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1.
  • Chatzidionysiou, K, et al. (author)
  • THE RISK OF LUNG CANCER IN RHEUMATOID ARTHRITIS AND IN RELATION TO AUTOANTIBODY POSITIVITY AND SMOKING
  • 2022
  • In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 247-247
  • Conference paper (other academic/artistic)abstract
    • Lung cancer is a common malignancy in rheumatoid arthritis (RA)1,2. Since smoking is a risk factor for both (seropositive) RA and lung cancer, it remains unclear whether RA, in itself, increases lung cancer risk.ObjectivesThe aim of this study was to examine whether and to what extent the increased risk of lung cancer in RA may (or may not) be attributable to smoking, and to examine this association, both in terms of absolute and relative risks, specifically in relation to RA serostatus.MethodsWe performed a population-based cohort study of RA patients and individually matched general population reference individuals identified in Swedish registers and from the EIRA early RA study, prospectively followed for lung cancer occurrence 1995 through 2018. We calculated incidence rates and performed Cox regression to estimate hazard ratios (HR) including 95% confidence intervals (CI) of lung cancer, taking smoking and sero-status into account.ResultsOverall, we included 44,101 RA patients (590 incident lung cancers, 56 per 100,000), and 216,495 matched general population individuals (1,691 incident lung cancers, 33 per 100,000), corresponding to a crude HR (95% CI) of 1.76 (1.60-1.93). In subset analyses this increased risk remained after adjustment for smoking (HR=1.77, 95% CI 1.06-2.97). Compared to general population subjects who were never smokers, RA patients who were ever smokers had almost 7 times higher risk of lung cancer.Positive autoantibody status was associated with an at least doubled risk of lung cancer in ACPA positive patients (vs. ACPA negative patients) and double seropositive (vs. double seronegative) patients after adjusting for comorbidities and smoking (Table 1).Table 1.Number of events, person-years of follow-up, number of events per 100,000 person-years, and relative risk of lung cancer according to autoantibody status in the EIRA sub-cohort. Five Hazard ratios are presented: a) crude; b) adjusted for age, sex, index year, county of residency (model A); c) age, sex, index year, county of residency and comorbidities (renal failure, heart failure, ischemic heart disease, COPD, respiratory infections, hospitalization) (model B) c) all the above plus smoking (model C) and d) as model C with packet-years instead of smoking ever vs. never.No of events (person years of follow-up; No of events/100 000 person years)Crude Hazard ratio (95% CI)Model A Hazard ratio* (95% CI)Model BHazard ratio** (95% CI)Model CHazard ratio** (95% CI)Model D with smoking as pack-years instead of ever/neverPositiveNegativeRF (N=2060)30(49,440; 60.7)6(49,440; 12.1)2.78 (1.16-6.69)3.01 (1.25-7.26)2.82 (1.17-6.82)2.44 (1.01-5.89)2.16 (0.88-5.28)ACPA (N=2060)30(49,440; 60.7)6(49,440; 12.1)3.13 (1.30-7.51)3.43 (1.42-8.25)3.22 (1.33-7.77)2.88 (1.19-6.95)3.29 (1.26-8.58)RF and/or ACPA (N=2060)34(49,440; 68.8)2(49,440; 4.0)6.38 (1.53-26.56)7.62 (1.83-31.83)7.20 (1.72-30.11)6.29 (1.51-26.30)5.76 (1.37-24.21)RF and ACPA (positive vs. double negative)(N=1608)26(38,592; 67.4)2(38,592; 5.2)6.67 (1.58-28.08)7.92 (1.87-33.50)7.08 (1.67-29.98)6.21 (1.47-26.33)5.86 (1.37-25.01)The average absolute five-year risk of lung cancer counting from RA diagnosis was 1.3% in ever-smoking seropositive RA. At 20 years the risk was almost 3% in RA overall, and over 4% for patients who were ever smokers and had at least one autoantibody.ConclusionRA seropositivity is a strong and at least seemingly independent risk factor for lung cancer in RA. The absolute risks point to the potential for regular lung cancer screening, at least in seropositive RA.References[1]Simon TA, Thompson A, Gandhi KK, et al. Incidence of malignancy in adult patients with rheumatoid arthritis: A meta-analysis. Arthritis Res Ther Published Online First: 2015.[2]Khurana R, Wolf R, Berney S, et al. Risk of development of lung cancer is increased in patients with rheumatoid arthritis: A large case control study in US veterans. J Rheumatol 2008.Disclosure of InterestsKaterina Chatzidionysiou Consultant of: consultancy fees from Eli Lilly, AbbVie and Pfizer, Daniela Di Giuseppe: None declared, Jonas Söderling: None declared, Anca Catrina: None declared, Johan Askling Grant/research support from: Karolinska Institutet has entered into agreements between Karolinska Institutet (JA as principal investigator) with AbbVie, BMS, MSD, Eli Lilly, Pfizer, Roche, Samsung Bioepis, Sanofi and UCB, mainly regarding safety monitoring of anti-rheumatic therapies
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  • Frodlund, M, et al. (author)
  • THE IMPACT OF IMMUNOMODULATING TREATMENT ON THE IMMUNOGENICITY OF COVID-19 VACCINES IN PATIENTS WITH IMMUNE-MEDIATED INFLAMMATORY RHEUMATIC DISEASES COMPARED TO HEALTHY CONTROLS. A SWEDISH NATIONWIDE STUDY (COVID19-REUMA)
  • 2022
  • In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 113-114
  • Conference paper (other academic/artistic)abstract
    • Initial studies on the immunogenicity of COVID-19 vaccines in patients with immune-mediated inflammatory rheumatic diseases (IRD) reported diminished antibody response in general, and particularly when treated with rituximab or abatacept (1). Additional data are needed, especially for patients with IRD and immunomodulatory treatments.ObjectivesTo elucidate the antibody response after two doses of COVID-19 vaccine in patients with IRD treated with biologic or targeted synthetic disease modifying anti-rheumatic drugs (b/ts DMARDs) as monotherapy or combined with conventional synthetic DMARDS (csDMARDs).MethodsAntibodies against two antigens representing Spike full length protein and Spike S1 and a Nucleocapsid C-terminal fragment (used to confirm previously COVID-19 infection) were measured in serum obtained before and after the second vaccination using a multiplex bead-based serology assay (2). Patients with IRD receiving immunomodulating treatment, followed at a rheumatology department and healthy individuals (controls) were recruited from five Swedish regions. Antibody positivity was classified as the signal passing an antigen specific cutoff based on the mean intensity signal of 12 selected negative pre-pandemic controls plus 6SD for Spike/S1 and 12SD for Nucleocapsid-C. Good vaccine response was defined as having antibodies over cut-off level for both spike antigens. Percentage of responders in each treatment group was compared to controls (Chi2 test). Predictors of antibody response were determined using logistic regression analysis.ResultsIn total, 414 patients (320 RA/JIA/psoriatic arthritis/axial spondylarthritis, 60 systemic vasculitis and 32 other IRD) and 61 controls participated. Patients receiving rituximab (n=145; 65% female; mean age 65years), abatacept (n=21; 77% female; mean age 66 years), IL6 inhibitors (n=77; 74% female; mean age 64years), JAK-inhibitors (n=58; 75% female, mean age 53years), TNF-inhibitors (n=68; 66% female; mean age 44years;), IL17 inhibitors (n=42; 54% female; mean age 44years) and controls (n=61; 74% female, mean age 49years) were studied. Patients receiving IL6 inhibitor (81.0%), abatacept (43.8%) or rituximab (33.8%) had a significantly lower antibody response rate compared to controls (98.4%), further pronounced if combined with csDMARD (p<0.001) (Figure 1). In the adjusted logistic regression analysis, higher age, rituximab, abatacept, concomitant csDMARD but not IL6 inhibitors, concomitant prednisolone, or a vasculitis diagnosis, remained significant predictors of antibody response (Table 1). All vaccines were well tolerated. 14 (3.4%) patients reported an increased activity in their IRD following vaccination.ConclusionIn this nationwide study including IRD patients receiving b/ts DMARDs a decreased immunogenicity of COVID-19 vaccines was observed in patients receiving rituximab, abatacept and to some extent IL-6 inhibitors. Concomitant csDMARD gave further attenuation. Patients on rituximab and abatacept should be prioritized for booster doses of COVID19 vaccine.References[1]Jena, et al. Response to SARS-CoV-2 vaccination in immune mediated inflammatory diseases: Systematic rev./meta-analysis. Autoim. Rev: 2021;102927[2]Hober, et al. Systematic evaluation of SARS-CoV-2 antigens enables a highly specific and sensitive multiplex serol. C-19 assay. Clin Transl Im. 2021;10(7): e1312Table 1.Predictors of antibody response to COVID-19 vaccineRituximab-1.799<0.0010.170.07-0.42Abatacept-1.9710.0010.140.04-0.45IL6 inhibitor0.0230.9651.020.36-2.94Age (years)-0.0810.0000.920.89-0.96csDMARD-1.1270.0020.320.16-0.66Prednisolone (mg/day)-0.0640.2060.940.85-1.04Frequency (%) of individuals with good antibody response to COVID-19 vaccineAcknowledgementsUnrestricted research grants have been received från Roche and starting grants from the Swedish Rheumatism AssociationDisclosure of InterestsMartina Frodlund Consultant of: Consultancy fees from AstraZeneca and GSK, Katerina Chatzidionysiou Consultant of: Consultancy fees from Eli Lilly, AbbVie and Pfizer, Anna Södergren: None declared, Eva Klingberg: None declared, Anders Bengtsson: None declared, Lars Klareskog Grant/research support from: Research grants from Pfizer, BMS, Affibody, Sonoma Biotherapeutics, Meliha C Kapetanovic: None declared
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  • Christiansen, SN, et al. (author)
  • SECULAR TRENDS IN BASELINE CHARACTERISTICS, TREATMENT RETENTION AND RESPONSE RATES IN 17453 BIONAIVE PSORIATIC ARTHRITIS PATIENTS INITIATING TNFI - RESULTS FROM THE EUROSPA COLLABORATION
  • 2021
  • In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 131-132
  • Conference paper (other academic/artistic)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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  • Aggarwal, R, et al. (author)
  • RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL TO EVALUATE EFFICACY AND SAFETY OF SC ABATACEPT IN ADULTS WITH ACTIVE IDIOPATHIC INFLAMMATORY MYOPATHY
  • 2022
  • In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 711-711
  • Conference paper (other academic/artistic)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. (author)
  • INTEGRATION OF GWAS AND EPIGENETIC STUDIES IDENTIFIES NOVEL GENES THAT ALTER EXPRESSION IN THE MINOR SALIVARY GLAND IN SJOGREN'S DISEASE
  • 2022
  • In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 72-73
  • Conference paper (other academic/artistic)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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7.
