| 11. |
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| 12. |
- Crisci, E., et al.
(författare)
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Complement Opsonization Promotes Herpes Simplex Virus 2 Infection of Human Dendritic Cells
- 2016
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Ingår i: Journal of Virology. - : American Society for Microbiology. - 0022-538X .- 1098-5514. ; 90:10, s. 4939-4950
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Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex virus 2 (HSV-2) is one of the most common sexually transmitted infections globally, with a very high prevalence in many countries. During HSV-2 infection, viral particles become coated with complement proteins and antibodies, both present in genital fluids, which could influence the activation of immune responses. In genital mucosa, the primary target cells for HSV-2 infection are epithelial cells, but resident immune cells, such as dendritic cells (DCs), are also infected. DCs are the activators of the ensuing immune responses directed against HSV-2, and the aim of this study was to examine the effects opsonization of HSV-2, either with complement alone or with complement and antibodies, had on the infection of immature DCs and their ability to mount inflammatory and antiviral responses. Complement opsonization of HSV-2 enhanced both the direct infection of immature DCs and their production of new infectious viral particles. The enhanced infection required activation of the complement cascade and functional complement receptor 3. Furthermore, HSV-2 infection of DCs required endocytosis of viral particles and their delivery into an acid endosomal compartment. The presence of complement in combination with HSV-1- or HSV-2-specific antibodies more or less abolished HSV-2 infection of DCs. Our results clearly demonstrate the importance of studying HSV-2 infection under conditions that ensue in vivo, i.e., conditions under which the virions are covered in complement fragments and complement fragments and antibodies, as these shape the infection and the subsequent immune response and need to be further elucidated. During HSV-2 infection, viral particles should become coated with complement proteins and antibodies, both present in genital fluids, which could influence the activation of the immune responses. The dendritic cells are activators of the immune responses directed against HSV-2, and the aim of this study was to examine the effects of complement alone or complement and antibodies on HSV-2 infection of dendritic cells and their ability to mount inflammatory and antiviral responses. Our results demonstrate that the presence of antibodies and complement in the genital environment can influence HSV-2 infection under in vitro conditions that reflect the in vivo situation. We believe that our findings are highly relevant for the understanding of HSV-2 pathogenesis.
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| 14. |
- Di Giuseppe, D, et al.
(författare)
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DIFFERENCES IN DRUG SURVIVAL BETWEEN ORIGINATOR AND BIOSIMILAR PRODUCTS AMONG FIRST USERS OF EACH MOLECULE
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 535-535
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Biosimilar products of biological disease-modifying antirheumatic drugs (bDMARDs) entered the Swedish market in 2015, with regulatory approvals based on head to head trials of limited duration. Longer-term comparative drug survival, in clinical practice, remains less well documented.Objectives:To compare survival on drug between biosimilars and their originator products among first starters of etanercept, infliximab, adalimumab and rituximab.Methods:Data from the Swedish Rheumatology Quality register (SRQ) was used to identify and follow patients who started a first ever treatment with etanercept since April 2015 (originator=ETA,biosimilar= SB4), infliximab since March 2014 (originator=IFX,biosimilar= CT-P13), adalimumab since January 2018 (originator=ADA biosimilars=SB5, ABP501), or rituximab since January 2018 (originator=RIT,biosimilar= GP2013), through December 31st, 2019, date of first discontinuation of the drug, or death. Discontinuation was defined as lack of effectiveness or adverse events, while other reasons for interruption of the drug (including non-medical switch) were considered censoring events. Descriptive characteristics were collected from the SRQ and tabulated. Hazard ratios (HR) of discontinuation were estimated using Cox regression, with each drug analyzed separately, adjusted for age,sex,indication,line of treatment,disease duration,year of treatment start,region and concomitant use of csDMARD.Results:9274 patients started etanercept(49% SB4), 3609 started infliximab(64% CT-P13), 3117 started adalimumab(27% SB5, 14% ABP 501), and 763 started rituximab(39% GP2013), Table 1. Patients starting CT-P13 and GP2013 were less likely to be biologics-naïve compared to those starting the originator product. Initiators of SB5,ABP501 and GP2013 were more likely,and those starting CT-P13 were less likely,to be on concomitant csDMARDs compared to those starting the originator products. Patients characteristics of ETA and SB4 were similar.The introduction of a biosimilar was typically followed by a decrease in the uptake of the originator, but for ETA a change in pricing in 2018 later led to a reversal of this pattern (Figure 1).For IFX,ADA,and RIT, survival on drug was similar for the originator and its biosimilar(s). For ETA,risk of discontinuation was somewhat lower for the biosimilar than for the originator(adjusted HR:0.87,95% confidence interval:0.79-0.95), Table 1.Table 