Objective. This study was designed to test the hypotheses that a 16-week, individualized, intensive strength training program in rheumatoid arthritis (RA) patients taking Remicade™ (Infliximab) would improve strength, body composition, disease activity, physical function, pain and quality of life outcomes , as compared to RA patients on Remicade™ with no strength training program. Methods. Twenty-four patients with RA taking Remicade™, participated in a randomized, controlled trial. The exercise group carried out a three time a week strength training program, with the control group continuing standard of care. Assessments were completed at baseline, 8-week, and 16-week time points . Maximal strength, physical function, disease activity, body composition, quality of life, and pain were measured with active tests and via questionnaires. Patients also completed exit evaluations on their satisfaction with the study. Results. Highly significant strength gains were seen in the exercise group according to 3 repetition maximums (3RMs) (p<.01), as well as in all 8 exercises performed in the gym (p<.01). The mean exercise attendance for the 16 weeks was 82.0±10.6%. Compared to the control group, there was a significant increase in right hand grip strength (p<.1), and lean tissue in the trunk (p<.01). Significant improvements were also seen in physical function according to 50-foot walk time (p<.01), the Arthritis Impact Measurement Scale 2 (AIMS2) hand and arm function subscales (p<.05), and the Medical Outcomes Study Short Form 36 (MOS SF-36) (p<.1), as compared to controls. The exercise group showed clinically important differences via the Health Assessment Questionnaire Disability Index (HAQ DI), with a mean change of -0.41±0.42. Significant reductions in pain, as measured by the Pain Visual Analogue Scale (VAS), also occurred (p<.1). The individualization of the strength training program and personal attention received by the patients was critical to the success of the study. Patient satisfaction with the study was high, with limitations due primarily to funding constraints. Conclusion. This 16-week high intensity strength training program led to statistically significant improvements in strength, lean soft tissue, disease activity, function, pain and quality of life in this RA population. No detrimental effects on the disease were seen in this study.

Objective: to assess the prevalence of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and spondyloarthropathy (SpA) in Vilnius, Lithuania. Methods: 3 prevalence studies were conducted: 1. Registry-based study of the prevalence of RA and SLE; 2. Population-based study of the prevalence of RA and SLE (interview conducted by mail); 3. Poulation-based study of the prevalence of RA and SpA (interview conducted by telephone). Results: according to the Vilnius RA and SLE registry, the prevalence of RA in Vilnius at the end of year 2004 was 0,14% (95% CI 0,13-0,15), and the prevalence of SLE was 0,0174% or 17,4/100 000 (95% CI 0,0137-0,0218). The population-based study, conducted by mail, revealed 15 RA and 2 SLE cases, accounting for a prevalence rate of RA of 0,37% (95% CI 0,21-0,62), and a prevalence of SLE rate of 0,0498% (95% CI 0,006-0,180). The standardized prevalence rate according to age and sex in the Vilnius population showed an RA prevalence of 0,32% (95% CI 0,18-0,57). The population-based study, conducted be telephone, detected 16 RA and 13 SpA cases, resulting in a crude prevalence of 0,76% (95% CI 0,44-1,24) for RA and 0,62% (95% CI 0,33-1,06) for SpA. The standardized prevalence rate according to age and sex in the Vilnius population showed an RA prevalence of 0,51% (95% CI 0,29-0,96) and a SpA prevalence of – 0,75% (95% CI 0,38-1,40). / Darbo tikslas: nustatyti reumatoidinio artrito (RA), seronegatyvių spondiloartropatijų (SpA) bei sisteminės raudonosios vilkligės (SRV) paplitimą Vilniaus mieste. Darbo metodika: Buvo atlikti 3 tyrimai: 1. RA ir SRV paplitimo Vilniaus mieste apskaičiavimas, remiantis Vilniaus miesto RA ir SRV sergančių asmenų duomenų baze; 2. RA ir