  • Ajeganova, S, et al. (author)
  • HIGHER LEVELS OF NATURAL ANTI-PHOSPHORYLCHOLINE ANTIBODIES ARE ASSOCIATED WITH LOWER RISK OF INCIDENT CARDIOVASCULAR EVENTS IN YOUNGER PATIENTS WITH RHEUMATOID ARTHRITIS
  • 2020
  • In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 939-939
  • Conference paper (other academic/artistic)abstract
    • The increased cardiovascular (CV) risk in rheumatoid arthritis (RA), especially in seropositive RA, is not fully explained by traditional risk factors. Immuno-inflammatory mechanisms and autoantibodies could be involved in the pathogenesis of atherosclerotic disease. Recent studies have suggested that anti-phosporylcholine antibodies (anti-PC) of IgM subclass counteract the generation of senescent and IL-17+ T-cells, have atheroprotective effects and may play a role in formation and stabilization of atherosclerotic plaque.Objectives:To investigate the association between IgM anti-PC antibodies with cardiovascular (CV) morbidity in patients with RA in age and sex groups and by serostatus.Methods:The study population was derived from the BARFOT early RA cohort, recruited in 1994-1999. The outcome was CV events i.e. AMI, angina pectoris, coronary intervention, ischemic stroke and TIA tracked through the Swedish Hospital Discharge and the National Cause of Death Registries. The RA-disease measures and traditional risk factors were assessed according to the protocol. Sera collected at inclusion and the 2-year visit were analyzed with ELISA to determine levels of anti-PC IgM (Athera CVDefine kit, Athera Biotechnologies AB). The Kaplan-Meier estimates and Cox proportional-hazards regression models were applied. Analysis were stratified by median level of IgM anti-PC and performed within strata of age, sex and RA-autoantibodies.Results:In all, 654 patients with early RA, 68% women, mean (SD) age 55(14.7) years, DAS28 5.2(1.3), 60% RF-positive and 60% ACPA-positive without prevalent CVD were included in this analysis. The level of IgM anti-PC at baseline was median (IQR) of 60.9(36.4-94.9) and at 2 years 56.0(32.3-84.2) U/ml. During follow-up of > 10 years, 141 incident CV events (21.6%) were registered. The levels of anti-PC both at inclusion and after 2 years of observation were lower in participants who experienced CV event than in those who did not, p=0.020 and p=0.012.The CV event-free survival differed between patients with levels of anti-PC above median compared with those with levels below, p=0.003 by log-rank test. The risk for incident CV event showed a 0.6-fold hazard (95% CI, 0.4-0.8) among patients with higher anti-PC levels as compared with those with lower levels, p=0.003. In the age groups, the risk for incident CV event was lower in patients aged <55 years at inclusion than in those who were older, hazard ratio (HR) 0.40 (0.17-0.94), p=0.036. This result persisted when adjusted for sex and all traditional risk factors, HR 0.36 (0.14-0.92), p=0.032. Also, the risk for incident CV events was lower in patients with higher anti-PC levels in females, HR 0.61 (0-39-0.45), and double RF- and ACPA- negative patients, 0.44 (0.21-0.90), in crude analyses.The favourable effect of anti-PC at baseline and the CV outcome was not observed in ages >55 years, males, ACPA+ and RF+ patients. There were no significant association between anti-PC level at 2 years and outcome.Conclusion:These results suggest that higher levels of IgM anti-PC are associated with a lower risk of incident CV events over 10 years in younger patients. The favourable atheroprotective effect of IgM anti-PC may be a part of explanation of lower risk of atherosclerotic disease in younger persons, females and in those with seronegative RA.Acknowledgments :6th Framework Program of the European Union (grant LSHM-CT-2006-037227 CVDIMMUNE)Disclosure of Interests:Sofia Ajeganova: None declared, Maria Andersson: None declared, Johan Frostegård Grant/research support from: Unconditional competitive grant from Amgen, related only to PCSK9, not the topic of this abstract, Ingiäld Hafström: None declared
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8.
  • Ajeganova, S, et al. (author)
  • TEAM-REHABILITATION BENEFITS BODY COMPOSITION AND FUNCTIONAL OUTCOME BEYOND TIME OF THE REHABILITATION PERIOD IN INFLAMMATORY ARTHRITIS, OF WHICH BODY COMPOSITION IS LINKED TO CHANGE IN LEVEL OF CARDIORESPIRATORY FITNESS, WHEREAS MUSCLE MASS AND STRENGTH ARE LINKED TO PHYSICAL FUNCTIONING
  • 2020
  • In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 1262-1263
  • Conference paper (other academic/artistic)abstract
    • Low physical activity, accumulated disability and disease chronicity contribute to adverse body composition and reduced cardiorespiratory fitness in patients with chronic inflammatory diseases. In the general population, physical exercise improves body composition, muscle strength and aerobic capacity but in inflammatory diseases it is not well established.Objectives:To investigate whether 1) exercise intervention in patients with arthritis affects body composition, physical and aerobic capacity, and whether 2) body composition and physical capacity could explain outcomes as HAQ and aerobic capacity.Methods:Consecutive patients with inflammatory arthritis and a clinical need for rehabilitation, ages 18-80 years, participated in a team-rehabilitation program for 4 weeks. Anthropometry, body composition assessed with bioelectrical impedance analysis, muscle force with hand grip strength and Times sit-to-stand test (TST), activity limitation with the HAQ score and cardiorespiratory fitness with the Åstrand 6-minute cycle test for VO2 max were measured pre-rehabilitation and after 3 and 12 months. The ANOVA model with Bonferroni correction, adjusted for age, sex and baseline measures, was used for the pairwise comparisons of repeated measures overtime. Association between body composition, physical functioning, and the course of HAQ and cardiorespiratory fitness for 12 months was determined with linear mixed models adjusted for age, gender and comorbidity.Results:The study evaluated 149 patients with rheumatoid arthritis (RA), psoriasis arthritis, spondylarthritis and juvenile idiopathic arthritis, aged mean (SD) 53(13) years, 74% women, disease duration 21(13) years, HAQ 1.1(0.6) at inclusion and DAS28 4.1(1.3) for those with RA.There was a statistically significant reduction of BMI between pre-rehabilitation and after 3 months, reduction of waist circumference, body fat, fat mass and the fat mass index after 3 and 12 months, adjusted p<0.05. The muscle mass of total body, arms and legs did not change significantly post-rehabilitation compared to pre-rehabilitation. Hand grip strength and TST improved together with reduction of HAQ and increased VO2 max after 3 and 12 months, adjusted p<0.05 adjusted for age, sex and baseline measures.The HAQ overtime was independently associated with total body muscle mass, legs muscle mass, hand grip strength, and TST pre-rehabilitation, but not to the change of body composition overtime.The course of VO2 max overtime was independently associated with pre-rehabilitation BMI, waist circumference, muscle mass of total body, arms and legs, fat mass, body fat, the fat mass index and TST, as well as with change of BMI, waist circumference, fat mass and the fat mass index between pre-rehabilitation and after 3 and 12 months.Conclusion:We observed benefits of intervention with a team-rehabilitation program for 4 weeks on body composition profile, functioning, physical limitation and cardiorespiratory fitness, which were presented beyond the time of the rehabilitation period for up to 12 months. Different aspects of body composition and physical capacity were associated with levels of disability measured with HAQ and with cardiorespiratory fitness. This study indicates that in patients with inflammatory arthritis, muscle mass and strength were linked to HAQ over time, whereas the measures of body composition could be more linked to cardiorespiratory fitness than to HAQ.Disclosure of Interests:None declared
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9.
