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- Alenius, Gerd-Marie, 1957-
(author)
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A Clinical and Genetic Study of Psoriatic Arthritis
- 2003
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Doctoral thesis (other academic/artistic)abstract
- Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. PsA has a heterogeneous pattern, expressed by different manifestations such as mild mono-oligoarthritis or very severe, erosive and destructive polyarthritis. Measurable inflammatory activity is not always prominent. The aetiology is unknown but genetic factors are believed to be of importance. The pattern of inheritance is proposed to be polygenic. The aim of this study was to estimate the prevalence of joint and axial manifestations, characterise the disease in relation to inflammatory and genetic markers, and to identify disease susceptibility gene(s) for PsA in patients from northern Sweden. All patients from the city of Umeå (n=276), selected from a community and hospital based psoriasis register (n=1737) at the Dept of Dermatology, were invited to a prevalence study. Two hundred-two patients were examined and 97 (48%) had inflammatory manifestations such as peripheral arthritis, axial disease, undifferentiated spondylarthropathy (uSpA) and enthesopathies. Of the 67 patients (33 %) with peripheral arthritis and/or axial disease, 30 were not previously diagnosed. The association of clinical manifestations and potential markers of aggressive joint disease with HLA associations were analysed in 88 patients with PsA. We were not able to confirm findings of other groups reporting strong association with several HLA-antigens. The prevalence of HLA-B17, B37 and B62 was increased compared with controls, but the strongest predictive factors among our patients for an aggressive disease, in a multiple logistic analysis, were polyarthritic disease and distal interphalangeal engagement. In order to investigate for disease susceptibility genes, five genetic loci were analysed with microsatellites and single nucleotide polymorphisms in an association study of 120 patients with PsA. There was a significant association with the TNFB locus on chromosome 6p but not with any other loci examined; 1q21 (PSORS4), 3q21 (PSORS5), 8q24 and CTLA4. When stratifying for the TNFB alleles the association was confined to allele 123. In a subgroup of patients who were HLA-typed (n=83), we were not able to verify linkage disequilibrium with the TNFB allele 123 and the HLA antigens; B17, B27, B37, B62 or Cw*0602. The presence of renal abnormalities was evaluated as a manifestation of systemic inflammation in 73 patients with PsA. Renal abnormalities defined as decreased creatinine-clearance (≤ mean - 2SD) and/or urinary albumin >25 mg/24 h was found in 23% of the patients. The predictive factors for renal abnormalities was inflammatory activity (ESR > 25 mm/h and/or CRP >15 mg/L) indicating a systemic effect in some of the patients. In conclusion, we found high prevalence of inflammatory manifestations in patients with psoriasis. There was no strong association between PsA and HLA antigens and predictive factors for aggressive disease were polyarthritic disease and DIP joint engagement. The TNFB locus was associated with PsA and there were no linkage disequilibrium with the HLA antigens B17, B27, B62 or Cw*0602. There were evidence for systemic effects as renal abnormalities in patients with PsA and measurable inflammatory activity.
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| 2. |
- Boman, Antonia, 1991-
(author)
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Early rheumatoid arthritis : biomarkers and hormonal factors in relation to disease progression
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Rheumatoid arthritis (RA) is a chronic inflammatory joint disease, affecting approximately 0.5 to 1% of the adult population. Although the aetiology is not fully known, a complex interaction between genetic, environmental and stochastic factors is thought to trigger the pathogenic mechanisms. A distinguishing feature of RA is the presence of disease associated autoantibodies, mainly rheumatoid factor (RF) and anti-cyclic citrullinated antibodies (ACPA), which are important in both diagnostic and prognostic purpose. The disease is systemic but primarily affects the joints, and can cause irreversible destructions of cartilage and bone, eventually leading to functional disabilities. Moreover, extra-articular features (i.e., symptoms outside the joints) can occur and the patients have an increased risk for comorbidities, predominantly cardiovascular disease. Since the disease is heterogenous, varying from mild to more severe forms, the prognosis can be difficult to predict. Improvements in early diagnosis and identification of patients at risk of a more severe disease course can lead to better outcomes for the patients. The overall aim of this thesis was to evaluate prognostic biomarkers, and to evaluate hormonal and reproductive factors in relation to cardiovascular events (CVE) in patients with newly diagnosed RA (symptoms <12 months).Methods: The patients were included in a prospective inception cohort from the years of 1996 to 2017 and followed-up regularly at the early RA clinics in the northern region of Sweden. Clinical and laboratory