Polymorphisms of the ITGAM Gene Confer Higher Risk of Discoid Cutaneous than of Systemic Lupus Erythematosus

Background Lupus erythematosus (LE) is a heterogeneous disease ranging from mainly skin-restricted manifestations (discoid LE [DLE] and subacute cutaneous LE) to a progressive multisystem disease (systemic LE [SLE]). Genetic association studies have recently identified several strong susceptibility genes for SLE, including integrin alpha M (ITGAM), also known as CD11b, whereas the genetic background of DLE is less clear. Principal findings To specifically investigate whether ITGAM is a susceptibility gene not only for SLE, but also for cutaneous DLE, we genotyped 177 patients with DLE, 85 patients with sporadic SLE, 190 index cases from SLE families and 395 population control individuals from Finland for nine genetic markers at the ITGAM locus. SLE patients were further subdivided by the presence or absence of discoid rash and renal involvement. In addition, 235 Finnish and Swedish patients positive for Ro/SSA-autoantibodies were included in a subphenotype analysis. Analysis of the ITGAM coding variant rs1143679 showed highly significant association to DLE in patients without signs of systemic disease (P-value = 4.73x10-11, OR = 3.20, 95% CI = 2.23-4.57). Significant association was also detected to SLE patients (P-value = 8.29x10-6, OR = 2.14, 95% CI = 1.52-3.00), and even stronger association was found when stratifying SLE patients by presence of discoid rash (P-value = 3.59x10-8, OR = 3.76, 95% CI = 2.29-6.18). Significance We propose ITGAM as a novel susceptibility gene for cutaneous DLE. The risk effect is independent of systemic involvement and has an even stronger genetic influence on the risk of DLE than of SLE.Peer reviewe

Photosensitivity in cutaneous Lupus Erythematosus clinical and experimental studies

Lupus erythematosus (LE) is an autoimmune disease in which the skin is one of the main target organs. Photosensitivity is a common feature for the different subtypes of cutaneous LE, but photosensitivity has not been well defined. Polymorphous light eruption (PLE) is a common form of photosensitivity in otherwise healthy individuals, and the differential diagnosis can be difficult. The keratinocytes and dermoepidermal junction have been extensively studied in LE, contrary to the cells in the dermis, especially fibroblasts and endothelial cells. We studied different aspects of UV-induced cutaneous reactions in LE patients, with emphasis on early cellular events in evolving lesions. We also investigated the roles of endothelial cells and fibroblasts. Methods A mailed questionnaire with questions about worsening by sunlight and about history of PLE was sent to 387 consecutive patients from dermatological university clinics in Finland and Sweden. Sixty- seven of the responders were interviewed about their photosensitivity, and went through phototesting and photoprovocations with UVB and UVA. Consecutive biopsies from UV-induced, evolving cutaneous reactions were obtained from LE and PLE patients until the reactions subsided, and from healthy, photoprovoked individuals. The biopsies were analysed with direct immunofluorescence using antibodies against IgG, IgM, C3 and C1q, with immunohistochemistry for expression of ICAM-1, VCAM-1 and E-selectin and with routine histopathology. Levels of soluble CAMs were analysed with ELISA kits in a retrospective study on frozen sera from LE patients and controls. Fibroblasts were cultured from scarring and non-scarring LE lesions and healthy controls. The cells were counted every third day during nine days. Cytokines and soluble CAMs in supernatants were analysed before and after irradiation of the cells with UVA. Results LE patients reported worsening by sunlight in 242 (72%) of 337 responders to the questionnaire. A history consistent with PLE was reported by 165 (49%). PLE had started before LE in the majority of patients with both diagnoses. UVA and UVB induced reactions with clinical and micromorphological features of LE or PLE. A specific, granular epidermal staining pattern ("dust-like particles"), was found in immunofluorescence biopsies from the first two weeks after irradiation in LE patients and within 3 days at the earliest. Complement (C1q) was often present. Specific patterns of CAM expression were seen in different diagnostic groups and as an early event in lesions of different duration. UVA but not UVB possibly had a direct influence on endothelial VCAM-1 and E-selectin expression. Soluble (s)E-selectin was elevated in serum from DLE patients with active, widespread lesions compared to controls and patients with limited disease. sICAM-1 and sVCAM-1 were elevated in patients with SLE and SCLE, and correlated to systemic but not to cutaneous symptoms. Cultured fibroblasts from scarring LE lesions, showed markedly impaired proliferation compared to fibroblasts from non-scarring LE lesions and controls. UVA irradiation did not significantly influence levels of cytokines and CAMs in supernatants from cultured fibroblasts. Conclusions The photosensitivity in LE patients displays a clinical spectrum from transient, PLE-like reactions to persistent, clinically typical LE lesions. CAM expression patterns are influenced by the patient's disease. Complement, endothelial cells and fibroblasts seem to play roles in the pathogenesis of UV-induced LE lesions. Hypothetically, an altered expression of CAMs, induced by an unbalanced cytokine network brought about by an altered T-cell/B-cell repertoire in genetically susceptible individuals, could be a unifying concept for the findings in our studies

