154 results on '"C Ciurtin"'
Search Results
2. S03.3 Patient-specific and disease-related determinants for cardiovascular disease (CVD) risk stratification in the apple (atherosclerosis prevention in paediatric lupus erythematosus) clinical trial cohort
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G Robinson, S Ardoin, L Schanberg, E Jury, C Ciurtin, and J Peng
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2022
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3. PO.6.126 Anti-rituximab antibodies demonstrate neutralising capacity, associate with lower circulating drug levels and early relapse in patients undergoing treatment for systemic lupus erythematosus
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C Wincup, N Dunn, C Ruetsch-Chelli, A Manouchehrinia, N Kharlamova, M Naja, B Seitz-Polski, D Isenberg, A Fogdell-Hahn, C Ciurtin, and E Jury
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- 2022
4. S03.3 Patient-specific and disease-related determinants for cardiovascular disease (CVD) risk stratification in the apple (atherosclerosis prevention in paediatric lupus erythematosus) clinical trial cohort
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J Peng, G Robinson, S Ardoin, L Schanberg, E Jury, and C Ciurtin
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- 2022
5. Sex hormones drive changes in lipoprotein metabolism
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GA, Robinson, primary, J, Peng, additional, H, Peckham, additional, A, Radziszewska, additional, G, Butler, additional, I, Pineda-Torra, additional, EC, Jury, additional, and C, Ciurtin, additional
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- 2022
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6. AB0433 ANTI-RITUXIMAB ANTIBODIES DEMONSTRATE NEUTRALISING CAPACITY, ASSOCIATE WITH LOWER CIRCULATING DRUG LEVELS AND EARLY RELAPSE IN PATIENTS UNDERGOING TREATMENT FOR SYSTEMIC LUPUS ERYTHEMATOSUS
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C. Wincup, N. Dunn, C. Ruetsch-Chelli, A. Manouchehrinia, N. Kharlamova, M. Naja, B. Seitz-Polski, D. Isenberg, A. Fogdell-Hahn, C. Ciurtin, and E. Jury
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Rheumatology ,Immunology ,Immunology and Allergy ,General Biochemistry, Genetics and Molecular Biology - Abstract
BackgroundA major limitation of biologic therapy is formation of anti-drug antibodies (ADA). We previously found ADA to rituximab (RTX) are more prevalent in patients undergoing treatment for systemic lupus erythematosus (SLE) than rheumatoid arthritis and vasculitis (1). In addition, we demonstrated that ADA to RTX predict subsequent infusion related reactions (2). However, little is known regarding the long-term dynamics of ADA to RTX in patients undergoing treatment for SLE.ObjectivesIn this study we evaluated the longitudinal impact of ADA positivity with particular focus on; 1) Risk factors for development of ADA. 2) Impact of ADA on treatment response. 3) Influence of ADA on RTX drug kinetics over time. 4) The capacity of ADA to neutralise RTX.MethodsPatients with SLE undergoing treatment with RTX were recruited to this study (n=35). Serum samples were collected at the following intervals post-treatment; 1-3 months (defined as ‘early’ post-treatment), 6 months, 12 months, 36 months (n=114).Clinical and laboratory data was collected pre-treatment and at each follow-up time point. Response to treatment was assessed by improvement in SLEDAI-2K score from baseline and also according to BILAG as previously described (3).ADA were detected using an electrochemiluminescent immunoassay. Serum RTX levels were measured by ELISA. ADA status was defined according to the following patterns over time; persistently negative, persistently positive (0-15 AU/ml) and persistently high positive (≥16 AU/ml, upper quartile). A complement dependent cytotoxic assay was used to determine neutralising capability of ADA in a subgroup of positive samples (n=38).ResultsADA to RTX were found to be persistently positive in 64.3% of patients over the 36-month follow-up period and there was no significant difference in baseline disease activity (BILAG / SLEDAI-2K) between those who were subsequently ADA positive vs negative. ADA positive patients had a younger age at diagnosis of SLE when compared with ADA negative (mean 22.50 ± 9.10 vs 37.29 ± 11.31 years, p=0.002, Figure 1 A). Multivariate logistic regression found a 22% decrease in risk of ADA positivity for each addition year after diagnosis (p=0.03).Figure 1.ADA positive patients had a significantly lower C3 level at baseline (mean 0.61 ± 0.23 g/L vs 0.87 ± 0.30 g/L, p=0.026), which remained lower at each subsequent time point post-treatment up to 12 months post-treatment (Figure 1B).At 1-3 months post-RTX, patients who were ADA positive had a significantly lower circulating drug level than ADA negative (pIn terms of clinical response, ADA positive patients had an initial significant improvement in disease activity (SLEDAI-2K) by 3 months (pBILAG defined relapse was more common at six months post-treatment in ADA positive patients (22%) and ADA highly positive patients (33%) than those who were ADA negative (in which there were no cases of relapse within the first six months, Figure 1 F). At 12-months post-RTX, a higher rate of BILAG defined Major Response was seen in those who were ADA negative (80%) when compared with ADA positive (44%) and high positive (36%) as shown in Figure 1 G.Finally, antibodies derived from all ADA positive samples (38/38) were found to neutralise RTX in vitro.ConclusionADA to RTX were common and persisted over the 36-month period of this study. ADA associated with earlier serum drug elimination, increased relapse rates and demonstrated neutralising capacity suggesting that ADA could be a significant limitation to sustained response to treatment in clinical practice.References[1]Faustini F et al. Arthritis research & therapy. 2021;23(1):211[2]Wincup C et al. Annals of the rheumatic diseases. 2019;78(8):1140-2[3]Md Yusof MY et al Annals of the rheumatic diseases. 2017;76(11):1829-36Disclosure of InterestsNone declared
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- 2022
7. POS0453 EXPLORATORY IMMUNOPHENOTYPE OF THE RARE DISEASE JUVENILE SJÖGREN’S SYNDROME REVEALS A DYSREGULATION OF B AND T MEMORY CELL FREQUENCIES
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L. Martin-Gutierrez, H. Peckham, A. Radziszewska, J. Peng, O. Nette, E. Jury, and C. Ciurtin
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Rheumatology ,Immunology ,Immunology and Allergy ,General Biochemistry, Genetics and Molecular Biology - Abstract
BackgroundSjögren’s syndrome (SS) is an autoimmune rheumatic disease characterised by dryness resulting from chronic lymphocytic infiltration of the exocrine glands. Patients also present with other extraglandular manifestations such as arthritis, anemia and fatigue or various organ and systems involvement. The disease is more frequent in women aged 30-50. However, in rare cases, the disease starts in childhood and is known as juvenile SS (JSS) or childhood SS. Children have different clinical manifestations compared to adults, with dryness being less common, making the diagnosis very challenging1.ObjectivesTo investigate in depth the immune cell profile of patients with JSS for better understanding of disease pathogenesis.MethodsPeripheral blood was collected from a cohort of patients with JSS while attending appointments at UCLH clinics. None had received B-cell depletion therapy. Immune-phenotyping of 29 immune-cell subsets, including B and T cells, in peripheral blood from patients with JSS (n=10) and age and sex-matched healthy controls (n=10) was performed using flow cytometry as we have performed previously for patients with adult onset SS2. Data were analysed using multiple t-tests and compared with the adult SS immune phenotype.ResultsPatients with JSS had an average age of 18 years (range 16-21) with an average age of disease onset at 14 years (range 12-18). Up to 60% of patients presented Anti-Ro autoantibodies while 50% presented Anti-La autoantibodies.Patients with JSS had an altered immune profile compared to age matched healthy controls (average of 18 years, range 15-25). In the B cell compartment, JSS patients had higher frequencies of Total CD19+ B cells (p=0.0044), Naïve B cells (CD19+IgD+CD27-) (p=0.0183) and bm2 (CD19+IgD+CD38+) (p=0.0490) whereas memory B cell subsets such as early bm5 (CD19+IgD-CD38+) and late bm5 (CD19+IgD-CD38-) were significantly reduced (p=0.0249, and p=0.0117 respectively), similar to the profile seen in patients with adult-SS. Interestingly, in the CD4+ T cell compartment, central memory (CD4+CD27+CD45RA-) T cells were significantly reduced (p=ConclusionThis is the first pilot study investigating the immunophenotype profile of patients with JSS. Our preliminary findings suggest altered immune phenotypes in both B-cell and T cell compartments and for B cells are in concordance with previous immunophenotyping studies in adult SS (predominance of naïve and lower frequencies of memory B cells), suggesting an immunological rationale for the use of similar therapies. Further studies, comparing the adult with the juvenile phenotype could help stratify patients for targetted therapies and improve treatment in this rare disease in children for which no evidence-based recommnedations exist.References[1]Ciurtin C et al. Barriers to translational research in Sjögren’s syndrome with childhood onset: challenges of recognising and diagnosing an orphan rheumatic disease. Lancet Rheumatology. 2021; https://doi.org/10.1016/S2665-9913(20)30393-3.[2]Martin-Gutierrez L, Peng J, et al. Stratification of Patients with Sjogren’s Syndrome and Patients With Systemic Lupus Erythematosus According to Two Shared Immune Cell Signatures, With Potential Therapeutic Implications. Arthritis Rheumatol. 2021;73(9):1626-37.Disclosure of InterestsNone declared.