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10.
  • Almeida-Brasil, Celline C., et al. (author)
  • Flares after hydroxychloroquine reduction or discontinuation : results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort
  • 2022
  • In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 81:3, s. 370-378
  • Journal article (peer-reviewed)abstract
    • OBJECTIVES: To evaluate systemic lupus erythematosus (SLE) flares following hydroxychloroquine (HCQ) reduction or discontinuation versus HCQ maintenance. METHODS: We analysed prospective data from the Systemic Lupus International Collaborating Clinics (SLICC) cohort, enrolled from 33 sites within 15 months of SLE diagnosis and followed annually (1999-2019). We evaluated person-time contributed while on the initial HCQ dose ('maintenance'), comparing this with person-time contributed after a first dose reduction, and after a first HCQ discontinuation. We estimated time to first flare, defined as either subsequent need for therapy augmentation, increase of ≥4 points in the SLE Disease Activity Index-2000, or hospitalisation for SLE. We estimated adjusted HRs (aHRs) with 95% CIs associated with reducing/discontinuing HCQ (vs maintenance). We also conducted separate multivariable hazard regressions in each HCQ subcohort to identify factors associated with flare. RESULTS: We studied 1460 (90% female) patients initiating HCQ. aHRs for first SLE flare were 1.20 (95% CI 1.04 to 1.38) and 1.56 (95% CI 1.31 to 1.86) for the HCQ reduction and discontinuation groups, respectively, versus HCQ maintenance. Patients with low educational level were at particular risk of flaring after HCQ discontinuation (aHR 1.43, 95% CI 1.09 to 1.87). Prednisone use at time-zero was associated with over 1.5-fold increase in flare risk in all HCQ subcohorts. CONCLUSIONS: SLE flare risk was higher after HCQ taper/discontinuation versus HCQ maintenance. Decisions to maintain, reduce or stop HCQ may affect specific subgroups differently, including those on prednisone and/or with low education. Further study of special groups (eg, seniors) may be helpful.
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11.
  • Andersson, KM, et al. (author)
  • GGTASE DEFICIENT MACROPHAGES ALTER INTEGRIN EXPRESSION ON LYMPHOCYTES AND FACILITATE DEVELOPMENT OF ARTHRITIS
  • 2020
  • In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 205-206
  • Conference paper (other academic/artistic)abstract
    • Geranylgeranyltransferase type I (GGTaseI) is the enzyme responsible for the prenylation/ lipidation of the RhoA family proteins, which keeps them attached to the cell membrane. We reported that GGTaseI-deficient (GLC) mice develop a spontaneous and age-dependent arthritis, reproducing the pathology of RA1. Targeting GGTaseI activates RhoA proteins.Objectives:To study which of the activated Rho proteins is responsible for development of arthritis, we deleted individual RhoA, Rac1 or Cdc42 genes in GLC mice. We study consequences of GGTaseI deficiency for lymphocyte function.Methods:Double deficient mice that lack Rac1 (GLC Rac1fl/fl), RhoA (GLC RhoAfl/fl) and Cdc42 (GLC Cdc42fl/fl) were developed by Cre-technology using the LysM-promotor, and were on a mixed genetic background (129Ola/Hsd-C57BL/6)2. Joints of the hind paws were assessed for signs of arthritis histologically and by micro CT at age of 16 weeks. Phenotype of spleen CD4 and CD8 T cells was analysis by flow cytometry. Proliferation and cytokine production was assessed in spleen cultures by ELISA. Gene expression profile was analyzed by RT-PCR.Results:Deletion of Rho proteins had divergent effect on development of arthritis in GLC mice. We observed a reduction of the arthritis index in GLC Rac1fl/fl (n=19, p=0.027) and GLC RhoAfl/fl (n=4, p=0.007) mice compared to GLC (n=16), while GLC Cdc42fl/fl (n=4) had no change in arthritis development. GLC RhoAfl/fl mice increased the bone mass compared to GLC (p=0.029).Flow cytometry analysis showed that RA-prone GLC and GLC Cdc42fl/fl mice had lower number of CD4 cells in spleen. CD4 cells of RA-prone GLC and GLC Cdc42 mice had significantly higher subsets of the regulatory FoxP3+ and FOXp3+CD25+ cells (p=0.016-0.029 and p=0.016-0.029 respectively) compared to control and GLC RhoAfl/fl mice. Additionally, RA-prone mice had higher expression of receptors to extracellular matrix proteins collagen (α2β2) and fibronectin (α5β1) compared to control mice (p=0.016 and p=0.011 resp) and to RA-protected mice (GLC Rac1fl/fl and GLC RhoAfl/fl, p=0.0004 and p=0.011, resp). In total, both the number of FoxP3+ CD4 cells and the expression of α5β1 receptors on CD4 cells correlated strongly with the synovitis score (r=0.72, p=0.0017 and r=0.59, p=0.012, respectively).GGTaseI gene lays under the control of HOX proteins essential for cell homing. Importantly, HOX regulate the expression of integrins. Studying the expression of HoxA genes in spleen, we found that RA prone GLC and GLC Cdc42 mice tended to have lower expression of HoxA2 and higher expression of HoxA9 compared to RA-protected GLC Rac1 and GLC RhoA and to control mice. The Hoxa9/Hoxa2 ratio was significantly higher in RA prone mice compared to RA-protected mice (p=0.0085) and control mice (p=0.019). This ratio correlated with α5β1 receptors (r=0.55, p=0.0084), FOXP3+ CD4 cells (r=0.50, p=0.017), and the arthritis index (r=0.50, p=0.033).Conclusion:Taken together this study shows that Rho proteins play divergent role in development of arthritis. Activation of Rac1 and RhoA by GGTaseI deletion changes the pattern of HOXA proteins and increases expression of integrin receptors, which facilitates leukocyte influx in the paw joints. Deletion of Rac1 and RhoA has RA-protective effect in GLC mice.References:[1]Khan, O.M., et al.J Clin Invest121, 628 (2011).[2]Akula, M.K., et al.Nat Commun10, 3975 (2019).Disclosure of Interests:None declared
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12.
  • Andersson, KM, et al. (author)
  • SURVIVIN INHIBITS TRANSCRIPTION OF PBX1 AND SUPPORTS THE EFFECTOR PHENOTYPE OF THE MEMORY CD4 T CELLS IN RHEUMATOID ARTHRITIS
  • 2020
  • In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 227-228
  • Conference paper (other academic/artistic)abstract
    • The oncogenic protein survivin is a marker of severe rheumatoid arthritis (RA). High serum levels of Survivin predict progressive joint damage1and poor treatment response2.Objectives:To study the role of survivin in the transcriptional regulation of phenotype in CD4+T cells.Methods:CD4+T cells of RA female patients were isolated from the perpheral blood. Activated CD4+cells were treated with survivin inhibitor YM155. Transcriptional analysis was done by RNAseq (Illumina) and conventional qPCR. Chromatin of CD4 cells was immunoprecipitated using polyclonal antibodies to survivin and subjected to deep sequencing (survivin ChIPseq, Hiseq2000, Illumina) and aligned to GRCh38. Statistical analysis of differentially expressed genes (DEG) was done in R-studio using Benjamini-Hochberg adjustment for multiple testing (Bioconductor, DESeq2 package).Results:Survivin ChIPseq of the activated CD4+T cells was enriched with the genes engaged in regulatory transcription factor specific DNA binding (GO:0000987, adj p=0.0005) and RNA polymerase II regulatory transcription (GO:0000978, adj p = 0.0004). Among survivin targets were the genes of HOX-B cluster and TALE family proteins MEIS, PKNOX and PBX1 controlling early leukopoesis and T cell maturation. Inhibition of survivin in PBMC resulted in significant upregulation of PBX1 (p=0.023), MEIS3 (p=0.0036), similar tendency was observed for HOXB6 and HOXC4 genes. RNAseq analysis CD4 cells of RA patients with different transcription of PBX1, identified 1636 genes (adj p<10-5). BIRC5, coding for survivin, was 8.3 folds higher in CD4+cells with low PBX1 (p=0.0005). Among the core transcription factors of T helper cell differentiation, we identifed NF-kB1 and NF-kB2, TBX21, IRF4, IRF8 and STAT3, BATF and BATF3. This followed by significantly higher TNF, IFNg and IL17A and IL17F in PBX1lo CD4 T cells. The pathway enrichment analysis of DEG identified strong over-representation of cytokine-specific genes (GO:005125, GO:0005126, GO:0048018, GO:0030545, FDR q-values 10-12-10-9). The genes of IL4, IL5, IL13, IL9, IL3 and CSF2 located within the chromosome 5 were common for all GO-lists, and were higher in PBX1lo, but none of those genes was identified by survivin-ChIPseq or PBX1-ChIPseq. Analysis of ChIPseq data identified the genes of STAT3, IRF4, IRF8 and BATF as common targets for PBX1 and survivin.Conclusion:This genome-wide analysis indicates that survivin regulates transcription of the TALE family protein PBX1 in CD4+ T cells, which has essential effect for differentiation and phenotype of Th subsets. Low PBX1 in RA patients is associated with terminally differentiated effector CD4+ T cells.References:[1]Svensson, B.et.al.Smoking in combination with antibodies to cyclic citrullinated peptides is associated with persistently high levels of survivin in early rheumatoid arthritis: a prospective cohort study.Arthritis Res Ther16, R12 (2014).[2]Levitsky, A.et.al.Serum survivin predicts responses to treatment in active rheumatoid arthritis: a post hoc analysis from the SWEFOT trial.BMC Med13, 247 (2015).Disclosure of Interests:None declared
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13.