parameters, and treatment were regularly recorded in the Swedish Rheumatology Quality Register (SRQ). Enzyme-linked immunosorbent assays (ELISA) and a multiplex assay were used to analyse bone remodelling factors and ACPA reactivities, respectively. Questionnaires regarding hormonal and reproductive factors were sent out to female patients ≤80 years. Information of CVE was extracted from the Swedish National Health Register and Cause of Death Register. Potential markers for disease progression i.e., bone remodelling factors and autoantibodies were analysed in relation to disease progression. Hormonal and reproductive factors were analysed in relation to CVE. Results: In paper I we found associations between receptor activator of nuclear factor kappa-B (RANKL), a central molecule of bone metabolism, and radiological findings at baseline, 24 months, and radiological progression analysed in 407 RA patients. The combination of RANKL and anti-CCP positivity indicated a more severe disease course in terms of joint destruction. Sclerostin was not associated with radiological outcome. Polymorphisms of the genes for sclerostin (SOST) and RANKL (TNFSF11) did not show significant associations with radiological outcome or with the concentrations, respectively. In paper II, we found that even though antibody status is considered in clinical practice and modern treatment reduces disease activity, the radiographic joint damage remained increased among anti-CCP positive patients. In paper III, 22 different ACPA reactivities were analysed in relation to disease courses of RA. The presence of a higher number of different ACPA reactivities, and different ACPA subtypes could provide prognostic information of disease activity and radiological destruction. In paper IV, we found that hormonal and reproductive factors were associated with CVE in female patients. A higher number of childbirths increased the risk for CVE, whilst oral contraceptives decreased the risk. The majority of patients with later CVE had their RA disease onset after menopause and had a longer duration from menopause until RA onset.Conclusion: RANKL can function as a prognostic marker for the disease course of RA. Even though anti-CCP antibodies are taken into account in clinical practice and treatment reduce disease activity, the joint damage can progress, supporting the direct bone degrading effects by ACPA. The number of, and different subtypes of ACPA, can predict different disease progression. These markers can be valuable to identify patients at need for more aggressive treatment and careful radiographic monitoring, even if disease activity is under control. Finally, hormonal factors such as childbirths, oral contraceptives and the timing of RA onset in relation to hormonal status can add value for the evaluation of CVE risk in female RA patients.
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| 3. |
- Juneblad, Kristina, 1965-
(author)
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Psoriatic arthritis: a complex disease : analyses on genetic and serological biomarkers and of comorbidity
- 2018
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Doctoral thesis (other academic/artistic)abstract
- Psoriatic Arthritis (PsA) is a heterogonous inflammatory arthritis associated with psoriasis. The disease leads to inflammation of peripheral joints, axial skeleton and/or enthesites, and can result in severe destruction of affected joints. In contrast to rheumatoid arthritis (RA), most individuals with PsA are seronegative for rheumatoid factor (RF) and/or anti-citrullinated protein/peptide antibodies (ACPA) and the distal interphalangeal (DIP) joints are often involved. Dactylitis, a diffuse swelling of an entire digit (finger or toe), is also common. Traditional markers of systemic inflammation, such as erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) are elevated in only 50% of the individuals with PsA.Underlying genetic factors are considered important for the aetiology, disease expression and prognosis of PsA. To date no specific biomarker for PsA disease or disease activity/severity is available and there is a need for diagnostic and prognostic tools to meet the challenge of early diagnosis and assessment of disease severity.An increased risk of co-morbidity, particularly cardiovascular disease (CVD), has been demonstrated in patients suffering from different rheumatic diseases, e.g. systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Corresponding data for patients with PsA are more limited, but evidence exists for an increased risk of mortality and cardiovascular morbidity. However, published results are conflicting and heterogeneity among studies makes interpretation of data difficult.The aim of this study was to investigate genetic and serological biomarkers, and also mortality and cardiovascular comorbidity, in different phenotypes of PsA and in comparison with healthy controls. Patients with PsA were included between 1995 and 2015, the majority from the county of Västerbotten, except for two cohorts from Örnsköldsvik (n=55) and Östersund (n=98).The genetic polymorphism PTPN22+1858C/T, previously found to be associated with several autoimmune diseases, was also found associated with PsA, the results were later confirmed in a genome wide association study (GWAS). Additionally, among PsA patients, the