Advances in molecular immunology and rapid technical evolution during the past two decades have led to a new class of medicines called biologics. Recently, a large number of biologics, or biologic immunomodulators, directed towards an array of immune–mediated diseases, have entered the market. This has lead to a dramatic change in the immunotherapy of autoimmune diseases, as biologics present new potential to improve or substitute conventional immunosuppressive therapies. According to literature, biologics are used by only a small number of a health plan’s members, (approximately one per cent), but a single occurrence can be relatively expensive. Furthermore, there is an indication that the frequency of use and cost of biologics are on the rise, and as more biologics enter the market, health plans and employers face the challenge of controlling costs while ensuring that biologics are affordable. The general objective of this study was to determine the prevalence and cost of biologic immunomodulating medicine in the treatment of certain autoimmune diseases during the period 2005 to 2008 in a section of the private health care sector of South Africa, by employing a medicine claims database as a source to obtain necessary information. A quantitative, retrospective drug utilisation review (rDUR) was performed on computerised medication records (medicine claims data) for four consecutive years (i.e. 2005 to 2008) provided by a pharmacy benefit management company (PBM). The study population consisted of all patients on the database who received at least one medicine item with adalimumab, etanercept, infliximab, interferon beta–1a, interferon 1–b or rituximab as active ingredient and who were diagnosed with either rheumatoid arthritis (RA), multiple sclerosis (MS) or Crohn’s disease between 1 January 2005 and 31 December 2008. Between 2005 and 2008, an average of 1,305,201 patients appeared on the total database, and of these 0.055% (n = 713) received biologic immunomodulating medicine. More than two thirds of biological users were female and most patients who received these medicine items were between the ages of 39 and 64 years, followed by those patients aged between 25 and 39 years. Biologic immunomodulating medicine items (n = 11,914) and biologic prescriptions (n = 9,537) represented 0.016% of the total number of medicine items (N = 76,129,173) and 0.030% of the total number of prescriptions (N = 31,985,153). The percentage contribution of biologic immunomodulators to the total number of medicine items and prescriptions on the total database increased each year, and in four years’ time the percentage of all the medicine items on the total database that included biologic immunomodulators had tripled, from 0.009% to 0.023%. The total cost of biologic immunomodulating medicine accounted for 1.278% of the total cost (N = R7, 483,759,176.23) of all medication claimed through the PBM between 2005 and 2008. The percentage contribution of biologic immunomodulators to the total medicine expenditure also increased from one year to another for the four–year study period. The average cost of a biologic immunomodulating medicine item increased with 71.10% from 2005 (R5602.71 ± 2166.61) to (R9586.25 ± 5956.56) in 2008. The CPI for biologic immunomodulators, (CPI = 60.00 for 2005; CPI = 74.62.17 for 2006; CPI = 85.26 for 2007; and CPI = 86.96 for 2008) indicated that biologic immunomodulating medicine items were relatively expensive and the d–value between the average cost per biologic immunomodulator and the average cost per non–biological medicine item (d–value = 2.54 in 2005, d–value = 3.32 in 2006, d–value = 2.23 in 2007 and d–value = 1.59 in 2008) furthermore indicated that the impact of biological therapies was large and practically significant. Rheumatoid arthritis patients represented 19.78% of the total number of patients (n = 713) who claimed the biologic immunomodulators during the four–year period, MS patients (n = 172) represented 24.12% and Crohn’s patients (n = 11) represented 1.5%. Biological drugs prescribed to RA patients represented 0.28% (n = R20, 708,818.82) of the total cost (N = R7, 483,759,176.23) of all medication claimed through the PBM during the four–year period, while those prescribed to MS patients represented 0.41% (R30, 922,520.07) and those prescribed to Crohn’s disease patients represented 0.015% (R1, 108,568.02). Although biologic immunomodulating medicine items used in the treatment of RA, MS and Crohn’s disease are relatively expensive, it seems that the number of other medication prescribed to patients with these diseases decreased after treatment with biologics, which may influence the medicine treatment cost of these patients. It can be concluded that even though biologic immunomodulators are used by only a very small percentage of the total patient population in a section of the private health care sector of South Africa, they are relatively expensive and have a considerable impact not only the medical aid scheme, but also on the patient. / Thesis (M.Pharm (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.

