Chronische Schmerzerkrankungen beeinflussen die Arbeitsfähigkeit deutlich. Ziel dieser systematischen Übersichtsarbeit ist es, arbeitsbezogene Studienendpunkte in randomisierten, placebokontrollierten Studien zu chronischen Schmerzerkrankungen und schmerzhaften rheumatologischen Erkrankungen zu analysieren. Datenbanktreffer einer Literaturrecherche in Medline (Pubmed) wurden als Abstracts gesichtet und potentiell relevante Studien danach im Volltext beurteilt. Die methodologische Studienqualität wurde mit der Oxford Quality Scale (OQS) bewertet. Verfügbare arbeitsbezogene und schmerzbezogene Endpunkte wurden in Meta-Analysen mit Hilfe von einem „fixed effect model“ oder einem „random effects model“ zusammengefasst. Lineare Regressionen zwischen arbeitsbezogenen Endpunkten und schmerzbezogenen Endpunkten wurden durchgeführt. Insgesamt 31 Publikationen mit einer Gesamtzahl von 11434 Patienten berichten über arbeitsbezogene Studienendpunkte; dies waren nur ungefähr 0,23% aller relevanten Publikationen. Eine Meta-Analyse aller arbeitsbezogenen Endpunkte, ohne Unterteilung nach vorgenommener Behandlung und der spezifischen vorliegenden Erkrankung, konnte einen allgemeinen Behandlungserfolg von 0,35, ausgedrückt als standardisierte Mittelwertsdifferenz (SMD), mit einem 95%-Konfidenzintervall (95%-KI) von 0,21 bis 0,50 beschreiben. Eine umfassende Meta-Analyse der Schmerzendpunkte derselben Studien ergab eine allgemeine Verbesserung bezüglich schmerzbezogener Endpunkte von 0,40, ausgedrückt als SMD (95%-KI: 0,25; 0,55). Weitere Meta-Analysen zeigten statistisch signifikante Verbesserungen in den Behandlungsgruppen für die folgenden Parameter: Beeinträchtigungen bei der Arbeit (0,62 Punkte auf einer 0- bis 10-Punkte-Skala; 95%-KI: 0,45; 0,79), Arbeitsproduktivität (SMD 0,53; 95%-KI: 0,18; 0,88), 30%ige Schmerzverbesserung relativ zu Studienbeginn (ausgedrückt als Verbesserung des relativen Risikos (RR) von 33%; 95%-KI: 15%; 53%) und 50%ige Schmerzverbesserung relativ zu Studienbeginn (RR 46%; 95%-KI: 22%; 74%), 20%iges (RR 184%; 95%-KI: 86%; 334%), 50%iges (RR 237%; 95%-KI: 84%; 715%) und 70%iges (RR 232%; 95%-KI: 65%; 571%) Ansprechen der Patienten bezogen auf die Kriterien des „American College of Rheumatology“ (ACR). Ergebnisse Arbeitsfehlzeiten und Beschäftigungsverhältnisse betreffend waren heterogen und nicht aussagekräftig. Lineare Regressionensanalysen von sowohl kontinuierlichen arbeitsbezogenen mit kontinuierlichen schmerzbezogenen Endpunkten, als auch von kontinuierlichen arbeitsbezogenen Endpunkten mit kategorischen schmerzbezogenen Ansprechraten, belegten einen statistisch signifikanten Zusammenhang. Abschließend kann berichtet werden, dass arbeitsbezogene Endpunkte nur sehr selten in placebokontrollierten Studien zu chronischen Schmerzerkrankungen untersucht wurden, und dass, wenn sie berichtet wurden, die Endpunkte und Berichterstattung heterogen waren. Es konnten wiederholt statistisch signifikante Behandlungseffekte für verschiedene arbeitsbezogene Endpunkte nachgewiesen werden. Weiterhin konnte gezeigt werden, dass eine starke lineare Relation zwischen arbeitsbezogenen Endpunkten und schmerzbezogenen Endpunkten vorliegt.

