Background: Psoriatic arthritis (PsA) is a chronic heterogenous inflammatory arthritis with five phenotypes. The two least studied phenotypes are investigated in this thesis, including: psoriatic spondyloarthropathy (PsSpA) and psoriatic arthritis mutilans (PAM). The aims of this thesis were to determine the prevalence, clinical characteristics and radiographic characteristics of PsSpA and PAM in a cohort of PsA patients, and serum-soluble bone- turnover biomarkers of these phenotypes. Aims: Comparisons were made with PsA patients without axial disease (pPsA), and ankylosing spondylitis (AS) patients. Methods: A prospective single-centre cross-sectional study was conducted of PsA and AS patients. Serum on psoriasis-only patients (PsC) and healthy controls (HC) were also obtained. Multivariate clinical, radiographic, genetic and serum biomarker comparisons were made between these five groups of subjects. Results: The study enrolled 201 PsA and 201 AS patients, who were then reclassified as 118 PsSpA, 127 pPsA and 157 AS cases, alongside 200 PsC and 50 HC subjects. Several clinical biomarkers, imaging biomarkers, serum-soluble biomarkers and genetic biomarkers were identified that differentiate PsSpA from pPsA and AS. PsSpA affected a significant proportion of PsA patients, and was not a milder version of AS. PsSpA involvement was as disabling and clinically impactful as AS. PAM was found to be associated with PsSpA, and clinical biomarkers of PAM occurrence and radiographic progression were identified. Conclusions: In conclusion, this thesis indicates that PsSpA is on a spectrum of musculoskeletal disease, in between pPsA and AS; with PsSpA comprising a continuum itself, and with a phenotype expression related to disease duration. These findings may prompt the inception of an international-consensus classification system for PsSpA, for which there is a great clinical need. Given that PsSpA has its own discrete clinical and biomarker signature, its clinical management and research should be tailored from that of pPsA and AS. Ultimately this may further the effort for stratified and personalised medicine.

Ankylosing spondylitis (AS) is a chronic, inflammatory rheumatic disease that has a highly variable disease course. Three biologic agents, adalimumab, etanercept, and infliximab, have been developed for the treatment of AS. We conducted three studies: 1) an exploratory analysis of a year-long longitudinal dataset to gain insight into the variability of disease activity, physical function, and well-being and to explore the relationship between these outcome measures; 2) a systematic review of the available evidence for the efficacy of biologic treatment; 3) a systematic review of potential adverse effects of this treatment. We found that repeated measures of disease activity, function and well-being fluctuate considerably between patients, with complex patterns occurring over time within patients. There was mostly high quality evidence that these biologics are efficacious against placebo. We did not find evidence of an increase in serious adverse events or serious infections from short-term randomized controlled trials.

No description available.

