Psoriatic arthritis (PsA) is an inflammatory arthritis that is associated with psoriasis. PsA is a complex disease that is influenced by both genetic and environmental factors. Genetic studies have been successful in identifying risk loci for PsA, the majority of which also confer risk for psoriasis. As PsA has been estimated to have a stronger genetic component compared to psoriasis, this suggests that there should be genetic loci that are associated with PsA and not with psoriasis, which I have defined to be PsA-specific. Therefore, the overall aim of my PhD project is to apply genetic experimental techniques to identify a novel risk locus that is associated with PsA and not psoriasis. Firstly, genotyping of 1,962 PsA cases was performed with the Immunochip, where I contributed to the identification of a novel PsA-specific association on chromosome 5q31, mapping to rs715285 (P=4.38x10-13). Bioinformatic analysis within the association region identified 3 potential causal genes and 4 potential causal variants. Statistical analysis identified CD8+ memory T cells to be the most critical cell type for PsA, and also gave evidence to suggest that rs10065787 is the causal variant within the 5q31 region. A cell-specific eQTL study was performed within this cell type which identified SLC22A5 to be a potential causal gene for PsA. The findings may suggest a potential mechanism by which the 5q31 region contributes towards PsA susceptibility. Variants that reached nominal association during the Immunochip study (P <1.0x10-4) were selected to follow-up in a candidate SNP study, in addition to other SNPs of interest which had been investigated for psoriasis risk but not PsA alone. This was performed within an independent cohort (914 PsA cases, 6,945 controls). Analysis of the independent samples replicated a PsA-specific association with rs12044149 (P = 4.03x10-6) at the IL23R locus. This association reached genome-wide significance during meta-analysis with the discovery Immunochip genotype data (P = 1.28x10-20). The PsA association with IL23R was found to be independent of the psoriasis association at the same locus when performing conditional analysis (Pcond = 4.86x10-06). The effect estimates for rs12044149 in PsA and psoriasis were found to be significantly different (P = 2.0x10-3). Furthermore, direct comparison of the genotypes for rs12044149 showed a significantly increased risk for PsA compared to psoriasis. Functional annotation was performed with credible SNPs sets defined for the PsA and psoriasis association signals at IL23R. This also revealed potential differences in the mechanisms of the two diseases, supporting the independence of their association with IL23R.A rare variant study was also performed as part of this PhD in order to identify a casual gene for PsA. 1,980 PsA cases and 5,913 controls were genotyped with the Illumina HumanCoreExome and HumanExome chips. Single-variant analysis was performed using the Fisher's Exact test. Analysis of common variants (MAF > 0.05) uncovered associations at known PsA and psoriasis loci that reached genome-wide significance, including TRAF3IP2 (P = 3.88x10-18). Analysis of rare (MAF <0.01) and low-frequency (MAF <0.05) variants identified an association with a coding-variant at IFIH1 (rs35667974, P = 2.39x10-6). This association was replicated within an independent cohort, and was found to be significantly associated during multiple-variant testing (P = 2.30x10-6, Pcorr = 5.60x10-6). The minor allele of the rare variant was found to exist in the same haplotype as the minor allele of the PsA-associated common variant at the IFIH1 locus. The rs36557974 SNP found to be associated with PsA independently of the common variant during conditional logistic regression and conditional haplotype analysis. Although the rare-coding variant has been previously reported for psoriasis, these findings demonstrate the use of rare variant analysis to find evidence of a casual gene for PsA.In summary, genetic and statistical approaches have been used to find evidence of causal genes and variants within PsA-specific association regions, as well as to identify a PsA association mapping to a coding region.

