Aysche Landmann

Ultraviolet light protection by a sunscreen prevents interferon-driven skin inflammation in cutaneous lupus erythematosus

Irradiation with ultraviolet (UV) light is an important exacerbating factor in cutaneous lupus erythematosus (CLE) and induces various effects in the skin of patients with the disease, such as cell death and inflammation. Recently, we demonstrated the ability of a broad‐spectrum sunscreen to prevent UV‐induced damage both in patients with CLE and healthy controls (HCs). The aim of this study was to evaluate whether the UV‐dependent activation of interferon (IFN)‐driven inflammation in CLE can also be prevented by application of the sunscreen. In 20 patients with different subtypes of CLE and 10 HCs, defined areas on the upper back were treated with a broad‐spectrum liposomal sunscreen 20 min prior to a combined standardized UVA/UVB irradiation. Immunohistological analyses using antibodies directed against MxA, CD11c, CD123 and CD68 were performed from skin biopsies taken from areas before UV irradiation as well as from sunscreen‐treated and sunscreen‐untreated areas 24 and 72 h after UV irradiation. The expression of MxA was completely prevented by the sunscreen applied prior to UV irradiation in CLE patients and HCs. Additionally, sunscreen protection significantly diminished the number of the CD11c‐ and CD123‐positive dendritic cells, which are suggested to be a major source of type I/III IFNs, in UV‐irradiated skin of patients with CLE. Moreover, the application of the sunscreen prevented the increase in CD68‐positive macrophages in both groups 72 h after UV irradiation. The data of this study demonstrate that UV protection reduces lesional tissue damage and inhibits the typical IFN‐driven inflammatory response in CLE.

Suppression of UV-induced damage by a liposomal sunscreen: a prospective, open-label study in patients with cutaneous lupus erythematosus and healthy controls.

This study aimed to determine whether a broad‐spectrum liposomal sunscreen with a very high sun protection factor (Daylong actinica) can prevent damage induced by ultraviolet (UV) irradiation in patients with cutaneous lupus erythematosus (CLE) and healthy controls (HCs) under standardised conditions. In 20 patients with CLE and 10 HCs, defined areas of sunscreen‐untreated and sunscreen‐treated skin on the upper back were irradiated with combined UVA/UVB light. Disease‐specific skin lesions were induced by UVA/UVB light in the untreated areas of nine patients with CLE; no specific eruptions or any sun damage was observed in the sunscreen‐treated areas in any of the CLE patients, nor in the HCs. Histological analysis of skin biopsy specimens confirmed the clinical results. In conclusion, the use of a high‐protection, broad‐spectrum sunscreen can prevent UV‐induced damage in patients with CLE and HCs.

S2k guideline for treatment of cutaneous lupus erythematosus – guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV)

Cutaneous lupus erythematosus (CLE) is a rare inflammatory autoimmune disease with heterogeneous clinical manifestations. To date, no therapeutic agents have been licensed specifically for patients with this disease entity, and topical and systemic drugs are mostly used ‘off‐label’. The aim of the present guideline was to achieve a broad consensus on treatment strategies for patients with CLE by a European subcommittee, guided by the European Dermatology Forum (EDF) and supported by the European Academy of Dermatology and Venereology (EADV). In total, 16 European participants were included in this project and agreed on all recommendations. Topical corticosteroids remain the mainstay of treatment for localized CLE, and further topical agents, such as calcineurin inhibitors, are listed as alternative first‐line or second‐line topical therapeutic option. Antimalarials are recommended as first‐line and long‐term systemic treatment in all CLE patients with severe and/or widespread skin lesions, particularly in patients with a high risk of scarring and/or the development of systemic disease. In addition to antimalarials, systemic corticosteroids are recommended as first‐line treatment in highly active and/or severe CLE. Second‐ and third‐line systemic treatments include methotrexate, retinoids, dapsone and mycophenolate mofetil or mycophenolate acid, respectively. Thalidomide should only be used in selected therapy‐refractory CLE patients, preferably in addition to antimalarials. Several new therapeutic options, such as B‐cell‐ or interferon α‐targeted agents, need to be further evaluated in clinical trials to assess their efficacy and safety in the treatment of patients with CLE.