Made available in DSpace on 2014-06-11T19:27:20Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-06-21Bitstream added on 2014-06-13T19:14:39Z : No. of bitstreams: 1 pereira_dfa_me_sjc.pdf: 933077 bytes, checksum: 1cf55e305807271fd95bf2e3e95495ba (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A espondilite anquilosante (EA) é uma doença inflamatória crônica de etiologia desconhecida, caracterizada pelo acometimento predominante do esqueleto axial. A terapia convencional inclui o uso de antiinflamatórios não hormonais e drogas anti-reumáticas modificadoras da evolução da doença (DMARDs). O uso de agentes imunobiológicos, como o anti-TNF, tem sido considerada uma excelente opção terapêutica em casos mais graves e refratários, porém estudos prévios demonstraram maior risco de infecções após o tratamento. Reservatórios bucais de microrganismos oportunistas podem causar infecções sistêmicas, uma vez que a cavidade bucal representa uma porta de entrada para patógenos, especialmente em pacientes imunocomprometidos. O objetivo do presente estudo foi avaliar a presença e a sensibilidade aos antimicrobianos de Candida spp., Staphylococcus spp., Enterobacteriaceae e Pseudomonas spp. na cavidade bucal de pacientes com EA em uso de anti-TNF comparando-os com indivíduos controle. Foram incluídos no estudo: grupo anti-TNF (35 indivíduos, diagnosticados portadores de EA com idade entre 17 a 63 anos e sob terapia anti-TNF); grupo Convencional (35 pacientes portadores de EA, com idade entre 21 e 74 anos sob tratamento convencional não imunobiológico; e respectivos grupos controle composto por indivíduos saudáveis pareados na idade, gênero e condições bucais aos grupos com EA. Foram realizados exame clínico, anamnese, bem como coleta de enxágüe bucal de cada indivíduo a qual foi semeada em meios de cultura específicos para cada microrganismo e posterior obtenção do número de unidades formadoras de colônia por militros (UFC/mL). Os isolados foram identificados pelo Sistema API, bem como fora realizados testes de sensibilidade aos antifúngicos dos isolados de leveduras, e, antibióticos dos isolados bacterianos... / The Ankylosing Spondylitis (AS) is a chronic inflammatory disease of unknown etiology, particularly characterized by a compromise of the axial skeleton. The conventional therapy includes the use of non-hormonal anti-inflammatory and Disease-modifying antirheumatic drugs (DMARDs). The use of immunobiological agents, such as anti-TNF, has been considered an excellent therapeutical option in more serious and refractory cases. However, previous studies demonstrated an increased risk of infections after the treatment is completed. Oral reservoirs of opportunist microorganisms can cause systemic infections, once that the oral cavity represents a door of entrance for pathogens, especially in immunocompromised patients. The aim of the present study was to evaluate the presence and antimicrobial susceptibility of Candida spp., Staphylococcus spp., Enterobacteriaceae and Pseudomonas spp. in the oral cavity of patients with AS treated with anti-TNF in comparison to healthy individuals. The following groups were included in the study: anti-TNF group (35 AS patients, aged between 17 and 63 years and under anti-TNF therapy); Conventional group (35 AS patients aged between 21 and 74 years under non-immunobiological conventional treatment); and respective Control groups (composed by healthy individuals paired in age, gender and oral conditions with AS groups). After clinical examination and anamnesis, oral rinses of each individual was collected. The rinses were plated in specific culture media for each microorganism. The number of colony-forming units per milliters (CFU/mL) was obtained. Isolates were identified by API system. Next, sensitivity tests to antifungicals agents were done for yeasts isolates and antibiotics for bacterial isolates. For Staphylococcus spp., the CFU counts for the anti-TNF group and Conventional group was statistically higher than the respective control groups... (Complete abstract click electronic access below)

