INTRODUÇÃO: O penfigoide bolhoso é uma doença autoimune, vesicobolhosa com incidência de 0,2 a 1,4 por 100.000 hab. Sua fisiopatologia caracteriza-se pela ação de autoanticorpos na junção dermoepidérmica dos hemidesmossomos, promovendo a formação de bolhas subepidérmicas na pele e mucosas. Estudos vêm sendo publicados demonstrando a associação de penfigoide com alelos do sistema HLA classe II em diferentes populações do mundo, entretanto não há dados sobre a população brasileira, uma das mais heterogêneas do mundo. PACIENTES E MÉTODOS: O grupo de estudo incluiu 17 pacientes brasileiros com diagnóstico confirmado de PB de um hospital na cidade de São Paulo, sudeste do Brasil. O DNA foi extraído a partir de sangue periférico utilizando kits Qiagen (QIAamp DNA Mini Kit®) e a tipagem HLA loci A, B, C, DR e DQ foi realizada por meio de PCR e a amplificação utilizando o oligonucleótido de sequência específica (SSO) contido nos kits LABType®. O grupo controle foi composto por um banco de dados de 297 doadores falecidos da cidade de São Paulo. Este banco de dados é parte do Sistema de Transplantes da Secretaria de Saúde do Governo do Estado de São Paulo. RESULTADOS: Os resultados mostram que os alelos HLA C*17, DQB1*03:01, DQA1*01:03 e DQA1*05:05 estão associados com o aparecimento da doença na população brasileira, com risco relativo de 8,31 (2,46 a 28,16), 3,76 (1,81 a 7,79), 3,57 (1,53 a 8,33) e 4,02 (1,87 a 8,64), respectivamente (p < 0,005). O nível de significância estatística foi ajustado utilizando a correção de Bonferroni, dependendo das frequências fenotípicas avaliadas para HLA de classe I (A, B e C) e classe II (DRB1, DQB1 e DQA1). DISCUSSÃO: Os dados indicam que pacientes brasileiros com PB apresentam a mesma predisposição genética ligada ao HLA-DQB1*03:01 relatado anteriormente em caucasianos e indivíduos iranianos e o estudo apresenta três novos alelos (C *17, DQA1*01:03 e DQA1* 05:05) envolvidos na fisiopatologia da PB. CONCLUSÕES: Os resultados mostram que os alelos HLA C*17, DQB1*03:01, DQA1*01:03 e DQA1*05:05 estão associados com o aparecimento da doença na população brasileira / BACKGROUND: Bullous pemphigoid (BP) is an autoimmune disease with bullous vesicles and an incidence of 0.2 to 1.4 per 100,000 inhabitants. Its pathophysiology is characterized by the action of autoantibodies on hemidesmosomes at the dermalepidermal junction, promoting subepidermal blister formation in the skin and mucous membranes. Many studies have been published demonstrating the association of pemphigoid with HLA class II system alleles in different populations, however there are no data on the Brazilian population, one of the most heterogeneous in the world. PATIENTS AND METHODS: The study group included 17 Brazilian patients with a confirmed diagnosis of BP from a hospital in Sao Paulo city, southeast Brazil. DNA was extracted from peripheral blood using Qiagen kits (QIAamp DNA Mini Kit®) and HLA A, B, C, DR and DQ typing was performed using PCR and amplification using Sequence-Specific Oligonucleotide (SSO) contained in LABType® kits. The control group was composed of a database of 297 deceased donors from the city of São Paulo. This database is part of the Transplants State System of the Government\'s Health Secretary from the State of Sao Paulo. RESULTS: Our findings show that alleles HLA C*17, DQB1*03:01, DQA1*01:03 and DQA1*05:05 are associated with the onset of the disease in the Brazilian population, with relative risks of 8.31 (2.46 to 28.16), 3.76 (1.81 to 7.79), 3.57 (1.53 to 8.33), and 4.02 (1.87 to 8.64), respectively (p < 0.005). The statistical significance level was adjusted using the Bonferroni correction depending on the phenotypic frequencies evaluated for HLA class I (A, B and C) and class II (DRB1, DQB1 and DQA1). DISCUSSION: Our data indicate that Brazilian patients with BP present the same genetic predisposition linked to HLA-DQB1*03:01 previously reported in Caucasian and Iranian individuals and our study introduces three new alleles (C*17, DQA1*01:03 and DQA1*05:05) involved in the pathophysiology of BP. CONCLUSIONS: Our findings show that alleles HLA C*17, DQB1*03:01, DQA1*01:03 and DQA1*05:05 are associated with the onset of the disease in the Brazilian population