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- 2022
8. POS0460 METABOLOMICS ACROSS AGE IDENTIFIES UNIQUE CHANGES IN THE SERUM METABOLIC PROFILE IN PATIENTS WITH SLE
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G. Robinson, A. Van Vijfeijken, L. Martin-Gutierrez, D. Isenberg, I. Pineda Torra, C. Ciurtin, and E. Jury
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Rheumatology ,Immunology ,Immunology and Allergy ,General Biochemistry, Genetics and Molecular Biology - Abstract
BackgroundCardiovascular disease (CVD) is a leading cause of mortality in patients with systemic lupus erythematosus (SLE, female:male ratio of 9:1) through accelerated atherosclerosis, the build-up of lipids and inflammation in the major artery walls, compared to age and sex matched healthy individuals. This is due to chronic inflammation, dyslipidaemia and other cardiometabolic defects that exacerbate with age (1). SLE in women aged of 35-44 increases the risk of coronary artery disease by 50 times and there is a 100-300-fold increased CVD-related mortality risk in young patients that develop SLE before the age of 18. Investigating metabolic defects in young patients and how they progress with age could help us understand the progressive mechanisms of atherosclerosis in SLE.ObjectivesThis study investigated detailed changes in the metabolomic profile of female patients with SLE and matched healthy controls across age.MethodsSerum NMR metabolomics (>250 metabolites, Nightingale) covering glycolysis metabolites, amino acids and 130 lipid measures was performed on serum from a cohort of female SLE patients (n=164, 13-72 years of age, median 35) and matched healthy controls (HCs, n=120, 15-76 years of age, median 36) and analysed by linear regression and Venn analysis. Multiple t-tests (corrected for multiple comparisons by false discovery rate) were used to assess unique metabolic changes by age group between SLE patients and HCs (≤25, n=62/43; 26-49, n=50/46; ≥50, n=52/31) and dysregulated metabolic pathways were assessed using metaboanalyst software. The metabolic impact of disease activity measures and treatments was assessed by Spearman correlations and unpaired t-tests respectively.ResultsTwenty-five metabolites were significantly altered in all SLE age groups compared to HCs, dominated by atheroprotective high density lipoprotein (HDL) subsets and their surface-bound peptide, apolipoprotein(Apo)A1, all of which were significantly decreased in SLE compared to HCs (pSeparately, metabolites associated with the glycolysis pathway (p=0.004, metaboanalyist), including acetone, citrate, creatinine, glycerol, lactate and pyruvate, had significant positive correlations with age in SLE patients, but not in HCs. These metabolites were not significantly associated with disease activity measures. However, pyruvate (p=0.01) and lactate (p=0.009) were significantly upregulated in prednisolone treated patients, whilst citrate (p=0.002) and creatinine (p= 0.005) were downregulated in hydroxychloroquine treated patients.ConclusionIncreasing HDL (ApoA1) levels whilst maintaining low disease activity in patients with SLE from a young age could improve cardiometabolic risk outcomes. This could be achieved through improved nutrition, lipid targeted therapies and better treatment strategies. Focusing on understanding and monitoring biomarkers of the glycolytic pathway could aid treatment decisions and help avoid adverse metabolic effects of current anti-inflammatory therapies in SLE (1).References[1]Robinson G.A, Pineda-Torra I, Ciurtin C, Jury E.C. Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies. J Clin Invest. 2022;132(2):e148552. https://doi.org/10.1172/JCI148552.AcknowledgementsThe authors would like to thank all of the patients and healthy blood donors, as well as Prof. Arne Akbar and Dr. Chris Wincup for additional patient and healthy donor samples.Disclosure of InterestsNone declared.
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- 2022
9. AB0571 DERIVATION AND INDEPENDENT VALIDATION OF THE LUPUS ARTHRITIS AND MUSCULOSKELETAL DISEASE ACTIVITY SCORE (LAMDA): A MORE SENSITIVE, SPECIFIC AND RESPONSIVE TOOL FOR LUPUS ARTHRITIS
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K. Mahmoud, A. Zayat, M. Y. MD Yusof, L. S. Teh, S. Khan, C. S. Yee, D. D’cruz, N. Ng, D. Isenberg, C. Ciurtin, P. G. Conaghan, P. Emery, C. J. Edwards, E. Hensor, and E. Vital
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Rheumatology ,Immunology ,Immunology and Allergy ,General Biochemistry, Genetics and Molecular Biology - Abstract
BackgroundThe MSK components of the BILAG and SLEDAI have limited sensitivity, specificity and responsiveness.ObjectivesTo develop a better disease activity tool for MSK lupus.Methods“LAMDA” was derived using data from the multicentre USEFUL study (PMID:33792659); 133 patients with inflammatory MSK pain received intramuscular depomedrone then were assessed for 66/68 SJC/TJC, BILAG-2004, SLEDAI-2K, physician MSK-VAS, inflammatory markers, patient pain and disease-activity-VAS and MSK-ultrasound. Baseline variables were modelled against US using penalized (Lasso) regression. For validation we evaluated: (i) responsiveness at week 6 in USEFUL and (ii) association with quality of life and treatment decision in an independent study (n=100).ResultsLAMDA was a composite of SJC, patient-MSK-pain-VAS, physician-MSK-disease-activity-VAS and ESR ranging from 0 to 26.5. Response effect size was greater for the LAMDA (0.37) than the BILAG-MSK (0.31), SLEDAI-MSK (0.27) and total US score (0.33). With active US at baseline, LAMDA’s effect size was 0.42.In the validation study LAMDA score correlated with better physical function (R = -0.49, pConclusionLAMDA is a continuous disease activity instrument for MSK lupus that is sensitive to imaging-synovitis without swelling, more responsive than other instruments and correlates with quality of life and treatment decision. LAMDA may improve the ability of clinicians to monitor and treat MSK lupus, and determine the efficacy of therapies in clinical trials.AcknowledgementsFunding: Lupus UK and NIHRDisclosure of InterestsKhaled Mahmoud: None declared, Ahmed Zayat: None declared, Md Yuzaiful Md Yusof: None declared, Lee-Suan Teh: None declared, Shah Khan: None declared, Chee-Seng Yee: None declared, David D’Cruz: None declared, Nora Ng: None declared, David Isenberg: None declared, Coziana Ciurtin: None declared, Philip G Conaghan: None declared, Paul Emery: None declared, Christopher John Edwards: None declared, Elizabeth Hensor: None declared, Edward Vital Speakers bureau: GSK, AstraZeneca, Consultant of: GSK, AstraZeneca, Roche, Aurinia, Lilly, ILTOO, Novartis, Grant/research support from: AstraZeneca, Sandoz
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- 2022
10. Supplemental material for Diet and lupus: what do the patients think?
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G A Robinson, T Mcdonnell, C Wincup, L Martin-Gutierrez, J Wilton, A Z Kalea, C Ciurtin, I Pineda-Torra, and E C Jury
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immune system diseases ,111702 Aged Health Care ,FOS: Health sciences ,skin and connective tissue diseases - Abstract
Supplemental Material for Diet and lupus: what do the patients think? by G A Robinson, T Mcdonnell, C Wincup, L Martin-Gutierrez, J Wilton, A Z Kalea, C Ciurtin, I Pineda-Torra and E C Jury in Lupus
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- 2019
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11. Development of CARRA/PReS-endorsed consensus Core and Expanded Datasets in childhood-onset systemic lupus erythematosus for international registry-based research.
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Sadun RE, Cooper JC, Belot A, Avcin T, Aggarwal A, Ainsworth J, Akinsete A, Ardoin SP, Beresford MW, Bortey L, Brunner HI, Chang JC, Ciurtin C, Daftary A, Eberhard B, Feldman CH, Hedrich CM, Hersh AO, Hiraki LT, Isenberg DA, Kamphuis S, Knight AM, Lambert L, Levy DM, Marks SD, Maxwell N, Migowa A, Moore K, Ozen S, Ramsey-Goldman R, Ravelli A, Reeve BB, Rubinstein TB, Saad-Magalhaes C, Sawhney S, Schanberg LE, von Scheven E, Scott C, Son MB, Tony G, Weitzman ER, Wenderfer SE, Woodside A, Lewandowski LB, and Smith EM
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Objectives: Childhood-onset systemic lupus erythematosus (cSLE), representing 15%-20% of individuals with SLE, has been difficult to study globally due to differences between registries. This initiative, supported by Childhood Arthritis Rheumatology Research Alliance (CARRA) and Paediatric Rheumatology European Society (PReS), aims to create Core and Expanded cSLE Datasets to standardise and enhance research worldwide., Methods: 21 international cSLE experts and 4 patients participated in a Delphi process (questionnaires, 2 topic-specific focus groups and 3 virtual consensus meetings) to create 2 standardised cSLE datasets. The Core cSLE Dataset was designed to include data essential to meaningful clinical research across many settings. The Expanded cSLE Dataset was designed for centres able to consistently collect data to address broader research questions. Final data items for the Core and Expanded datasets were determined by consensus defined as >80% agreement) using an adapted nominal group technique and voting., Results: The resulting Core cSLE Dataset contains 46 items, including demographics, clinical features, laboratory results, medications and significant adverse events. The Expanded cSLE Dataset adds 26 additional items and includes patient-reported outcomes. Consensus was also achieved regarding the frequency and time points for data collection: baseline, quarterly follow-up visits, annually and flare visits., Conclusion: Standardised Core and Expanded cSLE Datasets for registry-based international cSLE research were defined through the consensus of global experts and patient/caregiver representatives, endorsed by CARRA and PReS. These datasets incorporate disease-specific and patient-specific features, optimised for diverse settings to facilitate international collaborative research for children and adolescents with SLE worldwide., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)
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- 2024
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12. Active implementation of low disease activity state as a treatment endpoint in childhood-onset systemic lupus erythematosus in routine practice is both feasible and associated with better outcomes.
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Gotch R, Ahmed Y, Wilson R, Hawkins E, and Ciurtin C
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- Humans, Adolescent, Female, Male, Young Adult, Prospective Studies, Severity of Illness Index, Child, Treatment Outcome, Age of Onset, Remission Induction, Adult, Lupus Erythematosus, Systemic drug therapy, Feasibility Studies
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Introduction: Treat-to-target (T2T) strategies aim to facilitate tight disease control to improve outcomes. No previous studies evaluated prospectively the feasibility and impact of the T2T strategy in routine practice in childhood-onset SLE (cSLE)., Methods: Adolescents and young adults (AYA) with cSLE were recruited for T2T implementation from a large tertiary centre over a period of 6 months and followed up at least twice over a prospective period of 12 months., Results: During Oct 2022-April 2023, 135/162 (83.3%) AYA with cSLE had disease scores evaluated at their routine appointment to enable inclusion in the study, and 122/135 (91.2%) had their disease assessed, and a suitable treatment target agreed and documented at each routine clinical appointment over the 12 months prospective follow-up. T2T strategy led to improved disease control at 12 months: more AYA with cSLE achieved clinical remission off steroids (4.1% vs. 10.7%, P = 0.048), or minimum childhood-lupus low disease activity (cLLDAS) (81.9% vs. 91.8%, P = 0.022). Achieving minimum cLLDAS for longer than 3 months was associated with reduced damage accrual (HR = 1.7; 95%CI = 1.1-2.5; P < 0.0001) at 12 months., Conclusion: T2T strategy implementation was achievable and associated with improved cSLE control. Spending at least 3/12 months in cLLDAS led to less damage accumulation. Key Points • This is the first large prospective study in AYA with cSLE to evaluate the impact of active T2T implementation in routine practice. • T2T strategies were feasible to implement in 122/135 (91.2%) AYA with cSLE in routine practice. • The T2T approach was associated with improved disease control and decreased damage accrual at 12 months., (© 2024. The Author(s).)