SRV paplitimo Vilniaus mieste populiacinis tyrimas, apklausiant Vilniaus miesto gyventojus paštu; 3. RA ir SpA paplitimo Vilniaus mieste populiacinis tyrimas, apklausiant Vilniaus miesto gyventojus telefonu. Rezultatai: remiantis Vilniaus miesto RA ir SRV sergančiųjų duomenų baze, RA paplitimas Vilniaus mieste 2004m. pabaigoje buvo 0,14% (95% PI 0,13-0,15). Apskaičiuotas SRV paplitimas Vilniuje 2004m. pabaigoje buvo 0,0174% arba 17,4/100 000 gyventojų (95% PI 0,0137-0,0218). Atlikus RA ir SRV paplitimo tyrimą (apklausą paštu), nustatyta, kad RA paplitimas Vilniuje yra 0,37% (95% PI 0,21-0,62), o SRV paplitimas – 0,0498% (95% PI 0,006-0,180). RA paplitimas buvo standartizuotas pagal amžių ir lytį, remiantis 2004m. pradžios Vilniaus miesto populiacija, apskaičiuotas standartizuotas RA paplitimas yra 0,32% (95% PI 0,18-0,57). Atlikus RA ir SpA paplitimo tyrimą (apklausą telefonu), apskaičiuotas RA paplitimas buvo 0,76% (95% PI 0,44-1,24), o SpA paplitimas - 0,62% (95% PI 0,33-1,06). RA ir SpA paplitimas buvo standartizuotas pagal amžių ir lytį, remiantis 2004m. pradžios Lietuvos populiacija, apskaičiuotas standartizuotas RA paplitimas yra 0,51% (95%... [toliau žr. visą tekstą]

Darbo tikslas: nustatyti reumatoidinio artrito (RA), seronegatyvių spondiloartropatijų (SpA) bei sisteminės raudonosios vilkligės (SRV) paplitimą Vilniaus mieste. Darbo metodika: Buvo atlikti 3 tyrimai: 1. RA ir SRV paplitimo Vilniaus mieste apskaičiavimas, remiantis Vilniaus miesto RA ir SRV sergančių asmenų duomenų baze; 2. RA ir SRV paplitimo Vilniaus mieste populiacinis tyrimas, apklausiant Vilniaus miesto gyventojus paštu; 3. RA ir SpA paplitimo Vilniaus mieste populiacinis tyrimas, apklausiant Vilniaus miesto gyventojus telefonu. Rezultatai: remiantis Vilniaus miesto RA ir SRV sergančiųjų duomenų baze, RA paplitimas Vilniaus mieste 2004m. pabaigoje buvo 0,14% (95% PI 0,13-0,15). Apskaičiuotas SRV paplitimas Vilniuje 2004m. pabaigoje buvo 0,0174% arba 17,4/100 000 gyventojų (95% PI 0,0137-0,0218). Atlikus RA ir SRV paplitimo tyrimą (apklausą paštu), nustatyta, kad RA paplitimas Vilniuje yra 0,37% (95% PI 0,21-0,62), o SRV paplitimas – 0,0498% (95% PI 0,006-0,180). RA paplitimas buvo standartizuotas pagal amžių ir lytį, remiantis 2004m. pradžios Vilniaus miesto populiacija, apskaičiuotas standartizuotas RA paplitimas yra 0,32% (95% PI 0,18-0,57). Atlikus RA ir SpA paplitimo tyrimą (apklausą telefonu), apskaičiuotas RA paplitimas buvo 0,76% (95% PI 0,44-1,24), o SpA paplitimas - 0,62% (95% PI 0,33-1,06). RA ir SpA paplitimas buvo standartizuotas pagal amžių ir lytį, remiantis 2004m. pradžios Lietuvos populiacija, apskaičiuotas standartizuotas RA paplitimas yra 0,51% (95%... [toliau žr. visą tekstą] / Objective: to assess the prevalence of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and spondyloarthropathy (SpA) in Vilnius, Lithuania. Methods: 3 prevalence studies were conducted: 1. Registry-based study of the prevalence of RA and SLE; 2. Population-based study of the prevalence of RA and SLE (interview conducted by mail); 3. Poulation-based study of the prevalence of RA and SpA (interview conducted by telephone). Results: according to the Vilnius RA and SLE registry, the prevalence of RA in Vilnius at the end of year 2004 was 0,14% (95% CI 0,13-0,15), and the prevalence of SLE was 0,0174% or 17,4/100 000 (95% CI 0,0137-0,0218). The population-based study, conducted by mail, revealed 15 RA and 2 SLE cases, accounting for a prevalence rate of RA of 0,37% (95% CI 0,21-0,62), and a prevalence of SLE rate of 0,0498% (95% CI 0,006-0,180). The standardized prevalence rate according to age and sex in the Vilnius population showed an RA prevalence of 0,32% (95% CI 0,18-0,57). The population-based study, conducted be telephone, detected 16 RA and 13 SpA cases, resulting in a crude prevalence of 0,76% (95% CI 0,44-1,24) for RA and 0,62% (95% CI 0,33-1,06) for SpA. The standardized prevalence rate according to age and sex in the Vilnius population showed an RA prevalence of 0,51% (95% CI 0,29-0,96) and a SpA prevalence of – 0,75% (95% CI 0,38-1,40).

