| 1. |
- Aldridge, Jonathan, et al.
(författare)
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Blood chemokine levels are markers of disease activity but not predictors of remission in early rheumatoid arthritis.
- 2022
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Ingår i: Clinical and experimental rheumatology. - : Clinical and Experimental Rheumatology. - 0392-856X .- 1593-098X. ; 40:7, s. 1393-1402
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Tidskriftsartikel (refereegranskat)abstract
- In early rheumatoid arthritis (eRA) plasma levels of specific chemokines have been shown to correlate with disease activity. However, it is unclear whether pre-treatment chemokine levels can predict disease remission at week 24, and it is not known how biological treatments with different modes of action affect plasma chemokine levels in patients with untreated eRA.This study included 347 Swedish patients with untreated eRA from the larger NORD-STAR randomised treatment trial. Here, eRA patients were treated with methotrexate combined with either prednisolone, anti-TNF (certolizumab-pegol), CTLA-4Ig (abatacept) or anti-IL6 receptor (tocilizumab). The primary clinical outcome was remission by clinical disease activity index (CDAI) defined as CDAI ≤ 2.8. Disease activity was assessed by CDAI, DAS28-ESR, DAS28-CRP, swollen joint counts, tender joint counts, ESR and CRP. The plasma concentrations of 14 chemokines were measured at baseline and after 24 weeks of treatment by bead-based immunoassay or ELISA.Baseline plasma concentrations of CXCL10, CXCL8, CXCL9, CXCL11, CXCL5 and CCL2 correlated with baseline disease activity measures. After 24 weeks of treatment, plasma levels of CXCL10, CXCL8, CXCL9, CXCL11 and CXCL13 decreased in all treatment groups except in patients treated with anti-IL6 receptor. In multivariate factor analysis, plasma chemokine levels at baseline could not differentiate patients who attained remission by week 24 from those who did not in any of the treatment groups.In patients with untreated eRA, plasma levels of several chemokines correlate with disease activity at baseline but cannot predict remission after 24 weeks of treatment with methotrexate combined with prednisolone, anti‑TNF, CTLA‑4Ig or anti‑IL6R.
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| 2. |
- Gröndal, Gerður
(författare)
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Systemic lupus erythematosus : pathogenesis and genetics with special reference to multicase families
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE) is a prototype for systemic autoimmune disease. The etiology is largely unknown although valuable knowledge has been accomplished through intensive research in this field in recent years. The aim of this thesis was to achieve increased knowledge of the etiology and pathogenesis, in particular the role of genetic and environmental factors, by the use of a combined epidemiologic and experimental approach. Both Icelandic and Swedish SLE patients were investigated. The Icelandic population is rather homogeneous and offers unique possibilities for this kind of studies. The Swedish population has similar ethnic background. In the first study patients and their relatives and spouses in Icelandic SLE multicase families were characterised and a high frequency of autoimmune disorders (AID) was documented in these families. This was observed in the first-degree relatives, and also to some extent in the spouses of SLE patients (AID/ANA). These findings suggest that both genetic and environmental factors could be important in the susceptibility to autoimmune diesases. Cytokines are important molecules involved in regulation of the immune system. The second study deals with the possible role of cytokines, in particular interleukin- 10 (IL- 10), in the pathogenesis of SLE. Production and serum levels of type I and type 2 cytokines in Swedish SLE patients with various disease activity and clinical profile were investigated. Both the production and serum levels of the type 2 cytokines IL-10 and IL-6 were increased in SLE patients regardless of disease activity or clinical manifestations. However, there was a correlation between serum levels of IL-10 and anti-ds DNA antibody titres. These results support a role of IL- 10 in the pathogenesis of SLE and, furthermore, as IL-10 production was independent of disease activity and manifestations it could be constitutively increased. These findings were confirmed in the third study in which increased IL-10 production was found in SLE patients in Icelandic SLE- multicase families. In this study IL-10 production was also increased in first-degree relatives and in a limited number of spouses of SLE patients suggesting that not only genetic but also environmental factors could be involved in this abberrant cytokine production. One way that IL-10 could be involved in the pathogenesis of SLE is via apoptosis, which was investigated in the Icelandic SLE-multicase families in the fourth study. An increased degree of apoptosis of lymphocytes was observed in SLE patients and their spouses but not in their nonhousehold first-degree relatives, supporting a role of environmental factors to be involved in the disturbed apoptosis evident in SLE patients. No correlation, however, was found between IL- 10 and apoptosis. To further clarify the role of genetics in SLE a first approach was made by performing a genome scan of the Icelandic SLE-multicase families as well as Swedish SLE multicase families. A linkage to a region on chromosome 2q37 was determined, this locus was named hSLE1, now officially called SLEB2 and it is not syntenic to any hitherto described mouse SLE locus. In addition, genetic linkage analysis of SLE multicase families from Iceland, Sweden and Mexico revealed no linkage between the IL- 10 gene and SLE. In conclusion, the results of this thesis support a role of IL-10 as well as of apoptosis in the pathogenesis of SLE. Both environmental and genetic factors are important in the disturbed regulation of the immune system and complex interactions between these factors may lead to clinical disease.
