Primary scalp alopecia is classically divided into cicatricial (scarring) and non-cicatricial (non-scarring). Challenging cases are assessed with a scalp biopsy. The use of both horizontal and vertical sections (HoVert sections) has dramatically improved the accuracy of histopathological diagnosis. In this work, we have used immunostaining to address diagnostic difficulties, which persist despite all currently available tools. We performed an immunostain panel (CD3, CD4, CD8 and CD20) in order to distinguish pattern hair loss from alopecia aerate in cases which do not have the usual peribulbar lymphocytic infiltrate and showed that CD3+ T-lymphocytes within the empty fibrous follicular tracts favor a diagnosis of alopecia areata. We performed CD123 in order to distinguish lichen planopilaris from alopecia lupus erythematosus in cases with only a superficial lymphocytic infiltrate and an uninvolved interfollicular epidermis and showed that clusters of CD123+ plasmacytoid dendritic cells favor a diagnosis of lupus erythematosus. We performed cytokeratin 15 in order to assess whether the loss of the follicular bulge stem cells has diagnostic value in cicatricial alopecia and demonstrated that the loss of cytokeratin 15+ bulge stem cells is identified in lichen planopilaris, frontal fibrosing alopecia, and lupus erythematous, so cytokeratin 15 has no diagnostic value. We have attempted to integrate the new concepts and our findings into the traditional classifications of alopecia and proposed a new diagnostic algorithm. In conclusion, immunostaining combined with HoVert grossing advances the accuracy of histopathological diagnosis of primary scalp alopecia. / L’alopécie primitive du cuir chevelu est habituellement classée en cicatricielle et non-cicatricielle. Dans les cas difficiles, la biopsie du cuir chevelu peut aider au diagnostic. L’utilisation de coupes, à la fois verticales et horizontales sur le même spécimen (technique HoVert), a radicalement amélioré le diagnostic histopathologique. Dans ce travail, nous avons utilisé l’immunohistochimie pour évaluer les difficultés diagnostiques qui persistent malgré tous les outils actuels. Nous avons utilisé les CD3, CD4, CD8 et CD20 pour différencier l’alopécie androgénique de la pelade dépourvue de l’infiltrat lymphocytaire péribulbaire habituel et nous avons démontré que la présence de lymphocytes CD3+ dans les travées folliculaires fibreuses est en faveur de la pelade. Nous avons utilisé le CD123 pour différencier le lichen plan pilaire du lupus érythémateux alopécie avec infiltrat lymphocytaire superficiel et sans atteinte de l’épiderme interfolliculaire et nous avons démontré que la présence d’amas de cellules dendritiques plasmacytoïdes CD123+ est en faveur du lupus érythémateux. Nous avons utilisé la cytokératine 15 pour évaluer si la perte des cellules souches du bulge a une valeur diagnostique dans l’alopécie cicatricielle et nous avons démontré que cette perte s’observait de manière identique dans le lichen plan pilaire, l’alopécie frontale fibrosante comme dans le lupus érythémateux et n’avait donc aucune valeur diagnostique. Nous avons tenté d’intégrer les nouveaux concepts et nos données dans les classifications traditionnelles des alopécies et nous avons élaboré un nouvel algorithme diagnostique. L’association des immunomarquages avec la technique HoVert ouvre de nouvelles perspectives dans le diagnostic histopathologique des alopécies primaires du cuir chevelu. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

Le Lupus Erythémateux Systémique (LES) est une maladie autoimmune sévère dont laquelle les lymphocytes B (LB) jouent un rôle central. Afin de rechercher des anomalies génétiques propre à ces cellules, notre laboratoire a étudié l’expression des gènes dans les LB de patients atteints d’un LES, par rapport à des sujets témoins. Ce projet a pour but d’étudier un de ces gènes (FKBP11), surexprimé dans les LB au cours du LES. Pour cela nous avons créé, à l’aide de lentivirus, des souris transgéniques reproduisant de manière ubiquitaire la surexpression de ce gène. Ces souris développent une hyperplasie des organes lymphoïdes, une hyper gamma globulinémie de type IgG3, et présentent une réponse humorale augmentée après immunisation avec un antigène T-indépendant. Notre étude met en évidence que la surexpression de FKBP11 favorise le développement des plasmocytes dans leur phase initiale dépendante de l’expression de Pax5, après induction de la différenciation plasmocytaire in vitro. Enfin, les souris développent des autoanticorps variés. De plus, le rôle d’une surexpression de FKBP11 dans la rupture de tolérance B a été montré chez des souris transgéniques anti-ADN 56R, croisées avec notre modèle lentigénique, qui voient leur production d’autoanticorps augmentée. La surexpression de FKBP11 dans le modèle C57BL/6lpr/lpr accentue le caractère lymphoprolifératif et l’hyper gamma globulinémie présents dans ces souris. Au cours de ce projet de thèse, j’ai également initié l’étude de deux autres gènes surexprimés dans les LB de patients lupiques (PRDX4, TRIB1), par le développement de modèles transgéniques murins. / Systemic Lupus Erythematosus (SLE) is a severe autoimmune disease where B cells play a central role and carry intrinsic genetic abnormalities.Today, only a few SLE genes have been validated in humans. Looking for these intrinsic B cell abnormalities in SLE, we have performed a microarray analysis of the human transcriptoma in B cells from quiescent SLE patients, in comparison to normal subjects. The project proposes to explore the consequences of overexpression of one of these genes: FKBP11. For this purpose, a lentiviral construct allowing the ubiquitous overexpression of FKBP11 was produced, and has been used to generate lentigenic mice. These mice develop a hyperplasia of lymphoid organs, an IgG3 hypergammaglobulinemia and an increase of humoral immune response after immunisation with a T-independent antigen. Our study points out that the overexpression of FKBP11 promotes the plasmocyte development, at the initial stage which is dependent on Pax5 expression, after in vitro induction of the plasmacytic differentiation. Finally, these mice produce various autoantibodies. The role of FKBP11 overexpression in B cell central tolerance breakdown has been demonstrated in anti-DNA 56R transgenic mice crossed with our lentigenic model. These mice have an increase of autoantibody production. The FKBP11 overexpression in C57BL/6lpr/lpr model increases the lymphoproliferative syndrome and the hypergammaglobulinemia in this model. During this thesis, I have also initiated the study of two others genes which were found overexpressed in B cells of lupus patients (PRDX4, TRIB1), by the development of transgenic murine models.

