Psoriasis is a common chronic immune-mediated inflammatory skin disorder and begins in childhood in almost one-third of the cases. Although children present with the same clinical subtypes of ...psoriasis seen in adults, lesions may differ in distribution and morphology, and their clinical symptoms at presentation may vary from those reported by adult patients. Nevertheless, diagnosis of psoriasis is primarily based on clinical features. Pediatric psoriasis can have a profound long-term impact on the psychological health of affected children. Additionally, pediatric psoriasis has been associated with certain comorbidities, such as obesity, hypertension, hyperlipidemia, diabetes mellitus and rheumatoid arthritis, making early diagnosis and management essential. As guidelines are lacking and most (systemic) treatments are not approved for use in children, treatment of pediatric psoriasis remains a challenge. A prospective, multicenter, international registry is needed to evaluate these treatments in a standardized manner and ultimately to develop international guidelines on pediatric psoriasis. This article reviews current concepts in pediatric psoriasis including epidemiology, clinical features, diagnosis, the role of topical and systemic agents and the association with other morbidities in childhood.
Psoriasis is a common chronic inflammatory skin disease that results from interplay between the immune system and the epithelium. In the light of very successful anticytokine therapies for psoriasis, ...the focus has been directed towards the adaptive immune system. Expression studies, genetic studies and treatments specifically targeting players of the IL‐23/IL‐17 pathway, point at an important role for IL‐17 in the pathogenesis of psoriasis. IL‐17 stimulates the keratinocytes to produce psoriasis‐associated molecules, eventually leading to chronic skin inflammation. The current opinion is that IL‐17 is mainly produced by T cells, so‐called T‐helper 17 (Th17) cells, in psoriasis. However, evidence is accumulating that cells of the innate immune system, like neutrophils, mast cells, γδ T cells and innate lymphoid cells are the main source of IL‐17 in psoriasis, rather than T cells. The paradigm in this field of research is shifting. With this viewpoint article, we will address this novel concept by critically summarizing the current literature on this subject. In psoriatic arthritis and atherosclerosis, important conditions related to psoriasis, it was also found that the majority of IL‐17 is associated with cells of the innate immune system. This new concept changes our view of IL‐17. Blocking IL‐17 with targeted treatments might be more far‐reaching than previously thought; not only IL‐17 production by T cells but also by innate immune cells is blocked. Furthermore, therapies specifically targeting IL‐17 may not only improve psoriasis, but also comorbidity that is associated with the IL‐17 pathway, hereby preventing serious complications on the long term.
Summary
Background
Predictors for successful treatment are important for personalized medicine. Predictors for drug survival of biologics in psoriasis have been assessed, but not split for different ...biologics or for the reason of discontinuation.
Objectives
To compare long‐term drug survival between the outpatient biologics adalimumab, etanercept and ustekinumab in patients with psoriasis, and to elucidate predictors for overall survival and drug discontinuation due to ineffectiveness and side‐effects for each biologic separately.
Methods
Ten years of data were extracted from the prospective, multicentre, long‐term BioCAPTURE registry. Kaplan–Meier survival analyses and confounder‐corrected multivariate Cox regression analysis for drug survival (MCR‐DS) were performed to compare drug survival between biologics. To elucidate the predictors for different reasons of discontinuation for each biologic, univariate Cox regression analyses and multivariate Cox regression analyses for predictors (MCR‐P) with backward selection were performed.
Results
In total, 526 treatment episodes – 186 adalimumab, 238 etanercept and 102 ustekinumab – were included covering 1333 treatment years. MCR‐DS showed a significantly higher overall survival for ustekinumab compared with adalimumab and etanercept. MCR‐P showed that higher body mass index (BMI) was a predictor for discontinuation due to ineffectiveness for etanercept and ustekinumab and that female sex was a predictor for discontinuation due to side‐effects for adalimumab, etanercept and ustekinumab.
Conclusions
Ustekinumab has the highest confounder‐corrected long‐term drug survival in psoriasis treatment, compared with adalimumab and etanercept. Higher BMI is a predictor for discontinuation due to ineffectiveness in etanercept and ustekinumab, and female sex is a consistent predictor for discontinuation due to side‐effects in all three outpatient biologics.
What's already known about this topic?
Drug survival of biologics for psoriasis has been analysed, but few publications used prospective multicentre daily‐practice data.
These studies found that ustekinumab had the highest confounder‐corrected overall drug survival, but they did not split survival analysis for the different biologics or for different reasons of discontinuation.
Different predictors for overall drug survival were found in prospective and retrospective studies.
What does this study add?
This study reports on a longer period of drug survival than previous studies.
Ustekinumab has a higher confounder‐corrected drug survival and higher survival for discontinuation due to ineffectiveness and side‐effects than adalimumab and etanercept.
Higher body mass index (BMI) predicts discontinuation due to ineffectiveness in etanercept and ustekinumab, and female sex is a consistent predictor for discontinuation due to side‐effects in all three biologics.