Chronic pelvic pain (CPP) is defined as constant or intermittent lower, cyclical or non-cyclical abdominal pain of at least six months’ duration. In the United Kingdom, over 1 million women suffer from CPP, with an estimated annual healthcare cost above £150 million. The aetiology of CPP is unknown in up to 50% of women, and in the remainder, the symptoms of CPP is associated with endometriosis, pelvic adhesions, irritable bowel syndrome or painful bladder syndrome. CPP is often accompanied by painful periods, pain during sexual intercourse and defaecation. Fatigue, sleep disturbances and depression are also common among this group of women. CPP asserts a heavy emotional, social and economic burden. Standard treatments such as hormonal and analgesic regimens are often associated with unacceptable side effects, even if helpful for the pain, underlining an urgent need for a satisfactory treatment. The meridian balanced method (BM) electro-acupuncture (EA) treatment (acupuncture needling + traditional Chinese medicine health consultation [TCM HC]) may be effective in managing CPP symptoms. Thus, I have completed a pilot study comprising of a three-armed randomised controlled trial (RCT), using a mixed methods research (MMR) approach, to assess the feasibility of a future large-scale RCT to determine the effectiveness of the meridian BMEA treatment on CPP in women. My hypothesis is that it is feasible to conduct such a large-scale RCT for CPP in women. The primary objectives were to determine recruitment and retention rates. The secondary objectives were to evaluate the, acceptability of the methods of recruitment, randomisation, interventions and assessment tools and any signals of effectiveness of the interventions. Thirty (30) women with CPP were randomised into three groups: BMEA treatment, TCM HC, or National Health Service standard care (NHS SC) group. The effects of my interventions were assessed by validated pain, physical and emotional functioning questionnaires, completed at weeks 0, 4, 8 and 12 of the study. Semi-structured telephone interviews and focus group discussions to explore participants’ experience of the study were conducted. Of the 59 women who were referred to the study, 30 women (51%) were randomised. There was a statistically significant difference in retention rates between the three groups. The retention rates were 80% (95% CI 74-96), in the BMEA treatment group, 53 % (95% CI 36- 70) in the TCM HC group and 87% (95% CI 63-90) in the NHS SC group. (Chi-square test, p=0.08) The attendance rates of the BMEA treatment group were 90% compared to 56% in the TCM HC group. There was a statistically significant difference (Mann-Whitney test, p=0.023) in attendance between the two intervention groups. Telephone interviews regarding the acceptability of the methods of recruitment, randomisation, assessment tools and interventions were positive. No adverse effects that were directly related to BMEA treatments were reported or observed. A higher proportion of the BMEA treatment group achieved clinical significance in the VAS-pain, BPI-pain severity, interference, and sleep scores, when compared to the other two groups. Due to small sample sizes, there was insufficient power to show statistically significant difference. (Fishers Exact Test, p=1.0) Analyses of the questionnaire data per group showed statistically significant differences in the following: the BMEA treatment group experienced less in pain at weeks 4 (p=0.01) and 8 (p=0.005); less helplessness (p=0.03) and their anxiety and depression scores declined at week 4 (p=0.04). The NHS SC group also reported less pain at week 4 (p=0.04). However, this group scored higher in anxiety and depression at weeks 8 and 12 (p=0.04). No statistically significant differences were achieved between the three groups at baseline, weeks 4, 8 and 12 in all scores. The therapeutic benefits gained by the TCM HC group were less compared to those of the BMEA treatment group, but better when compared to the NHS SC group. The BMEA treatment and TCM HC groups showed lower scores in anxiety and depression while the NHS SC group showed higher scores in anxiety and depression. The NHS SC group also tended to ruminate and magnify their problems as well as feeling more helpless than the other two groups. The three key themes that emerged from thematic analysis of focus group discussions were the “whole person effects” where participants reported an improvement in pain, sleep and a general sense of wellbeing in the two intervention groups; the “experience of standard care” and “impact of living with CPP”. In conclusion, the results of my pilot study are supportive of the feasibility of a future large-scale study. There were signals of effectiveness of interventions but the sample size was too small to make a definitive conclusion.

