Canine cutaneous lupus erythematosus with prominent interdigital lesions in two greyhounds.

Canine cutaneous lupus erythematosus (CCLE) is a well-described, yet uncommon, autoimmune disease which can present clinically with different variants. This case report describes the clinical and histopathological presentation, and treatment response, of CCLE affecting a novel location, the interdigital skin, in two unrelated greyhounds.

O lúpus eritematoso cutâneo canino (LECC) é uma doença autoimune bem descrita, porém incomum, que pode se apresentar clinicamente com diferentes variantes. Este relato de caso descreve a apresentação clínica e histopatológica, e a resposta ao tratamento, do LECC afetando uma nova localização, a pele interdigital, em dois galgos não aparentados.

El lupus eritematoso cutáneo canino (CCLE) es una enfermedad autoinmune bien descrita, aunque poco frecuente, que puede presentarse clínicamente con diferentes variantes. Este informe de caso describe la presentación clínica e histopatológica, y la respuesta al tratamiento, de CCLE que afecta a una nueva ubicación, la piel interdigital, en dos galgos no relacionados.

Le lupus érythémateux cutané canin (LECC) est une maladie auto-immune bien documentée, mais peu fréquente, qui peut se présenter cliniquement sous différents variants. Ce rapport clinique décrit la présentation clinique et histopathologique, ainsi que la réponse au traitement, du LECC affectant une nouvelle localisation, la peau interdigitée, de deux lévriers non apparentés.

Cutaneous Lupus Erythematosus: Review and Considerations for Older Populations.

Though more common earlier in life, increasing attention is being focused on the development of cutaneous lupus erythematosus (CLE) in patients with advancing age. Studies show that CLE is more common in older populations than previously thought, and all CLE subtypes are possible in this group. Just like patients in the third or fourth decade of life, CLE may appear alongside or independent of systemic lupus erythematosus. Older populations manifesting CLE for the first time seem to have a lower risk of progression to systemic disease than younger peers, and are more commonly White. CLE must be carefully distinguished from other skin conditions that have a predilection for presentation in older populations, including rosacea, lichen planus, and other autoimmune conditions such as dermatomyositis or pemphigus/pemphigoid. It is thought that most CLE in older populations is drug-induced, with drug-induced subacute cutaneous lupus erythematosus being the most common subtype. Management of CLE in older patients focuses on eliminating unnecessary medications known to induce CLE, and otherwise treatment proceeds similarly to that in younger patients, with a few special considerations.

A rare case of cutaneous lupus erythematosus presenting with periorbital erythema and edema.

Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease that can manifest itself with a variety of skin symptoms. Periorbital erythema, a rare variant of CLE, presents challenges in terms of diagnosis and treatment. Here, we report a case of CLE presenting with periorbital erythema and edema. A 42-year-old female patient presented with complaints of erythema, edema, and scaling on the right eyelid that started four months ago. A skin biopsy was performed on the lesioned skin of the eyelid to differentiate dermatomyositis, cutaneous lupus erythematosus, sarcoidosis, lupus vulgaris, and cutaneous lymphoma. Histopathological examination revealed focal hyperkeratosis and parakeratosis on the surface of the epidermis, vacuolar degeneration in the basal layer of the epidermis, lymphocyte exocytosis with necrotic keratinocytes, edema in the dermis, melanophages, and perivascular, periadnexal lymphocytic reaction. Laboratory tests showed negative antinuclear antibody and anti-dsDNA, but positivity for anti-Ro-52. In the absence of any other complaints, the patient was diagnosed with cutaneous lupus erythematosus presenting with periorbital erythema based on clinical, histopathological, and laboratory findings. Hydroxychloroquine 200 mg/day, topical corticosteroid, and topical tacrolimus were administered. Two months later, significant improvement in the lesions was observed. In conclusion, it should be kept in mind that periorbital erythema can develop as a rare variant of CLE and can be misdiagnosed as contact dermatitis, dermatomyositis, sarcoidosis, or cutaneous lymphoma. Additionally, the ANA and anti-dsDNA antibodies are often found to be negative in these cases. In establishing the diagnosis, firstly considering the disease, followed by histopathological examinations and laboratory tests, is crucial.

