Os alelos HLA-DRB1, que codificam uma sequência de aminoácidos (QKRAA/QRRAA/RRRAA) nas posições 70 a 74 da terceira região hipervariável da cadeia &#61538;1 do gene DRB1, denominada epítopo compartilhado (EC), estão associados com maior susceptibilidade e gravidade para artrite reumatóide (AR) em diversas populações. Uma nova classificação proposta por Du Montcel et al tem sido desenvolvida para apurar a associação entre HLA-DRB1 e AR. Este estudo foi desenhado com o objetivo de determinar a frequência dos alelos HLA-DRB1 em pacientes brasileiros com AR, e sua associação com o fator reumatoide (FR), anticorpos antipeptídeos citrulinados (ACPA) e lesão radiográfica articular e óssea. Quatrocentos e doze pacientes com AR e 215 controles foram incluídos. A tipificação HLA-DRB1 foi realizada pela reação em cadeia de polimerase (PCR) usando primers específicos e hibridação com oligonucleotídeos de sequência específica (SSOP). A pesquisa de ACPA foi determinada pela técnica de ELISA e a do FR por nefelometria, a avaliação radiográfica realizada pelo método do índice de Sharp modificado de Van Der Heijde. Para análises estatísticas foram utilizados os testes do qui-quadrado, t de Student e a regressão logística. Nos pacientes com AR alelos HLA-DRB1*04:01, *04:04, *04:05 se associaram com AR (p<0,05), embora o amplo intervalo de confiança, vale a pena ressaltar a associação observada com o alelo DRB1*09:01 e a doença (p<0,05). Alelos HLA-DRB1 EC+ foram observados em 62,8% dos pacientes e em 31,1% do grupo controle (OR 3,62; p <0,001) e estiveram associados com ACPA (OR 2,03; p<0,001). Alelos DRB1 DERAA mostraram efeito protetor para a AR (OR 0,42; p<0,001). A análise da nova classificação de HLA-DRB1 mostra que S2 e S3P se associaram a AR (p<0,05). Alelos S2 e/ou S3P esteve presente em 65% dos pacientes e 32% do grupo controle (OR 3,86; p<0,001) e estiveram associados a ACPA (OR.2,11; p=0,001). Alelos S3D, S1, X mostraram efeito protetor para a AR. Os resultados obtidos neste estudo demonstram que pacientes brasileiros com AR de etnia majoritariamente mestiça, alelos HLA-DRB1 avaliados segundo a hipótese do EC e a classificação proposta por Du Montcel estiveram associados à suscetibilidade à doença e à presença de ACPA. / HLA-DRB1 alleles that encode an amino acid sequence at positions 70-74 of the third hypervariable region of the B chain of the DRB1 gene, called shared epitope (SE), are associated with increased susceptibility and severity to rheumatoid arthritis (RA) in different populations. A new classification proposed by Du Montcel et al has been developed to determine the association between HLA-DRB1 and RA. This study was designer to determine the frequency of HLA-DRB1 alleles in Brazilian patients with RA, and its association with rheumatoid factor (RF), citrullinated peptide antibodies (ACPA) and radiographic joint damage and bone. Four hundred and twelve patients with RA and 215 controls were included. The HLA-DRB1 typing was performed by polymerase chain reaction (PCR) using specific primers and hybridization with sequence specific oligonucleotides (SSOP). The survey of ACPA was determined by ELISA and the RF by nephelometry, the radiographic evaluation by index method modified Sharp Van Der Heijde. For statistical analysis we used the chi-square, Student and logistic regression. In patients with rheumatoid arthritis HLA-DRB1*04:01, *04:04, *04:05 are associated with RA (p<0,05), although the wide confidence interval, it is worth noting the association observed with the DRB1*09:01 allele and the disease (p<0,05). HLA-DRB1 SE+ were observed in 62.8% of patients and in 31.1% of the control group (OR 3.62, p<0,001) and were associated with ACPA (OR 2.03, p<0,001). DERRA alleles showed a protective effect against RA (OR 0,42, p<0,001). The analysis of the new classification of HLA-DRB1 shows that S2 and S3P were associated with RA (p<0,05). Alleles S2 and/or S3P was present in 65% and 32% of patients in the control group (OR 3,86, p<0,001) and were associated with ACPA (OR 2.11, p=0,001). S3D alleles, S1, X showed a protective effect against RA. The results of this study demonstrate that Brazilian patients with RA from mostly mixed ethnicity, HLA-DRB1 evaluated under the hypothesis of the SE and the classification proposed by Du Montcel et al were associated with disease susceptibility and the presence of ACPA.

