(1) Background: Numerous vaccines are under preclinical and clinical development for prevention of severe course and lethal outcome of coronavirus disease 2019 (COVID-19). In light of high efficacy rates and satisfactory safety profiles, some agents have already reached approval and are now distributed worldwide, with varying availability. Real-world data on cutaneous adverse drug reactions (ADRs) remain limited. (2) Methods: We performed a literature research concerning cutaneous ADRs to different COVID-19 vaccines, and incorporated our own experiences. (3) Results: Injection site reactions are the most frequent side effects arising from all vaccine types. Moreover, delayed cutaneous ADRs may occur after several days, either as a primary manifestation or as a flare of a pre-existing inflammatory dermatosis. Cutaneous ADRs may be divided according to their cytokine profile, based on the preponderance of specific T-cell subsets (i.e., Th1, Th2, Th17/22, Tregs). Specific cutaneous ADRs mimic immunogenic reactions to the natural infection with SARS-CoV-2, which is associated with an abundance of type I interferons. (4) Conclusions: Further studies are required in order to determine the best suitable vaccine type for individual groups of patients, including patients suffering from chronic inflammatory dermatoses.

Cutaneous lupus erythematosus (CLE) is a photosensitive autoimmune disease characterized by a strong type I IFN-associated inflammation. Keratinocytes are known to determine the interface dermatitis pattern in CLE by production of proinflammatory cytokines in the lower epidermis. These cytokines drive a cytotoxic anti-epithelial immune response resulting in keratinocytic cell death and release of endogenous nucleic acids. We hypothesized that these endogenous nucleic acids (RNA and DNA motifs) have the capacity to activate innate immune pathways in keratinocytes via pathogen recognition receptors. Gene expression analyses showed an excessive activation of innate immune response pathways with strong expression of IFN-regulated cytokines in CLE skin lesions. Cultured keratinocytes produce large amounts of these cytokines in response to stimulation of PRR with endogenous nucleic acids. UV stimulation enhances the immunogenicity of endogenous nucleic acids and induces CLE-like skin lesions in knockout mice lacking the cytosolic DNase TREX1. Our results provide evidence for a pathogenetic role of endogenous nucleic acids in CLE. They are released within the cytotoxic inflammation along the dermo-epidermal junction and have the capacity to drive the CLE-typical inflammation. UV irradiation supports this inflammation by generation of highly immunostimulatory DNA motifs (8-hydroxyguanosine). These findings explain the photosensitivity of patients with lupus and identify pathways of the innate immune system as targets for future therapies.

(1) Background: Coronavirus disease 2019 (COVID-19) vaccines are currently employed on a population-wide scale in most countries worldwide. Data about unusual cutaneous adverse drug reactions (ADR) are scant, though. (2) Methods: We retrospectively analyzed moderate to severe vaccine-related ADR in the Department of Dermatology and Allergy of the University Hospital Bonn between May to June 2021 and analyzed related skin biopsies. (3) Results: As a specialized dermatological academic center, we encountered a total of n = 19 clinically and pathologically heterogeneous cutaneous ADR with a female predominance. Delayed cutaneous ADR occurred as late as 30 days after vaccination. The majority of ADR were mild, though a few patients required systemic treatment (antihistamines, glucocorticosteroids). (4) Conclusions: The clinico-pathological spectrum of cutaneous side effects with COVID-19 vaccines is wide; however, the benefits outweigh the risks by far. More dermatopathological studies on cutaneous ADR not limited to COVID-19 vaccines are desirable to enable a better understanding of underlying pathophysiological mechanisms.

No abstract

Background: Cutaneous lupus erythematosus (CLE) is an interferon (IFN)-driven autoimmune skin disease characterized by an extensive cytotoxic lesional inflammation with activation of different innate immune pathways. Aim of our study was to investigate the specific role of Janus kinase 1 (JAK1) activation in this disease and the potential benefit of selective JAK1 inhibitors as targeted therapy in a preclinical CLE model. Methods: Lesional skin of patients with different CLE subtypes and healthy controls (N = 31) were investigated on JAK1 activation and expression of IFN-associated mediators via immunohistochemistry and gene expression analyses. The functional role of JAK1 and efficacy of inhibition was evaluated in vitro using cultured keratinocytes stimulated with endogenous nucleic acids. Results were confirmed in vivo using an established lupus-prone mouse model. Results: Proinflammatory immune pathways, including JAK/STAT signaling, are significantly upregulated within inflamed CLE skin. Here, lesional keratinocytes and dermal immune cells strongly express activated phospho-JAK1. Selective pharmacological JAK1 inhibition significantly reduces the expression of typical proinflammatory mediators such as CXCL chemokines, BLyS, TRAIL, and AIM2 in CLE in vitro models and also improves skin lesions in lupus-prone TREX1 −/−-mice markedly. Conclusion: IFN-associated JAK/STAT activation plays a crucial role in the pathophysiology of CLE. Selective inhibition of JAK1 leads to a decrease of cytokine expression, reduced immune activation, and decline of keratinocyte cell death. Topical treatment with a JAK1-specific inhibitor significantly improves CLE-like skin lesions in a lupus-prone TREX1 −/−-mouse model and appears to be a promising therapeutic approach for CLE patients.