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- 2024
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13. Patients with multiple sclerosis who develop immunogenicity to interferon-beta have distinct transcriptomic and proteomic signatures prior to treatment which are associated with disease severity.
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Coelewij L, Adriani M, Dönnes P, Waddington KE, Ciurtin C, Havrdova EK, Farrell R, Nytrova P, Pineda-Torra I, and Jury EC
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- Humans, Female, Male, Adult, Middle Aged, Severity of Illness Index, Biomarkers blood, Multiple Sclerosis drug therapy, Multiple Sclerosis immunology, Multiple Sclerosis blood, Interferon-beta therapeutic use, Interferon-beta immunology, Transcriptome, Multiple Sclerosis, Relapsing-Remitting drug therapy, Multiple Sclerosis, Relapsing-Remitting immunology, Multiple Sclerosis, Relapsing-Remitting blood, Proteomics
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Anti-drug antibodies (ADA) reduce the efficacy of immunotherapies in multiple sclerosis (MS) and are associated with increased disease progression risk. Blood biomarkers predicting immunogenicity to biopharmaceuticals represent an unmet clinical need. Patients with relapsing remitting (RR)MS were recruited before (baseline), three, and 12 (M12) months after commencing interferon-beta treatment. Neutralising ADA-status was determined at M12, and patients were stratified at baseline according to their M12 ADA-status (ADA-positive/ADA-negative). Patients stratified as ADA-positive were characterised by an early dampened response to interferon-beta (prior to serum ADA detection) and distinct proinflammatory transcriptomic/proteomic peripheral blood signatures enriched for 'immune response activation' including phosphoinositide 3-kinase-γ and NFκB-signalling pathways both at baseline and throughout the treatment course, compared to ADA-negative patients. These immunogenicity-associated proinflammatory signatures significantly overlapped with signatures of MS disease severity. Thus, whole blood molecular profiling is a promising tool for prediction of ADA-development in RRMS and could provide insight into mechanisms of immunogenicity., Competing Interests: Declaration of competing interest MA is now employed by Nxera Pharma UK, Translational Sciences, Granta Park Steinmetz Building, Cambridge, United Kingdom. KEW is now employed by Nucleome Therapeutics, Oxford, United Kingdom. EKH has received honoraria/research support from Biogen, Merck Serono, Novartis, Roche, and Teva; has served as a member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, and Sanofi Genzyme; has been supported by the Czech Ministry of Education – project Cooperatio LF1, research area Neuroscience, and the project National Institute for Neurological Research (Programme EXCELES, ID project No LX22NPO5107) – funded by the European Union-Next Generation EU. RF has received speaker honoraria and hospitality from Merck, Biogen, TEVA, Novartis, Genzyme, Abbvie, Merz and Ipsen. PN has received speaker honoraria and consultant fees from Biogen, Novartis, Merck, and Roche. The remaining authors (LC, PD, CC, IPT, ECJ) declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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14. Systemic lupus erythematosus patients have unique changes in serum metabolic profiles across age associated with cardiometabolic risk.
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Jury EC, Peng J, Van Vijfeijken A, Martin Gutierrez L, Woodridge L, Wincup C, Pineda-Torra I, Ciurtin C, and Robinson GA
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- Humans, Female, Adult, Middle Aged, Adolescent, Young Adult, Aged, Age Factors, Metabolome physiology, Case-Control Studies, Cardiovascular Diseases blood, Cardiovascular Diseases etiology, Metabolomics, Apolipoprotein A-I blood, Lupus Erythematosus, Systemic blood, Lupus Erythematosus, Systemic metabolism, Cardiometabolic Risk Factors
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Objectives: Cardiovascular disease through accelerated atherosclerosis is a leading cause of mortality for patients with systemic lupus erythematosus (SLE), likely due to increased chronic inflammation and cardiometabolic defects over age. We investigated age-associated changes in metabolomic profiles of SLE patients and healthy controls (HCs)., Methods: Serum NMR metabolomic profiles from female SLE patients (n = 164, age = 14-76) and HCs (n = 123, age = 13-72) were assessed across age by linear regression and by age group between patients/HCs (Group 1, age ≤ 25, n = 62/46; Group 2, age = 26-49, n = 50/46; Group 3, age ≥ 50, n = 52/31) using multiple t tests. The impact of inflammation, disease activity and treatments were assessed, and UK Biobank disease-wide association analysis of metabolites was performed., Results: Age-specific metabolomic profiles were identified in SLE patients vs HCs, including reduced amino acids (Group 1), increased very-low-density lipoproteins (Group 2), and increased low-density lipoproteins (Group 3). Twenty-five metabolites were significantly altered in all SLE age groups, dominated by decreased atheroprotective high-density lipoprotein (HDL) subsets, HDL-bound apolipoprotein (Apo)A1 and increased glycoprotein acetyls (GlycA). Furthermore, ApoA1 and GlycA were differentially associated with disease activity and serological measures, as well as atherosclerosis incidence and myocardial infarction mortality risk through disease-wide association. Separately, glycolysis pathway metabolites (acetone/citrate/creatinine/glycerol/lactate/pyruvate) uniquely increased with age in SLE, significantly influenced by prednisolone (increased pyruvate/lactate) and hydroxychloroquine (decreased citrate/creatinine) treatment and associated with type 1 and type 2 diabetes by disease-wide association., Conclusions: Increasing HDL (ApoA1) levels through therapeutic/nutritional intervention, whilst maintaining low disease activity, in SLE patients from a young age could improve cardiometabolic disease outcomes. Biomarkers from the glycolytic pathway could indicate adverse metabolic effects of current therapies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2024
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15. A simple, clinically usable whole-body MRI system of joint assessment in adolescents and young people with juvenile idiopathic arthritis.
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Choida V, Bray TJP, van Vucht N, Abbasi MA, Bainbridge AP, Parry T, Mallett S, Ciurtin C, and Hall-Craggs MA
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- Humans, Adolescent, Female, Male, Prospective Studies, Child, Joints diagnostic imaging, Joints pathology, Young Adult, Severity of Illness Index, Case-Control Studies, Reproducibility of Results, Observer Variation, Arthritis, Juvenile diagnostic imaging, Magnetic Resonance Imaging methods, Synovitis diagnostic imaging, Whole Body Imaging methods
- Abstract
Objectives: To introduce and evaluate a simple method for assessing joint inflammation and structural damage on whole-body MRI (WBMRI) in juvenile idiopathic arthritis (JIA), which is usable in clinical practice., Methods: The proposed system utilizes post-contrast Dixon WBMRI scans. Joints are assessed for synovitis (grade 0-2) and structural damage (present/absent) at 81 sites. The synovitis grading is based on features including above-normal intensity synovial enhancement, synovial hypertrophy, joint effusion, subarticular bone marrow oedema and peri-articular soft tissue oedema.This system was evaluated in a prospective study of 60 young people (47 patients with JIA and 13 controls with non-inflammatory musculoskeletal pain) who underwent a WBMRI. Three readers (blinded to diagnosis) independently reviewed all images and re-reviewed 20 individual scans. The intra- and inter-reader overall agreement (OA) and the intra- and inter-reader Gwet's agreement coefficients 2 (GAC2) were measured for the detection of a) participants with ≥1 joint with inflammation or structural damage and b) joint inflammation or structural damage for each joint., Results: The inter-reader OA for detecting patients with ≥1 joint with inflammation, defined as grade 2 synovitis (G2), and ≥1 joint with structural damage were 80% and 73%, respectively. The intra-reader OA for readers 1-3 was 80-90% and 75-90%, respectively. The inter-reader OA and GAC2 for joint inflammation (G2) at each joint were both ≥85% for all joints but were lower if grade 1 synovitis was included as positive., Conclusion: The intra- and inter-reader agreements of this WBMRI assessment system are adequate for assessing objective joint inflammation and damage in JIA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2024
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16. Detection of inflammation by whole-body MRI in young people with juvenile idiopathic arthritis.
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Choida V, Bray TJP, van Vucht N, Abbasi MA, Bainbridge A, Parry T, Sen D, Mallett S, Ciurtin C, and Hall-Craggs MA
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- Humans, Adolescent, Female, Male, Young Adult, Inflammation diagnostic imaging, Case-Control Studies, Biomarkers blood, Arthritis, Juvenile diagnostic imaging, Arthritis, Juvenile blood, Magnetic Resonance Imaging methods, Whole Body Imaging methods
- Abstract
Objectives: To assess the frequency of joint inflammation detected by whole-body MRI (WBMRI) in young people (YP) with JIA and controls, and to determine the relationship between WBMRI-detected inflammation and clinical findings., Methods: YP aged 14-24 years, with JIA (patients) or arthralgia without JIA (controls), recruited from one centre, underwent a WBMRI scan after formal clinical assessment. Consensus between at least two of the three independent radiologists was required to define inflammation and damage on WBMRI, according to predefined criteria. YP with JIA were deemed clinically active as per accepted definitions. The proportions of YP with positive WBMRI scans for joint inflammation (one or more inflamed joint) as well as serum biomarkers were compared between active vs inactive JIA patients and controls., Results: Forty-seven YP with JIA (25 active and 22 inactive patients) and 13 controls were included. WBMRI detected joint inflammation in 60% (28/47) of patients with JIA vs 15% (2/13) of controls (difference: 44%, 95% CI 20%, 68%). More active than inactive JIA patients had WBMRI-detected inflammation [76% (19/25) vs 41% (9/22), difference: 35% (95% CI 9%, 62%)], and this was associated with a specific biomarker signature. WBMRI identified inflammation in one or more clinically inactive joint in 23/47 (49%) patients (14/25 active vs 9/22 inactive JIA patients)., Conclusions: WBMRI's validity in joint assessment was demonstrated by the higher frequency of inflammation in JIA patients vs controls, and in active vs inactive JIA patients. WBMRI found unsuspected joint inflammation in 49% YP with JIA, which needs further investigation of potential clinical implications., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2024
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17. A tale of two functions: C-reactive protein complement-ary structures and their role in rheumatoid arthritis.
