RESUMO
Our objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review (01/2007-12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion.
Assuntos
Lúpus Eritematoso Sistêmico/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Comorbidade , Gerenciamento Clínico , Medicina Baseada em Evidências/métodos , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/complicações , Índice de Gravidade de DoençaRESUMO
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.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Fator Ativador de Células B/imunologia , Queratinócitos/metabolismo , Lúpus Eritematoso Cutâneo/metabolismo , Estudos de Casos e Controles , Epiderme/metabolismo , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Inflamação , Queratinócitos/citologia , Queratinócitos/imunologia , Lúpus Eritematoso Cutâneo/imunologia , Linfócitos/metabolismoRESUMO
INTRODUCTION: Due to a wide array of dermatologic manifestations, assessment of disease severity in cutaneous lupus erythematosus (CLE) remains challenging. Given a need for some standardization in this field, we conducted a worldwide questionnaire-based study among physicians experienced in CLE management. AIM: We asked about CLE assessment, their prophylactic measures advised to patients, and treatment recommendations. MATERIAL AND METHODS: A total of 83 completed questionnaires were received. Participating physicians recommended assessing disease severity at each patient's visit (39.1%), monthly (4.9%) or at least every third month (17.3%). Almost half of the responding physicians (47.0%) waited 2-3 months before identifying a specific treatment option as not effective. RESULTS: The vast part of the participants informed their patients about of the risks of sun exposure and advised adequate preventive measures. Smoking was less frequently a matter of discussion between physicians and their patients. Recommendations for the timing of CLE severity assessment likely depends on disease severity and the type of therapeutic intervention. CONCLUSIONS: Proper patient education about effective prophylactic measures should be included during routine CLE patient consultations.
RESUMO
OBJECTIVES: Treat-to-target recommendations have identified 'remission' as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE. METHODS: An international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%. RESULTS: The task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by . (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5â mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life. CONCLUSIONS: The work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.
Assuntos
Lúpus Eritematoso Sistêmico/tratamento farmacológico , Corticosteroides/uso terapêutico , Anticorpos Antinucleares/sangue , Antimaláricos/uso terapêutico , Proteínas do Sistema Complemento/metabolismo , Consenso , DNA/imunologia , Humanos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/sangue , Quimioterapia de Manutenção , Indução de Remissão , Índice de Gravidade de Doença , Exacerbação dos SintomasRESUMO
Spleen tyrosine kinase (SYK) is a protein kinase involved in cell proliferation and the regulation of inflammatory pathways. Due to the increasing evidence that kinase inhibitors have potential as specific anti-inflammatory drugs, we have investigated the potential for SYK inhibition as a therapeutic target in autoimmune diseases, particularly cutaneous lupus erythematosus (CLE). Skin samples of patients with different CLE subtypes and appropriate controls were analysed for the expression of SYK and SYK-associated pro-inflammatory mediators via gene expression analysis and immunohistochemistry. The functional role of SYK in keratinocytes was investigated in vitro, using LE-typical pro-inflammatory stimuli and a selective inhibitor of SYK. SYK-associated genes are strongly upregulated in CLE skin lesions. Importantly, phosphorylated SYK (pSYK) is strongly expressed by several immune cell types and also keratinocytes in CLE skin. In vitro, immunostimulatory nucleic acids are capable of inducing SYK phosphorylation in keratinocytes leading to the induction of pro-inflammatory cytokines, while small-molecule SYK inhibition decreases the expression of these proteins. The results demonstrate that pSYK is expressed by immune cells and keratinocytes in skin lesions of CLE patients. LE-typical stimuli induce the expression of pSYK in vitro. Small-molecule SYK inhibition leads to a reduction of pSYK expression and downregulation of pro-inflammatory cytokines in keratinocytes. We therefore believe that pSYK provides a potential future drug target for the treatment of patients who suffer from CLE and related skin disorders. Specifically, our study reveals evidence supporting the use of topical SYK inhibitors in treating lupus.
