Steps towards implementation of protocolized dose reduction of adalimumab, etanercept and ustekinumab for psoriasis in daily practice.

BACKGROUND: Dose reduction (DR) of adalimumab, etanercept and ustekinumab has proven to be (cost-)effective in psoriasis patients with low disease activity. Further implementation is needed to establish application of DR for eligible patients. OBJECTIVES: To evaluate the implementation of protocolized biologic DR in daily practice. METHODS: A pilot implementation study was performed in 3 hospitals during 6 months. By combining education and protocol development, involved healthcare providers (HCPs) were directed toward the adoption of protocolized DR. DR of adalimumab, etanercept, and ustekinumab was achieved by stepwise injection interval prolongation. Implementation outcomes (fidelity, feasibility) were assessed. Factors for optimizing implementation were explored in interviews with HCPs. Uptake was measured in patients by chart review. RESULTS: The implementation strategy was executed as planned. Implementation fidelity was less than 100% as not all provided tools were used across study sites. HCPs indicated the feasibility of implementing protocolized DR, although time investment was needed. Identified additional factors for successful implementation included support for patients, uptake of DR into guidelines, and supportive electronic health record systems. During the 6 months intervention period, 52 patients were eligible for DR of whom 26 (50%) started DR. The proposed DR protocol was followed in 22/26 patients (85%) on DR. CONCLUSION: Additional staff for support, extra time during consultations, education on DR for HCPs and patients, and effective tools such as a feasible protocol can lead to more patients on biologic DR.

Drug Survival, Safety, and Effectiveness of Biologics in Older Patients with Psoriasis: A Comparison with Younger Patients-A BioCAPTURE Registry Study.

BACKGROUND: Psoriasis is a common inflammatory disease in any age group, but also in older patients (≥ 65 years of age). Since older patients are often excluded from clinical trials, limited data specifically on this growing population are available, e.g. regarding the safety and performance of biological treatment. AIMS: We aimed to give insight into this specific population by comparing the drug survival and safety of biologics in older patients with that in younger patients. METHODS: In this real-world observational study, data from 3 academic and 15 non-academic centers in The Netherlands were extracted from the prospective BioCAPTURE registry. Biologics included in this study were tumor necrosis factor (TNF)-α, interleukin (IL)-17, IL-12/23, and IL-23 inhibitors. Patients were divided into two age groups: ≥ 65 years and < 65 years. The Charlson Comorbidity Index (CCI) was used to measure comorbid disease status, and all adverse events (AEs) that led to treatment discontinuation were classified according to the Medical Dictionary for Regulatory Activities (MedDRA) classification. All AEs that led to treatment discontinuation were studied to check whether they could be classified as serious AEs (SAEs). Kaplan-Meier survival curves for overall 5-year drug survival and split according to reasons of discontinuation (ineffectiveness or AEs) were constructed. Cox regression models were used to correct for possible confounders and to investigate associations with drug survival in both age groups separately. Psoriasis Area and Severity Index (PASI) scores during the first 2 years of treatment and at the time of treatment discontinuation were assessed and compared between age groups. RESULTS: A total of 890 patients were included, of whom 102 (11.4%) were aged ≥ 65 years. Body mass index, sex, and distribution of biologic classes (e.g. TNFα, IL12/23) were not significantly different between the two age groups. A significantly higher CCI score was found in older patients, indicative of more comorbidity (p < 0.001). The 5-year ineffectiveness-related drug survival was lower for older patients (44.5% vs. 60.5%; p = 0.006), and the 5-year overall (≥ 65 years: 32.4% vs. < 65 years: 42.1%; p = 0.144) and AE-related (≥ 65 years: 82.1% vs. < 65 years: 79.5%; p = 0.913) drug survival was comparable between age groups. Of all AEs (n = 155) that led to discontinuation, 16 (10.3%) were reported as SAEs but these only occurred in younger patients. After correcting for confounders, the same trends were observed in the drug survival outcomes. Linear regression analyses on PASI scores showed no statistical differences at 6, 12, 18, and 24 months of treatment between age groups. CONCLUSIONS: This study in a substantial, well-defined, prospective cohort provides further support that the use of biologics in older patients seems well-tolerated and effective. Biologic discontinuation due to AEs did not occur more frequently in older patients. Older patients discontinued biologic treatment more often due to ineffectiveness, although no clear difference in PASI scores was observed. More real-world studies on physician- and patient-related factors in older patients are warranted.