Linked Comment: Egeberg. Br J Dermatol 2016; 175:247–248
Plain language summary available online
Biologics revolutionized the treatment of psoriasis. Biologics are given in a fixed dose, but lower doses might be possible.
To investigate whether dose reduction (DR) of biologics in patients with ...stable psoriasis is noninferior to usual care (UC).
This pragmatic, open-label, prospective, controlled, noninferiority randomized clinical trial was conducted from March 1, 2016, to July 22, 2018, at 6 dermatology departments in the Netherlands. A total of 120 patients with plaque psoriasis and stable low disease activity who were receiving treatment with adalimumab, etanercept, or ustekinumab were studied.
Patients were randomized 1:1 to DR (n = 60) or UC (n = 60). In the DR group, injection intervals were prolonged stepwise, leading to 67% and 50% of the original dose.
The primary outcome was between-group difference in disease activity corrected for baseline at 12 months compared with the predefined noninferiority margin of 0.5. Secondary outcomes were Psoriasis Area and Severity Index (PASI) score and health-related quality of life (including Dermatology Life Quality Index DLQI and Medical Outcomes Study 36-Item Short Form Health Survey scores), proportion of patients with short and persistent flares (defined as PASI and/or DLQI scores >5 for ≥3 months), and proportion of patients with successful dose tapering.
Of 120 patients (mean SD age, 54.0 13.2 years; 82 68% male), 2 patients were lost to follow-up, 2 patients had a protocol violation, and 5 patients had a protocol deviation, leaving 111 patients for the per-protocol analysis (53 in the DR group and 58 in the UC group). The median PASI scores at month 12 were 3.4 (interquartile range IQR, 2.2-4.5) in the DR group and 2.1 (IQR, 0.6-3.6) in the UC group (mean difference, 1.2; 95% CI, 0.7-1.8). This indicates that noninferiority was not demonstrated for DR compared to UC. The median DLQI score at month 12 was 1.0 (IQR, 0.0-2.0) in the DR group and 0.0 (IQR, 0.0-2.0) in the UC group (mean difference, 0.8; 95% CI, 0.3-1.3), indicating noninferiority for DR compared with UC. No significant difference was found regarding persistent flares between groups (n = 5 in both groups). Twenty-eight patients (53%; 95% CI, 39%-67%) in the DR group tapered their dose successfully at 12 months. No severe adverse events related to the intervention occurred.
In this trial, noninferiority was not demonstrated for DR of adalimumab, etanercept, and ustekinumab based on the PASI in patients with psoriasis compared with UC with the chosen noninferiority margin. However, the strategy was noninferior based on the DLQI. Dose tapering did not lead to persistent flares or safety issues.
ClinicalTrials.gov Identifier: NCT02602925.
Article Note: Funding sources: this investigator-initiated study was conducted with financial support from Almirall. The funding source had no influence on study design, data collection and analysis, ...or the content of the manuscript. Conflicts of interest: M.E.C.v.W. has carried out investigator-initiated research with financial support from Almirall and has conducted clinical trials for AbbVie, Celgene, Janssen, Leo Pharma, Lilly and Novartis. E.L.M.t.H. has carried out investigator-initiated research with financial support from Almirall and has conducted clinical trials for Novartis. P.C.M.v.d.K. served as the chief medical officer of the International Psoriasis Council and received fees for lectures and consultancies from Bristol Mayer Squib, UCB, Leo Pharma, Eli Lilly and Company, Dermavant, Almirall, Celgene Novartis, Janssen and AbbVie. E.M.G.J.d.J. has received research grants for the independent research fund of the Department of Dermatology, Radboud University Medical Centre, Nijmegen from AbbVie, Pfizer, Novartis, Janssen Pharmaceutica and Leo Pharma, has acted as consultant and/or paid speaker for and/or participated in research sponsored by companies that manufacture drugs used for the treatment of psoriasis including AbbVie, Janssen Pharmaceutica, Novartis, Lily, Celgene, Leo Pharma, UCB and Almirall. All funding is not personal but goes to the independent research fund of the Department of Dermatology at Radboud University Medical Centre Nijmegen, the Netherlands. S.F.K.L. has received research grants for investigator-initiated research by Almirall.
Summary
Background
Drug survival is a marker for treatment success. To date, no analyses relating dermatological quality‐of‐life measures to drug survival have been published.
Objectives
(i) To ...describe 1‐year drug survival for adalimumab, etanercept and ustekinumab in a daily practice psoriasis cohort, and (ii) to introduce the concept of ‘happy’ drug survival, defined as Dermatology Life Quality Index (DLQI) ≤ 5 combined with being ‘on drug’ at a specific time point.
Methods
Data were extracted from a prospective registry. Drug survival was analysed using Kaplan–Meier estimates. ‘Happy’ drug survival was calculated, with data split into ‘happy’ (DLQI ≤ 5) vs. ‘unhappy’ (DLQI > 5) at baseline and months 3, 6, 9 and 12.