Advances in the treatment of cutaneous lupus erythematosus

Lupus erythematosus (LE) is a multifactorial autoimmune disease with clinical manifestations of differing severity which may present with skin manifestations as primary sign of the disease (cutaneous lupus erythematosus, CLE) or as part of a disease spectrum (systemic lupus erythematosus, SLE). To date, no drugs are approved specifically for the treatment of CLE and only single agents have been applied in randomized controlled trials. Therefore, topical and systemic agents are used “off-label”, primarily based on open-label studies, case series, retrospective analyses, and expert opinions. In contrast, several agents, such as hydroxychloroquine, chloroquine, cyclophosphamide, azathioprine, and belimumab, are approved for the treatment of SLE. Recent approaches in the understanding of the molecular pathogenesis of LE enabled the development of further new agents, which target molecules such as interleukin 6 (IL-6) and interferon (IFN). Only single trials, however, applied these new agents in patients with cutaneous involvement of the disease and/or included endpoints which evaluated the efficacy of these agents on skin manifestations. This article provides an updated review on new and recent approaches in the treatment of CLE.

Fumaric acid ester treatment in cutaneous lupus erythematosus (CLE): a prospective, open-label, phase II pilot study

Objective The aim of the study was to assess the efficacy and safety of fumaric acid esters (FAEs) in patients with cutaneous lupus erythematosus (CLE). Methods In this 24-week, prospective, open-label, phase II pilot study, 11 patients with CLE, refractory to topical corticosteroids, were included. The primary endpoint of the study was the evaluation of the efficacy of FAEs after 24 weeks of treatment as assessed by the Revised Cutaneous Lupus Disease Area and Severity Index (RCLASI). Results Compared to baseline, significant improvement in the mean total RCLASI activity score and the mean RCLASI activity score for skin lesions was observed in week 12 (p = 0.002, p = 0.002, respectively) and in week 24 (p = 0.009, p = 0.009, respectively). Most common adverse events included abdominal cramps and headache. Conclusions FAEs could be an alternative and safe treatment in patients with therapy-refractory CLE; however, randomized controlled trials are warranted to evaluate the efficacy and safety of FAEs in this disease.

Resistance to water and abrasion of a broad-spectrum sunscreen: a prospective, open-label study.

a prospective, open-label study Annegret Kuhn, Sabine Zahn, Nikolaos Patsinakidis, Aysche Landmann, Medina Graef, Cristina Sauerland, Christian Surber and Joerg Wenzel Interdisciplinary Center for Clinical Trials (IZKS), University Medical Center Mainz, Mainz, Germany; Division of Immunogenetics, German Cancer Research Center, Heidelberg, Germany; Department of Dermatology, University of Bonn, Bonn, Germany; Department of Dermatology and Allergology, Klinikum Bremen Mitte, Bremen, Germany; Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany; Department of Dermatology, University Clinic Basel, Basel, Switzerland; Department of Dermatology, University Clinic Z€ urich, Z€ urich, Switzerland Correspondence: Prof. Annegret Kuhn, MD, MBA, Interdisciplinary Center for Clinical Trials (IZKS), University Medical Center Mainz, Langenbeckstrasse 1, D-55131 Mainz, Germany, Tel.: +49 (0) 6131 17 9913, Fax: +49 (0) 6131 17 9914, e-mail: research@izks-unimedizin-mainz.de The research was conducted at the Department of Dermatology, University of Muenster, Germany.

The skin in autoimmune diseases-Unmet needs.

Treatment of skin manifestations in systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and dermatomyositis (DM) is based on the results of only few randomized controlled trials. The first-line treatment for disfiguring and widespread cutaneous involvement in SLE is antimalarials, but some patients are therapy resistant. Recently, the monoclonal antibody belimumab was approved for SLE as an adjunct therapy for patients with autoantibody-positive disease who despite standard therapy show high disease activity, intolerance of other treatments, or an unacceptably high need for corticosteroids. However, a validated skin score has not been used to confirm the efficacy of belimumab on mucocutaneous manifestations. In SSc, another multi-systemic progressive disease, involvement of the lung, kidney, and the heart is frequently treated with corticosteroids and immunosuppressives, but therapeutic modalities for cutaneous lesions, such as skin sclerosis and digital ulcers, are limited. In the past years, treatment with the endothelin-receptor antagonist bosentan has been proven to reduce the occurrence of new digital ulcers in SSc patients but has no or limited effect on healing of digital ulcers. DM is an idiopathic autoimmune disease characterized by inflammation of the muscles and skin, which is treated with immunosuppressives. Corticosteroids are the first-line treatment for muscle involvement in DM, but skin lesions often flare by reduction or discontinuation. In summary, there is a high unmet need for new therapeutic strategies focusing on skin involvement in systemic autoimmune diseases. Therefore, innovative designs of randomized controlled trials with validated skin scores are warranted to develop new therapeutic strategies for patients with cutaneous manifestations.