Predictive factors for Day 7 positive patch test readings at a secondary referral centre.

Background: Based on studies at tertiary centres it is known that patch test reading on Day (D) 7 may show additional positive reactions. Female gender, higher age and allergen groups of topicals and corticosteroids were identified as predictive factors. Objectives: The first aim was to study the value of reading patch tests on D2, D3 and D7 at a secondary referral centre. The second aim was to investigate the predictive potential of the factors sex, age, atopic dermatitis, body location, allergen group and clinical relevance for a positive reaction only on D7. Methods: Retrospective data from patients tested between 2013 and 2016 were evaluated. The factors sex, age, atopic dermatitis, body location, allergen group and clinical relevance were tested by regression analysis. Results: Two hundred and sixty-three out of a total of 396 patients had a positive reaction only on D2, D3 and D7 in 14 (2.5%), 152 (27.5%) and 61 (11.0%) occasions, observed in 10 (2.5%), 108 (27.3%) and 51 (12.9%) patients, respectively. These reactions were deemed relevant in 0 (0%), 12 (2.2%) and 9 (1.6%) occasions, observed 0 (0%), 11 (2.8%) and 9 (2.3%) patients, respectively. Higher age and allergen groups of metals, fragrances and resins were predictive for late positive reactions. Conclusions: D7 patch test reading should also be routinely adopted at secondary referral centres. D7 positive reactions were associated with higher age and sensitization to metals, fragrances and resins.

A Randomised Controlled Trial of Consent Procedures for the Use of Residual Tissues for Medical Research: Preferences of and Implications for Patients, Research and Clinical Practice.

BACKGROUND: Despite much debate, there is little evidence on consequences of consent procedures for residual tissue use. Here, we investigated these consequences for the availability of residual tissue for medical research, clinical practice, and patient informedness. METHODS: We conducted a randomised clinical trial with three arms in six hospitals. Participants, patients from whom tissue had been removed for diagnosis or treatment, were randomised to one of three arms: informed consent, an opt-out procedure with active information provision (opt-out plus), and an opt-out procedure without active information provision. Participants received a questionnaire six weeks post-intervention; a subsample of respondents was interviewed. Health care providers completed a pre- and post-intervention questionnaire. We assessed percentage of residual tissue samples available for medical research, and patient and health care provider satisfaction and preference. Health care providers and outcome assessors could not be blinded. RESULTS: We randomised 1,319 patients, 440 in the informed consent, 434 in the opt-out plus, and 445 in the opt-out arm; respectively 60.7%, 100%, and 99.8% of patients' tissue samples could be used for medical research. Of the questionnaire respondents (N = 224, 207, and 214 in the informed consent, opt-out plus, and opt-out arms), 71%, 69%, and 31%, respectively, indicated being (very) well informed. By questionnaire, the majority (53%) indicated a preference for informed consent, whereas by interview, most indicated a preference for opt-out plus (37%). Health care providers (N = 35) were more likely to be (very) satisfied with opt-out plus than with informed consent (p = 0.002) or opt-out (p = 0.039); the majority (66%) preferred opt-out plus. CONCLUSION: We conclude that opt-out with information (opt-out plus) is the best choice to balance the consequences for medical research, patients, and clinical practice, and is therefore the most optimal consent procedure for residual tissue use in Dutch hospitals. TRIAL REGISTRATION: Dutch Trial Register NTR2982.