Le lupus érythémateux disséminé (LES) est une maladie systémique auto-immune chronique dont le retentissement sur la vie des patients est très lourd. Au cours de la décennie écoulée, des échelles de qualité de vie spécifique du lupus systémique ont été développées pour compléter les données obtenues avec les questionnaires génériques. Dans une première partie de ce travail, nous exposons la définition du concept de qualité de vie et les différentes manières de la mesurer. Nous présentons ensuite l’état des connaissances sur les facteurs influençant la qualité de vie au cours du LES. Dans une seconde partie, nous exposons les résultats obtenus sur une cohorte de 182 patients atteints de LES (étude FRESHQOLA) ayant pour but de valider la version française du questionnaire spécifique LupusQoL. La validité et la fiabilité du questionnaire étaient satisfaisantes. Dans une seconde partie, nous présentons les résultats de la sensibilité au changement du même questionnaire, et nous montrons que le LupusQoL permet de capter un changement dans l’état de santé des patients, et qu’il serait plus sensible au changement que le questionnaire générique SF-36 pour mesurer une amélioration de leur état de santé. Dans une troisième partie, nous présentons les résultats de l’étude EQUAL sur 330 patients ayant pour objectif la validation du questionnaire SLEQOL. Outre la fiabilité et la validité du questionnaire, nous avons réalisé une analyse de fonctionnement différentiel d’item entre les patients de notre cohorte et un échantillon de patients issus de la cohorte de développement de l’échantillon à Singapour. Le SLEQOL était fiable et valide malgré 4 items montrant un fonctionnement différentiel modéré. Dans une quatrième partie, nous présentons l’analyse des facteurs associés à la qualité de vie mesurée par les questionnaires spécifiques LupusQoL, SLEQOL et les questionnaires génériques SF-36 et WHOQOL dans cette même cohorte de 330 patients. La qualité de vie dans les domaines physique, mental et social était fortement associée aux facteurs socio-économiques et en particulier la précarité sociale, telle que mesurée par le score EPICES. Les femmes avaient une altération de la qualité de vie spécifique, tandis que le surpoids et le tabagisme influençaient les questionnaires génériques mais pas les questionnaires spécifiques, suggérant que dans ces situations, les patients n’attribuent pas la gêne à leur lupus. Enfin, l’atteinte articulaire était la manifestation clinique de la maladie la plus fortement associée à une diminution de la qualité de vie. Ces résultats ouvrent donc des perspectives dans la compréhension du retentissement du lupus systémique sur le quotidien des patients et nous permettront de mieux comprendre les résultats des essais cliniques et études épidémiologiques à venir. / Systemic Lupus Erythematosus (SLE) is a chronic systemic auto-immune disease that considerably impairs patients’ daily living. During the past 10 years, disease-specific health related quality of life questionnaires have been developed in order to complete the information obtained using generic questionnaires in SLE patients. In the first part of our work, we present the definition of the concept of quality of life and the different way to measure it. In the second part, we present the results of a cohort study of 182 SLE patients that aimed to validate the French version of the SLE-specific questionnaire LupusQoL. Validity and reliability of the questionnaire were found to be satisfactory. In the second part, we present the results concerning responsiveness of the same questionnaire. We showed that LupusQol was able to capture a change in patients’ health state, and that it could be more responsive than the generic SF-36 questionnaire in patients with improving symptoms. In the third part, we present the results of a study involving 330 patients that aimed to validate the SLEQOL questionnaire. Besides determining the validity and reliability of the questionnaire, we conducted a differential item functioning analysis between patients of our cohort and patients from the development cohort of the SLEQOL in Singapore. The SLEQOL was found to be reliable and valid despite 4 items showing a moderate differential item functioning. In the fourth part, we present the results of the analysis of factors associated with quality of life in SLE patients, as measured by SLEQOL and LupusQoL specific questionnaires, and WHOQOL and SF-36 generic questionnaires in the same cohort of 330 patients. Quality of life in physical, mental and social domains was strongly associated with socio-economic factors, especially the social precariousness, as measured by the EPICES score. Women had a lower generic quality of life, whereas overweight and smoking influenced the generic questionnaires but not the specific ones, suggesting that in those situation, patients did not attribute their problem to lupus. Finally, articular involvement of the disease was the clinical symptom with the strongest association with quality of life impairment. This study opens up new areas of research that will lead to better understanding of SLE burden and improve the interpretation of results from future clinical trials and epidemiological studies.

