International exchange on the clinical practice and research of rheumatic skin diseases: A report of the 5th International Conference of Cutaneous Lupus Erythematosus.

The 5th International Conference of Cutaneous Lupus Erythematosus was held in Tokyo, Japan on May 9 and 10, 2023. The latest topics on the pathogenesis, diagnosis, assessment, and treatment of cutaneous lupus erythematosus, dermatomyositis, and scleroderma (systemic sclerosis, morphea) were presented by experts in each field and new developments discussed. In these rheumatic skin diseases, many clinical trials of novel therapies targeting cytokines, signaling molecules, plasmacytoid dendritic cells, B cells, and other molecules are currently underway, and standardization of outcome assessment was discussed. In addition, the selection of the therapeutic agents available for the diversity of each case is becoming more important, together with the ongoing pathophysiological analysis of the diseases. The achievements of this conference will further promote the development of clinical practice and research in rheumatic skin diseases through international exchange among researchers. We hope that by reporting a summary of the conference in this manuscript, we can share its contents with readers.

An update on clinical trials for cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) comprises dermatologic manifestations that may occur independently or with systemic lupus erythematosus (SLE). Despite advancements in refining CLE classification, establishing precise subtype criteria remains challenging due to overlapping presentations and difficulty in distinguishing morphology. Current treatments encompass preventive measures, topical therapies, and systemic approaches. Hydroxychloroquine and glucocorticoids are the sole US Food and Drug Administration (FDA)-approved medications for CLE, with numerous off-label treatments available. However, these treatments are often not covered by insurance, imposing a significant financial burden on patients. The exclusion of most CLE patients, particularly those without concurrent SLE, from trials designed for SLE has resulted in a lack of targeted treatments for CLE. To develop effective CLE treatments, validated outcome measures for tracking patient responsiveness are essential. The Cutaneous Lupus Erythematosus Disease Area and Severity Index is widely utilized for its reliability, validity, and ability to differentiate between skin activity and damage. In contrast, the FDA mandates the use of the Investigator's Global Assessment, a five-point Likert scale related to lesion characteristics, for skin-related therapeutic trials. It requires the disease to resolve or almost completely resolve to demonstrate improvement, which can be difficult when there is residual erythema or incomplete clearance that is meaningfully improved from a patient perspective. Various classes of skin lupus medications target diverse pathways, allowing tailored treatment based on the patient's lupus inflammatory profile, resulting in improved outcomes. Promising targeted therapeutic drugs include anifrolumab (anti-type 1 interferon), deucravacitinib (allosteric tyrosine kinase 2 inhibitor), litifilimab (plasmacytoid dendritic cell-directed therapy), iberdomide (cereblon-targeting ligand), and belimumab (B-cell directed therapy). Despite the significant impact of CLE on quality of life, therapeutic options remain inadequate. While promising treatments for cutaneous lupus are emerging, it is crucial to underscore the urgency for skin-focused treatment outcomes and the implementation of validated measures to assess therapeutic effectiveness in clinical trials.

Autoimmune Skin Conditions: Cutaneous Lupus Erythematosus.

Cutaneous lupus erythematosus (CLE) is a spectrum of autoimmune skin conditions associated with systemic lupus erythematosus (SLE). CLE and SLE may exist concurrently or independently. Accurate recognition of CLE is crucial because it may herald systemic disease onset. Lupus-specific skin conditions include acute cutaneous lupus erythematosus (ACLE) which manifests as a malar or butterfly rash; subacute cutaneous lupus erythematosus (SCLE); and chronic cutaneous lupus erythematosus, which includes discoid lupus erythematosus (DLE). All three types of CLE present as pink-violet macules or plaques with unique morphology, in areas of sun-exposed skin. Association with SLE differs: ACLE is most closely associated, with SCLE in the middle, and DLE the least so. All types of CLE are pruritic, sting, and burn, and DLE can result in disfiguring scarring. All CLE is exacerbated by UV light exposure and smoking. Diagnosis combines clinical evaluation with skin biopsy. Management focuses on mitigating modifiable risk factors and using pharmacotherapy. UV protection includes use of sun protective factor (SPF) 60 or higher sunscreens containing zinc oxide or titanium dioxide, avoidance of sun exposure, and use of physical barrier clothing. Topical therapies and antimalarial drugs are first-line, followed by systemic therapies (eg, disease-modifying antirheumatic drugs, biologic therapies [eg, anifrolumab, belimumab], or other advanced systemic drugs).

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.

