| 1. |
- Delcoigne, B., et al.
(författare)
-
SHORT- AND LONGER-TERM RISKS FOR ACUTE CORONARY SYNDROME IN PATIENTS WITH RHEUMATOID ARTHRITIS STARTING TREATMENT WITH DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS : A COLLABORATIVE OBSERVATIONAL HEAD-TO-HEAD STUDY ACROSS FIVE NORDIC RHEUMATOLOGY REGISTERS
- 2021
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 80, s. 63-64
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Rheumatoid Arthritis (RA) is associated with increased cardiovascular co-morbidity including acute coronary syndrome (ACS), partly due to effects of systemic inflammation. Disease-modifying anti-rheumatic drugs (DMARDs) may reduce RA disease activity, but act through several pathways and may themselves have an impact on cardiovascular risks. Whether the risks of ACS associated with biologic (b) and targeted synthetic (ts) DMARDs differ is still unknown.Objectives:To assess and compare incidences of ACS during treatment of RA with etanercept (ETA), adalimumab (ADA), infliximab (INF), certolizumab pegol (CTZ), golimumab (GOL), rituximab (RIT), abatacept (ABA), tocilizumab (TCZ), baricitinib (BAR) or tofacitinib (TOF).Methods:We defined and pooled treatment cohorts of patients starting any of the above treatments between 2008 and 2017 from clinical rheumatology registers in Denmark (DK), Finland (FI), Norway (NO), and Sweden (SE). One patient could contribute several treatment episodes. Age, sex, co-medication (methotrexate, prednisolone), number of previous b/tsDMARDs, CRP, comorbidities (cardiovascular (including ACS (defined as ICD-10: I20.0, I21.0-4, I21.9) and cerebrovascular disease, thromboembolic events, diabetes, hospitalized infection, cancer, kidney failure, COPD) and associated drugs were extracted and used as adjustment in Cox regression analyses comparing the incidence of ACS between treatments. We used several follow-up lengths (1, 2, and up to 5 years) and two different risk windows (ACS on drug [ending follow-up on treatment discontinuation] and ACS ever since treatment start [disregarding any treatment discontinuation]). We also stratified by age and number of previous b/tsDMARDs.Results:We included 40850 treatment courses in 24083 patients (DK 7271, FI 3732, NO 1540, and SE 11540; around 75% women). ETA was the most common treatment (27%) whereas BAR and TOF comprised <1%, and the other DMARDs 6-14% each. The proportions with a history of ACS at treatment start ranged from 1.2% (NO) to 1.8% (DK).We found 780 incident ACS events during 141 326 person-years (pyrs) in the 5-year follow-up time and “ACS ever since treatment start” risk window, resulting in a crude incidence rate of 5.5 events per 1000 pyrs. No event was recorded for BAR nor TOF, which also had the shortest follow-up. Adjusted hazard ratios (HR) increased slightly with longer follow-up times, but the two risk windows provided similar HRs. For the 5-year follow-up, RIT was associated with an increased risk of ACS compared to ETA (Table), while no association was observed for shorter follow-up times. Stratifying on age did not modify the associations. Separate analyses by number of previous b/tsDMARDs suggested that ABA (HR=1.8, 95% CI 1.0-3.3), INF (HR=2.2, 95% CI 1.0-4.6) and RIT (HR=1.9, 95% CI 1.1-3.4) were associated with increased risks of ACS compared to ETA in the subgroup of patients with two or more previous bDMARDs (Figure), whereas no differences were found among patients starting either drug as 1st/2nd bDMARD.Table 1.Comparisons of risks for ACS during a 5-year follow-up since start of bDMARD treatment.DrugN eventspyrsCrude incidence rate/ 1000 pyrsHR (95% CI)1ETA175359174.9ref.ADA115240934.81.0 (0.8-1.3)CTZ54141583.80.9 (0.6-1.2)GOL4090064.41.1 (0.8-1.5)INF106178036.01.2 (0.9-1.5)ABA70107956.51.1 (0.8-1.4)RIT158166229.51.3 (1.0-1.6)TCZ62128664.80.9 (0.5-1.2)BAR036TOF030Pyrs: person-years; HR: hazards ratio1 adjustment: see text.Conclusion:In this cohort including ≥ 24,000 patients followed for up to 5 years, the ACS incidence rate was 5.5/1000 pyrs, with RIT showing an increased risk compared to ETA. In clinical practice, the choice of bDMARD does not seem to influence ACS risk in the short term. In the longer term, differences in ACS risk between bDMARDs may reflect channeling to these, or truly differential effects in subpopulations of patients.Acknowledgements:Partly funded by Nordforsk and ForeumDisclosure of Interests:Bénédicte Delcoigne: None declared, Lotta Ljung: None declared, Sella Aa. Provan Speakers bureau: Novartis, Consultant of: Novartis, Grant/research support from: Boehringer- Ingelheim, Bente Glintborg Grant/research support from: Pfizer, BMS, AbbVie, Kathrine Lederballe Gron Grant/research support from: BMS, Merete L. Hetland Consultant of: Abbvie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V, Lundbeck Fonden, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis, Grant/research support from: Abbvie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V, Lundbeck Fonden, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis, Niels Steen Krogh: None declared, Nina Trokovic: None declared, Heikki Relas Speakers bureau: Abbvie, Celgene, Pfizer, Grant/research support from: Abbvie, Celgene, Pfizer, Carl Turesson Speakers bureau: Abbvie, Bristol-Myers Squibb, Medac, Pfizer, Roche, Consultant of: Roche, Brigitte Michelsen Consultant of: Novartis (paid to employer), Grant/research support from: Novartis (paid to employer), Johan Askling Consultant of: Abbvie, Astra-Zeneca, BMS, Eli Lilly, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB. These entities have entered into agreements with Karolinska Institutet with JA as principal investigator, mainly in the context of safety monitoring of biologics via the ARTIS national safety monitoring system.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
- Provan, SA, et al.
