La polyarthrite rhumatoïde (PR) est une maladie auto-immune (MAI) dans laquelle des anticorps anti-peptides citrullinés (ACPA) sont un outil diagnostique très spécifique. L’un des traitements clé de la PR est le méthotrexate (MTX). En plus de son action directe sur la maladie il renforce l’effet des anti-TNF alpha (aTNF). Ceci pourrait passer par une prévention de la formation d’anticorps anti-médicaments dirigés contre les aTNF ce qui leur fait perdre leur efficacité.Nous avons développé un modèle macaque pour reproduire la maladie humaine par immunisation avec des peptides citrullinés dans le contexte d’un facteur génétique favorisant la PR : l’épitope HLA partagé. L’immunisation de macaques avec divers peptides citrullinés en utilisant un boost intra-articulaire a déclenché une réponse T et B anti-citrulline et a entraîné une mono-arthrite chronique.Le rôle du MTX sur l’immunogénicité des aTNF a été étudié sur un modèle de souris autoimmunes, les souris BAFF transgéniques (tg) qui présentent une MAI. L’utilisation du MTX juste avant l’injection d’aTNF a permis de prévenir l’immunisation contre ce médicament uniquement chez ces souris BAFFtg et pas chez des souris sauvages ou chez des macaques. Nous avons démontré que ces souris BAFFtg surexprimaient CD73, ce qui permettait une sécrétion accrue d’adénosine et de cellules B régulatrices sous l’effet du MTX. L’interaction entre BAFF et le méthotrexate a été confirmée chez l’homme dans la cohorte ABIRISK : le MTX prévient plus efficacement l’immunogénicité chez les patients avec des taux de BAFF élevés.En conclusion, nous avons mis au point deux nouveaux modèles animaux permettant de mieux comprendre la physiopathologie de la PR et d’optimiser l’utilisation des traitements biologiques qui s’étend dans tous les domaines de la médecine. / Title : Development of new animal models to study the pathophysiology of RA and the role of methotrexate-induced tolerance.Keywords : Rheumatoid arthritis, shared epitope, ACPA, immunogenicity, methotrexate, TNF inhibitorsAbstract: Rheumatoid arthritis (RA) is an autoimmune disease (AID) where antibodies directed against citrullinated peptides (ACPA) are highly specific for the diagnosis. One of the key treatments of RA is methotrexate. It has an action on both the disease and reinforces the effect of second line TNF inhibitors (TNFi). MTX might act via prevention of anti-drug antibodies (ADAb) directed against TNFi that are implicated in loss of efficacy of TNFi. We have developed a macaque model to recapitulate the human disease by immunization with citrullinated peptides in the context of a genetic factor favoring RA: the shared epitope on the HLA. Immunization of macaques with citrullinated peptides and intra-articular boost cause an anti-citrulline T and B cell response and a chronic monoarthritis.The role of MTX-induced tolerance against TNFI has been studied in autoimmune BAFF transgenic (tg) mice using MTX just before treatment with TNFi we were able to prevent ADAb formation in BAFFtg mice and not wild type mice or macaques. We identified that BAFFtg mice expressed elevated CD73 leading to more adenosine and regulatory B cells as actors in MTX-induced tolerance. This MTX-BAFF interaction was further confirmed in humans in the ABIRISK cohort where MTX was more efficient to prevent ADAb formation in RA patients with elevated BAFF levels.Setting up two new animal models allows better understanding of RA pathophysiology and better use of biologics that extend to other domains of medicine.