Fumaric acid esters: a new therapeutic option for skin manifestations in lupus erythematosus?

telangiectasia, oedema, papules and pustules, as well as hyperplasia of nasal sebaceous glands. Patients may also complain of dry, burning and stinging sensations from the skin and eyes, and often suffer from migraines and gastrointestinal disorders. Rosacea is a common yet somewhat understudied disorder, and whether disease classification should be made according to subtypes or clinical features remains debated. However, rosacea is currently treated according to subtype, with therapeutic options ranging from topical agents to systemic antibiotics, laser treatments and even surgery. While off-label treatments may include drugs such as isotretinoin and topical calcineurin inhibitors, there have been reports of allergic contact dermatitis caused by approved rosacea treatments such as brimonidine tartrate gel and topical metronidazole. In the current issue of the BJD, an international group comprising 17 dermatologists and three ophthalmologists report their use of a modified Delphi process to formulate a consensus statement on the management of rosacea. Evidence was derived from a recent Cochrane review and a summarized literature search, which together with the participants’ clinical experience formed the basis for the treatment recommendations. Systematic Cochrane reviews are generally recognized as the highest standard in evidence-based health care. However, the sole inclusion of randomized clinical trials (RCTs) in Cochrane reviews may result in omission of large parts of available and valuable data. A particular strength of the present publication is therefore the panel’s addition to the Delphi process of a wider body of evidence in the form of a summarized literature review and clinical expertise. This allows for the recommendation of less common features such as phyma and ocular rosacea, of which RCTs are scarce. There is currently a wide range of approved and unapproved therapeutic options for rosacea, as well as emerging data suggesting that patients may also frequently suffer from certain other conditions at the same time. In light thereof, the present review, and its recommendations for shortand long-term disease management, is important as it may help clinicians to evaluate the relative merits and safety of the available therapies for their patients with rosacea.

High Expression of B Lymphocyte Stimulator (BLyS) in Lesional Keratinocytes of Patients with Cutaneous Lupus Erythematosus

Belimumab, an anti‐B lymphocyte stimulator (BLyS) monoclonal antibody, is approved for systemic lupus erythematosus; however, it is unclear if it can be used to treat specific skin lesions in this disease. In this analysis, we investigated the expression of BLyS and its receptors in skin lesions of different subtypes of cutaneous lupus erythematosus (CLE) using immunohistochemistry and gene expression analyses. Compared to healthy controls, the expression of BLyS was significantly higher in skin lesions of all included CLE subtypes. Similar results were seen for the BLyS receptors BAFF‐R and BCMA. Moreover, CLE‐typical pro‐inflammatory mediators (immunostimulatory DNAs) significantly enhanced the BLyS expression of keratinocytes in vitro. This study suggests a potential role for BLyS as therapeutic target in the treatment of CLE skin lesions.

Chapter 39 – Cutaneous Lupus Erythematosus

Lupus erythematosus (LE) is an inflammatory autoimmune disease, characterized by a heterogeneous clinical presentation. The skin lesions are one of the most frequent symptoms of the disease and present with a broad spectrum of LE-nonspecific and LE-specific cutaneous manifestations. Therefore, the development of a classification for skin lesions in the disease has proven difficult. For example, the LE-nonspecific cutaneous manifestations include livedo racemosa, thrombophlebitis, and leukocytoclastic vasculitis and can be associated with high disease activity and systemic organ involvement. The LE-specific cutaneous manifestations encompass the subtypes of cutaneous lupus erythematosus (CLE): acute CLE, subacute CLE, and chronic CLE, such as discoid LE, chilblain LE, and LE profundus/panniculitis. In the “Duesseldorf Classification”, LE tumidus is included as a separate entity, named intermittent CLE. In this chapter, we describe the characteristic features of the various cutaneous manifestations of the disease.