Patients with chronic inflammatory conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) experience premature cardiovascular mortality and morbidity compared with the general population. The increased risk of cardiovascular disease (CVD) may in part, result from an interaction between traditional and non-traditional risk factors, modulated by chronic inflammation. The aim of this project was to look at lipid associated biomarkers in patients with SLE/RA and the association between these markers and cardiovascular disease outcomes. We also aimed to study the effect of inflammation reduction on vascular biomarkers. In the first study we examined 168 SLE patients median (IQR) age was 53 (46-61) years and median disease duration 13 (7, 23) years and 56 healthy controls median age 50 (39-60) years. We demonstrated elevated level of oxidised-LDLin SLE patients compared with healthy controls (76 (57, 99) U/l vs 56 (42, 88)U/l P= 0.02). We further explored the association between oxidant stress and premature atherosclerosis as measured by carotid intima media thickness (cIMT) and plaque. In addition to age and systolic blood pressure, oxidised-LDL and urinary 8-isoprostane were significantly and independently associated with cIMTin SLE patients _ coefficient 95%CI [0.00007 (5.29−6, 0.0001) and 0.003 (0.0008,0.004)], respectively. In healthy controls, age was the only independent variable. In the Norfolk Arthritis Register, 1266 patients with early inflammatory polyarthritis (IP) were studied. A linear regression analysis revealed a significant negative association between CRP and lipid profile namely TC, LDL, TG and ApoA-1. During a median (IQR) follow up = 5.5 (3.7-7.7) years 100 (7%) patients died (all causes) of which 33% (33) deaths were attributed to CVD. Forward stepwise regression analysis demonstrated that a low total cholesterol was independently associated with all cause mortality HR (95%CI) 0.75 (0.61, 0.91) and CVD mortality HR (95%CI) 0.49 (0.29, 0.85). In a small cohort 27 SLE patients and 15 healthy controls. We measured endothelial function using flow mediated dilatation of the brachial artery. At baseline we found a significant increase in TG level [1.36 (0.9, 1.87) mmol/l vs0.88 (0.64, 1) mmol/l P= 0.009] and a significant impaired endothelial function in SLE patients compared to the healthy controls [2.86 (0.6, 5.3) vs 6.81 (3.46,8.57), P= 0.03]. After treatment, there was a trend towards reduced TG level and improved endothelial function. Oxidised-LDL did not change significantly. In conclusion, oxidant stress is increased in SLE patients and relates to some measures of subclinical atherosclerosis. Control of inflammation may not be sufficient to completely control this in routine practice. In early RA, active inflammationmay mask any tendency to hyperlipidemia in this population. Low total cholesterol may be the best biomarker of the overall metabolic and inflammatory status of the patients as well as indicating a group with increased risk of future mortality.