Stress-related diseases and burnout have increased in Sweden during the last decades. In 2006, the most common diagnoses for new cases of sickness compensation were mental and behavioural disorders in both women and men. In spite of the large group of people seeking care for and on long-term sickness absence due to stress-related diseases and burnout, there is no agreement on which treatment they should be offered. The overall aim of this thesis was to describe patients on longterm sick leave because of burnout and to evaluate rehabilitation programs for this patient group. Two patient samples were recruited from the Stress Clinic at the University Hospital in Umeå, Sweden: REST (Rehabilitation for stressrelated disease and burnout; n=136) and QIST (Qigong for stress-related disease and burnout; n=82). A general population sample was from the 2004 Northern Sweden MONICA survey (n=573). Patients in REST were randomised into a 1-year rehabilitation program to either program A (Cognitively-oriented Behavioural Rehabilitation (CBR) and Qigong), or to program B (Qigong alone). In Paper I, baseline data were compared with data from the MONICA sample. In paper II, programs A and B were compared regarding effects on psychological variables and sick leave rates, and in Paper III, 18 patients from program A and B were interviewed to explore subjective experiences of the rehabilitation programs. Patients in QIST were allocated to an intervention with Qigong twice a week for 12 weeks or a control group. Psychological and physical measurements were assessed in QIST. Data were collected by questionnaires, physical measurements, the register on sick leave, and interviews. Patients with burnout reported a more restricted social network and higher work demands than the general population. In relation to women from a general population, women with burnout more often worked “with people”, reported high job strain, a more sedentary work situation and less emotional support. A per-protocol analysis showed no significant differences in treatment effect between program A and B in REST or between the intervention and control group in QIST. All groups improved significantly over time with reduced levels of burnout, anxiety, depression, and fatigue. In REST, lower scores on obsessive-compulsive symptoms, stress behaviour, and sick leave rates were found in both programs and in QIST both groups increased dynamic balance and physical capacity. In an intention-to-treat analysis, patients in program A in REST had significantly fewer obsessive-compulsive symptoms, and larger effect sizes in stress behaviour and obsessive-compulsive symptoms compared to patients in program B. Patients in both REST programs perceived that the 1-year rehabilitation program gave them specific tools to use in secondary prevention. They also emphasised that the good encounters, affirmation and group cohesiveness they perceived during the 8 rehabilitation was a necessary basis for initiation of a behavioural change leading to recovery. In conclusion, compared to a general population, patients with burnout perceived more demands at work and less social support. Lack of emotional support seemed to be more associated with burnout among women. There were no differences in effect between CBR and Qigong compared to Qigong alone, or between a 12 week Qigong intervention compared to a control condition. Improvements were found in all groups in the rehabilitation programs. CBR combined with Qigong have some advantages compared to Qigong alone. An environment with good encounters and affirmation of the patients was experiences as important by the patients and group rehabilitation had advantages as recognition and support from the group. Early rehabilitation measures are important to prevent long-term sickness absence. In future rehabilitation programs it might be necessary to have a more individualized approach and choose treatments preferred by the patient.

Among elderly people, falls lead to a considerable amount of immobility, morbidity, and mortality. The purpose of this study was to develop and evaluate methods for predicting falls, and to evaluate a fall prevention program among elderly people living in residential care facilities. A fall was defined as any event in which the resident unintentionally came to rest on the floor or the ground regardless of whether or not an injury was sustained. In developing the prediction methods, it was hypothesised that older persons showing difficulties in performing a familiar second task while walking were more likely to fall within six months. For residents who stopped walking when talking, the relative risk of falling was 3.5 (95% CL2.0-6.2) compared to those who continued