Risk of candidiasis associated with interleukin-17 inhibitors:A real-world observational study of multiple independent sources

BACKGROUND: Biologics directed against the T-helper (Th)-17 pathway have been approved for several inflammatory diseases. Interleukin (IL)-17 is involved in anti-Candida host defense, and clinical trials suggested increased candidiasis incidence during IL-17 inhibitor therapy. We describe the worldwide epidemiology of candidiasis during Th17 inhibitor therapy, and immunological mechanisms involved in candidiasis susceptibility. METHODS: A comprehensive analysis of multiple independent sources reporting Candida adverse events during biologics inhibiting the Th17 pathway was performed. Association between Th17 inhibitors and candidiasis was assessed using safety reports of (1) WHO and (2) EMA, (3) a population-based prescriptions registry, and (4) a psoriasis cohort. In a cohort of psoriasis patients experiencing candidiasis during Th17 inhibitors, Candida killing by immune cells and serum inflammatory proteome were analyzed. FINDINGS: A strong association between IL-17 inhibitors and candidiasis (ROR 10·20) was found in the WHO database, particularly for cutaneous (ROR 12·28), oropharyngeal (ROR 19·18), and esophageal candidiasis (ROR 21·20). Risk was higher relative to TNF-α inhibitors (4–10-fold, depending on candidiasis type), confirmed by EMA reports (16–33-fold), prescriptions registry (2–42-fold), and a psoriasis cohort (3–25-fold). After start of IL-17 inhibitors, patients’ risk of candidiasis requiring antifungals increased 2–16 fold. In the psoriasis cohort, 58% of IL-17 treatment episodes were associated with candidiasis. In Th17 inhibitor recipients, proteins involved in anti-Candida immunity and Candida killing by mononuclear leukocytes were impaired. INTERPRETATION: IL-17 inhibitors are associated with an increased risk of oropharyngeal, esophageal, and cutaneous candidiasis, posing a significant disease burden for IL-17 inhibitor recipients. FUNDING: RadboudUMC

Dupilumab Drug Survival and Associated Predictors in Patients With Moderate to Severe Atopic Dermatitis Long-term Results From the Daily Practice BioDay Registry

IMPORTANCE Long-term data on dupilumab drug survival in patients with atopic dermatitis (AD) are scarce. Furthermore, little is known about the factors associated with drug survival of dupilumab in AD.OBJECTIVE To describe the drug survival of dupilumab in patients with AD and to identify associated predictors.DESIGN, SETTING, AND PARTICIPANTS This cohort studywas based on data from the multicenter prospective daily practice BioDay registry, in which 4 university and 10 nonuniversity hospitals in the Netherlands participated. Analysis included patients (age &gt;= 18 years) participating in the BioDay registry with a follow-up of at least 4 weeks. The first patient treated with dupilumab was recorded in the BioDay registry in October 2017; data lock took place in December 2020, and data analysis was performed from October 2017 to December 2020.MAIN OUTCOMES AND MEASURES Drug survivalwas analyzed by Kaplan-Meier survival curves and associated characteristics by using univariate and multivariate Cox regression analysis.RESULTS A total of 715 adult patients with AD (mean [SD] age, 41.8 [16.0] years; 418 [58.5%] were male) were included with a 1-year, 2-year, and 3-year overall dupilumab drug survival of 90.3%, 85.9%, and 78.6%, respectively. Characteristics associated with shorter drug survival owing to ineffectiveness were the use of immunosuppressant drugs at baseline (hazard ratio [HR], 2.64; 95% CI, 1.10-6.37) and being a nonresponder at 4 weeks (HR, 8.68; 95% CI, 2.97-25.35). Characteristics associated with shorter drug survival owing to adverse effects were the use of immunosuppressant drugs at baseline (HR, 2.69; 95% CI, 1.32-5.48), age 65 years or older (HR, 2.94; 95% CI, 1.10-7.87), and Investigator Global Assessment score of very severe AD (HR, 3.51; 95% CI, 1.20-10.28).CONCLUSIONS AND RELEVANCE This cohort study demonstrated a good overall 1-year, 2-year, and 3-year dupilumab drug survival. Patients using immunosuppressive therapy at baseline and those with an absence of treatment effect at week 4 tended to discontinue treatment owing to ineffectiveness more frequently. Using immunosuppressant drugs at baseline, older age, and Investigator Global Assessment score of very severe AD were characteristics associated with an increased risk for discontinuation owing to adverse effects. These data provide more insight and new perspectives regarding dupilumab treatment in AD and can contribute to the optimization of patient outcomes.</p

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

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 (RCTs). 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 1 episode of fungal infection. This is one of the first studies of drug survival of secukinumab in patients with psoriasis treated in daily practic

Health and health care utilisation among asylum seekers and refugees in the Netherlands: design of a study

