| 1. |
- Åkerman, Linda, 1983-
(författare)
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Aspects of the Pre-Diabetic Period in Type 1 Diabetes
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes (T1D) is an autoimmune disease characterized by insulin deficiency, due to immune-mediated destruction of beta cells. Current knowledge regarding the period preceding disease onset comes, to a large extent, from studying risk cohorts based on relatives of T1D-patients, as they have an increased disease risk. Among T1D patients in general, however, few have the disease in their immediate family. It is therefore important to study risk cohorts from the general population as well. An ongoing autoimmune reaction can often be seen in the blood long before disease onset, by detection of autoantibodies directed towards beta cell antigens. By autoantibody screening among participants in the ABIS (All Babies in the South-east of Sweden) cohort, we could identify a group of children from the general population with increased risk for T1D, positive for multiple autoantibodies. They were enrolled in a 2-year prospective follow-up aiming to characterize the prediabetic period and to identify factors indicative of progression/non-progression to T1D. We assessed glucose homeostasis and autoantibody titers over time, and searched for risk-biomarkers by analyzing the expression of immune-related genes (Th1-Th2-Th3) in peripheral blood mononuclear cells (PBMC) from these children, in comparison to healthy children and newly diagnosed T1D patients. In the same groups we also compared serum micro RNA (miRNA) profiles, knowing that miRNA molecules have desirable biomarker properties. We found that two specific autoantibodies, IA2A and ZnT8A, were detected at higher concentrations in risk-individuals who progressed to overt T1D during or after the follow-up period, compared to those who still have not. We also observed disturbed glucose homeostasis long before onset in the progressors, but it was seen among those who remain symptom free as well. Further, we found support for the possible role of insulin resistance as an accelerator of the disease process. For gene expression and serum miRNA, few differences were observed between risk-individuals and healthy children overall. However, for PBMC gene expression and serum miRNA both, there were associations to beta cell function and glucose homeostasis, and for miRNA also to islet autoantibodies. Although specific profiles for prediction of disease onset or identification of risk-individuals could not be found, these results are interesting and deserve to be evaluated further. As part of another sub-study within ABIS, the effects of physical activity on glucose homeostasis were assessed in healthy schoolchildren. The level of physical activity, measured by pedometers, was related to insulin resistance and beta cell-stress, and decreased physical activity was associated with increased insulin resistance and load on the insulin-producing beta cells, already at school-age.
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| 2. |
- Jonsson, Åsa, 1969-
(författare)
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How to create and analyze a Heart Failure Registry with emphasis on Anemia and Quality of Life
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background and aimsHeart failure (HF) is a major cause of serious morbidity and death in the population and one of the leading medical causes of hospitalization among people older than 60 years. The aim of this thesis was to describe how to create and how to analyze a Heart Failure Registry with emphasis on Anemia and Quality of Life. (Paper I) We described the creation of the Swedish Heart Failure Registry (SwedeHF) as an instrument, which may help to optimize the handling of HF patients and show how the registry can be used to improve the management of patients with HF. (Paper II) In order to show how to analyze a HF registry we investigated the prevalence of anemia, its predictors, and its association with mortality and morbidity in a large cohort of unselected patients with HFrEF included in the SwedeHF, and to explore if there are subgroups of HF patients identifying high--‐risk patients in need of treatment. (Paper III) In order to show another way of analyzing a HF registry we assessed the prevalence of, associations with, and prognostic impact of anemia in patients with HFmrEF and HFpEF. (Paper IV) Finally we examined the usefulness of EQ--‐ 5D as a measure of patient--‐reported outcomes among HF patients using different analytical models and data from the SwedeHF, and comparing results about HRQoL for patients with HFpEF and HFrEF.Methods An observational study based on the SwedeHF database, consisting of about 70 variables, was undertaken to describe how a registry is created and can be used (Paper I). One comorbidity (anemia) was applied to different types of HF patients, HFrEF (EF <40%) (II) and HFmrEF (EF 40--‐49% ) or HFpEF (> 50%) (III) analyzing the data with different statistical methods. The usefulness of EQ--‐5D as measure of patient--‐ reported outcomes was studied and the results about HRQoL were compared for patients with HFpEF and HFrEF (IV).ResultsIn the first paper (Paper I) we showed how to create a HF registry and presented some characteristics of the patients included, however not adjusted since this was not the purpose of the study. In the second paper (Paper II) we studied anemia in patients with HFrEF and found that the prevalence of anemia in HFrEF were 34 % and the most important independent predictors were higher age, male gender and renal dysfunction. One--‐year survival