The main purpose of this study was to evaluate medication use patterns (i.e., dose escalation, medication adherence, persistence, and switching) of rheumatoid arthritis (RA) patients on etanercept (ETN), infliximab (IFX) or adalimumab (ADA) and the associated healthcare utilization costs using Texas Medicaid data. Study participants were Medicaid beneficiaries (18-63 years) with an RA diagnosis (ICD-9-CM code 714.0x) who had no claim for a biologic agent in the 6-month pre-index period (July 1, 2003 - Dec 31, 2010). The index date was the first date when the patient had the first fill for any of the study TNF inhibitors (ETN, ADA or IFX) within the study identification period (Jan 1, 2004 – Aug 31, 2010). Data were extracted from July 1, 2003 to August 31, 2011. Prescription and medical claims were analyzed over an 18-month study period (i.e., 6-month pre-index and 12-month post-index periods). The primary study outcomes were adherence, persistence, dose escalation, switching and cost (i.e., total healthcare, RA-related and TNF inhibitor therapy cost). The study covariates were demographic factors (age, gender, race/ethnicity), pre-index use of other RA-related medications (pain, glucocorticoids and disease modifying antirheumatic drugs), total number of non-study RA-related medications used at index, pre-index RA and non-RA related visits, pre-index healthcare utilization cost and Charlson Comorbidity Index score. Conditional regression analyses, which accounts for matched samples, were used to address the study objectives. After propensity score matching, 822 patients (n=274/group) comprised the final sample. The mean age (±SD) was 48.9(±9.8) years, and the majority of the subjects were between 45 and 63 years (69.2%), Hispanic (53.7%) and female (88.0%). Compared to patients on ETN, the odds of having a dose escalation were ≈ 5 [Odds Ratio= 4.605 [95% CI= 1.605-12.677], p=0.0031] and ≈ 8 [Odds Ratio=7.520, [95% CI= 2.461-22.983], p=0.0004] times higher for IFX and ADA patients, respectively, while controlling for other variables in the model. Compared to ETN, patients on IFX (p=0.0171) were more adherent while adherence was comparable with patients on ADA (p=0.1144). Compared to patients on ETN, the odds of being adherent (MPR ≥ 80%) to IFX was ≈ 2 times higher [Odds Ratio= 2.437, [95% CI=1.592-3.731], p < 0.0001] while controlling for other variables in the model. Persistence to index TNF inhibitor therapy and likelihood to switch or discontinue index TNF inhibitor therapy were comparable among the 3 study groups. In addition, the duration of medication use (i.e., persistence) prior to switching or discontinuation of index therapy was comparable among the 3 study groups. Furthermore, for each of the cost variables (total healthcare, RA-related and TNF inhibitor therapy cost), costs incurred by patients on ETN were significantly lower (p < 0.01) than those incurred by ADA patients but significantly higher (p < 0.01) than those incurred by IFX patients. Finally, a positive and significant relationship (p < 0.0001) was found between RA-related healthcare cost, adherence and persistence to TNF inhibitor therapies. In conclusion, ETN was associated with lower rates of dose escalation compared to ADA or IFX. However, adherence was better and associated healthcare costs were lower with IFX. Clinicians should endeavor to work with each individual patient to identify patient-specific factors responsible for poor medication use behaviors with TNF-inhibitor therapies. Reducing the impact of these factors and improving adherence should be included as a major part of the treatment plan for each RA patient. RA patients need to be adequately educated on the importance of adhering and persisting to their TNF-inhibitor therapy as poor medication adherence/persistence negatively impacts the RA disease process. / text

Before market authorization of new medicines, their efficacy and safety are evaluated using randomized controlled trials. While there is no doubt about the scientific value of randomized trials, they are usually conducted in selected populations with questionable generalizability to routine care.  In the digital data revolution era, with healthcare data growing at an unprecedented rate, drug monitoring in routine care is still highly under-utilized. Although many countries have access to data on prescription drugs at the individual level in ambulatory care, such data are often missing for hospitals. This is a growing problem considering the clear trend towards more new and expensive drugs administered in the hospital setting. The aim of this thesis was therefore to develop methods for extracting data on drug use from a hospital-based electronic health record system and further to build and evaluate models for real-time monitoring of effectiveness and safety of new drugs in routine care using data from electronic health records and regional and national health care registers. Using the developed techniques, we were able to demonstrate drug use and health service utilization for inflammatory bowel disease and to evaluate the comparative effectiveness and safety of antiarrhythmic drugs. With a rapidly evolving drug development, it is important to optimize the evaluation of effectiveness, safety and health economic value of new medicines in routine care. We believe that the models described in this thesis could contribute to fulfil this need.

