Conjunctivitis in dupilumab clinical trials Akinlade, B.; Guttman‐Yassky, E.; Bruin‐Weller, M. ...
British journal of dermatology (1951),
September 2019, Letnik:
181, Številka:
3
Journal Article
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Summary
Background
Dupilumab blocks the shared receptor component for interleukin (IL)‐4 and IL‐13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate‐to‐severe atopic dermatitis ...(AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate‐to‐severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate‐to‐severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo.
Objectives
To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials.
Methods
We evaluated randomized placebo‐controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47).
Results
In most AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis.
Conclusions
Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab‐treated patients require further study.
What's already known about this topic?
Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD).
In most dupilumab AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than those receiving placebo.
Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare.
Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis.
What does this study add?
This analysis confirms and extends the results of the individual clinical trials.
Baseline disease‐related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation‐regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis.
Patients who responded well to dupilumab had reduced incidence of conjunctivitis.
Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab‐treated patients with AD.
Linked Editorial: Chia‐Yu Chu. Br J Dermatol 2019; 181:436–437.
Plain language summary available online
Respond to this article
Atopic dermatitis (AD) is a highly pruritic, chronic inflammatory skin disease. The diagnosis is made using evaluated clinical criteria. Disease activity and burden are best measured with a composite ...score, assessing both objective and subjective symptoms, such as SCORing Atopic Dermatitis (SCORAD). AD management must take into account clinical and pathogenic variabilities, the patient’s age and also target flare prevention. Basic therapy includes hydrating and barrier‐stabilizing topical treatment universally applied, as well as avoiding specific and unspecific provocation factors. Visible skin lesions are treated with anti‐inflammatory topical agents such as corticosteroids and calcineurin inhibitors (tacrolimus and pimecrolimus), which are preferred in sensitive locations. Topical tacrolimus and some mid‐potency corticosteroids are proven agents for proactive therapy, which is defined as the long‐term intermittent anti‐inflammatory therapy of frequently relapsing skin areas. Systemic anti‐inflammatory or immunosuppressive treatment is a rapidly changing field requiring monitoring. Oral corticosteroids have a largely unfavourable benefit–risk ratio. The IL‐4R‐blocker dupilumab is a safe, effective and licensed, but expensive, treatment option with potential ocular side‐effects. Other biologicals targeting key pathways in the atopic immune response, as well as different Janus kinase inhibitors, are among emerging treatment options. Dysbalanced microbial colonization and infection may induce disease exacerbation and can justify additional antimicrobial treatment. Systemic antihistamines (H1R‐blockers) only have limited effects on AD‐related itch and eczema lesions. Adjuvant therapy includes UV irradiation, preferably narrowband UVB or UVA1. Coal tar may be useful for atopic hand and foot eczema. Dietary recommendations should be patient‐specific, and elimination diets should only be advised in case of proven food allergy. Allergen‐specific immunotherapy to aeroallergens may be useful in selected cases. Psychosomatic counselling is recommended to address stress‐induced exacerbations. Efficacy‐proven 'Eczema school' educational programmes and therapeutic patient education are recommended for both children and adults.
Summary
Background
Atopic dermatitis is a chronic inflammatory skin disease that may require systemic therapy. Ciclosporin A (CsA) is a widely used, potent immunosuppressant but it is not effective ...in all patients with atopic dermatitis, and side‐effects limit its use. Dupilumab, a fully human anti‐interleukin 4 receptor‐alpha monoclonal antibody, inhibits signaling of IL‐4 and IL‐13, key drivers of Type 2/Th2‐mediated inflammation, and is approved in the U.S.A. and the European Union for the treatment of inadequately‐controlled moderate‐to‐severe atopic dermatitis in adults.
Objectives
To evaluate efficacy and safety of dupilumab with concomitant topical corticosteroids (TCS) in adults with atopic dermatitis with inadequate response to/intolerance of CsA, or for whom CsA treatment was medically inadvisable.
Methods
In this 16‐week, double‐blind, randomized, placebo‐controlled, phase III trial, patients were randomized 1 : 1 : 1 to subcutaneous dupilumab 300 mg weekly (qw) or every 2 weeks (q2w) or placebo. All received concomitant medium‐potency TCS from Week −2 through Week 16; dosage could be tapered if lesions cleared, or stopped for adverse reactions to TCS.
