7 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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J Peng, G Robinson, S Ardoin, L Schanberg, E Jury, and C Ciurtin
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- 2022
3. 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
- Subjects
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
4. 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
5. 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
6. 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
7. 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
- Published
- 2019
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