Paraneoplastic hypertrichosis lanuginosa acquisita: uncommon or overlooked?

Acquired hypertrichosis lanugo-type or hypertrichosis lanuginosa acquisita (HLA) is often associated with metabolic and endocrine disorders and use of certain drugs. The occurrence of HLA with malignancy was first noted in 1865, and it has since been described in 56 patients as a paraneoplastic syndrome both in women and in men. Sometimes HLA occurs concurrent with acanthosis nigricans, papillary hypertrophy of the tongue, and glossitis. The predominance of female cases is striking. Malignancy-associated HLA seems to occur especially in the age group 40-70 years. In women with HLA the most frequent malignancy is colorectal cancer, followed in order by lung cancer and breast cancer; in men lung cancer is the malignancy most frequently associated with HLA, followed by colorectal cancer. In 3 years we saw 10 patients with HLA, in whom the malignancy was usually metastasized. Only one patient had local disease; after removal of the primary tumour it took 2 years before the lanugo hair recurred. The aetiology of the syndrome is not clear: no specific hormonal or biochemical abnormalities have been identified as yet. The difference between hirsutism and lanugo-type hypertrichosis is discussed. It is stressed that the appearance of lanugo-type hypertrichosis in body areas previously perceived by patients as 'hairless' is highly indicative of internal malignancy.

Prediction of irritancy in the human skin irritancy model and occupational setting.

It is of great importance to find ways to lower the incidence of chronic irritant contact dermatitis. In this process, it is crucial to have insight in the factors that can predict irritancy. This review offers a survey of recent findings in the field of skin irritancy testing, discussed in the context of renowned, older work. Extrinsic and intrinsic factors that may determine the outcome of irritancy testing in the human skin model are considered. In recent decades, there has been increasing interest in factors influencing the development of occupational dermatitis by means of prospective cohort studies. This promising new area of investigation is discussed separately.

Irritancy ranking of anionic detergents using one-time occlusive, repeated occlusive and repeated open tests.

Discrepancies between the one-time patch test and the wash test regarding the ranking of irritancy of detergents have been found in the literature. The aim of the present study was to investigate the concordance of irritancy rank order of 4 anionic detergents tested by 3 different exposure methods, namely one-time occlusive, repeated short-time occlusive and repeated short-time open tests. These detergents were sodium cocoyl isethionate (ISE), sodium lauryl sulfate (SLS), soap and disodium lauryl 3-ethoxysulfosuccinate (SUC). The reactions were evaluated by visual scoring and by transepidermal water loss (TEWL) measurement. When scored visually, the rank order in the one-time test was: SOAP > or = SLS > or = ISE > SUC. The other test methods yielded a different order: SLS > ISE > or = SOAP > SUC. A similar rank order was obtained with TEWL measurement for all exposure methods. Generally, the concordance among the different exposure methods was high when evaluated by TEWL. The concordance was lower when evaluation was performed by visual scoring. The present study demonstrates that the choice of exposure model and evaluation method may be important variables influencing the outcome of irritancy testing. It is proposed that the repeated open test is the best way to simulate most in-use situations where the uncovered skin is exposed to detergents. The repeated occlusive test or the one-time patch test may be better to simulate situations in which the skin is occluded after irritation by detergents.

House-dust mite hypersensitivity, eczema, and other nonpulmonary manifestations of allergy.