  • Andersson, M., et al. (author)
  • Empowerment and Associations to Disease Activity and Pain in Patients with Rheumatoid Arthritis
  • 2021
  • In: Annals of the Rheumatic Diseases. - London : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 80:Supplement 1, s. 197-197
  • Journal article (peer-reviewed)abstract
    • The WHO describes empowerment as a process in which patients can take control and make informed decisions about their life and health. Empowerment is important for patients with rheumatoid arthritis (RA) since most of the care is provided by the patients themselves.Objectives:The aim was to study levels of empowerment and associated variables in individuals with RA and to investigate longitudinal clinical data in patients with low and high empowerment.Methods:This study involved patients with RA from the BARFOT (Better Anti-Rheumatic PharmacOTherapy) cohort, who were recruited between 1992 and 2006 and included in the study at the time for diagnosis (n = 2,837) [1]. The patients were assessed according to a structured protocol at inclusion and after 3, 6, 12, 24, 60, 96, and 180 months. At each follow-up DAS28-3, HAQ and pain were assessed. In 2017, a postal survey was sent to all still living patients (n=1542), with a response rate of 69% (n = 1,065). The questionnaire included disease characteristics, questions about lifestyle habits and the Swedish Rheumatic Disease Empowerment Scale (SWE-RES-23) [2]. The 844 patients who answered the SWE-RES-23 made up the study cohort. Differences in empowerment between groups (lowest third [LE], SWE-RES-23 ≤3.48 vs. highest third [HE], SWE-RES-23 ≥4.04) were analysed with t-tests. Logistic regression analysis was used to study associations with LE vs. all others. Thirdly, differences between LE and HE were studied with longitudinal data (seven time points) of pain, HAQ and disease activity.Results:Responders were mean 65 (SD13) years old, disease duration 15.6 (3.9) years, and 74% were women. The LE group (n=282) were older and were more often women, and reported worse overall health compared with the HE group (n=270), Table 1.Table 1.Descriptives at questionnaire 2017, including all participants and comparisons between highest and lowest third of SWE-RES-23AllMean (sd)Low SWERES*Mean (sd)High SWERES*Mean (sd)p-valueN844282270Sex, women, %7478690.015Age65 (13)66 (13)63 (12)0.002Disease duration, year15.6 (3.9)15.7 (4.1)15.6 (3.8)0.917TJC28 (0-28)5 (6)6 (8)4 (5)<0.001SJC28 (0-28)3 (5)3 (4)3 (4)0.334PatGA (0-10)3 (2)4 (3)2 (2)<0.001Pain (0-10)3 (2)4 (3)3 (2)<0.001Fatigue (0-10)4 (3)5 (3)3 (3)<0.001HAQ (0-3)0.62 (0.61)0.81 (0.69)0.42 (0.51)<0.001EQ5D (0-1)0.70 (0.25)0.62 (0.29)0.79 (0.19)<0.001SWERES3.8 (0.7)3.1 (0.3)4.6 (0.3)<0.001*tricotomized data, lowest third vs. highest thirdRegarding lifestyle habits, there were no differences between the groups in smoking habits, diets, or drinking habits. Moderate physical activity for ≥150 min/week was reported by 27% in the LE group vs. 41% in the HE group, p<0.001. Vigorous physical activity ≥60 min/week was reported by 22% vs. 37% in the LE and the HE group respectively, p<0.001.In the logistic regression analysis (n=844), several factors were associated with LE: being a woman (OR 1.40, 95% CI 1.00-1.97), pain-related factors as higher tender joint count (OR 1.04, 95% CI 1.01-1.06), worse patient global assessment (OR 1.19, 95% CI 1.12-1.27), pain (OR 1.14, 95% CI 1.08-1.21), fatigue (OR 1.14, 95% CI 1.09-1.21), HAQ (OR 2.08, 95% CI 1.64-2.64) and EQ-5D (OR 0.16, 95% CI 0.09-0.28). There were also associations between moderate physical activity (<150 min/week) (OR 1.60, 95% CI 1.16-2.19) and vigorous (< 60min/week) (OR 1.50, 95% CI 1.07-2.10) and LE.Analysing longitudinal data, the LE group reported worse pain and HAQ at all timepoints, a worse DAS28-3 at year 2 and 8, and a worse ESR at 15 years follow-up compared with the HE group (p<0.05).Conclusion:In patients with RA, low empowerment is associated with worse all over health. Interventions aimed to improve empowerment may include mastering of pain, physical function, and improved physical activity.References:[1]Hafstrom I et al. Open Access Rheumatol 2019;11:207-17.[2]Arvidsson S et al. Musculoskeletal Care 2012;10:101-9.Figure 1.Panel showing mean DAS28-3 (A), ESR (B), VAS pain (C) and HAQ (D) over 15 years in the different groups.Disclosure of Interests:None declared.
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14.
  • Andersson, Maria L.E. 1968-, et al. (author)
  • Metabolic factors associated to clinical hand osteoarthritis in individuals with knee pain
  • 2020
  • In: Annals of the Rheumatic Diseases. - London : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 79:Suppl. 1, s. 1734-1734
  • Journal article (peer-reviewed)abstract
    • Background: There is some evidence supporting associations between metabolic factors, clinical hand osteoarthritis (OA) and radiographic knee OA. However, more studies are needed regarding early knee OA.Objectives: The aim was to study associations between metabolic factors and clinical hand OA at baseline in a cohort of individuals with knee pain, with and without radiographic knee OA.Methods: In an ongoing five-year longitudinal study of knee pain, hand OA was assessed by clinical examinations in 296 of the included individuals at baseline [1]. BMI, waist circumference (WC) and blood pressure was measured. Body composition was assessed with Inbody 770. Fasting plasma glucose, triglycerides, cholesterol, HDL-and LDL-cholesterol and HbA1c was analysed. Metabolic syndrome (MetS)was present if central obesity (WC ≥94 cm in men and ≥80cm in women) plus any two of the following factors: raised blood pressure (systolic blood pressure ≥ 130 or diastolic blood pressure ≥ 85 mm Hg or treatment of hypertension), raised triglycerides (≥ 1.7 mmol/L or specific treatment), reduced HDL-cholesterol (men < 1.03 mmol/L and women < 1.29 mmol/L or specific treatment), raised glucose (glucose ≥ 5.6 mmol/L, or type 2 diabetes). Hand strength and self-reported disability of the arm, shoulder and hand (quickDASH) was assessed.The individuals were divided according to having clinical hand OA or not, according to Altman [1]. The associations between background factors and clinical hand OA were calculated by crude logistic regression analyses, adjusting for age and sex.Results: Fifty-five percent of the individuals in the study was overweight or obese, 40% had MetS and 23% had radiographic knee OA. In total 34% of the individuals had clinical hand OA. The group with hand OA were older, had higher proportion of body fat, fasting plasma glucose, HbA1C, worse quickDASH score and lower hand strength, table 1. Clinical hand OA was significantly associated to higher age (OR 1.04, 95%CI 1.01-1.07), higher fasting plasma glucose (1.56, 1.05-2.30), worse quickDASH (1.04, 1.02-1.06) and lower hand strength (0.99, 0.99 -0.998), but not to proportion of body fat and HbA1c.Conclusion: In this cross-sectional study, the only metabolic factor associated with clinical hand OA was fasting plasma glucose. Contrary to other studies, there were no gender differences found. The association between development of clinical hand OA and metabolic factors in individuals with knee pain need to be further assessed in longitudinal studies.
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15.
