Cutaneous involvement in Systemic Lupus Erythematosus: integrating modern diagnostic and monitoring strategies with targeted treatments for damage prevention

Cutaneous involvement represents one of the most frequent and clinically relevant manifestations of Systemic Lupus Erythematosus (SLE), affecting up to 80% of patients during the disease course. Beyond its high prevalence, skin disease in SLE constitutes a major source of disease burden, with a substantial impact on quality of life, psychosocial well-being, and long-term outcomes. Cutaneous lupus erythematosus encompasses a heterogeneous spectrum of inflammatory phenotypes, often associated with early and irreversible damage, such as scarring alopecia and disfiguring lesions, which may occur even in the presence of relatively low global disease activity. Despite its clinical relevance, cutaneous involvement remains challenging to assess and to treat, and is frequently underrepresented in composite disease activity indices and therapeutic decision-making. This thesis explores the clinical, diagnostic, and therapeutic complexity of cutaneous involvement in SLE, from disease burden and unmet needs to innovative monitoring strategies and targeted therapies within a treat-to-target (T2T) framework. The first aim was to explore novel tools for the assessment of skin lesions in SLE. Ultra-High Frequency Ultrasound (UHFUS) is a non-invasive imaging technique capable of visualizing epidermal and dermal structures with unprecedented resolution. In a prospective cohort of patients with active cutaneous SLE, UHFUS identified epidermal and dermal abnormalities, including dermal oedema and increased vascularization. Findings correlated with clinical activity and were sensitive to change over time, suggesting a potential role as an objective monitoring tool and enabling more precise evaluation of inflammatory activity. The second aim was to investigate the impact of targeted biological therapies on cutaneous disease. Advances in SLE pathogenesis, particularly the role of type I interferon (IFN-I) signalling, have led to therapies such as anifrolumab, a monoclonal antibody targeting the IFN-I receptor. In a multicenter real-world cohort of patients with refractory SLE, anifrolumab was associated with a rapid and sustained reduction in cutaneous disease activity, assessed by CLASI. Improvements were evident as early as one month and persisted over follow-up, alongside reductions in global disease activity, glucocorticoid tapering, and improved patient-reported outcomes (PROs). The nationwide prospective REVEAL study further characterised real-world outcomes in 355 patients initiating anifrolumab, 69% of whom had active mucocutaneous involvement. Skin disease was associated with higher disease activity and greater prior treatment exposure, confirming its role as part of a broader multisystemic phenotype. Baseline cutaneous damage was already present in a substantial proportion of patients. During follow-up, anifrolumab led to sustained improvement in skin activity, with reductions in CLASI activity scores and mucocutaneous SLEDAI-2K domains. CLASI damage scores remained stable, suggesting prevention of further damage accrual. Increasing proportions of patients achieved remission or low disease activity states, including CLASI50 and CLASI70 responses. Higher baseline cutaneous activity was associated with a lower probability of remission, highlighting the importance of early intervention. From the patient perspective, cutaneous involvement contributed significantly to disease burden. Although musculoskeletal activity was the strongest driver of patient-reported burden, improvements in skin disease were associated with sustained PROs improvements. Overall, this thesis supports a shift in the management of cutaneous SLE. The skin should be considered a key target organ, with high inflammatory activity, early damage accrual, and relevant impact on quality of life. UHFUS provides a promising tool for objective assessment, while targeted therapies such as anifrolumab enable effective disease control within a T2T strategy. Early identification and treatment of cutaneous involvement are essential to prevent irreversible damage and improve long-term outcomes.