Rheumatoid Arthritis (RA) is a disease in which the body has "turned on itself", with its immune system attacking mobility. In RA, an immune mechanism attacks and destroys the joints and limits mobility, in some circumstances to the point of needing replacement of joints. The aim of this research is the development of a less costly, widely accessible, passive sensing technology that provides a quantitative assessment of RA and that monitors the therapeutic effectiveness on joint-debilitating diseases. The proposed solution relies on a quantitative evaluation of human gestures. Such a quantitative assessment supports the comparison between the motion capabilities of a patient and that of a healthy person, using a kinematic model of the human skeleton. Criteria for the classification of severity were established, and tables were generated to classify the levels of severity as a function of the measurements extracted from processed videos of a subject performing predefined movements. This research project, while contributing a new tool to the process of classification of RA level of severity, opens the way for using widely accessible digital imaging for diagnosing and monitoring the evolution of the illness. Replacing MRI or HRUS with a cheaper and more accessible technology would have a major impact on health care services. From the clinical point of view, the proposed techniques based on digital images processing combined with a monitoring approach based on infrared images that was previously developed may provide a utility of care for patients with RA, as well as an alternative and automated approach for early detection of RA and active inflammation at a critical time.

Advances in molecular immunology and rapid technical evolution during the past two decades have led to a new class of medicines called biologics. Recently, a large number of biologics, or biologic immunomodulators, directed towards an array of immune–mediated diseases, have entered the market. This has lead to a dramatic change in the immunotherapy of autoimmune diseases, as biologics present new potential to improve or substitute conventional immunosuppressive therapies. According to literature, biologics are used by only a small number of a health plan’s members, (approximately one per cent), but a single occurrence can be relatively expensive. Furthermore, there is an indication that the frequency of use and cost of biologics are on the rise, and as more biologics enter the market, health plans and employers face the challenge of controlling costs while ensuring that biologics are affordable. The general objective of this study was to determine the prevalence and cost of biologic immunomodulating medicine in the treatment of certain autoimmune diseases during the period 2005 to 2008 in a section of the private health care sector of South Africa, by employing a medicine claims database as a source to obtain necessary information. A quantitative, retrospective drug utilisation review (rDUR) was performed on computerised medication records (medicine claims data) for four consecutive years (i.e. 2005 to 2008) provided by a pharmacy benefit management company (PBM). The study population consisted of all patients on the database who received at least one medicine item with adalimumab, etanercept, infliximab, interferon beta–1a, interferon 1–b or rituximab as active ingredient and who were diagnosed with either rheumatoid arthritis (RA), multiple sclerosis (MS) or Crohn’s disease between 1 January 2005 and 31 December 2008. Between 2005 and 2008, an average of 1,305,201 patients appeared on the total database, and of these 0.055% (n = 713) received biologic immunomodulating medicine. More than two thirds of biological users were female and most patients who received these medicine items were between the ages of 39 and 64 years, followed by those patients aged between 25 and 39 years. Biologic immunomodulating medicine items (n = 11,914) and biologic prescriptions (n = 9,537) represented 0.016% of the total number of medicine items (N = 76,129,173) and 0.030% of the total number of prescriptions (N = 31,985,153). The percentage contribution of biologic immunomodulators to the total number of medicine items and prescriptions on the total database increased each year, and in four years’ time the percentage of all the medicine items on the total database that included biologic immunomodulators had tripled, from 0.009% to 0.023%. The total cost of biologic immunomodulating medicine accounted for 1.278% of the total cost (N = R7, 483,759,176.23) of all medication claimed through the PBM between 2005 and 2008. The percentage contribution of biologic immunomodulators to the total medicine expenditure also increased from one year to another for the four–year study period. The average cost of a biologic immunomodulating medicine item increased with 71.10% from 2005 (R5602.71 ± 2166.61) to (R9586.25 ± 5956.56) in 2008. The CPI for biologic immunomodulators, (CPI = 60.00 for 2005; CPI = 74.62.17 for 2006; CPI = 85.26 for 2007; and CPI = 86.96 for 2008) indicated that biologic immunomodulating medicine items were relatively expensive and the d–value between the average cost per biologic immunomodulator and the average cost per non–biological medicine item (d–value = 2.54 in 2005, d–value = 3.32 in 2006, d–value = 2.23 in 2007 and d–value = 1.59 in 2008) furthermore indicated that the impact of biological therapies was large and practically significant. Rheumatoid arthritis patients represented 19.78% of the total number of patients (n = 713) who claimed the biologic immunomodulators during the four–year period, MS patients (n = 172) represented 24.12% and Crohn’s patients (n = 11) represented 1.5%. Biological drugs prescribed to RA patients represented 0.28% (n = R20, 708,818.82) of the total cost (N = R7, 483,759,176.23) of all medication claimed through the PBM during the four–year period, while those prescribed to MS patients represented 0.41% (R30, 922,520.07) and those prescribed to Crohn’s disease patients represented 0.015% (R1, 108,568.02). Although biologic immunomodulating medicine items used in the treatment of RA, MS and Crohn’s disease are relatively expensive, it seems that the number of other medication prescribed to patients with these diseases decreased after treatment with biologics, which may influence the medicine treatment cost of these patients. It can be concluded that even though biologic immunomodulators are used by only a very small percentage of the total patient population in a section of the private health care sector of South Africa, they are relatively expensive and have a considerable impact not only the medical aid scheme, but also on the patient. / Thesis (M.Pharm (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.