  • Andersson, Maria L.E. 1968-, et al. (author)
  • Metabolic Factors Associated to Radiographic Knee Osteoarthritis in Individuals with Knee Pain
  • 2020
  • In: Annals of the Rheumatic Diseases. - London : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 79:Suppl. 1, s. 793-793
  • Journal article (peer-reviewed)abstract
    • Metabolic factors have been shown to be associated to radiographic knee osteoarthritis (OA) [1]. More knowledge about associations between metabolic factors and early clinical knee OA is needed.Objectives:The aim was to study associations between metabolic factors and radiographic knee OA in individuals with knee painMethods:In total 272 individuals with radiographs at baseline, from an ongoing longitudinal study of knee pain (without cruciate ligament injury), were included in the present cross-sectional study. At baseline BMI, waist circumference (WC) and visceral fat area (VFA) were assessed. Fasting plasma glucose, triglycerides, cholesterol, HDL-and LDL-cholesterol were analysed. Metabolic syndrome (MetS) was present if central obesity (WC ≥94 cm in men and ≥80cm in women) plus any two of the following factors: raised blood pressure (systolic blood pressure ≥ 130 or diastolic blood pressure ≥ 85 mm Hg or treatment of hypertension), raised triglycerides (≥ 1.7 mmol/L or specific treatment), reduced HDL-cholesterol (men < 1.03 mmol/L and women < 1.29 mmol/L or specific treatment), raised glucose (glucose ≥ 5.6 mmol/L, or type 2 diabetes).The individuals were divided in two groups according to Ahlbäck [2], one group, who had grade I or more in at least one knee (radiographic knee OA, ROA) n=62 and the other group, not fulfilling Ahlbäck criteria (no radiograhic knee OA, No OA) n=211. The associations between metabolic factors and knee OA were calculated by crude logistic regression analyses, adjusting for age and sex.Results:The group with radiographic knee OA were older, had higher BMI, higher amount of visceral fat and more had central obesity, table 1. Ninety- four percent of the group with ROA had central obesity compared to 76%, p=0.002 in the no OA group. There was no difference between the groups regarding MetS, 44% in the ROA group vs. 39%, p=0.5. The group with ROA had increased cholesterol, triglycerides and LDL-cholesterol. There were no differences in fasting glucose between the groups, though both groups had a mean glucose value in the upper range of normal value, table 1. Factors associated to having radiographic knee OA were age (OR 1.11, 95% CI 1.06-1.17), BMI (1.07, 1.003-1.13), central obesity (3.91, 1.32-11.61) and raised triglycerides (2.35, 1.03-5.38).Table 1.Baseline descriptivesNo OAMean (sd)ROAMean(sd)p-valueN21162Age50 (9)56 (4)<0.001Sex, women, %66710.454BMI25.9 (4.7)27.7 (4.7)0.007VFA (cm2)109 (53)126 (52)0.026WC, cm94 (13)99 (13)0.006Raised Blood pressure, %66530.063Cholesterol (mmol/L)5.2 (1.0)5.5 (1.1)0.033Triglycerides (mmol/L)1.0 (0.6)1.2 (0.7)0.035Raised triglycerides, %9210.008LDL-cholesterol (mmol/L)3.4 (1.0)3.7 (1.1)0.027HDL-cholesterol (mmol/L)1.7 (0.4)1.7 (0.5)0.547Reduced HDL11150.460Glucose (mmol/L)5.5 (0.9)5.5 (0.5)0.858Conclusion:There were associations between some metabolic factors and radiographic knee OA in individuals with knee pain. Fasting glucose was increased in both groups. The associations between metabolic risk factors and the development of knee OA needs to be assessed in longitudinal studies.References:[1]Sellam J, Bone Spine 2013;80:568-73.[2]Ahlback S,. Acta Radiol Diagn (Stockh) 1968Suppl 277:7-72.Disclosure of Interests:None declared
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16.
  • Andersson, Åsa, Professor, 1960-, et al. (author)
  • Serum Protein Response To A Single High-Intensity Interval Training Bout – Comparison Between Individuals With Spondyloarthritis And Healthy Controls
  • 2022
  • In: Annals of the Rheumatic Diseases. - London : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 81:Suppl 1, s. 780-781
  • Journal article (peer-reviewed)abstract
    • Axial spondyloarthritis (axSpA) is a chronic inflammatory disease affecting mainly the axial skeleton. To decrease the risk of cardiovascular comorbidity, aerobic training is recommended as a part of disease management in patients with axSpA. High-intensity interval training (HIIT) interventions are, in addition to other recommended treatments, believed to positively affect the disease activity (1). However, the knowledge about the acute effects of HIIT on the inflammatory process at the molecular level is less studied. Understanding the acute HIIT effects on cytokines and additional serum proteins in axSpA is important for further long-term HIIT interventions and recording of the effect of HIIT on the axSpA disease profile.ObjectivesTo study the acute effects on serum proteins, such as cytokines, myokines, and inflammatory- and bone-related proteins, in response to a single bout of HIIT, and to compare the levels between baseline and post-HIIT in patients with axSpA and healthy controls (HC).MethodsThe pilot study included twenty-one participants (10 female, 11 male), mean (SD) age 40 (7) years, ten with axSpA, and eleven age and sex matched HC, who performed a single HIIT on a cycle ergometer consisting of 4x4 minutes interval (90% heart rate, HR-max) with three minutes active rest in between (70% of HR-max). Disease activity (BASDAI, 0-10) in patients with axSpA was 1.6 (0.8). Health status EuroQol (EQ5D, 0-1) were 0.87 (0.11) for axSpA, and 0.93 (0.10) for HC. The groups were well matched with no difference in baseline data for weight, BMI, EQ5D, blood pressure or aerobic capacity.Blood samples were taken before (baseline) and one hour after the single HIIT. The following serum proteins were analyzed on a Luminex MAGPIX System (Luminex corporation, Austin, TX USA): Interleukin (IL)-6, IL-17, IL-18, TNFαAGPIX System (Luminex corporatiosteoprotegerin, osteocalcin, osteopontin, and FGF-23. A three-way analysis of variance (ANOVA) was used to detect differences between groups, between sexes, and before and after a HIIT bout in a 2(group)*2(sex)*2(time) design. For main effects or interactions significant at p≤0.05, simple effect t-tests were used to determine the specific effects.ResultsA group main effect (p=0.048) showed that the serum level of IL-6 was increased one hour after the HIIT session primarily in the HC, 0.4 pg/ml (SD±0.4) at baseline vs. post-HIIT 1.8 (2.0). The concentration of the cytokines/chemokine IL-17, IL-18, TNFα group main effect (p=0.048) showed that the serum level of IL-6 was increased one hour after the HIIT session primarily in30) in VEGF-A showed that the axSpA group had significantly lower VEGF-A at baseline, 159 pg/ml (138) vs 326 (184) in the control group (which might be due to anti-inflammatory medication). A sex main effect (p=0.029) was observed from baseline to post-HIIT for the bone hormone osteocalcin, with a more pronounced decrease of serum osteocalcin in women with axSpA, 14.0 ng/ml (8.3) vs. post HIIT 13.2 (6.9). Moreover, the level of the multifunctional protein osteopontin was significantly lower (sex main effect, p=0.021) in women, 10.7 ng/ml (7.0) vs. men 20.4 (10.1), post-HIIT.ConclusionThis pilot study shows that one bout of HIIT influences the expression of proteins involved in inflammation and metabolism, and that sex is an important factor in the response to HIIT. The results should be followed up in longer intervention studies including higher numbers of participants.References[1]Sveaas, S. H. et al. (2019). High intensity exercise for 3 months reduces disease activity in axial spondyloarthritis (axSpA): a multicentre randomised trial of 100 patients. British journal of sports medicine, 54(5), 292-297.Disclosure of InterestsÅsa Andersson: None declared, Emma Haglund Consultant of: Novartis, Emma Berthold: None declared, Elisabeth Mogard Consultant of: Novartis, Anna Torell: None declared, M Charlotte Olsson: None declared
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17.
  • Andreasson, K, et al. (author)
  • PATIENTS WITH INFLAMMATORY MYOPATHIES WHO DO NOT REACH HEALTH ENHANCING LEVELS OF PHYSICAL ACTIVITY REPORT HIGHER LEVELS OF ANXIETY AND DEPRESSION - A CROSS-SECTIONAL STUDY OF SELF-REPORTED DATA
  • 2020
  • In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 1265-1265
  • Conference paper (other academic/artistic)abstract
    • The adult idiopathic inflammatory myopathies (IIM) comprise dermatomyositis (DM), polymyositis (PM), immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome (ASS), overlap myositis and inclusion body myositis (IBM). Impaired physical capacity, self-reported fatigue and pain are common features in IIM. Quality of life is reduced compared to population-based reference values. To our knowledge self-reported levels of physical activity has not been studied in patients with IIM. Further, anxiety and depression are common in other rheumatic diseases, such as SLE, but is less studied in IIM, and not previously in relation to levels of physical activity. There is evidence for symptom reducing effects of exercise for patients suffering from depression (1).Objectives:The objective of this study is to assess the levels of self-reported physical activity, depression and anxiety amongst adult patients with IIM. A further aim is to evaluate differences in anxiety/depression based on levels of physical activity as well as to analyze relationships between physical activity and anxiety/depression.Methods:All patients with IIM visiting the Rheumatology clinic at Karolinska University Hospital in Solna between February 2019 and January 2020 where asked to fill in questionnaires about their levels of physical activity for the last seven days using the International Physical Activities Questionnaire – short form (IPAQ), and anxiety and depression using Hospital Anxiety and Depression Scale (HADS). The myositis team nurse distributed the questionnaires. Spearman’s rho was used for correlation analysis. Kruskal-Wallis test and post-hoc adjustment with Bonferroni correction was used to analyze group differences. HADS is scored in two separate scales, one for depression (HADS-D) and one for anxiety (HADS-A). The cut-off value for probable depression or anxiety is ≥8 of a maximum of 21 per scale (2). IPAQ-results was scored as 1 (low, < 150 min/w), 2 (moderate, ≥ 150 min/w – health-enhancing levels of physical activity, HEPA, according to WHO) and 3 (high, ≥ 300 min/w).Results:A total of 61 patients answered the questionnaires. 52 (85 %) of the patients reported to reach HEPA and 24 of these patients reported to be active on a high level. 22 patients (36 %) scored probable anxiety or depression, with six scoring ≥8 for both depression and anxiety. Patients with low levels of physical activity (IPAQ-1) scored significantly higher anxiety and depression compared to those reaching HEPA (IPAQ-2 and IPAQ-3) p<0.0001 – 0.020. The correlation between physical activity and depression (Fig. 1) was rs=-0.48 (-0.66; -0.26) and between physical activity and anxiety (Fig. 2), rs=-0.27 (-0.49; -0.02).Conclusion:Self-reported data indicates that most patients with IIM in this sample reached HEPA level or higher. Patients who do not reach HEPA score significantly higher anxiety and depression compared to those reaching HEPA. However, levels of physical activity correlates moderately to depression and weakly to anxiety. The number of patients who reached HEPA is high compared to studies in rheumatoid arthritis or the general population. This could be explained by frequent visits to physical therapists early in the disease and yearly check-ups with a focus on exercise and physical activity. Further the inter-professional myositis team also has a focus on exercise and the importance of everyday physical activity. This is cross-sectional, self-reported data and longitudinal studies are needed also including objective measures. This is preliminary data with data collection ongoing throughout 2020.References:[1]Craft, LL et al. The benefits of exercise for the clinically depressed. Prim Care Companion J Clin Psychiatry. 2004;6(3):104-111[2]Zigmond, AS et al. The hospital anxiety and depression scale. Acta Psychiat. Scand. 1983;67(6):361-70Disclosure of Interests:None declared
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18.