Resumo: A espondilite anquilosante (EA) é uma doença inflamatória crônica de etiologia desconhecida, caracterizada pelo acometimento predominante do esqueleto axial. A terapia convencional inclui o uso de antiinflamatórios não hormonais e drogas anti-reumáticas modificadoras da evolução da doença (DMARDs). O uso de agentes imunobiológicos, como o anti-TNF, tem sido considerada uma excelente opção terapêutica em casos mais graves e refratários, porém estudos prévios demonstraram maior risco de infecções após o tratamento. Reservatórios bucais de microrganismos oportunistas podem causar infecções sistêmicas, uma vez que a cavidade bucal representa uma porta de entrada para patógenos, especialmente em pacientes imunocomprometidos. O objetivo do presente estudo foi avaliar a presença e a sensibilidade aos antimicrobianos de Candida spp., Staphylococcus spp., Enterobacteriaceae e Pseudomonas spp. na cavidade bucal de pacientes com EA em uso de anti-TNF comparando-os com indivíduos controle. Foram incluídos no estudo: grupo anti-TNF (35 indivíduos, diagnosticados portadores de EA com idade entre 17 a 63 anos e sob terapia anti-TNF); grupo Convencional (35 pacientes portadores de EA, com idade entre 21 e 74 anos sob tratamento convencional não imunobiológico; e respectivos grupos controle composto por indivíduos saudáveis pareados na idade, gênero e condições bucais aos grupos com EA. Foram realizados exame clínico, anamnese, bem como coleta de enxágüe bucal de cada indivíduo a qual foi semeada em meios de cultura específicos para cada microrganismo e posterior obtenção do número de unidades formadoras de colônia por militros (UFC/mL). Os isolados foram identificados pelo Sistema API, bem como fora realizados testes de sensibilidade aos antifúngicos dos isolados de leveduras, e, antibióticos dos isolados bacterianos... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The Ankylosing Spondylitis (AS) is a chronic inflammatory disease of unknown etiology, particularly characterized by a compromise of the axial skeleton. The conventional therapy includes the use of non-hormonal anti-inflammatory and Disease-modifying antirheumatic drugs (DMARDs). The use of immunobiological agents, such as anti-TNF, has been considered an excellent therapeutical option in more serious and refractory cases. However, previous studies demonstrated an increased risk of infections after the treatment is completed. Oral reservoirs of opportunist microorganisms can cause systemic infections, once that the oral cavity represents a door of entrance for pathogens, especially in immunocompromised patients. The aim of the present study was to evaluate the presence and antimicrobial susceptibility of Candida spp., Staphylococcus spp., Enterobacteriaceae and Pseudomonas spp. in the oral cavity of patients with AS treated with anti-TNF in comparison to healthy individuals. The following groups were included in the study: anti-TNF group (35 AS patients, aged between 17 and 63 years and under anti-TNF therapy); Conventional group (35 AS patients aged between 21 and 74 years under non-immunobiological conventional treatment); and respective Control groups (composed by healthy individuals paired in age, gender and oral conditions with AS groups). After clinical examination and anamnesis, oral rinses of each individual was collected. The rinses were plated in specific culture media for each microorganism. The number of colony-forming units per milliters (CFU/mL) was obtained. Isolates were identified by API system. Next, sensitivity tests to antifungicals agents were done for yeasts isolates and antibiotics for bacterial isolates. For Staphylococcus spp., the CFU counts for the anti-TNF group and Conventional group was statistically higher than the respective control groups... (Complete abstract click electronic access below) / Orientador: Cristiane Yumi Koga Ito / Coorientador: Marcelo de Medeiros Pinheiro / Banca: Fernanda Lourenção Brighenti / Banca: Emilia Inoue Sato / Mestre

Ankylosing spondylitis (AS) is a chronic, inflammatory rheumatic disease that has a highly variable disease course. Three biologic agents, adalimumab, etanercept, and infliximab, have been developed for the treatment of AS. We conducted three studies: 1) an exploratory analysis of a year-long longitudinal dataset to gain insight into the variability of disease activity, physical function, and well-being and to explore the relationship between these outcome measures; 2) a systematic review of the available evidence for the efficacy of biologic treatment; 3) a systematic review of potential adverse effects of this treatment. We found that repeated measures of disease activity, function and well-being fluctuate considerably between patients, with complex patterns occurring over time within patients. There was mostly high quality evidence that these biologics are efficacious against placebo. We did not find evidence of an increase in serious adverse events or serious infections from short-term randomized controlled trials.

