Early and Long-Term Effects of Dupilumab Treatment on Circulating T-Cell Functions in Patients with Moderate-to-Severe Atopic Dermatitis

Dupilumab, a mAb targeting IL-4 receptor alpha (IL-4Rα), markedly improves disease severity in patients with atopic dermatitis. However, the effect of IL-4Rα blockade on dynamics of circulating skin-homing T cells, which are crucial players in the pathologic mechanism of atopic dermatitis, has not been studied yet. In addition, it remains unknown whether dupilumab treatment induces long-lasting T- and B-cell polarization. Therefore, we studied the short- and long-term effects of dupilumab treatment on IL-4Rα expression and T-cell cytokine production within total and skin-homing (cutaneous lymphocyte antigen+/CCR4+) subpopulations in patients with moderate-to-severe atopic dermatitis. Dupilumab treatment completely blocked IL-4Rα expression and signal transducer and activator of transcription 6 phosphorylation in CD19+ B cells and CD4+ T cells within 2 hours of administration and through week 52. Although no change in the proportion of skin-homing T-cell subsets was found, dupilumab treatment significantly decreased the percentage of proliferating (Ki67+) and T helper type 2 and T helper type 22 cytokine-producing skin-homing CD4+ T cells at week 4. No evidence of general T helper type cell skewing following a year of dupilumab treatment was found. In summary, dupilumab treatment rapidly and stably inhibited IL-4Rα, which was accompanied by a strong early functional immunological effect specifically on skin-homing T cells without affecting overall T helper type cell skewing in the long term

Dupilumab-associated ocular surface disease in atopic dermatitis patients: clinical characteristics, ophthalmic treatment response, and conjunctival goblet cell analysis

BACKGROUND: Dupilumab-associated ocular surface disease (DAOSD) is frequently reported as side effect in atopic dermatitis (AD) patients. Therefore, the aim of this study was to investigate the frequency and severity of DAOSD, ophthalmic treatment response and to learn more about the effect of dupilumab on conjunctival goblet cells (GC). METHODS: This prospective study included dupilumab-treated AD patients between February 2020 and June 2022 from the University Medical Centre Utrecht. Patients were examined by an ophthalmologist and a dermatologist before start (baseline), and after 4 and 28 weeks of dupilumab treatment. Ophthalmological examination was assessed by the Utrecht Ophthalmic Inflammatory and Allergic disease (UTOPIA) score. DAOSD was defined as an increase in UTOPIA score of ≥3 points from baseline. To quantify conjunctival GCs and to investigate the percentage of Cytokeratin 19 (CK19)-CD45-Mucin 5 AC (MUC5AC)+ cells, conjunctival impression cytology samples were analysed. RESULTS: Ocular surface disease (OSD) was present in 91.3% (n = 63/69) patients at baseline. DAOSD was observed in 28.9% (n = 20/69) patients, in whom GC numbers remained stable and the percentage of CK19-CD45-MUC5AC+ cells decreased at onset of DAOSD compared with baseline. After 28 weeks of dupilumab treatment, DAOSD was seen in 14.5% (n = 10/69) patients. Of the 85.5% (n = 59/69) patients without DAOSD or with controlled DAOSD at Week 28, 40.7% (n = 24/59) patients received anti-inflammatory ophthalmic drugs. CONCLUSIONS: Ocular surface disease is common in moderate-to-severe AD patients before starting dupilumab. During treatment with dupilumab DAOSD severity improves with early ophthalmic treatment. The decrease in percentage of CK19-CD45-MUC5AC+ cells during dupilumab treatment suggests an impairment of the GC function due to dupilumab treatment

Ocular surface disease in moderate-to-severe atopic dermatitis patients and the effect of biological therapy

Atopic dermatitis (AD) is a chronic inflammatory skin disease for which new targeted therapies are currently available. Due to the increased rates of ocular surface disease (OSD) reported during treatment with these new targeted treatments, more insight into the occurrence and pathomechanism of OSD in moderate-to-severe AD patients is needed. Therefore, this review's first part highlights that most patients with moderate-to-severe AD already have characteristics of OSD before starting targeted treatment. Remarkably, not all AD patients with OSD report ocular symptoms. OSD in AD is associated with less conjunctival goblet cells (GC) compared to healthy controls. In addition, OSD severity in AD patients is associated with high AD activity, the presence of eyelid and/or facial eczema, and high levels of AD-related severity biomarkers in tear fluid. The second part of this review highlights that pre-existing ocular pathology (e.g. in combination with the use of ophthalmic medication or eyelid eczema) may be associated with the development of dupilumab-associated ocular surface disease (DAOSD). During dupilumab treatment, DAOSD (which can be new-onset OSD or worsening of pre-existing OSD) is observed in approximately one-third of the dupilumab-treated AD patients. Anti-inflammatory ophthalmic treatment improves DAOSD, and dose reduction of dupilumab may also be an effective treatment option. The pathomechanism of DAOSD is still not fully elucidated. In a prospective study low, but stable conjunctival GC numbers were observed in moderate-to-severe AD patients, before and during dupilumab treatment. However, the Mucin 5 AC (MUC5AC) expression of GCs decreased during dupilumab treatment, suggesting an impairment of the GC function by dupilumab treatment. In addition, higher dupilumab tear fluid levels were found in dupilumab-treated AD patients with moderate-to-severe OSD compared to patients with no or mild OSD, whereas the dupilumab serum levels are similar. Clinicians should be aware of the frequent occurrence of OSD in moderate-to-severe AD patients, and a low-threshold referral to an ophthalmologist is recommended

The nucleoporin RanBP2 tethers the cAMP effector Epac1 and inhibits its catalytic activity

Direct interaction between the catalytic domain of Epac1 and the nuclear pore component RanBP2 blocks Epac1 catalytic activity and downstream cAMP signaling

Pre-university Chemistry Students in a Mimicked Scholarly Peer Review

Peer review is a significant component in scientific research. Introducing peer review into inquiry processes may be regarded as an aim to develop student understanding regarding quality in inquiries. This study examines student understanding in inquiry peer reviews among pre-university chemistry students, aged 16-17, when they enact a design of a mimicked scholarly peer review. This design is based on a model of a human activity system. Twenty-five different schools in Brazil, Germany, Poland and The Netherlands participated. The students (n = 880) conducted in small groups (n = 428) open inquiries on fermentation. All groups prepared an inquiry report for peer review. These reports were published on a website. Groups were randomly paired in an internet symposium, where they posted review comments to their peers. These responses were qualitatively analyzed on small groups' level of understanding regarding seven categories: inquiry question, hypothesis, management of control variables, accurate measurement, presenting results, reliability of results, discussion and conclusion. The mimicked scholarly review prompted a collective practice. Student understanding was significantly well on presenting results, discussion and conclusion, and significantly less on inquiry question and reliability of results. An enacted design, based on a model of a human activity system, created student understanding of quality in inquiries as well as an insight in a peer-reviewing practice. To what extent this model can be applied in a broader context of design research in science education needs further study