(författare)
-
THE INCIDENCE OF INTERSTITIAL LUNG DISEASE IN PSORIATIC ARTHRITIS COMPARED TO RHEUMATOID ARTHRITIS. DATA FROM OVER 89 000 BDMARD TREATMENT COURSES DERIVED FROM FIVE NORDIC REGISTERS
- 2021
-
Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 133-134
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Interstitial lung disease (ILD) is an established extra-articular manifestation of rheumatoid arthritis (RA). Few studies have investigated the prevalence of ILD in patients with psoriatic arthritis (PsA). Methotrexate (MTX) is frequently used in the treatment of both RA and PsA and has been suggested to be a risk factor for the development of ILD. It is of interest to understand the interaction between disease and treatment in the development of ILD.Objectives:To compare the incidence of ILD between patient with PsA and RA treated with biologic disease modifying antirheumatic drugs (bDMARDS), with or without MTX as a co-medication.Methods:Cohorts of patients with RA and PsA starting bDMARD were identified in Nordic registers (Danish nationwide clinical register for patients with RA (DANBIO), Register on antirheumatic and biological therapy in Finland (ROB-FIN), Icelandic nationwide database of biologic therapy (ICEBIO), Norwegian Antirheumatic Drug Register (NOR-DMARD), and the Swedish Rheumatology Quality Register (SRQ)). Linkages to the National Patient Registers and to the Cause of Death Registers were performed in each country to identify cases of ILD. Each individual patient could contribute several treatment courses. ILD was identified as hospital or death certificate ICD10 codes of ILD (J84.1, J84.8, J84.9, J70.2, J70.3, J70.4, J99.0, J99.1, J99.8) given during the follow-up period which was defined as the treatment course duration, plus a 30-day wash-out period added to the end of treatment course period. MTX co-medication was specified as use of MTX at the start of bDMARD. Incidence rates (IR) for any ILD were calculated per 1000 person years at risk (PYR) for each country. The five cohorts were pooled and incidence rate ratios (IRR) for PsA vs. RA were calculated. Hazard ratios (HR) for any ILD in PsA vs. RA were estimated in Cox regression models adjusted for age, gender and repeated observations, and stratified for the use of MTX co-medication.Results:Overall 47 987 individual patients representing 89 239 bDMARD treatment courses and contributing 201 279 PYR were included in the study (Table 1). Methotrexate was reported as comedication in 29 916 (33.5 %) of the treatment courses (PsA vs. RA, 30.4 % vs 34.5 %). 970 cases of ILD were identified during the follow-up period. The risk of ILD was consistently lower in patients with PsA compared to patients with RA in all countries. In models stratified for co-medication the HR for ILD in PsA vs. RA was 0.34 (0.21-0.57) in patients treated with MTX and 0.26 (0.18-0.36) in patients not treated with MTX.Table 1.Interstitial lung disease in PsA vs. RA in five Nordic biologic registersDENMARKFINLANDICELANDNORWAYSWEDENRAPsARAPsARAPsARAPsARAPsANumber of individuals78293386494610916754701590999205966393Number of treatment courses17 07266408634184512808592379142738 27910 824Age baseline (SD)57.3 (13.1)49.0 (12.6)53.8 (13.4)48.8 (11.4)53.9 (14.2)50.1 (13.3)53.8 (13.7)48.7 (12.0)57.1 (13.7)50.6 (12.8)Female n (%)12 963 (76)3929 (59)6571 (76)933 (51)969 (76)551 (65)1815 (77)818 (57)29 635 (77)6162 (57)Number of PYR4023513986217984910451727994556265312033427412ILD-events within PYR2182213287232668028IR pr 1000 PYR5.41.66.11.61.50.77.02.35.71.0IRR PsA vs RA crude0.29 (0.18-0.45)0.27 (0.11-0.55)0.46 (0.05-2.42)0.32(0.11-0.78)0.18 (0.12-0.26)HR PsA vs RA0.31 (0.17-0.56)0.46 (0.22-0.96)0.62 (0.12-3.14)0.19 (0.06-0.54)0.25 (0.17-0.37)PYR: Patient years at risk, IR: Incidence rates, IRR: Incidence rate ratios, HR: Hazard RatiosConclusion:In these preliminary analyses, the incidence of ILD is lower in bDMARD treated PsA vs. RA patients, irrespective of co-medication with MTX. This indicates that the clinician should consider the rheumatological diagnosis when assessing the risk for future ILD in patients treated with bDMARDs and MTX.Acknowledgements:Partly funded by NordForsk and FOREUMDisclosure of Interests:Sella Aarrestad Provan Consultant of: Novartis, Grant/research support from: Boehringer-Ingelheim, Brigitte Michelsen: None declared, Lotta Ljung: None declared, Thorarinn Jonmundsson: None declared, Björn Gudbjornsson Speakers bureau: Amgen and Novartis, Daniela Di Giuseppe: None declared, Merete Lund Hetland Speakers bureau: Orion Pharma, Biogen, Pfizer, CellTrion, Merck and Samsung Bioepis, Consultant of: Eli Lilly, Grant/research support from: BMS, MSD, AbbVie, Roche, Novartis, Biogen and Pfizer, Guðrún Björk Reynisdóttir: None declared, Bente Glintborg: None declared, Eirik kristianslund: None declared, Heikki Relas: None declared, Kalle Aaltonen: None declared, Dan Nordström Speakers bureau: Abbvie, BMS, Celgene, Eli Lilly, MSD, Novartis, Pfizer, Roche and UCB., Consultant of: Abbvie, BMS, Celgene, Eli Lilly, MSD, Novartis, Pfizer, Roche and UCB., Tore K. Kvien Speakers bureau: Amgen, Celltrion, Egis, Evapharma, Ewopharma, Hikma, Oktal, Sandoz, Sanofi., Consultant of: AbbVie, Amgren, Biogen, Celltrion, Eli Lilly, Gilead, Mylan, Novartis, Pfizer, Roche, Sandoz, Sanofi., Johan Askling Grant/research support from: Abbvie, BMS, Eli Lilly, Merck, Pfizer, Roche, Samsung Bioepis, and Sanofi