Orientadores: Sandra Cecília Botelho Costa, Sandra Helena Alves Bonon / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T11:43:36Z (GMT). No. of bitstreams: 1 Peigo_MurilodeFreitas_M.pdf: 1466925 bytes, checksum: 094e2cd00645843fd5fa2c56ca66c2d5 (MD5) Previous issue date: 2012 / Resumo: O Lúpus Eritematoso Sistêmico (LES) é uma patologia sistêmica do tecido conjuntivo, que se apresenta de maneira variada na dependência do órgão afetado, da gravidade de seu acometimento e da idade do paciente, tendo influência de fatores raciais, de padrões imunológicos e ambientais. Pacientes lúpicos têm grande predisposição para desenvolver infecções graças à imunossupressão induzida pela própria doença como pelo uso de vários medicamentos em seu tratamento. Infecções causadas por herpesvírus, principalmente o Citomegalovírus Humano (CMV) e o Epstein-Barr (EBV), têm sido implicadas em várias doenças autoimunes graves, incluindo o LES. A reativação dos herpesvírus 6 e 7 (HHV-6 e HHV-7) geralmente ocorre em pacientes imunodeprimidos, mas seus papéis ainda são pouco estudados. As infecções por herpesvírus têm influência tanto no início do processo autoimune quanto na exacerbação da progressão da doença. A identificação de pacientes com alto risco de desenvolver doença pelos herpesvírus pode ser realizada utilizando técnicas de detecção de infecção ativa, como a Reação em Cadeia da Polimerase (Nested-PCR) e a detecção do antígeno pp65 do CMV (Antigenemia). Dependendo do caso, estes pacientes podem receber tratamento com antivirais. Diante do exposto, os objetivos deste estudo foram: monitorizar os pacientes com LES em relação à infecção ativa por CMV, EBV, HHV-6 e HHV-7, utilizando as técnicas de Nested-PCR e de antigenemia, bem como avaliar o impacto clínico dessas infecções. Foram incluídos neste trabalho, amostras de sangue de 71 pacientes em seguimento no Departamento de Reumatologia da Faculdade de Ciências Médicas ¿ UNICAMP, com diagnóstico de LES confirmado, sendo que 20/71 (28%) estavam com o lúpus ativo (SLEDAI ? 8) e 51/71 (72%) dos pacientes não tinham atividade lúpica (SLEDAI < 8). Das amostras de sangue pesquisadas, 10/71 (14%) foram positivas para os herpesvírus estudados, sendo que 90% destes pacientes com infecção ativa apresentavam o lúpus em atividade (p?0,006). Infecção ativa pelo CMV ocorreu em 4 pacientes (5,6%). HHV-7 foi detectado em 4 amostras (5,6%). Dois outros pacientes apresentaram dupla infecção por CMV e HHV-7 (2,8%). Infecção ativa pelo EBV e HHV-6 não foi detectada em nenhuma das amostras analisadas. Dois pacientes foram a óbito, sendo que um deles evoluiu com sepse de foco pulmonar (provável doença por CMV) e o outro com sepse por Psedomonas aeruginosa. Diante dos resultados obtidos, podemos observar que a infecção ativa pode ocorrer nos pacientes com LES, principalmente naqueles com a doença em atividade. Poucos estudos têm avaliado o impacto destas infecções no cuidado diário dos pacientes com LES. Acreditamos que este trabalho seja pioneiro e será de fundamental importância, contribuindo com este grupo de pacientes. Entretanto, futuros estudos deverão ser implementados com um número maior de pacientes e de coletas/paciente, principalmente naqueles com LES em atividade, que foram demonstrados com aqueles com fator de risco aumentado / Abstract: Systemic lupus erythematosus (SLE) is a connective tissue systemic pathology that presents itself in several ways, depending on the organ affected, the seriousness of the disease and patient¿s age, being influenced by racial factors, immunologic and environmental patterns. SLE patients have great predisposition to develop infections due to the immunosuppression induced by the disease itself and by the use of medicine in the treatment. Infections caused by herpesvirus, especially Human Cytomegalovirus (CMV) and Epstein-Barr (EBV), have been developed into several serious autoimmune diseases, including SLE. Herpesvirus 6 and 7 (HHV-6 and HHV-7) reactivation generally occurs in immunodepressed patients, but their roles are unclear. Herpesvirus infections have influence both on the beginning of the autoimmune process and on the aggravation of the disease progression. The patients that present high risks of developing herpesvirus related diseases can be identified using active infection detection techniques, such as the Nested polymerase chain reaction (Nested-PCR) and the CMV pp65 antigen detection (antigenemia). Depending on the case, the patients can receive treatment with antivirals. Face to the exposed, the objectives of this study were: to monitor the patients with SLE with regard to active infection by CMV using Nested-PCR and antigenemia techniques, and EBV, HHV-6, HHV-7 in serum, as well as to evaluate the clinic impact to these infections. There were included in this work blood samples of 71 patients that are being treated at the Department of Rheumatology, Faculty of Medical Sciences ¿ University of Campinas - UNICAMP, with a confirmed SLE diagnosis, given that 20/71 (28%) had active lupus (SLEDAI ? 8) and 51/71 (72%) of the patients didn¿t present lupic activity (SLEDAI < 8). Considering the blood samples researched, 10/71 (14%) were positive for the studied herpesvirus, and 90% of the patients with active infection presented lupus in activity (p ? 