Disertacija skirta nustatyti sergančiųjų spondiloartropatijomis (SpA) (AS, ReA, PsA, EnA) KMT pokyčių dėsningumus stuburo juosmeninėje ir šlaunikaulių proksimalinėse dalyse bei įvertinti ryšį tarp kaulų masės pokyčių ir ligos specifinių veiksnių (ligos trukmės, fizinės negalios ir judėjimo funkcijos sumažėjimo, vartojamų medikamentų, ligos aktyvumo). Darbe nustatyta, kad sergančiųjų SpA KMT nesiskiria nuo sergančiųjų reumatoidiniu artritu, ir yra reikšmingai mažesnis lyginant su sveikų asmenų KMT ir stuburo juosmeninėje, ir šlaunikaulių proksimalinėse dalyse. Panašūs KMT pokyčiai stuburo juosmeninėje ir šlaunikaulių proksimalinėse dalyse būdingi SpA pacientams, sergantiems įvairiomis SpA grupės ligomis, bei nepriklauso nuo vyraujančio sąnarių pažeidimo tipo. KMT pokyčius geriau atspindi ligos trukmė, skaičiuojant ją ne nuo klinikinės diagnozės nustatymo momento, o nuo pirmųjų ligos simptomų pasireiškimo. Ligos trukmei ilgėjant – šlaunikaulių KMT mažėja, o stubure – didėja. Vidutinis ir didelis ligos aktyvumas, kurį nustatė gydytojas reumatologas, turi įtakos stuburo juosmeninės ir šlaunikaulių proksimalinių dalių KMT sumažėjimui. KMT mažėjimas ir stuburo juosmeninėje, ir šlaunikaulių proksimalinėse dalyse susijęs su SpA sergančiojo judėjimo funkcijos sumažėjimu. Šį ryšį tiksliausiai atspindi tarpkulkšnelinio atstumo matmuo – šlaunikaulių proksimalinių dalių KMT rodmenys mažiausi, kai stuburo paslankumas įvertintas sunkiu sumažėjimo lygiu. Gliukokortikoidų kumuliacinė dozė... [toliau žr. visą tekstą] / The aim of this work was to determine consistent patterns of BMD changes at the lumbar spine and the upper part of the left and right femur in patients with SpA (AS, ReA, PsA, EnA) and to assess relation between changes of bone mass and specific factors of the disease (duration of the disease, physical disability and immobility, activity of the disease, medications in use). It was established that in patients with SpA BMD is the same as in patients with rheumatoid arthritis and is significantly lower in comparison with BMD of healthy subjects measured at the lumbar spine and upper part of the left and right femur. Similar BMD changes at the lumbar spine and upper part of the left and right femur are characteristic of SpA patients with various diseases belonging to SpA group and do not depend on the predominant type of joint lesion. The duration of the disease reflects changes in BMD better when it is calculated not from the time of the establishment of clinical diagnosis, but from the time of onset of first clinical symptoms. BMD decrease at the upper part of the left and right femur and increase at the spine with the increase of the duration of disease. Moderate and high activity of the disease established by rheumatologist contribute to BMD loss at the lumbar spine and upper parts of the both femurs. BMD reduction at the lumbar spine and the upper part of the left and right femur is associated with the decrease of mmobility of SpA patients. Intermalleolar distance is the... [to full text]

Disertacija skirta nustatyti sergančiųjų spondiloartropatijomis (SpA) (AS, ReA, PsA, EnA) KMT pokyčių dėsningumus stuburo juosmeninėje ir šlaunikaulių proksimalinėse dalyse bei įvertinti ryšį tarp kaulų masės pokyčių ir ligos specifinių veiksnių (ligos trukmės, fizinės negalios ir judėjimo funkcijos sumažėjimo, vartojamų medikamentų, ligos aktyvumo). Darbe nustatyta, kad sergančiųjų SpA KMT nesiskiria nuo sergančiųjų reumatoidiniu artritu, ir yra reikšmingai mažesnis lyginant su sveikų asmenų KMT ir stuburo juosmeninėje, ir šlaunikaulių proksimalinėse dalyse. Panašūs KMT pokyčiai stuburo juosmeninėje ir šlaunikaulių proksimalinėse dalyse būdingi SpA pacientams, sergantiems įvairiomis SpA grupės ligomis, bei nepriklauso nuo vyraujančio sąnarių pažeidimo tipo. KMT pokyčius geriau atspindi ligos trukmė, skaičiuojant ją ne nuo klinikinės diagnozės nustatymo