The pathogenetic role of house-dust mites (HDM) in atopic dermatitis (AD) remains controversial, mainly because there is no common agreement on a provocation test that mimics ordinary exposure to HDM. This is related to the lack of knowledge of the mechanism of how HDM allergens enter the body. Theoretically, there are two possible routes: directly through the epidermis, or by inhalation. In "atopy patch testing", a concentrated HDM suspension is tested on the skin under occlusion. This method is frequently used as a model of the epidermal route. The clinical relevance of this method as a provocation test for AD is discussed. As opposed to atopy patch testing, we describe another method, namely, "allergen inhalation testing", as a model of the respiratory route. Twenty patients with AD underwent bronchial provocations with HDM extract in a double-blind, randomized, placebo-controlled study. In nine out of 20 AD patients, bronchial challenge with HDM evoked skin symptoms. All patients with HDM-induced dermatitis had a history of asthma, and as a group they had a higher mean total log-transformed IgE level than the "negative skin responders". Thus, the respiratory route may be relevant in the provocation of AD in a subset of AD patients and may represent an appropriate model of provocation in these patients. Furthermore, the role of HDM in urticaria and allergic rhinitis is discussed.

Irritancy of antiseptics tested by repeated open exposures on the human skin, evaluated by non-invasive methods.

The aim of the study was to test the irritancy of 6 antiseptics in an open exposure model. The following agents were tested in their normal use concentrations using open exposures, 2x daily for 4 days in 20 subjects: chlorhexidine 4% (CH), chlorhexidine 0.5% in ethanol 70% (CE), ethanol 70% (ET), iodine 1% in ethanol 70% (IE), povidone-iodine 10% (PI) and sodium hypochlorite 0.25% (SH). Responses were evaluated by visual scoring, subjective irritancy scoring, stratum corneum hydration (Corneometer), transepidermal water loss and laser Doppler flowmetry. Exposure to SH had to be discontinued after 4 applications because of severe subjective irritation. The same held true for IE (7 applications), whereas the other agents were exposed 8x. All evaluation methods showed SH to be significantly more irritating than IE, which was in turn more irritating than CH, CE, ET and PI. Thus, it can be concluded that CH, CE, ET and PI were non-irritating in this open exposure model.

Severity scoring of atopic dermatitis: a comparison of three scoring systems.

In studies on atopic dermatitis (AD), different scoring systems are used to evaluate the severity of the disease. The objective of this study was to investigate agreement between observers in the assessment of the overall severity of AD, and interobserver variation in the assessment of severity of AD for each scoring item separately, using the Simple Scoring System (SSS), the Scoring Atopic Dermatitis (SCORAD) index, and the Basic Clinical Scoring System (BCSS), and, furthermore, to investigate agreement between these three scoring systems in the assessment of the overall severity of AD. Eighty-two patients (42 male) with AD, mean age 13.4 years (range 0.2-67.0), were included. Agreement between observers in assessing the overall AD severity scores, and interobserver variation in assessing AD severity of each scoring item separately were determined in 34 of these 82 patients by two physicians scoring the severity of AD by the three scoring systems. To determine agreement between the scoring systems, one physician scored the severity of AD in all patients with the three scoring systems. Agreement between observers and agreement between the three scoring systems was calculated by Cohen's kappa (kappa) and by the measure of agreement according to Bland & Altman. kappa > 0.4 represents fair agreement; kappa > 0.75 excellent agreement. In addition, interobserver variation for each scoring item separately was calculated by the Wilcoxon signed rank test. The mean differences (d) and the limits of agreement (d +/- 2 SD of the differences) between observers by the SSS and the SCORAD were -0.82 +/- 5.58 and -0.28 +/- 7.49, respectively, kappa between observers for the BCSS was 0.90 (95% CI 0.79-1.03). By the SSS, significant interobserver variation was found in assessing the severity of excoriations (P = 0.02) and scales (P = 0.02). By the SCORAD, significant interobserver variation was found in assessing the severity of edema/population (P = 0.04), erythema (P = 0.04), and excoriations (P = 0.01). No significant interobserver variation was found in assessing the extent of AD. The mean difference and the limits of agreement between the SSS and the SCORAD were -4.17 +/- 9.52. kappa between the SSS and the BCSS was 0.21 (95% CI 0.09-0.33), and kappa between the SCORAD and the BCSS was 0.38 (95% CI 0.26-0.51). We found good agreement between observers assessing the overall severity of AD in the lower and higher scoring rates by the SSS and the SCORAD, and excellent agreement by the BCSS. Significant interobserver variation was found on the isolated intensity items scales, excoriations, edema/population, and erythema. We found poor agreement between the three scoring systems in assessing the overall severity of AD, indicating that the SSS, the SCORAD, and the BCSS cannot be used interchangeably to assess the overall severity of AD.