1.Hazard ratios of discontinuation and descriptive characteristics of biosimilar vs. originator among first starters of each molecule, until 31st December 2019.EtanerceptInfliximabAdalimumabRituximabOriginatorSB4OriginatorCT-P13OriginatorSB5ABP 501OriginatorGP2013N47214553130823011834852431465298Discontinuation12891236582878399139805726Adjusted hazard ratios*Ref0.87 (0.79-0.95)Ref1.14 (0.99-1.31)Ref1.02 (0.83-1.26)1.16 (0.88-1.52)Ref1.12 (0.68-1.85)Age, mean years (std)51 (16)51 (15)49 (16)49 (16)48 (15)52 (15)51 (15)59 (15)60 (15)Female, %67%65%61%64%62%64%65%75%76%RA, %46%48%39%35%33%42%43%61%76%Bionaïve, %72%72%76%69%45%52%43%53%38%Disease duration, mean years (std)11 (12)11 (11)11 (11)11 (11)12 (13)12 (11)14 (15)14 (19)15 (11)DAS28, mean4.0 (1.3)4.0 (1.4)4.1 (1.4)4.1 (1.4)3.7 (1.4)3.8 (1.3)4.0 (1.3)4.5 (1.4)4.7 (1.4)Concomitant csDMARDs, %45%47%57%48%37%49%42%36%43%Abbreviations: RA=rheumatoid arthritis. csDMARDs=conventional synthetic DMARD, std=standard deviation.Figure 1.Number of starts of biosimilars compared to the originator during the follow-up time, by moleculeConclusion:Despite their identical indications and therapeutic positioning, there are some differences in the baseline characteristics between patients who start ADA, IFX and RIT and their biosimilars. There are no differences in drug survival between originator and biosimilar with the possible exception of etanercept although the observed difference should be interpreted in light of possible unmeasured or residual channeling.Disclosure of Interests:Daniela Di Giuseppe: None declared, Hannah Bower: None declared, Bénédicte Delcoigne: None declared, Thomas Frisell: None declared, Katerina Chatzidionysiou Consultant of: Eli Lilly, AbbVie and Pfizer, Ulf Lindström: None declared, Christopher Sjowall: None declared, Elisabet Lindqvist: None declared, Johan Askling Grant/research support from: Abbvie, Astra-Zeneca, BMS, Eli Lilly, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB,
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| 15. |
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| 16. |
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| 17. |
- Gomez, A., et al.
(författare)
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LOW-DOSE BELIMUMAB AND ANTIMALARIAL AGENTS PREVENT RENAL FLARES IN SYSTEMIC LUPUS ERYTHEMATOSUS : RESULTS FROM FOUR RANDOMISED CLINICAL TRIALS
- 2023
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Ingår i: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 82:Suppl. 1, s. 1467-1468
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Lupus nephritis (LN) is one of the most severe manifestations in systemic lupus erythematosus (SLE), constituting a substantial cause of end-stage kidney disease, dialysis, and mortality. Prompt and adequate treatment of LN, and prevention of renal flares are key components of disease management towards improved outcomes in patients with SLE.Objectives: We aimed to determine the effect of the use of antimalarial agents (AMA) and different doses and pharmaceutical forms of belimumab on preventing renal flares in patients with active SLE.Methods: We pooled data from the BLISS-52, BLISS-76, BLISS-SC and BLISS-Northeast Asia randomised clinical trials of belimumab (N=3225), that included patients with seropositive (antinuclear antibody titres ≥1:80 and/or anti-dsDNA levels ≥30 IU/mL), active SLE yet no severe ongoing renal disease. Participants were allocated to receive intravenous (IV) belimumab 1 mg/kg (N=559), IV belimumab 10 mg/kg (N=1033), subcutaneous (SC) belimumab 200 mg (N=556) or placebo (N=1077) in addition to standard therapy. Additionally, we classified patients as AMA users if they had received hydroxychloroquine, chloroquine, mepacrine, or quinine sulphate in stable doses for at least 30 days prior to the trial commencement. The outcome of the present post-hoc analysis was development of renal flares, defined according to the analysis plan within the BLISS programme. The hazard of renal flare was assessed with Cox proportional hazards regression models, adjusted for age, sex, ethnicity, previous renal involvement, baseline proteinuria and glomerular filtration rate, and use of glucocorticoids and immunosuppressants.Results: In total, 192 patients developed a renal flare after a median of 197 days. In multivariable Cox regression analysis, use of AMA was associated with a lower risk of renal flares (HR: 0.64; 95% CI: 0.54–0.96; p=0.026). Compared with placebo, the risk of renal flares was lower among patients receiving IV belimumab 1 mg/kg (HR: 0.44; 95% CI: 0.25–0.79; p=0.006) and IV belimumab 10 mg/kg (HR: 0.63; 95% CI: 0.45–0.87; p=0.005), but not SC belimumab 200 mg (HR: 0.90; 95% CI: 0.57–1.42; p=0.648). When analysing all study arms with and without antimalarials separately, patients receiving IV belimumab 1 mg/kg along with AMA experienced the lowest rate of renal flares (18.5 (7.4–38.1) cases per 1000 person-years). Using patients who received placebo but not AMA as the reference comparator, patients receiving IV belimumab 1 mg/kg (OR: 0.30; 95% CI: 0.13–0.70; p=0.005) and patients receiving IV belimumab 10 mg (OR: 0.45; 95% CI: 0.27–0.75; p=0.002) were protected against renal flares only when belimumab use was combined with AMA.Conclusion: In this RCT setting, belimumab and AMA protected against renal flares in patients with active seropositive SLE yet no ongoing severe renal involvement. The protective effect of IV belimumab against renal flares appeared optimal when belimumab was combined with AMA. The prominent effect of low-dose belimumab motivates investigation of the efficacy of intermediate doses of belimumab.
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