Cutaneous lupus erythematosus: An update

Lupus erythematosus (LE) is a chronic, autoimmune, multisystem disease that displays many diverse symptoms in which localized cutaneous LE (CLE) is on one end of the spectrum and severe systemic LE (SLE) on the other end. The underlying cause of LE is unknown but the etiology is thought to be multifactorial and polygenic. CLE is a disfiguring, chronic skin disease, with a significant impact on the patients′ everyday life. CLE are further divided into three main subsets: Acute CLE (ACLE), subacute CLE (SCLE) and chronic CLE (CCLE), where classic discoid LE (DLE) is the most common form. These subsets are defined by clinical symptoms, average duration of symptoms and histological and serological findings, although, the three subtypes can have overlapping clinical features. CLE patients display well-defined skin lesions, often in sun-exposed areas. The disease often has a chronic and relapsing course that can be induced or aggravated by UV light. It is important to confirm a CLE diagnosis histopathologically by a biopsy and in that there are several differential diagnoses and because CLE is a chronic disease in which regular follow-up is important and systemic treatment is sometimes indicated

Gender and the treatment of immune-mediated chronic inflammatory diseases : rheumatoid arthritis, inflammatory bowel disease and psoriasis: an observational study

Background: Rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis are immune-mediated inflammatory diseases with similarities in pathophysiology, and all can be treated with similar biological agents. Previous studies have shown that there are gender differences with regard to disease characteristics in RA and IBD, with women generally having worse scores on pain and quality of life measurements. The relationship is less clear for psoriasis. Because treatment differences between men and women could explain the dissimilarities, we investigated gender differences in the disease characteristics before treatment initiation and in the biologic treatment prescribed. Methods: Data on patients with RA or IBD were collected from two registries in which patients treated with biologic medication were enrolled. Basic demographic data and disease activity parameters were collected from a time point just before the initiation of the biologic treatment. For patients with psoriasis, the data were taken from the 2010 annual report of the Swedish Psoriasis Register for systemic treatment, which included also non-biologic treatment. For all three diseases, the prescribed treatment and disease characteristics were compared between men and women. Results: In total, 4493 adult patients were included in the study (1912 with RA, 131 with IBD, and 2450 with psoriasis). Most of the treated patients with RA were women, whereas most of the patients with IBD or psoriasis were men. There were no significant differences between men and women in the choice of biologics. At treatment start, significant gender differences were seen in the subjective disease measurements for both RA and psoriasis, with women having higher (that is, worse) scores than men. No differences in objective measurements were found for RA, but for psoriasis men had higher (that is, worse) scores for objective disease activity measures. A similar trend to RA was seen in IBD. Conclusions: Women with RA or psoriasis scored significantly higher on subjective, but not on objective, disease activity measures than men, and the same trend was seen in IBD. This indicates that at the same level of treatment, the disease has a greater effect in women. These findings might suggest that in all three diseases, subjective measures are discounted to some extent in the therapeutic decision-making process, which could indicate undertreatment in female patients

