| 1. |
- Askling, Johan, et al.
(författare)
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Cancer risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor alpha therapies : does the risk change with the time since start of treatment?
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:11, s. 3180-3189
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:To determine the short-term and medium-term risks of cancer in patients receiving anti-tumor necrosis factor alpha (anti-TNFalpha) therapies that have proven effective in the treatment of chronic inflammatory conditions.METHODS:By linking together data from the Swedish Biologics Register, Swedish registers of RA, and the Swedish Cancer Register, we identified and analyzed for cancer occurrence a national cohort of 6,366 patients with RA who first started anti-TNF therapy between January 1999 and July 2006. As comparators, we used a national biologics-naive RA cohort (n = 61,160), a cohort of RA patients newly starting methotrexate (n = 5,989), a cohort of RA patients newly starting disease-modifying antirheumatic drug combination therapy (n = 1,838), and the general population of Sweden. Relative risks (RRs) were estimated using Cox regression analyses, examining overall RR as well as RR by time since the first start of anti-TNF therapy, by the duration of active anti-TNF therapy, and by the anti-TNF agent received.RESULTS:During 25,693 person-years of followup in 6,366 patients newly starting anti-TNF, 240 first cancers occurred, yielding an RR of 1.00 (95% confidence interval 0.86-1.15) versus the biologics-naive RA cohort, and similar RRs versus the other 2 RA comparators. RRs did not increase with increasing time since the start of anti-TNF therapy, nor with the cumulative duration of active anti-TNF therapy. During the first year following the first treatment start, but not thereafter, dissimilar cancer risks for adalimumab, etanercept, and infliximab were observed.CONCLUSION:During the first 6 years after the start of anti-TNF therapy in routine care, no overall elevation of cancer risk and no increase with followup time were observed.
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| 2. |
- Askling, Johan, et al.
(författare)
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Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden
- 2005
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 52:7, s. 1986-1992
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:Because treatment with tumor necrosis factor (TNF) antagonists may increase the risk of tuberculosis (TB), and because knowledge of the risk of TB in rheumatoid arthritis (RA) not treated with biologics is scarce and of uncertain generalizability to low-risk populations, this study sought to determine the risk of TB among Swedish patients with RA.METHODS:Using data from Swedish nationwide and population-based registers and data from an ongoing monitoring program of TNF antagonists, the relative risks of TB in patients with RA (versus the general population) and of TB associated with TNF antagonists (versus RA patients not treated with biologics) were determined by comparing the incidence of hospitalization for TB in 3 RA cohorts and 2 general population cohorts from 1999 to 2001. We also reviewed the characteristics of all reported cases of TB in RA patients treated with TNF antagonists in Sweden and calculated the incidence of TB per type of TNF antagonist between 1999 and 2004.RESULTS:During 1999-2001, RA patients who were not treated with TNF antagonists were at increased risk of TB versus the general population (relative risk 2.0, 95% confidence interval [95% CI] 1.2-3.4). RA patients treated with TNF antagonists had a 4-fold increased risk of TB (relative risk 4.0, 95% CI 1.3-12) versus RA patients not treated with TNF antagonists. The reported TB cases during 1999-2004 in RA patients exposed to TNF antagonists (9 infliximab, 4 etanercept, 2 both) were predominantly pulmonary. TB occurred up to 3 years following the start of treatment.CONCLUSION:Irrespective of whether TNF antagonists are administered, Swedish patients with RA are at increased risk of TB. During 1999-2001, TNF antagonists were associated with an increased risk of TB, up to 4-fold in magnitude. This increased risk may persist over time during treatment and is related to both infliximab and etanercept.
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| 3. |
- Blomberg, Stina, et al.