Background: MicroRNAs (miRNAs) are small non-coding single-stranded RNAs involved in the posttranscriptional inhibition of gene expression and thereby regulating all cellular functions. Their dysregulation contributes to the pathophysiology of many diseases, including rheumatic diseases. MiRNAs can also be found extracellularly in body fluids and represent promising diagnostic and prognostic biomarkers. Our study aimed to investigate miRNAs as biomarkers of stage and activity and predictors of therapeutic response of two most common inflammatory rheumatic diseases: spondyloarthritis (SpA) and rheumatic arthritis (RA). Results: We found several circulating miRNAs differentially expressed in SpA patients reflecting the severity of axial involvement and/or disease activity. The decrease in circulating miR-145 in plasma of patients with ankylosing spondylitis 3 months of anti-TNF therapy predicted a good therapeutic response and low disease activity after a year of therapy. Circulating and intracellular expression of miR-125b in peripheral blood mononuclear cells (PBMC) was lower in treatment-naïve patients with early RA than in healthy controls. Baseline expression of miR-125 in PBMC predicted a (non)adequate therapeutic response. We also found the increased expression of miR-451 in PBMC in...

Background: Osteoblasts participating in the inflammation regulation gradually obtain concerns. However, its role in joint inflammation of rheumatoid arthritis (RA) is largely unknown. Here, we investigated the role of osteoblastic pleckstrin homology domain-containing family O member 1 (PLEKHO1), a negative regulator of osteogenic lineage activity, in regulating joint inflammation in RA. Methods: The level of osteoblastic PLEKHO1 in RA patients and collagen-induced arthritis (CIA) mice was examined. The role of osteoblastic PLEKHO1 in joint inflammation was evaluated by a CIA mice model which was induced in osteoblast-specific Plekho1 conditional knockout mice and mice expressing high Plekho1 exclusively in osteoblasts, respectively. The effect of osteoblastic PLEKHO1 inhibition was explored in a CIA mice model. The mechanism of osteoblastic PLEKHO1 in regulating joint inflammation was performed by a series of in vitro studies. Results: PLEKHO1 was highly expressed in osteoblasts from RA patients and CIA mice. Osteoblastic Plekho1 deletion ameliorated joint inflammation, whereas overexpressing Plekho1 only within osteoblasts exacerbated local inflammation in CIA mice. PLEKHO1 was required for TNF receptor-associated factor 2 (TRAF2)-mediated the ubiquitination of receptor-interacting serine/threonine-protein kinase 1 (RIP1) to activate nuclear factor kappa-light-chain-enhancer of activated B (NF-kB) pathway for inducing inflammatory cytokines production in osteoblasts. Moreover, osteoblastic PLEKHO1 inhibition improved joint inflammation and attenuated bone formation reduction in CIA mice. Conclusions: These data strongly suggest that highly expressed PLEKHO1 in osteoblasts mediates joint inflammation in RA. Targeting osteoblastic PLEKHO1 may exert dual therapeutic action of alleviating joint inflammation and promoting bone repair in RA.

The findings of association between alcohol consumption and arthritis are mixed while little is known about age differences in the associations of mental health and behavioral factors with arthritis. This study aimed to estimate the prevalence and associated factors of arthritis among US adults using data from the 2012 National Health Interview Survey. In total, 8,229 adults with arthritis and 26,256 controls were selected from the adult respondents. Weighted univariate and multiple logistic regression analyses were used to estimate the odds ratios (ORs) with 95 % confidence intervals. The overall prevalence of arthritis was 22.1 %. The prevalence increased with age (6.8, 29.6, and 47.9 % for 18-49, 50-64, and 65+ years of age, respectively). The prevalence of mental problems was higher in cases than controls [4 vs. 1 % for serious psychological distress (SPD), 29 vs. 16 % for anxiety, and 26 vs. 11 % for depression, respectively]. Multiple logistic regression analyses showed that being female, older age, smoking, alcohol consumption, obesity, SPD, depression, and anxiety were positively associated with arthritis. Stratified by age, SPD was associated with arthritis only in young adults (18-49 years old) while the ORs of anxiety and depression with arthritis decreased as age increased. Alcohol consumption revealed stronger associations in middle-aged adults and elderly. Using a large nationally representative sample in the USA, alcohol consumption, smoking, SPD, anxiety, and depression were associated with arthritis, and the associations varied across different age groups.