was 75 % with anemia vs. 81 % without (p<0,001). In the matched cohort after propensity score the hazard ratio associated with anemia was for all--‐cause death 1.34. Anemia was associated with greater risk with lower age, male gender, EF 30--‐39%, and NYHA--‐class I--‐II. In the third paper (Paper III) we studied anemia in other types of HF patients and found that the prevalence in the overall cohort in patients with EF > 40% was 42 %, in HFmrEF 38 % and in HFpEF (45%). Independent associations with anemia were HFpEF, male sex, higher age, worse New York Heart Association class and renal function, systolic blood pressure <100 mmHg, heart rate ≥70 bpm, diabetes, and absence of atrial fibrillation. One--‐year survival with vs. without anemia was 74% vs. 89% in HFmrEF and 71% vs. 84% in HFpEF (p<0.001 for all). Thus very similar results in paper II and III but in different types of HF patients. In the fourth paper (Paper IV) we studied the usefulness of EQ--‐5D in two groups of patients with HF (HFpEF and HFrEF)) and found that the mean EQ--‐5D index showed small reductions in both groups at follow--‐up. The patients in the HFpEF group reported worsening in all five dimensions, while those in the HFrEF group reported worsening in only three. The Paretian classification showed that 24% of the patients in the HFpEF group and 34% of those in the HFrEF group reported overall improvement while 43% and 39% reported overall worsening. Multiple logistic regressions showed that treatment in a cardiology clinic affected outcome in the HFrEF group but not in the HFpEF group (Paper IV).Conclusions The SwedeHF is a valuable tool for improving the management of patients with HF, since it enables participating centers to focus on their own potential for improving diagnoses and medical treatment, through the online reports (Paper I). Anemia is associated with higher age, male gender and renal dysfunction and increased risk of mortality and morbidity (II, III). The influence of anemia on mortality was significantly greater in younger patients in men and in those with more stable HF (Paper II, III). The usefulness of EQ--‐5D is dependent on the analytical method used. While the index showed minor differences between groups, analyses of specific dimensions showed different patterns of change in the two groups of patients (HFpEF and HFrEF). The Paretian classification identified subgroups that improved or worsened, and can therefore help to identify needs for improvement in health services (Paper IV).
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| 3. |
- Wirestam, Lina, 1986-
(författare)
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Biomarkers of disease activity and organ damage in systemic lupus erythematosus
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE) is a systemic inflammatory disease. Clinically, the distinction between ongoing inflammation attributed to SLE, and organ damage due to medication or co-morbidities remains challenging. In addition, SLE is a heterogeneous disease where the various disease phenotypes complicate the search for biomarkers that adequately reflect disease activity and/or signs of increasing organ damage. The aim of the thesis was to investigate and evaluate potential new biomarkers of disease activity and/or organ damage in SLE patients.High mobility group box protein-1 (HMGB1) is a nuclear non-histone protein that can shuttle to the cytoplasm, become secreted extracellularly, and participate in systemic inflammation. Administration of monoclonal anti-HMGB1 antibodies has been reported both to attenuate and intensify disease in animal models of arthritis and lupus. In Paper I of the thesis, circulating anti-HMGB1 was found in 23% of the SLE patients and correlated with disease activity variables. The biological role of these autoantibodies remains to be elucidated.As a consequence of massive circulating levels of cellular debris and immune complexes, SLE patients have insufficient capacity to remove such material via the reticuloendothelial system. Pentraxin 3 (PTX3) may possibly protect against lupus flares due to classical complement activation, opsonization of apoptotic cells, and cytokine induction. In Paper II, circulating PTX3 was found to be inhibited or exhausted by interferon (IFN)-α, a key cytokine of SLE pathogenesis, and serum levels of PTX3 in SLE patients were inversely related to IFN-α levels. Suppressed PTX3 levels may contribute to a vicious circle resulting in impaired waste clearance, autoantigen exposure and autoantibody production, and sustained disease activity.Osteopontin (OPN), a protein known to influence cell signaling and apoptosis, has been proposed as a marker of organ damage in pediatric lupus. In a Swedish cross-sectional study, circulating OPN levels were found to be raised in SLE (Paper III). In patients with recent-onset disease, OPN reflected disease activity, while in established disease, OPN appeared to mirror damage accrual and cardiovascular damage. In Paper IV, OPN was instead analyzed in an international longitudinal multi-center study based on patients with recent-onset SLE and follow-up data. OPN turned out to be a poor predictor of organ damage, but significant associations were observed between OPN and disease activity both at disease onset, as well as over 5 years of follow-up.In conclusion, increased anti-HMGB1 antibody and decreased PTX3 levels could potentially sustain the impaired waste-disposal. Of the molecules analyzed in this thesis, OPN seems to be the best marker of disease activity. Further studies of these proteins may help to better understand SLE pathogenesis and to optimize treatment of patients.
