Therapy For Cutaneous Lupus Erythematosus Research Articles

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.

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

ABSTRACT 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.

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.

Increased CD69+CCR7+ circulating activated T cells and STAT3 expression in cutaneous lupus erythematosus patients recalcitrant to antimalarials.

Antimalarials are first-line systemic therapy for cutaneous lupus erythematosus (CLE). While some patients unresponsive to hydroxychloroquine (HCQ) alone benefit from the addition of quinacrine (QC), a subset of patients is refractory to both antimalarials. We classified CLE patients as HCQ-responders, HCQ+QC-responders, or HCQ+QC-nonresponders to compare immune profiles. Immunohistochemistry, immunofluorescence, and qRT-PCR were used to characterize inflammatory cells and cytokines in lesional skin. Immunohistochemistry showed that CD69+ T cells were higher in HCQ+QC-nonresponders compared to HCQ- and HCQ+QC-responders (p < 0.05). Immunofluorescence further identified these cells as CD69+CCR7+ circulating activated T cells. Myeloid dendritic cells were significantly higher in HCQ+QC-responders compared to both HCQ-responders and HCQ+QC-nonresponders. Plasmacytoid dendritic cells were significantly increased in HCQ-responders compared to HCQ- and HCQ+QC-nonresponders. No differences were found in the number of autoreactive T cells, MAC387+ cells, and neutrophils among the groups. CLASI scores of the HCQ+QC-nonresponder group positively correlated with CD69+CCR7+ circulating activated T cells (r = 0.6335, p < 0.05) and MAC387+ cells (r = 0.5726, p < 0.05). IL-17 protein expression was higher in HCQ+QC-responders compared to HCQ-responders or HCQ+QC-nonresponders, while IL-22 protein expression did not differ. mRNA expression demonstrated increased STAT3 expression in a subset of HCQ+QC-nonresponders. An increased number of CD69+CCR7+ circulating activated T cells and a strong correlation with CLASI scores in the HCQ+QC-nonresponders suggest these cells are involved in antimalarial-refractory skin disease. STAT3 is also increased in HCQ+QC-nonresponders and may also be a potential target for antimalarial-refractory skin disease.

Hydroxychloroquine does not impair antibody response to 13-valent pneumococcal conjugate vaccine in patients with cutaneous lupus erythematosus-A pilot study.

Pneumococcal pneumonia is an important cause of morbidity and mortality among patients with lupus erythematosus. Therefore, a vaccination against pneumococcal infections prior to the immunosuppressive therapy is strongly recommended in these patients. Antimalarials are the standard first-line systemic therapy for cutaneous lupus erythematosus (CLE). However, as many as 50% of CLE patients can be recalcitrant to this treatment and may require more intense immunosuppressive management such as for example, methotrexate, mycophenolate mofetil or azathioprine. The main aim of the current study was to assess the immunogenicity of the pneumococcal conjugate vaccine (PCV) in patients with CLE receiving hydroxychloroquine (HCQ) for at least 6 months prior to the study entry. Twenty patients with CLE but not systemic lupus erythematosus (SLE) who were receiving HCQ and five age- and sex-matched healthy volunteers were included in this study. All individuals were vaccinated with 13-valent PCV. Levels of anti-pneumococcal capsular polysaccharide (anti-PCP) IgM and IgG antibodies were measured before and 6 weeks after vaccination. Anti-PCP IgM and IgG levels increased significantly in both CLE and controls upon vaccination (p < 0.0001 and p < 0.05, respectively). Ninety-five percentage of CLE patients and 80% of healthy volunteers achieved at least 2-fold increase in levels of anti-PCP IgG upon vaccination. Vaccination was good tolerated in both groups. The CLE activity score before vaccination was not modified thereafter. Hydroxychloroquine does not impair immune response to PCV13. The time period when patients with CLE are receiving HCQ could be used for immunization before more intense immunosuppressive therapy would be initiated.