Calcitonin is a hormone secreted by the C-cells of the thyroid gland in response to elevations of the plasma calcium level. It reduces bone resorption by inhibiting mature active osteoclasts and increases renal calcium excretion. It is used in the management of postmenopausal osteoporosis, Paget's disease of bone, and malignancy-associated hypercalcemia. Synthetic and recombinant calcitonin preparations are available; both have similar pharmacokinetic and pharmacodynamic profiles. As calcitonin is a peptide, the traditional method of administration has been parenteral or intranasal. This hinders its clinical use: adherence with therapy is notoriously low, and withdrawal from clinical trials has been problematic. An oral formulation would be more attractive, practical, and convenient to patients. In addition to its effect on active osteoclasts and renal tubules, calcitonin has an analgesic action, possibly mediated through β-endorphins and the central modulation of pain perception. It also exerts a protective action on cartilage and may be useful in the management of osteoarthritis and possibly rheumatoid arthritis. Oral formulations of calcitonin have been developed using different techniques. The most studied involves drug-delivery carriers such as Eligen® 8-(N-2hydroxy-5-chloro-benzoyl)-amino-caprylic acid (5-CNAC) (Emisphere Technologies, Cedar Knolls, NJ). Several factors affect the bioavailability and efficacy of orally administered calcitonin, including amount of water used to take the tablet, time of day the tablet is taken, and proximity to intake of a meal. Preliminary results looked promising. Unfortunately, in two Phase III studies, oral calcitonin (0.8 mg with 200 mg 5-CNAC, once a day for postmenopausal osteoporosis and twice a day for osteoarthritis) failed to meet key end points, and in December 2011, Novartis Pharma AG announced that it would not pursue further clinical development of oral calcitonin for postmenopausal osteoporosis or osteoarthritis. A unique feature of calcitonin is that it is able to uncouple bone turnover, reducing bone resorption without affecting bone formation and therefore increasing bone mass and improving bone quality. This effect, however, may be dose-dependent, with higher doses inhibiting both resorption and formation. Because so many factors affect the pharmacokinetics and pharmacodynamics of calcitonin, especially orally administered calcitonin, much work remains to be done to explore the full pharmacologic spectrum and potential of calcitonin and determine the optimum dose and timing of administration, as well as water and food intake.

No description available.

Background: Juvenile Idiopathic Arthritis (JIA) is a heterogeneous disease with unknown etiology of arthritis for more than six weeks in patients aged under 16 years. Human Cytomegalovirus (HCMV) is a lymphotropic betaherpesvirus that persists in the human body and causes ongoing stimulation of the effector T-cell system. For both, JIA and HCMV, a premature immunosenescence is shown. Aim: To investigate the potential influence of HCMV on the prematurely altered immune system of JIA patients. Methods: T-cell phenotype, intracellular cytokine production and the expression of chemokine receptors were measured by flow cytometry (FACS). HCMV serostatus was measured by enzyme-linked immunosorbent assay (ELISA). Phenotype and cytokine production of lymphocytes derived from JIA patients and healthy donors were compared regarding their HCMV serostatus. Results: Both JIA patients and healthy donors showed an association between HCMV seropositivity and immunosenescence resulting in low proportions of naive T-cells and relatively higher proportions of differentiated T-cells. Within the JIA patients HCMV seropositivity was associated with higher intracellular IFNγ production. T-cells in JIA patients showed a higher CCR5 expression in association with HCMV seropositivity. This association was not seen in healthy donors. Conclusion: The T-cell phenotype was similarly associated with HCMV in JIA patients and healthy donors. In contrast, JIA patients showed evidence of TH1 predominance in association with HCMV seropositivity. Regarding CCR5 this effect is significantly stronger in JIA patients than in healthy donors. The