walking. For residents with a time difference (diffTUG) of at least 4.5 seconds between two performances of the Timed Up&amp;Go test, with and without carrying a glass, the hazard ratio for falls was 4.7 (95% Cl: 1.5-14.2) compared to those with a shorter diffTUG. A screening tool, the Mobility Interaction Fall (MIF) chart, was developed and evaluated, then validated in a new sample. This tool included a mobility rating, ‘Stops walking when talking’, ‘diffTUG’, a test of vision, and a concentration rating. In the first sample, the hazard ratio was 12.1 (95% 0:4.6-31.8) for residents classified as ‘high-risk’ compared to ‘low-risk’. The positive predictive value was 78%, and the negative predictive value, the sensitivity, and the specificity were above 80% for falling in six months. In the second sample the prediction accuracy of the MIF chart was lower (hazard ratio 1.7, 95% Cl: 1.1-2.5) and a 6-month fall history or a global rating of fall risk by staff were at least equally valuable. A combination of any two of the methods - the MIF chart, staff judgement, fall history - was more accurate at identifying high risk residents than any method alone. Half of the residents classified by two methods as ‘high risk’ sustained a fall within 6 months. In a randomised study a prevention program directed to residents, staff, and environment resulted in a significant reduction in the number of residents falling (44% vs. 56%; odds ratio 0.62, 95% CF0.41-0.92), the incidence of falls (incidence rate ratio IRR 0.80, 95% CF0.69-0.94) and of femoral fractures (IRR 0.25, 95% 0:0.08-0.82) in the intervention compared to the control group. In conclusion, a combination of any two of the staff judgement, fall history or MIF chart has the potential to identify a large proportion of residents at particular high fall risk. A multidisciplinary and multifactorial fall prevention program directed to residents, staff, and the environment can reduce the numbnumber of residents falling, of falls and of femoral fractures. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 2000,, härtill 5 uppsatser</p> / digitalisering@umu

La Société Européenne de Cardiologie recommande pour les patients insuffisants cardiaques, en plus de la prise en charge médicamenteuse et interventionnelle, une prise en charge de type « éducation du patient » pour améliorer leur qualité de vie. En France, des programmes multidisciplinaires d’éducation du patient en hôpital ont mesuré leurs effets sur les ré-hospitalisations, la mortalité et le taux de participation des patients aux programmes. Certaines études internationales ont mesuré l’effet de programmes éducatifs délivrés par des équipes hospitalières multidisciplinaires, d’autres ont recruté des patients en soins primaires, mais les programmes étaient conduits par des infirmières ou des assistants des médecins généralistes. Ce type de programme ne reflète pas la situation actuelle en France où la plupart des patients sont suivis en ambulatoires par leurs médecins généralistes. Il semblait nécessaire de connaître plus précisément l'effet de programmes d'éducation du patient délivrés par les médecins généralistes auprès de leurs propres patients. L’objectif principal de l’étude ETIC (Education thérapeutique des patients insuffisants cardiaques) était d’évaluer si un programme d’éducation des patients insuffisants cardiaques délivré par leurs médecins traitants et suivis en médecine générale, améliorait leur qualité de vie. Cette étude interventionnelle, contrôlée, randomisée en grappes, a inclus 241 patients insuffisants cardiaques chroniques suivis par 54 médecins généralistes pendant 19 mois. Les médecins généralistes du groupe intervention ont été sensibilisés pendant 2 jours au programme d’éducation du patient et entrainés à adapter leurs propres objectifs d'éducation aux attentes du patient. Plusieurs séances d'éducation ont été simulées au cours de la formation des médecins. La 1re séance comportait un bilan éducatif explorant le mode de vie et les habitudes alimentaires, l'activité physique, les activités de loisirs, les projets et les ressources des patients. Les patients bénéficiaient de 4 séances d’éducation tous les 3 mois pendant 12 mois puis d’une séance d’éducation de synthèse au 19e mois de suivi. Le critère d’évaluation principal était la qualité de vie mesurée par une échelle de qualité de vie générique, la MOS 36-Item Short Form Health Survey (SF-36), et par une échelle de qualité de vie spécifique de l’insuffisance cardiaque, le Minnesota Living with Heart Failure Questionnaire (MLHFQ). La moyenne d’âge des patients était 74 ans (± 10.5), 62% était des hommes, et leur fraction d’éjection ventriculaire gauche moyenne était de 49.3% ± 14.3%. A