The CLASI, a validated tool for the evaluation of skin disease in lupus erythematosus: a narrative review.

Cutaneous lupus erythematosus (CLE) can present with or without features of systemic lupus erythematosus (SLE), with estimates of the incidence of isolated skin disease almost equaling the incidence of those with systemic disease. However, despite the impact CLE has on a patient’s quality of life (QoL), there has been no US Food and Drug Administration (FDA) approved treatment for the disease in the past 50 years. In addition, patients with skin predominant LE are often excluded from clinical SLE trials. In the rare trials that include patients with skin predominant LE, disease activity and progression in the skin are often difficult to evaluate using multi-organ outcome measures. The need for new therapies for CLE and the lack of focus on skin outcomes has led to the development of the Cutaneous Lupus Disease Area and Severity Index (CLASI), a validated organ-specific outcome measure that is not only responsive to change in disease activity and damage but also correlated to changes in a patient’s QoL. This paper will emphasize the extensive validation studies performed in developing the CLASI, as well as the importance of clinical trials using the CLASI to address the need for improved therapies for patients with lupus skin manifestations.

Emerging Therapies for Cutaneous Lupus Erythematosus

There is a recent shortage of antimalarial medications, the current first-line therapy for cutaneous lupus erythematosus, due to both an import alert in the United States on quinacrine placed in 2019 as well as the use of hydroxychloroquine and chloroquine in treating coronavirus disease 2019. Due to this shortage, the need for new and effective treatments is more critical than ever.

A review of the evidence and cost of therapies for cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE)-a common presentation of lupus erythematosus-may exist independently or as a part of the systemic manifestations of systemic lupus erythematosus. The effects of living with and treating a chronic condition such as CLE can be debilitating to a patient's health and finances. The management of patients with CLE is made particularly challenging by poor compliance, limited therapeutic options, scarcity of evidence supporting their use, and significant differences in costs of medications. Effective management of CLE should center on prevention, individualized treatment regimens, and a mutual understanding of the challenges that patients with CLE face. This article seeks to provide an overview of the efficacy, safety, and cost of therapeutic options for CLE.

Advancing understanding, diagnosis, and therapies for cutaneous lupus erythematosus within the broader context of systemic lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is an autoimmune disease that can be associated with systemic lupus erythematosus (SLE) symptoms. The pathogenesis of both CLE and SLE is multifactorial, involving genetic susceptibility, environmental factors, and innate and adaptive immune responses. Despite the efficacy of current medications, many patients remain refractory, highlighting the necessity for new treatment options. Unfortunately, owing to challenges related in part to trial design and disease heterogeneity, only one new biologic in the last 50 years has been approved by the US Food and Drug Administration for the treatment of SLE. Thus, although SLE and CLE have a similar pathogenesis, patients with CLE who do not meet criteria for SLE cannot benefit from this advancement. This article discusses the recent trials and emphasizes the need to include patients with single-organ lupus, such as CLE, in SLE trials.

Hydroxychloroquine Treatment for Discoid Lupus Erythematosus

Hydroxychloroquine is a first-line systemic therapy for cutaneous lupus erythematosus (LE), but many patients have limited response for reasons that

Inhibition of TNFR1 signaling by P60 PLAD protein ameliorates skin lesions in lupus MRL/lpr mice (50.24)

Abstract Skin disease is the second most common manifestation in patients with systemic lupus erythematosus (SLE). The etiology of skin injury remains unclear. There is urgent need to understand better the pathogenesis of skin lesions and to develop effective, non-toxic therapy for cutaneous lupus erythematosus. MRL/lpr mice develop pathology similar to human SLE including skin lesions. To understand whether tumor necrosis factor (TNF) contributes to the pathogenesis of cutaneous lupus erythematosus, we treated lupus MRL/lpr mice with TNF receptor (R) defined PLAD protein. P60 PLAD inhibits the function of TNFR1, whereas P80 PLAD inhibits the function of TNFR2. We found that P60 PLAD protein significantly inhibited skin injury but P80 PLAD failed to do so in MRL/lpr mice. Both PLAD proteins promoted the development of proteinuria. Immunohistochemistry studies of skin lesions demonstrated that TNFR1 but not TNFR2 in expressed in the skin lesion of MRL/lpr mice. P60 PLAD significantly inhibited NF-kB, MCP-1 and iNOS expression by skin keratinocytes. Our results indicate that TNFR1 contributes to the development of skin lesions in lupus-prone mice suggest that it can be targeted successfully to treat cutaneous SLE.