Results
249 treatment episodes were included (101 adalimumab, 82 etanercept, 66 ustekinumab). The 1‐year drug survival rates for ustekinumab, adalimumab and etanercept were 85%, 74% and 68%, respectively. Ustekinumab showed a better confounder‐corrected drug survival vs. etanercept hazard ratio (HR) 3·8, P = 0·02 and a trend towards better survival vs. adalimumab (HR 2·3, P = 0·1). At baseline, the majority (n = 115, 73%) was considered ‘unhappy’ and a minority ‘happy’ (n = 42, 27%) (ratio ‘happy’:‘unhappy’ was 1 : 2.7). The percentage of treatment episodes with ‘happy’ on‐drug patients increased to 79% after 1 year.
Conclusions
Ustekinumab showed a better overall drug survival than etanercept, and a trend towards a better overall drug survival than adalimumab. After 1 year, patients reported to be ‘happy’ in 79% of episodes and ‘unhappy’ in 21%. We introduced the new concept of ‘happy’ drug survival because the proportion of on‐drug patients with good quality of life is an important indicator for treatment success.
What's already known about this topic?
The Dermatology Life Quality Index is a validated score for dermatology‐specific quality‐of‐life measurements.
Drug survival studies of biologics for psoriasis show varying results and differ in study design and population.
To date, studies including drug survival rates for ustekinumab are scarce.
What does this study add?
The introduction of a concept named ‘happy’ drug survival, which combines drug survival rates with dermatology‐specific quality‐of‐life measures to evaluate treatments for psoriasis.
Analysis of ‘happy’ drug survival showed that the proportion of ‘on‐drug’ biologic users with a good quality of life increased from 27% to 79% after 1 year of treatment.
Ustekinumab showed a better overall drug survival vs. etanercept and a trend towards a better survival vs. adalimumab.
Summary
Background
The physical appearance of psoriasis can be cosmetically disfiguring, resulting in a substantial social burden for patients. An important aspect of this burden is the experience of ...stigmatization. While stigmatization is known to be disabling and stressful for patients, little is known about its correlates, and effective interventions are lacking.
Objectives
To examine predictor variables for perceived stigmatization in psoriasis.
Methods
Questionnaires were administered to 514 patients with psoriasis in a cross‐sectional study. Zero‐order correlation and multiple‐regression analyses were conducted including sociodemographic, disease‐related, personality, illness cognitions and social support predictor variables.
Results
Stigmatization was experienced by 73% of patients to some degree, and correlated with all five categories of predictor variables. In multiple‐regression analyses, stigmatization was associated with higher impact on daily life; lower education; higher disease visibility, severity and duration; higher levels of social inhibition; having a type D personality; and not having a partner.
Conclusions
The results indicate that perceived stigmatization is common in psoriasis, and can be predicted by sociodemographic, disease‐related and personality variables. These predictor variables provide indications of which patients are especially vulnerable regarding perceived stigmatization, which might be used in treatment.
What's already known about this topic?
Perceived stigmatization is common and distressing in patients with psoriasis.
Some of its predictors have been examined in small samples.
What does this study add?
This large study of 514 patients with psoriasis examined a combination of potential predictor variables, both previously examined and never before studied.
Sociodemographic, disease‐related and previously unstudied type D personality variables were found to be predictive of perceived stigmatization.
What are the clinical implications of this work?
These results provide an understanding of which patients may be especially vulnerable to stigmatization‐related problems, which may warrant special attention during treatment.
Placebo and nocebo effects are known to play a key role in treatment effects in a wide variety of conditions. These effects have frequently been investigated with regard to pain and also in other ...physical sensations, but have hardly been investigated with regard to itch. In addition, neither in pain nor in any other physical sensation, the single and combined contribution of the expectancy mechanisms of conditioning and verbal suggestion have ever been investigated in both placebo and nocebo effects within one design. For the first time, the role of verbal suggestion and conditioning in placebo and nocebo effects on itch was experimentally investigated. Expectations about itch stimuli were induced in healthy subjects by verbal suggestion, conditioning, or a combination of both procedures, and compared with a control group without expectation induction. Itch was induced electrically by means of quantitative sensory testing. Significant placebo and nocebo effects were induced in the group in which combined procedures of conditioning and verbal suggestion were applied in comparison with the control group. The conditioning and verbal suggestion procedures applied individually did not induce significant placebo and nocebo effects when compared with the control group. The results of this study extend existing evidence on different physical sensations, like pain, by showing that also for itch, the combination of conditioning and verbal suggestion is most promising in inducing both placebo and nocebo effects. More research on placebo and nocebo effects at a perceptive and neurobiological level is warranted to further elucidate the common and specific mechanisms underlying placebo and nocebo effects on itch and other physical sensations.
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