Psoriatic disease (PD) is an autoimmune disease that affects millions of women and currently has no cure. Examining the lived experience of women with PD who choose to treat their disease with alternative methods may allow for deeper understanding of how mental health professionals can support their choices. Using phenomenology, this study looked at the experiences of these women through theories of self-efficacy and self-in-relation theory, theories that empower and speak to women. The participants consisted of women who reported a diagnosis of PD, who reported they had abstained from pharmaceutical interventions for at least the previous six months. The sample size consisted of 7 participants, recruited through social media, from various parts of the world. Explication was used to assess the data and consisted of the following: bracketing and phenomenological reduction, delineating units of meaning, clustering of units of meaning to form themes, summarizing each interview, and extracting general and unique themes from all interviews and making a composite summary. The findings of this study showed that the participants reported feeling capable of pursuing health options that aligned with their values and were not opposed to pharmaceutical options at some point. In addition, findings indicated participants felt minimal, if any, support from their medical care providers. The results of the study may facilitate positive social change by informing women with PD about the benefits of taking an active role in treatment planning. Further, this study'€™s results may expand knowledge about treatment of women with PD and inform medical professionals, specifically mental health professionals, about what is important to these women in terms of a treatment plan.

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.

Aim: Most of the patients with Psoriatic Arthritis (PsA) develop arthritis following the onset of psoriasis. The aim of the project is to identify genetic and environmental risk factors for PsA among psoriasis patients. Methods: PsA and psoriasis patients from two prospective cohorts were analyzed. The incidence of PsA among a prospective cohort of psoriasis patients was assessed. The distribution of Human Leukocyte Antigen (HLA) alleles and Killer Cell Immunoglobulin like Receptors (KIRs) and their combinations was compared between PsA, psoriasis and healthy controls. In addition, the association between a wide range of environmental exposures and PsA was evaluated by comparing the frequencies of exposed individuals among patients with recent onset PsA and psoriasis. The association between smoking and PsA was further investigated. The prevalence of smoking was in PsA, psoriasis and the general population. The interaction between HLA-C*06 and smoking was also tested. Results: The genetic analysis revealed several HLA-B alleles and HLA haplotypes that are associated with PsA compared to psoriasis and can potentially serve as independent markers for PsA. Furthermore, several combinations of KIR genes and their respective HLA ligands were also found to be associated with PsA compared to psoriasis. The incidence of PsA among psoriasis patients was found to be higher than previously reported and its rate was constant over time. HLA-C*06 was associated with increased interval between psoriasis onset and PsA. Several environmental factors including occupational exposures, infections, injuries and smoking were associated with development of PsA. The prevalence of smoking was decreased among PsA patients compared to psoriasis. The interaction between HLA-C*06 and smoking was found to be significant. Conclusions: Genetic and environmental factors are associated with the development of PsA in patients with psoriasis. These factors may serve as specific markers to identify psoriasis patients at increased risk for PsA.

Aim: Most of the patients with Psoriatic Arthritis (PsA) develop arthritis following the onset of psoriasis. The aim of the project is to identify genetic and environmental risk factors for PsA among psoriasis patients. Methods: PsA and psoriasis patients from two prospective cohorts were analyzed. The incidence of PsA among a prospective cohort of psoriasis patients was assessed. The distribution of Human Leukocyte Antigen (HLA) alleles and Killer Cell Immunoglobulin like Receptors (KIRs) and their combinations was compared between PsA, psoriasis and healthy controls. In addition, the association between a wide range of environmental exposures and PsA was evaluated by comparing the frequencies of exposed individuals among patients with recent onset PsA and psoriasis. The association between smoking and PsA was further investigated. The prevalence of smoking was in PsA, psoriasis and the general population. The interaction between HLA-C*06 and smoking was also tested. Results: The genetic analysis revealed several HLA-B alleles and HLA haplotypes that are associated with PsA compared to psoriasis and can potentially serve as independent markers for PsA. Furthermore, several combinations of KIR genes and their respective HLA ligands were also found to be associated with PsA compared to psoriasis. The incidence of PsA among psoriasis patients was found to be higher than previously reported and its rate was constant over time. HLA-C*06 was associated with increased interval between psoriasis onset and PsA. Several environmental factors including occupational exposures, infections, injuries and smoking were associated with development of PsA. The prevalence of smoking was decreased among PsA patients compared to psoriasis. The interaction between HLA-C*06 and smoking was found to be significant. Conclusions: Genetic and environmental factors are associated with the development of PsA in patients with psoriasis. These factors may serve as specific markers to identify psoriasis patients at increased risk for PsA.