Introduction This thesis concerns the mosquito-borne arbovirus Ross River (RR) virus. The main objectives were to determine the vector associations, the incidence, costs and natural history of disease, and behavioural and environmental risks for infection in tropical Queensland. 1. Literature review On the basis of the literature review there is strong evidence that Aedes vigilax, Ae. camptorhynchus and Culex annulirostris are important vectors in Australia. Aedes camptorhychus does not occur in Queensland. There is evidence that two peri-domestic container-breeding mosquitoes, Ae. notoscriptus and Ae. aegypti, may be vectors of the virus. The virus has been isolated from many other species but the role of most of these is unclear. It is unclear which vertebrate species are the major reservoirs for human infection. Studies are inconsistent with regard to the prevalence, duration and severity of symptoms and debility during RR virus disease. Nearly all epidemiological studies of RR virus have been descriptive. Therefore one can only surmise what the risks for human infection might be. Epidemiological studies to determine the associations between exposures and risk for disease do not exist. 2. Virus isolation from mosquitoes During 1996-1998 61,619 mosquitoes were processed for virus isolation. Thirty-three isolates of RR virus were made. The largest number (14) were from Ae. carmenti. The minimum infection rate (MIR) per 1,000 was 2.4. Isolates were also made from Ae. imprimens (1 isolate, MIR 10.3), Ae. kochi (2, 0.2), Ae. lineatus (1, 0.2), Ae. notoscriptus (1, 1.6), Ae. vigilax (1, 0.3), Cx. annulirostris (9, 0.3), Cx. vicinus (1, 4.0) and Mansonia septempunctata (3, 5.8). Ross River virus has been isolated from Cx. annulirostris, Ae. vigilax, Ae. notoscriputus and Ae. kochi but not from the other species. Ross River virus was not isolated from Ae. aegypti. Twenty-six isolates came from in or near a colony of 15,000 spectacled flying-fox, Pteropus conspicillatus. The proportion of RR virus positive pools from within 1 km. of this colony was significantly greater than elsewhere for all species combined and for Cx. annulirostris but not for Ae. carmenti. 3. The incidence and costs of Ross River virus disease Unpublished data on National, State and Territory notifications was collected. Crude incidence rates using census figures for denominator data were calculated. The same was done for the areas in which the other studies described in the thesis were carried out. An estimate of the cost of Ross River virus disease in Australia was made. During the period 1991-1998 of the States and Territories the Northern Territory (NT) had the highest and the Australian Capital Territory (ACT) the lowest notification incidences. These were 62-281 and 0-3 per 100,000 per annum, respectively. During this period the notification incidence for Queensland ranged from 70 to 149 per 100,000 per annum. For the local government areas of Cairns and Mareeba, where the majority of cases of RR virus disease for the studies described in this thesis were recruited, the notification incidences were between 74 and 267, and 28 and 200, respectively. On the basis of an average of 4,800 cases per annum in Australia the cost of serological testing and medical consultations were estimated at $443,520 and $105,600. Lost earnings were estimated at $1,798,560. The total cost for medical consultations, serological testing and lost earnings will therefore be over $2 million in an average year. 4. The natural history of Ross River virus disease In 1998 incident cases of RR virus disease were ascertained. Fifty-seven eligible cases were recruited but only 47 could be reviewed on 3 occasions and data on these were analysed. Cases were followed for up to 197 days. Review included history, examination and the administration of the Clinical Health Assessment Questionnaire (CLINHAQ) and Short Form-36 (SF-36) . On initial review the 3 most common symptoms were arthralgia, joint stiffness and myalgia affecting 97.9, 89.4 and 59.6% of cases, respectively. The joint types most commonly affected by pain at the initial review were the ankles, wrists, interphalangeal joints of the fingers, knees and metacarpophalangeal joints. Objective signs of joint inflammation were rare. The prevalence of signs of inflammation decreased and the prevalence of normal joints on examination increased through the reviews. The prevalence of use of NSAIDs decreased through the reviews. On the basis of CLINHAQ items regarding work performance functioning at work improved through the course of the reviews. Linear regression with days since symptom onset as the independent variable was performed for some variables. The 8 dimensions of the SF-36 were standardized to the Queensland population and analyzed longitudinally . Analyses of the CLINHAQ functional disability index (FDI) and the visual analogue scales (VASs) for pain, global severity, fatigue, gastrointestinal complaints and sleep, and the depression and anxiety scales were also performed. The slopes of all fitted regressions except the SF-36 general health dimension were significantly different from zero. All measures of disease severity returned to normal by 8 months from onset, many in a shorter period. 