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Ciurtin C, Helmy GA, Ferreira AC, Manson JJ, Jury EC, and McDonnell T
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- Humans, Complement System Proteins metabolism, Complement System Proteins immunology, Complement Activation immunology, Animals, Biomarkers, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid metabolism, C-Reactive Protein metabolism, C-Reactive Protein immunology
- Abstract
C-reactive protein (CRP) is an inflammatory biomarker with associated clinical utility in a wide number of inflammatory disorders, including rheumatoid arthritis (RA). The interaction of CRP with pro-inflammatory cytokines has been explored before, however its role in complement regulation is more subtle, where CRP is capable of both up and downregulating the complement cascade. CRP is produced in a pentameric form and can dissociate to a monomeric form in circulation which has significant implications for its ability to interact with receptors and binding partners. This dichotomy of CRP structure could have relevance in patients with RA who have significant dysfunction in their complement cascade and also widely varying CRP levels including at the time of flare. This review aims to bring together current knowledge of CRP in its various forms, its effects on complement function and how this could influence pathology in the context of RA., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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18. Phytosterols in human serum as measured using a liquid chromatography tandem mass spectrometry.
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Teng YC, Gielen MC, de Gruijter NM, Ciurtin C, Rosser EC, and Karu K
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- Humans, Chromatography, Liquid methods, Cholesterol blood, Cholesterol analogs & derivatives, Phytosterols blood, Tandem Mass Spectrometry methods
- Abstract
Phytosterols are lipophilic compounds found in plants with structural similarity to mammalian cholesterol. They cannot be endogenously produced by mammals and therefore always originate from diet. There has been increased interest in dietary phytosterols over the last few decades due to their association with a variety of beneficial health effects including low-density lipoprotein cholesterol lowering, anti-inflammatory and anti-cancerous effects. They are proposed as potential moderators for diseases associated with the central nervous system where cholesterol homeostasis is found to be imperative (multiple sclerosis, dementia, etc.) due to their ability to reach the brain. Here we utilised an enzyme-assisted derivatisation for sterol analysis (EADSA) in combination with a liquid chromatography tandem mass spectrometry (LC-MS
n ) to characterise phytosterol content in human serum. As little as 100 fg of plant sterol was injected on a reversed phase LC column. The method allows semi-quantitative measurements of phytosterols and their derivatives simultaneously with measurement of cholesterol metabolites. The identification of phytosterols in human serum was based on comparison of their LC retention times and MS2 , MS3 spectra with a library of authentic standards. Free campesterol serum concentration was in the range from 0.30-4.10 µg/mL, β-sitosterol 0.16-3.37 µg/mL and fucosterol was at lowest concentration range from 0.05-0.38 µg/mL in ten individuals. This analytical methodology could be applied to the analysis of other biological fluids and tissues., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2024
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19. Investigation of the performance of validated cardiovascular risk scores in a global (UK/US) cohort of young people with childhood-onset systemic lupus erythematosus.
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Ciurtin C, Peng J, Gao Y, Niwa M, Ardoin SP, Schanberg LE, Lewandowski L, Jury EC, and Robinson GA
- Subjects
- Humans, Adolescent, Female, Child, Male, Age of Onset, Cohort Studies, Risk Assessment methods, Young Adult, Risk Factors, Adult, United Kingdom epidemiology, Lupus Erythematosus, Systemic complications, Lupus Erythematosus, Systemic diagnosis, Lupus Erythematosus, Systemic epidemiology, Cardiovascular Diseases epidemiology, Heart Disease Risk Factors
- Abstract
Competing Interests: Competing interests: None declared.
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- 2024
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20. Active juvenile systemic lupus erythematosus is associated with distinct NK cell transcriptional and phenotypic alterations.
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Radziszewska A, Peckham H, de Gruijter NM, Restuadi R, Wu WH, Jury EC, Rosser EC, and Ciurtin C
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- Humans, Female, Male, Adolescent, Child, Phenotype, Granzymes metabolism, Granzymes genetics, Perforin metabolism, Perforin genetics, Apoptosis genetics, Transcriptome, Gene Expression Profiling, Case-Control Studies, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Lupus Erythematosus, Systemic genetics, Lupus Erythematosus, Systemic immunology, Lupus Erythematosus, Systemic pathology
- Abstract
While adaptive immune responses have been studied extensively in SLE (systemic lupus erythematosus), there is limited and contradictory evidence regarding the contribution of natural killer (NK) cells to disease pathogenesis. There is even less evidence about the role of NK cells in the more severe phenotype with juvenile-onset (J)SLE. In this study, analysis of the phenotype and function of NK cells in a large cohort of JSLE patients demonstrated that total NK cells, as well as perforin and granzyme A expressing NK cell populations, were significantly diminished in JSLE patients compared to age- and sex-matched healthy controls. The reduction in NK cell frequency was associated with increased disease activity, and transcriptomic analysis of NK populations from active and low disease activity JSLE patients versus healthy controls confirmed that disease activity was the main driver of differential NK cell gene expression. Pathway analysis of differentially expressed genes revealed an upregulation of interferon-α responses and a downregulation of exocytosis in active disease compared to healthy controls. Further gene set enrichment analysis also demonstrated an overrepresentation of the apoptosis pathway in active disease. This points to increased propensity for apoptosis as a potential factor contributing to NK cell deficiency in JSLE., (© 2024. The Author(s).)
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- 2024
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21. Defining remission in childhood-onset lupus: PReS-endorsed consensus definitions by an international task force.
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Smith EMD, Aggarwal A, Ainsworth J, Al-Abadi E, Avcin T, Bortey L, Burnham J, Ciurtin C, Hedrich CM, Kamphuis S, Lambert L, Levy DM, Lewandowski L, Maxwell N, Morand E, Özen S, Pain CE, Ravelli A, Saad Magalhaes C, Pilkington C, Schonenberg-Meinema D, Scott C, Tullus K, and Beresford MW
- Subjects
- Humans, Child, Immunosuppressive Agents therapeutic use, Age of Onset, Delphi Technique, Advisory Committees, Lupus Erythematosus, Systemic drug therapy, Lupus Erythematosus, Systemic diagnosis, Remission Induction, Consensus
- Abstract
Objective: To derive childhood-onset SLE (cSLE) specific remission definitions for future treat-to-target (T2T) trials, observational studies, and clinical practice., Methods: The cSLE International T2T Task Force conducted Delphi surveys exploring paediatric perspectives on adult-onset SLE remission targets. A modified nominal group technique was used to discuss, refine, and agree on the cSLE remission target criteria., Results: The Task Force proposed two definitions of remission: 'cSLE clinical remission on steroids (cCR)' and 'cSLE clinical remission off steroids (cCR-0)'. The common criteria are: (1) Clinical-SLEDAI-2 K = 0; (2) PGA score < 0.5 (0-3 scale); (4) stable antimalarials, immunosuppressive, and biologic therapy (changes due to side-effects, adherence, weight, or when building up to target dose allowed). Criterion (3) in cCR is the prednisolone dose ≤0.1 mg/kg/day (maximum 5 mg/day), whereas in cCR-0 it is zero., Conclusions: cSLE definitions of remission have been proposed, maintaining sufficient alignment with the adult-SLE definition to facilitate life-course research., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests in relation to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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22. Overlap of International League of Associations for Rheumatology and Preliminary Pediatric Rheumatology International Trials Organization Classification Criteria for Nonsystemic Juvenile Idiopathic Arthritis in an Established UK Multicentre Inception Cohort.
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Shoop-Worrall SJW, Macintyre VG, Ciurtin C, Cleary G, McErlane F, Wedderburn LR, and Hyrich KL
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- Humans, Child, Male, Female, United Kingdom, Adolescent, Prospective Studies, Child, Preschool, Cohort Studies, Arthritis, Juvenile classification, Arthritis, Juvenile diagnosis, Arthritis, Juvenile blood, Rheumatology standards
- Abstract
Objective: The goal was to assess the degree of overlap between existing International League of Associations for Rheumatology (ILAR) and preliminary Paediatric Rheumatology International Trials Organisation (PRINTO) classification criteria for juvenile idiopathic arthritis (JIA)., Methods: Participants from the Childhood Arthritis Prospective Study, a multicenter UK JIA inception cohort, were classified using the PRINTO and ILAR classification criteria into distinct categories. Systemic JIA was excluded because several classification items were not collected in this cohort. Adaptations to PRINTO criteria were required to apply to a UK health care setting, including limiting the number of blood biomarker tests required. The overlap between categories under the two systems was determined, and any differences in characteristics between groups were described., Results: A total of 1,223 children and young people with a physician's diagnosis of JIA were included. Using PRINTO criteria, the majority of the patients had "other JIA" (69.5%). There was a high degree of overlap (91%) between the PRINTO enthesitis/spondylitis- and ILAR enthesitis-related JIA categories. The PRINTO rheumatoid factor (RF)-positive category was composed of 48% ILAR RF-positive polyarthritis and 52% undifferentiated JIA. The early-onset antinuclear antibodies-positive PRINTO category was largely composed of ILAR oligoarthritis (50%), RF-negative polyarthritis (24%), and undifferentiated JIA (23%). A few patients were unclassified under PRINTO (n = 3) and would previously have been classified as enthesitis-related JIA (n = 1) and undifferentiated JIA (n = 2) under ILAR., Conclusion: Under the preliminary PRINTO classification criteria for childhood arthritis, most children are not yet classified into a named category. These data can help support further delineation of the PRINTO criteria to ensure homogenous groups of children can be identified., (© 2024 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)
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- 2024
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23. Executive summary: British Society for Rheumatology guideline on management of adult and juvenile onset Sjögren disease.
