Dupilumab was first approved for the treatment of atopic dermatitis (AD) and blocks the signaling of interleukin (IL)-4 and -13. Several other chronic skin conditions share mechanistic overlaps with AD in their pathophysiology, i.e., are linked to type 2 inflammation. Most recently, dupilumab was approved by the U.S. Food and Drug Administration for prurigo nodularis (PN). Given its relatively good safety profile, effective off-label use of dupilumab has been reported for a multitude of dermatologic diseases and several clinical trials for dermatologic skin conditions are currently ongoing. We conducted a systematic review of applications of dupilumab in dermatology other than AD and PN by searching the databases PubMed/Medline, Scopus, Web of Science and Cochrane Library as well as the clinical trial registry ClinicalTrials.gov. We found several reports for effective treatment of bullous autoimmune diseases, eczema, prurigo, alopecia areata, chronic spontaneous urticaria, Netherton syndrome and a variety of other chronic inflammatory skin diseases.

Prurigo nodularis (PN) presents with intensely itchy hard nodules. Despite being limited to the skin, PN was noted to be associated with systemic diseases including diabetes and chronic renal failure. In previous smaller retrospective studies, several cardiac and vascular diseases were found more frequently in patients with PN. However, small cohort sizes, partially discrepant outcomes, missing data, and incomplete risk assessment limit these findings. Electronic health records (EHR)s of 64,801 patients (59.44% females) with PN and an equal sized propensity-matched control group were retrieved. In these cohorts, the risks to develop cardiac and vascular diseases and mortality following the diagnosis of PN were determined. Sub-analyses included stratification for sex, ethnicity, and treatments. PN was associated with a higher risk for a broad range of acute cardiac events including heart failure and myocardial infarction. For example, the hazard ratio of myocardial infarction was 1.11 (95%-CI: 1.041-1.184, p = 0.0015) following PN diagnosis. Also, all-cause mortality was higher in patients with PN. Further, chronic vascular as well as structural heart diseases, e.g., peripheral arterial disease, chronic ischaemic heart disease and valval disorders were found more frequently following a PN diagnosis. Risks were more pronounced in white and female patients. Having established an increased risk for death and cardiovascular disease, we next addressed if dupilumab that has been recently licenced for use in this indication can modulate these risks. The risk of death but not of any cardiovascular disease was slightly reduced in patients with PN treated with dupilumab as opposed to those treated with systemic therapies other than dupilumab. The study is limited by retrospective data collection and reliance on ICD10-disease classification. PN is associated with higher mortality and an increased risk for the development of a wide range of cardiac and vascular diseases. Health care professionals should take this into account when managing patients with PN. This work was supported by the University of Lübeck, the Deutsche Forschungsgemeinschaft and the State of Schleswig-Holstein.

Autoimmune skin diseases can expedite various systemic sequelae involving other organs. Although limited to the skin, cutaneous lupus erythematosus (CLE) was noted to be associated with thromboembolic diseases. However, small cohort sizes, partially discrepant outcomes, missing data on CLE subtypes, and incomplete risk assessment limits these findings. The Global Collaborative Network of TriNetX provides access to medical records of more than 120 million patients worldwide. We used TriNetX to elucidate the risk for cardiac and vascular diseases after diagnosis of CLE, and its subtypes chronic discoid (DLE) and subacute cutaneous lupus erythematosus (SCLE). We included 30,315 CLE, 27,427 DLE, and 1613 SCLE patients. We performed propensity-matched cohort studies determining the risk to develop cardiac and vascular diseases (ICD10CM:I00-99) following diagnosis of CLE, DLE, or SCLE. Patients with systemic lupus erythematosus were excluded. We document that CLE and its subtype DLE but less so SCLE are associated with a higher risk for various cardiac and vascular diseases. This included predominantly thromboembolic events such as pulmonary embolism, cerebral infarction, and acute myocardial infarction, but also peripheral vascular disease and pericarditis. For example, the hazard ratio of arterial embolism and thrombosis was 1.399 (confidence interval: 1.230-1.591, p < 0.0001) following CLE diagnosis. The study is limited by retrospective data collection and reliance on ICD10-disease classification. CLE and its major subtype DLE are associated with an increased risk for the development of a wide range of cardiac and vascular diseases. This research was funded by Deutsche Forschungsgemeinschaft (EXC 2167, CSSL/CS01-2022) and the Excellence-Chair Program of the State of Schleswig-Holstein.