Manifestation of subacute cutaneous lupus erythematosus during treatment with anti-PD-1 antibody cemiplimab - a case report.

Introduction: The anti-programmed cell death protein 1 (PD-1) antibody cemiplimab has shown promising results in the treatment of unresectable or metastatic squamous cell carcinoma, however, frequently leads to immune-related adverse events limiting therapy efficacy. Although cutaneous side effects are common, only very few cases of cutaneous lupus erythematosus have been reported under anti-PD-1 immunotherapy. So far, no case of cutaneous lupus has been described under treatment with cemiplimab. Case report: For the first time, we report the case of a patient with advanced squamous cell carcinoma, who developed clinical and histological findings in sun-exposed skin that were consistent with anti-SS-A/Ro antibody-positive subacute cutaneous lupus erythematosus (SCLE) under treatment with cemiplimab. Additionally, laboratory chemical analyses revealed a severe immune-related hepatitis without clinical symptoms. Both, the SCLE and the hepatitis, resolved after the administration of topical and systemic steroids and the discontinuation of anti-PD-1 therapy. Conclusion: Treatment with cemiplimab can be associated with the appearance of cutaneous lupus erythematosus in sun-exposed areas. Application of topical and systemic glucocorticoids can lead to a rapid resolution of the skin eruptions. Moreover, our case illustrates the possibility of simultaneously occurring severe immune-related adverse events. This highlights the importance of additional diagnostics to avoid overlooking additional immune-related adverse events.

Case series of anifrolumab for treatment of cutaneous lupus erythematosus and lupus-related mucocutaneous manifestations in patients with SLE.

OBJECTIVE: To assess the efficacy of anifrolumab, a type-1 interferon receptor subunit-1 monoclonal antibody, in treating refractory cutaneous lupus erythematosus (CLE) and lupus non-specific mucocutaneous manifestations in patients with systemic lupus erythematosus (SLE). METHODS: A case series comprising four SLE patients with refractory CLE received anifrolumab (300mg) as add-on therapy. Medical history, serological markers and images were collected. Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity (CLASI-A) was assessed at baseline and post-treatment visits. RESULTS: Patient 1: Anifrolumab effectively treated refractory chronic cutaneous lupus erythematosus with lupus panniculitis and calcinosis cutis.Patient 2: Anifrolumab demonstrated rapid improvement in generalised discoid lupus, achieving a substantial reduction in CLASI-A from 40 to 8.Patient 3: Switching from belimumab to anifrolumab led to notable improvement in photosensitivity and tumid lupus.Patient 4: Anifrolumab effectively managed refractory subacute cutaneous lupus erythematosus, resulting in remarkable cutaneous improvement and successful tapering of prednisone and mycophenolate mofetil. CONCLUSION: Anifrolumab demonstrates efficacy in treating refractory CLE subtypes and lupus non-specific mucocutaneous manifestations in SLE patients. Further studies are needed to establish response rates, optimal dosing, and long-term outcomes.

Cutaneous Toll-like Receptor 9 Pre-Defines Hydroxychloroquine Dosage in Patients with Both Discoid and Subacute Lupus Erythematosus.

Background and Objectives: Cutaneous lupus erythematosus (CLE) presents clinically heterogeneous manifestations, partially explained by the different expression of Toll-like receptors (TLRs) type 8 and 9, located to endosomal compartments where they are poised to recognize microbial nucleic acids. This disease is empirically treated with hydroxychloroquine (HCQ), which is hallmarked with a safe and effective profile, but induces a slow and sometimes clinically insufficient therapeutic response. Currently, no biomarkers predictive of response are validated or even proposed in the scientific literature. We aimed to evaluate endosomal TLR type 7, 8 and 9 as predictive biomarkers of HCQ efficacy. Materials and Methods: We conducted a case-control study comparing CLE patients retrospectively assigned to three subgroups based on 3-6-month Cutaneous LE Disease Area and Severity Index (CLASI) reduction upon treatment with HCQ (I = <40% vs. II = 40-80% vs. III = >80%). Before HCQ, lesional skin specimens were collected in untreated CLE and through immunohistochemistry; TLR-7, -8 and -9 expression was evaluated in the epidermis and the lymphocytic infiltrate was evaluated in the dermis. Results: Sixty-six lesional skin biopsies were compared with healthy controls. CLE patients displayed lower epidermal expression of total TLR 8 and 9 as well as infiltrating TLR-8, TLR9 + lymphocytes compared to controls. High HCQ responders differed from low responders for TLR-9 positivity (high vs. low) and for the lymphocytic dermal infiltrate (high vs. low). Conclusions: TLR9 could be envisaged as a possible biomarker to predict HCQ response level and dosage in CLE patients.