  • Andreoli, L., et al. (author)
  • COVID-19 VACCINE SAFETY DURING PREGNANCY AND BREASTFEEDING IN WOMEN WITH AUTOIMMUNE DISEASES : RESULTS FROM THE COVAD STUDY
  • 2023
  • In: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 82:Suppl. 1, s. 56-57
  • Journal article (other academic/artistic)abstract
    • Background: COVID-19 vaccine hesitancy among pregnant and breastfeeding women with autoimmune diseases (AID) is often attributed to the fear of adverse events (AE) and disease flares (DF). No data are available regarding COVID-19 vaccine safety in this population.Objectives: We aimed at describing delayed-onset (>7 days) vaccine-related AE (minor and major), DF, and related AID treatment modifications from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study.Methods: Among complete responses from 9201 participants as of June 21, 2022, 6787 (73.8%) were women. Six subgroups were identified upon diagnosis of AID vs healthy controls (HC) and their pregnancy/breastfeeding status at the time of any dose of vaccine (Figure 1).Results: Forty pregnant and 52 breastfeeding AID patients were identified and their vaccination rates (at least one dose) was 100% and 96.2%, respectively (Table 1). Overall AE, minor AE, and major AE were reported significantly more frequently by pregnant than non-pregnant patients (45% vs. 26%, p=0.01; 40% vs. 25.9%, p=0.03; 17.5% vs. 4.6%, p<0.01), but no difference was found in comparison with pregnant HC. No difference was observed between breastfeeding patients and HC. Post-vaccination DF were reported by 17.5% of pregnant and 20% of breastfeeding patients, and by 18% of age- and disease-matched control patients (n=2315). All DF in pregnant/breastfeeding patients were managed with glucocorticoids and a fifth of them required initiation or change in immunosuppressive treatment.Conclusion: This study provides the first insights into the safety of COVID-19 vaccination during the antenatal period in women with AID. While AEs were more commonly reported by pregnant patients with AID, these were no higher than among pregnant healthy controls without AID. These observations are reassuring, likely to strengthen physician-patient communication and overcome hesitancy as the benefits for the mother and fetus by passive immunization are likely to overweigh the potential risks of AE and DF.Reference: [1]Fazal ZZ, et al; COVAD Study Group. COVAD survey 2 long-term outcomes: unmet need and protocol. Rheumatol Int 2022; 42:2151-2158.
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19.
  • Angelini, Federico, et al. (author)
  • Osteoarthritis endotype discovery via clustering of biochemical marker data
  • 2022
  • In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:5, s. 666-675
  • Journal article (peer-reviewed)abstract
    • Objectives Osteoarthritis (OA) patient stratification is an important challenge to design tailored treatments and drive drug development. Biochemical markers reflecting joint tissue turnover were measured in the IMI-APPROACH cohort at baseline and analysed using a machine learning approach in order to study OA-dominant phenotypes driven by the endotype-related clusters and discover the driving features and their disease-context meaning. Method Data quality assessment was performed to design appropriate data preprocessing techniques. The k-means clustering algorithm was used to find dominant subgroups of patients based on the biochemical markers data. Classification models were trained to predict cluster membership, and Explainable AI techniques were used to interpret these to reveal the driving factors behind each cluster and identify phenotypes. Statistical analysis was performed to compare differences between clusters with respect to other markers in the IMI-APPROACH cohort and the longitudinal disease progression. Results Three dominant endotypes were found, associated with three phenotypes: C1) low tissue turnover (low repair and articular cartilage/subchondral bone turnover), C2) structural damage (high bone formation/resorption, cartilage degradation) and C3) systemic inflammation (joint tissue degradation, inflammation, cartilage degradation). The method achieved consistent results in the FNIH/OAI cohort. C1 had the highest proportion of non-progressors. C2 was mostly linked to longitudinal structural progression, and C3 was linked to sustained or progressive pain. Conclusions This work supports the existence of differential phenotypes in OA. The biomarker approach could potentially drive stratification for OA clinical trials and contribute to precision medicine strategies for OA progression in the future. Trial registration number NCT03883568.
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20.
  • Antovic, A, et al. (author)
  • OUTCOME FOLLOWING COVID-19 INFECTION IN ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-ASSOCIATED VASCULITIS
  • 2021
  • In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 898-898
  • Conference paper (other academic/artistic)abstract
    • Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) require immunosuppressive therapy for disease control and reduction of disease relapse and may be at risk for complications during Sars-CoV-2 (COVID-19) infection.Objectives:To analyze the consequences of COVID-19 in a large cohort of AAV patients regarding occurrence, need of hospitalization, treatment at the intensive care units (ICU), or death.Methods:Data were retrieved from March 2020 to mid-January 2021 from medical records from the AAV cohort (n=233). Patients diagnosed with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) or eosinophilic granulomatosis with polyangiitis (EGPA) were included. Data included age, gender, diagnosis, ongoing immunosuppressive medication at onset of COVID-19 or at last follow-up in non-COVID individuals. Renal involvement (ever) and estimated glomerular filtration rate (eGFR) were included. COVID-19 was confirmed either by a positive PCR test in the upper airways or by serology. Severe COVID-19 was defined as need of non-invasive ventilation, ICU care, and/or death.Results:The cohort comprised of 172 patients with GPA, 50 with MPA and 11 with EGPA. There were 121 females (52%). During the study period, 20 patients (8.6%) were diagnosed with COVID-19. The median age at data retrieval in all patients was 68 years (21-93), in the COVID-19 group 63 (29-93) and 68.5 (21-90) years in the non-COVID patients.Fourty-three patients in all (18%) were hospitalized during the study period of which 11 (4.7%) due to COVID-19 infection. In all, 8 deaths occurred of which 3 were related to COVID-19.At data retrieval, 110 (47%) patients were on prednisolone treatment, 10/20 (50%) in the COVID-19 group and 100 (47%) in the non-COVID-19 group (p=0.5), with significantly higher doses in COVID-19 patients (p<0.001). In patients hospitalized with COVID-19, 6/11 (54.5%) were on prednisolone, median dose 5 mg/day (0-50). In the total group 112 (48%) were on disease modifying anti-rheumatic drugs (DMARD) and 64 (27.5%) on rituximab as maintenance therapy. Eight patients were on induction treatment with either cyclophosphamide or rituximab.Of the 20 COVID-19 cases, 8 had severe COVID-19. Of these, 2 were inactive without immunosuppressive treatment, 4 had stable disease with prednisolone (5-7.5 mg/day) in combination with DMARDs, and 2 were active treated with high dose prednisolone (25-50 mg/day) in combination with cyclophosphamide and rituximab (n=1) or rituximab (n=1).A higher proportion of patients had active AAV (p=0.03) in the severe COVID-19 then in the non-COVID group (10/213 patients).In the group with the severe COVID-19, 1/8 (12%) patient had rituximab as maintenance therapy, compared to 61/213 (28.6%) in the group of non-COVID-19 patients (p=0.5).Renal involvement (ever) was present in 144 patients (62%), in 6 patients (30%) with COVID- 19, from which 5 (62%) were in the group of severe COVID-19 patients. Median eGFR did not differ between severe COVID-19 and remaining patients with renal involvement independently of COVID-19 infection.Conclusion:We found a high rate of severe COVID-19 infection in our cohort of AAV patients which indicates risk for serious complications, especially in patients with active disease and intense immunosuppressive therapy. Maintenance therapy with rituximab did not seem to increase the risk for severe COVID-19. The findings stress the need for continued shielding and early vaccination in AAV patients.Disclosure of Interests:None declared
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21.