|
|
| 5. |
- Hjorth, Stephan, 1953, et al.
(författare)
-
(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752)-a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent
- 2020
-
Ingår i: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0022-3565 .- 1521-0103. ; 374:3, s. 404-419
-
Tidskriftsartikel (refereegranskat)abstract
- Here we describe for the first time the distinctive pharmacological profile for (35)-3-(2,3-difluorophenyI)-3-nnethoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 mu mol/kg, s.c.) was characterized through extensive in vivo studies using behavioral, tissue neurochemical, and gene expression as well as microdialysis methods. Behaviorally, the compound normalized tetrabenazine-induced hypo-activity, whereas it was unable to stimulate basal locomotion in normal animals or either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across noradrenaline (NA)- and dopamine (DA)-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related immediate early genes (IEGs), however, increased by 1.5-fold to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600%-750% above baseline, whereas striatal DA remained unaltered, and NA rose to similar to 250%; cortical and hippocampal dialysate acetylcholine (ACh) increased to similar to 250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also procognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data coupled to drug exposure support the hypothesis that 5-hydroxytryptannine 7 receptor and alpha 2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on cate-cholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. SIGNIFICANCE STATEMENT This report describes the distinctive preclinical profile of (3S)3-(2,3-difluorophenyI)-3-nnethoxypyrrolidine (IRL752). Its in vivo neurochemical, behavioral, microdialysis, and gene expression properties are consistent with a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features. The pharmacological characteristics of IRL752 are in line with the clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
- Röer, Jan Philipp, et al.
(författare)
-
A Multilingual Preregistered Replication of the Semantic Mismatch Effect on Serial Recall
- 2022
-
Ingår i: Journal of Experimental Psychology. Learning, Memory and Cognition. - : American Psychological Association (APA). - 0278-7393 .- 1939-1285. ; 48:7, s. 966-974
-
Tidskriftsartikel (refereegranskat)abstract
- Visual-verbal serial recall is disrupted when task-irrelevant background speech has to be ignored. Contrary to previous suggestion, it has recently been shown that the magnitude of disruption may be accentuated by the semantic properties of the irrelevant speech. Sentences ending with unexpected words that did not match the preceding semantic context were more disruptive than sentences ending with expected words. This particular instantiation of a deviation effect has been termed the semantic mismatch effect. To establish a new phenomenon, it is necessary to show that the effect can be inde-pendently replicated and does not depend on speciï¬c boundary conditions such as the language of the stimulus material. Here we report a preregistered replication of the semantic mismatch effect in which we examined the effect of unexpected words in 4 different languages (English, French, German, and Swedish) across 4 different laboratories. Participants performed a serial recall task while ignoring sen-tences with expected or unexpected words that were recorded using text-to-speech software. Independent of language, sentences ending with unexpected words were more disruptive than sentences ending with expected words. In line with previous results, there was no evidence of habituation of the semantic mismatch effect in the form of a decrease in disruption with repeated exposure to the occur-rence of unexpected words. The successful replication and extension of the effect to different languages indicates the expression of a general and robust mechanism that reacts to violations of expectancies based on the semantic content of the irrelevant speech.
|
|
| 10. |
|
|