0,006). Active infection by CMV was observed in 4 patients (5,6%). HHV-7 was detected in 4 samples (5,6%). Two other patients presented double infection by CMV and HHV-7 (2,8%). Active infection by EBV and HHV-6 was not detected in any of the analyzed samples. Two patients have deceased, whose conditions developed into pulmonary sepsis (probable disease by CMV) and into Psedomonas aeruginosa sepsis, respectively. After analyzing the achieved results, we observe that active infection can appear in patients with SLE, especially in those with the disease in activity. Few studies have evaluated the impact of these infections on the daily care of patients with SLE. In this sense, we believe that this work is pioneer and that it will be of fundamental importance, contributing to this group of patients. However, future studies should be implemented, with a larger number of patients and samples, especially those with SLE in activity, which are the ones with increased risk factor as shown / Mestrado / Clinica Medica / Mestre em Clinica Medica

INTRODUÇÃO: O Lúpus Eritematoso Sistêmico (LES) é uma doença inflamatória crônica que pode acometer qualquer órgão ou sistema. O acometimento do coração pode ocorrer em até 50% dos casos e não existem estudos de prevalência de eventos arrítmicos (EA) em pacientes com LES, nem de correlações laboratoriais preditoras de sua ocorrência. OBJETIVOS: Estabelecer a taxa de ocorrência de EA e identificar variáveis laboratoriais preditoras de sua ocorrência em pacientes com LES em seguimento em ambulatório de hospital terciário; estabelecer a associação entre o uso de cloroquina com a ocorrência de EA e óbitos (tipo, número e tempo de seguimento). MÉTODOS: Foi realizado um estudo clínico descritivo, observacional e aberto com pacientes em seguimento ambulatorial no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo que foram submetidos a avaliação clínica, exames laboratoriais, ECG de repouso e Holter de 24h. A associação entre as variáveis e os EA foi avaliada por meio dos testes qui-quadrado, razão de verossimilhança, teste exato de Fisher, teste t-Student, teste não-paramétrico de Mann-Whitney, regressão logística múltipla e curva ROC. RESULTADOS: Entre agosto/2005 e agosto/2006 foram estudados 325 pacientes consecutivos, sendo 8 excluídos. A idade média foi de 40,25 anos, 91% mulheres. O tempo médio do diagnóstico de LES foi de 11,36 anos e apenas 6 pacientes apresentaram critérios para atividade do LES (escore SLEDAI). Duzentos e vinte e um pacientes estavam em uso de cloroquina. Alterações ao ECG ocorreram em 66 pacientes (20,82%): 5 bloqueios atrioventriculares de 1º grau; 4 bradicardias sinusais; 4 taquicardias sinusais e 1 supraventricular; 6 bloqueios do ramo direito (BRD); 2 bloqueios do ramo esquerdo (BRE); 45 QT prolongados. Ao Holter foram identificados 4 pacientes com pausas > 2,0 segundos; 45 com FC mínima < 50bpm; 90 com extrassístoles supraventriculares (ESV); 26 com taquiarritmias supraventriculares (FA/TA); 65 com extrassístoles ventriculares (EV). Foram registrados 7 óbitos (2,47%). Idade acima de 40 anos foi preditora da ocorrência de EA (p=0,002; OR=2,523; IC 95%= 1,389-5,583). A presença do anticorpo anticardiolipina foi preditora da ocorrência de BRD/BRE (p = 0,005; OR 3,989; IC 95% = 1,615-9,852). Títulos de C3 abaixo de 105mg% foram preditores de menor probabilidade de ocorrência de FC mínima < 50bpm (p=0,016; OR=1,018; IC 95%=1,003-1,033). Os preditores para a ocorrência de EV foram a idade (p=0,002; OR=1,051; IC95%=1,018-1,085) e a duração do QRS (p=0,005; OR=1,061; IC95%=1,018-1,106); quanto mais avançada a idade e quanto mais largo o QRS, maior a probabilidade de ocorrência de EV. Para a ocorrência de TA/FA, os preditores foram a idade (p<0,001; OR=1,100; IC95%=1,050-1,154) e o tempo de uso cloroquina (p=0,035; OR=0,921; IC95%=0,853-0,994); quanto mais avançada a idade e quanto menor o tempo de uso de cloroquina, maior a probabilidade de ocorrência de TA/FA. Pacientes com mais de 50 anos e tempo de uso de cloroquina inferior a 8 anos tiveram mais TA/FA. CONCLUSÕES: Neste estudo, que avaliou pacientes com LES em seguimento ambulatorial em hospital terciário, a taxa de ocorrência de EA foi elevada; a sua correlação com variáveis laboratoriais identificou como preditores de maior ocorrência: idade acima de 40 anos, título de C3 abaixo de 105mg% e presença de anticorpo anticardiolipina. A cloroquina demonstrou efeito protetor cardíaco sobre a evolução da doença. / INTRODUCTION: Systemic Lupus Erythematosus (SLE) is a chronic inflammatory illness that can affect any organ and system. Up to 50% of patients have their heart affected and there are no prevalence studies of arrhythmic events (AE) in SLE patients and laboratory predictors are also unknown. OBJECTIVES: To establish the rate of occurrence of AE and to identify laboratory predictors in outpatients with SLE; to establish the association between chloroquine use and the occurrence of AE and death (type, number and time of follow-up). METHODS: A descriptive, observational and opened clinical study was carried out with SLE oupatients selected from the Rheumatology clinic of São Paulo University Medical School, Brazil. They were submitted to clinical evaluation, laboratory exams, resting-ECG