Assuntos
Lúpus Eritematoso Cutâneo/enzimologia , Quinase Syk/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Citocinas/metabolismo , Humanos , FosforilaçãoRESUMO
Localized scleroderma designates a heterogeneous group of sclerotic skin disorders. Depending on the subtype, severity, and site affected, adjacent structures such as adipose tissue, muscles, joints, and bones may be involved. This is an update of the existing German AWMF (Association of the Scientific Medical Societies in Germany) guidelines (classification: S2k). These guidelines provide an overview of the definition, epidemiology, classification, pathogenesis, laboratory workup, histopathology, clinical scoring systems, as well as imaging and device-based workup of localized scleroderma. Moreover, consensus-based recommendations are given on the management of localized scleroderma depending on its clinical subtype. Treatment recommendations are presented in a therapeutic algorithm. No financial support was given by any pharmaceutical company. The guidelines are valid until July 2019.
Assuntos
Dermatologia/normas , Dermoscopia/normas , Imageamento por Ressonância Magnética/normas , Guias de Prática Clínica como Assunto , Esclerodermia Localizada/diagnóstico , Esclerodermia Localizada/terapia , Anti-Inflamatórios/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Alemanha , HumanosRESUMO
Cutaneous lupus erythematosus (CLE) is a chronic autoimmune disease of the skin with typical clinical manifestations. Here, we genotyped 906 600 single nucleotide polymorphisms (SNPs) in 183 CLE cases and 1288 controls of Central European ancestry. Replication was performed for 13 SNPs in 219 case subjects and 262 controls from Finland. Association was particularly pronounced at 4 loci, all with genomewide significance (P < 5 × 10(-8) ): rs2187668 (PGWAS = 1.4 × 10(-12) ), rs9267531 (PGWAS = 4.7 × 10(-10) ), rs4410767 (PGWAS = 1.0 × 10(-9) ) and rs3094084 (PGWAS = 1.1 × 10(-9) ). All mentioned SNPs are located within the major histocompatibility complex (MHC) region of chromosome 6 and near genes of known immune functions or associations with other autoimmune diseases such as HLA-DQ alpha chain 1 (HLA-DQA1), MICA, MICB, MSH5, TRIM39 and RPP21. For example, TRIM39/RPP21 read through transcript is a known mediator of the interferon response, a central pathway involved in the pathogenesis of CLE and systemic lupus erythematosus (SLE). Taken together, this genomewide analysis of disease association of CLE identified candidate genes and genomic regions that may contribute to pathogenic mechanisms in CLE via dysregulated antigen presentation (HLA-DQA1), apoptosis regulation, RNA processing and interferon response (MICA, MICB, MSH5, TRIM39 and RPP21).
Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Cutâneo/genética , Polimorfismo de Nucleotídeo Único , Proteínas de Transporte/genética , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Cromossomos Humanos Par 6/genética , Finlândia , Estudo de Associação Genômica Ampla , Alemanha , Cadeias alfa de HLA-DQ/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Lúpus Eritematoso Cutâneo/imunologia , Complexo Principal de Histocompatibilidade , Ribonuclease P/genética , Ubiquitina-Proteína LigasesRESUMO
The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012-2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that 'treating-to-target' can and will be applicable to the care of patients with SLE.
Assuntos
Comitês Consultivos , Lúpus Eritematoso Sistêmico/terapia , Planejamento de Assistência ao Paciente , Gerenciamento Clínico , Humanos , Indução de Remissão/métodos , Prevenção Secundária/métodosRESUMO
Lupus erythematosus (LE) is an inflammatory connective tissue disease of generalized autoimmunity characterized by pathogenic autoantibodies and immune complexes, attributed to loss of immune tolerance. Cutaneous involvement, which appears in the majority of patients with the disease, can present as LE-specific or LE-nonspecific manifestations. The LE-nonspecific manifestations include e.g. vascular skin changes and may be associated with systemic organ manifestations or other autoimmune diseases. In contrast, the LE-specific manifestations encompass the various subtypes of cutaneous lupus erythematosus (CLE), which are classified as separate entities without or with less severe systemic organ involvement. In the "Duesseldorf Classification", CLE is subdivided into four different categories: acute CLE (ACLE), subacute CLE (SCLE), chronic CLE (CCLE), and intermittent CLE (ICLE). Differentiation between these subtypes is based on clinical features and average duration of the cutaneous lesions, but can also consider histological changes of skin biopsy specimens and laboratory abnormalities. In addition, direct immunofluorescence and photoprovocation may be applied to confirm the diagnosis in specific cases. Further investigations should be considered dependent on the clinical symptoms of the CLE patient and the results of the laboratory tests. A revised scoring system, the Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI) has recently been validated to assess disease activity and damage in CLE. In this review, we focus on the classification of CLE and the diagnostic procedures to identify and confirm the different subtypes of the disease.
