<p>Adrenocortical cancer (ACC) is a rare disease that is often difficult to diagnose, and therefore often presents at an advanced stage. Various cytotoxic treatments have been tried with little success. Evaluation of new diagnostic methods and improvement of medical therapies are therefore crucial.</p><p>The diagnostic potential of 11C-metomidate positron emission tomography (PET) was evaluated in eleven ACC patients. PET visualized all viable tumors with high tracer uptake, including two lesions that CT failed to detect. Necrotic or fibrotic tumors were PET negative. Medication with adrenal steroid inhibitors and chemotherapy may decrease the tracer uptake.</p><p>We performed a phase-II study with streptozocin and o,p’-DDD (SO) combination therapy in 40 ACC patients. The SO therapy was found to have impact on the disease-free interval (P = 0.02) as well as on survival (P = 0.01) in patients who received adjuvant therapy after curative resection. Complete or partial response was obtained in 36.4% of patients with measurable disease.</p><p>The efficacy and tolerability of combination therapy with vincristine, cisplatin, teniposide, and cyclophosphamide (OPEC) were evaluated in eleven patients with advanced ACC after failure of SO therapy. The median survival was 21 months from the start of treatment. A partial response was achieved in two patients. Adverse events were mainly restricted to grade 1-2 toxicities, and grade 3 toxicities were observed in only two cycles.</p><p>We tested 21 ACC tumors to analyze the expression of receptor tyrosine kinases and 15 ACC for mutation analysis of c-Kit exon 11, which can be targeted by antagonists such as imatinib. All ACCs expressed one or more kinases: c-Kit in 19 ACC and phospho-c-Kit in three while 14 ACCs expressed PDGFR-beta, suggesting the potential usefulness of tyrosine kinase inhibitors. No c-Kit mutations were detected in exon 11. Further evaluation of other mutations targeted by this drug may be needed.</p>

<p>The regulation of serum phosphate (Pi) concentrations is a complex process and our current models are far from complete. Due to major advancements in biotechnology and the development of more powerful research tools, recent advances in the field of genetics has led to the identification of several candidates for the long sought-after phosphatonin(s), or Pi regulating hormones. One of these candidates is fibroblast growth factor 23 (FGF-23) and this thesis is based upon studies of the role of FGF-23 in Pi homeostasis. We demonstrate that FGF-23 is a secreted protein which is highly expressed in tumors giving rise to oncogenic hypophosphatemic osteomalacia (OOM). Furthermore, we have developed a two-site enzyme-linked immunosorbent assay for the detection of circulating FGF-23 and established that FGF-23 is present in the circulation of healthy individuals. Also, FGF-23 serum levels are elevated in patients with disturbances in Pi homeostasis such as OOM, X-linked hypophosphatemic rickets (XLH) and chronic kidney disease and are likely to play an important role in the pathogenesis of these disorders. A transgenic mouse model that express human FGF-23 under the control of the α1(I) collagen promoter exhibit similar clinical and biochemical characteristics as do patients with OOM, XLH and autosomal dominant hypophosphatemic rickets indicating that FGF-23 is an important determinant of Pi homeostasis, vitamin D metabolism and bone mineralization.</p>

The principal aim was to study selected aspects of indoor environment in dwellings and their association with symptoms compatible with the sick building syndrome (SBS). A validated questionnaire was developed specifically for residential indoor investigations, using sociological principles and test procedures. The questionnaire was mailed to 14,243 multi-family dwellings in Stockholm, selected by stratified random sampling. Females, subjects with a history of atopy, those above 65 y, and those in new buildings reported more symptoms. Subjects owning their own dwelling had less symptoms. A multiple regression model was developed, to identify residential buildings with a higher than expected occurrence of SBS. In total, 28.5% reported at least one sign of building dampness in their home (condensation on windows, humidity in the bathroom, mouldy odour, water leakage). All indicators of dampness were related to symptoms, even when adjusting for demographic data, and other building characteristics (OR=2.9-6.0). Associations between symptoms and other building data was evaluated in older houses, built before 1961. Subjects in older buildings with a mechanical ventilation system had fewer symptoms. Heating by electric radiators, and wood heating was associated with an increase of most types of symptoms (OR=1.2-5.0). Multiple sealing measures (OR=1.3), and major reconstruction (OR=1.1-1.9), was associated with an increase of symptoms. The effect of seasonal adapted ventilation (SAV) was studied in a small experimental study. A 20% reduction of ventilation flow from 0.5-0.8 ac/h to 0.4-0.5 ACH during the heating season increased the perception of poor indoor air quality in the dwelling in general, and in the bedroom. In conclusion, low building age, and building dampness in the dwelling are associated with SBS. In older houses, mechanical ventilation is beneficial. The thesis did not support the view that energy saving measures in general is an important risk factor for SBS, but major reconstruction and multiple sealing measures can be risk factor for symptoms. Reducing the outdoor ventilation flow below the current Swedish ventilation standard (0.5 ACH) may increase the perception of impaired air quality.