  • Aoude, M., et al. (author)
  • TREATMENT PATTERNS OF IDIOPATHIC INFLAMMATORY MYOPATHIES : RESULTS FROM AN INTERNATIONAL COHORT OF OVER 1,400 PATIENTS
  • 2022
  • In: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 81:Suppl. 1, s. 105-106
  • Journal article (other academic/artistic)abstract
    • Idiopathic inflammatory myopathies (IIM) are a group of heterogeneous autoimmune disorders with limited standardization of treatment protocols.ObjectivesTo evaluate frequency and patterns of various treatments used for IIM based on disease subtype, world region, and organ involvement.MethodsCross-sectional data from the international CoVAD self-report e-survey1 was extracted on Sep 14th, 2021. Patient details included demographics, IIM subtypes (dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), antisynthetase syndrome (ASSD), necrotizing myositis (NM) and overlap myositis (OM)), clinical symptoms, disease duration and activity, and current treatments. Treatments were categorized in corticosteroids (CS), antimalarials, immunosuppressants (IS), intravenous immunoglobulins (IVIG), biologics, and others. Typical clinical symptoms (dyspnea, dysphagia) were used as surrogate for organ involvement. Factors associated with IS were analyzed using multivariable logistic regression, adjusting for IIM subtype, demographics, world region, disease activity, and prevalent clinical symptoms (>10%).ResultsIn 1418 patients with IIM, median age was 61 years [IQR 49-70], 62.5% were females, median disease duration was 6 years [IQR 3-11], most common subset was DM (32.4%).The most used treatments were IS (49.4%, including Methotrexate 19.6%, Mycophenolate Mofetil 18.2%, Azathioprine 8.8%, Cyclosporine 2.7%, Tacrolimus 2%, Leflunomide 1.6%, Sulfasalazine 1%, and Cyclophosphamide 0.6%), followed by CS (40.8%), antimalarials (13.8%) and IVIG (9.4%). Biologics were used in 4.3% of patients.Treatment patterns differed significantly by IIM subtypes with a higher frequency of IS (77.7%) and CS (63.4%) use in ASSD; antimalarials (28.6%) and biologics (9.8%) use in OM and IVIG use in NM (24.6%) (Table 1). Also, treatment patterns were different in regions of the world (Figure 1), with a higher frequency of CS use in Europe (60.5%) and IS use in South America (77.2%). Antimalarials were most used in Asia (19.4%), while IVIG use was most common in Oceania (16.9%). Dyspnea was associated with higher use of IS (69.9%) and CS (65.8%) (p<0.001), whereas dysphagia was negatively associated with IS (39.7%) and CS (32.7%) likely due to a higher proportion in IBM patients reporting dysphagia.Table 1.Current Treatments for IIM, Stratified by Disease SubtypesDermatomyositisPolymyositisInclusion Body MyositisAnti-synthetase syndromeNecrotizing myositisOverlap syndromeAll IIMp-valueNumber of patients459182348148572241418Immunosuppressants*269 (58.6)107 (58.8)39 (11.2)115 (77.7)40 (70.2)130 (58.0)700 (49.4)<0.001Corticosteroids208 (48.0)81 (46.8)32 (9.7)90 (63.4)32 (59.3)103 (50.0)546 (40.8)<0.001Antimalarials99 (21.6)7 (3.8)0 (0.0)25 (16.9)1 (1.8)64 (28.6)196 (13.8)<0.001Intravenous Immunoglobulins54 (11.8)16 (8.8)19 (5.5)10 (6.8)14 (24.6)20 (8.9)133 (9.4)<0.001Biologics**17 (3.7)7 (3.8)0 (0.0)13 (8.8)2 (3.5)22 (9.8)61 (4.3)<0.001Others***6 (1.3)0 (0.0)0 (0.0)1 (0.7)0 (0.0)5 (2,2)12 (0.8)0.098*Methotrexate (278), Mycophenolate Mofetil (258), Azathioprine (125), Cyclosporine (38), Tacrolimus (28), Leflunomide (23), Sulfasalazine (14), Cyclophosphamide (9). **Rituximab (44), Abatacept (5), TNF inhibitors (4), Tocilizumab (3), Belimumab (3), Secukinumab (1). ***JAK(10) and PDE4 inhibitors (2)Multivariable logistic regression analysis showed an association of IS with the IIM subtype (least used in IBM (OR 0.07 [95%CI 0.04-0.13] compared to DM), world region (most used in South America (OR 2.35 [1.12-4.91] compared to North America), active and worsening disease activity (OR 3.49 [1.76-6.91] compared to remission), and some clinical features (dyspnea, fatigue, and muscle weakness).ConclusionIIM treatment patterns differ significantly by disease subtypes, world regions and organ involvement, highlighting the need for unified international consensus-driven guidelines.References[1]Parikshit S. et al. Rheumatol Int. 2022 Jan;42(1):23–9.Disclosure of InterestsNone declared
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22.
  • Argyriou, A, et al. (author)
  • SINGLE CELL SEQUENCING REVEALS CLONALLY EXPANDED CYTOTOXIC CD4+T CELLS IN THE JOINTS OF ACPA plus RA PATIENTS
  • 2021
  • In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 38-39
  • Conference paper (other academic/artistic)abstract
    • CD4+ T cells with cytotoxic functions (CD4+ CTL) have gained attention in recent years. Accumulating evidence supports their importance in defense against human viral infections such as CMV1, EBV2, dengue3, HIV4, 5 and SARS-CoV-26. Moreover, expansion of so called CD28null cytotoxic CD4+ T cells have been reported in the blood of patients with rheumatic diseases such as rheumatoid arthritis (RA)7, myositis8 and vasculitis9 as well as in cardiovascular diseases10.Objectives:Here, we aimed to investigate the presence and clonal expansion of CD4+ CTL in the peripheral blood (PB) and synovial fluid (SF) of RA patients using single cell technologies.Methods:We assessed the expression of cytotoxic effector molecules and transcription factors in CD4+ T cells in synovial fluid (n=21) and paired peripheral blood (n=16) from ACPA- and APCA+ RA patients by multi-parameter flow cytometry. We performed single cell sequencing, in combination with 5´ TCRab sequencing, on purified CD4+ T cells from the peripheral blood (PB) and synovial fluid (SF) of ACPA+ RA patients (n=7).Results:Flow cytometry experiments show that Granzyme-B+ Perforin-1+ CD4+ CTL are significantly increased in the SF of ACPA+ RA patients as compared to ACPA- RA patients (p=0.0072). The presence of CD4+ CTL could be confirmed by single cell sequencing in SF of each ACPA+ RA patient tested (n=7). Moreover, we found that the adhesion G-protein coupled receptor GPR56 is selectively expressed on the recently described peripheral helper (TPH) T-cell subset11 and associates with the expression of tissue resident memory markers LAG-3, CXCR6 and CD69. In blood, we confirmed a previous report12 showing that GPR56 delineates cytotoxic CD4+ T cells. Finally, expanded TCR clones expressing cytotoxic effector molecules were identified in synovial fluid of ACPA+ RA patients and, for some patients, in their corresponding peripheral blood.Conclusion:We identified GPR56 as a marker of TPH cells in SF of ACPA+ RA patients that associates with tissue residency receptors. The combination of single cell sequencing and multi-parameter flow cytometry highlights the importance of CD4+ CTL in ACPA+ RA and suggests a potential therapeutic target (Figure 1).References:[1]Casazza J. P. et al., J Exp Med2006,203 (13), 2865-77.[2]Landais E. et al., Blood2004,103 (4), 1408-16.[3]Kurane I. et al. J Exp Med1989,170 (3), 763-75.[4]Appay V. et al. J Immunol2002,168 (11), 5954-8.[5]Juno J. A. et al. Front Immunol2017,8, 19.[6]Meckiff B. J. et al. Cell2020,183 (5), 1340-1353 e16.[7]Schmidt D. et al. J Clin Invest1996,97 (9), 2027-37.[8]Fasth A. E. et al. J Immunol2009,183 (7), 4792-9.[9]Moosig F. et al. Clin Exp Immunol1998,114 (1), 113-8.[10]Sato K. et al. J Exp Med2006,203 (1), 239-50.[11]Rao D. A., et al. Nature2017,542 (7639), 110-114.[12]Peng Y. M. et al. J Leukoc Biol2011,90 (4), 735-40.Acknowledgements:We thank the patients who donated samples and the medical staff at the Rheumatology Clinic of Karolinska University Hospital. Julia Boström, Gloria Rostvall, and Susana Hernandez Machado are acknowledged for organizing the sampling, storage, and administration of biomaterial. This study is supported by grants from Dr. Margaretha Nilssons, the Nanna Svartz, the Ulla and Gustaf af Ugglas foundations and the Swedish association against rheumatism.Disclosure of Interests:Alexandra Argyriou: None declared, Marc H Wadsworth II Employee of: Pfizer, Inc, Cambridge, MA 02139, United States, Adrian Lendvai: None declared, Stephen Christensen Employee of: Pfizer, Inc, Cambridge, MA 02139, United States, Aase Hensvold: None declared, Christina Gerstner: None declared, Kellie Kravarik Employee of: Pfizer, Inc, Cambridge, MA 02139, United States, Aaron Winkler Employee of: Pfizer, Inc, Cambridge, MA 02139, United States, Vivianne Malmström: None declared, Karine Chemin: None declared
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23.