Thesis (Ph. D.)--University of Missouri-Columbia, 2007. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on November 27, 2007) Vita. Includes bibliographical references.

Inflammatory arthritis (IA) types such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and psoriatic arthritis (PsA) have been shown to exhibit common clinical features. As complex diseases they have a known genetic component, some of which is known to be shared. The aim of this study was to assess the genetic overlap between 3 types of IA (RA, JIA and PsA) using genotype data generated on the Immunochip array and to select a biologically promising overlapping region for further genetic and functional investigation. Overlap analysis was performed using association data generated for a large cohort of inflammatory arthritis cases and shared controls (11,475 RA; 2816 JIA; 929 PsA respectively). 50 genetic regions were identified as being associated with more than 1 type of IA (p < 1x10-3), with several interesting similarities and differences observed between the diseases. As several of the overlapping regions detected represented novel disease associations, they required replication in an independent sample cohort. 12 variants were selected for replication in an independent RA cohort of 3879 cases and 2561 controls. Of these, 2 variants in the CTLA4 and MTMR3 regions were successfully replicated in RA at p<0.05. Bioinformatics analysis was performed for the 50 overlapping regions, with one particularly promising region, RUNX1, selected for further investigation. In this region, the same variant (rs9979383) is associated across the 3 diseases, with similar odds ratios (OR 0.8-0.9) observed in each disease. As this region represented both a novel IA association and had not been densely genotyped on the Immunochip array, fine mapping was performed by genotyping 51 SNPS in 3491 cases and 2359 controls. This resulted in replication of the association at rs9979383 (p=0.02) with no additional significant genetic effects detected, therefore this variant was selected for further functional analysis. As rs9979383 lies ~280kb upstream of the RUNX1 gene, a cis-eQTL analysis was performed to identify if the variant acts by regulation of RUNX1 gene expression. This was performed in whole blood, CD4+ and CD8+ lymphocytes from 75 (and a subset of 23) healthy volunteers respectively. No significant eQTLs were detected between rs9979383 and RUNX1 in whole blood (p =0.9) or RUNX1/LOC100506403 CD4+ and CD8+ lymphocytes (p=0.1). This study has provided insight into the genetic similarities and differences between different types of inflammatory arthritis, which can be applied to further investigations into disease susceptibility. Although no significant cis-eQTL was detected in any of these tissues with either RUNX1 or the nearby lnc-RNA LOC100506403, in cells from healthy volunteers under unstimulated conditions, these findings will direct future functional investigations into the role of this overlapping region in the susceptibility of IA.

No / Agents which increase intracellular cyclic adenosine monophosphate (cAMP) may have an antagonistic effect on pro-inflammatory molecule production so that inhibitors of the cAMP degrading phosphodiesterases have been identified as promising drugs in chronic inflammatory disorders. Although many such inhibitors have been developed, their introduction in the clinic has been hampered by their narrow therapeutic window with side effects such as nausea and emesis occurring at sub-therapeutic levels. The latest generation of inhibitors selective for phosphodiesterase 4 (PDE4), such as apremilast and roflumilast, seems to have an improved therapeutic index. While roflumilast has been approved for the treatment of exacerbated chronic obstructive pulmonary disease (COPD), apremilast shows promising activity in dermatological and rheumatological conditions. Studies in psoriasis and psoriatic arthritis have demonstrated clinical activity of apremilast. Efficacy in psoriasis is probably equivalent to methotrexate but less than that of monoclonal antibody inhibitors of tumour necrosis factor (TNFi). Similarly, in psoriatic arthritis efficacy is less than that of TNF inhibitors. PDE4 inhibitors hold the promise to broaden the portfolio of anti-inflammatory therapeutic approaches in a range of chronic inflammatory diseases which may include granulomatous skin diseases, some subtypes of chronic eczema and probably cutaneous lupus erythematosus. In this review, the authors highlight the mode of action of PDE4 inhibitors on skin and joint inflammatory responses and discuss their future role in clinical practice. Current developments in the field including the development of topical applications and the development of PDE4 inhibitors which specifically target the subform PDE4B will be discussed.