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.

Case Report: Response of cutaneous lupus lesions in SLE to interferon receptor blockade parallels reduction of interferon score in blood.

Cutaneous lupus erythematosus (CLE), the main manifestation of systemic lupus erythematosus (SLE), is driven by type I interferons (IFNs) and often only partially responds to conventional therapies. Treatment of seven SLE patients with the monoclonal antibody anifrolumab induced fast and sustained remission of previously refractory CLE lesions, beginning within the first weeks of treatment. Decline in CLASI-A score was paralleled by a reduction in IFN score determined by mRNA expression of seven IFN-stimulated genes (ISGs) in blood. These data suggest that a subset of ISGs could be a valuable biomarker in CLE.

Nano-encapsulated anandamide reduces inflammatory cytokines in vitro and lesion severity in a murine model of cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune skin disease which occurs independently and in conjunction with systemic lupus erythematosus. Drug development for CLE is severely lacking. Anandamide (AEA) is a primary endocannabinoid which exhibits immunomodulatory effects through mixed cannabinoid receptor agonism. We evaluated AEA as topical treatment for CLE and assessed benefits of nanoparticle encapsulation (AEA-NP) on cutaneous drug penetration, delivery and biological activity. Compared to untreated controls, AEA-NP decreased IL-6 and MCP-1 in UVB-stimulated keratinocytes (p < 0.05) in vitro. In BALB/c mice, AEA-NP displayed improved cutaneous penetration, extended release and persistence of AEA in the follicular unit extending to the base after 24 h. Utilizing the MRL-lpr lupus murine model, twice weekly treatment of lesions with topical AEA-NP for 10 weeks led to decreased clinical and histologic lesion scores compared to unencapsulated AEA and untreated controls (p < 0.05). Prophylactic application of AEA-NP to commonly involved areas on MRL-lpr mice similarly resulted in decreased clinical and histologic scores when compared to controls (p < 0.05), and reduced C3 and IBA-1 in lesional tissue (p < 0.05). The demonstrated clinical and immunomodulatory effects of treatment with AEA support its potential as therapy for CLE. This work also suggests that encapsulation of AEA improves penetration and treatment efficacy. Future studies will be conducted to assess full therapeutic potential.

Efficacy and safety of Janus kinase inhibitors in systemic and cutaneous lupus erythematosus: A systematic review and meta-analysis.

BACKGROUND: Janus kinase (JAK) inhibitors have been proven to be effective and safe in various autoimmune diseases. However, there is still a lack of comprehensive evidence regarding their efficacy and safety in systemic and cutaneous lupus erythematosus. METHODS: We searched for systemic and cutaneous lupus erythematosus patients who were treated with JAK inhibitors in PubMed, Embase, Web of Science, and the Cochrane Library until February 28, 2023. The quality of clinical trials was assessed using the Cochrane risk-of-bias tool. Meta-analysis was conducted when at least three studies had comparable measures of outcome. If meta-analysis was not feasible, a descriptive review was carried out. RESULTS: We included 30 studies, consisting of 10 randomized controlled trials and 20 case series or reports, with a total of 2,460 patients. JAK inhibitors were found to be more effective than placebo in systemic lupus erythematosus (SLE) based on the percentage of achieving SLE Responder Index (SRI)-4 response (RR = 1.18; 95% CI 1.07 to 1.31; p = 0.001), British Isles Lupus Assessment Group -based Composite Lupus Assessment (BICLA) response (RR = 1.16; 95% CI 1.02 to 1.31; p = 0.02), Lupus Low Disease Activity State (LLDAS) (RR = 1.28; 95% CI 1.07 to 1.54; p = 0.008), and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K) remission of arthritis or rash (RR = 1.09; 95% CI 1.00 to 1.18; p = 0.04), particularly in treating musculoskeletal and mucocutaneous involvement. However, the effect of JAK inhibitors on cutaneous lupus erythematosus was uncertain. JAK inhibitors and placebo had a similar incidence of adverse events (RR = 1.01; 95% CI 0.97 to 1.04; p = 0.65). CONCLUSION: JAK inhibitors could be a potential treatment option for systemic and cutaneous lupus erythematosus, particularly in treating cutaneous and musculoskeletal lesions of SLE. JAK inhibitors had a safe profile.