Introdução: A artrite reumatóide (AR) é uma artropatia autoimune, de caráter inflamatório, com prevalência em torno de 1% da população. O tabagismo é considerado o principal fator de risco para o desenvolvimento da AR. O receptor de hidrocarbonetos de arila (AhR), um fator de transcrição intracelular ativado por hidrocarbonetos aromáticos componentes da fumaça do cigarro, foi identificado como alvo de regulação da diferenciação de células Th17. Objetivos: Avaliar se os polimorfismos genéticos do AhR estariam associados ao desenvolvimento da AR , e se este receptor estaria mais expresso em pacientes com AR. Pacientes e Métodos: Nós analisamos sete polimorfismos genéticos por mudança de única base (SNP) por PCR em tempo real utilizando sondas TaqMan em 138 pacientes com AR e 129 indivíduos saudáveis. A quantificação da expressão do mRNA do AhR em células mononucleares isoladas de pacientes com AR e indivíduos saudáveis foi realizada por PCR em tempo real. Resultados: Identificamos que haplótipos formados por SNPs no AhR estariam associados com desenvolvimento da AR, podendo ser fator protetor ou de risco para a doença. Em adição, os pacientes com haplótipos de risco apresentavam doença com índice de atividade elevado, principalmente quando o tabagismo estava presente. De fato, pacientes com AR apresentaram aumento na expressão de AhR (mRNA) em relação a indivíduos saudáveis. Conclusões: Em conjunto estes resultados sugerem que o AhR possui um papel importante para o desenvolvimento da artrite reumatóide. Possivelmente mutações neste receptor podem estar relacionadas com alterações na sua atividade e conseqüentemente na diferenciação de células Th17 e a susceptibilidade a AR. / Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune arthropaty with inflammatory characteristics and prevalence around 1% in the population. Tabagism is the main risk factor to RA development. The aryl hydrocarbon receptor (AhR) is an intracellular transcription factor activated by aromatic hydrocarbons present in smoking, whichwas identified to be a target of regulation of Th17 differentiation. Purpose: Study the relationship of genetic polymorphisms in AhR with RA development, and if this receptor expression is upregulated in RA patients. Patients and Methods: We analyzed seven genetic single nucleotide polymorphisms by Real-Time PCR using TaqMan probes in 138 patients with Rheumatoid Arthritis and 129 healthy controls. The AhR mRNA quantization in mononuclear cells isolated from AR patients and healthy controls has been done by Realt-Time PCR. Results: We identified that AhR haplotypes were associated with RA development and that they could be protector or risk factors to disease. In addition, patients with risk haplotypes showed higher disease activity index, mainly when smoking was present. Indeed, patients with RA showed upregulation in the AhR expression (mRNA) when compared with healthy controls. Conclusions: These results suggest that AhR has an important role in AR development. Probably, mutations in this receptor could be related with alterations in its activity and consequently in the differentiation of Th17 cells and RA susceptibility.

