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- Eriksson, Jonas K, et al.
(författare)
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Infliximab Versus Conventional Combination Treatment and Seven-Year Work Loss in Early Rheumatoid Arthritis : Results of a Randomized Swedish Trial
- 2016
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Ingår i: Arthritis Care and Research. - : Wiley. - 2151-4658 .- 2151-464X. ; 68:12, s. 1758-1766
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Tidskriftsartikel (refereegranskat)abstract
- Objective To compare long-term work loss in methotrexate-refractory early rheumatoid arthritis (RA) randomized to addition of infliximab or conventional combination treatment. Methods Multicentre, two-arm, parallel, randomized, active-controlled, open-label trial. RA patients with <1y symptom duration were recruited from 15 rheumatology clinics in Sweden between 2002-2005. Patients who did not achieve low disease activity after 3-4 months methotrexate therapy were randomized to addition of infliximab or conventional combination treatment with sulfasalazine+hydroxychloroquine. Yearly sick leave and disability pension days over 7 years after randomization were retrieved from nationwide registers kept by the Swedish Social Insurance Agency. Results Of 210 working age patients, 109 were randomized to infliximab (mean age=48.4y, 73% women) and 101 to conventional treatment (48.7y, 77%). The year before randomization the mean number of annual work days lost was 127 in the infliximab arm and 118 in the conventional treatment group (mean difference, 9; 95%CI, -23 to 39). Compared to the year before randomization, the mean changes at 7 years were -25 days in the infliximab and -26 days in the conventional treatment group (adjusted mean difference, 10; 95%CI, -25 to 46). The mean cumulative work loss days was 846 in the infliximab group and 701 in the conventional treatment group (adjusted mean difference, 104; 95%CI, -56 to 284). Conclusions Long-term work loss improved significantly in early RA randomized to infliximab+methotrexate or conventional combination therapy. No difference was detected between strategies, and the level of work loss days remained twice that observed in the general population.TRIAL REGISTRATION NUMBER: NCT00764725 This article is protected by copyright. All rights reserved.
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| 2. |
- Fekete, Tünde, et al.
(författare)
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Constraints for monocyte-derived dendritic cell functions under inflammatory conditions.
- 2012
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 42:2, s. 458-69
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Tidskriftsartikel (refereegranskat)abstract
- The activation of TLRs expressed by macrophages or DCs, in the long run, leads to persistently impaired functionality. TLR signals activate a wide range of negative feedback mechanisms; it is not known, however, which of these can lead to long-lasting tolerance for further stimulatory signals. In addition, it is not yet understood how the functionality of monocyte-derived DCs (MoDCs) is influenced in inflamed tissues by the continuous presence of stimulatory signals during their differentiation. Here we studied the role of a wide range of DC-inhibitory mechanisms in a simple and robust model of MoDC inactivation induced by early TLR signals during differentiation. We show that the activation-induced suppressor of cytokine signaling 1 (SOCS1), IL-10, STAT3, miR146a and CD150 (SLAM) molecules possessed short-term inhibitory effects on cytokine production but did not induce persistent DC inactivation. On the contrary, the LPS-induced IRAK-1 downregulation could alone lead to persistent MoDC inactivation. Studying cellular functions in line with the activation-induced negative feedback mechanisms, we show that early activation of developing MoDCs allowed only a transient cytokine production that was followed by the downregulation of effector functions and the preservation of a tissue-resident non-migratory phenotype.
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| 3. |
- Folkersen, Lasse, et al.
(författare)
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Integration of known DNA, RNA and protein biomarkers provides prediction of anti-TNF response in rheumatoid arthritis : results from the COMBINE study.
