Emerging immunotherapeutic strategies for cutaneous lupus erythematosus: an overview of recent phase 2 and 3 clinical trials.

INTRODUCTION: Cutaneous lupus erythematosus (CLE) is an autoimmune disease that is clinically heterogenous and may occur with or without the presence of systemic lupus erythematosus (SLE). While existing on a spectrum, CLE and SLE present differences in their underlying pathogenesis and therapeutic responses. No new therapies have been approved in recent decades by the U.S. Food and Drug Administration for CLE, although frequently refractory to conventional therapies. There is an unmet need to develop effective drugs for CLE as it significantly impacts patients' quality of life and may leave irreversible disfiguring damage. AREAS COVERED: This review provides an update on the latest phase 2 and 3 clinical trials performed in CLE or SLE using skin-specific outcome measures. Emergent therapies are presented alongside their mechanism of action as recent translational studies have permitted identification of critical targets among immune cells and/or pathways involved in CLE. EXPERT OPINION: While the recent literature has few trials for CLE, drugs targeting type I interferon, its downstream signaling and plasmacytoid dendritic cells have shown promising results. Further research is required to develop long-awaited effective therapies, and this review highlights the importance of implementing trials dedicated to CLE to fill the current gap in CLE therapeutics.

Cutaneous Lupus Erythematosus: An Update on Pathogenesis and Future Therapeutic Directions.

Lupus erythematosus comprises a spectrum of autoimmune diseases that may affect various organs (systemic lupus erythematosus [SLE]) or the skin only (cutaneous lupus erythematosus [CLE]). Typical combinations of clinical, histological and serological findings define clinical subtypes of CLE, yet there is high interindividual variation. Skin lesions arise in the course of triggers such as ultraviolet (UV) light exposure, smoking or drugs; keratinocytes, cytotoxic T cells and plasmacytoid dendritic cells (pDCs) establish a self-perpetuating interplay between the innate and adaptive immune system that is pivotal for the pathogenesis of CLE. Therefore, treatment relies on avoidance of triggers and UV protection, topical therapies (glucocorticosteroids, calcineurin inhibitors) and rather unspecific immunosuppressive or immunomodulatory drugs. Yet, the advent of licensed targeted therapies for SLE might also open new perspectives in the management of CLE. The heterogeneity of CLE might be attributable to individual variables and we speculate that the prevailing inflammatory signature defined by either T cells, B cells, pDCs, a strong lesional type I interferon (IFN) response, or combinations of the above might be suitable to predict therapeutic response to targeted treatment. Therefore, pretherapeutic histological assessment of the inflammatory infiltrate could stratify patients with refractory CLE for T-cell-directed therapies (e.g. dapirolizumab pegol), B-cell-directed therapies (e.g. belimumab), pDC-directed therapies (e.g. litifilimab) or IFN-directed therapies (e.g. anifrolumab). Moreover, Janus kinase (JAK) and spleen tyrosine kinase (SYK) inhibitors might broaden the therapeutic armamentarium in the near future. A close interdisciplinary exchange with rheumatologists and nephrologists is mandatory for optimal treatment of lupus patients to define the best therapeutic strategy.

Cutaneous lupus erythematosus: a review of etiopathogenic, clinical, diagnostic and therapeutic aspects.

Cutaneous lupus erythematosus is an autoimmune disease of varied clinical expression, which may present as an exclusively cutaneous disease or be one of the multiple manifestations of systemic lupus erythematosus. Its classification includes acute, subacute, intermittent, chronic and bullous subtypes, which are usually identified based on clinical features and histopathological and laboratory findings. Other non-specific cutaneous manifestations may be associated with systemic lupus erythematosus and are usually related to disease activity. Environmental, genetic and immunological factors play a role in the pathogenesis of skin lesions in lupus erythematosus. Recently, considerable progress has been made in elucidating the mechanisms involved in their development, which allows for foreseeing future targets for more effective treatments. This review proposes to discuss the main etiopathogenic, clinical, diagnostic and therapeutic aspects of cutaneous lupus erythematosus, aiming to update internists and specialists from different areas.

