| 1. |
- Bengtsson, Anders A, et al.
(författare)
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Pharmacokinetics, tolerability, and preliminary efficacy of ABR-215757, a new quinoline-3-carboxamide derivative, in murine and human SLE
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 64:5, s. 1579-1588
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess the efficacy of ABR-215757, a new immunomodulatory small molecule in a murine SLE model, to evaluate the pharmacokinetics and tolerability in SLE patients at doses predicted to be efficacious and safe, and to determine the maximum tolerated dose (MTD). METHODS: The efficacy of ABR-215757 was studied in lupus prone MRLlpr/lpr mice and compared with established SLE treatments. Dose response data of ABR-215757 were together with pharmacokinetic data used to calculate effective and safe clinical doses. The pharmacokinetics and tolerance of ABR-215757 were evaluated in a Phase Ib double-blind, placebo controlled, dose-escalation study where cohorts of SLE patients received daily oral treatment for 12 weeks. RESULTS: Disease inhibition in MRLlpr/lpr mice, comparable to that of prednisolone and mycophenolate mofetil, was obtained with ABR-215757. Prominent effects on disease manifestations, serological markers and a steroid sparing effect were seen for ABR-215757. The pharmacokinetic properties in SLE patients were linear and well suitable for once daily oral treatment. The majority of the adverse events (AEs) were mild or moderate and transient. The most frequent AEs were arthralgia and myalgia, reported at the highest (4.5 and 6 mg/day) dose levels. At 4.5 mg and higher some AEs of severe intensity and serious adverse events (SAEs) were reported. CONCLUSION: ABR-215757 effectively inhibited disease and had a steroid sparing effect in experimental lupus. Clinical doses up to 3 mg/day, dose levels predicted from pre-clinical studies to be efficacious and safe, were well tolerated in the SLE patients. The MTD was concluded to be 4.5 mg/day.
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| 2. |
- Bengtsson, Anders, et al.
(författare)
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Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR-215757), a new quinoline-3-carboxamide derivative: Studies in lupus-prone mice and a multicenter, randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study in patients with systemic lupus erythematosus
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 64:5, s. 1579-1588
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Tidskriftsartikel (refereegranskat)abstract
- Objective To assess the efficacy of paquinimod, a new immunomodulatory small molecule, in a murine lupus model, and to evaluate its pharmacokinetics and tolerability in systemic lupus erythematosus (SLE) patients at doses predicted to be efficacious and safe and determine the maximum tolerated dose. Methods The efficacy of paquinimod was studied in lupus-prone MRL-lpr/lpr mice and compared with that of established SLE treatments. Dose-response data and pharmacokinetic data were used to calculate effective and safe clinical doses of paquinimod. The pharmacokinetics and tolerability of paquinimod were evaluated in a phase Ib double-blind, placebo controlled, dose-ranging study in which cohorts of SLE patients received daily oral treatment for 12 weeks. Results Paquinimod treatment resulted in disease inhibition in MRL-lpr/lpr mice, comparable to that obtained with prednisolone and mycophenolate mofetil; prominent effects on disease manifestations and serologic markers and a steroid-sparing effect were observed. In patients with SLE, the pharmacokinetic properties of paquinimod were linear and well suitable for once-daily oral treatment. The majority of the adverse events (AEs) were mild or moderate, and transient. The most frequent AEs were arthralgia and myalgia, reported with the highest dose levels of paquinimod (4.5 mg/day and 6.0 mg/day). At the 4.5 mg/day dose level and higher, some AEs of severe intensity and serious adverse events were reported. Conclusion Paquinimod effectively inhibited disease and had a steroid-sparing effect in experimental lupus. Results from preclinical models together with pharmacokinetic data were successfully translated into a safe clinical dose range, and doses of up to 3.0 mg/day were well tolerated in the SLE patients. Taken together, the promising combined data from a murine model and human SLE support the future clinical development of paquinimod.
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| 3. |
- Blomberg, Jonas, et al.
(författare)
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Increased antiretroviral antibody reactivity in sera from a defined population of patients with systemic lupus erythematosus. Correlation with autoantibodies and clinical manifestations
- 1994
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 37:1, s. 57-66
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE. The implied role of retroviruses in the pathogenesis of murine systemic lupus erythematosus (SLE) led us to study antiretroviral antibodies in a population-based SLE cohort. METHODS. Immunoassays using whole virus and synthetic peptides were performed on sera from 72 patients with SLE and 88 control subjects. RESULTS. Reactions with whole baboon endogenous virus occurred more frequently in patients with SLE, and correlated with the presence of anti-RNP and anti-Sm. Some retroviral env and gag peptides, several of which were similar to U1 small nuclear RNP, reacted more strongly in patients with SLE, and their presence was correlated with discoid rash, hematologic disorder, and other symptoms. CONCLUSION. These results provide circumstantial evidence for involvement of retroviruses in the pathogenesis of human SLE; further studies should be carried out using other techniques for measurement of retroviral expression.
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| 6. |
- 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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| 7. |
- Lood, Christian, et al.
