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- Christiansen, SN, et al.
(författare)
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SECULAR TRENDS IN BASELINE CHARACTERISTICS, TREATMENT RETENTION AND RESPONSE RATES IN 17453 BIONAIVE PSORIATIC ARTHRITIS PATIENTS INITIATING TNFI - RESULTS FROM THE EUROSPA COLLABORATION
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 131-132
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Knowledge of changes over time in baseline characteristics and tumor necrosis factor inhibitor (TNFi) response in bionaïve psoriatic arthritis (PsA) patients treated in routine care is limited.Objectives:To investigate secular trends in baseline characteristics and retention, remission and response rates in PsA patients initiating a first TNFi.Methods:Prospectively collected data on bionaïve PsA patients starting TNFi in routine care from 15 European countries were pooled. According to year of TNFi initiation, three groups were defined a priori based on bDMARD availability: Group A (1999–2008), Group B (2009–2014) and Group C (2015–2018).Retention rates (Kaplan-Meier), crude and LUNDEX adjusted1 remission (Disease Activity Score (DAS28) <2.6, 28-joint Disease Activity index for PsA (DAPSA28) ≤4, Clinical Disease Activity Index (CDAI) ≤2.8) and ACR50 response rates were assessed at 6, 12 and 24 months. No statistical comparisons were made.Results:A total of 17453 PsA patients were included (4069, 7551 and 5833 in groups A, B and C).Patients in group A were older and had longer disease duration compared to B and C. Retention rates at 6, 12 and 24 months were highest in group A (88%/77%/64%) but differed little between B (83%/69%/55%) and C (84%/70%/56%).Baseline disease activity was higher in group A than in B and C (DAS28: 4.6/4.3/4.0, DAPSA28: 29.9/25.7/24.0, CDAI: 21.8/20.0/18.6), and this persisted at 6 and 12 months. Crude and LUNDEX adjusted remission rates at 6 and 12 months tended to be lowest in group A, although crude/LUNDEX adjusted ACR50 response rates at all time points were highest in group A. At 24 months, disease activity and remission rates were similar in the three groups (Table).Table 1.Secular trends in baseline characteristics, treatment retention, remission and response rates in European PsA patients initiating a 1st TNFiBaseline characteristicsGroup A(1999–2008)Group B(2009–2014)Group C(2015–2018)Age, median (IQR)62 (54–72)58 (49–67)54 (45–62)Male, %514847Years since diagnosis, median (IQR)5 (2–10)3 (1–9)3 (1–8)Smokers, %161717DAS28, median (IQR)4.6 (3.7–5.3)4.3 (3.4–5.1)4.0 (3.2–4.8)DAPSA28, median (IQR)29.9 (19.3–41.8)25.7 (17.2–38.1)24.0 (16.1–35.5)CDAI, median (IQR)21.8 (14.0–31.1)20.0 (13.0–29.0)18.6 (12.7–26.1)TNFi drug, % (Adalimumab / Etanercept / Infliximab / Certolizumab / Golimumab)27 / 43 / 30 / 0 / 036 / 31 / 14 / 5 / 1421 / 40 / 21 / 8 / 10Follow up6 months12 months24 monthsGr AGr BGr CGr AGr BGr CGr AGr BGr CRetention rates, % (95% CI)88 (87–89)83 (82–84)84 (83–85)79 (78–80)72 (71–73)72 (71–73)68 (67–69)60 (59–61)60 (59–62)DAS28, median (IQR)2.7 (1.9–3.6)2.4 (1.7–3.4)2.3 (1.7–3.2)2.5 (1.8–3.4)2.2 (1.6–3.1)2.1 (1.6–2.9)2.1 (1.6–3.1)2.0 (1.6–2.9)1.9 (1.5–2.6)DAPSA28, median (IQR)10.6 (4.8–20.0)9.5 (3.9–18.3)8.7 (3.6–15.9)9.1 (4.1–17.8)7.7 (3.1–15.4)7.6 (2.9–14.4)6.7 (2.7–13.7)6.6 (2.7–13.5)5.9 (2.4–11.8)CDAI, median (IQR)7.8 (3.0–15.2)8.0 (3.0–15.0)6.4 (2.6–12.2)6.4 (2.5–13.0)6.2 (2.5–12.1)5.8 (2.2–11.4)5.0 (2.0–11.0)5.5 (2.0–11.2)5.0 (2.0–9.0)DAS28 remission, %, c/L47 / 4255 / 4661 / 5153 / 4362 / 4566 / 4864 / 4268 / 3775 / 41DAPSA28 remission, %, c/L22 / 