5. Behavioural and environmental risks for infection Fifty-five incident cases of RR virus disease were recruited and formed the basis of a case-control study of behavioural and environmental risks. They were matched to 85 controls. In the year prior to symptom onset the only leisure exposure that significantly altered risk was camping [Odds ratio (OR) = 2.15; 95% confidence interval (CI) = 1.07-4.35]. No peri-domestic activities in the year prior to onset significantly altered disease risk. Leisure exposures were also assessed in a 3-week exposure period ending 4 days prior to symptom onset. None significantly altered risk. No peri-domestic activity in this period significantly altered risk and nor did exposure to vertebrates or mosquitoes. Containers and vegetation around the subject's dwelling did not significantly increase risk. The presence of ice cream containers and buckets was significantly protective when assessed by questionnaire, however this was also assessed by inspection and was found to increase risk though not significantly so. It was concluded that the former finding was due to differential misclassification of exposure status. The premise condition index (PCI) was measured. A low PCI for the subject's house was associated with a significantly increased risk (3-4 relative to 7-9 as reference category: OR = 3.15, 95% CI = 1.07-9.25). Window screening did not alter disease risk and air-conditioning in the house or the bedroom decreased risk but not significantly so. Use of protective measures, except bed nets, in the year prior to onset was found to decrease disease risk. Personal repellents, mosquito coils and citronella candles significantly decreased risk. A dose response was shown for the number of protective measures from personal repellents, aerosol and surface sprays, mosquito coils, citronella candles and mosquito "zappers" used in the year prior to symptom onset. Pet ownership and proximity of dwelling to horses did not significantly alter risk. A preference for light coloured clothing was significantly protective (0.37, 0.15-0.89). Stratification by gender, date of symptom onset and geographical area was performed. Stratification by geographical area included a coastal and tablelands stratum. There were differences between the stratum-specific odds ratios for camping in the year prior to symptom onset, the presence of bromeliads in the subject's garden and a preference for light coloured clothing. Multivariate analysis demonstrated confounding by use of personal repellents, mosquito coils and citronella candles. When modeled together these were found to cause confounding among themselves. They also caused significant confounding of camping, outdoor work and the presence of banana trees in the subject's yard. Multivariate analysis of the association between PCI and disease risk failed to demonstrate confounding by use of protective measures or time between symptom onset and review. 6. Synthesis and conclusions The three research Chapters form a coherent body of public health research on the epidemiology (Chapters 5 and 6) and ecology (Chapters 4 and 7) of RR virus, and the natural history of RR virus disease (Chapter 6) in tropical Queensland. Conclusions are drawn from the research in the thesis. A set of priorities for future public health research on RR virus is suggested, and a pilot control program for Ross River virus disease in tropical Queensland is recommended.

[Truncated abstract] Ross River virus (RRV) causes the most common arboviral disease in Australia, with approximately 5000 new cases reported each year, making this virus a major public health concern. The aim of this thesis was to link results from virological, pathogenesis and epidemiological studies to further define RRV disease in the south-west (SW) of Western Australia (WA), a region of endemic and epizootic RRV activity. A crosssectional seroprevalence study was used to show that 7.8 percent of SW communities were seropositive to RRV, comparable to other regions of Australia with similar temperate climates to the SW . . . RRV-specific IgM antibodies were found to persist for at least two years following RRV infection. A murine model was used to conclusively show differences in pathogenesis between RRV genotypes, the SW and northern-eastern (NE) genotypes, which are known to circulate throughout Australia. The SW genotype, unique to the SW of WA induced only poor neutralising antibody production and nonneutralising antibodies after the acute phase of infection. In comparison, the NE genotype which currently predominates in mosquito populations in the SW of WA, induced the most efficient neutralising antibody response and consequently produced the mildest disease in the mouse. These data in the mouse suggest that the infecting genotype will mostly likely influence disease outcome in humans and could at least partially explain why more severe and persistent disease has been reported from the SW of WA. Collectively, results from this thesis provide an important benchmark against which future investigations into BFV and RRV diseases can be measured.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2007. / Härtill 4 uppsatser.