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| 3. |
- Kristjánsdóttir, Helga, 1966-, et al.
(författare)
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Association of three systemic lupus erythematosus susceptibility factors, PD-1.3A, C4AQ0, and low levels of mannan-binding lectin, with autoimmune manifestations in Icelandic multicase systemic lupus erythematosus families
- 2008
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 58:12, s. 3865-3872
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To study autoimmune diseases and autoantibodies in Icelandic multicase systemic lupus erythematosus (SLE) families and to determine the association of 3 SLE susceptibility factors, PD-1.3A, C4AQ0, and low levels of mannan-binding lectin (MBL), with autoimmune disease in this population. Methods: Eight SLE multicase families were studied, comprising a total of 124 family members (23 patients with SLE and 101 relatives). The diagnosis of an autoimmune disease was established and autoantibodies were measured in each family. In addition, PD-1.3A alleles were genotyped, and C4AQ0 allotypes were established by electrophoresis and haplotype analysis. Low levels of MBL were determined using enzyme-linked immunosorbent assay and variant-allele genotyping. Results: In the SLE multicase families there was a high frequency of other autoimmune diseases (32.2%) and a high frequency of autoantibodies (53.2%). Of all family members, 59.7% were determined to have SLE, other autoimmune diseases, antinuclear antibodies, and/or other autoantibodies. The families showed genetic heterogeneity for PD-1.3A, C4AQ0, and low MBL levels; the frequency of each factor ranged from 0% to 85%. The frequencies of PD-1.3A and C4AQ0 were significantly increased in patients with SLE, relatives with other autoimmune diseases, and non-autoimmune disease relatives compared with controls. In the 7 families whose members had low levels of MBL, this factor was significantly associated with SLE, but the frequency of low MBL was decreased in relatives with other autoimmune diseases as compared with non-autoimmune disease relatives and controls. There were indications of an additive effect, and 91% of patients with SLE, 78% of relatives with other autoimmune diseases, and 75% of non-autoimmune disease relatives carried at least 1 of the 3 factors. Conclusion: These results demonstrate a high frequency of autoimmune diseases and autoantibodies in SLE multicase families. PD-1.3A and C4AQ0 are part of a predisposing genetic background. Other genetic and/or environmental factors are necessary for disease expression, demonstrated by a high frequency of PD-1.3A and C4AQ0 in non-autoimmune disease relatives. Low MBL levels may be one such contributing factor. The results of this study provide an example of epistatic genetic effects and overlapping genetics in autoimmune diseases.
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| 4. |
- Kristjánsdóttir, Helga, 1966-, et al.
