Background/Objectives: Cutaneous lupus erythematosus (CLE) is a complex autoimmune skin disease driven by genetic predisposition, environmental triggers, and immune dysregulation. Environmental factors such as ultraviolet radiation, smoking, and certain drugs can initiate disease onset by inducing keratinocyte apoptosis. The subsequent release of nucleic acids and danger-associated molecular patterns activates pattern recognition receptors (PRRs) on keratinocytes and immune cells, leading to the production of type I and type III interferons (IFNs) and pro-inflammatory cytokines. The objective of this review is to summarize recent advances in understanding the immunopathogenesis of CLE, with particular attention to emerging cellular players and their therapeutic implications. Methods: A narrative review of the recent literature was performed, including experimental, translational, and clinical studies investigating the cellular and molecular mechanisms underlying CLE and novel targeted treatments derived from these findings. Results: Although plasmacytoid dendritic cells (pDCs) have traditionally been considered the major producers of IFN-I, recent data indicate that pDCs in CLE are functionally impaired and are not the primary source. Other cells, such as keratinocytes have emerged as key producers of IFN-I, contributing to a prelesional, IFN-rich microenvironment. This promotes the recruitment and activation of dendritic cells and other inflammatory myeloid subsets, which are now recognized as central players in amplifying local inflammation. Concurrently, T cells infiltrate the skin, where cytotoxic CD8⁺ T cells attack keratinocytes and CD4⁺ T cells further propagate inflammation via cytokine production. B cells and plasma cells produce autoantibodies, forming immune complexes that perpetuate inflammation. Neutrophils release neutrophil extracellular traps (NETs), exposing autoantigens and further stimulating IFN pathways. Macrophages contribute by presenting autoantigens, producing pro-inflammatory mediators, and failing to effectively clear apoptotic cells and immune complexes. Conclusions: The dynamic interplay between the innate and adaptive immune systems sustains the chronic inflammatory state characteristic of CLE. Based on the pathogenetic novelties, new therapeutic agents targeting specific molecules have been developed, which may improve the treatment of this complex disease in the future.

Pruritus is a common and burdensome symptom in inflammatory, autoimmune, and connective tissue skin diseases, significantly impairing quality of life, sleep, and psychological well-being. Pruritus arises from a complex interplay between skin barrier dysfunction, immune activation, and neuronal sensitization involving cytokines, alarmins, neuropeptides, and sensory pathways. Increasing evidence indicates that both biological sex and gender-related factors influence itch perception, severity, and clinical expression, although these differences remain insufficiently explored. This review provides a comprehensive analysis of current evidence on sex- and gender-related differences in pruritus across dermatological diseases, with particular attention to the neuroimmune mechanisms underlying chronic itch. Available studies suggest that women more frequently report greater itch intensity, enhanced psychological burden, and higher impairment in daily activities and sleep, whereas men may exhibit different clinical and sensory profiles. However, findings remain heterogeneous because of methodological limitations, small cohorts, and the lack of standardized itch assessment tools. In addition to biological determinants, psychosocial and behavioral factors likely contribute to sex- and gender-specific differences in chronic pruritus. Overall, the available evidence highlights the need for more standardized and sex-informed research approaches to improve the understanding and management of pruritus in dermatological diseases.

Dercum’s disease (DD) is a rare chronic disorder characterized by painful subcutaneous lipomas, mostly affecting overweight or obese middle-aged women. The etiology remains unclear, and evidence for medical treatments is limited. Surgical approaches may reduce pain but are associated with frequent relapses and are difficult to implement in extensive clinical pictures. We investigated the outcomes of multiple medical and surgical therapeutic strategies. Particularly, we explored immunomodulators (methotrexate and infliximab), used alone or combined with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide, as well as the dual GIP (glucose-dependent insulinotropic polypeptide)/GLP-1 RAs tirzepatide. Five patients with DD were included in this retrospective single-center case series. Baseline clinical data, medical history, and longitudinal information on Dermatology Life Quality Index (DLQI), Visual Analogue Scale (VAS) for pain, and body mass index (BMI) were collected from existing medical records and scheduled follow-up visits conducted since 2021. Clinical trajectories differed across patients and regimens. Methotrexate and infliximab coincided with variable and often transient improvements in pain and quality of life. Combination regimens including GLP-1 RAs were accompanied by weight reduction and, in selected patients, by sustained improvements in pain and DLQI. In other cases, the benefit was limited or absent. Adverse events were manageable and consistent with the known safety profiles of these drugs. In this small real-world case series, therapeutic responses in DD were highly individualized, underscoring the absence of standardized medical treatment and the need for patient-tailored strategies. The observed patterns suggest that immunomodulatory and incretin-based therapies may represent exploratory options in selected patients, especially when surgery is not feasible. However, controlled studies are needed to clarify their role.

Dercum’s disease (DD) is a rare condition characterized by intense, asymmetrical, chronic burning pain localized in adipose tissue, often accompanied by subcutaneous fat nodules, leading to a significant reduction in quality of life. It typically affects overweight or obese adults between 35 and 50 years of age, with a marked female predominance. Despite numerous hypotheses proposed over time, the pathophysiology of DD remains poorly understood. Diagnosis is particularly challenging, as it relies solely on clinical evaluation. Given the overlapping features with other conditions, including symptoms, clinical course and inheritance pattern, a differential, accurate, and timely diagnosis is essential for the effective management of DD. Current treatment strategies focus primarily on pain relief, reflecting the still uncomplete understanding of DD etiopathogenesis. This review provides an updated overview of the current knowledge on DD, with particular emphasis on recent advances in pharmacological treatment strategies.