Assuntos
Lúpus Eritematoso Cutâneo/classificação , Lúpus Eritematoso Cutâneo/diagnóstico , Doença Aguda , Doença Crônica , Ensaios Clínicos como Assunto/normas , Humanos , Incidência , Lúpus Eritematoso Cutâneo/imunologia , Lúpus Eritematoso Discoide/classificação , Lúpus Eritematoso Discoide/diagnóstico , Lúpus Eritematoso Discoide/imunologia , Paniculite/classificação , Paniculite/diagnóstico , Paniculite/imunologia , Índice de Gravidade de Doença , Anormalidades da Pele/diagnóstico , Anormalidades da Pele/imunologia , Anormalidades da Pele/patologia , Raios Ultravioleta/efeitos adversosRESUMO
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.
Assuntos
Inflamação/metabolismo , Interferons/metabolismo , Lúpus Eritematoso Cutâneo/imunologia , Pele/patologia , Protetores Solares/administração & dosagem , Raios Ultravioleta , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígeno CD11c/metabolismo , Estudos de Casos e Controles , Humanos , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Lipossomos/química , Lúpus Eritematoso Cutâneo/metabolismo , Macrófagos/metabolismo , Macrófagos/efeitos da radiação , Proteínas de Resistência a Myxovirus/metabolismo , Fatores de Tempo , Raios Ultravioleta/efeitos adversosRESUMO
OBJECTIVE: We undertook a 2-part, phase I, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetics of multiple intravenous infusions of sirukumab, a human anti-interleukin-6 monoclonal antibody, in patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE). METHODS: In part A, patients with histologically confirmed CLE were randomized to 4 infusions of placebo or 1, 4, or 10 mg/kg sirukumab every 2 weeks. In part B, SLE patients diagnosed according to American College of Rheumatology criteria with a score of 5-12 on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index were randomized to 4 infusions of placebo or 10 mg/kg sirukumab every 2 weeks. RESULTS: We treated 31 CLE patients (23 with sirukumab, 8 with placebo) and 15 SLE patients (10 with sirukumab, 5 with placebo). Adverse events (AEs) occurred more often with sirukumab than placebo in CLE patients (91% versus 63%) and in SLE patients (90% versus 80%). Sirukumab led to sustained, dose-independent decreases in white blood cell counts, absolute neutrophil counts (neutropenia), and platelet counts (thrombocytopenia) and to minor elevations in total cholesterol levels. The majority of infections were mild respiratory infections. which were reported similarly across CLE cohorts but more often in sirukumab-treated than in placebo-treated SLE patients. Two serious AEs of infection occurred (pneumonia in the 10 mg/kg-treated group and iatrogenic wound infection in the 4 mg/kg-treated group). Sirukumab showed linear pharmacokinetics in CLE patients. Systemic exposure and half-life were comparable between CLE and SLE patients. No patient developed antibodies to sirukumab through 22 weeks. C-reactive protein and serum amyloid A mean concentrations were suppressed with sirukumab from week 1 to week 14. CONCLUSION: Treatment with intravenous sirukumab infusions was generally well tolerated in both CLE and SLE patients with mild, stable, active disease. Sirukumab demonstrated linear pharmacokinetics over the dose range studied and comparable systemic exposure and half-life in CLE and SLE patients.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Proteína C-Reativa/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Interleucina-6/imunologia , Cooperação Internacional , Lúpus Eritematoso Cutâneo/sangue , Lúpus Eritematoso Sistêmico/sangue , Masculino , Pessoa de Meia-Idade , Proteína Amiloide A Sérica/metabolismo , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
We compare public perceptions of restoring different ecosystems to increase CO2 uptake in Germany, through focus groups and a general population survey. Among focus group participants forests were highly popular, peatlands evoked negative associations, and seagrass was largely unknown. Nevertheless, the restoration of all ecosystems was viewed positively. We contrast these reactions to those of survey respondents who had not received additional information on restoration. They voiced narrower, less diverse opinions centering around afforestation. Further, focus group participants preferred expert-led restoration decisions, citing low trust in politicians' technical competence. Contrary to common policy recommendations, also beyond the German context, participants did not emphasize the need of citizen participation and were not strongly concerned about land use conflicts or compensation of affected user groups. The results imply that the public underestimates the political complexity of negotiation processes in ecosystem governance, which are becoming increasingly relevant in the international policy landscape.