momento, o nuo pirmųjų ligos simptomų pasireiškimo. Ligos trukmei ilgėjant – šlaunikaulių KMT mažėja, o stubure – didėja. Vidutinis ir didelis ligos aktyvumas, kurį nustatė gydytojas reumatologas, turi įtakos stuburo juosmeninės ir šlaunikaulių proksimalinių dalių KMT sumažėjimui. KMT mažėjimas ir stuburo juosmeninėje, ir šlaunikaulių proksimalinėse dalyse susijęs su SpA sergančiojo judėjimo funkcijos sumažėjimu. Šį ryšį tiksliausiai atspindi tarpkulkšnelinio atstumo matmuo – šlaunikaulių proksimalinių dalių KMT rodmenys mažiausi, kai stuburo paslankumas įvertintas sunkiu sumažėjimo lygiu. Gliukokortikoidų kumuliacinė dozė... [toliau žr. visą tekstą] / The aim of this work was to determine consistent patterns of BMD changes at the lumbar spine and the upper part of the left and right femur in patients with SpA (AS, ReA, PsA, EnA) and to assess relation between changes of bone mass and specific factors of the disease (duration of the disease, physical disability and immobility, activity of the disease, medications in use). It was established that in patients with SpA BMD is the same as in patients with rheumatoid arthritis and is significantly lower in comparison with BMD of healthy subjects measured at the lumbar spine and upper part of the left and right femur. Similar BMD changes at the lumbar spine and upper part of the left and right femur are characteristic of SpA patients with various diseases belonging to SpA group and do not depend on the predominant type of joint lesion. The duration of the disease reflects changes in BMD better when it is calculated not from the time of the establishment of clinical diagnosis, but from the time of onset of first clinical symptoms. BMD decrease at the upper part of the left and right femur and increase at the spine with the increase of the duration of disease. Moderate and high activity of the disease established by rheumatologist contribute to BMD loss at the lumbar spine and upper parts of the both femurs. BMD reduction at the lumbar spine and the upper part of the left and right femur is associated with the decrease of mmobility of SpA patients. Intermalleolar distance is the... [to full text]

Class of 2012 / Specific Aims: To evaluate the presence of statistical information from clinical studies in official product labeling specific for disease-modifying anti-rheumatic drugs (DMARDs) used in the treatment of rheumatoid arthritis. Methods: Data were abstracted from official product labeling DMARDs with FDA approval for treatment of rheumatoid arthritis. Each document was examined for the presence of statement regarding a priori type 1 error rate, p-values, and measures of variance. Medications were classified as either biologic or non-biologic. Main Results: A total of 14 DMARDs, 7 biologics (50%) and 7 non-biologics (50%), were found to be FDA approved for the treatment of rheumatoid arthritis. Primary outcomes consisted of American College of Rheumatology (ACR) response rates, radiographic changes, and health assessment questionnaire score (HAQ). Any measure of variance and the presence of a p-value were both found in six (43%) of the drug labels. Inclusion of p- values was found to be significantly greater in biologics compared to non-biologics for both ACR and radiographic results. Inclusion of variance was found to be significantly greater in biologics compared to non-biologics for radiographic changes only. No package inserts contained statements regarding the a priori type I error rate. Conclusions: Measures of variance are not frequently included in product labeling for either biologic or non-biologic DMARDs. However, inclusion of variance and p-values for ACR response rates and radiographic changes were more likely to be reported for biologics therapies as compared to non-biologics. A statement regarding Type 1 error rates were absent from labels regardless of outcome assessed.