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Price EJ, Benjamin S, Bombardieri M, Bowman S, Carty S, Ciurtin C, Crampton B, Dawson A, Fisher BA, Giles I, Glennon P, Gupta M, Hackett KL, Larkin G, Ng WF, Ramanan AV, Rassam S, Rauz S, Smith G, Sutcliffe N, Tappuni A, and Walsh SB
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- 2024
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24. Factors influencing the outcomes of non-pharmacological interventions for managing fatigue across the lifespan of people living with musculoskeletal (MSK) conditions: a scoping review protocol.
- Author
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Fishpool K, Young G, Ciurtin C, Cramp F, Erhieyovwe EO, Farisogullari B, Macfarlane GJ, Machado PM, Pearson J, Santos E, and Dures E
- Subjects
- Humans, Chronic Disease, Fatigue therapy, Musculoskeletal Diseases therapy, Research Design, Review Literature as Topic
- Abstract
Introduction: Fatigue is an important and distressing symptom for many people living with chronic musculoskeletal (MSK) conditions. Many non-pharmacological interventions have been investigated in recent years and some have been demonstrated to be effective in reducing fatigue and fatigue impact, however, there is limited guidance for clinicians to follow regarding the most appropriate management options. The objective of this scoping review is to understand and map the extent of evidence in relation to the factors that relate to the outcome of non-pharmacological interventions on MSK condition-related fatigue across the lifespan., Methods and Analysis: This scoping review will include evidence relating to people of all ages living with chronic MSK conditions who have been offered a non-pharmacological intervention with either the intention or effect of reducing fatigue and its impact. Databases including AMED, PsycINFO, CINAHLPlus, MEDLINE, EMBASE and Scopus will be searched for peer-reviewed primary research studies published after 1 January 2007 in English language. These findings will be used to identify factors associated with successful interventions and to map gaps in knowledge., Ethics and Dissemination: Ethical approval was not required for this review. Findings will be disseminated by journal publications, conference presentations and by communicating with relevant healthcare and charity organisations., Competing Interests: Competing interests: PMM has received consulting/speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this project. There are no competing interests in this project., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
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- 2024
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25. The impact of psoriasis on wellbeing and clinical outcomes in juvenile psoriatic arthritis.
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Low JM, Hyrich KL, Ciurtin C, McErlane F, Wedderburn LR, Geifman N, and Shoop-Worrall SJW
- Subjects
- Humans, Male, Female, Child, Adolescent, Prospective Studies, Psoriasis psychology, Psoriasis complications, Depression etiology, Severity of Illness Index, Arthritis, Juvenile psychology, Arthritis, Juvenile complications, Quality of Life, Patient Reported Outcome Measures, Arthritis, Psoriatic psychology, Arthritis, Psoriatic complications
- Abstract
Objectives: Juvenile PsA (JPsA) has varied clinical features that are distinctive from other JIA categories. This study investigates whether such features impact patient-reported and clinical outcomes., Methods: Children and young people (CYP) were selected if recruited to the Childhood Arthritis Prospective Study, a UK multicentre JIA inception cohort, between January 2001 and March 2018. At diagnosis, patient/parent-reported outcomes (as age-appropriate) included the parental global assessment (10 cm visual analogue scale), functional ability (Childhood Health Assessment Questionnaire (CHAQ)), pain (10 cm visual analogue scale), health-related quality of life (Child Health Questionnaire PF50 psychosocial score), mood/depressive symptoms (Moods and Feelings Questionnaire) and parent psychosocial health (General Health Questionnaire 30). Three-year outcome trajectories have previously been defined using active joint counts, physician and parent global assessments (PGA and PaGA, respectively). Patient-reported outcomes and outcome trajectories were compared in (i) CYP with JPsA vs other JIA categories and (ii) CYP within JPsA, with and without psoriasis via multivariable linear regression., Results: There were no significant differences in patient-reported outcomes at diagnosis between CYP with JPsA and non-JPsA. Within JPsA, those with psoriasis had more depressive symptoms (coefficient = 9.8; 95% CI: 0.5, 19.0) than those without psoriasis at diagnosis. CYP with JPsA had 2.3 times the odds of persistent high PaGA than other ILAR categories, despite improving joint counts and PGA (95% CI: 1.2, 4.6)., Conclusion: CYP with psoriasis at JPsA diagnosis report worse mood, supporting a greater disease impact in those with both skin and joint involvement. Multidisciplinary care with added focus to support wellbeing in children with JPsA plus psoriasis may help improve these outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2024
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26. Cardiovascular risk in young people with childhood onset systemic lupus erythematosus.
- Author
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Ciurtin C, Robinson G, Butt M, Peng J, Ardoin S, Schanberg L, Boteanu A, Bouchalova K, Demir S, Moraitis E, Migowa A, Glackin Y, Ainsworth J, Smith E, Jury E, Sahin S, Kamphuis S, and Lewandowski L
- Subjects
- Adolescent, Adult, Child, Female, Humans, Male, Young Adult, Age of Onset, Risk Factors, Cardiovascular Diseases epidemiology, Cardiovascular Diseases etiology, Heart Disease Risk Factors, Lupus Erythematosus, Systemic complications, Lupus Erythematosus, Systemic epidemiology
- Abstract
Competing Interests: CC is funded by a grant from the National Institute of Health Research. KB is supported by the Czech Ministry of Health (DRO FNOl, 00098892). The other authors declare no competing interests.
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- 2024
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27. A new tool for stratifying children with suspected Sjögren's disease.
- Author
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Ciurtin C and Jury EC
- Subjects
- Adolescent, Child, Humans, Sjogren's Syndrome diagnosis
- Abstract
Competing Interests: We declare no competing interests.
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- 2024
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28. Existing and Emerging Targeted Therapies in Juvenile Psoriatic Arthritis: Challenges and Unmet Needs.
- Author
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Lokhandwala S, Townsend J, and Ciurtin C
- Subjects
- Humans, Child, Arthritis, Juvenile drug therapy, Antirheumatic Agents therapeutic use, Molecular Targeted Therapy, Antibodies, Monoclonal therapeutic use, Arthritis, Psoriatic drug therapy
- Abstract
Juvenile psoriatic arthritis (JPsA) is a heterogeneous type of non-systemic chronic inflammatory arthritis affecting children and young people. This review focuses on highlighting challenges in harmonising recommendations for the use of available therapies in JPsA, according to its distinct clinical phenotypes, and explores the similarities and differences between the disease classification and management across age. We further explore the emerging therapeutic landscape, summarising the recently completed clinical trials in JPsA, and ongoing studies in both JPsA and adults with psoriatic arthritis, highlighting unmet needs and barriers for translational research in JPsA. The novel therapeutic agents in clinical development in JPsA range from monoclonal antibodies targeting interleukin (IL)-17, IL-12/23 and IL-23 blockades to synthetic small molecules targeting Janus kinase and tyrosine kinase and phosphodiesterase-4 inhibition. In addition, there are head-to-head clinical trials comparing tumour necrosis factor-α blockade with both IL-17 and IL-23 inhibition. Most of these new therapies have been tested in adults with psoriatic arthritis and have advanced to the phase III stage of drug development or received license for use, suggesting promising signals for efficacy and potentially acceptable safety and tolerability for JPsA. Further translational research in JPsA is required to improve our understanding of the impact of age at onset on treatment efficacy, as well as to provide opportunities for better management of refractory disease and improved long-term outcomes in JPsA, for ultimate patient benefit., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
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- 2024
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29. British Society for Rheumatology guideline on management of adult and juvenile onset Sjögren disease.
- Author
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Price EJ, Benjamin S, Bombardieri M, Bowman S, Carty S, Ciurtin C, Crampton B, Dawson A, Fisher BA, Giles I, Glennon P, Gupta M, Hackett KL, Larkin G, Ng WF, Ramanan AV, Rassam S, Rauz S, Smith G, Sutcliffe N, Tappuni A, and Walsh SB
- Abstract
Sjögren disease (SD) is a chronic, autoimmune disease of unknown aetiology with significant impact on quality of life. Although dryness (sicca) of the eyes and mouth are the classically described features, dryness of other mucosal surfaces and systemic manifestations are common. The key management aim should be to empower the individual to manage their condition-conserving, replacing and stimulating secretions; and preventing damage and suppressing systemic disease activity. This guideline builds on and widens the recommendations developed for the first guideline published in 2017. We have included advice on the management of children and adolescents where appropriate to provide a comprehensive guideline for UK-based rheumatology teams., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2024
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30. Comment on: Systemic lupus erythematosus patients have unique changes in serum metabolic profiles across age associated with cardiometabolic risk: Reply.
- Author
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Ciurtin C, Jury EC, and Robinson GA
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- 2024
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31. Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial.
- Author
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Cope AP, Jasenecova M, Vasconcelos JC, Filer A, Raza K, Qureshi S, D'Agostino MA, McInnes IB, Isaacs JD, Pratt AG, Fisher BA, Buckley CD, Emery P, Ho P, Buch MH, Ciurtin C, van Schaardenburg D, Huizinga T, Toes R, Georgiou E, Kelly J, Murphy C, and Prevost AT
- Subjects
- Adolescent, Adult, Humans, Abatacept adverse effects, Arthralgia, Pain, Rheumatoid Factor, Arthritis, Rheumatoid drug therapy, Synovitis
- Abstract
Background: Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept., Methods: The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18)., Findings: Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan-Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28-78; p<0·0001) at 12 months and 99 days (95% CI 38-161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment., Interpretation: Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests APC, PE, IBM, RT, KR, and TH received grant funding from Bristol Myers Squibb. APC, PE, and BAF received consulting fees from Bristol Myers Squibb. APC, PE, and MAD'A received speakers' bureau fees from Bristol Myers Squibb. MJ and SQ were beneficiaries of the APIPPRA study grant awarded by Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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32. Atherosclerosis Progression in the APPLE Trial Can Be Predicted in Young People With Juvenile-Onset Systemic Lupus Erythematosus Using a Novel Lipid Metabolomic Signature.