RESUMO
Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease. Different pathogenetic mechanisms, including the accumulation of apoptotic keratinocytes in CLE, have been reported. Therefore, we investigated whether CLE and other inflammatory skin diseases differ with regard to the epidermal expression of molecules that are crucial for the initiation and regulation of apoptosis. In this study, 241 skin biopsies from patients with CLE, psoriasis (PSO), lichen planus (LP) and healthy controls (HCs) were analysed immunohistochemically using the tissue microarray (TMA) technique. The TUNEL assay and anti-activated caspase-3 antibodies revealed a significant increase of apoptotic keratinocytes in CLE lesions compared with HCs. Furthermore, we detected a significant increase in the epidermal expression of CD95 in CLE specimens compared with PSO, LP and HCs. These data suggest that the accumulation of apoptotic keratinocytes in CLE might be due to the increased epidermal expression of CD95, resulting in increased activity of the extrinsic apoptotic pathway in the disease.
Assuntos
Apoptose , Regulação da Expressão Gênica , Lúpus Eritematoso Cutâneo/imunologia , Lúpus Eritematoso Cutâneo/metabolismo , Pele/metabolismo , Pele/patologia , Adulto , Idoso , Biópsia , Caspase 3/metabolismo , Epiderme/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Inflamação/patologia , Queratinócitos/citologia , Masculino , Pessoa de Meia-Idade , Análise Serial de Tecidos , Receptor fas/metabolismoRESUMO
Regulatory CD4(+)CD25(+) T cells are important in suppressing immune responses. The requirements for the maintenance of peripheral CD4(+)CD25(+) T cells remain incompletely understood. Receptor activator of NF-kappaB (RANK) and its ligand (RANKL; also known as CD254, OPGL and TRANCE) are key regulators of bone remodeling, mammary gland formation, lymph node development and T-cell/dendritic cell communication. Here we report that RANKL is expressed in keratinocytes of the inflamed skin. RANKL overexpression in keratinocytes resulted in functional alterations of epidermal dendritic cells and systemic increases of regulatory CD4(+)CD25(+) T cells. Thus, epidermal RANKL expression can change dendritic cell functions to maintain the number of peripheral CD4(+)CD25(+) regulatory T cells. Epidermal RANKL mediated ultraviolet-induced immunosuppression and overexpression of epidermal RANKL suppressed allergic contact hypersensitivity responses and the development of systemic autoimmunity. Therefore, environmental stimuli at the skin can rewire the local and systemic immune system by means of RANKL.
Assuntos
Células Dendríticas/fisiologia , Epiderme/fisiologia , Ligante RANK/fisiologia , Linfócitos T Reguladores/citologia , Animais , Autoimunidade , Contagem de Células , Células Epidérmicas , Epiderme/metabolismo , Tolerância Imunológica/efeitos da radiação , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ligante RANK/genética , Ligante RANK/metabolismo , Raios UltravioletaRESUMO
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.