Immune-mediated inflammatory diseases (IMID) represent a group of ostensibly unrelated, chronic and highly disabling diseases that preferentially affect different organ systems. IMID are assumed to manifest as a result of the accumulation of genetic, environmental and immunological factors. A fundamental commonality between IMID is the idiopathic nature of disease, and moreover, substantial similarities are apparent in disease etiopathogenesis. The complex assemblage of microbes and their genes that exists within and on the human body, collectively known as the microbiome has emerged as a critical factor in human health and, altered microbial populations within the gastrointestinal tract lumen and mucosa have been linked to several IMID. Accordingly, we conducted several studies investigating the association of the gut microbiome with IMID. Our main study investigated differences in the microbial profile and functional potential of multiple IMID utilizing 16S rDNA amplicon sequencing and analysis of stool. We also investigated the mucosal-associated microbiome in IBD to characterize the microbial populations and their functions residing in distinct gastrointestinal compartments from inflamed and noninflamed mucosa. We also explored a potential environmental factor; specifically assessing whether microbes present in drinking water in low or high incidence areas of IBD might contribute to disease etiology. The findings of these studies are manifold. First, we show important differences of the stool microbial profile in IMID. In doing so, we were able to identify distinct states of gut dysbiosis and have revealed numerous microbes that are consistently or uniquely disproportionate between IMID. Second, we have shown the microbial profile associated with inflamed and noninflamed mucosa and have reported that a localized dysbiosis is not observed in the presence of inflammation. Third, we have revealed that distinct gastrointestinal compartments are comprised of similar microbial communities. Lastly, we have reported the drinking water microbiome to differ between low and high incidence areas of IBD, thus suggesting a potential role in IBD etiology. Understanding the role of the gut microbiome in human disease will enable the development and application of more appropriate therapeutic strategies that specifically target microbes within the gut. / May 2017

La polyarthrite rhumatoïde (PR) est une maladie auto-immune qui mène à une inflammation chronique et à une destruction progressive des articulations. Les effecteurs principaux de cette pathologie sont les synoviocytes de type fibroblastique (FLS). Ces derniers utilisent les invadosomes, des structures riches en actine et en métalloprotéases, afin de dégrader la matrice extracellulaire (ECM). Ce phénotype pro-destructif résulte d’une activation des FLS par différents facteurs de croissance, dont le PDGF et le TGF-β. Les récepteurs à activité tyrosine kinase, dont le PDGFR, sont impliqués dans la pathogenèse de plusieurs maladies, incluant le cancer et la PR. Une activation de ces récepteurs peut mener, entre autres, à la survie, à la différenciation et à la prolifération des cellules. L’étude présentée dans ce mémoire montre que parmi les RTK les plus communs, le PDGFR est spécifiquement phosphorylé chez les cellules synoviales de patients atteints de PR, contrairement aux cellules de patients non arthritiques ou atteints d’arthrose. De plus, l’activation du PDGFR résulte en une augmentation de la formation d’invadosomes par les FLS. Nous avons aussi démontré que la formation d’invadosomes par le PDGFR nécessite l’activation de la voie de signalisation PI3K/Akt faisant intervenir les isoformes α et δ de la PI3K. De plus, l'inhibition de l’activation du PDGFR ou la neutralisation du PDGF endogène inhibe la formation des invadosomes et la dégradation de l'ECM par les synoviocytes, ce qui suggère la présence d'une boucle d'activation autocrine impliquant le PDGF. Parmi les isoformes du PDGF, nous avons démontré que le PDGF-B est exprimé de façon significativement plus élevée dans les synoviocytes provenant de patients atteints de PR. Nos données indiquent également une association entre le PDGF et le TGF-β dans la formation des invadosomes. Cette dernière implique la production autocrine de ligands du PDGFR induite par le TGFβ via la signalisation TβR1/Smad et PI3K/Akt. L’inhibition des isoformes de PI3K de classe I indique que le PI3Kα est impliquée de façon sélective dans l'expression de PDGF-B. Ces résultats démontrent que le PDGFR est un RTK nécessaire au phénotype destructeur des cellules synoviales d’arthrite. Ils fournissent aussi des preuves d'une association entre