  • Barbulescu, A, et al. (author)
  • COMPARATIVE EFFECTIVENESS OF JAKI VERSUS BDMARDS; A NATIONWIDE STUDY IN RA
  • 2021
  • In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 68-68
  • Conference paper (other academic/artistic)abstract
    • The Janus kinase inhibitors (JAKi) have been increasingly used for the treatment of rheumatoid arthritis (RA) in Sweden, with baricitinib representing ~80% of prescriptions. Evidence regarding the comparative effectiveness of JAKis versus biologics (bDMARDs), and in particular non- tumour-necrosis-factor inhibitor (TNFi) bDMARDs, in real-life is limited.Objectives:To compare RA patients treated with bDMARDs and JAKi in Sweden, in terms of: (1) patient characteristics at treatment start; (2) proportions of patients remaining on therapy, and response rates, at 12 months.Methods:RA patients starting treatment in 2017 and 2018 with either a TNFi, rituximab, abatacept, interleukin 6 inhibitors (IL6i) or a JAKi as different lines of treatment were identified in the Swedish Rheumatology Quality Register. One patient could contribute with more than one treatment episode.Treatment response at 12 months was measured as EULAR good response, HAQ improvement >0.2 units, DAS28 and CDAI remission, and as 0 tender and swollen joint counts (28JC). Patients were classified as non-responders if they stopped treatment before evaluation due to safety or inefficacy. Responses for patients who stopped treatment due to pregnancy or death and patients on treatment but with missing response were imputed using multiple imputation.Proportions of responders and differences in proportions between treatment groups, adjusted using inverse probability of treatment weighting, were estimated using linear regression with robust standard errors.Results:JAKi were often used after bDMARDs, and less frequently prescribed in combination with methotrexate. Measured comorbidities were less frequent among JAKi initiators than among non-TNFi biologic initiators, but RA activity was similar (Table).Table 1.Patient characteristics at treatment initiationCharacteristicMedian (IQR) or N (%)AbataceptIL6iRituximabTNFiJAKiTreatment Starts6945346923497905Age63 (53-71)59 (48-70)65 (54-73)59 (47-68)60 (51-70)Female543 (78)441 (83)519 (75)2739 (78)759 (84)RA duration (years)13 (5-21)10 (5-18)12 (6-22)9 (3-17)13 (7-22)Rheum. factor535 (79)385 (73)588 (87)2405 (70)686 (77)DAS284.8 (3.9-5.6)4.9 (4.0-5.7)4.7 (3.8-5.5)4.4 (3.4-5.3)4.7 (3.9-5.7)HAQ1.3 (0.8-1.6)1.3 (0.8-1.8)1.3 (0.8-1.8)1.0 (0.5-1.4)1.3 (0.8-1.8)Tender joints5 (2-9)6 (3-10)5 (2-9)4 (2-8)6 (2-10)Swollen joints4 (2-6)4 (2-7)4 (2-7)3 (1-6)4 (2-7)ts/bDMARD line3 (2-4)3 (2-4)2 (1-4)1 (1-2)4 (2-6)At least one prev. TNFi539 (78)442 (83)457 (66)1448 (41)770 (85)At least one prev. non-TNFi271 (39)220 (41)243 (35)441 (13)584 (65)Methotrexate co-treatment264 (50)172 (40)286 (53)1708 (62)296 (40)Glucocorticoids co-treatment247 (47)186 (43)275 (51)1126 (41)389 (53)Cancer*90 (2.8)64 (2.3)363 (7.7)410 (1.8)20 (2.2)Cardio-vascular dis.*245 (7.5)123 (4.4)322 (6.8)749 (3.4)41 (4.4)Chronic respiratory dis.*303 (9.3)140 (5.0)473 (10.0)721 (3.2)50 (5.4)Diabetes*324 (9.9)216 (7.7)456 (9.7)1479 (6.7)69 (7.5)* any diagnosis within 5 years before start Adjusted differences in proportion with each response outcomeIn a crude comparison, 65% (61%-68%) of JAKi, 62% (59%-66%) of abatacept, 58% (53%-62%) of IL6i, 80% (77%-83%) of rituximab and 68% (67%-70%) of TNFi initiators remained on treatment at 12 months after start. Also, JAKi showed lower overall responder proportions than TNFi, rituximab and IL6i.After adjustment for demographic and socio-economic factors, RA disease activity, previous use of ts/bDMARDs, co-medication with glucocorticoids and methotrexate and comorbidities at baseline, no significant differences in responder proportions between JAKi and bDMARDs remained (Figure). Furthermore, the adjusted proportions of patients on treatment were higher for JAKi and rituximab than for the other bDMARDs.Conclusion:This preliminary analysis of patients treated in clinical practice found no statistically significant difference in effectiveness between JAKi and bDMARDs.Disclosure of Interests:Andrei Barbulescu: None declared, Johan Askling Grant/research support from: 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, Katerina Chatzidionysiou Speakers bureau: Eli Lilly, Abbvie and Pfizer, Consultant of: Eli Lilly, Abbvie and Pfizer, Helena Forsblad-d’Elia: None declared, Alf Kastbom Employee of: Sanofi, Ulf Lindström: None declared, Carl Turesson Speakers bureau: Abbvie, Bristol-Myers Squibb, Medac, Pfizer, Roche, Consultant of: Roche, Grant/research support from: Bristol-Myers Squibb, Thomas Frisell: None declared
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24.
  • Bech, B, et al. (author)
  • 2018 update of the EULAR recommendations for the role of the nurse in the management of chronic inflammatory arthritis
  • 2020
  • In: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 79:1, s. 61-68
  • Journal article (peer-reviewed)abstract
    • To update the European League Against Rheumatism (EULAR) recommendations for the role of the nurse in the management of chronic inflammatory arthritis (CIA) using the most up to date evidence. The EULAR standardised operating procedures were followed. A task force of rheumatologists, health professionals and patients, representing 17 European countries updated the recommendations, based on a systematic literature review and expert consensus. Higher level of evidence and new insights into nursing care for patients with CIA were added to the recommendation. Level of agreement was obtained by email voting. The search identified 2609 records, of which 51 (41 papers, 10 abstracts), mostly on rheumatoid arthritis, were included. Based on consensus, the task force formulated three overarching principles and eight recommendations. One recommendation remained unchanged, six were reworded, two were merged and one was reformulated as an overarching principle. Two additional overarching principles were formulated. The overarching principles emphasise the nurse’s role as part of a healthcare team, describe the importance of providing evidence-based care and endorse shared decision-making in the nursing consultation with the patient. The recommendations cover the contribution of rheumatology nursing in needs-based patient education, satisfaction with care, timely access to care, disease management, efficiency of care, psychosocial support and the promotion of self-management. The level of agreement among task force members was high (mean 9.7, range 9.6-10.0). The updated recommendations encompass three overarching principles and eight evidence-based and expert opinion-based recommendations for the role of the nurse in the management of CIA.
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25.
  • Becker, Mike O., et al. (author)
  • Development and validation of a patient-reported outcome measure for systemic sclerosis : the EULAR Systemic Sclerosis Impact of Disease (ScleroID) questionnaire
  • 2022
  • In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 81:4, s. 507-515
  • Journal article (peer-reviewed)abstract
    • OBJECTIVES: Patient-reported outcome measures (PROMs) are important for clinical practice and research. Given the high unmet need, our aim was to develop a comprehensive PROM for systemic sclerosis (SSc), jointly with patient experts. METHODS: This European Alliance of Associations for Rheumatology (EULAR)-endorsed project involved 11 European SSc centres. Relevant health dimensions were chosen and prioritised by patients. The resulting Systemic Sclerosis Impact of Disease (ScleroID) questionnaire was subsequently weighted and validated by Outcome Measures in Rheumatology criteria in an observational cohort study, cross-sectionally and longitudinally. As comparators, SSc-Health Assessment Questionnaire (HAQ), EuroQol Five Dimensional (EQ-5D), Short Form-36 (SF-36) were included. RESULTS: Initially, 17 health dimensions were selected and prioritised. The top 10 health dimensions were selected for the ScleroID questionnaire. Importantly, Raynaud's phenomenon, impaired hand function, pain and fatigue had the highest patient-reported disease impact. The validation cohort study included 472 patients with a baseline visit, from which 109 had a test-retest reliability visit and 113 had a follow-up visit (85% female, 38% diffuse SSc, mean age 58 years, mean disease duration 9 years). The total ScleroID score showed strong Pearson correlation coefficients with comparators (SSc-HAQ, 0.73; Patient's global assessment, Visual Analogue Scale 0.77; HAQ-Disability Index, 0.62; SF-36 physical score, -0.62; each p<0.001). The internal consistency was strong: Cronbach's alpha was 0.87, similar to SSc-HAQ (0.88) and higher than EQ-5D (0.77). The ScleroID had excellent reliability and good sensitivity to change, superior to all comparators (intraclass correlation coefficient 0.84; standardised response mean 0.57). CONCLUSIONS: We have developed and validated the EULAR ScleroID, which is a novel, brief, disease-specific, patient-derived, disease impact PROM, suitable for research and clinical use in SSc.
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