Le lymphocyte B (LB) joue un rôle important dans la polyarthrite rhumatoïde (PR), en produisant des auto-anticorps qui ont un rôle pathogène, en activant les lymphocytes T, en sécrétant des cytokines pro-inflammatoires et en permettant la formation de centres germinatifs. Plus récemment, il a été montré que le LB pouvait également produire de l'interleukine (IL) 10, une cytokine anti-inflammatoire qui lui procure des fonctions régulatrices. Ces B régulateurs ont notamment la capacité de différencier les lymphocytes T en T régulateurs. De nombreux traitements sont actuellement disponibles dans la PR, notamment les anti-TNF alpha et les inhibiteurs du récepteur de l'IL-6 (tocilizumab). Dans la première partie de cette thèse, nous avons comparé les LB circulants de patients atteints de PR et de contrôles. Nous avons étudié l'influence de l'activité de la maladie et des traitements sur les LB. Nous avons montré qu'il existait une lymphopénie B globale chez les patients atteints de PR avec une répartition des différents sous-types de LB superposable à celle des contrôles. Les patients ayant une maladie active avaient significativement plus de LB mémoires totaux, pré- et post-switch, CD24hiCD27+ et double négatifs que les patients ayant une maladie peu active. Les traitements anti-TNF et le tocilizumab ne modifiaient pas la répartition des sous-types de LB. Nous avons également montré qu'un taux de plus de 26% de LB mémoires CD27+ avant l'instauration d'un traitement par anti-TNF était associé à la réponse clinique à 3 mois. Les LB mémoires semblent produire plus de TNF que les LB naïfs et par ce biais pourraient induire une réponse Th1. Dans la seconde partie de cette thèse, nous avons tout d'abord cherché à mieux définir les LB régulateurs. Nous avons ensuite étudié leur présence et leur rôle dans la PR. Chez les sujets sains, les LB CD24hiCD27+ et CD24hiCD38hi semblent produire plus d'IL-10 que les autres LB, qui peuvent néanmoins en sécréter. Il semble donc plus adapter de définir les B régulateurs comme B producteurs d'IL-10 ou B10. Les patients atteints de PR avaient significativement moins de B10 que les contrôles en pourcentage et en valeur absolue. Chez les patients ayant un facteur rhumatoïde (FR) positif, il y avait une corrélation inverse entre le pourcentage de B10 et le taux de FR. Il y avait une corrélation inverse entre l'activité de la maladie (DAS28) et le pourcentage de B10, qui était particulièrement marquée pour les PR évoluant depuis moins de 5 ans. Chez ces patients, il y avait également une corrélation inverse entre les B10 et l'inflammation biologique (protéine C réactive). L'instauration d'anti-TNF ou de tocilizumab ne modifiait pas le taux de B10. Les CD24hiCD27+ et CD24hiCD38hi induisaient plus de lymphocytes T régulateurs chez les contrôles que les autres LB (CD24lo/-) alors que ça n'était plus le cas chez les patients atteints de PR, montrant que ces sous-types ont perdu cette fonction régulatrice dans la PR. En conclusion, bien qu'il existe une lymphopénie B, la répartition des sous-types de LB ne semble pas différente entre les patients atteints de PR et les contrôles. Néanmoins, il existe des anomalies fonctionnelles avec notamment une perte de la capacité à produire de l'IL-10 et à induire des T régulateurs chez les patients atteints de PR. / B cells play an important role in rheumatoid arthritis (RA), producing autoantibodies which have a pathogenic role, activating T cells, secreting pro-inflammatory cytokines and allowing the formation of germinal centers. More recently, it was shown that the B cells could also produce interleukin (IL)-10, an anti-inflammatory cytokine which provides their regulatory functions. Those regulatory B cells have the ability to differentiate T cell into regulatory T cells. Many treatments are currently available in RA, including TNF-alpha inhibitors and IL-6 receptor inhibitor (tocilizumab). In the first part, we compared circulating B cells in RA patients and in controls, and we studied the influence of disease activity and treatment on B cells. We have shown that there is a global B cell lymphopenia in RA patients with a similar B cell subtype distribution as controls. Patients with active disease had significantly more pre- and post-switch, CD24hiCD27+ and double negative memory B cells than patients with low disease activity. Anti -TNF treatment and tocilizumab did not change the distribution of B cell subsets. We also showed than patient with more than 26% of CD27+ memory B cells prior TNF inhibitor initiation was associated with clinical response at 3 months. Memory B cells produced more TNF alpha than naive B cells and can potentially induce a Th1 response. B cell subtypes were not associated with response to tocilizumab. In the second part, we first sought to better define regulatory B cells. We then studied their presence and role in RA. In healthy subjects, CD24hiCD27+ and CD24hiCD38hi B cells seem to produce more IL-10 than the other B cells that can nevertheless rarely produce some. It seemed more acurate to define regulatory B cells as IL-10 producing B cells also called B10 cells. Patients with RA had significantly less B10 cells than controls in percentage and absolute values. In rheumatoid factor (RF) positive patients, there was an inverse correlation between the percentage of B10 and the rate of RF. There was an inverse correlation between disease activity (DAS28) and the percentage of B10, which was particularly significant for patients with a disease duration of less than 5 years. In these patients, there was also an inverse correlation between B10 and biological inflammation (C-Reactive Protein). TNF inhibitors or tocilizumab did not change B10 cell rate. The CD24hiCD27 + and CD24hiCD38hi induce more regulatory T cells in controls than other LB (CD24lo/-) while it was not the case in patients with RA, indicating that these subtypes have lost this regulatory function in RA. In conclusion, although there are B cell lymphopenia, the distribution of B cell subsets does not seem to differ between RA patients and controls. Nevertheless, there are functional abnormalities including a loss of the ability to produce IL -10 and induce regulatory T in patients with RA.