La polyarthrite rhumatoïde (PR) est la maladie auto-immune la plus fréquente d’une prévalence de 1%. Les cellules résidentes de la cavité synoviale, les fibroblast-like synoviocytes (FLS), sont des acteurs majeurs de la PR. Leur activation par des récepteurs de l’immunité innée participe à l’acquisition d’un phénotype agressif menant à la destruction ostéo-articulaire. Dans cette étude, nous avons évalué le rôle régulateur de miARN sur les voies de signalisation des Toll-like receptors (TLR). L’activation de TLR2 et de TLR4 dans les FLS induit la diminution de l’expression de plusieurs miARN, dont miR-19a et b (miR-19), alors que TLR2 est surexprimé. Nous avons pu ainsi montrer que miR-19 régule Tlr2 et que la transfection de mir-19 dans les FLS activés induit une diminution de l’expression de TLR2 et de la synthèse d’IL-6 et de MMP-3. Mir-19 appartient au cluster miR-17~92, dont l’expression est abaissée dans les FLS. Il code pour 6 miARN dont miR-20a. miR-20a est également sous-régulé après activation de TLR2 et TLR4 dans les FLS et les THP-1. Nous avons montré que miR-20a régule directement l’expression d’Ask1, impliquée et surexprimée après activation de TLR4. La transfection de miR-20a in vitro nous a permis de montrer que miR-20a contrôle l’expression d’ASK1 et induit une inhibition de la synthèse de cytokines majeures de la PR dans les FLS et les THP-1. Des résultats équivalents ont été obtenus ex vivo chez la souris. Ces travaux ont permis d’identifier dans les FLS rhumatoïdes des miARN anti-inflammatoires dont la baisse d’expression permet une augmentation de l’expression de TLR2 et d’ASK1. Ces miARN pourraient donc constituer de nouvelles cibles thérapeutiques. / Rheumatoid arthritis (RA) is the most frequently autoimmune disease with a prevalence of 1%. Resident cells of joints, the fibroblast-like synoviocytes (FLS), act as key players in RA. Their activation through Pattern-recognition receptors leads to an aggressive phenotype, leading in the osteo-articular destruction of the joints. In this study, we aimed to discuss the link between Toll-like receptors (TLR) and miRNA pathway. We established the down-regulation of a few miRNA when FLS were activated through TLR2 and TLR4, including miR-19a and miR-19b (miR-19). We showed that miR-19 regulates directly Tlr2 and that transfection of miR-19 mimics leads to a decrease of IL-6 and MMP-3 synthesis in FLS. miR-19 belongs to the cluster miR-17~92, which is also down-regulated in activated FLS. This primary transcript encodes for 6 miRNA, including miR-20a, which is also down regulated upon TLR2 and TLR4 activation in FLS and further in THP-1, a monocyte cell-line. Then, we validated the predicted regulation of miR-20a on Ask1, an important kinase involved in TLR4 pathway. The transfection of miR-20a mimics in vitro represses ASK1 expression and inhibits several major cytokines in RA both in FLS and THP-1. Further, we confirmed these results on ex vivo experiments on peritoneal macrophages. These works allowed us to identify new anti-inflammatory miRNA that are downregulated and allow overexpression of TLR2 and ASK1 in RA FLS. These results open new experiments on in vivo models. All together, these data give new insights for identify new therapeutics in RA.