Cutaneous lupus-erythematosus-like reaction arising after COVID-19 vaccination.

Multiple adverse cutaneous reactions have been described following vaccination against COVID-19. This case report describes a reaction to the Pfizer-BioNTech (BNT162b2) vaccine that histopathologically resembles cutaneous lupus erythematosus with vacuolar interface alteration, superficial to mid-dermal perivascular and periadnexal lymphocytic infiltrate with clusters of CD123+ cells, and mildly increased dermal mucin.

Subacute Cutaneous Lupus as a Paraneoplastic Manifestation of Non-Hodgkin Lymphoma.

Malignancies have been associated with paraneoplastic syndromes, such as dermatomyositis. Subacute cutaneous lupus erythematosus (SCLE) can occur due to a wide array of cancers. Paraneoplastic SCLE obeys McLean's criteria and often regresses after the underlying malignancy has been treated appropriately. Anti-Ro/SSA antibodies are often present in patients with paraneoplastic SCLE; however, there have been many instances where anti-Ro may not be present. We report a case of non-Hodgkin lymphoma causing SCLE, a malignancy not previously known to be associated with paraneoplastic SCLE. We also highlight the importance of perhaps prompt chemotherapy to treat the underlying malignancy, as a failure to do so may lead to worse patient outcomes.

B Cell Signatures Distinguish Cutaneous Lupus Erythematosus Subtypes and the Presence of Systemic Disease Activity.

Cutaneous lupus erythematosus (CLE) is a chronic inflammatory skin disease characterized by a diverse cadre of clinical presentations. CLE commonly occurs in patients with systemic lupus erythematosus (SLE), and CLE can also develop in the absence of systemic disease. Although CLE is a complex and heterogeneous disease, several studies have identified common signaling pathways, including those of type I interferons (IFNs), that play a key role in driving cutaneous inflammation across all CLE subsets. However, discriminating factors that drive different phenotypes of skin lesions remain to be determined. Thus, we sought to understand the skin-associated cellular and transcriptional differences in CLE subsets and how the different types of cutaneous inflammation relate to the presence of systemic lupus disease. In this study, we utilized two distinct cohorts comprising a total of 150 CLE lesional biopsies to compare discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), and acute cutaneous lupus erythematosus (ACLE) in patients with and without associated SLE. Using an unbiased approach, we demonstrated a CLE subtype-dependent gradient of B cell enrichment in the skin, with DLE lesions harboring a more dominant skin B cell transcriptional signature and enrichment of B cells on immunostaining compared to ACLE and SCLE. Additionally, we observed a significant increase in B cell signatures in the lesional skin from patients with isolated CLE compared with similar lesions from patients with systemic lupus. This trend was driven primarily by differences in the DLE subgroup. Our work thus shows that skin-associated B cell responses distinguish CLE subtypes in patients with and without associated SLE, suggesting that B cell function in skin may be an important link between cutaneous lupus and systemic disease activity.

A novel humanized cutaneous lupus erythematosus mouse model mediated by IL-21-induced age-associated B cells.

Cutaneous lupus erythematosus (CLE) is a relapsing autoimmune disease, but key elements that drive disease initiation and progression remain elusive. To date, the lack of ideal murine model which resemble human cutaneous lupus makes it extremely challenging for moving mechanistic discoveries and novel therapeutics. Here, we prompt a humanized murine model to develop an inducible rapid-onset murine that performs cutaneous rather than systemic lupus, depending on the successful human immune system reconstruction from active lupus patients and UVB irradiation as for essentially pathogenic triggers. In addition, we demonstrate a newly discovered population of B cell with a unique phenotype, that of the age-associated B cell (ABC, T-bet+ CD11b+), exhibits B cell clusters in humanized cutaneous lupus. In the response of IL-21 and TLR7/9 signals, recruitment of autoreactive B cells to the position of inflammation with subsequent localized antibody production of IgG2a, IgG2b, IgG3, has the potential to exacerbate ongoing inflammation and thus driving lupus-like autoimmunity in a B-cell-dominant fashion. Overall, our model provides a relevant system for exploring the pathophysiology of cutaneous lupus, a suitable model for drug development, as well as updating a potential role of IL-21 and TLR7/9 to be targeted by biologics.