Gender and the treatment of immune-mediated chronic inflammatory diseases : rheumatoid arthritis, inflammatory bowel disease and psoriasis: an observational study

Background: Rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis are immune-mediated inflammatory diseases with similarities in pathophysiology, and all can be treated with similar biological agents. Previous studies have shown that there are gender differences with regard to disease characteristics in RA and IBD, with women generally having worse scores on pain and quality of life measurements. The relationship is less clear for psoriasis. Because treatment differences between men and women could explain the dissimilarities, we investigated gender differences in the disease characteristics before treatment initiation and in the biologic treatment prescribed. Methods: Data on patients with RA or IBD were collected from two registries in which patients treated with biologic medication were enrolled. Basic demographic data and disease activity parameters were collected from a time point just before the initiation of the biologic treatment. For patients with psoriasis, the data were taken from the 2010 annual report of the Swedish Psoriasis Register for systemic treatment, which included also non-biologic treatment. For all three diseases, the prescribed treatment and disease characteristics were compared between men and women. Results: In total, 4493 adult patients were included in the study (1912 with RA, 131 with IBD, and 2450 with psoriasis). Most of the treated patients with RA were women, whereas most of the patients with IBD or psoriasis were men. There were no significant differences between men and women in the choice of biologics. At treatment start, significant gender differences were seen in the subjective disease measurements for both RA and psoriasis, with women having higher (that is, worse) scores than men. No differences in objective measurements were found for RA, but for psoriasis men had higher (that is, worse) scores for objective disease activity measures. A similar trend to RA was seen in IBD. Conclusions: Women with RA or psoriasis scored significantly higher on subjective, but not on objective, disease activity measures than men, and the same trend was seen in IBD. This indicates that at the same level of treatment, the disease has a greater effect in women. These findings might suggest that in all three diseases, subjective measures are discounted to some extent in the therapeutic decision-making process, which could indicate undertreatment in female patients

Gender and the treatment of immune-mediated chronic inflammatory diseases: rheumatoid arthritis, inflammatory bowel disease and psoriasis: an observational study

Abstract Background Rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis are immune-mediated inflammatory diseases with similarities in pathophysiology, and all can be treated with similar biological agents. Previous studies have shown that there are gender differences with regard to disease characteristics in RA and IBD, with women generally having worse scores on pain and quality of life measurements. The relationship is less clear for psoriasis. Because treatment differences between men and women could explain the dissimilarities, we investigated gender differences in the disease characteristics before treatment initiation and in the biologic treatment prescribed. Methods Data on patients with RA or IBD were collected from two registries in which patients treated with biologic medication were enrolled. Basic demographic data and disease activity parameters were collected from a time point just before the initiation of the biologic treatment. For patients with psoriasis, the data were taken from the 2010 annual report of the Swedish Psoriasis Register for systemic treatment, which included also non-biologic treatment. For all three diseases, the prescribed treatment and disease characteristics were compared between men and women. Results In total, 4493 adult patients were included in the study (1912 with RA, 131 with IBD, and 2450 with psoriasis). Most of the treated patients with RA were women, whereas most of the patients with IBD or psoriasis were men. There were no significant differences between men and women in the choice of biologics. At treatment start, significant gender differences were seen in the subjective disease measurements for both RA and psoriasis, with women having higher (that is, worse) scores than men. No differences in objective measurements were found for RA, but for psoriasis men had higher (that is, worse) scores for objective disease activity measures. A similar trend to RA was seen in IBD. Conclusions Women with RA or psoriasis scored significantly higher on subjective, but not on objective, disease activity measures than men, and the same trend was seen in IBD. This indicates that at the same level of treatment, the disease has a greater effect in women. These findings might suggest that in all three diseases, subjective measures are discounted to some extent in the therapeutic decision-making process, which could indicate undertreatment in female patients.</p