Efficacy and safety of methotrexate in recalcitrant cutaneous lupus erythematosus: results of a retrospective study in 43 patients

The therapy of cutaneous lupus erythematosus (CLE) is often challenging, especially in patients resistant to topical treatment and established first-line systemic drugs such as antimalarials. Systemic corticosteroids are effective, but their use is limited due to well-known side-effects, especially in long-term treatment. In recent years several other immunosuppressive agents have been successfully applied in CLE. However, there are no large studies or explicit guidelines on the use of these drugs in CLE. To perform a retrospective investigation of the efficacy of low-dose methotrexate (MTX) in the treatment of CLE. One hundred and thirty-nine patients with CLE were seen at our department between 2001 and 2003, of whom 43 patients required low-dose MTX. All had histologically confirmed CLE lesions. Clinical data including disease activity, additional treatment, laboratory parameters and side-effects were recorded carefully at the time of presentation. Statistical analyses were performed by paired nonparametric Wilcoxon test and Student's t-test using SPSS 11 software. MTX led to a highly significant (P < 0.01) decline in disease activity. An improvement of the cutaneous lesions was recorded in nearly all patients treated with MTX (42 of 43; 98%). Severe side-effects necessitating discontinuation of MTX treatment were recorded in seven patients (16%), which quickly resolved when MTX was discontinued. Life-threatening complications were not observed. Intravenous application was tolerated better than oral administration. Interestingly, we observed a significant increase in circulating lymphocyte numbers in patients with lymphopenia (< 1.0 x 10(9) cells L(-1)) prior to MTX treatment. Our study supports earlier findings reporting the efficacy of low-dose MTX in CLE lesions, particularly in recalcitrant clinical courses. MTX treatment appears to be safe if patients are carefully selected and monitored, with particular attention to side-effects and contraindications.

Topical Tacrolimus: Adjunctive Therapy for Cutaneous Lupus Erythematosus?

Cutaneous lesions of lupus erythematosus (LE) may persist despite aggressive therapy with topical and systemic agents. To determine the efficacy of 0.1% tacrolimus ointment in such cases, researchers treated 12 patients who had treatment-resistant lesions of various types with the agent in an open-label study. …

Alte Substanzen, neue Erkenntnisse: Immunmodulatoren und Immunsuppressiva beim kutanen Lupus erythematodes

For therapy of cutaneous lupus erythematosus the precise classification of the clinical subset is necessary. The most frequently found LE subsets are chronic discoid LE (CDLE) and subacute cutaneous LE (SCLE). Extension of the cutaneous lesions and presence of visceral involvement are criteria for therapy choice. Basic therapeutics for cutaneous LE are antimalarials (chloroquine, hydroxychloroquine) alone or in combination with systemic corticosteroids. For visceral involvement others than arthralgia/arthritis azathioprin is the first line therapy. In 80-90% of the patients disease can be controlled by these standard therapies. In the remaining cases oral retinoids, thalidomide, methotrexate or diaminodiphenylsulfon can be tried. Recently, a few case reports have been published on a good therapeutic effect of local tacrolimus and systemic mycophenolate mofetil in cutaneous LE.