Base teórica: A introdução de agentes biológicos, especialmente os bloqueadores do fator de necrose tumoral (anti-TNF), para o tratamento de doenças reumáticas aumentou o risco de desenvolver tuberculose (TB). O rastreio para infecção tuberculosa latente (ILTB) é fortemente recomendado antes de iniciar a terapia com agentes anti-TNF. Os objetivos deste estudo foram identificar a prevalência de ILTB e TB entre pacientes com doenças reumáticas em uso dos medicamentos anti-TNF. Métodos: Estudo transversal. Foram revisados os registros médicos eletrónicos de todos os doentes adultos (≥ 18 anos) em uso da terapia anti-TNF. Todos os pacientes foram submetidos ao teste tuberculínico (TT) antes de iniciar o tratamento com os medicamentos anti-TNF. Resultados: No total, 176 pacientes foram incluídos no estudo. A idade média de todos os pacientes foi de 51,9 ± 12,4 anos, 34,7% eram do sexo masculino e 90,9% eram brancos. As doenças subjacentes mais comuns foram: Artite Reumatóide (AR) em 89 pacientes (50,6%), Espondilite Anquilosante (EA) em 49 (27,8%) e Artrite Psoriática (AP) em 31 (17,6%). A prevalência de TT positivo foi de 29,5%. O contato domiciliar com TB foi significativamente associado com TT positivo (p = 0,020). Os pacientes com AR apresentaram reações TT menores do que os pacientes com EA (p = 0,022). Houve seis casos de TB (3,4%) diagnosticados durante a terapia anti-TNF. Conclusões: Demonstrou-se alta prevalência de TT positivo (29,5%) em pacientes com doenças reumáticas em uma região com alta prevalência de TB. Nossos dados corroboram a recomendação do Colégio Americano de Reumatologia (ACR) de que os pacientes que vivem em configurações de alta incidência de TB devem ser testados anualmente para ILTB. / Background: The introduction of biological agents, especially the blockers of tumor necrosis factor (anti-TNF), for the treatment of rheumatic diseases increased the risk of developing tuberculosis (TB). Screening for latent TB infection (LTBI|) is strongly recommended before starting therapy with anti-TNF agents. The objectives of this study were to identify the prevalence of LTBI and TB among patients with rheumatic diseases on anti-TNF drugs. Methods: Cross-sectional study. The electronic medical records of all adult patients (≥ 18 years old) undergoing anti-TNF treatment were reviewed. Every patient underwent TST test before starting anti-TNF treatment. Results: In total, 176 patients were included in the study. The mean age of all patients was 51.9 ± 12.4 years, 34.7% were males, and 90.9% were white. The most common underlying diseases were: RA in 89 patients (50.6%), AS in 49 (27.8%), and PA in 31 (17.6%). The prevalence of positive TST was 29.5%. Household contact with TB was significantly associated with a positive TST (p=0.020). RA patients had lower TST reactions than AS patients (p=0.022). There were six cases of TB (3.4%) diagnosed during anti-TNF therapy. Conclusions: We demonstrated a high prevalence of positive TST (29.5%) among patients with rheumatic diseases in a region with high TB prevalence. Our data corroborates the ACR’s recommendation that patients who live in high TB incidence settings should be tested annually for LTBI.

A artrite reumatoide (AR) é uma doença autoimune, inflamatória, crônica, sistêmica e de etiologia desconhecida que pode ser induzida experimentalmente em animais por administração de colágeno e adjuvante (CIA). Os medicamentos biológicos contra o fator de necrose tumoral (TNF)-α são indicações terapêuticas atualmente consolidadas para os casos mais severos de AR. As limitações ao uso dessa classe de medicamentos têm sido o alto custo e a dificuldade em fabricar genéricos ou similares com composição, qualidade e desempenho equivalentes na mesma dose e via de administração. O presente estudo avaliou a hipótese de que drogas sintéticas que inibam a produção de TNF-α e / ou fatores relacionados teriam potencial para tornarem-se terapias complementares ou alternativas eficientes para esta doença. Para isso, foram utilizados ratos submetidos ao modelo CIA e tratados cronicamente com pentoxifilina (PTX), rolipram (ROL), talidomida (TAL) e rupatadina (RUP). Um tratamento com prednisolona (PRED) foi também efetuado para avaliar sua influência na eventual ação antiartrítica de PTX, ROL, TAL e RUP, de modo a mimetizar seu efeito imunossupressor, quando administrada agudamente (AG) antes de medicamentos biológicos, bem como pelo seu conhecido efeito anti-inflamatório, quando administrada cronicamente (CR) no tratamento da AR. O desenvolvimento da AR e a efetividade dessas drogas sobre a AR foram avaliadas, de forma seletiva e sequencial, por meio da detecção de eritema e cianose, bem como medidas de edema, massa corporal, hemograma, TNF-α no plasma, fator