Modulation of Immune Cells as a Therapy for Cutaneous Lupus Erythematosus.

Cutaneous lupus erythematosus (CLE) is an autoimmune disorder like systemic lupus erythematosus (SLE). Both SLE and CLE characterize autoantibody secretion and immune cell recruitment. In particular, CLE can be divided into three more frequent types, varying in the severity of the skin lesions they present. The role of type I IFN was shown to be one of the leading causes of the development of this pathology in the skin. Different treatments have been developed and tested against these different variants of CLE to decrease the increasing levels of CLE in humans. In this article, a literature revision discussing the similarities between SLE and CLE is carried out. In addition, new advances in understanding the development of CLE and the leading treatments being evaluated in animal models and clinical trials are reviewed.

Lupus Erythematosus Tumidus Clinical Characteristics and Treatment: A Retrospective Review of 25 Patients.

Lupus erythematosus tumidus (LET) is a rare photosensitive der-matosis that was considered a subtype of chronic cutaneous lupus erythematosus (CLE); however, its clinical course and favorable prognosis led to its reclassification into another category called intermittent CLE. Although known for more than 100 years, LET's association with systemic lupus erythematosus (SLE), autoantibody profile, and disease prognosis is not well characterized. The purpose of this study was to describe the demographics, clinical characteristics, autoantibody profile, comorbidities, and treatment of LET.

Lupus erythematosus: Management of cutaneous manifestations during pregnancy.

Lupus erythematosus is an autoimmune disease that often affects the skin. Cutaneous manifestations are generally subdivided into different subtypes, including acute, subacute, and chronic courses. Management of lupus erythematosus cutaneous manifestations during pregnancy remains a clinical challenge until nowadays. To date, no recommendations have been published specifically for the treatment of this condition in pregnant women, so therapeutic strategies are mainly based on recommendations for general population and other rheumatologic and dermatologic diseases during pregnancy. This challenge is compounded by a lack of evidence-based studies, as clinical trials in pregnant women are considered unethical in many circumstances, so data are often extrapolated from low-evidence sources. The aim of this article consists in review currently evidence of treatment of lupus erythematosus cutaneous lesion in pregnant women.

Development of a working core outcome set for cutaneous lupus erythematosus: a practical approach to an urgent unmet need.

OBJECTIVE: The lack of standardised outcomes and outcome measures for cutaneous lupus erythematosus (CLE) represents a substantial barrier to clinical trial design, comparative analysis and approval of novel investigative treatments. We aimed to develop a working core outcome set (COS) for CLE randomised controlled trials and longitudinal observational studies. METHODS: We conducted a multistage literature review of CLE and SLE studies to generate candidate domains and outcome measures. Domains were narrowed to a working core domain set. Outcome measures for core domains were identified and examined. RESULTS: Proposed core domains include skin-specific disease activity and damage, investigator global assessment (IGA) of disease activity, symptoms (encompassing itch, pain and photosensitivity), health-related quality of life (HRQoL) and patient global assessment (PtGA) of disease activity. Recommended physician-reported outcome measures include the Cutaneous Lupus Erythematous Disease Area and Severity Index (CLASI) and Cutaneous Lupus Activity IGA (CLA-IGA). For the domains of symptoms, HRQoL and PtGA of disease activity, we were unable to recommend one clearly superior instrument. CONCLUSION: This work represents a starting point for further refinement pending formal consensus activities and more rigorous evaluations of outcome measure quality. In the interim, the proposed working COS can serve as a much-needed guide for upcoming CLE clinical trials.