(författare)
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Expression of the markers BDCA-2 and BDCA-4 and production of interferon-alpha by plasmacytoid dendritic cells in systemic lupus erythematosus
- 2003
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 48:9, s. 2524-32
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To study the expression of blood dendritic cell antigen 2 (BDCA-2) and BDCA-4 molecules by plasmacytoid dendritic cells (PDCs) in the blood of patients with systemic lupus erythematosus (SLE), and to study PDC production of interferon-alpha (IFN alpha) and its inhibition by anti-BDCA-2 and anti-BDCA-4 antibodies. METHODS: Peripheral blood mononuclear cells (PBMCs) from SLE patients (SLE PBMCs) and from healthy controls were induced to produce IFN alpha in vitro by SLE serum containing an endogenous IFN alpha-inducing factor (SLE-IIF) or by herpes simplex virus type 1 (HSV-1). The frequencies and numbers of BDCA-2-, BDCA-3-, and BDCA-4-expressing cells were analyzed by flow cytometry, and the effects of anti-BDCA-2 and anti-BDCA-4 monoclonal antibodies (mAb) on IFN alpha production were investigated. RESULTS: IFN alpha production by SLE PBMCs induced by SLE-IIF or HSV-1 was decreased compared with that of healthy control PBMCs (P = 0.002 and P = 0.0007, respectively). The proportions of BDCA-2- and BDCA-3-expressing cells in SLE PBMCs were reduced compared with those in PBMCs from healthy controls (P = 0.01 and P = 0.004, respectively). IFN alpha producers in culture, especially among SLE PBMCs, displayed reduced BDCA-2 expression and constituted only a minority of the BDCA-2-positive cells, at least in healthy control PBMCs (median 18%). IFN alpha production by both SLE and healthy control PBMCs stimulated by SLE-IIF or HSV-1 was markedly reduced by anti-BDCA-2 mAb (median 81-98% inhibition). Anti-BDCA-4 mAb only partially inhibited SLE-IIF-induced IFN alpha production. CONCLUSION: SLE patients had a reduced number of BDCA-2-expressing PDCs, also termed natural IFN alpha-producing cells, and their IFN alpha production could be inhibited by anti-BDCA-2/4 mAb. Such mAb may be a therapeutic option for inhibiting the ongoing IFN alpha production in SLE patients.
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| 4. |
- Brodin, N., et al.
(författare)
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Coaching patients with early rheumatoid arthritis to healthy physical activity : A multicenter, randomized, controlled study
- 2008
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Ingår i: Arthritis and Rheumatism. - Hoboken, NJ : Wiley. - 0004-3591 .- 1529-0131. ; 59:3, s. 325-331
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To investigate the effect of a 1-year coaching program for healthy physical activity on perceived health status, body function, and activity limitation in patients with early rheumatoid arthritis. Methods. A total of 228 patients (169 women, 59 men, mean age 55 years, mean time since diagnosis 21 months) were randomized to 2 groups after assessments with the EuroQol visual analog scale (VAS), Grippit, Timed-Stands Test, Escola Paulista de Medicina Range of Motion scale, walking in a figure-of-8, a visual analog scale for pain, the Health Assessment Questionnaire disability index, a self-reported physical activity questionnaire, and the Disease Activity Score in 28 joints. All patients were regularly seen by rheumatologists and underwent rehabilitation as prescribed. Those in the intervention group were further individually coached by a physical therapist to reach or maintain healthy physical activity (=30 minutes, moderately intensive activity, most days of the week). Results. The retention rates after 1 year were 82% in the intervention group and 85% in the control group. The percentages of individuals in the intervention and control groups fulfilling the requirements for healthy physical activity were similar before (47% versus 51%, P > 0.05) and after (54% versus 44%, P > 0.05) the intervention. Analyses of outcome variables indicated improvements in the intervention group over the control group in the EuroQol VAS (P = 0.025) and muscle strength (Timed-Stands Test, P = 0.000) (Grippit, P = 0.003), but not in any other variables assessed. Conclusion. A 1-year coaching program for healthy physical activity resulted in improved perceived health status and muscle strength, but the mechanisms remain unclear, as self-reported physical activity at healthy level did not change. © 2008, American College of Rheumatology.
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| 5. |
- Enocsson, Helena, et al.
(författare)
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Interferon-alpha Mediates Suppression of C-Reactive Protein Explanation for Muted C-Reactive Protein Response in Lupus Flares?
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:12, s. 3755-3760
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Tidskriftsartikel (refereegranskat)abstract
- Objective. C-reactive protein (CRP) is synthesized by hepatocytes in response to interleukin-6 (IL-6) during inflammation. Despite raised IL-6 levels and extensive systemic inflammation, serum CRP levels remain low during most viral infections and disease flares of systemic lupus erythematosus (SLE). Because both viral infections and SLE are characterized by high levels of interferon-alpha (IFN alpha), the aim of this study was to determine whether this cytokine can inhibit the induction of CRP. Methods. The interference of all 12 IFN alpha subtypes with CRP promoter activity induced by IL-6 and IL-1 beta was studied in a CRP promoter- and luciferase reporter-transfected human hepatoma cell line, Hep-G2. CRIP secretion by primary human hepatocytes was analyzed by enzyme-linked immunosorbent assay. Results. CRP promoter activity was inhibited by all single IFN alpha subtypes, as well as by 2 different mixtures of biologically relevant IFN alpha subtypes. The most prominent effect was seen using a leukocyte-produced mixture of IFN alpha (56% inhibition at 1,000 IU/ml). The inhibitory effect of IFN alpha was confirmed in primary human hepatocytes. CRP promoter inhibition was dose dependent and mediated via the type I IFN receptor. Transferrin production and Hep-G2 proliferation/viability were not affected by IFN alpha. Conclusion. The current study demonstrates that IFN alpha is an inhibitor of CRP promoter activity and CRP secretion. This finding concords with previous observations of up-regulated IFN alpha and a muted CRP response during SLE disease flares. Given the fundamental role of both IFN alpha and CRP in the immune response, our results are of importance for understanding the pathogenesis of SLE and may also contribute to understanding the differences in the CRP response between viral and bacterial infections.