Background: Psoriasis is associated with a significant comorbidity burden, especially cardiovascular and metabolic complications. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, used to treat obesity and diabetes, could potentially reduce comorbidities in patients with psoriasis. Objectives: To investigate all-cause mortality, cardiovascular, inflammatory and psychiatric outcomes, and adverse events in patients with psoriasis treated with GLP-1RAs. Methods: This retrospective population-based cohort study used real-world data from the US TriNetX database. Patients with psoriasis who were treated for diabetes or obesity with a GLP-1RA during the follow-up period of 2 years were compared with those treated with other systemic antidiabetic or antiobesity drugs. After 1 : 1 propensity score matching for relevant risk factors, 3048 participants were included in each cohort. Primary outcomes included the risk of cardiometabolic, psychiatric and autoimmune sequelae of psoriasis, as well as all-cause mortality and potential adverse drug events. The analysis was repeated using cohorts without psoriasis and the results were further validated through two sensitivity analyses involving (i) later follow-up periods or (ii) the exclusion of patients with pustular psoriasis. Results: In the matched cohorts of 3048 patients with psoriasis treated with a GLP-1RA [60.4% women, mean (SD) age 56.94 (12.02) years] vs. other antidiabetic and antiobesity drugs [61.9% women, mean (SD) age 56.42 (14.16) years], GLP-1RA treatment was associated with significantly decreased all-cause mortality [hazard ratio (HR) 0.219, 95% confidence interval (CI) 0.123–0.391; P < 0.001] and reduced risk of major adverse cardiac events (HR 0.561, 95% CI 0.442–0.714; P < 0.001). Additionally, lower risks for alcohol (HR 0.346, 95% CI 0.174–0.685; P = 0.009) and substance abuse (HR 0.510, 95% CI 0.350–0.743; P = 0.002) were found. Typical adverse drug events were not more frequent in the GLP-1RA cohort. The risk reductions were more pronounced in the cohorts with psoriasis than in those with obesity or diabetes without psoriasis. The findings were consistent across all sensitivity analyses. Conclusions: GLP-1RA treatment was safe and associated with reduced risks of cardiovascular and psychiatric comorbidities, as well as lower mortality in patients with psoriasis, with risk reductions markedly higher than in cohorts without psoriasis. Physicians should consider this drug class for patients with psoriasis and comorbid obesity or diabetes.

Human cytomegalovirus (HCMV) causes serious complications to immune compromised hosts. Dendritic cells (iDCgB) expressing granulocyte-macrophage colony-stimulating factor, interferon-alpha and HCMV-gB were developed to promote de novo antiviral adaptive responses. Mice reconstituted with a human immune system (HIS) were immunized with iDCgB and challenged with HCMV, resulting into 93% protection. Immunization stimulated the expansion of functional effector memory CD8⁺ and CD4⁺ T cells recognizing gB. Machine learning analyses confirmed bone marrow T/CD4⁺, liver B/IgA⁺ and spleen B/IgG⁺ cells as predictive biomarkers of immunization (≈87% accuracy). CD8⁺ and CD4⁺ T cell responses against gB were validated. Splenic gB-binding IgM^-/IgG⁺ B cells were sorted and analyzed at a single cell level. iDCgB immunizations elicited human-like IgG responses with a broad usage of various IgG heavy chain V gene segments harboring variable levels of somatic hypermutation. From this search, two gB-binding human monoclonal IgGs were generated that neutralized HCMV infection in vitro. Passive immunization with these antibodies provided proof-of-concept evidence of protection against HCMV infection. This HIS/HCMV in vivo model system supported the validation of novel active and passive immune therapies for future clinical translation. Human cytomegalovirus (HCMV) is a ubiquitous pathogen. As long as the immune system is functional, T and B cells can control HCMV. Yet, for patients who have debilitated immune functions, HCMV infections and reactivations cause major complications. Vaccines or antibodies to prevent or treat HCMV are not yet approved. Novel animal models for testing new immunization approaches are emerging and are important tools to identify biomedical products with a reasonable chance to work in patients. Here, we used a model based on mice transplanted with human immune cells and infected with a traceable HCMV. We tested a cell vaccine (iDCgB) carrying gB, a potent HCMV antigen. The model showed that iDCgB halted the HCMV infection in more than 90% of the mice. We found that antibodies were key players mediating protection. Using state-of-the-art methods, we were able to use the sequences of the human antibodies generated in the mice to construct and produce monoclonal antibodies in the laboratory. Proof-of-concept experiments indicated that administration of these monoclonal antibodies into mice protected them against HCMV infection. In summary, this humanized mouse model was useful to test a vaccine and to generate and test novel antibodies that can be further developed for human use.

Background: Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease characterized by intense itch, and impacting heavily on patients’ and caregivers’ quality of life. Its clinical presentation is accompanied by a variety of comorbidities associated with type 2 inflammation, such as asthma, hay fever and food allergies. However, current data on cardiovascular comorbidities are inconsistent. Objectives: To identify the risk of cardiovascular diseases (CVDs) in patients with AD. Methods: Data from electronic health records of 1 070 965 patients with AD and equally distributed propensity-score matched controls were retrieved from the US Collaborative Network, part of the federated TriNetX network. Hazard ratios (HRs) for the risk of onset of CVDs with a prevalence of ≥ 1% in both cohorts within 20 years after diagnosis were determined. Results: In total, 55 CVDs belonging to 8 major cardiovascular groups were identified. Of those, 53 diagnoses displayed a significantly increased risk in patients with AD. Different diagnoses of heart failure and heart disease were found most often, followed by valve insufficiencies, arrhythmia, tachycardia, atrial fibrillation and flutter, but also major adverse cardiovascular events and venous thromboembolism. The highest HRs were displayed by the individual diagnoses of venous insufficiency, atherosclerosis of native arteries of the extremities, and unspecified diastolic (congestive) heart failure. Conclusions: AD is associated with an increased risk for multiple CVDs.