Psoriatic arthritis is an inflammatory arthritis affecting a fifth of patients with skin psoriasis. Inflammation of the joints and tendons causes pain, stiffness, reduced function and disability. Work disability is increasingly recognised as an important, patient centred, functional measure of disease yet little is known about work disability in psoriatic arthritis. The overall aim of my thesis is to examine patient reported work disability in psoriatic arthritis by undertaking the following; • A systematic review of the relevant literature • Classification of a cohort of patients to study • Validation of a commonly used work outcome measure used in other rheumatic diseases • Selection of a suitable measure of structural damage to inflamed joints for investigating the associations of work disability in longitudinal observational studies. The results of the systematic review identified limited data reporting high levels of work disability associated with a wide variety of disease and non-disease related factors. The review also identified the lack of a validated outcome measure for use in psoriatic arthritis. I report the classification of a large single centre longitudinal cohort of patients with psoriatic arthritis and evidence supporting the retrospective application of a psoriatic arthritis classification criterion. Subsequently I report a preliminary validation study of the work productivity and activity impairment questionnaire to measure work disability in psoriatic arthritis and a further study comparing the existing measures of structural damage in psoriatic arthritis. Finally I developed and supervised a multicentre observational study to examine the associations of work disability in psoriatic arthritis. The study identified reduced work effectiveness to be associated with measures of disease activity, whereas unemployment was associated with recent disease onset, greater age and worse physical function. The study will provide a valuable cohort for prospective study of work disability and the effect of medical treatment and will form part of my planned post-doctoral studies.

Orientador: Manoel Barros Bértolo / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-16T11:36:12Z (GMT). No. of bitstreams: 1 Bonfiglioli_Rubens_D.pdf: 4535259 bytes, checksum: c162b3d3293837dabf58f540050f6b46 (MD5) Previous issue date: 2009 / Resumo: Este estudo prospectivo analisou a epidemiologia, clínica e perfil genético de 102 pacientes brasileiros com Artrite Psoriásica. A associação do complexo maior de histocompatibilidade (MHC) de classe I, e os alelos do HLA-B27 com aquelas variáveis foram avaliados e comparados com sadios controles, HLA-B27 positivos, compondo um grupo de 111 indivíduos. A predominância foi do sexo masculino (59,8%), raça caucasóide (89,2%) e HLA-B27 negativos (79,4%). Oligoartrite assimétrica (62,7%) foi o subgrupo de Artrite Psoriásica mais observado, seguido pela forma espondilítica (16,7%) e poliarticular (15,7%). O sexo masculino e o subgrupo dos espondilíticos foram estatisticamente mais associados ao HLA-B27, e o subgrupo oligoarticular ao HLA-B27 negativo. Entre os 21 pacientes com Artrite Psoriásica e HLA-B27 positivos existiu uma significante prevalência do HLA-B*2705 (90,5%), similar ao observado no grupo controle (80,2%); HLA-B*2703 e HLA-B*2707 foram estatisticamente associados ao grupo controle / Abstract: This prospective study analyzed the epidemiologic, clinical and genetic profile of 102 Brazilian patients with psoriatic arthritis (PsA). The association of the major histocompatibility complex (MHC) class I and the HLA-B27 alleles with these variants was outlined, and compared to a control healthy HLA-B27 positive group of 111 individuals. There was a predominance of male gender (59.8%), Caucasian race (89.2%) and negative HLA-B27 (79.4%) patients. Asymmetric oligoarthritis (62.7%) was the most frequently observed clinical PsA subgroup, followed by spondylitis (16.7%) and polyarthritis (15.7%). Male gender and the spondylitis subgroup were statistically associated to the positive HLAB27 and the oligoarthritis subgroup was associated to the negative HLA-B27. Among the 21 HLA-B27 positive PsA patients, there was a significant prevalence of the HLA-B*2705 allele (90.5 %), similar to that observed in the control group (80.2%); HLA-B*2703 and HLA-B*2707 were statistically associated to the control group. Other antigens such as HLA- B07 (14 patients), HLA-B08 (14 patients) and HLA-B44 (13 patients) among others, were found in HLA-B27-negative patients / Doutorado / Clinica Medica / Doutor em Clínica Médica