la fin du suivi, le score MLHFQ moyen dans les groupes intervention et témoin étaient respectivement 33.4 ± 22.1 versus 27.2 ± 23.3; p = 0.74, intra-cluster coefficient [ICC] = 0.11. A la fin du suivi, la moyenne des scores SF-36 mental et physique dans les groupes intervention et témoin étaient respectivement 58 ± 22.1 versus 58.7 ± 23.9 (p = 0.58, ICC = 0.01) et 52.8 ± 23.8 versus 51.6 ± 25.5 (p = 0.57, ICC = 0.01). Le nombre de patients insuffisants cardiaques à fraction d’éjection conservée (ICFEp) était de 93 (80.9%) dans le groupe intervention et de 94 (74.6%) dans le groupe témoin (p = 0.24). Une étude exploratoire a été réalisée pour décrire les traitements prescrits dans la population de cette étude : évaluation de l’adhésion des médecins généralistes aux recommandations pour les patients à fraction d’éjection réduite (ICFEr) et description des traitements prescrits aux patients ICFEp. Le programme d’éducation du patient délivré dans le cadre de l’étude ETIC, n’a pas fait la preuve d’une amélioration de la qualité de vie des patients. D’autres recherches sont nécessaires pour améliorer la qualité de vie de ces patients. Les stratégies et les méthodes d’éducation restent un champ de recherche à développer. / The European Society of Cardiology guidelines recommend non-pharmacological management to improve patients’ quality of life. In France, patient education programs delivered by hospital multidisciplinary teams in outpatient clinics have been assessed for their impact in patients with heart failure (HF). Some international studies assessed patient education interventions for heart failure patients recruited in the hospital. These programs were delivered by hospital multidisciplinary teams. Others have recruited patients with heart failure in primary care but the patient education programs were delivered by nurses or general practitioner assistants. This does not reflect the situation of the majority of patients in France, most of whom are ambulatory and cared for by general practitioners (GPs). Therefore, more evidence is needed on the effect of patient education programs delivered by GPs. As GPs are the doctors closest to patients, we hypothesized that their patient education could improved the HF patients quality of life. The ETIC (Education thérapeutique des patients insuffisants cardiaques) trial aimed to determine whether a pragmatic education intervention in general practice could improve the quality of life of patients with chronic heart failure (CHF) compared with routine care. This cluster randomised controlled clinical trial included 241 patients with CHF attending 54 general practitioners (GPs) in France and involved 19 months of follow-up. The GPs in the intervention group were trained during an interactive 2-day workshop to provide a patient education program. Several patient education sessions were simulated during the 2-day workshop. Patients had a further four education sessions, at 4, 7, 10 and 13 months, followed by an overview session at 19 months. The primary outcome was patients’ quality of life, as measured by the MOS 36-Item Short Form Health Survey (SF-36), a generic instrument, and the Minnesota Living with Heart Failure Questionnaire (MLHFQ). The mean age of the patients was 74 years (± 10.5), 62% were men and their mean left-ventricular ejection fraction was 49.3% (± 14.3). At the end of the follow-up period, the mean MLHFQ scores in the Intervention and Control Groups were 33.4 ± 22.1 versus 27.2 ± 23.3 (p = 0.74, intra-cluster coefficient [ICC] = 0.11). At the end of the follow-up period, SF-36 mental and physical scores in the Intervention and Control Groups were 58 ± 22.1 versus 58.7 ± 23.9 (p = 0.58, ICC = 0.01) and 52.8 ± 23.8 versus 51.6 ± 25.5 (p = 0.57, ICC = 0.01), respectively. Patients with heart failure with preserved ejection fraction (HFpEF) in the intervention group and in the control group were respectively: 93 (80.9%) and 94 (74.6%) (p = 0.24). A comprehensive data set of this trial was used to assess the prescription behaviour of GPs: GP’s guideline adherence for pharmacotherapy of heart failure with reduced ejection fraction (HFrEF) patients and to describe pharmacotherapy of HFpEF patients. Conclusions Patient education delivered by GPs to elderly patients with stable heart failure in the ETIC program did not demonstrate an improvement in their quality of life compared with routine care. Further research on improving the quality of life of elderly patients with CHF in primary care is needed. Patient education strategies and methods, as well as relevant tools and adapted criteria used to assess them, remain a field of research to develop. This area of investigation will be the following of this work.