OBJETIVO: Determinar os valores séricos do ligante do receptor do ativador do fator nuclear Kappa B (RANKL) e da osteoprotegerina (OPG) em pacientes com Artrite Idiopática Juvenil de início poliarticular (AIJp) em atividade e avaliar a possível correlação destes valores com a presença radiológica de erosões ósseas. MÉTODOS: Trinta pacientes do sexo feminino com diagnóstico de AIJ de início poliarticular segundo os critérios da ILAR (International League of Associations for Rheumatology) em atividade e trinta crianças saudáveis (controles) pareadas por idade e sexo foram selecionadas consecutivamente para este estudo. Todas as articulações comprometidas foram radiografadas e avaliadas, com especial interesse, para a presença de erosões ósseas. Concentrações séricas do RANKL e OPG foram medidas por enzima-imunoensaio (Biomedica, Vienna, Austria). RESULTADOS: Pacientes com AIJp em atividade apresentaram altos valores séricos de RANKL e menores taxas de OPG/RANKL comparadas com controles [2,90 (0,1-37,4) vs. 0,25 (0,1-5,7) pg/ml, p=0,007 e 21,25 (1,8- 897,6) vs. 347,5 (9-947,8)] pg/ml, p=0,005). Diferentemente, não houve diferença em relação à concentração sérica de OPG quando se comparou os pacientes e controles [55,24 (28,34-89,76) vs. 64,42 (30,68-111,28) pg/ml, p=0,256]. Maiores concentrações de RANKL e menores taxas de OPG/RANKL também foram observadas em pacientes com AIJp em atividade com erosões ósseas comparadas com controles [3,49 (0,1-37,4) vs. 0,25 (0,1-5,7) pg/ml, p=0,0115 e 14,3 (1,8-897.6) vs. 347,5 (9-947,8) p=0,016]. Em contraste, valores séricos de RANKL e a taxa de OPG/RANKL foram semelhantes em pacientes com AIJp sem erosões ósseas comparadas com controles [1,75 (0,1-10,9) vs 0,25 (0,1-5,7) pg/ml, p=0,055 e 29,2 (3,3-756,8) vs. 347,5 (9- 947,8), p=0,281]. CONCLUSÃO: Estes dados sugerem que pacientes com AIJp em atividade com erosões ósseas apresentam altos valores séricos de RANKL e baixa taxa de OPG/RANKL indicando que estas alterações podem refletir o comprometimento ósseo nesta doença. / OBJECTIVE: To determine the serum levels of receptor activator of nuclear factor kB-ligand (RANKL) and osteoprotegerin (OPG) in active polyarticularonset Juvenile Idiopathic Arthritis patients (pJIA) and evaluate its possible correlation with bone erosions on the X-ray. METHODS: Thirty female girls with active pJIA diagnosis according ILAR criteria (International League of Associations for Rheumatology) and 30 healthy children gender and agematched controls were consecutively selected for this study. All involved articulations were evaluated by X-ray and analyzed for the presence of bone erosions. The serum levels of RANKL and OPG were measured using an enzyme-linked immunosorbent (Biomedica, Vienna, Austria). RESULTS: Results: Patients with active pJIA had higher levels of serum RANKL and lower OPG/RANKL ratio compared to controls [2.90 (0.1-37.4) vs. 0.25 (0.1- 5.7) pg/ml, p=0.007] and 21.25 (1.8-897.6) vs. 347.5 (9-947.8) pg/ml, p=0.005]. However, levels of OPG were comparable in both groups [55.24 (28.34-89.76) vs. 64.42 (30.68-111.28) pg/ml, p=0.256]. Higher levels of serum RANKL and lower OPG/RANKL ratio was also observed in active pJIA patients with bone erosions compared to controls [3.49 (0.1-37.4) vs. 0.25 (0.1-5.7) pg/ml, p=0.0115 and 14.3 (1.8-897.6) vs. 347.5 (9-947.8), p=0.016]. In contrast, RANKL levels and OPG/RANKL ratio were alike in pJIA patients without bone erosion and controls [1.75 (0.1-10.9) vs. 0.25 (0.1- 5.7) pg/ml, p=0.055 and 29.2 (3.3-756.8) vs. 347.5 (9-947.8), p=0.281]. CONCLUSION: These data suggest that active pJIA with bone erosion is associated with high serum levels of RANKL and low OPG/RANKL ratio indicating that these alterations may reflect bone damage in this disease.