- Author
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Peng J, Dönnes P, Ardoin SP, Schanberg LE, Lewandowski L, Robinson G, Jury EC, and Ciurtin C
- Subjects
- Humans, Child, Adolescent, Atorvastatin therapeutic use, Carotid Intima-Media Thickness, Biomarkers, Risk Factors, Atherosclerosis, Lupus Erythematosus, Systemic drug therapy, Carotid Artery Diseases
- Abstract
Objective: Patients with juvenile-onset systemic lupus erythematosus (JSLE) have increased atherosclerosis risk. This study investigated novel atherosclerosis progression biomarkers in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, the largest investigator-led randomized control trial of atorvastatin versus placebo for atherosclerosis progression in JSLE, using carotid intima-media thickness (CIMT) as the primary outcome., Methods: Unsupervised clustering of baseline CIMT and CIMT progression over 36 months was used to stratify patients with JSLE. Disease characteristics, cardiovascular risk scores, and baseline serum metabolome were investigated in CIMT-stratified patients. Machine learning techniques were used to identify and validate a serum metabolomic signature of CIMT progression., Results: Baseline CIMT stratified patients with JSLE (N = 151) into three groups with distinct high, intermediate, and low CIMT trajectories irrespective of treatment allocation, despite most patients having low cardiovascular disease risk based on recommended assessment criteria. In the placebo group (n = 60), patients with high versus low CIMT progression had higher total (P = 0.001) and low-density lipoprotein (LDL) (P = 0.002) cholesterol levels, although within the reference range. Furthermore, a robust baseline metabolomic signature predictive of high CIMT progression was identified in the placebo arm (area under the curve, 80.7%). Patients treated with atorvastatin (n = 61) had reduced LDL cholesterol levels after 36 months, as expected; however, despite this, 36% still had high atherosclerosis progression, which was not predicted by metabolomic biomarkers, suggesting nonlipid drivers of atherosclerosis in JSLE with management implications for this subset of patients., Conclusion: Significant baseline heterogeneity and distinct subclinical atherosclerosis progression trajectories exist in JSLE. Metabolomic signatures can predict atherosclerosis progression in some patients with JSLE with relevance for clinical trial stratification., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)
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- 2024
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33. Measuring response to treatment in axial spondyloarthritis using quantitative imaging biomarkers: a prospective observational cohort study.
- Author
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Jones A, Bray TJ, Sakai NS, Bainbridge AJ, Ciurtin C, and Hall-Craggs MA
- Subjects
- Humans, Prospective Studies, Reproducibility of Results, Longitudinal Studies, Magnetic Resonance Imaging methods, Inflammation, Biomarkers, Diffusion Magnetic Resonance Imaging methods, Axial Spondyloarthritis
- Abstract
Objective: Objective assessments of disease activity and response to treatment in axial spondyloarthritis (axSpA) remain a challenge; quantitative imaging biomarkers (QIBs) of inflammation could enhance assessments of disease activity and therapeutic response. We aimed to determine the responsiveness of QIBs obtained from diffusion-weighted imaging (DW-MRI) and chemical shift-encoded MRI (CSE-MRI) using the partially automated Bone Edema and Adiposity Characterisation with Histograms (BEACH) software tool in axSpA patients undergoing biologic therapy., Methods: We conducted a prospective longitudinal cohort study, including 30 patients with axSpA undergoing biologic therapy. Patients were scanned before and after biologic therapy using conventional MRI, DWI and CSE-MRI at 3T. Apparent diffusion coefficient (ADC) and proton density fat fraction (PDFF) were assessed using the BEACH tool (https://github.com/TJPBray/BEACH), and conventional MR images were assessed using established visual scoring methods by expert radiologists. Responsiveness - the ability of the MRI measurements to capture changes in disease occurring as a result of biologic therapy - was assessed using the standardized response mean (SRM). Inter-reader reliability of the ADC and PDFF maps was assessed using Bland-Altman limits of agreement analysis and the intraclass correlation coefficient., Results: Responsiveness to therapy was moderate for ADC-based parameters (SRM 0.50) and comparable to established visual scoring methods for bone marrow oedema (SRM 0.53). Interobserver variability was lower for QIBs compared with conventional visual scores methods., Conclusions: QIBs measured using the BEACH tool are sensitive to changes in inflammation in axSpA following biologic therapy, with similar responsiveness and lower interobserver variability to visual scoring by expert radiologists., Advances in Knowledge: QIBs measured using the partially automated BEACH tool offer an objective measure of response to biologic therapy in axSpA.
- Published
- 2023
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34. DAS28(3)CRP is a reliable measure of disease activity in pregnant women with rheumatoid arthritis.
- Author
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Raine C, Ciurtin C, Jury EC, Williams DJ, Bennett D, Manson JJ, and Giles I
- Subjects
- Humans, Female, Pregnancy, Prospective Studies, Reproducibility of Results, Pilot Projects, Severity of Illness Index, Pregnant Women, Arthritis, Rheumatoid diagnostic imaging
- Abstract
Objectives: The disease activity of rheumatoid arthritis (RA) in pregnancy is most commonly assessed with the modified Disease Activity Score (DAS)-28, the DAS28(3)CRP. However, the performance of the DAS28(3)CRP in pregnancy has not been compared to musculoskeletal ultrasound (MSK-US) as a gold standard. We performed a prospective pilot study to test the hypothesis that pregnancy-related factors limit the reliability of the DAS28(3)CRP., Methods: Pregnant women with RA were recruited from an Obstetric Rheumatology clinic and assessed during pregnancy (second (T2) and third (T3) trimesters) and postpartum with DAS28(3)CRP and MSK-US scores, with quantification of power Doppler (PD) signal in small joints (hands and feet). Age-matched non-pregnant women with RA underwent equivalent assessments. PD scores were calculated as mean scores of all joints scanned., Results: We recruited 27 pregnant and 20 non-pregnant women with RA. DAS28(3)CRP was sensitive and specific for active RA in pregnancy and postpartum as defined by positive PD signal, but not in non-pregnancy. There were significant correlations between DAS28(3)CRP and PD scores throughout pregnancy (T2, r=0.82 (95% CI [0.42, 0.95], p<0.01); T3, r=0.68 (95% CI [0.38, 0.86], p<0.01)) and postpartum, r=0.84 (95% CI [0.60, 0.94], p<0.01), while this correlation in non-pregnancy was weaker (r=0.47 (95% CI [0, 0.77], p<0.05)., Conclusions: This pilot study found that DAS28(3)CRP is a reliable measure of disease activity in pregnant women with RA. Based on these data, pregnancy does not appear to confound clinical evaluation of the tender and/or swollen joint counts.
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- 2023
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35. Pulmonary hypertension in juvenile-onset systemic lupus erythematosus: a case series.
- Author
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Platt C, Longthorpe C, Sit J, Marks SD, Harmer M, Ciurtin C, Ramanan AV, and Beresford MW
- Subjects
- Age of Onset, Humans, Retrospective Studies, Male, Female, Child, Adolescent, Young Adult, Adult, Cohort Studies, Child, Preschool, Hypertension, Pulmonary etiology, Lupus Erythematosus, Systemic complications
- Abstract
Objectives: Systemic lupus erythematosus (SLE) is a rare multisystem autoimmune disorder with a variable clinical phenotype. Pulmonary hypertension (PHTN) is a recognised (and not uncommonly asymptomatic) complication of the condition with an associated poor prognosis in adults. It is relatively rare in juvenile-onset SLE (JSLE)., Methods: We present a retrospective descriptive case series of four female children aged 4 to 15 years at presentation of JSLE and aged 8 to 27 years at time of diagnosis of PHTN from the United Kingdom. All cases were identified through the UK JSLE Cohort Study., Results: Of 665 children with JSLE in the UK cohort study to date (data from 2006-2020), four (0.6%) were identified as having PHTN. 3/4 of the PHTN cases presented with cardiovascular symptoms and / or signs at presentation.3/4 were treated with Rituximab and had a good long-term outcome. Shared clinical features include high baseline disease activity scores., Conclusions: JSLE has a high associated cardiovascular morbidity and mortality and early identification of treatable complications such as PHTN is vital. We suggest that children with high baseline disease activity scores and those presenting with cardiovascular symptoms and signs are most likely to have concurrent PHTN. Routine echocardiography is an effective screening tool and should be used as part of a standard diagnostic work-up.
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- 2023
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36. The impact of immunocompromise on outcomes of COVID-19 in children and young people-a systematic review and meta-analysis.
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Greenan-Barrett J, Aston S, Deakin CT, and Ciurtin C
- Subjects
- Adolescent, Adult, Child, Humans, Asymptomatic Infections, Hospitalization, Immunocompromised Host, Immunosuppression Therapy, COVID-19
- Abstract
Background: Despite children and young people (CYP) having a low risk for severe coronavirus disease 2019 (COVID-19) outcomes, there is still a degree of uncertainty related to their risk in the context of immunodeficiency or immunosuppression, primarily due to significant reporting bias in most studies, as CYP characteristically experience milder or asymptomatic COVID-19 infection and the severe outcomes tend to be overestimated., Methods: A comprehensive systematic review to identify globally relevant studies in immunosuppressed CYP and CYP in general population (defined as younger than 25 years of age) up to 31 October 2021 (to exclude vaccinated populations) was performed. Studies were included if they reported the two primary outcomes of our study, admission to intensive therapy unit (ITU) and mortality, while data on other outcomes, such as hospitalization and need for mechanical ventilation were also collected. A meta-analysis estimated the pooled proportion for each severe COVID-19 outcome, using the inverse variance method. Random effects models were used to account for interstudy heterogeneity., Findings: The systematic review identified 30 eligible studies for each of the two populations investigated: immunosuppressed CYP ( n = 793) and CYP in general population ( n = 102,022). Our meta-analysis found higher estimated prevalence for hospitalization (46% vs. 16%), ITU admission (12% vs. 2%), mechanical ventilation (8% vs. 1%), and increased mortality due to severe COVID-19 infection (6.5% vs. 0.2%) in immunocompromised CYP compared with CYP in general population. This shows an overall trend for more severe outcomes of COVID-19 infection in immunocompromised CYP, similar to adult studies., Interpretation: This is the only up-to-date meta-analysis in immunocompromised CYP with high global relevance, which excluded reports from hospitalized cohorts alone and included 35% studies from low- and middle-income countries. Future research is required to characterize individual subgroups of immunocompromised patients, as well as impact of vaccination on severe COVID-19 outcomes., Systematic Review Registration: PROSPERO identifier, CRD42021278598., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Greenan-Barrett, Aston, Deakin and Ciurtin.)