Die axiale Spondyloarthritis (axSpA) ist eine chronische entzündlich-rheumatische Erkrankung unbekannter Ursache, die durch Entzündungen in den Sakroiliakalgelenken (SIG) und an den Gelenken der Wirbelsäule gekennzeichnet ist. Darüber hinaus kann es im Krankheitsverlauf zu einer Ankylose in den SIG und zur Entwicklung von Syndesmophyten an den Wirbelkörpern kommen. Da ein Großteil der axSpA-Patienten auch sub-klinische mukosale Entzündungen aufweist, werden mukosale Antigene als Trigger der Entzündung diskutiert. Für die Diagnose und Prognose der axSpA existieren bisher wenige serologische Marker mit hoher Sensitivität. In dieser Arbeit konnte gezeigt werden, dass die Serumkonzentrationen von CTX-II, BMP-2 und LBP ein hohes diagnostisches Potenzial für die axSpA aufweisen, während die Serumkonzentrationen von BMP-2, PINP und VEGF als Marker für die Vorhersage röntgenolgischer Progression geeignet sein könnten. Weiterhin konnten erhöhte LPS-, LBP- und IL-6-Serum-Konzentrationen bei axSpA-Patienten nachgewiesen werden, die auf eine Translokation bakterieller Antigene hinweisen. Die Charakterisierung der Monoyzten zeigte erhöhte Frequenzen der CD14++CD16- und einen verminderten Anteil an CD14++CD16+ Monozyten in Patienten mit axSpA. Funktionell wiesen die Monozyten von axSpA-Patienten eine in vivo Präaktivierung mit erhöhter spontaner und durch suboptimale bakterielle Stimuli induzierter Freisetzung proinflammatorischer Zytokine bei gleichzeitig verminderter Reaktivität auf LPS in vitro auf. Diese Präaktivierung war bei Patienten unter Standardtherapie, nicht aber unter TNF-Blocker-Therapie, nachweisbar. Interessanterweise bestand bei Patienten unter Standardtherapie ein Zusammenhang zwischen der Krankheitsaktivität und der Frequenz zytokinproduzierender Monozyten. Somit konnten mit dieser Arbeit Biomarker mit diagnostischer und prognostischer Bedeutung für die axSpA identifiziert werden, deren Bedeutung in unabhängigen Kohorten weiter untersucht werden muss. / Axial Spondyloarthitis (axSpA) is a chronic inflammatory-rheumatic disease of unknown cause. It is characterized by inflammations of the sacroiliac joints (SIG) and the spinal joints. In addition an ankylosis in the SIG can develop in the progression of the disease as well as syndesmophytes at the vertebral body. Since the majority of axSpA-patients also have sub-clinical mucosal inflammations, mucosal anti-gens are discussed as triggers of the inflammation. For the diagnosis and prognosis of axSpA there are only a few serological markers with high sensitivity and specificity until now. In this thesis it could be shown that the serum concentration of CTX-II, BMP-2 and LBP exhibit a high diagnostic potential for axSpA, while the serum concentration of BMP-2, PINP and VEGF could be suitable markers for the forecast of radiographic progression. Furthermore increased LPS-, LBP- and IL-6-serum concentrations could be verified, which can be an indicator for the translocation of bacterial antigenes. The monocyte characterization showed increased frequencies of the pro-inflammatory CD14++CD16- sub population and a reduced portion of CD14++CD16+ monocytes in patients with axSpA. Functionally the monocytes of axSpA-patients showed an in vivo pre-activation with increased spontaneous and by suboptimal bacterial stimuli induced release of pro-inflammatory cytokines with simultaneously reduced reactivity towards LPS in vitro. This pre-activation could be detected for patients undergoing standard therapy, but not for those under TNF-blocker-therapy. Interestingly for the standard therapy patients there was a connection between the activity of the disease, meaning the BASDAI, and the frequency of the cytokine-producing monocytes. Therefore biomarkers with diagnostic and prognostic relevance could be identified in line with this thesis. The significance of these biomarkers has to be researched further in independent cohorts.

Thesis (M.S.W.)--University of Hong Kong, 1991.