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| 6. |
- Forsman, Huamei, et al.
(författare)
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Galectin 3 Aggravates Joint Inflammation and Destruction in Antigen-Induced Arthritis
- 2011
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Ingår i: ARTHRITIS AND RHEUMATISM. - : John Wiley and Sons, Ltd. - 0004-3591 .- 1529-0131. ; 63:2, s. 445-454
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Galectin 3, an endogenous beta galactoside-binding lectin, plays an important role in the modulation of immune responses. The finding that galectin 3 is present in the inflamed synovium in patients with rheumatoid arthritis suggests that the protein is associated with the pathogenesis of this disease. We undertook this study to investigate the influence of galectin 3 deficiency in a murine model of arthritis. Methods. Wild-type (WT) and galectin 3-deficient (galectin 3(-/-)) mice were subjected to antigen-induced arthritis (AIA) through immunization with methylated bovine serum albumin. The concentration of serum cytokines (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNF alpha]) and antigen-specific antibodies was evaluated using a cytometric bead array platform and enzyme-linked immunosorbent assay (ELISA). Cellular IL-17 responses were examined by flow cytometry, ELISA, and enzyme-linked immunospot assay. Results. The joint inflammation and bone erosion of AIA were markedly suppressed in galectin 3(-/-) mice as compared with WT mice. The reduced arthritis in galectin 3(-/-) mice was accompanied by decreased levels of antigen-specific IgG and proinflammatory cytokines. The frequency of IL-17-producing cells in the spleen was reduced in galectin 3(-/-) mice as compared with WT mice. Exogenously added recombinant galectin 3 could partially restore the reduced arthritis and cytokines in galectin 3(-/-) mice. Conclusion. Our findings show that galectin 3 plays a pathogenic role in the development and progression of AIA and that the disease severity is accompanied by alterations of antigen-specific IgG levels, systemic levels of TNF alpha and IL-6, and frequency of IL-17-producing T cells. To our knowledge, this is the first report of in vivo evidence that galectin 3 plays a crucial role in the development of arthritis.
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| 7. |
- Kastbom, Alf, et al.
(författare)
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Fcγ receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis
- 2007
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 56:2, s. 448-452
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To determine whether a functional single-nucleotide polymorphism in the gene encoding Fc receptor type IIIA (FcRIIIA) correlates with the response to treatment with tumor necrosis factor inhibitors in rheumatoid arthritis (RA). Methods: The study population comprised 282 Swedish patients with RA in whom the therapeutic efficacy of conventional disease-modifying antirheumatic drugs had been insufficient. Infliximab or etanercept treatment was initiated, and patients were evaluated after 3 months, using the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 or the European League Against Rheumatism (EULAR) criteria. The chi-square test was used to compare response rates across FcRIIIA genotypes. Results: No differences in genotype distribution were observed among nonresponders compared with ACR20 responders (P = 0.80), ACR50 responders (P = 0.56), or ACR70 responders (P = 0.91). Similar results were observed when analyzing infliximab and etanercept separately or when using the EULAR response criteria. Conclusion: Unlike the findings of a previous study, the results of the current study suggest that the 158V/F polymorphism of FcRIIIA is very unlikely to influence the clinical efficacy of infliximab or etanercept in patients with RA.
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| 8. |
- Liedberg, Gunilla, et al.
(författare)
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Factors of Importance for Work Disability in Women with Fibromyalgia : An Interview Study
- 2002
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Ingår i: Arthritis Care and Research. - 1529-0131. ; 47:3, s. 266-274
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Fibromyalgia symptoms such as continuous pain, tiredness, hyperalgesia, and allodynia limit gainful employment. The present study examines which factors influence the decision to remain in a work role for women with fibromyalgia. This information is important for the individual and for public finances. Methods: Qualitative interviews were performed with 39 women, 19 of whom were gainfully employed and 20 who had stopped working. The transcribed interviews were analyzed and divided into categories and subcategories. Results: Four categories appear, at societal and individual levels, that were regarded as important by the women for remaining in a work role. Conclusions: The ability to remain at work depends not only on limitations in work capacity, but also on the capacity of society to adjust work environments and work tasks. More individual solutions are needed to allow women with fibromyalgia to maintain work roles.