(författare)
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Lower expression levels of the programmed death 1 receptor on CD4+CD25+ T cells and correlation with the PD-1.3A genotype in patients with systemic lupus erythematosus
- 2010
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 62:6, s. 1702-1711
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE.: A genetic polymorphism, PD1.3A, in the PDCD1 gene encoding the co-inhibitory immunoreceptor PD-1, has been associated with SLE. The aim of the study was to assess PD-1 receptor expression in SLE patients, relatives and controls and correlate with PD-1.3A. METHODS.: Icelandic and Swedish SLE patients, relatives and controls were studied. PBMCs were stimulated with alphaCD3/CD28 and PD-1 expression analyzed by flow cytometry. PD-1.3A/G genotyping was performed by PCR-RFLP. RESULTS: I. PD-1 expression on PBMCs was induced after stimulation, by 2.1-fold in SLE patients, 3.1-fold in relatives and 5.1-fold in controls.II. The frequency of PD-1+ cells was significantly lower in SLE patients compared to relatives and controls. PD-1 expression on PD-1+ cells was significantly lower in SLE patients and relatives.III. PD-1 expression on CD4+CD25+ T cells was significantly lower in SLE patients and relatives.IV. PD-1 expression was significantly higher on CD25(high) compared to CD25(intermediate) and (low) cells.V. PD-1 expression on CD25(high) and CD25(intermediate) cells was significantly lower in SLE patients compared to controls.VI. PD-1 was expressed on both FoxP3- and FoxP3+ cells.VII. Lower PD-1 expression was significantly correlated with the PD-1.3A/G genotype. CONCLUSION.: The study demonstrates significantly lower PD-1 receptor expression in SLE patients and relatives and a significant correlation of lower PD-1 expression with the PD-1.3A allele. We conclude that PD-1.3A may be contributory to abnormalities in PD-1 receptor expression on CD4+CD25+ T-cells in SLE, providing support for an important role for the PD-1 pathway in SLE and possibly other autoimmune diseases.
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| 5. |
- Michelsen, Brigitte, et al.
(författare)
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Differences and similarities between the EULAR/ASAS-EULAR and national recommendations for treatment of patients with psoriatic arthritis and axial spondyloarthritis across Europe
- 2023
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Ingår i: The Lancet Regional Health - Europe. - 2666-7762. ; 33
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Forskningsöversikt (refereegranskat)abstract
- This is the first report comparing EULAR and national treatment recommendations for PsA patients across Europe, and the first this decade to compare ASAS-EULAR and national treatment recommendations in axSpA patients. An electronic survey was completed from October 2021–April 2022 by rheumatologists in 15 European countries. One and four countries followed all EULAR and ASAS-EULAR recommendations, respectively. Five countries had no national treatment recommendations for PsA and/or axSpA, but followed other regulations. In several countries, national treatment recommendations predated the most recent EULAR/ASAS-EULAR recommendations. Entry criteria for starting biologic/targeted synthetic disease-modifying anti-rheumatic drugs varied considerably. In several countries, for PsA patients with significant skin involvement, interleukin-17 inhibitors were not given preference. The positioning of Janus Kinase inhibitors differed and Phosphodiesterase-4 inhibitors were not in use/reimbursed in most countries. This study may motivate European countries to update their national treatment recommendations, to align them better with the latest international recommendations.
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| 6. |
- Prokunina, Ludmila, et al.
(författare)
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A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans
- 2002
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 32:4, s. 666-669
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Recension (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE, OMIM 152700) is a complex autoimmune disease that affects 0.05% of the Western population, predominantly women. A number of susceptibility loci for SLE have been suggested in different populations, but the nature of the susceptibility genes and mutations is yet to be identified. We previously reported a susceptibility locus (SLEB2) for Nordic multi-case families. Within this locus, the programmed cell death 1 gene (PDCD1, also called PD-1) was considered the strongest candidate for association with the disease. Here, we analyzed 2,510 individuals, including members of five independent sets of families as well as unrelated individuals affected with SLE, for single-nucleotide polymorphisms (SNPs) that we identified in PDCD1. We show that one intronic SNP in PDCD1 is associated with development of SLE in Europeans (found in 12% of affected individuals versus 5% of controls; P = 0.00001, r.r. (relative risk) = 2.6) and Mexicans (found in 7% of affected individuals versus 2% of controls; P = 0.0009, r.r. = 3.5). The associated allele of this SNP alters a binding site for the runt-related transcription factor 1 (RUNX1, also called AML1) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans.
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