INTRODUÇÃO: O penfigoide bolhoso é uma doença autoimune, vesicobolhosa com incidência de 0,2 a 1,4 por 100.000 hab. Sua fisiopatologia caracteriza-se pela ação de autoanticorpos na junção dermoepidérmica dos hemidesmossomos, promovendo a formação de bolhas subepidérmicas na pele e mucosas. Estudos vêm sendo publicados demonstrando a associação de penfigoide com alelos do sistema HLA classe II em diferentes populações do mundo, entretanto não há dados sobre a população brasileira, uma das mais heterogêneas do mundo. PACIENTES E MÉTODOS: O grupo de estudo incluiu 17 pacientes brasileiros com diagnóstico confirmado de PB de um hospital na cidade de São Paulo, sudeste do Brasil. O DNA foi extraído a partir de sangue periférico utilizando kits Qiagen (QIAamp DNA Mini Kit®) e a tipagem HLA loci A, B, C, DR e DQ foi realizada por meio de PCR e a amplificação utilizando o oligonucleótido de sequência específica (SSO) contido nos kits LABType®. O grupo controle foi composto por um banco de dados de 297 doadores falecidos da cidade de São Paulo. Este banco de dados é parte do Sistema de Transplantes da Secretaria de Saúde do Governo do Estado de São Paulo. RESULTADOS: Os resultados mostram que os alelos HLA C*17, DQB1*03:01, DQA1*01:03 e DQA1*05:05 estão associados com o aparecimento da doença na população brasileira, com risco relativo de 8,31 (2,46 a 28,16), 3,76 (1,81 a 7,79), 3,57 (1,53 a 8,33) e 4,02 (1,87 a 8,64), respectivamente (p < 0,005). O nível de significância estatística foi ajustado utilizando a correção de Bonferroni, dependendo das frequências fenotípicas avaliadas para HLA de classe I (A, B e C) e classe II (DRB1, DQB1 e DQA1). DISCUSSÃO: Os dados indicam que pacientes brasileiros com PB apresentam a mesma predisposição genética ligada ao HLA-DQB1*03:01 relatado anteriormente em caucasianos e indivíduos iranianos e o estudo apresenta três novos alelos (C *17, DQA1*01:03 e DQA1* 05:05) envolvidos na fisiopatologia da PB. CONCLUSÕES: Os resultados mostram que os alelos HLA C*17, DQB1*03:01, DQA1*01:03 e DQA1*05:05 estão associados com o aparecimento da doença na população brasileira / BACKGROUND: Bullous pemphigoid (BP) is an autoimmune disease with bullous vesicles and an incidence of 0.2 to 1.4 per 100,000 inhabitants. Its pathophysiology is characterized by the action of autoantibodies on hemidesmosomes at the dermalepidermal junction, promoting subepidermal blister formation in the skin and mucous membranes. Many studies have been published demonstrating the association of pemphigoid with HLA class II system alleles in different populations, however there are no data on the Brazilian population, one of the most heterogeneous in the world. PATIENTS AND METHODS: The study group included 17 Brazilian patients with a confirmed diagnosis of BP from a hospital in Sao Paulo city, southeast Brazil. DNA was extracted from peripheral blood using Qiagen kits (QIAamp DNA Mini Kit®) and HLA A, B, C, DR and DQ typing was performed using PCR and amplification using Sequence-Specific Oligonucleotide (SSO) contained in LABType® kits. The control group was composed of a database of 297 deceased donors from the city of São Paulo. This database is part of the Transplants State System of the Government\'s Health Secretary from the State of Sao Paulo. RESULTS: Our findings show that alleles HLA C*17, DQB1*03:01, DQA1*01:03 and DQA1*05:05 are associated with the onset of the disease in the Brazilian population, with relative risks of 8.31 (2.46 to 28.16), 3.76 (1.81 to 7.79), 3.57 (1.53 to 8.33), and 4.02 (1.87 to 8.64), respectively (p < 0.005). The statistical significance level was adjusted using the Bonferroni correction depending on the phenotypic frequencies evaluated for HLA class I (A, B and C) and class II (DRB1, DQB1 and DQA1). DISCUSSION: Our data indicate that Brazilian patients with BP present the same genetic predisposition linked to HLA-DQB1*03:01 previously reported in Caucasian and Iranian individuals and our study introduces three new alleles (C*17, DQA1*01:03 and DQA1*05:05) involved in the pathophysiology of BP. CONCLUSIONS: Our findings show that alleles HLA C*17, DQB1*03:01, DQA1*01:03 and DQA1*05:05 are associated with the onset of the disease in the Brazilian population