INTRODUÇÃO: A diminuição da massa óssea e mudanças na composição corporal são comuns em pacientes com artrite reumatóide, particularmente nos usuários de glicocorticóide (GC). OBJETIVO: Analisar o comprometimento dos componentes da composição corporal e densidade mineral óssea (DMO) na artrite reumatóide (AR) e seus aspectos clínicos. MÉTODOS: 83 mulheres com AR realizaram densitometria óssea para análise de massa óssea total e regional e estudo da composição corporal (CC). Além disso, foram submetidas à realização laboratorial de provas inflamatórias, dosagem de fator reumatóide e aplicados questionários para avaliação da atividade da doença, classe funcional, atividade física, e inquérito alimentar. RESULTADOS: A prevalência de osteoporose nas pacientes menopausadas foi de 21,4%, 46,4% com osteopenia e 32,1% com valores normais e ocorreu de forma semelhante em coluna lombar e colo do fêmur. As mulheres na pré-menopausa apresentaram maiores valores nas médias de DMO. A idade teve efeito negativo nas medidas DMO e de CC enquanto que o índice de massa corpórea (IMC) mostrou efeito positivo nestas variáveis. A atividade física apresentou efeito positivo na DMO de fêmur total. A duração da AR teve efeito negativo na DMO de coluna lombar. O GC foi o determinante negativo na massa magra total e aumentou o percentual de gordura. CONCLUSÕES: O achado de valores reduzidos de DMO sugere que devam ser aplicadas medidas para a prevenção e tratamento de osteoporose. A doença (AR) também influenciou negativamente a DMO nestas pacientes e a utilização de GC modificou a CC, reduzindo a massa muscular e aumentando o percentual de gordura. A preservação da massa muscular é importante ao equilíbrio das pacientes, com conseqüente diminuição de quedas e futuras fraturas. / INTRODUCTION: The reduction of bone mass and changes in body compositions are usual in patients with rheumatoid arthritis specialty in users of glucocorticoid (GC). OBJECTIVE: To evaluate the bone mineral density (BMD) and body composition (BC) including its correlation to factors of rheumatoid arthritis (RA) and clinics concerns. METHODS: BMD and body composition (total and regional) were measured by densitometry in 83 patients with RA. Furthermore, it was performed laboratory exams (rheumatoid factor, inflammatory exams) and activity of disease, functional class, physical activity and alimentary data were colleted by specific questionnaires. RESULTS: The prevalence of osteoporosis in menopausal patients was 21,4%, 46,4% of osteopenia and 32,1% were normal and osteoporosis was similar in lumbar spine and femoral neck. Premenopausal women had the biggest values of BMD medias. Dose of GC was negative determinant of total lean mass and made positive effect in total fat percentual. Age made negative effect in BMD and body composition. BMI showed positive effect in all CC variables. The physical activity made positive effect in BMD in total femur. The RA duration had negative effect in BMD in lumbar spine. CONCLUSIONS: The finding of low BMD suggests a better approach to prevention and treatment. The disease (RA) also made a negative influence in BMD in these patients and the use of GC cause changes in body composition, with reduction in lean mass and improvement of total fat percentual. Recommendations to preservation of lean mass are important to reduction of falls and consequent diminution of fractures.

Introdução A artrite reumatoide (AR) é uma doença crônica autoimune degenerativa, de alta prevalência e alta morbimortalidade, com difícil diagnóstico em todo o mundo. O seu pronto diagnóstico e o rápido início com medicamentos modificadores do curso da doença (MMCD) impactam de forma relevante o prognóstico do paciente. Para alguns pacientes os MMCDs sintéticos não serão eficazes e este paciente deverá receber então um MMCD biológico, medicamento este de alto custo para o paciente e o sistema de saúde. Objetivo - Explorar as trajetórias percorridas na busca por cuidado por pacientes com AR em uso de MMCD biológico no município de São Paulo. Métodos - Pesquisa qualitativa, de caráter exploratório, com orientação analítico-descritiva, mediante entrevistas semiestruturadas com questões abertas, iniciada após prévia aprovação do Comitê de Ética em Pesquisa e consentimento esclarecido dos entrevistados. Os sujeitos são pacientes em uso de MMCD biológico para tratamento de AR dispensados pelo SUS. Foi utilizada a ferramenta do itinerário terapêutico (IT) para entendimento do caminho escolhido por estes pacientes na busca por cuidado em saúde. Resultados e Discussão Entre os entrevistados, a busca de cuidado ocorreu tardiamente, normalmente sem a suspeita de que se tratasse de doença reumática degenerativa. Os primeiros profissionais acessados foram o médico clínico geral ou