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| 4. |
- Danielsson, Olof, 1963-
(författare)
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The Clinical and Pathological Spectrum of Idiopathic Inflammatory Myopathies : Implications for pathogenesis, classification and diagnosis
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of diseases with severe consequences for the life of affected patients. Dermatomyositis, polymyositis and inclusion body myositis (IBM) are the classical representatives of this group. The treatments given today often have limited effects, and are taken at the cost of side effects. Major obstacles in the search for more effective treatments are; (1) an incomplete understanding of the disease mechanisms, (2) difficulties to delineate homogeneous disease groups for clinical studies and (3) the sometimes challenging task to diagnose these diseases.Aims: We addressed a number of “loose ends” in the areas of pathogenesis, classification and diagnosis; mechanisms of muscle fiber degeneration in IIM, with a focus of programmed cell death (apoptosis) and invasion of muscle fibers by inflammatory cells (partial invasion); protecting and mediating factors present in muscle; the association of other diseases with IIM, in particular celiac disease ; the evaluation of two classification systems and laboratory methods for increased diagnostic performance.The studies: We included 106 patients, diagnosed at the Neuromuscular unit in Linköping, Sweden, with pathological muscle findings consistent with IIM. The incidence in the county of Östergötland (during 5 years) was 7.3 per million/year (3 patients each year). Of 88 patients with confirmed IIM 4 (4.5 %) had celiac disease, 33 (38%) had an associated systemic inflammatory disease and 5 (5.7 %) had a malignancy. Ninety-nine patients were included for a comparison of two classification systems using criteria of the European Neuromuscle Centre (Amato/ENMC), and the widely used Bohan and Peter classification, both with the addition of IBM according to Griggs et al. Using the Amato/ENMC criteria the most prevalent diagnostic group after IBM (30%) was nonspecific myositis (23%), followed by polymyositis (20%) and dermatomyositis 17%). A substantial number of patients meeting Bohan and Peter (or Griggs) criteria were excluded by Amato/ENMC criteria, most (21/23) due to lack of detectable muscle weakness. Extended muscle sectioning increased the sensitivity of a muscle biopsy by 15 % and the specificity by 22%, and showed an overlap between disease groups. Muscle biopsies from patients with IIM and controls were used to investigate pathological findings considered specific for disease groups, and for the presence of programmed cell death (apoptosis) and disease protecting and mediating factors in muscle. The presence of apoptotic muscle fiber nuclei was detected in muscle with partial invasion (however not in the invaded fibers) in the presence of granzyme B and CD8+ cytotoxic T cells. The major apoptosis inhibiting protein Bcl-2 was shown to be constitutionally expressed in healthy muscle but weakened in IIM.Conclusion: We present apoptosis as a possible disease mechanism in parallel with partial invasion of fibers. Furthermore, partial invasion may not be a suitable distinguishing feature in the pathogenesis, or for classification and diagnosis of IIM. We also introduce the anti-apoptotic Bcl-2 as a possible relevant muscle fiber protecting factor. A more extensive pathological work-up improves classification and diagnosis of IIM. The proposed Amato/ENMC creates a substantial portion of patients with non-specific or unclassified myositis. Associated diseases are common in IIM, and also include celiac disease.
