published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

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Introduction: Osteoporotic fractures, a major public health problem in aging populations, can lead to increased disability and mortality. Though rheumatoid arthritis (RA) patients have a higher risk for fractures than healthy populations, it is not known how hip structural geometry and body composition, two factors associated with bone strength, affect fracture risk in this population. The overall goal of this dissertation is to examine the association between RA, fracture, hip structural geometry, and body composition, in the participants of the Women's Health Initiative (WHI).Methods: The association between probable RA and fracture risk was tested using the entire WHI cohort (n=161,808). The association between probable RA and hip structural geometry was tested, both cross-sectionally and longitudinally, in a smaller sample (n=11,020) of participants from the WHI Bone Density Centers (WHI-BMD). The last study, testing the association between probable RA and body composition was also conducted in the WHI-BMD cohort.Results: In comparison to the non-arthritic group, the probable RA group had a significant 50%, 2-fold, and 3-fold increase in any, spine, and hip fracture, respectively. The association was not mot modified by age or ethnicity, but glucocorticoid use altered the association between RA and spine fractures. In terms of geometry, the probable RA had a significantly lower (p<0.05) mean hip BMD, outer diameter, cross-sectional area, and section modulus at the narrow neck region compared to control groups, indicating reduced bone strength. Body composition changes were present between the probable RA and the control group, with the probable RA group having statistically lower estimate of lean mass and statistically higher estimates of fat mass compared to the non-arthritic control group cross-sectionally and over the study.Conclusion: These studies confirm the increased risk for fracture among RA patients, while providing evidence that RA alters bone strength, especially at the hip, and negatively effects body composition by reducing lean mass and increasing fat mass. Additional research is needed link structural geometry and body composition to bone strength to lead to tailored interventions to minimize decreases in bone strength in this high fracture risk population.

Aim: To describe the predictive validity of reaching low disease activity (LDA) at 1 year on future disability and joint damage in patients with early rheumatoid arthritis (ERA). Methods: First a systematic literature review of prognostic studies assessing the association between disease activity and functional or radiographic outcomes in ERA was performed. Then data from the Study Of New-Onset RA (SONORA) were used to evaluate the impact of year-one LDA on 3-year disability and 2-year radiographic progression using multivariate regression analyses. Results: Our review demonstrated evidence for relationship between baseline disease activity and future disability and join damage. However evidence for the impact of early treatment response on long-term outcomes in ERA is sparse. Analysis of 984 patients showed year one LDA predicts lower HAQ (p<.0001) and less damage (p=0.04) in future. Conclusion: Reaching LDA early is associated with better long-term functional and radiographic outcomes in patients with early RA.