and 24-hour Holter monitoring. Statistics: The association between the variables and the occurrence of AE was assessed by chi-square, likelihood ratio, Fishers test, t-Student, Mann-Whitney, ROC curve and logistic regressions. RESULTS: Between august/05-august/06, 325 consecutive patients were studied. Resting-ECG abnormalities were found in 66 patients, rate of 20.82%. The average age was 40.25yo, 91% female. The average time of SLE diagnosis was of 11.36y and only 6 presented criteria for diseases activity (SLEDAI score). There were 221 patients using chloroquine. ECG disturbances found: 5 1st degree AV-block; 4 sinus bradycardia; 4 sinus tachycardia and 1 supraventricular tachycardia; 6 RBBB; 2 LBBB; 45 long QT. At Holter monitoring: 4 pauses>2.0s; 45 HR<50bpm; 90 atrial ectopies; 26 atrial tachyarrhythmia; 65 ventricular ectopies. Seven death were registered (2.47%). Age above 40yo was predictor of AE (p=0.002; OR=2.5; 95%IC=1.4-5.6). Presence of anticardiolipine antibody was predictor of QRS>120ms occurrence (p = 0.005; OR 3.989; IC 95% = 1.615-9.852). C3 level bellow 105mg% was predictor of non-occurrence of HR<50bpm (p=0.02; OR=1.02;95% IC=1.003-1.03). The predictor for ventricular ectopies (VE) occurrence were age (p=0,002; OR=1,051; IC95%=1,018-1,085) and QRS duration (p=0,005; OR=1,061; IC95%=1,018-1,106); advanced age and longer QRS predicted greater probability of VE. For supraventricular tachyarrhythmia (AT/AF) the predictors were age (p<0,001; OR=1,100; IC95%=1,050-1,154) and time of Chloroquine use (p=0,035; OR=0,921; IC95%=0,853-0,994); advanced age and short time of Chloroquine use are related to greater probability of AT/AF. Patients older than 50y and using chloroquine for less than 8y had more AT/AF. CONCLUSIONS: The rate of AE occurrence was high (20%) and the correlation with laboratory variables identified predictors of occurrence of AE: age above 40 years, C3 level below 105mg% and anticardiolipin antibody. Chloroquine demonstrated cardiac protection effect.

Chilblain lupus erythematosus is a rare form of cutaneous lupus erythematosus characterized by bluish red infiltrates in acral locations of the body mostly affecting middle-aged women. We recently described a familial form of chilblain lupus manifesting in early childhood caused by a heterozygous mutation in the TREX1 gene, which encodes a 3′-5′ DNA exonuclease. Thus, familial chilblain lupus represents the first monogenic form of cutaneous lupus erythematosus. Here we describe the unusual clinical course of this newly defined genodermatosis in an 18-year-old female member of the family in which familial chilblain lupus was originally described. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

While clearly different in their aims and means, classification and diagnosis both try to accurately label the disease patients are suffering from. For systemic lupus erythematosus (SLE), this is complicated by the multi-organ nature of the disease and by our incomplete understanding of its pathophysiology. Hallmarks of SLE are the presence of antinuclear antibodies (ANA), and multiple immune-mediated organ symptoms that are largely independent. In an attempt to overcome limitations of the current sets of SLE classification criteria, a new fourphase approach is being developed, which is jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). This review attempts to delineate the performance of the current sets of criteria, the reasons for the decision for classification, and not diagnostic, criteria, and to provide a background of the current approach taken.

Objective: The European League Against Rheumatism and the American College of Rheumatology jointly embarked on a new classification criteria for systemic lupus erythematosus (SLE) project. Its first phase involved generation of a broad set of items potentially useful for classification of SLE. This study was undertaken to add the patient perspective to an expert Delphi approach and an early patient cohort study. Methods: A national cross-sectional study was conducted. A self-report questionnaire was published in the ‘‘Schmetterling’’ (Butterfly), the quarterly journal of the German SLE patient association. Individuals with SLE were asked to anonymously complete the questionnaire, which asked for demographic details, organ manifestations, autoantibodies and symptoms. Results: A total of 339 completed questionnaires out of 2498 were returned, a response rate of 13.6%; 83.2% reported they were ANA positive and 81.7% reported joint, 66.1% skin and 33.0% renal involvement. For the time before and in the first year after their SLE diagnosis, the majority reported fatigue (89.4%), joint pain (86.7%), photosensitivity (79.4%) and myalgia (76.1%). Of interest, more than half of the patients reported fever as an early symptom (53.7%). Conclusion: For a Caucasian European SLE patient population, the overall characteristics suggest meaningful representation. While many symptoms were reported as expected, the high percentage of patients reporting fever and the significant number of patients with unexpected gastrointestinal complaints are of particular interest. These data add to the information on early SLE symptoms informing the development process of new SLE classification criteria.

