Superficial Conjunctival Cells from Dupilumab-treated Atopic Dermatitis Patients with Ocular Adverse Events Display a Transcriptomic Psoriasis Signature.

Dupilumab has demonstrated efficacy in the treatment of atopic dermatitis (AD). However, a subset of patients experiences ocular adverse events (OAE), including conjunctivitis and dry eye syndrome, the pathological mechanisms of which are still unknown. In a bicentric study, we used DNA microarray analysis to compare the transcriptome of AD patient conjunctival cells collected by impression cytology before (M0) and 4 months after (M4) initiating dupilumab treatment. Thirty-six patients were included and divided in two groups according to their ophthalmological status at M4: 12 with OAE (OAE+) and 24 without (OAE-). The analysis revealed 52 differentially expressed genes (DEG) between OAE+ and OAE- patients at M0, and 113 at M4. Ingenuity Pathway Analysis enrichment revealed a psoriasis signature in OAE+ patients, both before and after OAE outcomes. Additionally, we noticed the overexpression of several genes involved in keratinocyte differentiation, particularly encoding cornified envelope components. Among the 16 DEG selected for real-time RT-PCR validation, 9 were confirmed as upregulated at M4 in OAE+ vs OAE- patients, validating the psoriasis signature, while MUC-7 was downregulated. In conclusion, these results suggest that a conjunctival transcriptomic profile predisposes some AD patients to develop OAE upon dupilumab treatment.

Dupilumab-Associated Adverse Events During Treatment of Allergic Diseases.

Among the new biological therapies for atopic diseases, dupilumab is a fully human monoclonal antibody directed against IL-4Rα, the common chain of interleukin-4 and interleukin-13 receptors. Dupilumab showed clinical improvements in patients with atopic dermatitis, asthma, and chronic rhinosinusitis and is currently under development for other indications. While dupilumab is considered to be well tolerated, a number of recent publications have reported various adverse events. This review aims to summarize the current knowledge about these adverse events, which may help clinicians to improve the follow-up of patients on dupilumab. Injection-site reactions are the most common reported adverse event. However, dupilumab has also been shown to cause ophthalmic complications (e.g., dry eyes, conjunctivitis, blepharitis, keratitis, and ocular pruritus), head and neck dermatitis, onset of psoriatic lesions, progression of cutaneous T-cell lymphoma exacerbation, alopecia areata, hypereosinophilia, and arthritis. Most are managed during dupilumab treatment continuation, but some (e.g., severe conjunctivitis) may result in a discontinuation of treatment. Their molecular origin is unclear and requires further investigations. Among other hypothesis, it has been suggested that T helper (Th)2-mediated pathway inhibition may worsen Th1/Th17-dependent immune responses. An ophthalmological examination for the presence of potential predictive indicators of ophthalmic adverse events is recommended before initiation of dupilumab therapy.

Progerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools.

Chromatin organization within the nuclear volume is essential to regulate many aspects of its function and to safeguard its integrity. A key player in this spatial scattering of chromosomes is the nuclear envelope (NE). The NE tethers large chromatin domains through interaction with the nuclear lamina and other associated proteins. This organization is perturbed in cells from Hutchinson-Gilford progeria syndrome (HGPS), a genetic disorder characterized by premature aging features. Here, we show that HGPS-related lamina defects trigger an altered 3D telomere organization with increased contact sites between telomeres and the nuclear lamina, and an altered telomeric chromatin state. The genome-wide replication timing signature of these cells is perturbed, with a shift to earlier replication for regions that normally replicate late. As a consequence, we detected a higher density of replication forks traveling simultaneously on DNA fibers, which relies on limiting cellular dNTP pools to support processive DNA synthesis. Remarkably, increasing dNTP levels in HGPS cells rescued fragile telomeres, and improved the replicative capacity of the cells. Our work highlights a functional connection between NE dysfunction and telomere homeostasis in the context of premature aging.