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| 5. |
- Erelund, Sofia, 1983-
(författare)
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Heart and lung function - in health and disease : methodological studies in clinical physiology
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human heart and lungs constitute an intricate and dynamic system. Various clinical physiological examinations can be used to evaluate cardio-pulmonary function and identify abnormalities. Thus, it is important to understand how normal physiology presents, to be able to identify pathological findings. To distinguish normal from abnormal findings in a patient population compared to healthy controls, adequate, accurate and up-to-date reference materials are required. There is currently a lack of well-established sex and age specific reference materials that clearly state boundaries of normality for electrocardiography (ECG) variables. For lung function examinations there are several different reference materials available, being discordant between ethnicities. In addition, the relation between lung function, age, sex, and height has generally been difficult to model in an optimal way. This highlights the need for more adequate sex-specific models regarding age- and height-dependency of spirometry variables. Heart rate variability (HRV) is a method for evaluating the autonomic nervous system (ANS) and its influence on heart rate and blood pressure. Autonomic disturbances are characterized by an imbalance between the sympathetic and the parasympathetic nervous systems. It is well known that decreased HRV is associated with increased mortality. Autonomic imbalances are also associated with various pathological conditions, of which rheumatoid arthritis (RA) and ischemic heart disease (IHD) are studied in this thesis.The purpose of this thesis was to describe the properties of different clinical physiological examinations and to investigate reference values relating to cardiovascular and pulmonary function in healthy individuals regarding age and sex. In addition, the aim was to assess the relationship between HRV, RA and CVD both cross sectionally and longitudinally. In a subjectively healthy population (n=219) of varying age, there were age and sex-dependent differences in ECG examinations. This emphasizes former findings and supports the need to establish age- and sex-specific reference values in the future. Lung function examinations in subjectively healthy persons (n=285) support and emphasize that the reference values presented by the Global Lung function Initiative (GLI) underestimate the pulmonary function in the adult Swedish population. The study showed that the model used in GLI can be updated with new values that are specific for the Caucasian population in Sweden. Patients with RA (n=50) presented with lower HRV than healthy controls (n=100) during autonomic provocation tests, both at baseline examinations and after five years. This indicates a cardiac autonomic imbalance. Furthermore, increased systolic blood pressure was associated with reduced HRV, thus a decrease in HRV could be a risk marker for developing arterial hypertension in this patient group.Females with IHD (n=197) presented with lower HRV compared to controls (n=141) at baseline, and a higher mortality rate after 15 years. The higher mortality rate was only present in females < 60 years of age. For measurements obtained in the upright position, HRV was higher in females that died during follow-up compared to those who were alive. This thesis emphasizes the importance of validated and updated sex- and age- specific reference materials, and models that are well suited for different clinical physiological examinations. Additionally, HRV examinations exposed changes in the ANS related to RA as well as IHD, where findings were shown to be persistent over time and particularly pronounced during provocations. In the future, HRV assessment could be a useful tool to identify the increased risk of developing hypertension in patients with RA, or to customize treatment based on ANS response as the field of personalized medicine continues to evolve.
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| 6. |
- Law, Lucy, 1987-
(författare)
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Subclinical cardiovascular disease and health related quality of life in patients with radiographic axial spondyloarthritis