Guidelines on sodium lauryl sulfate (SLS) exposure tests. A report from the Standardization Group of the European Society of Contact Dermatitis.

This report reviews the clinical and histopathological reactions caused by sodium lauryl sulfate (SLS), and the non-invasive methods that can characterize these reactions. Furthermore, SLS exposure techniques and factors that may influence the outcome of these exposures are discussed. Finally, guidelines are introduced for each exposure technique in order to have a uniform approach to SLS testing in man. Since different study aims warrant different testing conditions, we have proposed 2 categories, namely susceptibility testing and provocative testing, tailored to the aim with which the study is performed.

Irritancy testing of sodium laurate and other anionic detergents using an open exposure model.

BACKGROUND/AIMS: The irritant potency of soap (sodium laurate, LAU) as opposed to other anionic detergents is not uniformly agreed upon. The aim of the study was to compare the irritancy of sodium laurate with that of sodium laurylsulphate (SLS), sodium cocoyl isethionate and disodium lauryl 3-ethoxysulphosuc-cinate by means of a 4-day repeated open exposure model in order to achieve a more realistic mimicry of daily practice. METHODS: The effects of the exposures were evaluated by: a) number of fulfilled exposures, b) visual score after exposures, and c) transepidermal water loss (TEWL) after exposures. RESULTS: In the majority of subjects, exposure to LAU had to be stopped because of burning sensations, erythema and/or scaling. The number of fulfilled exposures to LAU was lower than that of SLS. The other agents were tolerated very well. These less irritative agents had much lower visual scores and TEWL values after the repeated exposures compared with LAU and SLS. CONCLUSIONS: The explanation for the irritant nature of LAU in the present study might be the type of alkyl chain length distribution. Its 12-carbon chain content was ≤ 99%, and this agent can therefore be designated as pure sodium laurate. The same holds true for SLS. In daily practice, however, soap is a mixture of different - less irritant - chain lengths. Therefore, these findings cannot be extrapolated to commercially available soap bars.

Induction of atopic dermatitis by inhalation of house dust mite.

BACKGROUND: The pathogenetic role of house dust mite in atopic dermatitis remains controversial. Recent studies have shown that intensive epicutaneous contact of house dust mite allergen with premanipulated skin may induce dermatitis. It is, however, uncertain whether such conditions are met during natural contact with house dust mite. In the past, allergen inhalation has been suggested to induce exacerbation of atopic dermatitis. The aim of this study was to investigate whether dermatitis could be induced in patients with atopic dermatitis by inhalation of house dust mite. METHODS: Twenty patients with atopic dermatitis underwent bronchial provocations with house dust mite. Challenge tests were performed with four concentrations of a standardized house dust mite extract in a double-blind, randomized, placebo-controlled fashion. Spirometry was performed, and FEV1 was measured before and after each challenge dose. Changes in severity or localization of itching or erythema were recorded. RESULTS: In nine of 20 patients with atopic dermatitis bronchial challenge with house dust mite induced unequivocal skin symptoms after 1.5 to 17 hours. Pruritic erythematous lesions on noninvolved sites together with exacerbations of existing lesions were seen in three patients. Three patients had an exacerbation only, and three other patients had new lesions only. In eight of nine patients with house dust mite inhalation-induced dermatitis, skin symptoms were preceded by an early bronchial reaction. All patients with house dust mite-induced dermatitis had a history of asthma, and as a group they had a higher mean blood total IgE level compared with the "negative skin responders." One patient had pruritic erythema on the placebo challenge day, without a preceding bronchoconstrictive reaction. The number of patients who had a skin response on the house dust mite challenge day was significantly higher than the number of patients who had a skin response on the placebo day (p = 0.011 [Prescott's test]). CONCLUSIONS: The respiratory route may be relevant in the induction and exacerbation of dermatitis in a subset of patients with atopic dermatitis who have early bronchial reactions after house dust mite inhalation, a history of asthma, and an elevated blood total IgE level. Furthermore, these findings suggest a possible causal relationship between bronchial reactions and skin reactions.