(författare)
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C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells : a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:10, s. 3081-3090
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: C1q deficiency is the strongest risk factor known for the development of systemic lupus erythematosus (SLE), since almost all humans with a genetic deficiency of C1q develop this disease. Low C1q serum concentration is also a typical finding in SLE during flares, emphasizing the involvement of C1q in SLE pathogenesis. Recent studies have revealed that C1q has a regulatory effect on Toll-like receptor-induced cytokine production. Therefore, we undertook this study to investigate whether C1q could regulate production of interferon-alpha (IFNalpha). METHODS: Peripheral blood mononuclear cells (PBMCs) and plasmacytoid dendritic cells (PDCs) were stimulated with 3 known interferogenic stimuli and cultured with physiologic concentrations of C1q. IFNalpha production was determined by an immunoassay. RESULTS: C1q significantly inhibited PBMC IFNalpha production induced by RNA-containing immune complexes (ICs), herpes simplex virus (HSV), and CpG DNA. C1q also inhibited PDC IFNalpha production induced by ICs and CpG DNA but increased PDC IFNalpha production induced by HSV. The regulatory role of C1q was not specific for IFNalpha but was also seen for interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha. We demonstrated binding of C1q to PDCs both by surface plasmon resonance interaction analysis and by flow cytometry, and we also demonstrated intracellular detection of 2 C1q binding proteins. CONCLUSION: Our findings contribute to the understanding of why C1q deficiency is such a strong risk factor for SLE and suggest an explanation for the up-regulation of the type I IFN system seen in SLE patients.
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| 8. |
- Lood, Christian, et al.
(författare)
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IgG glycan hydrolysis by endoglycosidase S diminishes the proinflammatory properties of immune complexes from patients with systemic lupus erythematosus: A possible new treatment?
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 64:8, s. 2698-2706
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Tidskriftsartikel (refereegranskat)abstract
- Objective Systemic lupus erythematosus (SLE) is an autoimmune disease with chronic or episodic inflammation in several organ systems, related to the presence of circulating and tissue-deposited immune complexes (ICs) that stimulate leukocytes through Fc? receptors (Fc?R) with subsequent inflammation. Treatment with endoglycosidase S (EndoS), an IgG glycanhydrolyzing bacterial enzyme from Streptococcus pyogenes, has shown beneficial effects in several experimental animal models of chronic inflammatory disease. This study was undertaken to investigate whether EndoS affects the proinflammatory properties of ICs and has the potential to be developed as a therapy for SLE. Methods ICs purified from SLE patients or RNA-containing ICs formed in vitro were treated with EndoS and used in several assays reflecting different important features of SLE pathogenesis, such as phagocytosis by polymorphonuclear cells (PMNs) and plasmacytoid dendritic cells (PDCs), complement activation, and interferon-a (IFNa) production by PDCs. Results EndoS treatment abolished all proinflammatory properties of the ICs investigated. This included Fc?R-mediated phagocytosis by PDCs (P = 0.001) and subsequent production of IFNa (P = 0.002), IC-induced classical pathway of complement activation (P = 0.008), chemotaxis, and oxidative burst activity of PMNs (P = 0.002). EndoS treatment also had a direct effect on the molecular structure of ICs, causing decreased IC size and glycosylation. Conclusion Our findings indicate that EndoS treatment has prominent effects on several pathogenetically important IC-mediated events, and suggest that EndoS has the potential to be developed as a novel therapy for SLE.
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| 9. |
- Lood, Christian, et al.
(författare)
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IgG glycan hydrolysis by EndoS diminishes the pro-inflammatory properties of immune complexes from patients with SLE : a possible new treatment?
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 64:8, s. 2698-2706
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVESystemic lupus erythematosus (SLE) is an autoimmune disease with chronic or episodic inflammation in several organ systems, related to the presence of circulating and tissue-deposited immune complexes (ICs) which stimulate leukocytes through FcγRs with subsequent inflammation. Treatment with EndoS, an IgG glycan hydrolyzing bacterial enzyme from Streptococcus pyogenes, has shown beneficial effects in several experimental animal models of chronic inflammatory disease. In the present study we asked if EndoS could affect pro-inflammatory properties of ICs and have the potential to be developed as a therapy in SLE.METHODSICs, purified from SLE patients or RNA-containing ICs formed in vitro, were treated with EndoS and used in several assays reflecting different important parts of SLE pathogenesis such as phagocytosis by polymorphonuclear neutrophils (PMNs) and plasmacytoid dendritic cells (pDCs), complement activation and IFNα production by pDCs.RESULTSOur results demonstrate that EndoS treatment could abolish all pro-inflammatory properties of ICs investigated. This includes FcγR-mediated phagocytosis by pDCs (p<0.0001) and subsequent production of IFNα (p<0.0001), IC-induced classical complement pathway activation (p<0.0001), chemotaxis and oxidative burst activity of PMNs (p=0.002). We could also demonstrate direct effects on the molecular structure of ICs after EndoS treatment with decreased size and glycosylation patterns.CONCLUSIONSProminent effects of EndoS treatment were seen in several pathogenetically important IC-mediated events and our data suggest that EndoS have the potential to be developed as a novel therapy in SLE.
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