The Human Leukocyte Antigen (HLA)-B27 is a Major Histocompability Complex (MHC) class I antigen that is strongly associated with development of a group of closely related arthritic diseases, collectively known as the spondyloarthropathies (SpA). However, the mechanism by which HLA-B27 confers this susceptibility is unclear. Studies have shown that HLA-B27 heavy chains can form classical heterotrimers associated with peptide and β2-microglobulin (B27HT), and also non-classical heavy chain homodimers (B27₂). B27₂ assemble intracellularly during maturation and are also expressed at the cell surface following endosomal recycling of B27HT. A pathogenic role for B27₂ has been proposed in two of the current theories of pathogenesis: the B27 homodimer theory and the B27 misfolding and UPR theory. Yet, determinations of the extent, distribution, and triggers of B27₂ expression, as well as the functional consequences of its receptor interactions in AS pathogenesis, have been hampered by the lack of a specific detection reagent. Therefore, to investigate the role of B27₂ in AS, we generated a novel antibody to B27₂ – HD6 – using phage display technology, which binds to in vitro refolded B27₂ but not B27HT complexes by ELISA. This thesis provides evidence that HD6-reactive molecules, which include B27₂, are expressed at the cell surface in both cell lines and in the context of a disease setting. Recognition is B27-specific and strongly correlated with the magnitude of B27 expression, which could account for the lack of staining in some cell subsets. Moreover, staining was comparable in cell lines expressing the disease-associated B*27:05 and the less disease-associated subtype B*27:09. In addition, I have shown cells expressing physiologic levels of B27, including EBV-transformed BCLs and AS patient PBMCs, are capable of expressing the HD6 epitope upon low pH treatment. Interestingly, these ‘acid-inducible HD6’ molecules were absent from cells lacking a functional PLC. Finally, I have shown that HD6-reactive molecules can derive from pre-existing folding B27 molecules at the cell surface, which may be inhibited by the addition of exogenous B27-binding peptides. These findings are consistent with a mechanism of pathogenesis involving the surface expression and recognition of B27₂ and/or other aberrantly folded forms of B27, as proposed in the homodimer theory. HD6 will be a powerful tool to address the potential pathogenic role of B27₂ in SpA and may additionally have therapeutic potential.

Submitted by Franciele Moreira (francielemoreyra@gmail.com) on 2018-04-18T16:32:15Z No. of bitstreams: 2 Tese - Denise Russi Rodrigues - 2018.pdf: 2158988 bytes, checksum: 99eb6ec528fea195f2c424de85538a6f (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2018-04-19T12:24:00Z (GMT) No. of bitstreams: 2 Tese - Denise Russi Rodrigues - 2018.pdf: 2158988 bytes, checksum: 99eb6ec528fea195f2c424de85538a6f (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-04-19T12:24:00Z (GMT). No. of bitstreams: 2 Tese - Denise Russi Rodrigues - 2018.pdf: 2158988 bytes, checksum: 99eb6ec528fea195f2c424de85538a6f (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-02-08 / Vertebral osteomyelitis is an emerging disease in the world poultry industry, characterized by immobility and mortality of broilers and breeders chicken due to the infectious process in the fourth thoracic vertebra (T4). The aim of this study was to develop an experimental model induced by enteric stress to better understand the pathogenesis of vertebral osteomyelitis, as well as to investigate the role of enteric stress in intestinal permeability and bacterial translocation to liver, spleen and vertebral column of broiler chickens. Enterococcus cecorum strains (11 TXs and 11 TXb) that presented the virulence genes virulence factors: capsular polysaccharide I and II, enterococcal polysaccharide antigen M and P, protein lipoate synthase and surface protein LPTXG3 were inoculated after enteric stress induced by the use of dexamethasone for seven days in the diet (DEX), dried distilled grain with solubles - DDGS (30%) in the diet and the 24-hour food restriction (RA). The macroscopic