present study suggests that HCMV associated changes of the T-cell differentiation may be corroborated in JIA patients. / Hintergrund: Die Juvenile Idiopathische Arthritis (JIA) ist eine heterogene Erkrankung mit unbekannter Ätiologie der Arthritis bei Patientinnen und Patienten unter 16 Jahren für mehr als sechs Wochen. Das Humane Zytomegalievirus (HCMV) ist ein lymphotropes Betaherpesvirus, das im menschlichen Körper persistiert und eine anhaltende Stimulation des Effektor-T-Zell-Systems bewirkt. Sowohl für JIA als auch für HCMV zeigt sich eine vorzeitige Immunoseneszenz. Ziel: Untersuchung des potenziellen Einflusses von HCMV auf das vorzeitig gealterte Immunsystem von JIA-Patientinnen und Patienten. Methoden: T-Zell-Phänotyp, intrazelluläre Zytokinproduktion und die Expression von Chemokinrezeptoren wurden mittels Durchflusszytometrie (FACS) gemessen. Der HCMV-Serostatus wurde mittels Enzyme-Linked Immunosorbent Assay (ELISA) gemessen. Phänotyp und Zytokinproduktion von Lymphozyten von JIA-Patientinnen und Patienten und Gesundkontrollen wurden hinsichtlich ihres HCMV-Serostatus verglichen. Ergebnisse: Sowohl JIA-Patientinnen und Patienten als auch Gesundkontrollen zeigten einen Zusammenhang zwischen HCMV-Seropositivität und Immunseneszenz, nämlich geringere Anteile naiver T-Zellen und relativ höhere Anteile an differenzierten T-Zellen. Bei den JIA-Patientinnen und Patienten war die HCMV-Seropositivität mit einer höheren intrazellulären IFNγ-Produktion verbunden. T-Zellen bei JIA-Patientinnen und Patienten zeigten eine höhere CCR5-Expression in Verbindung mit HCMV-Seropositivität. Diese Assoziation wurde bei Gesundkontrollen nicht beobachtet. Schlussfolgerung: Der T-Zell-Phänotyp war bei JIA-Patientinnen und Patienten und Gesundkontrollen ähnlich mit HCMV assoziiert. Im Gegensatz dazu zeigten JIA-Patientinnen und Patienten Hinweise auf eine TH1-Dominanz in Verbindung mit HCMV-Seropositivität. Bei CCR5 ist dieser Effekt bei JIA-Patientinnen und Patienten signifikant stärker als bei Gesundkontrollen. Die vorliegende Studie legt nahe, dass HCMV-assoziierte Veränderungen der T-Zell-Differenzierung bei JIA-Patientinnen und Patienten bestätigt werden können.

The purpose of this project was to examine the effect of hypnosis as a treatment in the control of pain in a population of rheumatoid arthritic patients and further to examine any associated change in emotionality. Three groups of patients suffering from the pain of rheumatoid arthritis were selected. One group served as a control group. The other two groups served as a modified control group and as a treatment group, respectively. All three groups were pre, mid, and post-tested using the McGill Pah Questionnaire, the Minnesota Multiphasic Personality Inventory, the California Personality Inventory Well-Being scale items, and a check of their medication intake. The testing periods were before any treatment procedures were introduced, after a 6 week therapy involvement period for the modified control group and treatment group, and after another 6 week period with no further interaction of the patients with the therapists. The treatment group received hypnosis instruction for the treatment of pain, the modified control group received a ventilation or talk therapy, and the control group was not seen by any therapist. It was fond that self-hypnosis offers a viable and practical treatment technique to individuals in the control of their pain. individuals were not only able to reduce their perception of pain and its effect on their lives, but they were also able to be the ones in control of the process. Both the treatment group and the modified control group were able to achieve positive change in several emotional factors. The treatment group was able to achieve a more significant change and one that persisted after the therapy sessions were terminated. The members of the treatment group were thus able to increase their emotional functioning and decrease their dependency on medications. The treatment group was the only group able to decrease medication intake significantly thus gain indicating the importance of learning self-help procedure for controlling pain. It would seem from the results of this study that using self-hypnosis for pain control is useful and practical.