Recognition and Management of Cutaneous Connective Tissue Diseases.

Connective tissue diseases (CTDs) encompass a broad spectrum of clinical presentations that involve multidisciplinary management. Cutaneous findings are common in CTD and careful examination of these features aids in appropriate diagnosis and subsequent evaluation. Thorough work-up of CTD is crucial to properly identify disease subtypes and systemic involvement. Management plans can be developed based on diagnosis and systemic manifestations of disease. Disease management often requires treatment with pharmacotherapies with potential for toxicities, further underscoring the importance of diagnostic accuracy in this patient population. Evolving research strives to better elucidate the pathogenic mechanisms of CTDs allowing for more targeted treatment modalities.

Subacute cutaneous lupus erythematosus triggered after measles vaccination.

Subacute cutaneous lupus erythematosus (SCLE) is a subtype of cutaneous lupus erythematosus that can be triggered by endogenous or exogenous factors. Among the exogenous factors are some medications, drugs, tobacco, infections, and vaccines. In this context, the benefits of vaccination are questioned because although it is important to prevent infections in immunosuppressed patients a theoretical risk of developing systemic lupus erythematosus (SLE) remains in these patients. This report presents a case of a previously healthy female patient who developed SCLE after measles vaccination and progressed to SLE and thereby suggests a possible trigger of the disease.

New-onset cutaneous lupus erythematosus after the COVID-19 vaccine.

Vaccine development for COVID-19 has progressed expeditiously. To date, the Food and Drug Administration (FDA) has authorized the Moderna/mRNA-1273, Pfizer-BioNTech (BNT162b2), and Johnson & Johnson's Janssen (JNJ-78436735) vaccines for use in the United States. Immediate side effects have included myalgia fatigue, chills, fever, and headache. We report an elderly patient with a history of lung cancer and no prior history of autoimmune disease who developed cutaneous lupus erythematosus two ½ months after the second dose of the Pfizer-BioNTech COVID-19 vaccine.

The pathogenesis of cutaneous lupus erythematosus: The aberrant distribution and function of different cell types in skin lesions.

Cutaneous lupus erythematosus (CLE) is an autoimmune disease with a broad range of cutaneous manifestations. In skin lesions of CLE, keratinocytes primarily undergo apoptosis. Interferon-κ(IFN-κ) is belonged to type I interferons (type I IFNs) and is selectively produced by keratinocytes. Recently, keratinocytes selectively produced IFN-κ is identified to be a key to trigger type I interferon responses in CLE. Other immune cells such as plasmacytoid dendritic cells (pDCs) are identified to be relevant origin of type I interferons (type I IFNs) which are central to the development of CLE lesions and responsible for mediating Th1 cell activity. Other types of cells such as neutrophils, B cells and Th17 cells also are involved in the development of this disease. The close interaction of those cells composes a comprehensive and complicated network in CLE. In this review, we discussed the aberrant distribution and function of different cells types involved in this disease and will offer a new direction for research and therapy in the near future.

Immunopathogenesis of skin injury in systemic lupus erythematosus.

PURPOSE OF REVIEW: Skin injury is the most common clinical manifestation of SLE and is disfiguring, difficult to treat, and incompletely understood. We provide an overview of recently published articles covering the immunopathogenesis of skin injury in SLE. RECENT FINDINGS: Skin of SLE has an inherent susceptibility to apoptosis, the cause of which may be multifactorial. Chronic IFN overexpression leads to barrier disruption, infiltration of inflammatory cells, cytokine production, and release of autoantigens and autoantibody production that result in skin injury. Ultraviolet light is the most important CLE trigger and amplifies this process leading to skin inflammation and potentially systemic disease flares. SUMMARY: The pathogenesis of skin injury in CLE is complex but recent studies highlight the importance of mechanisms driving dysregulated epidermal cell death likely influenced by genetic risk factors, environmental triggers (UV light), and cytotoxic cells and cellular signaling.