Results
In total, 390 patients were screened, 325 were randomized, and 318 completed the trial. Treatment groups had similar baseline characteristics. Significantly more patients in the dupilumab qw + TCS and q2w + TCS groups achieved ≥ 75% improvement from baseline in the Eczema Area and Severity Index at Week 16 vs. the placebo + TCS group (primary end point) (59·1% and 62·6% vs. 29·6%, respectively; P < 0·001 vs. placebo + TCS, both doses). Other clinical outcomes and atopic dermatitis symptoms were significantly improved in the dupilumab qw + TCS and q2w + TCS groups, including pruritus, pain, sleep disturbance, symptoms of anxiety and depression, and quality of life (QoL). Treatment groups had similar overall rates of adverse events (qw + TCS, q2w + TCS and placebo + TCS groups: 69·1%, 72·0% and 69·4%, respectively) and serious adverse events (1·8%, 1·9% and 1·9%, respectively). Conjunctivitis was more frequent with dupilumab + TCS; skin infections were more frequent with placebo + TCS.
Conclusions
Dupilumab + TCS significantly improved signs and symptoms of atopic dermatitis and QoL in adults with a history of inadequate response to/intolerance of CsA, or for whom CsA treatment was medically inadvisable. No new safety signals were identified.
What's already known about this topic?
Patients with atopic dermatitis that is inadequately controlled with topical therapy have few systemic treatment options.
Ciclosporin A (CsA) is a systemic immunosuppressant approved for atopic dermatitis in most European countries and Japan, but not all patients respond, and side‐effects limit its use.
Dupilumab (monoclonal antibody against interleukin‐4 receptor‐alpha) with/without topical corticosteroids (TCS) is approved in the U.S.A. and the European Union for the treatment of adults with inadequately‐controlled moderate‐to‐severe atopic dermatitis.
What does this study add?
In this 16‐week trial in adults with atopic dermatitis and history of inadequate response or intolerance to CsA, or for whom CsA treatment was medically inadvisable, dupilumab administered weekly or every 2 weeks with concomitant TCS significantly improved signs and symptoms and quality of life, with no new safety signals.
These data support the use of dupilumab in this difficult‐to‐treat population.
Linked Editorial: Schmitt. Br J Dermatol 2018; 178:992–993.
Linked Letter: Thyssen. Br J Dermatol 2018; 178:1220.
Plain language summary available online
Respond to this article
Background: Eosinophils may play an important role in the pathogenesis of atopic dermatitis (AD). Interleukin‐5 is essential for eosinophil growth, differentiation and migration. A monoclonal ...antibody to human interleukin‐5 (mepolizumab) was developed for atopic diseases. This study was designed to study the effect of mepolizumab in AD.
Methods: Two single doses of 750 mg mepolizumab, given 1 week apart, were studied in patients with moderate to severe AD using a randomized, placebo‐controlled parallel group design. The primary endpoint of ‘success’ to treatment was defined as the percentage of patients with at least ‘marked improvement’ after 2 weeks as assessed by the Physician's Global Assessment of Improvement (PGA). Furthermore, SCORing AD (SCORAD), pruritus scoring, number of blood eosinophils and serum thymus and activation‐regulated chemokine (TARC) values served as secondary endpoints. Fluticason propionate cream 0.05%, once daily could be used as rescue medication from day 16 if no improvement was recorded.
Results: Eighteen patients received mepolizumab and 22 placebo treatment. Peripheral blood eosinophil numbers were significantly reduced in the treatment group compared with placebo (P < 0.05). No clinical success was reached by PGA assessment (P = 0.115), SCORAD (P = 0.293), pruritus scoring and TARC values in the mepolizumab‐treated group compared with placebo. However, modest improvement (<50% improvement) assessed by PGA was scored significantly more in the mepolizumab‐treated group compared with placebo (P < 0.05).
Conclusion: Two single doses of 750 mg mepolizumab did not result in clinical success in patients with AD, despite a significant decrease in peripheral blood eosinophils.
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.
Developing expertise in flexible bronchoscopy is limited by inadequate opportunities to train on difficult airways. The new ORSIM bronchoscopy simulator aims to address this by creating virtual ...patients with difficult airways. This study aims to provide evidence on the validity and reliability of the ORSIM for assessment of subjects on both normal and abnormal airway simulations.
Novice, trainee, and expert subjects performed seven simulations of varying difficulty and scored the perceived difficulty for each. Time to completion was measured. Three blinded raters independently scored videos of each subject's performance. We measured inter-rater agreement and the difference in raters’ scores between subject groups.
We recruited 28 study subjects, generating 196 videos for analysis. Expert subjects consistently completed the scenarios faster than novices. Overall performance scores showed significant differences between subject groups (P<0.0001). Inter-rater reliability of scores was >0.8.