reumatoide (FR) e anticorpo antinuclear (ANA) no soro, interleucina (IL)-1β e IL-6 no soro e líquido sinovial, atividade de aminopeptidase básica (APB) na fração solúvel (FS) do tecido sinovial (TS) e de células mononucleares do sangue periférico (PBMCs), densitometria óssea e análise histológica. A hepatotoxicidade dessas drogas foi avaliada pelas medidas de alanina-transaminase (ALT) e aspartato-transaminase (AST) no plasma. A AR caracterizou-se pelo aumento de TNF-α plasmático e de IL-1β e IL-6 no líquido sinovial, alterações histológicas na articulação tíbio-tarsal, bem como edema, cianose, eritema, diminuição de linfócitos e atividade APB de FS aumentada no TS e diminuída em PBMCs. A AR aumentou ALT e AST. O tratamento com PRED crônico promoveu um efeito antiedematogênico. O coquetel (MIX de PTX+ROL+RUP+TAL) também apresentou efeito antiedematogênico. A administração concomitante de PRED AG ou PRED CR com MIX não produziu sinergismo ou potenciação do efeito antiedematogênico da administração isolada do MIX ou da PRED crônica. Além do MIX, ROL e TAL diminuíram o edema. MIX, ROL e TAL melhoraram TNF-α no plasma e APB na FS do TS e não causaram hepatotoxicidade, tal como refletido nos níveis de ALT e AST. TAL recuperou ALT e AST, sem alteração do hemograma. Uma vez que PTX e RUP não apresentaram efeito antiedematogênico, ROL e TAL foram hipotetizados como os prováveis responsáveis pela atividade antiartrítica do MIX. Então, os tratamentos com ROL, TAL e ROL+TAL foram selecionados para avaliação da histologia óssea e medidas de parâmetros diferenciais entre animais controles sadios e artríticos. Esta avaliação mostrou que o tratamento isolado da AR com ROL ou TAL não alterou IL-6, mas recuperou IL-1β no líquido sinovial, efeitos esses que não se diferenciaram do tratamento combinado de ROL+TAL, exceto pelo fato de que essa combinação também diminuiu a massa corporal. TAL se destacou por seu efeito hepatoprotetor nos animais AR. Considerando os efeitos conhecidos de RUP, PTX, TAL e ROL é possível hipotetizar que a ação antiartrítica de TAL e ROL deve-se à inibição da síntese de TNF-α decorrente da inibição de PDE4 em suas principais fontes celulares. Os dados deste estudo prospectivo fornecem subsídios adicionais que estimulam a realização de novos ensaios clínicos, mais amplos e sistematizados, sobre os efeitos antiartríticos de ROL e TAL. Conclui-se que o uso isolado de TAL emerge como uma alternativa terapêutica econômica, simples e eficaz para a AR, enquanto a combinação de ROL+TAL pode ser uma opção viável para portadores de AR com sobrepeso ou obesidade / Rheumatoid arthritis (RA) is an autoimmune, inflammatory, chronic and systemic disease with unknown etiology that can be experimentally induced in animals by administration of collagen and adjuvant (CIA). Biological drugs against tumor necrosis factor (TNF)- α are therapeutic indications currently consolidated for the most severe cases of RA. The limitations for the use of this class of drugs have been the high cost and the difficulty to manufacture a generic or similar ones with equivalent composition, quality and performance under the same dosage and route of administration. The present study evaluated the hypothesis that synthetic drugs that inhibit the production of TNF-α and/or related factors would have potential to become efficient complementary or alternative therapies for this disease. For this purpose, male rats submitted to the CIA model were chronically treated with pentoxifylline (PTX), rolipram (ROL), thalidomide (TAL) and rupatadine (RUP). The treatment with prednisolone (PRED) was also performed to evaluate its influence on the possible antiarthritic action of PTX, ROL, TAL and RUP, in order to mimic its immunosuppressive effect when acutely (AG) administered prior to biological drugs, as well as due to its known anti-inflammatory effect when administered chronically (CR) to treat RA. The development of RA and the efficacy of these drugs on RA were evaluated, by selective and sequential ways, through the detection of erythema and cyanosis, as well as measurements of edema, body mass, hemogram, plasma TNF-α, rheumatoid factor (FR) and anti-nuclear antibody (ANA) in serum, interleukin (IL)-1β and IL-6 in serum and synovial fluid, basic aminopeptidase activity (APB) in soluble fraction (FS) from synovial tissue (TS) and from peripheral blood mononuclear cells (PBMCs), bone densitometry and histological analysis. The hepatotoxicity of these drugs was evaluated by measurements of alanine-transaminase (ALT) and aspartate-transaminase (AST). RA was characterized by increased TNF-α in plasma and IL-1β and IL-6 in synovial fluid, histological alterations in the tibio-tarsal joint, as well as edema, cyanosis, erythema, decreased lymphocyte