1926 / 2228 / 2325 / 2031 / 2232 / 2336 / 2334 / 1938 / 21CDAI remission, %, c/L23 / 2123 / 1926 / 2227 / 2127 / 2029 / 2134 / 2231 / 1735 / 19ACR50 response, %, c/L26 / 2322 / 1824 / 2027 / 2223 / 1721 / 1523 / 1518 / 1014 / 8Gr, Group; c/L, crude/LUNDEX.Conclusion:Over the past 20 years, patient age, disease duration and disease activity level at the start of the first TNFi in PsA patients have decreased. Furthermore, TNFi retention rates have decreased while remission rates have increased, especially remission rates within the first year of treatment. These findings may reflect a greater awareness of early diagnosis in PsA patients, a lowered threshold for initiating TNFi and the possibility for earlier switching in patients with inadequate treatment response.References:[1]Arthritis Rheum 2006; 54: 600-6.Acknowledgements:Novartis Pharma AG and IQVIA for supporting the EuroSpA Research Collaboration Network.Disclosure of Interests:Sara Nysom Christiansen Speakers bureau: BMS and GE, Grant/research support from: Novartis, Lykke Midtbøll Ørnbjerg Grant/research support from: Novartis, Simon Horskjær Rasmussen: None declared, Anne Gitte Loft Speakers bureau: AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, UCB, Consultant of: AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, UCB, Grant/research support from: Novartis, Johan K Wallman Consultant of: Celgene, Eli Lilly, Novartis, Florenzo Iannone Speakers bureau: Abbvie, MSD, Novartis, Pfizer and BMS, Brigitte Michelsen Consultant of: Novartis, Grant/research support from: Novartis, Michael J. Nissen Speakers bureau: Novartis, Eli Lilly, Celgene, and Pfizer, Consultant of: Novartis, Eli Lilly, Celgene, and Pfizer, Jakub Zavada: None declared, Maria Jose Santos Speakers bureau: AbbVie, Novartis, Pfizer, Manuel Pombo-Suarez: None declared, Kari Eklund: None declared, Matija Tomsic Speakers bureau: Abbvie, Amgen, Biogen, Medis, MSD, Novartis, Pfizer, Consultant of: Abbvie, Amgen, Biogen, Medis, MSD, Novartis, Pfizer, Björn Gudbjornsson Speakers bureau: Amgen and Novartis, İsmail Sari: None declared, Catalin Codreanu Speakers bureau: AbbVie, Amgen, Egis, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, Amgen, Egis, Novartis, Pfizer, UCB, Daniela Di Giuseppe: None declared, Bente Glintborg Grant/research support from: Pfizer, Biogen, AbbVie, Marco Sebastiani: None declared, Karen Minde Fagerli: None declared, Burkhard Moeller: None declared, Karel Pavelka Speakers bureau: AbbVie, Roche, MSD, UCB, Pfizer, Novartis, Egis, Gilead, Eli Lilly, Consultant of: AbbVie, Roche, MSD, UCB, Pfizer, Novartis, Egis, Gilead, Eli Lilly, Anabela Barcelos: None declared, Carlos Sánchez-Piedra: None declared, Heikki Relas: None declared, Ziga Rotar Speakers bureau: Abbvie, Amgen, Biogen, Medis, MSD, Novartis, Pfizer, Consultant of: Abbvie, Amgen, Biogen, Medis, MSD, Novartis, Pfizer, Thorvardur Love: None declared, Servet Akar: None declared, Ruxandra Ionescu Speakers bureau: Abbvie, Amgen, Boehringer-Ingelheim Eli-Lilly,Novartis, Pfizer, Sandoz, UCB, Gary Macfarlane Grant/research support from: GlaxoSmithKline, Marleen G.H. van de Sande: None declared, Merete L. Hetland Speakers bureau: Abbvie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V, Lundbeck Fonden, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis., Mikkel Østergaard Speakers bureau: AbbVie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB and Wyeth, Consultant of: AbbVie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB and Wyeth
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| 4. |
- Aggarwal, R, et al.