Guideline for the diagnosis, treatment and long-term management of cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is an inflammatory, autoimmune disease encompassing a broad spectrum of subtypes including acute, subacute, chronic and intermittent CLE. Among these, chronic CLE can be further classified into several subclasses of lupus erythematosus (LE) such as discoid LE, verrucous LE, LE profundus, chilblain LE and Blaschko linear LE. To provide all dermatologists and rheumatologists with a practical guideline for the diagnosis, treatment and long-term management of CLE, this evidence- and consensus-based guideline was developed following the checklist established by the international Reporting Items for Practice Guidelines in Healthcare (RIGHT) Working Group and was registered at the International Practice Guideline Registry Platform. With the joint efforts of the Asian Dermatological Association (ADA), the Asian Academy of Dermatology and Venereology (AADV) and the Lupus Erythematosus Research Center of Chinese Society of Dermatology (CSD), a total of 25 dermatologists, 7 rheumatologists, one research scientist on lupus and 2 methodologists, from 16 countries/regions in Asia, America and Europe, participated in the development of this guideline. All recommendations were agreed on by at least 80% of the 32 voting physicians. As a consensus, diagnosis of CLE is mainly based on the evaluation of clinical and histopathological manifestations, with an exclusion of SLE by assessment of systemic involvement. For localized CLE lesions, topical corticosteroids and topical calcineurin inhibitors are first-line treatment. For widespread or severe CLE lesions and (or) cases resistant to topical treatment, systemic treatment including antimalarials and (or) short-term corticosteroids can be added. Notably, antimalarials are the first-line systemic treatment for all types of CLE, and can also be used in pregnant patients and pediatric patients. Second-line choices include thalidomide, retinoids, dapsone and MTX, whereas MMF is third-line treatment. Finally, pulsed-dye laser or surgery can be added as fourth-line treatment for localized, refractory lesions of CCLE in cosmetically unacceptable areas, whereas belimumab may be used as fourth-line treatment for widespread CLE lesions in patients with active SLE, or recurrence of ACLE during tapering of corticosteroids. As for management of the disease, patient education and a long-term follow-up are necessary. Disease activity, damage of skin and other organs, quality of life, comorbidities and possible adverse events are suggested to be assessed in every follow-up visit, when appropriate.

Treatments for disease damage in cutaneous lupus erythematosus: A narrative review.

Cutaneous lupus erythematosus (CLE) is an autoimmune photosensitive disorder that affects the skin. CLE lesions can have signs of skin damage including dyspigmentation, scarring, atrophy and/or alopecia. Disease damage secondary to CLE can be cosmetically disfiguring and causes patients significant distress. While many current treatments for CLE focus primarily on reducing inflammation, there are few options for managing disease damage. Providers currently lack strong guidance on managing CLE damage due to the paucity of literature on this topic. Because of this knowledge gap, we aim to provide an overview of what is currently known about the pathogenesis and management of signs of disease damage in CLE. In this narrative review, Pubmed, Ovid Medline, and Google scholar were searched for relevant articles assessing pathogenesis and treatment of disease damage. Therapeutic options for CLE damage, including hyperpigmentation (laser and camouflage), hypopigmentation (melanocyte grafting and camouflage), scarring (laser, dermabrasion, and camouflage), atrophy (filler, fat transplantation, and flap procedures), and scarring alopecia (hair transplantation and camouflage) were identified. We found that investigations of therapeutics for CLE disease damage primarily consist of case reports and small case series. Reported adverse events due to treatment for CLE disease damage range from temporary erythema and discomfort to disease reactivation and pigmentary defects. There are various treatments for disease damage for each sign of disease damage. However, more robust investigations are needed to assess disease pathogenesis and improve treatments of disease damage due to CLE.

Interventions for cutaneous disease in systemic lupus erythematosus.