Litifilimab (BIIB059), a promising investigational drug for cutaneous lupus erythematosus.

INTRODUCTION: There are no U.S. Food and Drug Administration (FDA) approved therapies for cutaneous lupus erythematosus (CLE). Litifilimab is a monoclonal antibody against BDCA2, a plasmacytoid dendritic cell-specific antigen, currently under investigation for systemic lupus erythematosus (SLE) and CLE. The LILAC study, published in the New England Journal of Medicine, is a phase II randomized controlled trial for CLE which demonstrated superiority of Litifilimab over placebo using a skin directed outcome measure. AREAS COVERED: This review identifies challenges that have hindered the development of any approved treatments for CLE, recent SLE trials that include skin disease data, and the pharmacological properties of litifilimab. We review the clinical efficacy and safety of litifilimab for both SLE and CLE in the phase I and II clinical trials. This review aims to highlight the need for more CLE-specific clinical trials and examine the potential of litifilimab as the first FDA approved therapy for CLE. (Clinical trial registration: www.clinicaltrials.gov identifier is NCT02847598.). EXPERT OPINION: Litifilimab demonstrated efficacy in a randomized phase II clinical trial as a standalone CLE trial using validated skin-specific outcome measures, making it the first successful clinical trial for a CLE targeted therapy. If approved, litifilimab will be a pivotal change in the landscape of CLE management especially for severe and refractory disease.

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.

German Shorthaired Pointer dogs with exfoliative cutaneous lupus erythematosus develop immune-complex membranous glomerulonephropathy.

German Shorthaired Pointer (GSHP) dogs with a UNC93B1 gene mutation develop exfoliative cutaneous lupus erythematosus (ECLE) and kidney disease resembling lupus nephritis in humans. The objective of this study was to characterize the kidney disease by light microscopy, immunofluorescence, and electron microscopy in a population of GSHP dogs with ECLE. Medical records were reviewed, and light microscopy of kidneys from 7 GSHP dogs with a previous histologic diagnosis of ECLE was performed. Immunofluorescence of fresh-frozen kidney from 1 dog and transmission electron microscopy of kidney from that dog and 2 additional dogs were performed. Five of 7 dogs had proteinuria diagnosed by urinalysis or urine protein-to-creatinine ratio. Two of 7 dogs were intermittently hypoalbuminemic, and none were azotemic. Histologic findings included early (2 dogs) to late (5 dogs) membranous glomerulonephropathy characterized by mild-to-severe glomerular capillary loop thickening and tubular proteinosis. In all 7 cases, trichrome staining revealed red granular immune deposits on the subepithelial surface of the glomerular basement membrane. Immunofluorescence revealed strong granular labeling for immunoglobulins and complement protein C3. Electron microscopy demonstrated subepithelial electron-dense immune deposits encircled by the remodeled glomerular basement membrane. These findings are diagnostic of immune-complex membranous glomerulonephropathy and are similar to class V lupus in humans. This cohort of GSHP dogs with ECLE developed immune-complex membranous glomerulonephropathy, which we hypothesize is a manifestation of systemic lupus erythematosus. GSHP dogs with ECLE should undergo clinical evaluation of renal function for early identification and treatment.