minor allele, T, was associated with the number of deformed joints and dactylitis (Paper I). Genetic polymorphisms in genes related to the inflammasome were also investigated, both in comparison with healthy controls and in relation to different phenotypes of PsA (Paper II). An association was identified between patients with PsA and the polymorphism CARD8-C10X in comparison with controls. In addition, associations between various inflammasome polymorphisms and different clinical phenotypes of PsA were detected.To investigate the relation of serological biomarkers and PsA, individuals with blood samples collected in conjunction with clinical investigation were selected (Paper III). Associations with different biomarkers and different clinical phenotypes of PsA were identified In addition, associations were found with different biomarkers and patients with moderate/high disease activity at clinical investigation, confirming the inflammatory nature of the disease.Mortality and incidence of acute cardiovascular disease were investigated with standardized mortality rateratio (SMR) and standardized incidence ratio (SIR) compared with the general population of Västerbotten (Paper IV). An increased SMR for diseases of the circulatory system in PsA compared with controls was found. Among PsA patients, death was associated with a composite disease activity index (DAI) and with a disease phenotype including both axial- and peripheral joint involvement. In conclusion, associations were found with different clinical phenotypes of PsA, both with genetic polymorphisms and serological biomarkers that confirm the inflammatory nature of the disease and illustrate the disease heterogeneity. As in many other inflammatory diseases, an increased cardiovascular mortality was found that highlights the importance of considering cardiovascular risk factors in patients with PsA.
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| 4. |
- Karlsson Sundbaum, Johanna, 1969-
(author)
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Studies of drug safety in the treatment of rheumatoid arthritis
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting mainly smaller joints. Patients are at risk for complications as joint destruction, but starting treatment soon after onset of disease, has reduced the risk for complications. Methotrexate (MTX) is the anchor drug in the treatment of RA and has proven effects on both inflammatory symptoms and joint destruction. apy. Identifying patients at risk for MTX-induced hepatotoxicity before treatment could be a way to minimize the risk for Adverese effects.Following the introduction of pre-treatment screening, the risk of tuberculosis (TB) among patients with RA starting biologic treatment has decreased. By contrast, the risk remains several-fold increased in RA patients non-exposed to biological treatment. Knowledge about risk factors for TB and TB characteristics in this group of patients, and thus optimal clinical risk stratification and preven-tion, is still limited.In Paper I, only a small number of ALT tests (7%) performed during MTX therapy in RA patients, capture an elevation of ALT > upper limit of normal (ULN). ALT >1.5 × ULN was observed in 44 (21%) patients and the strongest predictor was a pre-treatment elevation of ALT. Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions. The results support a more individualized approach to monitoring and handling of ALT elevations during MTX therapy. In Paper II MTHFR A1298C (rs1801131) was nominally associated with ALT >1.5 x ULN within 6 months after the start of MTX (OR=1.7 [95% CI 1.04-2.9], p=0.03). In a multi-ple regression analysis for ALT >1.5 X ULN within 6 months of treatment start, including known risk factors for ALT elevation and MTHFR A1298C, the C-statistic was 0.734. A mod-el containing clinical risk factors and MTHFR A1298C might be used for prediction of ALT elevation in MTX treated patients. In Paper III a Genome-Wide Association Study (GWAS) and analysis of candidate Single Nucleotide Polymorphisms (SNPs) were performed. Four SNPs in and upstream of the ribonucleoprotein, PTB Binding 2 gene on chromosome 1 were associated with max ALT within 6 months on a genome wide level (p<5x10-8). Our results indicate that the RAVER2 and/or JAK1 genes might play a role in MTX- induced hepatotoxici-ty, but further studies are necessary for confirmation of the results. In Paper IV, we performed a population based case-control study. Several RA-associated risk factors (treatment with leflunomide, azathioprine or prednisolone and concomitant obstructive lung disease) may contribute to the increased TB risk in biologics-naïve RA patients. We could not confirm previous findings of an association with the use of moderate to high doses of prednisolone (≥15 mg). TB risk seems difficult to predict with precision in the individual biologics-naïve patient based on RA-associated risk factors. This suggests TB screening should be considered in biologics-naïve patients.In conclusion, results from these studies suggest that several factors could increase the risk of AEs in RA patients. The risk might be reduced by utilizing prediction models that include knowledge about the medical history of the individual patient and genetic data in combination with screening for TB.
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