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| 9. |
- Liu Carlsen, Anting, et al.
(författare)
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Circulating MicroRNA Expression Profiles Associated With Systemic Lupus Erythematosus
- 2013
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Ingår i: Arthritis and Rheumatism. - : Wiley-Blackwell. - 0004-3591 .- 1529-0131. ; 65:5, s. 1324-1334
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Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate the specificity of expression patterns of cell-free circulating microRNAs (miRNAs) in systemic lupus erythematosus (SLE). Methods Total RNA was purified from plasma, and 45 different specific, mature miRNAs were determined using quantitative reverse transcriptionpolymerase chain reaction assays. A total of 409 plasma samples were obtained from 364 different patients with SLE, healthy control subjects, and control subjects with other autoimmune diseases. The results in the primary cohort of 62 patients with SLE and 29 healthy control subjects were validated in 2 independent cohorts: a validation cohort comprising 68 patients with SLE and 68 healthy control subjects, and a disease control cohort comprising 20 patients with SLE (19 of whom were from the other validation cohort), 46 healthy control subjects, 38 patients with vasculitis, 18 patients with rheumatoid arthritis, and 20 immunosuppressed patients. Results Seven miRNAs were statistically significantly differentially expressed in plasma from patients with SLE. The expression of miRNA-142-3p (miR-142-3p) and miR-181a was increased, and the expression of miR-106a, miR-17, miR-20a, miR-203, and miR-92a was decreased. In addition, the expression of miR-342-3p, miR-223, and miR-20a was significantly decreased in SLE patients with active nephritis. A predictive model for SLE based on 2 or 4 miRNAs differentiated patients with SLE from control subjects (76% accuracy) when validated independently (P andlt; 2 x 109). Use of the 4-miRNA model provided highly significant differentiation between the SLE group and disease controls, except for those with vasculitis. Conclusion Circulating miRNAs are systematically altered in SLE. A 4-miRNA signature was diagnostic of SLE, and a specific subset of miRNA profiles was associated with nephritis. All of the signature miRNAs target genes in the transforming growth factor signaling pathways. Other targets include regulation of apoptosis, cytokinecytokine receptors, T cell development, and cytoskeletal organization. These findings highlight possible dysregulated pathways in SLE and suggest that circulating miRNA patterns distinguish SLE from other immunoinflammatory phenotypes.
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| 10. |
- Magnusson, Mattias, 1972, et al.
(författare)
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Requirement of type I interferon signaling for arthritis triggered by double-stranded RNA
- 2006
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Ingår i: Arthritis Rheum. - : Wiley. - 0004-3591 .- 1529-0131. ; 54:1, s. 148-57
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Arthralgias and overt arthritides are often associated with viral infections. Viral infections expose the infected host to proinflammatory double-stranded RNA (dsRNA), which can cause joint inflammation and is a potent activator of interferon-alpha (IFNalpha). The aim of this study was to determine the role of IFNalpha and dsRNA-related signaling molecules in the onset of joint inflammation induced by viral dsRNA. METHODS: IFNalpha and different forms of RNA were injected into the knee joints of wild-type mice, mice lacking the type I interferon receptor (IFNAR(-/-)), and mice deficient in dsRNA-dependent protein kinase (PKR(-/-)). Histologic evidence of joint damage and the ability of splenocytes to produce cytokines in response to dsRNA or IFNalpha were assessed. RESULTS: Viral dsRNA, but not short single-stranded RNA, induced arthritis. The arthritis was aggravated by intracellular delivery of dsRNA. The expression of PKR was not mandatory for dsRNA-induced joint inflammation. In contrast, IFNalpha/beta signaling was important for dsRNA-induced joint inflammation because IFNAR(-/-) mice did not develop arthritis. Furthermore, intraarticular deposition of IFNalpha induced arthritis in PKR(-/-) and control mice, whereas IFNAR(-/-) mice were protected. The arthritogenic effect of IFNalpha was attenuated by in vivo depletion of monocyte/macrophages. CONCLUSION: Arthritis triggered by dsRNA is not dependent on the expression of the dsRNA-signaling molecule PKR (or Toll-like receptor 3, as previously shown), but is associated with the ability to produce type I IFN and is critically dependent on type I IFN receptor signaling. The intrinsic arthritogenic properties of IFNalpha implicate a role of this cytokine in joint manifestations triggered by various interferogenic stimuli.
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