Topical Tacrolimus as a Therapeutic Adjunct in Patients with Cutaneous Lupus erythematosus

The topical therapy of cutaneous lupus erythematosus (LE) consists mainly of corticosteroids which may lead to significant side effects when overused. We report the efficacy of topical tacrolimus as a therapeutic adjunct in 3 patients with cutaneous LE of the face. All patients, 1 with systemic LE and a malar rash, 1 with annular subacute cutaneous LE, the other with a papular variant of subacute cutaneous LE, experienced significant improvement following application of tacrolimus ointment. Treatment with topical tacrolimus was tolerated well without major side effects in all patients. The presented cases are in line with recent reports that topical tacrolimus may be effective in facial LE.

Thalidomide therapy of cutaneous lupus erythematosus

Immunosuppressive and immune-modulating substances such as corticosteroids, chloroquin, hydroxychloroquin, azathioprin, methotrexate, and others are standards in therapy of cutaneous lupus erythematosus. However, alternative substances are necessary when standard therapy regimens fail or are associated with side effects. Describing the course of disease in five female patients, we demonstrate alternative treatment of subacute cutaneous lupus erythematosus with thalidomide, showing good symptom response and possible side effects. By careful patient selection, we observed no polyneuropathy as it is most commonly described. In two cases, maculopapulous exanthema induced by medication was seen. The teratogeny of the substance must be taken into account in prescription. In selected cases, thalidomide can be a highly effective therapeutic option in the treatment of subacute cutaneous lupus erythematosus.

Thalidomide therapy for cutaneous lupus erythematosus: historical and practical considerations

ABSTRACT: Connective tissue diseases are notoriously difficult to treat and the cutaneous manifestations of lupus erythematosus (LE) can be severe, leading to significant and progressive disfigurement. Fortunately several modalities exist for the treatment of this condition. However, oftentimes patients manifest severe disease and are refractory to conventional treatment. Second- and third-line agents used to treat cutaneous LE (CLE) can also exhibit many intolerable side effects. Thalidomide, a drug with a notorious past, has been found to be efficacious in the treatment of most of these patients. Response can be dramatic and patients are often maintained on thalidomide as a monotherapy. We review thalidomide's past, with a focus on its use in the treatment of CLE. We also discuss the practical issues involved in safely administering this drug, using three case histories. In conclusion, thalidomide is very effective in the treatment of CLE, however, prolonged use is often needed to maintain long-term remission. Properly used, thalidomide is very safe, with minimal and mild side effects. However, proper implementation and monitoring is imperative to guard against known serious side effects of teratogenicity and neuropathy.

Treatment of nonmelanotic hyperpigmentation with the Q-switched ruby laser

Hyperpigmentation of the skin is often refractory to conventional therapies, but has significant cosmetic implications if located on visible areas. Because laser systems are capable of removing pigment deposits caused by selective photothermolysis, we addressed the issue of whether the Q-switched ruby laser could be a useful alternative in the treatment of nonmelanotic hyperpigmented skin lesions. We report the successful treatment of a patient with hyperpigmentation caused by iatrogenic human herpesvirus 8–associated Kaposi’s sarcoma and a patient with hyperpigmentation caused by long-term antimalarial therapy for cutaneous lupus erythematosus. In both patients, clinical lightening of the darkly pigmented lesions was seen after a single treatment, and a significant improvement was observed after 3 laser applications. The patients tolerated the laser therapy well without any short-term side effects and did not experience either scarring or considerable textural skin changes. Histologic examination was performed before and after laser treatment to confirm the reduction of the pigment deposits. Our data indicate that treatment of nonmelanotic skin hyperpigmentation with the Q-switched ruby laser might be a safe and powerful therapeutic method. (J Am Acad Dermatol 2000;43:272-4.)

Management of cutaneous lupus erythematosus

Therapy of cutaneous lupus erythematosus is both an art and a science. The interplay of cosmetic and systemic factors must be understood and managed by the physician, who must, following recognition and diagnosis of the problem, discuss prognosis and life-style modification with the patient. Extensive reassurance usually is necessary. This all requires adequate and appropriate study. Patient education is an important on-going process. Finally, therapeutic modalities are administered, and frequently modified, to control the disease.