<p><strong>ABSTRACT</strong></p> <p><strong>Background and Objectives</strong>:<strong> </strong>Informed health care decision making depends on the available evidence base. Where the available evidence comes from different sources methods are required that can synthesise all of the evidence. The synthesis of different types of evidence poses various methodological challenges. The objective of this thesis is to investigate the use of Bayesian methods for combining evidence on effects from randomised and non-randomised studies and additional evidence from the literature with patient level trial data. <strong> </strong></p> <p><strong>Methods</strong>: Using a Bayesian three-level hierarchical model an approach was proposed to combine evidence from randomised and non-randomised studies while adjusting for potential imbalances in patient covariates. The proposed approach was compared to four other Bayesian methods using a case study of endovascular versus open surgical repair for the treatment of abdominal aortic aneurysms. In order to assess the performance of the proposed approach beyond this single applied example a simulation study was conducted. The simulation study examined a series of Bayesian approaches under a variety of scenarios. The subsequent research focussed on the use of informative prior distributions to integrate additional evidence with patient level data in a Bayesian cost-effectiveness analysis comparing endovascular and open surgical repair in terms of incremental costs and life years gained.</p> <p><strong>Results and Conclusions</strong>: The shift in the estimated odds ratios towards those of the more balanced randomised studies, observed in the case study, suggested that the proposed Bayesian approach was capable of adjusting for imbalances. These results were reinforced in the simulation study. The impact of the informative priors in terms of increasing estimated mean life years in the control group, demonstrated the potential importance of incorporating all available evidence in the context of an economic evaluation. In addressing these issues this research contributes to comprehensive evidence based decision making in health care.</p> / Doctor of Philosophy (PhD)

I performed two randomised controlled trials (RCTs) to determine the best treatments for enteric fever in Kathmandu, Nepal, an area with a high proportion of nalidixic acid resistant S. Typhi and S. Paratyphi A isolates. I recruited 844 patients with suspected enteric fever to compare chloramphenicol versus gatifloxacin. 352 patients were culture confirmed. 14/175 patients treated with chloramphenicol and 12/177 patients treated with gatifloxacin experienced treatment failure (HR=0.86 (95% CI 0.40 to 1.86), p=0.70). The median times to fever clearance were 3.95 and 3.90 days, respectively (HR=1.06 [CI 0.86 to 1.32], p=0.59). The second RCT compared ofloxacin versus gatifloxacin and recruited 627 patients. Of the 170 patients infected with nalidixic acid resistant strains, the number of patients with treatment failure was 6/83 in the ofloxacin group and 5/87 in the gatifloxacin group (Hazard Ratio, HR=0.81, 95% CI 0.25 to 2.65; p=0.73); the median times to fever clearance were 4.7 and 3.3 days respectively (HR=1.59 [CI 1.16 to 2.18], p=0.004). I compared conventional blood culture against an electricity free culture approach. 66 of 304 patients with suspected enteric fever were positive for S. Typhi or S. Paratyphi A, 55 (85%) isolates were identified by the conventional blood culture and 60 (92%) isolates were identified by the experimental method. The percentages of positive and negative agreement for diagnosis of enteric fever were 90.9% and 96.0%, respectively. This electricity free blood culture system may have utility in resource-limited settings or potentially in disaster relief and refugee camps. I performed a literature review of RCTs of enteric fever which showed that trial design varied greatly. I was interested in the perspective of patients and what they regarded as cure. 1,481 patients were interviewed at the start of treatment, 860 (58%) reported that the resolution of fever would mean cure to them. At the completion of treatment, 877/1,448 (60.6%) reported that they felt cured when fever was completely gone. We suggest that fever clearance time is the best surrogate for clinical cure in patients with enteric fever and should be used as the primary outcome in future RCTs for the treatment of enteric fever.

Evidence-based practice is an integral part of multi-disciplinary healthcare, but its routine clinical implementation remains a challenge internationally. Written asthma action plans are an example of sub-optimal evidence-based practice because, despite being recommended, these plans are under-issued by health professionals and under-used by patients/carers. This thesis is a critical analysis of the generation and implementation of evidence in this area and provides fresh insight into this specific theory/practice gap. This submission brings together, in five published papers, a body of work conducted by the candidate. Findings report that known barriers to action plan use (such as a lack of practitioner time) are symptomatic of deeper and more complex underlying factors. In particular, over-reliance on knowledge derived from randomised controlled trials and their systematic review, as the primary and sole source of evidence for healthcare practice, hindered the implementation of these plans. A lack of evidence reflecting the personal experience of using these plans in the real world, rather than in trial settings, contributed to a mismatch between what patients/carers want from asthma action plans and what they are currently being provided with by professionals. This submission illustrates the benefits of utilising a broader range of knowledge as a basis for clinical practice. The presented papers report how new and innovative research methodologies (including meta-ethnography and cross-study synthesis) can be used to synthesise individual studies reporting the personal experiences of patients and professionals and how such findings can then be used to better understand why interventions can be implemented in trial settings rather than everyday practice. Whilst these emerging approaches have great potential to contribute to evidence-based practice by, for example, strengthening the ‘weight’ of experiential knowledge, there are methodological challenges which, whilst acknowledged, have yet to be fully addressed.