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Radiographic axial spondyloarthritis (r-axSpA) is a chronic inflammatory rheumatic disease predominantly affecting the axial skeleton. The global prevalence of r-axSpA is between 0.1-1.4%. The disease is associated with extra-musculoskeletal manifestations (EMMs) such as anterior uveitis (AU), as well as increased risk of cardiovascular disease (CVD)-related comorbidities such as atherosclerosis that significantly contribute to mortality and the burden of disease in patients with r-axSpA. The increased CVD risk is not fully explained by traditional CVD risk factors, and little is known about the difference in CVD risk profiles between the sexes. Moreover, the association of disease related variables and subclinical signs of CVD by ultrasound remain to be comprehensively investigated in a well-characterized and sex stratified patient cohort. Additionally, studies investigating factors related to health-related quality of life (HRQoL) in patients with r-axSpA acknowledge that r-axSpA patients have a lower HRQoL than the general population. However, constancy in study methods and comparison to general population controls, especially stratified by sex, are limited. Objectives: The global aim of this thesis was to explore novel methods relating to the evaluation, detection, and monitoring of factors contributing to the burden of CVD in patients with r-axSpA, and to increase knowledge about HRQoL. More specifically, to study the impact of r-axSpA on HRQoL (Paper 1) and identify novel ultrasound markers of subclinical CVD (Papers 2-4) in patients with r-axSpA, overall, stratified by sex, and compared to controls. Materials and methods: Paper 1: The Short Form-36 (SF-36) questionnaire was used to assess HRQoL in patients with r-axSpA from Western Sweden (n=210, females 42.4%). Each patient was compared to 5 age- and sex-matched persons from the SF-36 Swedish normative population database (n=1055). Papers 2-4: Ultrasound was used to (i) assess bilateral common carotid arterial (CCA) stiffness by calculation of b-stiffness index and circumferential 2D strain (Paper 2); (ii) measure mean bilateral carotid intima media thickness (cIMT) and investigate its relationship with biomarkers of inflammation (Paper 3); and (iii) assess the mean thickness of the epicardial adipose tissue (EAT) deposit and its associations with traditional CVD related risk factors (Paper 4). Papers 2-4 used a well characterized patient group from Northern Sweden (‘Backbone cohort’, n=155, female 31.0%). The control group for paper 2 included 46 age- and sex- matched persons from the local population, with no traditional CVD risk factors. The control group for papers 3 and 4, was derived from the Umeå region Swedish CArdioPulmonary bioImaging Study (SCAPIS) recall study (n= 400, females 51.0%). All results were presented stratified by sex. Uni- and multi-variate regression analysis methods were used to evaluate associations with disease and demographic variables. All studies were of cross-sectional design.Results: Paper 1: Patients exhibited significantly lower HRQoL compared to controls (P<0.001). Upon stratification by sex, both sexes scored significantly lower physical compared to the mental HRQoL scores. Multivariable logistic regression analysis found that patients with a longer disease duration, worse physical function (assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI), high disease activity (measured by the Ankylosing Spondylitis Disease Activity Score (ASDAS)), or who lived alone had significantly lower physical HRQoL. Lower mental HRQoL was associated with fatigue, high ASDAS and living alone. Some differences in sex were also found. Paper 2: Patients had higher mean bilateral CCA b-stiffness index, and lower 2D CCA circumferential strain, compared to controls. Multivariate linear regression analysis found that several disease related parameters, in addition to age, were related to 2D circumferential strain (R2 0.33), whereas only age was related to b-stiffness index (R2 0.19). Paper 3: Linear regression analysis, with various adjustment models, showed that patients had increased cIMT compared to controls. White blood cell (WBC)- and monocyte- count were the only inflammatory biomarkers associated with cIMT. This association was only seen in male patients and remained after adjustments. Paper 4: Mean EAT was thicker in r-axSpA patients overall and stratified by sex compared to controls. No difference in mean EAT was found between the sexes. There were borderline significant associations between EAT thickness and cholesterol levels in male patients.Conclusion: Patients with r-axSpA have decreased HRQoL and increased subclinical indicators of CVD compared to controls. By modifying factors, such as ASDAS-CRP and fatigue, HRQoL may be improved in patients with r-axSpA. Additionally, ultrasound methods are non-invasive, and easily obtainable, offering additional insights into the factors that influence the risk of CVD in r-axSpA patients. Although further studies are required to validate novel ultrasound methods, these techniques represent a powerful approach to non-invasively to detect, monitor, and help manage CVD related comorbidities.
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| 7. |
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| 8. |
- Chalise, Jaya Prakash
(författare)
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Immune tolerance by interferon-alpha in experimental arthritis