Diese Arbeit untersucht die Wirksamkeit des monoklonalen Antikörpers Belimumab bei Patient*innen mit systemischem Lupus erythematodes in einer monozentrischen Routinekohorte. Besonderes Augenmerk lag auf der Betrachtung des Ansprechens einzelner Organmanifestationen. Es sollten Subgruppen mit hoher oder niedriger Wahrscheinlichkeit für ein Ansprechen identifiziert werden. Es erfolgte eine retrospektive Auswertung von regelmäßig und standardisiert erhobenen Patient*innendaten. Betrachtet wurden dokumentierte Symptome, Laborparameter und daraus abgeleitete klinische Scores. Betrachtet wurden 4 Zeitpunkte in den ersten 12 Monaten der Therapie und ein weiterer Last visit-Zeitpunkt zur Evaluation des Langzeiterfolges. Bei Patient*innen, deren Therapie vorzeitig beendet wurde, wurden die Werte der letzten Beobachtung unter Therapie übernommen. Es erfolgte eine Auswertung in Untergruppen, abhängig vom Nachweis von Organmanifestationen zu Therapiebeginn. Untersucht wurde ein aussagekräftiges Studienkollektiv mit eher niedriger Krankheitsaktivität. Die Therapie mit Belimumab am UKD wurde für die meisten Patient*innen als erfolgreich bewertet; von 27 Therapien wurden 21 (78 %) von den behandelnden Ärzt*innen als erfolgreich eingeschätzt, was auf eine gute Wirksamkeit in der Population hinweist. Die Zahl symptomfreier Personen stieg innerhalb von 12 Monaten von 1 auf 7 und im weiteren Therapieverlauf auf 10. Es zeigten sich signifikante Änderungen von klinischen Scores und Komplementproteinen; so fiel der mediane SLEDAI von 6 auf 4 Punkte und das mediane C4 stieg von 0,09 g/l innerhalb von 12 Monaten auf normwertige 0,10 g/l sowie im weiteren Verlauf auf 0,16 g/l. Die mittlere Prednisolondosierung wurde innerhalb von 12 Monaten von 5,8 mg/d auf 5,0 mg/d und langfristig auf 3,3 mg/d gesenkt. Belimumab zeigte sich bei 6 von 6 Patient*innen mit Exanthem und 4 von 6 Patient*innen mit Arthritis mit fast vollständigem Symptomrückgang sehr gut wirksam. Von 10 Patient*innen mit einem initialem Prednisolonbedarf von ≥ 7,5mg/d konnten 6 ihre Prednisolondosis um mindestens 25 % senken. Das Symptom Fatigue wurde bei 6 von 18 Patient*innen nach 12 Monaten nicht mehr dokumentiert. Von 11 Patient*innen mit Raynaud-Symptomatik wurde ebendiese nach 12 Monaten nur noch von 7 dokumentiert. Es zeigten sich keine Hinweise auf eine Wirksamkeit auf Leuko- oder Thrombopenie. In weiteren Studien könnte die Wirksamkeit von Belimumab bei Patient*innen mit Lupusnephritis, Raynaud-Symptomatik, Fatigue, hämatologischer Beteiligung und niedriger Krankheitsaktivität weiter untersucht werden.:INHALTSVERZEICHNIS III ABKÜRZUNGSVERZEICHNIS VIII 1 EINLEITUNG 10 1.1 Systemischer Lupus erythematodes (SLE) 10 1.1.1 Geschichte 10 1.1.2 Epidemiologie 11 1.1.3 Ätiologie und Pathogenese 11 1.1.4 Symptome 12 1.1.4.1 Konstitutionell 14 1.1.4.2 Hämatologisch 14 1.1.4.3 Neuropsychiatrisch 14 1.1.4.4 Mukokutan 14 1.1.4.5 Serositis 15 1.1.4.6 Muskuloskelettal 15 1.1.4.7 Renal 15 1.1.4.8 weitere Symptome 15 1.1.5 Diagnostik 16 1.1.5.1 Anamnese 16 1.1.5.2 Klinische Untersuchung 16 1.1.5.3 Labordiagnostik 16 1.1.6 Aktivitätsmessung 17 1.1.7 Letalität 17 1.1.8 Sozioökonomische Belastung und QOL-Einschränkung 18 1.1.9 Klassifikationskriterien 19 1.1.10 Aktivitätsscores 20 1.1.11 Therapie 20 1.1.11.1 Basismaßnahmen 21 1.1.11.2 Glukokortikoide 21 1.1.11.3 DMARDs (disease-modifying anti-rheumatic drugs) 21 1.1.11.4 Cyclophosphamid 22 1.2 Belimumab 23 1.2.1 Wirkmechanismus 23 1.2.2 Zulassungsstudien 23 1.2.2.1 