Anti-Ro52 Autoantibodies from Patients with Sjögren's Syndrome Inhibit the Ro52 E3 Ligase Activity by Blocking the E3/E2 Interface

Ro52 (TRIM21) is an E3 ligase of the tripartite motif family that negatively regulates proinflammatory cytokine production by ubiquitinating transcription factors of the interferon regulatory factor family. Autoantibodies to Ro52 are present in patients with lupus and Sjögren's syndrome, but it is not known if these autoantibodies affect the function of Ro52. To address this question, the requirements for Ro52 E3 ligase activity were first analyzed in detail. Scanning a panel of E2 ubiquitin-conjugating enzymes, we found that UBE2D1–4 and UBE2E1–2 supported the E3 ligase activity of Ro52 and that the E3 ligase activity of Ro52 was dependent on its RING domain. We also found that the N-terminal extensions in the class III E2 enzymes affected their interaction with Ro52. Although the N-terminal extension in UBE2E3 made this E2 enzyme unable to function together with Ro52, the N-terminal extensions in UBE2E1 and UBE2E2 allowed for a functional interaction with Ro52. Anti-Ro52-positive patient sera and affinity-purified anti-RING domain autoantibodies inhibited the E3 activity of Ro52 in ubiquitination assays. Using NMR, limited proteolysis, ELISA, and Ro52 mutants, we mapped the interactions between Ro52, UBE2E1, and anti-Ro52 autoantibodies. We found that anti-Ro52 autoantibodies inhibited the E3 ligase activity of Ro52 by sterically blocking the E2/E3 interaction between Ro52 and UBE2E1. Our data suggest that anti-Ro52 autoantibodies binding the RING domain of Ro52 may be actively involved in the pathogenesis of rheumatic autoimmune disease by inhibiting Ro52-mediated ubiquitination.Funding agencies|Swedish Research Council||Swedish Foundation for Strategic Research||VINNOVA||CeNano||Swedish Cancer Society||Karolinska Institutet||Linkoping University||King Gustaf Vs 80-Year Foundation||Heart-Lung Foundation||Stockholm County Council||Gustafsson Foundation||Soderberg Foundation||National Cancer Institute of Canada||Swedish Rheumatism Association||Wallenberg Foundation||</p

Developing classification criteria for discoid lupus erythematosus: an update from the World Congress of Dermatology 2015 meeting

Currently, no standardized classification criteria exist for cutaneous lupus erythematosus. With increased interest in studying cutaneous lupus erythematosus, specifically discoid lupus erythematosus, it is our aim to apply previously adopted methods from rheumatology to dermatologic diseases to develop feasible, validated, and standardized classification criteria useful in both academic and community practice. Here we report the progress to date to define discoid lupus erythematosus using clinical, histopathologic, and serologic features by means of a Delphi method—using a series of iterative questionnaires sent to expert stakeholders. We present specific updates from the World Congress of Dermatology 2015 meeting, at which a nominal group of expert stakeholders met to discuss the results of round 1 of the Delphi process to further clarify and harmonize specific classification items for inclusion into round 2

Development of classification criteria for discoid lupus erythematosus: Results of a Delphi exercise

Background: No classification criteria currently exist for discoid lupus erythematosus (DLE), which has led to problematic heterogeneity in both observational and interventional research efforts. Objectives: We sought to develop DLE classification criteria based on consensus of international expert opinion of relevant stakeholders in the field. Methods: Using a Delphi consensus process and nominal group techniques, potential items for classification criteria were generated. Experts ranked items in terms of their appropriateness and ability to discriminate DLE from other diagnoses, and items were subsequently eliminated using consensus exercises. Results: A final list of 12 clinical and histopathologic items was generated for potential inclusion into a set of DLE classification criteria through a formal ongoing validation process. Limitations: The participants are predominantly composed of DLE experts in North America and Europe. Conclusion: This work represents a key step toward the development of formal DLE classification criteria