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type I Interferons (mainly IFN-α & IFN-β) belong to a family of cytokines that possess strong antiviral and immunomodulatory properties. Pro- and/or anti-inflammatory effects of type I IFN have been observed in infectious diseases and several autoimmune diseases including SLE, MS, RA and experimental models thereof, but what defines either outcome is largely obscure. The main aim of this thesis is to understand how IFN-α may act anti-inflammatory in a model of antigen-induced arthritis (AIA). In this model, mice are sensitised with methylated-BSA (mBSA) emulsified in Freund’s adjuvant at day 1 and 7 followed by intra-articular injection of mBSA in the knee joint at day 21, which induces arthritis within 1 week.Administration of IFN-α at the time of mBSA sensitisations (day 1 and day 7) but not at induction of arthritis (day 21) clearly protected against arthritis in a type I IFN receptor dependent manner. Humoral immunity might not be involved in this protection as the levels of antigen-specific IgG (total, IgG1, IgG2a and IgG2b), IgA, IgE in serum were not altered in IFN-α treated mice. However, IFN-α-protection was accompanied by delayed and decreased antigen-specific proliferative responses in spleen and lymph node cells ex vivo, including impaired proliferative recall responses after intra-articular antigenic challenge.In the course of AIA, IFN-α inhibited the increase of circulatory IL-6, IL-10, IL-12, and TNF in the sensitisation phase (day 0-21) and also the re-call response of IL-1β, IL-10, IL-12, TNF, IFN-γ, and IL-17 induced by intra-articular mBSA challenge in arthritis phase (day 21-28). This IFN-α-inhibition of cytokines was also apparent in mBSA-re-stimulated spleen and lymph node cell cultures ex vivo, including inhibited cytokine production in CD4+ T helper cells and macrophages. In contrast to the inhibition of pro-inflammatory cytokines, the levels of immunomodulatory TGF-β was clearly enhanced in IFN-α-treated mice, both in serum and in re-stimulated leucocytes cultures including both macrophages, especially in the sensitisation phase, and in CD4+ T cells in the arthritis phase. By inhibiting TGF-β signalling in vivo, the protective effect of IFN-α was shown to be dependent on TGF-β signalling in the sensitisation phase.The cytokine TGF-β is an activator of the indoleamine 2,3 dioxygnese (IDO1), a potent immuneregulatory component that acts via enzymatic production of kynurenine (Kyn) and signalling activity. The IFN-α-protective effect in AIA was associated with both increased expression and enzymatic activity of IDO1 and the IFN-α-protection was totally ablated in mice lacking IDO1 expression (IDO1 KO mice) and in mice treated with the inhibitor of the enzymatic activity of IDO1 (1-Methyl Tryptophan; 1-MT). Interestingly, administration of the IDO-metabolite Kyn protected mice from AIA in an IFNARindependent manner. These observations show that the IDO1 enzymatic activity is important for the protective effect of IFN-α. Using 1-MT, it was further shown that the enzymatic activity of IDO1 was, like TGF-β, crucial only at the sensitisation but not in the arthritis phase of AIA for IFN-α to protect against arthritis. Instead, IDO1’s non-enzymatic signalling activity, characterized by sustained expression of IDO1 and non-canonical NF-κB activation in pDCs, was observed in the arthritis phase in spleen cells from mice treated with IFN-α.Regulatory T cells (Treg cells) were also found to be important for IFN-α-protection in AIA. Transient depletion of Treg cells by diphtheria toxin in DEREG mice in the arthritis phase, but not during the sensitisation phase abolished IFN-α-protection. Treatment with IFN-α enhanced the numbers of Treg cells in the course of AIA and their function; compared to untreated mice, Treg cells isolated at day 10 and 20 of AIA from IFN-α- treated mice exhibited higher suppressive activity against mBSA-stimulated proliferation of responder T cells. The enhancing effect of IFN-α on Treg cell numbers was observed in blood, spleen, LNs and also in ex-vivo cultures of leucocytes re-stimulated with mBSA and IFN-α. Although IFN-α clearly increased the suppressive activity of Treg cells, adoptive transfer of Treg cells from mBSA immunized mice, regardless of IFN-α treatment, prevented the development of arthritis.ConclusionIn the presence of IFN-α during antigen sensitisation, a state of tolerance is established, which is able to prevent joint inflammation induced by antigenic re-challenge. This immunological tolerance is created in the sensitisation phase of AIA and is characterized by inhibition of pro-inflammatory cytokines, increased TGF-β production and activity of the IDO1 enzyme, the latter two being indispensable for IFN-α-induced protection. Administration of Kyn, the metabolite of the enzymatic activity of IDO1, in the sensitisation phase also protected against AIA downstream of type I IFN signalling. In the arthritis phase regulatory T cells, whose numbers and suppressive capacity was clearly enhanced by IFN-α, mediate the actual prevention of arthritis development in IFN-α-treated animals. We have thus identified molecular and cellular components of the anti-inflammatory program elicited by IFN-α including Kyn that may not have the pro-inflammatory effects associated with IFN.