le TGF-β et le PDGFR dans la formation d’invadosomes chez les synoviocytes de patients atteints de la PR. / Abstract : Rheumatoid arthritis (RA) is an autoimmune disease that leads to chronic inflammation and progressive joint destruction. The main effectors of this pathology are fibroblast-like synoviocytes (FLS). They use invadosomes, actin-rich structures that concentrate metalloproteinases to degrade the extracellular matrix (ECM). This pro-destructive phenotype is due to the activation of FLS by various growth factors, including PDGF and TGF-β. Receptor tyrosine kinases, including PDGFR, are involved in the pathogenesis of several diseases, including cancer and RA. Activation of these receptors may lead to cell survival, differentiation and proliferation. The study presented in this thesis shows that among the most common RTKs, PDGFR is specifically phosphorylated in synovial cells of RA patients, unlike cells of non-arthritic or osteoarthritic patients. In addition, activation of PDGFR results in an increase in invadosome formation by FLS. We also shown that formation of invadosome by PDGFR requires the activation of the signaling pathway PI3K/Akt, that specifically involves the α and δ isoforms of PI3K. In addition, inhibition of PDGFR activation or neutralization of endogenous PDGF inhibits the formation of invadosomes and the degradation of the ECM by synoviocytes, suggesting the presence of an autocrine activation loop involving PDGF. Among the PDGF isoforms, we demonstrate that PDGF-B expression is significantly higher in synoviocyte cell lines from RA patients. Our data also indicates an association between PDGF and TGF-β for invadosome formation that involves autocrine production of PDGF-B induced by TGF-β through the Smad/T β R1 and PI3K/Akt pathways. Inhibition of class I PI3K isoforms indicates that PI3K α is selectively involved in the expression of PDGF-B. These results demonstrate that PDGFR is an RTK necessary for the pro-destructive phenotype of RAFLS. They also provide evidence of an association between TGF-β and PDGFR in invadosome formation by synovial cells from RA patients.

N-linked glycosylation is the most common post-translational modification (PTM) of proteins that exist in nature. N-glycosylation and change in cells serve as a criterion to monitor the activity of developmental stages and diseases severity. Currently, there is an increasing application of mass spectrometry on glycoprotein for malicious, chronic or acute diseases, such as cancers, rheumatoid arthritis (RA) or influenza. In this dissertation, several mass spectrometric assays have been utilized to, quantitatively and qualitatively, characterize protein N-glycosylation at the glycan, glycopeptide and peptide levels. The goals are to identify serum-based RA biomarker (Chapter 2), or to determine possible glycan structures from monoclonal antibody (Chapter 3), or comprehensively to study one influenza glycoprotein, hemagglutinin (Chapter 4). In Chapter 2, LC-MS/MS with CID as MS 2 is the primary technique that is applied to collect raw data for RA biomarker screening; western blot is the verification method for newfound biomarkers. This mass spectrometry based comparative analysis of N-glycoprotein in RA and healthy patients’ sera reveal 41 potential biomarkers for RA that can be applied in clinical research. Chapter 3 describes another LC-MS/MS based method developed for the structural analysis of N-glycan released from the monoclonal antibody, immunoglobin G. Higher-energy collision dissociation (HCD) was the surprior technique utilized to identify glycopeptide fragments. The results show that 19 and 23 N-glycan structures were determined from standard and modified mAb samples respectively by using SimGlycan software, while 38 and 35 glycan structures were recognized by manually mapping respectively. 13 N-glycoforms, out of 26 overlapped glycan structures, were identified with significant alterations by comparing standard sample (sample A) and modified mAb (sample B) utilizing our method. In Chapter 4, we comprehensively studied hemagglutinin by using LC-MS/MS and MALDI from both proteomic perspective and glycomics prospective. After confirmed and verified protein sequence and glycosylation sites, galactose-specific quantitation was performed with exoglycosidase digestion combined HPLC with fluorescence detection. The MALDI-MS/MS based method was utilized to confirm glycan structures. The results in this dissertation provide insights into the significance of protein glycosylation alterations as RA biomarkers, and these quantitative methods can be reapplied to any other disease biomarkers screening for clinical researchers.