o ortopedista, que raras vezes investigaram com atenção os sintomas relatados para em seguida proceder o encaminhamento adequado e rápido do paciente para o reumatologista. Nos ITs descritos, os tratamentos na sua maioria são constituídos apenas pelos medicamentos, e sem a participação de outros profissionais no acompanhamento além do reumatologista. Os pacientes entrevistados chegaram até o MMCD biológico após tentativa de controle da doença com os MMCDs sintéticos, conforme descreve o protocolo de tratamento do Ministério da Saúde. Há nos ITs descritos diversos atores representantes da iniciativa privada, que apoiam e influenciam estes pacientes na escolha dos seus caminhos por cuidado de saúde, que devem ser melhor compreendidos em estudos futuros / Introduction Rheumatoid arthritis (RA) is a chronic degenerative autoimmune disease of high prevalence and with high morbidity and mortality, worldwide difficult to diagnose. Its prompt diagnosis and rapid onset with disease modifying drugs (DMARD) have a relevant impact on the patient\'s prognosis. For some patients, the synthetic DMARDs will not be effective so these patients should receive a biological DMARD - a high cost medication both to the patient and the health system. Objective - To explore the trajectories performed by patients with RA using biological DMARD in the search for care in the city of São Paulo. Methods - Qualitative research, with an exploratory character, with analytical-descriptive orientation, through semi-structured interviews with open questions, initiated after prior approval of the Committee on Ethics in Research and informed consent of the interviewees. The subjects are patients using biological DMARD to treat RA that were dispensed by SUS. The therapeutic itinerary tool (TI) was used to understand the path chosen by these patients in the search for health care. Results and Discussion Among those interviewees, the search for care occurred late, usually without the suspicion that there was a degenerative rheumatic disease. The first accessed professionals were the general practitioner or the orthopedist, who rarely ever investigated the reported symptoms with attention to direct the patient to the rheumatologist quickly. In the described TIs, the treatments are mostly composed only by the medicines, and without the participation of other professionals in the follow-up besides the rheumatologist. The patients interviewed reached the biological DMARDs after an attempt to control the disease with synthetic DMARD, as described in the Ministry of Health recommendations. There are several actors representing the private sector described in the TI\'s, who support and influence the patients in the choice of their care pathways, which should be better understood in future studies

OBJETIVO: Determinar os valores séricos do ligante do receptor do ativador do fator nuclear Kappa B (RANKL) e da osteoprotegerina (OPG) em pacientes com Artrite Idiopática Juvenil de início poliarticular (AIJp) em atividade e avaliar a possível correlação destes valores com a presença radiológica de erosões ósseas. MÉTODOS: Trinta pacientes do sexo feminino com diagnóstico de AIJ de início poliarticular segundo os critérios da ILAR (International League of Associations for Rheumatology) em atividade e trinta crianças saudáveis (controles) pareadas por idade e sexo foram selecionadas consecutivamente para este estudo. Todas as articulações comprometidas foram radiografadas e avaliadas, com especial interesse, para a presença de erosões ósseas. Concentrações séricas do RANKL e OPG foram medidas por enzima-imunoensaio (Biomedica, Vienna, Austria). RESULTADOS: Pacientes com AIJp em atividade apresentaram altos valores séricos de RANKL e menores taxas de OPG/RANKL comparadas com controles [2,90 (0,1-37,4) vs. 0,25 (0,1-5,7) pg/ml, p=0,007 e 21,25 (1,8- 897,6) vs. 347,5 (9-947,8)] pg/ml, p=0,005). Diferentemente, não houve diferença em relação à concentração sérica de OPG quando se comparou os pacientes e controles [55,24 (28,34-89,76) vs. 64,42 (30,68-111,28) pg/ml, p=0,256]. Maiores concentrações de RANKL e menores taxas de OPG/RANKL também foram observadas em pacientes com AIJp em atividade com erosões ósseas comparadas com controles [3,49 (0,1-37,4) vs. 0,25 (0,1-5,7) pg/ml, p=0,0115 e 14,3 (1,8-897.6) vs. 347,5 (9-947,8) p=0,016]. Em contraste, valores séricos de RANKL e a taxa de OPG/RANKL foram semelhantes em pacientes com AIJp sem erosões ósseas comparadas com controles [1,75 (0,1-10,9) vs 0,25 (0,1-5,7) pg/ml, p=0,055 e 29,2 (3,3-756,8) vs. 347,5 (9- 947,8), p=0,281]. CONCLUSÃO: Estes dados sugerem que pacientes com AIJp em atividade com erosões ósseas apresentam altos valores séricos de RANKL e baixa taxa de OPG/RANKL indicando que estas alterações podem refletir o