findings of lesions responsible for claudication affected 19.37% (186/960) of the birds submitted to enteric stress and 9.06% (87/960) had vertebral osteomyelitis. The group that presented enteric inflammation induced by DDGS in the diet had an increase (p<0.05) in the incidence of vertebral osteomyelitis and lameness. The intestinal permeability, as assessed by serum FITC-d levels, increased (p<0.05) in DEX at 16, 23 e 30 days of age and RA at 30 days of age. After inoculation of E. cecorum, there was an increase (p<0.05) in microaerophilic bacteria in the liver and spleen in the DEX group at 20 days. Likewise, an increase of these bacteria was observed in T4 in the RA group at 27 days of age and in the DEX group at 34 days. Bacterial isolation identified a diversity of bacteria as species of Enterococcus, Streptococcus, Staphylococcus, Lactobacillus, as well as Escherichia coli in T4, suggesting that other microbial agents besides E. cecorum may be involved in vertebral osteomyelitis lesions. Therefore, the experimental reproduction model of vertebral osteomyelitis induced by enteric stress in broilers makes it possible to study vertebral osteomyelitis lesions, which favors its use in the applied research of preventive and therapeutic strategies for this disease. In addition, it is concluded that enteric stress increases intestinal permeability and promotes the translocation of opportunistic bacteria to the liver, spleen and spine of broiler chickens, which may lead to the development of vertebral osteomyelitis in broilers. / A osteomielite vertebral é uma doença emergente na avicultura mundial, caracterizada por imobilidade e mortalidade de frangos e matrizes de corte devido ao processo infeccioso na quarta vértebra torácica (T4). Assim, objetivou-se desenvolver um modelo experimental induzido pelo estresse entérico para o melhor entendimento da patogênese de osteomielite vertebral, além de investigar o papel do estresse entérico na permeabilidade intestinal e translocação bacteriana para fígado, baço e coluna vertebral de frangos de corte. As cepas de Enterococcus cecorum (11 TXs e 11 TXb) que apresentavam os fatores de virulência: polissacarídeo capsular I e II, antígeno de polissacarídeo enterocócico M e P, proteína lipoato sintase e proteína de superfície LPTXG3 foram inoculadas após estresse entérico induzido pela utilização de dexametasona por sete dias na ração (DEX), grãos secos de destilaria com solúveis- DDGS (30%) na dieta e a restrição alimentar (RA) de 24 horas. Os achados macroscópicos de lesões responsáveis pela claudicação afetaram 19,37% (186/960) das aves submetidas ao estresse entérico e 9,06% (87/960) apresentaram osteomielite vertebral. O grupo que apresentou inflamação entérica induzida por DDGS na dieta apresentou aumento (p<0,05) na ocorrência de osteomielite vertebral e claudicação. A permeabilidade intestinal, avaliada pelos níveis séricos de FITC-d, aumentou (p<0,05) significativamente nos tratamentos DEX aos 16, 23 e 30 dias de idade e RA aos 30 dias de idade. Após inoculação de E. cecorum, houve aumento (p<0,05) da contagem de bactérias microaerófilas no fígado e baço no grupo DEX aos 20 dias. Da mesma forma, foi verificado um aumento dessas bactérias na T4 no grupo RA aos 27 dias de idade e no grupo DEX aos 34 dias. Por meio de isolamento bacteriano, identificou-se uma diversidade de bactérias como espécies de Enterococcus, Streptococcus, Staphylococcus, Lactobacillus, bem como Escherichia coli na T4, sugerindo que outros agentes microbianos, além de E. cecorum, podem estar envolvidos nas lesões de osteomielite vertebral. Portanto, o modelo de reprodução experimental de osteomielite vertebral induzido pelo estresse entérico em frangos de corte possibilita o estudo de lesões da osteomielite vertebral, o que favorece sua utilização na pesquisa aplicada de estratégias preventivas e terapêuticas para essa doença. Além disso, conclui-se que o estresse entérico aumenta a permeabilidade intestinal e propicia a translocação de bactérias oportunistas para o fígado, baço e coluna vertebral de frangos de corte podendo levar o desenvolvimento de osteomielite vertebral em frangos de corte.