Studienpopulation 24 1.2.2.2 nachgewiesene Effekte 24 Unerwünschte Arzneimittelwirkungen (UAW) in den Zulassungsstudien 25 1.2.2.3 Zulassung 26 1.2.3 Belimumab in der klinischen Anwendung 26 2 FRAGESTELLUNG 27 3 MATERIAL UND METHODEN 28 3.1 Studienkollektiv 28 3.2 Ethik 28 3.3 Erhobene Daten 28 3.3.1 Charakterisierung des Studienkollektivs 29 3.3.2 Datumsangaben 29 3.3.3 Zeitpunkte 29 3.3.4 Zeitpunktabhängige Parameter 30 3.3.5 Erhobene, nicht aussagekräftige Daten 32 3.3.6 Organmanifestationen 32 3.4 Quellen 33 3.4.1 Patient*innenakte 34 3.4.2 Ärztliche Verlaufsdokumentation 34 3.4.3 Medikamente 35 3.4.4 SLE-Bogen 35 3.4.5 Laborwerte 36 3.4.6 Berechnung von klinischen Scores 37 3.4.7 Therapieerfolg 37 3.4.8 Dokumentationsungenauigkeiten 37 3.5 Statistische Verfahren 38 3.5.1 Normalverteilung 38 3.5.2 Signifikanztests 39 4 ERGEBNISSE 41 4.1 Studienkollektiv 41 4.1.1 Allgemeine Zusammensetzung 41 4.1.2 Erfüllung der EULAR/ACR2019-Kriterien 43 4.1.3 Antikörperstatus 44 4.1.4 Charakterisierung der einzelnen Patient*innen 45 4.2 Zeitpunktübergreifende Ergebnisse 49 4.2.1 Auswertungszeitraum 49 4.2.2 Therapiedauer 50 4.2.3 Zeitpunkte und beendete Therapien 50 4.2.4 Therapieerfolg 51 4.2.5 Krankheitsschübe und Prednisolonstoßtherapien 52 4.2.6 weitere Medikamente 53 4.2.7 Unerwünschte Arzneimittelwirkungen 53 4.3 Zeitpunktabhängige Ergebnisse 55 4.3.1 Datumsdifferenzen 55 4.3.2 Prednisolonbasistherapie 56 4.3.3 Symptome 56 4.3.4 Paraklinik 58 4.3.5 Scores 58 4.3.6 Angaben auf der visuellen Analogskala 59 4.4 Auswertung nach Patient*innengruppen 61 4.4.1 Indikationsrelevante Organbeteiligungen 61 4.4.2 Patient*innen mit Arthritis 62 4.4.3 Patient*innen mit Fatigue 64 4.4.4 Patient*innen mit Exanthem 67 4.4.5 Patient*innen mit Raynaud-Symptomatik 68 4.4.6 Patient*innen mit hämatologischer Beteiligung 70 4.4.7 Patient*innen mit hohem Prednisolonbedarf 74 4.4.8 Patient*innen mit aktiver Lupusnephritis 76 5 DISKUSSION 78 5.1 Stärken und Schwächen der Studie 78 5.1.1 Anzahl der Patient*innen 78 5.1.2 Definition des Therapieerfolgs 78 5.1.3 Schubförmiger Verlauf der Erkrankung 79 5.1.4 Systematischer Fehler der Scores 79 5.1.5 Fortführung der letzten Beobachtung bei Patient*innen mit beendeter Therapie 80 5.1.6 Last visit-Zeitpunkt 80 5.1.7 Auswertung nach Patient*innengruppen 80 5.2 Studienkollektiv 82 5.2.1 Allgemeine Zusammensetzung 82 5.2.2 Erfüllung der EULAR/ACR2019-Kriterien 84 5.2.3 Antikörperstatus 86 5.3 Zeitpunktübergreifende Ergebnisse 87 5.3.1 Therapieerfolg 87 5.3.2 Krankheitsschübe und Prednisolonstoßtherapien 87 5.3.3 weitere Medikamente 87 5.3.4 Unerwünschte Arzneimittelwirkungen 87 5.4 Zeitpunktabhängige Ergebnisse 89 5.4.1 Datumsdifferenzen 89 5.4.2 Prednisolonbasistherapie 89 5.4.3 Symptome 89 5.4.4 Paraklinik 89 5.4.5 Scores 90 5.4.6 Angaben auf der visuellen Analogskala 91 5.5 Auswertung nach Patient*innengruppen 92 5.5.1 Indikationsrelevante Organbeteiligungen 92 5.5.2 Patient*innen mit Arthritis 93 5.5.3 Patient*innen mit Fatigue 93 5.5.4 Patient*innen mit Exanthem 93 5.5.5 Patient*innen mit Raynaud-Symptomatik 94 5.5.6 Patient*innen mit hämatologischer Beteiligung 94 5.5.7 Patient*innen mit hohem Prednisolonbedarf 94 5.5.8 Patient*innen mit aktiver Lupusnephritis 95 5.6 Relevanteste Ergebnisse 96 5.7 Ausblick 97 6 ZUSAMMENFASSUNG 98 7 SUMMARY 99 LITERATURVERZEICHNIS 106 ANHANG 123 DANKSAGUNG 124 ANLAGE 1: ERKLÄRUNG ZUR ERÖFFNUNG DES PROMOTIONSVERFAHRENS 125 ANLAGE 2: ERKLÄRUNG ZUR EINHALTUNG AKTUELLER GESETZLICHER VORGABEN 126