- 2016
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Ingår i: Molecular Medicine. - : Springer Science and Business Media LLC. - 1076-1551 .- 1528-3658. ; 22, s. 322-328
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: In rheumatoid arthritis (RA) several recent efforts have sought to discover means of predicting which patients would benefit from treatment. However, results have been discrepant with few successful replications. Our objective was to build a biobank with DNA, RNA and protein measurements to test the claim that the current state-of-the-art precision medicine will benefit RA patients.METHODS: We collected 451 blood samples from 61 healthy individuals and 185 RA patients initiating treatment, before treatment initiation and at a 3 month follow-up time. All samples were subjected to high-throughput RNA sequencing, DNA genotyping, extensive proteomics and flow cytometry measurements, as well as comprehensive clinical phenotyping. Literature review identified 2 proteins, 52 single-nucleotide polymorphisms (SNPs) and 72 gene-expression biomarkers that had previously been proposed as predictors of TNF inhibitor response (∆DAS28-CRP).RESULTS: From these published TNFi biomarkers we found that 2 protein, 2 SNP and 8 mRNA biomarkers could be replicated in the 59 TNF initiating patients. Combining these replicated biomarkers into a single signature we found that we could explain 51% of the variation in ∆DAS28-CRP. This corresponds to a sensitivity of 0.73 and specificity of 0.78 for the prediction of three month ∆DAS28-CRP better than -1.2.CONCLUSIONS: The COMBINE biobank is currently the largest collection of multi-omics data from RA patients with high potential for discovery and replication. Taking advantage of this we surveyed the current state-of-the-art of drug-response stratification in RA, and identified a small set of previously published biomarkers available in peripheral blood which predicts clinical response to TNF blockade in this independent cohort.
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| 4. |
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| 5. |
- Vivar, Nancy
(författare)
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Altered T cell homeostasis during HIV-1 infection : consequences of lymphopenia and chronic T cell activation
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Despite all the intense efforts and important progress achieved worldwide by the scientific community and public-health organizations, the HIV pandemic remains without effective solutions. The pathogenic mechanisms underlying the immunodeficiency that follows HIV-1 infection are still poorly understood. This lack of understanding is likely the main reason why at present there is neither a cure nor a vaccine for HIV-1 infection. In this thesis I address two main aspects of the pathogenesis of HIV-1 infection 1) the enhancement of T cell sensitivity to apoptotic and proliferative signals during lymphopenic conditions and 2) the role of chronic T cell activation in the generation of terminally differentiated T cells that might further contribute to the exacerbation of immune activation observed during HIV-1 infection. In paper I we showed that IL-7, a cytokine that was primarily associated with anti-apoptotic and proliferative effects of T lymphocytes, can potently induce Fas expression on T cells. This implied also an increased sensitivity to Fas mediated apoptosis. The correlation found between serum levels of IL-7, Fas expression and sensitivity to Fas mediated apoptosis exhibited by T cells from HIV-1 infected individuals strongly indicated a role for IL-7 in the enhanced sensitivity of T cells to Fas-mediated apoptosis observed during HIV-1 infection. In paper II, we demonstrate that Fas, previously associated to cell death, can act as a potent co-stimulatory molecule during HIV-1 infection. Of relevance is that the rates of proliferation greatly exceeded the levels of apoptosis upon Fas signals. Moreover, we demonstrate that IL-7 primes T cells to Fas co-stimulatory signals. Hence, the high levels of serum IL-7 associated with HIV-1 infection may enhance the sensitivity of non-activated T cells to Fas mediated apoptosis, while in the case of T cells able to recognize low affinity antigens it might enhance Fas-mediated proliferation. In Paper III, we studied the phenotypic and functional characteristics of CD28- T lymphocytes from both healthy and HIV-1 infected individuals treated with HAART or naïve to treatment. We show that these cells exhibit certain characteristics of senescence and an apoptosis prone phenotype, independently if they originated from healthy or HIV-1 infected individuals. Interestingly, only CD28- T cells from untreated patients showed high levels of apoptosis upon TCR triggering whereas the CD28- T cells from patients undergoing HAART exhibited a strong proliferative response. Our findings suggest viral replication as an important factor regulating the homeostasis of CD28- T cells. In Paper IV we show that naturally occurring CD28- cells, either from healthy or HIV-1 infected individuals, contributed to enhance DC activation. This paper provides evidence for a role of CD28- T cell population in the accelerated inflammatory reactions and immune activation through promoting the production of inflammatory cytokines by DCs. In summary, the work presented in this thesis, possibly provides further insights into the pathogenesis of HIV-1 infection, characterized by a vicious circle formed between lymphopenia-induced rescue mechanisms and chronic immune activation, main inducers of immunodeficiency through the alteration of T cell homeostasis.
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