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- 2023
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37. Anti-rituximab antibodies demonstrate neutralizing capacity, associate with lower circulating drug levels and earlier relapse in lupus.
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Wincup C, Dunn N, Ruetsch-Chelli C, Manouchehrinia A, Kharlamova N, Naja M, Seitz-Polski B, Isenberg DA, Fogdell-Hahn A, Ciurtin C, and Jury EC
- Subjects
- Humans, Rituximab therapeutic use, Chronic Disease, Recurrence, Antibodies, Neutralizing, Antibodies, Lupus Erythematosus, Systemic drug therapy
- Abstract
Objectives: High rates of anti-drug antibodies (ADA) to rituximab have been demonstrated in patients undergoing treatment for SLE. However, little is known with regard to their long-term dynamics, impact on drug kinetics and subsequent implications for treatment response. In this study, we aimed to evaluate ADA persistence over time, impact on circulating drug levels, assess clinical outcomes and whether they are capable of neutralizing rituximab., Methods: Patients with SLE undergoing treatment with rituximab were recruited to this study (n = 35). Serum samples were collected across a follow-up period of 36 months following treatment (n = 114). Clinical and laboratory data were collected pre-treatment and throughout follow-up. ADA were detected via electrochemiluminescent immunoassays. A complement dependent cytotoxicity assay was used to determine neutralizing capacity of ADA in a sub-cohort of positive samples (n = 38)., Results: ADA persisted over the 36-month study period in 64.3% of patients undergoing treatment and titres peaked earlier and remained higher in those who had previously been treated with rituximab when compared with than those who were previously treatment naive. ADA-positive samples had a significantly lower median drug level until six months post rituximab infusion (P = 0.0018). Patients with persistent ADA positivity showed a significant early improvement in disease activity followed by increased rates of relapse. In vitro analysis confirmed the neutralizing capacity of ADA to rituximab., Conclusions: ADA to rituximab were common and persisted over the 36-month period of this study. They associated with earlier drug elimination, an increased rate of relapse and demonstrated neutralizing capacity in vitro., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2023
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38. Potential relevance of type I interferon-related biomarkers for the management of polygenic autoimmune rheumatic diseases with childhood onset.
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Ciurtin C
- Subjects
- Humans, Child, Biomarkers, Interferon Type I therapeutic use, Autoimmune Diseases drug therapy, Autoimmune Diseases genetics, Rheumatic Diseases drug therapy, Rheumatic Diseases genetics
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- 2023
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39. Impact of puberty, sex determinants and chronic inflammation on cardiovascular risk in young people.
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Allalou A, Peng J, Robinson GA, Marruganti C, D'Aiuto F, Butler G, Jury EC, and Ciurtin C
- Abstract
Worrying trends of increased cardiovascular disease (CVD) risk in children, adolescents and young people in the Modern Era have channelled research and public health strategies to tackle this growing epidemic. However, there are still controversies related to the dynamic of the impact of sex, age and puberty on this risk and on cardiovascular health outcomes later in life. In this comprehensive review of current literature, we examine the relationship between puberty, sex determinants and various traditional CVD-risk factors, as well as subclinical atherosclerosis in young people in general population. In addition, we evaluate the role of chronic inflammation, sex hormone therapy and health-risk behaviours on augmenting traditional CVD-risk factors and health outcomes, ultimately aiming to determine whether tailored management strategies for this age group are justified., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Allalou, Peng, Robinson, Marruganti, D'Aiuto, Butler, Jury and Ciurtin.)
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- 2023
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40. Towards development of treat to target (T2T) in childhood-onset systemic lupus erythematosus: PReS-endorsed overarching principles and points-to-consider from an international task force.
- Author
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Smith EMD, Aggarwal A, Ainsworth J, Al-Abadi E, Avcin T, Bortey L, Burnham J, Ciurtin C, Hedrich CM, Kamphuis S, Levy DM, Lewandowski LB, Maxwell N, Morand EF, Ozen S, Pain CE, Ravelli A, Saad Magalhaes C, Pilkington CA, Schonenberg-Meinema D, Scott C, Tullus K, and Beresford MW
- Subjects
- Adult, Child, Humans, Surveys and Questionnaires, Remission Induction, Advisory Committees, Quality of Life, Lupus Erythematosus, Systemic drug therapy
- Abstract
Objectives: Application of 'treat-to-target' (T2T) in childhood-onset systemic lupus erythematosus (cSLE) may improve care and health outcomes. This initiative aimed to harmonise existing evidence and expert opinion regarding T2T for cSLE., Methods: An international T2T Task Force was formed of specialists in paediatric rheumatology, paediatric nephrology, adult rheumatology, patient and parent representatives. A steering committee formulated a set of draft overarching principles and points-to-consider, based on evidence from systematic literature review. Two on-line preconsensus meeting Delphi surveys explored healthcare professionals' views on these provisional overarching principles and points-to-consider. A virtual consensus meeting employed a modified nominal group technique to discuss, modify and vote on each overarching principle/point-to-consider. Agreement of >80% of Task Force members was considered consensus., Results: The Task Force agreed on four overarching principles and fourteen points-to-consider. It was agreed that both treatment targets and therapeutic strategies should be subject to shared decision making with the patient/caregivers, with full remission the preferred target, and low disease activity acceptable where remission cannot be achieved. Important elements of the points-to-consider included: aiming for prevention of flare and organ damage; glucocorticoid sparing; proactively addressing factors that impact health-related quality of life (fatigue, pain, mental health, educational challenges, medication side effects); and aiming for maintenance of the target over the long-term. An extensive research agenda was also formulated., Conclusions: These international, consensus agreed overarching principles and points-to-consider for T2T in cSLE lay the foundation for future T2T approaches in cSLE, endorsed by the Paediatric Rheumatology European Society., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)
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- 2023
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41. Successful stopping of biologic therapy for remission in children and young people with juvenile idiopathic arthritis.
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Kearsley-Fleet L, Baildam E, Beresford MW, Douglas S, Foster HE, Southwood TR, Hyrich KL, and Ciurtin C
- Subjects
- Humans, Child, Adolescent, Treatment Outcome, Biological Factors therapeutic use, Biological Therapy, Arthritis, Juvenile drug therapy, Antirheumatic Agents therapeutic use, Biological Products therapeutic use
- Abstract
Objectives: Clinicians concerned about long-term safety of biologics in JIA may consider tapering or stopping treatment once remission is achieved despite uncertainty in maintaining drug-free remission. This analysis aims to (i) calculate how many patients with JIA stop biologics for remission, (ii) calculate how many later re-start therapy and after how long, and (iii) identify factors associated with re-starting biologics., Methods: Patients starting biologics between 1 January 2010 and 7 September 2021 in the UK JIA Biologics Register were included. Patients stopping biologics for physician-reported remission, those re-starting biologics and factors associated with re-starting, were identified. Multiple imputation accounted for missing data., Results: Of 1451 patients with median follow-up of 2.7 years (IQR 1.4, 4.0), 269 (19%) stopped biologics for remission after a median of 2.2 years (IQR 1.7, 3.0). Of those with follow-up data (N = 220), 118 (54%) later re-started therapy after a median of 4.7 months, with 84% re-starting the same biologic. Patients on any-line tocilizumab (prior to stopping) were less likely to re-start biologics (vs etanercept; odds ratio [OR] 0.3; 95% CI: 0.2, 0.7), while those with a longer disease duration prior to biologics (OR 1.1 per year increase; 95% CI: 1.0, 1.2) or prior uveitis were more likely to re-start biologics (OR 2.5; 95% CI: 1.3, 4.9)., Conclusions: This analysis identified factors associated with successful cessation of biologics for remission in JIA as absence of uveitis, prior treatment with tocilizumab and starting biologics earlier in the disease course. Further research is needed to guide clinical recommendations., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2023
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42. PReS-endorsed international childhood lupus T2T task force definition of childhood lupus low disease activity state (cLLDAS).
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Smith EMD, Aggarwal A, Ainsworth J, Al-Abadi E, Avcin T, Bortey L, Burnham J, Ciurtin C, Hedrich CM, Kamphuis S, Lambert L, Levy DM, Lewandowski L, Maxwell N, Morand E, Ozen S, Pain CE, Ravelli A, Saad Magalhaes C, Pilkington C, Schonenberg-Meinema D, Scott C, Tullus K, and Beresford MW
- Subjects
- Adult, Child, Humans, Severity of Illness Index, Prednisolone, Consensus, Immunosuppressive Agents therapeutic use, Lupus Erythematosus, Systemic diagnosis, Lupus Erythematosus, Systemic drug therapy
- Abstract
Objective: To achieve a consensus-based definition of Low Disease Activity (LDA) for use in cSLE trials., Methods: The International cSLE T2T Task Force, comprising of paediatric rheumatologists/nephrologists, and adult rheumatologists undertook a series of Delphi surveys/consensus meetings to discuss, refine, and vote upon cSLE LDA criteria., Results: The Task Force agreed that LDA should be based upon the adult-SLE Lupus Low Disease Activity State definition (LLDAS), with modifications to make it applicable to cSLE (cLLDAS). They agreed upon five cLLDAS criteria: (1) SLE Disease Activity Index (SLEDAI)-2 K ≤4, with no activity in major organ systems; (2) no new features of lupus disease activity compared with the last assessment; (3) Physician Global Assessment score of ≤1 (0-3 scale); (4) prednisolone dose of ≤0.15 mg/kg/day, 7.5 mg/day/maximum; while on (5) stable antimalarials, immunosuppressives, and biologics., Conclusions: A cSLE-appropriate definition of cLLDAS has been generated, maintaining alignment with the adult-SLE definition to promote life-course research., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests in relation to this manuscript., (Copyright © 2023. Published by Elsevier Inc.)