Abstract Bullous pemphigoid (BP) is an autoimmune skin disease predominantly found in elderly people, which causes blistering of the skin and severe itching. The incidence of BP reported by previous studies has varied greatly between 0.05 and 42.8 per 1 million persons per year. Higher incidences have been reported in Western Europe and the USA, while countries around the Mediterranean have reported lower rates. However, the epidemiology of BP has not previously been studied in any Scandinavian country. The one-year mortality of BP is highly variable with estimates between 11% and 41% worldwide. As for comorbidities, the previous studies have shown that BP is associated with neurological disorders. The aim of this study was to investigate the incidence and mortality of BP in Finland, to assess the treatments used for BP, and the potential contribution of systemic glucocorticoid treatment to the high mortality rate found in BP patients. A further aim was to obtain more specific information about the neurological diseases associated with BP, and to clarify the less studied association with psychiatric disorders. For these purposes, we collected the records of all immunologically confirmed BP patients diagnosed in the Oulu University Hospital between 1985 and 2012, and, for a sub-study III, data for all patients diagnosed with BP in Finnish hospitals between 1987 and 2013. We found that the incidence of BP in Northern Finland has increased over the past two decades to approximately 27 new BP cases per 1 million persons per year. The one-year mortality of BP patients is 17%, and the standardized mortality ratio (SMR) is 7.6. Common comorbidities found in the sample of BP patients were: cardiovascular diseases (76%), neurodegenerative diseases (41%), skin conditions other than BP (37%) and type 2 diabetes (23%). Many neurodegenerative diseases of the central nervous system were associated with BP, as were many psychiatric disorders. The association was strongest between multiple sclerosis (MS) and BP, with MS patients having almost a 6-fold higher risk of BP than controls. The present study reports for the first time the incidence and mortality of BP in Finland, and provides new information about the association between BP and neurological and psychiatric disorders. / Tiivistelmä Rakkulainen pemfigoidi (josta jatkossa käytetään nimitystä pemfigoidi) on autoimmuunisairaus, joka esiintyy yleensä iäkkäillä, ja aiheuttaa ihon rakkulointia ja hankalaa kutinaa. Aiemmissa tutkimuksissa pemfigoidin ilmaantuvuus on vaihdellut 0,05:sta 42,8:aan tapaukseen miljoonaa ihmistä kohden vuodessa. Ilmaantuvuuden on havaittu olevan korkeampi Länsi-Euroopassa, kun taas Välimeren ympäristössä ilmaantuvuus on matalampi. Pemfigoidia sairastavien kuolleisuus vuoden kuluessa diagnoosista vaihtelee noin 11-41%:n välillä. Aiemmat tutkimukset ovat myös osoittaneet, että pemfigoidi liittyy neurologisiin sairauksiin. Pemfigoidin epidemiologiaa ei ole kuitenkaan tutkittu Suomessa tai muissa Pohjoismaissa. Tämän tutkimuksen tarkoituksena oli selvittää pemfigoidin ilmaantuvuus ja kuolleisuus Suomessa, tutkia sen hoitoon käytettyjä lääkkeitä sekä arvioida systeemisen glukokortikoidihoidon osuutta korkeaan kuolleisuuteen. Lisäksi tavoitteena oli saada yksityiskohtaista tietoa pemfigoidiin liittyvistä neurologisista sairauksista ja selvittää lisää aiemmissa tutkimuksissa ristiriitaiseksi jäänyttä yhteyttä psykiatrisiin sairauksiin. Tätä varten keräsimme tiedot kaikista Oulun yliopistollisessa sairaalassa diagnosoiduista, immunologisesti varmennetuista pemfigoiditapauksista vuosilta 1985-2012. Kolmannessa osatyössä käytimme kansallista aineistoa, joka sisälsi kaikkialla Suomessa diagnosoidut pemfigoidia sairastavat potilaat vuosilta 1987-2013. Pemfigoidin ilmaantuvuus kasvoi seuranta-aikana ollen nykyisin Pohjois-Suomessa noin 27 tapausta miljoonaa ihmistä kohden vuodessa. Kuolleisuus vuoden kuluessa diagnoosista oli 17% ja vakioitu kuolleisuussuhde (standardized mortality ratio) 7,6. Yleisiä oheissairauksia pemfigoidia sairastavilla olivat sydän- ja verisuonisairaudet (76%), neurodegeneratiiviset sairaudet (41%), muut ihosairaudet (37%) sekä tyypin 2 diabetes (23%). Tutkimuksessa todettiin, että monet neurogeneratiiviset sairaudet ja monet psykiatriset sairaudet liittyvät pemfigoidiin. Yhteys oli vahvin pesäkekovettumataudin (MS-tauti) ja pemfigoidin välillä, ja MS-tautia sairastavilla riski sairastua pemfigoidiin oli lähes 6-kertainen verrattuna kontrollipotilaisiin. Tämä tutkimus on ensimmäinen, joka raportoi pemfigoidin ilmaantuvuuden ja kuolleisuuden Suomessa. Tutkimus antaa lisäksi uutta tietoa pemfigoidin yhteydestä neurologisiin ja psykiatrisiin sairauksiin.

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.