Irritant susceptibility and weal and flare reactions to bioactive agents in atopic dermatitis. I. Influence of disease severity.

The two main pathogenetic characteristics of atopic dermatitis (AD) are: (i) antigen-dependent 'specific' reactivity, and (ii) altered non-immunological 'non-specific' reactivity. Our understanding of the role of non-specific reactivity is hampered by the fact that methods available for its quantification are limited. The aim of the present study was to assess the usefulness of two parameters as quantitative measures of non-specific skin reactivity in AD: (i) susceptibility to repeated epicutaneous exposure to an irritant (sodium lauryl sulphate, SLS), assessed by visual scoring and transepidermal water loss (TEWL) measurement, and (ii) reactivity to intracutaneously injected bioactive agents (codeine, FMLP, histamine, methacholine, substance P, trypsin), assessed by measurement of weal and flare size. These two parameters were tested in a group of AD patients, subdivided according to the severity of their dermatitis, and a control group. The visual score and TEWL after SLS exposure tended to be higher in the AD group than in the control group. Furthermore, visual score and post-exposure TEWL were positively correlated with the dermatitis severity score. Weal size following injection of codeine, histamine and substance P, and flare size following injection of all agents, except methacholine, were significantly lower in the AD group than in the control group. Negative correlations were found between weal and flare sizes and the dermatitis severity score. These findings can be explained by down-regulation of structures involved in weal and flare reactions. In conclusion, we propose that epicutaneous irritant susceptibility and reactivity to intracutaneous bioactive agents may be useful indicators of non-specific skin reactivity in AD.

Irritant susceptibility and weal and flare reactions to bioactive agents in atopic dermatitis. II. Influence of season.

Many atopic dermatitis (AD) patients have exacerbations of their skin disease in winter. These exacerbations may be caused by non-immunological 'non-specific' factors, such as low sun exposure and low temperature. To date, the influence of season on non-specific skin reactivity in AD has not been studied. The aim of the present investigation was to assess the influence of season on two skin parameters which may be used as quantitative measures of non-specific skin reactivity in AD: (i) susceptibility to repeated epicutaneous irritant (sodium lauryl sulphate, SLS) exposure, and (ii) weal and flare responses to intracutaneous injection of bioactive agents (codeine, FMLP, histamine, methacholine, substance P, trypsin). Four of 16 AD patients had dermatitis which was more severe in November than in July. Susceptibility to SLS was increased in November, both in AD patients and in control subjects. AD patients were more susceptible to SLS than control subjects in both July and November. Pre-exposure barrier function and skin hydration were reduced in November. The increased irritant susceptibility in November may be attributed to reduced barrier function, reduced skin hydration, and/or absence of the beneficial effects of ultraviolet light on cellular targets beneath the stratum corneum. Flare responses to codeine, methacholine, substance P and trypsin were also increased in November compared with July, especially in AD patients. However, smaller flares were observed in AD patients than in control subjects, in both July and November. Flare values were negatively correlated with dermatitis severity, probably because of down-regulation. Weal responses did not show a clear seasonal variation. Hence, susceptibility to epicutaneous irritants and reactivity to intracutaneously injected bioactive agents are parameters which may be used to monitor season-dependent changes in non-specific skin reactivity.