Adrenocortical cancer (ACC) is a rare disease that is often difficult to diagnose, and therefore often presents at an advanced stage. Various cytotoxic treatments have been tried with little success. Evaluation of new diagnostic methods and improvement of medical therapies are therefore crucial. The diagnostic potential of 11C-metomidate positron emission tomography (PET) was evaluated in eleven ACC patients. PET visualized all viable tumors with high tracer uptake, including two lesions that CT failed to detect. Necrotic or fibrotic tumors were PET negative. Medication with adrenal steroid inhibitors and chemotherapy may decrease the tracer uptake. We performed a phase-II study with streptozocin and o,p’-DDD (SO) combination therapy in 40 ACC patients. The SO therapy was found to have impact on the disease-free interval (P = 0.02) as well as on survival (P = 0.01) in patients who received adjuvant therapy after curative resection. Complete or partial response was obtained in 36.4% of patients with measurable disease. The efficacy and tolerability of combination therapy with vincristine, cisplatin, teniposide, and cyclophosphamide (OPEC) were evaluated in eleven patients with advanced ACC after failure of SO therapy. The median survival was 21 months from the start of treatment. A partial response was achieved in two patients. Adverse events were mainly restricted to grade 1-2 toxicities, and grade 3 toxicities were observed in only two cycles. We tested 21 ACC tumors to analyze the expression of receptor tyrosine kinases and 15 ACC for mutation analysis of c-Kit exon 11, which can be targeted by antagonists such as imatinib. All ACCs expressed one or more kinases: c-Kit in 19 ACC and phospho-c-Kit in three while 14 ACCs expressed PDGFR-beta, suggesting the potential usefulness of tyrosine kinase inhibitors. No c-Kit mutations were detected in exon 11. Further evaluation of other mutations targeted by this drug may be needed.

Acute myocardial infarction (AMI), caused by ischaemic heart disease (IHD), is a leading cause of death in both men and women in the western society. Hypertension, diabetes, and smoking are examples of well-known risk factors of IHD, but also there are psychosocial factors, such as stress, vital exhaustion (unusual fatigue, irritability, and demoralization) and depression that have been associated with an increased risk in both genders. After an AMI, however, women are more likely than men to be psychosocially impaired resulting in suffering and a presumed increase in the risk of recurrent cardiac events. Psychosocial factors may be targeted in secondary prevention, complementary to drug treatment and conventional lifestyle advice. There is some evidence of beneficial effects on both psychosocial well-being and cardiac outcomes by psychosocial interventions in men. Far fewer women have been studied and the results have been inconsistent. It is not clear how psychosocial factors convey the increased risk of cardiac events, but many possible psychopathological mechanisms, including biochemical and physiological links, have been suggested. In the Women’s Hearts study we have, in a randomised controlled trial, evaluated a one-year cognitive-behavioural stress management programme designed specifically for women with IHD. We included 198 women with IHD, with a mean age of 61 years and from the county of Västerbotten in Northern Sweden, who were randomised to either conventional treatment and follow-up, or to stress management in addition to conventional care. Extensive questionnaires, blood samplings, and biomedical and physiologic data were obtained before randomisation, as well as at follow-ups approximately one and two years after randomisation. Two groups of healthy controls were included for comparisons with women with IHD. Compared to women without IHD, women with IHD reported more stress behaviour and vital exhaustion. Women with IHD also had a lower heart rate variability (HRV) than the healthy controls, possibly reflecting a dysfunctional autonomic nervous regulation of the heart. Reduced HRV has been shown to increase the risk of cardiac arrhythmias and sudden death. At the first follow-up, performed at the end of the one-year stress management programme, women who had participated in the programme had reduced the stress behaviour and vital exhaustion, compared to the women in the conventional care group. We could not find any evidence of a direct cause-effect relationship between stress management and biological cardiovascular risk indicators, or HRV; the intervention and control groups did not differ in insulin resistance, inflammatory, haemostatic and fibrinolytic factors, or HRV. At second follow-up one year later, several additional psychosocial domains were studied. The stress management programme had accelerated psychosocial recovery at the first follow-up over and above that observed in the control group. At the second follow-up, there was further marked improvement in the control group, so the differences in psychosocial variables between the intervention and control groups were no longer significant. In conclusion, a cognitive-behavioural stress management programme could accelerate psychosocial improvement in women with IHD, and thus reduce the amount of psychological and psychosocial suffering. We could not find any evidence that the stress management programme was associated with a concomitant improvement in biological cardiovascular risk indicators, or HRV. Our results suggest that the women with the greatest psychosocial burden should be identified and targeted in new clinical trials of cognitive-behavioural interventions in women with IHD. Future studies within the Women’s Hearts project will evaluate the psychosocial effects at a five-year follow-up, as well as investigations of other possible pathways by which psychosocial interventions might mediate beneficial effects on cardiac events.

The regulation of serum phosphate (Pi) concentrations is a complex process and our current models are far from complete. Due to major advancements in biotechnology and the development of more powerful research tools, recent advances in the field of genetics has led to the identification of several candidates for the long sought-after phosphatonin(s), or Pi regulating hormones. One of these candidates is fibroblast growth factor 23 (FGF-23) and this thesis is based upon studies of the role of FGF-23 in Pi homeostasis. We demonstrate that FGF-23 is a secreted protein which is highly expressed in tumors giving rise to oncogenic hypophosphatemic osteomalacia (OOM). Furthermore, we have developed a two-site enzyme-linked immunosorbent assay for the detection of circulating FGF-23 and established that FGF-23 is present in the circulation of healthy individuals. Also, FGF-23 serum levels are elevated in patients with disturbances in Pi homeostasis such as OOM, X-linked hypophosphatemic rickets (XLH) and chronic kidney disease and are likely to play an important role in the pathogenesis of these disorders. A transgenic mouse model that express human FGF-23 under the control of the α1(I) collagen promoter exhibit similar clinical and biochemical characteristics as do patients with OOM, XLH and autosomal dominant hypophosphatemic rickets indicating that FGF-23 is an important determinant of Pi homeostasis, vitamin D metabolism and bone mineralization.

Made available in DSpace on 2014-12-17T14:54:49Z (GMT). No. of bitstreams: 1 HelianaBS_da_capa_ate_cap4.pdf: 2361373 bytes, checksum: 3e1e43e8ba1aadc274663b8b8e3de72f (MD5) Previous issue date: 2008-02-22 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / The skin cancer is the most common of all cancers and the increase of its incidence must, in part, caused by the behavior of the people in relation to the exposition to the sun. In Brazil, the non-melanoma skin cancer is the most incident in the majority of the regions. The dermatoscopy and videodermatoscopy are the main types of examinations for the diagnosis of dermatological illnesses of the skin. The field that involves the use of computational tools to help or follow medical diagnosis in dermatological injuries is seen as very recent. Some methods had been proposed for automatic classification of pathology of the skin using images. The present work has the objective to present a new intelligent methodology for analysis and classification of skin cancer images, based on the techniques of digital processing of images for extraction of color characteristics, forms and texture, using Wavelet Packet Transform (WPT) and learning techniques called Support Vector Machine (SVM). The Wavelet Packet Transform is applied for extraction of texture characteristics in the images. The WPT consists of a set of base functions that represents the image in different bands of frequency, each one with distinct resolutions corresponding to each scale. Moreover, the characteristics of color of the injury are also computed that are dependants of a visual context, influenced for the existing colors in its surround, and the attributes of form through the Fourier describers. The Support Vector Machine is used for the classification task, which is based on the minimization principles of the structural risk, coming from the statistical learning theory. The SVM has the objective to construct optimum hyperplanes that represent the separation between classes. The generated hyperplane is determined by a subset of the classes, called support vectors. For the used database in this work, the results had revealed a good performance getting a global rightness of 92,73% for melanoma, and 86% for non-melanoma and benign injuries. The extracted describers and the SVM classifier became a method capable to recognize and to classify the analyzed skin injuries / O c?ncer de pele ? o mais comum de todos os c?nceres e o aumento da sua incid?ncia deve-se, em parte, ao comportamento das pessoas em rela??o ? exposi??o ao sol. No Brasil, o c?ncer de pele n?o melanoma ? o mais incidente na maioria das regi?es. A dermatoscopia e ideodermatoscopia s?o os principais tipos de exames para o diagn?stico de doen?as da pele dermatol?gicas. O campo que envolve o uso de ferramentas computacionais para o aux?lio ou acompanhamento do diagn?stico m?dico em les?es dermatol?gicas ainda ? visto como muito recente. V?rios m?todos foram propostos para classifica??o autom?tica de patologias da pele utilizando imagens. O presente trabalho tem como objetivo apresentar uma nova metodologia inteligente para an?lise e classifica??o de imagens de c?ncer de pele, baseada nas t?cnicas de processamento digital de imagens para extra??o de caracter?sticas de cor, forma e textura, utilizando a Transformada Wavelet Packet (TWP) e a t?cnicas de aprendizado de m?quina denominada M?quina de Vetor de Suporte (SVM Support Vector Machine). A Transformada Wavelet Packet ? aplicada para extra??o de caracter?sticas de textura nas imagens. Esta consiste de um conjunto de fun??es base que representa a imagem em diferentes bandas de freq??ncia, cada uma com resolu??es distintas correspondente a cada escala. Al?m disso, s?o calculadas tamb?m as caracter?sticas de cor da les?o que s?o dependentes de um contexto visual, influenciada pelas cores existentes em sua volta, e os atributos de forma atrav?s dos descritores de Fourier. Para a tarefa de classifica??o ? utilizado a M?quina de Vetor de Suporte, que baseia-se nos princ?pios da minimiza??o do risco estrutural, proveniente da teoria do aprendizado estat?stico. A SVM tem como objetivo construir hiperplanos ?timos que apresentem a maior margem de separa??o entre classes. O hiperplano gerado ? determinado por um subconjunto dos pontos das classes, chamado vetores de suporte. Para o banco de dados utilizado neste trabalho, os resultados apresentaram um bom desempenho obtendo um acerto global de 92,73% para melanoma, e 86% para les?es n?o-melanoma e benigna. O potencial dos descritores extra?dos aliados ao classificador SVM tornou o m?todo capaz de reconhecer e classificar as les?es analisadas

Abstract Glucocorticoids are the most important and widely used treatment modality in dermatology. A large variety of topical as well as systemic preparations is available. Most patients treated with glucocorticoids respond quickly to the treatment, but some are considered insensitive or even resistant to glucocorticoid therapy. Currently, there is no known measurable variable, through which the response can be predicted. Glucocorticoids mediate their actions through glucocorticoid receptors (GR). Several isoforms of GR exist, but the α (GRα) and β (GRβ) isoforms are clinically the most important. Based on previous studies, it has been proposed that the abundance of GR isoforms or the GRβ: GRα –ratio could affect individual responsiveness to corticosteroid treatment. In particular, up-regulation of GRβ expression has been shown to be linked to resistance to corticosteroid treatment. This thesis comprises three sub-studies. Firstly, we wanted to determine whether GRα and GRβ are expressed in inflammatory skin diseases. Secondly, we examined if the expression is altered by corticosteroid treatment in eczema atopicum, bullous pemphigoid and psoriasis. Finally, we measured the effects of a topical vitamin D3 analogue (calcipotriol) combined with betamethasone compared with betamethasone monotherapy on inflammatory biomarkers of psoriasis. Our studies provide detailed novel data about the expression of GRα and GRβ. GRα and GRβ were shown to be expressed in the blood lymphocytes and lesional skin of patients with eczema atopicum, bullous pemphigoid and psoriasis, as well as in the skin of patients with eczema nummulare, lichen simplex chronicus and lichen ruber planus. Systemic corticosteroid treatment was shown to affect the expression of GRα and GRβ in eczema atopicum and bullous pemphigoid, but the inconsistent variation in their expression between patients prevented us from drawing firm conclusions. Neither GRα nor GRβ as a single marker were found to be a suitable predictor of corticosteroid responsiveness. Clinical and laboratory analyses showed that topical treatment of psoriasis with calcipotriol/betamethasone combination ointment is more beneficial measured by both than betamethasone monotherapy. / Tiivistelmä Glukokortikoideja (”kortisoni”) käytetään tulehduksellisten ihotautien hoidossa paikallisesti tai systeemisenä lääkkeenä. Suurin osa potilaista reagoi hoitoon nopeasti, mutta osalla hoitovaste on heikompi tai ilmenee hitaasti. Tällä hetkellä ei tunneta keinoja ennustaa luotettavasti kortisonihoidon vastetta. Glukokortikoidit vaikuttavat elimistössä glukokortikoidireseptorien (GR) kautta. Glukokortikoidireseptorista tunnetaan