Les rhumatismes inflammatoires juvéniles sont des maladies chroniques débutant avant l’âge de 16 ans. Comprennent des pathologies classées dans un continuum, allant de la dérégulation de l’immunité innée à la dérégulation de l‘immunité adaptative. L’arthrite juvénile idiopathique (AJI) reste la plus fréquemment diagnostiqué. Les options thérapeutiques se sont élargies à partir des années 2000 avec le développement des thérapies ciblées, les biothérapies, associés aux traitements standard utilisés en rhumatologie pédiatrique (ex : anti-inflammatoires non stéroïdiens, corticostéroïdes, méthotrexate, et autres immunosuppresseurs). L’objectif de ce travail de thèse était d’estimer la relation bénéfice-risque des biothérapies utilisés dans les rhumatismes inflammatoires juvéniles à partir des essais cliniques randomisés (ECR) et d’explorer la tolérance à long cours à partir des essais observationnels. Premièrement, en utilisant une approche méta-analitique, les données des ECR en double aveugle contre placebo ou en ouvert dans l’AJI ont été analysées pour modéliser la relation bénéfice-risque des biothérapies avec le bénéfice net. Pour cela, l’efficacité clinique, mesuré par un score composite clinique et biologique (ACRped30), a été confronté à la tolérance clinique pendant la phase randomisée des ECR. Le critère de tolérance était la survenue d’un évènement indésirable (EI) grave (EIG). La balance bénéfice-risque reste favorable pour les biothérapies. Cependant, ces résultats sont limités par le suivi de faible durée, qui peut sous-estimer l’incidence des EI. Deuxièmement, nous avons conduit une étude observationnelle pour étudier la tolérance à moyen et long-terme des biothérapies utilisant les EI et les EIG décrits dans une base de données multicentrique rétrospective. La sécurité globale des biothérapies a été acceptable chez les enfants atteints de rhumatismes inflammatoires. Nous avons observé une variation des EIG au cours du temps et que la prescription concomitante des immunosuppresseurs a représenté un risque indépendant pour la survenue des EI. Afin d’explorer ces éléments et connaître la tolérance au long-terme, une méta-analyse des études observationnelles a été fait. Nous avons utilisé les EIG pour étudier précisément la tolérance à court et à long terme / Juvenile inflammatory rheumatism is a chronic disease that begins before the age of 16. Includes conditions classified along a continuum, ranging from the deregulation of innate immunity to the deregulation of adaptive immunity. Juvenile idiopathic arthritis (JIA) remains the most frequently diagnosed disease. Therapeutic options have expanded since the 2000s with the development of targeted therapies: biological agents (BAs). They can be combined with standard treatments used in paediatric rheumatology (e.g. non-steroidal anti-inflammatory drugs, corticosteroids, methotrexate, and other immunosuppressive drugs). The objective of the work of this thesis was to model the benefit-risk balance of BAs used in JIA from randomized clinical trials (RCTs) and to explore long-term tolerance from observational trials. First, using a meta-analytical approach, the data from double-blind, placebo-controlled or open RCTs in JIA were analysed for modelling the benefit-risk balance of BAs. For this purpose, the efficacy measured by a composite clinical and biological score (ACRped30), was compared with clinical safety during the randomized phase of RCTs. Safety criterion was the occurrence of adverse events (AEs). The risk-benefit balance remains favourable for biotherapies. However, these results are limited by the short follow-up period, which may underestimate the incidence of AEs. Second, we conducted an observational study to investigate the medium- and long-term safety of biotherapies using AEs and serious AEs described in a retrospective multicentre database. The overall safety of biotherapies has been acceptable in children with inflammatory rheumatic diseases. We observed a variation in the SAEs over time and that the concomitant prescription of immunosuppressants represented an independent risk for the occurrence of AEs. In order to explore these elements and long-term safety, a meta-analysis of observational studies was conducted. We used the SAEs to study precisely the short and long-term tolerance