number and increased APB activity in TS and decreased APB activity in PBMCs. RA produced increased ALT and AST. As expected, the chronic treatment with PRED promoted an antiedematogenic effect. The cocktail (MIX of PTX+ROL+RUP+TAL) also presented antiedematogenic effect. Concomitant administration of acute or chronic PRED with MIX did not produce synergism or potentiation of the antiedematogenic effect due to the single administration of MIX or chronic PRED. In addition to MIX, ROL and TAL were also antiedematogenic. MIX, ROL and TAL ameliorated plasma TNF-α and APB in FS from TS without hepatotoxicity, as reflected by ALT and AST levels. TAL recovered ALT and AST, but it did not affect the hemogram. Since PTX and RUP did not present antiedematogenic effects, ROL and TAL were hypothesized as probable responsible for the antiarthritic activity of MIX. Thus, the treatments with ROL, TAL and ROL+TAL were selected for evaluation of bone histology and measurements of differential parameters between healthy control and arthritic animals. This evaluation showed that the treatment of RA with ROL or TAL alone did not alter IL-6 levels, but recovered IL-1β in the synovial fluid. Both these effects were not different from those of the concomitant treatment with ROL+TAL, except that this combination also decreases the body mass. TAL stands out for its hepatoprotective effect in RA animals. Considering the known effects of RUP, PTX, TAL and ROL it can be hypothesized that antiarthritic action of TAL and ROL is due to the inhibition of TNF-α synthesis as consequence of its inhibition in its main cellular sources by PDE4. Data from this prospective study provide additional subsidies that stimulate further and more comprehensive clinical trials on the antiarthritic effects of ROL and TAL. In conclusion, the treatment with TAL alone emerges as an economical, simple and effective therapeutical alternative for RA, while the combination of ROL+TAL can be a viable option for RA sufferers with overweight or obesity

Made available in DSpace on 2016-12-06T17:06:55Z (GMT). No. of bitstreams: 1 Rodrigo da Rosa Iop.pdf: 1224669 bytes, checksum: 3bae5d9fc8b8bd98eb6a51475f81d1e3 (MD5) Previous issue date: 2013-06-04 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Este estudo teve como objetivo analisar os parâmetros da curva de força de preensão manual isométrica máxima em mulheres com artrite reumatoide e a sua relação com a atividade da doença. Participaram deste estudo 9 mulheres com artrite reumatoide e 10 mulheres saudáveis, pareadas por idade. A média de idade das mulheres com artrite foi de 56,66±11,81 e das saudáveis foi de 56,0±11,42. Foram utilizada ficha de avaliação, escala de Graffar para determinar o nível sociocenômico e o inventário de Edinburg, a fim de determinar a dominância lateral. Para avaliar o nível da atividade da doença foi utilizado Disease Activity Score por meio da Proteína C-Reativa. Para avaliação dos parâmetros da curva força vs tempo de preensão manual foi utilizado dinamômetro digital produzido pelo Laboratório de Instrumentação da Udesc por meio de janelas de tempo (0-30ms; 0-50ms; 0-100ms) Os parâmetros analisados foram: força de preensão máxima, tempo para atingir a força de preensão máxima, taxa de desenvolvimento da força e o pico da taxa de desenvolvimento da força para o lado dominante e não dominante. Para comparar a média dos parâmetros da curva de força de preensão manual isométrica máxima vs tempo entre os grupos foi utilizado o Teste T para amostras independentes. A relação entre os parâmetros da curva de força de preensão e o Disease Activity Score, bem como a Proteina C-Reativa nas mulheres com artrite foi verificada por meio da correlação de Pearson. A relação entre os parâmetros da curva de força de preensão manual isométrica máxima vs tempo e o número de articulações dolorosa, edemaciadas e a percepção geral de saúde foi verificada através do teste de Spearman. A força máxima e o pico da taxa de desenvolvimento apresentaram diferença significativa entre os grupos. Foi possível verificar associação linear entre o Disease Activity Score com tempo para atingir a força máxima do lado não dominante e com a taxa de desenvolvimento da força (0-100ms) do lado dominante, bem como entre a Proteína C-Reativa com a força máxima, tempo para atingir a força máxima dominante e a taxa de desenvolvimento da força (0-100ms) dominante e o pico da taxa de desenvolvimento da força de ambos os lados. As informações sobre os parâmetros da curva força vs tempo durante a contração isométrica máxima podem contribuir na avaliação da fraqueza muscular e incapacidade gerada pelo processo inflamatório em pacientes com artrite, tornando-se uma ferramenta útil para fins preventivos e de reabilitação.