useita alatyyppejä, joista tärkeimmät ovat α (GRα) ja β (GRβ). Aiemman tiedon pohjalta on pidetty mahdollisena, että GR-alatyyppien suhteella tai määrällä on merkitystä kortisonivasteen syntymisessä. Erityisesti on arveltu, että ylimäärä GRβ:aa voisi estää kortisonihoidon vaikutusta. Tässä väitöskirjassa tavoitteena on ollut selvittää, tapahtuuko GR-alatyyppien ilmenemisessä muutoksia tulehduksellisia ihosairauksia sairastavilla potilailla sekä tutkia, miten kortisonihoito vaikuttaa GR-tasoihin atooppista ihottumaa, pemfigoidia ja psoriaasia sairastavilla potilailla. Lisäksi olemme verranneet paikallishoitoa pelkällä kortisonivoiteella D-vitamiinijohdos kalsipotriolin ja kortisonin yhdistelmähoitoon psoriaatikoilla. Tutkimus on antanut uutta yksityiskohtaista tietoa GRα:n ja GRβ:n esiintymisestä ihossa ja tulehdussoluissa ihosairauksia sairastavilla potilailla. Tutkimustulosten perusteella voidaan todeta, että GRα ja GRβ esiintyvät atooppista ihottumaa, pemfigoidia ja psoriaasia sairastavien potilaiden ihossa ja veren tulehdussoluissa sekä nummulaari-ihottumaa, neurodermatiittia ja punajäkälää sairastavien potilaiden ihossa. Suun kautta annettu kortisonihoito vaikuttaa GRα- ja GRβ–lähetti-RNA:n ilmenemiseen, mutta potilaskohtaiset erot ovat suuret, eikä kumpikaan, GRα tai GRβ, sovellu yksinään ennustamaan kortisonihoidon vastetta. Paikallisella kortisonihoidolla D-vitamiinijohdos kalsipotrioliin yhdistettynä on suotuisampi vaikutus psoriaasin tulehduksellisiin välittäjäaineisiin ja tulehdussoluihin kuin pelkällä paikallisella kortisonihoidolla.

Aufgrund der hohen Prävalenz und Inzidenz von berufsbedingten Hauterkrankungen kommt wirksamen primär-, sekundär- und tertiärpräventiven Interventionen eine große Bedeutung zu. Die Beurteilung der Wirksamkeit ist Aufgabe der Evaluationsforschung, deren Güte sich an wissenschaftlichen, forschungsmethodischen Maßstäben und Kriterien bemisst. Das Ziel der vorliegenden Dissertation ist es, durch drei Untersuchungen dazu beizutragen, bestehende Forschungslücken im Kontext der Wirksamkeitsevaluation von Präventionsmaßnahmen in der Berufsdermatologie zu schließen. Hierfür erfolgt eine Untersuchung und Systematisierung des aktuellen Forschungsstandes anhand theoretisch abgeleiteter Kriterien. Analysiert werden das Interventionsziel, die untersuchten Outcomeparameter, das Evaluationsdesign, die Erhebungszeitpunkte sowie die Objektivität, Reliabilität, Validität und Änderungssensitivität der Erhebungsmethode. Basierend auf diesen Analysen werden Forschungslücken abgeleitet und begründet. Dies bildet den theoretischen Rahmen dieser Dissertation. Die drei durchgeführten Untersuchungen zur Evaluation der Wirksamkeit von präventiven Interventionen werden in diesen theoretischen Rahmen eingeordnet und vor dem Hintergrund der identifizierten Forschungslücken der jeweilige Beitrag zum aktuellen Stand der Forschung begründet. Alle drei Untersuchungen weisen konkrete Zielformulierungen sowie darauf abgestimmte Outcomeparameter auf, die sowohl auf der biomedizinischen als auch auf der psychischen und sozialen Ebene verortet sind. Die besondere Stärke von Untersuchung I liegt in ihrem kontrollierten Studiendesign. Aufgrund der Anzahl und Auswahl der Erhebungszeitpunkte schließen die Untersuchungen I und II Forschungslücken hinsichtlich der Untersuchung der Nachhaltigkeit und des Verlaufs des Interventionseffektes. Untersuchung III zeichnet sich durch eine objektive, reliable, valide und änderungssensitive Erhebungsmethode aus. Aus den drei Untersuchungen sowie aus der vorliegenden Dissertation in ihrer Gesamtheit leiten sich zahlreiche Ansatzpunkte für Forschungsdesiderata ab. Es lässt sich subsumieren, dass es langfristig ausgerichteter Evaluationsstudien bedarf, die eine angemessenen Zahl an Einzelerhebungen einschließen und in deren Rahmen objektive, reliable, valide und änderungssensitive Erhebungsverfahren eingesetzt werden. Ferner sollte künftig vermehrt eine Systematisierung der bislang als äußerst heterogen zu charakterisierenden Outcomeparameter erfolgen, indem die Parameter in einem theoretisch begründeten Rahmen verortet werden. Diese Optimierungen der gegenwärtigen Evaluationskultur dienen nicht nur wissenschaftlich-theoretischen Zwecken, sondern tragen langfristig zur Verbesserung der Versorgungsstrukturen mit Blick auf die Primär-, Sekundär- und Tertiärprävention berufsbedingter Hauterkrankungen bei.

Le pemphigus est une maladie bulleuse auto-immune sévère causée par des auto- anticorps (Ac) ciblant la desmogléine (Dsg) 1 et/ou 3, principalement de la sous-classe IgG4. Certains Ac non spécifiques à la Dsg ont été décrits, comme la desmocolline 3 (Dsc3), mais leur pertinence est peu connue. Suite à l’étude RITUX3 en 2017, le traitement de première intention du pemphigus est le rituximab (RTX). Ce projet comprend trois volets qui s’inscrivent dans la caractérisation immunologique des patients inclus dans l’étude RITUX3, visant à mieux comprendre la pathogénèse et la prise en charge du pemphigus. Nous avons d’abord étudié la diversité isotypique des Ac anti-Dsg3. Nous avons démontré qu’un nombre d’isotypes plus élevé mène à un risque de rechute, particulièrement l’IgG3 anti-Dsg3 qui était détecté chez 71% des rechuteurs, comparativement à 12% des patients en rémission complète. Ensuite, nous avons étudié la prévalence et la pathogénicité in vitro des Ac anti-Dsc3. Ils étaient détectés chez 21% des patients, soit significativement plus qu’une population de donneurs sains. L’isotype principal était l’IgA, et leur pathogénicité in vitro a été démontrée à partir de sérums de patients et de souris immunisées. La présence de ces Ac permettait d’expliquer une bonne proportion des cas de discordance entre le profil sérologique d’anti-Dsg et le phénotype clinique des patients. Finalement, nous avons étudié la prévalence d’Ac anti-rituximab (ARA) chez les patients traités par RTX. Ils étaient détectés chez 31% des patients, mais n’affectaient pas l’atteinte d’une rémission complète et ne seraient pas une contre-indication à des perfusions subséquentes. Par contre, un petit groupe de patients qui présentaient des ARA fonctionnels étaient à risque de rechute. / Pemphigus is a severe auto-immune blistering disease caused by auto-antibodies (Abs) targeting desmoglein (Dsg) 1 and/or 3, mainly of the IgG4 subclass. Several Abs non-specific to the Dsg have been described, including desmocollin (Dsc) 3, but their relevance is not well known. Since the RITUX3 clinical trial in 2017, rituximab (RTX) is recommended as the first-line treatment for moderate-to-severe pemphigus. This project consists of three parts with the main goal of immunologically characterizing patients who were included in the RITUX3 trial, to allow a better understanding of the pathogenesis and treatment of pemphigus. First, we studied the diversity of IgG anti-Dsg3 subclasses. A higher number of subclasses was associated with a significant risk of relapse, especially with IgG3 anti-Dsg3 detected in 71% of relapsing patients, compared to 12% of patients in complete remission. Then, we studied the prevalence and pathogenicity of anti-Dsc3 Abs. They were detected in 21% of patients, significantly more than healthy donors. The main isotype was IgA, and their in vitro pathogenicity was demonstrated with sera from patients and immunized mice. Their presence explained a good proportion of cases who presented discrepancies between the clinical phenotype and the serological profile of anti-Dsg Abs. Finally, we studied the prevalence of anti-RTX Abs (ARA) in patients treated with RTX. They were detected in 31% of patients but did not affect the rate of complete remission and are not a contra-indication to receive subsequent perfusions. However, a small group of patients who presented functional ARA were at risk of relapse.