comprometimento ósseo nesta doença. / OBJECTIVE: To determine the serum levels of receptor activator of nuclear factor kB-ligand (RANKL) and osteoprotegerin (OPG) in active polyarticularonset Juvenile Idiopathic Arthritis patients (pJIA) and evaluate its possible correlation with bone erosions on the X-ray. METHODS: Thirty female girls with active pJIA diagnosis according ILAR criteria (International League of Associations for Rheumatology) and 30 healthy children gender and agematched controls were consecutively selected for this study. All involved articulations were evaluated by X-ray and analyzed for the presence of bone erosions. The serum levels of RANKL and OPG were measured using an enzyme-linked immunosorbent (Biomedica, Vienna, Austria). RESULTS: Results: Patients with active pJIA had higher levels of serum RANKL and lower OPG/RANKL ratio compared to controls [2.90 (0.1-37.4) vs. 0.25 (0.1- 5.7) pg/ml, p=0.007] and 21.25 (1.8-897.6) vs. 347.5 (9-947.8) pg/ml, p=0.005]. However, levels of OPG were comparable in both groups [55.24 (28.34-89.76) vs. 64.42 (30.68-111.28) pg/ml, p=0.256]. Higher levels of serum RANKL and lower OPG/RANKL ratio was also observed in active pJIA patients with bone erosions compared to controls [3.49 (0.1-37.4) vs. 0.25 (0.1-5.7) pg/ml, p=0.0115 and 14.3 (1.8-897.6) vs. 347.5 (9-947.8), p=0.016]. In contrast, RANKL levels and OPG/RANKL ratio were alike in pJIA patients without bone erosion and controls [1.75 (0.1-10.9) vs. 0.25 (0.1- 5.7) pg/ml, p=0.055 and 29.2 (3.3-756.8) vs. 347.5 (9-947.8), p=0.281]. CONCLUSION: These data suggest that active pJIA with bone erosion is associated with high serum levels of RANKL and low OPG/RANKL ratio indicating that these alterations may reflect bone damage in this disease.

<p>The overall aim was to improve the knowledge and understanding of eating habits of older men with somatic diseases, and the men's perceptions about managing food-related habits, such as grocery shopping and cooking. A total of 67 men between 64 and 89 years of age were visited in their homes on two occasions with 1-2 weeks in between. The participants were diagnosed with one of the three diseases Parkinson’s disease, rheumatoid arthritis, or stroke. A food survey, with repeated 24-h recall, was used to assess food intake and meal patterns. Interviews with 18 participants were conducted with open-ended questions. The interviews were further analysed with a thematic framework approach.The findings showed that eating events were distributed over a 24-h period.Further, co-living men had a significantly larger number of eating events over the day (p=0.001). No differences in daily energy intake were observed between co-living and single-living men. Co-living men’s hot eating events were compared with those of single-living men more often cooked from fresh ingredients (p=0.001), including a greater mix of vegetables/roots (p=0.003).Thematic analysis revealed three different approaches to food-related activities(FRA), namely ‘Cooking as a pleasure’, describing joy in cooking; ‘Cooking as a need’, indicating no habits or skills in cooking; and ‘Food is served’, that is, being served meals by a partner. The men's approaches to FRA were affected in particular by gender-related roles, but also by changed life circumstances, activity limitations, personal interests, and a wish to maintain continuity and independence. Further adaptive strategies were used among the men in attempts to maintain continuity and independence in FRA. In conclusion, single-living older men, especially those with activity limitations, were identified as being a vulnerable group from a nutritional perspective. Further, health care efforts in promoting FRA should preferably be individualised with respect to the older man’s approach to these activities.</p>

<p>Predisposition to autoimmune diseases such as, rheumatoid arthritis, diabetes, and multiple sclerosis, is caused by the effect of multiple genes and a strong influence from the environment. </p><p>In this study, I have investigated genetic factors that confer susceptibility to rheumatoid arthritis in a rat model. This work has led to the identification of several chromosomal regions, containing uncharacterized genes that directly or indirectly are associated to the arthritis development in these rats. We have observed that timing, gender, and genetic interactions are features that play a part in the effect that these genetic factors exert. </p><p>Unarguably, animal models for human disorders display differences to the human form of disease. An important fact is however that the same chromosomal regions are identified in both rodent and human studies, which suggests that there are genetic factors that we have in common, which are involved directly or indirectly with