(författare)
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RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL TO EVALUATE EFFICACY AND SAFETY OF SC ABATACEPT IN ADULTS WITH ACTIVE IDIOPATHIC INFLAMMATORY MYOPATHY
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 711-711
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Limited therapies are available for patients with idiopathic inflammatory myopathy (IIM), a heterogenous group of chronic, systemic, autoimmune inflammatory diseases characterized by progressive muscle weakness and/or distinct skin rashes.1 Abatacept, a selective co-stimulation modulator, may be a useful treatment option.2ObjectivesTo evaluate efficacy, safety, and tolerability of abatacept + standard of care (SOC) in patients with IIM compared with SOC alone (placebo).MethodsA 24-week, randomized, double-blind, placebo-controlled phase 3 trial of SC abatacept (125 mg weekly) + SOC (corticosteroids and immunosuppressants alone or combined; NCT02971683) in patients with active, treatment-refractory IIM (Manual Muscle Testing-8 [MMT-8] ≤ 135) was performed. Primary endpoint was proportion of patients meeting International Myositis Assessment and Clinical Studies definition of improvement (IMACS DOI) at week 24. Change from baseline in myositis Functional Index-2 (FI-2), HAQ-DI, Myositis Disease Activity Assessment Tool (MDAAT), and Myositis Response Criteria (MRC) were secondary endpoints with safety. Post hoc analyses by disease subtype were performed.ResultsOverall, 148 patients were randomized (75 abatacept; 73 placebo); IIM subtypes were dermatomyositis (DM; 53.3% vs 57.5%), polymyositis (PM; 25.3% vs 34.2%), and autoimmune necrotizing myopathy (ANM; 21.3% vs 8.2%). Mean baseline MMT-8 and HAQ-DI scores were 112.7 and 1.5, respectively. Approximately 90% of patients completed week 24. Week 24 IMACS DOI rates were abatacept 56.0% vs placebo 42.5% (adjusted odds ratio, 1.8 [95% CI, 0.9–3.5]; P = 0.083). Pre-specified IMACS DOI analysis showed no differences for patients with DM but notable benefit for those with non-DM subtypes, PM and ANM (Table 1). Secondary endpoints showed similar differences (Table 1). MRC at day 169 by category is shown in Figure 1. Proportion of AEs (69.3% and 75.3%) and serious AEs (5.3% and 5.5%) were similar in the abatacept and placebo arms.Table 1.Primary and secondary (mean change from baseline at week 24) endpointsOutcomeIIMAbataceptPlaceboNominal P value (abatacept vs placebo) or adjusted mean difference from placebo (95% CI)IMACS DOI,a n/N (%)All42/75 (56.0)31/73 (42.5)P = 0.083DM22/40 (55.0)21/42 (50.0)P = 0.679Non-DM20/35 (57.1)10/31 (32.3)P = 0.040FI-2All4.1 (1.3)1.2 (1.4)2.9 (0 to 5.8)DM2.3 (1.6)0.3 (1.4)1.9 (−2.3 to 6.2)Non-DM3.2 (1.4)−0.6 (1.5)3.7 (−0.3 to 7.8)HAQ-DIAll−0.31 (0.07)0.20 (0.07)−0.12 (−0.28 to 0.04)DM−0.31 (0.08)−0.19 (0.07)−0.11 (−0.32 to 0.10)Non-DM−0.25 (0.09)−0.07 (0.09)−0.18 (−0.44 to 0.07)MDAAT, Extramuscular Global