BACKGROUND: This article discusses the design of a study on the prevalence of health problems (both physical and mental) and the utilisation of health care services among asylum seekers and refugees in the Netherlands, including factors that may be related to their health and their utilisation of these services. METHODS/DESIGN: The study will include random samples of adult asylum seekers and refugees from Afghanistan, Iran and Somali (total planned sample of 600), as these are among the largest groups within the reception centres and municipalities in the Netherlands. The questionnaire that will be used will include questions on physical health (chronic and acute diseases and somatization), mental health (Hopkins Symptoms Checklist-25 and Harvard Trauma Questionnaire), utilisation of health care services, pre- and post-migratory traumatic experiences, life-style, acculturation, social support and socio-demographic background. The questionnaire has gone through a translation process (translation and back-translation, several checks and a pilot-study) and cross-cultural adaptation. Respondents will be interviewed by bilingual and bicultural interviewers who will be specifically trained for this purpose. This article discusses the selection of the study population, the chosen outcome measures, the translation and cross-cultural adaptation of the measurement instrument, the training of the interviewers and the practical execution of the study. The information provided may be useful for other researchers in this relatively new field of epidemiological research among various groups of asylum seekers and refugees

Role of HLA- C*06 in clinical response to ustekinumab: evidence from real-life in a large cohort of European patients.

Little is known about role of HLA-C*06 related to response to psoriasis treatments. OBJECTIVES: This study that involved four European centres aims to confirm the role of HLA-C*06 in a new large cohort of patients, as a pharmacogenetic marker of response to ustekinumab. METHODS: In this retrospective multicenter study we reviewed data of 255 psoriasis patients genotyped for HLA-C*06, which have started ustekinumab treatment between January 2014 and March 2015. The severity of psoriasis and response to treatment were evaluated using the PASI score at baseline and then at follow up visits on weeks 4, 12, 28, 40 and 52. The primary endpoint was the proportion of patients achieving at least 50% reduction in the PASI score (PASI 50) at week 4. A 75% reduction in the PASI score (PASI 75) and a 90% reduction in the PASI score (PASI 90) after 12 weeks were our secondary endpoints. RESULTS: PASI 50 at week 4, was seen in 71.7% and 35.2% of HLA-C*06 (C*06POS) and HLA-C*06-negative (C*06NEG) patients, respectively. At week 12, 84.1% of C*06POS patients reached PASI 75, while 40.5% of C*06NEG patients reached PASI 75. After 52 weeks, 85.7% of C*06POS patients reached PASI 75, while 58.8% of C*06NEG patients reached PASI 75. CONCLUSIONS: In this paper we reported a new data of a large cohort of European patients, treated with ustekinumab in daily clinical practice. Our new results confirmed the role HLA-C*06 as a potential predictor of response to ustekinumab. This article is protected by copyright. All rights reserved

Nonmelanoma huidkanker tijdens behandeling met TNF-blokkers bij psoriasis en reumatoïde artritis

To investigate if there was a difference in time to the occurrence of first non-melanoma skin cancer (NMSC) and in the incidence of NMSC between psoriasis patients and rheumatoid arthritis (RA) patients on TNF inhibitors. Prospective observational cohort study. We compared the time to first NMSC (expressed as hazard ratio) and the incidence of NMSC (expressed as incidence ratio) in psoriasis and RA patients in the Netherlands who were treated with TNF inhibitors and had a follow-up of at least one year. Cox regression and Poisson regression analyses were used; both were corrected for confounders (age, gender, disease duration, prior NMSC, duration of anti-TNF and other systemic therapies). The NMSC risk was significantly higher in the psoriasis group (fully adjusted hazard ratio: 6.0 [1.6 - 22.4 95% CI]) and time to first NMSC in psoriasis compared with RA was also shorter (1.6 years and 3.7 years, respectively). The incidence of NMSC was 5.5 times higher in psoriasis patients (2.2 - 13.4 95% CI) than in those with RA. The time to first NMSC was significantly shorter and the incidence of NMSC was significantly higher in psoriasis than in RA. This indicates that disease-related factors such as phototherapy may be important contributing factors to the occurrence of NMSC in psoriasis patients treated with TNF inhibitor

Drug survival for azathioprine and enteric-coated mycophenolate sodium in a long-term daily practice cohort of adult patients with atopic dermatitis

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Dose reduction of the new generation biologics (IL-17 and IL-23 inhibitors) in psoriasis : study protocol for an international, pragmatic, multicenter, randomized, controlled, non-inferiority study : the BeNeBio study

Background: Psoriasis is a chronic immune-mediated inflammatory skin disease for which biologics are effective treatments. Dose reduction (DR) of the first generation biologics seems a promising way for more efficient use of expensive biologics. A substantial part of patients on tumor necrosis factor (TNF)-alfa inhibitors and ustekinumab could successfully lower their dose, after following a tightly controlled DR strategy. The objective of this study is to assess whether controlled DR of interleukin (IL)-17 and IL-23 inhibitors in psoriasis patients with low disease activity is non-inferior (NI) to usual care (UC). Methods: This is an international, prospective, multicenter, pragmatic, randomized, non-inferiority trial. A total of 244 patients with stable low disease activity (Psoriasis Area and Severity Index (PASI) 5 for >= 3 months), which will be compared between arms. Secondary outcomes include proportion of patients with successful DR, (course of) PASI and DLQI, serious adverse events (SAEs), health-related quality of life, costs, and pharmacokinetic profile. Outcomes of DR will be compared to UC. Discussion: With this study, we aim to assess whether DR of IL-17 and IL-23 inhibiting biologics can be achieved for psoriasis patients with low disease activity, without losing disease control. Reducing the dose may lead to more efficient use of biologics