Dans la prise en charge de la polyarthrite rhumatoïde (PR), l’identification de biomarqueurs associés à un diagnostic, un pronostic mais surtout à une bonne réponse thérapeutique est un des enjeux de la prochaine décennie, d’autant que de nombreux outils sont maintenant disponibles grâce à l’étude du génome, du transcriptome et du protéome. Au cours de mon travail de thèse, je me suis intéressée à l’identification de différentes classes de biomarqueurs prédictifs de la réponse au traitement par biothérapies.Tout d’abord par une approche protéomique, j’ai identifié une combinaison de biomarqueurs protéiques sériques, MCP-1 et EGF, permettant à l’initiation du traitement par étanercept (anti-TNFα), puis par rituximab (anti-CD20), de prédire la réponse clinique à 3 mois. En parallèle, toujours chez des patients PR traités par rituximab, j’ai recherché un biomarqueur cellulaire par cytométrie de flux. J’ai ainsi pu montrer que la densité de CCR5 à la surface des lymphocytes T CD4+ circulants est faible chez les patients PR . Celle-ci est corrélée positivement à l’activité de la maladie et négativement au taux intracellulaire d’ARNm de CCR5. Trois mois après l’initiation du traitement, la densité de CCR5 à la surface des lymphocytes T CD4+ circulants augmente proportionnellement à la diminution de l’activité de la maladie. J’ai également étudié l’intérêt de biomarqueurs génétiques. Tout d’abord, en analysant le profil d’expression de 723 micro(mi)ARNs dans le sang de patients PR, j’ai montré que l’expression de 37 miARNs était dérégulée par rapport à des donneurs sains. Par ailleurs, j’ai montré que le niveau d’expression de miR-125b dans le sang des patients PR à l’initiation du traitement par rituximab permet de prédire la réponse à 3 mois. J’ai enfin exploré les polymorphismes de gènes de cytokines et de récepteurs aux cytokines afin de prédire la réponse au traitement par rituximab à 6 mois chez 63 patients atteints de PR active. Douze polymorphismes de nucléotides uniques (SNPs) ont été génotypés et ont permis d’identifier 2 SNPs du facteur de croissance transformant beta 1 (TGFb1) codon 25 et codon 10 prédictifs d’une bonne réponse au rituximab.Je me suis aussi intéressée à la thérapie génique qui est un outil thérapeutique pour délivrer des agents anti-TNF dans la PR. En effet le transfert de gène permet à l’organisme de synthétiser in situ la protéine médicament et d’éviter des administrations répétées comme c’est le cas avec les biothérapies. Le défi de demain réside plus dans le développement de vecteurs fiables et efficients. Dans un premier travail réalisé dans l’équipe de recherche du Pr Hirsch à Pittsburgh (E.U), j’ai évalué in vitro l’intérêt d’un virus adéno-associé recombinant de sérotype 2 (rAAV2) contenant un ARN double brin pour le transfert de gène dans les synoviocytes humains. Dans un contexte inflammatoire, celui-ci s’est révélé efficace lorsqu’associé à un inhibiteur du protéasome, le zLLL. Lors d’un deuxième stage effectué au sein du laboratoire du Pr Jorgensen (Montpellier), j’ai évalué le potentiel thérapeutique d’un rAAV de sérotype 5 (rAAV5) exprimant un petit ARN interférant ciblant le TNF-α dans un modèle expérimental d’arthrite. L’inhibition du TNF-α a été validée in vitro sur des macrophages murins, puis in vivo dans le modèle murin d’arthrite au collagène, après injection dans les articulations arthritiques. Depuis la fin des années 90, l’avènement des biothérapies a permis de bouleverser l’évolution de la PR. Les biomarqueurs, en particulier ceux permettant le suivi des traitements, sont des outils de choix à développer pour notre pratique clinique courante afin de choisir d’emblée le traitement le plus efficace et le mieux toléré pour chaque patient. D’autres thérapies innovantes, telles que la thérapie génique, s’appuient sur les succès des biothérapies pour permettre d’autres avancées en choisissant d’emblée les cibles les plus pertinentes. / Rheumatoid arthritis (RA) is a chronic inflammatory disease. The effective use of biologics, which block key molecules involved in the pathogenesis of RA, has dramatically improved the treatment of this chronic disease over recent years. However, for at least one-third of patients with RA biologic treatments will produce an inadequate response. Therefore, the use of predictive biomarkers of response to identify individuals who are likely to respond to specific treatments will provide benefit. An individualised approach will allow patients to receive effective treatment without unnecessary exposure to potentially toxic side effects.During my thesis, I identified predictive biomarkers in RA patients treated with biologics by using proteomics, genetics and cellular biomarkers.Genen therapy could be used to optimise drug administration by avoiding repetitive administration. I validated the interest of a recombinant adeno-associated virus in RA synovial fibroblasts.