Activity, (95% CI)bAll−1.56 (−1.96 to −1.16)−1.40 (−1.81 to −0.99)−0.16 (−0.63 to 0.30)DM−1.90 (−2.43 to −1.37)−1.85 (−2.35 to 1.36)−0.05 (−0.77 to 0.68)Non-DM−1.09 (−1.46 to −0.72)−0.85 (−1.27 to −0.43)−0.24 (−0.80 to 0.32)MMT-8All12.9 (1.9)11.0 (2.0)1.8 (−2.7 to 6.4)DM14.4 (2.2)14.0 (2.2)0.4 (−5.7 to 6.4)Non-DM12.1 (2.5)7.8 (2.7)4.3 (−3.0 to 11.7)Physician Global AssessmentbAll−2.89 (0.30)−2.69 (0.30)−0.20 (−0.92 to 0.52)DM−2.78 (0.29)−2.43 (0.28)−0.35 (−1.15 to 0.46)Non-DM−2.35 (0.43)−2.21 (0.48)−0.14 (−1.43 to 1.15)Patient Global AssessmentbAll−1.4 (0.31)−0.98 (0.32)−0.38 (−1.11 to 0.35)DM−1.4 (0.33)−1.4 (0.31)−0.00 (−0.91 to 0.90)Non-DM−1.2 (0.41)−0.3 (0.44)−0.93 (−2.14 to 0.29)Data are adjusted mean change from baseline score (SE) unless stated.aDefined as improvement of ≥ 20% in 3 IMACS core measures, worsening by ≥ 25% in ≤ 2 IMACS core measure scores, and a reduction of < 25% in MMT-8; b100 mm visual analog scale.ConclusionIn this double-blind trial of SC abatacept vs placebo, abatacept failed to meet primary or secondary endpoints. Post hoc analyses suggest a treatment benefit in patients with PM and ANM (not DM) when treated with abatacept. Abatacept use was well tolerated.References[1]Dalakas MC, Hohlfeld R. Lancet 2003;362:971–82.[2]Tjärnlund A, et al. Ann Rheum Dis 2018;77:55–62.AcknowledgementsThis study was sponsored by Bristol Myers Squibb. Medical writing and editorial assistance were provided by Fiona Boswell, PhD, of Caudex and were funded by Bristol Myers Squibb. Study execution was by Sandra Overfield and Robin Scully.Disclosure of InterestsRohit Aggarwal Consultant of: AbbVie, Alexion, Argenx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Corbus, CSL Behring, EMD Serono, Janssen, Jubilant, Kezar, Kyverna, Mallinckrodt, Octapharma, Orphazyme, Pfizer, Q32, Roivant (personal fees), Grant/research support from: Bristol Myers Squibb, EMD Serono, Genentech, Mallinckrodt, Pfizer, Q32, Ingrid E. Lundberg Shareholder of: Novartis, Roche, Consultant of: Argenx, AstraZeneca, Corbus, EMD Serono, Janssen, Kezar, Octapharma, Orphazyme (personal fees), Grant/research support from: Bristol Myers Squibb, Yeong Wook Song: None declared, Aziz Shaibani: None declared, Victoria P Werth Consultant of: AbbVie, Akari, Amgen, Argenx, AstraZeneca, Bayer, Beacon Bioscience, Biogen, Bristol Myers Squibb, Celgene, Corcept, Crisalis, CSL Behring, Cugene, EMD Serono, Genentech, Gilead, GlaxoSmithKline, Horizon, Idera, Incyte, Janssen, Kezar, Kwoya Kirin, Lilly, Medimmune, Medscape, Merck, Nektar, Octapharma, Pfizer, Principia, Regeneron, Resolve, Rome Pharmaceuticals, Sanofi, UCB, Viela Bio, Grant/research support from: Amgen, Argenx, AstraZeneca, Biogen, Bristol Myers Squibb, Celgene, Corbus Pharmaceuticals, CSL Behring, Genentech, Gilead, Janssen, Pfizer, q32 Bio, Regeneron, Syntimmune, Ventus, Viela, Michael A Maldonado Employee of: Bristol Myers Squibb
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- Aghakhanian, F, et al.