BACKGROUND: Lupus erythematosus is an autoimmune disease with significant morbidity and mortality. Cutaneous disease in systemic lupus erythematosus (SLE) is common. Many interventions are used to treat SLE with varying efficacy, risks, and benefits. OBJECTIVES: To assess the effects of interventions for cutaneous disease in SLE. SEARCH METHODS: We searched the following databases up to June 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, Wiley Interscience Online Library, and Biblioteca Virtual em Saude (Virtual Health Library). We updated our search in September 2020, but these results have not yet been fully incorporated. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of interventions for cutaneous disease in SLE compared with placebo, another intervention, no treatment, or different doses of the same intervention. We did not evaluate trials of cutaneous lupus in people without a diagnosis of SLE. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Primary outcomes were complete and partial clinical response. Secondary outcomes included reduction (or change) in number of clinical flares; and severe and minor adverse events. We used GRADE to assess the quality of evidence. MAIN RESULTS: Sixty-one RCTs, involving 11,232 participants, reported 43 different interventions. Trials predominantly included women from outpatient clinics; the mean age range of participants was 20 to 40 years. Twenty-five studies reported baseline severity, and 22 studies included participants with moderate to severe cutaneous lupus erythematosus (CLE); duration of CLE was not well reported. Studies were conducted mainly in multi-centre settings. Most often treatment duration was 12 months. Risk of bias was highest for the domain of reporting bias, followed by performance/detection bias. We identified too few studies for meta-analysis for most comparisons. We limited this abstract to main comparisons (all administered orally) and outcomes. We did not identify clinical trials of other commonly used treatments, such as topical corticosteroids, that reported complete or partial clinical response or numbers of clinical flares. Complete clinical response Studies comparing oral hydroxychloroquine against placebo did not report complete clinical response. Chloroquine may increase complete clinical response at 12 months' follow-up compared with placebo (absence of skin lesions) (risk ratio (RR) 1.57, 95% confidence interval (CI) 0.95 to 2.61; 1 study, 24 participants; low-quality evidence). There may be little to no difference between methotrexate and chloroquine in complete clinical response (skin rash resolution) at 6 months' follow-up (RR 1.13, 95% CI 0.84 to 1.50; 1 study, 25 participants; low-quality evidence). Methotrexate may be superior to placebo with regard to complete clinical response (absence of malar/discoid rash) at 6 months' follow-up (RR 3.57, 95% CI 1.63 to 7.84; 1 study, 41 participants; low-quality evidence). At 12 months' follow-up, there may be little to no difference between azathioprine and ciclosporin in complete clinical response (malar rash resolution) (RR 0.83, 95% CI 0.46 to 1.52; 1 study, 89 participants; low-quality evidence). Partial clinical response Partial clinical response was reported for only one key comparison: hydroxychloroquine may increase partial clinical response at 12 months compared to placebo, but the 95% CI indicates that hydroxychloroquine may make no difference or may decrease response (RR 7.00, 95% CI 0.41 to 120.16; 20 pregnant participants, 1 trial; low-quality evidence). Clinical flares Clinical flares were reported for only two key comparisons: hydroxychloroquine is probably superior to placebo at 6 months' follow-up for reducing clinical flares (RR 0.49, 95% CI 0.28 to 0.89; 1 study, 47 participants; moderate-quality evidence). At 12 months' follow-up, there may be no difference between methotrexate and placebo, but the 95% CI indicates there may be more or fewer flares with methotrexate (RR 0.77, 95% CI 0.32 to 1.83; 1 study, 86 participants; moderate-quality evidence). Adverse events Data for adverse events were limited and were inconsistently reported, but hydroxychloroquine, chloroquine, and methotrexate have well-documented adverse effects including gastrointestinal symptoms, liver problems, and retinopathy for hydroxychloroquine and chloroquine and teratogenicity during pregnancy for methotrexate. AUTHORS' CONCLUSIONS: Evidence supports the commonly-used treatment hydroxychloroquine, and there is also evidence supporting chloroquine and methotrexate for treating cutaneous disease in SLE. Evidence is limited due to the small number of studies reporting key outcomes. Evidence for most key outcomes was low or moderate quality, meaning findings should be interpreted with caution. Head-to-head intervention trials designed to detect differences in efficacy between treatments for specific CLE subtypes are needed. Thirteen further trials are awaiting classification and have not yet been incorporated in this review; they may alter the review conclusions.

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.

Systematic Review: Monoclonal Antibody-Induced Subacute Cutaneous Lupus Erythematosus.

BACKGROUND: Subacute cutaneous lupus erythematosus (SCLE) lacks consensus diagnostic criteria and the pathogenesis is poorly understood. There are increasing reports of SCLE induced by monoclonal antibodies (mAbs), but there are limited data on the aetiology, clinical characteristics and natural course of this disease. METHODS: We devised a set of diagnostic criteria for SCLE in collaboration with a multinational, multispecialty panel. This systematic review employed a two-layered search strategy of five databases for cases of mAb-induced SCLE (PROSPERO registered protocol CRD42019116521). To explore the relationship between relative mAb use and the number of SCLE cases reported, the estimated number of mAb users was modelled from 2013 to 2018 global commercial data and estimated annual therapy costs. RESULTS: From 40 papers, we identified 52 cases of mAb-induced SCLE, occurring in a cohort that was 73% female and with a median age of 61 years. Fifty percent of cases were induced by anti-tumour necrosis factor (TNF)-ɑ agents. A median of three drug doses preceded SCLE onset and the lesions lasted a median of 7 weeks after drug cessation. Oral and topical corticosteroids were most frequently used. Of the licensed mAbs, adalimumab, denosumab, rituximab, etanercept and infliximab were calculated to have the highest relative number of yearly users based on global sales data. Comparing the number of mAb-induced SCLE cases with estimated yearly users, the checkpoint inhibitors pembrolizumab and nivolumab showed strikingly high rates of SCLE relative to their global use, but ipilimumab did not. CONCLUSION: We present the first systematic review characterising mAb-induced SCLE with respect to triggers, clinical signs, laboratory findings, prognosis and treatment approaches. We identify elevated rates associated with the use of checkpoint inhibitors and anti-TNFɑ agents.