Bakgrund: Reumatoid artrit (RA) är en autoimmun sjukdom som påverkar leder, senor och skelettvävnad genom att den orsakar inflammation. Det finns evidens för ärftlighet och även immunologiska faktorer spelar en roll men varför sjukdomen utvecklas är ännu inte känd. Omvårdnad sker främst i form av utbildning om egenvård och träning samt medicinering. Syfte: Syftet var att beskriva vilka faktorer som påverkar livskvaliteten hos personer med Reumatoid Artrit. Metod: Arbetet är en litteraturöversikt. Urvalskriterierna var att artiklarna ska vara på engelska, publicerade inom de senaste fem åren (2016–2021), peer-reviewed och deltagare ska vara vuxna. De valda databaserna var PubMed och Cinahl complete. Databasernas fokusområden är omvårdnadsforskning och medicin vilket är relevant för det som eftersöks i arbetet. Sökmetoden var boolesk och sökorden var rheumatoid arthritis och quality of life. Artiklar som bedömts relevanta för att besvara syftet valdes ut. Resultat: Resultatet visar att de faktorer som kan påverka den mentala och fysiska livskvaliteten negativt hos personer med RA var smärta, depression, trötthet, sjukdomsaktivitet, övervikt, brist på sömn samt hög ålder. Kunskap om sjukdomen, inställning, stark identitet, hög motståndskraft samt psykologisk rådgivning, socialt stöd, träning, goda relationer, god ekonomi, hög utbildning och arbete sågs kunna påverka livskvaliteten positivt. Sammanfattning: RA påverkar personers livskvalitet i olika dimensioner på flera olika sätt. Sjukdomsaktivitet, information om sjukdomen och socialt stöd sågs vara några av de mest avgörande faktorerna för livskvaliteten. Som sjuksköterskor och omvårdnadsledare är det viktigt att undersöka faktorer som bidrar till bättre/sämre livskvalitet för att kunna främja patientens förmåga till egenvård. Sjuksköterskan bär ett ansvar för att säkra varje patients enskilda rätt till vård, vilket är en förutsättning för ett jämlikt samhälle. / Background: Rheumatoid arthritis (RA) is an autoimmune disease that affects joints, tendons and tissues by causing inflammation in them. There is evidence of the disease having hereditary and immunological factors that contribute to the emergence of Rheumatoid Arthritis, but the cause behind it is still unknown. Care is primarily focused on information about selfcare and exercise as well as medication. Aim: The aim was to describe the factors influencing the quality of life for people with Rheumatoid Arthritis. Method: This paper is a literature review. The inclusion criterias are that the articles are in English, published within the last five years (2016–2021), they are peer-reviewed and participants in studies are adults. The chosen databases were PubMed and Cinahl complete which both focus on nursing and medicine which are relevant for this review. The search method was boolean, and search words were rheumatoid arthritis and quality of life. The articles used for the assignment were chosen based on their abstract, how well the article could serve to answer the aim. Results: The results found that factors that can decrease the quality in life in people with Rheumatoid Arthritis is pain, depression, fatigue, disease activity, overweight, lack of sleep and old age. Knowledge about the disease, positive attitude, clear sense of identity, high resilience as well as therapy, social support, physical activity, marriage, good financial health, high education and employment was seen to improve the quality of life. Conclusion: RA affects people's quality of life in different dimensions and ways. Disease-activity, information about the disease and social support were seen as some of the most crucial factors in determining the quality of life. As nurses and leading care-givers it is important to know what factors can contribute a better/worse quality of life in order to encourage selfcare. Nurses carry a responsibility to ensure every patient’s right to medical treatment and care which is a prerequisite for an equal society.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21630号 / 医博第4436号 / 新制||医||1033(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 古川 壽亮, 教授 髙橋 良輔, 教授 妻木 範行 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM