Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Dermatoloji Anabilim Dalı, 2003. / Bibliyografya var.

Thesis (Ph.D.)--Flinders University, Dept. of Medicine-Biotechnology. / Typescript bound. Includes bibliographical references: (leaves 267-307) Also available online.

Includes bibliographical references and index.

Dermatite atópica (DA) é uma dermatose inflamatória, de caráter crônico e recidivante, com alta prevalência mundial, caracterizada por eczema localizado ou generalizado, xerose cutânea e prurido intenso, mais comum em crianças, porém podendo acometer adultos, muitas vezes prejudicando de forma considerável a qualidade de vida dos pacientes e seus familiares. O diagnóstico de alergia inclui testes in vivo (testes cutâneos de hipersensibilidade imediata ou prick test) e testes in vitro com mensuração de anticorpos IgE no sangue. Está disponível método para detecção de alergia baseado no princípio de diagnóstico por componentes, o ImmunoCAP Immunosorbent Allergen CHIP (ImmunoCAP-ISAC) que marca a transição para o diagnóstico molecular de alergia. No presente estudo, tivemos por objetivos determinar o perfil de resposta IgE a alérgenos purificados, naturais ou recombinantes, em pacientes adultos com DA e comparar o valor do diagnóstico de alergia por componentes com métodos diagnósticos existentes. Foram selecionados 39 pacientes adultos com DA dentre aqueles Atendidos nos Ambulatórios de Alergia e Dermatologia do HCFMRP-USP. A idade dos pacientes variou de 14-66 anos (média ± DP 34,3 ± 2.1 anos), 64% mulheres. O tempo médio de doença foi de 16 anos. SCORAD médio foi de 36,6 (2-90). Média geométrica (MG) de IgE total foi 1,963 kU/L (24-63,000 kU/L). Alérgenos de ácaros foram dominantes, com sensibilização a Der p1 e a Der f1, Der p2 e Der f2 em 82% e 85% dos pacientes, com MG 27,6; 50; 39,2; 45,4 ISU-E respectivamente, seguidos de gato (38%), cachorro (36%) e pólen de gramíneas (36%). IgE para alérgenos de baratas, fungos, pólen de árvores, látex e veneno de insetos foi encontrada em menos de 20% dos pacientes em baixos níveis. Sensibilização para castanhas (33%) e camarão (31%) foram os alérgenos mais prevalentes entre os alimentos, enquanto a reatividade IgE para leite e ovo esteve presente em 10% ou menos dos pacientes, com baixos níveis de anticorpos IgE na maioria dos casos. Apenas 6 pacientes (15,4%) apresentaram IgE para o panalérgeno tropomiosina, e 3/39 (7,7%) foram negativos para todos os 112 componentes de alérgenos testados no ImmunoCAP-ISAC, com níveis de IgE total de 24, 38,7 e 156 kU/L. Concluímos que o perfil de sensibilização IgE entre os pacientes adultos com dermatite atópica difere daquele entre os pacientes com alergiarespiratória, apresentando menos sensibilização para baratas e para o panalérgeno tropomiosina, e difere ainda do perfil presente em crianças com DA, com predomínio de sensibilização IgE a castanhas e camarão, e baixa taxa de sensibilização a alérgenos de leite de vaca e ovo. / Atopic dermatitis (AD) is an inflammatory, chronic, relapsing dermatosis with a high global prevalence characterized by localized or generalized eczema, cutaneous xerosis and intense pruritus, more common in children, but it can affect adults, often causing considerable damage to the quality of life of patients and their families. The diagnosis of allergy includes in vivo tests (skin tests of immediate hypersensitivity or prick test) and in vitro tests with measurement of IgE antibodies in the blood. An allergy detection method based on the principle of component diagnosis is available, ImmunoCAP Immunosorbent Allergen CHIP (ImmunoCAP-ISAC), and marks the transition to the molecular diagnosis of allergy. In the present study, we aimed to determine the IgE response profile to purified, natural or recombinant allergens in adult patients with AD and to compare the value of component allergy diagnosis with existing diagnostic methods. Thirty-nine adult patients with AD were selected from among those attending the Outpatient Clinic of Allergy and Dermatology at HCFMRP-USP. The age of the patients ranged from 14-66 years (mean ± SD 34,3 ± 2.1 years), 64% women. The mean duration of illness was 16 years. SCORAD mean was 36,6 (2- 90). Geometric mean (GM) of total IgE was 1,963 kU / L (24-63,000 kU / L). Mite allergens were dominant, with sensitization to Der p1 and Der f1, Der p2 and Der f2 in 82% and 85% of the patients, with GM 27,6; 50; 39.2; 45.4 ISU-E respectively, followed by cat (38%), dog (36%) and grass pollen (36%). IgE for cockroach, fungus, tree pollen, latex and insect venom allergens was found in less than 20% of patients at low levels. Sensitization to nuts (33%) and shrimp (31%) were the most prevalent allergens among foods, while IgE reactivity to milk and egg was present in 10% or less of the patients, with low levels of IgE antibodies in most cases. Only 6 patients (15.4%) presented IgE for the pan-allergen tropomyosin, and 3/39 (7.7%) were negative for all 112 allergen components tested on ImmunoCAP-ISAC, with total IgE levels of 24; 38,7 and 156 kU / L. We concluded that the IgE sensitization profile among adult patients with atopic dermatitis differs from that among patients with respiratory allergy, presenting less sensitization to cockroaches and to the pan-allergen tropomyosin, andalso differs from the profile present in children with AD, with a predominance of IgE sensitization to nuts and shrimp, and low sensitization rate to cow\'s milk and egg allergens.

Bakgrund: Atopisk dermatit (AD) är en vanlig kronisk inflammatorisk hudsjukdom som kännetecknas av eksematösa vätskande sår och intensiv klåda. AD är dels en T-hjälparcell (TH) - 2 driven sjukdom vilket innefattar den akuta fasen av sjukdomen där TH2-cellerna blir aktiverade och börjar producera cytokinerna interleuin (IL)-4, IL-5 samt IL13. I den kroniska fasen ses i stället en dominans av TH1-celler som i stället främst uttrycker cytokiner som γ-interferon (IFN- γ) och IL-12 vilket bidrar till en kronisk inflammation. Personer som har milda symtom kan ofta kontrollera sjukdomen med enbart topikala medel. För personer som har svårare symtom kan fototerapi eller systemisk behandling behövas. Abrocitinib/Upadacitinib är selektiva janus-kinas (JAK)1-hämmare och hämmar signalvägen som annars resulterar i produktion av proinflammatoriska cytokiner och tillväxtfaktorer. Behandlingen resulterar i minskad inflammation i huden. Dupilumab är en monoklonal antikropp som hämmar IL-4 och IL-13 vilket också resulterar i minskad inflammation.  Syfte: Syftet medstudien var att kritiskt granska utfallet i publicerade studier vad gäller abrocitinib/upadacatinib och dubilumab samt att jämföra skillnaden i effekt och säkerhet för att bedöma hur stor betydelse den nya behandlingen kan ha för patienter med måttlig till svår AD.  Metod: Arbetet är en litteraturstudie som är baserad på sex vetenskapliga artiklar som är hämtade via databasen PubMed. Studier inkluderades som innefattade monoterapi samt om dess primära utfallsvariabel var EASI75 eller IGA.  Resultat: Två studier uppvisade signifikant förbättrad effekt av abrocitinib i två styrkor mot placebo. Studien som jämförde upadacitinib i två styrkor mot placebo visade på signifikant förbättrad effekt mot placebo. Jämförelse av 300 mg dupilumab mot placebo uppvisade också signifikant förbättrad effekt. I en studie där 30 mg upadacitinib jämfördes mot 300 mg dupilumab visade upadacitinib på signifikant förbättrad effekt mot dupilumab. I en annan studie där 100 mg respektive 200 mg abrocitinib jämfördes mot dupilumab och placebo uppvisade abrocitinib förbättrad effekt mot både dupilumad och placebo, dock ej statistiskt signifikant. Biverkningar rapporterades i högre grad för 200 mg-gruppen samt 30 mg upadacitinib-gruppen jämfört med dupilumab. Samtliga studier är sponsrade av läkemedelsföretag som har utvecklat respektive studieläkemedel vilket kan öka risk för bias då företagen vill att deras produkt ska visa på så god effekt som möjligt.  Slutsats: Abrocitinib/upadacitinib anses vara bra behandlingsalternativ för patienter med måttlig till svår AD då det visar på god effekt jämfört med placebo. Dupilumab visar likaså på bra effekt jämfört med placebo. Jämförande studier mellan abrocitinib/upadacitinib mot dupilumab visar på bättre effekt av andelen patienter som uppnådde det primära effektmåttet. Dock är resultatet mellan studieläkemedlena inte markant överlägset någon annan även om abrocitinib/upadacitinib visar på bättre effekt än dupilumab i båda jämförande studierna där resultatet i studie är statistiskt signifikant. / Atopic dermatitis (AD) is a common well-known chronic inflammatory skin disease characterized by eczematous exuding wounds and intense itching. AD is partly a disease driven by the t-helper (TH) 2-cells and involves activation of the acute phase of the disease that starts to produce cytokines interleukin (IL) – 4, IL-5 and IL-13. TH1-cells stands mainly for the expression of cytokines as g-interferon (IFN-g) and IL-12 which contribute to the chronic inflammation. For people with mild symptoms it is usually enough to treat with topical steroids but people who suffer from more severe symptoms, systemic treatment may be needed. Abrocitinib/Upadacitinib is a new selective JAK-1 inhibitor that inhibit the pathway which otherwise results in production of proinflammatory cytokines and growth factors. That results in less inflammation in skin. Dupilumab, that is an inhibitor of IL-4 and IL-13 also results in less inflammation in skin, has been the only approved biological treatment against moderate to severe AD until abrocitinib and upadacitinb was discovered. There is a need of more alternative and safe systemic therapies. This study aims to critically examine the results in different published articles to criticize which treatment of the comparable drugs is the best for patients considering both effect and safety with patients suffering from moderate to severe AD.  This study is based on six scientific articles from PubMed. Studies included if the patients was treated with monotherapy and if the primary outcome was EASI75 and IGA. Two studies presented significantly improved effect of abrocitinib in two different strengths against placebo. One study that compared upadacitinib in two strengths against placebo also showed on significantly improved effect. Comparison of dupilumab 300 mg against placebo showed on significantly improved effect. One study that compared 30 mg upadacitinib against 300 mg dupilumab showed significantly improved effect against dupilumab. The last study that compared 100 mg respectively 200 mg abrocitinib against 300 mg dupilumab showed improved effect of abrocitinib against dupilumab, although it was not significant. Side effects were reported most frequently in the 200 mg abrocitinib study group and also in the 30 mg upadacitinib study group comparable to dupilumab. All of the studies are funded by pharmaceutical companies that also have developed the different study-drugs that is investigated which may increase the risk of bias.   In summary, abrocitinib/upadacitinib is considered a good treatment option for patients suffering from moderate to severe AD comparable with placebo. Treatment with dupilumab also shows on a good treatment comparable to placebo. Studies comparing abrocitinib/upadacitinib with dupilumab shows on more effect of the amount of patients that achieved primary outcome. However, the results between the drugs are not remarkable superior to any other even though abrocitinib/upadacitinib shows on a better effect than dupilumab in both comparative studies.

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<p>Asthma is a lung disease characterized by wide variations in airflow over short periods of time. Exacerbations of asthma can be accompanied by symptoms of chest tightness, shortness of breath and wheezing; airway inflammation characterized by an influx of eosinophils and/or neutrophils; and the expression of pro-inflammatory cytokines in the airway. There is strong evidence supporting a central role for the T cell in asthma. In atopic asthma, T cells are documented components of the late-phase response to inhaled allergen, driving airway inflammation, mucus hypersecretion, and bronchoconstriction through the release of cytokines and other mediators. T cells have also been shown to produce inflammatory cytokines in response to allergen in nonatopic asthmatics, indicating a potential role in mediating disease in this phenotype. In both atopic and nonatopic asthma, aberrant T cell responses to allergen may drive the infiltration of neutrophils and eosinophils into the airway through the production of pro- inflammatory cytokines, leading to exacerbations of disease. This project has investigated the role of several T cell cytokines in driving disease and acting as biomarkers in asthma: interleukin-5, interleukin-17A, interleukin-23, interleukin- 10, and interferon-γ. We have measured allergen-induced cytokine production by peripheral blood mononuclear cells (PBMCs) and examined its ability to distinguish between different asthma phenotypes: asthma vs normal, atopic vs nonatopic asthma, eosinophilic bronchitis vs noneosinophilic bronchitis, and neutrophilic vs nonneutrophilic bronchitis. Our data shows that allergen-induced peripheral blood mononuclear cell responses to allergen are not good biomarkers of disease in asthma. No differences in PBMC cytokine production are seen in patients with asthma, compared with normal controls, or between patients with different asthmatic phenotypes. It is not possible to determine a patient’s disease state, atopic status, or type of bronchitis by examining their PBMC cytokine responses to allergen.</p> / Master of Science (MSc)