement imply that substantial changes are needed in clinical research in order to rule out measurement error. The results illustrate a difficulty, even for experienced HS experts, to agree on the type and number of lesions when evaluating disease severity. The apparent caveats call for global efforts, such as the HIdradenitis SuppuraTiva cORe outcomes set International Collaboration (HISTORIC) to reach consensus on how best to measure physical signs of HS reliably in randomized trials.
What's already known about this topic?
Without valid and reliable instruments to measure outcomes, researchers and clinicians lack the necessary benchmarks to assess primary and secondary end points of interventional trials properly.
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease.
Several outcome measure instruments exist for HS, but their validation is generally incomplete or of relatively low methodological quality.
What does this study add?
Using a prospective completely balanced design this study examined inter‐rater reliability with HS‐experienced dermatologists as the rater population of interest.
The study did not find very good reliability for any included instrument or lesion counts.
This study illustrates the difficulty in finding agreement on the type and number of HS lesions, even among experts.
The results question whether physical signs are best measured by a traditional physician lesion count instrument.
What are the clinical implications of this work?
For staging, Hurley staging and physician global visual analogue scale proved to be acceptable instruments in terms of inter‐rater reliability.
For the instruments designed to measure changes in health status, our study illustrates how difficult it is, even for experts, to measure the physical signs of HS using a simple rater counting.
Consequently, other assessment methods of physicals signs, such as ultrasound evaluation, require consideration.
Linked Comment: Oosterhaven. Br J Dermatol 2019; 181:438–439.
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Summary
Background
Economic evidence for vitiligo treatments is absent.
Objectives
To determine the cost‐effectiveness of (i) handheld narrowband ultraviolet B (NB‐UVB) and (ii) a combination of ...topical corticosteroid (TCS) and NB‐UVB compared with TCS alone for localized vitiligo.
Methods
Cost‐effectiveness analysis alongside a pragmatic, three‐arm, placebo‐controlled randomized controlled trial with 9 months’ treatment. In total 517 adults and children (aged ≥ 5 years) with active vitiligo affecting < 10% of skin were recruited from secondary care and the community and were randomized 1: 1: 1 to receive TCS, NB‐UVB or both. Cost per successful treatment (measured on the Vitiligo Noticeability Scale) was estimated. Secondary cost–utility analyses measured quality‐adjusted life‐years using the EuroQol 5 Dimensions 5 Levels for those aged ≥ 11 years and the Child Health Utility 9D for those aged 5 to < 18 years. The trial was registered with number ISRCTN17160087 on 8 January 2015.
Results
The mean ± SD cost per participant was £775 ± 83·7 for NB‐UVB, £813 ± 111.4 for combination treatment and £600 ± 96·2 for TCS. In analyses adjusted for age and target patch location, the incremental difference in cost for combination treatment compared with TCS was £211 (95% confidence interval 188–235), corresponding to a risk difference of 10·9% (number needed to treat = 9). The incremental cost was £1932 per successful treatment. The incremental difference in cost for NB‐UVB compared with TCS was £173 (95% confidence interval 151–196), with a risk difference of 5·2% (number needed to treat = 19). The incremental cost was £3336 per successful treatment.
Conclusions
Combination treatment, compared with TCS alone, has a lower incremental cost per additional successful treatment than NB‐UVB only. Combination treatment would be considered cost‐effective if decision makers are willing to pay £1932 per additional treatment success.
What is already known about this topic?
Vitiligo is a common skin condition with significant psychological impact.
Topical corticosteroids (TCS) are standard care for vitiligo. Narrowband ultraviolet B (NB‐UVB) is only available in secondary care as full‐body treatment.
Economic evidence for handheld NB‐UVB in combination with TCS is absent.
What does this study add?
Combination treatment, compared with TCS alone, has the lowest incremental cost per successful treatment. Whether this is considered cost‐effective depends on decision makers’ judgement on how much they are willing to pay to achieve a successful treatment.
Generic utility instruments, such as the EuroQol 5 Dimensions 5 Levels, may not be appropriate for vitiligo studies due to high ceiling effects. Measurement of quality of life for this condition warrants further research.
This study provides results that can be compared with those of new emerging vitiligo treatments.
Summary
Background
There is no consensus on core outcome domains for hidradenitis suppurativa (HS). Heterogeneous outcome measure instruments in clinical trials likely leads to outcome‐reporting bias ...and limits the ability to synthesize evidence.
Objectives
To achieve global multistakeholder consensus on a core outcome set (COS) of domains regarding what to measure in clinical trials for HS.
Methods
Six stakeholder groups participated in a Delphi process that included five anonymous e‐Delphi rounds and four face‐to‐face consensus meetings to reach consensus on the final COS. The aim was for a 1 : 1 ratio of patients to healthcare professionals (HCPs).
Results
A total of 41 patients and 52 HCPs from 19 countries in four continents participated in the consensus process, which yielded a final COS that included five domains: pain, physical signs, HS‐specific quality of life, global assessment and progression of course. A sixth domain, symptoms, was highly supported by patients and not by HCPs but is recommended for the core domain set.
Conclusions
Routine adoption of the COS in future HS trials should ensure that core outcomes of importance to both patients and HCPs are collected.
What's already known about this topic?
Outcome measure instruments used for hidradenitis suppurativa (HS) are markedly heterogeneous with 30 instruments recently found in 12 randomized trials.
Lack of consensus regarding outcome measure instruments limits evidence synthesis and increases the risk of outcome reporting bias.
A core domain set is an agreed minimum set of what to measure that should be reported in all clinical trials of a specific condition.
What does this study add?
Our study provides global multistakeholder consensus on core outcome domains for HS.
The final core domain set includes five domains: pain, physical signs, HS‐specific quality of life, global assessment and progression of course.
A sixth domain, symptoms, was highly supported by patients and not by healthcare professionals; it is recommended by the steering committee as an additional core domain, in the context of being a patient‐reported domain.
What are the clinical implications of this work?
The routine adoption of this core outcome set in future HS trials should ensure that outcome domains of importance to both patients and HCPs are included and reported.
Linked Editorial: Kottner & Schmitt. Br J Dermatol 2018; 179:549–550.
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Here, we present a search for subsolar mass ultracompact objects in data obtained during Advanced LIGO's second observing run. In contrast to a previous search of Advanced LIGO data from the first ...observing run, this search includes the effects of component spin on the gravitational waveform. We identify no viable gravitational-wave candidates consistent with subsolar mass ultracompact binaries with at least one component between $0.2 M_{⊙}-1.0 M_{⊙}$. We use the null result to constrain the binary merger rate of ($0.2 M_{⊙}, 0.2 M_{⊙}$) binaries to be less than $3.7×10^{5} Gpc^{-3} yr^{-1}$ and the binary merger rate of ($1.0 M_{⊙}, 1.0 M_{⊙}$) binaries to be less than $5.2×10^{3} Gpc^{-3} yr^{-1}$. Subsolar mass ultracompact objects are not expected to form via known stellar evolution channels, though it has been suggested that primordial density fluctuations or particle dark matter with cooling mechanisms and/or nuclear interactions could form black holes with subsolar masses. Assuming a particular primordial black hole (PBH) formation model, we constrain a population of merging $0.2 M_{⊙}$ black holes to account for less than 16% of the dark matter density and a population of merging $1.0 M_{⊙}$ black holes to account for less than 2% of the dark matter density. We discuss how constraints on the merger rate and dark matter fraction may be extended to arbitrary black hole population models that predict subsolar mass binaries.
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