(författare)
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INTEGRATION OF GWAS AND EPIGENETIC STUDIES IDENTIFIES NOVEL GENES THAT ALTER EXPRESSION IN THE MINOR SALIVARY GLAND IN SJOGREN'S DISEASE
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 72-73
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Sjogren’s disease (SjD) is an autoimmune disease characterized by reduced function of exocrine glands (i.e., salivary and lacrimal glands). Epithelial cell damage resulting from lymphocytic infiltration has been implicated in SjD etiology [1]. How genetic and epigenetic changes influence epithelial-immune cell interactions in SjD pathogenesis remain understudied.ObjectivesEvaluate the role of SjD risk loci in salivary gland tissue to gain insights into the potential genes involved in salivary gland dysfunction.MethodsSNPs from 16 regions with SNP-SjD associations (P<5x10-8) in our GWAS study (3232 SjD cases) and meta-analysis of ImmunoChip data (619 SjD cases) [2] were interrogated for eQTLs using Genotype-Tissue Expression (GTEx) minor salivary gland data. Subsequent analysis identified genes that were both eQTLs in the minor salivary gland and significantly expressed in RNA-seq and ATAC-seq data from the submaxillary salivary gland epithelial cell line, A253. Pathway enrichment analysis was performed using gProfiler on the genes where coalescence of eQTL, RNA-seq, and ATAC-seq data was observed. To further validate the results, we performed transcriptome-wide association study (TWAS) analysis using GWAS summary statistics and minor salivary gland eQTL GTEx data.ResultsIn total, 5884 genome-wide significant SNPs from 16 SjD risk loci were identified as potential minor salivary gland eQTLs using two discovery thresholds: p(FDR)<0.05 provided by eQTL study (3566 SNPs) and p(FDR)>0.05 and p<0.05 in eQTL study (2318 SNPs). Further analysis revealed 10 SjD risk loci with SNPs that were minor salivary gland eQTLs for a total of 155 unique genes that had a coalescence of RNA- and ATAC-seq data in A253 cells. Many SNPs altered the expression of the nearest gene to the risk allele (i.e., index gene), such as IRF5 and TNPO3 on chromosome 7 at 128Mb; however, this locus had 12 additional genes that were eQTLs in minor salivary gland. In contrast, other loci had no reported eQTLs for the index gene, but several reported eQTLs for other genes, such TYK2 on chromosome 19 at 10Mb that showed no change in TYK2 expression but eQTLs for 8 distant genes, including ICAM1. Pathway enrichment analysis revealed an enrichment in Butyrophilin (BTN) family interactions (R-HSA-8851) (PAdj=1.564x10-5), including the BTN2A1, BTN2A2, BTN3A1, BTN3A2 and BTN3A3 gene cluster in the MHC region. In further support, TWAS of the minor salivary gland and the SjD GWAS summary statistics (after Bonferroni correction) showed association between SjD and BTN3A2 (p=1.24x10-42), as well as many other loci in the MHC region. In addition, several long non-coding (lnc) RNAs on chromosome 17 were significant, peaking at RP11-259G18.1 (p=4.43x10-10).ConclusionThis study shows that SjD-associated risk alleles influence disease by altering gene expression in immune cells and minor salivary glands. Further, our analysis suggests that altered gene expression in the minor salivary gland expands beyond effects on the index gene to several genes on each locus. Interestingly, we observed minor salivary gland eQTLs for several BTN family genes, which act as cell-surface binding partners to regulate cell-cell interactions, including interactions between epithelial cells and activated T cells [3]. Future work will assess chromatin-chromatin-interactions within the 10 SjD risk loci in salivary gland cells and tissues to map local chromatin regulatory networks that regulate gene expression. Additional transcriptional studies of SjD minor salivary gland tissues will provide further insights into how altered gene expression in the salivary gland influences SjD pathology.References[1]Verstappen. Nat Rev Rheumatol 2021;17(6):333-348.[2]Khatri, et al. Annals of Rheumatic Diseases 2020;79:30-31.[3]Arnett HA, Viney JL. Nature Reviews Immunology 2014;14:559-569.Disclosure of InterestsFarhang Aghakhanian: None declared, Mandi M Wiley: None declared, Bhuwan Khatri: None declared, Kandice L Tessneer: None declared, Astrid Rasmussen: None declared, Simon J. Bowman Consultant of: Abbvie, Galapagos, and Novartis in 2020-2021., Lida Radfar: None declared, Roald Omdal: None declared, Marie Wahren-Herlenius: None declared, Blake M Warner: None declared, Torsten Witte: None declared, Roland Jonsson: None declared, Maureen Rischmueller: None declared, Patrick M Gaffney: None declared, Judith A. James: None declared, Lars Ronnblom: None declared, R Hal Scofield: None declared, Xavier Mariette: None declared, Marta Alarcon-Riquelme: None declared, Wan Fai Ng: None declared, Kathy Sivils Employee of: Current employee of Janssen, Gunnel Nordmark: None declared, Umesh Deshmukh: None declared, A Darise Farris: None declared, Christopher Lessard: None declared
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