Cutaneous lupus erythematosus: factors related to cutaneous activity and damage in a cohort of 260 patients from A Coruña, Spain.

BACKGROUND: Cutaneous lupus erythematosus is a chronic autoimmune disease that can leave important sequelae. OBJECTIVE: To determine the factors that predict the activity and damage of the skin disease, and the impact of tobacco on the efficacy of antimalarials using the Cutaneous Lupus Erythematosus Disease Area and Severity Index. MATERIALS AND METHODS: A consecutive case series was performed on 260 patients with cutaneous lupus erythematosus (α = 0.05; precision ± 6.5%). We carried out a descriptive analysis of the variables included, with a multivariate analysis to measure the association of variables with the Cutaneous Lupus Erythematosus Disease Area and Severity Index activity and damage (p value < 0.05). RESULTS: The Cutaneous Lupus Erythematosus Disease Area and Severity Index activity was greater in smokers than non-smokers (4.0 ±5.3 vs 1.2 ±3.4, p = 0.006). No significant differences were observed in the Cutaneous Lupus Erythematosus Disease Area and Severity Index activity when the efficacy of antimalarials was analyzed between smokers and non-smokers. Cutaneous Lupus Erythematosus Disease Area and Severity Index damage was higher in smokers than in non-smokers (2.0 ± 3.6 vs 1.2 ± 2.6, p = 0.029). Cutaneous Lupus Erythematosus Disease Area and Severity Index activity was associated with: (a) being an active smoker (odds ratio 3.04, 95% confidence interval 1.68-5.51, p < 0.001; regression coefficient 2.05, 95% confidence interval 0.69-3.42, p = 0.003); (b) the chronic cutaneous lupus erythematosus subtype (odds ratio 1.98, 95% confidence interval 1.02-3.84, p = 0.044); and (c) C-reactive protein increase (≥0.5 mg/dL) (regression coefficient 2.56, 95% confidence interval 0.40-4.71, p = 0.020). Cutaneous Lupus Erythematosus Disease Area and Severity Index damage was associated with: (a) the activity (regression coefficient 0.11, 95% confidence interval 0.01-0.20, p = 0.024); (b) the chronic cutaneous lupus erythematosus subtype (regression coefficient 2.46, 95% confidence interval 1.37-3.56, p < 0.001); (c) the use of topical treatment (regression coefficient 1.31, 95% confidence interval 0.01-2.61, p = 0.049); and (d) systemic treatment (regression coefficient 1.44, 95% confidence interval 0.35-2.53, p < 0.010). CONCLUSION: Smoking is related to an increase risk and a greater activity of cutaneous lupus erythematosus. The chronic cutaneous lupus erythematosus subtype and an increased C-reactive protein level were also associated with a higher disease activity. The sequelae were related to the activity, the chronic cutaneous lupus erythematosus subtype, and the use of topical and systemic treatment. The impact of tobacco on the efficacy of antimalarials may be caused by an increase in the severity of the disease more than by resistance in smokers.

Cutaneous Lupus Erythematosus: Progress and Challenges.

PURPOSE OF REVIEW: The review provides an update on the diagnosis, pathogenesis, and treatment of cutaneous lupus erythematosus (CLE). RECENT FINDINGS: Diagnostic challenges exist in better defining CLE as an independent disease distinct from systemic lupus erythematosus with cutaneous features and further classifying CLE based on clinical, histological, and laboratory features. Recent mechanistic studies revealed more genetic variations, environmental triggers, and immunologic dysfunctions that are associated with CLE. Drug induction specifically has emerged as one of the most important triggers for CLE. Treatment options include topical agents and systemic therapies, including newer biologics such as belimumab, rituximab, ustekinumab, anifrolumab, and BIIB059 that have shown good clinical efficacy in trials. CLE is a group of complex and heterogenous diseases. Future studies are warranted to better define CLE within the spectrum of lupus erythematosus. Better insight into the pathogenesis of CLE could facilitate the design of more targeted therapies.