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| 9. |
- Bremell, Daniel, 1978
(författare)
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Lyme Neuroborreliosis - Diagnosis and Treatment
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lyme neuroborreliosis, the infection of the nervous system by the tick-borne bacterium Borrelia burgdorferi, is a common infection in the temperate parts of the Northern hemisphere. Manifestations of the disease include facial palsy, radicular pain, sensory disturbances, and occasionally CNS symptoms such as confusion and paraparesis. The diagnosis of Lyme neuroborreliosis is based on medical history, clinical examination and cerebrospinal fluid (CSF) analysis. Recommended antibiotic treatment is oral doxycycline or intravenous ceftriaxone. The overall aims of this thesis were to improve the diagnosis and treatment of Lyme neuroborreliosis. In paper I, 102 patients with peripheral facial palsy were studied. Onset of symptoms in July to October, additional neurological symptoms and CSF pleocytosis were factors that discriminate patients with peripheral facial palsy caused by Lyme neuroborreliosis from patients with Bell’s palsy. In paper II, it was shown that CSF levels of the chemokine CXCL13 are highly elevated in Lyme neuroborreliosis and that levels decline after treatment, but high and overlapping CXCL13 levels were also seen in patients with asymptomatic HIV-infection and the decrease in CXCL13 is correlated to the decrease in CSF cell count. The additional diagnostic value of CXCL13 analysis is therefore limited. In paper III, new reference ranges for CSF cell counts when analyzed with automatic cell counters were determined, based on CSF sampling of 80 healthy volunteers. The differentiation of mononuclear cells into lymphocytes and monocytes was shown to be of limited value in the discrimination between Lyme neuroborreliosis and viral CNS infections. In paper IV, it was shown that treatment with oral doxycycline resulted in a similar decrease in CSF mononuclear cell counts in patients with Lyme neuroborreliosis with CNS symptoms compared with patients with peripheral nervous systems symptoms, and that all patients with CNS symptoms improved on treatment with no need for retreatment. Oral doxycycline can therefore be considered an effective treatment for Lyme neuroborreliosis, irrespective of the severity of symptoms.
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| 10. |
- Drivelegka, Panagiota
(författare)
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The population burden of gout and urate in Western Sweden : Prevalence, incidence, comorbidities, and association with cardiovascular disease
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Gout is the most common type of inflammatory arthritis and is associated with several comorbidities and an increased risk of cardiovascular disease (CVD). However, data on the epidemiology and comorbidity patterns of gout in Sweden are scarce, and whether its association with CVD is causal or not, is not clear. Objectives: This thesis aimed to study: I. The incidence and prevalence of gout, and use of urate lowering treatment (ULT) in Western Sweden in 2012; II. The comorbidity pattern of gout at the time of first diagnosis; III. The association between urate levels and markers of subclinical atherosclerosis; IV. The risk of first-time acute coronary syndrome (ACS) in patients with incident gout, compared to the general population. Methods: Part I. By using data from the population-based register VEGA, we identified all patients with ≥1 ICD-coded diagnosis of gout at both primary and specialized health care in Western Sweden. Their dispensed prescriptions were identified through linkage with Prescribed Drug Register. Part II. Cases with first ICD-coded gout diagnosis in the period 2006-2012 were matched to population controls on age, sex, and county at first gout diagnosis. We estimated crude, and age-standardized prevalence and prevalence ratios. Part III. Participants of the pilot Swedish CArdioPulmonary bioImage Study (SCAPIS) underwent radiographic investigations for estimation of Coronary Artery Calcification score (CAC), carotid intima-media thickness (CIMT) and carotid plaque score. Their association with urate levels was assessed with logistic regression analysis. Part IV. Cohorts of patients with incident gout and population controls followed prospectively. Incidence rates (IRs), incidence rate ratios (IRRs), and hazard ratios (HRs) were used for risk estimations. Results: Part I. The prevalence of gout in adults aged ≥ 20 years in 2012 was 1.8% and the incidence was 190 cases per 100,000 person-years. The incidence increased by 50% from 2005 to 2012. Only 42% of gout patients received ULT in 2012. Part II. At the time of first diagnosis, 77% of gout patients had at least one comorbidity, as compared to 56% of the controls. Women with gout were six years older and had higher occurrence of most comorbidities, compared to men. Part III. Serum urate levels >308 µmol/L were associated with the presence of CAC in men (p-value <0.05), but not in women, whereas urate levels were not associated with CIMT or carotid plaques in either men or women. Part IV. Patients with incident gout were at increased risk of first-time ACS, compared to the general population (HR, 1.44; 95%CI, 1.33-1.56). After adjustments for traditional cardiovascular risk factors, this risk was attenuated, but remained significant (HR, 1.15; 95%CI, 1.06-1.25). Conclusions: Gout has an increasing incidence in Western Sweden, but only a minority of gout patients received ULT. The comorbidity burden at the time of first gout diagnosis is high, particularly in women. Urate may be associated with coronary calcification in men. Gout patients are at increased risk of first-time ACS, which is mainly depending on the underlying comorbidities and, to a lesser extent, on gout itself. Our results imply the importance of improvements in the management of gout and its comorbidities in the Swedish health care system, for increased longevity and better quality of life for these patients.
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