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- 2023
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43. Volume of hyperintense inflammation (VHI): A quantitative imaging biomarker of inflammation load in spondyloarthritis, enabled by human-machine cooperation.
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Hepburn C, Jones A, Bainbridge A, Ciurtin C, Iglesias JE, Zhang H, Hall-Craggs MA, and Bray TJP
- Subjects
- Humans, Prospective Studies, Magnetic Resonance Imaging methods, Edema, Inflammation diagnostic imaging, Image Processing, Computer-Assisted methods, Spondylarthritis diagnostic imaging
- Abstract
Qualitative visual assessment of MRI scans is a key mechanism by which inflammation is assessed in clinical practice. For example, in axial spondyloarthritis (axSpA), visual assessment focuses on the identification of regions with increased signal in the bone marrow, known as bone marrow oedema (BMO), on water-sensitive images. The identification of BMO has an important role in the diagnosis, quantification and monitoring of disease in axSpA. However, BMO evaluation depends heavily on the experience and expertise of the image reader, creating substantial imprecision. Deep learning-based segmentation is a natural approach to addressing this imprecision, but purely automated solutions require large training sets that are not currently available, and deep learning solutions with limited data may not be sufficiently trustworthy for use in clinical practice. To address this, we propose a workflow for inflammation segmentation incorporating both deep learning and human input. With this 'human-machine cooperation' workflow, a preliminary segmentation is generated automatically by deep learning; a human reader then 'cleans' the segmentation by removing extraneous segmented voxels. The final cleaned segmentation defines the volume of hyperintense inflammation (VHI), which is proposed as a quantitative imaging biomarker (QIB) of inflammation load in axSpA. We implemented and evaluated the proposed human-machine workflow in a cohort of 29 patients with axSpA who had undergone prospective MRI scans before and after starting biologic therapy. The performance of the workflow was compared against purely visual assessment in terms of inter-observer/inter-method segmentation overlap, inter-observer agreement and assessment of response to biologic therapy. The human-machine workflow showed superior inter-observer segmentation overlap than purely manual segmentation (Dice score 0.84 versus 0.56). VHI measurements produced by the workflow showed similar or better inter-observer agreement than visual scoring, with similar response assessments. We conclude that the proposed human-machine workflow offers a mechanism to improve the consistency of inflammation assessment, and that VHI could be a valuable QIB of inflammation load in axSpA, as well as offering an exemplar of human-machine cooperation more broadly., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hepburn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2023
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44. The Development and Evaluation of a Combined Infection-Rheumatology Assessment Service in Response to the Chikungunya Fever Epidemic.
- Author
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Krutikov M, Donovan J, Lambourne J, Ciurtin C, Brown M, Bailey R, and Manson JJ
- Subjects
- Humans, Arthralgia, Chikungunya Fever diagnosis, Chikungunya Fever epidemiology, Chikungunya Fever therapy, Rheumatology, Chikungunya virus, Epidemics
- Abstract
The chikungunya virus is an arthritogenic alphavirus. Acute infection may be followed by persistent arthralgia, often causing significant functional impairment. The 2014-2015 chikungunya fever (CHIKF) epidemic resulted in a marked increase in cases presenting to rheumatology and tropical diseases services. A combined multidisciplinary rheumatology-tropical diseases service for assessment, management, and follow-up of patients with proven CHIKF and persistent (≥ 4 weeks) arthralgia was proposed and rapidly developed at The Hospital for Tropical Diseases in London. Rapid set up of a multidisciplinary clinic in response to the epidemic was achieved. Of a total of 54 patients, 21 (38.9%) patients with CHIKF developed persistent arthralgia and were reviewed by the multidisciplinary service. A combined assessment approach enabled comprehensive multidisciplinary assessment of CHIKF, assessment of joint pathology through ultrasound, and appropriate follow-up. A combined rheumatology-tropical diseases service was successfully used to identify and assess CHIKF-associated morbidity. Future outbreaks may be approached by establishing tailored multidisciplinary clinics.
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- 2023
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45. Quantitative magnetic resonance imaging (qMRI) in axial spondyloarthritis.
- Author
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Thorley N, Jones A, Ciurtin C, Castelino M, Bainbridge A, Abbasi M, Taylor S, Zhang H, Hall-Craggs MA, and Bray TJP
- Subjects
- Biomarkers, Diffusion Magnetic Resonance Imaging, Inflammation diagnostic imaging, Reference Standards, Humans, Axial Spondyloarthritis diagnostic imaging, Magnetic Resonance Imaging
- Abstract
Imaging, and particularly MRI, plays a crucial role in the assessment of inflammation in rheumatic disease, and forms a core component of the diagnostic pathway in axial spondyloarthritis. However, conventional imaging techniques are limited by image contrast being non-specific to inflammation and a reliance on subjective, qualitative reader interpretation. Quantitative MRI methods offer scope to address these limitations and improve our ability to accurately and precisely detect and characterise inflammation, potentially facilitating a more personalised approach to management. Here, we review quantitative MRI methods and emerging quantitative imaging biomarkers for imaging inflammation in axial spondyloarthritis. We discuss the potential benefits as well as the practical considerations that must be addressed in the movement toward clinical translation of quantitative imaging biomarkers.
- Published
- 2023
- Full Text
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46. Panel sequencing links rare, likely damaging gene variants with distinct clinical phenotypes and outcomes in juvenile-onset SLE.
- Author
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Charras A, Haldenby S, Smith EMD, Egbivwie N, Olohan L, Kenny JG, Schwarz K, Roberts C, Al-Abadi E, Armon K, Bailey K, Ciurtin C, Gardner-Medwin J, Haslam K, Hawley DP, Leahy A, Leone V, McErlane F, Modgil G, Pilkington C, Ramanan AV, Rangaraj S, Riley P, Sridhar A, Beresford MW, and Hedrich CM
- Subjects
- Humans, Cohort Studies, Age of Onset, Kidney, Phenotype, Lupus Erythematosus, Systemic complications
- Abstract
Objectives: Juvenile-onset systemic lupus erythematosus (jSLE) affects 15-20% of lupus patients. Clinical heterogeneity between racial groups, age groups and individual patients suggests variable pathophysiology. This study aimed to identify highly penetrant damaging mutations in genes associated with SLE/SLE-like disease in a large national cohort (UK JSLE Cohort Study) and compare demographic, clinical and laboratory features in patient sub-cohorts with 'genetic' SLE vs remaining SLE patients., Methods: Based on a sequencing panel designed in 2018, target enrichment and next-generation sequencing were performed in 348 patients to identify damaging gene variants. Findings were integrated with demographic, clinical and treatment related datasets., Results: Damaging gene variants were identified in ∼3.5% of jSLE patients. When compared with the remaining cohort, 'genetic' SLE affected younger children and more Black African/Caribbean patients. 'Genetic' SLE patients exhibited less organ involvement and damage, and neuropsychiatric involvement developed over time. Less aggressive first line treatment was chosen in 'genetic' SLE patients, but more second and third line agents were used. 'Genetic' SLE associated with anti-dsDNA antibody positivity at diagnosis and reduced ANA, anti-LA and anti-Sm antibody positivity at last visit., Conclusion: Approximately 3.5% of jSLE patients present damaging gene variants associated with younger age at onset, and distinct clinical features. As less commonly observed after treatment induction, in 'genetic' SLE, autoantibody positivity may be the result of tissue damage and explain reduced immune complex-mediated renal and haematological involvement. Routine sequencing could allow for patient stratification, risk assessment and target-directed treatment, thereby increasing efficacy and reducing toxicity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2023
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47. Whole-body MRI for juvenile idiopathic arthritis.
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Ciurtin C, Bray T, Choida V, and Hall-Craggs MA
- Subjects
- Humans, Magnetic Resonance Imaging, Whole Body Imaging, Arthritis, Juvenile diagnostic imaging
- Abstract
Competing Interests: CC reports grant funding from Action Medical Research. TB is funded by a National Institute for Health and Care Research (NIHR) Clinical Lectureship and reports grant funding from NIHR Biomedical Research Centre, and honorarium for manuscript writing from the National Ankylosing Spondylitis Society. VC reports grant funding from the British Society of Rheumatology. MAH-C declares no competing interests.
- Published
- 2023
- Full Text
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48. Editorial: Sex bias in autoimmunity: From animal models to clinical research and applications.
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Robinson GA, Peckham H, Jury EC, Taneja V, and Ciurtin C
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2022
- Full Text
- View/download PDF
49. COVID-19 in Immunocompromised Children and Adolescents.
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Greenan-Barrett J and Ciurtin C
- Subjects
- Adolescent, Child, Humans, Immunocompromised Host, Risk Factors, COVID-19
- Abstract
Competing Interests: The authors have no funding or conflicts of interest to disclose.
- Published
- 2022
- Full Text
- View/download PDF
50. CD8 + T Cell Phenotype and Function in Childhood and Adult-Onset Connective Tissue Disease.
- Author
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Radziszewska A, Moulder Z, Jury EC, and Ciurtin C
- Subjects
- CD8-Positive T-Lymphocytes, Cytokines, Humans, Phenotype, Connective Tissue Diseases, Lupus Erythematosus, Systemic, Polymyositis, Scleroderma, Systemic, Sjogren's Syndrome
- Abstract
CD8
+ T cells are cytotoxic lymphocytes that destroy pathogen infected and malignant cells through release of cytolytic molecules and proinflammatory cytokines. Although the role of CD8+ T cells in connective tissue diseases (CTDs) has not been explored as thoroughly as that of other immune cells, research focusing on this key component of the immune system has recently gained momentum. Aberrations in cytotoxic cell function may have implications in triggering autoimmunity and may promote tissue damage leading to exacerbation of disease. In this comprehensive review of current literature, we examine the role of CD8+ T cells in systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, polymyositis, and dermatomyositis with specific focus on comparing what is known about CD8+ T cell peripheral blood phenotypes, CD8+ T cell function, and CD8+ T cell organ-specific profiles in adult and juvenile forms of these disorders. Although, the precise role of CD8+ T cells in the initiation of autoimmunity and disease progression remains to be elucidated, increasing evidence indicates that CD8+ T cells are emerging as an attractive target for therapy in CTDs.- Published
- 2022
- Full Text
- View/download PDF
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