Aim: To describe the predictive validity of reaching low disease activity (LDA) at 1 year on future disability and joint damage in patients with early rheumatoid arthritis (ERA). Methods: First a systematic literature review of prognostic studies assessing the association between disease activity and functional or radiographic outcomes in ERA was performed. Then data from the Study Of New-Onset RA (SONORA) were used to evaluate the impact of year-one LDA on 3-year disability and 2-year radiographic progression using multivariate regression analyses. Results: Our review demonstrated evidence for relationship between baseline disease activity and future disability and join damage. However evidence for the impact of early treatment response on long-term outcomes in ERA is sparse. Analysis of 984 patients showed year one LDA predicts lower HAQ (p<.0001) and less damage (p=0.04) in future. Conclusion: Reaching LDA early is associated with better long-term functional and radiographic outcomes in patients with early RA.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with an unknown aetiology characterized by joint destruction. Both genetic and environmental factors contribute to the disease development with HLA-DRB1* alleles and smoking identified as most important. The disease is characterized by the presence of autoantibodies, originally by rheumatoid factor (RF) and more recently by anti citrullinated protein/peptide antibodies (ACPA) and antibodies against carbamylated peptides (CarP). These autoantibodies are present, not only after the onset of disease, but also prior to the onset of symptoms. The development of RA is a gradual process lasting several years before the onset of any joint symptom, but when and if there is a temporal difference in the development both between and within the different antibody systems is currently unknown. B-cells produce the antibodies, and a subset of B-cells, i.e., B-regulatory (Breg) cells, produces interleukin-10, and thus have the ability to down-regulate pro-inflammatory cytokines. Whether the Breg cells are involved in the pathogenesis of RA is, as yet, unknown. The aim of this thesis was to increase knowledge of the pathophysiological processes in the development of RA through identification of factors involved. The analyses involved detection of autoantibodies to post-translationally modified peptides/proteins in addition to RF isotypes, cell surface markers on immune cells in asymptomatic individuals, who have an increased risk of developing RA. In a co-analysis of the registers of patients with RA attending the Department of Rheumatology, with the registers from population based screening programmes within the Biobank of Northern Sweden, blood samples collected from individuals prior to the onset of symptoms were identified, as were those from population control subjects. A cohort of pre-symptomatic individuals also donated samples at the time of receiving a diagnosis of RA. First-degree relatives (FDR) of patients with RA were also identified and included for analyses. The levels of ten different ACPAs, i.e., (fibrinogen (Fib) α563-583(573), Fibα580-600(591), Fibβ62-81a(72), Fibβ62-81b(74), Fibβ36-52, a-enolase (CEP-1), triple helical collagen type II (citC1III), filaggrin (Fil307-324), vimentin (Vim) 2-17, and Vim60-75) were measured using the ImmunoCAP ISAC system (Phadia/ThermoFischer, Uppsala, Sweden) in blood samples from individuals before the onset of symptoms and when diagnosed with RA in comparison with those in population based controls. In a subset of samples, the levels of anti-CarP antibodies were measured using ELISA coated with anti-CarP-FCS, as well as analysis of RF of IgM, IgG and IgA isotype using the EliA assay (Phadia, Uppsala, Sweden). Breg cells were analysed both with and without stimulation ex vivo along with other cell types using flow cytometry in samples from patients with RA, their first degree relatives (FDR) and healthy controls. In paper I it was shown that levels of ACPA were initially restricted to a few antibodies but disseminated over time to involve additional different antibodies. The levels of antibodies to CEP-1, Fibß36-52, and filaggrin were significantly increased. In paper II, anti-CarP antibodies were positive in 5-13% of the individuals negative for the various ACPA studied. The presence of anti-CarP antibodies was significantly related to radiological destruction of joints at baseline, at follow-up after 24 months and to the radiological progress between baseline and 24months. In paper III, the relationships between the frequencies of RF isotypes, the ten different ACPA, anti-CCP2 and anti-CarP antibodies before the onset of any symptoms and the presence of certain combinations of antibodies were associated with a very high risk of developing RA. In paper IV Breg cells from patients with RA are functionally impaired and FDR showed a similar pattern by responding less to stimulation ex vivo than cells from healthy controls. In conclusion, individuals who subsequently develop RA have an increased number and amount of ACPAs, anti-CarP antibodies and RF of IgM, IgG and IgA isotype, several years before symptom onset. Most of the different antibodies analysed remain associated with disease development after adjustments for each separate antibody. In FDRs, Breg cells were functionally altered in that they produce less IL-10 and consequently contribute to a more inflammation-prone status, as in their relatives with RA. These findings contribute to information about the development of RA as well as a given individual’s risk(s) of developing RA and its progression.

Biologic therapies have revolutionized the treatment of rheumatoid arthritis, a common chronic inflammatory disease, mainly characterized by the chronic inflammation of the joints. The activity and progression of the disease are highly variable, both between subjects and between the successive assessments for the same subject. Standardized assessments of clinical variables have been developed to reflect the disease activity and evaluate new therapies. Pharmacokinetics-pharmacodynamic (PKPD) models and methods for analyzing the generated time-course data are needed to improve the interpretation of the clinical trials’ outcomes, and to describe the variability between subjects, including patients characteristics, disease factors and the use of concomitant treatments that may affect the response to treatment. In addition, good simulation properties are also desirable for predicting clinical responses for various populations or for different dosing schedules. The aim of this thesis was to develop methods and models for analyzing pharmacokinetic and pharmacokinetic-pharmacodynamic (PKPD) data from rheumatoid arthritis patients, illustrated by treatment with a new anti-TNFα biologic drug under clinical development, certolizumab pegol. Two models were developed that characterized the relationship between the exposure to the drug and the efficacy ACR variables that represent improvement of the disease; a logistic-type Markov model for 20% improvement (ACR20) and a continuous-type Markov model for simultaneous analysis of 20% (ACR20), 50% (ACR50) and 70% (ACR70) improvement. Both models accounted for the within-subjects correlation in the successive clinical assessments and were able to capture the observed ACR responses over time. Simulations from these models of the ACR20 response rate supported dosing regimens of 400 mg at weeks 0, 2 and 4 to achieve a rapid onset of response to the treatment, followed by 200 mg every 2 weeks, or alternative maintenance regimen of 400 mg every 4 weeks. The immunogenicity induced by the biologic drug was characterized by a time to event model describing the time to appearance of antibodies directed against the drug. The immunogenicity was predicted to appear mainly during the first 3 months following the start of the treatment and to be reduced at higher trough concentrations of CZP, as well as with concomitant administration of MTX. The full time-course of sequential events, such as dose-exposure-efficacy relations, is most accurately described by a simultaneous analysis of all data. However, due to the complexity and runtime limitations of such an analysis, alternatives are often used. In this thesis, a method, IPPSE, was developed and compared to the reference simultaneous method and to existing alternative methods. The IPPSE method was shown to provide accuracy and precision of estimates similar to the simultaneous method, but with easier implementation and shorter run times. In conclusion, two PKPD models and one immunogenicity model were developed for evaluation of the response of a biologic drug against rheumatoid arthritis that allowed accurate analysis and simulation of clinical trial data, as well as serving as examples for how a model-informed basis for decisions about biological drugs can be created.