Our results provide initial evidence on the validity and reliability of the ORSIM bronchoscopy simulator, supporting its potential value in training and assessment.
Beneficial microbes in the microbiome of plant roots improve plant health. Induced systemic resistance (ISR) emerged as an important mechanism by which selected plant growth-promoting bacteria and ...fungi in the rhizosphere prime the whole plant body for enhanced defense against a broad range of pathogens and insect herbivores. A wide variety of root-associated mutualists, including Pseudomonas, Bacillus, Trichoderma, and mycorrhiza species sensitize the plant immune system for enhanced defense without directly activating costly defenses. This review focuses on molecular processes at the interface between plant roots and ISR-eliciting mutualists, and on the progress in our understanding of ISR signaling and systemic defense priming. The central role of the root-specific transcription factor MYB72 in the onset of ISR and the role of phytohormones and defense regulatory proteins in the expression of ISR in aboveground plant parts are highlighted. Finally, the ecological function of ISR-inducing microbes in the root microbiome is discussed.
The value of workplace-based assessments such as the mini-clinical evaluation exercise (mini-CEX), and clinicians’ confidence and engagement in the process, has been constrained by low reliability ...and limited capacity to identify underperforming trainees. We proposed that changing the way supervisors make judgements about trainees would improve score reliability and identification of underperformers. Anaesthetists regularly make decisions about the level of trainee independence with a case, based on how closely they need to supervise them. We therefore used this as the basis for a new scoring system.
We analysed 338 mini-CEXs where supervisors scored trainees using the conventional system, and also scored trainee independence, based on the need for direct, or more distant, supervision. As supervisory requirements depend on case difficulty, we then compared the actual trainee independence score and the expected trainee independence score obtained externally.
Compared with the conventional scoring system used in previous studies, reliability was very substantially improved using a system based on a trainee’s level of independence with a case. Reliability improved further when this score was corrected for case difficulty. Furthermore, the new scoring system overcame the previously identified problem of assessor leniency and identified a number of trainees performing below expectations.
Supervisors’ judgements on trainee independence with a case, based on the need for direct or more distant supervision, can generate reliable scores of trainee ability without the need for an onerous number of assessments, identify trainees performing below expectations, and track trainee progress towards independent specialist practice.
Summary The management of primary CNS lymphoma is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the very few controlled studies available. In ...2013, the European Association of Neuro-Oncology created a multidisciplinary task force to establish evidence-based guidelines for immunocompetent adults with primary CNS lymphoma. In this Review, we present these guidelines, which provide consensus considerations and recommendations for diagnosis, assessment, staging, and treatment of primary CNS lymphoma. Specifically, we address aspects of care related to surgery, systemic and intrathecal chemotherapy, intensive chemotherapy with autologous stem-cell transplantation, radiotherapy, intraocular manifestations, and management of elderly patients. The guidelines should aid clinicians in their daily practice and decision making, and serve as a basis for future investigations in neuro-oncology.
Malassezia is a genus of medically-important, lipid-dependent yeasts that live on the skin of warmblooded animals. The 17 described species have been documented primarily on humans and domestic ...animals, but few studies have examined Malassezia species associated with
more diverse host groups such as wildlife. While investigating the skin mycobiota of healthy bats, we isolated a Malassezia sp. that exhibited only up to 92 % identity with other known species in the genus for the portion of the DNA sequence of the internal transcribed spacer region
that could be confidently aligned. The Malassezia sp. was cultured from the skin of nine species of bats in the subfamily Myotinae; isolates originated from bats sampled in both the eastern and western United States. Physiological features and molecular characterisation at seven
additional loci (D1/D2 region of 26S rDNA, 18S rDNA, chitin synthase, second largest subunit of RNA polymerase II, β-tubulin, translation elongation factor EF-1α, and minichromosome maintenance complex component 7) indicated that all of the bat Malassezia isolates likely
represented a single species distinct from other named taxa. Of particular note was the ability of the Malassezia sp. to grow over a broad range of temperatures (7-40 °C), with optimal growth occurring at 24 °C. These thermal growth ranges, unique among the described
Malassezia, may be an adaptation by the fungus to survive on bats during both the host's hibernation and active seasons. The combination of genetic and physiological differences provided compelling evidence that this lipid-dependent yeast represents a novel species described herein as
Malassezia vespertilionis sp. nov. Whole genome sequencing placed the new species as a basal member of the clade containing the species M. furfur, M. japonica, M. obtusa, and M. yamatoensis. The genetic and physiological uniqueness of Malassezia vespertilionis
among its closest relatives may make it important in future research to better understand the evolution, life history, and pathogenicity of the Malassezia yeasts.
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