an autoimmune response. </p><p>Focusing the interest on these similarities, and on the possibility to apply a wide set of genetic tools, make animal models an invaluable, and probably necessary, instrument to dissect the genetic component of complex disorders. To fully comprehend the genetic basis for a complex disorder like this, will require understanding of how multiple genes interact with each other to cause disease. </p><p>We have been able to demonstrate that chronic arthritis, in a rat model for rheumatoid arthritis, is regulated by several genes and that these act during different temporal phases of the disease. These findings will hopefully contribute to our understanding of the etiology and progression of rheumatoid arthritis.</p>

<p>In the present studies, aspects of some disease activity measures in rheumatoid arthritis (RA) have been investigated, including the effect of glucocorticoids on this activity. In RA, serum interleukin(IL)-6 levels were elevated and were shown to have a circadian rhythm, with peak levels in the morning, declining towards low or normal levels in the afternoon and evening. In contrast, serum levels of tumour necrosis factor(TNF) alpha were low and stable. In other connective tissue diseases, serum TNF alpha levels were elevated but without circadian variation, while IL-6 levels were low and stable. Nocturnal administration (at 2:00 a.m.) of low-dose prednisolone a few hours before the early morning peak of IL-6 was shown to be significantly more effective in reducing clinical symptoms of disease activity and serum IL-6 levels than the traditional morning administration (at 7:30 a.m.) of the same dose of prednisolone. Circulating monocytes are activated in RA, expressing receptors related to adhesion and phagocytosis. Treatment with glucocorticoids suppressed the expression of these receptors on monocytes, and this may be one mechanism of the beneficial effect of glucocorticoids in RA. Endogenous levels of cortisol seem to play a minor role in expression of monocyte receptors. The different acute phase markers used to assess disease activity in RA showed good corrrelations with each other and with serum IL-6 levels. There were especially strong corrrelations between C-reactive protein (CRP) and Serum amyloid protein A (SAA), and between fibrinogen and erythrocyte sedimentation rate (ESR). Fibrinogen and CRP showed stronger correlation than ESR with the Modified Health Assessment Questionnaire (MHAQ) score and with the neutrophil count. Four simple objective function tests were each compared with the HAQ score a with a radiological joint damage score (Larsen score). The objective function tests correlated with the MHAQ score, and each of these two methods of assessing physical disability correlated with pain, CRP and ESR. In addition, most of the objective function tests correlated significantly with radiological joint damage, while the MHAQ score did not.</p>

<p>Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation. We developed a novel multiplexed method for SNP genotyping based on four-color fluorophore tag-microarray minisequencing. This method allows simultaneous genotyping of 80 samples and up to 200 SNPs in any allele combination. In study I we set up the method for a panel of SNPs from genes in the type I interferon system, and applied it in study III. In study II we used the technique to genotype SNPs from the coding region of the mitochondrial genome. A panel of 150 SNPs was genotyped in 265 individuals representing nine different populations. We demonstrated that the multiplexed SNP genotyping method for mitochondrial DNA increases the power of forensic identification in combination with sequencing of the hypervariable region of mitochondrial DNA. </p><p>In study III we performed a genetic association study of SNPs in genes related to the type I Interferon system in Systemic Lupus Erythematosus (SLE). SLE is a chronic autoimmune inflammatory disease with a complex etiology. The SNPs were genotyped in DNA samples from Swedish, Finnish, and Icelandic patients with SLE, unaffected family members, and unrelated controls. The analysis identified SNPs in two genes, the tyrosine kinase 2 (TYK2) and interferon regulatory factor 5 (IRF5) genes that are highly associated with SLE with p-values <10^-7 for joint linkage and association. </p><p>Study IV describes the analysis of the TYK2 and IRF5 SNPs in a large Rheumatoid Arthritis (RA) sample cohort. We found that SNPs in the IRF5 gene were significantly associated with RA with a p-value = 0.00008. In contrast, we did not detect an association with SNPs in the TYK2 gene. These findings demonstrate that SLE and RA may have a common genetic background in the case of IRF5, while the TYK2 variants appear to be unique for SLE. </p>